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VACCINE Peer Review

The History Of The Global Vaccination Program In 1000 Peer Reviewed Reports And
Studies

1915-2015 A Jeff Prager Publication

“Dissent is crucial for the advancement of science.
Disagreement is at the heart of peer review and is important for uncovering
unjustified assumptions, flawed methodologies and problematic reasoning.” I. de
Melo-Martín and K. Intemann, Division of Medical Ethics, Department of Public
Health, Weill Cornell Medical College, New York, USA

“the harm from vaccines has seriously exceeded the benefit of disease prevention”
Dr. Harold Buttram

“No batch of vaccine can be proved safe before it is given to children”
Surgeon General of the United States, Leonard Scheele, addressing an AMA
convention in 1955

“The only safe vaccine is a vaccine that is never used”
Dr. James A. Shannon, National Institutes of Health

“Immune challenges during early development,
including those vaccine-induced, can lead to permanent detrimental alterations
of the brain and immune function.

Experimental evidence also shows that simultaneous administration of as little
as two to three immune adjuvants can overcome genetic resistance to
autoimmunity. In some developed countries, by the time children are 4 to 6
years old, they will have received a total of 126 antigenic compounds along
with high amounts of aluminum adjuvants through routine vaccinations.

According to the US Food and Drug Administration, safety assessments for
vaccines have often not included appropriate toxicity studies because vaccines
have not been viewed as inherently toxic. Taken together, these observations
raise plausible concerns about the overall safety of current childhood
vaccination programs.” From the Journal Lupus, February 2012 by Lucija
Tomljenovic & CA Shaw, Neural Dynamics Research Group

Institutional Corruption of Pharmaceuticals
and the Myth of Safe and Effective Drugs Donald W. Light Rowan University,
School of Osteopathic Medicine Harvard University - Edmond J. Safra Center for
Ethics Joel Lexchin York University Jonathan J. Darrow Harvard Medical School
Donald W. Light, Ph.D., is a fellow for 2012-2013 at the Edmond J. Safra Center
for Ethics at Harvard University in Cambridge, MA. He received his Ph.D. in
sociology from Brandeis University and is a professor of comparative health
policy at Rowan University, School of Osteopathic Medicine. Joel Lexchin,
M.Sc., M.D., has been teaching health policy for 12 years at York University in
Toronto, ON. He received his M.D. from the University of Toronto in 1977 and
since 1988 has been an emergency physician at the University Health Network in
Toronto. Jonathan J. Darrow, J.D., M.B.A., LL.M., S.J.D., is a research fellow
at Harvard Medical School and a lecturer on law at Bentley University in
Waltham, MA. He received his S.J.D. from Harvard in 2013. ~ June 1, 2013 ~
Journal of Law, Medicine and Ethics, 2013, Vol. 14, No. 3:590-610 Abstract Over
the past 35 years, patients have suffered from a largely hidden epidemic of
side effects from drugs that usually have few offsetting benefits. The
pharmaceutical industry has corrupted the practice of medicine through its
influence over what drugs are developed, how they are tested, and how medical
knowledge is created. Since 1906, heavy commercial influence has compromised
Congressional legislation to protect the public from unsafe drugs. The
authorization of user fees in 1992 has turned drug companies into the FDA’s
prime clients, deepening the regulatory and cultural capture of the agency.
Industry has demanded shorter average review times and, with less time to
thoroughly review evidence, increased hospitalizations and deaths have
resulted. Meeting the needs of the drug companies has taken priority over
meeting the needs of patients. Unless this corruption of regulatory intent is
reversed, the situation will continue to deteriorate. We offer practical
suggestions including: separating the funding of clinical trials from their
conduct, analysis, and publication: independent FDA leadership; full public
funding for all FDA activities; measures to discourage R&D on drugs with few if
any new clinical benefits; and the creation of a National Drug Safety Board.

Institutional corruption is a normative concept of growing importance that
embodies the systemic dependencies and informal practices that distort an
institution’s societal mission. An extensive range of studies and lawsuits
already documents strategies by which pharmaceutical companies hide, ignore, or
misrepresent evidence about new drugs; distort the medical literature; and
misrepresent products to prescribing physicians. We focus on the consequences
for patients: millions of adverse reactions. After defining institutional
corruption, we focus on evidence that it lies behind the epidemic of harms and
the paucity of benefits. It is our thesis that institutional corruption has
occurred at three levels. First, through large-scale lobbying and political
contributions, the pharmaceutical industry has influenced Congress to pass
legislation that has compromised the mission of the Food and Drug
Administration (FDA). Second, largely as a result of industry pressure,
Congress has underfunded FDA enforcement capacities since 1906, and turning to
industry-paid “user fees” since 1992 has biased funding to limit the FDA’s
ability to protect the public from serious adverse reactions to drugs

that have few offsetting advantages. Finally, industry has commercialized the role of physicians and undermined their position as independent, trusted advisers to patients.
Institutional Integrity: The Baseline of Corruption If “corruption” is defined
as an impairment of integrity or moral principle, then institutional corruption
is an institution’s deviation from a baseline of integrity. In the case of
Congress, integrity demands that democratically elected representatives should
be dedicated solely to the best interests of the people they represent.
According to seminal essays on institutional corruption by Dennis Thompson and
Larry Lessig, this baseline of integrity is corrupted because elections are not
publicly funded. As a result, congressional representatives must constantly
raise funds from a tiny percent of the population and respond to their
priorities. This dependency corruption creates an “economy of influence,” even
if individual actors are well-intentioned. Lessig’s examples portray how
secrecy and rationalizations disguise distortions in the democratic process and
mission. The concept of institutional corruption highlights numerous
distinctions — between what is legal and illegal; between good people doing bad
things, not bad people doing bad things; between influence, not money,
affecting decisions. These are the ends of continua, and there is a need to
recognize degrees of corruption in between. Special interests also influence
members of Congress to make legal what has been illegal or else to game the
rules, thereby blurring the line between legal and illegal as well as making it
hard to determine the law’s intent. Just as a proper electoral democracy is
devoted to the public good, health care systems are founded on the moral
principles of beneficence, nonmaleficence (“ first, do no harm”), respect for
autonomy, and the just distribution of scarce resources. Based on these
principles, health care workers are obliged to use the best medical science to
relieve suffering and pain, treat illness, and address risks to health. The
institutional corruption of health care consists of deviations from these
principles. The major patent-based research pharmaceutical companies also
nominally commit themselves to improving health and relieving suffering. For
example, Merck promises “to provide innovative, distinctive products that save
and improve lives ... and to provide investors with a superior rate of return.”
Pfizer is dedicated “to applying science and our global resources to improve
health and well-being at every stage of life.” Pharmaceutical companies
continuously emphasize how deeply society depends on their development of
innovative products to improve health. But in fact, these companies are mostly
developing drugs that are little better than existing products but have the
potential to cause widespread adverse reactions even when appropriately
prescribed. This deviation from the principles of health care by institutions
allegedly dedicated to health care is institutional corruption. We present
evidence that industry has a hidden business model to maximize profits on
scores of drugs with clinically minor additional benefits. Physician commitment
to better health is compromised as the industry spends billions to create what
Lessig calls a “gift economy” of interdependent reciprocation. New research
finds that truly innovative new drugs sell themselves in the absence of such
gift-economy marketing.

Regulators such as the FDA and the Environmental Protection Agency arise when
unregulated competition is perceived to cause serious harm to society and
government regulation is needed to address the problem. The FDA was founded to
protect the public’s health from the fraudulent cures peddled in the 19th
century. Through a series of legislative enactments, often in response to a
drug disaster, the pharmaceutical regulatory side of the FDA has acquired
ever-wider responsibilities to ensure that new drugs do more good than harm.
Institutional corruption consists of distortions of these responsibilities,
such as approving drugs that are mostly little better than existing
medications, failing to ensure sufficient testing for serious risks, and
inadequately guarding the public from harmful side effects. These distortions
serve commercial interests well and public health poorly. For the past 50
years, patent-based research companies have objected to the FDA’s gatekeeping
function as being too rigid and too slow. They have claimed that an obsessive
concern about safety has undermined patient access to drugs that could save
lives or reduce the burdens of ill health. This message is increasingly being
accepted by the FDA. Flooding the Market with Drugs of Little Benefit In
response to the emphasis by pharmaceutical companies, their lobbyists, and
their trade association — the Pharmaceutical Research Manufacturers of America
(PhRMA) — on the high risk and cost of research and development (R&D), Congress
has authorized billions in taxpayer contributions to support R&D, exemptions
from market competition, and special privileges. Patents, of course, can be
found in all industries, but lobbyists for the pharmaceutical industry have
successfully pressured Congress to provide several forms of market protection
beyond patents. Therapeutic Value of Drugs Marketed in France, 2002-2011 The
industry measures “innovation” in terms of new molecular entities (NMEs), but
most NMEs provide at best minor clinical advantages over existing ones and may
lawfully be approved by the FDA even if they are inferior to previously
approved drugs. The preponderance of drugs without significant therapeutic gain
dates back at least 35 years. From the mid-1970s through the mid-1990s,
multiple assessments have found that only 11 to 15.6 percent of NMEs provide an
important therapeutic gain. Millions of patients benefit from the one out of
six drugs that are therapeutically significant advances; but most R&D dollars
are devoted to developing molecularly different but therapeutically similar
drugs, which tends to involve less risk and cost for manufacturers. These drugs
are then sold through competition based on brand name, patent status, and
newness, rather than on their therapeutic merits. An analysis of data from the
National Science Foundation by Donald Light and Joel Lexchin indicates that
patent-based pharmaceutical companies — often deemed by Congress, the press,
the public, and themselves to be “innovative” — in fact devote only 1.3 percent
of revenues, net of taxpayer subsidies, to discovering new molecules. The 25
percent of revenues spent on promotion is about 19 times more than the amount
spent on discovering new molecules. In short, the term “R&D” as used by
industry primarily means “development” of variations rather than the
path-breaking “research” that onlookers might like to imagine. The independent
drug bulletin, La revue Prescrire, analyzes the clinical value of every

new drug product or new indication approved in France. From 1981 to 2001, it found that
about 12 percent offered therapeutic advantages.But in the following decade,
2002- 2011, as shown in Figure 1, only 8 percent offered some advantages and
nearly twice that many — 15.6 percent – were judged to be more harmful than
beneficial. A mere 1.6 percent offered substantial advantages. Assessments by
the Canadian advisory panel to the Patented Medicine Prices Review Board and by
a Dutch general practice drug bulletin have come to similar conclusions. No
comparable review has been done in the United States on the 229 NMEs approved
by the FDA between 2002 and 2011. This decrease does not come from the
“innovation crisis” of fewer new molecules entering trials or eventually being
approved but from fewer new drugs being clinically superior. The number of
products put into trials has actually increased as the number of clinically
superior drugs has decreased. These facts provide evidence that companies are
using patents and other protections from market competition primarily to
develop drugs with few if any new therapeutic benefits and to charge inflated
prices protected by their strong IP rights. Despite the small number of
clinically superior drugs, sales and profits have soared as successful
marketing persuades physicians to prescribe the much more costly new products
that are at best therapeutically equivalent to established drugs. Both an
American and a Canadian study found that 80 percent of the increase in drug
expenditures went to paying for these minor-variation new drugs, not for
important advances. Companies claim that R&D costs are “unsustainable.” But
over the past 15 years, revenues have increased six times faster than has
investment in R&D. Almost a decade ago, Jerry Avorn, a widely respected
pharmacoepidemiologist and author of a book on the risks of drugs, described
how the big pharmaceutical companies exploited patents and concluded that
“[l]aws designed to encourage and protect meaningful innovation had been turned
into a system that rewarded trivial pseudo-innovation even more profitably than
important discoveries.” He also noted that efforts in Congress to introduce a
“reasonable pricing clause” that would reflect large taxpayer contributions to
new drugs were defeated by industry lobbyists. An Epidemic of Harmful Side
Effects Most new drugs approved and promoted since the 1970s lack additional
clinical advantages over existing drugs and — as with all drugs — they have
been accompanied by harmful side effects. A systematic review of the 39
methodologically strongest studies performed in the U.S. between 1964 and 1995
examined patients who were hospitalized due to a serious adverse drug reaction
(ADR) or who experienced an ADR while in the hospital. The review found that
4.7 percent of hospital admissions were due to serious reactions from
prescription drugs that had been appropriately prescribed and used. In
addition, 2.1 percent of in-hospital patients who received correctly prescribed
medications experienced a serious ADR, for a total of 6.8 percent of hospital
patients having serious ADRs. Applying this 6.8 percent hospital ADR rate to
the 40 million annual admissions in U.S. acute care hospitals indicates that up
to 2.7 million hospitalized Americans each year have experienced a serious
adverse reaction. Of all hospitalized patients, 0.32 percent died due to ADRs,
which means that an estimated 128,000 hospitalized patients died annually,
matching stroke as the 4th leading cause of death. Deaths and serious reactions
outside of hospitals would significantly increase the totals.

An analysis conducted in 2011, based on a year of ADRs reported to the FDA,
came to similar conclusions: Americans experienced “2.1 million serious
injuries, including 128,000 patient deaths.” Other studies reveal that one in
every five NMEs eventually caused enough serious harm in patients to warrant a
severe warning or withdrawal from the market. Of priority drugs that were
reviewed in slightly more than half the normal time, at least one in three of
them caused serious harm. The public health impacts are even greater when
milder adverse reactions are taken into account. Given estimates that about 30
ADRs occur for every one that leads to hospitalization, about 81 million side
effects are currently experienced every year by the 170 million Americans who
use pharmaceuticals. Groups such as pregnant women, elderly patients, and those
who are taking multiple medications are especially at risk. Most of these
medically minor adverse reactions are never brought to clinical attention, but
even minor reactions can impair productivity or functioning, lead to falls, and
cause potentially fatal motor vehicle accidents. Contributors to More Harm and
Less Benefit Are the adverse side effects we have just been describing simply
the “price of progress or an unavoidable risk of drug therapy?” In fact,
evidence suggests that commercial distortions of the review process and
aggressive marketing contribute to both undermining beneficence as health
care’s raison d’être and to the epidemic of harm to patients. Distorting,
Limiting, and Circumventing Safety Regulations Since at least the 1890s, the
public has clamored for Congress to regulate contaminated or adulterated foods
and harmful or ineffective medicines (medicines that may delay truly useful
treatments). At that time, lobbyists — paid from drug profits — argued that
even bills to require accurate listing of secret ingredients would destroy the
industry. These lobbyists had managed to have earlier bills sent to die in the
Committee on Manufactures until President Roosevelt intervened to secure
passage of the 1906 Food and Drug Act, which still only required that
statements on labels be true and provided no budget for enforcement. Work on
what would become the 1938 food and drug law began in 1933 with a bill that
would prohibit misstatements in advertising and require manufacturers to prove
to the FDA that drugs were safe before being allowed to sell them. The
companies’ two trade associations launched “well-choreographed screams of
protest” and letter-writing campaigns to mislead Congress and to distort its
mission to protect its constituents from harm. Employees of drug makers wrote
to Congress, arguing that requiring companies to make honest claims about safe
drugs would put thousands out of work. The FDA staff wanted the legislation
passed but were stopped by threats of prosecution if they campaigned for it.
Then a manufacturer added diethylene glycol (antifreeze) to a sulfa drug to
make a sweet-tasting elixir and children started dying. Public response trumped
industry lobbyists and Congress passed the 1938 law, requiring that drugs be
safe but leaving it to companies to decide how to define and test for safety.

For the next 25 years, drugs were approved within 180 days unless the FDA objected,
based on the companies’ tests and reports of safety. Some companies “tested”
their products by sending samples out to providers for feedback, keeping no
records of the results, and denying serious harms when reported by doctors.
Daniel Carpenter, the author of a book considered to be a definitive work on
the politics of the FDA, has detailed how the FDA staff dedicated themselves to
enforcing the rules and developing better criteria for safety and efficacy. But
as Malcolm Salter, at the Harvard Business School emphasizes, companies
institutionalize corruption by getting legislative and administrative rules
shaped to serve their interests, either directly or by crafting rules in ways
they can game. In his review of new pharmaceutical products in the 1940s and
1950s, Dr. Henry Dowling, an AMA senior officer and expert, found that
companies launched 200-400 a year but only three on average were clinically
useful. Physicians, swamped with far more drugs than they could know much
about, relied on sales reps to brief them, entertain them, and leave an ample
supply of free samples as gifts that the physicians could then give to their
patients — a two-stage economy of reciprocation. In effect, through political
pressure and lobbying, companies minimized the role of the FDA as the protector
of public health for its first 56 years. Following the 1962 amendments,
propelled to passage by the thalidomide tragedy, the FDA commissioned the
National Research Council, as part of the National Academy of Sciences, to
review the effectiveness of all 2820 drugs (available in 4350 different
versions) approved between 1938 to 1962. Companies were required to submit
substantial evidence of effectiveness. The review concluded that seven percent
of the drugs reviewed were completely ineffective for every claim they made and
a further 50 percent were only effective for some of the claims made for them.
Although the FDA has acted to remove many of these ineffective drugs from the
market, some pre-1962 drugs are — more than 50 years later — still under-going
review and are among the “several thousand drug products” that, according to a
2011 FDA guidance document, are today “marketed illegally without required FDA
approval.” Regulatory capture begins with the dependency corruption of
Congress, which passes the regulations and provides the funding for agencies to
protect the public. While the 1962 amendments ushered in the modern era of
testing for safety and efficacy before a drug can be approved, three key
features of the modern drug-testing system actually work for industry profits
and against the development of safe drugs that improve health. First, three
criteria used by the FDA contribute to the large number of new drugs approved
with few therapeutic advantages. New drugs are often tested against placebos
rather than against established effective treatments, and the use of surrogate
or substitute end points, rather than actual effects on patients’ health.
Noninferiority trials that merely show that the product is not worse than
another drug used to treat the same condition by more than a specified margin
are accepted, rather than requiring superiority trials. Silvio Garattini,
founder of the Mario Negri Institute for Pharmacological Research, points out
that placebo and noninferiority trials violate international ethical standards
and provide no useful information for prescribing. Second, allowing companies
to test their own products has led them — as rational economic actors — to
design trials in ways that minimize detection and reporting of harms and
maximize evidence of benefits. Furthermore, clinical trials for new drugs are
designed

to test primarily for efficacy and generally are not able to detect less common
adverse events. Industry-friendly rules allow companies to exclude those
patients most likely to have adverse reactions, while including those most
likely to benefit, so that drugs look safer and more effective than they are in
practice. Approvals based on scientifically compromised trials underlie the
large number of heavily marketed new drugs with few or no new therapeutic
benefits to offset their under-tested risks of harm. Third, companies have
created what can be characterized as the trial-journal pipeline because
companies treat trials and journals as marketing vehicles. They design trials
to produce results that support the marketing profile for a drug and then hire
“publication planning” teams of editors, statisticians, and writers to craft
journal articles favorable to the sponsor’s drug. Articles that present the
conclusions of commercially funded clinical trials are at least 2.5 times more
likely to favor the sponsor’s drug than are the conclusions in articles
discussing non-commercially funded clinical trials. Yet, journal approval is
deemed to certify what constitutes medical knowledge. Published papers
legitimate the pharmaceutical products emerging from the R&D pipeline and
provide the key marketing materials. Furthermore, companies are much less
likely to publish negative results, and they have threatened researchers who
break the code of secrecy and confidentiality about those results. Positive
results are sometimes published twice — or even more often — under different
guises. This further biases meta-analyses — a method of statistically combining
the results of multiple studies — and clinical guidelines used for prescribing.
The result is “a massive distortion of the clinical evidence.” For decades, the
FDA has kept silent about these practices and about the discrepancies between
the data submitted to the FDA by companies and the findings published in
journal articles, to the detriment of patients but much to the benefit of the
companies. In sum, testing and FDA criteria approval provide little or no
information to clinicians on how to prescribe new drugs, a vacuum filled by
company-shaped “evidence” that misleads physicians to prescribe drugs that are
less safe and effective than indicated by evidence that the FDA possesses.
PDUFA: Conflict-of-Interest Payments In 1992, after years of underfunding and
cuts in the 1980s that contributed to drug review times ballooning from 6 to 30
months, Congress passed the Prescription Drug User Fee Act (PDUFA), authorizing
the FDA to collect “user fees” from drug companies that would allow it to hire
600 more reviewers and thereby speed up drug review. Supporters claimed that
fees would increase incentives for innovation and improve health; but aside
from clearing the backlog of NMEs waiting for approval, industry fees have not
increased innovation as measured by clinically superior drugs. In return for
paying user fees, companies required the FDA to guarantee that it would review
priority applications within six months and standard applications within 12
months of submission. Shortened review times led to substantial increases in
serious harms. An in-depth analysis found that each 10-month reduction in
review time — which could take up to 30 months — resulted in an 18.1-percent
increase in serious adverse reactions, a 10.9percent increase in
hospitalizations, and a 7.2-percent increase in deaths. Now, 20 years

later, what Carpenter calls “corrosive capture” has set in — a weakened application of regulatory tools and
a cultural capture of rhetoric about saving lives by getting new drugs to
patients more quickly. For the FDA, the reduction in review time combined with
the fear that missing review deadlines will jeopardize continued PDUFA funding
has also led to an increase in “up against the wall” approvals as review
deadlines approach. Carpenter and his colleagues found that “the probability of
a drug approved in the two months before the deadline receiving a new black-box
warning (the most serious safety warning that the FDA can issue) is 3.27 times
greater than a drug approved at some other time” and the likelihood of a drug
being withdrawn from the market because of serious adverse events is 6.92 times
greater. These detailed studies corroborate what FDA staff told the Office of
the Inspector General, namely, that concerns arising near the end of the review
period are not adequately addressed, that needed meetings with advisory
committees are not held, and that label warnings and contraindications are
hastily written. As a result, there are “tens of thousands of additional
hospitalizations, adverse drug reactions, and deaths.” The 1998 withdrawal of
five drugs, used by 19.8 million Americans, prompted critical reflection. Three
distinguished physicians were struck by how little information had been
gathered about the harmful side effects of these drugs before they were
withdrawn. They attributed inaction to the FDA’s lack of interest in safety,
lack of funds, and to “the lack of a proactive, comprehensive and independent
system to evaluate the long-term safety, efficacy, and toxicity of drugs” after
FDA approval. To compensate for the FDA’s failures, they called for an
independent National Drug Safety Board — akin to the National Transportation
Safety Board that investigates each plane crash and holds public meetings — so
that the same part of the FDA that approves drugs, the Center for Drug
Evaluation and Research (CDER), would not later be asked to decide whether that
drug should be restricted or withdrawn. In other words, public health would not
depend on FDA officials’ willingness to admit their own mistakes. Such an
independent board should establish an active monitoring system and gather
comparative data across a given therapeutic class so it could provide objective
information and develop better strategies for addressing adverse reactions as a
major cause of death. In 1997, a year before these five withdrawals, Congress
had passed PDUFA II and companies had insisted that none of the fees collected
be spent on post-market surveillance or on drug-safety programs. PDUFA II, III,
IV, and V and related legislation provided the FDA with steeply increasing user
fees but included lower criteria for approval, mandated that an industry
representative be on FDA scientific advisory committees, lowered barriers to
promotional efforts by companies, and required FDA officers to consult and
negotiate with industry on the agency’s goals and plans. Offsetting the harms
associated with PDUFA I’s shortened approval framework are several tools
created in PDUFA III through V for detecting, managing, and raising awareness
of risks such as the Sentinel system and the Risk Evaluation and Mitigation
Strategies; but there is no clear evidence these are reducing the epidemic of
harms. These tools are inadequate to counterbalance the increase in risks — let
alone to improve safety. The additional $10 million of funding provided by
PDUFA III for the Office of Drug Safety and the $7.5 million provided for the
FDA’s advertising enforcement arm are tiny in comparison to the more than $690
Read the rest:

https://app.box.com/s/5414zf7lufhtwf3czjfo9msafnoz6ht5

or:

million in user fees that flow to the FDA each year. In sum, PDUFA allocates
user fees overwhelmingly to ensure speedy review of new drug applications while
leaving safety and enforcement dependent on grossly inadequate funding,
perpetuating a history of underfunding safety. Granting priority status to more
drugs further increases the number of drugs reviewed in the shortest time and
the chance of a major safety issue increases from one drug in five to one in
three. Between 1999 and 2008, the FDA gave priority review status to almost 47
percent (114 of 244) of new drug applications, more than four times the
proportion of drugs found to have superior clinical effects by independent
review groups. Reflecting the cultural and corrosive capture of the FDA, its
Commissioner said recently that “an increasing number of treatments are being
approved under the agency’s fast-track, priority review ... to get critical and
innovative medicines to market more rapidly.” Quicker reviews and less evidence
of clinical benefit have rewarded the hidden business model of developing still
more drugs with minor benefits. The FDA’s obligation to serve the public is
being corroded by pressures to serve the companies it regulates. As for
post-market surveillance — “the single most important function…for protecting
the public against the dangers of harmful drugs” — it is put largely in the
hands of the manufacturers and the FDA Center for Drug Evaluation and Research
(CDER), the part of the FDA that companies pay to review their new drug
applications. After approval, aggressive marketing of new drugs to doctors for
both approved and unapproved uses before good safety information is available
maximizes the number of patients exposed to risks from the roughly 25 to 40 new
NMES approved annually. Field studies find that most drug representatives do
not discuss adverse side effects. Although the law requires companies to submit
some marketing materials for review, Congress and the FDA allocate only a small
budget and staff to review about 75,000 submissions a year for false or
misleading information. Further, the small stream of letters ordering that
inaccuracies be corrected is subject to a review process that delays their
reaching the companies. Marketing for unapproved or “off-label” uses worsens
the balance of harm and benefit and undermines the purpose of testing to show
that a drug is effective and safe for a specific use. While trying drugs for
new uses is clinically important, especially for certain populations such as
children and cancer patients, 75 percent of off-label prescribing is neither
supported by sound evidence nor accompanied by an organized means for gathering
such evidence. Companies retain leading experts to expand use, broaden clinical
guidelines, and conduct small, short sham trials that companies get published
and hand out to their physician-customers as “evidence.” A 15-month
investigation by the Committee on Government Reform of the U.S. House of
Representatives found “a growing laxity in FDA’s surveillance and enforcement
procedures, a dangerous decline in regulatory vigilance, and an obvious
unwillingness to move forward even on claims from its own field offices.” The
resulting 2006 report also documented a 53.7-percent decline in warning
letters. Since then, FDA leadership has shifted to talking about being a
“partner” with industry to get more drugs to patients more quickly. For the
reasons we explained above, the proportion of new products with clinical
advantages seems to have moved from about 1 in 8 down to 1 in 12, while the
proportion with serious harms has gone up from 1 in 5 towards 1 in 3 as the
number of drugs given priority status increases.
http://ethics.harvard.edu/news/institutional-corruption-and-pharmaceutical-policy

Direct from author:
https://www.academia.edu/6750219/Institutional_Corruption_and_the_Myth_of_Safe_and_Effective_Drugs

Medical Veritas • 2008

The truth behind the vaccine cover-up Russell L. Blaylock, MD Abstract On June
7-8, 2000 a secret conference was held at the Simpsonwood Conference Center in
Norcross, Georgia to discuss a study examining the link between increasing
doses of Thimerosal and neurodevelopmental disorders. The study was done using
the Vaccine Safety Datalink (VSD) data-base, an official governmental data bank
collecting patient vaccination information on the children from the health
maintenance organizations (HMOs) being paid to participate. Attending were 51
scientists, representatives of pharmaceutical vaccine manufacturing companies
and a representative of the World Health Organization; the public and the media
were unlawfully excluded. The conclusions of this meeting were quite startling,
since it confirmed a dose-response link between Thimerosal and
neurodevelopmental disorders that held up to rigorous statistical analyses. In
their discussion, they make plain why the meeting was held in secret: the
conclusions would have destroyed the public’s confidence in the vaccine
program, and more importantly, their faith in vaccine authorities. When the
results of this study were published three years later in the journal
Pediatrics, the “problem” had been fixed, in that by adding another set of data
from a third HMO, reorganizing the criteria for inclusion and restructuring the
patient groupings, a less than statistically significant link was demonstrated.
In my analysis I discuss the more outrageous statements made during the meeting
and how accepted experts in the field of mercury neurotoxicity were excluded
from the meeting. I was asked to write a paper on some of the newer mechanisms
of vaccine damage to the nervous system, but in the interim I came across an
incredible document that should blow the lid off the cover-up being engineered
by the pharmaceutical companies in conjunction with powerful governmental
agencies. continued on page 725-726

“There is a great deal of evidence to prove that immunization of children does more harm than good”
Dr. J. Anthony Morris, former Chief Vaccine Control Officer, FDA

Table of Contents Chapter One

Manufacturing Biologics

Page 24

Chapter Two

Thimerosal • Mercury

Page 129

Chapter Three

Alum • Aluminum Salts

Page 308

Chapter Four

The HPV Vaccine

Page 489

Chapter Five

Vaccination History 1915 - 2015

Page 525

Chapter Six

On Autism

Page 980

Chapter Seven

Short Essays On Vaccination

Page 1041

Featured Full-Length Reports

Page 186 ........ Mercury toxicity: Genetic susceptibility and synergistic
effects Page 199 ........ Heavy-Metal Toxicity—With Emphasis on Mercury Page
430 ........ Do aluminum vaccine adjuvants contribute to the rising prevalence
of autism? Page 437 ........ Aluminum Vaccine Adjuvants: Are they Safe? Page
440 ........ Mechanisms of aluminum adjuvant toxicity and autoimmunity in
pediatric populations Page 470 ........ Aluminum-induced entropy in biological
systems: implications for neurological disease Page 503 ........ Who Profits
From Uncritical Acceptance of Biased Estimates of Vaccine Efficacy and Safety?
Page 505 ........ No autoimmune safety signal after vaccination with
quadrivalent HPV vaccine Gardasil? Page 507 ........ Death after Quadrivalent
Human Papillomavirus (HPV) Vaccination: Causal or Coincidental? Page 509
........ HPV vaccines and cancer prevention, science versus activism Page 624
........ Vaccines and Autism Page 645 ........ Biological Evidence of
Significant Vaccine Related Side-effects Resulting in Neurodevelopmental
Disorders Page 649 ........ Chronic Microglial Activation and Excitotoxicity
Secondary to Excessive Immune Stimulation: Possible Factors in Gulf War
Syndrome and Autism Page 697 ........ FDA Science and Mission at Risk Page 698
........ Current childhood vaccine programs Page 699 ........ Vaccines,
depression, and neurodegeneration after age 50 years: another reason to avoid
the recommended vaccines Page 705 ........ Modeling Neurodevelopment Outcomes
and Ethylmercury Exposure from Thimerosal-Containing Vaccines Page 720 ........
Current childhood vaccine programs: An overview with emphasis on the
Measles-Mumps-Rubella (MMR) vaccine Page 726 ........ The truth behind the
vaccine cover-up Page 818 ........ Vaccination: Why the ‘one size fits all’
vaccination argument does not fit all! Page 872 ........ Hidden in Plain Sight:
Vaccines as a Major Risk Factor for Chronic Disease Page 912 ........
Methodological issues and evidence of malfeasance in research purporting to
show thimerosal in vaccines is safe Page 998 ........ A possible central
mechanism in autism spectrum disorders Part 1 Page 999 ........ A possible
central mechanism in autism spectrum disorders Part 2 Page 1000 ...... A
possible central mechanism in autism spectrum disorders Part 3

January 2016 • Vaccine Peer Review • The History Of The Global Vaccination
Program In 1000 Peer Reviewed Reports And Studies • 1915-2015 • Jeff Prager
Books • for Camillie, Syrena and Illiana

http://jprager9.wix.com/jeffpragerbooks

Introduction

V

accines are not the product of altruistic and generous or benevolent action on
the part of the manufacturers. Gardasil alone sells for well over 100 dollars
per injection. As a consequence, each of us at birth immediately represents
thousands of dollars worth of income across the over 188 injections we’ll
receive in a lifetime—according to the complete recommended US vaccination
schedule—starting with 128 antigen, adjuvant and excipient injections before
reaching adulthood. Vaccines are sold under an extremely clever marketing
strategy that encompasses not only a “must-have” scenario for each of us but
included with that is absolutely no liability for harm. What do you suppose
motivated the vaccine manufacturers to work so exceedingly hard through public
and governmental processes to establish a “lawsuit-free zone” for vaccines? Was
it to avoid any chance at all of legal challenges? The extraordinary harm
you’ll read about here is directly related to seeking that discharge of legal
responsibility for damage. Many of us won’t remember that years ago the
lawsuits were mounting and the vaccine business was about to come to an end.
This collection of reports reveals the gruesome and stark reality that lies
hidden behind what is actually “open-source and public” medical literature
that, for reasons unknown, the general public will rarely see. Perhaps the
difficulty in finding representative material is an obstacle. Maybe the
complexities surrounding the issue are an impediment to fruitful searches. This
PDF was created for these reasons. Admittedly, this is a large collection of
data that can’t be examined properly in a weekend. Yet the totality of the data
is what’s so very important. If one person told us that repeatedly injecting
aluminum, mercury, antigens or excipients could be dangerous we might question
the theory but when 100s of professionals make a medically supported claim, we
should listen closely, don’t you think? The vaccine industry is rife with
corruption and fraud and that’s about the only thing that isn’t actually
printed. The human damage and the collateral toll from vaccination is carefully
recorded and this collection discloses some of that harm. While there may be
1000 peer reviewed reports here, I can assure you that there are 1000s more
just the same. This collection provides the reader with the peer review that is
less complex and easier to understand. Some of you, hopefully, will research
the more complex issues further on your own using terms, authors and subject
matter found here. If you take the time to read all of the reports collected
here you’ll come to understand certain uncomfortable realities. For example,
that all of the 350plus vaccines currently in use are nothing more than
population-wide experiments. The pre-licensing trials are so short and with
small cohorts and they

use only very healthy, robust people, that they can’t gain any knowledge at all
regarding adverse events in the general population. It’s common knowledge
within the industry that a vaccine isn’t tested and that adverse events are
virtually unknown, until after it’s been used for some time in large segments
of the population. Several years to a decade or more later they may find that
there are serious problems related to a particular vaccine. This is what
happened with Thimerosal. The scientific evidence came in decades later that
autism, neurological disorders and other human diseases were promoted by and
often caused by Thimerosal. You’ll read peer reviewed reports here from
respected journals about the epidemic human damage and the cover-up. In fact,
if not for the cover-up we might have been able to reduce or even eventually
halt the autism epidemic. Instead, the issue has been concealed from the public
and Thimerosal was quietly replaced with aluminum. Thimerosal was not “removed”
from vaccines. All Thimerosal-containing vaccines (TCVs) were used up and the
new lots of vaccine were made with a new adjuvant. Various aluminum salts,
adjuvants used in many vaccines, may be even more insidious than Thimerosal.
Numerous authors from around the world believe so. A new disease, encompassing
nearly 100 different disorders and affecting as many as 50 million people in
the US, has been named and studied. ASIA, autoimmune/inflammatory syndrome
induced by adjuvants, was officially named by the medical research community in
2013. To paraphrase one of the authors within these pages, we’ve reached a
point in time where the damage from vaccines has exceeded the hoped for
protection from disease. To paraphrase further, childhood illnesses like
chicken pox, measles, mumps and others are “challenge viruses” that strengthen
the immune system and we’ve removed a significant and very important immune
fortifying evolutionary step from humankind by vaccinating.

rophagic Myofasciitis (MMF), Multiple Sclerosis (MS), Alzheimers Disease (AD),
Learning Disabilities (ADHD), Arthritis, Inflammatory Bowel Disease, Crohn’s
Disease (CD), Autoimmune And Inflammatory Syndrome Induced By Adjuvants (ASIA),
Hodgkin and non-Hodgkin lymphomas, Allergies, Asthma and nearly 100 more
diseases and disorders are all reaching epidemic proportions. They’re all
caused by vaccines. Yet the greatest human epidemic of the 20th and 21st
centuries will be the enormous spectrum of neurological and biological symptoms
and complications associated with autism, ADHD and learning disabilities. Taken
together, these neuro-bio-disorders affect one in 6 children in the USA and
they are directly related to the US vaccine schedule. The material collected
herein will inform the reader that vaccines cause disorders that increase the
profits on tablet and capsule style drugs substantially and that vaccines are
not safe, nor are they effective. The collateral damage currently being caused
by what the reader will come to know as a very primitive and largely unknown
and unproven science, is beyond imaginable and beyond description. It requires
100s of pages of text to accurately describe the full gamut of human damage
caused by the global vaccination programs and that’s exactly what we’ve
collected here.

Misleading advertising campaigns with deceptive and often times unproven claims
accompanied by well organized sham-marketing strategies have completely misled
the average consumer who buys vaccines like lattes. The resulting tragedy is a
series of epidemics of disease and disorder that translates into nothing short
of the very definition of the word “pandemic.”

The reports within these pages were written by many celebrated, accomplished
and esteemed authors who are well known within their fields, independent
authors whose integrity hasn’t been compromised by influence or wealth.
Represented here are hundreds of prominent and duly recognized medical
professionals and specialists, scientists, clinicians and researchers from
around the world, people such as Dr. Christopher Exley, one of the worlds
leading experts on Aluminum, and whose sense of humor in the face of
extraordinary, planet-wide adversity, is a welcomed respite. I hope you’ll
become acquainted with Dr. Jose Dorea, Dr. CA Shaw, Dr. Harold Buttram, Dr.
Joachim Mutter, Dr. Russell Blaylock and Dr. Lucija Tomljenovic and their
varied, prescient and wholly honest writing styles. There are many others.
These are just some of my favorites. Look for them and read what they have to
say and your understanding of vaccination will grow accordingly. After all,
they’re writing to you.

Across the globe the vaccination programs have traded several childhood
diseases for nearly 100 new disorders many of which were virtually unknown just
a century ago. Measles, mumps, rubella, chicken pox and other tolerable,
“immune system fortifying” childhood illnesses have been replaced by epidemics,
and I’m not using that word lightly. Epidemics of Autistic Spectrum Disorder
(ASD), Guillain-Barre Syndrome (GBS), Mac-

These issues are so critically important to these professionals that they write
about them repeatedly. You can literally hear their voices in their writing.
Many of the 100s of authors within these pages may be risking career
advancement to expose the truth— that the harm from vaccines has seriously
exceeded the benefit of disease prevention—yet none of these authors have
compromised their morals. Please, listen to them.

Preface
Most of the ingredients in vaccines—including aluminum, mercury, formaldehyde,
B2 glycoprotein, Triton X-100®, Polysorbate or Tween 80®, 60 and 20,
2-Phenoxyethanol, etc.—are neurotoxins, toxic to cells, cell structure and
neurons. Vaccines are designed such that “tissue damage” is a necessary
component of antibody creation to acquire some level of assumed immunity.
Tissue damage, cell death or apoptosis are required aspects of vaccination
success. The key is to cause tissue damage without damaging the person herself.
After 100 years of vaccination science we are still as yet unable to achieve
that goal. Vaccine damage is ubiquitous. There are low-responders and
non-responders the medical profession fails to discuss publicly and inform us
about. Within every country-population cohort—people that will respond to
vaccination with low or zero recognizable titers and whose immune system simply
will not “take” to the vaccine—make up a normal and expected percentage of the
population. Non- and low-responders can be responsible for outbreaks of disease
just as fully vaccinated individuals can acquire and spread the illnesses they
were vaccinated for. Vaccination is never, ever 100% and comes with no
guarantees of protection or immunity to disease nor guarantees against serious
harm or death. Historically, the innate immune system was at the forefront of
disease defense and it mobilized epithelial barriers (referring to the skin and
the thin tissue covering the body’s surface and lining the alimentary canal and
other hollow structures of the ears, eyes, nose and throat), special
lymphocytes called “ natural killer (NK)” cells, plasma proteins and other
immune system components. Vaccination bypasses the innate immune system and
directly affects only the humoral immune system (referring to antibodies in
body fluids as distinct from cells). Decades of bypassing the innate immune
system along with removal of common and tolerable childhood “challenge”
diseases—mumps, chicken pox, measles, etc.—has caused a reversal in the way our
bodies fight viral and bacterial infection. Evolutions first line of defense
and the faster, stronger primary system, the innate immune system, has been
relegated to second place with vaccination causing the slower acting humoral
immune system to occupy the first line of defense. The result of repeated
vaccination to perturb the human immune system into developing antibodies to
less than 2 dozen different tolerable childhood ailments—antibodies which have
never been proven to be markers of immunity—has manifest as 100 or more human
disorders after little more than 100 years of vaccination. The epidemic of
disease we can now see surrounding us is staggering. The reasons for these
epidemics of disease are outlined herein and are supported not by any
individual report or study but by the totality of the collected evidence. I
sincerely hope that the material represented here helps you to better
understand a very important aspect of life in this 21st century. The link below
accesses a collection of 44 full-length reports in PDF format that are free to
download and that are also included herein in shorter abstract form:
https://app.box.com/s/xa75ta0j9jbe05e615gd5xto9ff1mz4a

“It is now universally recognized that we have a steadily growing epidemic
of childhood autism, learning disabilities, and other developmental disorders,
with comparable increases in asthma and allergies.” Medical Veritas
International Inc • 2007

Reminiscences of America’s children in the 1930s as compared with today, and
the possible role of vaccines in causing retrogressive changes Editorial by
Harold Buttram, MD, FAACP 5724 Clymer Road Quakertown, PA 18951
HButtrum@woodmed.com Abstract It is now universally recognized that we have a
steadily growing epidemic of childhood autism, learning disabilities, and other
developmental disorders, with comparable increases in asthma and allergies. By
any measure now available, these conditions were rare during the 1930s and
1940s. If this trend is to be reversed, we must seek for causes. As largely
disclosed during the U.S. Congressional Hearings on issues of vaccine safety,
which took place from 1999 to December, 2004, there are gross deficiencies in
vaccine safety testing. Because of this lack, we have no means of identifying
or proving adverse reactions when they do occur. Almost totally lacking until
now, the great need is for definitive before-and-after tests specifically
designed to search for adverse effects of vaccines on the neurological and
immune systems as well as genetics of our children, and in findings adverse
effects to make appropriate safety modifications in vaccine programs. Over the
years there have been a scattering of before-and-after vaccine tests showing
that there can be harm to the immune and central nervous systems, bringing
suspicion on vaccines as an underlying cause of current childhood epidemics.
However, these have always been of limited scale, seldom if ever with adequate
follow-up. In the opinion of this observer, until the safety of vaccine
programs can be assured by such testing, any further mandating of childhood
vaccines will remain morally and ethically untenable.
http://www.medicalveritas.com/images/00166.pdf

Lucija Tomljenovic, PhD
Neural Dynamics Research Group Department of Ophthalmology and Visual Sciences,
University of British Columbia 828 W. 10th Ave, Vancouver, BC, V5Z 1L8 tel:
604-875-4111 (68375)

Regarding H.527 Distinguished Members of the Vermont House, The argument of
forcing a parent to vaccinate their child in the name of the “greater good
argument” is flawed both scientifically and ethically. Firstly, all drugs are
associated with some risks of adverse reactions. Because vaccines represent a
special category of drugs which are by and large given to healthy individuals,
and for prophylaxis against diseases to which an individual may never be
exposed, the margin of tolerance for side effects is very narrow (in fact, the
U.S. Food and Drug Administration (FDA) concurs with this point [1]) and
careful assessment of risks versus benefits essential in deciding whether one
should be vaccinated or not. Removing the “philosophical exemption” as a means
to opt out from vaccination will put vulnerable but otherwise healthy
individuals at risk of serious adverse reactions to vaccinations. Such an
outcome should be of concern since cases of permanent neurodevelopmental
disabilities and deaths following vaccination in children with underlying
genetic and other susceptibilities have been firmly established in scientific
literature [2-4]. Please consider carefully whether you wish to be responsible
for such potential outcomes should you facilitate this legislation to come to
pass. Secondly, medical ethics demand that vaccination should be carried out
with the participant’s full and informed consent. This necessitates an
objective disclosure of the known or foreseeable vaccination benefits and
risks. The way in which pediatric vaccines are often promoted by various health
authorities indicates that such disclosure is rarely given from the basis of
best available knowledge but rather, largely unproven and/or untenable
assumptions on both, vaccine safety and effectiveness. I shall herein elaborate
on these arguments. Is Vaccine Safety Evidence “Rock Solid”? The statement by
Dr Chen that “the science behind vaccination safety is rock solid” is factually
inaccurate and contradicts a large body of scientific literature published on
this subject [3-35]. As with any medication, vaccines can carry risks of
adverse reactions (ADRs). However, in spite of the widespread notion that
vaccines are largely safe and serious adverse complications are extremely rare,
a close scrutiny of the scientific literature does not support this view
[10-12]. For example, to date the clinical trials that could adequately address
vaccine safety issues have not been conducted (i.e., comparing health outcomes
in vaccinated versus non-vaccinated children). The lack of such controlled
trials may be because historically, vaccines have been assumed safe [12]. There
is also a view that conducting such trials would be extraordinarily difficult
or unethical; the first is simply not correct, the second is not a scientific
issue per se. It is also often assumed that vaccines face a tougher safety
standard than most pharmaceutical products. However, according to the U.S. FDA,
“Historically, the non-clinical safety assessment for preventive vaccines has
often not included toxicity studies in animal models. This is because vaccines
have not been viewed as inherently toxic” [1]. This is a startling admission
from an Agency which according to its own mission statement is ”responsible for
protecting the public health by assuring the safety, efficacy, and security of
human and veterinary drugs”[36]. Essentially, what the FDA workshop [1]
revealed is that not only are vaccines not adequately evaluated for toxicity
but also, that the reason for such an oversight rested on a belief rather than
scientific evidence. Science is not a religion

in which dogmatic statements of faith can replace adequately powered,
controlled, longitudinal vaccine safety studies in animals and people.
Furthermore, such assumptions of safety, in the absence of actual experimental
data, are not only dangerous but have historically hampered serious scrutiny of
potential vaccine harms. To illustrate a recent example of grave consequences
that resulted from pushing a poorly tested vaccine to young children, note that
there have been a large numbers of major ADRs from seasonal influenza vaccines.
Consequently, they have been suspended for use in children under five years of
age in Australia. In a series of Rapid Responses addressing this issue,
published in British Medical Journal, titled “Adverse events following
influenza vaccination in Australia-should we be surprised?” Collignon (Director
of Infectious Diseases & Microbiology at Australian National University) and
colleagues from the Cochrane Collaboration review panel concluded: “There is
poor evidence on how well influenza vaccines prevent any influenza
complications in children and other age groups. There is good evidence that
influenza vaccines study reports cherry pick results and achieve spurious
notoriety. Exposing human beings to uncertain effects is a risky business”
[25].The authors also noted that worldwide, the recommendations from public
health authorities regarding influenza vaccination has been “misguided”[26]. It
important to note that even those in the scientific community who are strong
proponents of vaccinations have come to question the scientific legitimacy of
“one-size fits all” vaccination practices [37]. For example, Poland (Editor in
Chief of the journal Vaccine and co-author of “The age-old struggle against the
antivaccinationists” [38]) and colleagues rightly ask whether “with the
advances coming from the new biology of the 21st Century”, it is time to
consider “how might new genetic and molecular biology information inform
vaccinology practices of the future?” [37]. In light of this question Poland et
al. conclude that “one-size fits all” approach for all vaccines and all persons
should be abandoned. According to Poland, this conclusion applies to both
vaccine efficacy, as well as safety [37]. Regarding the latter, the widely held
view that serious vaccine-related ADRs are rare needs revision, as current
worldwide vaccination policies indeed operate on “one-size fits all”
assumption. This assumption persists despite the fact that historically,
vaccine trials have routinely excluded vulnerable individuals with a variety of
pre-existing conditions (i.e., premature birth, personal or family history of
developmental delay or neurologic disorders including epilepsy/seizures,
hypersensitivity to vaccine constituents etc. [39-43]). Because of such
selection bias, the occurrence of serious ADRs resulting from vaccinations may
be considerably underestimated. As mentioned previously, such an outcome should
be of concern in view of documented evidence of permanent neurodevelopmental
disabilities and deaths following vaccination in children with underlying
genetic and other susceptibilities [2-4]. Poland et al.’s current data may thus
have far broader implications for understanding vaccines, not only in terms of
efficacy and the desired immune response, but also in terms of safety. Indeed,
vulnerable populations will neither have the same antibody response nor the
same level of tolerance to serious ADRs as non-vulnerable populations [37,44].
The Quality of Existing Vaccine Safety Data A further obfuscation of the actual
rate of serious vaccine-associated ADRs may also be due to methodological
inadequacy of existing vaccine trials (i.e, the frequent exclusion of
individuals with potential pre-existing susceptibilities to vaccine-associated
ADRs) [12], and due to the fact that the vast majority of such trials use an
aluminum adjuvant-containing placebo or another aluminum-containing vaccine as
the “control group” [45]. That aluminum is a demonstrated neurotoxin has been
known for over 100 years [46] and in this context, it is becoming clear to a
number of investigators that its use as a placebo control is scientifically
untenable [45,47]. Furthermore, with regard to the studies which allegedly
demonstrably show no link between autism and vaccines, it has to be emphasized
that once such studies undergo proper expert scrutiny, the “evidence” against
the link becomes rather flimsy. In reviewing the published literature on
measles- mumps-rubella (MMR) vaccine (139

studies), the respected Cochrane Collaboration review panel concluded that, “The design and reporting of safety outcomes in
MMR vaccine studies, both pre- and post-marketing, are largely inadequate”
[48]. Moreover, none of the 31 studies that were included in the review met the
Cochrane Collaboration’s methodological criteria. More specifically, referring
to the 2001 Fombonne and Chakrabarti study [49] which was widely regarded by
medical health authorities as most persuasive in disproving the link between
the MMR vaccine and autism, the Cochrane Collaboration commented the following:
“The number and possible impact of biases in this study was so high that
interpretation of the results is impossible” [48]. Although the Cochrane Review
on the safety of MMR concluded that there was no credible link between MMR
vaccination and autism and Crohn’s disease, as pointed out earlier, the
majority of the studies included in the evaluation were methodologically
inadequate. The question thus is what “credible” or “rock solid” evidence can
be derived from inadequate studies? Demonstrated Toxicity of Vaccine
Constituents Vaccines contain known neurotoxins (i.e., mercury, aluminum,
formaldehyde), potent adjuvants designed to hyperstimulate the immune system,
as well as various antigenic compounds [10,50] albeit all in relatively small
amounts. Thus a typical vaccine formulation contains all the necessary
biochemical components to induce both autoimmune as well as neuoroimmune
disorders. The question is not whether these compounds are in vaccines or if
they are toxic, rather if in such concentrations alone or combined, they can
harm the nervous and other systems. Experimental evidence indeed shows that
some of these constituents (mercury and aluminum) can cause long-term
neurological impairments in animal models when individually administered in
vaccine-relevant human exposures [7,51-57]. Furthermore, data also demonstrate
that over-stimulating the host’s immune system by repeated immunization with
immune antigens and/or adjuvants inevitably leads to autoimmunity even in
genetically non-susceptible animals [58,59]. Specifically, simultaneous
administration of as little as two to three immune adjuvants can overcome
genetic resistance to autoimmunity [59]. Yet in spite of these observations,
according to the current U.S. immunization schedule by the time children are 4
to 6 years old, they will have received a total of 126 antigenic compounds
along with high amounts of Al adjuvants [10]. Given the scarcity of evidence of
safety of the combined pediatric schedule and the fact that administration of
only a few vaccines in human adults can lead to brain dysfunction and a variety
of autoimmune conditions [8,16,17,19], the concerns about the overall safety of
current childhood vaccination programs are scientifically plausible and thus
require urgent consideration [10]. Full Report with References
http://www.vaxchoicevt.com/wp-content/uploads/2012/04/Lucija-Tomljenovic-PhD-letter.pdf
https://app.box.com/s/ev8bhi6vb3rofhrkavum3v3hpt2xlil9
http://vaccinechoicecanada.com/wp-content/uploads/Forced-Vaccinations-For-the-Greater-Good-Tomljenovic.pdf

“According to the Autism Society of America, autism is now considered to be an epidemic.”
Journal Of Toxicology And Environmental Health Part B, Critical Review •
November 2006

Evidence of toxicity, oxidative stress, and neuronal insult in autism Author
information Kern JK1, Jones AM. Department of Psychiatry University of Texas
Southwestern Medical Center at Dallas Dallas, Texas 75390-9119, USA
janet.kern@UTSouthwestern.edu Abstract According to the Autism Society of
America, autism is now considered to be an epidemic. The increase in the rate
of autism revealed by epidemiological studies and government reports implicates
the importance of external or environmental factors that may be changing. This
article discusses the evidence for the case that some children with autism may
become autistic from neuronal cell death or brain damage sometime after birth
as result of insult; and addresses the hypotheses that toxicity and oxidative
stress may be a cause of neuronal insult in autism. The article first describes
the Purkinje cell loss found in autism, Purkinje cell physiology and
vulnerability, and the evidence for postnatal cell loss. Second, the article
describes the increased brain volume in autism and how it may be related to the
Purkinje cell loss. Third, the evidence for toxicity and oxidative stress is
covered and the possible involvement of glutathione is discussed. Finally, the
article discusses what may be happening over the course of development and the
multiple factors that may interplay and make these children more vulnerable to
toxicity, oxidative stress, and neuronal insult.
http://www.ncbi.nlm.nih.gov/pubmed/17090484

Medical Veritas • 2005

Vaccination and autoimmunity: reassessing evidence Marc Girard, MSc, MD 1 bd de
la République 78000-Versailles, France Phone:+330139670110 Fax:+330139670111
agosgirard@free.fr Abstract The autoimmune risks of vaccines seem frequently
overlooked. Whereas most available vaccinations are supposed to produce
long-lasting immunity, the fact that they can also produce long-term
detrimental immune effects seems to be ignored as evidenced by the short
duration of safety studies during development. Likewise, whereas it seems
natural to simply rely on surrogate markers, such as antibodies, to demonstrate
vaccine efficacy, the levels of evidence required to acknowledge adverse
effects is far higher. Reports to the Vaccine Adverse Event Reporting System
(VAERS) are deemed more conclusive when reassuring than when suggesting
significant toxicity. As a result of these blatant biases in clinical and/or
epidemiological research, experts on autoimmunity and vaccine critics are
limited to demonstrating theoretical mechanisms because evidence in practice is
lacking. Known as the bias of the selective assessment, this unbalance in the
demonstration of the benefits as compared to the risks is the bête noire of
evidence-based medicine. Therefore, when readjusted to the demonstrative level
normally viewed as sufficient in clinical research in general and in vaccine
science specifically, the corpus of data on the autoimmune hazards of vaccines
appears certainly more impressive than generally recognized and calls for
further research, for an overall reassessment of the benefit/risk ratio of
vaccines including multiple vaccinations. Because vaccines are now aimed at
preventing diseases which may be quite rare, the Hippocratic principle of
prudence is more than ever a very topical issue. Many other examples of poor
methodology, selective assessment or dissimulation of data could be given. This
suggests that research and development on vaccines are still at the zero- level
of evidence-based medicine (EBM). As assessed with the same units of measure
used with other drugs, some vaccines and specifically the hepatitis B vaccine
have an unacceptable benefit/risk ratio, especially in countries where the
diseases they claim to control are not endemic. For obvious reasons of profit,
the threats to the scientific and medical ethics of our job have reached a
worrying level: it is the personal responsibility of each of us to resist – and
to support those who are the most under pressure.
http://www.know-vaccines.org/PDF/VaccinationAutoimmunity.pdf

“The autoimmune risks of vaccines seem frequently overlooked. Many other
examples of poor methodology, selective assessment or dissimulation of data
could be given. This suggests that research and development on vaccines are
still at the zero-level of evidence-based medicine (EBM) ... It is the personal
responsibility of each of us to resist”

Pace Environmental Law Review, vol. 28, no. 2 • 2011

Unanswered Questions A Review of Compensated Cases of Vaccine-Induced Brain
Injury by Mary Holland, Louis Conte, Robert Krakow and Lisa Colin Executive
Summary In 1986, Congress created the Vaccine Injury Compensation Program
(VICP) under the National Childhood Vaccine Injury Act (1986 Law). This Program
has original jurisdiction for children’s claims of vaccine injury. Because
almost all children receive multiple vaccinations for daycare and school, it is
critically important that the Program provides fundamental fairness, due
process and transparency. This empirical investigation, published in a
peer-reviewed law journal, examines claims that the VICP compensated for
vaccine-induced encephalopathy and seizure disorder. The VICP has compensated
approximately 2,500 claims of vaccine injury since the inception of the
program. This study found 83 cases of acknowledged vaccineinduced brain damage
that include autism, a disorder that affects speech, social communication and
behavior. In 21 published cases of the Court of Federal Claims, which
administers the VICP, the Court stated that the petitioners had autism or
described autism unambiguously. In 62 remaining cases, the authors identified
settlement agreements where Health and Human Services (HHS) compensated
children with vaccine-induced brain damage, who also have autism or an autism
spectrum disorder.

“Using publicly available information, the investigation shows that the Vaccine
Injury Compensation Program (VICP) has been compensating cases of
vaccine-induced brain damage associated with autism for more than twenty years.
This investigation suggests that

Parents reported the existence of autism in telephone interviews and supplied
supplemental materials including medical diagnoses, school records, and
completed, standard autism screening questionnaires to verify their reports. In
39 of the 83 cases, or 47% of the cases of vaccine injury reviewed, there is
confirmation of autism or autism spectrum disorder beyond parental report.

officials at HHS, the Department of Justice and the

This finding of autism in compensated cases of vaccine injury is significant.
U.S. government spokespeople have been asserting no vaccine-autism link for
more than a decade. This finding calls into question the decisions of the Court
of Federal Claims in the Omnibus Autism Proceeding in 2009 and 2010 and the
statement of Health and Human Services on its website that “HHS has never
concluded in any case that autism was caused by vaccination.”

this association but failed to publicly disclose it.”

Using publicly available information, the investigation shows that the VICP has
been compensating cases of vaccine-induced brain damage associated with autism
for more than twenty years. This investigation suggests that officials at HHS,
the Department of Justice and the Court of Federal Claims may have been aware
of this association but failed to publicly disclose it. The study calls on
Congress to thoroughly investigate the VICP, including a medical investigation
of compensated claims of vaccine injury. This investigation calls on Congress
to get answers to these critically important unanswered questions.
http://www.ebcala.org/unanswered-questions

Court of Federal Claims may have been aware of

“This eBook is free because the truth should always be free”
~ Jeff Prager

Chapter One
The Business Of Manufacturing Biologics 1969 - 2015 If the global vaccination
programs are causing epidemic incidents of death and disease, and they are,
then it’s our responsibility to do something about it and revealing it using
respected, independent peer review is a critically important component of that
exposure. Here we provide basic insight into the highly complex and tricky
business of manufacturing injectable products. Laboratory creation of safe
injectable’s is a dirty business fraught with risk and unpredictable
circumstances at every turn. Viruses mutate and new viruses appear out of
nowhere to sully the product. Most, if not all, vaccine lots are contaminated.
Enteroviruses, pestiviruses, DNA and RNA fragments, bovine and porcine viruses
and other components of the virus manufacturing process remain in the final
product. We’re told there’s no harm related to injecting these vagrant
particles but the truth is, there’s absolutely no scientific data to support
that claim. Mutating viruses with the high potential for undiscovered
contamination will eventually win over man in his misguided attempt to
repeatedly vaccinate every living human being. We’re each faced with almost 200
vaccines in our lifetime—128 antigen, adjuvant and excipient injections by
adulthood if the vaccine schedule is followed—and that extraordinary volume of
repeatedly injected material is now causing devastating populationwide effects.
The increase in disease and disorder is readily apparent to anyone that looks.
This chapter describes the dirty business of biological manufacturing.

“A cell line (MDCK) of dog kidney origin grows on a glass surface
as a mosaic of epithelium with many multicellular hemispherical vesicles. The
cells lining the blisters actively secrete into the cyst cavities. Suspensions
of these cells injected intravenously in the chick embryo produce brain
metastases resembling adenocarcinoma.” Science • January 1969

Secretory activity and oncogenicity of a cell line (MDCK) derived from canine
kidney A cell line (MDCK) of dog kidney origin grows on a glass surface as a
mosaic of epithelium with many multicellular hemispherical vesicles. The cells
lining the blisters actively secrete into the cyst cavities. Suspensions of
these cells injected intravenously in the chick embryo produce brain metastases
resembling adenocarcinoma. [Editors Note: The MDCK (NBL-2) (ATCC® CCL-34™) cell
line has been used since 1958 to produce influenza and other vaccines]
http://www.sciencemag.org/content/163/3866/472.long MDCK cell line:
http://www.atcc.org/products/all/CCL-34.aspx

“The phage contamination of virus
vaccines and its possible consequences need further investigations.” Journal of
Biological Standardization Volume 3, Issue 3, July 1975 Pages 307–308

Bacteriophage contamination in live poliovirus vaccine by Hedda Milch†, F.
Fornosi† Abstract Bacteriophages lytic for Escherichia coli strains were
isolated from two lots of oral poliomyelitis vaccine. From one ultracentrifuged
sample bacteriophages of four different plaque patterns were demonstrable with
E. coli C 3000 (2·8 × 102 PFU/ml) and E. coli (1·1 × 102 PFU/ml) as indicator
strains. The phage contamination of virus vaccines and its possible
consequences need further investigations. Purchase Price - $31.50
http://www.sciencedirect.com/science/article/pii/0092115775900347

“The determination of the total 5,224 base-pair DNA sequence of the virus SV40
has enabled us to locate precisely the known genes on the genome.” Nature • May
1978

Complete nucleotide sequence of SV40 DNA Fiers W, Contreras R, Haegemann G,
Rogiers R, Van de Voorde A, Van Heuverswyn H, Van Herreweghe J, Volckaert G,
Ysebaert M. Abstract The determination of the total 5,224 base-pair DNA
sequence of the virus SV40 has enabled us to locate precisely the known genes
on the genome. At least 15.2% of the genome is presumably not translated into
polypeptides. Particular points of interest revealed by the complete sequence
are the initiation of the early t and T antigens at the same position and the
fact that the T antigen is coded by two non-contiguous regions of the genome;
the T antigen mRNA is spliced in the coding region. In the late region the gene
for the major protein VP1 overlaps those for proteins VP2 and VP3 over 122
nucleotides but is read in a different frame. The almost complete amino acid
sequences of the two early proteins as well as those of the late proteins have
been deduced from the nucleotide sequence. The mRNAs for the latter three
proteins are presumably spliced out of a common primary RNA transcript. The use
of degenerate codons is decidedly non-random, but is similar for the early and
late regions. Codons of the type NUC, NCG and CGN are absent or very rare.
https://www.ncbi.nlm.nih.gov/pubmed/205802

“Preservatives in multidose vaccine vials do not prevent short-term bacterial contamination.”
Pediatrics • February 1985

Outbreaks of group A streptococcal abscesses following diphtheria-tetanus
toxoid-pertussis vaccination Stetler HC, Garbe PL, Dwyer DM, Facklam RR,
Orenstein WA, West GR, Dudley KJ, Bloch AB. Abstract Two outbreaks of group A
streptococcal abscesses following receipt of diphtheria-tetanus
toxoid-pertussis (DTP) vaccine from different manufacturers were reported to
the Centers for Disease Control (CDC) in 1982. The clustering of the
immunization times of cases, the isolation of the same serotype of
Streptococcus from all cases in each outbreak, and the absence of reported
abscesses associated with receipt of the same lots of vaccine in other regions
of the country, suggest that each outbreak was probably caused by contamination
of a single 15-dose vial of vaccine. The preservative thimerosal was present
within acceptable limits in unopened vials from the same lot of DTP vaccine in
each outbreak. Challenge studies indicate that a strain of Streptococcus from
one of the patients can survive up to 15 days in DTP vaccine at 4 degrees C.
Contamination of vials during manufacturing would have required survival of
streptococci for a minimum of 8 months. Preservatives in multidose vaccine
vials do not prevent short-term bacterial contamination. Options to prevent
further clusters of streptococcal abscesses are discussed. The only feasible
and cost-effective preventive measure now available is careful attention to
sterile technique when administering vaccine from multidose vials.
http://www.ncbi.nlm.nih.gov/pubmed/3881728

Lancet • April 1987

Possible Role Of Pestiviruses In Microcephaly Author Information BarbaraJ.
Potts, JohnL. Sever, NancyR. Tzan, David Huddleston, GregoryA. Elder Infectious
Diseases Branch National Institute of Neurological and Communicative Disorders
and Stroke National Institutes of Health, Bethesda, Maryland 20892, USA
Abstract “The background of this suggestion was that, first, although usually a
pathogen in cattle and sheep, pestivirus infection can occur in children
(Yolken et al. 1989). Second, an association has been reported between
pestivirus exposure and microcephaly in newborns (Potts et al. 1987), which
might be due to a generalized reduction in white matter bulk. Third,
dysmyelination (Potts et al. 1985, Anderson et al. 1987b), frank brain damage
(Hewicker-Trautwein and Trautwein 1994), and hypothyroxinemia (Anderson et al.
1987a) are characteristics of perinatal pestivirus infection in lamb models,
are found in preterm infants (Leviton and Gilles 1996, Reuss et al. 1997), and
are associated with each other among preterm infants (Den Ouden et al. 1996,
Leviton et al. 1999). “ Report available for purchase
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(87)90311-4/abstract

“... an association has been reported between pestivirus exposure and
microcephaly in newborns, which might be due to a generalized reduction in
white matter bulk. Third, dysmyelination, frank brain damage and
hypothyroxinemia are characteristics of perinatal pestivirus infection in lamb
models, are found in preterm infants, and are associated with each other among
preterm infants ...”

“Vaccine produced on contaminated cells may in turn be contaminated,
leading to seroconversion or disease in the vaccine.” Developments In
Biological Standardization • 1991

Bovine viral diarrhea virus contamination of nutrient serum, cell cultures and
viral vaccines Author information Levings RL1, Wessman SJ. National Veterinary
Services Laboratories Animal and Plant Health Inspection Service USDA, Ames, IA
50010 Abstract Bovine viral diarrhea virus (BVDV) infection is common in the
bovine population. Infection in utero leads to virus and antibody contamination
of the fetal bovine serum used in cell cultures. These contaminants can
interfere with diagnosis of viral infection. The high frequency of virus and
antibody detection in individual animal or small pool samples suggests that any
large pool of unscreened sera will be contaminated. Infection of cell cultures
with BVDV can lead to interference with the growth of other viruses. Vaccine
produced on contaminated cells may in turn be contaminated, leading to
seroconversion or disease in the vaccine. The safety, purity, and efficacy of
viral vaccines require BVDV testing of ingredients, cell substrates and final
product. Methods for detection of BVDV in nutrient serum, cell cultures, seed
viruses, and viral vaccines, and the frequency of their detection at the
National Veterinary Services Laboratories are discussed.
http://www.ncbi.nlm.nih.gov/pubmed/1665461

Developments In Biological Standardization • 1991

Viral contamination of fetal bovine serum used for tissue culture: risks and
concerns Author information Erickson GA1, Bolin SR, Landgraf JG. Rollins Animal
Disease Diagnostic Laboratory Raleigh, NC 27605 Abstract Four viral
contaminants have been routinely detected in unprocessed and commercial lots of
fetal bovine serum: bacteriophage, infectious bovine rhinotracheitis,
parainfluenza-3 and bovine viral diarrhea virus (BVDV). Of those, BVDV is
consistently present in a majority of commercial lots of fetal bovine serum.
Methods for BVDV detection and removal are reviewed. The tentative role of an
unclassified pestivirus in microcephaly of infants has been reported. Its
significance remains uncertain. http://www.ncbi.nlm.nih.gov/pubmed/1665460

“Four viral contaminants have been routinely detected in unprocessed and
commercial lots of fetal bovine serum: bacteriophage, infectious bovine
rhinotracheitis, parainfluenza-3 and bovine viral diarrhea virus (BVDV). Of
those, BVDV is consistently present in a majority of commercial lots of fetal
bovine serum. Methods for BVDV detection and removal are reviewed. The
tentative role of an unclassified pestivirus in microcephaly of infants has
been reported. Its significance remains uncertain.”

Journal Of Clinical Microbiology • June 1994

Evidence of pestivirus RNA in human virus vaccines Author information Harasawa
R1, Tomiyama T. Animal Center for Biomedical Research Faculty of Medicine,
University of Tokyo, Japan Abstract We examined live virus vaccines against
measles, mumps, and rubella for the presence of pestivirus RNA or of
pestiviruses by reverse transcription PCR. Pestivirus RNA was detected in two
measles-mumps-rubella combined vaccines and in two monovalent vaccines against
mumps and rubella. Nucleotide sequence analysis of the PCR products indicated
that a modified live vaccine strain used for immunization of cattle against
bovine viral diarrhea is not responsible for the contamination of the vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8077414

“Pestivirus RNA was detected in two measles-mumps-rubella combined vaccines and
in two monovalent vaccines against mumps and rubella.”

“Sixty-one % of the neoplastic patients positive for SV40 sequences
had an age excluding exposure to SV40-contaminated polio vaccines, suggesting a
contagious transmission of SV40.” Cancer Research • October 1996

SV40 early region and large T antigen in human brain tumors, peripheral blood
cells, and sperm fluids from healthy individuals Author information Martini F1,
Iaccheri L, Lazzarin L, Carinci P, Corallini A, Gerosa M, Iuzzolino P,
Barbanti-Brodano G, Tognon M. Institute of Histology and General Embryology
School of Medicine, University of Ferrara, Italy Abstract SV40 T antigen (Tag)
coding sequences were detected by PCR amplification followed by Southern blot
hybridization in human brain tumors and tumor cell lines, as well as in
peripheral blood cells and sperm fluids of healthy donors. SV40 early region
sequences were found in 83% of choroid plexus papillomas, 73% of ependymomas,
47% of astrocytomas, 33% of glioblastoma multiforme cases, 14% of meningiomas,
50% of glioblastoma cell lines, and 33% of astrocytoma cell lines and in 23% of
peripheral blood cell samples and 45% of sperm fluids from normal individuals.
None of the 13 normal brain tissues were positive for SV40 DNA, nor were seven
oligodendrogliomas, two spongioblastomas, one neuroblastoma, one meningioma, or
four neuroblastoma cell lines. Expression of SV40 early region was found by
reverse transcription PCR, and SV40-specific Tag was detected by indirect
immunofluorescence in glioblastoma cell lines. DNA sequence analysis, performed
in four positive samples, confirmed that the amplified PCR products belong to
the SV40 early region. Sixty-one % of the neoplastic patients positive for SV40
sequences had an age excluding exposure to SV40-contaminated polio vaccines,
suggesting a contagious transmission of SV40. The possible role of SV40 Tag in
the etiopathogenesis of human brain tumors and the spread of SV40 by horizontal
infection in the human population are discussed.
http://www.ncbi.nlm.nih.gov/pubmed/8841004

Biologicals • December 1996

Application of PCR for detection of mycoplasma DNA and pestivirus RNA in human
live viral vaccines Author information Sasaki T1, Harasawa R, Shintani M,
Fujiwara H, Sasaki Y, Horino A, Kenri T, Asada K, Kato I, Chino F. Department
of Safety Research on Biologics National Institute of Health, Tokyo, Japan
Abstract PCR techniques were applied for the detection of mycoplasma DNA and
pestivirus RNA to 43 lots of live viral vaccines (measles, mumps, rubella, and
oral poliomyelitis) produced by six manufacturers in Japan. Although mycoplasma
DNA was not detected in any of the vaccines tested, pestivirus RNA was detected
in 12 lots (28%). The incidence of contamination among the four viral vaccines
was in the range of 20 to 37%, and the incidence among the six manufacturers
varied from 0 to 56%. http://www.ncbi.nlm.nih.gov/pubmed/9088554

“The incidence of contamination among the four viral vaccines was in the range
of 20 to 37%, and the incidence among the six manufacturers varied from 0 to
56%.”

“These issues have received relatively little attention hitherto but are likely to achieve
greater prominence as development of such preparations proceeds.” Developments
In Biological Standardization • 1996

Reasons for instability of bacterial vaccines Author information Corbel MJ.
Division of Bacteriology National Institute for Biological Standards & Control
Potters Bar, United Kingdom Abstract Stability problems in relation to
bacterial vaccines vary widely between different types of product. Killed whole
cell bacterial vaccines including pertussis, cholera and typhoid vaccines
generally show a high degree of stability of potency. Reversion to toxicity may
occur in incompletely inactivated pertussis vaccines. Live attenuated vaccines
such as BCG and Ty21a typhoid vaccines lose potency through loss of viability
when exposed to adverse conditions. Both vaccines are susceptible to ultra
violet radiation but Ty21a also has low thermal stability. Its fragility is
probably a consequence of multiple mutations affecting structural and metabolic
factors. Diphtheria and tetanus toxoids generally show high stability of
potency. Reversion to toxicity may occur if the toxoiding process is
inadequate. Decline in potency may result from exposure to adverse conditions,
such as freezing, that affect the interaction with the adjuvant. Similar
problems may be encountered with purified subunit vaccines such as acellular
pertussis preparations. Some components, in particular pertussis toxin and
filamentous haemagglutinin, show inherent low stability and degrade on storage
at refrigerator temperatures unless stabilized by a protein cross-linking
agent. Bacterial proteases carried over from the cell cultures may also be
responsible for degradation of purified components. Purified bacterial
polysaccharides usually show high stability if freeze-dried under appropriate
conditions. Catalytic degradation may occur however, if the stabilizers are of
inadequate purity. Polysaccharide-protein conjugates such as Haemophilus
influenzae b (Hib) polyribosylribityl phosphate-protein conjugates show high
thermal stability if freeze dried. In the liquid state, such conjugates tend to
degrade by hydrolysis of the polysaccharide chains. Combined vaccines may
present special stability problems because of the interaction of the various
components in the liquid state. It can be difficult to freeze-dry some
components of such vaccines, particularly aluminium hydroxide-adsorbed
diphtheria-tetanus-pertussis (DTP) components. Slow release vaccines based on
polyglycolide-factolide microspheres may show suboptimal stability of
encapsulated antigen under both in vitro conditions as a result of gradual
acidification through polymer hydrolysis. Vaccines based on the use of live
recombinant strains to express heterologous protective antigens may present
special stability problems. Apart from the carrier strains, heterologous genes
carried on plasmids may be subject to spontaneous deletion under adverse
conditions. These issues have received relatively little attention hitherto but
are likely to achieve greater prominence as development of such preparations
proceeds. http://www.ncbi.nlm.nih.gov/pubmed/8854008

Monaldi Archives For Chest Disease • April 1998

Simian virus 40 and human cancer Author information Mutti L1, Carbone M,
Giordano GG, Giordano A. S. Maugeri Foundation, IRCCS Rehabilitation Institute
of Veruno/Varallo S., Italy Abstract Deoxyribonucleic acid (DNA) oncoviruses
can induce neoplastic transformation by interfering with proliferative
proteins. Simian virus 40 (SV40) has been shown to induce brain tumors,
osteosarcoma, lymphoid tumors and malignant mesothelioma in hamsters and
SV40-like DNA sequences corresponding to the Rb-pocket binding domain of SV40
Tantigen (Tag) have been detected in the same human tumors. Since only a small
percentage of people exposed to asbestos fibers develop a malignant
mesothelioma, SV40 has been suspected to co-operate with the fibers in the
neoplastic transformation or even to itself induce the onset of malignant
mesothelioma in patients without expositive history. The mechanism that seems
to be involved in the SV40-induced carcinogenesis process is mediated by
interaction of Tag, both with p53 and Rb proteins, leading to their functional
inactivation that is responsible for the removal of their inhibitory cell cycle
effect which determines the increase of the number of cells entering the G1-S
phase. Up to now the source of SV40 human infections has not yet been
completely identified even though administration from 1957-1965 of SV40
contaminated polio vaccines is highly suspected. Horizontal infection by sexual
transmission has been also hypothesized. Due to the important public health
implications further investigations are required in order to establish both the
source and the carcinogenetic role of simian virus 40 in humans.
http://www.ncbi.nlm.nih.gov/pubmed/9689809

“Up to now the source of SV40 human infections has not yet been completely
identified even though administration from 1957-1965 of SV40 contaminated polio
vaccines is highly suspected. Horizontal infection by sexual transmission has
been also hypothesized.”

Monaldi Archives Of Chest Disease • April 1998

The biological activities of simian virus 40 large-T antigen and its possible
oncogenic effects in humans Author information Matker CM1, Rizzo P, Pass HI, Di
Resta I, Powers A, Mutti L, Kast WM, Carbone M. Cardinal Bernardin Cancer
Center Loyola University of Chicago Maywood, IL 60153, USA Abstract Simian
virus 40 (SV40) is an oncogenic virus which induces tumors in hamsters and
transforms human cells in tissue culture. Between 1955 and 1963, polio vaccines
and adenovaccines were contaminated with SV40; therefore, millions of people
were exposed to this oncogenic virus. The SV40 proteins responsible for in vivo
oncogenesis and in vitro cell transformation are encoded by the early region of
the virus. These proteins are called T (tumor) antigens (Tags), because animals
with tumors induced by SV40 have antibodies against these viral proteins.
Recently, we and other research laboratories have found SV40 in specific types
of human tumors: mesothelioma, ependymoma and choroid plexus tumors,
osteosarcoma and sarcoma. The same tumor types will develop in hamsters which
have been injected systemically with SV40. SV40 causes cell transformation in
tissue culture and tumors in animals, because SV40 Tag binds and inactivates
the cellular tumor suppressor gene products, Rb and p53. We found that SV40 Tag
binds p53 and Rb in human mesotheliomas, possibly contributing to the malignant
phenotype. http://www.ncbi.nlm.nih.gov/pubmed/9689808

“Between 1955 and 1963, polio vaccines and adenovaccines were contaminated with
SV40; therefore, millions of people were exposed to this oncogenic virus.”

Monaldi Archives For Chest Diseases • April 1998

The detection of simian virus 40 in human tumors by polymerase chain reaction
Author information Rizzo P1, Di Resta I, Powers A, Matker CM, Zhang A, Mutti L,
Kast WM, Pass H, Carbone M. Loyola University of Chicago Cardinal Bernardin
Cancer Center Maywood, IL, USA Abstract Simian virus (SV) 40 is a
deoxyribonucleic acid (DNA) virus that induces mesotheliomas, ependymomas, bone
tumors, and lymphomas in hamsters. In recent years SV40 sequences have been
detected in approximately 60% of mesotheliomas and ependymomas, in 33% of bone
tumors and sarcomas, and in 13% of lymphomas. Because the amount of human
specimens available for molecular studies is usually minimal, the method most
commonly used to demonstrate SV40 in human specimens is the polymerase chain
reaction (PCR). PCR is a highly sensitive and useful technique. In the PCR
reaction, different sets of primers are used for targeting different regions of
DNA. The regions of the SV40 genome targeted by PCR include the large
T-antigen, the small t-antigen, the origin of replication, and viral protein-1
capsid protein. The use of these different sets of primers to test human tumor
specimens for SV40 produce a different percentage of positive results. This is
because these experiments revealed that some primers are more specific than
others which may also detect sequences belonging to other DNA papovaviruses.
Therefore, the combined use of different sets of primers is recommended when it
is important to distinguish SV40 from other related papovaviruses such as BK
and JC, which can also be occasionally present in human cells. Furthermore,
these experiments demonstrated that polymerase chain reaction analyses for
simian virus 40 can be performed better and easier when using deoxyribonucleic
acid extracted from fresh and/or frozen tissue. Deoxyribonucleic acid from
paraffin embedded specimens should not be used routinely for simian virus 40
testing because of the high risk of obtaining false negative results. However,
these paraffin derived deoxyribonucleic acids can be used reliably in molecular
laboratories specialized in these type of analyses. This paper describes the
methods that we have developed to test simian virus 40 in human specimens.
http://www.ncbi.nlm.nih.gov/pubmed/?term=9689810

“This paper describes the methods that we have developed to test simian virus
40 in human specimens.”

BioDrugs • July 1998

Practical considerations in converting from plasma-derived to recombinant
hepatitis B vaccines Author information Lee PI1, Lee CY. Department of
Paediatrics National Taiwan University Hospital Taipei, Taiwan Abstract
Plasma-derived and recombinant vaccines have been developed to prevent
hepatitis B virus infections. Both types of vaccine perform very well with
respect to safety, immunogenicity and protective efficacy. The protection
afforded by both types of vaccine is satisfactory for at least 5 to 10 years
after vaccination, and a further booster dose is not necessary during this
period. However, the plasma-derived vaccine is costly to produce and there is
an unjustified but prevalent fear that it may be contaminated by potential
pathogens. The supply of human plasma for production of the plasma-derived
vaccine cannot be assured once use of hepatitis B vaccines becomes universal.
It is therefore inevitable that the recombinant vaccine will replace the
plasma-derived vaccine. If necessary, both vaccines can be used in combination.
Future directions for hepatitis B vaccine development include: determination of
the need for incorporation of pre-S gene products to enhance immunogenicity;
defining a practical strategy to combat the problem of escape mutants after
vaccination; and development of combination vaccines containing other
inactivated antigens to allow complete immunisation against several diseases
with a minimal number of injections.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18020583

“the plasma-derived vaccine is costly to produce and there is an unjustified
but prevalent fear that it may be contaminated by potential pathogens. The
supply of human plasma for production of the plasma-derived vaccine cannot be
assured once use of hepatitis B vaccines becomes universal.”

Journal Of The National Cancer Institute • January 1999

Cell and molecular biology of simian virus 40: implications for human
infections and disease Author information Butel JS1, Lednicky JA. Division of
Molecular Virology Baylor College of Medicine Houston, TX 77030-3498, USA
jbutel@bcm.tmc.edu Abstract Simian virus 40 (SV40), a polyomavirus of rhesus
macaque origin, was discovered in 1960 as a contaminant of polio vaccines that
were distributed to millions of people from 1955 through early 1963. SV40 is a
potent DNA tumor virus that induces tumors in rodents and transforms many types
of cells in culture, including those of human origin. This virus has been a
favored laboratory model for mechanistic studies of molecular processes in
eukaryotic cells and of cellular transformation. The viral replication protein,
named large T antigen (T-ag), is also the viral oncoprotein. There is a single
serotype of SV40, but multiple strains of virus exist that are distinguishable
by nucleotide differences in the regulatory region of the viral genome and in
the part of the T-ag gene that encodes the protein’s carboxyl terminus. Natural
infections in monkeys by SV40 are usually benign but may become pathogenic in
immunocompromised animals, and multiple tissues can be infected. SV40 can
replicate in certain types of simian and human cells. SV40-neutralizing
antibodies have been detected in individuals not exposed to contaminated polio
vaccines. SV40 DNA has been identified in some normal human tissues, and there
are accumulating reports of detection of SV40 DNA and/or T-ag in a variety of
human tumors. This review presents aspects of replication and cell
transformation by SV40 and considers their implications for human infections
and disease pathogenesis by the virus. Critical assessment of virologic and
epidemiologic data suggests a probable causative role for SV40 in certain human
cancers, but additional studies are necessary to prove etiology.
http://www.ncbi.nlm.nih.gov/pubmed/9923853

“Critical assessment of virologic and epidemiologic data suggests a probable
causative role for SV40 in certain human cancers, but additional studies are
necessary to prove etiology.”

“These data suggest that there may be an increased incidence of certain cancers
among the 98 million persons exposed to contaminated polio vaccine in the U.S.”
Anticancer Research • May 1999

Cancer risk associated with simian virus 40 contaminated polio vaccine Author
information Fisher SG1, Weber L, Carbone M. Cancer Cause and Prevention Program
Loyola University Medical Center Maywood, Illinois 60153, USA Abstract
BACKGROUND The presence of SV40 in monkey cell cultures used in the preparation
of the polio vaccine from 1955 through 1961 is well documented. Investigations
have consistently demonstrated the oncogenic behavior of SV40 in animal models.
Early epidemiologic studies were inadequate in demonstrating an increase in
cancer incidence associated with contaminated vaccine. Recently, investigators
have provided persuasive evidence that SV40 is present in human ependymomas,
choroid plexus tumors, bone tumors, and mesotheliomas, however, the etiologic
role of the virus in tumorigenesis has not been established. MATERIALS AND
METHODS Using data from SEER, we analyzed the incidence of brain tumors, bone
tumors, and mesotheliomas from 1973-1993 and the possible relationship of these
tumors with the administration of the SV40 contaminated vaccine. RESULTS Our
analysis indicates increased rates of ependymomas (37%), osteogenic sarcomas
(26%), other bone tumors (34%) and mesothelioma (90%) among those in the
exposed as compared to the unexposed birth cohort. CONCLUSIONS These data
suggest that there may be an increased incidence of certain cancers among the
98 million persons exposed to contaminated polio vaccine in the U.S.; further
investigations are clearly justified.
http://www.ncbi.nlm.nih.gov/pubmed/10472327

Cancer Research • December 1999

Unique strains of SV40 in commercial poliovaccines from 1955 not readily
identifiable with current testing for SV40 infection Author information Rizzo
P1, Di Resta I, Powers A, Ratner H, Carbone M. Loyola University Medical
Center, Cardinal Bernardin Cancer Center Department of Pathology, Maywood,
Illinois 60153, USA Abstract SV40 was first identified as a contaminant of
poliovaccines used from 1955 until 1963. Recently, SV40 has been detected in
several human tumors. The virus detected in human tumors often contained only
one 72-bp enhancer in the regulatory region, in contrast to the SV40 originally
isolated from poliovaccines, which contained two 72-bp enhancers. The origin of
viruses with one 72-bp enhancer in humans was unknown, because it was thought
that these viruses were not present in poliovaccines. It was also thought that
all poliovaccine vials produced from 1955 until 1963 had been discarded, thus
the possibility that one 72-bp virions contaminated those vials could not be
tested. We unexpectedly obtained what appear to be the last available vials of
poliovaccine produced in 1955. In these vials, we detected and sequenced SV40
containing only one 72-bp enhancer in the regulatory region. The tissue culture
cytopathic test currently used in the United States to screen oral
poliovaccines was designed to detect rapidly proliferating SV40 virions
containing two 72-bp enhancers. We found that this test is not sensitive enough
to detect low amounts of the slow-replicating SV40 virions containing one 72-bp
enhancer. This virus was easily detected in the same cells by immunostaining
and PCR. Twelve current vials of poliovaccines tested uniformly negative for
SV40, suggesting that the precaution of preparing poliovaccines from kidneys
obtained from monkeys bred in isolated colonies prevented SV40 contamination.
Our data demonstrate that humans were exposed to SV40 viruses with both one
72-bp enhancer and two 72-bp enhancers SV40 through contaminated vaccines. Our
data also suggest that instead of cytopathic tests, immunohistochemical and/or
molecular studies should be used to screen poliovaccines for SV40 to completely
eliminate the risk of occasional contamination.
https://www.ncbi.nlm.nih.gov/pubmed/10626798

“SV40 was first identified as a contaminant of poliovaccines used from 1955
until 1963. Recently, SV40 has been detected in several human tumors.”

“... in litigation involving the Lederle oral polio vaccine,
the manufacturer’s internal documents failed to reveal such removal in all of
the seeds.” Anticancer Research • November 2000

Oral polio vaccine and human cancer: a reassessment of SV40 as a contaminant
based upon legal documents Author information Kops SP. stankops@aol.com
Abstract To date, the scientific literature and research examining SV40 and
cancer-related diseases has been based upon an assumption that SV40 was not
present in any poliovirus vaccine administered in the United States and was
removed from the killed polio vaccine by 1963. The basis for this presumption
has been that the regulations for live oral polio vaccine required that SV40 be
removed from the seeds and monovalent pools ultimately produced in the
manufacturing process. The Division of Biologic Standards permitted an
additional two tissue culture passages--from three to five--in order to allow
manufacturers the ability to remove this contaminant from the oral poliovirus
vaccines then awaiting licensure. The confirmation of the removal by one drug
manufacturer, Lederle, has been made public at an international symposium in
January 1997, where its representatives stated that all of Lederle’s seeds had
been tested and screened to assure that it was free from SV40 virus. However,
in litigation involving the Lederle oral polio vaccine, the manufacturer’s
internal documents failed to reveal such removal in all of the seeds. The
absence of confirmatory testing of the seeds, as well as testimony of a Lederle
manager, indicate that this claim of removal of SV40 and the testing for SV40
in all the seeds cannot be fully substantiated. These legal documents and
testimony indicate that the scientific community should not be content with
prior assumptions that SV40 could not have been in the oral polio vaccine. Only
further investigation by outside scientific and independent researchers who can
review the test results claimed in the January 1997 meeting and who can conduct
their own independent evaluations by testing all the seeds and individual
mono-valent pools will assure that SV40 has not been present in commercially
sold oral poliovirus vaccine manufactured by Lederle.
http://www.ncbi.nlm.nih.gov/pubmed/11205211

Journal Of Veterinary Medical Science • July 2001

Genotypes of pestivirus RNA detected in live virus vaccines for human use
Author information Giangaspero M1, Vacirca G, Harasawa R, Büttner M, Panuccio
A, De Giuli Morghen C, Zanetti A, Belloli A, Verhulst A. Institute of Special
Pathology and Veterinary Medical Clinic Faculty of Veterinary Medicine, The
University of Milan, Italy Abstract Live virus vaccines for human use, 29
monovalent vaccines against measles, mumps, rubella or polio, eight polyvalent
vaccines against measlesmumps-rubella and one bacterial polyvalent vaccine
against Streptococcus pneumoniae, were tested by reverse transcriptase-nested
PCR for the presence of petivirus or pestivirus RNA. Twenty-four samples were
selected from European manufacturers, ten were from U.S.A. and four from Japan.
Five (13.1%) out of 38 tested samples were positive for pestivirus RNA. Three
vaccines (rubella and two measles) were from Europe and two (mumps and rubella)
from Japan. The 5’-untranslated genomic region of the contaminant pestivirus
RNA were amplified by reverse transcription-PCR and sequenced. Analyses based
on primary nucleotide sequence homology and on secondary structures,
characteristic to genotypes, revealed that the cDNA sequences belonged to
bovine viral diarrhea virus (BVDV). A cDNA sequence, detected from one measles
sample, belonged to BVDV-1b genotype. Pestiviral cDNA detected from the
Japanese mumps and rubella vaccine samples, belonged to the BVDV genotypes 1a
and 1c, respectively. Analysis on two cDNA sequences detected from measles and
rubella vaccine samples from Europe showed their appurtenance to a new
genotype, BVDV-1d. These findings indicate that contamination by animal
pestivirus may occur in biological products for human use.
http://www.ncbi.nlm.nih.gov/pubmed/11503899

“Twenty-four samples were selected from European manufacturers, ten were from
U.S.A. and four from Japan. Five (13.1%) out of 38 tested samples were positive
for pestivirus RNA. Three vaccines (rubella and two measles) were from Europe
and two (mumps and rubella) from Japan.”

Vaccine • October 2001

What are the limits of adjuvanticity? Author information Del Giudice G1, Podda
A, Rappuoli R. IRIS Research Center, Chiron SpA, Via Fiorentina 1, 53100,
Siena, Italy Abstract Vaccines developed traditionally following empirical
approaches have often limited problems of immunogenicity, probably due to the
low level of purity of the active component(s) they contain. The application of
new technologies to vaccine development is leading to the production of purer
(e.g. recombinant) antigens which, however, tend to have a poorer
immunogenicity as compared to vaccines of the previous generation. The search
for new vaccine adjuvants involves issues related to their potential limits.
Since the introduction of aluminium salts as vaccine adjuvants more than 70
years ago, only one adjuvant has been licensed for human use. The development
of some of these new vaccine adjuvants has been hampered by their inacceptable
reactogenicity. In addition, some adjuvants work strongly with some antigens
but not with others, thus, limiting their potentially widespread use. The need
to deliver vaccines via alternative routes of administration (e.g. the mucosal
routes) in order to enhance their efficacy and compliance has set new
requirements in basic and applied research to evaluate their efficacy and
safety. Cholera toxin (CT) and labile enterotoxin (LT) mutants given along with
intranasal or oral vaccines are strong candidates as mucosal adjuvants. Their
potential reactogenicity is still matter of discussions, although available
data support the notion that the effects due to their binding to the cells and
those due to the enzymatic activity can be kept separated. Finally,
adjuvanticity is more often evaluated in terms of antigen-specific antibody
titers induced after parenteral immunization. It is known that, in many
instances, antigen-specific antibody titers do not correlate with protection.
In addition, very little is known on parameters of cell-mediated immunity which
could be considered as surrogates of protection. Tailoring of new adjuvants for
the development of vaccines with improved immunogenicity/efficacy and reduced
reactogenicity will represent one of the major challenges of the ongoing
vaccine-oriented research. http://www.ncbi.nlm.nih.gov/pubmed/11587808

“Vaccines developed traditionally following empirical approaches have often
limited problems of immunogenicity, probably due to the low level of purity of
the active component(s) they contain.”

American Journal Of Health-System Pharmacy • February 2002

Implications of prion-induced diseases for animal-derived pharmaceutical
products Author information Erstad BL. Department of Pharmacy Practice and
Science College of Pharmacy, University of Arizona 1703 E. Mabel Street,
Tucson, AZ 85721-0207, USA Abstract The implications of prion-induced diseases
for the use of medications that theoretically could harbor the infectious
pathogens are discussed. Prions have been identified as protein particles that
lack nucleic acids. There is evidence that prions cause the transmissible
neurodegenerative diseases known as transmissible spongiform encephalopathies.
Of these diseases, bovine spongiform encephalopathy (BSE) and the human
spongiform encephalopathy to which it has been linked, new variant
Creutzfeldt-Jakob disease (CJD), have generated the most attention. The first
cases of new variant CJD appeared in Britain in the mid-1990s. Ingestion of
prion-infected beef remains the only known cause of new variant CJD. No cases
of BSE or new variant CJD have been documented in the United States. The time
from exposure to the development of clinical sequelae appears to be about 10
years. The median duration of illness is 14 months, and the outcome is
invariably death. There is no treatment; currently the only available approach
is prevention. There is no reliable method of predicting the number of new
cases that might occur because of lack of definitive information on the
efficiency of transmission from animals to humans and the number of people
currently infected and at risk for infection. The infectivity of medications
and plasma fractionation products containing material from cattle with BSE is
unknown, but the risk is believed to be very low. No cases of such transmission
have been identified. Guidelines to keep the risk of transmission via
medications low have been promulgated by FDA, and further research is
warranted. There have been no reports of medications or plasma fractionation
products being contaminated with the prions that cause new variant CJD. Ongoing
vigilance and research are appropriate, however.
http://www.ncbi.nlm.nih.gov/pubmed/?term=11862637

“The infectivity of medications and plasma fractionation products containing
material from cattle with BSE is unknown, but the risk is believed to be very
low.”

“This analysis confirmed higher concentrations of endotoxin
in whole-cell DTP vaccines compared with DTaP or DT vaccines. As high
concentrations of endotoxin may be correlated with a higher incidence of
adverse events ...” Annals Of Pharmacotherapeutics • May 2002

Clinical implications of endotoxin concentrations in vaccines Author
information Geier DA1, Geier MR. Genetic Centers of America, 14 Redgate Court,
Silver Spring, MD 20905-5726, USA Abstract BACKGROUND A previous study
suggested that high concentrations of endotoxin may be present in whole-cell
diphtheria/tetanus/pertussis (DTP) vaccine, and the scientific literature
contains many studies examining the reactivity of whole-cell DTP vaccine. The
medical and scientific communities have previously reported that the presence
of endotoxin in commercial vaccines may have negative effects on vaccine
recipients. OBJECTIVE To determine the endotoxin concentrations in whole-cell
DTP, acellular DTP(DTaP), and DT vaccines and determine the clinical experience
with each vaccine. METHODS To study the endotoxin concentrations in vaccines,
the Limulus amebocyte lysate (LAL) assay was used. The vaccines analyzed with
the LAL assay were whole-cell DTP vaccine lots manufactured by Connaught,
Lederle, the Michigan and Massachusetts Departments of Health, and Wyeth; DTaP
vaccine lots manufactured by Merieux and Takeda; and DT vaccine lots
manufactured by Wyeth and Lederle. The incidence of adverse reactions following
whole-cell DTP, DTaP, and DT vaccines were determined based on analysis of the
Vaccine Adverse Events Reporting System (VAERS) database. RESULTS The results
of the LAL assay showed that whole-cell DTP vaccines contained considerably
more endotoxin than either DTaP or DT vaccines. The VAERS showed that
statistically significantly more adverse reactions were associated with
whole-cell DTP vaccine than DTaP or DT vaccines. CONCLUSIONS This analysis
confirmed higher concentrations of endotoxin in whole-cell DTP vaccines
compared with DTaP or DT vaccines. As high concentrations of endotoxin may be
correlated with a higher incidence of adverse events, the switch from
whole-cell DTP to DTaP for routine vaccinations in the US seems well justified.
http://www.ncbi.nlm.nih.gov/pubmed/?term=11978151

Anticancer Research • November 2002

SV40 in human tumors: new documents shed light on the apparent controversy
Author information MacLachlan DS. MacLachlan Law Offices LLC 487 Goffle Road
Ridgewood, New Jersey 07450, USA Abstract BACKGROUND Presently there are over
61 reports from 49 different laboratories that have detected SV40 in human
mesothelioma, lymphoma, brain and bone tumors, versus three reports (two from
Dr. Shah’s laboratory who performed his study under contract from Dr. Strickler
at the Viral Epidemiology Branch (VEB) National Cancer Institute (USA) that
have failed to detect SV40 in some of these same tumor types. To address
whether the negative reports were caused by lack of sensitivity of the
technique used in Shah’s laboratory, or whether the positive reports were
caused by contamination within the greater number of laboratories reporting
SV40 detection, two multi-center studies were conducted. The first study, Testa
et al., 1998, confirmed the presence of SV40 in mesothelioma. The second study,
Strickler et al., produced irregular results indicating that: (a) though never
reporting SV40 detection to date, Dr. Shah’s laboratory reported the most
sensitive technique of all participating laboratories; (b) all participating
laboratories essentially agreed the DNA extracts provided under contract to the
VEB were negative; (c) all participating laboratories agreed one-half of the
negative controls prepared by the VEB contract laboratory were positive due to
contamination by the contract laboratory. In addition, (d) the authors
concluded the

laboratories previously detecting SV40 in human tissue specimens were not
reporting contamination. Scientists in the field have since debated how these
seemingly contradictory results were produced. MATERIALS During the course of
litigation representing patients with SV40-positive tumors, the author obtained
correspondence among members of the VEB multi-center study and sworn testimony
by Dr. Shah that address some of the incongruities of the study. RESULTS Dr.
Shah’s laboratory technique used in 1996 was apparently not sufficiently
sensitive to detect SV40 in human tumors. When this became apparent, during
unilateral pre-trial testing of positive controls by Dr. Shah, the study
coordinator of the VEB, Dr. Strickler, apparently compromised the blinded
nature of the study and allowed Dr. Shah to modify and improve his technique.
When one of the participating laboratories questioned irregularities in the
data from Dr. Shah’s laboratory and directly questioned Dr. Strickler, the
study organizer, about the potential irregularity, Dr. Strickler and Dr. Shah
offered letters stating that such irregularities had not occurred and
re-confirmed that they had not deviated from the standard protocol. CONCLUSION
The facts indicating that Dr. Shah’s laboratory technique was not sufficiently
sensitive to detect SV40 were not made available to the other laboratories
participating in the study and were not published. Instead, according to Dr.
Shah’s testimony, Dr. Strickler, the VEB multi-center study coordinator,
compromised the masked positive controls and knowingly permitted Dr. Shah to
re-test and adjust his technique during pre-trial testing. The actual negative
pre-trial test results were never published alongside the published trial
results indicating Dr. Shah’s laboratory had the most sensitive technique to
detect SV40 among the nine participating laboratories.

http://www.ncbi.nlm.nih.gov/pubmed/12552945

“When one of the participating laboratories questioned irregularities in the
data from Dr. Shah’s laboratory and directly questioned Dr. Strickler, the
study organizer, about the potential irregularity, Dr. Strickler and Dr. Shah
offered letters stating that such irregularities had not occurred and
re-confirmed that they had not deviated from the standard protocol.”

[it was found that they had lied]

Biologicals • December 2002

Detection and characterization of pestivirus contaminations in human live viral
vaccines Author information Studer E1, Bertoni G, Candrian U. Official
Medicines Control Laboratory Biologika and R&D Unit Division of Biologicals,
Swiss Federal Office of Public Health P.O. Box 3003, Bern, Switzerland Abstract
In view of the use of potentially contaminated foetal calf serum (FCS) in cell
cultures pestiviruses may be present in live viral vaccines. Thirty-six lots of
human live viral vaccines produced by three manufacturers were tested for the
presence of pestiviruses. Bovine viral diarrhoea virus (BVDV) RNA was detected
in 33% of the vaccine lots. All positive results were caused by the mumps
component of a single manufacturer. Partial sequences of the 5’ untranslated
region of BVD viral RNA were determined. The sequences were closely related to
that of the NADL strain of BVDV. The amount of BVDV RNA in the vaccines was
determined by real-time RT-PCR using the LightCycler. Between 3.3*10(2) and
6.2*10(5) RNA copies per dose were found to be present in the vaccine
samples.Additionally, culture tests were done with FCS and human diploid cells
used in the vaccine production of the manufacturer whose vaccines were positive
by PCR. All attempts to detect virus antigen in MRC-5 human diploid cells or to
infect these cells with BVDV failed. This suggests that BVDV RNA detected in
human live viral vaccines represents passive carry over of BVDV from
contaminated FCS rather than active virus replication in human diploid cells.
Our results indicate that contamination with BVDV of FCS used in vaccine
production does not appear to be of immediate concern to human health.
Furthermore, our results indicate that gamma-irradiation of FCS destroys BVDV
particles and is also effective in preventing the presence of BVDV RNA in the
vaccines. http://www.ncbi.nlm.nih.gov/pubmed/12421586

“This suggests that BVDV RNA detected in human live viral vaccines represents
passive carry over of BVDV from contaminated foetal calf serum rather than
active virus replication in human diploid cells. Our results indicate that
contamination with BVDV of foetal calf serum used in vaccine production does
not appear to be of immediate concern to human health.”

Institute of Medicine (US) Immunization Safety Review Committee • 2002

Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer
Washington, DC National Academies Press

Editors Stratton K, Almario DA, McCormick MC. Excerpt Some of the polio vaccine
administered from 1955–1963 was contaminated with a virus, called simian virus
40 (SV40). The virus came from the monkey kidney cell cultures used to produce
the vaccine. Most, but not all, of the contamination was in the inactivated
polio vaccine (IPV). Once the contamination was recognized, steps were taken to
eliminate it from future vaccines. Researchers have long wondered about the
effects of the contaminated vaccine on people who received it. Although SV40
has biological properties consistent with a cancer-causing virus, it has not
been conclusively established whether it might have caused cancer in humans.
Studies of groups of people who received polio vaccine during 1955–1963 provide
evidence of no increased cancer risk. However, because these epidemiologic
studies are sufficiently flawed, the Institute of Medicine’s Immunization
Safety Review Committee concluded that the evidence was inadequate to conclude
whether or not the contaminated polio vaccine caused cancer. In light of the
biological evidence supporting the theory that SV40-contamination of polio
vaccines could contribute to human cancers, the committee recommends continued
public health attention in the form of policy analysis, communication, and
targeted biological research. http://www.ncbi.nlm.nih.gov/pubmed/?term=25057632
Full Report http://www.ncbi.nlm.nih.gov/books/NBK221113/

“ In light of the biological evidence supporting the theory that
SV40-contamination of polio vaccines could contribute to human cancers, the
committee recommends continued public health attention in the form of policy
analysis, communication, and targeted biological research.”

Leukemia & Lymphoma • 2003

Association between SV40 and non-Hodgkin’s lymphoma Author information Butel
JS1, Vilchez RA, Jorgensen JL, Kozinetz CA. Department of Molecular Virology
and Microbiology Baylor College of Medicine, Mail Stop BCM385, One Baylor Plaza
Houston, TX 77030, USA jbutel@bcm.tmc.edu Abstract Millions of people worldwide
were inadvertently exposed to live simian virus 40 (SV40) between 1955 and 1963
through immunization with SV40-contaminated polio vaccines. Although the
prevalence of SV40 infections in humans is not known, numerous studies suggest
that SV40 is a pathogen resident in the human population today. SV40 is a
potent DNA tumor virus that is known to induce primary brain cancers, bone
cancers, mesotheliomas, and lymphomas in laboratory animals. SV40 oncogenesis
is mediated by the viral large tumor antigen (T-ag), which inactivates the
tumor suppressor proteins p53 and pRb. During the last decade, independent
studies using different molecular biology techniques have shown the presence of
SV40 DNA, T-ag, or other viral markers in primary human brain and bone cancers
and malignant mesotheliomas. Evidence suggests that there may be geographic
differences in the frequency of these virus-positive tumors. Recent large
independent controlled studies have shown that SV40 T-ag DNA is significantly
associated with human non-Hodgkin’s lymphoma (NHL). In our study, we analyzed
systemic NHL from 76 HIV-1-positive and 78 HIV-1-negative patients, and
nonmalignant lymphoid samples from 79 HIV-1-positive and 107 HIV-1-negative
patients without tumors; 54 colon and breast carcinoma samples served as cancer
controls. We used polymerase chain reaction (PCR) followed by Southern blot
hybridization and DNA sequence analysis to detect DNAs of polyomaviruses and
herpesviruses. SV40-specific DNA sequences were detected in 64 (42%) of 154
NHL, none of 186 nonmalignant lymphoid samples, and none of 54 control cancers.
For NHL from HIV-1-positive patients, 33% contained SV40 DNA and 39% Epstein
Barr virus (EBV) DNA, whereas NHLs from HIV-1-negative patients were 50%
positive for SV40 and 15% positive for EBV. Few tumors were positive for both
SV40 and EBV. Human herpesvirus type 8 was not detected. SV40 sequences were
found most frequently in diffuse large B cell and follicular-type lymphomas. We
conclude that SV40 is significantly associated with some types of NHL and that
lymphomas should be added to the types of human cancers associated with SV40.
http://www.ncbi.nlm.nih.gov/pubmed/15202523

“Millions of people worldwide were inadvertently exposed to live simian virus
40 (SV40) between 1955 and 1963 through immunization with SV40-contaminated
polio vaccines. We conclude that SV40 is significantly associated with some
types of non-Hodgkins Lymphoma and that lymphomas should be added to the types
of human cancers associated with SV40.”

Cancer Epidemiological Biomarkers And Prevention • May 2003

Serum antibodies to JC virus, BK virus, simian virus 40, and the risk of
incident adult astrocytic brain tumors Author information Rollison DE1,
Helzlsouer KJ, Alberg AJ, Hoffman S, Hou J, Daniel R, Shah KV, Major EO.
Department of Epidemiology The Johns Hopkins Bloomberg School of Public Health
Baltimore, Maryland 21205, USA Abstract Genomic sequences of the human
polyomaviruses, JC virus (JCV) and BK virus (BKV), and simian virus 40 (SV40)
have been reported from several types of human brain tumors, but there have
been no population-based seroepidemiologic studies to evaluate the association
between polyomavirus infection and brain tumors. We conducted a case-control
study, nested within a prospective cohort, to investigate the association
between antibodies to JCV, BKV, and SV40, as measured in serum collected 1-22
years before diagnosis and incident primary malignant brain tumors. Brain tumor
cases (n = 44) and age-, gender-, and race-matched controls (n = 88) were
identified from participants of two specimen banks in Washington County,
Maryland. IgG antibodies to the capsid proteins of JCV and BKV were assessed
using ELISAs. SV40-neutralizing antibodies were measured using plaque
neutralization assays. Similar to the general population, the prevalence of JCV
and BKV infection was high in our study population (77 and 85%, respectively).
Antibodies to SV40 were less prevalent (11%). The odds ratio for subsequent
brain tumor development was 1.46 [95% confidence interval (CI), 0.61-3.5] for
JCV, 0.66 for BKV (95% CI, 0.221.95), and 1.00 for SV40 (95% CI, 0.30-3.32).
Given the high prevalence of JCV and BKV infections and the millions who were
potentially exposed to SV40 through contaminated polio vaccines, future studies
should attempt to replicate these findings.
http://www.ncbi.nlm.nih.gov/pubmed/12750243

“Given the high prevalence of JCV and BKV infections and the millions who were
potentially exposed to SV40 through contaminated polio vaccines, future studies
should attempt to replicate these findings.”

American Journal Of Medicine • June 2003

Simian virus 40 in human cancers Author information Vilchez RA1, Kozinetz CA,
Arrington AS, Madden CR, Butel JS. Department of Medicine, Section of
Infectious Diseases Baylor College of Medicine, BCM 286, Room N1319 One Baylor
Plaza, Houston, TX 77030, USA rvilchez@bcm.tmc.edu Abstract BACKGROUND Many
studies have reported the presence of simian virus 40 (SV40) deoxyribonucleic
acid (DNA) or protein in human brain tumors and bone cancers, malignant
mesothelioma, and non-Hodgkin’s lymphoma. However, the small samples and lack
of control groups in some reports have made it difficult to assess their
reliability. METHODS Studies were included in this analysis if they met the
following criteria: original studies of patients with primary brain tumors and
bone cancers, malignant mesothelioma, or non-Hodgkin’s lymphoma; the
investigation of SV40 was performed on primary cancer specimens; the analysis
included a control group; and the same technique was used for cases and
controls. Included reports were published from 1975 to 2002. RESULTS Thirteen
studies fulfilled the criteria for the investigation of primary brain cancers
(661 tumors and 482 control samples). Specimens from patients with brain tumors
were almost four times more likely to have evidence of SV40 infection than were
those from controls (odds ratio [OR] = 3.9; 95% confidence interval [CI]: 2.6
to 5.8). The association was even stronger for mesothelioma (OR = 17; 95% CI:
10 to 28; based on 15 studies with 528 mesothelioma samples and 468 control
samples) and for bone cancer (OR = 25; 95% CI: 6.8 to 88; based on four studies
with 303 cancers and 121 control samples). SV40 DNA was also more frequent in
samples from patients with non-Hodgkin’s lymphoma (OR = 5.4; 95% CI: 3.1 to
9.3; based on three studies with 301 cases and 578 control samples) than from
controls. CONCLUSION These results establish that SV40 is associated
significantly with brain tumors, bone cancers, malignant mesothelioma, and
non-Hodgkin’s lymphoma. Studies are needed to assess current prevalence of SV40
infections. http://www.ncbi.nlm.nih.gov/pubmed/12798456

“These results establish that SV40 is associated significantly with brain
tumors, bone cancers, malignant mesothelioma, and non-Hodgkin’s lymphoma.”

Oncogene • August 2003

New developments about the association of SV40 with human mesothelioma Author
information Carbone M1, Pass HI, Miele L, Bocchetta M. Department of Pathology,
Cardinal Bernardin Cancer Center Cancer Immunology Program, Loyola University
Chicago Maywood, IL 60153, USA mcarbon@orion.it.luc.edu Abstract Simian virus
40 (SV40) has been detected in human tumors in over 40 different laboratories.
Many of these reports linked SV40 to human mesotheliomas. The Vaccine Safety
Committee of the Institute of Medicine (IOM), National Academy of Sciences,
USA, recently reviewed the evidence associating polio vaccines and/or SV40 with
human tumors. The IOM conclusions about polio vaccines and human cancer were:
(1) ‘the evidence is inadequate to accept or reject a causal relation between
SV40-containing polio vaccines and cancer’ because the ‘epidemiological studies
are sufficiently flawed’; (2) ‘the biological evidence is of moderate strength
that SV40 exposure from the polio vaccines is related to SV40 infection in
humans’. The epidemiological studies were considered flawed because it was not
possible to distinguish reliably among exposed and nonexposed cohorts.
Concerning SV40, the IOM concluded that (1) ‘the evidence is strong that SV40
is a transforming virus; (2) the evidence is of moderate strength that SV40
exposure could lead to cancer in humans under natural conditions’ (IOM, 2002).
Similar conclusions were reached at an International consensus meeting on SV40
and human tumors held at the University of Chicago in 2001. G Klein and C
Croce, who chaired the final panel that reviewed all the published evidence
linking SV40 to human tumors, stated that ‘the presence of SV40 in human tumors
has been convincingly demonstrated’ (Klein et al., 2002). In addition, a
workshop organized by the Biological Carcinogenesis Branch of the National
Cancer Institute, Bethesda, MD, chaired by J Pagano, has reached similar
conclusions (Wong et al., 2002). Therefore, three independent scientific panels
have all agreed that there is compelling evidence that SV40 is present in some
human cancers and that SV40 could contribute to the pathogenesis of some of
them. It should be noted that the presence of SV40 in mesothelioma and other
human tumor types has been challenged by a research team that has consistently
reported negative findings (Strickler et al., 2001). However, a member of this
research team has recently acknowledged - in sworn testimony -sensitivity
problems and possible irregularities that raise concerns about these negative
reports (MacLachlan, 2002). These revelations, together with the conclusions of
the three independent panels mentioned above, appear to bring to an end the
apparent controversy about the presence of SV40 in human mesotheliomas and
brain tumors. http://www.ncbi.nlm.nih.gov/pubmed/12910254

“Therefore, three independent scientific panels have all agreed that there is
compelling evidence that SV40 is present in some human cancers and that SV40
could contribute to the pathogenesis of some of them.”

[foetal calf serum is used in vaccine production]

Biologicals • September 2003

Bovine viral diarrhoea virus antigen in foetal calf serum batches and
consequences of such contamination for vaccine production Author information
Makoschey B1, van Gelder PT, Keijsers V, Goovaerts D. Virological R&D
Department Intervet International b.v., Wim de Körverstraat 35 NL-5831 AN,
Boxmeer, The Netherlands Birgit.Makoschey@Intervet.com Abstract A protocol to
test foetal calf serum (FCS) for contamination with bovine viral diarrhoea
virus (BVDV) is described. Following this protocol, which combines cell culture
methods and detection of pestivirus RNA, seven batches of FCS were tested.
Infectious BVDV was detected in four of those batches. One of the remaining
batches contained a relatively high number of non-infectious BVDV particles. A
sample of this batch was formulated with aluminium hydroxide and aluminium
phosphate as adjuvant into an experimental vaccine preparation. This product
was injected twice into BVDV seronegative cattle with a 4 week interval. Blood
samples taken 4 weeks after the second application were negative for BVDV
specific antibodies. Our data stress that detection of BVDV RNA is not
sufficient for a complete risk assessment on FCS. Discrimination between
infectious and non-infectious BVDV is essential. This can only be achieved by
cell culture methods. http://www.ncbi.nlm.nih.gov/pubmed/12935809

“Our data stress that detection of BVDV RNA is not sufficient for a complete
risk assessment on Foetal Calf Serum. Discrimination between infectious and
non-infectious BVDV is essential. This can only be achieved by cell culture
methods.”

Veterinaria Italiana • January 2004

Genotypes of Pestivirus RNA detected in anti-influenza virus vaccines for human
use Author information Giangaspero M1, Vacirca G, Harasawa R, Buttner M,
Panuccio A, De Giuli Morghen C, Zanetti A, Belloli A, Verhulst A. Dipartimento
di Scienze Cliniche Veterinarie Facoltà di Medicina Veterinaria, Università
degli Studi Milan, Italy Abstract Nine polyvalent human influenza virus
vaccines were tested by reverse transcriptase-polymerase chain reaction
(RT-PCR) for the presence of pestivirus RNA. Samples were selected from
manufacturers in Europe and the USA. Three samples of the nine vaccines tested
(33.3%) gave positive results for pestivirus RNA. The 5’-untranslated genomic
region sequence of the contaminant pestivirus RNA was analysed based on primary
nucleotide sequence homology and on secondary sequence structures
characteristic to genotypes. Two sequences belonged to Pestivirus type-1
(bovine viral diarrhoea virus [BVDV]) species, genotypes BVDV-1b and BVDV-1e.
These findings confirm previous reports, suggesting an improvement in
preventive measures against contamination of biological products for human use.
http://www.ncbi.nlm.nih.gov/pubmed/?term=20437384 Full Report (In Italian)
http://www.izs.it/vet_italiana/2004/40_1/7.pdf

“Samples were selected from manufacturers in Europe and the USA. Three samples
of the nine vaccines tested (33.3%) gave positive results for pestivirus RNA.”

Virology • January 2004

Simian virus 40 infection in humans and association with human diseases:
results and hypotheses Author information Barbanti-Brodano G1, Sabbioni S,
Martini F, Negrini M, Corallini A, Tognon M. Department of Experimental and
Diagnostic Medicine Section of Microbiology, Center of Biotechnology University
of Ferrara, I-44100, Ferrara, Italy Abstract Simian virus 40 (SV40) is a monkey
virus that was introduced in the human population by contaminated
poliovaccines, produced in SV40-infected monkey cells, between 1955 and 1963.
Epidemiological evidence now suggests that SV40 may be contagiously transmitted
in humans by horizontal infection, independent of the earlier administration of
SV40-contaminated poliovaccines. This evidence includes detection of SV40 DNA
sequences in human tissues and of SV40 antibodies in human sera, as well as
rescue of infectious SV40 from a human tumor. Detection of SV40 DNA sequences
in blood and sperm and of SV40 virions in sewage points to the hematic, sexual,
and orofecal routes as means of virus transmission in humans. The site of
latent infection in humans is not known, but the presence of SV40 in urine
suggests the kidney as a possible site of latency, as it occurs in the natural
monkey host. SV40 in humans is associated with inflammatory kidney diseases and
with specific tumor types: mesothelioma, lymphoma, brain, and bone. These human
tumors correspond to the neoplasms that are induced by SV40 experimental
inoculation in rodents and by generation of transgenic mice with the SV40 early
region gene directed by its own early promoter-enhancer. The mechanisms of SV40
tumorigenesis in humans are related to the properties of the two viral
oncoproteins, the large T antigen (Tag) and the small t antigen (tag). Tag acts
mainly by blocking the functions of p53 and RB tumor suppressor proteins, as
well as by inducing chromosomal aberrations in the host cell. These chromosome
alterations may hit genes important in oncogenesis and generate genetic
instability in tumor cells. The clastogenic activity of Tag, which fixes the
chromosome damage in the infected cells, may explain the low viral load in
SV40-positive human tumors and the observation that Tag is expressed only in a
fraction of tumor cells. “Hit and run” seems the most plausible mechanism to
support this situation. The small tag, like large Tag, displays several
functions, but its principal role in transformation is to bind the protein
phosphatase PP2A. This leads to constitutive activation of the Wnt pathway,
resulting in continuous cell proliferation. The possibility that SV40 is
implicated as a cofactor in the etiology of some human tumors has stimulated
the preparation of a vaccine against the large Tag. Such a vaccine may
represent in the future a useful immunoprophylactic and immunotherapeutic
intervention against human tumors associated with SV40.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15015494

“Simian virus 40 (SV40) is a monkey virus that was introduced in the human
population by contaminated poliovaccines, produced in SV40-infected monkey
cells, between 1955 and 1963. Epidemiological evidence now suggests that SV40
may be contagiously transmitted in humans by horizontal infection, independent
of the earlier administration of SV40-contaminated poliovaccines.”

Medical Hypotheses • 2005

Multiple sclerosis and hepatitis B vaccination: could minute contamination of
the vaccine by partial hepatitis B virus polymerase play a role through
molecular mimicry? Author information Faure E. E.R. Biodiversity and
Environment, case 5 University of Provence, Place Victor Hugo 13331 Marseilles
cedex 3, France eric.faure@up.univ-mrs.fr Abstract Reports of multiple
sclerosis developing after hepatitis B vaccination have led to the concern that
this vaccine might be a cause of multiple sclerosis in previously healthy
subjects. Some articles evidenced that minor Hepatitis B virus (HBV) polymerase
proteins could be produced by alternative transcriptional or translational
strategies. Their detection is very difficult because they are in minute
concentration and probably enzymatically inactive, however, it was shown that
they could be exposed on the outside of the virus particles and also be
immunogenic. In addition, HBV polymerase shares significant amino acid
similarities with the human myelin basic protein. We hypothesise that some of
the apparent adverse reactions to the vaccine could be due to a process called
of molecular mimicry, the HBV polymerase, which could be a contaminant in the
recombinant or plasma-derived vaccines, could act as autoantigens and induce
autoimmune demyelinating diseases such as multiple sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/15908138

“We hypothesise that some of the apparent adverse reactions to the vaccine
could be due to a process called of molecular mimicry, the Hepatitus B Virus
polymerase, which could be a contaminant in the recombinant or plasma-derived
vaccines, could act as autoantigens and induce autoimmune demyelinating
diseases such as multiple sclerosis.”

Cancer Research • November 2005

Some oral poliovirus vaccines were contaminated with infectious SV40 after 1961
Author information Cutrone R1, Lednicky J, Dunn G, Rizzo P, Bocchetta M,
Chumakov K, Minor P, Carbone M. Thoracic Oncology Program, Cardinal Bernardin
Cancer Center Loyola University, Chicago, Illinois, USA

“It has been assumed that all polio vaccines were SV40 free in the United
States after 1961 and in other countries after 1962.

Abstract Some polio vaccines prepared from 1954 to 1961 were contaminated with
infectious SV40. It has been assumed that all polio vaccines were SV40 free in
the United States after 1961 and in other countries after 1962. Following a WHO
requirement that was prompted by the detection of SV40 in some human tumors, we
conducted a multilaboratory study to test for SV40 polio vaccines prepared
after 1961. Vaccine samples from 13 countries and the WHO seed were initially
tested by PCR. The possible presence of intact and/or infectious SV40 DNA in
PCR-positive samples was tested by transfection and infection of permissive
CV-1 cells. All results were verified by immunohistochemistry, cloning, and
sequencing. All the vaccines were SV40 free, except for vaccines from a major
eastern European manufacturer that contained infectious SV40. We determined
that the procedure used by this manufacturer to inactivate SV40 in oral
poliovirus vaccine seed stocks based on heat inactivation in the presence of
MgCl2 did not completely inactivate SV40. These SV40-contaminated vaccines were
produced from early 1960s to about 1978 and were used throughout the world. Our
findings underscore the potential risks of using primary monkey cells for
preparing poliovirus vaccines, because of the possible contamination with SV40
or other monkey viruses, and emphasize the importance of using
well-characterized cell substrates that are free from adventitious agents.
Moreover, our results indicate possible geographic differences in SV40 exposure
and offer a possible explanation for the different percentage of SV40-positive
tumors detected in some laboratories.
http://www.ncbi.nlm.nih.gov/pubmed/16288015

These SV40-contaminated vaccines were produced from early 1960s to about 1978
and were used throughout the world. Our findings underscore the potential risks
of using primary monkey cells for preparing poliovirus vaccines, because of the
possible contamination with SV40 or other monkey viruses, and emphasize the
importance of using well-characterized cell substrates that are free from
adventitious agents.”

Brain Research Reviews • December 2005

Human polyomaviruses and brain tumors Author information White MK1, Gordon J,
Reiss K, Del Valle L, Croul S, Giordano A, Darbinyan A, Khalili K. Center for
Neurovirology and Cancer Biology College of Science and Technology, Temple
University 1900 North 12th Street, 015-96, Room 203 Philadelphia, PA 19122, USA
Abstract Polyomaviruses are DNA tumor viruses with small circular genomes.
Three polyomaviruses have captured attention with regard to their potential
role in the development of human brain tumors: JC virus (JCV), BK virus (BKV),
and simian vacuolating virus 40 (SV40). JCV is a neurotropic polyomavirus that
is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a
fatal demyelinating disease of the central nervous system occurring mainly in
AIDS patients. BKV is the causative agent of polyomavirus-associated
nephropathy (PVN) which occurs after renal transplantation when BKV reactivates
from a latent state during immunosuppressive therapy to cause allograft
failure. SV40, originating in rhesus monkeys, gained notoriety when it entered
the human population via contaminated polio vaccines. All three viruses are
highly oncogenic when injected into the brain of experimental animals. Reports
indicate that these viruses, especially JCV, are associated with brain tumors
and other cancers in humans as evidenced from the analysis of clinical samples
for the presence of viral DNA sequences and expression of viral proteins. Human
polyomaviruses encode three non-capsid regulatory proteins: large T-antigen,
small t-antigen, and agnoprotein. These proteins interact with a number of
cellular target proteins to exert effects that dysregulate pathways involved in
the control of various host cell functions including the cell cycle, DNA
repair, and others. In this review, we describe the three polyomaviruses, their
abilities to cause brain and other tumors in experimental animals, the evidence
for an association with human brain tumors, and the latest findings on the
molecular mechanisms of their actions.
http://www.ncbi.nlm.nih.gov/pubmed/15982744

“In this review, we describe the three polyomaviruses, [SV40, JC virus (JCV)
and BK virus (BKV)] their abilities to cause brain and other tumors in
experimental animals, the evidence for an association with human brain tumors,
and the latest findings on the molecular mechanisms of their actions.”

Developments In Biologicals (Basel) • 2006

Vaccine cell substrates: bovine and porcine virus considerations

“The use of materials of animal origin

Author information

to supplement cell cultures used in

Wessman SJ

vaccine production, viral diagnostic

USDA, APHIS, VS Center for Veterinary Biologics Ames, Iowa 50010, USA
stephen.j.wessman@aphis.usda.gov Abstract The use of materials of animal origin
to supplement cell cultures used in vaccine production, viral diagnostic
testing, or materials testing may lead to contamination of the vaccines, with
seroconversion or disease in the vaccinated animals, and possible misdiagnosis
of diagnostic samples or incorrect test results. The methods used by the Center
for Veterinary Biologics to monitor serum and cell cultures are described.
Considerations for the use of animal origin materials, especially bovine and
porcine, as substrates or additives, plus the possibility of crossovers to
humans are discussed. http://www.ncbi.nlm.nih.gov/pubmed/16566453

testing, or materials testing may lead to contamination of the vaccines, with
seroconversion or disease in the vaccinated animals, and possible misdiagnosis
of diagnostic samples or incorrect test results.”

Archives de Pediatrie • February 2006

Pharmacovigilance of vaccines Author information Autret-Leca E1,
Bensouda-Grimaldi L, Jonville-Béra AP, Beau-Salinas F. Service de
Pharmacologie, Hôpital Bretonneau Université François-Rabelais de Tours Centre
Régional de Pharmacovigilance et d’Information sur le Médicament CHRU de Tours,
2, boulevard Tonnellé, 37044 Tours, cedex 09, France
autret-leca@med.univ-tours.fr Abstract Safety of vaccines must be excellent to
make vaccine’s strategy acceptable, since it usually has a deferred individual
benefit but immediate adverse drug reactions (ADRs). Pharmacovigilance of
vaccines after their marketing is crucial because, prior to its availability on
the market, the size of clinical trials is insufficient to identify rare or
deferred adverse effects. The Pharmacovigilance is based on “spontaneous
reporting” of ADRs to the Pharmacovigilance Regional Centre (PVRC) which
establishes a relationship between each drug taken by the patient and the ADRs
occurrence (imputability). This method is crucial to generate alerts, but
under-estimates the real frequency of ADRs (1 to 10% of severe ADRs are
reported). Thus pharmacoepidemiology studies are necessary to confirm the
alerts identified by spontaneous reporting. ADRs can be specific, related to
the antigen of an attenuated alive virus vaccine (lymphocyte meningitis after
anti-mumps vaccine) or non-specific, related to a component different from the
antigen (aluminium hydroxide involved in the “macrophagic myofasciitis”,
allergic reactions to neomycin, latex, egg or gelatine). Importance of
Pharmacovigilance of vaccines is illustrated. Data, especially case-control
studies, about the relationship between multiple sclerosis and hepatitis B
vaccine are summarised. Data about the relationship between Crohn’s disease or
autism and MMR vaccine are analysed. As vaccines are used in healthy people,
their safety must be excellent to be accepted. To monitor them after their
marketing is the unique way to detect rare ADRs. This surveillance is made
through reporting of ADRs to the PVRC. However, an active and intensive
surveillance of ADRs as the one set up from the marketing of Prevenar should be
systematic. http://www.ncbi.nlm.nih.gov/pubmed/16343870

“Pharmacovigilance of vaccines after their marketing is crucial because, prior
to its availability on the market, the size of clinical trials is insufficient
to identify rare or deferred adverse effects.”

Developments In Biology, Basel • March 2006

Polio vaccines, SV40 and human tumours, an update on false positive and false
negative results Author information Elmishad AG1, Bocchetta M, Pass HI, Carbone
M. Loyola University Medical Center Cardinal Bernardin Cancer Center Department
of Pathology, Maywood, IL 60153, USA Abstract Simian virus 40 (SV40) has been
detected in different human tumours in numerous laboratories. The detection of
SV40 in human tumours has been linked to the administration of
SV40-contaminated polio vaccines from 1954 until 1963. Many of these reports
linked SV40 to human mesothelioma. Some studies have failed to detect SV40 in
human tumours and this has caused a controversy. Here we review the current
literature. Moreover, we present evidence showing how differences in the
sensitivities of methodologies can lead to a very different interpretation of
the same study. The same 20 mesothelioma specimens all tested negative, 2/20
tested positive or 7/20 tested positive for SV40 Tag by simply changing the
detection method on the same immuno-precipitation/western blot membranes. These
results provide a simple explanation for some of the apparent discordant
results reported in the literature. http://www.ncbi.nlm.nih.gov/pubmed/16566440

“we present evidence showing how differences in the sensitivities of
methodologies can lead to a very different interpretation of the same study.”

Cancer Investigation • April 2006

High prevalence of SV40 infection in patients with nodal non-Hodgkin’s lymphoma
but not acute leukemia independent of contaminated polio vaccines in Taiwan
Author information Chen PM1, Yen CC, Yang MH, Poh SB, Hsiao LT, Wang WS, Lin
PC, Lee MY, Teng HW, Bai LY, Chu CJ, Chao SC, Yang AH, Chiou TJ, Liu JH, Chao
TC. Division of Medical Oncology Department of Medicine, Taipei Veteran General
Hospital Taipei, Taiwan, Republic of China Abstract Recent studies have linked
simian virus 40 (SV40) to non-Hodgkin’s lymphoma (NHL), especially in countries
in which people were exposed to contaminated polio vaccines prior to 1963. In
Taiwan, nearly all children were not exposed to contaminated polio vaccine
during this period; the relationship between SV40 infection and hematological
malignancies is unclear and deserves to be studied. Using PCR amplification of
SV40 large T antigen DNA, confirmed by Southern blot hybridization and sequence
analysis, 91 frozen lymph nodes from NHL patients were examined. Thirteen (14.3
percent) showed positive for SV40. All other test samples, including diagnostic
bone marrow from patients with acute leukemia, peripheral blood from 10
relatives of SV40 positive-patients and 91 age-matched normal volunteers, and 5
reactive hyperplastic lymphoid tissues, showed negative. These results may
reflect that human-to-human transmission of SV40 is independent of contaminated
polio vaccines; and SV40 is possibly associated with the development of NHL in
Taiwan (p = 0.0001). Prospective studies are needed to determine the prevalence
of SV40 infections in our and other human populations and to explore the means
of transmission of the virus. http://www.ncbi.nlm.nih.gov/pubmed/16809147

“These results may reflect that human-to-human transmission of SV40 is
independent of contaminated polio vaccines; and SV40 is possibly associated
with the development of non-Hodgkin’s lymphoma in Taiwan ...”

Journal of Public Health Management & Practice • July 2006

The Legal Environment Underlying Influenza Vaccine Allocation and Distribution
Strategies Hodge, James G. Jr JD, LLM; O’Connell, Jessica P. JD/MPH Abstract In
the fall of 2004, the United States faced a national shortage of influenza
vaccine after a major vaccine manufacturer was unable to produce millions of
doses of the vaccine due to potential contamination. Many public and private
sector entities had far fewer doses of influenza vaccine to allocate than they
had anticipated. In response, federal, state, and local public health
officials, private vaccine distributors, and healthcare providers collaborated
to distribute available doses of influenza vaccine. However, the existing legal
framework through which allocations were made is murky. This article examines
major legal issues regarding allocation strategies involving limited supplies
of influenza vaccines, addressing in particular (1) existing legal requirements
for allocating and distributing influenza vaccines among public health
authorities and healthcare providers at the federal, state, and local levels;
(2) the legal capacity of public health authorities to acquire existing vaccine
supplies from healthcare providers; and (3) specific legal responses
implemented by states in response to the 2004–2005 influenza vaccine shortage.

“In the fall of 2004, the United States faced a national shortage of influenza
vaccine after a major vaccine manufacturer was unable to produce millions of
doses of the vaccine due to potential contamination.”

http://journals.lww.com/jphmp/pages/articleviewer.aspx?year=2006&issue=07000&article=00007&type=abstract

Proceedings Of The National Academy Of Science USA • September 2006

Crocidolite asbestos and SV40 are co-carcinogens in human mesothelial cells and
in causing mesothelioma in hamsters Barbara Kroczynska,* Rochelle Cutrone,*
Maurizio Bocchetta,* Haining Yang,* Amira G. Elmishad,* Pamela Vacek,† Maria
Ramos-Nino,‡ Brooke T. Mossman,‡ Harvey I. Pass,§ and Michele Carbone*

	
Thoracic Oncology Program Cardinal Bernardin Cancer Center Loyola University

Chicago, Maywood, IL 60153 Departments of †Medical Biostatistics and
‡Pathology, College of Medicine, University of Vermont, Burlington, VT 05404
and §Department of Thoracic Surgery, New York University, New York, NY 10016
ABSTRACT Only a fraction of subjects exposed to asbestos develop malignant
mesothelioma (MM), suggesting that additional factors may render some
individuals more susceptible. We tested the hypothesis that asbestos and Simian
virus (SV40) are cocarcinogens. Asbestos and SV40 in combination had a
costimulatory effect in inducing ERK1/2 phosphorylation and activator protein-1
(AP-1) activity in both primary Syrian hamster mesothelial cells (SHM) and
primary human mesothelial cells (HM). Ap-1 activity caused the expression and
activation of matrix metalloprotease (MMP)-1 and MMP-9, which in turn led to
cell invasion. Experiments using siRNA and chemical inhibitors confirmed the
specificity of these results. The same effects were observed in HM and SHM.
Experiments in hamsters showed strong cocarcinogenesis between asbestos and
SV40: SV40 did not cause MM, asbestos caused MM in 20% of hamsters, and
asbestos and SV40 together caused MM in 90% of hamsters. Significantly lower
amounts of asbestos were sufficient to cause MM in animals infected with SV40.
Our results indicate that mineral fibers and viruses can be cocarcinogens and
suggest that lower amounts of asbestos may be sufficient to cause MM in
individuals infected with SV40. Full Report:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1599923/

“Our results indicate that mineral fibers and viruses can be cocarcinogens and
suggest that lower amounts of asbestos may be sufficient to cause malignant
mesothelioma in individuals infected with SV40.”

Inhalation Toxicology • November 2006

The role of SV40 in malignant mesothelioma and other human malignancies Author
information Pershouse MA1, Heivly S, Girtsman T. Center for Environmental
Health Sciences Department of Biomedical and Pharmaceutical Sciences University
of Montana, Missoula, Montana 59812, USA mark.pershouse@umontana.edu Abstract
SV40 is a DNA tumor virus thrust upon human populations primarily as a
contaminant in various vaccine preparations. Some estimates suggest that
millions of people are currently infected with the virus. The virus causes
primary brain tumors, bone tumors, lymphomas, and mesotheliomas when injected
into some rodent models. It has also been detected in a similar spectrum of
human tumors. However, epidemiological studies have failed to conclusively
demonstrate a higher incidence of disease in affected populations. To date,
over 60 reports from 49 different laboratories have shown SV40 sequences in
tissues from human cancer patients. Six studies, however, have failed to detect
evidence of virus in similar tissues. Some have suggested that SV40 may act as
a cocarcinogen with asbestos to cause mesothelioma formation, or that it may be
responsible for the 10-20% of mesotheliomas with no reported history of
asbestos exposure. This report briefly covers the historical evidence for SV40
carcinogenesis and then covers experiments now underway to better understand
the role of SV40 in human mesotheliomas.
https://www.ncbi.nlm.nih.gov/pubmed/16920674

“Some have suggested that SV40 may act as a co-carcinogen with asbestos ‘to
cause mesothelioma formation, or that it may be responsible for the 10-20% of
mesotheliomas with no reported history of asbestos exposure.”

“The use of materials of animal origin to supplement cell cultures used in vaccine production,
viral diagnostic testing, or materials testing may lead to contamination of the
vaccines ...” Developments In Biologicals (Basel) • 2006

Vaccine cell substrates: bovine and porcine virus considerations Author
information Wessman SJ. USDA, APHIS, VS, Center for Veterinary Biologics, Ames,
Iowa 50010, USA stephen.j.wessman@aphis.usda.gov Abstract The use of materials
of animal origin to supplement cell cultures used in vaccine production, viral
diagnostic testing, or materials testing may lead to contamination of the
vaccines, with seroconversion or disease in the vaccinated animals, and
possible misdiagnosis of diagnostic samples or incorrect test results. The
methods used by the Center for Veterinary Biologics to monitor serum and cell
cultures are described. Considerations for the use of animal origin materials,
especially bovine and porcine, as substrates or additives, plus the possibility
of crossovers to humans are discussed.
http://www.ncbi.nlm.nih.gov/pubmed/16566453

Cellular And Molecular Life Sciences • April 2007

SV40 association with human malignancies and mechanisms of tumor immunity by
large tumor antigen Author information Lowe DB1, Shearer MH, Jumper CA, Kennedy
RC. Department of Microbiology and Immunology Texas Tech University Health
Sciences Center Lubbock, TX 79430-6591, USA Abstract SV40 was discovered as a
contaminate of poliovirus vaccine lots distributed to millions of individuals
in the United States between 1955 and 1963 while contaminated vaccine batches
were later circulated worldwide. After SV40 was observed to cause in vitro
animal and human cell transformations and in vivo tumor formations in animals,
the search for a connection between the virus and human malignancies has
continued to the present day. Different molecular methods have been used to
detect SV40 gene products in a variety of human cancers, though SV40 causality
in these tumor types has yet to be established. These data, however, are not
without controversial issues related to inconclusive SV40 serological and
epidemiological evidence alongside tools and methodologies that may contribute
to false-positive results in human specimens. This review will also explore how
vaccination against SV40 protein products may be used to help prevent and treat
individuals with SV40-expressing cancers.
http://www.ncbi.nlm.nih.gov/pubmed/17260087

“SV40 was discovered as a contaminate of poliovirus vaccine lots distributed to
millions of individuals in the United States between 1955 and 1963 while
contaminated vaccine batches were later circulated worldwide.”

Immunology Letters • June 2007

Mycoplasma contamination and viral immunomodulatory activity: dendritic cells
open Pandora’s box Author information Alves MP1, Carrasco CP, Balmelli C,
Ruggli N, McCullough KC, Summerfield A. Institute of Virology and
Immunoprophylaxis Sensemattstrasse 293, CH-3147 Mittelhäusern, Switzerland
Abstract During in vitro investigations on the interaction of classical swine
fever virus (CSFV)-an immunosuppressive viral pathogen--with monocyte-derived
dendritic cells (MoDC) a soluble factor with a strong anti-proliferative
activity for T lymphocytes was found. This activity, with an inhibitory
dilution 50% (ID(50)) of 10(3)-10(7), was induced after virus infection of
monocytes differentiating into DC. UV--inactivation of the supernatants and
blocking experiments with a monoclonal antibody against the E2 envelope protein
of CSFV initially indicated a virus-dependency. However, further investigations
including filtration and centrifugation experiments as well as antibiotic
treatment demonstrated the involvement of mycoplasma. This was confirmed by a
Hoechst 33258 staining, PCR and mycoplasma cultures--Mycoplasma hyorhinis was
identified as the contaminant. Elucidation of a mycoplasma presence occurred
under conditions in which the original virus stocks prepared in SK6 cells were
negative for mycoplasma using the above tests. Moreover, conventional passage
of the virus on the SK6 cells used for this purpose did not reveal any
mycoplasma. It was the passage of virus in MoDC rather than SK6 cells that was
required to expose the contamination. Three passages of the anti-proliferative
supernatants on MoDC cultures increased the ID(50) 10(3)-fold; only when these
MoDC-derived supernatants were employed was the mycoplasma contaminant also
detectable on SK6 cells. In conclusion, these data demonstrate that regular
testing of cell lines and virus stocks for mycoplasma does not necessarily
identify their presence, and that application of passage in MoDC cultures could
prove an aid for identifying initially undetectable levels of mycoplasma
contamination. http://www.ncbi.nlm.nih.gov/pubmed/?term=17532055

“... these data demonstrate that regular testing of cell lines and virus stocks
for mycoplasma does not necessarily identify their presence ...”

Cellular And Molecular Life Sciences • July 2007

Oncogenic potentials of the human polyomavirus regulatory proteins Author
information Moens U1, Van Ghelue M, Johannessen M. Department of Microbiology
and Virology Faculty of Medicine, University of Tromsø N-9037, Tromsø, Norway
ugom@fagmed.uit.no Abstract The polyomaviruses BK, JC and SV40 are common in
the human population. Their DNA genomes encode large T-antigen, small
t-antigen, agnoprotein, and the capsid proteins VP1-3. Studies with these
viruses have contributed extensively to the understanding of processes such as
replication, transcriptional and posttranscriptional regulation, and cell cycle
control. All three viruses can transform human cells in vitro, can induce
tumours in animal models, and are strongly association with certain human
cancers. It is generally assumed that large T-antigen is the major protein
involved in neoplastic processes and that large T-antigen predominantly exerts
its effect through deregulation of the tumour suppressors p53 and the
retinoblastoma family members. However, additional properties of large
T-antigen as well as the other viral proteins contribute to oncogenic
processes. This review presents the different mechanisms by which the
polyomavirus proteins can induce transformation and discusses which mechanisms
may be operational in polyomavirus-positive cancers.
https://www.ncbi.nlm.nih.gov/pubmed/17483871

“This review presents the different mechanisms by which the polyomavirus
proteins can induce transformation and discusses which mechanisms may be
operational in polyomavirus-positive cancers.”

“... determining the origin of the SV40 sequences detected in human tumors might be difficult.”
Virology • January 2008

Recovery of strains of the polyomavirus SV40 from rhesus monkey kidney cells
dating from the 1950s to the early 1960s Keith Pedena, Li Shenga, Romelda
Omeira, Maureen Yacobuccia, Michael Klutchb, †, Majid Laassric, Konstantin
Chumakovc, Achintya Palb, 1, Haruhiko Murataa, b, Andrew M. Lewis Jr.b a.
Laboratory of Retrovirus Research, Division of Viral Products, Center for
Biologics Evaluation and Research Food and Drug Administration, 29 Lincoln
Drive, Bethesda, MD 20892, USA b. Laboratory of DNA Viruses, Division of Viral
Products, Center for Biologics Evaluation and Research Food and Drug
Administration, Bethesda, MD 20892, USA c. Laboratory of Methods Development,
Division of Viral Products, Center for Biologics Evaluation and Research Food
and Drug Administration, Bethesda, MD 20892, USA Abstract From stocks of
adenovirus and poliovirus prepared in primary rhesus macaque kidney cells and
dating from 1956 to 1961, the time when SV40 contaminated some poliovirus
vaccine lots, we have recovered ten isolates of SV40. Of these ten isolates,
based on the C-terminal region of T antigen, five novel strains of SV40 have
been identified. Additionally, three pairs of isolates were found to be the
same strain: one pair was strain 777, one pair was strain 776 archetype, and
the third pair represented a novel strain. All strains had identical protein
sequences for VP2 and VP3. There were two variants of agnoprotein and the small
t antigen and three variants of VP1. These results, and those of others,
suggest that a limited number of SV40 strains might exist in rhesus macaques in
the United States, and thus determining the origin of the SV40 sequences
detected in human tumors might be difficult. Full Report:
http://www.sciencedirect.com/science/article/pii/S0042682207004321

Journal Of Pharmaceutical And Biomedical Analysis • February 2008

Strategy for identification of leachables in packaged pharmaceutical liquid
formulations Author information Pan C1, Harmon F, Toscano K, Liu F, Vivilecchia
R. Pharmaceutical and Analytical Development Novartis Pharmaceuticals
Corporation, One Health Plaza East Hanover, NJ 07936, USA
charles.pan@novartis.com Abstract Drug stability is one of the key properties
to be monitored in pharmaceutical drug development. Drug degradation products,
impurities and/or leachables from the drug product and packages may have
significant impacts on drug efficacy, safety profile and storage conditions. In
the registration stability samples of an ophthalmic pharmaceutical drug
product, an unknown compound was found at a level of 0.19% by HPLC analysis.
Subsequent liquid chromatography/mass spectrometry (LC/MS) analysis with
electrospray ionization (ESI) indicated that the unknown was not related to the
drug substance and was most likely a leachable. Identification of this unknown
leachable was needed to evaluate the impact on drug safety. Through systematic
extraction of various components or component combination of the packaging
materials, and subsequently LC/MS analysis, the unknown was found to be a
leachable coming from the varnish applied to the label. In general, using LC/MS
alone is not sufficient to elucidate the structure of a complete unknown. Gas
chromatography/mass spectrometry (GC/MS) was then conducted with a chemical
ionization (CI) source to determine the retention time and mass of the compound
of interest. Both CI and ESI sources generated the same protonated molecular
ion [M+H] and similar fragmentation ions, which provides a good correlation of
the unknown eluted in the liquid chromatogram and in the gas chromatogram.
GC/MS with electron impact (EI) was then conducted to obtain the EI mass
spectrum of this unknown. It was identified as monomethyl derivative of
mephenesin through the NIST library search. The identification strategy
utilized electrospray LC/MS and GC/MS with chemical and electron ionization
sources which provided complimentary information for structure elucidation of
this unknown compound. This combination approach in conjunction with systematic
extraction was necessary for the determination of the source of this unknown in
the pharmaceutical drug stability studies.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18180126

“Drug degradation products, impurities and/or leachables from the drug product
and packages may have significant impacts on drug efficacy, safety profile and
storage conditions.”

International Journal Of Nanomedicine • June 2008

Drug delivery and nanoparticles: Applications and hazards Wim H De Jong1 and
Paul JA Borm2,3 1. Laboratory for Toxicology, Pathology and Genetics, National
Institute for Public Health and the Environment (RIVM) Bilthoven, The
Netherlands 2. Zuyd University, Centre of Expertise in Life Sciences Heerlen,
The Netherlands 3. Magnamedics GmbH, Aachen, Germany Abstract The use of
nanotechnology in medicine and more specifically drug delivery is set to spread
rapidly. Currently many substances are under investigation for drug delivery
and more specifically for cancer therapy. Interestingly pharmaceutical sciences
are using nanoparticles to reduce toxicity and side effects of drugs and up to
recently did not realize that carrier systems themselves may impose risks to
the patient. The kind of hazards that are introduced by using nanoparticles for
drug delivery are beyond that posed by conventional hazards imposed by
chemicals in classical delivery matrices. For nanoparticles the knowledge on
particle toxicity as obtained in inhalation toxicity shows the way how to
investigate the potential hazards of nanoparticles. The toxicology of
particulate matter differs from toxicology of substances as the composing
chemical(s) may or may not be soluble in biological matrices, thus influencing
greatly the potential exposure of various internal organs. This may vary from a
rather high local exposure in the lungs and a low or neglectable exposure for
other organ systems after inhalation. However, absorbed species may also
influence the potential toxicity of the inhaled particles. For nanoparticles
the situation is different as their size opens the potential for crossing the
various biological barriers within the body. From a positive viewpoint,
especially the potential to cross the blood brain barrier may open new ways for
drug delivery into the brain. In addition, the nanosize also allows for access
into the cell and various cellular compartments including the nucleus. A
multitude of substances are currently under investigation for the preparation
of nanoparticles for drug delivery, varying from biological substances like
albumin, gelatine and phospholipids for liposomes, and more substances of a
chemical nature like various polymers and solid metal containing nanoparticles.
It is obvious that the potential interaction with tissues and cells, and the
potential toxicity, greatly depends on the actual composition of the
nanoparticle formulation. This paper provides an overview on some of the
currently used systems for drug delivery. Besides the potential beneficial use
also attention is drawn to the questions how we should proceed with the safety
evaluation of the nanoparticle formulations for drug delivery. For such testing
the lessons learned from particle toxicity as applied in inhalation toxicology
may be of use. Although for pharmaceutical use the current requirements seem to
be adequate to detect most of the adverse effects of nanoparticle formulations,
it can not be expected that all aspects of nanoparticle toxicology will be
detected. So, probably additional more specific testing would be needed. Full
Report: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527668/

“for pharmaceutical use the current requirements seem to be adequate to detect
most of the adverse effects of nanoparticle formulations, it can not be
expected that all aspects of nanoparticle toxicology will be detected.”

Collegium Antropologicum • June 2008

The role of polio-vaccine in pleural mesothelioma— an epidemiological
observation Author information Sarin M1, Curin K, Varnai VM. Institute for
Medical Research and Occupational Health Zagreb, Croatia marko@imi.hr Abstract
From the Croatian Cancer Registry (period 1991-1997) 194 malignant pleural
mesothelioma patients were collected. According to participation in polio
vaccination mass campaign in 1961 that covered the entire Croatian population
aged 3 months to 20 years, mesothelioma patients were divided in vaccinated
(N=58), and non-vaccinated (N=136) subjects. Significantly higher percentage of
those with a history of occupational exposure to asbestos was found in
vaccinated (79%) compared to non-vaccinated group (63%). This is the opposite
to what would be expected if potential SV40 contamination of polio vaccine used
had a causative role in the development of the tumour. On the other hand,
shorter latency period reflected by very high percentage of 45-year-old or
younger mesothelioma patients in vaccinated group (15 out of 58), with all of
them having a history of occupational asbestos exposure, raises a question for
a possible enhancing effect of the vaccine used to asbestos exposure, if it was
contaminated with SV40. http://www.ncbi.nlm.nih.gov/pubmed/18756898

“... raises a question for a possible enhancing effect of the vaccine used to
asbestos exposure ...”

Vaccine • June 2008

A quantitative risk assessment of exposure to adventitious agents in a cell
culture-derived subunit influenza vaccine Author information Gregersen JP.
Novartis Behring, Marburg, Germany jens-peter.gregersen@novartis.com Abstract A
risk-assessment model has demonstrated the ability of a new cell culture-based
vaccine manufacturing process to reduce the level of any adventitious agent to
a million-fold below infectious levels. The cell culture-derived subunit
influenza vaccine (OPTAFLU), Novartis Vaccines and Diagnostics) is produced
using Madin-Darby canine kidney (MDCK) cells to propagate seasonal viral
strains, as an alternative to embryonated chicken-eggs. As only a limited range
of mammalian viruses can grow in MDCK cells, similar to embryonated eggs, MDCK
cells can act as an effective filter for a wide range of adventitious agents
that might be introduced during vaccine production. However, the introduction
of an alternative cell substrate (for example, MDCK cells) into a vaccine
manufacturing process requires thorough investigations to assess the potential
for adventitious agent risk in the final product, in the unlikely event that
contamination should occur. The risk assessment takes into account the entire
manufacturing process, from initial influenza virus isolation, through to
blending of the trivalent subunit vaccine and worst-case residual titres for
the final vaccine formulation have been calculated for >20 viruses or virus
families. Maximum residual titres for all viruses tested were in the range of
10(-6) to 10(-16) infectious units per vaccine dose. Thus, the new cell
culture-based vaccine manufacturing process can reduce any adventitious agent
to a level that is unable to cause infection.
http://www.ncbi.nlm.nih.gov/pubmed/18485545

“... the ability of a new cell culture-based vaccine manufacturing process to
reduce the level of any adventitious agent to a million-fold below infectious
levels.”

“Two tetanus outbreaks in 1901 — from contaminated diphtheria antitoxin in St. Louis, Missouri,
and contaminated smallpox vaccine in Camden, New Jersey — raised public concern
about pharmaceutical safety.” Perspectives In Biology And Medicine • Spring
2008

The first pharmacoepidemiologic investigations: national drug safety policy in
the United States, 1901-1902 Author information Lilienfeld DE.
lilienfeld@comcast.net Abstract The pharmaceutical industry developed in the
late 19th century as a consequence of both scientific and commercial
innovations, such as the development of diphtheria antitoxin and the
commercialization of smallpox vaccine. Two tetanus outbreaks in 1901 — from
contaminated diphtheria antitoxin in St. Louis, Missouri, and contaminated
smallpox vaccine in Camden, New Jersey — raised public concern about
pharmaceutical safety. In St. Louis, errant manufacturing processes were found
to be the source of the outbreak. In Camden, investigation identified
contaminated vaccine from one manufacturer as the cause. These investigations,
the first known pharmacoepidemiologic studies, were widely reported. They
formed the basis for the 1902 Biologics Control Act, which focused on the
safety of biologics produced and sold by the pharmaceutical industry and
established a precedent of federal regulation of this industry. That power,
welcomed by manufacturers to restore the public’s trust in their products, was
enhanced in the 1906 Food and Drug Act, which created the Food and Drug
Administration. http://www.ncbi.nlm.nih.gov/pubmed/18453724

Virology • December 2008

SV40 DNA replication: From the A gene to a nanomachine Author Information Ellen
Fanning* and Kun Zhao Department of Biological Sciences and Vanderbilt-Ingram
Cancer Center Vanderbilt University, Nashville, TN 37235-1634 Abstract
Duplication of the simian virus 40 (SV40) genome is the best understood
eukaryotic DNA replication process to date. Like most prokaryotic genomes, the
SV40 genome is a circular duplex DNA organized in a single replicon. This small
viral genome, its association with host histones in nucleosomes, and its
dependence on the host cell milieu for replication factors and precursors led
to its adoption as a simple and powerful model. The steps in replication, the
viral initiator, the host proteins, and their mechanisms of action were
initially defined using a cellfree SV40 replication reaction. Although our
understanding of the vastly more complex host replication fork is advancing, no
eukaryotic replisome has yet been reconstituted and the SV40 paradigm remains a
point of reference. This article reviews some of the milestones in the
development of this paradigm and speculates on its potential utility to address
unsolved questions in eukaryotic genome maintenance. Full Report:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718763/

“Duplication of the simian virus 40 genome is the best understood eukaryotic
DNA replication process to date.”

BMJ • March 2009

Suspected contamination leads to recall of meningitis C vaccine Caroline White
Two batches of meningitis C vaccine distributed to general practices across
England have been recalled by the medicines watchdog amid fears that they may
have been contaminated. The manufacturer, Novartis Vaccines, raised the alarm
last week after routine sampling of a shipment of doses from the same two
batches air freighted to the United States showed contamination with
Staphylococcus aureus. The sterility of the solvent, aluminium hydroxide, which
is used to mix the vaccine, had been compromised. Purchase the full report for
$23 http://www.bmj.com/content/338/bmj.b896.long

“The sterility of the solvent, aluminium hydroxide, which is used to mix the
vaccine, had been compromised.”

Pharmacoepidemiological Drug Safety • March 2010

Safety assessment of recalled Haemophilus influenzae type b (Hib) conjugate
vaccines United States, 2007-2008 Author information Huang WT1, Chang S, Miller
ER, Woo EJ, Hoffmaster AR, Gee JE, Clark TA, Iskander JK, Ball R, Broder KR.
Epidemic Intelligence Service, Career Development Division Office of the
Workforce and Career Development Centers for Disease Control and Prevention
(CDC) Atlanta, GA 30333, USA Abstract PURPOSE On 13 December 2007, Merck & Co.,
Inc. voluntarily recalled 1.2 million doses of Haemophilus influenzae type b
(Hib) vaccines that had been distributed since April 2007 for concerns
regarding potential Bacillus cereus contamination. Enhanced postrecall
surveillance was conducted to detect vaccine-associated B. cereus infections.

“On 13 December 2007, Merck & Co., Inc.

METHODS We reviewed reports involving recalled Hib vaccines received by the
Vaccine Adverse Event Reporting System (VAERS) during 1 April 2007-29 February
2008. For each reported death, autopsy review sought evidence of B. cereus
infections. For each specified outcome, the proportional reporting ratios
(PRRs) were calculated to compare the recalled Hib vaccines with the
manufacturer’s nonrecalled Hib vaccines in the VAERS databases. On 20 December
2007, we used the Epidemic Information Exchange (Epi-X) to solicit
nongastrointestinal vaccine-associated B. cereus infections, and requested B.
cereus isolates for genotyping to compare with the manufacturing facility
isolate.

Haemophilus influenzae type b (Hib) vaccines

RESULTS VAERS received 75 reports involving recalled Hib vaccines; none
described a confirmed B. cereus infection. Comparative analyses did not reveal
disproportionate reporting of specified outcomes for recalled Hib vaccines. The
Epi-X posting triggered one report of vaccine-associated B. cereus bacteremia
from a child who received a nonrecalled Hib vaccine manufactured by Merck; the
genotypes of isolates from the patient and the manufacturing facility differed.
CONCLUSIONS No evidence of vaccine-associated B. cereus infection had been
found in recipients of recalled Hib vaccines. Conducting laboratory
surveillance through Epi-X was feasible and may enhance public health response
capacities for future vaccine safety emergencies.
http://www.ncbi.nlm.nih.gov/pubmed/20084617

voluntarily recalled 1.2 million doses of

that had been distributed since April 2007 ...”

Journal Of Virology • April 2010

Isolation of an Infectious Endogenous Retrovirus in a Proportion of Live
Attenuated Vaccines for Pets Takayuki Miyazawa,1,‡* Rokusuke Yoshikawa,1,‡
Matthew Golder,2 Masaya Okada,1 Hazel Stewart,2 and Massimo Palmarini2,* 1.
Laboratory of Signal Transduction Institute for Virus Research, Kyoto
University 53 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan 2. Institute
of Comparative Medicine University of Glasgow Faculty of Veterinary Medicine
464 Bearsden Road, Glasgow G61 1QH, Scotland2 Abstract The genomes of all
animal species are colonized by endogenous retroviruses (ERVs). Although most
ERVs have accumulated defects that render them incapable of replication, fully
infectious ERVs have been identified in various mammals. In this study, we
isolated a feline infectious ERV (RD-114) in a proportion of live attenuated
vaccines for pets. Isolation of RD-114 was made in two independent laboratories
using different detection strategies and using vaccines for both cats and dogs
commercially available in Japan or the United Kingdom. This study shows that
the methods currently employed to screen veterinary vaccines for retroviruses
should be reevaluated.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838105/?tool=pubmed

“ In this study, we isolated a feline infectious ERV (RD-114) in a proportion
of live attenuated vaccines for pets. Isolation of RD-114 was made in two
independent laboratories using different detection strategies and using
vaccines for both cats and dogs commercially available in Japan or the United
Kingdom. This study shows that the methods currently employed to screen
veterinary vaccines for retroviruses should be reevaluated.”

Veterinary Microbiology • April 2010

Atypical ‘HoBi’-like pestiviruses— recent findings and implications thereof
Author information Ståhl K1, Beer M, Schirrmeier H, Hoffmann B, Belák S,
Alenius S. The Joint R&D Division in Virology the National Veterinary Institute
(SVA) and The Swedish University of Agricultural Sciences (SLU) Uppsala, Sweden
karl.stahl@bvf.slu.se Abstract In 2004, an atypical pestivirus named
D32/00_’HoBi’, isolated from foetal calf serum (FCS) originating from Brazil,
was described (Schirrmeier et al., 2004). A few years later, a closely related
virus (Th/04_KhonKaen) was detected in serum from a calf in Thailand,
indicating that this group of atypical pestiviruses already is spread in cattle
populations in various regions of the world. At the
Friedrich-Loeffler-Institute, Insel Riems, Germany, FCS batches are regularly
tested for pestivirus contamination, in general with positive PCR results, and
in some cases the contaminants have been typed as ‘HoBi’-like. At the National
Veterinary Institute (SVA) in Uppsala, Sweden, a recent event with contaminated
FCS ruined much of the ongoing cell culture work. From the FCS and the
contaminated cells we were able to amplify and sequence nucleic acid from three
different pestivirus strains, including BVDV-1, -2 and ‘HoBi’-like; this in a
commercial FCS that had been tested free from pestivirus by the manufacturer.
In this short communication we review the current status of atypical
‘HoBi’-like pestiviruses, describe recent findings and discuss the implications
thereof. http://www.ncbi.nlm.nih.gov/pubmed/?term=19857934

“From the Fetal Calf Serum and the contaminated cells we were able to amplify
and sequence nucleic acid from three different pestivirus strains, including
BVDV-1, -2 and ‘HoBi’-like; this in a commercial FCS that had been tested free
from pestivirus by the manufacturer.”

Biologicals • May 2010

Endogenous retroviruses as potential hazards for vaccines Author information
Miyazawa T1. Laboratory of Signal Transduction Department of Cell Biology
Institute for Virus Research Kyoto University, 53 Shogoin-Kawaracho Sakyo-ku,
Kyoto 606-8507, Japan takavet@gmail.com Abstract Retroviruses are classified as
exogenous or endogenous according to their mode of transmission. Generally,
endogenous retroviruses (ERVs) are not pathogenic in their original hosts;
however, some ERVs induce diseases. In humans, a novel gammaretrovirus was
discovered in patients with prostate cancer or chronic fatigue syndrome. This
virus was closely related to xenotropic murine leukemia virus (X-MLV) and
designated as xenotropic murine leukemia virus-related virus (XMRV). The origin
and transmission route of XMRV are still unknown at present; however, XMRV may
be derived from ERVs of rodents because X-MLVs are ERVs of inbred and wild
mice. Many live attenuated vaccines for animals are manufactured by using cell
lines from animals, which are known to produce infectious ERVs; however, the
risks of infection by ERVs from xenospecies through vaccination have been
ignored. This brief review gives an overview of ERVs in cats, the potential
risks of ERV infection by vaccination, the biological characteristics of RD114
virus (a feline ERV), which possibly contaminates vaccines for companion
animals, and the methods for detection of infectious RD114 virus.
http://www.ncbi.nlm.nih.gov/pubmed/20378372

“Many live attenuated vaccines for animals are manufactured by using cell lines
from animals, which are known to produce infectious ERVs; however, the risks of
infection by ERVs from xenospecies through vaccination have been ignored. This
brief review gives an overview of ERVs in cats, the potential risks of ERV
infection by vaccination, the biological characteristics of RD-114 virus (a
feline ERV), which possibly contaminates vaccines for companion animals, and
the methods for detection of infectious RD-114 virus.”

BMJ • May 2010

Australia suspends seasonal flu vaccination of young children by Melissa Sweet
Australia has extended a suspension of vaccination of children aged 5 years and
under against seasonal flu, pending further investigations into an apparent
spike in febrile convulsions associated with the vaccine. A temporary
suspension was first announced on 23 April, after concerns emerged in Western
Australia about an increase in the number of young children presenting to
hospitals with febrile convulsion after receiving the trivalent seasonal flu
vaccine. The federal government’s chief medical officer, Jim Bishop, announced
on 30 April that more time was needed to complete epidemiological and
scientific investigations. “Given the ongoing and incomplete scientific and
clinical case review, the moratorium on the use of seasonal influenza vaccine
in children 5 years and less will continue,” he said. Figures released by the
national Department of Health and Ageing show that 77 cases of febrile
convulsion in children aged 5 or under and associated with the vaccination have
recently been reported to the Therapeutic Goods Administration. Of these, 57
were in Western Australia, the only Australian state to provide free seasonal
flu vaccination for all children aged 6 months to 4 years. It introduced the
vaccination programme in 2008 after the highly publicised deaths of three young
children with flu and because of concerns that this age group has the highest
hospitalisation rates for flu. About 35% of children under 5 in Western
Australia are estimated to have received at least one dose of flu vaccine in
2008 and 2009, but it is not yet known how many have been vaccinated this
season, Paul Armstrong of the state’s health department told the BMJ. A range
of experts have said that it is unclear whether the cases of fever relate to a
specific batch or product or to inclusion of the pandemic vaccine in a
trivalent vaccine. Three companies market seasonal flu vaccines in Australia.
They contain the components recommended by the Australian Influenza Vaccine
Committee for the 2010 season (A/H1N1, A/H3N2, and B)
(www.tga.gov.au/committee/aivc.htm). The TGA is continuing to recommend the
pandemic vaccine (active only against H1N1) for adults and children
(www.tga.gov.au/alerts/medicines/fluvaccine.htm). Other possibilities being
investigated are whether febrile illness has increased more broadly this winter
or whether the Western Australian programme has uncovered an increased risk
among young children in particular.

Peter Richmond, a paediatrician in Perth, told ABC television this week that
the association of fevers with the vaccination was striking
(www.abc.net.au/7.30/content/2010/s2885203. htm). “This year has been something
that I’ve never seen in 20 years as a paediatrician,” he said. “We have had a
large number of children presenting to their doctors who were previously well
who received the flu vaccine, and they had a very sudden onset of this high
fever. And obviously for parents of young children it was very scary, and
unfortunately some of these children actually had febrile convulsions.”
Professor Bishop told the BMJ he had an “open mind” about whether there was a
real increase in side effects. “In the meantime it is prudent and safe to
proceed cautiously,” he said. An industry funded group, the Influenza
Specialist Group, has said that Queensland’s government is also working closely
with a local coroner regarding the death of a 2 year old girl who was found
dead in her cot several hours after receiving a seasonal flu vaccine in early
April
(www.influenzaspecialistgroup.org.au/news-recent/143-seasonal-flu-vaccination-and-in-children-5-years-and-under-).
Professor Bishop said that this case had not been reported to the Therapeutic
Goods Administration. A statement from the Department of Health and Ageing said
that batch testing of the vaccine by the Therapeutic Goods Administration and
other independent experts had so far shown the vaccine to be satisfactory,
while testing by the major flu vaccine manufacturer CSL had found no
abnormalities in its product. Further testing and experiments are planned.
Meanwhile, Julie Leask, a senior research fellow at the National Centre for
Immunisation Research & Surveillance, said that public confidence in flu
vaccination is likely to suffer, resulting in reduced vaccination coverage
across all ages. Peter Collignon, an infectious diseases specialist at the
Australian National University, Canberra, said that the situation showed the
need for better surveillance and evaluation of flu vaccination. “We’re in a
situation now where the government can’t tell us how many doses of the vaccine
have been given out or how many people have side effects,” he said. Dr
Armstrong said that the vaccination programme would resume in Western Australia
only when it was clear that it was safe to do so. He said, “The first thing we
need to do is to work out [whether there] is a problem and what the magnitude
is, and then to work out what the problem is; we don’t know that at the
moment.” http://www.ncbi.nlm.nih.gov/pubmed/20442237

BMJ • May 2010
Australia suspends seasonal flu vaccination of young children

Adverse events following influenza vaccination in Australia— should we be
surprised? There have been large numbers of major adverse reactions to this
year’s seasonal influenza vaccine in Australia, and the vaccine has been
suspended for use in children aged five and under [1,2]. These reactions have
occurred across the country and involved multiple batches of vaccine [2]. In
the state of Western Australia where the problem was first detected, reports
suggest that of the 20,000 to 30,000 children vaccinated, more than 250 had
adverse reactions and 55 had febrile convulsions before vaccination was
suspended in young children [2]. Assuming all convulsions were in children,
about one child in every 500 vaccinated had a febrile convulsion. Across
Australia, media accounts indicate that more than 400 adverse reactions [3]
including 77 cases of febrile convulsion [1] have been reported by regulators.
While attention remains focused on reactions in very young children, reports
suggest only one-third of the reactions may have occurred in children under
five [4]. Although this situation has triggered considerable controversy in
Australia, the story has attracted little to no media attention in the US and
Europe. Similarly, the media has paid little attention to a US H1N1 federal
vaccine safety advisory committee which recently reported detecting signals for
Guillain-Barre syndrome (GBS), Bell’s palsy, and thrombocytopenia in the
monovalent H1N1 (swine flu) vaccine [5]. The same monovalent H1N1 antigen
component under review in the US is scheduled to be added to the US trivalent
seasonal vaccine and is contained in the Australian trivalent seasonal vaccine
and will be given to children, pregnant women and adults [6]. Data from a
previous Australian study of H1N1 vaccine show that a large percentage of
children developed fevers following vaccination — in children less than 3
years, between three and six in every ten vaccinated, depending on dose [7,8].
The data also show a dose response effect — the larger the vaccine dose, the
more severe the harms. There was also an age relationship: children under the
age of three developed fevers at more than twice the rate of older children
[7,8]. The study was however underpowered to detect febrile convulsions at the
current rates in Australia, with only 162 children below the age of three. The
size problem was further aggravated by stratification by age group and antigen
dose. Presumably the vaccine manufacturer CSL, which sponsored the trial, and
Australia’s regulatory body, the Therapeutic Goods Administration (TGA), which
used this data in approving the vaccine for children, were aware of these
important findings. But authors of the study published earlier this year did
not discuss the high incidence of fever associated with vaccination [7]; data
were instead only reported in online-only supplementary tables [8].

Overall, the percentages of children under three who developed a fever after
vaccination appear very high; thirty five per cent with the 15 ug dose and 62%
after a 30 ug dose [7,8]. Of those that received a 7.5 ug dose in the seasonal
influenza vaccine, 23% develop a fever of >38 degrees Celsius [6].

“The large number of children

The large number of children suffering harms — and subsequent suspension of the
vaccine — challenges the assumption that regulators are ensuring the safety and
efficacy of all marketed therapeutics. Should we be surprised that these
problems have occurred with influenza vaccine, a vaccine used for over 60
years, said to have “an established record of safety in all age groups”? [9]

challenges the assumption that

There are actually relatively little data on the effects of vaccinating young
children against influenza [10]. Some manufacturers have even withheld data
from public scrutiny amidst general indifference [10,11]. Evidence from all
comparative influenza vaccine studies shows that harms, when they are
investigated, are not reported consistently and systematically [10,11].

surprised that these problems have

As pandemic vaccines are provided to governments and not individuals and
manufacturers are indemnified for damages caused to users [12-14], there seem
to be few incentives for investigation of harms. Last winter, the likelihood
that a child without risk factors would die from swine flu was less than one in
a million [15]. When such a high proportion of children develop moderate to
severe febrile reactions to the influenza vaccine, it’s likely that more harm
than good will occur by vaccinating the entire population. If such a large
proportion of children develop high fevers, it is also likely that a
substantial number will develop febrile convulsions as a result of vaccination.
It is thus surprising the vaccine was approved for this age group. It is also
surprising that more explicit warnings about the high risk of adverse reactions
were not given to parents when their children were being vaccinated. Passive
surveillance (as in Australia and elsewhere) is a relatively weak mechanism to
detect and evaluate post-vaccination adverse events [16]. Unlike most drugs,
vaccines are used on a population basis triggered by public health policy. As
such, evidence of their safety and efficacy needs to be extraordinarily
rigorous and evaluation methods and data should be open to independent
scrutiny. We need much better and larger studies on both safety and efficacy
before we roll out influenza vaccine programs to all populations, especially to
children who appear to have much higher rates of adverse reactions. Finally,
decisions to use a vaccine in a population must consider its safety profile,
but principally its effectiveness. There is poor evidence on how well influenza
vaccines prevent any influenza complications in children [10] and other age
groups. There is good evidence that influenza vaccines study reports cherry
pick results and achieve spurious notoriety [17]. Exposing human beings to
uncertain effects is a risky business. Report available for purchase Try a
14-day free trial at BMJ.com or Google the title of the report for more
information

suffering harms — and subsequent suspension of the vaccine — regulators are
ensuring the safety and efficacy of all marketed therapeutics. Should we be
occurred with influenza vaccine, a vaccine used for over 60 years, said to have
“an established record of safety in all age groups”? There are actually
relatively little data on the effects of vaccinating young children against
influenza. Some manufacturers have even withheld data from public scrutiny
amidst general indifference. Evidence from all comparative influenza vaccine
studies shows that harms, when they are investigated, are not reported
consistently and systematically. As pandemic vaccines are provided to
governments and not individuals and manufacturers are indemnified for damages
caused to users, there seem to be few incentives for investigation of harms.”

Journal Of Virology • June 2010

Viral Nucleic Acids in Live-Attenuated Vaccines: Detection of Minority Variants
and an Adventitious Virus † Author Information Joseph G. Victoria,1,2 Chunlin
Wang,3 Morris S. Jones,4 Crystal Jaing,5 Kevin McLoughlin,5 Shea Gardner,5 and
Eric L. Delwart1,2* 1. Blood Systems Research Institute, San Francisco,
California 94118 2. Dept. of Laboratory Medicine, University of California, San
Francisco, California 94118 3. Stanford Genome Technology Center, Stanford,
California 94304 4. Clinical Investigation Facility, David Grant USAF Medical
Center, Travis AFB, California 94535 5. Lawrence Livermore National Laboratory,
Livermore, California 94551 Highly effective, safe, and relatively inexpensive,
live-attenuated viruses protect against numerous human and animal viral
infections. Attenuation is achieved by genetically adapting viruses for
replication in a different host species or under nonphysiological conditions,
such that viruses lose their pathogenic potential in their original host
species while remaining sufficiently antigenic to induce lasting protective
immunity. Live-attenuated vaccines are highly efficacious due to the
physiologic presentation of native antigen to the host’s immune system and
include the earliest human vaccine developed by serial passages of rabies virus
in rabbits. In very rare instances, one attenuated viral vaccine, the oral
poliovirus vaccine (OPV), can accumulate mutations as well as recombine with
other coinfecting enteroviruses and revert to a pathogenic state (18, 24).
Attenuated live vaccines also carry a potential risk of contamination with
adventitious viruses introduced during the attenuation process, from the cell
lines used, and/or from the animal sera or other biologics often used in cell
cultures. Very early Theiler’s yellow fever attenuated virus was once “stabi-
lized” with human plasma thought to contain hepatitis B virus, resulting in
many cases of hepatitis (5, 28). Some early Sabin poliovirus vaccines were
contaminated with the simian virus 40 (SV40) polyomavirus from the monkey cells
used to amplify polioviruses. While carcinogenic in rodents, SV40 has no
epidemiologic association with human cancers (10). Avian leuko- sis virus (ALV)
and endogenous avian virus (AEV) have been reported in attenuated vaccines
grown in chicken embryo fi- broblasts (CEF), but extensive testing has also
ruled out hu- man infections (14, 15). Vaccine-associated ALV and AEV are
thought to originate from endogenous retroviruses in the chicken germ line (14,
15, 17). Because the chemical inactivation used in the manufacture of
killed-virus vaccines is also likely to inactivate adventitious viruses, we
focused on eight live-attenuated viruses, OPV (Biopolio), rubella (Meruvax-II),
measles (Attenuvax), yellow fever (YF-Vax), human herpesvirus 3 (HHV-3)
(Varivax), rotavirus (Rotarix and Rotateq), and multivalent measles/
mumps/rubella (MMR-II), to resequence the attenuated viruses and test for the
presence of adventitious viruses after viral particle purification, massively
parallel pyrosequencing, and viral sequence similarity searches. Vaccine
nucleic acids were also analyzed using a panmicrobial microarray. Published
ahead of print on 7 April 2010 † The authors have paid a fee to allow immediate
free access to this article. Full Report:
http://jvi.asm.org/content/84/12/6033.full.pdf

“In very rare instances, one attenuated viral vaccine, the oral poliovirus
vaccine (OPV), can accumulate mutations as well as recombine with other
coinfecting enteroviruses and revert to a pathogenic state.”

“Recently discovered contamination of 2 rotavirus vaccines
by pig viruses is unlikely to pose a human health threat, according to the US
Food and Drug Administration (FDA).” Journal Of The American Medical
Association (JAMA) • July 2010 Medical News and Perspectives

FDA: Benefits of Rotavirus Vaccination Outweigh Potential Contamination Risk by
Bridget M. Kuehn Recently discovered contamination of 2 rotavirus vaccines by
pig viruses is unlikely to pose a human health threat, according to the US Food
and Drug Administration (FDA). The agency recommended in May that physicians
resume use of one vaccine, Rotarix, and continue use of the other vaccine,
RotaTeq. On March 22, the FDA had recommended that physicians suspend the use
of Rotarix after the agency learned that academic researchers made the
unexpected finding that the vaccine contained DNA from porcine circovirus 1
(PCV1), a virus that is common in US swine but not associated with illness in
pigs or humans (Victoria JG et al. J Virol. 2010;84[12]:6033-6040). This
finding was confirmed by scientists from the FDA and the vaccine’s maker,
GlaxoSmithKline. http://jama.jamanetwork.com/article.aspx?articleid=186166

Expert Review Of Vaccines • October 2010

MF59; as a vaccine adjuvant: a review of safety and immunogenicity Author
information El Sahly H. Department of Molecular Virology and Microbiology
Baylor College of Medicine, Houston, TX 77030, USA hanae@bcm.edu Abstract
Approximately 70 years passed between the licensing of alum salts as vaccine
adjuvants and that of MF59, an oil-in-water emulsion, is currently licensed for
use in the elderly as an adjuvant in seasonal influenza vaccines. Its mechanism
of action is not fully understood, but enhancement of the interaction between
the antigen and the dendritic cell seems to be involved. When used with
seasonal influenza vaccines, an increase occurs in the hemagglutination
inhibition antibody titers against some, but not all, seasonal vaccine
influenza strains. The adjuvant effect is more pronounced when MF59 is combined
with novel influenza antigens such as H9 and H5. The use of the adjuvant is
associated with an increase in the frequency of local and systemic early
post-vaccine adverse events (3-7 days), but no increase in adverse events was
observed thereafter. Currently, MF59 is under evaluation as an adjuvant with
other antigens such as pandemic influenza antigens and cytomegalovirus
antigens. http://www.ncbi.nlm.nih.gov/pubmed/20923265

“Currently, MF59 [squalene] is under evaluation as an adjuvant with other
antigens such as pandemic influenza antigens and cytomegalovirus antigens.”

Toxicology • December 2010

Interindividual variations in the efficacy and toxicity of vaccines Author
information Thomas C1, Moridani M. Department of Pharmaceutical Sciences School
of Pharmacy, Lake Erie College of Osteopathic Medicine Bradenton, FL 34211, USA
Abstract A number of currently available vaccines have shown significant
differences in the magnitude of immune responses and toxicity in individuals
undergoing vaccination. A number of factors may be involved in the variations
in immune responses, which include age, gender, race, amount and quality of the
antigen, the dose administered and to some extent the route of administration,
and genetics of immune system. Hence, it becomes imperative that researchers
have tools such as genomics and proteomics at their disposal to predict which
set of population is more likely to be non-responsive or develop toxicity to
vaccines. In this article, we briefly review the influence of pharmacogenomics
biomarkers on the efficacy and toxicity of some of the most frequently reported
vaccines that showed a high rate of variability in response and toxicity
towards hepatitis B, measles, mumps, rubella, influenza, and AIDS/HIV.
http://www.ncbi.nlm.nih.gov/pubmed/19837123

“A number of currently available vaccines have shown significant differences in
the magnitude of immune responses and toxicity in individuals undergoing
vaccination.”

“When Eric Delwart couldn’t find the right email addresses online to contact GlaxoSmithKline ...”
Nature Medicine • 2010

Vaccine contamination prompts safety review Megan Scudellari When Eric Delwart
couldn’t find the right email addresses online to contact GlaxoSmithKline (GSK)
in early February, he posted a good old-fashioned letter to the Belgian
headquarters of the pharma giant to inform the company that one of its vaccines
was contaminated with a pig virus. Months earlier, Delwart, a viral… Purchase
this report full text PDF: $18
http://www.nature.com/nm/journal/v16/n5/full/nm0510-493.html

Vaccine • April 2011

Plaque purification as a method to mitigate the risk of adventitious-agent
contamination in influenza vaccine virus seeds Author information Murata H1,
Macauley J, Lewis AM Jr, Peden K. Laboratory of DNA Viruses Division of Viral
Products CBER, FDA, Bethesda, MD 20892, USA haruhiko.murata@fda.hhs.gov
Abstract At present, the seed viruses for the manufacture of licensed seasonal
inactivated influenza vaccines in the United States are derived from primary
egg isolates as a result of concerns associated with adventitious agents.
According to the prevailing view, the passage of influenza viruses through eggs
serves as a filtering step to remove potential contaminating viruses. We have
investigated the feasibility of addressing adventitious-agent risk by
subjecting influenza virus to a plaque-purification procedure using MDCK cells.
SV40 and canine adenovirus-1 (representing viruses for which MDCK cells are
non-permissive and permissive, respectively) were used as challenge viruses to
model agents of concern that might be co-isolated along with the influenza
virus. By mixing influenza virus strain A/PR/8/34 with varying amounts of each
challenge virus and then performing a plaque assay for influenza virus using
MDCK cells, we have attempted to determine the efficiency by which the
challenge virus is removed. Our data suggest that substantial removal can be
achieved even after a single round of plaque purification. If cell-derived
isolates were deemed to be acceptable following a plaque-purification
procedure, the manufacture of seasonal influenza vaccine would be facilitated
by: (1) the expansion of the repertoire of viruses from which seed virus
candidates could be generated for licensed egg-derived vaccines as well as for
vaccines manufactured in mammalian cells; and (2) the mitigation of
adventitious-agent risk associated with the seed virus, and hence the
elimination of the need to passage seed viruses in eggs for vaccines
manufactured in mammalian cells. http://www.ncbi.nlm.nih.gov/pubmed/21354480

“At present, the seed viruses for the manufacture of licensed seasonal
inactivated influenza vaccines in the United States are derived from primary
egg isolates as a result of concerns associated with adventitious agents.
According to the prevailing view, the passage of influenza viruses through eggs
serves as a filtering step to remove potential contaminating viruses.”

Vaccine • October 2011

Investigations of porcine circovirus type 1 (PCV1) in vaccine-related and other
cell lines Hailun Ma, Syed Shaheduzzaman, Dhanya K. Willliams, Yamei Gao, Arifa
S. Khan Division of Viral Products Office of Vaccines Research and Review
Center for Biologics Evaluation and Research US Food and Drug Administration
Bethesda, MD 20892, USA Abstract Porcine circovirus type 1 (PCV1) is highly
prevalent in swine and was recently reported in some rotavirus vaccines. Since
animal-derived raw materials, such as cells, trypsin, and serum, can be a major
source of introducing virus contamination in biological products, we have
investigated PCV1 in several cell lines obtained from ATCC that have broad use
in research, diagnostics, or vaccine development. It is expected that these
cell lines have been exposed to bovine and porcine viruses during their
establishment and passage history due to the use of serum and trypsin that was
not qualified according to current testing guidances or processed using new
virus-inactivation methods. This study showed that Vero, MRC-5, and CEFs, which
represent cell substrates used in some U.S. licensed vaccines, and other cell
lines used in investigational vaccines, such as MDCK, HEK-293, HeLa, and A549,
were negative for PCV1 using a nested PCR assay; some were also confirmed
negative by infectivity analysis. However, MDBK cells, which are used for some
animal vaccines, contained PCV1 sequences, although no virus was isolated.
Although the results showed that PCV infection may not have occurred under
previous culture conditions, the recent cases of vaccine contamination
emphasizes the need for continued efforts to reduce the likelihood of
introducing viruses from animal-derived materials used in product manufacture.
http://www.sciencedirect.com/science/article/pii/S0264410X1101173X [click
Science Direct]

“Although the results showed that Porcine Circovirus infection may not have
occurred under previous culture conditions, the recent cases of vaccine
contamination emphasizes the need for continued efforts to reduce the
likelihood of introducing viruses from animal-derived materials used in product
manufacture.”

Expert Review Of Respiratory Medicine • October 2011

Simian virus 40 transformation, malignant mesothelioma and brain tumors Author
information Qi F1, Carbone M, Yang H, Gaudino G. University of Hawaii Cancer
Center Honolulu, HI, USA Abstract Simian virus 40 (SV40) is a DNA virus
isolated in 1960 from contaminated polio vaccines, that induces mesotheliomas,
lymphomas, brain and bone tumors, and sarcomas, including osteosarcomas, in
hamsters. These same tumor types have been found to contain SV40 DNA and
proteins in humans. Mesotheliomas and brain tumors are the two tumor types that
have been most consistently associated with SV40, and the range of positivity
has varied about from 6 to 60%, although a few reported 100% of positivity and
a few reported 0%. It appears unlikely that SV40 infection alone is sufficient
to cause human malignancy, as we did not observe an epidemic of cancers
following the administration of SV40-contaminated vaccines. However, it seems
possible that SV40 may act as a cofactor in the pathogenesis of some tumors. In
vitro and animal experiments showing cocarcinogenicity between SV40 and
asbestos support this hypothesis. Full Report:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241931/

“it seems possible that SV40 may act as a cofactor in the pathogenesis of some
tumors. In vitro and animal experiments showing cocarcinogenicity between SV40
and asbestos support this hypothesis.”

Journal of Public Health Management & Practice • November 2011

Using an Immunization Information System to Facilitate a Vaccine Recall in New
York City 2007 Papadouka, Vikki PhD, MPH; Metroka, Amy MSW, MPH; Zucker, Jane
R. MD, MSc Abstract Background In December 2007, Merck & Co, Inc, initiated a
voluntary recall of 10 lots of PedvaxHIB, and 2 lots of COMVAX when the
potential of contamination was identified during routine testing of the
manufacturing equipment. Merck recommended that providers stop vaccinating
children using these vaccine lots.

“In December 2007, Merck & Co, Inc, initiated

Objective To describe how the New York City (NYC) Immunization Information
System was used in the effort to recall vaccines.

of COMVAX when the potential of contamination was

Methods Immediately following Merck’s announcement, NYC’s Bureau of
Immunization used the New York Citywide Immunization Registry (CIR) to (a) fax
and e-mail all pediatric facilities a letter informing them of the recall and
asking that they immediately remove recalled vaccines from their refrigerators;
(b) identify facilities that had used the recalled lots, on the basis of data
reported to the CIR, and contact them individually by phone; and (c) monitor
the success of the recall by examining the number of recalled doses
administered and reported to the CIR before and after the recall.

a voluntary recall of 10 lots of PedvaxHIB, and 2 lots

identified during routine testing of the manufacturing equipment. Merck
recommended that providers stop vaccinating children using these vaccine lots.”

Results The alert was faxed and e-mailed to 1928 pediatric facilities informing
them of the recall. In addition, the Bureau of Immunization identified 105
facilities that had reported doses of vaccine from the recalled lots to the CIR
and called to ask them to check their refrigerators for remaining supplies and
discontinue use of this vaccine. The number of doses with the affected lot
numbers reported to the CIR decreased sharply following CIR recall
notification. Furthermore, the Centers for Disease Control and Prevention and
Merck reported the return of nearly 50% of publicly and privately purchased
vaccines from the recalled lots that had been distributed to NYC providers.
Conclusion Immunization Information Systems can be effective tools for quickly
identifying providers in possession of recalled vaccine lots, particularly when
lot numbers are well reported, and for facilitating rapid vaccine recall in
support of vaccine safety.

http://journals.lww.com/jphmp/pages/articleviewer.aspx?year=2011&issue=11010&article=00014&type=abstract

“Because the product is itself a virus,
traditional viral clearance steps are generally not included in the
manufacturing process ...” PDA Journal Of Pharmaceutical Science And Technology
• November 2011

Application of Risk Assessments in the Design of the Overall Viral Control
Strategy Used during the Manufacture and Testing of Live Virus Vaccines Author
information Pennathur S. MedImmune, LLC, One MedImmune Way, Gaithersburg, MD
20878 Abstract CONFERENCE PROCEEDING Proceedings of the PDA/FDA Adventitious
Viruses in Biologics: Detection and Mitigation Strategies Workshop in Bethesda,
MD, USA; December 1-3, 2010 Guest Editors: Arifa Khan (Bethesda, MD), Patricia
Hughes (Bethesda, MD) and Michael Wiebe (San Francisco, CA) It is important to
include a risk assessment process in the overall viral control strategy used
during the manufacture and testing of live virus vaccines. Because the product
is itself a virus, traditional viral clearance steps are generally not included
in the manufacturing process, and there is normally no inactivation step in the
manufacturing process either. The risk assessment is therefore necessary to
identify potential sources for entry of adventitious agents into the vaccine,
and to develop a strategy to minimize or eliminate the sources through which
adventitious agents can enter the vaccine. The risk assessment can also be used
to tailor the biosafety testing that is performed on raw materials, vaccine
seeds, vaccine bulk materials, and final product. Biosafety testing is normally
designed to ensure the detection of both known and unknown adventitious agents,
but the results of the risk assessment can be used to put in place a biosafety
testing strategy designed to maximize the detection of an adventitious agent
that is potentially likely to be present in the vaccine. The risk assessment
therefore enables the development of a comprehensive viral control strategy and
provides a higher level of assurance that the vaccine will be free from
contamination by adventitious agents.
http://www.ncbi.nlm.nih.gov/pubmed/22294607

J Neurology, Neurosurgery And Psychiatry • 2012

Contamination with gangliosides in brain-derived rabies vaccine may trigger
Guillain–Barré syndrome Author Information Hiromichi Sakai1, Faqeehah Mohamed
Harun1, Naoki Yamamoto1,2, Nobuhiro Yuki1,2 1. Department of Microbiology,
National University of Singapore, Singapore 2. Department of Medicine, National
University of Singapore, Singapore Abstract Guillain–Barré syndrome (GBS) is an
autoimmune-mediated peripheral neuropathy typically occurring after microbial
infections such as Campylobacter jejuni enteritis. It can also occur following
vaccinations such as the 1976 swine flu vaccine in the USA.1 GBS is divided
into demyelinating and axonal subtypes. There is now good evidence that
gangliosides or similar components trigger the development of axonal GBS.2
Axonal GBS associated with IgG anti-GM1 or anti-GD1a antibodies after bovine
brain ganglioside administration have been recorded in several patients.
Sensitisation of rabbits with bovine brain gangliosides or isolated GM1
produced a replica of axonal GBS. Based on these findings, it has been
suggested that C jejuni components mimic human gangliosides GM1 and GD1a, and C
jejuni infection induces the production of autoantibodies against the
gangliosides that are expressed in the peripheral nerves, resulting in the limb
weakness seen in GBS. By contrast, the mechanism by which certain vaccines
elicit the development of GBS remains unresolved, although there have been
studies to suggest that the 1976 swine flu vaccine could elicit anti-GM1
antibodies in mice and that the GM1 epitope was present in the influenza
haemagglutinin.3 It is important to understand the pathogenesis of
postvaccination GBS to allow safer vaccines to be developed.
http://jnnp.bmj.com/content/83/4/467.extract

“There is now good evidence that gangliosides or similar components trigger the
development of axonal Guillain–Barré syndrome (GBS).”

Biologicals • January 2012

A need for careful evaluation of endotoxin contents in acellular
pertussis-based combination vaccines Michiyo Kataoka, Masaki Ochiai, Akihiko
Yamamoto, Yoshinobu Horiuchi Department of Bacterial Pathogenesis and Infection
Control National Institute of Infectious Diseases 4-7-1 Gakuen,
Musashimurayama-shi Tokyo 208-0011, Japan Abstract Two batches each of
diphtheria-tetanus-acellular pertussis vaccine (DTaP) and that combined with
inactivated polio vaccine purchased from foreign markets were tested by mouse
body weight decreasing (BWD) toxicity test and Limulus amaebocyte lysate (LAL)
test. Three out of the four imported vaccine batches showed the levels of BWD
toxicity even comparable to that of DT-whole cell pertussis vaccine. BWD
toxicity test is based on endotoxin dose-dependent weight loss of mice and has
been used for controlling endotoxin in DTaP. Although of the strong BWD
toxicity of the imported vaccines, there was no marked difference in LAL test
results between the imported vaccines and Japanese DTaP. However, one imported
DTaP batch showed very strong interference with LAL activity of spiked
lipopolysaccharide (LPS). The batch interfered not only with LAL activity but
also with pyrogenicity and prostaglandin E2 induction activity. However, the
pyrogenicity of the spiked LPS could be recovered from the precipitated
fraction of the batch by treating with phosphate buffer to suggest the
possibility of recovering in vivo toxicity. As an adequate in vitro test method
could not be identified for controlling the safety of the interfering batch, an
appropriate in vivo test would be required for testing such vaccines.
http://www.sciencedirect.com/science/article/pii/S1045105611001977

“However, the pyrogenicity of the spiked LPS could be recovered from the
precipitated fraction of the batch by treating with phosphate buffer to suggest
the possibility of recovering in vivo toxicity. As an adequate in vitro test
method could not be identified for controlling the safety of the interfering
batch, an appropriate in vivo test would be required for testing such
vaccines.”

Pharmacoepidemiology And Drug Safety • April 2012

Vaccine discontinuation and switching following regulatory interventions in
response to rotavirus vaccine contamination with porcine circovirus DNA
fragments Author information Dore DD1, Turnbull BR, Seeger JD. Departments of
Health Services Policy and Practice and Epidemiology Program in Public Health
The Warren Alpert Medical School of Brown University Providence, RI, USA
david_dore@brown.edu Abstract PURPOSE The Food and Drug Administration
temporarily suspended monovalent rotavirus vaccine (RV1) use following
discovery of contamination with porcine circovirus fragments and subsequently
announced similar contamination of the pentavalent rotavirus vaccine (RV5) but
recommended continued use of the product. We assessed the utilization of these
vaccines in relation to the announcements. METHODS Using claims submitted to a
commercial health insurer for administration of RV1 and RV5, we estimated the
number of administrations of the vaccines and the extent of switching between
RV1 and RV5. Procedure codes on submitted claims identified vaccine
administrations among infants ≤ 1 year old through 16 June 2010. Among infants
who received a first dose of vaccine before the corresponding announcement, and
whose second dose was anticipated following the announcement, we estimated the
number who received no second dose of rotavirus vaccine. RESULTS There were 31
178 RV1 initiators and 514 357 RV5 initiators. We observed a 93% reduction in
RV1 doses in the month following the recommended suspension of use, coupled
with extensive switching to RV5 (90% of subsequent doses) and a reduction in
second RV1 doses (from 35.5% incomplete to 40.9%). There was a 15% increase in
number of RV5 administrations following announcement of its contamination, with
little switching to RV1 but with a possible decrease in completion. CONCLUSIONS
Recommended suspension of RV1 use led to a substantial decrease in use and
extensive switching to RV5. The announcement that RV5 was similarly
contaminated, but without a corresponding recommendation to suspend use, had
little effect on use. http://www.ncbi.nlm.nih.gov/pubmed/22290786

“The Food and Drug Administration temporarily suspended monovalent rotavirus
vaccine (RV1) use following discovery of contamination with porcine circovirus
fragments and subsequently announced similar contamination of the pentavalent
rotavirus vaccine (RV5) but recommended continued use of the product.”

Biologicals • July 2012

Investigation of porcine circovirus contamination in human vaccines Author
Information Sarah M. Gillilanda, Lindsay Forresta, Heather Carrea, Adrian
Jenkinsb, Neil Berryb, Javier Martina, Philip Minora, Silke Schepelmanna,
Abstract DNA from porcine circovirus type 1 (PCV1) and 2 (PCV2) has recently
been detected in two vaccines against rotaviral gastroenteritis from
manufacturers A and B. We investigated if PCV1 sequences are present in other
viral vaccines. We screened seeds, bulks and final vaccine preparations from
ten manufacturers using qRT-PCR. We detected 3.8 × 103 to 1.9 × 107 PCV1 DNA
copies/milliliter in live poliovirus seeds for inactivated polio vaccine (IPV)
from manufacturer A, however, following inactivation and purification, the
finished IPV was PCV1-negative. PCV1 DNA was not detectable in live polio
preparations from other vaccine producers. There was no detectable PCV1 DNA in
the measles, mumps, rubella and influenza vaccines analysed including material
supplied by manufacturer A. We confirmed that the PCV1 genome in the rotavirus
vaccine from manufacturer A is near full-length. It contains two mutations in
the PCV cap gene, which may result from viral adaptation to Vero cells. Bulks
of this vaccine contained 9.8 × 1010 to 1.8 × 1011 PCV1 DNA copies/millilitre
and between 4.1 × 107 and 5.5 × 108 DNA copies were in the final doses. We
found traces of PCV1 and PCV2 DNA in the rotavirus vaccine from manufacturer B.
This highlights the issue of vaccine contamination and may impact on vaccine
quality control.
http://www.sciencedirect.com/science/article/pii/S1045105612000267

“We found traces of PCV1 and PCV2 DNA in the rotavirus vaccine from
manufacturer B. This highlights the issue of vaccine contamination and may
impact on vaccine quality control.”

Voprosy Virusologii • September 2012

Analysis of the cell tissue culture contamination with the bovine viral
diarrhea virus and mycoplasmas Author Information Uryvaevaev LV, Ionova KS,
Dedova AV, Dedova LV, Selivanova TK, Parasiuk NA, Mezentseva MV, Kostina LV,
Gushchina EA, Podcherniaeva RIa, Grebennikova TV. Abstract Different cell
tissue cultures and commercial fetal calf sera (FTS) used in biological and
virological research were screened for the bovine viral diarrhea virus (BVDV,
Pestivirus genus, Flaviviridae family) and mycoplasma contamination. BVDV was
detected using RT-PCR and Indirect immunofluorescence (with monoclonal
antibodies) methods in 33% cases of the studied cell lines and in > 60% cases
of FCS. BVDV was shown to present and reproduce in high spectra of human cell
lines, as well as in monkey, pig, rabbit, goat, dog, and cat cells at high
levels (up to 100-1000 genome-equivalent copies per cell) and reached up to
10(3)-10(7) genome-equivalent copies per serum ml. The molecular mechanisms of
the long virus persistence without definite signs of destruction should be
studied. http://www.ncbi.nlm.nih.gov/pubmed/?term=23248854

“Bovine Viral Diarrhea Virus was detected using RT-PCR and Indirect
immunofluorescence (with monoclonal antibodies) methods in 33% cases of the
studied cell lines and in > 60% cases of Fetal Calf Serum.”

PLoS Pathogens • November 2012

A Wolf in Sheep’s Clothing: SV40 Co-opts Host Genome Maintenance Proteins to
Replicate Viral DNA Gregory A. Sowd and Ellen Fanning* Richard C. Condit,
Editor Department of Biological Sciences, Vanderbilt University Nashville,
Tennessee, USA University of Florida, USA Abstract Simian virus 40 (SV40) was
discovered in 1960 as a contaminant in early polio vaccines. Its discovery
coincided with an explosion of knowledge in the new field of molecular biology,
and SV40 was quickly adopted as a model to study eukaryotic genome structure,
expression, replication, and cell growth regulation in cultured cells [1]. With
a genome of only 5.2 kbp, SV40 relies heavily on host cell machinery to
propagate, affording investigators a powerful tool to discover key host
proteins that the virus manipulates. Indeed, a single multifunctional viral
protein, the large tumor (T) antigen (Tag) (Figure 1A), is sufficient to
orchestrate the replication of the viral mini-chromosome in infected monkey
cells [2], [3]. The origin DNA binding domain of Tag binds specifically to the
viral origin of DNA replication, and the C-terminal helicase domain of Tag
unwinds parental DNA at SV40 replication forks. The development of a cell-free
reaction containing purified Tag and primate cell extract enabled the
identification of ten evolutionarily conserved host proteins that are necessary
and sufficient, together with Tag, to replicate SV40 DNA in vitro [3], [4].
Thus, much remains to be learned about how SV40 infection activates DNA damage
signaling and uses it to facilitate viral propagation. Full Report:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493471/

“Simian virus 40 (SV40) was discovered in 1960 as a contaminant in early polio
vaccines ... much remains to be learned about how SV40 infection activates DNA
damage signaling and uses it to facilitate viral propagation.”

Journal Of Inorganic Biochemistry • December 2012

“Medical practitioners in nine countries submitted samples of

Detection of human papillomavirus (HPV) L1 gene DNA possibly bound to
particulate aluminum adjuvant in the HPV vaccine Gardasil

Gardasil (Merck & Co.) to be tested for the presence of human

Author information Lee SH. Milford Hospital and Milford Molecular Laboratory
2044 Bridgeport Avenue, Milford, CT 06460, USA shlee01@snet.net Abstract
Medical practitioners in nine countries submitted samples of Gardasil (Merck &
Co.) to be tested for the presence of human papillomavirus (HPV) DNA because
they suspected that residual recombinant HPV DNA left in the vaccine might have
been a contributing factor leading to some of the unexplained post-vaccination
side effects. A total of 16 packages of Gardasil were received from Australia,
Bulgaria, France, India, New Zealand, Poland, Russia, Spain and the United
States. A nested polymerase chain reaction (PCR) method using the MY09/MY11
degenerate primers for initial amplification and the GP5/GP6based nested PCR
primers for the second amplification were used to prepare the template for
direct automated cycle DNA sequencing of a hypervariable segment of the HPV L1
gene which is used for manufacturing of the HPV L1 capsid protein by a DNA
recombinant technology in vaccine production. Detection of HPV DNA and HPV
genotyping of all positive samples were finally validated by BLAST (Basic Local
Alignment Search Tool) analysis of a 45-60 bases sequence of the
computer-generated electropherogram. The results showed that all 16 Gardasil
samples, each with a different lot number, contained fragments of HPV-11 DNA,
or HPV-18 DNA, or a DNA fragment mixture from both genotypes. The detected HPV
DNA was found to be firmly bound to the insoluble, proteinase-resistant
fraction, presumably of amorphous aluminum hydroxyphosphate sulfate (AAHS)
nanoparticles used as adjuvant. The clinical significance of these residual HPV
DNA fragments bound to a particulate mineral-based adjuvant is uncertain after
intramuscular injection, and requires further investigation for vaccination
safety. http://www.ncbi.nlm.nih.gov/pubmed/23078778

papillomavirus (HPV) DNA because they suspected that residual recombinant HPV
DNA left in the vaccine might have been a contributing factor leading to some
of the unexplained post-vaccination side effects. A total of 16 packages of
Gardasil were received from Australia, Bulgaria, France, India, New Zealand,
Poland, Russia, Spain and the United States.

The results showed that all 16 Gardasil samples, each with a different lot
number, contained fragments of HPV-11 DNA, or HPV-18 DNA, or a DNA fragment
mixture from both genotypes. The detected HPV DNA was found to be firmly bound
to the insoluble, proteinase-resistant fraction, presumably of amorphous
aluminum hydroxyphosphate sulfate (AAHS) nanoparticles used as adjuvant. The
clinical significance of these residual HPV DNA fragments bound to a
particulate mineral-based adjuvant is uncertain after intramuscular injection
...”

“This enables quick, safe, and cost-effective vaccine production
that would be required in case of a pandemic.” Journal of Laboratory Automation
• December 2012

Automated production of plant-based vaccines and pharmaceuticals Author
information Wirz H1, Sauer-Budge AF, Briggs J, Sharpe A, Shu S, Sharon A.
Fraunhofer CMI, Brookline, MA 02446, USA Abstract A fully automated “factory”
was developed that uses tobacco plants to produce large quantities of vaccines
and other therapeutic biologics within weeks. This first-of-a-kind factory
takes advantage of a plant viral vector technology to produce specific proteins
within the leaves of rapidly growing plant biomass. The factory’s
customdesigned robotic machines plant seeds, nurture the growing plants,
introduce a viral vector that directs the plant to produce a target protein,
and harvest the biomass once the target protein has accumulated in the
plants-all in compliance with Food and Drug Administration (FDA) guidelines
(e.g., current Good Manufacturing Practices). The factory was designed to be
time, cost, and space efficient. The plants are grown in custom multiplant
trays. Robots ride up and down a track, servicing the plants and delivering the
trays from the lighted, irrigated growth modules to each processing station as
needed. Using preprogrammed robots and processing equipment eliminates the need
for human contact, preventing potential contamination of the process and
economizing the operation. To quickly produce large quantities of protein-based
medicines, we transformed a laboratory-based biological process and scaled it
into an industrial process. This enables quick, safe, and cost-effective
vaccine production that would be required in case of a pandemic.
http://www.ncbi.nlm.nih.gov/pubmed/23015521

Archives Of Virology • January 2013

Genetic characterization of bovine viral diarrhoea (BVD) viruses: confirmation
of the presence of BVD genotype 2 in Africa Author information Ularamu HG1,
Sibeko KP, Bosman AB, Venter EH, van Vuuren M. Department of Veterinary
Tropical Diseases Faculty of Veterinary Science, University of Pretoria
Onderstepoort 0110, South Africa ularamuhussaini@yahoo.co.uk Abstract Bovine
viral diarrhoea virus (BVDV) has emerged as one of the economically important
pathogens in cattle populations, with a worldwide distribution and causing a
complex of disease syndromes. Two genotypes, BVDV 1 and 2, exist and are
discriminated on the basis of the sequence of the 5’ non-coding region (5’ NCR)
using real-time PCR. Real-time PCR is more sensitive, specific, and less
time-consuming than conventional PCR, and it has less risk of
cross-contamination of samples. Limited information exists on BVDV genetic
subtypes in South Africa. The aim of this study was to determine the genotypes
of BVDV currently circulating in South African feedlots. A total of 279
specimens (219 tissue samples, 59 trans-tracheal aspirates and 1 blood sample)
were collected from dead and living cattle with lesions or clinical signs
compatible with BVDV infection. Pooled homogenates from the same animals were
prepared, and total RNA was extracted. A screening test was performed on the
pooled samples, and positive pools were investigated individually. A Cador BVDV
Type 1/2 RT-PCR Kit (QIAGEN, Hilden, Germany) was used for the real-time PCR
assay on a LightCycler(®) V2.0 real-time PCR machine (Roche Diagnostics,
Mannheim, Germany). The results were read at 530 and 640 nm for BVDV 1 and 2,
respectively. Bovine viral diarrhoea virus was detected in a total of 103
samples that included 91 tissue samples, 1 blood sample and 11 trans-tracheal
aspirates. Eighty-five (82.5 %) of the strains were genotype 1 and 18 (17.5 %)
were genotype 2. Comparing the sequencing data, genotypes 1 and 2 from the
field strains did not cluster with vaccine strains currently used in feedlots
in South Africa. The present study revealed the presence of BVDV genotype 2 in
cattle in South Africa based on the high sequence similarity between genotype 2
field strains and strain 890 from North America. The presence of genotype 2
viruses that phylogenetically belong to different clusters and coexist in
feedlots is consistent with the possibility of multiple virus introductions.
These results represent the first documented evidence for the presence of BVDV
genotype 2 in African cattle. http://www.ncbi.nlm.nih.gov/pubmed/?term=23011308

“These results represent the first documented evidence for the presence of BVDV
genotype 2 in African cattle.”

Journal Of Veterinary Diagnostic Investigation • January 2013

HoBi-like viruses: an emerging group of pestiviruses Author information
Bauermann FV1, Ridpath JF, Weiblen R, Flores EF. Department of Preventive
Veterinary Medicine, Virus Section Federal University of Santa Maria, Santa
Maria, Rio Grande do Sul, Brazil Abstract The genus Pestivirus is composed of 4
important pathogens of livestock: Bovine viral diarrhea virus 1 and 2 (BVDV-1
and BVDV-2), Classical swine fever virus (CSFV), and Border disease virus of
sheep (BDV). BVDV are major pathogens of cattle, and infection results in
significant economic loss worldwide. A new putative pestivirus species,
tentatively called “HoBi-like,” “BVDV-3,” or “atypical pestiviruses,” was first
identified in Europe in fetal bovine serum (FBS) imported from Brazil.
HoBi-like viruses are related to BVDV at the genetic and antigenic levels.
Further, the disease caused by these new viruses resembles clinical
presentations historically associated with BVDV infection, including growth
retardation, reduced milk production, respiratory disease, reduced reproductive
performance, and increased mortality among young stock. Current BVDV diagnostic
tests may fail to detect HoBi-like viruses or to differentiate between BVDV and
HoBi-like viruses. Further, commercial tests for BVDV exposure, based on
serological response, do not reliably detect HoBi-like virus exposure, and
cross protection against HoBi-like viruses conferred by current BVDV vaccines
is likely limited. As many HoBi-like viruses, characterized to date, were
isolated from FBS originating from Brazil, it is assumed that the agent is
probably widespread in Brazilian herds. Nevertheless, reports of natural
infection in Southeast Asia and Europe demonstrate that these viruses are not
restricted to South America. Increased demand for FBS has led to widespread
distribution of FBS originating in HoBi-like virus endemic regions. The
contamination of such FBS with HoBi-like viruses may lead to spread of this
virus to other regions. http://www.ncbi.nlm.nih.gov/pubmed/?term=23345268 Full
Report http://vdi.sagepub.com/content/25/1/6.long

“Increased demand for fetal bovine serum has led to widespread distribution of
fetal bovine serum originating in HoBi-like virus endemic regions. The
contamination of such fetal bovine serum with HoBi-like viruses may lead to
spread of this virus to other regions.”

[fetal bovine serum is an important element of cell research and cell culture
applications, especially in vaccine research. Estimated sales of fetal bovine
serum in 2008 reached 700,000 liters globally]

ISRN Biochemistry • May 2013

Nanoparticles for Brain Drug Delivery Massimo Masserini Department of Health
Sciences University of Milano-Bicocca Via Cadore 48, 20900 Monza, Italy
Abstract The central nervous system, one of the most delicate microenvironments
of the body, is protected by the blood-brain barrier (BBB) regulating its
homeostasis. BBB is a highly complex structure that tightly regulates the
movement of ions of a limited number of small molecules and of an even more
restricted number of macromolecules from the blood to the brain, protecting it
from injuries and diseases. However, the BBB also significantly precludes the
delivery of drugs to the brain, thus, preventing the therapy of a number of
neurological disorders. As a consequence, several strategies are currently
being sought after to enhance the delivery of drugs across the BBB. Within this
review, the recently born strategy of brain drug delivery based on the use of
nanoparticles, multifunctional drug delivery systems with size in the order of
one-billionth of meters, is described. The review also includes a brief
description of the structural and physiological features of the barrier and of
the most utilized nanoparticles for medical use. Finally, the potential
neurotoxicity of nanoparticles is discussed, and future technological
approaches are described. The strong efforts to allow the translation from
preclinical to concrete clinical applications are worth the economic
investments. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392984/

“several strategies are currently being sought after to enhance the delivery of
drugs across the Blood Brain Barrier ... based on the use of nanoparticles ...
the potential neurotoxicity of nanoparticles is discussed”

Vaccine • July 2013

Transposon leads to contamination of clinical pDNA vaccine Author information
van der Heijden I1, Gomez-Eerland R, van den Berg JH, Oosterhuis K, Schumacher
TN, Haanen JB, Beijnen JH, Nuijen B. Department of Pharmacy & Pharmacology
Slotervaart Hospital/The Netherlands Cancer Institute Amsterdam, The
Netherlands Iris.vanderHeijden@slz.nl Abstract We report an unexpected
contamination during clinical manufacture of a Human Papilomavirus (HPV) 16 E6
encoding plasmid DNA (pDNA) vaccine, with a transposon originating from the
Escherichia coli DH5 host cell genome. During processing, presence of this
transposable element, insertion sequence 2 (IS2) in the plasmid vector was not
noticed until quality control of the bulk pDNA vaccine when results of
restriction digestion, sequencing, and CGE analysis were clearly indicative for
the presence of a contaminant. Due to the very low level of contamination, only
an insert-specific PCR method was capable of tracing back the presence of the
transposon in the source pDNA and master cell bank (MCB). Based on the presence
of an uncontrolled contamination with unknown clinical relevance, the product
was rejected for clinical use. In order to prevent costly rejection of clinical
material, both in-process controls and quality control methods must be
sensitive enough to detect such a contamination as early as possible, i.e.
preferably during plasmid DNA source generation, MCB production and ultimately
during upstream processing. However, as we have shown that contamination early
in the process development pipeline (source pDNA, MCB) can be present below
limits of detection of generally applied analytical methods, the introduction
of “engineered” or transposon-free host cells seems the only 100% effective
solution to avoid contamination with movable elements and should be considered
when searching for a suitable host cell-vector combination.
http://www.ncbi.nlm.nih.gov/pubmed/23707695

“We report an unexpected contamination during clinical manufacture of a Human
Papilomavirus (HPV) 16 E6 encoding plasmid DNA (pDNA) vaccine, with a
transposon originating from the Escherichia coli DH5 host cell genome. During
processing, presence of this transposable element, insertion sequence 2 (IS2)
in the plasmid vector was not noticed until quality control of the bulk pDNA
vaccine when results of restriction digestion, sequencing, and CGE analysis
were clearly indicative for the presence of a contaminant. Due to the very low
level of contamination, only an insert-specific PCR method was capable of
tracing back the presence of the transposon in the source pDNA and master cell
bank (MCB).”

Human Vaccines And Immunotherapy • November 2013

Investigation of a regulatory agency enquiry into potential porcine circovirus
type 1 contamination of the human rotavirus vaccine, Rotarix: approach and
outcome Author information Dubin G1, Toussaint JF, Cassart JP, Howe B, Boyce D,
Friedland L, Abu-Elyazeed R, Poncelet S, Han HH, Debrus S. GlaxoSmithKline
Vaccines; King of Prussia, PA USA Abstract In January 2010, porcine circovirus
type 1 (PCV1) DNA was unexpectedly detected in the oral live-attenuated human
rotavirus vaccine, Rotarix (GlaxoSmithKline [GSK] Vaccines) by an academic
research team investigating a novel, highly sensitive analysis not routinely
used for adventitious agent screening. GSK rapidly initiated an investigation
to confirm the source, nature and amount of PCV1 in the vaccine manufacturing
process and to assess potential clinical implications of this finding. The
investigation also considered the manufacturer’s inactivated poliovirus
(IPV)-containing vaccines, since poliovirus vaccine strains are propagated
using the same cell line as the rotavirus vaccine strain. Results confirmed the
presence of PCV1 DNA and low levels of PCV1 viral particles at all stages of
the Rotarix manufacturing process. PCV type 2 DNA was not detected at any
stage. When tested in human cell lines, productive PCV1 infection was not
observed. There was no immunological or clinical evidence of PCV1 infection in
infants who had received Rotarix in clinical trials. PCV1 DNA was not detected
in the IPV-containing vaccine manufacturing process beyond the purification
stage. Retrospective testing confirmed the presence of PCV1 DNA in Rotarix
since the initial stages of its development and in vaccine lots used in
clinical studies conducted pre- and post-licensure. The acceptable safety
profile observed in clinical trials of Rotarix therefore reflects exposure to
PCV1 DNA. The investigation into the presence of PCV1 in Rotarix could serve as
a model for risk assessment in the event of new technologies identifying
adventitious agents in the manufacturing of other vaccines and biological
products. http://www.ncbi.nlm.nih.gov/pubmed/24056737

“In January 2010, porcine circovirus type 1 (PCV1) DNA was unexpectedly
detected in the oral live-attenuated human rotavirus vaccine, Rotarix
(GlaxoSmithKline [GSK] Vaccines) by an academic research team investigating a
novel, highly sensitive analysis not routinely used for adventitious agent
screening.”

Biologicals • November 2013

Detection of contaminants in cell cultures, sera and trypsin Author information
Pinheiro de Oliveira TF1, Fonseca AA Jr, Camargos MF, de Oliveira AM, Pinto
Cottorello AC, Souza Ados R, de Almeida IG, Heinemann MB. Laboratório de
Biologia Molecular/Laboratório de Diagnóstico de Doenças Virais Laboratório
Nacional Agropecuário de Minas Gerais Pedro Leopoldo, Minas Gerais, Brazil
oliveiratfp@yahoo.com.br Abstract The aim of this study was standardization and
application of polymerase chain reaction (PCR) for the detection of
contaminants in cell cultures, sera and trypsin. Five PCR protocols were
standardized to assess the presence of genetic material from mycoplasma,
porcine circovirus 1 (PCV1), bovine leukemia virus (BLV) or bovine viral
diarrhea virus (BVDV) in cell culture samples. PCR reactions for the genes
GAPDH and beta-actin were used to evaluate the efficiency of nucleic acid
extraction. The PCR protocols were applied to 88 cell culture samples from
eight laboratories. The tests were also used to assess potential contamination
in 10 trypsin samples and 13 fetal calf serum samples from different lots from
five of the laboratories. The results showed the occurrence of the following as
DNA cell culture contaminants: 34.1% for mycoplasma, 35.2% for PCV1, 23.9% for
BVDV RNA and 2.3% for BLV. In fetal calf sera and trypsin samples BVDV RNA and
PCV1 DNA was detected. The results demonstrated that cell culture, sera and
trypsin used by different laboratories show a high rate of contaminants. The
results highlight the need for monitoring cell cultures and controlling for
biological contaminants in laboratories and cell banks working with these
materials. http://www.ncbi.nlm.nih.gov/pubmed/?term=24071554

“The results showed the occurrence of the following as DNA cell culture
contaminants: 34.1% for mycoplasma, 35.2% for porcine circovirus 1, 23.9% for
bovine viral diarrhea virus RNA and 2.3% for bovine leukemia virus. The results
demonstrated that cell culture, sera and trypsin used by different laboratories
show a high rate of contaminants. ”

Journal Of Pharmaceutical Sciences • March 2014

Mechanism of a decrease in potency for the recombinant influenza A virus
hemagglutinin H3 antigen during storage Author information Hickey JM1, Holtz
KM, Manikwar P, Joshi SB, McPherson CE, Buckland B, Srivastava IK, Middaugh CR,
Volkin DB. Department of Pharmaceutical Chemistry Macromolecule and Vaccine
Stabilization Center University of Kansas, Lawrence, Kansas, 66047 Abstract The
recombinant hemagglutinin (rHA)-based influenza vaccine Flublok® has recently
been approved in the United States as an alternative to the traditional
egg-derived flu vaccines. Flublok is a purified vaccine with a hemagglutinin
content that is threefold higher than standard inactivated influenza vaccines.
When rHA derived from an H3N2 influenza virus was expressed, purified, and
stored for 1 month, a rapid loss of in vitro potency (∼50%) was observed as
measured by the single radial immunodiffusion (SRID) assay. A comprehensive
characterization of the rHA protein antigen was pursued to identify the
potential causes and mechanisms of this potency loss. In addition, the
biophysical and chemical stability of the rHA in different formulations and
storage conditions was evaluated over time. Results demonstrate that the
potency loss over time did not correlate with trends in changes to the higher
order structure or hydrodynamic size of the rHA. The most likely mechanism for
the early loss of potency was disulfide-mediated cross-linking of rHA, as the
formation of non-native disulfidelinked multimers over time correlated well
with the observed potency loss. Furthermore, a loss of free thiol content,
particularly in specific cysteine residues in the antigen’s C-terminus, was
correlated with potency loss measured by SRID.
http://www.ncbi.nlm.nih.gov/pubmed/24425059

“When rHA derived from an H3N2 influenza virus was expressed, purified, and
stored for 1 month, a rapid loss of in vitro potency (<50%) was observed as
measured by the single radial immunodiffusion (SRID) assay.”

Currents In Medical Chemistry • March 2014

Melting profiles may affect detection of residual HPV L1 gene DNA fragments in
Gardasil Author information Lee SH. Milford Hospital and Milford Molecular
Laboratory 2044 Bridgeport Avenue, Milford, CT 06460, USA shlee01@snet.net
Abstract Gardasil® is a quadrivalent human papillomavirus (HPV) protein-based
vaccine containing genotype-specific L1 capsid proteins of HPV-16, HPV-18,
HPV-6 and HPV-11 in the form of virus-like-particles (VLPs) as the active
ingredient. The VLPs are produced by a DNA recombinant technology. It is
uncertain if the residual HPV L1 gene DNA fragments in the vaccine products are
considered contaminants or excipients of the Gardasil® vaccine. Because naked
viral DNA fragments, if present in the vaccine, may bind to the insoluble
amorphous aluminum hydroxyphosphate sulfate (AAHS) adjuvant which may help
deliver the foreign DNA into macrophages, causing unintended pathophysiologic
effects, experiments were undertaken to develop tests for HPV L1 gene DNA
fragments in the final products of Gardasil® by polymerase chain reaction (PCR)
and direct DNA sequencing. The results showed that while the HPV-11 and HPV-18
L1 gene DNA fragments in Gardasil® were readily amplified by the common
GP6/MY11 degenerate consensus primers, the HPV-16 L1 gene DNA may need
specially designed nondegenerate PCR primers for amplification at different
regions of the L1 gene and different stringency conditions for detection. These
variable melting profiles of HPV DNA in the insoluble fraction of the Gardasil®
vaccine suggest that the HPV DNA fragments are firmly bound to the aluminum
AAHS adjuvant. All methods developed for detecting residual HPV DNA in the
vaccine Gardasil® for quality assurance must take into consideration the
variable melting profiles of the DNA to avoid false negative results.
http://www.ncbi.nlm.nih.gov/pubmed/?term=24083601

“All methods developed for detecting residual HPV DNA in the vaccine Gardasil®
for quality assurance must take into consideration the variable melting
profiles of the DNA to avoid false negative results.”

Journal Of Adolescent Health • March 2014

The role of media and the Internet on vaccine adverse event reporting: a case
study of human papillomavirus vaccination Author information Eberth JM1, Kline
KN2, Moskowitz DA3, Montealegre JR4, Scheurer ME5. 1. South Carolina Cancer
Prevention and Control Program, University of South Carolina Columbia, South
Carolina; Department of Epidemiology and Biostatistics, University of South
Carolina Columbia, South Carolina; Department of Communication, University of
Texas at San Antonio, San Antonio TX 2. Department of Epidemiology and
Biostatistics, University of South Carolina, Columbia, South Carolina
Department of Communication, University of Texas at San Antonio, San Antonio,
Texas 3. Department of Epidemiology and Community Health, New York Medical
College, NY, New York 4. Department of Epidemiology, Human Genetics and
Environmental Sciences, University of Texas School of Public Health, Houston,
Texas; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
5. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas,
Department of Pediatrics Baylor College of Medicine, Houston, Texas Abstract

“We demonstrate that media coverage and Internet search activity, in
particular, may promote increased adverse event reporting. Public health
officials who have long recognized

PURPOSE This study aimed to determine the temporal association of print media
coverage and Internet search activity with adverse events reports associated
with the human papillomavirus vaccine Gardasil (HPV4) and the meningitis
vaccine Menactra (MNQ) among United States adolescents.

the importance of proactive engagement with

METHODS We used moderated linear regression to test the relationships between
print media reports in top circulating newspapers, Internet search activity,
and reports to the Vaccine Adverse Event Reporting System (VAERS) for HPV4 and
MNQ during the first 2.5 years after Food and Drug Administration approval.

meaningful participation in Internet discussions.”

RESULTS Compared with MNQ, HPV4 had more coverage in the print media and
Internet search activity, which corresponded with the frequency of VAERS
reports. In February 2007, we observed a spike in print media for HPV4.
Although media coverage waned, Internet search activity remained stable and
predicted the rise in HPV4-associated VAERS reports. CONCLUSIONS We demonstrate
that media coverage and Internet search activity, in particular, may promote
increased adverse event reporting. Public health officials who have long
recognized the importance of proactive engagement with news media must now
consider strategies for meaningful participation in Internet discussions. Full
Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943880/

news media must now consider strategies for

“Porcine circovirus-1 (PCV1) was recently identified as a contaminant in live Rotavirus vaccines ...”
Vaccine • April 2014

Reduction of spiked porcine circovirus during the manufacture of a Vero
cell-derived vaccine Author information Lackner C, Leydold SM, Modrof J, Farcet
MR, Grillberger L, Schäfer B, Anderle H, Kreil TR. Global Pathogen Safety,
Baxter BioScience, Vienna, Austria Cell Culture Fermentation, Baxter
BioScience, Orth/Donau, Austria Vaccine R&D, Baxter BioScience, Orth/Donau,
Austria Biologicals R&D, Baxter BioScience, Vienna, Austria Global Pathogen
Safety, Baxter BioScience, Vienna, Austria Abstract Porcine circovirus-1 (PCV1)
was recently identified as a contaminant in live Rotavirus vaccines, which was
likely caused by contaminated porcine trypsin. The event triggered the
development of new regulatory guidance on the use of porcine trypsin which
shall ensure that cell lines and porcine trypsin in use are free from PCV1. In
addition, manufacturing processes of biologicals other than live vaccines
include virus clearance steps that may prevent and mitigate any potential virus
contamination of product. In this work, artificial spiking of down-scaled
models for the manufacturing process of an inactivated pandemic influenza virus
vaccine were used to investigate inactivation of PCV1 and the
physico-chemically related porcine parvovirus (PPV) by formalin and
ultraviolet-C (UV-C) treatment as well as removal by the purification step
sucrose gradient ultracentrifugation. A PCV1 infectivity assay, using a
real-time PCR infectivity readout was established. The formalin treatment
(0.05% for 48h) showed substantial inactivation for both PCV1 and PPV with
reduction factors of 3.0log10 and 6.8log10, respectively, whereas UV-C
treatment resulted in complete PPV (≥5.9log10) inactivation already at a dose
of 13mJ/cm but merely 1.7log10 at 24mJ/cm(2) for PCV1. The UV-C inactivation
results with PPV were confirmed using minute virus of mice (MVM), indicating
that parvoviruses are far more sensitive to UV-C than PCV1. The sucrose density
gradient ultracentrifugation also contributed to PCV1 clearance with a
reduction factor of 2log10. The low pH treatment during the production of
procine trypsin was investigated and showed effective inactivation for both
PCV1 (4.5log10) and PPV (6.4log10). In conclusion, PCV1 in general appears to
be more resistant to virus inactivation than PPV. Still, the inactivated
pandemic influenza vaccine manufacturing process provides for robust virus
reduction, in addition to the already implemented testing for PCV1 to avoid any
contaminations. http://www.ncbi.nlm.nih.gov/pubmed/24560672

Vaccine • May 2014

Systematic evaluation of in vitro and in vivo adventitious virus assays for the
detection of viral contamination of cell banks and biological products Author
Information James Gombolda, Stephen Karakasidisa, Paula Niksab, John Podczasya,
Kitti Neumanna, James Richardsonc, Nandini Sanec, Renita Johnson-Levac, Valerie
Randolphd, Jerald Sadoffe, Phillip Minorf, Alexander Schmidtg, Paul Duncanh,
Rebecca L. Sheetsi a .Charles River Laboratories, 358 Technology Drive,
Malvern, PA 19355, United States b. Charles River Laboratories, 251 Ballardvale
St. Wilmington, MA 01887, United States c. Advanced BioScience Laboratories,
9800 Medical Center Dr. Bldg. D, Rockville, MD 20850, United States d. Wyeth,
401N Middletown Rd., Pearl River, NY 10965, United States e. Crucell, Newtonweg
1, 2333 CP Leiden, PO Box 2048, 2301 CA Leiden, The Netherlands f. National
Institute for Biologics Standards and Control, Blanche Lane, South Mimms,
Potters Bar, UK g. GSK Vaccines, Rue de l’Insitut 89, 1330 Rixensart, Belgium
(formerly NIH/NIAID) h. Merck and Co., Inc., WP17-101, 770 Sumneytown Pike,
P.O. Box 4, West Point, PA 19486, United States i. NIH/NIAID Division of AIDS,
6700B Rockledge Dr., Rm. 5145, Bethesda, MD 20892, United States Abstract Viral
vaccines and the cell substrates used to manufacture them are subjected to
tests for adventitious agents, including viruses, contaminate. Some of the
compendial methods (in vivo and in vitro in cell culture) were established in
the mid-20th century. These methods have not been subjected to current assay
validation, as new methods would need to be. This study was undertaken to
provide insight into the breadth (selectivity) and sensitivity (limit of
detection) of the routine methods, two such validation parameters. Sixteen
viral stocks were prepared and characterized. These stocks were tested in
serial dilutions by the routine methods to establish which viruses were
detected by which methods and above what limit of detection. Sixteen out of
sixteen viruses were detected in vitro, though one (bovine viral diarrhea
virus) required special conditions to detect and another (rubella virus) was
detected with low sensitivity. Many were detected at levels below 1 TCID50 or
PFU (titers were established on the production cell line in most cases). In
contrast, in vivo, only 6/11 viruses were detected, and 4 of these were
detected only at amounts one or more logs above 1 TCID50 or PFU. Only influenza
virus and vesicular stomatitis virus were detected at lower amounts in vivo
than in vitro. Given the call to reduce, refine, or replace (3Rs) the use of
animals in product safety testing and the emergence of new technologies for the
detection of viruses, a re-examination of the current adventitious virus
testing strategies seems warranted. Suggested pathways forward are offered.
http://www.sciencedirect.com/science/article/pii/S0264410X14001947

“Given the call to reduce, refine, or replace (3Rs) the use of animals in
product safety testing and the emergence of new technologies for the detection
of viruses, a re-examination of the current adventitious virus testing
strategies seems warranted. Suggested pathways forward are offered.”

“The biopharmaceutical industry continues to face enormous pressure
to accelerate time to market, improve productivity and efficiency, and reduce
costs.” PDA Journal Of Pharmaceutical Science And Technology • July 2014

Advantages of single-use technology for vaccine fill-finish operations Author
information Jenness E, Walker S. Process Solutions, Mobius Product Manager EMD
Millipore Corporation, 80 Ashby Road, Bedford, MA sue.walker@emdmillipore.com
Abstract The biopharmaceutical industry continues to face enormous pressure to
accelerate time to market, improve productivity and efficiency, and reduce
costs. Vaccine manufacturers face additional challenges, including small batch
sizes, varied product portfolios, pandemic outbreaks that require rapid
responses and highly potent ingredients that place large demands on cleaning
processes. Given these pressures, single-use fill-finish assemblies can
represent an attractive option for vaccine manufacturing facilities. This
article describes the implementation of a single-use fill-finish system at a
large vaccine manufacturer. The new assembly enabled flexibility while reducing
set-up time, capital investment, cross-contamination risk, and cleaning
requirements. LAY ABSTRACT Overall the biopharmaceutical industry is constantly
being challenged to bring new products more quickly and efficiently to market
while keeping costs as low as possible. One specific segment of this industry
is the companies that manufacture vaccines. Vaccines present unique challenges
because they tend to be made in smaller amounts for a larger number of
individual products. The products can also be very potent, which can require
special handling methods. Another challenge is the potential outbreak of a
disease that may affect a large area or a large part of the population and
would require immediate action. Single-use assemblies for filling the product
into its final container are an attractive option for vaccine manufacturing
facilities. This article describes the implementation of a single-use filling
system at a large vaccine manufacturer. The new assembly was flexible enough to
meet the demands of the manufacturer while allowing quick and efficient
implementation with low upfront investment.
http://www.ncbi.nlm.nih.gov/pubmed/25035260

Biologicals • September 2014

Adventitious agents in viral vaccines: Lessons learned from 4 case studies
Author Information John Petricciania, Rebecca Sheetsb, Elwyn Griffiths, Ivana
Knezevicd IABS, POB 1925, Palm Springs, CA 92263, USA Grimalkin Partners, 13401
Norden Drive, Silver Spring, MD 20906, USA The Farthings, Kingston Upon Thames,
Surrey KT2 7PT, UK Group Lead, Norms and Standards for Biologicals Department
of Essential Medicines and Health Products (EMP) Health Systems and Innovation
(HIS) Cluster WHO L276, Avenue Appia 20, 1211 Geneva 27, Switzerland Abstract
Since the earliest days of biological product manufacture, there have been a
number of instances where laboratory studies provided evidence for the presence
of adventitious agents in a marketed product. Lessons learned from such events
can be used to strengthen regulatory preparedness for the future. We have
therefore selected four instances where an adventitious agent, or a signal
suggesting the presence of an agent, was found in a viral vaccine, and have
developed a case study for each. The four cases are: a) SV40 in polio vaccines;
b) bacteriophage in measles and polio vaccines; c) reverse transcriptase in
measles and mumps vaccines; and d) porcine circovirus and porcine circovirus
DNA sequences in rotavirus vaccines. The lessons learned from each event are
discussed. Based in part on those experiences, certain scientific principles
have been identified by WHO that should be considered in regulatory risk
evaluation if an adventitious agent is found in a marketed vaccine in the
future. http://www.sciencedirect.com/science/article/pii/S1045105614000748

“We have therefore selected four instances where an adventitious agent, or a
signal suggesting the presence of an agent, was found in a viral vaccine, and
have developed a case study for each. The four cases are: a) SV40 in polio
vaccines; b) bacteriophage in measles and polio vaccines; c) reverse
transcriptase in measles and mumps vaccines; and d) porcine circovirus and
porcine circovirus DNA sequences in rotavirus vaccines.”

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz • October 2014

Viral safety of biological medicinal products Author information Stühler A1,
Blümel J. Paul-Ehrlich-Institut Paul-Ehrlich-Straße 51-59 63225, Langen,
Deutschland Abstract Viral safety of blood donations, plasma products, viral
vaccines and gene therapy medicinal products, biotechnical-derived products and
tissue and cell therapy products is a particular challenge. These products are
manufactured using a variety of human or animal-derived starting materials and
reagents; therefore, extensive testing of donors and of cell banks established
for production is required. Furthermore, the viral safety of reagents, such as
bovine sera, porcine trypsin and human transferrin or albumin needs to be
considered. Whenever possible, manufacturing steps for inactivation or removal
of viruses should be introduced; however, sometimes it is not possible to
introduce such steps for tissues or cell-based medicinal products as the
activity and viability of cells will be compromised. It might be possible to
implement steps for inactivation or removal of potential contaminating
enveloped viruses only for production of small and stable non-enveloped viral
gene vectors. http://www.ncbi.nlm.nih.gov/pubmed/?term=25123140

“Viral safety of blood donations, plasma products, viral vaccines and gene
therapy medicinal products, biotechnical-derived products and tissue and cell
therapy products is a particular challenge.”

Journal Of Pharmaceutical Science • November 2014

Historical Data Analyses and Scientific Knowledge Suggest Complete Removal of
the Abnormal Toxicity Test as a Quality Control Test Joerg H O Garbe,1 Susanne
Ausborn,1 Claire Beggs,2 Martin Bopst,3 Angelika Joos,4 Alexandra A Kitashova,5
OLga Kovbasenco,6 Claus-Dieter Schiller,1 Martina Schwinger,7 Natalia
Semenova,8 Lilia Smirnova,9 Fraser Stodart,10 Thomas Visalli,11 and Lisette
Vromans4 1. F. Hoffmann-La Roche Ltd., Pharma Global Technical Operations,
Basel, Switzerland 2. AbbVie Ltd., Maidenhead, England 3. F. Hoffmann-La Roche
Ltd., Roche Pharma and Early Development, Roche Innovation Center, Basel,
Switzerland 4. MSD Europe Inc., Brussels, Belgium 5. GlaxoSmithKline, Moscow,
Russian Federation 6. Genzyme, Moscow, Russian Federation 7. Novartis Pharma
AG, Basel, Switzerland 8. Bristol-Myers Squibb, Moscow, Russian Federation 9.
MSD Pharmaceuticals, Moscow, Russian Federation 10. Eisai Ltd, Hatfield,
England 11. Eisai Inc, Woodcliff Lake, New Jersey

Abstract In the early 1900s, the abnormal toxicity test (ATT) was developed as
an auxiliary means to ensure safe and consistent antiserum production. Today,
the ATT is utilized as a quality control (QC) release test according to
pharmacopoeial or other regulatory requirements. The study design has not been
changed since around 1940. The evidence of abnormal toxicity testing as a
prediction for harmful batches is highly questionable and lacks a scientific
rationale. Numerous reviews of historical ATT results have revealed that no
reliable conclusions can be drawn from this QC measure. Modern pharmaceutical
manufacturers have thorough control of the manufacturing process and comply
with good manufacturing practice rules. Contaminants are appropriately
controlled by complying with the validated manufacturing processes and strict
QC batch release confirming batch-to-batch consistency. Recognizing that
product safety, efficacy, and stability can be ensured with strict QC measures,
nowadays most regulatory authorities do not require the ATT for most product
classes. In line with the replacement, reduction, and refinement (3Rs)
initiative, the test requirement has been deleted from approximately 80
monographs of the European Pharmacopoeia and for the majority of product
classes in the United States. For these reasons, it is recommended that the ATT
should be consistently omitted world-wide and be removed from pharmacopoeias
and other regulatory requirements.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278562/

[Here, several divisions of F. Hoffman-La Roche Ltd., AbbVie Ltd., divisions of
MSD Europe inc., GlaxoSmithKline, Genzyme, Novartis Pharma AG,
Bristol-Myers-Squibb and divisions of Eisai Ltd., write a report justifying the
removal of the “Abnormal Toxicity Test” as a quality control element of vaccine
production]

Human Vaccines And Immunotherapeutics • 2014

Annual World Vaccine Congress 2014: a re-evaluation of the value proposition
for increasing vaccine thermostability Author information Derwand R. Leukocare
AG; Martinsried Munich, Germany Abstract The 14th Annual World Vaccine Congress
was held in Washington DC, March 24-26, 2014
(http://www.terrapinn.com/vaccine2014). More than 400 experts from different
regions participated in this scientific event for vaccine professionals from
industry, academia, non-profit organizations and government to discuss
challenges and successes from all the major vaccine stakeholders. In more than
70 presentations, round tables, and plenary discussions major topics like
emerging and re-emerging infectious disease, vaccine production, and innovative
technologies were debated. While most contributions focused on specific
questions in vaccine research development, some like the one by a
representative of the Bill and Melinda Gates Foundation (BMGF) reported about
supply chain, logistics topics, and challenges in vaccine implementation.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25483655

“While most contributions focused on specific questions in vaccine research
development, some like the one by a representative of the Bill and Melinda
Gates Foundation (BMGF) reported about supply chain, logistics topics, and
challenges in vaccine implementation.”

Human Vaccines And Immunotherapeutics • 2014

Adjuvants and myeloid-derived suppressor cells: enemies or allies in
therapeutic cancer vaccination Author information Fernández A1, Oliver L,
Alvarez R, Fernández LE, Lee KP, Mesa C. Immunobiology Division Center of
Molecular Immunology; Havana, Cuba Abstract Adjuvants are a critical but
largely overlooked and poorly understood component included in vaccine
formulations to stimulate and modulate the desired immune responses to an
antigen. However, unlike in the protective infectious disease vaccines,
adjuvants for cancer vaccines also need to overcome the effect of tumor-induced
suppressive immune populations circulating in tumor-bearing individuals.
Myeloid-derived suppressor cells (MDSC) are considered to be one of the key
immunosuppressive populations that inhibit tumor-specific T cell responses in
cancer patients. This review focuses on the different signals for the
activation of the immune system induced by adjuvants, and the close
relationship to the mechanisms of recruitment and activation of MDSC. This work
explores the possibility that a cancer vaccine adjuvant may either strengthen
or weaken the effect of tumorinduced MDSC, and the crucial need to address this
in present and future cancer vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25483674

“This work explores the possibility that a cancer vaccine adjuvant may either
strengthen or weaken the effect of tumor-induced Myeloid-derived suppressor
cells ...”

“This may affect the integrity of the adjuvant, alter its interaction with the drug substance
or change the physical characteristics of the drug product.” Journal Of
Pharmaceutical Sciences • February 2015

Shear effects on aluminum phosphate adjuvant particle properties in vaccine
drug products Author information Kolade OO1, Jin W, Tengroth C, Green KD,
Bracewell DG. The Advanced Centre for Biochemical Engineering Department of
Biochemical Engineering University College London, Gordon Street, London WC1H
0AH, UK Abstract Adjuvant-containing drug products can be exposed to high
levels of interfacial shear during manufacture. This may affect the integrity
of the adjuvant, alter its interaction with the drug substance or change the
physical characteristics of the drug product. In this study, a solid-liquid
interfacial shear device was used to investigate the shear response of aluminum
phosphate adjuvant alone and two adjuvant containing vaccine drug products (DP1
and DP2). The relationship between the shear sensitivity of each and its
resuspension properties was determined. Changes in the particle dimensions of
the bulk adjuvant were minimal at shear strain rates of 10,900 s(-1) . However,
at 25,500 s(-1) , the median particle diameter was reduced from 6.2 to 3.5 μm
and was marked by the presence of sub-micron fines. A formulation without drug
substance and DP2 produced similar shear responses but with less impact on
particle diameter. The behavior of DP1 was less predictable. Sheared DP1 was
characterized by prolonged sedimentation because of the presence of fine
particulates and required in excess of 300 rotations to resuspend after
extended storage. The study confirms that the solid-liquid interfacial shear
device may be applied to understand product shear sensitivity associated with
vaccine manufacturing. http://www.ncbi.nlm.nih.gov/pubmed/?term=25175154

“The ability to accurately measure and report trace amounts of residual formaldehyde impurity
in a vaccine product is not only critical in the product release but also a
regulatory requirement.” Journal Of Pharmaceutical And Biomedical Analysis •
March 2015

Determining trace amounts and the origin of formaldehyde impurity in Neisseria
meningitidis A/C/Y/W-135-DT conjugate vaccine formulated in isotonic aqueous 1×
PBS by improved C18-UPLC method Author information Gudlavalleti SK, Crawford
EN, Tran NN, Orten DJ, Harder JD, Reddy JR. JN International Medical
Corporation, 2720 N 84th Street, Omaha, NE 68134 USA Abstract The ability to
accurately measure and report trace amounts of residual formaldehyde impurity
in a vaccine product is not only critical in the product release but also a
regulatory requirement. In many bacterial or viral vaccine manufacturing
procedures, formaldehyde is used either at a live culture inactivation step or
at a protein de-toxification step or at both. Reported here is a validated and
improved C18-UPLC method (developed based on previously published C-8 HPLC
method) to determine the traces of formaldehyde process impurity in a liquid
form Neisseria meningitidis A/C/Y/W-135-DT conjugate vaccine formulated in
isotonic aqueous 1× PBS. UPLC C-18 column and the conditions described
distinctly resolved the 2,4-DNPH-HCHO adduct from the un-reacted 2,4-DNPH as
detected by TUV detector at 360 nm. This method was shown to be compatible with
PBS formulation and extremely sensitive (with a quantitation limit of 0.05 ppm)
and aided to determine formaldehyde contamination sources by evaluating the
in-process materials as a track-down analysis. Final nanogram levels of
formaldehyde in the formulated single dose vialed vaccine mainly originated
from the diphtheria toxoid carrier protein used in the production of the
conjugate vaccine, whereas relative contribution from polysaccharide API was
minimal. http://www.ncbi.nlm.nih.gov/pubmed/25668795

Biologicals • June 2015

Genetic detection and characterization of emerging HoBi-like viruses in
archival foetal bovine serum batches Author Information M. Giammariolia, J.F.
Ridpathb, E. Rossia, M. Bazzucchia, C. Casciaria, G.M. De Miaa a. Istituto
Zooprofilattico Sperimentale dell’Umbria e delle Marche, via Salvemini 1, 06126
Perugia, Italy b. Ruminant Diseases and Immunology Research Unit, National
Animal Disease Center, Agricultural Research Service, U.S. Department of
Agriculture, 1920 Dayton Avenue, Ames, IA 50010, USA Abstract Bovine viral
diarrhea viruses (BVDV) are members of the Pestivirus genus within the family
Flaviviridae. Based on antigenic and nucleotide differences, BVDV are
classified into two recognized species, BVDV-1 and BVDV-2. More recently, a new
putative pestivirus species, tentatively called “HoBi-like”, has been
associated with bovine viral diarrhea. HoBi-like viruses were first identified
in fetal bovine serum (FBS) imported from Brazil. Subsequently, a number of
HoBi-like viruses have been detected as contaminants in FBS or cell culture and
in live ruminants. To further investigate the possible pestivirus contamination
in commercially available FBS batches, 26 batches of FBS with various countries
of origin, were tested in this study for the presence of bovine pestiviruses.
All the 26 batches were positive by RT-PCR for at least one species of bovine
pestiviruses. HoBi-like viruses were detected in 15 batches. Analysis of the
5’UTR and Npro sequences of 15 newly identified HoBi-like viruses combined with
analysis of additional sequences from GenBank, identified 4 genetic groups
tentatively named 3a–3d. The current study confirmed the presence of the
emerging HoBi-like viruses in FBS products labeled with different geographic
origins. This finding has obvious implications for the safety of biological
products, such as cell lines and vaccines.
http://www.sciencedirect.com/science/article/pii/S1045105615000536

“... a new putative pestivirus species, tentatively called “HoBi-like”, has
been associated with bovine viral diarrhea. To further investigate the possible
pestivirus contamination in commercially available Fetal Bovine Serum (FBS)
batches, 26 batches of FBS with various countries of origin, were tested in
this study for the presence of bovine pestiviruses. All the 26 batches were
positive by RT-PCR for at least one species of bovine pestiviruses. HoBi-like
viruses were detected in 15 batches.”

Animal Health Research Reviews • June 2015

Pestivirus control programs: how far have we come and where are we going?
Author information Moennig V1, Becher P1. Department of Infectious
Diseases,Institute for Virology University of Veterinary Medicine Bünteweg
17,D-30559 Hannover,Germany Abstract Classical swine fever (CSF) is endemic in
large parts of the world and it is a major threat to the pig industry in
general. Vaccination and stamping out have been the most successful tools for
the control and elimination of the disease. The systematic use of modified live
vaccines (MLV), which are very efficacious and safe, has often preceded the
elimination of CSF from regions or countries. Oral vaccination using MLV is a
powerful tool for the elimination of CSF from wild boar populations. Bovine
virus diarrhea (BVD) is endemic in bovine populations worldwide and programs
for its control are only slowly gaining ground. With two genotypes BVD virus
(BVDV) is genetically more diverse than CSF virus (CSFV). BVDV crosses the
placenta of pregnant cattle resulting in the birth of persistently infected
(PI) calves. PI animals shed enormous amounts of virus for the rest of their
lives and they are the reservoir for the spread of BVDV in cattle populations.
They are the main reason for the failure of conventional control strategies
based on vaccination only. In Europe two different approaches for the
successful control of BVD are being used: Elimination of PI animals without or
with the optional use of vaccines, respectively.
http://www.ncbi.nlm.nih.gov/pubmed/?term=26050577

“They are the main reason for the failure of conventional control strategies
based on vaccination only. In Europe two different approaches for the
successful control of Bovine virus diarrhea are being used: Elimination of
persistently infected animals without or with the optional use of vaccines,
respectively.”

International Journal Of Nanomedicine • July 2015

Central nervous system toxicity of metallic nanoparticles Xiaoli Feng,1 Aijie
Chen,1 Yanli Zhang,1 Jianfeng Wang,2 Longquan Shao,1 and Limin Wei2 1. Nanfang
Hospital, Southern Medical University Guangzhou, People’s Republic of China 2.
School and Hospital of Stomatology, Wenzhou Medical University Wenzhou,
People’s Republic of China Abstract Nanomaterials (NMs) are increasingly used
for the therapy, diagnosis, and monitoring of disease- or drug-induced
mechanisms in the human biological system. In view of their small size, after
certain modifications, NMs have the capacity to bypass or cross the blood–brain
barrier. Nanotechnology is particularly advantageous in the field of neurology.
Examples may include the utilization of nanoparticle (NP)-based drug carriers
to readily cross the blood–brain barrier to treat central nervous system (CNS)
diseases, nanoscaffolds for axonal regeneration, nanoelectromechanical systems
in neurological operations, and NPs in molecular imaging and CNS imaging.
However, NPs can also be potentially hazardous to the CNS in terms of
nano-neurotoxicity via several possible mechanisms, such as oxidative stress,
autophagy, and lysosome dysfunction, and the activation of certain signaling
pathways. In this review, we discuss the dual effect of NMs on the CNS and the
mechanisms involved. The limitations of the current research are also
discussed. Summary There are still many unanswered questions concerning
nanoneurotoxicity. For instance, after bypassing the BBB, where do NPs go? How
do they leave the brain? The degradation of NP coatings and NP cores inside the
cell environment is an important issue that deserves serious consideration when
designing safe and functional NMs. No results have been reported on this issue
to date. When NPs enter the body, the surface properties of NPs may change by
adsorbing proteins from biological fluids (such as blood, plasma, or
interstitial fluid), leading to a distinct new epitope, for example, protein
corona exposure in the biological microenvironment. Furthermore, serum protein
binding to the NPs can alter the surface charge and accelerate the cellular
uptake of NPs through receptor-regulated endocytosis. However, so far, studies
addressing the cell surface protein corona interactions with NPs remain
limited. Data regarding the distribution of metal-based NPs in the brain
parenchyma are scarce, including data regarding the disruption of the BBB and
adverse brain alterations caused by metal-based NPs. The effects of the
persistence of poorly soluble metal-based NPs are of particular concern, and
few studies have considered the effect of NPs on the CNS. Full Report:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498719/

“The effects of the persistence of poorly soluble metal-based nano-particles
are of particular concern, and few studies have considered the effect of
nano-particles on the Central Nervous System.”

“Endotoxin was present in all tested samples and the final product.”
PDA Journal Of Pharmaceutical Science And Technology • July 2015

Quality Control Testing for Tracking Endotoxin-Producing Gram-Negative Bacteria
during the Preparation of Polyvalent Snake Antivenom Immunoglobulin Author
information Sheraba NS1, Diab MR1, Yassin AS2, Amin MA3, Zedan HH3. Vacsera,
The Holding Company for Biological Products and Vaccines, Giza, Egypt
Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo
University, Cairo, Egypt Abstract Snake bites represent a serious public health
problem, particularly in rural areas worldwide. Antitoxic sera preparations are
antibodies from immunized animals and are considered to be the only treatment
option. The purification of antivenom antibodies should aim at obtaining
products of consistent quality, safety, efficacy, and adherence to good
manufacturing practice principles. Endotoxins are an integral component of the
outer cell surface of Gram-negative bacteria. They are common contaminates of
the raw materials and processing equipment used in the manufacturing of
antivenoms. In this work, and as a part of quality control testing, we
establish and examine an environmental monitoring program for identification of
potential sources of endotoxin-producing Gram-negative bacteria throughout the
whole steps of antivenom preparation. In addition, we follow all the steps of
preparation starting from crude plasma till finished product using a validated
sterility and endotoxin testing.Samples from air, surface, and personnel were
collected and examined through various stages of manufacturing for the
potential presence of Gram-negative bacteria. A validated sterility and
endotoxin test was carried out in parallel at the different production steps.
The results showed that air contributed to the majority of bacterial isolates
detected (48.43%), followed by surfaces (37.5%) and then personnel (14%). The
most common bacterial isolates detected were Achromobacter xylosoxidans,
Ochrobactrum anthropi, and Pseudomonas aeruginosa, which together with
Burkholderia cepacia were both also detected in cleaning water and certain
equipment parts. A heavy bacterial growth with no fungal contamination was
observed in all stages of antivenom manufacturing excluding the formulation
stage. All samples were positive for endotoxin including the

finished product.Implementation and continued evaluation of quality assurance
and quality improvement programs in aseptic preparation is essential in
ensuring the safety and quality of these products. LAY ABSTRACT Antitoxic sera
preparations are the only treatment option for snake bites worldwide. They are
prepared by immunizing animals, usually horses, with snake venom and collecting
horse plasma, which is then subjected to several purification steps in order to
finally prepare the purified immunoglobulins. Components of the bacterial cell
wall known as endotoxins can constitute a potential hazardous contamination
known as pyrogen in antisera, which can lead to fever and many other adverse
reactions to the person subjected to it.In this work, we monitored the
environment associated with the different steps of production and purification
of snake antivenom prepared from immunized horses. We examined the air quality,
surface, and personnel for possible sources of contamination, particularly the
presence of Gram-negative bacteria, which is the major source of endotoxin
presence. We also monitored all stages of preparation by sterility and
endotoxin testing. Our results showed that air contributed to the majority of
bacterial isolates. Sterility testing revealed the presence of bacterial
contamination in all the intermediate steps, as only the final preparation
after filtration was sterile. Endotoxin was present in all tested samples and
the final product. Good manufacturing practice procedures are essential in any
facility involved in antisera production.

http://www.ncbi.nlm.nih.gov/pubmed/26242786

“A possible disadvantage of using human cell lines
is the potential for human-specific viral contamination ...” Critical Reviews
In Biotechnology • September 2015

Human cell lines for biopharmaceutical manufacturing: history, status, and
future perspectives Author information Dumont J1, Euwart D1, Mei B1, Estes S1,
Kshirsagar R1. 1. Biogen, Cambridge, MA, USA Abstract Biotherapeutic proteins
represent a mainstay of treatment for a multitude of conditions, for example,
autoimmune disorders, hematologic disorders, hormonal dysregulation, cancers,
infectious diseases and genetic disorders. The technologies behind their
production have changed substantially since biotherapeutic proteins were first
approved in the 1980s. Although most biotherapeutic proteins developed to date
have been produced using the mammalian Chinese hamster ovary and murine myeloma
(NS0, Sp2/0) cell lines, there has been a recent shift toward the use of human
cell lines. One of the most important advantages of using human cell lines for
protein production is the greater likelihood that the resulting recombinant
protein will bear post-translational modifications (PTMs) that are consistent
with those seen on endogenous human proteins. Although other mammalian cell
lines can produce PTMs similar to human cells, they also produce non-human
PTMs, such as galactose-a 1,3-galactose and N-glycolylneuraminic acid, which
are potentially immunogenic. In addition, human cell lines are grown easily in
a serum-free suspension culture, reproduce rapidly and have efficient protein
production. A possible disadvantage of using human cell lines is the potential
for human-specific viral contamination, although this risk can be mitigated
with multiple viral inactivation or clearance steps. In addition, while human
cell lines are currently widely used for biopharmaceutical research, vaccine
production and production of some licensed protein therapeutics, there is a
relative paucity of clinical experience with human cell lines because they have
only recently begun to be used for the manufacture of proteins (compared with
other types of cell lines). With additional research investment, human cell
lines may be further optimized for routine commercial production of a broader
range of biotherapeutic proteins. http://www.ncbi.nlm.nih.gov/pubmed/26383226

Transplant Infectious Disease • November 2015

High rate of vaccine failure after administration of acellular pertussis
vaccine pre- and post-liver transplantation in children at a children’s
hospital in Japan Author information Ito K1,2, Kasahara M3, Saitoh A1,4, Honda
H5, Miyairi I1. 1. Division of Pediatric Infectious Diseases, Department of
Medical Specialties, National Center for Child Health and Development, Tokyo,
Japan 2. Department of Infectious Diseases, Tokyo Metropolitan Children’s
Medical Center, Tokyo, Japan 3. Division of Transplant Surgery, Department of
Surgical Subspecialties, National Center for Child Health and Development,
Tokyo, Japan 4. Department of Pediatrics, Niigata University Graduate School of
Medical and Dental Science, Niigata, Japan 5. Division of Infectious Diseases,
Tokyo Metropolitan Tama General Medical Center, Tokyo, Japan

Abstract We assessed the serological response to pertussis vaccines
administered pre- and post-liver transplantation in 58 pediatric patients at a
children’s hospital in Japan. A high rate of pertussis vaccine failure was
observed, 44.8% against the pertussis toxin and 69.0% against filamentous
hemagglutinin, with no difference in the seropositivity rate with respect to
the timing of the vaccination during the peritransplant period.
http://www.ncbi.nlm.nih.gov/pubmed/26565897

“A high rate of pertussis vaccine failure was observed, 44.8% against the
pertussis toxin and 69.0% against filamentous hemagglutinin ...”

Chapter Two
Thimerosal • Ethyl Mercury 1972 - 2015 Environmental Sources Of Mercury Mercury
Concentration

Form

Biological Significance

0.4ppb

MetHg

Median chronic intake of contaminated fish (0.4ug/kg body weight) causes
delayed speech and autistic-like symptoms in male children (Corbett & Poor,
2008)

1.6ppb

MetHg

Provisional Tolerable Weekly Intake (PTWI) based on body weight for infants and
pregnant women (1.6ug/kg; Food & Agricultural Association/World Health
Organization 2006)

2.0ppb

Inorganic Mercury

US EPA limit for drinking water (US EPA, 2011)

200ppb

Various

Level in liquid that the US EPA classifies as hazardous waste based on toxocity
characteristics (US EPA, 2010)

600ppb

EtHg

Concentration of mercury in vaccines containing trace amounts of thimerosal
(0.3ug/0.5 ml. dose, or 600ug/L;Halsey, 1999)

25,000-50,000ppb

EtHg

Concentration in Thimerosal containing multi-dose influenza, meningococcal
pneumococcal polysaccharide and diphtheria-tetanus vaccines (Offit & Jew, 2003)

“The ubiquitous and largely unchecked place of Thimerosal in pharmaceuticals,
therefore, represents a medical crisis.” Quoted from:

“A review of Thimerosal (Merthiolate) and its ethyl mercury breakdown product:
specific historical considerations regarding safety and effectiveness” by DA
Geier, LK Sykes and MR Geier

Postgraduate Medical Journal • July 1972

Six cases of poisoning after a parenteral organic mercurial compound
(Merthiolate) J. H. M. Axton
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2495252/?page=5

Bulletin Of The World Health Organization • May 1976

An outbreak of organomercury poisoning among Iraqi farmers Al-Tikriti K,
Al-Mufti AW. Abstract An outbreak of organomercury poisoning due to the
consumption of treated grain by farmers and their families occurred in Iraq in
1971-72. A total of 6530 cases were admitted to hospital and of these 459 died.
However, there were many more with minor symptoms of poisoning who consulted
outpatient departments. This outbreak constituted the largest poisoning
epidemic ever recorded. No age was exempt and no pronounced sex difference was
apparent. The latent period of up to 60 days between dosage and the onset of
symptoms was probably the major factor contributing to the size of the
epidemic. Measures taken to limit the outbreak are outlined. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2366398/

“A total of 6530 cases were admitted to hospital and of these 459 died.”

American Journal Of Obstetrics And Gynecology • October 1976

Mercury toxicity in the pregnant woman, fetus, and newborn infant A review Koos
BJ, Longo LD. Abstract This paper reviews the reported cases of mercury
poisoning in pregnancy and the data based on sources of contamination, maternal
uptake, and distribution. It analyzes current knowledge of placental transfer
of various mercury compounds, fetal uptake, and distribution. It identifies the
embryopathic and fetal toxic effects of mercury in general while emphasizing
the greater toxicity of methylmercury compounds. Since maternal exposure to
methylmercury is primarily through fish consumption, it recommends that women
of childbearing age should not consume more than 350 Gm. of fish per week. In
addition, they should not be occupationally exposed to air concentrations of
mercury vapor greater than 0.01 mg. per cubic meter, of inorganic and
phenylmercuric compounds greater than 0.02 mg. per cubic meter, or any
detectable concentration of methylmercury.
http://www.ncbi.nlm.nih.gov/pubmed/786026

“This paper reviews the reported cases of mercury poisoning in pregnancy and
the data based on sources of contamination, maternal uptake, and distribution.
It analyzes current knowledge of placental transfer of various mercury
compounds, fetal uptake, and distribution.”

British Journal Of Industrial Medicine • May 1982

Elemental mercury exposure: peripheral neurotoxicity Levine SP, Cavender GD,
Langolf GD, Albers JW. Abstract Nerve conduction tests were performed on the
right ulnar nerve of factory workers exposed to elemental mercury vapour. Time
integrated urine mercury indices were used to measure the degree of exposure.
Workers with prolonged distal latencies had significantly higher urine mercury
concentrations when compared with those with normal latencies. Significant
correlations between increasing urine mercury concentrations and prolonged
motor and sensory distal latencies were established. Elemental mercury can
affect both motor and sensory peripheral nerve conduction and the degree of
involvement may be related to time-integrated urine mercury concentrations.
http://www.ncbi.nlm.nih.gov/pubmed/6279139

“Significant correlations between increasing urine mercury concentrations and
prolonged motor and sensory distal latencies were established. Elemental
mercury can affect both motor and sensory peripheral nerve conduction and the
degree of involvement may be related to time-integrated urine mercury
concentrations.”

Annals Of Neurology • November 1988

Neurological abnormalities associated with remote occupational elemental
mercury exposure Author information Albers JW1, Kallenbach LR, Fine LJ, Langolf
GD, Wolfe RA, Donofrio PD, Alessi AG, Stolp-Smith KA, Bromberg MB. Department
of Neurology University of Michigan, Ann Arbor Abstract We examined 502
subjects, 247 of whom had occupational elemental mercury exposures 20 to 35
years previously, to identify potential exposure-related neurological
abnormalities. Few significant (p less than 0.05) differences existed between
exposed and unexposed subjects. However, multiple linear regression analysis
demonstrated several significant correlations between declining neurological
function and increasing exposure as determined by urine mercury measurements
from the exposure interval. Subjects with urine mercury peak levels above 0.6
mg/L demonstrated significantly decreased strength, decreased coordination,
increased tremor, decreased sensation, and increased prevalence of Babinski and
snout reflexes when compared with the remaining subjects. Furthermore, subjects
with clinical polyneuropathy had significantly higher peak levels than normal
subjects (0.85 vs 0.61 mg/L; p = 0.04), but not increased exposure duration
(20.1 vs 20.8 quarters; p = 0.34), and 28% of subjects with peak levels above
0.85 mg/L had clinical evidence of polyneuropathy, compared with 10% of
remaining subjects (p = 0.005). Although exposure was not age dependent,
several neurological measures showed significant agemercury interaction,
suggesting that natural neuronal attrition may unmask prior exposure-related
subclinical abnormalities. http://www.ncbi.nlm.nih.gov/pubmed/2849369

“... multiple linear regression analysis demonstrated several significant
correlations between declining neurological function and increasing exposure as
determined by urine mercury measurements from the exposure interval. Subjects
with urine mercury peak levels above 0.6 mg/L demonstrated significantly
decreased strength, decreased coordination, increased tremor, decreased
sensation, and increased prevalence of Babinski and snout reflexes when
compared with the remaining subjects.”

Journal Of Toxicology And Environmental Health. • 1989

Brain and tissue levels of mercury after chronic methylmercury exposure in the
monkey Author information Rice DC1. Toxicology Research Division Health
Protection Branch Health and Welfare Ottawa, Ontario, Canada Abstract Estimated
half-lives of mercury following methylmercury exposure in humans are 52-93 d
for whole body and 49-164 d for blood. In its most recent 1980 review, the
World Health Organization concluded that there was no evidence to suggest that
brain half-life differed from whole-body half-life. In the present study,
female monkeys (Macaca fascicularis) were dosed for at least 1.7 yr with 10,
25, or 50 micrograms/kg.d of mercury as methylmercuric chloride. Dosing was
discontinued, and blood half-life was determined to be about 14 d.
Approximately 230 d after cessation of dosing, monkeys were sacrificed and
organ and regional brain total mercury levels determined. One monkey that died
while still being dosed had brain mercury levels three times higher than levels
in blood. Theoretical calculations were performed assuming steady-state
brain:blood ratios of 3, 5, or 10. Brain mercury levels were at least three
orders of magnitude higher than those predicted by assuming the half-life in
brain to be the same as that in blood. Estimated half-lives in brain were
between 56 (brain:blood ratio of 3) and 38 (brain: blood ratio of 10) d. In
addition, there was a dose-dependent difference in half-lives for some brain
regions. These data clearly indicate that brain half-life is considerably
longer than blood half-life in the monkey under conditions of chronic dosing.
http://www.ncbi.nlm.nih.gov/pubmed/2499694

“These data clearly indicate that brain half-life is considerably longer than
blood half-life in the monkey under conditions of chronic dosing.”

“This review gives an up-to-date account of mercury’s physical and chemical properties
and its interaction with biologically active sites pertinent to transport
across the blood-brain barrier ...” Neuroscience & Biobehavioral Reviews •
Summer 1990

Mercury neurotoxicity: Mechanisms of blood-brain barrier transport Michael
Aschner *, 1, Judy Lynn Aschner *Department of Pharmacology and Toxicology and
the Interdisciplinary Neuroscience Program Medical College, Albany, NY 12208,
USA †Department of Pediatrics, Division of Neonatal Medicine Albany Medical
College Albany, NY 12208, USA Abstract Mercury exists in a wide variety of
physical and chemical states, each of which has unique characteristics of
target organ toxicity. The classic symptoms associated with exposure to
elemental mercury vapor (Hg0) and methylmercury (Ch3Hg+; MeHg) involve the
central nervous system (CNS), while the kidney is the target organ for the
mono- and divalent salts of mercury (Hg+ and Hg++, respectively). Physical
properties and redox potentials determine the qualitative and quantitative
differences in toxicity among inorganic mercury compounds, while the ability of
MeHg to cross the blood-brain barrier accounts for its accumulation in the CNS
and a clinical picture that is dominated by neurological disturbances. This
review gives an up-to-date account of mercury’s physical and chemical
properties and its interaction with biologically active sites pertinent to
transport across the blood-brain barrier, a major regulator of the CNS millieu.
http://www.sciencedirect.com/science/article/pii/S0149763405802179

Contact Dermatitis • March 1991

A probable role for vaccines containing thimerosal in thimerosal
hypersensitivity Author information Osawa J1, Kitamura K, Ikezawa Z, Nakajima
H. Department of Dermatology Yokohama City University School of Medicine
Kanagawa, Japan Abstract We patch tested 141 patients with 0.05% aq. thimerosal
and 222 patients with 0.05% aq. mercuric chloride, including 63 children. The
frequency of positive patch test reactions to thimerosal was 16.3%. There was a
marked preponderance in the young age groups after vaccination, while none of
36 infants (aged 3-48 months) reacted to thimerosal. Positive reactions to
mercuric chloride were found in 23 (10.4%) of 222 patients. We also sensitized
guinea pigs with diphtheriapertussis-tetanus (DPT) vaccine containing 0.01%
thimerosal and succeeded in inducing hypersensitivity to thimerosal. From patch
testing in humans and animal experiments, it is suggested that 0.01% thimerosal
in vaccines can sensitize children, and that hypersensitivity to thimerosal is
due to the thiosalicylic part of the molecule and correlates with
photosensitivity to piroxicam.
http://www.ncbi.nlm.nih.gov/pubmed/1868700?dopt=Abstract

“... it is suggested that 0.01% thimerosal in vaccines can sensitize children
...”

Environmental Research • February 1993

Psychological effects of low exposure to mercury vapor: application of a
computer-administered neurobehavioral evaluation system Author information
Liang YX1, Sun RK, Sun Y, Chen ZQ, Li LH. Department of Occupational Health
Shanghai Medical University People’s Republic of China Abstract A
computer-administered neurobehavioral evaluation system in a Chinese language
version (NES-C) and a mood inventory of the profile of mood states (POMS) were
applied to assess the psychological effects of low-level exposure to mercury
vapor in a group of 88 workers (19 males and 69 females, with mean age of 34.2
years) exposed to mercury vapor (average duration of exposure 10.4 years). The
well-matched group of 97 nonexposed workers was treated as the control. The
intensity of current mercury vapor was relatively mild as reflected by the
average level of mercury in the air of the workplace (0.033 mg/m3) and in urine
(0.025 mg/liter). The results indicated that the profile of mood states posed
was moving to the negative side in Hg-exposed group and most of the NES-C
performances, in particular, the mental arithmetic, two-digit search, switching
attention, visual choice reaction time, and finger tapping, were also
significantly affected compared with those obtained from controls (P <
0.05-0.01). The present study and the previous study on the validation of the
system suggest that the NES-C we developed is valid for the neurotoxicity
screening among the working population exposed to neurotoxic agents.
http://www.ncbi.nlm.nih.gov/pubmed/8472661

“The results indicated that the profile of mood states posed was moving to the
negative side in mercury-exposed group and most of the NES-C performances, in
particular, the mental arithmetic, two-digit search, switching attention,
visual choice reaction time, and finger tapping, were also significantly
affected compared with those obtained from controls ...”

“... neurotoxic effects of inorganic mercury could be partially due to
the irreversible blockade of voltage-activated calcium channels.” Brain
Research • December 1993

Mercury (Hg2+) decreases voltage-gated calcium channel currents in rat DRG and
Aplysia neurons M. Pekel, B. Platt, D. Büsselberg Abstract Inorganic mercury
(Hg2+) reduced voltage-gated calcium channel currents irreversibility in two
different preparations. In cultured rat dorsal root ganglion (DRG) neurons,
studied with the whole cell patch clamp technique, a rapid
concentration-dependent decrease in the L/N-type currents to a steady state was
observed with an IC50 of 1.1 μM and a Hill coefficient of 1.3 T-currents were
blocked with Hg2+ in the same concentration range (0.5–2 μM). With increasing
Hg2+ concentrations a slow membrane current was additionally activated most
obviously at concentrations over 2 μM Hg2+. This current was irreversible and
might be due to the opening of other (nonspecific) ion channels by Hg2+. The
current-voltage (I–V) relation of DRG neurons shifted to more positive values,
suggesting a binding of Hg2+ to the channel protein and/or modifying its gating
properties. In neurons of the abdominal ganglion of Aplysia californica,
studied with the two electrode voltage clamp technique, a continous decrease of
calcium channel currents was seen even with the lowest used concentration of
Hg2+ (5 μM). A steady state was not reached and the effect was irreversible
without any change on resting membrane currents, even with high concentrations
(up to 50 μM). No shift of the I–V relation of the calcium channel currents was
observed. Effects on voltage-activated calcium channel currents with Hg2+
concentrations such low have not been reported before. We conclude that
neurotoxic effects of inorganic mercury could be partially due to the
irreversible blockade of voltage-activated calcium channels.
http://www.sciencedirect.com/science/article/pii/000689939391146J

European Journal Of Pediatrics • August 1994

Mercury burden of human fetal and infant tissues Author information Drasch G1,
Schupp I, Höfl H, Reinke R, Roider G. Institut für Rechtsmedizin München,
Germany Abstract

“The mercury of fetuses

The total mercury concentrations in the liver (Hg-L), the kidney cortex (Hg-K)
and the cerebral cortex (Hg-C) of 108 children aged 1 day-5 years, and the Hg-K
and HgL of 46 fetuses were determined. As far as possible, the mothers were
interviewed and their dental status was recorded. The results were compared to
mercury concentrations in the tissues of adults from the same geographical
area. The Hg-K (n = 38) and Hg-L (n = 40) of fetuses and Hg-K (n = 35) and Hg-C
(n = 35) of older infants (11-50 weeks of life) correlated significantly with
the number of dental amalgam fillings of the mother. The toxicological
relevance of the unexpected high Hg-K of older infants from mothers with higher
numbers of dental amalgam fillings is discussed.

and mercury of older infants (11-50 weeks of life)

CONCLUSION Future discussion on the pros and cons of dental amalgam should not
be limited to adults or children with their own amalgam fillings, but also
include fetal exposure. The unrestricted application of amalgam for dental
restorations in women before and during the child-bearing age should be
reconsidered.

older infants from mothers with higher numbers

http://www.ncbi.nlm.nih.gov/pubmed/7957411

correlated significantly with the number of dental amalgam fillings of the
mother. The toxicological relevance of the unexpected high kidney cortex of

of dental amalgam fillings is discussed.”

Developmental Brain Research • March 1995

The effect of mercury vapour on cholinergic neurons in the fetal brain: studies
on the expression of nerve growth factor and its low- and high-affinity
receptors Author information Söderström S1, Fredriksson A, Dencker L, Ebendal
T. Department of Developmental Neuroscience Uppsala University, Sweden Abstract
The effects of mercury vapour on the production of nerve growth factor during
development have been examined. Pregnant rats were exposed to two different
concentrations of mercury vapour during either embryonic days E6-E11 (early) or
E13-E18 (late) in pregnancy, increasing the postnatal concentration of mercury
in the brain from 1 ng/g tissue to 4 ng/g tissue (low-dose group) or 11 ng/g
(high-dose group). The effect of this exposure in offspring was determined by
looking at the NGF concentration at postnatal days 21 and 60 and comparing
these levels to age-matched controls from sham-treated mothers. Changes in the
expression of mRNA encoding NGF, the low- and high-affinity receptors for NGF
(p75 and p140 trk, respectively) and choline acetyltransferase (ChAT) were also
determined. When rats were exposed to high levels of mercury vapour during
early embryonic development there was a significant (62%) increase in
hippocampal NGF levels at P21 accompanied by a 50% decrease of NGF in the basal
forebrain. The expression of NGF mRNA was found to be unaltered in the dentate
gyrus. The expression of p75 mRNA was significantly decreased to 39% of control
levels in the diagonal band of Broca (DB) and to approximately 50% in the
medial septal nucleus (MS) whereas no alterations in the level of trk mRNA
expression were detectable in the basal forebrain. ChAT mRNA was slightly
decreased in the DB and MS, significantly in the striatum. These findings
suggest that low levels of prenatal mercury vapour exposure can alter the
levels of the NGF and its receptors, indicating neuronal damage and disturbed
trophic regulations during development.
http://www.ncbi.nlm.nih.gov/pubmed/7781173

“These findings suggest that low levels of prenatal mercury vapour exposure can
alter the levels of the NGF and its receptors, indicating neuronal damage and
disturbed trophic regulations during development.”

Canadian Journal Of Physiology • February 1996

Altered porphyrin metabolism as a biomarker of mercury exposure and toxicity
Author information Woods JS. Department of Environmental Health University of
Washington, Seattle, USA Abstract Changes in urinary porphyrin excretion
patterns (porphyrin profiles) have been described in response to a variety of
drugs and chemicals. The present studies were conducted to define the specific
changes in the urinary porphyrin profile associated with prolonged exposure to
mercury and mercury compounds. In rats, exposure for a prolonged period to
mercury as methyl mercury hydroxide was associated with urinary porphyrin
changes, which were uniquely characterized by highly elevated levels of 4- and
5-carboxyl porphyrins and by the expression of an atypical porphyrin
(“precoproporphyrin”) not found in urine of unexposed animals. These distinct
changes in urinary porphyrin concentrations were observed as early as 1-2 weeks
after initiation of mercury exposure, and increased in a dose- and time-related
fashion with the concentration of mercury in the kidney, a principal target
organ of mercury compounds. Following cessation of mercury exposure, urinary
porphyrin concentrations reverted to normal levels, consistent with renal
mercury clearance. In human studies, a comparable change in the urinary
porphyrin profile was observed among subjects with occupational exposure to
mercury as mercury vapor sufficient to elicit urinary mercury levels greater
than 20 micrograms/L. Urinary porphyrin profiles were also shown to correlate
significantly with mercury body burden and with specific neurobehavioral
deficits associated with low level mercury exposure. These findings support the
utility of urinary porphyrin profiles as a useful biomarker of mercury exposure
and potential health effects in human subjects.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8723034

“These findings support the utility of urinary porphyrin profiles as a useful
biomarker of mercury exposure and potential health effects in human subjects.”

Clinical Neuropathology • May 1996

Demonstration of mercury in the human brain and other organs 17 years after
metallic mercury exposure Author information Opitz H1, Schweinsberg F,
Grossmann T, Wendt-Gallitelli MF, Meyermann R. Department of Neuropathology
University of Tübingen, Germany Abstract A male subject became exposed to
metallic mercury vapor at work in 1973. He excreted 1,850 mg Hg/l urine
initially. Controls of urine mercury excretion after D-penicillamine
administration led to the assumption of a total body clearance of mercury
latest since 1976. Subsequently he developed an organic psychosyndrome without
detectable signs of classical mercurialism. He never returned to work again and
died of lung cancer in 1990. In different organs (brain, kidney, and lung)
which were sampled at autopsy elevated levels of mercury were documented by
atomic absorption analysis. Histological examination of the tissue by the
Danscher and Schroder method, which is specific for mercury, showed a highly
positive staining in the majority of nerve cells and cells of other organs.
Ultrastructurally mercury could be demonstrated by elemental x-ray analysis
within lipofuscin deposits. The lipofuscin content was increased in the mercury
positive nerve cells as demonstrated by a strong positive autofluorescence.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8793247

“He never returned to work again and died of lung cancer in 1990. In different
organs (brain, kidney, and lung) which were sampled at autopsy elevated levels
of mercury were documented by atomic absorption analysis.”

Neurotoxicology • Fall 1996

Effect of subchronic mercury exposure on electrocorticogram of rats Author
information Dési I1, Nagymajtényi L, Schulz H. Department of Public Health
Albert Szent-Györgyi Medical University Szeged, Hungary Abstract Mercury is a
neurotoxic compound causing irreversible disorders of the central and
peripheral nervous system. In some of the previous human and experimental
studies mercury also affected some functional neurological parameters such as
EEG, and cortical evoked potentials. In the present study, the effect of
subchronic (4, 8, and 12 weeks) relatively low-level (0.4, 0.8, and 1.6 mg/kg
mercury in form of HgCl2, per os by gavage) treatment on the basic cortical
activity was investigated. Certain parameters of electrocorticogram (ECoG)
recorded simultaneously from the primary somatosensory, visual and auditory
centres were analyzed. The results showed that mercury had a dose- and
timedependent effect on the examined ECoG parameters, and the changes became
significant by the end of the experiment of week 12.
http://www.ncbi.nlm.nih.gov/pubmed/9086494

“Mercury is a neurotoxic compound causing irreversible disorders of the central
and peripheral nervous system.”

Neurotoxicology And Teratology • November 1997

Cognitive deficit in 7-year-old children with prenatal exposure to
methylmercury Author information Grandjean P1, Weihe P, White RF, Debes F,
Araki S, Yokoyama K, Murata K, Sørensen N, Dahl R, Jørgensen PJ. Institute of
Community Health Odense University, Denmark p.grandjean@winsloew.ou.dk Abstract
A cohort of 1022 consecutive singleton births was generated during 1986-1987 in
the Faroe Islands. Increased methylmercury exposure from maternal consumption
of pilot whale meat was indicated by mercury concentrations in cord blood and
maternal hair. At approximately 7 years of age, 917 of the children underwent
detailed neurobehavioral examination. Neuropsychological tests included Finger
Tapping; HandEye Coordination; reaction time on a Continuous Performance Test;
Wechsler Intelligence Scale for Children-Revised Digit Spans, Similarities, and
Block Designs; Bender Visual Motor Gestalt Test; Boston Naming Test; and
California Verbal Learning Test (Children). Clinical examination and
neurophysiological testing did not reveal any clear-cut mercury-related
abnormalities. However, mercury-related neuropsychological dysfunctions were
most pronounced in the domains of language, attention, and memory, and to a
lesser extent in visuospatial and motor functions. These associations remained
after adjustment for covariates and after exclusion of children with maternal
hair mercury concentrations above 10 microgram(s) (50 nmol/g). The effects on
brain function associated with prenatal methylmercury exposure therefore appear
widespread, and early dysfunction is detectable at exposure levels currently
considered safe. http://www.ncbi.nlm.nih.gov/pubmed/9392777

“The effects on brain function associated with prenatal methylmercury exposure
therefore appear widespread, and early dysfunction is detectable at exposure
levels currently considered safe.”

General Pharmacology • July 1999

Thimerosal: a versatile sulfhydryl reagent, calcium mobilizer, and cell
function-modulating agent Author information Elferink JG. Department of
Molecular Cell Biology, University of Leiden, The Netherlands Abstract An
overview of the literature concerning the effects of thimerosal is presented.
Because of its antibacterial effect, thimerosal is used for a variety of
practical purposes such as antiseptic and preservative. In biomedical studies,
thimerosal is used as a sulfhydryl reagent, and as a calcium-mobilizing agent.
The ability of thimerosal to act as a sulfhydryl group is related to the
presence of mercury. Relatively little study has been devoted to the mechanism
of the reaction of thimerosal with the sulfhydryl group; the sulfhydryl
reactive capacity is mostly concluded on the basis of inactivation of the
effect by dithiothreitol (DTT). Thimersal causes a release of calcium from
intracellular stores in many cells types; this is followed by an influx of
extracellular calcium. Both InsP3- and ryanodine-sensitive calcium stores may
be affected. Studies with permeabilized cells or organelles show that the
effect of thimerosal on calcium is dependent on the concentration: low
concentrations of thimerosal stimulate calcium release, high concentrations are
inhibitory. This dependence is not found in intact cells. Thimerosal may
activate or inhibit a number of cell functions. These are often related to the
ability to release calcium or with the sulfhydryl reactivity. In platelets,
thimerosal causes aggregation, increase of arachidonic acid metabolism, and
exocytotic release of serotonin. In neutrophils, thimerosal causes, besides an
increase of cytosolic free calcium, an increase of
formyl-methionyl-leucyl-phenylalanine (fMLP)-activated leukotriene release, and
a modulation of chemotactic migration and exocytosis. At low concentrations,
thimerosal induces chemotactic migration of neutrophils, in the absence of
other chemoattractants. The effect is also observed with thiosalicylic acid,
indicating that the stimulation of migration was due to the thiosalicylic acid
moiety of the thimerosal molecule. At higher concentrations, thimerosal causes
inhibition of fMLP-activated migration. Low concentrations of thimerosal, but
not of thiosalicylic acid, induced exocytotic enzyme release from neutrophils.
High concentrations of thimerosal inhibited fMLP-activated exocytosis. The
results point to an involvement of calcium mobilization and calcium influx of
activation, and reaction with sulfhydryl groups for inhibition.
http://www.ncbi.nlm.nih.gov/pubmed/?term=10428009

“Thimerosal may activate or inhibit a number of cell functions.”

Journal Of Neurochemistry • January 2000

Mercury induces cell cytotoxicity and oxidative stress and increases
beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells
Author information Olivieri G1, Brack C, Müller-Spahn F, Stähelin HB, Herrmann
M, Renard P, Brockhaus M, Hock C. Neurobiology Laboratory Psychiatric
University Hospital Basel, Switzerland Olivieri@ubaclu.unibas.ch Abstract
Concentrations of heavy metals, including mercury, have been shown to be
altered in the brain and body fluids of Alzheimer’s disease (AD) patients. To
explore potential pathophysiological mechanisms we used an in vitro model
system (SHSY5Y neuroblastoma cells) and investigated the effects of inorganic
mercury (HgCl2) on oxidative stress, cell cytotoxicity, beta-amyloid
production, and tau phosphorylation. We demonstrated that exposure of cells to
50 microg/L (180 nM) HgCl2 for 30 min induces a 30% reduction in cellular
glutathione (GSH) levels (n = 13, p<0.001). Preincubation of cells for 30 min
with 1 microM melatonin or premixing melatonin and HgCl2 appeared to protect
cells from the mercury-induced GSH loss. Similarly,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity
assays revealed that 50 microg/L HgCl2 for 24 h produced a 50% inhibition of
MTT reduction (n = 9, p<0.001). Again, melatonin preincubation protected cells
from the deleterious effects of mercury, resulting in MTT reduction equaling
control levels. The release of beta-amyloid peptide (Abeta) 1-40 and 1-42 into
cell culture supernatants after exposure to HgCl2 was shown to be different:
Abeta 1-40 showed maximal (15.3 ng/ml) release after 4 h, whereas Abeta 1-42
showed maximal (9.3 ng/ml) release after 6 h of exposure to mercury compared
with untreated controls (n = 9, p<0.001). Preincubation of cells with melatonin
resulted in an attenuation of Abeta 1-40 and Abeta 1-42 release. Tau
phosphorylation was significantly increased in the presence of mercury (n = 9,
p<0.001), whereas melatonin preincubation reduced the phosphorylation to
control values. These results indicate that mercury may play a role in
pathophysiological mechanisms of AD.
http://www.ncbi.nlm.nih.gov/pubmed/10617124

“These results indicate that mercury may play a role in pathophysiological
mechanisms of Alzheimer’s disease.”

Journal Of Pediatrics • May 2000

Iatrogenic exposure to mercury after hepatitis B vaccination in preterm infants
Author information Stajich GV1, Lopez GP, Harry SW, Sexson WR. Mercer
University Southern School of Pharmacy Atlanta, Georgia 30341, USA Abstract
Thimerosal, a derivative of mercury, is used as a preservative in hepatitis B
vaccines. We measured total mercury levels before and after the administration
of this vaccine in 15 preterm and 5 term infants. Comparison of pre- and
post-vaccination mercury levels showed a significant increase in both preterm
and term infants after vaccination. Additionally, post-vaccination mercury
levels were significantly higher in preterm infants as compared with term
infants. Because mercury is known to be a potential neurotoxin to infants,
further study of its pharmacodynamics is warranted.
http://www.ncbi.nlm.nih.gov/pubmed/10802503

“Comparison of pre- and post-vaccination mercury levels showed a significant
increase in both preterm and term infants after vaccination.”

MMWR Morbidity And Mortality Weekly Report • July 14, 2000

Summary of the joint statement on thimerosal in vaccines American Academy of
Family Physicians American Academy of Pediatrics Advisory Committee on
Immunization Practices Public Health Service Centers for Disease Control and
Prevention (CDC)

“AAFP, AAP, ACIP, and PHS recommend continuation of the

Abstract

current policy of moving rapidly to

In June 2000, a joint statement on thimerosal in vaccines was prepared by the
American Academy of Family Physicians (AAFP), the American Academy of
Pediatrics (AAP), the Advisory Committee on Immunization Practices (ACIP), and
the Public Health Service (PHS) in response to 1) the progress in achieving the
national goal declared in July 1999 to remove thimerosal from vaccines in the
recommended childhood vaccination schedule, and 2) results of recent studies
that examined potential associations between exposure to mercury in
thimerosal-containing vaccines and health effects. In this statement, AAFP,
AAP, ACIP, and PHS recommend continuation of the current policy of moving
rapidly to vaccines that are free of thimerosal as a preservative. Until
adequate supplies are available, use of vaccines that contain thimerosal as a
preservative is acceptable.

vaccines that are free of thimerosal

http://www.ncbi.nlm.nih.gov/pubmed/?term=10914930

as a preservative. Until adequate supplies are available, use of vaccines that
contain thimerosal as a preservative is acceptable.”

Drugs • 2001

Vaccines without thiomersal: why so necessary, why so long coming? Author
information van’t Veen AJ. Department of Dermatology and Venereology Erasmus
University Hospital Rotterdam-Dijkzigt Rotterdam, The Netherlands Abstract The
inorganic mercurial thiomersal (merthiolate) has been used as an effective
preservative in numerous medical and non-medical products since the early
1930s. Both the potential toxicity of thiomersal and sensitisation to
thiomersal in relation to the application of thiomersal-containing vaccines and
immunoglobulins, especially in children, have been debated in the literature.
The very low thiomersal concentrations in pharmacological and biological
products are relatively non-toxic, but probably not in utero and during the
first 6 months of life. The developing brain of the fetus is most susceptible
to thiomersal and, therefore, women of childbearing age, in particular, should
not receive thiomersal-containing products. Definitive data of doses at which
developmental effects occur are not available. Moreover, revelation of subtle
effects of toxicity needs long term observation of children. The ethylmercury
radical of the thiomersal molecule appears to be the prominent sensitiser. The
prevalence of thiomersal hypersensitivity in mostly selected populations varies
up to 18%, but higher figures have been reported. The overall exposure to
thiomersal differs considerably between countries. In many cases a positive
routine patch test to thiomersal should be considered an accidental finding
without or, probably more accurately, with low clinical relevance. In practice,
some preventive measures can be taken with respect to thiomersal
hypersensitivity. However, with regard to the debate on primary sensitisation
during childhood and renewed attention for a reduction of children’s exposure
to mercury from all sources, the use of thiomersal should preferably be
eliminated or at least be reduced. In 1999 the manufacturers of vaccines and
immunoglobulins in the US and Europe were approached with this in mind. The
potential toxicity in children seems to be of much more concern to them than
the hidden sensitising properties of thiomersal. In The Netherlands, unlike
many other countries, the exposure to thiomersal from pharmaceutical sources
has already been reduced. Replacement of thiomersal in all products should have
a high priority in all countries.
http://www.ncbi.nlm.nih.gov/pubmed/?term=11368282

“The potential toxicity in children seems to be of much more concern to them
[the vaccine manufacturers] than the hidden sensitising properties of
thiomersal. Replacement of thiomersal in all products should have a high
priority in all countries. In 1999 the manufacturers of vaccines and
immunoglobulins in the US and Europe were approached with this in mind.”

Medical Hypotheses • April 2001

Autism: a novel form of mercury poisoning Author information Bernard S1,
Enayati A, Redwood L, Roger H, Binstock T. ARC Research, Cranford, New Jersey
07901, USA Abstract Autism is a syndrome characterized by impairments in social
relatedness and communication, repetitive behaviors, abnormal movements, and
sensory dysfunction. Recent epidemiological studies suggest that autism may
affect 1 in 150 US children. Exposure to mercury can cause immune, sensory,
neurological, motor, and behavioral dysfunctions similar to traits defining or
associated with autism, and the similarities extend to neuroanatomy,
neurotransmitters, and biochemistry. Thimerosal, a preservative added to many
vaccines, has become a major source of mercury in children who, within their
first two years, may have received a quantity of mercury that exceeds safety
guidelines. A review of medical literature and US government data suggests
that: (i) many cases of idiopathic autism are induced by early mercury exposure
from thimerosal; (ii) this type of autism represents an unrecognized mercurial
syndrome; and (iii) genetic and non-genetic factors establish a predisposition
whereby thimerosal’s adverse effects occur only in some children.
http://www.ncbi.nlm.nih.gov/pubmed/11339848

“A review of medical literature and US government data suggests that many cases
of idiopathic autism are induced by early mercury exposure from thimerosal.”

Neuroreport • May 2001

Retrograde degeneration of neurite membrane structural integrity of nerve
growth cones following in vitro exposure to mercury Author information Leong
CC1, Syed NI, Lorscheider FL. Faculty of Medicine Department of Physiology and
Biophysics University of Calgary, Alberta, Canada Abstract Inhalation of
mercury vapor (Hg0) inhibits binding of GTP to rat brain tubulin, thereby
inhibiting tubulin polymerization into microtubules. A similar molecular lesion
has also been observed in 80% of brains from patients with Alzheimer disease
(AD) compared to age-matched controls. However the precise site and mode of
action of Hg ions remain illusive. Therefore, the present study examined
whether Hg ions could affect membrane dynamics of neurite growth cone
morphology and behavior. Since tubulin is a highly conserved cytoskeletal
protein in both vertebrates and invertebrates, we hypothesized that growth
cones from animal species could be highly susceptible to Hg ions. To test this
possibility, the identified, large Pedal A (PeA) neurons from the central ring
ganglia of the snail Lymnoea stagnalis were cultured for 48 h in 2 ml brain
conditioned medium (CM). Following neurite outgrowth, metal chloride solution
(2 microl) of Hg, Al, Pb, Cd, or Mn (10(7) M) was pressure applied directly
onto individual growth cones. Time-lapse images with inverted microscopy were
acquired prior to, during, and after the metal ion exposure. We demonstrate
that Hg ions markedly disrupted membrane structure and linear growth rates of
imaged neurites in 77% of all nerve growth cones. When growth cones were
stained with antibodies specific for both tubulin and actin, it was the
tubulin/microtubule structure that disintegrated following Hg exposure.
Moreover, some denuded neurites were also observed to form neurofibrillary
aggregates. In contrast, growth cone exposure to other metal ions did not
effect growth cone morphology, nor was their motility rate compromised. To
determine the growth suppressive effects of Hg ions on neuronal sprouting,
cells were cultured either in the presence or absence of Hg ions. We found that
in the presence of Hg ions, neuronal somata failed to sprout, whereas other
metalic ions did not effect growth patterns of cultured PeA cells. We conclude
that this visual evidence and previous biochemical data strongly implicate Hg
as a potential etiological factor in neurodegeneration.
http://www.ncbi.nlm.nih.gov/pubmed/?term=11277574

“We found that in the presence of mercury ions, neuronal somata failed to
sprout, whereas other metalic ions did not effect growth patterns of cultured
PeA cells. We conclude that this visual evidence and previous biochemical data
strongly implicate mercury as a potential etiological factor in
neurodegeneration.”

Neurotoxicology • October 2001

Predicted mercury concentrations in hair from infant immunizations: cause for
concern Author information Redwood L1, Bernard S, Brown D. Coalition for Safe
Minds, Cranford, NJ 07016, USA tlredwood@mindspring.com Abstract Mercury (Hg)
is considered one of the worlds most toxic metals. Current thinking suggests
that exposure to mercury occurs primarily from seafood contamination and rare
catastrophic events. Recently, another common source of exposure has been
identified. Thimerosal (TMS), a preservative found in many infant vaccines,
contains 49.6% ethyl mercury (EtHg) by weight and typically contributes 25
microg of EtHg per dose of infant vaccine. As part of an ongoing review, the
Food and Drug Administration (FDA) announced in 1999 that infants who received
multiple TMS-preserved vaccines may have been exposed to cumulative Hg in
excess of Federal safety guidelines. According to the centers for disease
control (CDC) recommended immunization schedule, infants may have been exposed
to 12.5 microg Hg at birth, 62.5 microg EtHg at 2 months, 50 microg EtHg at 4
months, 62.5 microg EtHg at 6 months, and 50 microg EtHg at approximately 18
months, for a total of 237.5 microg EtHg during the first 18 months of life, if
all TMS-containing vaccines were administered. Neurobehavioral alterations,
especially to the more susceptible fetus and infant, are known to occur after
relatively low dose exposures to organic mercury compounds. In effort, to
further elucidate the levels of ethyl mercury resulting from exposure to
vaccinal TMS, we estimated hair Hg concentrations expected to result from the
recommended CDC schedule utilizing a one compartment pharmacokinetic model.
This model was developed to predict hair concentrations from acute exposure to
methymercury (MeHg) in fish. Modeled hair Hg concentrations in infants exposed
to vaccinal TMS are in excess of the Environmental Protection Agency (EPA)
safety guidelines of 1 ppm for up to 365 days, with several peak concentrations
within this period. More sensitive individuals and those with additional
sources of exposure would have higher Hg concentrations. Given that exposure to
low levels of mercury during critical stages of development has been associated
with neurological disorders in children, including ADD, learning difficulties,
and speech delays, the predicted hair Hg concentration resulting from childhood
immunizations is cause for concern. Based on these findings, the impact which
vaccinal mercury has had on the health of American children warrants further
investigation. http://www.ncbi.nlm.nih.gov/pubmed/?term=11770890

“Given that exposure to low levels of mercury during critical stages of
development has been associated with neurological disorders in children,
including ADD, learning difficulties, and speech delays, the predicted hair
ethyl mercury concentration resulting from childhood immunizations is cause for
concern.”

Molecular Psychiatry • 2002

The role of mercury in the pathogenesis of autism S Bernard, A Enayati, H
Roger, T Binstock and L Redwood Safe Minds, Cranford, NJ, USA Autism Spectrum
Disorder (ASD) is a neurodevelopmental disorder of unknown etiology in most
cases. Studies of monozygotic twins report an average 60% concordance rate,
indicating a role for both genetic and environmental factors in disease
expression.1 Recent reviews in environmental health have suggested that early
exposure to hazardous substances may underlie some cases of neurodevelopmental
disorders, including ADHD, learning disabilities, and speech/language
difficulties.2 In 1999, thimerosal used as a vaccine preservative was
identified as a widespread source of organic mercury exposure in infants.3
Mercury (Hg), a heavy metal, is considered highly neurotoxic.4 The amount of
mercury in vaccines, while small, exceeded USEPA safety guidelines on a
cumulative basis.3 Certain individuals may exhibit severe adverse reactions to
low doses of Hg which are otherwise largely benign to the majority of those
exposed.5 Some individuals with idiopathic autism spectrum disorder may
represent such a sensitive population. As summarized in this paper, disease
characteristics suggest this possibility: (a) ASD traits are known to arise
from mercury exposure; (b) onset of ASD symptoms is temporally associated with
administration of immunizations; (c) the reported increase in the prevalence of
autism in the 1990s closely follows the introduction of two mercury-containing
vaccines; and (d) elevated mercury has been detected in biological samples of
autistic patients. Since ASD may now affect as many as one in 150 US children,6
and since thimerosal is still used in many products worldwide, confirmation of
thimerosal as an environmental agent in autism pathogenesis has important
societal and patient implications. Full Report
http://www.nature.com/mp/journal/v7/n2s/pdf/4001177a.pdf

“... onset of ASD symptoms is temporally associated with administration of
immunizations; the reported increase in the prevalence of autism in the 1990s
closely follows the introduction of two mercury-containing vaccines; and
elevated mercury has been detected in biological samples of autistic patients.”

Genes And Immunity • August 2002

Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a
major role of mitochondrial pathway Author information Makani S1, Gollapudi S,
Yel L, Chiplunkar S, Gupta S. Cellular and Molecular Immunology Laboratories
Division of Basic and Clinical Immunology University of California, Irvine
92697, USA Abstract The major source of thimerosal (ethyl mercury
thiosalicylate) exposure is childhood vaccines. It is believed that the
children are exposed to significant accumulative dosage of thimerosal during
the first 2 years of life via immunization. Because of health-related concerns
for exposure to mercury, we examined the effects of thimerosal on the
biochemical and molecular steps of mitochondrial pathway of apoptosis in Jurkat
T cells. Thimerosal and not thiosalcylic acid (non-mercury component of
thimerosal), in a concentration-dependent manner, induced apoptosis in T cells
as determined by TUNEL and propidium iodide assays, suggesting a role of
mercury in T cell apoptosis. Apoptosis was associated with depolarization of
mitochondrial membrane, release of cytochrome c and apoptosis inducing factor
(AIF) from the mitochondria, and activation of caspase9 and caspase-3, but not
of caspase-8. In addition, thimerosal in a concentration-dependent manner
inhibited the expression of XIAP, cIAP-1 but did not influence cIAP-2
expression. Furthermore, thimerosal enhanced intracellular reactive oxygen
species and reduced intracellular glutathione (GSH). Finally, exogenous
glutathione protected T cells from thimerosal-induced apoptosis by upregulation
of XIAP and cIAP1 and by inhibiting activation of both caspase-9 and caspase-3.
These data suggest that thimerosal induces apoptosis in T cells via
mitochondrial pathway by inducing oxidative stress and depletion of GSH.
http://www.ncbi.nlm.nih.gov/pubmed/?term=12140745

“The major source of thimerosal (ethyl mercury thiosalicylate) exposure is
childhood vaccines. It is believed that the children are exposed to significant
accumulative dosage of thimerosal during the first 2 years of life via
immunization. These data suggest that thimerosal induces apoptosis in T cells
via mitochondrial pathway by inducing oxidative stress and depletion of
intracellular glutathione.”

Society for Experimental Biology and Medicine • 2003

Neurodevelopmental Disorders after Thimerosal-Containing Vaccines: A Brief
Communication Mark Geier And David A. Geier The Genetic Centers of America
Silver Spring, Maryland 20905 Abstract We were initially highly skeptical that
differences in the concentrations of thimerosal in vaccines would have any
effect on the incidence rate of neurodevelopmental disorders after childhood
immunization. This study presents the first epidemiologic evidence, based upon
tens of millions of doses of vaccine administered in the United States, that
associates increasing thimerosal from vaccines with neurodevelopmental
disorders. Specifically, an analysis of the Vaccine Adverse Events Reporting
System (VAERS) database showed statistical increases in the incidence rate of
autism (relative risk [RR] = 6.0), mental retardation (RR = 6.1), and speech
disorders (RR = 2.2) after thimerosalcontaining diphtheria, tetanus, and
acellular pertussis (DTaP) vaccines in comparison with thimerosal-free DTaP
vaccines. The male/female ratio indicated that autism (17) and speech disorders
(2.3) were reported more in males than females after thimerosal-containing DTaP
vaccines, whereas mental retardation (1.2) was more evenly reported among male
and female vaccine recipients. Controls were employed to determine if biases
were present in the data, but none were found. It was determined that overall
adverse reactions were reported in similar-aged populations after
thimerosal-containing DTaP (2.4 ± 3.2 years old) and thimerosal-free DTaP (2.1
± 2.8 years old) vaccinations. Acute control adverse reactions such as deaths
(RR = 1.0), vasculitis (RR = 1.2), seizures (RR = 1.6), ED visits (RR = 1.4),
total adverse reactions (RR = 1.4), and gastroenteritis (RR = 1.1) were
reported similarly after thimerosal- containing and thimerosal-free DTaP
vaccines. An association between neurodevelopmental disorders and
thimerosal-containing DTaP vaccines was found, but additional studies should be
conducted to confirm and extend this study. In recent years, thimerosal, an
organic mercury compound that is metabolized to ethylmercury and thiosalicylate
and has been present since the 1930s as a preservative in some vaccines and
pharmaceutical products to prevent bacterial and fungal contamination, has come
under scrutiny. It was determined by the U.S. Food and Drug Administration
(FDA) in 1999 under the recommended childhood immunization schedule that
infants might be exposed to cumulative doses of ethylmercury that exceed some
federal safety guidelines established for exposure to methylmercury, another
form of organic mercury (1). The hypothesis that exposure to
thimerosal-containing vaccines could be associated with neurodevelopmental
disorders is not established and rests on indirect and incomplete information,
primarily from analogies with methylmercury and levels of maximum mercury
exposure from vaccines given in children. The hypothesis is biologically
possible, but the possible relationship between thimerosal from vaccines and
neurodevelopmental disorders of autism, attention deficit/hyperactivity
disorder (ADHD), and speech or language delay remains seriously suspect. As of
the present, there are no peer-reviewed epidemiological studies in the
scientific literature examining the potential association between
thimerosal-containing vaccines and neurodevelopmental disorders. Here, we show
the first epidemiologic evidence, based upon tens of millions of doses of
vaccine administered in the United States, that associates increasing
thimerosal from vaccines with neurodevelopmental disorders. Full Report:
http://www.autismhelpforyou.com/EXPERT%20PAPER%20-%20Geier%20-%20Internet%20File.pdf

“... we show the first epidemiologic evidence, based upon tens of millions of
doses of vaccine administered in the United States, that associates increasing
thimerosal from vaccines with neurodevelopmental disorders.”

Neurotoxic Research • February 2003

Neurotoxicity of organomercurial compounds Author information Sanfeliu C1,
Sebastià J, Cristòfol R, Rodríguez-Farré E. Department of Pharmacology and
Toxicology Institut d’Investigacions Biomèdiques de Barcelona, CSIC, IDIBAPS
Rossellò 161, 08036 Barcelona, Spain cspfat@iibb.csic.es Abstract Mercury is a
ubiquitous contaminant, and a range of chemical species is generated by human
activity and natural environmental change. Elemental mercury and its inorganic
and organic compounds have different toxic properties, but all them are
considered hazardous in human exposure. In an equimolecular exposure basis,
organomercurials with a short aliphatic chain are the most harmful compounds
and they may cause irreversible damage to the nervous system. Methylmercury
(CH(3)Hg(+)) is the most studied following the neurotoxic outbreaks identified
as Minamata disease and the Iraq poisoning. The first description of the CNS
pathology dates from 1954. Since then, the clinical neurology, the
neuropathology and the mechanisms of neurotoxicity of organomercurials have
been widely studied. The high thiol reactivity of CH(3)Hg(+), as well as all
mercury compounds, has been suggested to be the basis of their harmful
biological effects. However, there is clear selectivity of CH(3)Hg(+) for
specific cell types and brain structures, which is not yet fully understood.
The main mechanisms involved are inhibition of protein synthesis, microtubule
disruption, increase of intracellular Ca(2+) with disturbance of
neurotransmitter function, oxidative stress and triggering of excitotoxicity
mechanisms. The effects are more damaging during CNS development, leading to
alterations of the structure and functionality of the nervous system. The major
source of CH(3)Hg(+) exposure is the consumption of fish and, therefore, its
intake is practically unavoidable. The present concern is on the study of the
effects of low level exposure to CH(3)Hg(+) on human neurodevelopment, with a
view to establishing a safe daily intake. Recommendations are 0.4 micro g/kg
body weight/day by the WHO and US FDA and, recently, 0.1 micro g/kg body
weight/day by the US EPA. Unfortunately, these levels are easily attained with
few meals of fish per week, depending on the source of the fish and its
position in the food chain. http://www.ncbi.nlm.nih.gov/pubmed/12835120

“Elemental mercury and its inorganic and organic compounds have different toxic
properties, but all them are considered hazardous in human exposure.
Recommendations are 0.4 micro g/kg body weight/day by the WHO and US FDA and,
recently, 0.1 micro g/kg body weight/day by the US EPA. Unfortunately, these
levels are easily attained with few meals of fish per week, depending on the
source of the fish and its position in the food chain.”

“The evidence presented here shows that the occurrence of neurodevelopmental disorders
following thimerosal-containing childhood vaccines does not appear to be
coincidental.” Pediatric Rehabilitation • April 2003

An assessment of the impact of thimerosal on childhood neurodevelopmental
disorders Author information Geier DA1, Geier MR. The Genetic Centers of
America 14 Redgate Court, Silver Spring, MD 20905, USA Abstract The prevalence
of autism in the US has risen from 1 in approximately 2500 in the mid-1980s to
1 in approximately 300 children in the mid-1990s. The purpose of this study was
to evaluate whether mercury from thimerosal in childhood vaccines contributed
to neurodevelopmental disorders. Neurodevelopmental disorder dose-response
curves for increasing mercury doses of thimerosal in childhood vaccines were
determined based upon examination of the Vaccine Adverse Events Reporting
System (VAERS) database and the 2001 US’ Department of Education Report. The
instantaneous dosage of mercury children received in comparison to the Food and
Drug Administration (FDA)’s maximum permissible dose for the oral ingestion of
methylmercury was also determined. The dose-response curves showed increases in
odds ratios of neurodevelopmental disorders from both the VAERS and US
Department of Education data closely linearly correlated with increasing doses
of mercury from thimerosalcontaining childhood vaccines and that for overall
odds ratios statistical significance was achieved. Similar slopes and linear
regression coefficients for autism odds ratios in VAERS and the US Department
of Education data help to mutually validate each other. Controls employed in
the VAERS and US Department of Education data showed minimal biases. The
evidence presented here shows that the occurrence of neurodevelopmental
disorders following thimerosal-containing childhood vaccines does not appear to
be coincidental. http://www.ncbi.nlm.nih.gov/pubmed/14534046

“An association between neurodevelopmental disorders
and thimerosal-containing DTaP vaccines was found ...” Experiments In
Biological Medicine • June 2003

Neurodevelopmental disorders after thimerosal-containing vaccines: a brief
communication Author information Geier MR1, Geier DA. The Genetic Centers of
America, Silver Spring, Maryland 20905, USA mgeier@erols.com Abstract We were
initially highly skeptical that differences in the concentrations of thimerosal
in vaccines would have any effect on the incidence rate of neurodevelopmental
disorders after childhood immunization. This study presents the first
epidemiologic evidence, based upon tens of millions of doses of vaccine
administered in the United States, that associates increasing thimerosal from
vaccines with neurodevelopmental disorders. Specifically, an analysis of the
Vaccine Adverse Events Reporting System (VAERS) database showed statistical
increases in the incidence rate of autism (relative risk [RR] = 6.0), mental
retardation (RR = 6.1), and speech disorders (RR = 2.2) after
thimerosal-containing diphtheria, tetanus, and acellular pertussis (DTaP)
vaccines in comparison with thimerosal-free DTaP vaccines. The male/female
ratio indicated that autism (17) and speech disorders (2.3) were reported more
in males than females after thimerosal-containing DTaP vaccines, whereas mental
retardation (1.2) was more evenly reported among male and female vaccine
recipients. Controls were employed to determine if biases were present in the
data, but none were found. It was determined that overall adverse reactions
were reported in similar-aged populations after thimerosal-containing DTaP (2.4
+/- 3.2 years old) and thimerosal-free DTaP (2.1 +/- 2.8 years old)
vaccinations. Acute control adverse reactions such as deaths (RR = 1.0),
vasculitis (RR = 1.2), seizures (RR = 1.6), ED visits (RR = 1.4), total adverse
reactions (RR = 1.4), and gastroenteritis (RR = 1.1) were reported similarly
after thimerosal-containing and thimerosal-free DTaP vaccines. An association
between neurodevelopmental disorders and thimerosal-containing DTaP vaccines
was found, but additional studies should be conducted to confirm and extend
this study. http://www.ncbi.nlm.nih.gov/pubmed/12773696

Environmental Toxicology • June 2003

Environmental exposure to mercury and its toxicopathologic implications for
public health Author information Tchounwou PB1, Ayensu WK, Ninashvili N, Sutton
D. Cellomics and Toxicogenomics Research Laboratory NIH Center for
Environmental Health, School of Science and Technology Jackson State
University, 1400 Lynch Street, Box 18540 Jackson, Mississippi 39217, USA.
paul.b.tchounwou@jsums.edu Abstract Mercury is a toxic and hazardous metal that
occurs naturally in the earth’s crust. Natural phenomena such as erosion and
volcanic eruptions, and anthropogenic activities like metal smelting and
industrial production and use may lead to substantial contamination of the
environment with mercury. Through consumption of mercury in food, the
populations of many areas, particularly in the developing world, have been
confronted with catastrophic outbreaks of mercury-induced diseases and
mortality. Countries such as Japan, Iraq, Ghana, the Seychelles, and the Faroe
Islands have faced such epidemics, which have unraveled the insidious and
debilitating nature of mercury poisoning. Its creeping neurotoxicity is highly
devastating, particularly in the central and peripheral nervous systems of
children. Central nervous system defects and erethism as well as arrythmias,
cardiomyopathies, and kidney damage have been associated with mercury exposure.
Necrotizing bronchitis and pneumonitis arising from inhalation of mercury vapor
can result in respiratory failure. Mercury is also considered a potent
immunostimulant and -suppressant, depending on exposure dose and individual
susceptibility, producing a number of pathologic sequelae including
lymphoproliferation, hypergammaglobulinemia, and total systemic hyper- and
hyporeactivities. In this review we discuss the sources of mercury and the
potential for human exposure; its biogeochemical cycling in the environment;
its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health
effects; and the dietary influences on its toxicity; as well as the important
considerations in risk assessment and management of mercury poisoning.
http://www.ncbi.nlm.nih.gov/pubmed/12740802

“Its creeping neurotoxicity is highly devastating, particularly in the central
and peripheral nervous systems of children.”

“... the present study provides further insight into one possible mechanism
by which early mercury exposures could increase the risk of autism.”
International Journal Of Toxicology • July 2003

Reduced levels of mercury in first baby haircuts of autistic children Author
information Holmes AS1, Blaxill MF, Haley BE. SafeMinds, Cambridge,
Massachusetts, USA Abstract Reported rates of autism have increased sharply in
the United States and the United Kingdom. One possible factor underlying these
increases is increased exposure to mercury through thimerosal-containing
vaccines, but vaccine exposures need to be evaluated in the context of
cumulative exposures during gestation and early infancy. Differential rates of
postnatal mercury elimination may explain why similar gestational and infant
exposures produce variable neurological effects. First baby haircut samples
were obtained from 94 children diagnosed with autism using Diagnostic and
Statistical Manual of Mental Disorders, 4th edition (DSM IV) criteria and 45
age- and gender-matched controls. Information on diet, dental amalgam fillings,
vaccine history, Rho D immunoglobulin administration, and autism symptom
severity was collected through a maternal survey questionnaire and clinical
observation. Hair mercury levels in the autistic group were 0.47 ppm versus
3.63 ppm in controls, a significant difference. The mothers in the autistic
group had significantly higher levels of mercury exposure through Rho D
immunoglobulin injections and amalgam fillings than control mothers. Within the
autistic group, hair mercury levels varied significantly across mildly,
moderately, and severely autistic children, with mean group levels of 0.79,
0.46, and 0.21 ppm, respectively. Hair mercury levels among controls were
significantly correlated with the number of the mothers’ amalgam fillings and
their fish consumption as well as exposure to mercury through childhood
vaccines, correlations that were absent in the autistic group. Hair excretion
patterns among autistic infants were significantly reduced relative to control.
These data cast doubt on the efficacy of traditional hair analysis as a measure
of total mercury exposure in a subset of the population. In light of the
biological plausibility of mercury’s role in neurodevelopmental disorders, the
present study provides further insight into one possible mechanism by which
early mercury exposures could increase the risk of autism.
http://www.ncbi.nlm.nih.gov/pubmed/12933322

Toxicological Science • August 2003

Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell
death in cultured human neurons and fibroblasts Author information Baskin DS1,
Ngo H, Didenko VV. Department of Neurosurgery Baylor College of Medicine 6560
Fannin Suite 944 Houston, Texas 77030, USA dbaskin@tmh.tmc.edu Abstract
Thimerosal is an organic mercurial compound used as a preservative in
biomedical preparations. Little is known about the reactions of human neuronal
and skin cells to its micro- and nanomolar concentrations, which can occur
after using thimerosal-containing products. A useful combination of fluorescent
techniques for the assessment of thimerosal toxicity is introduced. Short-term
thimerosal toxicity was investigated in cultured human cerebral cortical
neurons and in normal human fibroblasts. Cells were incubated with 125-nM to
250-microM concentrations of thimerosal for 45 min to 24 h. A 4’,
6-diamidino-2-phenylindole dihydrochloride (DAPI) dye exclusion test was used
to identify nonviable cells and terminal transferase-based nick-end labeling
(TUNEL) to label DNA damage. Detection of active caspase-3 was performed in
live cell cultures using a cell-permeable fluorescent caspase inhibitor. The
morphology of fluorescently labeled nuclei was analyzed. After 6 h of
incubation, the thimerosal toxicity was observed at 2 microM based on the
manual detection of the fluorescent attached cells and at a 1-microM level with
the more sensitive GENios Plus Multi-Detection Microplate Reader with Enhanced
Fluorescence. The lower limit did not change after 24 h of incubation. Cortical
neurons demonstrated higher sensitivity to thimerosal compared to fibroblasts.
The first sign of toxicity was an increase in membrane permeability to DAPI
after 2 h of incubation with 250 microM thimerosal. A 6-h incubation resulted
in failure to exclude DAPI, generation of DNA breaks, caspase-3 activation, and
development of morphological signs of apoptosis. We demonstrate that thimerosal
in micromolar concentrations rapidly induce membrane and DNA damage and
initiate caspase-3-dependent apoptosis in human neurons and fibroblasts. We
conclude that a proposed combination of fluorescent techniques can be useful in
analyzing the toxicity of thimerosal.
http://www.ncbi.nlm.nih.gov/pubmed/12773768

“We demonstrate that thimerosal in micromolar concentrations rapidly induce
membrane and DNA damage and initiate caspase-3-dependent apoptosis in human
neurons and fibroblasts.”

“This study provides strong epidemiological evidence for a link between
increasing mercury from thimerosal-containing childhood vaccines and
neurodevelopment disorders and heart disease.” Journal of American Physicians
and Surgeons • Volume 8, Number 1 • Spring 2003

Thimerosal in Childhood Vaccines, Neurodevelopment Disorders, and Heart Disease
in the United States Mark R. Geier, M.D., Ph.D. David A. Geier Abstract In this
study, we evaluated doses of mercury from thimerosal-containing childhood
immunizations in compari- son to US Federal Safety Guidelines and the effects
of increasing doses of mercury on the incidence of neurodevelopment disorders
and heart disease. This study showed that children received mercury from this
source in excess of the Federal Safety Guidelines for the oral ingestion of
methylmercury. Our analyses showed increasing relative risks for
neurodevelopment disorders and heart disease with increasing doses of mercury.
This study provides strong epidemiological evidence for a link between mercury
exposure from thimerosal-containing childhood vaccines and neurodevelopment
disorders. Conclusion This study provides strong epidemiological evidence for a
link between increasing mercury from thimerosal-containing childhood vaccines
and neurodevelopment disorders and heart disease. In light of voluminous
literature supporting the biologic mechanisms for mercuryinduced adverse
reactions, the presence of amounts of mercury in thimerosal-containing
childhood vaccines exceeding Federal Safety Guidelines for the oral ingestion
of mercury, and previous epidemiological studies showing adverse reactions from
such vaccines, a causal relationship between thimerosal- containing childhood
vaccines and neurodevelopment disorders and heart disease appears to be
confirmed. It is to be hoped that complete removal of thimerosal from all
childhood vaccines will help to stem the tragic, apparently iatrogenic epidemic
of autism and speech disorders that the United States is now facing. Full
Report http://www.jpands.org/vol8no1/geier.pdf

Toxicology And Applied Pharmacology • October 2003

Brain barrier systems: a new frontier in metal neurotoxicological research
Author information Zheng W1, Aschner M, Ghersi-Egea JF. School of Health
Sciences Purdue University West Lafayette, IN 47907, USA wz18@purdue.edu
Abstract The concept of brain barriers or a brain barrier system embraces the
blood-brain interface, referred to as the blood-brain barrier, and the
blood-cerebrospinal fluid (CSF) interface, referred to as the blood-CSF
barrier. These brain barriers protect the CNS against chemical insults, by
different complementary mechanisms. Toxic metal molecules can either bypass
these mechanisms or be sequestered in and therefore potentially deleterious to
brain barriers. Supportive evidence suggests that damage to blood-brain
interfaces can lead to chemical-induced neurotoxicities. This review article
examines the unique structure, specialization, and function of the brain
barrier system, with particular emphasis on its toxicological implications.
Typical examples of metal transport and toxicity at the barriers, such as lead
(Pb), mercury (Hg), iron (Fe), and manganese (Mn), are discussed in detail with
a special focus on the relevance to their toxic neurological consequences.
Based on these discussions, the emerging research needs, such as construction
of the new concept of blood-brain regional barriers, understanding of chemical
effect on aged or immature barriers, and elucidation of the susceptibility of
tight junctions to toxicants, are identified and addressed in this newly
evolving field of neurotoxicology. They represent both clear challenges and
fruitful research domains not only in neurotoxicology, but also in
neurophysiology and pharmacology. http://www.ncbi.nlm.nih.gov/pubmed/14554098

“This review article examines the unique structure, specialization, and
function of the brain barrier system, with particular emphasis on its
toxicological implications. Typical examples of metal transport and toxicity at
the barriers, such as ... mercury ... are discussed in detail with a special
focus on the relevance to their toxic neurological consequences.”

Toxicology And Applied Pharmacology • January 2004

Dose-response study of thimerosal-induced murine systemic autoimmunity Author
information Havarinasab S1, Lambertsson L, Qvarnström J, Hultman P. Molecular
and Immunological Pathology (AIR) Department of Molecular and Clinical Medicine
Linköping University, SE-581 85 Linköping, Sweden Abstract The organic compound
ethylmercurithiosalicylate (thimerosal), which is primarily present in the
tissues as ethylmercury, has caused illness and several deaths due to erroneous
handling when used as a disinfectant or as a preservative in medical
preparations. Lately, possible health effects of thimerosal in childhood
vaccines have been much discussed. Thimerosal is a well-known sensitizing
agent, although usually of no clinical relevance. In rare cases, thimerosal has
caused systemic immune reactions including acrodynia. We have studied if
thimerosal might induce the systemic autoimmune condition observed in
genetically susceptible mice after exposure to inorganic mercury. A.SW mice
were exposed to 1.25-40 mg thimerosal/l drinking water for 70 days.
Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed
in a dose-related pattern and first appeared after 10 days in the two highest
dose groups. The lowest observed adverse effect level (LOAEL) for
antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an
absorbed dose of 147 microg Hg/kg bw and a concentration of 21 and 1.9 microg
Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for
tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and
IgG2a showed a significant dose-related increase in thimerosal-treated mice,
with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/ l for
IgG2a. The polyclonal B-cell activation showed a significant dose-response
relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces
in genetically susceptible mice a systemic autoimmune syndrome very similar to
that seen after treatment with inorganic mercury, although a higher absorbed
dose of Hg is needed using thimerosal. The autoimmune syndrome induced by
thimerosal is different from the weaker and more restricted autoimmune reaction
observed after treatment with an equipotent dose of methylmercury.
http://www.ncbi.nlm.nih.gov/pubmed/14736497

“... thimerosal induces in genetically susceptible mice a systemic autoimmune
syndrome ...”

Toxicology • January 2004

Effect of thimerosal, a preservative in vaccines, on intracellular Ca2+
concentration of rat cerebellar neurons Author information Ueha-Ishibashi T1,
Oyama Y, Nakao H, Umebayashi C, Nishizaki Y, Tatsuishi T, Iwase K, Murao K, Seo
H. Laboratory of Cellular Signaling Faculty of Integrated Arts and Sciences The
University of Tokushima Tokushima 770-8502, Japan Abstract The effect of
thimerosal, an organomercurial preservative in vaccines, on cerebellar neurons
dissociated from 2-week-old rats was compared with those of methylmercury using
a flow cytometer with appropriate fluorescent dyes. Thimerosal and
methylmercury at concentrations ranging from 0.3 to 10 microM increased the
intracellular concentration of Ca2+ ([Ca2+]i) in a concentration-dependent
manner. The potency of 10 microM thimerosal to increase the [Ca2+]i was less
than that of 10 microM methylmercury. Their effects on the [Ca2+]i were greatly
attenuated, but not completely suppressed, under external Ca(2+)-free
condition, suggesting a possibility that both agents increase membrane Ca2+
permeability and release Ca2+ from intracellular calcium stores. The effect of
10 microM thimerosal was not affected by simultaneous application of 30 microM
L-cysteine whereas that of 10 microM methylmercury was significantly
suppressed. The potency of thimerosal was similar to that of methylmercury in
the presence of L-cysteine. Both agents at 1 microM or more similarly decreased
the cellular content of glutathione in a concentration-dependent manner,
suggesting an increase in oxidative stress. Results indicate that thimerosal
exerts some cytotoxic actions on cerebellar granule neurons dissociated from
2-week-old rats and its potency is almost similar to that of methylmercury.
http://www.ncbi.nlm.nih.gov/pubmed/14698570

“Results indicate that thimerosal exerts some cytotoxic actions on cerebellar
granule neurons ... its potency is almost similar to that of methylmercury.”

Medical Science Monitor • March 2004

A comparative evaluation of the effects of MMR immunization and mercury doses
from thimerosal-containing childhood vaccines on the population prevalence of
autism Author information Geier DA1, Geier MR. President, MedCon, Inc, Silver
Spring, MD, USA Abstract BACKGROUND The purpose of the study was to evaluate
the effects of MMR immunization and mercury from thimerosal-containing
childhood vaccines on the prevalence of autism. MATERIAL/METHODS Evaluations of
the Biological Surveillance Summaries of the Centers for Disease Control and
Prevention (CDC), the U.S. Department of Education datasets, and the CDC’s
yearly live birth estimates were undertaken. RESULTS It was determined that
there was a close correlation between mercury doses from thimerosal--containing
childhood vaccines and the prevalence of autism from the late 1980s through the
mid-1990s. In contrast, there was a potential correlation between the number of
primary pediatric measles-containing vaccines administered and the prevalence
of autism during the 1980s. In addition, it was found that there were
statistically significant odds ratios for the development of autism following
increasing doses of mercury from thimerosal-containing vaccines (birth cohorts:
1985 and 1990-1995) in comparison to a baseline measurement (birth cohort:
1984). The contribution of thimerosal from childhood vaccines (>50% effect) was
greater than MMR vaccine on the prevalence of autism observed in this study.
CONCLUSIONS The results of this study agree with a number of previously
published studies. These studies have shown that there is biological
plausibility and epidemiological evidence showing a direct relationship between
increasing doses of mercury from thimerosal-containing vaccines and
neurodevelopmental disorders, and measles-containing vaccines and serious
neurological disorders. It is recommended that thimerosal be removed from all
vaccines, and additional research be undertaken to produce a MMR vaccine with
an improved safety profile. http://www.ncbi.nlm.nih.gov/pubmed/14976450

“The results of this study agree with a number of previously published studies.
These studies have shown that there is biological plausibility and
epidemiological evidence showing a direct relationship between increasing doses
of mercury from thimerosal-containing vaccines and neurodevelopmental
disorders, and measles-containing vaccines and serious neurological disorders.”

Medical Hypotheses • March 2004

Thimerosal and autism? A plausible hypothesis that should not be dismissed
Author information Blaxill MF1, Redwood L, Bernard S. Safe Minds (Sensible
Action For Ending Mercury-Induced Neurological Disorders) 14 Commerce Drive, PH
Cranford, New Jersey 07016, USA blaxill@comcast.net Abstract The autism-mercury
hypothesis first described by Bernard et al. has generated much interest and
controversy. The Institute of Medicine (IOM) reviewed the connection between
mercury-containing vaccines and neurodevelopmental disorders, including autism.
They concluded that the hypothesis was biologically plausible but that there
was insufficient evidence to accept or reject a causal connection and
recommended a comprehensive research program. Without citing new experimental
evidence, a number of observers have offered opinions on the subject, some of
which reject the IOM’s conclusions. In a recent review, Nelson and Bauman argue
that a link between the preservative thimerosal, the source of the mercury in
childhood vaccines, is improbable. In their defense of thimerosal, these
authors take a narrow view of the original hypothesis, provide no new evidence,
and rely on selective citations and flawed reasoning. We provide evidence here
to refute the Nelson and Bauman critique and to defend the autismmercury
hypothesis. http://www.ncbi.nlm.nih.gov/pubmed/?term=15082108

“We provide evidence here to refute the Nelson and Bauman critique and to
defend the autism-mercury hypothesis.”

Molecular Psychiatry • April 2004

Activation of methionine synthase by insulin-like growth factor-1 and dopamine:
a target for neurodevelopmental toxins and thimerosal Author information Waly
M1, Olteanu H, Banerjee R, Choi SW, Mason JB, Parker BS, Sukumar S, Shim S,
Sharma A, Benzecry JM, Power-Charnitsky VA, Deth RC. Department of
Pharmaceutical Sciences Northeastern University, Boston, MA 02115, USA Abstract
Methylation events play a critical role in the ability of growth factors to
promote normal development. Neurodevelopmental toxins, such as ethanol and
heavy metals, interrupt growth factor signaling, raising the possibility that
they might exert adverse effects on methylation. We found that insulin-like
growth factor-1 (IGF-1)and dopamine-stimulated methionine synthase (MS)
activity and folate-dependent methylation of phospholipids in SH-SY5Y human
neuroblastoma cells, via a PI3kinase- and MAP-kinase-dependent mechanism. The
stimulation of this pathway increased DNA methylation, while its inhibition
increased methylation-sensitive gene expression. Ethanol potently interfered
with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas
it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1
and dopamine-stimulated MS activity, as well as folate-dependent phospholipid
methylation: Cu(2+) promoted enzyme activity and methylation, while Cu(+),
Pb(2+), Hg(2+) and Al(3+) were inhibitory. The ethylmercury-containing
preservative thimerosal inhibited both IGF-1- and dopaminestimulated
methylation with an IC(50) of 1 nM and eliminated MS activity. Our findings
outline a novel growth factor signaling pathway that regulates MS activity and
thereby modulates methylation reactions, including DNA methylation. The potent
inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal
suggests that it may be an important target of neurodevelopmental toxins.
http://www.ncbi.nlm.nih.gov/pubmed/14745455

“The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and
thimerosal suggests that it may be an important target of neurodevelopmental
toxins.”

International Journal Of Hygiene And Environmental Health • September 2004

Amalgam studies: disregarding basic principles of mercury toxicity Author
information Mutter J1, Naumann J, Sadaghiani C, Walach H, Drasch G. Institute
for Environmental Medicine and Hospital Epidemiology University Hospital,
Freiburg, Germany jmutter@iuk3.ukl.uni-freiburg.de Abstract Dental amalgam,
which has been used for over 150 years in dental practice, consists of about
50% metallic mercury. Studies on animal and humans show that mercury is
continuously released from dental amalgam and absorbed by several body tissues.
It is widely accepted that the main source of mercury vapor is dental amalgam
and it contributes substantially to mercury load in human body tissues. There
is still a controversy about the consequences of this additional mercury
exposure from amalgam to human health. Many studies were performed to evaluate
possible adverse effects. In this comment, these studies were analyzed with
regard to their methodical quality by considering the newest findings on
mercury toxicity and metabolism. In sum, a number of studies are methodically
flawed drawing inaccurate conclusions as to the safety of dental amalgam.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15471104

“Studies on animal and humans show that mercury is continuously released from
dental amalgam and absorbed by several body tissues. It is widely accepted that
the main source of mercury vapor is dental amalgam and it contributes
substantially to mercury load in human body tissues. In sum, a number of
studies are methodically flawed drawing inaccurate conclusions as to the safety
of dental amalgam.”

Molecular Psychiatry • September 2004

Neurotoxic effects of postnatal thimerosal are mouse strain dependent Author
information Hornig M1, Chian D, Lipkin WI. Jerome L and Dawn Greene Infectious
Disease Laboratory Department of Epidemiology, Mailman School of Public Health
Columbia University, New York, NY 10032, USA mady.hornig@columbia.edu Abstract
The developing brain is uniquely susceptible to the neurotoxic hazard posed by
mercurials. Host differences in maturation, metabolism, nutrition, sex, and
autoimmunity influence outcomes. How population-based variability affects the
safety of the ethylmercury-containing vaccine preservative, thimerosal, is
unknown. Reported increases in the prevalence of autism, a highly heritable
neuropsychiatric condition, are intensifying public focus on environmental
exposures such as thimerosal. Immune profiles and family history in autism are
frequently consistent with autoimmunity. We hypothesized that autoimmune
propensity influences outcomes in mice following thimerosal challenges that
mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice
showed growth delay; reduced locomotion; exaggerated response to novelty; and
densely packed, hyperchromic hippocampal neurons with altered glutamate
receptors and transporters. Strains resistant to autoimmunity, C57BL/6J and
BALB/cJ, were not susceptible. These findings implicate genetic influences and
provide a model for investigating thimerosal-related neurotoxicity.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15184908

“These findings implicate genetic influences and provide a model for
investigating thimerosal-related neurotoxicity.”

Toxicology In Vitro • October 2004

Property of thimerosal-induced decrease in cellular content of glutathione in
rat thymocytes: a flow cytometric study with 5-chloromethylfluorescein
diacetate Author information Ueha-Ishibashi T1, Tatsuishi T, Iwase K, Nakao H,
Umebayashi C, Nishizaki Y, Nishimura Y, Oyama Y, Hirama S, Okano Y. Laboratory
of Cellular Signaling, Faculty of Integrated Arts and Sciences The University
of Tokushima, Minami-Jyosanjima 1-1 Tokushima 770-8502, Japan Abstract There is
a concern on the part of public health community that adverse health
consequences by thimerosal, a preservative in vaccines for infants, may occur
among infants during immunization schedule. Therefore, the effect of thimerosal
on cellular content of glutathione was examined on thymocytes obtained from
4-week-old rats using a flow cytometer and 5-chloromethylfluorescein diacetate.
Thimerosal at concentrations ranging from 1 to 10 microM reduced the cellular
content of glutathione in a concentration-dependent manner, and the complete
depletion of cellular glutathione was observed when the cells were treated with
30 microM thimerosal. L-Cysteine significantly attenuated the actions of
thimerosal to reduce the glutathione content and to increase the intracellular
Ca2+ concentration. Prolonged incubation (24 h) with 1-3 microM thimerosal
induced the apoptosis. The cytotoxic action of thimerosal was greatly augmented
when the cells suffered oxidative stress induced by H2O2. It may be unlikely
that thimerosal exerts potent cytotoxic action under the in vivo condition
because the blood concentration of thimerosal after receiving vaccines does not
seem to reach micromolar range and nonprotein thiols at micromolar
concentrations are present in the blood.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15251173

“Thimerosal at concentrations ranging from 1 to 10 microM reduced the cellular
content of glutathione in a concentration-dependent manner, and the complete
depletion of cellular glutathione was observed when the cells were treated with
30 microM thimerosal.”

“The present study provides additional epidemiological evidence
supporting previous epidemiological, clinical and experimental evidence that
administration of thimerosal-containing vaccines in the United States resulted
in a significant number of children developing Neurological Disorders.”
International Journal Of Toxicology • November 2004

Neurodevelopmental disorders following thimerosal-containing childhood
immunizations: a follow-up analysis Author information Geier D1, Geier MR.
MedCon, Inc., Maryland, USA Abstract The authors previously published the first
epidemiological study from the United States associating thimerosal from
childhood vaccines with neurodevelopmental disorders (NDs) based upon
assessment of the Vaccine Adverse Event Reporting System (VAERS). A number of
years have gone by since their previous analysis of the VAERS. The present
study was undertaken to determine whether the previously observed effect
between thimerosal-containing childhood vaccines and NDs are still apparent in
the VAERS as children have had a chance to further mature and potentially be
diagnosed with additional NDs. In the present study, a cohort of children
receiving thimerosal-containing diphtheria-tetanus-acellular pertussis (DTaP)
vaccines in comparison to a cohort of children receiving thimerosal-free DTaP
vaccines administered from 1997 through 2000 based upon an assessment of
adverse events reported to the VAERS were evaluated. It was determined that
there were significantly increased odds ratios (ORs) for autism (OR = 1.8, p <
.05), mental retardation (OR = 2.6, p < .002), speech disorder (OR = 2.1, p <
.02), personality disorders (OR = 2.6, p < .01), and thinking abnormality (OR =
8.2, p < .01) adverse events reported to the VAERS following
thimerosal-containing DTaP vaccines in comparison to thimerosal-free DTaP
vaccines. Potential confounders and reporting biases were found to be minimal
in this assessment of the VAERS. It was observed, even though the media has
reported a potential association between autism and thimerosal exposure, that
the other NDs analyzed in this assessment of the VAERS had significantly higher
ORs than autism following thimerosal-containing DTaP vaccines in comparison to
thimerosal-free DTaP vaccines. The present study provides additional
epidemiological evidence supporting previous epidemiological, clinical and
experimental evidence that administration of thimerosal-containing vaccines in
the United States resulted in a significant number of children developing NDs.
http://www.ncbi.nlm.nih.gov/pubmed/15764492

Washington, D.C. • 2004

Vaccines And Autism Immunization Safety Review Committee Board on Health
Promotion and Disease Prevention Institute Of Medicine Of The National
Academies The National Academies Press http://www.nap.edu/read/10997/chapter/1

“It has been estimated that about 15% of the population may show enhanced
susceptibility to mercury exposure.”

“We provide evidence here to refute the Nelson and Bauman critique
and to defend the autism-mercury hypothesis.” Medical Hypotheses • 2004

Thimerosal and autism? A plausible hypothesis that should not be dismissed
Author information Blaxill MF1, Redwood L, Bernard S. Sensible Action For
Ending Mercury-Induced Neurological Disorders SAFE MINDS 14 Commerce Drive, PH
Cranford, New Jersey 07016, USA blaxill@comcast.net Abstract The autism-mercury
hypothesis first described by Bernard et al. has generated much interest and
controversy. The Institute of Medicine (IOM) reviewed the connection between
mercury-containing vaccines and neurodevelopmental disorders, including autism.
They concluded that the hypothesis was biologically plausible but that there
was insufficient evidence to accept or reject a causal connection and
recommended a comprehensive research program. Without citing new experimental
evidence, a number of observers have offered opinions on the subject, some of
which reject the IOM’s conclusions. In a recent review, Nelson and Bauman argue
that a link between the preservative thimerosal, the source of the mercury in
childhood vaccines, is improbable. In their defense of thimerosal, these
authors take a narrow view of the original hypothesis, provide no new evidence,
and rely on selective citations and flawed reasoning. We provide evidence here
to refute the Nelson and Bauman critique and to defend the autism-mercury
hypothesis. http://www.ncbi.nlm.nih.gov/pubmed/15082108

Neurotoxicology • January 2005

Thimerosal neurotoxicity is associated with glutathione depletion: protection
with glutathione precursors Author information James SJ1, Slikker W 3rd, Melnyk
S, New E, Pogribna M, Jernigan S. Department of Pediatrics University of
Arkansas for Medical Sciences and Arkansas Children’s Hospital Research
Institute Little Rock, AR 72202 USA jamesjill@uams.edu Abstract Thimerosol is
an antiseptic containing 49.5% ethyl mercury that has been used for years as a
preservative in many infant vaccines and in flu vaccines. Environmental methyl
mercury has been shown to be highly neurotoxic, especially to the developing
brain. Because mercury has a high affinity for thiol (sulfhydryl (-SH)) groups,
the thiol-containing antioxidant, glutathione (GSH), provides the major
intracellular defense against mercury-induced neurotoxicity. Cultured
neuroblastoma cells were found to have lower levels of GSH and increased
sensitivity to thimerosol toxicity compared to glioblastoma cells that have
higher basal levels of intracellular GSH. Thimerosal-induced cytotoxicity was
associated with depletion of intracellular GSH in both cell lines. Pretreatment
with 100 microM glutathione ethyl ester or N-acetylcysteine (NAC), but not
methionine, resulted in a significant increase in intracellular GSH in both
cell types. Further, pretreatment of the cells with glutathione ethyl ester or
NAC prevented cytotoxicity with exposure to 15 microM Thimerosal. Although
Thimerosal has been recently removed from most children’s vaccines, it is still
present in flu vaccines given to pregnant women, the elderly, and to children
in developing countries. The potential protective effect of GSH or NAC against
mercury toxicity warrants further research as possible adjunct therapy to
individuals still receiving Thimerosal-containing vaccinations.
http://www.ncbi.nlm.nih.gov/pubmed/15527868

“Although Thimerosal has been recently removed from most children’s vaccines,
it is still present in flu vaccines given to pregnant women, the elderly, and
to children in developing countries.”

Archives Of Environmental Occupational Health • January 2005

Genetic influences on the retention of inorganic mercury Author information
Custodio HM1, Harari R, Gerhardsson L, Skerfving S, Broberg K. Department of
Occupational and Environmental Medicine Lund University Hospital, Lund, Sweden
Abstract Mercury is eliminated as glutathione (GSH) conjugates. GSH production
is mediated by glutamyl-cysteine ligase (GCL), and conjugation by glutathione
S-transferases (GST). This study tested if polymorphisms in GCL and GST genes
modify mercury retention in humans exposed to elemental mercury vapor. Total
mercury concentrations in whole blood, plasma and urine, and genotypes for
GCLC, GCLM, GSTA1, GSTM1, GSTP1, and GSTT1 were determined in 309 gold miners,
gold buyers and controls. The presence of the GCLM-588T allele was associated
with increased blood, plasma and urine mercury levels. These results indicate
that genotypes with decreased GSH availability for mercury conjugation affect
the metabolism of inorganic mercury.
http://www.ncbi.nlm.nih.gov/pubmed/?term=16961004

“These results indicate that genotypes with decreased glutathione availability
for mercury conjugation affect the metabolism of inorganic mercury.”

Medical Science Monitor • April 2005

A two-phased population epidemiological study of the safety of
thimerosal-containing vaccines: a follow-up analysis Author information Geier
DA1, Geier MR. MedCon, Inc., USA Abstract BACKGROUND Thimerosal is an
ethylmercury-containing preservative in vaccines. Toxicokinetic studies have
shown children received doses of mercury from thimerosal-containing vaccines
(TCVs) that were in excess of safety guidelines. Previously, an ecological
study showing a significant association between TCVs and neurodevelopmental
disorders (NDs) in the US was published in this journal. MATERIAL/METHODS A two
phased population-based epidemiological study was undertaken. Phase one
evaluated reported NDs to the Vaccine Adverse Event Reporting System (VAERS)
following thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis (DTaP)
vaccines in comparison to thimerosal-free DTaP vaccines administered from 1997
through 2001. Phase two evaluated the automated Vaccine Safety Datalink (VSD)
for cumulative exposures to mercury from TCVs at 1-, 2-, 3-, and 6-months-ofage
for infants born from 1992 through 1997 and the eventual risk of developing
NDs. RESULTS Phase one showed significantly increased risks for autism, speech
disorders, mental retardation, personality disorders, and thinking
abnormalities reported to VAERS following thimerosal-containing DTaP vaccines
in comparison to thimerosal-free DTaP vaccines. Phase two showed significant
associations between cumulative exposures to thimerosal and the following types
of NDs: unspecified developmental delay, tics, attention deficit disorder
(ADD), language delay, speech delay, and neurodevelopmental delays in general.
CONCLUSIONS This study showed that exposure to mercury from TCVs administered
in the US was a consistent significant risk factor for the development of NDs.
It is clear from these data and other recent publications linking TCVs with NDs
that additional ND research should be undertaken in the context of evaluating
mercury-associated exposures and thimerosal-free vaccines should be made
available. http://www.ncbi.nlm.nih.gov/pubmed/?term=15795695

“This study showed that exposure to mercury from Thimerosal containing vaccines
administered in the US was a consistent significant risk factor for the
development of NDs.”

Neurotoxicology • June 2005

Mitochondrial mediated thimerosal-induced apoptosis in a human neuroblastoma
cell line (SK-N-SH) Author information Humphrey ML1, Cole MP, Pendergrass JC,
Kiningham KK. Department of Pharmacology Joan C. Edwards School of Medicine
Marshall University Huntington, WV 25704-9388, USA Abstract Environmental
exposure to mercurials continues to be a public health issue due to their
deleterious effects on immune, renal and neurological function. Recently the
safety of thimerosal, an ethyl mercury-containing preservative used in
vaccines, has been questioned due to exposure of infants during immunization.
Mercurials have been reported to cause apoptosis in cultured neurons; however,
the signaling pathways resulting in cell death have not been well
characterized. Therefore, the objective of this study was to identify the mode
of cell death in an in vitro model of thimerosal-induced neurotoxicity, and
more specifically, to elucidate signaling pathways which might serve as
pharmacological targets. Within 2 h of thimerosal exposure (5 microM) to the
human neuroblastoma cell line, SK-N-SH, morphological changes, including
membrane alterations and cell shrinkage, were observed. Cell viability,
assessed by measurement of lactate dehydrogenase (LDH) activity in the medium,
as well as the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
(MTT) assay, showed a time- and concentration-dependent decrease in cell
survival upon thimerosal exposure. In cells treated for 24 h with thimerosal,
fluorescence microscopy indicated cells undergoing both apoptosis and
oncosis/necrosis. To identify the apoptotic pathway associated with
thimerosal-mediated cell death, we first evaluated the mitochondrial cascade,
as both inorganic and organic mercurials have been reported to accumulate in
the organelle. Cytochrome c was shown to leak from the mitochondria, followed
by caspase 9 cleavage within 8 h of treatment. In addition, poly(ADP-ribose)
polymerase (PARP) was cleaved to form a 85 kDa fragment following maximal
caspase 3 activation at 24 h. Taken together these findings suggest deleterious
effects on the cytoarchitecture by thimerosal and initiation of
mitochondrial-mediated apoptosis. http://www.ncbi.nlm.nih.gov/pubmed/15869795

“Taken together these findings suggest deleterious effects on the
cytoarchitecture by thimerosal and initiation of mitochondrial-mediated
apoptosis.”

Toxicology Science • July 2005

Effects of thimerosal on NGF signal transduction and cell death in
neuroblastoma cells Author information Parran DK1, Barker A, Ehrich M.
Virginia-Maryland Regional College of Veterinary Medicine Laboratory for
Neurotoxicity Studies, Virginia Tech 1 Duckpond Drive, Blacksburg, Virginia
24061-0442, USA Abstract Signaling through neurotrophic receptors is necessary
for differentiation and survival of the developing nervous system. The present
study examined the effects of the organic mercury compound thimerosal on nerve
growth factor signal transduction and cell death in a human neuroblastoma cell
line (SH-SY5Y cells). Following exposure to 100 ng/ml NGF and increasing
concentrations of thimerosal (1 nM-10 microM), we measured the activation of
TrkA, MAPK, and PKC-delta. In controls, the activation of TrkA MAPK and
PKC-delta peaked after 5 min of exposure to NGF and then decreased but was
still detectable at 60 min. Concurrent exposure to increasing concentrations of
thimerosal and NGF for 5 min resulted in a concentration-dependent decrease in
TrkA and MAPK phosphorylation, which was evident at 50 nM for TrkA and 100 nM
for MAPK. Cell viability was assessed by the LDH assay. Following 24-h exposure
to increasing concentrations of thimerosal, the EC50 for cell death in the
presence or absence of NGF was 596 nM and 38.7 nM, respectively. Following 48-h
exposure to increasing concentrations of thimerosal, the EC50 for cell death in
the presence and absence of NGF was 105 nM and 4.35 nM, respectively. This
suggests that NGF provides protection against thimerosal cytotoxicity. To
determine if apoptotic versus necrotic cell death was occurring,
oligonucleosomal fragmented DNA was quantified by ELISA. Control levels of
fragmented DNA were similar in both the presence and absence of NGF. With and
without NGF, thimerosal caused elevated levels of fragmented DNA appearing at
0.01 microM (apoptosis) to decrease at concentrations >1 microM (necrosis).
These data demonstrate that thimerosal could alter NGF-induced signaling in
neurotrophin-treated cells at concentrations lower than those responsible for
cell death. Full Report http://toxsci.oxfordjournals.org/content/86/1/132.long

“These data demonstrate that thimerosal could alter NGF-induced signaling in
neurotrophin-treated cells at concentrations lower than those responsible for
cell death.”

Toxicology And Applied Pharmacology • August 2005

The association between genetic polymorphisms of coproporphyrinogen oxidase and
an atypical porphyrinogenic response to mercury exposure in humans Author
information Woods JS1, Echeverria D, Heyer NJ, Simmonds PL, Wilkerson J, Farin
FM. Department of Environmental and Occupational Health Sciences University of
Washington, Seattle, WA 98101, USA Battelle Centers for Public Health Research
and Evaluation Seattle, WA 98105, USA jwoods@u.washington.edu Abstract Previous
studies have demonstrated highly specific urinary porphyrin profile (UPP)
changes in response to mercury (Hg) exposure in animals and human subjects and
have defined the biochemical etiology of this effect as selective alteration of
the heme pathway enzymes, uroporphyrinogen decarboxylase (UROD), and
coproporphyrinogen oxidase (CPOX) by Hg in the kidney. Ongoing validation
studies in a population of dental practitioners with low-level occupational Hg
exposure have demonstrated the predicted UPP change among approximately 85% of
subjects. This study focused on the genetic etiology of an atypical
porphyrinogenic response (APR) seen among the remaining 15% of Hg-exposed
subjects, characterized by excess excretion of 4- and 5-carboxyl porphyrins and
also of the atypical ketoisocoproporphyrin (KICP). Automated
DNA-sequencing-based assays were developed to examine the 7 exons and flanking
intron-exon boundaries of the CPOX gene. Among several polymorphisms
identified, an A814C variant in exon 4 encoding a N272H substitution was found
to be predominant among subjects with the APR. Studies suggest that this
variant CPOX preferentially converts the upstream 5-carboxylporphyrin (5-CP) to
KICP. By partially inhibiting the 5- to 4-decarboxylation step of UROD, Hg
promotes 5-CP accumulation, accounting for excess KICP excretion and the APR in
Hg-exposed subjects carrying the variant CPOX gene. This finding represents the
first report of a polymorphism in a human gene that modifies the effect of Hg
on a biological process. The APR might serve as a biomarker of both Hg exposure
and susceptibility to Hg toxicity.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15967199

“This finding represents the first report of a polymorphism in a human gene
that modifies the effect of ethyl mercury on a biological process. The atypical
porphyrinogenic response might serve as a biomarker of both mercury exposure
and susceptibility to mercury toxicity.”

“The results indicate that methyl mercury
is not a suitable reference for risk assessment from exposure to
thimerosal-derived ethyl mercury.”

Environmental Health Perspectives • August 2005

Comparison of blood and brain mercury levels in infant monkeys exposed to
methylmercury or vaccines containing thimerosal Author information Burbacher
TM1, Shen DD, Liberato N, Grant KS, Cernichiari E, Clarkson T. Department of
Environmental and Occupational Health Sciences, School of Public Health and
Community Medicine University of Washington, Seattle, Washington 98195, USA
tmb@u.washington.edu Thimerosal is a preservative that has been used in
manufacturing vaccines since the 1930s. Reports have indicated that infants can
receive ethylmercury (in the form of thimerosal) at or above the U.S.
Environmental Protection Agency guidelines for methylmercury exposure,
depending on the exact vaccinations, schedule, and size of the infant. In this
study we compared the systemic disposition and brain distribution of total and
inorganic mercury in infant monkeys after thimerosal exposure with those
exposed to MeHg. Monkeys were exposed to MeHg (via oral gavage) or vaccines
containing thimerosal (via intramuscular injection) at birth and 1, 2, and 3
weeks of age. Total blood Hg levels were determined 2, 4, and 7 days after each
exposure. Total and inorganic brain Hg levels were assessed 2, 4, 7, or 28 days
after the last exposure. The initial and terminal half-life of Hg in blood
after thimerosal exposure was 2.1 and 8.6 days, respectively, which are
significantly shorter than the elimination half-life of Hg after MeHg exposure
at 21.5 days. Brain concentrations of total Hg were significantly lower by
approximately 3-fold for the thimerosal-exposed monkeys when compared with the
MeHg infants, whereas the average brainto-blood concentration ratio was
slightly higher for the thimerosal-exposed monkeys (3.5 +/- 0.5 vs. 2.5 +/-
0.3). A higher percentage of the total Hg in the brain was in the form of
inorganic Hg for the thimerosal-exposed monkeys (34% vs. 7%). The results
indicate that MeHg is not a suitable reference for risk assessment from
exposure to thimerosal-derived Hg. Knowledge of the toxicokinetics and
developmental toxicity of thimerosal is needed to afford a meaningful
assessment of the developmental effects of thimerosal-containing vaccines. Full
Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280342/ Editors note: most
current risk assessments of biological thimerosal (ethyl mercury) use are based
on the false assumption that ethyl mercury and methyl mercury behave similarly
in vivo and in vitro

Environmental Toxicology And Pharmacology • September 2005

Low dose mercury toxicity and human health Author information Zahir F1, Rizwi
SJ, Haq SK, Khan RH. Interdisciplinary Brain Research Centre JN Medical
College, AMU, Aligarh, U.P., India Abstract Post Minamata incident there has
been awareness about mercury toxicity even among the general public. Previous
researches contributed a vast amount of data regarding acute mercury exposure,
but gradually information about the low dose [Ninomiya, T., Ohmori, H.,
Hashimoto, K., Tsuruta, K., Ekino, S., 1995. Expansion of methylmercury
poisoning outside minamata: an epidemiological study on chronic methylmercury
poisoninig outside of Minamata. Environ. Res. 70 (1) 47-50; Lebel, J., Mergler,
D., Lucotte, M., Amorim, M., Dolbec, J., Miranda, D., Arantes, G., Rheault, I.,
Pichet, P., 1996. Evidence of early nervous system dysfunction in Amazonian
populations exposed to low-levels of methylmercury. Neurotoxicology 17 (1)
157-167] of mercury toxicity has been trickling in. With mercury contaminating
rain-, ground- and sea-water no one is safe. Polluted water leads to mercury
laced fish, meat and vegetable. In aquatic environments, inorganic mercury is
microbiologically transformed into lipophilic organic compound ‘methylmercury’.
This transformation makes mercury more prone to biomagnification in food
chains. Consequently, populations with traditionally high dietary intake of
food originating from fresh or marine environment have highest dietary exposure
to mercury. Extensive research done on locals across the globe have already
established this, persons who routinely consume fish or a particular species of
fish are at an increased risk of methylmercury poisoning. The easy access of
the toxicant to man through multiple pathways air, water, food, cosmetic
products and even vaccines increase the exposure. Foetus and children are more
susceptible towards mercury toxicity. Mothers consuming diet containing mercury
pass the toxicant to foetus and to infants through breast milk. Decreased
performance in areas of motor function and memory has been reported among
children exposed to presumably safe mercury levels. Similarly, disruption of
attention, fine motor function and verbal memory was also found in adults on
exposure to low mercury levels. It is an occupational hazard for dental staff,
chloralkali factory workers and goldminers, etc. Mercury has been found to be a
causative agent of various sorts of disorders, including neurological,
nephrological, immunological, cardiac, motor, reproductive and even genetic.
Recently heavy metal mediated toxicity has been linked to diseases like
Alzeihemer’s, Parkinson’s, Autism, Lupus, Amyotrophic lateral sclerosis, etc.
Besides this, it poses danger to wildlife. Therefore, it becomes imperative to
spread the information regarding the threat of mercury exposure amongst the
scientists and masses. http://www.ncbi.nlm.nih.gov/pubmed/?term=21783611

“Recently heavy metal mediated toxicity has been linked to diseases like
Alzeihemer’s, Parkinson’s, Autism, Lupus, Amyotrophic lateral sclerosis, etc.
Besides this, it poses danger to wildlife. Therefore, it becomes imperative to
spread the information regarding the threat of mercury exposure amongst the
scientists and masses.”

“Repetitive doses of thimerosal leads to neurobehavioral deteriorations ...”
Neuro Endocrinology Letters • October 2005

Mercury and autism: accelerating evidence? Author information Mutter J1,
Naumann J, Schneider R, Walach H, Haley B. Institute for Environmental Medicine
and Hospital Epidemiology University Hospital Freiburg, Germany
joachim.mutter@uniklinik-freiburg.de Abstract The causes of autism and
neurodevelopmental disorders are unknown. Genetic and environmental risk
factors seem to be involved. Because of an observed increase in autism in the
last decades, which parallels cumulative mercury exposure, it was proposed that
autism may be in part caused by mercury. We review the evidence for this
proposal. Several epidemiological studies failed to find a correlation between
mercury exposure through thimerosal, a preservative used in vaccines, and the
risk of autism. Recently, it was found that autistic children had a higher
mercury exposure during pregnancy due to maternal dental amalgam and
thimerosal-containing immunoglobulin shots. It was hypothesized that children
with autism have a decreased detoxification capacity due to genetic
polymorphism. In vitro, mercury and thimerosal in levels found several days
after vaccination inhibit methionine synthetase (MS) by 50%. Normal function of
MS is crucial in biochemical steps necessary for brain development, attention
and production of glutathione, an important antioxidative and detoxifying
agent. Repetitive doses of thimerosal leads to neurobehavioral deteriorations
in autoimmune susceptible mice, increased oxidative stress and decreased
intracellular levels of glutathione in vitro. Subsequently, autistic children
have significantly decreased level of reduced glutathione. Promising treatments
of autism involve detoxification of mercury, and supplementation of deficient
metabolites. http://www.ncbi.nlm.nih.gov/pubmed/16264412

International Journal Of Molecular Medicine • December 2005

Thimerosal induces neuronal cell apoptosis by causing cytochrome c and
apoptosis-inducing factor release from mitochondria Author information Yel L1,
Brown LE, Su K, Gollapudi S, Gupta S. Department of Medicine University of
California, Irvine, CA 92697, USA lyel@uci.edu Abstract There is a worldwide
increasing concern over the neurological risks of thimerosal (ethylmercury
thiosalicylate) which is an organic mercury compound that is commonly used as
an antimicrobial preservative. In this study, we show that thimerosal, at
nanomolar concentrations, induces neuronal cell death through the mitochondrial
pathway. Thimerosal, in a concentration- and time-dependent manner, decreased
cell viability as assessed by calcein-ethidium staining and caused apoptosis
detected by Hoechst 33258 dye. Thimerosal-induced apoptosis was associated with
depolarization of mitochondrial membrane, generation of reactive oxygen
species, and release of cytochrome c and apoptosis-inducing factor (AIF) from
mitochondria to cytosol. Although thimerosal did not affect cellular expression
of Bax at the protein level, we observed translocation of Bax from cytosol to
mitochondria. Finally, caspase-9 and caspase-3 were activated in the absence of
caspase-8 activation. Our data suggest that thimerosal causes apoptosis in
neuroblastoma cells by changing the mitochondrial microenvironment.
http://www.ncbi.nlm.nih.gov/pubmed/16273274

“Our data suggest that thimerosal causes apoptosis in neuroblastoma cells by
changing the mitochondrial microenvironment.”

Medical Veritas • 2005

Mercury toxicity: Genetic susceptibility and synergistic effects Boyd E. Haley,
PhD Professor and Chair • Department of Chemistry University of Kentucky
Abstract Mercury toxicity and intoxication (poisoning) are realities that every
American needs to face. Both the Environmental Protection Agency and National
Academy of Science state that between 8 to 10% of American women have mercury
levels that would render any child they gave birth to neurological disorders.
One of six children in the USA have a neurodevelopmental disorder according to
the Centers for Disease Control and Preven- tion. Yet our dentistry and
medicine continue to expose all patients to mercury. This article discusses the
obvious sources of mercury exposures that can be easily prevented. It also
points out that genetic susceptibility and exposures to other materials that
synergistically enhance mercury and ethyl- mercury toxicity need to be
evaluated, and that by their existence prevent the actual determination of a
“safe level” of mercury exposure for all. The mercury sources we consider are
from dentistry and from drugs, mainly vaccines, that, in today’s world are not
only unnecessary sources, but also sources that are being increasingly
recognized as being significantly deleterious to the health of many. Excerpts

circles will cause the death of about 70% of the neurons within 24 hours. The
synergistic effects of aluminum, neomycin and tes- tosterone are shown (Fig. 6)
and are as follows: Aluminum: Aluminum hydroxide alone at 500 nM showed no
significant death of cells at 6 hours, and only slight toxicity over the
24-hour period. Thimerosal at 50 nM effected only a slight increase in neuron
death at 6 hours. However, in the presence of 50 nM thimerosal plus 500 nM
aluminum hydroxide (open triangles [Δ]), the neuronal death increases to
roughly 60%, an amazing increase and clearly demonstrates the synergistic
effects of other metals on mercury toxicity and certainly thimerosal toxicity.
Neomycin: At 1.75 mcg neomycin alone (solid squares) did not cause a
significant increase in neuronal death after 12 hours. In the presence of 50 nM
thimerosal (open squares) the rate of death at same point increased from about
40% to 60%, a 20% increase in rate of death. 4. Hormonal effects: Testosterone
and Estrogen

3. Synergistic effects: Thimerosal, aluminum hydroxide and Neomycin It is well
documented in the literature that mercury toxicity is synergistic with other
heavy metals such as cadmium and lead. It is also known that certain
antibiotics greatly enhance the toxicity of thimerosal in ocular solutions and
that antibiotics prevent test animals from effectively excreting mercury. The
major known difference between males and females is their hormones. We
therefore investigated the possible involvement of aluminum cation (found in
vaccines), antibiotics (neomycin) and male versus female (estrogen versus
testosterone) on the toxic effects of 50 nanomolar (nM) thimerosal on neurons
in culture. Neurons can be cultured for 24 hours without much death (Fig. 6).
Fifty nanomolar thimerosal alone (solid

Testosterone and estrogen-like compounds give vastly dif- ferent results. Using
female hormones we found them not toxic to the neurons alone and to be
consistently protective against thimerosal toxicity. In fact, at high levels
they could afford total protection for 24 hours against neuronal death in this
test sys- tem (data not plotted). However, testosterone which appeared
protective at very low levels (0.01 to 0.1 micromolar), dramati- cally
increased neuron death at higher levels (0.5 to 1.0 micro- molar). In fact, 1.0
micromolar levels of testosterone that by itself did not significantly increase
neuron death (red flattened oval), within 3 hours when added with 50 nanomolar
thimerosal (solid circles) caused 100% neuron death. Fifty nanomolar thimerosal
at this time point did not significantly cause any cell death.

Full Report http://www.1796kotok.com/pdfs/haley.pdf

“In fact, 1.0 micromolar levels of testosterone that by itself did not
significantly increase neuron death, within 3 hours when added with 50
nanomolar thimerosal caused 100% neuron death.”

“... there are a number of other diseases that may have a chronic mercury toxicity component,
such as Alzheimer’s disease, heart disease, obesity, ALS, asthma, and other
various forms of autoimmune disorders ...” Medical Hypotheses • 2005

The potential importance of steroids in the treatment of autistic spectrum
disorders and other disorders involving mercury toxicity Author information
Geier MR1, Geier DA. The Genetic Centers of America, 14 Redgate Ct., Silver
Spring, MD 20905, USA mgeier@comcast.net Abstract Autism is a
neurodevelopmental disorder that according to the Centers for Disease Control
and Prevention (CDC) affects 1 in 150 children in the United States. Autism is
characterized by impairments in social relatedness and communication,
repetitive behaviors, abnormal movements, and sensory dysfunction. Recently
emerging evidence suggests that mercury, especially from childhood vaccines,
appears to be a factor in the development of the autistic disorders, and that
autistic children have higher than normal body-burdens of mercury. In
considering mercury toxicity, it has previously been shown that testosterone
significantly potentates mercury toxicity, whereas estrogen is protective.
Examination of autistic children has shown that the severity of autistic
disorders correlates with the amount of testosterone present in the amniotic
fluid, and an examination of a case-series of autistic children has shown that
some have plasma testosterone levels that were significantly elevated in
comparison neurotypical control children. A review of some of the current
biomedical therapies for autistics, such as glutathione and cysteine,
chelation, secretin, and growth hormone, suggests that they may in fact lower
testosterone levels. We put forward the medical hypothesis that autistic
disorders, in fact, represents a form of testosterone mercury toxicity, and
based upon this observation, one can design novel treatments for autistics
directed towards higher testosterone levels in autistic children. We suggest a
series of experiments that need to be conducted in order to evaluate the exact
mechanisms for mercury-testosterone toxicity, and various types of clinical
manipulations that may be employed to control testosterone levels. It is hoped
by devising therapies that address the steroid hormone pathways, in addition to
the current treatments that successful lower heavy metal body-burdens of
mercury, will work synergistically to improve clinical outcomes. In light of
the fact that there are a number of other diseases that may have a chronic
mercury toxicity component, such as Alzheimer’s disease, heart disease,
obesity, ALS, asthma, and other various forms of autoimmune disorders, it is
imperative that further research should be conducted to understand
mercury-testosterone toxicity. http://www.ncbi.nlm.nih.gov/pubmed/15780490

Toxicology Letters • February 2006

A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase
(CPOX) polymorphism on the heme biosynthetic pathway and porphyrin production
Author information Heyer NJ1, Bittner AC Jr, Echeverria D, Woods JS. Battelle
Centers for Public Health Research and Evaluation 1100 Dexter Avenue N, Suite
400, Seattle, WA 98109, USA Abstract Mercury (Hg) exposure in various forms
remains a persistent public health concern in many parts of the world. In
previous studies, we have described a biomarker of mercury exposure
characterized by increased urinary concentrations of specific porphyrins,
pentacarboxyporphyrin (5-CP) and coproporphyrin (4-CP), and the atypical
keto-isocoproporphyrin (KICP), based on selective interference with the fifth
(uroporphyrinogen decarboxylase, UROD) and sixth (coproporphyrinogen oxidase,
CPOX) enzymes of the heme biosynthetic pathway. Whereas this response occurs in
a predictable manner among approximately 85% of subjects with Hg exposure, an
atypical porphyrinogenic response (APR) has been observed in approximately 15%
of Hg-exposed persons, in which the three porphyrins that are affected by Hg,
i.e., 5-CP, 4-CP and, KICP, are excreted in substantial excess of that
predicted on the basis of Hg exposure alone. This APR has been attributed to a
specific polymorphism in exon 4 of the CPOX gene (CPOX4). In the present study,
we sought to further confirm the hypothesis that the observed changes in
porphyrin excretion patterns might serve as a biomarker of Hg exposure and
potential toxicity by statistically modeling the cascading effects on porphyrin
concentrations within the heme biosynthetic pathway of Hg exposure and CPOX4
polymorphism in a human population with long-term occupational exposure to
elemental mercury. Our results are highly consistent with this hypothesis.
After controlling for precursor porphyrin concentrations, we demonstrated that
5-CP and 4-CP are independently associated with Hg concentration, while KICP is
associated only with the CPOX4. An unpredicted association of Hg with
heptacarboxyporphyrin (7-CP) may indicate a previously unidentified point of
mercury inhibition of UROD. These findings lend further support to the proposed
utility of urinary porphyrin changes as a biomarker of exposure and potential
toxicity in subjects with mercury exposure. Additionally, these findings
demonstrate the successful application of a computational model for
characterizing complex metabolic responses and interactions associated with
both toxicant exposure and genetic variation in human subjects.
http://www.ncbi.nlm.nih.gov/pubmed/?term=16214298

“Mercury (Hg) exposure in various forms remains a persistent public health
concern in many parts of the world ... these findings demonstrate the
successful application of a computational model for characterizing complex
metabolic responses and interactions associated with both toxicant exposure and
genetic variation in human subjects.”

Neuro Endocrinology Letters • February 2006

Metal-specific lymphocyte reactivity is downregulated after dental metal
replacement Author information Yaqob A1, Danersund A, Stejskal VD, Lindvall A,
Hudecek R, Lindh U. Foundation for Metal Biology, Uppsala, Sweden Abstract
OBJECTIVES This study was done to evaluate the results and clinical relevance
of an optimized lymphocyte proliferation test, MELISA, for metal-induced
inflammation in patients with CFS-like symptoms. The treatment of patients
consisted of the replacement of incompatible dental materials (RID) together
with supportive anti-oxidant therapy. DESIGN OF THE STUDY 513 patients were
tested by MELISA at the beginning of the study. Out of this group, 248 patients
were available for follow-up MELISA after RID. METHODS In MELISA, lymphocytes
are isolated from the blood and cultivated with different metal salts in tissue
culture medium containing 10% inactivated human AB+ serum or autologous serum.
After 5 days, the presence of metal-reactive lymphocytes are measured by
isotope labelling of newly formed DNA in growing lymphoblasts and evaluated by
calculating the Stimulation Index. RESULTS Nickel was the most common
sensitizer, followed by inorganic mercury, thimerosal, lead, cadmium, palladium
and gold. After RID treatment, a decrease of metal-specific lymphocyte
responses in patients who reacted to metals at the beginning of the study could
be observed. The cultivation of lymphocytes in autologous and homologous serum
did not significantly affect the results. Simultaneous, the health status of
patients improved as well. CONCLUSIONS Replacement of incompatible dental
materials resulted in down-regulation of metalinduced lymphocyte sensitivity in
vitro, as well as in the improvement of health status of majority of patients
with unspecific CFS-like symptoms. http://www.ncbi.nlm.nih.gov/pubmed/16648791

“Replacement of incompatible dental materials resulted in down-regulation of
metal-induced lymphocyte sensitivity in vitro, as well as in the improvement of
health status of majority of patients with unspecific Chronic Fatigue-like
symptoms.”

Oxford Journals
Toxicological Sciences • April 2006

Thimerosal Induces Apoptosis in a Neuroblastoma Model via the cJun N-Terminal
Kinase Pathway Author Information Michelle L. Herdman*, Aileen Marcelo*, Ying
Huang† Richard M. Niles†, Sanjit Dhar‡ and Kinsley Kelley Kiningham*
Departments of *Pharmacology, Physiology and Toxicology and †Biochemistry and
Microbiology Joan C. Edwards School of Medicine, Marshall University
Huntington, West Virginia 25704 ‡Graduate Center for Toxicology University of
Kentucky Lexington, Kentucky 40536 kiningham@marshall.edu. Abstract The cJun
N-terminal kinase (JNK)-signaling pathway is activated in response to a variety
of stimuli, including environmental insults, and has been implicated in
neuronal apoptosis. In this study, we investigated the role that the JNK
pathway plays in neurotoxicity caused by thimerosal, an ethylmercury-containing
preservative. SK-NSH cells treated with thimerosal (0–10μM) showed an increase
in the phosphorylated (active) form of JNK and cJun with 5 and 10μM thimerosal
treatment at 2 and 4 h. To examine activator protein-1 (AP-1) transcription,
cells were transfected with a pGL2 vector containing four AP-1 consensus
sequences and then treated with thimerosal (0–2.5μM) for 24 h. Luciferase
studies showed an increase in AP-1 transcriptional activity upon thimerosal
administration. To determine the components of the AP-1 complex, cells were
transfected with a dominant negative to either cFos (A-Fos) or cJun (TAM67).
Reporter analysis showed that TAM67, but not A-Fos, decreased AP1
transcriptional activity, indicating a role for cJun in this pathway. To assess
which components are essential to apoptosis, cells were treated with a
cell-permeable JNK inhibitor II (SP600125) or transfected with TAM67, and the
downstream effectors of apoptosis were analyzed. Cells pretreated with SP600125
showed decreases in activation of caspases 9 and 3, decreases in degradation of
poly(ADP-ribose) polymerase (PARP), and decreased levels of proapoptotic Bim,
in comparison to cells treated with thimerosal alone. However, cells
transfected with TAM67 showed no changes in those same components. Taken
together, these results indicate that thimerosal-induced neurotoxicity occurs
through the JNK-signaling pathway, independent of cJun activation, leading
ultimately to apoptotic cell death.
http://toxsci.oxfordjournals.org/content/92/1/246.long

“Taken together, these results indicate that thimerosal-induced neurotoxicity
occurs through the JNK-signaling pathway, independent of cJun activation,
leading ultimately to apoptotic cell death.”

Medical Science Monitor • June 2006

An assessment of downward trends in neurodevelopmental disorders in the USA
following removal of Thimerosal from childhood vaccines Author Information
Geier DA1, Geier MR. Department of Biochemistry George Washington University,
Washington, DC, USA Abstract BACKGROUND The US is in the midst of an epidemic
of neurodevelopmental disorders (NDs). Thimerosal is an ethylmercury-containing
compound added to some childhood vaccines. Several previous epidemiological
studies conducted in the US have associated Thimerosal-containing vaccine (TCV)
administration with NDs. MATERIAL/METHODS An ecological study was undertaken to
evaluate NDs reported to the Vaccine Adverse Event Reporting System (VAERS)
from 1991 through 2004 by date of receipt and by date of vaccine
administration. The NDs examined included autism, mental retardation, and
speech disorders. Statistical trend analysis was employed to evaluate the
effects of removal of Thimerosal on the proportion of NDs reported to VAERS.
RESULTS There was a peak in the proportion of ND reports received by VAERS in
2001-2002 and in the proportion of ND reports by date of vaccine administration
in 1998. There were significant reductions in the proportion of NDs reported to
VAERS as Thimerosal was begun to be removed from childhood vaccines in the US
from mid1999 onwards. CONCLUSIONS The present study provides the first
epidemiological evidence showing that as Thimerosal was removed from childhood
vaccines, the number of NDs has decreased in the US. The analysis techniques
utilized attempted to minimize chance or bias/ confounding. Additional research
should be conducted to further evaluate the relationship between TCVs and NDs.
This is especially true because the handling of vaccine safety data from the
National Immunization Program of the CDC has been called into question by the
Institute of Medicine of the National Academy of Sciences in 2005.
http://www.ncbi.nlm.nih.gov/pubmed/16733480

“The present study provides the first epidemiological evidence showing that as
Thimerosal was removed from childhood vaccines, the number of
neurodevelopmental disorders has decreased in the US.

Neuro Endocrinology Letters • August 2006

A meta-analysis epidemiological assessment of neurodevelopmental disorders
following vaccines administered from 1994 through 2000 in the United States
Author information Geier DA1, Geier MR. The Institute for Chronic Illnesses,
Inc., Silver Spring, MD 20905, USA mgeier@comcast.net Abstract BACKGROUND
Thimerosal is an ethylmercury-containing compound (49.6% mercury by weight)
used as at the preservative level in vaccines (0.005% to 0.01%). METHODS
Statistical modeling in a meta-analysis epidemiological assessment of the
Vaccine Adverse Event Reporting System (VAERS) for neurodevelopment disorders
(NDs) reported following Diphtheria-Tetanus-whole-cell-Pertussis (DTP) vaccines
in comparison to Diphtheria-Tetanus-whole-cell-Pertussis-Haemophilus Influenzae
Type b (DTPH) vaccines (administered: 1994-1997) and following
Thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis (DTaP), vaccines
in comparison to Thimerosal-free DTaP vaccines (administered: 19972000), was
undertaken. RESULTS Significantly increased adjusted (sex, age, vaccine type,
vaccine manufacturer) risks of autism, speech disorders, mental retardation,
personality disorders, thinking abnormalities, ataxia, and NDs in general, with
minimal systematic error or confounding, were associated with TCV exposure.
CONCLUSION It is clear from the results of the present epidemiological study
and other recently published data associating mercury exposure with childhood
NDs, additional ND research should be undertaken in the context of evaluating
mercury-associated exposures, especially from Thimerosal-containing vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/16807526

“It is clear from the results of the present epidemiological study and other
recently published data associating mercury exposure with childhood
neurological disorders.”

“Autism was recently associated with a urinary porphyrin pattern indicative of mercury toxicity ...”
Neurotoxicity Research • August 2006

A prospective assessment of porphyrins in autistic disorders: a potential
marker for heavy metal exposure Author information Geier DA1, Geier MR. The
Institute for Chronic Illnesses, Silver Spring, MD 20905, USA Abstract Autism
was recently associated with a urinary porphyrin pattern indicative of mercury
toxicity in a large cohort of French children. The IRB of the Institute for
Chronic Illnesses approved the present study. A total of 37 consecutive
American patients (> or = 7 years-old) with autism spectrum disorders (ASDs)
(Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-DSM IV),
born from 1983-1998, that presented to the Genetic Centers of America for
outpatient genetic evaluations were prospectively examined for urinary
prophryin levels (LabCorp, Inc.) from June 2005-June 2006. Imaging and
laboratory testing were conducted on each patient to rule-out other causal
factors for their ASDs. As controls, age-, sex-, and race-matched neurotypical
ASD siblings were examined. An apparent dose-response effect was observed
between autism severity and increased urinary coproporphyrins. Patients with
non-chelated autism (2.25-fold, 83% had levels > 2 SD above the control mean)
and non-chelated ASDs (2-fold, 58% had levels > 2 SD above the control mean),
but not patients with non-chelated pervasive developmental delay-not otherwise
specified (PDD-NOS) or Asperger’s disorder (1.4-fold, 46% had levels > 2 SD
above the control mean), had significantly increased median coproporphyrin
levels versus controls. A significant increase (1.7-fold) in median
coproporphyrin levels was observed among non-chelated ASD patients versus
chelated ASD patients. Porphyrins should be routinely clinically measured in
ASDs, and potential ASD treatments should consider monitoring porphyrin levels.
Additional research should be conducted to evaluate the potential role for
mercury exposure in some ASDs. http://www.ncbi.nlm.nih.gov/pubmed/17000470

“Significantly increased odds ratios for autism, speech disorders,
mental retardation, infantile spasms, and thinking abnormalities reported to
VAERS were found following DTP vaccines in comparison to DTPH vaccines with
minimal bias or systematic error.” Journal Of Toxicology And Environmental
Health Part A • August 2006

An evaluation of the effects of thimerosal on neurodevelopmental disorders
reported following DTP and Hib vaccines in comparison to DTPH vaccine in the
United States Author information Geier DA1, Geier MR. The Genetic Centers of
America, Silver Spring, Maryland 20905, USA mgeier@comcast.net Abstract
Thimerosal is an ethylmercury (49.55% mercury by weight) preservative
historically added to some vaccines. Toxicokinetic studies showed children in
the United States received doses of mercury from Thimerosal-containing vaccines
(TCVs) in excess of safety guidelines. In the United States during the 1990s,
diphtheria-tetanus-pertussis (DTP) and Haemophilus influenzae type b (Hib)
vaccines (maximally, 50 mug mercury per joint administration) and
diphtheria-tetanus-pertussis-Haemophilus influenzae type b (DTPH) vaccines (25
mug mercury per administration) were given to children in the same childhood
vaccination schedule at 2, 4, 6, and 15-18 mo, so that children receiving DTP
and Hib vaccines may have maximally received an additional 100 mug more mercury
exposure from TCVs than children administered DTPH vaccines. A case-control
epidemiological study of neurodevelopmental disorders (NDs) reported to the
Vaccine Adverse Event Reporting System (VAERS) (online public access version;
updated 31 August 2004) following administration of DTP vaccines in comparison
DTPH vaccines manufactured by Lederle Laboratories (Pearl River, NY) from 1994
through 1998 was undertaken. Significantly increased odds ratios for autism,
speech disorders, mental retardation, infantile spasms, and thinking
abnormalities reported to VAERS were found following DTP vaccines in comparison
to DTPH vaccines with minimal bias or systematic error. Additional ND research
should be undertaken in the context of evaluating mercury-associated exposures,
especially since in 2005 the Institute of Medicine issued a report calling into
question handling of vaccine safety data by the National Immunization Program
of the Centers for Disease Control and Prevention.
http://www.ncbi.nlm.nih.gov/pubmed/16766480

Environmental Toxicology And Pharmacology • September 2006

Thimerosal induces oxidative stress in HeLa S epithelial cells Author
information Lee S1, Mian MF, Lee HJ, Kang CB, Kim JS, Ryu SH, Suh PG, Kim E.
Laboratory of Toxicology Institute of Animal Medicine College of Veterinary
Medicine Gyeongsang National University Gajwa-Dong, Jinju 660-701 Republic of
Korea Abstract Thimerosal is one of the most widely used preservatives and is
found in a variety of biological products, including vaccines, contact lens
cleaning solutions, and cosmetics. It has been reported to have harmful effects
on epithelial tissues, such as causing conjunctivitis or contact dermatitis.
However, the molecular mechanism of its toxicity has not been characterized
using epithelial tissues. In the present study, we report that reactive oxygen
species play a key role in thimerosal-induced cytotoxicity in HeLa S epithelial
cells. Thimerosal significantly reduced HeLa S cell viability and it was
associated with a decrease in intracellular glutathione levels. Flow cytometric
cell cycle analysis showed a marked increase in the hypodiploidic cell
population, indicating apoptosis of thimerosal-treated cells. The apoptotic
cell death of epithelial cells was confirmed by observing a significant
increase of caspase-3 activity in the cytosolic fraction of the treated cells.
Thimerosal also induced a concentration-dependent increase of genomic DNA
fragmentation, a biochemical hallmark of apoptosis. Hoechst 33342 nuclear
staining demonstrated apoptoticfragmented multinuclei in thimerosal-treated
cells. All the thimerosal-mediated toxic responses observed in the present
study were almost completely suppressed by pretreating cells with
N-acetyl-lcysteine, a radical scavenger. Taken together, these results suggest
for the first time that epithelial cytotoxicity of thimerosal is mediated by
oxidative stress. http://www.ncbi.nlm.nih.gov/pubmed/?term=21783709

“[thimerosal] has been reported to have harmful effects on epithelial tissues,
such as causing conjunctivitis or contact dermatitis. Thimerosal also induced a
concentration-dependent increase of genomic DNA fragmentation, a biochemical
hallmark of apoptosis. Taken together, these results suggest for the first time
that epithelial cytotoxicity of thimerosal is mediated by oxidative stress.”

“... some autism spectrum disorders may result from ... exposure to mercury.”
Neuro Endocrinology Letters • December 2006

A clinical trial of combined anti-androgen and anti-heavy metal therapy in
autistic disorders Author information Geier DA1, Geier MR. Institute of Chronic
Illnesses, Silver Spring, MD 20905, USA Abstract BACKGROUND A medical
hypothesis has suggested that some autism spectrum disorders (ASDs) may result
from interactions between the methionine cycle-transsulfuration and androgen
pathways following exposure to mercury. METHODS The IRB of the Institute for
Chronic Illnesses approved the present study. A novel treatment was utilized
combining LUPRON (leuprolide acetate, TAP Pharmaceuticals, Inc.) and CHEMET
(meso-2, 3-dimercaptosuccinic acid--DMSA, McNeil Consumer Products Company) on
11 consecutive children with ASDs. RESULTS A significant (p<0.01) overall
improvement from the 70-79th percentile of severity (median baseline score=87)
at baseline to the 40-49th percentile of severity (median end of study period
score=63) at the end of the study was observed for patients treated for a
median of approximately 4 months. Significant improvements in sociability,
cognitive awareness, behavior, and clinical symptoms/behaviors of
hyperandrogenemia were also observed. Significant decreases in blood androgens
and increases in urinary heavy metal concentrations were observed. Minimal drug
adverse effects were found. CONCLUSION This study provides the first clinical
evidence for the benefit that combined anti-androgen and anti-heavy metal
therapy may have on some children with ASDs. Additional studies should examine
androgen and heavy metal mechanisms of action in ASDs, and future ASD treatment
protocols should consider androgens and heavy metals.
http://www.ncbi.nlm.nih.gov/pubmed/17187010

[an example of disagreement within the research community]

Critical Reviews In Toxicology • December 2007

The toxicology of mercury and its chemical compounds

Comments on the article “the toxicology of mercury and its chemical compounds”
by Clarkson and Magos (2006)

Author information

Author information

Clarkson TW1, Magos L.

Mutter J1, Naumann J, Guethlin C.

Department of Environmental Medicine University of Rochester School of Medicine
New York, USA Twc30@aol.co

University Hospital Institute for Environmental Medicine and Hospital
Epidemiology Freiburg, Germany joachim.mutter@uniklinik-freiburg.de

Abstract

Abstract

This review covers the toxicology of mercury and its compounds. Special
attention is paid to those forms of mercury of current public health concern.
Human exposure to the vapor of metallic mercury dates back to antiquity but
continues today in occupational settings and from dental amalgam. Health risks
from methylmercury in edible tissues of fish have been the subject of several
large epidemiological investigations and continue to be the subject of intense
debate. Ethylmercury in the form of a preservative, thimerosal, added to
certain vaccines, is the most recent form of mercury that has become a public
health concern. The review leads to general discussion of evolutionary aspects
of mercury, protective and toxic mechanisms, and ends on a note that mercury is
still an “element of mystery.”

Clarkson and Magos (2006) provide their perspectives on the toxicology of
mercury vapor and dental amalgam. As scientists who are involved in preparing a
German federal guideline regarding dental amalgam, we welcome additional
scientific data on this issue. However, Clarkson and Magos do not present all
the relevant studies in their review.

Critical Reviews In Toxicology • December 2006

http://www.ncbi.nlm.nih.gov/pubmed/16973445

The additional data provided here show that: (a) Dental amalgam is the main
source of human total mercury body burden, because individuals with amalgam
have 2-12 times more mercury in their body tissues compared to individuals
without amalgam; (b) there is not necessarily a correlation between mercury
levels in blood, urine, or hair and in body tissues, and none of the parameters
correlate with severity of symptoms; (c) the half-life of mercury deposits in
brain and bone tissues could last from several years to decades, and thus
mercury accumulates over time of exposure; (d) mercury, in particular mercury
vapor, is known to be the most toxic nonradioactive element, and is toxic even
in very low doses, and (e) some studies which conclude that amalgam fillings
are safe for human beings have important methodogical flaws. Therefore, they
have no value for assessing the safety of amalgam.
http://www.ncbi.nlm.nih.gov/pubmed/17661216

Toxicology • February 2007

Cell death and cytotoxic effects in YAC-1 lymphoma cells following exposure to
various forms of mercury Author information Yole M1, Wickstrom M, Blakley B.
Department of Veterinary Biomedical Sciences Western College of Veterinary
Medicine 52 Campus Drive, University of Saskatchewan Saskatoon SK S7N 5B4,
Canada yole@sask.usask.ca Abstract The effects of 1 min-4 h exposures to four
Hg compounds (mercuric chloride [HgCl2], methyl mercuric chloride [CH3HgCl],
p-chloromercuribenzoate [p-CMB] and thimerosal [TMS;
ethylmercurithiosalicylate]) on cell death, microtubules, actin, CD3 receptor
expression, protein tyrosine phosphorylation (PTyr-P) and intracellular calcium
([Ca2+]i) levels were investigated in YAC-1 lymphoma cells using flow
cytometry. YOPRO-1 (YP) and propidium iodide (PI) dye uptake indicated all
forms of Hg tested were toxic at concentrations ranging from 25.8-48.4 microM,
with two distinct patterns of effects. Early apoptosis was prolonged for
CH3HgCl- and TMS-treated cells, with more than 50% remaining YP+/PI- after 4h.
Both CH3HgCl and TMS induced complete loss of beta-tubulin fluorescence,
indicative of microtubule depolymerization and inhibition of tubulin synthesis
and/ or beta-tubulin degradation, while F-actin fluorescence diminished to a
lesser degree and only after loss beta-tubulin. CH3HgCl and TMS induced an
almost immediate two-fold increase in CD3 fluorescence, with levels returning
to baseline within minutes. With continued exposure, CD3 fluorescence was
reduced to approximately 50% of baseline values. Both compounds also increased
PTyr-P two- to three-fold immediately, with levels returning to baseline at 4h.
Similarly, two- to three-fold increases in [Ca2+]i were noted after 1 min
exposure. [Ca2+]i increased progressively, reaching levels five- to eight-fold
greater than control values. In contrast, dye uptake was delayed with HgCl2 and
p-CMB, although cell death proceeded rapidly, with almost all non-viable cells
being late apoptotic (YP+/PI+) by 4h. p-CMB produced early reductions in
F-actin, and after 4h, complete loss of F-actin with only partial reduction of
total beta-tubulin was seen with both p-CMB and HgCl2. HgCl2 reduced CD3
expression and PTyr-P slightly within minutes, while p-CMB produced similar
effects on CD3 only at 4h, at which time PTyr-P was increased two- to
three-fold. Both compounds increased [Ca2+]i within minutes, though levels
remained under twice the baseline concentration after 15 min exposure. With
continued exposure, [Ca2+]i increased to levels two- to five-fold greater than
control values. These findings indicate the two groups of Hg compounds may
induce cell death by distinct pathways, reflecting interactions with different
cellular targets leading to cell death.
http://www.ncbi.nlm.nih.gov/pubmed/?term=17210217

“These findings indicate the two groups of mercury compounds may induce cell
death by distinct pathways, reflecting interactions with different cellular
targets leading to cell death.”

Integrative Medicine • Vol. 6, No. 2 • April 2007

Heavy-Metal Toxicity—With Emphasis on Mercury by John Neustadt, ND, and Steve
Pieczenik, MD, PhD • Recommended

Report •

http://montanaim.com/pubs/Heavy_Metals_Article.pdf

“8 of 9 patients examined were exposed to significant mercury
from Thimerosal-containing biologic/vaccine preparations during their
fetal/infant developmental periods, and subsequently, between 12 and 24 mo of
age, these previously normally developing children suffered mercury toxic
encephalopathies that manifested with clinical symptoms consistent with
regressive Autistic Spectrum Disorders.” Journal Of Toxicology And
Environmental Health Part A • May 2007

A case series of children with apparent mercury toxic encephalopathies
manifesting with clinical symptoms of regressive autistic disorders Author
information Geier DA1, Geier MR. Institute of Chronic Illnesses, Inc., Silver
Spring, Maryland, USA Abstract Impairments in social relatedness and
communication, repetitive behaviors, and stereotypic abnormal movement patterns
characterize autism spectrum disorders (ASDs). It is clear that while genetic
factors are important to the pathogenesis of ASDs, mercury exposure can induce
immune, sensory, neurological, motor, and behavioral dysfunctions similar to
traits defining or associated with ASDs. The Institutional Review Board of the
Institute for Chronic Illnesses (Office for Human Research Protections, U.S.
Department of Health and Human Services, IRB number IRB00005375) approved the
present study. A case series of nine patients who presented to the Genetic
Centers of America for a genetic/developmental evaluation are discussed. Eight
of nine patients (one patient was found to have an ASD due to Rett’s syndrome)
(a) had regressive ASDs; (b) had elevated levels of androgens; (c) excreted
significant amounts of mercury post chelation challenge; (d) had biochemical
evidence of decreased function in their glutathione pathways; (e) had no known
significant mercury exposure except from Thimerosal-containing
vaccines/Rho(D)-immune globulin preparations; and (f) had alternate causes for
their regressive ASDs ruled out. There was a significant dose-response
relationship between the severity of the regressive ASDs observed and the total
mercury dose children received from Thimerosal-containing vaccines/Rho
(D)-immune globulin preparations. Based upon differential diagnoses, 8 of 9
patients examined were exposed to significant mercury from
Thimerosal-containing biologic/vaccine preparations during their fetal/infant
developmental periods, and subsequently, between 12 and 24 mo of age, these
previously normally developing children suffered mercury toxic encephalopathies
that manifested with clinical symptoms consistent with regressive ASDs.
Evidence for mercury intoxication should be considered in the differential
diagnosis as contributing to some regressive ASDs.
http://www.ncbi.nlm.nih.gov/pubmed/17454560

Journal Of Maternal, Fetal And Neonatal Medicine • May 2007

A prospective study of thimerosal-containing Rho(D)-immune globulin
administration as a risk factor for autistic disorders Author information Geier
DA1, Geier MR. The Institute of Chronic Illnesses, Silver Spring, MD, USA
Abstract BACKGROUND This study evaluated the relationship between prenatal
mercury exposure from thimerosal (49.55% mercury by weight)-containing
Rho(D)-immune globulins (TCRs) and autism spectrum disorders (ASDs). METHODS
The Institutional Review Board of the Institute for Chronic Illnesses approved
the present study. A total of 53 consecutive non-Jewish Caucasian patients with
ASDs (Diagnostic and statistical manual of mental disorders, fourth ed. - DSM
IV) born between 1987 and 2001 who presented to the Genetic Centers of America
for outpatient genetic/developmental evaluations were prospectively collected
from June 1, 2005 through March 31, 2006. Imaging and laboratory testing were
conducted on each patient to rule out other causal factors for their ASDs. As
race-matched controls, the frequency of Rh negativity was determined from 926
non-Jewish Caucasian pregnant women who had presented for outpatient prenatal
genetics care to the Genetic Centers of America between 1980 and 1989. RESULTS
Children with ASDs (28.30%) were significantly more likely (odds ratio 2.35,
95% confidence interval 1.17-4.52, p < 0.01) to have Rh-negative mothers than
controls (14.36%). Each ASD patient’s mother was determined to have been
administered a TCR during her pregnancy. CONCLUSION The results provide
insights into the potential role prenatal mercury exposure may play in some
children with ASDs. http://www.ncbi.nlm.nih.gov/pubmed/17674242

“Each Autisic Spectrum Disorder patient’s mother was determined to have been
administered a Thimerosal-containing vaccine during her pregnancy … The results
provide insights into the potential role prenatal mercury exposure may play in
some children with Autisic Spectrum Disorders.”

American Journal Of Perinatology • August 2007

Exposure to mercury during the first six months via human milk and vaccines:
modifying risk factors Author information Dórea JG. Faculty of Health Sciences
Universidade de Brasília Brasília, Brazil Abstract Breastfeeding is the best
natural protection infants have against morbidity and mortality, and the
development of safe and effective vaccines has made it possible to immunize
children against infectious disease. Both of these mechanisms for ensuring good
health in children may be compromised by contact with mercury (Hg). Maternal
exposure to environmental Hg during pregnancy can predispose nursing children
to neurodevelopmental disorders. Despite the World Health Organization
assurance that thimerosalpreserved vaccines are safe to use in infants, the
United States, the European Union, and dozens of other countries have
eliminated thimerosal as a vaccine preservative and stopped the immunization of
children with such vaccines. Because of the increase in environmental pollution
and the need to produce cheap and safe vaccines, there is a need to address the
uncertainty of vaccine-ethylmercury risk of toxicity and Hg exposure during
breastfeeding. http://www.ncbi.nlm.nih.gov/pubmed/17564957

“Maternal exposure to environmental mercury during pregnancy can predispose
nursing children to neurodevelopmental disorders.”

European Journal Of Pediatrics • September 2007

Hair mercury in breast-fed infants exposed to thimerosal-preserved vaccines
Author information Marques RC1, Dórea JG, Fonseca MF, Bastos WR, Malm O.
Fundação Universidade Federal de Rondônia Porto Velho, RO, Brazil Abstract
Because of uncertainties associated with a possible rise in neurodevelopmental
deficits among vaccinated children, thimerosalpreserved vaccines have not been
used since 2004 in the USA (with the exception of thimerosal-containing
influenza vaccines which are routinely recommended for administration to
pregnant women and children), and the EU but are widely produced and used in
other countries. We investigated the impact of thimerosal on the total Hg in
hair of 82 breast-fed infants during the first 6 months of life. The infants
received three doses of the hepatitisB vaccine (at birth, 1 and 6 months) and
three DTP (diphtheria, tetanus, and pertussis) doses at 2, 4 and 6 months,
according to the immunization schedule recommended by the Ministry of Health of
Brazil. The thimerosal in vaccines provided an ethylmercury (EtHg) exposure of
25 microgHg at birth, 30, 60 and 120 days, and 50 microgHg at 180 days. The
exposure to vaccine-EtHg represents 80% of that expected from total breast
milk-Hg in the first month but only 40% of the expected exposure integrated in
the 6 months of breastfeeding. However, the Hg exposure corrected for body
weight at the day of immunization was much higher from thimerosal- EtHg (5.7 to
11.3 microgHg/kg b.w.) than from breastfeeding (0.266 microgHg/kg b.w.). While
mothers showed a relative decrease (-57%) in total hair-Hg during the 6 months
lactation there was substantial increase in the infant’s hair-Hg (446%). We
speculate that dose and parenteral mode of thimerosal-EtHg exposure modulated
the relative increase in hair-Hg of breast-fed infants at 6 months of age.
http://www.ncbi.nlm.nih.gov/pubmed/17237965

“Because of uncertainties associated with a possible rise in
neuro-developmental deficits among vaccinated children, thimerosal-preserved
vaccines have not been used since 2004 in the USA (with the exception of
thimerosal-containing influenza vaccines which are routinely recommended for
administration to pregnant women and children) ...”

Journal Of Toxicology And Environmental Health Part A • October 2007

A prospective study of mercury toxicity biomarkers in autistic spectrum
disorders Author information Geier DA1, Geier MR. Institute of Chronic
Illnesses Silver Spring, Maryland, USA Abstract Porphyrins are derivatives
formed in the heme synthesis pathway and porphyrins afford a measure of
xenobiotic exposure. The steps in the heme pathway most vulnerable to heavy
metal inhibition are uroporphyrin decarboxylase (UROD) and coproporphyrinogen
oxidase (CPOX) reactions. Mercury toxicity was associated with elevations in
urinary coproporphyrin (cP), pentacarboxyporphyrin (5cxP), and
precoproporphyrin (prcP) (also known as keto-isocoproporphyrin) levels. Two
cohorts of autistic patients in the United States and France had urine
porphyrin levels associated with mercury toxicity. A prospective study of
urinary porphyrin testing at LabCorp (United States) and the Laboratoire
Philippe Auguste (France) involving 71 autism spectrum disorder (ASD) patients,
neurotypical sibling controls, and general population controls was undertaken.
ASD patients had significant elevations in urinary levels of cP, 5cxP, and prcP
relative to controls, and > 50% of ASD patients had urinary cP levels more than
2 standard deviations above the mean values for neurotypical sibling controls.
Significant reductions in urinary 5cxP and cP levels were observed in ASD
patients following chelation. A significant correlation was found between
urinary porphyrins measured at LabCorp and those measured at the Laboratoire
Philippe Auguste on individual ASD patients. The established developmental
neurotoxicity attributed to mercury and biochemical/genomic evidence for
mercury susceptibility/toxicity in ASDs indicates a causal role for mercury.
Urinary porphyrin testing is clinically available, relatively inexpensive, and
noninvasive. Porphyrins need to be routinely measured in ASDs to establish if
mercury toxicity is a causative factor and to evaluate the effectiveness of
chelation therapy. http://www.ncbi.nlm.nih.gov/pubmed/17885929

“The established developmental neurotoxicity attributed to mercury and
biochemical/genomic evidence for mercury susceptibility/toxicity in Autistic
Spectrum Disorders indicates a causal role for mercury”

Toxicological Sciences • October 2007

Modeling Neurodevelopment Outcomes and Ethylmercury Exposure from
Thimerosal-Containing Vaccines Author Information José G. Dórea*,1 and Rejane
C. Marques† *Universidade de Brasília, Brasília, DF, Brazil †Fundação
Universidade Federal de Rondônia, Porto Velho, RO, Brazil dorea@rudah.com.br
Dear Editor The neurotoxic effects of ethylmercury (EtHg) accidentally consumed
in Iraq were sufficient to withdraw ethylmercury-containing fungicides as seed
dressing. Despite that, not only did thimerosal continue to be used in
pharmaceutical preparations but also toxicological interest in EtHg-derived
substances diminished considerably and was never addressed with regard to the
small quantities used as a vaccine preservative. Thimerosal-containing vaccines
(TCV) have no record of overt clinical neurological consequences due to EtHg,
and the plausibility of subtle neurotoxic effects in children has been
recognized only recently by the United States and other industrialized
countries. In this context, we welcome the interesting work of Berman et al.
(2008); it is clear that this assiduous study (in immunologically susceptible
mice) took into consideration doses and schedules of TCV-Hg concentrations that
had been used in infants in the United States. Their mice model does not,
however, cover the full extent of modifying factors associated with TCV-Hg
exposure in the majority of immature and newborns around the world that still
have to depend on TCV. According to Berman et al. (2008), the United States
vaccination scheduled exposed a total of 125 μgHg distributed at 2, 2, and 6
months through TCV (hepatitis B and DTP). This type of vaccine is no longer
used in industrialized countries but it is still used all over the world. We
know that thimerosal concentrations vary among brands of vaccines and also that
immunization schedules vary depending on a country’s health policy; not only
that but new outbreaks of disease introduce additional new vaccines (which may
contain thimerosal) during the first year of life. As an example, the public
health services of Brazil, like other countries, still uses several brands of
hepatitis B vaccine (containing thimerosal as preservative) with concentrations
ranging from 12.5 to 50 μgHg per 0.5 ml shot. Another salient difference
between countries that use TCV (like Brazil) and the United States is that in
the former country hepatitis B inoculation starts within the first 12–24 h
after birth (Marques et al., 2007) and is administered to low-birth weight
≥2000 g (Ministério, da Saúde, 2006 and premature babies who are also
recommended a fourth shot as an additional booster (DI/DH/CVE, 2006). In such
situations, not only toxicokinetics (TK) but especially toxicodynamics (TD) of
EtHg are entirely different between a 1-dayold (with different stages of
immaturity and birth weight) and a 60-day-old child (as modeled). The newborn
presents several physiological degrees of immaturity in the excretory system
(kid-

neys and bile formation) and target organ (central nervous system, CNS) that
are important modifiers of EtHg TK and TD. These features are inversely
accentuated by gestational age and birth weight. Under such circumstances,
unbound circulating EtHg in a newborn (and immature) may not be eliminated as
fast as in a 2-month-old baby and thus will be readier to cross the more
vulnerable blood-brain barrier (BBB). The newborn BBB increases in
effectiveness with age; therefore, the free EtHg can more easily penetrate the
immature CNS (Dorea, 2007). As a consequence, the smaller the body size and
blood volume, the more altered the TD and TK of EtHg. Indeed, Stajich et al.
(2000) showed that preterm infants do not metabolize Hg efficiently.
Collectively, studies show that larger babies have significantly higher mean
liver metallothionein than smaller babies (Dorea, 2007). Factors associated
with protein-binding capacity, excretion mechanisms, and enzyme activities are
immature in the neonate and modulate differences in adverse effects between
newborns and infants exposed to neurotoxic substances. During the period of
immaturity, not only plasma albumin but also total protein concentrations
decrease (Dorea, 2007). The best example in differences between neurotoxic
effects is the type of albumin and competition for binding sites (due to
increased circulatory concentrations of bilirubin). Albumin binding (to
bilirubin) is less effective during the first postnatal days and, as a
consequence, excess free bilirubin can cross the BBB at early stages of the
postnatal CNS immaturity and cause brainstem abnormalities; albumin priming can
be effective in attenuating effects caused by unbound bilirubin (Dorea, 2007).
We do not dispute the conclusions drawn by Berman et al. regarding Hg and the
neurobiology of autism; however, we think it is possible to take their findings
one step further in regards to thimerosal neurotoxicity. We contend that these
findings are appropriate for U.S.-like scenarios (as intended by the authors)
but are not sufficient to address the current TCV schedules in the majority of
newborns and infants around the world. TCV are used worldwide in vaccination
schedules that include more of these vaccines at an earlier age. Unfortunately,
the differences that set newborns (especially low-birth-weights and prematures)
apart from 2-month-old infants have not yet been modeled in experimental
studies and remain neglected in TK and TD knowledge of TCV-EtHg exposure. We
hope that studies like Berman et al. (2008) can inspire conventional toxicology
to address uncertainties regarding current serial EtHg exposure in newborns and
infants that have to take TCV.

http://toxsci.oxfordjournals.org/content/103/2/414.long#ref-1

“the hair sample analysis results offer some support for the idea that persons with autism
may be less efficient and more variable at eliminating mercury from the blood.”
Journal Of Child Neurology • November 2007

Blood levels of mercury are related to diagnosis of autism: a reanalysis of an
important data set Author information Desoto MC1, Hitlan RT. Department of
Psychology University of Northern Iowa Cedar Falls, Iowa 50614, USA
cathy.desoto@uni.edu Abstract The question of what is leading to the apparent
increase in autism is of great importance. Like the link between aspirin and
heart attack, even a small effect can have major health implications. If there
is any link between autism and mercury, it is absolutely crucial that the first
reports of the question are not falsely stating that no link occurs. We have
reanalyzed the data set originally reported by Ip et al. in 2004 and have found
that the original p value was in error and that a significant relation does
exist between the blood levels of mercury and diagnosis of an autism spectrum
disorder. Moreover, the hair sample analysis results offer some support for the
idea that persons with autism may be less efficient and more variable at
eliminating mercury from the blood. http://www.ncbi.nlm.nih.gov/pubmed/18006963

The Journal Of Toxicology And Environmental Health Part B - Critical Reviews • December 2007

A review of Thimerosal (Merthiolate) and its ethylmercury breakdown product:
specific historical considerations regarding safety and effectiveness Author
Information Geier DA1, Sykes LK, Geier MR. The Institute of Chronic Illnesses,
Inc. Silver Spring, Maryland, USA Abstract Thimerosal (Merthiolate) is an
ethylmercury-containing pharmaceutical compound that is 49.55% mercury and that
was developed in 1927. Thimerosal has been marketed as an antimicrobial agent
in a range of products, including topical antiseptic solutions and antiseptic
ointments for treating cuts, nasal sprays, eye solutions, vaginal spermicides,
diaper rash treatments, and perhaps most importantly as a preservative in
vaccines and other injectable biological products, including Rho(D)-immune
globulin preparations, despite evidence, dating to the early 1930s, indicating
Thimerosal to be potentially hazardous to humans and inffective as an
antimicrobial agent. Despite this, Thimerosal was not scrutinized as part of
U.S. pharmaceutical products until the 1980s, when the U.S. Food and Drug
Administration finally recognized its demonstrated ineffectiveness and toxicity
in topical pharmaceutical products, and began to eliminate it from these.
Ironically, while Thimerosal was being eliminated from topicals, it was
becoming more and more ubiquitous in the recommended immunization schedule for
infants and pregnant women. Furthermore, Thimerosal continues to be
administered, as part of mandated immunizations and other pharmaceutical
products, in the United States and globally. The ubiquitous and largely
unchecked place of Thimerosal in pharmaceuticals, therefore, represents a
medical crisis. http://www.ncbi.nlm.nih.gov/pubmed/18049924

“The ubiquitous and largely unchecked place of Thimerosal in pharmaceuticals,
therefore, represents a medical crisis.”

Anales de la Facultad de Medicina • 2007

Neurotoxic effects of thimerosal at vaccines doses on the encephalon and
development in 7 day-old hamsters Laurente, Jonny, et al. Objectives To
determine if thimerosal administration in amounts equivalent to vaccines
content produces neurotoxic effects on the encephalon in postnatal hamsters and
on experimentation animals’ development. Design Experimental, prospective,
bietapic study. Setting San Fernando Faculty of Medicine, Universidad Nacional
Mayor de San Marcos. Biologic material Seven-day old hamsters. Material We
divided 45 postnatal hamsters in three groups: group A (n = 15), group B (n =
15) and group C (n = 15). We administered three intramuscular equivalent doses
of sucrose and thimerosal in 20 μL of physiological serum respectively to
groups B and C on birth-days 7 (0,227 μg), 9 (0,216 μg) and 11 (0,220 μg).
Group A received only 20 μL of saline solution. Main outcome measures Body
weight, encephalon weight, hamster’s stature and encephalon histopathological
alterations. Results Anova and student t tests showed statistical significance
in favor of low body weight, low encephalon weight and smaller stature in group
C with respect to groups A and B hamsters (p<0,000). ∼2 statistical
significance in relation to the presence of histopathological alterations in
group C was also obtained (p<0,000). We observed greater relative risk of
encephalic alterations in group C. Conclusions The administration of thimerosal
in doses equivalent to vaccines content was associated with low corporal
weight, low encephalon weight and smaller stature in postnatal hamsters.
Neurotoxic effects were also produced at encephalic level, at hippocampus
(regions CA1, CA3, DG), cerebral cortex and cerebellum (Purkinje cells and
granuloses cells) with decrease in neuronal density, neuronal necrosis, axonal
dismyelinization and gliosis. In addition, risk increase in developing any of
these alterations was high in the animal group receiving thimerosal.
http://www.scielo.org.pe/scielo.php?pid=S1025-55832007000300003&script=sci_abstract&tlng=en

“The administration of thimerosal in doses equivalent to vaccines content was
associated with low corporal weight, low encephalon weight and smaller stature
in postnatal hamsters. Neurotoxic effects were also produced at encephalic
level, at hippocampus (regions CA1, CA3, DG), cerebral cortex and cerebellum
(Purkinje cells and granuloses cells) with decrease in neuronal density,
neuronal necrosis, axonal dismyelinization and gliosis. In addition, risk
increase in developing any of these alterations was high in the animal group
receiving thimerosal.”

Pediatrics • February 2008

Mercury levels in newborns and infants after receipt of thimerosal-containing
vaccines Author information Pichichero ME1, Gentile A, Giglio N, Umido V,
Clarkson T, Cernichiari E, Zareba G, Gotelli C, Gotelli M, Yan L, Treanor J.
Department of Microbiology/Immunology, Pediatrics and Medicine University of
Rochester, Rochester, New York 14642, USA michael_pichichero@urmc.rochester.edu
Abstract OBJECTIVES Thimerosal is a mercurial preservative that was widely used
in multidose vaccine vials in the United States and Europe until 2001 and
continues to be used in many countries throughout the world. We conducted a
pharmacokinetic study to assess blood levels and elimination of ethyl mercury
after vaccination of infants with thimerosal-containing vaccines. METHODS
Blood, stool, and urine samples were obtained before vaccination and 12 hours
to 30 days after vaccination from 216 healthy children: 72 newborns (group 1),
72 infants aged 2 months (group 2), and 72 infants aged 6 months (group 3).
Total mercury levels were measured by atomic absorption. Blood mercury
pharmacokinetics were calculated by pooling the data on the group and were
based on a 1-compartment first-order pharmacokinetics model. RESULTS For groups
1, 2, and 3, respectively, (1) mean +/- SD weights were 3.4 +/- 0.4, 5.1 +/-
0.6, and 7.7 +/- 1.1 kg; (2) maximal mean +/- SD blood mercury levels were 5.0
+/- 1.3, 3.6 +/1.5, and 2.8 +/- 0.9 ng/mL occurring at 0.5 to 1 day after
vaccination; (3) maximal mean +/- SD stool mercury levels were 19.1 +/- 11.8,
37.0 +/- 27.4, and 44.3 +/- 23.9 ng/g occurring on day 5 after vaccination for
all groups; and (4) urine mercury levels were mostly nondetectable. The blood
mercury half-life was calculated to be 3.7 days and returned to prevaccination
levels by day 30. CONCLUSIONS The blood half-life of intramuscular ethyl
mercury from thimerosal in vaccines in infants is substantially shorter than
that of oral methyl mercury in adults. Increased mercury levels were detected
in stools after vaccination, suggesting that the gastrointestinal tract is
involved in ethyl mercury elimination. Because of the differing
pharmacokinetics of ethyl and methyl mercury, exposure guidelines based on oral
methyl mercury in adults may not be accurate for risk assessments in children
who receive thimerosal-containing vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18245396

“Because of the differing pharmacokinetics of ethyl and methyl mercury,
exposure guidelines based on oral methyl mercury in adults may not be accurate
for risk assessments in children who receive thimerosal-containing vaccines.”

Chemical Research In Toxicology • February 2008

Thiol-modulated mechanisms of the cytotoxicity of thimerosal and inhibition of
DNA topoisomerase II alpha Author information Wu X1, Liang H, O’Hara KA,
Yalowich JC, Hasinoff BB. Faculty of Pharmacy University of Manitoba 50 Sifton
Road, Winnipeg Manitoba, R3T 2N2, Canada Abstract Thimerosal is an organic
mercury compound that is widely used as a preservative in vaccines and other
solution formulations. The use of thimerosal has caused concern about its
ability to cause neurological abnormalities due to mercury accumulation during
a normal schedule of childhood vaccinations. While the chemistry and the
biological effects of methylmercury have been well-studied, those of thimerosal
have not. Thimerosal reacted rapidly with cysteine, GSH, human serum albumin,
and single-stranded DNA to form ethylmercury adducts that were detectable by
mass spectrometry. These results indicated that thimerosal would be quickly
metabolized in vivo because of its reactions with protein and nonprotein
thiols. Thimerosal also potently inhibited the decatenation activity of DNA
topoisomerase II alpha, likely through reaction with critical free cysteine
thiol groups. Thimerosal, however, did not act as a topoisomerase II poison and
the lack of cross-resistance with a K562 cell line with a decreased level of
topoisomerase II alpha (K/VP.5 cells) suggested that inhibition of
topoisomerase II alpha was not a significant mechanism for the inhibition of
cell growth. Depletion of intracellular GSH with buthionine sulfoximine
treatment greatly increased the K562 cell growth inhibitory effects of
thimerosal, which showed that intracellular glutathione had a major role in
protecting cells from thimerosal. Pretreatment of thimerosal with glutathione
did not, however, change its K562 cell growth inhibitory effects, a result
consistent with the rapid exchange of the ethylmercury adduct among various
thiol-containing cellular reactants. Thimerosal-induced single and double
strand breaks in K562 cells were consistent with a rapid induction of
apoptosis. In conclusion, these studies have elucidated some of the chemistry
and biological activities of the interaction of thimerosal with topoisomerase
II alpha and protein and nonprotein thiols and with DNA.
http://www.ncbi.nlm.nih.gov/pubmed/18197631

“Thimerosal-induced single and double strand breaks in K562 cells were
consistent with a rapid induction of apoptosis. In conclusion, these studies
have elucidated some of the chemistry and biological activities of the
interaction of thimerosal with topoisomerase II alpha and protein and
nonprotein thiols and with DNA.”

“This study associates Thimerosal-containing Rho(D) immune globulins
exposure with some Neurodevelopmental Disorders in children.” Neuro
Endocrinology Letters • April 2008

Neurodevelopmental disorders, maternal Rh-negativity, and Rho(D) immune
globulins: a multi-center assessment Author information Geier DA1, Mumper E,
Gladfelter B, Coleman L, Geier MR. The Institute of Chronic Illnesses, Inc.,
Silver Spring, MD 20905, USA Abstract BACKGROUND Many formulations of
Thimerosal (49.55% mercury by weight)-containing Rho(D) immune globulins (TCRs)
were routinely administered to Rh-negative mothers in the US prior to 2002.
OBJECTIVES It was hypothesized: (1) if prenatal Rho(D)-immune globulin
preparation exposure was a risk factor for neurodevelopmental disorders (NDs)
then more children with NDs would have Rh-negative mothers compared to
controls; and (2) if Thimerosal in the Rho(D)-immune globulin preparations was
the ingredient associated with NDs, following the removal of Thimerosal from
all manufactured Rho(D)-immune globulin preparations from 2002 in the US the
frequency of maternal Rh-negativity among children with NDs should be similar
to control populations. METHODS Maternal Rh-negativity was assessed at two
sites (Clinic A-Lynchburg, VA; Clinic B-Rockville and Baltimore, MD) among 298
Caucasian children with NDs and known Rh-status. As controls, maternal
Rh-negativity frequency was determined from 124 Caucasian children (born
1987-2001) without NDs at Clinic A, and the Rh-negativity frequency was
determined from 1,021 Caucasian pregnant mothers that presented for prenatal
genetic care at Clinic B (1980-1989). Additionally, 22 Caucasian patients with
NDs born from 2002 onwards (Clinics A and B) were assessed for maternal
Rh-negativity. RESULTS There were significant and comparable increases in
maternal Rh-negativity among children with NDs (Clinic: A=24.2%), autism
spectrum disorders (Clinic: A=28.3%, B=25.3%), and
attention-deficit-disorder/attention-deficit-hyperactivity-disorder (Clinic:
A=26.3%) observed at both clinics in comparison to both control groups (Clinic:
A=12.1%, B=13.9%) employed. Children with NDs born post-2001 had a maternal
Rh-negativity frequency (13.6%) similar to controls. CONCLUSION This study
associates TCR exposure with some NDs in children.
http://www.ncbi.nlm.nih.gov/pubmed/18404135

Journal Of Neurological Science • August 2008

Thimerosal exposure in infants and neurodevelopmental disorders: an assessment
of computerized medical records in the Vaccine Safety Datalink Author
information Young HA1, Geier DA, Geier MR. The George Washington University
School of Public Health and Health Services Department of Epidemiology and
Biostatistics, United States Abstract The study evaluated possible associations
between neurodevelopmental disorders (NDs) and exposure to mercury (Hg) from
Thimerosal-containing vaccines (TCVs) by examining the automated Vaccine Safety
Datalink (VSD). A total of 278,624 subjects were identified in birth cohorts
from 1990-1996 that had received their first oral polio vaccination by 3 months
of age in the VSD. The birth cohort prevalence rate of medically diagnosed
International Classification of Disease, 9th revision (ICD-9) specific NDs and
control outcomes were calculated. Exposures to Hg from TCVs were calculated by
birth cohort for specific exposure windows from birth-7 months and birth-13
months of age. Poisson regression analysis was used to model the association
between the prevalence of outcomes and Hg doses from TCVs. Consistent
significantly increased rate ratios were observed for autism, autism spectrum
disorders, tics, attention deficit disorder, and emotional disturbances with Hg
exposure from TCVs. By contrast, none of the control outcomes had significantly
increased rate ratios with Hg exposure from TCVs. Routine childhood vaccination
should be continued to help reduce the morbidity and mortality associated with
infectious diseases, but efforts should be undertaken to remove Hg from
vaccines. Additional studies should be conducted to further evaluate the
relationship between Hg exposure and NDs.
http://www.ncbi.nlm.nih.gov/pubmed/18482737

“Consistent significantly increased rate ratios were observed for autism,
autism spectrum disorders, tics, attention deficit disorder, and emotional
disturbances with ethyl mercury exposure from thimerosal containing vaccines.”

Indian Journal Of Medical Research • October 2008

A comprehensive review of mercury provoked autism Author information Geier DA1,
King PG, Sykes LK, Geier MR. The Institute of Chronic Illnesses, Silver Spring,
MD, USA mgeier@comcast.net Abstract Emerging evidence supports the theory that
some autism spectrum disorders (ASDs) may result from a combination of
genetic/biochemical susceptibility, specifically a reduced ability to excrete
mercury (Hg), and exposure to Hg at critical developmental periods.
Elemental/inorganic Hg is released into the air/water where it becomes
methylated and accumulates in animal tissues. The US population is primarily
exposed to methyl-Hg by fish consumption. In addition, many pharmaceuticals
have been, and some continue to be, a ubiquitous source of danger because they
contain mercurials. Mercurials may be found in drugs for the eye, ear, nose,
throat, and skin; in bleaching creams; as preservatives in cosmetics, tooth
pastes, lens solutions, vaccines, allergy test and immunotherapy solutions; in
antiseptics, disinfectants, and contraceptives; in fungicides and herbicides;
in dental fillings and thermometers; and many other products. Hg has been found
to cause immune, sensory, neurological, motor, and behavioural dysfunctions
similar to traits defining/associated with ASDs, and that these similarities
extend to neuroanatomy, neurotransmitters, and biochemistry. Furthermore, a
review of molecular mechanisms indicates that Hg exposure can induce death,
disorganization and/or damage to selected neurons in the brain similar to that
seen in recent ASD brain pathology studies, and this alteration may likely
produce the symptoms by which ASDs are diagnosed. Finally, a review of
treatments suggests that ASD patients who undergo protocols to reduce Hg and/or
its effects show significant clinical improvements in some cases. In
conclusion, the overwhelming preponderance of the evidence favours acceptance
that Hg exposure is capable of causing some ASDs.
http://www.ncbi.nlm.nih.gov/pubmed/19106436

“In conclusion, the overwhelming preponderance of the evidence favours
acceptance that ethyl mercury exposure is capable of causing some Autistic
Spectrum Disorders.”

Alternative Therapies In Health And Medicine • November 2008

A possible central mechanism in autism spectrum disorders, part 1 Author
information Blaylock RL. Belhaven College Jackson, Mississippi, USA Abstract
The autism spectrum disorders (ASD) are a group of related neurodevelopmental
disorders that have been increasing in incidence since the 1980s. Despite a
considerable amount of data being collected from cases, a central mechanism has
not been offered. A careful review of ASD cases discloses a number of events
that adhere to an immunoexcitotoxic mechanism. This mechanism explains the link
between excessive vaccination, use of aluminum and ethylmercury as vaccine
adjuvants, food allergies, gut dysbiosis, and abnormal formation of the
developing brain. It has now been shown that chronic microglial activation is
present in autistic brains from age 5 years to age 44 years. A considerable
amount of evidence, both experimental and clinical, indicates that repeated
microglial activation can initiate priming of the microglia and that subsequent
stimulation can produce an exaggerated microglial response that can be
prolonged. It is also known that one phenotypic form of microglia activation
can result in an outpouring of neurotoxic levels of the excitotoxins, glutamate
and quinolinic acid. Studies have shown that careful control of brain glutamate
levels is essential to brain pathway development and that excesses can result
in arrest of neural migration, as well as dendritic and synaptic loss. It has
also been shown that certain cytokines, such as TNF-alpha, can, via its
receptor, interact with glutamate receptors to enhance the neurotoxic reaction.
To describe this interaction I have coined the term immunoexcitotoxicity, which
is described in this article. http://www.ncbi.nlm.nih.gov/pubmed/?term=19043938

“This mechanism explains the link between excessive vaccination, use of
aluminum and ethylmercury as vaccine adjuvants, food allergies, gut dysbiosis,
and abnormal formation of the developing brain.”

Current Medicinal Chemistry • December 2008

Kawasaki’s disease, acrodynia, and mercury Author information Mutter J1, Yeter
D. Department of Environmental and Complementary Medicine Salusmed Medical
Center, Wieslistrasse 34, CH - 8267 Berlingen, Switzerland jo.mutter@web.de
Abstract A superantigen or autoimmunity has been hypothesized to be the main
cause of the Kawasaki’s Disease but the etiology is unknown. Medical
literature, epidemiological findings, and some case reports have suggested that
mercury may play a pathogenic role. Several patients with Kawasaki’s Disease
have presented with elevated urine mercury levels compared to matched controls.
Most symptoms and diagnostic criteria which are seen in children with
acrodynia, known to be caused by mercury, are similar to those seen in
Kawasaki’s Disease. Genetic depletion of glutathione S-transferase , a
susceptibility marker for Kawasaki’s Disease, is known to be also a risk factor
for acrodynia and may also increase susceptibility to mercury. Coinciding with
the largest increase (1985-1990) of thimerosal (49.6% ethyl mercury) in
vaccines, routinely given to infants in the U.S. by 6 months of age (from
75microg to 187.5microg), the rates of Kawasaki’s Disease increased ten times,
and, later (1985-1997), by 20 times. Since 1990 88 cases of patients developing
Kawasaki’s Disease some days after vaccination have been reported to the
Centers of Disease Control (CDC) including 19% manifesting symptoms the same
day. The presented pathogenetic model may lead to new preventive- and
therapeutic strategies for Kawasaki’s disease.
http://www.ncbi.nlm.nih.gov/pubmed/19075648

“Coinciding with the largest increase (1985-1990) of thimerosal in vaccines,
routinely given to infants in the U.S. by 6 months of age (from 75microg to
187.5microg), the rates of Kawasaki’s Disease increased ten times, and, later
(1985-1997), by 20 times. Since 1990 eighty-eight cases of patients developing
Kawasaki’s Disease some days after vaccination have been reported to the
Centers of Disease Control (CDC) including 19% manifesting symptoms the same
day.”

Journal Of Toxicology And Environmental Health Part A • 2008

An investigation of porphyrinuria in Australian children with autism Author
information Austin DW1, Shandley K. Swinburne Autism Bio-Research Initiative
(SABRI) Faculty of Life and Social Sciences, Swinburne University of Technology
Melbourne, Australia daustin@swin.edu.au Abstract Two recent studies, from
France (Nataf et al., 2006) and the United States (Geier & Geier, 2007),
identified atypical urinary porphyrin profiles in children with an autism
spectrum disorder (ASD). These profiles serve as an indirect measure of
environmental toxicity generally, and mercury (Hg) toxicity specifically, with
the latter being a variable proposed as a causal mechanism of ASD (Bernard et
al., 2001; Mutter et al., 2005). To examine whether this phenomenon occurred in
a sample of Australian children with ASD, an analysis of urinary porphyrin
profiles was conducted. A consistent trend in abnormal porphyrin levels was
evidenced when data was compared with those previously reported in the
literature. The results are suggestive of environmental toxic exposure
impairing heme synthesis. Three independent studies from three continents have
now demonstrated that porphyrinuria is concomitant with ASD, and that Hg may be
a likely xenobiotic to produce porphyrin profiles of this nature.
http://www.ncbi.nlm.nih.gov/pubmed/18704827

“These profiles serve as an indirect measure of environmental toxicity
generally, and mercury toxicity specifically, with the latter being a variable
proposed as a causal mechanism of Autistic Spectrum Disorder (Bernard et al.,
2001; Mutter et al., 2005).”

“... present observations are compatible with increased oxidative stress and a decreased detoxification capacity,
particularly of mercury, in patients diagnosed with Autistic Spectrum
Disorders.” Neurochemical Research • February 2009

A prospective study of transsulfuration biomarkers in autistic disorders Author
information Geier DA1, Kern JK, Garver CR, Adams JB, Audhya T, Geier MR.
Institute of Chronic Illnesses, Inc., Silver Spring, MD, USA Abstract The goal
of this study was to evaluate transsulfuration metabolites in participants
diagnosed with autism spectrum disorders (ASDs). Transsulfuration metabolites,
including: plasma reduced glutathione (GSH), plasma oxidized glutathione
(GSSG), plasma cysteine, plasma taurine, plasma sulfate, and plasma free
sulfate among participants diagnosed with ASDs (n = 38) in comparison to
age-matched neurotypical controls were prospectively evaluated. Testing was
conducted using Vitamin Diagnostics, Inc. (CLIA-approved). Participants
diagnosed with ASDs had significantly (P < 0.001) decreased plasma reduced GSH,
plasma cysteine, plasma taurine, plasma sulfate, and plasma free sulfate
relative to controls. By contrast, participants diagnosed with ASDs had
significantly (P < 0.001) increased plasma GSSG relative to controls. The
present observations are compatible with increased oxidative stress and a
decreased detoxification capacity, particularly of mercury, in patients
diagnosed with ASDs. Patients diagnosed with ASDs should be routinely tested to
evaluate transsulfuration metabolites, and potential treatment protocols should
be evaluated to potentially correct the transsulfuration abnormalities
observed. http://www.ncbi.nlm.nih.gov/pubmed/18612812

Experimental And Toxicological Pathology • March 2009

Gender-selective toxicity of thimerosal Author information

“Thus, our studies, although not directly

Branch DR

addressing the controversy surrounding

Departments of Medicine and Laboratory Medicine and Pathobiology University of
Toronto, Ontario, Canada don.branch@utoronto.ca Abstract A recent report shows
a correlation of the historical use of thimerosal in therapeutic immunizations
with the subsequent development of autism; however, this association remains
controversial. Autism occurs approximately four times more frequently in males
compared to females; thus, studies of thimerosal toxicity should take into
consideration gender-selective effects. The present study was originally
undertaken to determine the maximum tolerated dose (MTD) of thimersosal in male
and female CD1 mice. However, during the limited MTD studies, it became
apparent that thimerosal has a differential MTD that depends on whether the
mouse is male or female. At doses of 38.4-76.8mg/kg using 10% DMSO as diluent,
seven of seven male mice compared to zero of seven female mice tested succumbed
to thimerosal. Although the thimerosal levels used were very high, as we were
originally only trying to determine MTD, it was completely unexpected to
observe a difference of the MTD between male and female mice. Thus, our
studies, although not directly addressing the controversy surrounding
thimerosal and autism, and still preliminary due to small numbers of mice
examined, provide, nevertheless, the first report of gender-selective toxicity
of thimerosal and indicate that any future studies of thimerosal toxicity
should take into consideration gender-specific differences.
http://www.ncbi.nlm.nih.gov/pubmed/18771903

thimerosal and autism, and still preliminary due to small numbers of mice
examined, provide, nevertheless, the first report of gender-selective toxicity
of thimerosal and indicate that any future studies of thimerosal toxicity
should take into consideration gender-specific differences.”

[autism occurs at a 4-1 ratio for boys to girls. Four boys to every one girl
are damaged with autism]

Health Place • March 2009

Proximity to point sources of environmental mercury release as a predictor of
autism prevalence Author information Palmer RF1, Blanchard S, Wood R.
University of Texas Health Science Center San Antonio Department of Family and
Community Medicine 7703 Floyd Curl Drive, San Antonio Texas Mail Code 7794, TX
78229-3900, USA palmerr@uthscsa.edu Abstract The objective of this study was to
determine if proximity to sources of mercury pollution in 1998 were related to
autism prevalence in 2002. Autism count data from the Texas Educational Agency
and environmental mercury release data from the Environmental Protection Agency
were used. We found that for every 1000 pounds of industrial release, there was
a corresponding 2.6% increase in autism rates (p<.05) and a 3.7% increase
associated with power plant emissions(P<.05). Distances to these sources were
independent predictors after adjustment for relevant covariates. For every 10
miles from industrial or power plant sources, there was an associated decreased
autism Incident Risk of 2.0% and 1.4%, respectively (p<.05). While design
limitations preclude interpretation of individual risk, further investigations
of environmental risks to child development issues are warranted.
http://www.ncbi.nlm.nih.gov/pubmed/18353703

“We found that for every 1000 pounds of industrial release, there was a
corresponding 2.6% increase in autism rates (p<.05) and a 3.7% increase
associated with power plant emissions(P<.05). For every 10 miles from
industrial or power plant sources, there was an associated decreased autism
Incident Risk of 2.0% and 1.4%, respectively (p<.05).”

Journal Of Neurological Science • May 2009

Biomarkers of environmental toxicity and susceptibility in autism Author
information Geier DA1, Kern JK, Garver CR, Adams JB, Audhya T, Nataf R, Geier
MR. Institute of Chronic Illnesses, Inc., Silver Spring, Maryland, USA Abstract
Autism spectrum disorders (ASDs) may result from a combination of
genetic/biochemical susceptibilities in the form of a reduced ability to
excrete mercury and/or increased environmental exposure at key developmental
times. Urinary porphyrins and transsulfuration metabolites in participants
diagnosed with an ASD were examined. A prospective, blinded study was
undertaken to evaluate a cohort of 28 participants with an ASD diagnosis for
Childhood Autism Rating Scale (CARS) scores, urinary porphyrins, and
transsulfuration metabolites. Testing was conducted using Vitamin Diagnostics,
Inc. (CLIA-approved) and Laboratoire Philippe Auguste (ISO-approved).
Participants with severe ASDs had significantly increased mercury
intoxication-associated urinary porphyrins (pentacarboxyporphyrin,
precoproporphyrin, and coproporphyrin) in comparison to participants with mild
ASDs, whereas other urinary porphyrins were similar in both groups.
Significantly decreased plasma levels of reduced glutathione (GSH), cysteine,
and sulfate were observed among study participants relative to controls. In
contrast, study participants had significantly increased plasma oxidized
glutathione (GSSG) relative to controls. Mercury intoxication-associated
urinary porphyrins were significantly correlated with increasing CARS scores
and GSSG levels, whereas other urinary porphyrins did not show these
relationships. The urinary porphyrin and CARS score correlations observed among
study participants suggest that mercury intoxication is significantly
associated with autistic symptoms. The transsulfuration abnormalities observed
among study participants indicate that mercury intoxication was associated with
increased oxidative stress and decreased detoxification capacity.
http://www.ncbi.nlm.nih.gov/pubmed/18817931

“The urinary porphyrin and CARS score correlations observed among study
participants suggest that mercury intoxication is significantly associated with
autistic symptoms.”

Toxicology And Environmental Chemistry • June 2009

Mitochondrial dysfunction, impaired oxidative-reduction activity, degeneration,
and death in human neuronal and fetal cells induced by low-level exposure to
thimerosal and other metal compounds Author information Geier DA1, King PG2,
Geier MR3. 1. Institute of Chronic Illnesses, Inc., Silver Spring, Maryland,
USA 2. CoMeD, Inc., Silver Spring, Maryland, USA 3. The Genetic Centers of
America, Silver Spring, Maryland, USA Abstract Thimerosal
(ethylmercurithiosalicylic acid), an ethylmercury (EtHg)-releasing compound
(49.55% mercury (Hg)), was used in a range of medical products for more than 70
years. Of particular recent concern, routine administering of
Thimerosal-containing biologics/childhood vaccines have become significant
sources of Hg exposure for some fetuses/infants. This study was undertaken to
investigate cellular damage among in vitro human neuronal (SH-SY-5Y
neuroblastoma and 1321N1 astrocytoma) and fetal (nontransformed) model systems
using cell vitality assays and microscope-based digital image capture
techniques to assess potential damage induced by Thimerosal and other metal
compounds (aluminum (Al) sulfate, lead (Pb)(II) acetate, methylmercury (MeHg)
hydroxide, and mercury (Hg)(II) chloride) where the cation was reported to
exert adverse effects on developing cells. Thimerosal-associated cellular
damage was also evaluated for similarity to pathophysiological findings
observed in patients diagnosed with autistic disorders (ADs).
Thimerosal-induced cellular damage as evidenced by concentration- and
time-dependent mitochondrial damage, reduced oxidative-reduction activity,
cellular degeneration, and cell death in the in vitro human neuronal and fetal
model systems studied. Thimerosal at low nanomolar (nM) concentrations induced
significant cellular toxicity in human neuronal and fetal cells.
Thimerosal-induced cytoxicity is similar to that observed in AD
pathophysiologic studies. Thimerosal was found to be significantly more toxic
than the other metal compounds examined. Future studies need to be conducted to
evaluate additional mechanisms underlying Thimerosal-induced cellular damage
and assess potential co-exposures to other compounds that may increase or
decrease Thimerosal-mediated toxicity. Full Report:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924342/

“Thimerosal at low nanomolar concentrations induced significant cellular
toxicity in human neuronal and fetal cells. Thimerosal-induced cytoxicity is
similar to that observed in Autistic Disorder pathophysiologic studies.
Thimerosal was found to be significantly more toxic than the other metal
compounds examined.”

American Journal Of Perinatology • August 2009

Neonate exposure to thimerosal mercury from hepatitis B vaccines Author
information Dórea JG1, Marques RC, Brandão KG. Universidade de Brasília, DF,
Brazil dorea@rudah.com.br Abstract Infant exposure to ethylmercury (EtHg) has
not only increased but is starting earlier as a result of the current
immunization schedule that uses thimerosal-containing vaccines (TCVs). Although
vaccination schedule varies considerably between countries, infants in
less-developed countries continue to be exposed to EtHg derived from more
affordable TCVs. We studied the exposure of newborns to EtHg from hepatitis B
vaccines; hospital records (21,685) were summarized for the years 2001 to 2005
regarding date of birth, vaccination date, and birth weight. Most of the
vaccinations occurred in the first 24 hours postdelivery; over the 5 years,
there was an increase in vaccinations within hours of birth (same day), from
7.4% (2001) to 87.8% (2005). Nearly 94.6% of infants are now being vaccinated
within the first 24 hours. Range of mercury exposure spread from 4.2 to 21.1
microg mercury/kg body weight for those receiving TCVs with the highest
thimerosal concentration; these exposure levels are conservative for 2% of
children receiving vaccines within 2 to 3 postnatal days, when they are still
going through physiological postnatal weight loss. Because of the particular
timing (transitioning from in utero to ex utero metabolism) and specific
aspects of exposure (i.e., parenteral mode, bypassing gastroenteric barriers)
and dose (related to vaccine manufacturer and with variation in birth weight),
this study reveals critical issues that can modulate toxicokinetics and
toxicodynamics of organomercurials in neonates.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19283656

“Infant exposure to ethylmercury (EtHg) has not only increased but is starting
earlier as a result of the current immunization schedule that uses
thimerosal-containing vaccines (TCVs) ... this study reveals critical issues
that can modulate toxicokinetics and toxicodynamics of organomercurials in
neonates.”

Toxicology In Vitro • September 2009

Increase in intracellular Zn2+ concentration by thimerosal in rat thymocytes:
intracellular Zn2+ release induced by oxidative stress Author information
Hashimoto E1, Oyama TB, Oyama K, Nishimura Y, Oyama TM, Ueha-Ishibashi T, Okano
Y, Oyama Y. Laboratory of Cellular Signaling Faculty of Integrated Arts and
Sciences The University of Tokushima Tokushima 770-8502, Japan Abstract
Thimerosal (TMR), an ethylmercury-containing preservative in pharmaceutical
products, was recently reported to increase intracellular Zn(2+) concentration.
Therefore, some health concerns about the toxicity of TMR remain because of
physiological and pathological roles of Zn(2+). To reveal the property of
TMR-induced increase in intracellular Zn(2+) concentration, the effect of TMR
on FluoZin-3 fluorescence, an indicator of intracellular Zn(2+), of rat
thymocytes was examined. TMR at concentrations ranging from 0.3 microM to 10
microM increased the intensity of FluoZin-3 fluorescence in a
concentration-dependent manner under external Ca(2+)- and Zn(2+)-free
condition. The threshold concentration was 0.3-1 microM. The increase in the
intensity was significant when TMR concentration was 1 microM or more.
N,N,N’,N’-Tetrakis(2pyridylmethyl)ethylenediamine (TPEN), a chelator for
intracellular Zn(2+), completely attenuated the TMR-induced augmentation of
FluoZin-3 fluorescence. Hydrogen peroxide (H(2)O(2)) and N-ethylmaleimide,
reducing cellular thiol content, significantly increased FluoZin-3 fluorescence
intensity and decreased 5-chloromethylfluorescein (5-CMF) fluorescence
intensity, an indicator for cellular thiol. The correlation coefficient between
TMR-induced augmentation of FluoZin-3 fluorescence and attenuation of 5-CMF
fluorescence was -0.882. TMR also attenuated the 5-CMF fluorescence in the
presence of TPEN. Simultaneous application of H(2)O(2) and TMR synergistically
augmented the FluoZin-3 fluorescence. It is suggested that TMR increases
intracellular Zn(2+) concentration via decreasing cellular thiol content.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19497362

“It is suggested that Thimerosal increases intracellular Zn(2+) concentration
via decreasing cellular thiol content.”

Biometals • December 2009

Assessment of chronic mercury exposure within the U.S. population, National
Health and Nutrition Examination Survey 1999–2006 Author information Laks DR.
Mental Retardation Research Center David Geffen School of Medicine at UCLA 635
Charles E. Young Dr. South Neuroscience Research Bldg., Room 379 (lab) Los
Angeles, CA 90095-7332, USA dlaks@mednet.ucla.edu Abstract The purpose of this
study was to assess chronic mercury exposure within the US population. Time
trends were analyzed for blood inorganic mercury (I-Hg) levels in 6,174 women,
ages 18-49, in the NHANES, 1999-2006 data sets. Multivariate logistic
regression distinguished a significant, direct correlation within the US
population between I-Hg detection and years since the start of the survey (OR =
1.49, P < 0.001). Within this population, I-Hg detection rose sharply from 2%
in 1999-2000 to 30% in 2005-2006. In addition, the population averaged mean
I-Hg concentration rose significantly over that same period from 0.33 to 0.39
μ/L (Anova, P < 0.001). In a separate analysis, multivariate logistic
regression indicated that I-Hg detection was significantly associated with age
(OR = 1.02, P < 0.001). Furthermore, multivariate logistic regression revealed
significant associations of both I-Hg detection and mean concentration with
biomarkers for the main targets of mercury deposition and effect: the liver,
immune system, and pituitary. This study provides compelling evidence that I-Hg
deposition within the human body is a cumulative process, increasing with age
and in the population over time, since 1999, as a result of chronic mercury
exposure. Furthermore, our results indicate that I-Hg deposition is associated
with the significant biological markers for main targets of exposure,
deposition, and effect. Accumulation of focal I-Hg deposits within the human
body due to chronic mercury exposure provides a mechanism which suggests a time
dependent rise in the population risks for associated disease.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19697139

“Within this population, inorganic mercury detection rose sharply from 2% in
1999-2000 to 30% in 2005-2006. In addition, the population averaged mean
inorganic mercury concentration rose significantly over that same period from
0.33 to 0.39 μ/L (Anova, P < 0.001).”

“... thimerosal administration to suckling or adult rats impairs sensitivity to pain ...”
Brain Research • December 2009

Neonatal administration of a vaccine preservative, thimerosal, produces lasting
impairment of nociception and apparent activation of opioid system in rats
Author information Olczak M1, Duszczyk M, Mierzejewski P, Majewska MD.
Department of Pharmacology and Physiology of the Nervous System Institute of
Psychiatry and Neurology Warsaw, Poland Abstract Thimerosal (THIM), an
organomercury preservative added to many child vaccines is a suspected factor
in pathogenesis of neurodevelopmental disorders. We examined the
pharmacokinetics of Hg in the brain, liver and kidneys after i.m. THIM
injection in suckling rats and we tested THIM effect on nociception. THIM
solutions were injected to Wistar and Lewis rats in a vaccination-like mode on
PN days 7, 9, 11 and 15 in four equal doses. For Wistar rats these were: 12,
48, 240, 720, 1440, 2160, 3000 microg Hg/kg and for Lewis: 54, 216, 540 and
1080 microg Hg/kg. Pharmacokinetic analysis revealed that Hg from THIM
injections accumulates in the rat brain in significant amounts and remains
there longer than 30 days after the injection. At the 6th week of age animals
were examined for pain sensitivity using the hot plate test. THIM treated rats
of both strains and sexes manifested statistically significantly elevated pain
threshold (latency for paw licking, jumping) on a hot plate (56 degrees C).
Wistar rats were more sensitive to this effect than Lewis rats. Protracted
THIM-induced hypoalgesia was reversed by naloxone (5 mg/kg, i.p.) injected
before the hot plate test, indicative of involvement of endogenous opioids.
This was confirmed by augmented catalepsy after morphine (2.5 mg/kg, s.c.)
injection. Acute THIM injection to 6-week-old rats also produced hypoalgesia,
but this effect was transient and was gone within 14 days. Present findings
show that THIM administration to suckling or adult rats impairs sensitivity to
pain, apparently due to activation the endogenous opioid system.
http://www.ncbi.nlm.nih.gov/pubmed/19747466

Acta Neurobiologia Experimentalis • 2009

A prospective study of prenatal mercury exposure from maternal dental amalgams
and autism severity Author information Geier DA1, Kern JK, Geier MR. Institute
of Chronic Illnesses, Inc., Silver Spring, Maryland, USA Abstract Dental
amalgams containing 50% mercury (Hg) have been used in dentistry for the last
150 years, and Hg exposure during key developmental periods was associated with
autism spectrum disorders (ASDs). This study examined increased Hg exposure
from maternal dental amalgams during pregnancy among 100 qualifying
participants born between 1990-1999 and diagnosed with DSM-IV autism (severe)
or ASD (mild). Logistic regression analysis (age, gender, race, and region of
residency adjusted) by quintile of maternal dental amalgams during pregnancy
revealed the ratio of autism:ASD (severe:mild) were about 1 (no effect) for <
or =5 amalgams and increased for > or =6 amalgams. Subjects with
> or =6 amalgams were 3.2-fold significantly more likely to be diagnosed with
autism (severe) in comparison to ASD (mild) than subjects with < or =5
amalgams. Dental amalgam policies should consider Hg exposure in women before
and during the child-bearing age and the possibility of subsequent fetal
exposure and adverse outcomes. Full Report
http://www.ncbi.nlm.nih.gov/pubmed/19593333

“Hg [ethyl mercury] exposure during key developmental periods was associated
with autism spectrum disorders … Subjects with > or =6 amalgams were 3.2-fold
significantly more likely to be diagnosed with autism (severe) in comparison to
ASD (mild) than subjects with < or =5 amalgams.”

“A significant correlation was observed between increasing cP levels and CARS scores.”
Journal Of Toxicology And Environmental Health Part A • 2009

A prospective blinded evaluation of urinary porphyrins verses the clinical
severity of autism spectrum disorders Author information Geier DA1, Kern JK,
Geier MR. Institute of Chronic Illnesses, Inc., Silver Spring, Maryland, USA
mgeier@comcast.net Abstract A prospective, blinded study evaluated the
relationship between autism spectrum disorder (ASD) severity measured by
Childhood Autism Rating Scale (CARS) scores and urinary porphyrins among a
cohort of participants (n = 26). LabCorp (CLIA-approved) tested for
uroporphyrins, heptacarboxylporphyrins, hexacarboxylporphyrins,
pentacarboxylporphyrins, coproporphyrin (cP) I, and cP III levels. Participants
with severe ASD had significantly increased cP I, cP III, and total cP levels
in comparison to participants with mild ASD. A significant correlation was
observed between increasing cP levels and CARS scores. Significant correlations
were also noted for comparative urinary porphyrin testing between LabCorp and
the Laboratoire Philippe Auguste (ISO-approved) for total cP. Finally, total cP
measured at LabCorp was found to significantly correlate with precoproporphryin
(a specific porphyrin marker for mercury toxicity) measured at the Laboratoire
Philippe Auguste. Since urinary porphyrin testing is clinically available,
relatively inexpensive, and noninvasive, it may be used to help suggest whether
heavy metal toxicity is associated with ASD.
http://www.ncbi.nlm.nih.gov/pubmed/20077233

Toxicology And Applied Pharmacology • March 2010

Mercury toxicokinetics dependency on strain and gender Author information
Ekstrand J1, Nielsen JB, Havarinasab S, Zalups RK, Söderkvist P, Hultman P.
Molecular and Immunological Pathology Department of Clinical and Experimental
Medicine Linköping University, SE-58185 Linköping, Sweden Abstract Mercury (Hg)
exposure from dental amalgam fillings and thimerosal in vaccines is not a major
health hazard, but adverse health effects cannot be ruled out in a small and
more susceptible part of the exposed population. Individual differences in
toxicokinetics may explain susceptibility to mercury. Inbred, H-2-congenic A.SW
and B10.S mice and their F1- and F2hybrids were given HgCl2 with 2.0 mg Hg/L
drinking water and traces of (203)Hg. Whole-body retention (WBR) was monitored
until steady state after 5 weeks, when the organ Hg content was assessed.
Despite similar Hg intake, A.SW males attained a 20-30% significantly higher
WBR and 2- to 5-fold higher total renal Hg retention/concentration than A.SW
females and B10.S mice. A selective renal Hg accumulation but of lower
magnitude was seen also in B10.S males compared with females. Differences in
WBR and organ Hg accumulation are therefore regulated by non-H-2 genes and
gender. Lymph nodes lacked the strain- and gender-dependent Hg accumulation
profile of kidney, liver and spleen. After 15 days without Hg A.SW mice showed
a 4-fold higher WBR and liver Hg concentration, but 11-fold higher renal Hg
concentration, showing the key role for the kidneys in explaining the slower Hg
elimination in A.SW mice. The trait causing higher mercury accumulation was not
dominantly inherited in the F1 hybrids. F2 mice showed a large inter-individual
variation in Hg accumulation, showing that multiple genetic factors influence
the Hg toxicokinetics in the mouse. The genetically heterogeneous human
population may therefore show a large variation in mercury toxicokinetics.
http://www.ncbi.nlm.nih.gov/pubmed/19732784

“The genetically heterogeneous human population may therefore show a large
variation in mercury toxicokinetics.”

Journal Of Neuroinflammation • March 2010

Mercury induces inflammatory mediator release from human mast cells Author
information Kempuraj D1, Asadi S, Zhang B, Manola A, Hogan J, Peterson E,
Theoharides TC. Molecular Immunopharmacology and Drug Discovery Laboratory
Department of Pharmacology and Experimental Therapeutics Tufts University
School of Medicine and Tufts Medical Center Boston, MA 02111, USA Abstract
BACKGROUND Mercury is known to be neurotoxic, but its effects on the immune
system are less well known. Mast cells are involved in allergic reactions, but
also in innate and acquired immunity, as well as in inflammation. Many patients
with Autism Spectrum Disorders (ASD) have “allergic” symptoms; moreover, the
prevalence of ASD in patients with mastocytosis, characterized by numerous
hyperactive mast cells in most tissues, is 10-fold higher than the general
population suggesting mast cell involvement. We, therefore, investigated the
effect of mercuric chloride (HgCl2) on human mast cell activation. METHODS
Human leukemic cultured LAD2 mast cells and normal human umbilical cord
blood-derived cultured mast cells (hCBMCs) were stimulated by HgCl2 (0.1-10
microM) for either 10 min for beta-hexosaminidase release or 24 hr for
measuring vascular endothelial growth factor (VEGF) and IL-6 release by ELISA.
RESULTS HgCl2 induced a 2-fold increase in beta-hexosaminidase release, and
also significant VEGF release at 0.1 and 1 microM (311 +/- 32 pg/106 cells and
443 +/- 143 pg/106 cells, respectively) from LAD2 mast cells compared to
control cells (227 +/- 17 pg/106 cells, n = 5, p < 0.05). Addition of HgCl2
(0.1 microM) to the proinflammatory neuropeptide substance P (SP, 0.1 microM)
had synergestic action in inducing VEGF from LAD2 mast cells. HgCl2 also
stimulated significant VEGF release (360 +/- 100 pg/106 cells at 1 microM, n =
5, p < 0.05) from hCBMCs compared to control cells (182 +/- 57 pg/106 cells),
and IL-6 release (466 +/- 57 pg/106 cells at 0.1 microM) compared to untreated
cells (13 +/- 25 pg/106 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 microM)
to SP (5 microM) further increased IL-6 release. CONCLUSIONS HgCl2 stimulates
VEGF and IL-6 release from human mast cells. This phenomenon could disrupt the
bloodbrain-barrier and permit brain inflammation. As a result, the findings of
the present study provide a biological mechanism for how low levels of mercury
may contribute to ASD pathogenesis. Full Report:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850891/

“... the findings of the present study provide a biological mechanism for how
low levels of mercury may contribute to Autistic Spectrum Disorder
pathogenesis.”

“... association between premature puberty and exposure to mercury from thimerosal-containing vaccines ...”
Indian Journal Of Medical Research • April 2010

Thimerosal exposure & increasing trends of premature puberty in the vaccine
safety datalink Author information Geier DA1, Young HA, Geier MR. The Institute
of Chronic Illnesses, Inc., Silver Spring, MD 20905, USA mgeier@comcast.net
Abstract BACKGROUND & OBJECTIVES The US Agency for Toxic Substances and Disease
Registry (ATSDR) reports that mercury (Hg) is a known endocrine disruptor and
it adversely affects the steroid synthesis pathway in animals and humans, and
may interact to enhance the risk for a child developing premature puberty. An
association between premature puberty and exposure to Hg from
thimerosal-containing vaccines (TCVs) was evaluated in computerized medical
records within the Vaccine Safety Datalink (VSD). METHODS A total of 278,624
subjects were identified in birth cohorts from 1990-1996. The birth cohort
prevalence rates of medically diagnosed International Classification of
Disease, 9(th) revision (ICD-9) premature puberty and control outcomes were
calculated. Exposures to Hg from TCVs were calculated by birth cohort for
specific exposure windows from birth-7 months and birth-13 months of age.
Poisson regression analysis was used to model the association between the
prevalence of outcomes and Hg doses from TCVs. RESULTS Significantly increased
(P<0.0001) rate ratios were observed for premature puberty for a 100 microg
difference in Hg exposure from TCVs in the birth-7 months (rate ratio=5.58) and
birth-13 months (rate ratio=6.45) of age exposure windows. By contrast, none of
the control outcomes had significantly increased rate ratios with Hg exposure
from TCVs. INTERPRETATION & CONCLUSIONS Routine childhood vaccination should be
continued to help reduce the morbidity and mortality associated with infectious
diseases, but efforts should be undertaken to remove Hg from vaccines.
Additional studies should be done to evaluate the relationship between Hg
exposure and premature puberty. Full report available at this link:
http://www.ncbi.nlm.nih.gov/pubmed/20424300

Indian Journal Of Medical Research • April 2010

Exposure to low-dose mercury (from thimerosal) & premature puberty - a new
avenue for research with the vaccine safety datalink Author information Dórea
JG. Universidade de Brasilia, Brasilia, DF. Brazil dorea@rudah.com.br Abstract
The paper by Geier et al1 addresses the plausible association of premature
puberty after a typical pattern of exposure to ethylmercury in
thimerosal-containing vaccines (TCVs) taken by young children in the USA before
TCVs were discontinued. Both precocious puberty and low-level mercury are per
se high-profile topics of public health interest. Given that TCVs are still
currently given to pregnant women, infants and young children around the world,
the paper raises a unique opportunity for discussing the role of mercury- based
preservatives. The study took advantage of the vaccine-safety datalink (VSD)
system of the USA. Black et al2 summarized the advantage of the VSD over the
former Vaccine Adverse Event Reporting System (VAERS) in use until 1991 in the
USA. Until then, potential vaccine safety issues could only be evaluated by the
passive data collected through the VAERS. The current VSD system links outcome
and vaccine exposure information, demographic and other covariate information,
from the automated clinical databases within several Health Maintenance
Organizations (HMOs). As pointed out by Black et al2 this data bank can be
utilized to screen for possible associations of events after vaccination and
also, as in the case of Geier et al1, to evaluate hypotheses. Geier et al1
analyzed the data from 1990 to 1996 (n = 278,624) and explored a possible link
of premature puberty to TCV received at young ages by comparing this outcome to
outcomes not related to mercury exposure (controls). It is worth mentioning the
disproportionate percentage of males (7%) in the sample. If encountered in
future studies, this information confirms gender differences in thimerosal
toxicity3. Constitutional differences in gender determine hormonal balance and
represent a biologic variable4 to be considered in reproductive and neurologic
outcomes.

Premature sexual development is a topic of current interest because of social
and attendant health- associated issues, especially for girls. Unwanted teenage
pregnancy and sexually transmitted diseases are among the important social and
biological issues affecting poor countries and disadvantaged segments of rich
countries. Reports from different parts of the world indicate that precocious
gynaecological-age is significantly associated with early sexual initiation5
and with teenage pregnancy6,7. Additionally, as reviewed by Karaolis-Danckert
et al8, an accelerated age of puberty onset may influence the life-time risk
for breast and testicular cancer, insulin resistance, and adiposity. It is
becoming clear that environmental factors are strongly associated with
precocious puberty9. Studies indicate that increasing rates of precocious
puberty are among the endocrine-system related effects of endocrine-disruptor
chemicals found in the environment10. Generally described as endocrine
disruptors, there are a broad range of these substances capable of affecting
the endocrine system. Some of these can act specifically on the reproductive
system having estrogenic, anti-estrogenic, androgenic, and anti- androgenic
activity. Besides that, these chemicals can also interfere with the
hypthalamo-pituitary unit, and also disrupt estrous cyclicity. The
endocrine-disrupting activity of these pollutants on developmental toxicology
depends on timing and dosage. However, since these occur as mixtures, it is not
yet possible to know if their end-point effects are additive or antagonistic.
Therefore, this type of exposure is difficult to study because of the variety
of possible outcomes10. A wide range of endocrine disruptors listed by Abaci et
al18 include biocides (herbicides, fungicides, insecticides, nematocides), and
industrial compounds made up of organic substances and metals (that includes
mercury).

Full report available at this link: http://www.ncbi.nlm.nih.gov/pubmed/20424297

Toxicology • August 2010

Sensitization effect of thimerosal is mediated in vitro via reactive oxygen
species and calcium signaling Author information Migdal C1, Foggia L,
Tailhardat M, Courtellemont P, Haftek M, Serres M. EA 41-69, Université Lyon 1,
Pavillon R Hôpital Edouard Herriot 69437 Lyon Cedex 03, France Abstract
Thimerosal, a mercury derivative composed of ethyl mercury chloride (EtHgCl)
and thiosalicylic acid (TSA), is widely used as a preservative in vaccines and
cosmetic products and causes cutaneous reactions. Since dendritic cells (DCs)
play an essential role in the immune response, the sensitization potency of
chemicals was studied in vitro using U937, a human promyelomonocytic cell line
that is used as a surrogate of monocytic differentiation and activation.
Currently, this cell line is under ECVAM (European Center for the Validation of
Alternative Methods) validation as an alternative method for discriminating
chemicals. Thimerosal and mercury derivatives induced in U937 an overexpression
of CD86 and interleukin (IL)-8 secretion similarly to
1-chloro-2,4-dinitrobenzene (DNCB), a sensitizer used as a positive control for
DC activation. Non-sensitizers, dichloronitrobenzene (DCNB), TSA and sodium
dodecyl sulfate (SDS), an irritant, had no effect. U937 activation was
prevented by cell pretreatment with N-acetyl-L-cysteine (NAC) but not with
thiol-independent antioxidants except vitamin E which affected CD86 expression
by preventing lipid peroxidation of cell membranes. Thimerosal, EtHgCl and DNCB
induced glutathione (GSH) depletion and reactive oxygen species (ROS) within 15
min; another peak was detected after 2h for mercury compounds only. MitoSOX, a
specific mitochondrial fluorescent probe, confirmed that ROS were essentially
produced by mitochondria in correlation with its membrane depolarization.
Changes in mitochondrial membrane permeability induced by mercury were reversed
by NAC but not by thiol-independent antioxidants. Thimerosal and EtHgCl also
induced a calcium (Ca2+) influx with a peak at 3h, suggesting that Ca2+ influx
is a secondary event following ROS induction as Ca2+ influx was suppressed
after pretreatment with NAC but not with thiol-independent antioxidants. Ca2+
influx was also suppressed when culture medium was deprived of Ca2+ confirming
the specificity of the measure. In conclusion, these data suggest that
thimerosal induced U937 activation via oxidative stress from mitochondrial
stores and mitochondrial membrane depolarization with a primordial effect of
thiol groups. A cross-talk between ROS and Ca2+ influx was demonstrated.
http://www.ncbi.nlm.nih.gov/pubmed/20457211

“In conclusion, these data suggest that thimerosal induced U937 activation via
oxidative stress from mitochondrial stores and mitochondrial membrane
depolarization with a primordial effect of thiol groups. A cross-talk between
ROS and Ca2+ in ux was demonstrated.”

Environmental Health Perspectives • October 2010

Urinary porphyrin excretion in neurotypical and autistic children Author
information Woods JS1, Armel SE, Fulton DI, Allen J, Wessels K, Simmonds PL,
Granpeesheh D, Mumper E, Bradstreet JJ, Echeverria D, Heyer NJ, Rooney JP.
Department of Environmental and Occupational Health Sciences University of
Washington, Seattle, Washington 98105, USA jwoods@u.washington.edu Abstract
BACKGROUND Increased urinary concentrations of pentacarboxyl-, precopro- and
copro-porphyrins have been associated with prolonged mercury (Hg) exposure in
adults, and comparable increases have been attributed to Hg exposure in
children with autism (AU).

“Increased urinary

OBJECTIVES This study was designed to measure and compare urinary porphyrin
concentrations in neurotypical (NT) children and same-age children with autism,
and to examine the association between porphyrin levels and past or current Hg
exposure in children with autism.

pentacarboxyl-, precopro-

METHODS This exploratory study enrolled 278 children 2-12 years of age. We
evaluated three groups: AU, pervasive developmental disorder-not otherwise
specified (PDD-NOS), and NT. Mothers/caregivers provided information at
enrollment regarding medical, dental, and dietary exposures. Urine samples from
all children were acquired for analyses of porphyrin, creatinine, and Hg.
Differences between groups for mean porphyrin and Hg levels were evaluated.
Logistic regression analysis was conducted to determine whether porphyrin
levels were associated with increased risk of autism.

have been associated with

RESULTS Mean urinary porphyrin concentrations are naturally high in young
children and decline by as much as 2.5-fold between 2 and 12 years of age.
Elevated copro- (p < 0.009), hexacarboxyl- (p < 0.01) and pentacarboxyl- (p <
0.001) porphyrin concentrations were significantly associated with AU but not
with PDD-NOS. No differences were found between NT and AU in urinary Hg levels
or in past Hg exposure as determined by fish consumption, number of dental
amalgam fillings, or vaccines received. CONCLUSIONS These findings identify
disordered porphyrin metabolism as a salient characteristic of autism. Hg
exposures were comparable between diagnostic groups, and a porphyrin pattern
consistent with that seen in Hg-exposed adults was not apparent. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957928/

concentrations of

and copro-porphyrins

prolonged mercury (Hg) exposure in adults, and comparable increases have been
attributed to Hg exposure in children with autism.”

“These data document that exposure to thimerosal during early postnatal life
produces lasting alterations in the densities of brain opioid receptors along
with other neuropathological changes, which may disturb brain development.”
Neurochemistry Research • November 2010

Neonatal administration of thimerosal causes persistent changes in mu opioid
receptors in the rat brain Author information Olczak M1, Duszczyk M,
Mierzejewski P, Bobrowicz T, Majewska MD. Department of Pharmacology and
Physiology of the Nervous System Institute of Psychiatry and Neurology, Warsaw,
Poland Abstract Thimerosal added to some pediatric vaccines is suspected in
pathogenesis of several neurodevelopmental disorders. Our previous study showed
that thimerosal administered to suckling rats causes persistent, endogenous
opioid-mediated hypoalgesia. Here we examined, using immunohistochemical
staining technique, the density of μ-opioid receptors (MORs) in the brains of
rats, which in the second postnatal week received four i.m. injections of
thimerosal at doses 12, 240, 1,440 or 3,000 μg Hg/kg. The periaqueductal gray,
caudate putamen and hippocampus were examined. Thimerosal administration caused
dose-dependent statistically significant increase in MOR densities in the
periaqueductal gray and caudate putamen, but decrease in the dentate gyrus,
where it was accompanied by the presence of degenerating neurons and loss of
synaptic vesicle marker (synaptophysin). These data document that exposure to
thimerosal during early postnatal life produces lasting alterations in the
densities of brain opioid receptors along with other neuropathological changes,
which may disturb brain development. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957583/

“our data demonstrated that the toxicokinetics of Thimerosal (ethyl mercury)
is completely different from that of methyl mercury.” Archives of Toxicology •
Inorganic Compounds • November 2010

Identification and distribution of mercury species in rat tissues following
administration of thimerosal or methylmercury Jairo L. Rodrigues, Juliana M.
Serpeloni, Bruno L. Batista, Samuel S. Souza, Fernando BarbosaJr Abstract
Methylmercury (Met-Hg) is one the most toxic forms of Hg, with a considerable
range of harmful effects on humans. Sodium ethyl mercury thiosalicylate,
thimerosal (TM) is an ethylmercury (Et-Hg)-containing preservative that has
been used in manufacturing vaccines in many countries. Whereas the behavior of
Met-Hg in humans is relatively well known, that of ethylmercury (Et-Hg) is
poorly understood. The present study describes the distribution of mercury as
(-methyl, -ethyl and inorganic mercury) in rat tissues (brain, heart, kidney
and liver) and blood following administration of TM or Met-Hg. Animals received
one dose/day of Met-Hg or TM by gavage (0.5 mg Hg/kg). Blood samples were
collected after 6, 12, 24, 48, 96 and 120 h of exposure. After 5 days, the
animals were killed, and their tissues were collected. Total blood mercury
(THg) levels were determined by ICP-MS, and methylmercury (Met-Hg),
ethylmercury (Et-Hg) and inorganic mercury (Ino-Hg) levels were determined by
speciation analysis with LC-ICP-MS. Mercury remains longer in the blood of rats
treated with Met-Hg compared to that of TM-exposed rats. Moreover, after 48 h
of the TM treatment, most of the Hg found in blood was inorganic. Of the total
mercury found in the brain after TM exposure, 63% was in the form of Ino-Hg,
with 13.5% as Et-Hg and 23.7% as Met-Hg. In general, mercury in tissues and
blood following TM treatment was predominantly found as Ino-Hg, but a
considerable amount of Et-Hg was also found in the liver and brain. Taken
together, our data demonstrated that the toxicokinetics of TM is completely
different from that of Met-Hg. Thus, Met-Hg is not an appropriate reference for
assessing the risk from exposure to TM-derived Hg. It also adds new data for
further studies in the evaluation of TM toxicity.
http://link.springer.com/article/10.1007%2Fs00204-010-0538-4

Clinica Chimica Acta • November 2010

Making sense of epidemiological studies of young children exposed to thimerosal
in vaccines Author information Dórea JG. C.P. 04322, Universidade de Brasilia
70919-970 Brasilia, DF, Brazil dorea@rudah.com.br Abstract OBJECTIVE: To
compare epidemiological studies dealing with neurological issues (compatible
with Hg toxicity) linked to exposing newborns and infants to intramuscular
doses of preservative-Hg resulting from vaccination with thimerosal-containing
vaccines (TCV). METHODS: Major databases were searched for studies that
addressed neurodevelopment outcomes other than autism. Eight studies were
identified and compared. RESULTS: Information extracted from the studies done
in the USA, the UK, and Italy is important in understanding the complex
interplay of variables but insufficient to establish non-toxicity for infants
and young children still receiving TCV: a) there is ambiguity in some studies
reporting neurodevelopment outcomes that seem to depend on confounding
variables; b) the risk of neurotoxicity due to low doses of thimerosal is
plausible at least for susceptible infants; c) there is a need to address these
issues in less developed countries still using TCV in pregnant mothers,
newborns, and young children. CONCLUSIONS: Since the use of TCV is still
inevitable in many countries, this increases the need to protect vulnerable
infants and promote actions that strengthen neurodevelopment. Developing
countries should intensify campaigns that include breastfeeding among efforts
to help prime the central nervous system to tolerate exposure to neurotoxic
substances, especially thimerosal-Hg.
http://www.ncbi.nlm.nih.gov/pubmed/20638374?dopt=Abstract

“Since the use of thimerosal-containing vaccines is still inevitable in many
countries, this increases the need to protect vulnerable infants ...”

“The neurotoxic effects of both mercurials are interwoven with their modulatory actions on
GABA(A) and NMDA receptors, which most likely involve binding to these
macromolecules.” Journal Of Physiological Pharmacology • December 2010

Intermingled modulatory and neurotoxic effects of thimerosal and mercuric ions
on electrophysiological responses to GABA and NMDA in hippocampal neurons
Author information Wyrembek P1, Szczuraszek K, Majewska MD, Mozrzymas JW.
Laboratory of Neuroscience, Department of Biophysics Wroclaw Medical
University, Wroclaw, Poland paulina_wyrembek@op.pl Abstract The
organomercurial, thimerosal, is at the center of medical controversy as a
suspected factor contributing to neurodevelopmental disorders in children. Many
neurotoxic effects of thimerosal have been described, but its interaction with
principal excitatory and inhibitory neurotransmiter systems is not known. We
examined, using electrophysiological recordings, thimerosal effects on GABA and
NMDA-evoked currents in cultured hippocampal neurons. After brief (3 to 10 min)
exposure to thimerosal at concentrations up to 100 μM, there was no significant
effect on GABA or NMDA-evoked currents. However, following exposure for 60-90
min to 1 or 10 μM thimerosal, there was a significant decrease in NMDA-induced
currents (p<0.05) and GABAergic currents (p<0.05). Thimerosal was also
neurotoxic, damaging a significant proportion of neurons after 60-90 min
exposure; recordings were always conducted in the healthiest looking neurons.
Mercuric chloride, at concentrations 1 μM and above, was even more toxic,
killing a large proportion of cells after just a few minutes of exposure.
Recordings from a few sturdy cells revealed that micromolar mercuric chloride
markedly potentiated the GABAergic currents (p<0.05), but reduced NMDA-evoked
currents (p<0.05). The results reveal complex interactions of thimerosal and
mercuric ions with the GABA(A) and NMDA receptors. Mercuric chloride act
rapidly, decreasing electrophysiological responses to NMDA but enhancing
responses to GABA, while thimerosal works slowly, reducing both NMDA and GABA
responses. The neurotoxic effects of both mercurials are interwoven with their
modulatory actions on GABA(A) and NMDA receptors, which most likely involve
binding to these macromolecules. http://www.ncbi.nlm.nih.gov/pubmed/21224507

“... results show an association between the apparent level of mercury toxicity
as measured by recognized urinary porphyrin biomarkers of mercury toxicity and
the magnitude of the specific hallmark features of autism ...” Biometals •
December 2010

A biomarker of mercury body-burden correlated with diagnostic domain specific
clinical symptoms of autism spectrum disorder Author information Kern JK1,
Geier DA, Adams JB, Geier MR. Autism Treatment Center, Dallas, TX, USA
jkern@dfwair.net Abstract The study purpose was to compare the quantitative
results from tests for urinary porphyrins, where some of these porphyrins are
known biomarkers of heavy metal toxicity, to the independent assessments from a
recognized quantitative measurement, the Autism Treatment Evaluation Checklist
(ATEC), of specific domains of autistic disorders symptoms (Speech/Language,
Sociability, Sensory/Cognitive Awareness, and Health/Physical/Behavior) in a
group of children having a clinical diagnosis of autism spectrum disorder
(ASD). After a Childhood Autism Rating Scale (CARS) evaluation to assess the
development of each child in this study and aid in confirming their
classification, and an ATEC was completed by a parent, a urinary porphyrin
profile sample was collected and sent out for blinded analysis. Urinary
porphyrins from twenty-four children, 2-13 years of age, diagnosed with autism
or PDD-NOS were compared to their ATEC scores as well as their scores in the
specific domains (Speech/ Language, Sociability, Sensory/Cognitive Awareness,
and Health/Physical/Behavior) assessed by ATEC. Their urinary porphyrin samples
were evaluated at Laboratoire Philippe Auguste (which is an ISO-approved
clinical laboratory). The results of the study indicated that the participants’
overall ATEC scores and their scores on each of the ATEC subscales
(Speech/Language, Sociability, Sensory/Cognitive Awareness, and
Health/Physical/Behavior) were linearly related to urinary porphyrins
associated with mercury toxicity. The results show an association between the
apparent level of mercury toxicity as measured by recognized urinary porphyrin
biomarkers of mercury toxicity and the magnitude of the specific hallmark
features of autism as assessed by ATEC.
http://www.ncbi.nlm.nih.gov/pubmed/20532957

“... there has been a great deal of information
... that repetitive mercury exposure during pregnancy, through thimerosal,
dental amalgam, and fish consumption, and after birth, through
thimerosal-containing vaccinations ... is one potential factor in autism.”
Education and Training in Autism and Developmental Disabilities • 2010

Mercury and Autism: A Review Jie Zhang John J. Wheeler The College at
Brockport, SUNY Tennessee Technological University Abstract The prevalence of
autism has increased approximately four times in children in nearly one decade
(California Health and Human Services Agency, 2003). It has been reported that
explanations such as immigration, shifts in the interpretation of diagnostic
criteria, improved identification, or diagnostic accuracies cannot explain the
observed increase (Geier & Geier, 2005). One potential cause that has alarmed
many has been the presence of thimersol, the mercury-based preservative found
among immunizations. Although many refute this, concern has been leveled by
many families and professionals concerning the potential impact of mercury
poisoning as a causal factor. Researchers have proposed that autism may be in
part caused by mercury, because there was cumulative mercury exposure through
dental amalgam, fish consumption, environment pollution, and additionally,
through increased thimerosal-containing vaccines for both mothers and newborns
(Mutter, Naumann, Schneider, Walach, & Haley, 2005). The purpose of this study
is to review the information from studies concerning the relationship between
mercury exposure and autism. Conclusion To sum up, there has been a great deal
of information from different studies that seems to indicate that repetitive
mercury exposure during pregnancy, through thimerosal, dental amalgam, and fish
consumption, and after birth, through thimerosal-containing vaccinations and
pollution, in genetically susceptible individuals is one potential factor in
autism. Certainly this question continues to stir debate among professionals
across the medical and behavioral sciences. It serves as a grey area for many
families as they seek to quell their anxiety invoked by this debate by
discovering the facts. The purpose of this article was to synthesize the
findings relative to this question to hopefully serve as a resource to
educators as we seek to become more well-informed on this timely issue. As the
prevalence rate for autism in children continues to rise, more research is
needed to better understand causal factors. It is also crucial that quality
reviews be conducted to synthesize a body of knowledge pertaining to these
questions if the puzzle is to be solved pertaining to the link between mercury
exposure and autism.

http://www.daddcec.org/Portals/0/CEC/Autism_Disabilities/Research/Publications/Education_Training_Development_Disabilities/2010v45_Journals/ETDD_201003v45n1p107-115_Mercury_Autism_A_Review.pdf

Acta Neurobiologiea Experimentalis • 2010

Age-dependent lower or higher levels of hair mercury in autistic children than
in healthy controls Author information Majewska MD1, Urbanowicz E, Rok-Bujko P,
Namyslowska I, Mierzejewski P. 1Department of Pharmacology and Physiology of
the Nervous System Institute of Psychiatry and Neurology, Warsaw, Poland
majewska@ipin.edu.pl Abstract An association between autism and early life
exposure to mercury is a hotly debated issue. In this study, 91 autistic Polish
children, male and female, 3-4 and 7-9 years old, were compared to 75 age- and
sex-matched healthy children with respect to: demographic, perinatal, clinical
and developmental measures, parental age, birth order, morphometric measures,
vaccination history, and hair mercury content. In demographic and perinatal
measures there were no consistent differences between the autistic and control
groups. Autistic children had a significantly greater prevalence of adverse
reactions after vaccinations and abnormal development than controls. Between 45
and 80% of autistic children experienced developmental regress. Autistic
children significantly differed from healthy peers in the concentrations of
mercury in hair: younger autistics had lower levels, while older - higher
levels than their respective controls. The results suggest that autistic
children differ from healthy children in metabolism of mercury, which seems to
change with age. http://www.ncbi.nlm.nih.gov/pubmed/?term=20628443

“The results suggest that autistic children differ from healthy children in
metabolism of mercury, which seems to change with age.”

Acta Neurobiologiea Experimentalis • 2010

Sorting out the spinning of autism: heavy metals and the question of incidence
Author information Desoto MC1, Hitlan RT. 1Department of Psychology University
of Northern Iowa Cedar Falls, Iowa, USA cathy.desoto@uni.edu Abstract The
reasons for the rise in autism prevalence are a subject of heated professional
debate. Featuring a critical appraisal of some research used to question
whether rising levels of autism are related to environmental exposure to toxins
(Soden et al. 2007, Barbaresi et al. 2009, Thompson et al. 2007) we aim to
evaluate the actual state of scientific knowledge. In addition, we surveyed the
empirical research on the topic of autism and heavy metal toxins. In our
opinion empirical investigations are finding support for a link with heavy
metal toxins. The various causes that have led to the increase in autism
diagnosis are likely multi-faceted, and understanding the causes is one of the
most important health topics today. We argue that scientific research does not
support rejecting the link between the neurodevelopmental disorder of autism
and toxic exposures. http://www.ncbi.nlm.nih.gov/pubmed/?term=20628440

“In our opinion empirical investigations are finding support for a link with
heavy metal toxins. We argue that scientific research does not support
rejecting the link between the neurodevelopmental disorder of autism and toxic
exposures.”

Journal Of Toxicology And Environmental Health Part A • 2010

Delayed acquisition of neonatal reflexes in newborn primates receiving a
thimerosal-containing hepatitis B vaccine: influence of gestational age and
birth weight Author information Hewitson L1, Houser LA, Stott C, Sackett G,
Tomko JL, Atwood D, Blue L, White ER. Department of Obstetrics and Gynecology
University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, USA
lch1@pitt.edu Abstract This study examined whether acquisition of neonatal
reflexes in newborn rhesus macaques was influenced by receipt of a single
neonatal dose of hepatitis B vaccine containing the preservative thimerosal
(Th). Hepatitis B vaccine containing a weight-adjusted Th dose was administered
to male macaques within 24 h of birth (n = 13). Unexposed animals received
saline placebo (n = 4) or no injection (n = 3). Infants were tested daily for
acquisition of nine survival, motor, and sensorimotor reflexes. In exposed
animals there was a significant delay in the acquisition of root, snout, and
suck reflexes, compared with unexposed animals. No neonatal responses were
significantly delayed in unexposed animals. Gestational age (GA) and birth
weight (BW) were not significantly correlated. Cox regression models were used
to evaluate main effects and interactions of exposure with BW and GA as
independent predictors and time-invariant covariates. Significant main effects
remained for exposure on root and suck when controlling for GA and BW, such
that exposed animals were relatively delayed in time-to-criterion. Interaction
models indicated there were various interactions between exposure, GA, and BW
and that inclusion of the relevant interaction terms significantly improved
model fit. This, in turn, indicated that lower BW and/or lower GA exacerbated
the adverse effects following vaccine exposure. This primate model provides a
possible means of assessing adverse neurodevelopmental outcomes from neonatal
Th-containing hepatitis B vaccine exposure, particularly in infants of lower GA
or BW. The mechanisms underlying these effects and the requirements for Th
requires further study. http://www.ncbi.nlm.nih.gov/pubmed/?term=20711932

“This primate model provides a possible means of assessing adverse
neurodevelopmental outcomes from neonatal Thimerosal-containing hepatitis B
vaccine exposure, particularly in infants ...”

Acta Neurobiologia Experimentalis • 2010

Blood mercury levels in autism spectrum disorder: Is there a threshold level?
Author information Geier DA1, Audhya T, Kern JK, Geier MR. Institute of Chronic
Illnesses, Inc. Silver Spring, MD, USA Abstract Mercury (Hg) may significantly
impact the pathogenesis of autism spectrum disorders (ASDs). Lab results
generated by Vitamin Diagnostics (CLIA-approved) from 2003-2007, were examined
among subjects diagnosed with an ASD (n=83) in comparison to neurotypical
controls (n=89). Blood Hg levels were determined by analyzing Hg content in red
blood cells (RBC) using cold vapor analysis, and consistent Hg measurements
were observed between Vitamin Diagnostics and the University of Rochester.
Adjusted (age, gender, and date of collection) mean Hg levels were 1.9-fold
significantly (P<.0001) increased among subjects diagnosed with an ASD (21.4
microg/L) in comparison to controls (11.4 microg/L). Further, an adjusted
significant (P<.0005) threshold effect >15 microg/L) was observed for Hg levels
on the risk of a subject being diagnosed with an ASD in comparison to controls
(odds ratio=6.4). The weight of scientific evidence supports Hg as a causal
factor in subjects diagnosed with an ASD. Full Report:
http://www.ncbi.nlm.nih.gov/pubmed/20628441

“The weight of scientific evidence supports ethyl mercury as a causal factor in
subjects diagnosed with an Autistic Spectrum Disorder”

“These findings document neurotoxic effects of thimerosal,
at doses equivalent to those used in infant vaccines ...” Folia Neuropathology
• 2010

Lasting neuropathological changes in rat brain after intermittent neonatal
administration of thimerosal Author information Olczak M1, Duszczyk M,
Mierzejewski P, Wierzba-Bobrowicz T, Majewska MD. Department of Pharmacology
and Physiology of the Nervous System, Institute of Psychiatry and Neurology,
ul. Sobieskiego 9, Warsaw, Poland Abstract Thimerosal, an organomercurial added
as a preservative to some vaccines, is a suspected iatrogenic factor, possibly
contributing to paediatric neurodevelopmental disorders including autism. We
examined the effects of early postnatal administration of thimerosal (four i.m.
injections, 12 or 240 μg THIM-Hg/kg, on postnatal days 7, 9, 11 and 15) on
brain pathology in Wistar rats. Numerous neuropathological changes were
observed in young adult rats which were treated postnatally with thimerosal.
They included: ischaemic degeneration of neurons and “dark” neurons in the
prefrontal and temporal cortex, the hippocampus and the cerebellum,
pathological changes of the blood vessels in the temporal cortex, diminished
synaptophysin reaction in the hippocampus, atrophy of astroglia in the
hippocampus and cerebellum, and positive caspase-3 reaction in Bergmann
astroglia. These findings document neurotoxic effects of thimerosal, at doses
equivalent to those used in infant vaccines or higher, in developing rat brain,
suggesting likely involvement of this mercurial in neurodevelopmental
disorders. http://www.ncbi.nlm.nih.gov/pubmed/?term=21225508

“... investigators have long recognized that Hg is a neurodevelopmental poison;
it can cause problems in neuronal cell migration and division, and can
ultimately cause cell degeneration and death.” Acta Neurobiologia
Experimentalis • 2010

The biological basis of autism spectrum disorders: Understanding causation and
treatment by clinical geneticists Author information Geier DA1, Kern JK, Geier
MR. The Institute of Chronic Illnesses, Inc., Silver Spring, Maryland, USA
Abstract Autism spectrum disorders (ASDs) also known as pervasive developmental
disorders (PDD) are a behaviorally defined group of neurodevelopmental
disorders that are usually diagnosed in early childhood. ASDs
disproportionately affect male children. Mercury (Hg) a heavy metal, is
widespread and persistent in the environment. Mercury is a ubiquitous source of
danger in fish, drugs, fungicides/herbicides, dental fillings, thermometers,
and many other products. Elevated Hg concentrations may remain in the brain
from several years to decades following exposure. This is important because
investigators have long recognized that Hg is a neurodevelopmental poison; it
can cause problems in neuronal cell migration and division, and can ultimately
cause cell degeneration and death. Case-reports of patients have described
developmental regressions with ASD symptoms following fetal and/or early
childhood Hg exposure, and epidemiological studies have linked exposure to Hg
with an elevated risk of a patient being diagnosed with an ASD. Immune,
sensory, neurological, motor, and behavioral dysfunctions similar to traits
defining or associated with ASDs were reported following Hg intoxication with
similarities extending to neuroanatomy, neurotransmitters, and biochemistry.
The sexual dimorphism of ASDs may result from synergistic neurotoxicity caused
by the interaction of testosterone and Hg; in contrast, estrogen is protective,
mitigating the toxicity of Hg. Mercury exposure may significantly increase
androgen levels, and as a result, patients diagnosed with an ASD may
significantly benefit from anti-androgen therapy. Finally, the clinical
geneticist has a wealth of biomarkers to evaluate and treat patients diagnosed
with an ASD. Access to full report: http://www.ncbi.nlm.nih.gov/pubmed/20628444

Neurotoxicity Research • January 2011

Correlations Between Gene Expression and Mercury Levels in Blood of Boys With
and Without Autism Boryana Stamova,1,9,10 Peter G. Green,2 Yingfang Tian,1,9,10
Irva Hertz-Picciotto,3,9,10 Isaac N. Pessah,4,9,10 Robin Hansen,5,9,10 Xiaowei
Yang,3 Jennifer Teng,1 Jeffrey P. Gregg,6,9,10 Paul Ashwood,7,9,10 Judy Van de
Water,8,9,10 and Frank R. Sharp1,9,10 1. Department of Neurology, University of
California at Davis Medical Center, Sacramento, CA 95817 USA 2. Department of
Civil and Environmental Engineering, University of California at Davis,
Sacramento, CA USA 3. Department of Public Health Sciences, University of
California at Davis Medical Center, Sacramento, CA USA 4. Department of VM:
Molecular Biosciences, University of California at Davis Medical Center,
Sacramento, CA USA 5. Department of Pediatrics, University of California at
Davis Medical Center, Sacramento, CA USA 6. Department of Pathology, University
of California at Davis Medical Center, Sacramento, CA USA 7. Department of
Medical Microbiology and Immunology, University of California at Davis Medical
Center, Sacramento, CA USA 8. Division of Rheumatology, Allergy and Clinical
Immunology, University of California at Davis Medical Center, Sacramento, CA 9.
The MIND Institute, University of California at Davis Medical Center, 2805 50th
Street, Room 2434, Sacramento, CA USA 10. UC Davis Center for Children’s
Environmental Health and Disease Prevention, Sacramento, CA USA

Abstract Gene expression in blood was correlated with mercury levels in blood
of 2- to 5-year-old boys with autism (AU) compared to age-matched typically
developing (TD) control boys. This was done to address the possibility that the
two groups might metabolize toxicants, such as mercury, differently. RNA was
isolated from blood and gene expression assessed on whole genome Affymetrix
Human U133 expression microarrays. Mercury levels were measured using an
inductively coupled plasma mass spectrometer. Analysis of covariance (ANCOVA)
was performed and partial correlations between gene expression and mercury
levels were calculated, after correcting for age and batch effects. To reduce
false positives, only genes shared by the ANCOVA models were analyzed. Of the
26 genes that correlated with mercury levels in both AU and TD boys, 11 were
significantly different between the groups (P(Diagnosis*Mercury) ≤ 0.05). The
expression of a large number of genes (n = 316) correlated with mercury levels
in TD but not in AU boys (P ≤ 0.05), the most represented biological functions
being cell death and cell morphology. Expression of 189 genes correlated with
mercury levels in AU but not in TD boys (P ≤ 0.05), the most represented
biological functions being cell morphology, amino acid metabolism, and antigen
presentation. These data and those in our companion study on correlation of
gene expression and lead levels show that AU and TD children display different
correlations between transcript levels and low levels of mercury and lead.
These findings might suggest different genetic transcriptional programs
associated with mercury in AU compared to TD children.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006666/

“These data and those in our companion study on correlation of gene expression
and lead levels show that Autistic and Typically Developing children display
different correlations between transcript levels and low levels of mercury and
lead. These findings might suggest different genetic transcriptional programs
associated with mercury in Autistic compared to Typically Developing children.”

Journal Of Occupational Medicine And Toxicology • January 2011

Is dental amalgam safe for humans? The opinion of the scientific committee of
the European Commission Author information Mutter J. Department of
Environmental and integrative medicine Lohnerhofstraße 2, 78467
Constance/Germany jm@zahnklinik.de.

“The half-life of mercury in the brain can last from several years to decades,
thus mercury accumulates over time

Abstract It was claimed by the Scientific Committee on Emerging and Newly
Identified Health Risks (SCENIHR)) in a report to the EU-Commission that “....
no risks of adverse systemic effects exist and the current use of dental
amalgam does not pose a risk of systemic disease...” [1, available from:
http:// ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_016.
pdf].SCENIHR disregarded the toxicology of mercury and did not include most
important scientific studies in their review. But the real scientific data show
that:(a) Dental amalgam is by far the main source of human total mercury body
burden. This is proven by autopsy studies which found 2-12 times more mercury
in body tissues of individuals with dental amalgam. Autopsy studies are the
most valuable and most important studies for examining the amalgam-caused
mercury body burden.(b) These autopsy studies have shown consistently that many
individuals with amalgam have toxic levels of mercury in their brains or
kidneys.(c) There is no correlation between mercury levels in blood or urine,
and the levels in body tissues or the severity of clinical symptoms. SCENIHR
only relied on levels in urine or blood.(d) The half-life of mercury in the
brain can last from several years to decades, thus mercury accumulates over
time of amalgam exposure in body tissues to toxic levels. However, SCENIHR
state that the half-life of mercury in the body is only “20-90 days”.(e)
Mercury vapor is about ten times more toxic than lead on human neurons and with
synergistic toxicity to other metals.(f) Most studies cited by SCENIHR which
conclude that amalgam fillings are safe have severe methodical flaws. Full
Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025977/

of amalgam exposure in body tissues to toxic levels. However, SCENIHR state
that the half-life of mercury in the body is only “20-90 days”. Mercury vapor
is about ten times more toxic than lead on human neurons and with synergistic
toxicity to other metals. Most studies cited by SCENIHR which conclude that
amalgam fillings are safe have severe methodical flaws.”

Toxicology And Environmental Chemistry • February 2011

Toxicity biomarkers among US children compared to a similar cohort in France: a
blinded study measuring urinary porphyrins Author information Kern JK1, Geier
DA2, Ayzac F3, Adams JB4, Mehta JA5, Geier MR6. 1. Genetic Consultants of
Dallas, 408 North Allen Drive, Allen, TX Autism Treatment Center, 10503 Metric
Drive, Dallas, TX University of Texas Southwestern Medical Center at Dallas
5323 Harry Hines Boulevard, Dallas, TX 2. CoMeD, Inc. and Institute of Chronic
Illnesses, Inc. 14 Redgate Court, Silver Spring, MD 20905 3. Autism Research
Institute, 4182 Adams Avenue, San Diego, CA 92116 4. Department of Chemical and
Materials Engineering, Arizona State University 7001 East Williams Field Road,
Mesa, AZ 85212 5. Department of Communication Sciences and Disorders, Texas
Woman’s University 304 Administration Drive, Denton, Texas 76204, USA 6. Autism
Spectrum Disorder Centers, LLC 14 Redgate Court, Silver Spring, MD 20905, USA
Abstract The purpose of this blinded study was to evaluate potential
environmental toxicity in a cohort of neurotypical children (n = 28) living in
a suburban area of north-central Texas in the United States (US) with a
comparable age- and gender-matched cohort of neurotypical children (n = 28)
living in a suburban area of southeastern France using urinary porphyrin
testing: uroporphyrin (uP), heptacarboxyporphyrin (7cxP), hexacarboxyporphyrin
(6cxP), pentacarboxyporphyrin (5cxP), precoproporphyrin (prcP), and
coproporphyrin (cP). Results showed significantly elevated 6cxP, prcP (an
atypical, mercury-specific porphyrin), and cP levels, and increasing trends in
5cxP levels, among neurotypical children in the USA compared to children in
France. Data suggest that in US neurotypical children, there is a significantly
increased body-burden of mercury (Hg) compared to the body-burden of Hg in the
matched neurotypical children in France. The presence of lead contributing to
the higher levels of cP also needs to be considered. Further, other factors
including genetics can not be completely ruled out. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898545/

“Data suggest that in US neurotypical children, there is a significantly
increased body-burden of mercury compared to the body-burden of mercury in the
matched neurotypical children in France.”

Biometals • April 2011

A significant relationship between mercury exposure from dental amalgams a nd
urinary porphyrins: a further assessment of the Casa Pia children’s dental
amalgam trial Author information Geier DA1, Carmody T, Kern JK, King PG, Geier
MR. Institute of Chronic Illnesses, Inc., Silver Spring, MD, USA
mgeier@comcast.net Abstract Previous studies noted specific changes in urinary
porphyrin excretion patterns associated with exposure to mercury (Hg) in
animals and humans. In our study, urinary porphyrin concentrations were
examined in normal children 8-18 yearsold from a reanalysis of data provided
from a randomized, prospective clinical trial that was designed to evaluate the
potential health consequences of prolonged exposure to Hg from dental amalgam
fillings (the parent study). Our analysis examined dose-dependent correlations
between increasing Hg exposure from dental amalgams and urinary porphyrins
utilizing statistical models with adjustments for the baseline level (i.e.
study year 1) of the following variables: urinary Hg, each urinary porphyrin
measure, gender, race, and the level of lead (Pb) in each subject’s blood.
Significant dose-dependent correlations between cumulative exposure to Hg from
dental amalgams and urinary porphyrins associated with Hg body-burden
(pentacarboxyporphyrin, precoproporphyrin, and coproporphyrin) were observed.
Overall, 5-10% increases in Hg-associated porphyrins for subjects receiving an
average number of dental amalgam fillings in comparison to subjects receiving
only composite fillings were observed over the 8-year course of the study. In
contrast, no significant correlations were observed between cumulative exposure
to Hg from dental amalgams and urinary porphyrins not associated with Hg
body-burden (uroporphyrin, heptacarboxyporphyrin, and hexacarboxyporphyrin). In
conclusion, our study, in contrast to the no-effect results published from the
parent study, further establishes the sensitivity and specificity of specific
urinary porphyrins as a biomarker for low-level Hg body-burden, and also
reveals that dental amalgams are a significant chronic contributor to Hg
body-burden. http://www.ncbi.nlm.nih.gov/pubmed/?term=21053054

“In conclusion, our study, in contrast to the no-effect results published from
the parent study, further establishes the sensitivity and specificity of
specific urinary porphyrins as a biomarker for low-level mercury body-burden,
and also reveals that dental amalgams are a significant chronic contributor to
mercury body-burden.”

“Recent studies suggest that children diagnosed with an autism spectrum disorder
have significantly increased levels of urinary porphyrins associated with
mercury (Hg) toxicity ...” Pediatrics International • April 2011

Toxicity biomarkers in autism spectrum disorder: a blinded study of urinary
porphyrins Author information Kern JK1, Geier DA, Adams JB, Mehta JA,
Grannemann BD, Geier MR. Research Department, Genetics Consultants of
Dallas/ASD Centers, LLC., 408 N. Allen Dr, Allen, TX 75013, USA
jkern@dfwair.net Abstract BACKGROUND Recent studies suggest that children
diagnosed with an autism spectrum disorder (ASD) have significantly increased
levels of urinary porphyrins associated with mercury (Hg) toxicity, including
pentacarboxyporphyrin (5cxP), precoproporphyrin (prcP), and coproporphyrin
(cP), compared to typically developing controls. However, these initial studies
were criticized because the controls were not age- and gender-matched to the
children diagnosed with an ASD. METHODS Urinary porphyrin biomarkers in a group
of children (2-13 years of age) diagnosed with an ASD (n= 20) were compared to
matched (age, gender, race, location, and year tested) group of typically
developing controls (n= 20). RESULTS Participants diagnosed with an ASD had
significantly increased levels of 5cxP, prcP, and cP in comparison to controls.
No significant differences were found in non-Hg associated urinary porphyrins
(uroporphyrins, hexacarboxyporphyrin, and heptacarboxyporphyrin). There was a
significantly increased odds ratio for an ASD diagnosis relative to controls
among study participants with precoproporphyrin (odds ratio = 15.5, P < 0.01)
and coproporphyrin (odds ratio = 15.5, P < 0.01) levels in the second through
fourth quartiles in comparison to the first quartile. CONCLUSION These results
suggest that the levels of Hg-toxicity-associated porphyrins are higher in
children with an ASD diagnosis than controls. Although the pattern seen
(increased 5cxP, prcP, and cP) is characteristic of Hg toxicity, the influence
of other factors, such as genetics and other metals cannot be completely ruled
out. http://www.ncbi.nlm.nih.gov/pubmed/20626635

“Mercury (Hg) is recognized as a ubiquitous environmental neurotoxin and there is
mounting evidence linking it to neurodevelopmental disorders, including
autism.” Toxicology And Environmental Chemistry • May 2011

The plausibility of a role for mercury in the etiology of autism: a cellular
perspective Matthew Garrecht and David W. Austin Swinburne Autism Bio-Research
Initiative Faculty of Life and Social Sciences Swinburne University of
Technology Hawthorn, Victoria 3122, Australia Abstract Autism is defined by a
behavioral set of stereotypic and repetitious behavioral patterns in
combination with social and communication deficits. There is emerging evidence
supporting the hypothesis that autism may result from a combination of genetic
susceptibility and exposure to environmental toxins at critical moments in
development. Mercury (Hg) is recognized as a ubiquitous environmental
neurotoxin and there is mounting evidence linking it to neurodevelopmental
disorders, including autism. Of course, the evidence is not derived from
experimental trials with humans but rather from methods focusing on biomarkers
of Hg damage, measurements of Hg exposure, epidemiological data, and animal
studies. For ethical reasons, controlled Hg exposure in humans will never be
conducted. Therefore, to properly evaluate the Hg-autism etiological
hypothesis, it is essential to first establish the biological plausibility of
the hypothesis. This review examines the plausibility of Hg as the primary
etiological agent driving the cellular mechanisms by which Hg-induced
neurotoxicity may result in the physiological attributes of autism. Key areas
of focus include: (1) route and cellular mechanisms of Hg exposure in autism;
(2) current research and examples of possible genetic variables that are linked
to both Hg sensitivity and autism; (3) the role Hg may play as an environmental
toxin fueling the oxidative stress found in autism; (4) role of mitochondrial
dysfunction; and (5) possible role of Hg in abnormal neuroexcitory and
excitotoxity that may play a role in the immune dysregulation found in autism.
Future research directions that would assist in addressing the gaps in our
knowledge are proposed. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173748/

Neurochemical Research • June 2011

Integrating experimental (in vitro and in vivo) neurotoxicity studies of
low-dose thimerosal relevant to vaccines Author information Dórea JG. Faculty
of Health Sciences Universidade de Brasília CP 04322, 70919-970, Brasília, DF,
Brazil dorea@rudah.com.br Abstract There is a need to interpret neurotoxic
studies to help deal with uncertainties surrounding pregnant mothers, newborns
and young children who must receive repeated doses of Thimerosal-containing
vaccines (TCVs). This review integrates information derived from emerging
experimental studies (in vitro and in vivo) of low-dose Thimerosal (sodium
ethyl mercury thiosalicylate). Major databases (PubMed and Web-of-science) were
searched for in vitro and in vivo experimental studies that addressed the
effects of low-dose Thimerosal (or ethylmercury) on neural tissues and animal
behaviour. Information extracted from studies indicates that: (a) activity of
low doses of Thimerosal against isolated human and animal brain cells was found
in all studies and is consistent with Hg neurotoxicity; (b) the neurotoxic
effect of ethylmercury has not been studied with co-occurring adjuvant-Al in
TCVs; (c) animal studies have shown that exposure to Thimerosal-Hg can lead to
accumulation of inorganic Hg in brain, and that (d) doses relevant to TCV
exposure possess the potential to affect human neuro-development. Thimerosal at
concentrations relevant for infants’ exposure (in vaccines) is toxic to
cultured human-brain cells and to laboratory animals. The persisting use of TCV
(in developing countries) is counterintuitive to global efforts to lower Hg
exposure and to ban Hg in medical products; its continued use in TCV requires
evaluation of a sufficiently nontoxic level of ethylmercury compatible with
repeated exposure (co-occurring with adjuvant-Al) during early life.
http://www.ncbi.nlm.nih.gov/pubmed/21350943

“... activity of low doses of Thimerosal against isolated human and animal
brain cells was found in all studies and is consistent with mercury
neurotoxicity ... animal studies have shown that exposure to Thimerosal-Hg can
lead to accumulation of inorganic mercury in brain, and that doses relevant to
Thimerosal-containing vaccine exposure possess the potential to affect human
neuro-development.”

Biological Trace Elements Research • June 2011

Automated speciation of mercury in the hair of breastfed infants exposed to
ethylmercury from thimerosal-containing vaccines Author information Dórea JG1,
Wimer W, Marques RC, Shade C. Universidade de Brasília, C.P.04322, 70919-970
Brasília, Federal District, Brasil dorea@rudah.com.br Abstract A simplified
thiourea-based chromatography method, originally developed for methyl and
inorganic mercury, was adapted to separate methylmercury (MeHg), ethylmercury
(EtHg), and inorganic mercury (Hg(II)) in infants’ hair. Samples were weighed
and leached with an acidic thiourea solution. Leachates were concentrated on a
polymeric resin prior to analysis by Hg-thiourea liquid chromatography/cold
vapor atomic fluorescence spectrometry. All but one sample showed small amounts
of EtHg, and four of the six analyzed samples had proportionally higher Hg(II)
as a percent of total Hg. Breastfed infants from riverine Amazonian communities
are exposed to mercury in breast milk (from high levels of maternal sources
that include both fish consumption and dental amalgam) and to EtHg in vaccines
(from thimerosal). The method proved sensitive enough to detect and quantify
acute EtHg exposure after shots of thimerosalcontaining vaccines. Based on work
with MeHg and Hg(II), estimated detection limits for this method are 0.050,
0.10, and 0.10 ng g∼¹ for MeHg, Hg(II), and EtHg, respectively, for a 20-mg
sample. Specific limits depend on the amount of sample extracted and the amount
of extract injected. http://www.ncbi.nlm.nih.gov/pubmed/?term=20419397

“The method proved sensitive enough to detect and quantify acute Ethyl Mercury
exposure after shots of thimerosal-containing vaccines.”

“... significant elevation in the concentration of copper, lead and mercury ...”
Biological Trace Element Research • August 2011

Level of trace elements (copper, zinc, magnesium and selenium) and toxic
elements (lead and mercury) in the hair and nail of children with autism Author
information Lakshmi Priya MD1, Geetha A. Department of Biochemistry, Bharathi
Women’s College Chennai, 600 108 Tamil Nadu, India Abstract Autism is a
multi-factorial pathology observed in children with altered levels of essential
and elevated levels of toxic elements. There are also studies reporting a
decrease in nutritional trace elements in the hair and nail of autistic
children with healthy controls; moreover, bioelements have been shown to play
an important role in the central nervous system. Therefore, the purpose of the
present study was to assess the levels of trace elements like copper (Cu), zinc
(Zn), magnesium (Mg), and selenium (Se) and toxic elements like mercury (Hg),
and lead (Pb) in the hair and nail samples of autistic children and to evaluate
whether the level of these elements could be correlated with the severity of
autism. The subjects of the study were 45 autistic children with different
grades of severity (low (LFA), medium (MFA), and high (HFA) functioning autism)
according to Childhood Autism Rating Scale, n = 15 children in each group and
50 healthy children (age and sex matched). The boys and girls ratio involved in
this study was 4:1, and they were 4-12 years of age. The study observed a valid
indication of Cu body burden in the autistic children. The children with
different grades of autism showed high significance (p < 0.001) in the level of
copper in their hair and nail samples when compared to healthy controls. The
level of Cu in the autistic children could be correlated with their degree of
severity (more the Cu burden severe is autism). The study showed a significant
elevation (p < 0.001) in the levels of toxic metals Pb and Hg in both hair and
nail samples of autistic children when compared to healthy control group. The
elevation was much pronounced in LFA group subjects when compared among
autistic groups MFA and HFA. The levels of trace elements Mg and Se were
significantly decreased (p < 0.001) in autistic children when compared to
control. The trace element Zn showed significant variation in both hair and
nails of LFA group children when compared to control group and other study
groups. The significant elevation in the concentration of Cu, Pb, and Hg and
significant decrease in the concentration of Mg and Se observed in the hair and
nail samples of autistic subjects could be well correlated with their degrees
of severity. http://www.ncbi.nlm.nih.gov/pubmed/20625937

The Science Of The Total Environment • September 2011

Mercury exposure and risks from dental amalgam in the US population post-2000
Author information Richardson GM1, Wilson R, Allard D, Purtill C, Douma S,
Gravière J. SNC-Lavalin Environment, Suite 110 20 Colonnade Road, Ottawa, ON
Canada mark.richardson@snclavalin.com Abstract Dental amalgam is 50% metallic
mercury (Hg) by weight and Hg vapour continuously evolves from in-place dental
amalgam, causing increased Hg content with increasing amalgam load in urine,
faeces, exhaled breath, saliva, blood, and various organs and tissues including
the kidney, pituitary gland, liver, and brain. The Hg content also increases
with maternal amalgam load in amniotic fluid, placenta, cord blood, meconium,
various foetal tissues including liver, kidney and brain, in colostrum and
breast milk. Based on 2001 to 2004 population statistics, 181.1 million
Americans carry a grand total of 1.46 billion restored teeth. Children as young
as 26 months were recorded as having restored teeth. Past dental practice and
recently available data indicate that the majority of these restorations are
composed of dental amalgam. Employing recent US population-based statistics on
body weight and the frequency of dentally restored tooth surfaces, and recent
research on the incremental increase in urinary Hg concentration per
amalgam-filled tooth surface, estimates of Hg exposure from amalgam fillings
were determined for 5 age groups of the US population. Three specific exposure
scenarios were considered, each scenario incrementally reducing the number of
tooth surfaces assumed to be restored with amalgam. Based on the least
conservative of the scenarios evaluated, it was estimated that some 67.2
million Americans would exceed the Hg dose associated with the reference
exposure level (REL) of 0.3 μg/m(3) established by the US Environmental
Protection Agency; and 122.3 million Americans would exceed the dose associated
with the REL of 0.03 μg/m(3) established by the California Environmental
Protection Agency. Exposure estimates are consistent with previous estimates
presented by Health Canada in 1995, and amount to 0.2 to 0.4 μg/day per
amalgam-filled tooth surface, or 0.5 to 1 μg/day/amalgam-filled tooth,
depending on age and other factors.
http://www.ncbi.nlm.nih.gov/pubmed/?term=21782213

“Based on the least conservative of the scenarios evaluated, it was estimated
that some 67.2 million Americans would exceed the mercury dose associated with
the reference exposure level (REL) of 0.3 μg/m(3) established by the US
Environmental Protection Agency; and 122.3 million Americans would exceed the
dose associated with the REL of 0.03 μg/m(3) established by the California
Environmental Protection Agency.”

“These data document that early postnatal Thimerosal administration
causes lasting neurobehavioral impairments and neurochemical alterations in the
brain ...” Behavioral Brain Research • September 2011

Persistent behavioral impairments and alterations of brain dopamine system
after early postnatal administration of thimerosal in rats Author information
Olczak M1, Duszczyk M, Mierzejewski P, Meyza K, Majewska MD. Department of
Pharmacology and Physiology of the Nervous System Institute of Psychiatry and
Neurology, 02-957 Warsaw, Poland Abstract The neurotoxic organomercurial
thimerosal (THIM), used for decades as vaccine preservative, is a suspected
factor in the pathogenesis of some neurodevelopmental disorders. Previously we
showed that neonatal administration of THIM at doses equivalent to those used
in infant vaccines or higher, causes lasting alterations in the brain opioid
system in rats. Here we investigated neonatal treatment with THIM (at doses 12,
240, 1440 and 3000 μg Hg/kg) on behaviors, which are characteristically altered
in autism, such as locomotor activity, anxiety, social interactions, spatial
learning, and on the brain dopaminergic system in Wistar rats of both sexes.
Adult male and female rats, which were exposed to the entire range of THIM
doses during the early postnatal life, manifested impairments of locomotor
activity and increased anxiety/neophobia in the open field test. In animals of
both sexes treated with the highest THIM dose, the frequency of prosocial
interactions was reduced, while the frequency of asocial/antisocial
interactions was increased in males, but decreased in females. Neonatal THIM
treatment did not significantly affect spatial learning and memory.
THIM-exposed rats also manifested reduced haloperidol-induced catalepsy,
accompanied by a marked decline in the density of striatal D2 receptors,
measured by immunohistochemical staining, suggesting alterations to the brain
dopaminergic system. Males were more sensitive than females to some
neurodisruptive/neurotoxic actions of THIM. These data document that early
postnatal THIM administration causes lasting neurobehavioral impairments and
neurochemical alterations in the brain, dependent on dose and sex. If similar
changes occur in THIM/mercurial-exposed children, they could contribute do
neurodevelopmental disorders. http://www.ncbi.nlm.nih.gov/pubmed/?term=21549155

Neuroscience Letters • October 2011

Chronic inorganic mercury exposure induces sex-specific changes in central TNF
expression: importance in autism? Author information Thomas Curtis J1, Chen Y,
Buck DJ, Davis RL. Department of Pharmacology/Physiology Oklahoma State
University Center for Health Sciences 1111 West 17th Street, Tulsa, OK 74107,
United States Abstract Mercury is neurotoxic and increasing evidence suggests
that environmental exposure to mercury may contribute to neuropathologies
including Alzheimer’s disease and autism spectrum disorders. Mercury is known
to disrupt immunocompetence in the periphery, however, little is known about
the effects of mercury on neuroimmune signaling. Mercury-induced effects on
central immune function are potentially very important given that mercury
exposure and neuroinflammation both are implicated in certain neuropathologies
(i.e., autism). Furthermore, mounting evidence points to the involvement of
glial activation in autism. Therefore, we utilized an in vivo model to assess
the effects of mercury exposure on neuroimmune signaling. In prairie voles, 10
week mercury exposure (60ppm HgCl(2) in drinking water) resulted in a
male-specific increase in TNF protein expression in the cerebellum and
hippocampus. These findings are consistent with our previously reported
male-specific mercury-induced deficits in social behavior and further support a
role for heavy metals exposure in neuropathologies such as autism. Subsequent
studies should further evaluate the mechanism of action and biological
consequences of heavy metals exposure. Additionally, these observations
highlight the potential of neuroimmune markers in male voles as biomarkers of
environmental mercury toxicity. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443965/

“These findings are consistent with our previously reported male-specific
mercury-induced deficits in social behavior and further support a role for
heavy metals exposure in neuropathologies such as autism.”

“... statistically significant differences in the mean urine levels of aluminum, barium, cerium, mercury ...”
Maedica Bucharest • October 2011

Heavy metals and trace elements in hair and urine of a sample of arab children
with autistic spectrum disorder Author information Blaurock-Busch E1, Amin OR,
Rabah T. Lecturer and Advisor International Board of Clinical Metal Toxicology
& German Medical Association of Clinical Metal Toxicology Abstract General
information: Autism is a severe developmental disorder which involves social
withdrawal, communication deficits, and stereotypic/repetitive behavior. The
pathophysiological etiologies which precipitate autism symptoms remain elusive
and controversial in many cases, but both genetic and environmental factors
(and their interactions) have been implicated. While autism is considered
multicausal, environmental factors have received significant attention.
International discussion has ocused on neurotoxins such as mercury and lead,
suggesting that these and other toxic metals contribute to the development of
the disorder. An epidemiological study released in 2006 (Palmer et al.) linking
Toxic Release Inventory (TRI) data on mercury to special education data in
Texas reported a 61% increase in autism prevalence rates (or 17% adjusted) per
1000 pounds of mercury released into the environment (1). We attempted to
further evaluate whether exposure to variable environmental contributes to the
genesis of autistic spectrum disorder, and thus is a factor increasing the risk
for developing autism symptoms in utero or in early childhood.

Hospital in Jeddah, KSA. Samples were collected during the period of June 2006
to March 2008. A control group of 25 children without any psychiatric or
medical disorders was agematched and sex-matched. All parents signed informed
consent forms. All autistic children were subjected to a full clinical child
psychiatric sheet for the diagnosis of autism spectrum disorder and exclusion
of other psychiatric disorders according to the Diagnostic and Statistical
Manual of Mental Disorders, 4th Edition (DSM IV). The severity of autistic
symptomatology was measured by the Childhood Autism Rating Scale (CARS) and
Autism Behavior Checklist (ABC) using the Arabic versions. Both groups were
subjected to the Questionnaire on Exposure to Heavy Metals, Physical Symptoms,
and Child Development. Hair and baseline urine samples (i.e. unprovoked urine)
were taken from both groups and sent to the German clinical and environmental
laboratory Micro Trace Minerals Gmbh, for the detection of heavy metals and
trace elements levels where metal testing was performed via ICP-MS spectroscopy
utilizing cell technique.

PURPOSE The purpose of this study is to examine possible environmental risk
factors and sources of exposure to mercury and other heavy metals in children
with autism spectrum disorder versus controls. Through laboratory diagnostics
we are able to distinguish between present and past exposure (i.e. hair
analysis measurements reflect past exposure), urinary excretion levels of
unprovoked urine represent immediate exposure. By assessing a spectrum of trace
elements and heavy metals in hair and urine of both autistic and control
groups, we focused on the participants≈ past and present exposure.

RESULTS By comparing the ASD Group to the Control Group, we found a
statistically significant difference in the mean hair levels of arsenic,
cadmium, barium, cerium and lead (p=0.01, 0.03, 0.003, 0.003, and 0.03
respectively), and in the mean hair levels of magnesium and zinc (p=0.001 and
0.003 respectively). There were also statistically significant differences in
the mean urine levels of aluminum, barium, cerium, mercury, and lead (p=0.004,
002, 0.014, 0.006 and 0.004 respectively), and in the mean urine levels of
copper and germanium (p=0.049 and 0.02 respectively). An agreement was found in
both specimen (hair and urine) for barium and lead. The statistically
significant differences in mean hair levels of arsenic, cadmium, and cerium
were not supported by urine baseline levels. Also, the statistically
significant magnesium and zinc levels of hair were not supported by urine
levels. A disagreement was also found with copper and germanium concentrations.

METHODOLOGY The participants were 25 Autistic Spectrum Disorder (ASD) children
(22 boys and 3 girls) between the age of 3 and 9 years. They were either
diagnosed previously by other psychiatrist, psychologist, and developmental
pediatrician or suspected by their parents as being autistic. All children were
attendants to the Child Psychiatric Clinic in Erfan Psychiatric

Full Report: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391939/

Journal Of Toxicology • 2011

Toxicity of volatile methylated species of bismuth, arsenic, tin, and mercury
in Mammalian cells in vitro Author information Dopp E1, von Recklinghausen U,
Hippler J, Diaz-Bone RA, Richard J, Zimmermann U, Rettenmeier AW, Hirner AV.
Institute of Hygiene and Occupational Medicine University of Duisburg-Essen,
Hufelandstraße 55 45122 Essen, Germany Abstract The biochemical transformation
of mercury, tin, arsenic and bismuth through formation of volatile alkylated
species performs a fundamental role in determining the environmental processing
of these elements. While the toxicity of inorganic forms of most of these
compounds are well documented (e.g., arsenic, mercury) and some of them are of
relatively low toxicity (e.g., tin, bismuth), the more lipid-soluble
organometals can be highly toxic. In the present study we investigated the
cyto- and genotoxicity of five volatile metal(loid) compounds:
trimethylbismuth, dimethylarsenic iodide, trimethylarsine, tetramethyltin, and
dimethylmercury. As far as we know, this is the first study investigating the
toxicity of volatile metal(loid) compounds in vitro. Our results showed that
dimethylmercury was most toxic to all three used cell lines (CHO-9 cells, CaCo,
Hep-G2) followed by dimethylarsenic iodide. Tetramethyltin was the least toxic
compound; however, the toxicity was also dependend upon the cell type. Human
colon cells (CaCo) were most susceptible to the toxicity of the volatile
compounds compared to the other cell lines. We conclude from our study that
volatile metal(loid) compounds can be toxic to mammalian cells already at very
low concentrations but the toxicity depends upon the metal(loid) species and
the exposed cell type. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189616/

“We conclude from our study that volatile metal(loid) compounds can be toxic to
mammalian cells already at very low concentrations but the toxicity depends
upon the metal(loid) species and the exposed cell type.”

Journal Of Toxicology And Environmental Health Part A • 2011

Ancestry of pink disease (infantile acrodynia) identified as a risk factor for
autism spectrum disorders Author information Shandley K1, Austin DW. Swinburne
Autism Bio-Research Initiative (SABRI) Brain and Psychological Sciences
Research Centre Swinburne University of Technology Hawthorn, Victoria,
Australia Abstract Pink disease (infantile acrodynia) was especially prevalent
in the first half of the 20th century. Primarily attributed to exposure to
mercury (Hg) commonly found in teething powders, the condition was developed by
approximately 1 in 500 exposed children. The differential risk factor was
identified as an idiosyncratic sensitivity to Hg. Autism spectrum disorders
(ASD) have also been postulated to be produced by Hg. Analogous to the pink
disease experience, Hg exposure is widespread yet only a fraction of exposed
children develop an ASD, suggesting sensitivity to Hg may also be present in
children with an ASD. The objective of this study was to test the hypothesis
that individuals with a known hypersensitivity to Hg (pink disease survivors)
may be more likely to have descendants with an ASD. Five hundred and twenty-two
participants who had previously been diagnosed with pink disease completed a
survey on the health outcomes of their descendants. The prevalence rates of ASD
and a variety of other clinical conditions diagnosed in childhood (attention
deficit hyperactivity disorder, epilepsy, Fragile X syndrome, and Down
syndrome) were compared to well-established general population prevalence
rates. The results showed the prevalence rate of ASD among the grandchildren of
pink disease survivors (1 in 22) to be significantly higher than the comparable
general population prevalence rate (1 in 160). The results support the
hypothesis that Hg sensitivity may be a heritable/genetic risk factor for ASD.
http://www.ncbi.nlm.nih.gov/pubmed/21797771

“Pink disease was especially prevalent in the first half of the 20th century.
Primarily attributed to exposure to mercury commonly found in teething powders,
the condition was developed by approximately 1 in 500 exposed children.”

Journal Of Toxicology And Environmental Health • 2011

A positive association found between autism prevalence and childhood
vaccination uptake across the U.S. population Author information Delong G.
Department of Economics and Finance Baruch College/City University of New York
New York, New York, USA gayle.delong@baruch.cuny.edu Abstract The reason for
the rapid rise of autism in the United States that began in the 1990s is a
mystery. Although individuals probably have a genetic predisposition to develop
autism, researchers suspect that one or more environmental triggers are also
needed. One of those triggers might be the battery of vaccinations that young
children receive. Using regression analysis and controlling for family income
and ethnicity, the relationship between the proportion of children who received
the recommended vaccines by age 2 years and the prevalence of autism (AUT) or
speech or language impairment (SLI) in each U.S. state from 2001 and 2007 was
determined. A positive and statistically significant relationship was found:
The higher the proportion of children receiving recommended vaccinations, the
higher was the prevalence of AUT or SLI. A 1% increase in vaccination was
associated with an additional 680 children having AUT or SLI. Neither parental
behavior nor access to care affected the results, since vaccination proportions
were not significantly related (statistically) to any other disability or to
the number of pediatricians in a U.S. state. The results suggest that although
mercury has been removed from many vaccines, other culprits may link vaccines
to autism. Further study into the relationship between vaccines and autism is
warranted. http://www.ncbi.nlm.nih.gov/pubmed/21623535

“The results suggest that although mercury has been removed from many vaccines,
other culprits may link vaccines to autism.”

“Our data supports the historic evidence that heavy metals
play a role in the development of Autistic Spectrum Disorder.” Maedica
Bucharest • January 2012

Toxic Metals and Essential Elements in Hair and Severity of Symptoms among
Children with Autism Author information Blaurock-Busch E1, Amin OR, Dessoki HH,
Rabah T. Lecturer and Advisor International Board of Clinical Metal Toxicology
and German Medical Association of Clinical Metal Toxicology Hersbruck, Germany
Abstract OBJECTIVE The objective of this study was to assess the levels of ten
toxic metals and essential elements in hair samples of children with autism,
and to correlate the level of these elements with the severity of autism.
METHOD The participants were 44 children, age 3 to 9 years, with Autistic
Spectrum Disorder (ASD) according to Diagnostic and Statistical Manual of
Mental Disorders 4th Edition, (DSM-IV). The severity of autistic symptomatology
was measured by the Childhood Autism Rating Scale (CARS). Hair analysis was
performed to evaluate the long term metal exposure and mineral level. RESULTS
By comparing hair concentration of autistic vs nonautistic children, elevated
hair concentrations were noted for aluminum, arsenic, cadmium, mercury,
antimony, nickel, lead, and vanadium. Hair levels of calcium, iron, iodine,
magnesium, manganese, molybdenum, zinc, and selenium were considered deficient.
There was a significant positive correlation between lead & verbal
communication (p = 0.020) and general impression (p = 0.008). In addition,
there was a significant negative correlation between zinc & fear and
nervousness (p = 0.022). CONCLUSION Our data supports the historic evidence
that heavy metals play a role in the development of ASD. In combination with an
inadequate nutritional status the toxic effect of metals increase along with
the severity of symptoms. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484795/

Neurochemical Research • February 2012

Administration of thimerosal to infant rats increases overflow of glutamate and
aspartate in the prefrontal cortex: protective role of dehydroepiandrosterone
sulfate Author information Duszczyk-Budhathoki M1, Olczak M, Lehner M, Majewska
MD. Marie Curie Chairs Program Department of Pharmacology and Physiology of
Nervous System Institute of Psychiatry and Neurology, 02-957, Warsaw, Poland
Abstract Thimerosal, a mercury-containing vaccine preservative, is a suspected
factor in the etiology of neurodevelopmental disorders. We previously showed
that its administration to infant rats causes behavioral, neurochemical and
neuropathological abnormalities similar to those present in autism. Here we
examined, using microdialysis, the effect of thimerosal on extracellular levels
of neuroactive amino acids in the rat prefrontal cortex (PFC). Thimerosal
administration (4 injections, i.m., 240 μg Hg/kg on postnatal days 7, 9, 11,
15) induced lasting changes in amino acid overflow: an increase of glutamate
and aspartate accompanied by a decrease of glycine and alanine; measured 10-14
weeks after the injections. Four injections of thimerosal at a dose of 12.5 μg
Hg/kg did not alter glutamate and aspartate concentrations at microdialysis
time (but based on thimerosal pharmacokinetics, could have been effective soon
after its injection). Application of thimerosal to the PFC in perfusion fluid
evoked a rapid increase of glutamate overflow. Coadministration of the
neurosteroid, dehydroepiandrosterone sulfate (DHEAS; 80 mg/kg; i.p.) prevented
the thimerosal effect on glutamate and aspartate; the steroid alone had no
influence on these amino acids. Coapplication of DHEAS with thimerosal in
perfusion fluid also blocked the acute action of thimerosal on glutamate. In
contrast, DHEAS alone reduced overflow of glycine and alanine, somewhat
potentiating the thimerosal effect on these amino acids. Since excessive
accumulation of extracellular glutamate is linked with excitotoxicity, our data
imply that neonatal exposure to thimerosal-containing vaccines might induce
excitotoxic brain injuries, leading to neurodevelopmental disorders. DHEAS may
partially protect against mercurials-induced neurotoxicity. Abstract:
http://www.ncbi.nlm.nih.gov/pubmed/?term=22015977 Full Report:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264864/

“Since excessive accumulation of extracellular glutamate is linked with
excitotoxicity, our data imply that neonatal exposure to thimerosal-containing
vaccines might induce excitotoxic brain injuries, leading to neurodevelopmental
disorders.”

PLoS One • 2012

Thimerosal-induced apoptosis in mouse C2C12 myoblast cells occurs through
suppression of the PI3K/Akt/survivin pathway Author information Li WX1, Chen
SF, Chen LP, Yang GY, Li JT, Liu HZ, Zhu W. Department of Toxicology Guangzhou
Center for Disease Control and Prevention Guangzhou, China Abstract BACKGROUND
Thimerosal, a mercury-containing preservative, is one of the most widely used
preservatives and found in a variety of biological products. Concerns over its
possible toxicity have reemerged recently due to its use in vaccines.
Thimerosal has also been reported to be markedly cytotoxic to neural tissue.
However, little is known regarding thimerosal-induced toxicity in muscle
tissue. Therefore, we investigated the cytotoxic effect of thimerosal and its
possible mechanisms on mouse C2C12 myoblast cells. METHODOLOGY/PRINCIPAL
FINDINGS The study showed that C2C12 myoblast cells underwent inhibition of
proliferation and apoptosis after exposure to thimerosal (125-500 nM) for 24,
48 and 72 h. Thimerosal caused S phase arrest and induced apoptosis as assessed
by flow cytometric analysis, Hoechst staining and immunoblotting. The data
revealed that thimerosal could trigger the leakage of cytochrome c from
mitochondria, followed by cleavage of caspase-9 and caspase-3, and that an
inhibitor of caspase could suppress thimerosalinduced apoptosis. Thimerosal
inhibited the phosphorylation of Akt(ser473) and survivin expression.
Wortmannin, a PI3K inhibitor, inhibited Akt activity and decreased survivin
expression, resulting in increased thimerosal-induced apoptosis in C2C12 cells,
while the activation of PI3K/Akt pathway by mIGF-I (50 ng/ml) increased the
expression of survivin and attenuated apoptosis. Furthermore, the inhibition of
survivin expression by siRNA enhanced thimerosal-induced cell apoptosis, while
overexpression of survivin prevented thimerosal-induced apoptosis. Taken
together, the data show that the PI3K/Akt/survivin pathway plays an important
role in the thimerosal-induced apoptosis in C2C12 cells.
CONCLUSIONS/SIGNIFICANCE Our results suggest that in C2C12 myoblast cells,
thimerosal induces S phase arrest and finally causes apoptosis via inhibition
of PI3K/Akt/survivin signaling followed by activation of the mitochondrial
apoptotic pathway. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492179/

“Our results suggest that in C2C12 myoblast cells, thimerosal induces S phase
arrest and finally causes apoptosis via inhibition of PI3K/Akt/survivin
signaling followed by activation of the mitochondrial apoptotic pathway.”

Journal On Developmental Disabilities • 2012

A Link Between mercury exposure, Autism Spectrum Disorder, and other
neurodevelopmental Disorders? Implications for thimerosal-containing Vaccines
Lucija Tomljenovic,1 José G. Dórea,2 Christopher A. Shaw,1 1. Department of
Ophthalmology and Visual Sciences University of British Columbia, Vancouver, BC
2. Faculty of Health Sciences Universidade de Brasilia, Brasilia, Brazil
Abstract Autism is a multisystem developmental disorder characterized by
dysfunctional immunity and impaired brain function. Although autism is partly
determined by genetic susceptability factors, reported dramatic increases in
the prevalence of autism in developed countries have intensified scientific
focus on environmental exposures. Pre and perinatal immunotoxic insults are now
strongly suspected as contributors to this increase. Mercury (Hg) is both a
neuro and an immuno toxin and continues to be used in some pediatric vaccines
in the form of the preservative thimerosal. Although currently there are no
direct human studies on the risks of Hg exposure from thimerosalcontaining
vaccines (TCVs), animal studies show that doses relevant to human TCV exposure
can result in adverse neurodevelopmental outcomes. To date, TCVs continue to be
administered on a regular basis to potentially the most vulnerable populations:
pregnant women and children. In light of existing experimental evidence, the
rationale for using this known immunotoxic and neurotoxic substance in human
vaccines should be reconsidered. Given the dramatic and rapidly-growing
reported prevalence of autism spectrum disorder (ASD) (Newschaffer, Falb, &
Gurney, 2005), a clear answer to the etiology of this apparent epidemic would
serve parents as well as the medical community entrusted with the health of all
children. The focus of this commentary is on the possible involvement of
thimerosal (49% ethylmercury (EtHg)) in neurodevelopmental disorders. In the
past, thimerosal was used worldwide as a preservative in vaccines. Although
this practice has largely been discontinued due to safety concerns (Offit &
Jew, 2003), thimerosal continues to be used in less-developed and developing
countries (Dórea, Marques, & Brandao, 2009)), as well as in the preservation of
multi-dose vaccine vials in Canada and the United States (Centers for Disease
Control and Prevention, 2011; Public Health Agency of Canada, 2011). The use of
thimerosal-containing vaccines (TCVs) continues to be a highly contentious
issue. The fact that a causal link between thimerosal exposure and
neurodevelopmental disorders in children is not supported by many studies
(Andrews et al., 2004; Hviid, Stellfeld, Wohlfahrd, & Melbye, 2003; Parker,
Schwartz, Todd, & Pickering, 2004; Verstraeten et al., 2003) fails to put this
issue at rest. Full Report:
http://www.oadd.org/docs/41011_JoDD_18-1_34-42_Tomljenovic_et_al.pdf

“Given the dramatic and rapidly-growing reported prevalence of autism spectrum
disorder (ASD) (Newschaffer, Falb, & Gurney, 2005), a clear answer to the
etiology of this apparent epidemic would serve parents as well as the medical
community entrusted with the health of all children. The fact that a causal
link between thimerosal exposure and neurodevelopmental disorders in children
is not supported by many studies fails to put this issue at rest.”
Environmental Sources Of Mercury Mercury Concentration

Form

Biological Significance

0.4ppb

MetHg

Median chronic intake of contaminated fish (0.4ug/kg body weight) causes
delayed speech and autistic-like symptoms in male children (Corbett & Poor,
2008)

1.6ppb

MetHg

Provisional Tolerable Weekly Intake (PTWI) based on body weight for infants and
pregnant women (1.6ug/kg; Food & Agricultural Association/World Health
Organization 2006)

2.0ppb

Inorganic Mercury

US EPA limit for drinking water (US EPA, 2011)

200ppb

Various Types Of Mercury

Level in liquid that the US EPA classifies as hazardous waste based on toxocity
characteristics (US EPA, 2010)

600ppb

EtHg

Concentration of mercury in vaccines containing trace amounts of thimerosal
(0.3ug/0.5 ml. dose, or 600ug/L;Halsey, 1999)

25,000-50,000ppb

EtHg

Concentration in Thimerosal containing multi-dose influenza, meningococcal
pneumococcal polysaccharide and diphtheria-tetanus vaccines (Offit & Jew, 2003)

Journal Of Toxicology • June 2012

Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes:
Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA Martyn
A. Sharpe, * Andrew D. Livingston, and David S. Baskin Department of
Neurosurgery, The Methodist Hospital 6565 Fannin Street, Houston, TX 77030, USA
Abstract Thimerosal generates ethylmercury in aqueous solution and is widely
used as preservative. We have investigated the toxicology of Thimerosal in
normal human astrocytes, paying particular attention to mitochondrial function
and the generation of specific oxidants. We find that ethylmercury not only
inhibits mitochondrial respiration leading to a drop in the steady state
membrane potential, but also concurrent with these phenomena increases the
formation of superoxide, hydrogen peroxide, and Fenton/Haber-Weiss generated
hydroxyl radical. These oxidants increase the levels of cellular
aldehyde/ketones. Additionally, we find a five-fold increase in the levels of
oxidant damaged mitochondrial DNA bases and increases in the levels of mtDNA
nicks and blunt-ended breaks. Highly damaged mitochondria are characterized by
having very low membrane potentials, increased superoxide/hydrogen peroxide
production, and extensively damaged mtDNA and proteins. These mitochondria
appear to have undergone a permeability transition, an observation supported by
the five-fold increase in Caspase-3 activity observed after Thimerosal
treatment. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395253/

“We find that ethylmercury not only inhibits mitochondrial respiration leading
to a drop in the steady state membrane potential, but also concurrent with
these phenomena increases the formation of superoxide, hydrogen peroxide, and
Fenton/Haber-Weiss generated hydroxyl radical. These oxidants increase the
levels of cellular aldehyde/ketones. Additionally, we find a five-fold increase
in the levels of oxidant damaged mitochondrial DNA bases and increases in the
levels of mtDNA nicks and blunt-ended breaks.”

Cerebellum • June 2012

Maternal thimerosal exposure results in aberrant cerebellar oxidative stress,
thyroid hormone metabolism, and motor behavior in rat pups; sex- and
strain-dependent effects Author information Sulkowski ZL1, Chen T, Midha S,
Zavacki AM, Sajdel-Sulkowska EM. Department of Psychiatry Harvard Medical
School and Brigham and Women’s Hospital Boston, MA, USA Abstract Methylmercury
(Met-Hg) and ethylmercury (Et-Hg) are powerful toxicants with a range of
harmful neurological effects in humans and animals. While Met-Hg is a
recognized trigger of oxidative stress and an endocrine disruptor impacting
neurodevelopment, the developmental neurotoxicity of Et-Hg, a metabolite of
thimerosal (TM), has not been explored. We hypothesized that TM exposure during
the perinatal period impairs central nervous system development, and
specifically the cerebellum, by the mechanism involving oxidative stress. To
test this, spontaneously hypertensive rats (SHR) or Sprague-Dawley (SD) rat
dams were exposed to TM (200 μg/kg body weight) during pregnancy (G10-G15) and
lactation (P5-P10). Male and female neonates were evaluated for auditory and
motor function; cerebella were analyzed for oxidative stress and thyroid
metabolism. TM exposure resulted in a delayed startle response in SD neonates
and decreased motor learning in SHR male (22.6%), in SD male (29.8%), and in SD
female (55.0%) neonates. TM exposure also resulted in a significant increase in
cerebellar levels of the oxidative stress marker 3-nitrotyrosine in SHR female
(35.1%) and SD male (14.0%) neonates. The activity of cerebellar type 2
deiodinase, responsible for local intra-brain conversion of thyroxine to the
active hormone, 3’,3,5-triiodothyronine (T3), was significantly decreased in
TM-exposed SHR male (60.9%) pups. This coincided with an increased (47.0%)
expression of a gene negatively regulated by T3, Odf4 suggesting local
intracerebellar T3 deficiency. Our data thus demonstrate a negative
neurodevelopmental impact of perinatal TM exposure which appears to be both
strain- and sex-dependent. http://www.ncbi.nlm.nih.gov/pubmed/22015705

“Our data thus demonstrate a negative neurodevelopmental impact of perinatal
Thimerosal exposure which appears to be both strain- and sex-dependent.”

Journal Of Biomedics And Biotechnology • July 2012

Toxic effects of mercury on the cardiovascular and central nervous systems
Author information Fernandes Azevedo B1, Barros Furieri L, Peçanha FM, Wiggers
GA, Frizera Vassallo P, Ronacher Simões M, Fiorim J, Rossi de Batista P,
Fioresi M, Rossoni L, Stefanon I, Alonso MJ, Salaices M, Valentim Vassallo D.
Programa de Pós-Graduação em Ciências Fisiológicas Universidade Federal do
Espírito Santo 29042-755 Vitória, ES, Brazil Abstract Environmental
contamination has exposed humans to various metal agents, including mercury.
This exposure is more common than expected, and the health consequences of such
exposure remain unclear. For many years, mercury was used in a wide variety of
human activities, and now, exposure to this metal from both natural and
artificial sources is significantly increasing. Many studies show that high
exposure to mercury induces changes in the central nervous system, potentially
resulting in irritability, fatigue, behavioral changes, tremors, headaches,
hearing and cognitive loss, dysarthria, incoordination, hallucinations, and
death. In the cardiovascular system, mercury induces hypertension in humans and
animals that has wide-ranging consequences, including alterations in
endothelial function. The results described in this paper indicate that mercury
exposure, even at low doses, affects endothelial and cardiovascular function.
As a result, the reference values defining the limits for the absence of danger
should be reduced. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395437/

“The results described in this paper indicate that mercury exposure, even at
low doses, affects endothelial and cardiovascular function.”

Journal Of Biomedicine And Biotechnology • September 2012

Mercury Toxicity João B. T. Rocha, Michael Aschner, José G. Dórea, Sandra
Ceccatelli, Marcelo Farina and Luiz Carlos L. Silveira Abstract

Mercury (Hg) is one of the most toxic elements in the periodic table. Although
Hg is present in nature, it has also been released into the environment for
centuries as a result of anthropogenic activities. Nowadays, there are efforts
to reduce its anthropogenic use; however, its environmental presence is
significant and will persist. We are pleased to present this special issue on
mercury toxicity. The objective of collecting research findings in a single
issue devoted to the toxicology of mercury was to compile reports on the latest
findings on Hg’s toxicity from renowned research groups across the world. This
special issue affords the opportunity to bring together a wide range of review
and research papers devoted both to basic and applied toxicity associated with
various exposure scenarios and Hg species (dental material, iatrogenic
ethylmercury, fish-methylmercury) along with comprehensive description on
experimental models. While human studies demonstrated the noxious effects of
these forms of Hg, experimental studies have assisted in defining mechanistic
pathways central to Hg’s toxicity in various tissues and organ systems. The
volume is dedicated in part to articles that provide new insights on important
considerations of subtle effects of exposure to multiple forms of organic
mercury (ethylmercury in thimerosal-containing vaccines and methylmercury
(MeHg) derived from maternal fish consumption) and neurological outcomes in
infants (J. G. Dórea et al.). In addition, hypersensitivity to low-dose Hg
exposure from dental amalgam fillings is detailed, showing exquisite
sensitivity to amalgam-derived Hg in sensitized individuals (H. McParland and
S. Warnakulasuriya). Local effects of amalgam and Hg dental restoration
represent the most important nonoccupational exposure to inorganic mercury,
while fish consumption represents the most common source of MeHg exposure. The
impacts of exposure to fish-derived MeHg at levels below those considered to
pose neurological risk (hair level: 50 μg/g) were explored by Japanese
researchers in subjects of the Niigata mercury poisoning (K. Maruyama et al.).
Experimental research papers from this issue confirmed and extended
observations that exposure of immature rodents to different chemical forms of
Hg is associated with differential bodily distribution Hg (M. Blanuša et al.;
C.-F. Huang et al.). C.-F. Huang et al. demonstrated that exposure of
developing rats to cinnabar (HgS) caused long-lasting neurobehavioral and
neurochemical toxic effect, indicating that the use of this millenary component
of traditional Chinese medicine continues to represent a toxicological concern.
Using an important, yet little explored experimental mouse model, J. P.
Bourdineaud and colleagues demonstrated that the ingestion of MeHg-adulterated
fish led to higher neurotoxicity in comparison to the

ingestion of the “free salt” of methylmercury chloride (MeHgCl). The scarcity
of studies on this subject highlights the need for future studies to address
these persistent toxicological issues. The molecular, subcellular, cellular,
and systemic toxicity of Hg was also addressed here in this volume. The
cardiovascular toxicity of Hg in humans and rodents was reviewed by B. F.
Azevedo et al. The impact of Hg exposure on endothelial cell physiology is well
established; however, the limit of dietary-derived Hg needed to trigger
cardiotoxic effects is still debatable. The negative impact of oral exposure to
Hg(II) on reproductive performance of male rats was demonstrated by J. C. Heath
and collaborators, highlighting the need for detailed studies to determine the
nonobservable adverse effect level (NOAEL) of Hg(II) in the male reproductive
system, as well as Hg deposition in target tissues. The comparative renal and
hepatic toxicity of Hg(II) and MeHg in fish was addressed by V. Branco et al.,
demonstrating that both forms of mercury targeted the antioxidant selenoenzyme
thioredoxin-reductase (TrxR) and reinforcing the central role of disrupted
selenoprotein function in mercurial toxicity. The in vitro and in vivo
targeting of the critical sulfhydryl-containing enzyme, Na+, K+-ATPase was
reviewed by I. Kade and addressed by T. S. Huang et al., noting divergent
effects in vitro and in vivo. The role of mitochondria and calcium in the
neurotoxicity of MeHg was reviewed by D. Roos et al., providing evidence that
Ca2+, glutamate, oxidative stress, and mitochondria play a central role in its
neurotoxicity. The efficacy of the marine n-3 fatty acids, eicosapentaenoic
acid (EPA), and docosahexaenoic acid (DHA) in attenuating MeHg-induced toxicity
was studied in fish and mammalian cell cultures. O. J. Nøstbakken et al.
demonstrated that DHA decreased MeHg uptake into mammalian cells but increased
MeHg-induced apoptosis in fish cells. We hope that the new findings on the
subtle effects of combined exposure to iatrogenic ethylmercury (from
thimerosal-containing vaccines) and maternal MeHg (from fish consumption), as
well as the results of experimental studies and the critical reviews presented
herein can shed novel information on mercury’s absorption, distribution,
metabolism, and excretion, as well as its ill effects at the cellular,
molecular, and organismal levels. Understanding of these facets of research is
required for derivation on environmental and health policies as well as
guidance for the most promising future research venues. Finally, we would like
to thank all the reviewers that have contributed their time and insight to this
special issue as well as the journal’s personnel (particularly Doaa Hassan) for
their support and making possible the publication of this special issue.

www.hindawi.com/journals/bmri/2012/831890/

Neurotoxicology And Teratology • November 2012

Neonatal exposure to Thimerosal from vaccines and child development in the
first 3 years of life Author information Mrozek-Budzyn D1, Majewska R, Kieltyka
A, Augustyniak M. Epidemiology and Preventive Medicine Jagiellonian University
Medical College, Krakow, Poland dorota.mrozek-budzyn@uj.edu.pl Abstract
BACKGROUND: Despite the common use of Thimerosal as a preservative in childhood
vaccines since the 1930s, there are not many studies on ethylmercury
toxicokinetics and toxicodynamics in infants. The knowledge of ethylmercury’s
potential adverse effects is derived mostly from parallel methylmercury
research or from animal and theoretical models. AIM OF THE STUDY: This study
was designed to examine the relationship between neonatal exposure to
Thimerosal-containing vaccine (TCV) and child development. MATERIAL AND
METHODS: The study sample consisted of 196 infants born between January 2001
and March 2003 to mothers attending ambulatory prenatal clinics in the first
and second trimesters of pregnancy in Krakow. Vaccination history (date and the
type of the vaccine) was extracted from physicians’ records. Child development
was assessed using the Bayley Scales of Infant Development (BSID-II) measured
in one-year intervals over 3years. General Linear Model (GLM) and Generalized
Estimating Equation (GEE) models adjusted for potential confounders were used
to assess the association. RESULTS: An adverse effect of neonatal TCV exposure
was observed for the psychomotor development index (PDI) only in the 12th and
24th months of life (ß=-6.44, p<0.001 and ß=-5.89, p<0.001). No significant
effect of neonatal TCV exposure was found in the 36th month. The overall
deficit in the PDI attributable to neonatal TCV exposure measured over the
course of the three-year follow-up (GEE) was significantly higher in TCV group
(ß=-4.42, p=0.001). MDI scores did not show the adverse association with
neonatal TCV exposure. http://www.ncbi.nlm.nih.gov/pubmed/23069197

“Despite the common use of Thimerosal as a preservative in childhood vaccines
since the 1930s, there are not many studies on ethylmercury toxicokinetics and
toxicodynamics in infants. An adverse effect of neonatal TCV exposure was
observed for the psychomotor development index ...”

American Journal Of Epidemiology • November 2012

Re: “Prenatal Exposure to Mercury and Infant Neurodevelopment in a Multicenter
Cohort in Spain: Study of Potential Modifiers” Author Information José G. Dórea
Department of Nutrition, Faculty of Health Sciences Universidade de Brasilia,
70919-970 Brasilia, DF, Brazil dorea@rudah.com.br) Abstract In an interesting
study, Llop et al. (1) addressed the vulnerability of the central nervous
system to mercury during early development. Their findings suggested a negative
association between total cord blood mercury levels and psychomotor development
at approximately 14 months of age only in girls. Although I welcome these
interesting findings, I would like to raise the issue of a source of organic
mercury exposure during the perinatal period, namely ethylmercury in vaccines
that contain Thimerosal (Noah Technologies Corporation, San Antonio, Texas).
During recruitment of mothers (in November 2003) and infants born in 2004 in
the study by Llop et al., Thimerosal-containing vaccines (TCVs) were still used
in some European Union countries and probably in Spain (2). Therefore, it is
reasonable to assume that additional mercury exposure could have occurred, at
least for some of the sampled subjects. According to Spain’s vaccination
schedule, some children could be exposed to TCV ethylmercury (mainly in
diphtheria-tetanus-pertussis and hepatitis B vaccines); furthermore, during
pregnancy, some mothers were also likely to be exposed to TCVs. Neither infant
vaccines nor maternal exposure to TCVs, anti- Rho(D) immune globulin (to
Rh-negative participants), or dental amalgams during pregnancy were mentioned
in the otherwise assiduous study of Llop et al. Assuming that there was a
gradual discontinuation of TCVs in Spain, readers familiar with the changes
occurring in vaccine type used in European Union countries during the early
2000s could benefit from a post hoc discussion of this confounding mercury
source. The pertinence of this discussion is further justified by the recent
reports that a subtle but significant association with psychomotor development
can be shown in young children as a result of exposure to TCVs in Poland (3),
Korea (4), and Brazil (5). Indeed, ecologic and epidemiologic studies in the
United States, United Kingdom, and

Italy (6) that addressed children’s neurodevelopment associated with
ethylmercury exposure in TCVs indicated collectively that “a) there is
ambiguity in some studies reporting neurodevelopment outcomes that seem to
depend on confounding variables; b) the risk of neurotoxicity due to low doses
of Thimerosal is plausible at least for susceptible infants” (6, p. 1580).
Furthermore, recent findings have shown that neurologic responses in animals
(mice, rats, and rhesus monkeys) exposed to ethylmercury from the hepatitis B
vaccine in the early postnatal life presented statistically significant
differences when compared with controls (7); there is also strong in vitro
evidence of Thimerosal neurotoxicity in small doses relevant to TCVs (7).
Ethylmercury has a shorter half-life than does methylmercury; therefore, it is
unlikely that it could contribute to total mercury levels in cord blood
measured by Llop et al. (1). Nevertheless, ethylmercury exposure can be
ascertained from vaccination cards (3–5). Information on the association of
neurodevelopment and coexposure to multiple forms of mercury is limited, and
despite the current widespread use of TCVs (in most countries), it is even
scarcer for specific exposure to small amounts of ethylmercury (8). Therefore,
only studies like that of Llop et al. (1) can offer the opportunity to explore
possible cumulative insults resulting from maternal environmental
(methylmercury) exposure and additional infant ethylmercury exposure due to
differential (TCV) immunization. Although I do not question the statistical
model, results, or interpretation of the study by Llop et al. (1), I hope to
provoke a post hoc discussion highlighting possible ethylmercury exposure
during pregnancy and postnatal periods via TCVs. Without proper testing, we
will never discover whether additional TCV-related mercury exposure in early
life can affect neurodevelopment tests.

www.http://aje.oxfordjournals.org/content/early/2012/11/15/aje.kws386

“... a subtle but significant association with psychomotor development can be
shown in young children as a result of exposure to Thimerosal containing
vaccines in Poland, Korea, and Brazil ... there is also strong in vitro
evidence of Thimerosal neurotoxicity in small doses relevant to Thimerosal
containing vaccines.”

Brain Development • March 2013

Prenatal exposure to organomercury, thimerosal, persistently impairs the
serotonergic and dopaminergic systems in the rat brain: implications for
association with developmental disorders Author information Ida-Eto M1, Oyabu
A, Ohkawara T, Tashiro Y, Narita N, Narita M. Department of Anatomy II Mie
University Graduate School of Medicine Tsu, Mie 514-8507, Japan
etom@doc.medic.mie-u.ac.jp Abstract Thimerosal, an organomercury compound, has
been widely used as a preservative. Therefore, concerns have been raised about
its neurotoxicity. We recently demonstrated perturbation of early serotonergic
development by prenatal exposure to thimerosal (Ida-Eto et al. (2011) [11]).
Here, we investigated whether prenatal thimerosal exposure causes persistent
impairment after birth. Analysis on postnatal day 50 showed significant
increase in hippocampal serotonin following thimerosal administration on
embryonic day 9. Furthermore, not only serotonin, striatal dopamine was
significantly increased. These results indicate that embryonic exposure to
thimerosal produces lasting impairment of brain monoaminergic system, and thus
every effort should be made to avoid the use of thimerosal.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22658806

“These results indicate that embryonic exposure to thimerosal produces lasting
impairment of brain monoaminergic system, and thus every effort should be made
to avoid the use of thimerosal.”

“... dental amalgams contribute to ongoing kidney damage ... in a dose-dependent fashion.”
Human Experiments In Toxicology • April 2013

A significant dose-dependent relationship between mercury exposure from dental
amalgams and kidney integrity biomarkers: a further assessment of the Casa Pia
children’s dental amalgam trial Author information Geier DA1, Carmody T, Kern
JK, King PG, Geier MR. Institute of Chronic Illnesses, Inc., Silver Spring, USA
Abstract Dental amalgams are a commonly used dental restorative material.
Amalgams are about 50% mercury (Hg), and Hg is known to significantly
accumulate in the kidney. It was hypothesized that because Hg accumulates in
the proximal tubules (PTs), glutathione-S-transferases (GST)-a (suggestive of
kidney damage at the level of PT) would be expected to be more related to Hg
exposure than GST-π (suggestive of kidney damage at the level of the distal
tubules). Urinary biomarkers of kidney integrity were examined in children of
8-18 years old, with and without dental amalgam fillings, from a completed
clinical trial (parent study). Our study determined whether there was a
significant dose-dependent correlation between increasing Hg exposure from
dental amalgams and GST-a and GST-π as biomarkers of kidney integrity. Overall,
the present study, using a different and more sensitive statistical model than
the parent study, revealed a statistically significant dose-dependent
correlation between cumulative exposure to Hg from dental amalgams and urinary
levels of GST-a, after covariate adjustment; where as, a nonsignificant
relationship was observed with urinary levels of GST-π. Furthermore, it was
observed that urinary GST-a levels increased by about 10% over the 8-year
course of the study among individuals with an average exposure to amalgams
among the study subjects from the amalgam group, in comparison with study
subjects with no exposure to dental amalgams. The results of our study suggest
that dental amalgams contribute to ongoing kidney damage at the level of the
PTs in a dose-dependent fashion. http://www.ncbi.nlm.nih.gov/pubmed/22893351

“This suggests certain individuals with a mild mitochondrial defect
may be highly susceptible to mitochondrial specific toxins like the vaccine
preservative thimerosal.” Journal Of Toxicology • June 2013

B-lymphocytes from a population of children with autism spectrum disorder and
their unaffected siblings exhibit hypersensitivity to thimerosal Author
information Sharpe MA1, Gist TL, Baskin DS. Department of Neurosurgery, The
Methodist Neurological Institute 6560 Fannin Street, Scurlock Tower No. 944,
Houston, TX 77030, USA Abstract The role of thimerosal containing vaccines in
the development of autism spectrum disorder (ASD) has been an area of intense
debate, as has the presence of mercury dental amalgams and fish ingestion by
pregnant mothers. We studied the effects of thimerosal on cell proliferation
and mitochondrial function from B-lymphocytes taken from individuals with
autism, their nonautistic twins, and their nontwin siblings. Eleven families
were examined and compared to matched controls. B-cells were grown with
increasing levels of thimerosal, and various assays (LDH, XTT, DCFH, etc.) were
performed to examine the effects on cellular proliferation and mitochondrial
function. A subpopulation of eight individuals (4 ASD, 2 twins, and 2 siblings)
from four of the families showed thimerosal hypersensitivity, whereas none of
the control individuals displayed this response. The thimerosal concentration
required to inhibit cell proliferation in these individuals was only 40% of
controls. Cells hypersensitive to thimerosal also had higher levels of
oxidative stress markers, protein carbonyls, and oxidant generation. This
suggests certain individuals with a mild mitochondrial defect may be highly
susceptible to mitochondrial specific toxins like the vaccine preservative
thimerosal. http://www.ncbi.nlm.nih.gov/pubmed/?term=23843785

“... decreased glutathione reserve capacity in children with an Autistic Spectrum Disorder
could make them more susceptible to the toxic effects of Thimerosal routinely
administered as part of mandated childhood immunization schedules.”
International Journal Of Environmental Research And Public Health • August 2013

Thimerosal exposure and the role of sulfation chemistry and thiol availability
in autism Author information Kern JK1, Haley BE, Geier DA, Sykes LK, King PG,
Geier MR. Institute of Chronic Illnesses, Inc., Silver Spring, MD 20905, USA
jKern@dfwair.net Abstract Autism spectrum disorder (ASD) is a neurological
disorder in which a significant number of the children experience a
developmental regression characterized by a loss of previously acquired skills
and abilities. Typically reported are losses of verbal, nonverbal, and social
abilities. Several recent studies suggest that children diagnosed with an ASD
have abnormal sulfation chemistry, limited thiol availability, and decreased
glutathione (GSH) reserve capacity, resulting in a compromised
oxidation/reduction (redox) and detoxification capacity. Research indicates
that the availability of thiols, particularly GSH, can influence the effects of
thimerosal (TM) and other mercury (Hg) compounds. TM is an organomercurial
compound (49.55% Hg by weight) that has been, and continues to be, used as a
preservative in many childhood vaccines, particularly in developing countries.
Thiol-modulating mechanisms affecting the cytotoxicity of TM have been
identified. Importantly, the emergence of ASD symptoms post-6 months of age
temporally follows the administration of many childhood vaccines. The purpose
of the present critical review is provide mechanistic insight regarding how
limited thiol availability, abnormal sulfation chemistry, and decreased GSH
reserve capacity in children with an ASD could make them more susceptible to
the toxic effects of TM routinely administered as part of mandated childhood
immunization schedules. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774468/

Journal Of Applied Toxicology • August 2013

Toxicity of ethylmercury (and Thimerosal): a comparison with methylmercury José
G. Dórea1,*, Marcelo Farina2 andJoão B. T. Rocha3 Department of Nutrition,
Faculty of Health Sciences Universidade de Brasilia, Brasilia, DF, Brazil
Departamento de Bioquímica, Centro de Ciências Biológicas Universidade Federal
de Santa Catarina, Florianópolis, SC, Brazil Departamento de Química, Centro de
Ciências Naturais e Exatas Universidade Federal de Santa Maria, Santa Maria,
RS, Brazil Abstract Ethylmercury (etHg) is derived from the metabolism of
thimerosal (o-carboxyphenyl-thio-ethyl-sodium salt), which is the most widely
used form of organic mercury. Because of its application as a vaccine
preservative, almost every human and animal (domestic and farmed) that has been
immunized with thimerosal-containing vaccines has been exposed to etHg.
Although methylmercury (meHg) is considered a hazardous substance that is to be
avoided even at small levels when consumed in foods such as seafood and rice
(in Asia), the World Health Organization considers small doses of thimerosal
safe regardless of multiple/repetitive exposures to vaccines that are
predominantly taken during pregnancy or infancy. We have reviewed in vitro and
in vivo studies that compare the toxicological parameters among etHg and other
forms of mercury (predominantly meHg) to assess their relative toxicities and
potential to cause cumulative insults. In vitro studies comparing etHg with
meHg demonstrate equivalent measured outcomes for cardiovascular, neural and
immune cells. However, under in vivo conditions, evidence indicates a distinct
toxicokinetic profile between meHg and etHg, favoring a shorter blood
half-life, attendant compartment distribution and the elimination of etHg
compared with meHg. EtHg’s toxicity profile is different from that of meHg,
leading to different exposure and toxicity risks. Therefore, in real-life
scenarios, a simultaneous exposure to both etHg and meHg might result in
enhanced neurotoxic effects in developing mammals. However, our knowledge on
this subject is still incomplete, and studies are required to address the
predictability of the additive or synergic toxicological effects of etHg and
meHg (or other neurotoxicants). http://www.ncbi.nlm.nih.gov/pubmed/23401210

“the World Health Organization considers small doses of thimerosal safe
regardless of multiple/repetitive exposures to vaccines that are predominantly
taken during pregnancy or infancy ... in real-life scenarios, a simultaneous
exposure to both etHg and meHg might result in enhanced neurotoxic effects in
developing mammals. However, our knowledge on this subject is still incomplete,
and studies are required to address the predictability of the additive or
synergic toxicological effects of etHg and meHg (or other neurotoxicants).”

“Ethylmercury (EtHg) ... has received significant toxicological attention
due to its presence in thimerosal-containing vaccines.” Neuro Toxicology •
September 2013

Comparative study on methyl- and ethylmercury-induced toxicity in C6 glioma
cells and the potential role of LAT-1 in mediating mercurial-thiol complexes
uptake Luciana T. Zimmermanna, Danúbia B. Santosa, Aline A. Naimea, Rodrigo B.
Leala, José G. Dóreab, Fernando Barbosa Jr.c, Michael Aschnerd, João Batista T.
Rochae, Marcelo Farinaa a. Departamento de Bioquímica, Centro de Ciências
Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa
Catarina, Brazil b. Departamento de Nutrição, Faculdade de Ciências da Saúde,
Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil c.
Laboratório de Toxicologia e Essencialidade de Metais, Faculdade de Ciências,
Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP,
Brazil d. Department of Pediatrics, Vanderbilt University Medical Center,
Nashville, TN 37232, USA e. Departamento de Química, Universidade Federal de
Santa Maria, Santa Maria, Rio Grande do Sul, Brazil Abstract Various forms of
mercury possess different rates of absorption, metabolism and excretion, and
consequently, toxicity. Methylmercury (MeHg) is a highly neurotoxic organic
mercurial. Human exposure is mostly due to ingestion of contaminated fish.
Ethylmercury (EtHg), another organic mercury compound, has received significant
toxicological attention due to its presence in thimerosal-containing vaccines.
This study was designed to compare the toxicities induced by MeHg and EtHg, as
well as by their complexes with cysteine (MeHg-S-Cys and EtHg-SCys) in the C6
rat glioma cell line. MeHg and EtHg caused significant (p < 0.0001) decreases
in cellular viability when cells were treated during 30 min with each mercurial
following by a washing period of 24 h (EC50 values of 4.83 and 5.05 μM,
respectively). Significant cytotoxicity (p < 0.0001) was also observed when
cells were treated under the same conditions with MeHg-S-Cys and EtHg-S-Cys,
but the respective EC50 values were significantly increased (11.2 and 9.37 μM).
l-Methionine, a substrate for the l-type neutral amino acid carrier transport
(LAT) system, significantly protected against the toxicities induced by both
complexes (MeHg-S-Cys and EtHg-S-Cys). However, no protective effects of
l-methionine were observed against MeHg and EtHg toxicities. Corroborating
these findings, l-methionine significantly decreased mercurial uptake when
cells were exposed to MeHg-S-Cys (p = 0.028) and EtHg-S-Cys (p = 0.023), but
not to MeHg and EtHg. These results indicate that the uptake of MeHg-S-Cys and
EtHg-S-Cys into C6 cells is mediated, at least in part, through the LAT system,
but MeHg and EtHg enter C6 cells by mechanisms other than LAT system.
http://www.sciencedirect.com/science/article/pii/S0161813X13000922

Biological Trace Element Research • September 2013

Mercury transfer during pregnancy and breastfeeding: hair mercury
concentrations as biomarker Author information Marques RC1, Bernardi JV, Dórea
JG, Leão RS, Malm O. Universidade Federal do Rio de Janeiro Campus Macaé, Rio
de Janeiro, RJ, Brazil Abstract Hair mercury (HHg) concentration is a biomarker
of exposure that is widely used to assess environmental contamination by fish
methylmercury and neurodevelopment in children. In the Rio Madeira basin
(Brazilian Amazon), total HHg concentrations in 649 mother-infant pairs were
measured at birth (prenatal exposure) and after 6 months of exclusive
breastfeeding; these mother-infant pairs were from high fish-eating communities
(urban, n = 232; rural, n = 35; and Riverine, n = 262) and low fish-eating
tinminer settlers (n = 120). Differences in kinetics were seen between Hg
exposure from fish consumption and environmental exposure to a tin-ore mining
environment. Overall maternal HHg concentrations (at childbirth and after 6
months of lactation) were higher than those of infant HHg. However, the
relative change in HHg after 6 months of lactation showed that mothers
decreased HHg while infants increased HHg. The relative change showed a
consistently higher increase for girls than boys with a statistical
significance only in high fish-eating mothers. The correlation coefficients
between maternal and newborn hair were high and statistically significant for
mothers living in urban (r = 0.66, p < 0.001), rural (r = 0.89, p < 0.001), and
Riverine (r = 0.89, p < 0.001) communities not for tin miner settlers (r =
0.07, p = 0.427). After 6 months of exclusive breastfeeding, correlation
coefficients showed high correlation coefficients and statistical significance
for all groups (urban, r = 0.73, p < 0.001; rural, r = 0.88, p < 0.001;
Riverine, r = 0.91, p < 0.001) except for Tin miners (r = -0.07, p = 0.428). A
linear model analysis was used to assess the longitudinal associations of
maternal total HHg and total HHg at birth (0 days) and 6 months of age in
exclusively breastfed infants. Regression analysis significantly predicted HHg
in newborn from maternal HHg for high fish-eating maternal-infant pairs.
CONCLUSION: The concentration of mercury accumulated in newborn tissues (in
utero and during breastfeeding) relevant to both, maternal sources and infant
exposure, can be reliably assessed from maternal hair.
http://www.ncbi.nlm.nih.gov/pubmed/23836367

“The concentration of mercury accumulated in newborn tissues (in utero and
during breastfeeding) relevant to both, maternal sources and infant exposure,
can be reliably assessed from maternal hair.”

Toxicological and Environmental Chemistry • September 2013

Thimerosal in childhood vaccines contributes to accumulating mercury toxicity
in the kidney Maria Fernanda Hornos Carneiro, Christudas Morais, Fernando
Barbosa Jr, Glenda C Gobe Abstract Mercury (Hg) is a hazardous chemical that
accumulates in many cells and tissues, thereby producing toxicity. The kidney
is a key target organ for Hg accumulation and toxicity. The contributing
factors to Hg accumulation in humans include: (1) elemental and inorganic Hg
exposure, often occurring by inhalation of Hg vapors; (2) exposure to methyl Hg
(meHg), for example, through contaminated seafood; and (3) exposure to ethyl
mercury (etHg) via thimerosal-containing vaccines. Systematic investigations on
the toxic effects of etHg/thimerosal on the nervous system were carried out,
and etHg/thimerosal emerged as a possible risk factor for autism and other
neurodevelopmental disorders. There is, however, little known about the
mechanisms and molecular interactions underlying toxicity of etHg/thimerosal in
the kidney, which is the focus of the current review. Susceptible populations
such as infants, pregnant women, and the elderly are exposed to etHg through
thimerosal-containing vaccines, and in-depth study of the potential adverse
effects on the kidney is needed. In general, toxicity occurring in association
with different forms of Hg is related to: intracellular thiol metabolism and
oxidative stress reactions; mitochondrial function; intracellular distribution
and build-up of calcium; apoptosis; expression of stress proteins; and also
interaction with the cytoskeleton. Available evidence for the etHg-induced
toxicity in the kidney was examined, and the main mechanisms and molecular
interactions of cytotoxicity of etHg/thimerosal exposure in kidney described.
Such accumulating knowledge may help to indicate molecular pathways that, if
modulated, may better handle Hg-mediated toxicity.

“Systematic investigations on the toxic effects of ethyl mercury/thimerosal on
the nervous system were carried out, and ethyl mercury/thimerosal emerged as a
possible risk factor for autism and other neurodevelopmental disorders.”

https://www.researchgate.net/publication/260943204_Thimerosal_in_childhood_vaccines_contributes_to_accumulating_mercury_toxicity_in_the_kidney

International Journal Of Environmental Research And Public Health • October 2013

The kinetic signature of toxicity of four heavy metals and their mixtures on
MCF7 breast cancer cell line Author information Egiebor E1, Tulu A, Abou-Zeid
N, Aighewi IT, Ishaque A. Abstract This study evaluated the kinetic signature
of toxicity of four heavy metals known to cause severe health and environmental
issues--cadmium (Cd), mercury (Hg) lead (Pb) arsenic (As)--and the mixture of
all four metals (Mix) on MCF7 cancer cells, in the presence and absence of the
antioxidant glutathione (GSH). The study was carried out using real time cell
electronic sensing (RT-CES). RT-CES monitors in real time the electrical
impedance changes at the electrode/culture medium interface due to the number
of adhered cells, which is used as an index of cell viability. Cells were
seeded for 24 h before exposure to the metals and their mixtures. The results
showed that in the presence and absence of cellular glutathione, arsenic was
the most cytotoxic of all five treatments, inducing cell death after 5 h of
exposure. Lead was the least cytotoxic in both scenarios. In the presence of
cellular GSH, the cytotoxic trend was As > Cd > MIX > Hg > Pb, while in the
absence of GSH, the cytotoxic trend was As > Hg > MIX > Cd > Pb. The findings
from this study indicate the significance of glutathione-mediated toxicity of
the metals examined--particularly for mercury--and may be clinically relevant
for disorders such as autism spectrum disorder where decreased
glutathione-based detoxification capacity is associated with increased mercury
intoxication. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822392/

“The findings from this study indicate the significance of glutathione-mediated
toxicity of the metals examined—particularly for mercury—and may be clinically
relevant for disorders such as autism spectrum disorder where decreased
glutathione-based detoxification capacity is associated with increased mercury
intoxication.”

World Journal Of Pediatrics • November 2013

Effect of thimerosal on the neurodevelopment of premature rats Author
information Chen YN1, Wang J, Zhang J, Li SJ, He L, Shao DD, Du HY. The Key
Laboratory of Biomedical Information Engineering of Ministry of Education and
Institute of Biomedical Engineering School of Life Science and Technology Xi’an
Jiaotong University, Xi’an, 710049, China Abstract BACKGROUND This study was
undertaken to determine the effect of thimerosal on the neurodevelopment of
premature rats. METHODS Thimerosal was injected into premature SD rats at a
dose of 32.8, 65.6, 98.4 or 131.2 μg/kg on postnatal day 1. Expression of
dopamine D4 receptor (DRD4) and serotonin 2A receptor (5-HT2AR), apoptosis in
the prefrontal cortex on postinjection day 49, and learning and memory function
were studied and compared with those in a control group injected with saline.
RESULTS Expression of DRD4 and 5-HT2AR and learning function decreased, and
apoptosis increased significantly in the 131.2 μg/kg group (P<0.001). Memory
function was significantly impaired by 65.6 (P<0.05), 98.4 and 131.2 μg/kg
(P<0.001). CONCLUSIONS The negative adverse consequences on neurodevelopment
observed in the present study are consistent with previous studies; this study
raised serious concerns about adverse neurodevelopmental disorder such as
autism in humans following the ongoing worldwide routine administration of
thimerosalcontaining vaccines to infants.
http://www.ncbi.nlm.nih.gov/pubmed/?term=24235069

“The negative adverse consequences on neurodevelopment observed in the present
study are consistent with previous studies; this study raised serious concerns
about adverse neurodevelopmental disorder such as autism in humans following
the ongoing worldwide routine administration of thimerosal containing vaccines
to infants.”

International Journal Of Environmental Research And Public Health • December 2013

Proposed toxic and hypoxic impairment of a brainstem locus in autism Author
information McGinnis WR1, Audhya T, Edelson SM. Autism Research Institute, 4182
Adams Avenue, San Diego, CA 92116, USA woody.mcginnis@gmail.com Abstract
Electrophysiological findings implicate site-specific impairment of the nucleus
tractus solitarius (NTS) in autism. This invites hypothetical consideration of
a large role for this small brainstem structure as the basis for seemingly
disjointed behavioral and somatic features of autism. The NTS is the brain’s
point of entry for visceral afference, its relay for vagal reflexes, and its
integration center for autonomic control of circulatory, immunological,
gastrointestinal, and laryngeal function. The NTS facilitates normal
cerebrovascular perfusion, and is the seminal point for an ascending
noradrenergic system that modulates many complex behaviors. Microvascular
configuration predisposes the NTS to focal hypoxia. A subregion--the
“pNTS”--permits exposure to all blood-borne neurotoxins, including those that
do not readily transit the blood-brain barrier. Impairment of
acetylcholinesterase (mercury and cadmium cations, nitrates/nitrites,
organophosphates, monosodium glutamate), competition for hemoglobin (carbon
monoxide, nitrates/nitrites), and higher blood viscosity (net systemic
oxidative stress) are suggested to potentiate microcirculatory insufficiency of
the NTS, and thus autism.

“A subregion—the “pNTS”—permits exposure to all blood-borne neurotoxins,
including those that do not readily transit the blood-brain barrier. Impairment
of acetylcholinesterase (mercury and cadmium cations, nitrates/nitrites,
organophosphates, monosodium glutamate), competition for hemoglobin (carbon
monoxide, nitrates/nitrites), and higher blood viscosity (net systemic
oxidative stress) are suggested to potentiate microcircula-

Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881151/

tory insufficiency of the NTS, and thus autism.”

“... the present study provides new epidemiological evidence
supporting an association between increasing organic-mercury exposure from
Thimerosal-containing childhood vaccines and the subsequent risk of an Autistic
Spectrum Disorder diagnosis.” Translational Neurodegeneration • December 2013

A two-phase study evaluating the relationship between Thimerosal-containing
vaccine administration and the risk for an autism spectrum disorder diagnosis
in the United States Author information Geier DA, Hooker BS, Kern JK, King PG,
Sykes LK, Geier MR1. The Institute of Chronic Illnesses Inc, 14 Redgate Ct,
Silver Spring, MD, USA mgeier@comcast.net Abstract BACKGROUND Autism spectrum
disorder (ASD) is defined by standardized criteria of qualitative impairments
in social interaction, qualitative impairments in communication, and restricted
and stereotyped patterns of behavior, interests, and activities. A significant
number of children diagnosed with ASD suffer a loss of previously-acquired
skills, which is suggestive of neurodegeneration or a type of progressive
encephalopathy with an etiological pathogenic basis occurring after birth. To
date, the etiology of ASD remains under debate, however, many studies suggest
toxicity, especially from mercury (Hg), in individuals diagnosed with an ASD.
The present study evaluated concerns about the toxic effects of organic-Hg
exposure from Thimerosal (49.55% Hg by weight) in childhood vaccines by
conducting a two-phased (hypothesis generating/hypothesis testing) study with
documented exposure to varying levels of Thimerosal from vaccinations. METHODS
A hypothesis generating cohort study was undertaken to evaluate the
relationship between exposure to organic-Hg from a Thimerosal-containing
Diphtheria-Tetanus-acellular-Pertussis (DTaP) vaccine in comparison to a
Thimerosal-free DTaP vaccine administered, from 1998 through 2000, for the risk
of ASD as reported in the Vaccine Adverse Event Reporting System (VAERS)
database (phase I). A hypothesis testing case-control study was undertaken to
evaluate the relationship between organic-Hg exposure from

Thimerosal-containing hepatitis B vaccines administered at specific intervals
in the first six months of life among cases diagnosed with an ASD and controls
born between 1991 through 1999 in the Vaccine Safety Datalink (VSD) database
(phase II). RESULTS In phase I, it was observed that there was a significantly
increased risk ratio for the incidence of ASD reported following the
Thimerosal-containing DTaP vaccine in comparison to the Thimerosal-free DTaP
vaccine. In phase II, it was observed that cases diagnosed with an ASD were
significantly more likely than controls to receive increased organic-Hg from
Thimerosalcontaining hepatitis B vaccine administered within the first, second,
and sixth month of life. CONCLUSIONS Routine childhood vaccination is an
important public health tool to reduce the morbidity and mortality associated
with infectious diseases, but the present study provides new epidemiological
evidence supporting an association between increasing organic-Hg exposure from
Thimerosal-containing childhood vaccines and the subsequent risk of an ASD
diagnosis. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878266/

Current Medical Chemistry • 2013

Low-dose mercury exposure in early life: relevance of thimerosal to fetuses,
newborns and infants Author information Dórea JG. Faculty of Health Sciences
Universidade de Brasilia 70919-970 Brasilia, DF, Brazil jg.dorea@gmail.com
Abstract This review explores the different aspects of constitutional factors
in early life that modulate toxicokinetics and toxicodynamics of low-dose
mercury resulting from acute ethylmercury (etHg) exposure in
Thimerosal-containing vaccines (TCV). Major databases were searched for human
and experimental studies that addressed issues related to early life exposure
to TCV. It can be concluded that: a) mercury load in fetuses, neonates, and
infants resulting from TCVs remains in blood of neonates and infants at
sufficient concentration and for enough time to penetrate the brain and to
exert a neurologic impact and a probable influence on neurodevelopment of
susceptible infants; b) etHg metabolism related to neurodevelopmental delays
has been demonstrated experimentally and observed in population studies; c)
unlike chronic Hg exposure during pregnancy, neurodevelopmental effects caused
by acute (repeated/cumulative) early life exposure to TCV-etHg remain
unrecognized; and d) the uncertainty surrounding low-dose toxicity of etHg is
challenging but recent evidence indicates that avoiding cumulative insults by
alkyl-mercury forms (which include Thimerosal) is warranted. It is important to
a) maintain trust in vaccines while reinforcing current public health policies
to abate mercury exposure in infancy; b) generally support WHO policies that
recommend vaccination to prevent and control existing and impending infectious
diseases; and c) not confuse the ‘need’ to use a specific ‘product’ (TCV) by
accepting as ‘innocuous’ (or without consequences) the presence of a proven
‘toxic alkyl-mercury’ (etHg) at levels that have not been proven to be
toxicologically safe. http://www.ncbi.nlm.nih.gov/pubmed/?term=23992327

“... mercury load in fetuses, neonates, and infants resulting from TCVs remains
in blood of neonates and infants at sufficient concentration and for enough
time to penetrate the brain and to exert a neurologic impact and a probable
influence on neurodevelopment of susceptible infants ...”

Toxicology And Applied Pharmacology • February 2014

The retention time of inorganic mercury in the brain a systematic review of the
evidence Author information Rooney JP. Academic Unit of Neurology Trinity
Biomedical Sciences Institute Trinity College, 152-160 Pearse Street Dublin 2,
Ireland jrooney@rcsi.ie Abstract Reports from human case studies indicate a
half-life for inorganic mercury in the brain in the order of
years-contradicting older radioisotope studies that estimated half-lives in the
order of weeks to months in duration. This study systematically reviews
available evidence on the retention time of inorganic mercury in humans and
primates to better understand this conflicting evidence. A broad search
strategy was used to capture 16,539 abstracts on the Pubmed database. Abstracts
were screened to include only study types containing relevant information. 131
studies of interest were identified. Only 1 primate study made a numeric
estimate for the half-life of inorganic mercury (227-540 days). Eighteen human
mercury poisoning cases were followed up long term including autopsy. Brain
inorganic mercury concentrations at death were consistent with a half-life of
several years or longer. 5 radionucleotide studies were found, one of which
estimated head half-life (21 days). This estimate has sometimes been
misinterpreted to be equivalent to brain half-life-which ignores several
confounding factors including limited radioactive half-life and radioactive
decay from surrounding tissues including circulating blood. No autopsy cohort
study estimated a half-life for inorganic mercury, although some noted
bioaccumulation of brain mercury with age. Modelling studies provided some
extreme estimates (69 days vs 22 years). Estimates from modelling studies
appear sensitive to model assumptions, however predications based on a long
half-life (27.4 years) are consistent with autopsy findings. In summary,
shorter estimates of half-life are not supported by evidence from animal
studies, human case studies, or modelling studies based on appropriate
assumptions. Evidence from such studies point to a half-life of inorganic
mercury in human brains of several years to several decades. This finding
carries important implications for pharmcokinetic modelling of mercury and
potentially for the regulatory toxicology of mercury.
http://www.ncbi.nlm.nih.gov/pubmed/24368178

“Evidence from such studies point to a half-life of inorganic mercury in human
brains of several years to several decades. This finding carries important
implications for pharmcokinetic modelling of mercury and potentially for the
regulatory toxicology of mercury.”

“These and other studies suggest that susceptibility to mercury toxicity differs
among individuals based on multiple genes, not all of which have been
identified. These studies further suggest that the levels of exposure to
mercury vapor from dental amalgams may be unsafe for certain subpopulations.”
Biometals • February 2014

New science challenges old notion that mercury dental amalgam is safe Author
information Homme KG1, Kern JK, Haley BE, Geier DA, King PG, Sykes LK, Geier
MR. International Academy of Oral Medicine and Toxicology Champions Gate, FL,
33896, USA khomme@sbcglobal.net Abstract Mercury dental amalgam has a long
history of ostensibly safe use despite its continuous release of mercury vapor.
Two key studies known as the Children’s Amalgam Trials are widely cited as
evidence of safety. However, four recent reanalyses of one of these trials now
suggest harm, particularly to boys with common genetic variants. These and
other studies suggest that susceptibility to mercury toxicity differs among
individuals based on multiple genes, not all of which have been identified.
These studies further suggest that the levels of exposure to mercury vapor from
dental amalgams may be unsafe for certain subpopulations. Moreover, a simple
comparison of typical exposures versus regulatory safety standards suggests
that many people receive unsafe exposures. Chronic mercury toxicity is
especially insidious because symptoms are variable and nonspecific, diagnostic
tests are often misunderstood, and treatments are speculative at best.
Throughout the world, efforts are underway to phase down or eliminate the use
of mercury dental amalgam. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905169/

Current Neuropharmacology • March 2014

Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites,
Immuno-inflammation, Autoimmunity and the Amygdala Author information Anderson
G1, Maes M2. 1. CRC, Rm:30, 57 Laurel Street, Glasgow, Scotland 2. Department
of Psychiatry, Chulalongkorn University, Bangkok, Thailand Department of
Psychiatry, Deakin University, Geelong, Australia Abstract The autistic
spectrum disorders (ASD) form a set of multi-faceted disorders with significant
genetic, epigenetic and environmental determinants. Oxidative and nitrosative
stress (O&NS), immuno-inflammatory pathways, mitochondrial dysfunction and
dysregulation of the tryptophan catabolite (TRYCATs) pathway play significant
interactive roles in driving the early developmental etiology and course of
ASD. O&NS interactions with immuno-inflammatory pathways mediate their effects
centrally via the regulation of astrocyte and microglia responses, including
regional variations in TRYCATs produced. Here we review the nature of these
interactions and propose an early developmental model whereby different ASD
genetic susceptibilities interact with environmental and epigenetic processes,
resulting in glia biasing the patterning of central interarea interactions. A
role for decreased local melatonin and N-acetylserotonin production by immune
and glia cells may be a significant treatment target. Perinatal Mercury
Maternal prenatal mercury levels have sharply increased in recent decades, with
foetal cord blood levels being significantly increased versus maternal levels
[61,62]. This suggests that prenatal mercury, which can induce many of the
changes evident in ASD, including increased O&NS and immuno-inflammation, as
well as decreased endogenous anti-oxidants and mitochondrial functioning, may
play a significant role in the etiology of ASD. As to whether mercury interacts
with the consequences of prenatal infection in the offspring is unknown,
although not unlikely given that mercury significantly modulates murine viral
immune response [63,64] and viral infection increases brain mercury levels
[65]. SNPs in genes involved in mercury regulation associate with ASD [66]. It
also requires testing as to whether mercury has any impact on the development
of foetal gamma-delta (∼∼) T cells and prenatal epigenetic regulation.
http://www.ncbi.nlm.nih.gov/pubmed/?term=24669209

“Maternal prenatal mercury levels have sharply increased in recent decades,
with foetal cord blood levels being significantly increased versus maternal
levels. This suggests that prenatal mercury, which can induce many of the
changes evident in Autistic Spectrum Disorder, including increased O&NS and
immuno-inflammation, as well as decreased endogenous anti-oxidants and
mitochondrial functioning, may play a significant role in the etiology of
Autistic Spectrum Disorder.”

PLoS One • April 2014

Suppression by Thimerosal of Ex-Vivo CD4+ T Cell Response to Influenza Vaccine
and Induction of Apoptosis in Primary Memory T Cells Emily Loison,1 Béatrice
Poirier-Beaudouin,1 Valérie Seffer,1 Audrey Paoletti,2 Vered Abitbol,3 Eric
Tartour,4 Odile Launay,5 and Marie-Lise Gougeon1,* Jon C.D. Houtman, Editor 1.
Antiviral Immunity Biotherapy and Vaccine Unit, Institut Pasteur, Paris, France
2. Inserm U1030, Institut Gustave Roussy, Villejuif, France 3. Gastroenterology
Department, Hôpital Cochin, AP-HP, Paris, France 4. Inserm U970, Université
Paris Descartes, PARCC/HEGP, Paris, France 5. Centre d’Investigation Clinique
BT-505, Hôpital Cochin, AP-HP, Paris, France University of Iowa, United States
of America Competing Interests

“Overall these results underline the proapoptotic effect of thimerosal on
primary human lymphocytes at concentrations 100 times less to those

CrossJect provided the academic research/private research partnership to fund a
CIFRE fellowship used in this study. There are no patents, products in
development or marketed products to declare. This does not alter the authors’
adherence to all the PLOS ONE policies on sharing data and materials.

contained in the multidose vaccine, and

Abstract

preservative on T-cell proliferation and

Thimerosal is a preservative used widely in vaccine formulations to prevent
bacterial and fungal contamination in multidose vials of vaccine. Thimerosal
was included in the multidose non-adjuvanted pandemic 2009 H1N1 vaccine
Panenza. In the context of the analysis of the ex-vivo T cell responses
directed against influenza vaccine, we discovered the in vitro toxicity
Panenza, due to its content in thimerosal. Because thimerosal may skew the
immune response to vaccines, we investigated in detail the ex-vivo effects of
thimerosal on the fate and functions of T cells in response to TCR ligation. We
report that ex-vivo exposure of quiescent or TCR-activated primary human T
cells to thimerosal induced a dose-dependent apoptotic cell death associated
with depolarization of mitochondrial membrane, generation of reactive oxygen
species, cytochrome c release from the mitochondria and caspase-3 activation.
Moreover, exposure to non-toxic concentrations of thimerosal induced cell cycle
arrest in G0/G1 phase of TCR-activated T cells, and inhibition of the release
of proinflammatory cytokines such as IFN gamma, IL-1 beta, TNF alpha, IL-2, as
well as the chemokine MCP1. No shift towards Th2 or Th17 cells was detected.
Overall these results underline the proapoptotic effect of thimerosal on
primary human lymphocytes at concentrations 100 times less to those contained
in the multidose vaccine, and they reveal the inhibitory effect of this
preservative on T-cell proliferation and functions at nanomolar concentrations.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972181/

they reveal the inhibitory effect of this

functions at nanomolar concentrations.”

Environmental Toxicology And Chemistry • June 2014

Ecogenetics of mercury: from genetic polymorphisms and epigenetics to risk
assessment and decision-making Author information Basu N1, Goodrich JM, Head J.
Department of Environmental Health Sciences University of Michigan School of
Public Health Ann Arbor, Michigan, USA Faculty of Agricultural and
Environmental Sciences McGill University, Montreal, Quebec, Canada Abstract The
risk assessment of mercury (Hg), in both humans and wildlife, is made
challenging by great variability in exposure and health effects. Although
disease risk arises following complex interactions between genetic (“nature”)
and environmental (“nurture”) factors, most Hg studies thus far have focused
solely on environmental factors. In recent years, ecogenetic-based studies have
emerged and have started to document genetic and epigenetic factors that may
indeed influence the toxicokinetics or toxicodynamics of Hg. The present study
reviews these studies and discusses their utility in terms of Hg risk
assessment, management, and policy and offers perspectives on fruitful areas
for future research. In brief, epidemiological studies on populations exposed
to inorganic Hg (e.g., dentists and miners) or methylmercury (e.g., fish
consumers) are showing that polymorphisms in a number of environmentally
responsive genes can explain variations in Hg biomarker values and health
outcomes. Studies on mammals (wildlife, humans, rodents) are showing Hg
exposures to be related to epigenetic marks such as DNA methylation. Such
findings are beginning to increase understanding of the mechanisms of action of
Hg, and in doing so they may help identify candidate biomarkers and pinpoint
susceptible groups or life stages. Furthermore, they may help refine
uncertainty factors and thus lead to more accurate risk assessments and
improved decision-making. http://www.ncbi.nlm.nih.gov/pubmed/24038486

“In recent years, ecogenetic-based studies have emerged and have started to
document genetic and epigenetic factors that may indeed influence the
toxicokinetics or toxicodynamics of mercury.”

Human Vaccines & Immunotherapeutics • June 2014

Thimerosal compromises human dendritic cell maturation, IL-12 production,
chemokine release, and T-helper polarization by Emily Loison & Marie-Lise
Gougeon Abstract In conclusion, our study indicates that ex-vivo exposure of
human immature dendritic cells to very low nontoxic concentrations of
thimerosal alters the LPS-induced maturation process and dampens their
proinflammatory response, in particular the production of the T-helper
polarizing cytokine IL-12. Moreover, thimerosal exposure of DCs corrupts their
interaction with naïve CD4+ T cells, leading to a decreased production of IFN-∼
IP10 and GM-CSF and increased levels of IL-8, IL-9, and MIP-1∼. Today, except
for some flu vaccines in multi-dose vials, no recommended childhood vaccines
contain thimerosal as a preservative. It must be stressed that the toxicity and
immunomodulatory effects of thimerosal that we report ex-vivo on human
monocytederived DCs may occur in vivo and induce an alteration of the immune
response to the vaccine. These observations highlight the need to use this
preservative with caution and avoid it if possible. Full Report
https://app.box.com/s/0dg5ksp3f377qes3m5qsp16rl1gxws8l

“These observations highlight the need to use this preservative with caution
and avoid it if possible.”

“Our results indicate that higher dose of neonatal thimerosal-mercury
is capable of inducing long-lasting substantial dysregulation of
neurodevelopment, synaptic function, and endocrine system, which could be the
causal involvements of autistic-like behavior in mice.” Toxicology Science •
June 2014

Transcriptomic analyses of neurotoxic effects in mouse brain after intermittent
neonatal administration of thimerosal Author information Li X1, Qu F, Xie W,
Wang F, Liu H, Song S, Chen T, Zhang Y, Zhu S, Wang Y, Guo C, Tang TS. State
Key Laboratory of Biomembrane and Membrane Biotechnology Institute of Zoology,
Chinese Academy of Sciences, Beijing 100101, China Abstract Thimerosal is a
vaccine antimicrobial preservative which has long been suspected an iatrogenic
factor possibly contributing to neurodevelopmental disorders including autism.
The association between infant vaccine thimerosal exposure and autism remains
an open question. Although thimerosal has been removed from mandatory childhood
vaccines in the United States, thimerosal-preserved vaccines are still widely
used outside of the United States especially in developing countries. Notably,
thimerosal-containing vaccines are being given to the newborns within the first
12-24 h after birth in some countries. To examine the possible neurotoxic
effects of early neonatal exposure to a higher level of thimerosal, FVB mice
were subcutaneously injected with thimerosal-mercury at a dose which is 20×
higher than that used for regular Chinese infant immunization during the first
4 months of life. Thimerosal-treated mice exhibited neural development delay,
social interaction deficiency, and inclination of depression. Apparent
neuropathological changes were also observed in adult mice neonatally treated
with thimerosal. High-throughput RNA sequencing of autistic-behaved mice brains
revealed the alternation of a number of canonical pathways involving neuronal
development, neuronal synaptic function, and the dysregulation of endocrine
system. Intriguingly, the elevation of anterior pituitary secreting hormones
occurred exclusively in male but not in female thimerosal-treated mice,
demonstrating for the first time the gender bias of thimerosal-mercury toxicity
with regard to endocrine system. Our results indicate that higher dose of
neonatal thimerosal-mercury (20× higher than that used in human) is capable of
inducing long-lasting substantial dysregulation of neurodevelopment, synaptic
function, and endocrine system, which could be the causal involvements of
autistic-like behavior in mice. http://www.ncbi.nlm.nih.gov/pubmed/24675092

Environmental Toxicology And Chemistry • June 2014

Ecogenetics of mercury: From genetic polymorphisms and epigenetics to risk
assessment and decision-making Author Information Niladri Basu, Jaclyn M.
Goodrich and Jessica Head Cooperative Institute for Limnology and Ecosystems
Research School of Natural Resources and Environment, University of Michigan
Ann Arbor, Michigan, USA

Abstract The risk assessment of mercury (Hg), in both humans and wildlife, is
made challenging by great variability in exposure and health effects. Although
disease risk arises following complex interactions between genetic (“nature”)
and environmental (“nurture”) factors, most Hg studies thus far have focused
solely on environmental factors. In recent years, ecogenetic-based studies have
emerged and have started to document genetic and epigenetic factors that may
indeed influence the toxicokinetics or toxicodynamics of Hg. The present study
reviews these studies and discusses their utility in terms of Hg risk
assessment, management, and policy and offers perspectives on fruitful areas
for future research. In brief, epidemiological studies on populations exposed
to inorganic Hg (e.g., dentists and miners) or methylmercury (e.g., fish
consumers) are showing that polymorphisms in a number of environmentally
responsive genes can explain variations in Hg biomarker values and health
outcomes. Studies on mammals (wildlife, humans, rodents) are showing Hg
exposures to be related to epigenetic marks such as DNA methylation. Such
findings are beginning to increase understanding of the mechanisms of action of
Hg, and in doing so they may help identify candidate biomarkers and pinpoint
susceptible groups or life stages. Furthermore, they may help refine
uncertainty factors and thus lead to more accurate risk assessments and
improved decision-making.
http://onlinelibrary.wiley.com/doi/10.1002/etc.2375/abstract

“In brief, epidemiological studies on populations exposed to inorganic mercury
(e.g., dentists and miners) or methylmercury (e.g., fish consumers) are showing
that polymorphisms in a number of environmentally responsive genes can explain
variations in mercury biomarker values and health outcomes.”

[polymorphosms explain why some individuals injected with an aluminum
containing vaccine will become autistic and others will not. Polymorphism is
the genetic variant]

Pediatric Neurology • July 2014

Effect of low-level prenatal mercury exposure on neonate neurobehavioral
development in China Author information Wu J1, Ying T2, Shen Z2, Wang H2.
Zhoushan Women’s & Children’s Health Hospital Zhoushan, Zhejiang, China
Abstract BACKGROUND: This study aimed to assess the effects of low-level
prenatal mercury exposure on neonate neurobehavioral development in China.
METHODS: In total, 418 mother-neonate pairs were included in the study.
Maternal urine, hair, and blood samples and cord blood samples were used to
document prenatal exposure to mercury. The Neonatal Behavioral Neurological
Assessment was used to estimate neurobehavioral development in the neonates at
3 days of age. RESULTS: Total mercury level was significantly higher in cord
blood than that in maternal blood. A strong correlation was found between total
mercury levels in maternal blood and those in cord blood (r = 0.7431; P <
0.0001). Trend analysis revealed that mothers who consumed more fish had higher
blood and cord blood mercury levels (all P < 0.0001). Significant differences
were also found between male and female cord blood mercury levels among groups
with different fish consumption frequencies (all P < 0.0001). Cord blood
mercury level was significantly associated with total Neonatal Behavioral
Neurological Assessment scores (ß = 0.03; standard error = 0.01; P = 0.0409),
passive muscle tone (odds ratio = 1.07; 95% confidence interval = 1.12-1.13; P
= 0.0071), and active muscle tone (odds ratio = 1.06; 95% confidence interval =
1.01-1.11; P = 0.0170) scores after adjustment, respectively. CONCLUSIONS:
Neonatal neurodevelopment was associated with prenatal exposure to mercury.
Women with high mercury levels should avoid intake seafood excessively during
pregnancy. Long-term effects of exposure to mercury on childhood development
need to be further explored. Full Report
http://www.pedneur.com/article/S0887-8994(14)00195-7/fulltext

“Neonatal neurodevelopment was associated with prenatal exposure to mercury.
Women with high mercury levels should avoid intake seafood excessively during
pregnancy.”

International Journal Of Environmental Research And Public Health • September 2014

A Dose-Response Relationship between Organic Mercury Exposure from
Thimerosal-Containing Vaccines and Neurodevelopmental Disorders David A.
Geier,1 Brian S. Hooker,2 Janet K. Kern,1,3 Paul G. King,4 Lisa K. Sykes,4 and
Mark R. Geier1 1. Institute of Chronic Illnesses, Inc., 14 Redgate Ct., Silver
Spring, MD 20905, USA 2. Department of Biology, Simpson University, 2211
College View Dr., Redding, CA 96003, USA 3. Department of Psychiatry,
University of Texas Southwestern Medical Center at Dallas 5353 Harry Hine
Blvd., Dallas, TX 75390, USA 4. CoMeD, Inc., 14 Redgate Ct., Silver Spring, MD
20905, USA Abstract A hypothesis testing case-control study evaluated concerns
about the toxic effects of organic-mercury (Hg) exposure from
thimerosal-containing (49.55% Hg by weight) vaccines on the risk of
neurodevelopmental disorders (NDs). Automated medical records were examined to
identify cases and controls enrolled from their date-of-birth (1991–2000) in
the Vaccine Safety Datalink (VSD) project. ND cases were diagnosed with
pervasive developmental disorder (PDD), specific developmental delay, tic
disorder or hyperkinetic syndrome of childhood. In addition, putative
nonthimerosal-related outcomes of febrile seizure, failure to thrive and
cerebral degenerations were examined. The cumulative total dose of Hg exposure
from thimerosal-containing hepatitis B vaccine (T-HBV) administered within the
first six months of life was calculated. On a per microgram of organic-Hg
basis, PDD (odds ratio (OR) = 1.054), specific developmental delay (OR =
1.035), tic disorder (OR = 1.034) and hyperkinetic syndrome of childhood (OR =
1.05) cases were significantly more likely than controls to receive increased
organic-Hg exposure. By contrast, none of the non-thimerosal related outcomes
were significantly more likely than the controls to have received increased
organic-Hg exposure. Routine childhood vaccination may be an important public
health tool to reduce infectious disease-associated morbidity/mortality, but
the present study significantly associates organic-Hg exposure from T-HBV with
an increased risk of an ND diagnosis. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199012/

“Routine childhood vaccination may be an important public health tool to reduce
infectious disease-associated morbidity/mortality, but the present study
significantly associates organic-mercury exposure from thimerosal-containing
hepatitis B vaccine with an increased risk of an neurodevelopmental disorder
diagnosis.”

“... the present study supports an association between increasing organic-mercury exposure from
Thimerosal-containing childhood vaccines and the subsequent risk of specific
delays in development ...” North American Journal Of Medical Science • October
2014

Thimerosal-containing hepatitis B vaccination and the risk for diagnosed
specific delays in development in the United States: a case-control study in
the vaccine safety datalink Author information Geier DA1, Kern JK2, Hooker BS3,
King PG4, Sykes LK4, Geier MR1. 1. Institute of Chronic Illnesses, Inc, Silver
Spring, Maryland, USA 2. Institute of Chronic Illnesses, Inc, Silver Spring,
Maryland, USA Department of Psychiatry, University of Texas Southwestern
Medical Center, Dallas, Texas, USA 3. Biology Department, Simpson University,
Redding, California, USA 4. CoMeD, Inc, Silver Spring, Maryland, USA Abstract
BACKGROUND Within the first 3 years of life, the brain develops rapidly. Its
development is characterized by critical developmental periods for speech,
vision, hearing, language, balance, etc.; and alteration in any of the
processes occurring in those critical periods can lead to specific delays in
development. AIMS The present study evaluated the potential toxic effects of
organic-mercury exposure from Thimerosal (49.55% mercury by weight) in
childhood vaccines and its hypothesized possible relationship with specific
delays in development. MATERIALS AND METHODS A hypothesis testing case-control
study was undertaken to evaluate the relationship between exposure to
Thimerosal-containing hepatitis B vaccines administered at specific intervals
in the first 6 months among cases diagnosed with specific delays in development
and controls born between 1991-2000, utilizing data in the Vaccine Safety
Datalink database. RESULTS Cases were significantly more likely than controls
to have received increased organic-mercury from Thimerosal-containing hepatitis
B vaccine administered in the first, second, and sixth month of life.
CONCLUSION Though routine childhood vaccination may be an important public
health tool to reduce the morbidity and mortality associated with infectious
diseases, the present study supports an association between increasing
organic-mercury exposure from Thimerosal-containing childhood vaccines and the
subsequent risk of specific delays in development among males and females.
http://www.ncbi.nlm.nih.gov/pubmed/25489565

Indian Journal Of Medical Ethics • October 2014

Thimerosal as discrimination: vaccine disparity in the UN Minamata Convention
on mercury Author information Sykes LK1, Geier DA2, King PG1, Kern JK3, Haley
BE1, Chaigneau CG1, Megson MN4, Love JM5, Reeves RE1, Geier MR2. 1. CoMeD, Inc,
Silver Spring, MD USA 2. CoMeD, Inc, Silver Spring, MD; Institute of Chronic
Illnesses, Inc, Silver Spring, MD USA 3. Institute of Chronic Illnesses, Inc,
Silver Spring, MD USA 4. Pediatric and Adolescent Ability Center, Richmond, VA
USA 5. CoMeD, Inc, Silver Spring, MD USA Abstract When addressing toxins, one
unmistakable parallel exists between biology and politics: developing children
and developing nations are those most vulnerable to toxic exposures. This
disturbing parallel is the subject of this critical review, which examines the
use and distribution of the mercury (Hg)based compound, thimerosal, in
vaccines. Developed in 1927, thimerosal is 49.55% Hg by weight and breaks down
in the body into ethyl-Hg chloride, ethyl-Hg hydroxide and sodium
thiosalicylate. Since the early 1930s, there has been evidence indicating that
thimerosal poses a hazard to the health of human beings and is ineffective as
an antimicrobial agent. While children in the developed and predominantly
western nations receive doses of mostly no-thimerosal and reduced-thimerosal
vaccines, children in the developing nations receive many doses of several
unreduced thimerosal-containing vaccines (TCVs). Thus, thimerosal has continued
to be a part of the global vaccine supply and its acceptability as a component
of vaccine formulations remained unchallenged until 2010, when the United
Nations (UN), through the UN Environment Programme, began negotiations to write
the global, legally binding Minamata Convention on Hg. During the negotiations,
TCVs were dropped from the list of Hg-containing products to be regulated.
Consequently, a double standard in vaccine safety, which previously existed due
to ignorance and economic reasons, has now been institutionalised as global
policy. Ultimately, the Minamata Convention on Hg has sanctioned the
inequitable distribution of thimerosal by specifically exempting TCVs from
regulation, condoning a two-tier standard of vaccine safety: a predominantly
no-thimerosal and reduced-thimerosal standard for developed nations and a
predominantly thimerosal-containing one for developing nations. This disparity
must now be evaluated urgently as a potential form of institutionalised
discrimination. http://www.ncbi.nlm.nih.gov/pubmed/?term=25101548

“While children in the developed and predominantly western nations receive
doses of mostly no-thimerosal and reduced-thimerosal vaccines, children in the
developing nations receive many doses of several unreduced
thimerosal-containing vaccines (TCVs).”

“... the preponderance of evidence suggests that mercury exposure from
dental amalgams may cause or contribute to many chronic conditions.” Neuro
Endocrinology Letters • 2014

Evidence supporting a link between dental amalgams and chronic illness,
fatigue, depression, anxiety, and suicide Author information Kern JK1, Geier
DA1, Bjørklund G2, King PG3, Homme KG4, Haley BE5, Sykes LK3, Geier MR1. 1.
Institute of Chronic Illnesses, Inc., Silver Spring, MD, USA 2. Council for
Nutritional and Environmental Medicine, Mo i Rana, Norway 3. CoMeD, Inc.,
Silver Spring, MD, USA 4. International Academy of Oral Medicine and
Toxicology, ChampionsGate, FL, USA 5. University of Kentucky, Lexington, KY,
USA Abstract The purpose of this review is to examine the evidence for a
relationship between mercury (Hg) exposure from dental amalgams and certain
idiopathic chronic illnesses--chronic fatigue syndrome (CFS), fibromyalgia
(FM), depression, anxiety, and suicide. Dental amalgam is a commonly used
dental restorative material that contains approximately 50% elemental mercury
(Hg0) by weight and releases Hg0 vapor. Studies have shown that chronic Hg
exposure from various sources including dental amalgams is associated with
numerous health complaints, including fatigue, anxiety, and depression--and
these are among the main symptoms that are associated with CFS and FM. In
addition, several studies have shown that the removal of amalgams is associated
with improvement in these symptoms. Although the issue of amalgam safety is
still under debate, the preponderance of evidence suggests that Hg exposure
from dental amalgams may cause or contribute to many chronic conditions. Thus,
consideration of Hg toxicity may be central to the effective clinical
investigation of many chronic illnesses, particularly those involving fatigue
and depression. http://www.ncbi.nlm.nih.gov/pubmed/25617876

Reviews Of Environmental Contamination And Toxicology • 2014

Mercury toxicity and neurodegenerative effects Author information Carocci A1,
Rovito N, Sinicropi MS, Genchi G. Dipartimento di Farmacia-Scienze del Farmaco
Università degli Studi di Bari “A. Moro” Bari, 70125, Italia Abstract Mercury
is among the most toxic heavy metals and has no known physiological role in
humans. Three forms of mercury exist: elemental, inorganic and organic. Mercury
has been used by man since ancient times. Among the earliest were the Chinese
and Romans, who employed cinnabar (mercury sulfide) as a red dye in ink
(Clarkson et al. 2007). Mercury has also been used to purify gold and silver
minerals by forming amalgams. This is a hazardous practice, but is still
widespread in Brazil’s Amazon basin, in Laos and in Venezuela, where tens of
thousands of miners are engaged in local mining activities to find and purify
gold or silver. Mercury compounds were long used to treat syphilis and the
element is still used as an antiseptic,as a medicinal preservative and as a
fungicide. Dental amalgams, which contain about 50% mercury, have been used to
repair dental caries in the U.S. since 1856.Mercury still exists in many common
household products around the world.Examples are: thermometers, barometers,
batteries, and light bulbs (Swain et al.2007). In small amounts, some organo
mercury-compounds (e.g., ethylmercury tiosalicylate(thimerosal) and
phenylmercury nitrate) are used as preservatives in some medicines and vaccines
(Ballet al. 2001).Each mercury form has its own toxicity profile. Exposure to
Hg0 vapor and MeHg produce symptoms in CNS, whereas, the kidney is the target
organ when exposures to the mono- and di-valent salts of mercury (Hg+ and Hg++,
respectively)occur. Chronic exposure to inorganic mercury produces stomatitis,
erethism and tremors. Chronic MeHg exposure induced symptoms similar to those
observed in ALS, such as the early onset of hind limb weakness (Johnson and
Atchison 2009).Among the organic mercury compounds, MeHg is the most
biologically available and toxic (Scheuhammer et al. 2007). MeHg is neurotoxic,
reaching high levels of accumulation in the CNS; it can impair physiological
function by disrupting endocrine glands (Tan et al. 2009).The most important
mechanism by which mercury causes toxicity appears to bemitochondrial damage
via depletion of GSH (Nicole et al. 1998), coupled with binding to thiol groups
(-SH), which generates free radicals. Mercury has a high affinity for thiol
groups (-SH) and seleno groups (-SeH) that are present in amino acids as
cysteine and N-acetyl cysteine, lipoic acid, proteins, and enzymes.
N-acetylcysteine and cysteine are precursors for the biosynthesis of GSH, which
is among the most powerful intracellular antioxidants available to protect
against oxidative stress and inflammation.Mercury and methylmercury induce
mitochondrial dysfunction, which reduces ATP synthesis and increases lipid,
protein and DNA peroxidation. The content of metallothioneines, GSH, selenium
and fish high in omega-3 fatty acids appear to be strongly related with degree
of inorganic and organic mercury toxicity, and with the protective detoxifying
mechanisms in humans. In conclusion, depletion of GSH, breakage of
mitochondria, increased lipid peroxidation, and oxidation of proteins and DNA
in the brain, induced by mercury and his salts, appear to be important factors
in conditions such as ALS and AD (Bains and Shaw 1997; Nicole et al.
1998;Spencer et al. 1998; Alberti et al. 1999).
http://www.ncbi.nlm.nih.gov/pubmed/24515807

“In conclusion, depletion of GSH, breakage of mitochondria, increased lipid
peroxidation, and oxidation of proteins and DNA in the brain, induced by
mercury and his salts, appear to be important factors in conditions such as
Amyotrophic Lateral Sclerosis and Alzheimers Disease ...”

“These findings suggest that the epidemiological link between environmental mercury exposure
and an increased risk of developing autism may be mediated through
mitochondrial dysfunction ...” Journal of Toxicology • January 2015

Increased Susceptibility to Ethylmercury-Induced Mitochondrial Dysfunction in a
Subset of Autism Lymphoblastoid Cell Lines Shannon Rose, Rebecca Wynne, Richard
E. Frye, Stepan Melnyk, and S. Jill James Department of Pediatrics, University
of Arkansas for Medical Sciences Arkansas Children’s Hospital Research
Institute 13 Children’s Way, Slot 512-41B Little Rock, AR 72202, USA Abstract
The association of autism spectrum disorders with oxidative stress, redox
imbalance, and mitochondrial dysfunction has become increasingly recognized. In
this study, extracellular flux analysis was used to compare mitochondrial
respiration in lymphoblastoid cell lines (LCLs) from individuals with autism
and unaffected controls exposed to ethylmercury, an environmental toxin known
to deplete glutathione and induce oxidative stress and mitochondrial
dysfunction. We also tested whether pretreating the autism LCLs with N-acetyl
cysteine (NAC) to increase glutathione concentrations conferred protection from
ethylmercury. Examination of 16 autism/control LCL pairs revealed that a
subgroup (31%) of autism LCLs exhibited a greater reduction in ATP-linked
respiration, maximal respiratory capacity, and reserve capacity when exposed to
ethylmercury, compared to control LCLs. These respiratory parameters were
significantly elevated at baseline in the ethylmercury-sensitive autism
subgroup as compared to control LCLs. NAC pretreatment of the sensitive
subgroup reduced (normalized) baseline respiratory parameters and blunted the
exaggerated ethylmercury-induced reserve capacity depletion. These findings
suggest that the epidemiological link between environmental mercury exposure
and an increased risk of developing autism may be mediated through
mitochondrial dysfunction and support the notion that a subset of individuals
with autism may be vulnerable to environmental influences with detrimental
effects on development through mitochondrial dysfunction.
http://www.hindawi.com/journals/jt/2015/573701/

“... the present study provides new epidemiological evidence of a significant relationship between
increasing organic ethyl mercury exposure from Thimerosal-containing vaccines
and the subsequent risk of pervasive developmental disorder diagnosis ...”
Biological Trace Element Research • February 2015

A case-control study evaluating the relationship between thimerosal-containing
haemophilus influenzae type b vaccine administration and the risk for a
pervasive developmental disorder diagnosis in the United States Author
information Geier DA1, Kern JK, King PG, Sykes LK, Geier MR. The Institute of
Chronic Illnesses, Inc, 14 Redgate Ct, Silver Spring, MD, 20905, USA Abstract
Thimerosal is an organic mercury (Hg)-containing compound (49.55 % Hg by
weight) historically added to many multi-dose vials of vaccine as a
preservative. A hypothesis testing case-control study evaluated automated
medical records in the Vaccine Safety Datalink (VSD) for organic Hg exposure
from Thimerosal in Haemophilus influenzae type b (Hib)-containing vaccines
administered at specific times within the first 15 months of life among
subjects diagnosed with pervasive developmental disorder (PDD) (n = 534) in
comparison to controls. The generally accepted biologically non-plausible
linkage between Thimerosal exposure and subsequent diagnosis of febrile seizure
(n = 5886) was examined as a control outcome. Cases diagnosed with PDD received
significantly more organic Hg within the first 6 months of life (odds ratio
(OR) = 1.97, p < 0.001) and first 15 months of life (OR = 3.94, p < 0.0001)
than controls, whereas cases diagnosed with febrile seizure were no more likely
than controls to have received increased organic Hg. On a per microgram of
organic Hg basis, cases diagnosed with a PDD in comparison to controls were at
significantly greater odds (OR = 1.0197, p < 0.0001) of receiving increasing
organic Hg exposure within the first 15 months of life, whereas cases diagnosed
febrile seizure were no more likely than controls (OR = 0.999, p > 0.20) to
have received increasing organic Hg exposure within the first 15 months of
life. Routine childhood vaccination is an important public health tool to
reduce the morbidity and mortality associated with infectious diseases, but the
present study provides new epidemiological evidence of a significant
relationship between increasing organic Hg exposure from Thimerosal-containing
vaccines and the subsequent risk of PDD diagnosis in males and females.
http://www.ncbi.nlm.nih.gov/pubmed/25382662

Clinica Chimica Acta • April 2015

Thimerosal: clinical, epidemiologic and biochemical studies Author information
Geier DA1, King PG2, Hooker BS3, Dórea JG4, Kern JK5, Sykes LK6, Geier MR7. 1.
Institute of Chronic Illnesses, Inc., 14 Redgate Ct., Silver Spring, MD 20905,
USA 2. CoMeD, Inc., 14 Redgate Ct., Silver Spring, MD 20905, USA 3. Biology
Department, Simpson University, 2211 College View Drive, Redding, CA 96001, USA
4. Health Sciences, Universidade de Brasilia, 70919-970 Brasilia, DF, Brazil.
Electronic address: jg.dorea@gmail.com. 5. Institute of Chronic Illnesses,
Inc., 14 Redgate Ct., Silver Spring, MD 20905, USA. Electronic address:
jkern@dfwair.net. 6. CoMeD, Inc., 14 Redgate Ct., Silver Spring, MD 20905, USA.
Electronic address: syklone5@verizon.net. 7. Institute of Chronic Illnesses,
Inc., 14 Redgate Ct., Silver Spring, MD 20905, USA. Electronic address:
mgeier@comcast.net

Abstract INTRODUCTION Thimerosal (or Thiomersal) is a trade name for an
organomercurial compound (sodium ethyl-mercury (Hg) thiosalicylate) that is
49.55% Hg by weight, which rapidly decomposes in aqueous saline solutions into
ethyl-Hg hydroxide and ethyl-Hg chloride. Developed in 1927, it has been and is
still being used as a preservative in some cosmetics, topical pharmaceuticals,
and biological drug products, including vaccines. Concerns have been voiced
about its use because it is toxic to human cells. Although it is banned in
several countries, it continues to be added to some vaccines in the United
States and many vaccines in the developing world. DISCUSSION This critical
review focuses on the clinical, epidemiological, and biochemical studies of
adverse effects from Thimerosal in developing humans. This review will include
research that examines fetal, infant, and childhood death; birth defects;
neurodevelopmental testing deficits in children; and neurodevelopmental
disorders (attention deficit/hyperactivity disorder, autism spectrum disorder,
tic disorder, and specific developmental delays). The review will also look at
the research that examined the outcomes of acute accidental ethyl-Hg poisoning
in humans. The studies that examine the underlying biochemical insights into
the neuronal cellular damage will also be explored. CONCLUSION The culmination
of the research that examines the effects of Thimerosal in humans indicates
that it is a poison at minute levels with a plethora of deleterious
consequences, even at the levels currently administered in vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25708367

“The culmination of the research that examines the effects of Thimerosal in
humans indicates that it is a poison at minute levels with a plethora of
deleterious consequences, even at the levels currently administered in
vaccines.”

“During the decade in which Thimerosal-containing hepatitis B vaccines were routinely recommended
and administered to US infants, an estimated 0.5-1 million additional US
children were diagnosed with specific delays in development as a consequence of
25μg or 37.5μg organic mercury from Thimerosal-containing hepatitis B vaccines
... The resulting lifetime costs to the United States may exceed $1 trillion.”
Journal Of Epidemiology And Global Health • July 2015

A longitudinal cohort study of the relationship between Thimerosal-containing
hepatitis B vaccination and specific delays in development in the United
States: Assessment of attributable risk and lifetime care costs Author
information Geier DA1, Kern JK2, Hooker BS3, King PG4, Sykes LK4, Geier MR1. 1.
Institute of Chronic Illnesses, Inc, Silver Spring, MD, USA. 2. Institute of
Chronic Illnesses, Inc, Silver Spring, MD, USA. Electronic address:
jkern@dfwair.net. 3 .Biology Department, Simpson University, Redding, CA, USA.
4. CoMeD, Inc, Silver Spring, MD, USA. Abstract Epidemiological evidence
suggests a link between mercury (Hg) exposure from Thimerosal-containing
vaccines and specific delays in development. A hypothesis-testing longitudinal
cohort study (n=49,835) using medical records in the Vaccine Safety Datalink
(VSD) was undertaken to evaluate the relationship between exposure to Hg from
Thimerosal-containing hepatitis B vaccines (T-HBVs) administered at specific
intervals in the first 6months of life and specific delays in development
[International Classification of Disease, 9th revision (ICD-9): 315.xx] among
children born between 1991 and 1994 and continuously enrolled from birth for at
least 5.81years. Infants receiving increased Hg doses from T-HBVs administered
within the first month, the first 2 months, and the first 6 months of life were
significantly more likely to be diagnosed with specific delays in development
than infants receiving no Hg doses from T-HBVs. During the decade in which
T-HBVs were routinely recommended and administered to US infants (1991-2001),
an estimated 0.5-1 million additional US children were diagnosed with specific
delays in development as a consequence of 25μg or 37.5μg organic Hg from T-HBVs
administered within the first 6 months of life. The resulting lifetime costs to
the United States may exceed $1 trillion. Full Report
http://www.sciencedirect.com/science/article/pii/S2210600615000647

[an epidemic with a multi-trillion-dollar cost]

Science And Engineering Ethics • October 2015

Systematic Assessment of Research on Autism Spectrum Disorder and Mercury
Reveals Conflicts of Interest and the Need for Transparency in Autism Research
Author information Kern JK1, Geier DA2, Deth RC3, Sykes LK4, Hooker BS5, Love
JM6, Bjørklund G7, Chaigneau CG8, Haley BE9, Geier MR10. 1. Institute of
Chronic Illnesses, Inc., 14 Redgate Court, Silver Spring, MD, 20905 2.
Institute of Chronic Illnesses, Inc., 14 Redgate Court, Silver Spring, MD,
20905 3. Nova Southeastern University, Fort Lauderdale, FL, USA.
rdeth@nova.edu. 4. CoMeD, Inc., Silver Spring, MD, USA. syklone5@verizon.net.
5. Simpson University, Redding, CA, USA. bhooker@simpsonu.edu. 6. CoMeD, Inc.,
Silver Spring, MD, USA. jlove@titushillis.com. 7. Council for Nutritional and
Environmental Medicine, Mo i Rana, Norway. bjorklund@conem.org. 8. CoMeD, Inc.,
Silver Spring, MD, USA. mamadelchinito@gmail.com. 9. University of Kentucky,
Lexington, KY, USA. behaley@ctiscience.com. 10. Institute of Chronic Illnesses,
Inc., 14 Redgate Court, Silver Spring, MD, 20905 mgeier@comcast.net Abstract
Historically, entities with a vested interest in a product that critics have
suggested is harmful have consistently used research to back their claims that
the product is safe. Prominent examples are: tobacco, lead, bisphenol A, and
atrazine. Research literature indicates that about 80-90 % of studies with
industry affiliation found no harm from the product, while only about 10-20 %
of studies without industry affiliation found no harm. In parallel to other
historical debates, recent studies examining a possible relationship between
mercury (Hg) exposure and autism spectrum disorder (ASD) show a similar
dichotomy. Studies sponsored and supported by industry or entities with an
apparent conflict of interest have most often shown no evidence of harm or no
“consistent” evidence of harm, while studies without such affiliations report
positive evidence of a Hg/autism association. The potentially causal
relationship between Hg exposure and ASD differs from other toxic products
since there is a broad coalition of entities for whom a conflict of interest
arises. These include influential governmental public health entities, the
pharmaceutical industry, and even the coal burning industry. This review
includes a systematic literature search of original studies on the potential
relationship between Hg and ASD from 1999 to date, finding that of the studies
with public health and/or industry affiliation, 86 % reported no relationship
between Hg and ASD. However, among studies without public health and/or
industry affiliation, only 19 % find no relationship between Hg and ASD. The
discrepancy in these results suggests a bias indicative of a conflict of
interest. http://www.ncbi.nlm.nih.gov/pubmed/26507205

This review includes a systematic literature search of original studies on the
potential relationship between Hg [ethyl mercury] and ASD [Autisitic Spectrum
Disorder] from 1999 to date, finding that of the studies with public health
and/or industry affiliation, 86% reported no relationship between Hg [ethyl
mercury] and ASD [Autisitic Spectrum Disorder]. However, among studies without
public health and/or industry affiliation, only 19% find no relationship
between Hg [ethyl mercury] and ASD [Autisitic Spectrum Disorder]. The
discrepancy in these results suggests a bias indicative of a conflict of
interest.”

Journal of Toxicology • 2015

Increased Susceptibility to Ethylmercury-Induced Mitochondrial Dysfunction in a
Subset of Autism Lymphoblastoid Cell Lines Shannon Rose, Rebecca Wynne, Richard
E. Frye, Stepan Melnyk, and S. Jill James Department of Pediatrics University
of Arkansas for Medical Sciences Arkansas Children’s Hospital Research
Institute 13 Children’s Way, Slot 512-41B, Little Rock, AR 72202, USA Abstract
The association of autism spectrum disorders with oxidative stress, redox
imbalance, and mitochondrial dysfunction has become increasingly recognized. In
this study, extracellular flux analysis was used to compare mitochondrial
respiration in lymphoblastoid cell lines (LCLs) from individuals with autism
and unaffected controls exposed to ethylmercury, an environmental toxin known
to deplete glutathione and induce oxidative stress and mitochondrial
dysfunction. We also tested whether pretreating the autism LCLs with N-acetyl
cysteine (NAC) to increase glutathione concentrations conferred protection from
ethylmercury. Examination of 16 autism/control LCL pairs revealed that a
subgroup (31%) of autism LCLs exhibited a greater reduction in ATP-linked
respiration, maximal respiratory capacity, and reserve capacity when exposed to
ethylmercury, compared to control LCLs. These respiratory parameters were
significantly elevated at baseline in the ethylmercury-sensitive autism
subgroup as compared to control LCLs. NAC pretreatment of the sensitive
subgroup reduced (normalized) baseline respiratory parameters and blunted the
exaggerated ethylmercury-induced reserve capacity depletion. These findings
suggest that the epidemiological link between environmental mercury exposure
and an increased risk of developing autism may be mediated through
mitochondrial dysfunction and support the notion that a subset of individuals
with autism may be vulnerable to environmental influences with detrimental
effects on development through mitochondrial dysfunction.
http://www.hindawi.com/journals/jt/2015/573701/

“These findings suggest that the epidemiological link between environmental
mercury exposure and an increased risk of developing autism may be mediated
through mitochondrial dysfunction and support the notion that a subset of
individuals with autism may be vulnerable to environmental influences with
detrimental effects on development through mitochondrial dysfunction.”

Eli Lilly And The History of Thimerosal
The following is a summary of the history of thimerosal. It is not a complete
list, as there is much more information out there but we hit the high points
and we give a good frame of reference for where the discussion of the safety of
this product and its relationship to autism and neurodevelopmental disorders
should begin. Invented in the 1920’s by Eli Lilly, thimerosal is 49.6%
ethlymercury by weight, a neurotoxin known to be more than a hundreds times
more lethal to tissue than lead. Eli Lilly’s safety testing of the product
consists of a 1930 study of 22 patients dieing from mengiococcal meningitis in
an Indiana hospital. Patients are injected with the solutions and followed
until their death, which is within days. Because the patients die of
meningitis, they are declared to show no adverse reaction to thimerosal and the
product is declared safe for use. Thimerosal is subsequently introduced for use
in vaccines and in over the counter remedies as a preservative to kill bacteria
in the product. When the FDA is created, Thimerosal is grandfathered in and is
not subjected to any additional safety testing. The 1930 study remains the only
safety testing done on the substance even after being in use for over 75 years.

ing a baby, seek the advice of a health professional before using this
product.” The FDA orders the withdrawal of over the counter thimerosal
containing products within a 6 month period. It does not order removal from
vaccines, but recommends that the issue be studied and that the incidence of
neurological problems in unvaccinated populations like the Amish be compared to
the vaccinated population. [22 years later no such study has yet been done. On
July 19, 2005 Dr. Julie Gerberding, head of the CDC says that such a study
would be difficult to undertake because of genetic confounders. This seems
contrary to the scientific process because if indeed such a study is done and
it is found that the Amish have a lower incidence of neurodevelopmental
disorders, the next step would be to undertake genetic studies to see if their
genes differ dramatically from the general population and if their differences
can help us locate the genetic component of autism. In addition studies
designed to see if the small number of vaccinated Amish differ in their risk
for NDDs to the larger Amish population would offer information about increased
risk from thimerosal.] In the 1930’s the average child only received three
vaccines in their young life. Many vaccines are added to the schedule over the
years, with an increase in the 1980’s and with 3 vaccines added to the schedule
in 1991 alone. The current vaccine schedule calls for 31 vaccines in the first
18 months of life, 48 with full flu vaccination by 72 months of life.

Through FOIA requests and documents acquired as a part of discovery process in
lawsuits against Lilly, it is clear that they have been warned about, and have
been aware of the dangers of the product since at least 1947.

A Merck internal memo is obtained during discovery discloses that in 1991 a
Merck researcher added up the amount of mercury that is in the new vaccine
schedule and sounded an alarm at the company that children who are vaccinated
according to it would receive amounts of mercury far and above that considered
to be safe by the EPA. Merck takes no action in regard to the information.

The use of thimerosal in teething powders for infants leads to a fatal out
break of Acrodynia, or “Pink’s Disease”, a form of mercury poisoning. This
illness has many symptoms in common with Autism. The link to mercury powders
was found in the 1940’s and by the 1950’s Pink’s disease was disappearing.

During the 1990’s, autism rates begin to rise dramatically. Parents complain to
the health authorities that they believe that their children’s developmental
disorders are related to their vaccines.

In 1963 Eli Lilly was forwarded an article that read in part: “There is another
point of practical significance: does the parenteral injection of thimerosal -
containing fluids cause disturbances in thimerosal-sensitive patients?” “It is
known that persons that are contact sensitive to a drug may tolerate the same
medications internally, but it seems advisable to use a preservative other than
thimerosal for injections in thimerosal-sensitive people.”

In 1998, a researcher at the CDC does the same math that Merck did 7 years
previously. She finds that children are getting as much as 125 times the EPA
limit of mercury for their weight. The EPA limit is based on the ingestion of
methlymercury in food by a healthy adult. Because 90% of ingested mercury is
excreted in the digestive track and never enters the blood stream, so even the
EPA limit may be drastically lacking considering that thimerosal is injected
directly into the blood stream and is not subject to the bodies natural
defenses against toxic poisoning.

On August 17, 1967 the Medical/Science department requests that the claim
“non-toxic” on thimerosal labels be deleted in next printing run. Two weeks
later the label is changed to “non-irritating to body tissues,” and the phrase
non-toxic omitted. In 1972 The British Medical Journal reports case of skin
burns resulting from the chemical interaction of thimerosal and aluminum.
“Mercury is known to act as a catalyst and to cause aluminum to oxidize
rapidly, with the production of heat.” The manufacturers who supply us with
thimerosal have been informed.” [Thimerosal is being used in vaccines which
also contain aluminum]. In the 1970’s six newborns at one hospital die as a
result of having a thimerosal containing antiseptic wiped on their wounds. In
1982 the FDA reviews the use of thimerosal. Their statement reads in part: “At
the cellular level, thimerosal has been found to be more toxic for human
epithelial cells in vitro than mercuric chloride, mercuric nitrate, and
merbromim (mercurichrom). “It was found to be 35.3 times more toxic for
embryonic chick heart tissue than for staphylococcus areus.” [a pathogen that
the thimerosal is intended to kill]. A 1950 study showed that thimerosal was no
better than water in protecting mice from potential fatal streptococcal
infection.” “The Panel concludes that thimerosal is not safe for over the
counter topical use because of its potential for cell damage if applied to
broken skin and its allergy potential. It is not effective as a topical
antimicrobial because its bacteriastatic action can be reversed.” Additional
language added to some Lilly labels: “As with any drug, if you are pregnant or
nurs-

In 1999, the CDC and the American Association of Pediatrics issue a joint
statement saying that although they find no “evidence of harm” from the mercury
exposure that children are getting in their vaccines, they are calling on
vaccine manufacturers to remove it from vaccines on a voluntary basis as a
precautionary measure because “some children may” get more than the EPA limit
for mercury at their 6 month visits. Manufactures begin the process in 1999,
but do not remove it from all vaccines. No legal ban on thimerosal is issued.
No recall of the mercury laden vaccines is issued and companies continue to
sell lots already manufactured. Some of these vaccines containing full doses of
thimerosal have been found in doctors’ offices by parents who request to read
package inserts with expiration dates as late as 2007. No independent or
government testing of vaccines is done to confirm that thimerosal has been
removed. FDA denies parents request that they set up a system to verify
manufacturers claims of low dose or thimerosal free vaccines. No statement is
issued to pediatricians to alert them to the symptoms of mercury poisoning. No
recommendation is made to pediatricians to screen children who suffered the
onset of neurological impairment after vaccination for mercury toxicity.
Vaccines with 25mcg of thimerosal are still shipped to developing countries.
Most flu shots still contain a full dose

of thimerosal. The EPA estimates that a person must weigh 550 lbs. to safely tolerate this amount of mercury.
In November of 1999, the CDC commissions one of its new employees, a Belgian
named Thomas Verstraten, to study the Vaccine Safety Datalink to find the risk
of autism and other NDDs in relation to thimerosal exposure. Verstraten’s first
draft of the study finds a relative risk above 7 for children who receive the
highest dose of thimerosal to develop autism. In simple terms, such children
have more than a 600% higher chance of developing autism than children who
don’t receive any thimerosal. A relative risk of 2 is sufficient proof in U.S.
courts to find for vaccine injury. Verstraten and other scientists at the CDC
spend 4 years trying to change the study so that the relationship between the
preservative and NDD’s is significantly reduced or eliminated. The Center for
Disease Control will later describe these changes to the study as
“improvements”. When the study is published in 2003, it concludes that “no
consistent significant associations are found between thimerosal containing
vaccines and neurodevelopmental outcomes.” By this time Thomas Verstraten, who
is listed as a CDC employee on the study, has been an employee of
GlaxoSmithKlein (a defendant in thimerosal law suits) for more than 2 years. In
November of 2000, despite being born almost two months prematurely and despite
the assurance of my pediatrician that thimerosal had been removed from
vaccines, my son Webster is injected with a DTaP vaccine that was 74.5 times
the EPA limit for mercury exposure for his weight, just two weeks past his due
date. He will go on to develop verbal apraxia and sensory integration disorder.
In 2001 Bernard et. al. publish their hypothesis: Autism: A Novel Form of
Mercury Poisoning. It reads in part: “Exposure to mercury can cause immune,
sensory, neurological, motor, and behavioral dysfunctions similar to traits
defining or associated with autism, and the similarities extend to
neuroanatomy, neurotransmitters, and biochemistry. Thimerosal, a preservative
added to many vaccines, has become a major source of mercury in children who,
within their first two years, may have received a quantity of mercury that
exceeds safety guidelines. A review of medical literature and US government
data suggests that: (i) many cases of idiopathic autism are induced by early
mercury exposure from thimerosal; (ii) this type of autism represents an
unrecognized mercurial syndrome; and (iii) genetic and non-genetic factors
establish a predisposition whereby thimerosal’s adverse effects occur only in
some children.” In 2001 the Institute of Medicine is commissioned by the CDC to
undertake a comprehensive review of all research into the thimerosal/autism
connection. At their first meeting, Dr Stratton, head of the commission, when
discussing what the process and product of the working group would be states
that, “We said this before you got here, and I think we said this yesterday,
the point of no return, the line we will not cross in public policy is to pull
the vaccine, change the schedule. We could say it is time to revisit this, but
we would never recommend that level. Even recommending research is
recommendations for policy. We wouldn’t say compensate, we wouldn’t say pull
the vaccine, we wouldn’t say stop the program”. When the transcript of the
meeting is made public through a FOIA request, many interpret this to mean that
no matter what they find, they will not publicly say that there is any link
between the thimerosal and autism. Dr. Harvey Fineberg, head of the IOM, states
that this is an incorrect interpretation of the comments, but will not offer
any alternate interpretation of what else they could mean.

GFCF diet. He will go on to be diagnosed with both Autism and mercury poisoning
at age 2. I later discover that the “trace amount” of thimerosal is still just
over the EPA limit of mercury for his weight. In 2003 the Verstraten Study is
published in Pediatrics with no mention of the conflict of interest of the lead
researcher. Later a private contractor would testify before congress that he
was ordered to destroy the original data sets used in the 1999 version of the
study that found the dramatic link between thimerosal and autism in the
interest of “patient confidentiality”. The entire Vaccine Safety Datalink is
eventually moved to an offshore private company and can no longer be accessed
by FOIA request. In February of 2004, the IOM rushes to hold public hearings
where researchers on both sides of the issues present their studies. The
meeting is considered to be a “draw” between the two sides by many of those in
attendance. A link is neither proved nor disproved, but new research in to the
mechanism of how mercury can trigger autism and NDDs in a genetically
vulnerable sub population is presented, along with case studies of successful
treatment of autistic symptoms based on the new research. In May of the same
year, the IOM issues their final conclusion on the link between Thimerosal and
NDDs. They state that, “the body of epidemiological evidence favors rejection
of a causal relationship between thimerosalcontaining vaccines and autism. The
committee further finds that potential biological mechanisms for vaccineinduced
autism that have been generated to date are theoretical only.” They then go on
to take the unusual step of recommending that research into a link between the
two be abandoned and funds be spent on other lines of inquiry. The conclusion
relies heavily on Verstraten and several other epidemiological studies that are
considered to implement fatally flawed methods and to be riddled with conflict
of interest by members of the autism community. Parent groups are enraged. The
IOM panel disbands. Later that year, Thomas Verstraten publishes a letter in
Pediatrics in response to those who criticize his study and his conflict of
interest. His letter does not address the substance of the charges made against
the study and the changes that were made to it over it’s 4 year evolution, but
instead says that continuing to debate the validity of the 1999 study would be
a “waste of scientific energy and not to the benefit of the safety of US
children or of all the children world wide that have the privilege of being
vaccinated.” He goes on to say that any suggestion of impropriety on the part
of himself, the CDC or GSK is an insult and accuses his critics of having
“pitiable attitudes”. In July of 2005, in the face of continuing criticism of
the IOM findings, the head of the IOM, Dr. Harvey Fineberg, issues a letter
stating that Dr. Stratton’s 2001 comments that they would not say “pull the
vaccine” or “change the schedule” were taken out of context and did not suggest
that the IOM decision was compromised. Dr. Fineberg has not, despite requests,
offered an alternative interpretation of what her comments meant in context. In
March of 2005, Author David Kirby released his book, “Evidence of Harm -
Mercury in Vaccines and the Autism Epidemic: A Medical Controversy” detailing
the history of thimerosal in vaccines and its relationship to autism. In April
of 2005 the CDC posts a notice on their web site stating that they were in the
process of reviewing “Evidence of Harm” and would be responding to the book.

In 2001 Verstraten presents a version of his study to the IOM. He begins his
presentation by telling the panel that as of 8 am that morning, he had become
an employee of Glaxo Smith Klein. Despite the conflict of interest and the
drastic changes made over the course of the study, the IOM will rely heavily on
the study in making their determination. Dr. Verstraten returns to Belgium and
except for a letter published in Pediatrics, little is heard from him again.

In June of 2005 Robert F. Kennedy Jr. echoed the information found in the book
and charged the CDC and Eli Lilly of malfeasance in covering up evidence of a
causal effect between thimerosal and autism in an article published in Rolling
Stone and Salon.com. It is entitled “Deadly Immunity: Robert F. Kennedy Jr.
investigates the government cover-up of a mercury/autism scandal”.

In March of 2002 my son Chandler, who was born one month early, is injected
with Hepatitis B vaccine containing a “trace amount” of thimerosal (currently
still on the schedule), despite the fact that he has no risk factors for
Hepatitis B, and he is still two weeks from reaching his due date. Within days
he develops fevers and uncontrollable crying that lasts for three months and
bowel problems that persist for two years until he is placed on the

July 19, 2005. The CDC holds a press conference to: “communicate the importance
of infants and children receiving their recommended vaccinations on time, and
reassure parents that vaccines are safe. The renewed attention to the potential
causal link between thimerosal, a vaccine preservative, and autism will also be
addressed during the press conference.” Vaccine safety groups are not informed
of the press conference nor invited. The conference

presents no new information and does not answer important questions raised in Evidence of Harm or Deadly Immunity about the conduct of the CDC the IOM or the reliability of the research that continues to be used to show
no link between thimerosal and autism. In June of 2007 the first vaccinated v.
unvaccinated study is finally done ... by parents. Generation Rescue funded a
survey using the CDC’s techniques for determining incidence of a disorder and
found that vaccinated children are two and a half times more likely to have a
neurodevelopmental disorder. CDC spokesman Curtis Allen said, “We look forward
to learning more about the survey.” On June 25, 2007 Congresswoman Carolyn
Maloney (D-NY) introduced the “Comprehensive Comparative Study of Vaccinated
and Unvaccinated Populations Act of 2007” (H.R. 2832), legislation that would
require the National Institutes of Health (NIH) to conduct a comprehensive
comparative study of vaccinated and unvaccinated populations. Her stated
purpose is to resolve the controversy about the possible link between autism
and mercury or other vaccine components. The study is never done. Today,
January 2016, autism, ADHD and learning disabilities are at truly epidemic
levels with one in six children presenting. The government and the
pharmaceutical companies will claim that mercury has not been used in the
manufacture of most vaccines for some time now, is used only in influenza
vaccines and appears only in trace amounts in others. In the next chapter
you’ll read about aluminum which is even more deadly than mercury.

Chapter Three
Aluminum • Alum 1911 - 2015 Aluminum rescued Big Pharma from the mercury-autism
connection. Not only does aluminum cause the symptoms found on the autistic
spectrum, it also causes nearly 100 more disorders. Big Pharma can rest easy.
Vaccines no longer contain mercury and the autism epidemic continues to grow.
Obviously it couldn’t have been the mercury ...

JAMA • September 2, 1911

Some Objections To The Use Of Alum Baking Powder by William J. Gies, Ph.D.
Abstract During a period of about seven years I have occasionally conducted
experiments on the effects of aluminum salts. These studies have convinced me
that the use in food of alum or any other aluminum compound is a dangerous
practice. That the aluminum ion is very toxic is well known. That “aluminized”
food yields soluble aluminum compounds to gastric juice (and stomach contents)
has been demonstrated. That such soluble aluminum is in part absorbed and
carried to all parts of the body by the blood can no longer be doubted. That
the organism can “tolerate” such treatment without suffering harmful
consequences has not been shown. It is believed that the facts in this paper
will give emphasis to my conviction that aluminum should be excluded from food.
http://jama.jamanetwork.com/article.aspx?articleid=448038

“That the aluminum ion is very toxic is well known.

That “aluminized” food yields soluble aluminum compounds to gastric juice (and
stomach contents) has been demonstrated.

That such soluble aluminum is in part absorbed and carried to all parts of the
body by the blood can no longer be doubted.

That the organism can “tolerate” such treatment without suffering harmful
consequences has not been shown.”

“I was recently called to see a man ...”
The Lancet • June 18, 1921

Case Of Aluminum Poisoning by Dr. John Spofforth L.R.C.P.EDIN., Membership At
The Royal College Of Surgeons, England Abstract I was recently called to see a
man, aged 46, who was then employed at a firm of metalworkers. He was in a
state of great exhaustion and suffering from very severe and persistent
vomiting. The pulse was slow and irregular. I suspected metallic poisoning and
later sent a specimen of his urine to …, analytical chemists, who reported that
it contained a large amount of aluminium, also of phosphates. The patient said
he had been dipping red-hot metal articles, contained in an aluminium holder,
into concentrated nitric acid. Aluminium produces a rather slow intoxication.
In this case it caused loss of memory, tremor, jerking movements and impaired
co-ordination. There was also a chronic constipation and incontinence of urine.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)24927-7/abstract

JAMA • February 17, 1945

Early immunization against Pertussis with Alum precipitated vaccine by Wallace
Sako, MD., Ph.D., W. L. Treuting, MD., MPH., David B. Witt, Samuel J. Nichamin
Abstract According to the recent mortality records the majority of deaths from
pertussis occur in infants. Between 1938 and 1940 inclusive almost 67 per cent
of the 10,730 deaths from whooping cough reported in the United States occurred
during the first year of life and 47 per cent of these deaths were in infants
under 7 months of age (table 1 and fig. 1). The exceptionally high mortality
which pertussis exacts in the first half year of life calls for thorough
investigation of the possibility of increasing the resistance of young infants
to the disease by immunizing them shortly after birth. This procedure has been
objected to chiefly because of the belief that young infants do not possess the
ability to develop active immunity. No extensive study has been carried out,
however, to establish the earliest age at which immunity to pertussis can be
acquired.
http://jama.jamanetwork.com/article.aspx?articleid=272944&resultClick=3

“This procedure has been objected to chiefly because of the belief that young
infants do not possess the ability to develop active immunity. No extensive
study has been carried out, however, to establish the earliest age at which
immunity to pertussis can be acquired.”

“Aluminium intoxication ... is associated with periorbital bleeding, lethargy, anorexia, and death.
It is recommended that aluminium salts should be withdrawn from use in patients
with renal failure and their use restricted in normal persons pending
clarification of the issue.” The Lancet • Volume 299, No. 7750, p564–568 •
March 1972

Aluminium Toxicity In Rats G.M. Berlyne, J. Ben Ari, E. Knopf, R. Yagil, G.
Weinberger, G.M. Danovitch Department of Nephrology Negev Central Hospital and
Division of Life Sciences Negev Arid Zone Research Institute and Faculty of
Natural Science University of Negev, Beer Sheva, Israel Abstract Aluminium
intoxication has been demonstrated in the uræmic and non-uræmic rat after
modest doses of oral and parenteral aluminium salts. The clinical syndrome is
associated with periorbital bleeding, lethargy, anorexia, and death.
Plasma-levels of aluminium were greatly raised, as were tissue levels in liver,
heart, striated muscle, brain, and bone. Histological changes were found in the
cornea. Liver oxygen consumption was reduced by giving the animals aluminium
salts before death or by adding aluminium in vitro to normal liver homogenates.
It is recommended that aluminium salts should be withdrawn from use in patients
with renal failure and their use restricted in normal persons pending
clarification of the issue. http://www.ncbi.nlm.nih.gov/pubmed/4110051

Science • May 1973

Brain aluminum distribution in Alzheimer’s disease and experimental
neurofibrillary degeneration Crapper DR, Krishnan SS, Dalton AJ. Abstract
Neurofibrillary degeneration is an important pathological finding in senile and
presenile dementia of the Alzheimer type. Experimentally, aluminum induces
neurofibrillary degeneration in neurons of higher mammals. Aluminum
concentrations approaching those used experimentally have been found in some
regions of the brains of patients with Alzheimer’s disease.
http://www.ncbi.nlm.nih.gov/pubmed/4735595

“Experimentally, aluminum induces neurofibrillary degeneration in neurons of
higher mammals.”

Physiology & Behavior • May 1973

Alterations in short-term retention, conditioned avoidance response acquisition
and motivation following aluminum induced neurofibrillary degeneration D.R.
Crapper Departments of Physiology and Medicine Faculty of Medicine, University
of Toronto Toronto, Canada A.J. Dalton Department of Psychology Mental
Retardation Centre, Toronto, Canada Abstract Aluminum chloride induced
neurofibrillary degeneration may provide a useful model for the study of a
human dementia process. This possibility was assessed in cats trained to
perform on a delayed-response task, a conditioned avoidance task, visual and
temporal discrimination tasks and a motivational task involving rewarding
intracranial electrical stimulation. After an initial asymptomatic period short
term retention and acquisition of a conditioned avoidance response were
selectively impaired. The associated ultrastructural abnormalities plausibly
implicate the cytoplasmic streaming mechanism in the cellular substrate for
some retention and acquisition phenomena.
http://www.sciencedirect.com/science/article/pii/0031938473900632

“Aluminum chloride induced neurofibrillary degeneration may provide a useful
model for the study of a human dementia process.”

“... exerted selective and differential effects on the transport systems
of neurotransmitter substances in the synaptosomal membrane.” Journal of
Inorganic Biochemistry • 1981

Selective inhibition of L-glutamate and gammaaminobutyrate transport in nerve
ending particles by aluminium, manganese, and cadmium chloride Patrick C.L.
Wong, James C.K. Lai, Louis Lim, Alan N. Davison Abstract AlCl3, MnCl2, and
CdCl2 inhibited the rates of accumulation of 14C] L-glutamate and 3H]
gammaaminobutyrate (GABA) in purified rat forebrain nerve-ending particles in a
dose-dependent fashion. The concentrations that would give 50% inhibition
(IC50) of GABA transport were 316 μM, 7.4 mM, and 1.4 mM, respectively. Ca2+ (1
mM) enhanced the inhibitory effect of Al3+ (IC50 decreased to 149 μM) but
antagonized that of Mn2+ (IC50 = 10 mM) and Cd2+ (IC50 = 2.1 mM). For glutamate
transport 1 mM Ca2+ changed the IC50 values from 299 to 224 μm for Al3+, 7.1 to
10 mM for Mn2+, and 2 to 3 mM for Cd2+. In contrast, the rates of accumulation
of 14C] 2-deoxy-glucose and 3H] L-phenylalanine were mostly unaffected by these
metal ions. The results indicate that Al3+, Mn2+, and Cd2+ exerted selective
and differential effects on the transport systems of neurotransmitter
substances in the synaptosomal membrane.
http://www.sciencedirect.com/science/article/pii/S0162013400800057

Journal Of Neurochemistry • February 1984

Inhibition of brain glycolysis by aluminum Lai JC, Blass JP. Abstract Aluminum
inhibited both the cytosolic and mitochondrial hexokinase activities in rat
brain. The IC50 values were between 4 and 9 microM. Aluminum was effective at
mildly acidic (pH 6.8) or slightly alkaline (pH 7.2-7.5) pH, in the presence of
a physiological level of magnesium (0.5 mM). However, saturating (8 mM)
magnesium antagonized the effect of aluminum on both forms of hexokinase
activity. Other enzymes examined were considerably less sensitive to inhibition
by aluminum. The IC50 of aluminum for phosphofructokinase was 1.8 mM and for
lactate dehydrogenase 0.4 mM. At 10-600 microM, aluminum actually stimulated
pyruvate kinase. Aluminum also inhibited lactate production by rat brain
extracts: this effect was much more marked with glucose as substrate than with
glucose-6phosphate. However, the IC50 for inhibiting lactate production using
glucose as substrate was 280 microM, higher than that required to inhibit
hexokinase. This concentration of aluminum is comparable to those reportedly
found in the brains of patients who had died with dialysis dementia and in the
brains of some of the patients who had died with Alzheimer disease. Inhibition
of carbohydrate utilization may be one of the mechanisms by which aluminum can
act as a neurotoxin. http://www.ncbi.nlm.nih.gov/pubmed/6229606

“This concentration of aluminum is comparable to those reportedly found in the
brains of patients who had died with dialysis dementia and in the brains of
some of the patients who had died with Alzheimer disease. Inhibition of
carbohydrate utilization may be one of the mechanisms by which aluminum can act
as a neurotoxin.”

Journal Of Neurology, Neurosurgery And Psychiatry • February 1984

Experimental aluminium encephalopathy: quantitative EEG analysis of aluminium
bioavailability Cutrufo C, Caroli S, Delle Femmine P, Ortolani E, Palazzesi S,
Violante N, Zapponi GA, Loizzo A. Abstract Single oral doses of aluminium
hydroxide (50 to 200 mg/kg) were found to induce in mice a dose-dependent
diminution of the power of the 7.5 to 12 Hz frequency band, with a parallel
dose-dependent increase of aluminium content in the brain, as early as 45 min
after administration, and indicated that aluminium hydroxide is readily
absorbed through an empty stomach or duodenum and is able to induce alterations
of background EEG rhythms at doses equivalent to the ones used in human
therapy. These data suggest that the EEG disturbances of the background type,
(which are observed during the early stage of dialysis encephalopathy in man),
may be partly due to a pharmacological and therefore reversible effect induced
by an increase in aluminium level in the brain. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1027694/

“Single oral doses of aluminium hydroxide were found to induce in mice a
dose-dependent diminution of the power of the 7.5 to 12 Hz frequency band, with
a parallel dose-dependent increase of aluminium content in the brain, as early
as 45 min after administration, and indicated that aluminium hydroxide is
readily absorbed through an empty stomach or duodenum and is able to induce
alterations of background EEG rhythms at doses equivalent to the ones used in
human therapy.”

Acta Neuropathology • 1985

Histochemical localization of aluminum in the rabbit Central Nervous System Wen
GY, Wisniewski HM. Abstract Aluminum was observed in the nucleolus,
interchromatin granules, rough endoplasmic reticulum, free ribosomes,
euchromatin, and the heterochromatin of the neuron. The association of aluminum
with the first four r-RNA-containing cellular components and with the last two
DNA-containing chromatins suggests the association of aluminum with the nucleic
acids. The aluminum may interfere with the normal mechanism of the protein
synthesis of r-RNA and of the transcription or gene modulation of DNA. Aluminum
was also observed in the astrocytic process and in the nuclei of endothelial
cells, pericytes, and the muscle cells of the blood vessels. The detection of
aluminum in the pyrimidal cells of the cerebral cortex and hippocampus and in
the spinal cord neurons, was observed 1 h after i.v. injection, indicating a
rapid entry of aluminum from the injection site through the blood-brain barrier
(BBB) to the neurons. Using Morin stain, pyramidal neurons of the cerebral
cortex and hippocampus, motoneurons of spinal cord, ganglion cells, and bipolar
cells of retina and Purkinje cells of cerebellum, exhibited yellow
fluorescence, with peak intensity at 560 nm. Tangles were observed in these six
types of neurons. The granule cells of hippocampus and cerebellum and the
photoreceptors of the retina exhibited green fluorescence with the peak
intensity at 490-500 nm. Tangles were not observed in these three types of
neurons. http://www.ncbi.nlm.nih.gov/pubmed/?term=2417440

“The detection of aluminum in the pyrimidal cells of the cerebral cortex and
hippocampus and in the spinal cord neurons, was observed 1-hour after i.v.
injection, indicating a rapid entry of aluminum from the injection site through
the blood-brain barrier (BBB) to the neurons.”

Environmental Health Perspectives • March 1986

Metabolism and possible health effects of aluminum by P. O. Ganrot Abstract
Literature regarding the biochemistry of aluminum and eight similar ions is
reviewed. Close and hitherto unknown similarities were found. A hypothetical
model is presented for the metabolism, based on documented direct observations
of Al3+ and analogies from other ions. Main characteristics are low intestinal
absorption, rapid urinary excretion, and slow tissue uptake, mostly in skeleton
and reticuloendothelial cells. Intracellular Al3+ is probably first confined in
the lysosomes but then slowly accumulates in the cell nucleus and chromatin.
Large, long-lived cells, e.g., neurons, may be the most liable to this
accumulation. In heterochromatin, Al3+ levels can be found comparable to those
used in leather tannage. It is proposed that an accumulation may take place at
a subcellular level without any significant increase in the corresponding
tissue concentration. The possible effects of this accumulation are discussed.
As Al3+ is neurotoxic, the brain metabolism is most interesting. The normal and
the lethally toxic brain levels of Al3+ are well documented and differ only by
a factor of 3-10. The normal brain uptake of Al3+ is estimated from data on
intestinal uptake of Al3+ and brain uptake of radionuclides of similar ions
administered intravenously. The uptake is very slow, 1 mg in 36 years, and is
consistent with an assumption that Al3+ taken up by the brain cannot be
eliminated and is therefore accumulated. The possibility that Al3+ may cause or
contribute to some specific diseases, most of them related to aging, is
discussed with the proposed metabolic picture in mind.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1474689/

“The uptake is very slow, 1 mg in 36 years, and is consistent with an
assumption that Al3+ taken up by the brain cannot be eliminated and is
therefore accumulated.”

The Society of Toxicology • May 1987

Maternal and Developmental Toxicity of Chronic Aluminum Exposure in Mice Author
Information Mari S. Golub*, M. Eric Gershwin*, James M. Donald*, Scott Negri,
Carl L. Keen* *Department of Internal Medicine, University of California Davis,
California 95616 a Department of Nutrition, University of California Davis,
California 95616 Abstract The present study demonstrated aluminum-induced
neurotoxicity in mouse dams and developmental retardation in their offspring
following oral exposure to several dose levels during gestation and lactation.
Female mice fed aluminum lactate (AL) at levels of 500 or 1000 ppm in their
diet from Day 0 gestation to Day 21 postpartum were compared to mice which
received a 100 ppm aluminum diet either ad libitum or pair-fed to the 1000 ppm
AL group. Dams receiving the 500 and 1000 ppm AL diets showed signs of
neurotoxicity beginning at Days 12–15 postpartum and showed significant weight
loss. Offspring showed dose-dependent decreases in body weight (F = 6.47, p <
0.001), crown-rump length (F = 1.11, p < 0.0001), and ponderal index (F = 6.90,
p < 0.0002), at birth and preweaning. Absolute and relative liver and spleen
weights were lower in pups from the high AL groups compared to controls (F =
3.34, p < 0.025 and F = 15.54, p < 0.001, respectively). Neurobehavioral
development was somewhat delayed in aluminum-treated pups, but not in their
pair-fed controls (F = 5.52, p < 0.005). In addition to showing oral toxicity
of excess AL during development dose-dependent toxic effects of parenteral
aluminum exposure were demonstrated in pregnant mice which were injected
subcutaneously with aluminum lactate solution at 10, 20, or 40 mg Al/kg body wt
on Days 3, 5, 7, 9, 12, 13, and 15 of gestation. Maternal spleen and liver
weights were significantly increased in aluminum treated animals (p < 0.001 and
p < 0.05, respectively). Fetal crown-rump lengths were significantly reduced in
the 20 mg/kg aluminum group (F = 9.79, p < 0.001).
http://toxsci.oxfordjournals.org/content/8/3/346

“The present study demonstrated aluminum-induced neurotoxicity in mouse dams
and developmental retardation in their offspring following oral exposure to
several dose levels during gestation and lactation.”

Neurotoxicology • Fall 1988

Neuropathologic, neurochemical and immunocytochemical characteristics of
aluminum-induced neurofilamentous degeneration Author information Pendlebury
WW1, Beal MF, Kowall NW, Solomon PR. Department of Pathology University of
Vermont College of Medicine, Burlington Abstract Inoculation of aluminum salts
or metallic aluminum into the central nervous system of rabbits produces an
encephalomyelopathy accompanied by widespread neurofibrillary degeneration
(NFD) affecting restricted neuronal populations. Some investigators have
suggested that this preparation may serve as an animal model for human
neurodegenerative disorders, such as Alzheimer’s disease (AD), in which
neurofibrillary tangle (NFT) formation is a prominent histopathologic finding.
However, neurochemical, immunocytochemical and behavioral features of the model
are largely unknown and its neuropathology only partially described. We have
undertaken a series of experiments designed to further characterize these
aspects of the model. We have used an intraventricular route of injection of
aluminum chloride and found that the distribution of NFD in rabbit brain is
similar to the distribution of NFT formation in AD. Immunocytochemical probes
demonstrate that phosphorylated neurofilaments accumulate in neuronal perikarya
containing NFD, and double labelling techniques suggest that NFD affects
primarily projection type neurons. The neurochemical profile of aluminum
intoxicated rabbits shows both similarities and discrepancies to that of AD.
Finally, as reported in a companion article in this issue of Neurotoxicology
(Solomon and Pendlebury, 1988), aluminum-exposed rabbits develop learning and
memory deficits which are strongly correlated with the degree of whole brain
NFD but not with motor, sensory or motivational factors. We conclude that
aluminum-induced NFD may have relevance for understanding NFT formation in AD
and other neurodegenerative disorders in which abnormalities of the neuronal
cytoskeletal architecture are present.
http://www.ncbi.nlm.nih.gov/pubmed/?term=3200512

“... aluminum-induced neurofibrillary degeneration may have relevance for
understanding neurofibrillary tangle formation in Alzheimer’s disease and other
neurodegenerative disorders ...”

Neuroscience And Biobehavioral Reviews • Spring 1989

Aluminum-induced neurotoxicity: alterations in membrane function at the
blood-brain barrier Author information Banks WA1, Kastin AJ. 1Veterans
Administration Medical Center New Orleans, LA Abstract Aluminum is established
as a neurotoxin, although the basis for its toxicity is unknown. It recently
has been shown to alter the function of the blood-brain barrier (BBB), which
regulates exchanges between the central nervous system (CNS) and peripheral
circulation. The BBB owes its unique properties to the integrity of the cell
membranes that comprise it. Aluminum affects some of the membrane-like
functions of the BBB. It increases the rate of transmembrane diffusion and
selectively changes saturable transport systems without disrupting the
integrity of the membranes or altering CNS hemodynamics. Such alterations in
the access to the brain of nutrients, hormones, toxins, and drugs could be the
basis of CNS dysfunction. Aluminum is capable of altering membrane function at
the BBB; many of its effects on the CNS as well as peripheral tissues can be
explained by its actions as a membrane toxin.
http://www.ncbi.nlm.nih.gov/pubmed/2671833

“Aluminum is established as a neurotoxin ... Aluminum affects some of the
membrane-like functions of the BBB ... many of its effects on the CNS as well
as peripheral tissues can be explained by its actions as a membrane toxin.”

Kidney International • May 1989

Micromolar aluminum levels reduce 3H-thymidine incorporation by cell line UMR
106-01 Author information Blair HC1, Finch JL, Avioli R, Crouch EC, Slatopolsky
E, Teitelbaum SL. Department of Pathology and Laboratory Medicine Jewish
Hospital, Washington University Medical Center St. Louis, Missouri Abstract
Aluminum-induced osteomalacia is a frequent complication observed in patients
on maintenance hemodialysis. However, it is not known whether there are direct
effects of aluminum on osteoblasts, or alternatively, whether the observed
changes are due to changes in PTH or other factors. We sought to determine the
effect of micromolar levels of aluminum on osteoblasts using a well-defined
cell line derived from a 32P induced osteosarcoma of rat, UMR 106-01, which is
alkaline-phosphatase positive, responds to PTH, and synthesizes type I
collagen. Aluminum exposure was controlled using tissue culture media with [Al
] less than 1 microgram/liter (40 nM), produced by precipitation of aluminum
salts at pH 8.5. The effect of defined [Al ], from 20 to 800 micrograms/liter
(0.7 to 30 microM), was then determined by adding back aluminum while measuring
DNA and protein synthesis. We found that aluminum depressed DNA synthesis, as
determined by 3H-thymidine incorporation, by 60%, with half maximal effect at
20 micrograms/liter (740 nM) in cells at a density of 20,000/cm2.
Alternatively, protein synthesis, as determined by 3H-leucine incorporation,
did not decline, and in some cases increased. However, qualitative analysis of
matrix proteins produced with and without 800 micrograms/liter (30 mM) [Al ]
showed no differences. Direct measurements of cell number and protein synthesis
confirmed these findings. Al does not alter the PTH-induced cAMP response of
these cells. Thus, aluminum has a direct effect on cell division, and probably
on protein synthesis, in this osteoblast-like cell line. These effects occur at
levels of aluminum below those commonly contaminating tissue culture media, and
thus are seen reproducibly only in media of defined [Al ].
http://www.ncbi.nlm.nih.gov/pubmed/2549294

“... aluminum has a direct effect on cell division, and probably on protein
synthesis ...”

Clinical Science • London England • November 1989

Effect of aluminium on superoxide dismutase Author information
Shainkin-Kestenbaum R1, Adler AJ, Berlyne GM, Caruso C. Nephrology Section
Brooklyn VA Medical Center New York 11209 Abstract 1. The effect of Al3+ on
superoxide dismutase in vitro was studied, since in uraemia there is excessive
superoxide production and frequently an elevated serum Al3+ level. Thus, the
protective role of superoxide dismutase is particularly important.

“The combination of

2. Al3+ in concentrations similar to those found in the serum of uraemic
patients inhibits superoxide dismutase activity. The degree of inhibition is
directly proportional to the Al3+ level.

with an increased aluminum level may contribute

3. The combination of excessive oxygen free radical production with an
increased Al3+ level may contribute to a variety of complications, including
aluminium dementia or initiation and promotion of carcinogenic processes, which
are known to be more common in uraemic patients.
http://www.ncbi.nlm.nih.gov/pubmed/2582719

excessive oxygen free radical production

to a variety of complications, including aluminium dementia or initiation and
promotion of carcinogenic processes ...”

Environmental Geochemistry And Health • March 1990

Aluminum neurotoxicity in mammals Author information Wisniewski HM1, Moretz RC,
Sturman JA, Wen GY, Shek JW. Institute for Basic Research in Developmental
Disabilities Departments of Pathological and Neurobiology New York State Office
of Mental Retardation and Developmental Disabilities, USA Abstract Although
aluminum comprises a large percentage of the Earth’s crust, it is excluded from
body tissues, and especially from the central nervous system. When aluminum is
experimentally introduced to the central nervous system, several neurotoxic
effects are observed: i.e. neurofibrillary changes, behavioral and cognitive
deficits and enzymatic and neurotransmitter changes, as well as certain types
of epileptic seizures. The localization of relatively high levels of aluminum
in Alzheimer disease, Guamanian amyotrophic lateral sclerosis and
Parkinsonism-dementia has led to the implication of aluminum as a pathogenic
factor in these diseases. Recent studies have shown that microtubule-associated
proteins are part of the paired helical filaments which make up the
intraneuronal neurofibrillary tangle. Other studies have identified the protein
making the vascular and neuritic (senile) plaque amyloid and located the gene
responsible for this protein to chromosome 21.Our electron microprobe analysis
studies have not found the levels of aluminum or silicon in either the
neurofibrillary tangles or amyloid cores reported elsewhere, nor have the
levels of aluminum been elevated in approximately one half of the tangles and
plaque cores examined to date.
http://www.ncbi.nlm.nih.gov/pubmed/?term=24202577

“When aluminum is experimentally introduced to the central nervous system,
several neurotoxic effects are observed: i.e. neurofibrillary changes,
behavioral and cognitive deficits and enzymatic and neurotransmitter changes,
as well as certain types of epileptic seizures.”

Biofactors • July 1990

Aluminum, a neurotoxin which affects diverse metabolic reactions Author
information Joshi JG. Department of Biochemistry University of Tennessee
Knoxville 37996-0840 Abstract Experimental evidence is summarized to support
the hypothesis that chronic exposure to low levels of aluminum may lead to
neurological disorders. These disorders result from defective
phosphorylation--dephosphorylation reactions, reduced glucose utilization and
site-specific damage inflicted by free radicals produced by altered iron
metabolism. The brain is a highly compartmentalized organ. Therefore, a
co-localization of critical mass of metabolic errors rather than a single event
may be essential to precipitate a neural disease. Aluminum appears to
participate in formulating this critical mass. Patients with dialysis dementia
get partial relief by desferroxamine which chelates aluminum. However, it also
chelates iron and therefore limits its applicability. While the specific
chelator for aluminum is yet to be made available, exercising a caution in
aluminum intake appears prudent.
http://www.ncbi.nlm.nih.gov/pubmed/?term=2198876

“Experimental evidence is summarized to support the hypothesis that chronic
exposure to low levels of aluminum may lead to neurological disorders.”

Journal Of Pharmacology And Experimental Therapeutics • July 1990

Mechanism of aluminum-induced inhibition of hepatic glycolysis: inactivation of
phosphofructokinase Author information Xu ZX1, Fox L, Melethil S, Winberg L,
Badr M. School of Pharmacy University of Missouri-Kansas City Abstract
Aluminum, an abundant element in the earth’s crust, has been implicated in
various pathological disorders and low concentrations of this element have
recently been shown to inhibit brain glycolysis. However, despite the fact that
aluminum accumulates in high concentrations in the liver, potential effects of
this metal on hepatic intermediary metabolism have not been explored. In
perfused livers from untreated rats, maximal rates of production of lactate
plus pyruvate (glycolysis) were 93 +/- 15 mumols/g/hr. Glycolysis was severely
inhibited in livers from aluminum-treated rats (0.5 mg/kg, 6 hr before
experiment) with maximal rates of only 23 +/- 4 mumols/g/hr. In contrast,
glucose production (glycogenolysis) and hepatic oxygen uptake were not altered
significantly by prior treatment with aluminum. In livers from fasted rats,
pretreatment with aluminum did not influence gluconeogenesis or production of
lactate and pyruvate from fructose (5 mM). This finding indicates that pyruvate
kinase is not inhibited by aluminum and implicates phosphofructokinase,
hexokinase and/or glucokinase as sites for the inhibitory effect of aluminum on
glycolysis. In liver homogenates from untreated rats, increasing concentrations
of aluminum did not show any appreciable effect on hexokinase or glucokinase
activity but did cause progressive decreases in phosphofructokinase activity.
Therefore, aluminum-induced inhibition of liver phosphofructokinase, an
important control site in the glycolytic pathway, is most likely responsible
for aluminum-induced inhibition of hepatic glycolysis.
http://www.ncbi.nlm.nih.gov/pubmed/2142221

“Aluminum, an abundant element in the earth’s crust, has been implicated in
various pathological disorders and low concentrations of this element have
recently been shown to inhibit brain glycolysis.”

“These studies clearly demonstrate the philosophy that chronic rather than acute
experimental models of toxicity are necessary in order to enhance our
understanding of human neurodegenerative disorders with long-latency and slow
progression.” Neurotoxicology • Fall 1991

Pacific paradigms of environmentally-induced neurological disorders: clinical,
epidemiological and molecular perspectives Author information Garruto RM
Laboratory of Central Nervous System Studies National Institutes of Health,
Bethesda, Maryland 20892 Abstract During the past quarter century biomedical
scientists have begun to recognize the unique opportunities for studying
disease etiology and mechanisms of pathogenesis in non-Western anthropological
populations with focal, endemic diseases. Such natural experiments as they are
called, are important paradigms for solving etiological and epidemiological
problems of widespread medical significance, with an ultimate goal towards
treatment and prevention. The systematic search for etiological factors and
mechanisms of pathogenesis of neurodegenerative disorders is perhaps nowhere
better exemplified than in the western Pacific. During the past three decades,
the opportunistic and multidisciplinary study of hyperendemic foci of
amyotrophic lateral sclerosis and parkinsonism-dementia which occur in
different cultures, in different ecological zones and among genetically
divergent populations have served as natural models that have had a major
impact on our thinking and enhanced our understanding of these and other
neurodegenerative disorders such as Alzheimer disease and the process of early
neuronal aging. Our cross-disciplinary approach to these intriguing
neurobiological problems and the accumulated epidemiological, genetic, cellular
and molecular evidence strongly implicates environmental factors in their
causation, specifically the role of aluminum and its interaction with calcium
in neuronal degeneration. As a direct consequence of our studies in these
Pacific populations, we have undertaken the long-term development of
experimental models of neuronal degeneration, in an attempt to understand the
cellular and molecular mechanisms by which these toxicants affect the central
nervous system. Our experimental studies have resulted in the establishment of
an aluminum-induced chronic myelopathy in rabbits and the development of
neurofilamentous lesions after low-dose aluminum administration in cell
culture. These studies clearly demonstrate the philosophy that chronic rather
than acute experimental models of toxicity are necessary in order to enhance
our understanding of human neurodegenerative disorders with longlatency and
slow progression. Finally, the ultimate significance of these Pacific paradigms
may well depend on our ability to comprehensively evaluate and synthesize the
growing body of relevant scientific data from other human disorders and from
widely divergent academic fields, as well as our ability to recognize emerging
new models in nature. http://www.ncbi.nlm.nih.gov/pubmed/?term=1745428

Annals Of Neurology • March 1992

Selective accumulation of aluminum and iron in the neurofibrillary tangles of
Alzheimer’s disease: a laser microprobe (LAMMA) study Author information Good
PF1, Perl DP, Bierer LM, Schmeidler J. Department of Pathology Mount Sinai
School of Medicine New York, NY 10029 Abstract We report the results of an
examination of the elemental content of neurofibrillary tangle-bearing and
neurofibrillary tangle-free neurons identified within the hippocampus of 10
subjects with Alzheimer’s disease and 4 neuropathologically intact age-matched
control subjects. The study employed laser microprobe mass analysis (LAMMA), a
technique that provides extremely sensitive multielement detection in
plastic-embedded, semithin-sectioned tissues. Evidence for the selective
accumulation of aluminum within the neurofibrillary tangle-bearing neurons was
obtained in all 10 subjects with Alzheimer’s disease. The site of aluminum
deposition within these cells was the neurofibrillary tangle itself, and not
the “nuclear region,” as we previously reported. Iron accumulation was also
detected within neurofibrillary tangles. Evaluation for the accumulation of
other elements within the tangle-bearing neurons failed to reveal any other
metallic element as being consistently present. In addition, probe sites
directed to neurons identified in snap-frozen cryostat sections from 2 subjects
with Alzheimer’s disease revealed similar spectra with prominent
aluminum-related peaks, confirming that our findings are not related to
exogenous contamination through fixation, embedding, or other procedures prior
to analysis. This study further confirms the association of aluminum and
neurofibrillary tangle formation in Alzheimer’s disease.
http://www.ncbi.nlm.nih.gov/pubmed/1637136

“This study further confirms the association of aluminum and neurofibrillary
tangle formation in Alzheimer’s disease.”

Pharmacology And Toxicology • April 1992

Aluminium-adjuvanted vaccines transiently increase aluminium levels in murine
brain tissue Author information Redhead K1, Quinlan GJ, Das RG, Gutteridge JM.
Division of Bacteriology National Institute for Biological Standards and
Control Herts., UK Abstract Aluminium is widely used as an adjuvant in human
vaccines, and children can often receive up to 3.75 mg of parenteral aluminium
during the first six months of life. We show that intraperitoneal injection of
aluminium adsorbed vaccines into mice causes a transient rise in brain tissue
aluminium levels peaking around the second and third day after injection. This
rise is not seen in the saline control group of animals or with vaccine not
containing aluminium. It is likely that aluminium is transported to the brain
by the iron-binding protein transferrin and enters the brain via specific
transferrin receptors. http://www.ncbi.nlm.nih.gov/pubmed/1608913

“... children can often receive up to 3.75 mg of parenteral aluminium during
the first six months of life We show that intraperitoneal injection of
aluminium adsorbed vaccines into mice causes a transient rise in brain tissue
aluminium levels peaking around the second and third day after injection.”

Life Sciences • June 1992

Long-term effects of aluminium on the fetal mouse brain Author information
Clayton RM1, Sedowofia SK, Rankin JM, Manning A. Division of Biological
Sciences University of Edinburgh Abstract Potentially noxious substances may
act as fetal teratogens at levels far lower than those required to produce
detectable effects in adults, and behavioural teratogenicity may occur at
levels lower than those which produce morphological teratogenesis. Aluminium
(Al) is a potential neurotoxin in adults. Since pregnant women may be exposed
to untoward levels of Al compounds under certain conditions, we have examined
the long-term effects of treating the pregnant mouse with intraperitoneal or
oral aluminium sulphate on brain biochemistry and behaviour of the offspring.
The cholinergic system, as evaluated by the activity of choline
acetyltransferase (ChAT), was affected differentially in different regions of
the brain, and still showed significant effects in the adult. Differences
between the intraperitoneal and oral series in the magnitude of effect seen in
the regions of the brain probably reflect differences in the effective level of
exposure. Growth rate and psychomotor maturation in the pre-weaning mouse were
affected in the intraperitoneal series only, showing a marked post-natal
maternal effect. http://www.ncbi.nlm.nih.gov/pubmed/?term=1453876

“Potentially noxious substances may act as fetal teratogens at levels far lower
than those required to produce detectable effects in adults, and behavioural
teratogenicity may occur at levels lower than those which produce morphological
teratogenesis.”

Neurotoxicology • Summer 1992

Aluminum inhibits glutamate release f rom transverse rat hippocampal slices:
role of G proteins, Ca channels and protein kinase C Author information Provan
SD1, Yokel RA. College of Pharmacy University of Kentucky Lexington 40536-0082
Abstract Aluminum (Al) has been shown to produce deficits in learning and
memory. The present experiments tested the hypothesis that Al-induced
inhibition of learning may be due to its effect on glutamate release secondary
to changes in calcium channel function and/or intracellular events triggering
glutamate release. Calcium-dependent potassium (K)-evoked [14C]-glutamate
release from 400 microns transverse rat hippocampal slices was inhibited by Al
in a concentration dependent manner (IC50 = 40 microM). Aluminum (30, 100
microM) noncompetitively inhibited Bay K 8644evoked glutamate release.
4-Aminopyridine (30, 1000 microM) noncompetitively attenuated the Al inhibition
of glutamate release, suggesting an Al-induced alteration of Ca channel
function. Activation of the Gi protein by R(-)phenylisopropyladenosine (PIA; 1
microM) reduced K-evoked glutamate release 69%, whereas 300 microM Al produced
an 84% reduction. These effects were prevented by the Gi protein inhibitor
N-ethylmaleimide (NEM; 100 microM), suggesting an effect of Al on the Gi
protein to inhibit glutamate release. Phorbol myristate acetate (0.16
microM)-induced glutamate release was inhibited by 300 microM Al and 80 microM
polymyxin B, suggesting an Al modulation of protein kinase C (PKC)-evoked
glutamate release. These results demonstrate an Al inhibition of glutamate
release that may be mediated by multiple, but interconnected mechanisms (e.g.,
via interactions with Ca systems), providing multiple targets for an Al-induced
alteration of neuronal function.
http://www.ncbi.nlm.nih.gov/pubmed/?term=1359483

“Aluminum (Al) has been shown to produce deficits in learning and memory.”

Journal Of Theoretical Biology • November 1992

The cellular toxicity of aluminium Author information Exley C, Birchall JD.
Institute of Aquaculture University of Stirling Scotland, UK Abstract Aluminium
is a serious environmental toxicant and is inimical to biota. Omnipresent, it
is linked with a number of disorders in man including Alzheimer’s disease,
Parkinson’s dementia and osteomalacia. Evidence supporting aluminium as an
aetiological agent in such disorders is not conclusive and suffers principally
from a lack of consensus with respect to aluminium’s toxic mode of action.
Obligatory to the elucidation of toxic mechanisms is an understanding of the
biological availability of aluminium. This describes the fate of and response
to aluminium in any biological system and is thus an important influence of the
toxicity of aluminium. A general theme in much aluminium toxicity is an
accelerated cell death. Herein mechanisms are described to account for cell
death from both acute and chronic aluminium challenges. Aluminium associations
with both extracellular surfaces and intracellular ligands are implicated. The
cellular response to aluminium is found to be biphasic having both stimulatory
and inhibitory components. In either case the disruption of second messenger
systems is observed and GTPase cycles are potential target sites. Specific
ligands for aluminium at these sites are unknown though are likely to be
proteins upon which oxygen-based functional groups are orientated to give
exceptionally strong binding with the free aluminium ion.
http://www.ncbi.nlm.nih.gov/pubmed/?term=1291812

“A general theme in much aluminium toxicity is an accelerated cell death.”

Toxicology • 1992

Role of aluminium in skin reactions after
diphtheria-tetanus-pertussis-poliomyelitis vaccination: an experimental study
in rabbits Author information Pineau A1, Durand C, Guillard O, Bureau B,
Stalder JF. Laboratoire de Toxicologie et d’Hygiène Industrielle Faculté de
Pharmacie, Centre Hospitalier Régional Universitaire Nantes, France Abstract
The occurrence of subcutaneous nodules at the injection site is one of the
complications of diphtheria-tetanus-pertussis-poliomyelitis vaccination, but
the causes and mechanisms involved are still poorly understood. An experimental
study in the New Zealand rabbit enabled us to determine the frequency of
occurrence of these nodules, how long they persist and the histopathologic
features of the cells involved. Aluminium (Al) assays by electrothermal atomic
absorption spectrometry allowed us to study concentrations both in nodules and
the organism (serum, normal skin). The results show an absence of Al diffusion
outside nodules, a correlation between infiltrate intensity and Al
concentration in nodules and modifications in the histological constituents of
nodule cells. The histological picture indicates a foreign body reaction to Al.
All these data underscore the role of Al in the formation of early postvaccinal
nodules at the injection site. http://www.ncbi.nlm.nih.gov/pubmed/?term=1589878

“All these data underscore the role of Aluminum in the formation of early
postvaccinal nodules at the injection site.”

[this is one of the earliest examples of “nodules at the injection site”
mentioned in the medical literature. As you’ll see, eventually this phenomenon
leads to a new disorder, Macrophagic Myofasciitis and the coining of the term
“ASIA,” a wide variety of nearly 100 recognized autoimmune and inflammatory
disorders induced by the Aluminum adjuvant in vaccines]

“Generally, the intake of aluminium from foods is less than 1% of that
consumed by individuals using aluminium-containing pharmaceuticals. Currently
the real scientific question is not the amount of aluminium in foods but the
availability of the aluminium in foods and the sensitivity of some population
groups to aluminium.” Ciba Foundation Symposium • 1992

Dietary and other sources of aluminium intake Author information Greger JL.
Department of Nutritional Sciences University of Wisconsin, Madison 53706
Abstract Aluminium in the food supply comes from natural sources including
water, food additives, and contamination by aluminium utensils and containers.
Most unprocessed foods, except for certain herbs and tea leaves, contain low (<
5 micrograms Al/g) levels of aluminium. Thus most adults consume 1-10 mg
aluminium daily from natural sources. Cooking in aluminium containers often
results in statistically significant, but not practically important, increases
in the aluminium content of foods. Intake of aluminium from food additives
varies greatly (0 to 95 mg Al daily) among residents in North America, with the
median intake for adults being about 24 mg daily. Generally, the intake of
aluminium from foods is less than 1% of that consumed by individuals using
aluminium-containing pharmaceuticals. Currently the real scientific question is
not the amount of aluminium in foods but the availability of the aluminium in
foods and the sensitivity of some population groups to aluminium. Several
dietary factors, including citrate, may affect the absorption of aluminium.
Aluminium contamination of soy-based formulae when fed to premature infants
with impaired kidney function and aluminium contamination of components of
parenteral solutions (i.e. albumin, calcium and phosphorus salts) are of
concern. http://www.ncbi.nlm.nih.gov/pubmed/?term=1490425

Food And Chemical Toxicology • May 1993

Neurotoxic effect of enteral aluminium Author information Bilkei-Gorzó A.
Pharmacological Department Chinoin Pharmaceutical and Chemical Works Co. Ltd
Budapest, Hungary Abstract Long Evans rats were treated for 90 days with
water-soluble, insoluble or chelated aluminium compounds. The daily treatments
given were as follows: controls, NaCl (100 mg/kg body weight) plus citric acid
(30 mg/kg); AlCl3 (30 or 100 mg/kg); Al(OH)3 (100 mg/kg) plus citric acid (30
mg/kg); Al(OH)3 (300 mg/kg). Their learning ability was determined in the
labyrinth test at day 90, and the choline-acetyltransferase,
acetylcholinesterase activity and aluminium content of the brains were
measured. Soluble and chelated aluminium compounds seriously worsened the
learning ability, and the aluminium content of the brain was elevated.
Acetylcholinesterase activity increased and choline-acetyltransferase activity
decreased, resulting in a diminished cholinergic activity, which is a
characteristic of Alzheimer’s disease.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8505021

“... resulting in a diminished cholinergic activity, which is a characteristic
of Alzheimer’s disease.”

Vaccine • 1993

Adjuvants— a balance between toxicity and adjuvanticity Author information
Gupta RK1, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta CK.
Massachusetts Public Health Biologic Laboratories Boston 02130 Abstract
Adjuvants have been used to augment the immune response in experimental
immunology as well as in practical vaccination for more than 60 years. The
chemical nature of adjuvants, their mode of action and the profile of their
side effects are highly variable. Some of the side effects can be ascribed to
an unintentional stimulation of different mechanisms of the immune system
whereas others may reflect general adverse pharmacological reactions. The most
common adjuvants for human use today are still aluminium hydroxide, aluminium
phosphate and calcium phosphate although oil emulsions, products from bacteria
and their synthetic derivatives as well as liposomes have also been tested or
used in humans. In recent years monophosphoryl lipid A, ISCOMs with Quil-A and
Syntex adjuvant formulation (SAF) containing the threonyl derivative of muramyl
dipeptide have been under consideration for use as adjuvants in humans. At
present the choice of adjuvants for human vaccination reflects a compromise
between a requirement for adjuvanticity and an acceptable low level of side
effects. http://www.ncbi.nlm.nih.gov/pubmed/8447157

“At present the choice of adjuvants for human vaccination reflects a compromise
between a requirement for adjuvanticity and an acceptable low level of side
effects.”

[today those “Side Effects” are at epidemic proportions]

“Vaccines adsorbed onto aluminium salts
are a more frequent cause of local post-vaccinal reactions than plain
vaccines.” Roczniki Panstwowego Zakladu Higieny • 1993

Aluminum as an adjuvant in vaccines and post-vaccine reactions Author
information Fiejka M1, Aleksandrowicz J. Zakladu Badania Surowic Warszawie
Abstract Aluminium compounds have been widely used as adjuvants in prophylactic
and therapeutic vaccines. Adjuvants are able to stimulate the immune system in
a nonspecific manner, i.e. high antibody level can be obtained with minimal
dose of the antigen and with reduced number of inoculations. Adjuvants use has
been mostly empirically determined by such factors as efficacy and safety. The
mechanism of action of the aluminium adjuvants is not completely understood and
is very complex. The basic factors of the mode of action: 1) the complex of
antigen and aluminium gel is more immunogenic in structure than free antigen,
2) effect “depot”--The antigen stimulus last longer, 3) the production of local
granulomas. Vaccines adsorbed onto aluminium salts are a more frequent cause of
local post-vaccinal reactions than plain vaccines. 5-10% those vaccinated can
develop a nodule lasting several weeks at the injection site. In some rare
cases the nodules may become inflammatory and even turn into an aseptic
abscess. The nodules persisting more than 6 weeks may indicate development of
aluminium hypersensitivity. Finally aluminium adjuvant immunogens induce the
production of IgE antibodies. http://www.ncbi.nlm.nih.gov/pubmed/?term=8235346

Annali dell’istituto Superiore di Sanita • 1993

Behavioural effects of gestational exposure to aluminium Author information
Rankin J1, Sedowofia K, Clayton R, Manning A. Institute of Cell, Animal and
Population Biology Edinburgh, UK Abstract The involvement of aluminium in the
aetiology of a number of human pathological diseases has altered its status
from being a nontoxic, nonabsorbable, harmless element. This maybe of
particular concern to the developing foetus which is more susceptible to agents
and at lower levels than the adult. Little attention has been given to
aluminium’s potential reproductive toxicity until recently and further research
is required for a full evaluation of its toxicity. Our preliminary results
demonstrate behavioural and neurochemical alterations in the offspring of mice
exposed to aluminium during gestation. Further, the effects of such exposure
are also present in the adult animal suggesting persistent changes in behaviour
following prenatal exposure. http://www.ncbi.nlm.nih.gov/pubmed/8129261

“Our preliminary results demonstrate behavioural and neurochemical alterations
in the offspring of mice exposed to aluminium during gestation. Further, the
effects of such exposure are also present in the adult animal suggesting
persistent changes in behaviour following prenatal exposure.”

Vaccine • 1993

Studies on the toxicities of aluminium hydroxide and calcium phosphate as
immunological adjuvants for vaccines Author information Goto N1, Kato H,
Maeyama J, Eto K, Yoshihara S. Department of Safety Research on Biologics
National Institute of Health, Tokyo, Japan Abstract Aluminium hydroxide (Al)
and calcium phosphate (Ca) have been used for many years as immunological
adjuvants for biologicals. We investigated the toxic effects of both adjuvants
with different physical properties. Al-gel elicited vascular
permeability-increasing and toxic effects to macrophages (M phi), while its
haemolytic effect was weak. Ca-gel elicited a significantly stronger haemolytic
effect, but no other toxic effect. Incubation of M phi or polymorphonuclear
leucocytes with Al-suspension resulted in the largest release of lactate
dehydrogenase. Ca-suspension caused haemolysis of about 50% of that caused by
Ca-gel. http://www.ncbi.nlm.nih.gov/pubmed/8212836

“Aluminum-gel elicited vascular permeability-increasing and toxic effects to
macrophages ...”

Brazilian Journal Of Medical And Biological Research • January 1994

Effects of aluminum on the mechanical and electrical activity of the
Langendorff-perfused rat heart Author information Gomes MG1, Moreira CA, Mill
JG, Massaroni L, Oliveira EM, Stefanon I, Vassallo DV. Departamento de Ciências
Fisiológicas Universidade Federal do Espírito Santo Vitória, Brasil Abstract
The effect of aluminum (Al3+) chloride (1, 5, 10, 50 and 100 microM) on
myocardial electromechanical activity was studied in 10 Langendorff-perfused
hearts from adult female Wistar rats. Al3+ decreased the development of
isovolumic systolic pressure from 34.3 +/- 2.95 mmHg under control conditions
to 11.8 +/- 1.53 mmHg at 100 microM AlCl3 (P < 0.01) (diastolic pressure = 0
mmHg). The atrial and ventricular rates also decreased, but only with AlCl3
concentrations greater than 1 microM (from 180 +/- 5 to 94 +/- 11 bpm for
atrial rate and from 180 +/- 5 to 78 +/- 7 bpm for ventricular rate). Reduction
of coronary flow was also observed, reaching 60% at 100 microM Al3+. A delay in
atrioventricular conduction occurred at 10 microM Al3+, increasing
progressively up to 100 microM (62.3 +/- 4 ms in the Al(3+)-free solution to
143 +/- 34 ms in the presence of 100 microM Al3+, P < 0.01, ANOVA). QRS
duration did not change as a function of increasing Al3+ concentrations (37.1
+/- 1.7 ms in the Al(3+)-free solution vs 32.1 +/- 1.6 ms in the presence of
100 microM Al3+). No qualitative changes in ECG were observed. These data show
that the toxic effects of Al3+ on the myocardium are reflected in reduced
systolic pressure development and coronary flow and increased PR interval.
These effects are discussed in terms of the inhibition of nucleotide hydrolysis
by Al3+. http://www.ncbi.nlm.nih.gov/pubmed/8173535

“These data show that the toxic effects of aluminum chloride on the myocardium
are reflected in reduced systolic pressure development and coronary flow and
increased PR interval.”

Food Additives And Contaminants • January 1995

Estimates of dietary exposure to aluminium Author information Pennington JA1,
Schoen SA. Food and Drug Administration Center for Food Safety and Applied
Nutrition Washington, DC 20204, USA Abstract Daily intakes of aluminium were
estimated for 14 age-sex groups based on the Food and Drug Administration’s
(FDA) Total Diet Study dietary exposure model. The aluminium content of the
core foods of the FDA Total Diet Study were determined by analyses, recipe
calculation, or literature values and coupled with information on food
consumption from the 1987-88 US Department of Agriculture Nationwide Food
Consumption Survey. Estimates of aluminium intakes ranged from 0.7 mg/day for
6-11-month-old infants to 11.5 mg/day for 14-16-year-old males. Average intakes
for adult men and women were 8-9 and 7 mg/day, respectively. The major
contributors to daily intake of aluminium were foods with aluminium-containing
food additives, e.g. grain products and processed cheese.
http://www.ncbi.nlm.nih.gov/pubmed/7758626

“Estimates of aluminium intakes ranged from 0.7 mg/day for 6-11-month-old
infants to 11.5 mg/day for 14-16-year-old males. Average intakes for adult men
and women were 8-9 and 7 mg/day, respectively.”

“Although aluminum (Al) contributes to a variety of cognitive dysfunctions and mental diseases,
the underlying mechanisms of Al interactions with the nervous system are still
unknown.” Experimental Neurology • July 1995

Aluminum impairs hippocampal long-term potentiation in rats in vitro and in
vivo Author information Platt B1, Carpenter DO, Büsselberg D, Reymann KG,
Riedel G. New York State Department of Health Wadsworth Center for Laboratories
and Research, Albany 12201, USA Abstract Although aluminum (Al) contributes to
a variety of cognitive dysfunctions and mental diseases, the underlying
mechanisms of Al interactions with the nervous system are still unknown. We
have studied the action of Al on synaptic transmission and long-term
potentiation (LTP) by performing electrophysiological recordings both in vivo,
using freely moving animals, and in vitro, using hippocampal slices. In vivo
recordings of the population spikes (PSs) of dentate gyrus granule cells in
response to medial perforant path stimulation were performed on both acutely
and chronically (Al each day for 5 days) intraventricularly injected animals.
Acute Al-infusion (calculated brain concentrations of 0.27, 0.68, and 2.7
micrograms/ml) had no influence on baseline values. Al at 0.27 microgram/ml did
not alter the induction and maintenance of LTP, but 0.68 and especially 2.7
micrograms/ml Al lead to a reduction in LTP, and the potentiation declined to
baseline within 2 h. In chronic animals their neuronal responsiveness was
reduced and in 30% of the rats the PS was completely lost. High-frequency
tetanization failed to induce LTP. In slices, field potentials were evoked
stimulating Schaffer collaterals and recording pyramidal cells of the CA1
region. Bath application of 0.68 microgram/ml Al increased the baseline
amplitude of the PS slightly, whereas 2.7 micrograms/ml decreased the amplitude
and concentrations > 5.4 micrograms/ml blocked the PS completely. Induction of
LTP in the presence of 0.68 microgram/ml Al led to a smaller increase of the PS
amplitude compared to controls, but the duration of LTP was not affected. In
the presence of 2.7 micrograms/ml Al LTP was further reduced and declined to
baseline levels within 60 min. Given that LTP is a form of synaptic plasticity
underlying some forms of learning, our data suggest that both preparations are
suitable models for investigating actions of Al-induced neurotoxicity.
http://www.ncbi.nlm.nih.gov/pubmed/?term=7672040

Neurotoxicology And Teratology • July 1995

Reproductive and developmental toxicity of aluminum: a review Author
information Domingo JL1. Laboratory of Toxicology and Biochemistry School of
Medicine, Rovira i Virgili University, Reus, Spain Abstract It is well known
that aluminum is a developmental toxicant when administered parenterally.
However, until recently, there was little concern about embryo/fetal
consequences of aluminum ingestion because bioavailability was considered low.
The importance of the route of exposure and the chemical form of the aluminum
compound on the developmental toxicity of this element are now well
established. Although no evidence of maternal and embryo/fetal toxicity was
observed when high doses of aluminum hydroxide were given orally to pregnant
rats and mice during organogenesis, signs of maternal and developmental
toxicity were found in mice when aluminum hydroxide was given concurrently with
citric or lactic acids. On the other hand, studies in rabbits have shown that
aluminum-induced behavioral toxicity is greater in adult and aged animals than
in young adults. However, maternal dietary exposure to excess A1 during
gestation and lactation which did not produce maternal toxicity would be
capable of causing permanent neurobehavioral deficits in weanling mice and
rats. Adverse effects of parenteral aluminum administration on the mouse male
reproductive system have also been reported. The embryo/fetal toxicity of
aluminum administration, the potential reproductive toxicology of aluminum
exposure, and the neurodevelopmental effects of aluminum are here reviewed.
http://www.ncbi.nlm.nih.gov/pubmed/?term=7565498

“The embryo/fetal toxicity of aluminum administration, the potential
reproductive toxicology of aluminum exposure, and the neurodevelopmental
effects of aluminum are here reviewed.”

Vaccine • October 1995

Adjuvants for human vaccines— current status, problems and future prospects
Author information Gupta RK1, Siber GR. Massachusetts Public Health Biologic
Laboratories State Laboratory Institute, Boston 02130, USA Abstract Adjuvants
help antigen to elicit an early, high and long-lasting immune response with
less antigen, thus saving on vaccine production costs. In recent years,
adjuvants received much attention because of the development of purified,
subunit and synthetic vaccines which are poor immunogens and require adjuvants
to evoke the immune response. With the use of adjuvants immune response can be
selectively modulated to major histocompatibility complex (MHC) class I or MHC
class II and Th1 or Th2 type, which is very important for protection against
diseases caused by intracellular pathogens such as viruses, parasites and
bacteria (Mycobacterium). A number of problems are encountered in the
development and use of adjuvants for human vaccines. The biggest issue with the
use of adjuvants for human vaccines, particularly routine childhood vaccines,
is the toxicity and adverse side-effects of most of the adjuvant formulations.
At present the choice of adjuvants for human vaccination reflects a compromise
between a requirement for adjuvanticity and an acceptable low level of
side-effects. Other problems with the development of adjuvants include
restricted adjuvanticity of certain formulations to a few antigens, use of
aluminum adjuvants as reference adjuvant preparations under suboptimal
conditions, non-availability of reliable animal models, use of non-standard
assays and biological differences between animal models and humans leading to
the failure of promising formulations to show adjuvanticity in clinical trials.
The most common adjuvants for human use today are still aluminum hydroxide and
aluminum phosphate, although calcium phosphate and oil emulsions also have some
use in human vaccinations. During the last 15 years much progress has been made
on development, isolation and chemical synthesis of alternative adjuvants such
as derivatives of muramyl dipeptide, monophosphoryl lipid A, liposomes, QS21,
MF-59 and immunostimulating complexes (ISCOMS). Other areas in adjuvant
research which have received much attention are the controlled release of
vaccine antigens using biodegradable polymer microspheres and reciprocal
enhanced immunogenicity of protein-polysaccharide conjugates. Biodegradable
polymer microspheres are being evaluated for targeting antigens on mucosal
surfaces and for controlled release of vaccines with an aim to reduce the
number of doses required for primary immunization. Reciprocal enhanced
immunogenicity of protein-polysaccharide conjugates will be useful for the
development of combination vaccines. http://www.ncbi.nlm.nih.gov/pubmed/8585280

“Adjuvants help antigen to elicit an early, high and long-lasting immune
response with less antigen, thus saving on vaccine production costs.

Journal Of Inorganic Biochemistry • November 1995

Spectroscopic study of the interaction of aluminum ions with human transferrin
Author information Tang S1, MacColl R, Parsons PJ. Department of Environmental
Health and Toxicology School of Public Health, State University of New York at
Albany, USA Abstract Transferrin is the plasma protein responsible for
transporting Fe3+ from the absorption to the utilization site. Interactions of
apo- and holo-transferrin with Al3+ were studied by circular dichroism (CD),
UV-visible, and fluorescence spectrometry. Binding of Al3+ to both metal-ion
binding sites of apo-transferrin was confirmed by fluorescence studies. No
interaction of Al3+ with holo-transferrin was observed, indicating that Al3+
cannot displace Fe3+ under the experimental conditions employed. An increase in
tryptophan fluorescence (lambda max at 330 nm) by excitation at either 280 or
295 nm was observed after Al3+ interaction with apo-transferrin. There was no
shift in wavelength of the fluorescence band of apo-transferrin after
interaction with Al3+, but the intensity did increase. Since excitation at 295
nm is specific for tryptophan residues, tryptophan but not tyrosine must be
responsible for the change in fluorescence intensity. Decreased fluorescence is
the result of Fe3+ binding to apo-transferrin. The CD spectrum of
apo-transferrin was slightly affected in the far UV by Al3+ binding, but a
salient change was noted in the near UV at approximately 288 nm where tyrosine
and tryptophan absorb. It is concluded that a small conformational change in
the protein was induced by Al3+ binding to apo-transferrin.
http://www.ncbi.nlm.nih.gov/pubmed/8586971

“It is concluded that a small conformational change in the protein was induced
by Al3+ binding to apo-transferrin.”

Biochimica et Biophysica Acta • January 1996

Altered calcium homeostasis: a possible mechanisms of aluminium-induced
neurotoxicity Author information Julka D1, Gill KD. Department of Biochemistry
Postgraduate Institute of Medical Education and Research Chandigarh, India
Abstract The effect of aluminium, A1(3+) (10 mg/kg body weight/day i.p.) for a
period of 4 weeks was examined on the calcium homeostatic mechanisms in rat
central nervous system. Incubation of synaptosomes prepared from rat brain,
with aluminium in vitro had a detrimental effect on the activity of Ca2+ ATPase
which could be reversed completely on exogenous addition of desferrioxamine (10
microM) and partially with glutathione (1 mM). In vivo administration also
revealed a similar observation. A marked increase in the levels of
intracellular calcium was observed after aluminium treatment. Concomitant to
the increased levels of intracellular calcium, there was an increase in the
levels of lipid peroxidation and a consequent decrease in fluidity of synaptic
plasma membranes. In addition, aluminium also had an inhibitory effect on the
depolarization-induced calcium uptake which was found to be of a competitive
type. The biological activity of calcium regulatory proteins calmodulin and
protein kinase C was considerably affected by aluminium. The results suggest
that aluminium exerts its toxic effects by modification of the intracellular
calcium messenger system with detrimental consequences on neuronal functioning.
http://www.ncbi.nlm.nih.gov/pubmed/8611646

“The results suggest that aluminium exerts its toxic effects by modification of
the intracellular calcium messenger system with detrimental consequences on
neuronal functioning.”

“Macrophages at the base of human gut associated lymphoid tissue (GALT),
become loaded early in life with dark granular pigment that is rich in
aluminium ...” Gut • March 1996

Characterisation of inorganic microparticles in pigment cells of human gut
associated lymphoid tissue Author information Powell JJ1, Ainley CC, Harvey RS,
Mason IM, Kendall MD, Sankey EA, Dhillon AP, Thompson RP. Gastrointestinal
Laboratory, Rayne Institute St Thomas’ Hospital, London Abstract Macrophages at
the base of human gut associated lymphoid tissue (GALT), become loaded early in
life with dark granular pigment that is rich in aluminium, silicon, and
titanium. The molecular characteristics, intracellular distribution, and source
of this pigment is described. Laser scanning and electron microscopy showed
that pigmented macrophages were often closely related to collagen fibres and
plasma cells in GALT of both small and large intestine and contained numerous
phagolysosomes, previously described as granules, that are rich in electron
dense submicron sized particles. Morphological assessment, x ray microanalysis,
and image electron energy loss spectroscopy showed three distinct types of
microparticle: type I - spheres of titanium dioxide, 100-200 nm diameter,
characterised as the synthetic food-additive polymorph anatase; type II -
aluminosilicates, < 100-400 nm in length, generally of flaky appearance, often
with adsorbed surface iron, and mostly characteristic of the natural clay
mineral kaolinite; and type III - mixed environmental silicates without
aluminium, 100-700 nm in length and of variable morphology. Thus, this cellular
pigment that is partly derived from food additives and partly from the
environment is composed of inert inorganic microparticles and loaded into
phagolysosomes of macrophages within the GALT of all human subjects. These
observations suggest that the pathogenicity of this pigment should be further
investigated since, in susceptible individuals, the same intracellular
distribution of these three types of submicron particle causes chronic latent
granulomatous inflammation. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1383068/

“... the mechanisms of Aluminum neurotoxicity are reviewed ...”
Journal Of Toxicology And Environmental Health • August 1996

Can the mechanisms of aluminum neurotoxicity be integrated into a unified
scheme? Author information Strong MJ1, Garruto RM, Joshi JG, Mundy WR, Shafer
TJ. Department of Clinical Neurological Sciences University of Western Ontario,
London, Canada mstrong@julian.uwo.ca Abstract Regardless of the host, the route
of administration, or the speciation, aluminum is a potent neurotoxicant. In
the young adult or developmentally mature host, the neuronal response to Al
exposure can be dichotomized on morphological grounds. In one, intraneuronal
neurofilamentous aggregates are formed, whereas in the other, significant
neurochemical and neurophysiological perturbations are induced without
neurofilamentous aggregate formation. Evidence is presented that the induction
of neurofilamentous aggregates is a consequence of alterations in the
posttranslational processing of neurofilament (NF), particularly with regard to
phosphorylation state. Although Al has been reported to impact on gene
expression, this does not appear to be critical to the induction of
cytoskeletal pathology. In hosts responding to Al exposure without the
induction of cytoskeletal pathology, impairments in glucose utilization,
agonist-stimulated inositol phosphate accumulation, free radical-mediated
cytotoxicity, lipid peroxidation, reduced cholinergic function, and altered
protein phosphorylation have been described. The extent to which these
neurochemical modifications correlate with the induction of a characteristic
neurobehavioral state is unknown. In addition to these paradigms, Al is toxic
in the immediate postnatal interval. Whether unique mechanisms of toxicity are
involved during development remains to be determined. In this article, the
mechanisms of Al neurotoxicity are reviewed and recommendations are put forth
with regard to future research. Primary among these is the determination of the
molecular site of Al toxicity, and whether this is based on Al substitution for
divalent metals in a number of biological processes. Encompassed within this is
the need to further understand the genesis of host- and developmental-specific
responses. http://www.ncbi.nlm.nih.gov/pubmed/?term=8772801

Journal Of Toxicology And Environmental Health • August 1996

Speciation of aluminum in biological systems Author information Harris WR1,
Berthon G, Day JP, Exley C, Flaten TP, Forbes WF, Kiss T, Orvig C, Zatta PF.
Department of Chemistry University of Missouri-St. Louis 63121 USA Abstract As
a “hard”, trivalent metal ion, Al3- binds strongly to oxygen-donor ligands such
as citrate and phosphate. The aqueous coordination chemistry of Al is
complicated by the tendency of many Al complexes to hydrolyze and form
polynuclear species, many of which are sparingly soluble. Thus there is
considerable variation among the Al stability constants reported for several
important ligands. The complexity in the aqueous chemistry of Al has also
affected Al toxicity studies, which have often utilized poorly characterized Al
stock solutions. Serum fractionation studies show that most Al is protein
bound, primarily to the serum iron transport protein transferrin. Albumin
appears to play little, if any, role in serum transport. There is little
agreement as to the speciation of the remaining low-molecular mass fraction of
serum Al. The lability of the Al3+ion precludes the simple separation and
identification of individual Al complexes. Computational methods are available
for detailed computer calculations of the Al speciation in serum, but efforts
in this area have been severely hampered by the uncertainties regarding the
stability constants of the low molecular mass Al complexes with citrate,
phosphate, and hydroxide. Specific recommendations for further research on Al
speciation include: (1) Determine more accurate Al stability constants with
critical low molecular mass ligands such as citrate and phosphate; (2)
supplement traditional potentiometric studies on Al complexes with data from
other techniques such as 27Al-NMR and accelerator mass spectrometry with 26Al;
(3) develop new methods for generating reliable linear free energy
relationships for Al complexation; (4) determine equilibrium and rate constants
for Al binding to transferrin at 37 degrees C; (5) confirm the possible
formation of low-molecular-mass Alprotein complexes following desferrioxamine
therapy; (6) continue research efforts to incorporate kinetic considerations
into the present equilibrium speciation calculations; (7) improve methods for
preparing chemically well-defined stock solutions for toxicological studies;
(8) incorporate more detailed speciation data into studies on Al toxicity and
pharmacokinetics; and (9) incorporate more detailed speciation data into future
epidemiological studies on the relationship between Al toxicity and various
water quality parameters. http://www.ncbi.nlm.nih.gov/pubmed/?term=8772798

[this report explains why determining the fate of aluminum in the human body is
so difficult]

Journal Of Toxicology And Environmental Health • August 1996

What we know and what we need to know about developmental aluminum toxicity
Author information Golub MS1, Domingo JL. Department of Internal Medicine
University of California, Davis 95616, USA Abstract Information concerning
developmental aluminum (Al) toxicity is available from clinical studies and
from animal testing. An Al toxicity syndrome including encephalopathy,
osteomalacia, and anemia has been reported in uremic children receiving
dialysis. In addition, some components of the syndrome, particularly
osteomalacia, have been reported in non-dialyzed uremic children receiving
Al-based phosphate binders, nonuremic infants receiving parenteral nutrition
with Al-containing fluids, and nonuremic infants given high doses of Al
antacids. The number of children in clinical populations that are at risk of Al
toxicity is not known and needs to be determined. Work in animal models (rats,
mice, and rabbits) demonstrates that Al is distributed transplacentally and is
present in milk. Oral Al administration during pregnancy produces a syndrome
including growth retardation, delayed ossification, and malformations at doses
that also lead to reduced maternal weight gain. The severity of the effects is
highly dependent on the form of Al administered. In the postnatal period,
reduced pup weight gain and effects on neuromotor development have been
described as a result of developmental exposures. The significance of these
findings for human health requires better understanding of the amount and
bioavailability of Al in food, drinking water, and medications and from sources
unique to infants and children such as breast milk, soil ingestion, and
medications used specifically by pregnant women and children. We also need a
better understanding of the unique biological actions of Al that may occur
during developmental periods, and unique aspects of the developing organism
that make it more or less susceptible to Al toxicity.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8772800

“The number of children in clinical populations that are at risk of Al toxicity
is not known and needs to be determined. Work in animal models demonstrates
that Aluminum is distributed transplacentally and is present in milk.”

Journal Of Toxicology And Environmental Health • August 1996

Aluminum toxicokinetics Author information Exley C1, Burgess E, Day JP, Jeffery
EH, Melethil S, Yokel RA. Department of Chemistry, Keele University,
Staffordshire United Kingdom cha38@keele.ac.uk Abstract In this study of the
toxicokinetics of aluminum we have examined some of the fundamental issues that
currently define our understanding of the toxicology of aluminum in humans.
There is a vast literature on this subject, and it was not our aim to review
this literature but to use it to develop our understanding of the
toxicokinetics of aluminum and to identify critical and unresolved issues
related to its toxicity. In undertaking this task we have chosen to define the
term toxicokinetics to encompass those factors that influence both the lability
of aluminum in a body and the sites at which aluminum is known to accumulate,
with or without consequent biological effect. We have approached our objective
from the classical pharmacological approach of ADME: the absorption,
distribution, metabolism, and excretion of aluminum. This approach was
successful in identifying several key deficits in our understanding of aluminum
toxicokinetics. For example, we need to determine the mechanisms by which
aluminum crosses epithelia, such as those of the gastrointestinal tract and the
central nervous system, and how these mechanisms influence both the subsequent
transport and fate of the absorbed aluminum and the concomitant nature and
severity of the biological response to the accumulation of aluminum. Our hope
in highlighting these unresolved issues (summarized in Table 1) is that they
will be addressed in future research.
http://www.ncbi.nlm.nih.gov/pubmed/8772799

“... we need to determine the mechanisms by which aluminum crosses epithelia,
such as those of the gastrointestinal tract and the central nervous system, and
how these mechanisms influence both the subsequent transport and fate of the
absorbed aluminum and the concomitant nature and severity of the biological
response to the accumulation of aluminum.”

“Subtle neurocognitive and psychomotor effects and electroencephalograph (EEG) abnormalities
have been reported at plasma Aluminum levels as low as 50 micrograms/L. Infants
could be particularly susceptible to Al accumulation and toxicity ...” Journal
Of Toxicology And Environmental Health • August 1996

Status and future concerns of clinical and environmental aluminum toxicology
Author information Flaten TP1, Alfrey AC, Birchall JD, Savory J, Yokel RA.
Department of Chemistry, Norwegian University of Science and Technology
Trondheim, Norway trond.flaten@avh.unit.no Abstract A wide range of toxic
effects of aluminum (Al) have been demonstrated in plants and aquatic animals
in nature, in experimental animals by several routes of exposure, and under
different clinical conditions in humans. Aluminum toxicity is a major problem
in agriculture, affecting perhaps as much as 40% of arable soils in the world.
In fresh waters acidified by acid rain, Al toxicity has led to fish extinction.
Aluminum is a very potent neurotoxicant. In humans with chronic renal failure
on dialysis, Al causes encephalopathy, osteomalacia, and anemia. There are also
reports of such effects in certain patient groups without renal failure. Subtle
neurocognitive and psychomotor effects and electroencephalograph (EEG)
abnormalities have been reported at plasma Al levels as low as 50 micrograms/L.
Infants could be particularly susceptible to Al accumulation and toxicity,
reduced renal function being one contributory cause. Recent reports clearly
show that Al accumulation occurs in the tissues of workers with long-term
occupational exposure to Al dusts or fumes, and also indicate that such
exposure may cause subtle neurological effects. Increased efforts should be
directed toward defining the full range of potentially harmful effects in
humans. To this end, multidisciplinary collaborative research efforts are
encouraged, involving scientists from many different specialties. Emphasis
should be placed on increasing our understanding of the chemistry of Al in
biological systems, and on determining the cellular and molecular mechanisms of
Al toxicity. http://www.ncbi.nlm.nih.gov/pubmed/?term=8772797

New England Journal Of Medicine • May 1997

Aluminum Neurotoxicity in Preterm Infants Receiving Intravenous-Feeding
Solutions Nicholas J. Bishop, M.D., Ruth Morley, M.B., B.Chir., J. Philip Day,
Ph.D., and Alan Lucas, M.D. BACKGROUND Aluminum, a contaminant of commercial
intravenous-feeding solutions, is potentially neurotoxic. We investigated the
effect of perinatal exposure to intravenous aluminum on the neurologic
development of infants born prematurely. METHODS We randomly assigned 227
premature infants with gestational ages of less than 34 weeks and birth weights
of less than 1850 g who required intravenous feeding before they could begin
enteral feeding to receive either standard or specially constituted,
aluminum-depleted intravenous-feeding solutions. The neurologic development of
the 182 surviving infants who could be tested was assessed by using the Bayley
Scales of Infant Development at 18 months of age. RESULTS The 90 infants who
received the standard feeding solutions had a mean (±SD) Bayley Mental
Development Index of 95±22, as compared with 98±20 for the 92 infants who
received the aluminum-depleted solutions (P = 0.39). In a planned subgroup
analysis of infants in whom the duration of intravenous feeding exceeded the
median and who did not have neuromotor impairment, the mean values for the
Bayley Mental Development Index for the 39 infants who received the standard
solutions and the 41 infants who received the aluminum-depleted solutions were
92±20 and 102±17, respectively (P = 0.02). The former were significantly more
likely (39 percent, vs. 17 percent of the latter group; P = 0.03) to have a
Mental Development Index of less than 85, increasing their risk of subsequent
educational problems. For all 157 infants without neuromotor impairment,
increasing aluminum exposure was associated with a reduction in the Mental
Development Index (P = 0.03), with an adjusted loss of one point per day of
intravenous feeding for infants receiving the standard solutions. CONCLUSIONS
In preterm infants, prolonged intravenous feeding with solutions containing
aluminum is associated with impaired neurologic development.
http://www.nejm.org/doi/full/10.1056/NEJM199705293362203

“In preterm infants, prolonged intravenous feeding with solutions containing
aluminum is associated with impaired neurologic development.”

Molecular And Chemical Neuropathology • September 1997

Aluminum potentiates glutamate-induced calcium accumulation and iron-induced
oxygen free radical formation in primary neuronal cultures Author information
Mundy WR1, Freudenrich TM, Kodavanti PR. Neurotoxicology Division US
Environmental Protection Agency Research Triangle Park, NC 27711, USA Abstract
Aluminum is a neurotoxic metal that may be involved in the progression of
neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral
sclerosis (ALS). Although the mechanism of action is not known, aluminum has
been shown to alter Ca2+ flux and homeostasis, and facilitate peroxidation of
membrane lipids. Since abnormal increases of intracellular Ca2+ and oxygen free
radicals have both been implicated in pathways leading to neurodegeneration, we
examined the effect of aluminum on these parameters in vitro using primary
cultures of cerebellar granule cells. Exposure to glutamate (1-300 microM)
caused a concentration-dependent uptake of 45Ca in granule cells to a maximum
of 280% of basal. Pretreatment with AlCl3 (1-1000 microM) had no effect on 45Ca
accumulation, but increased the uptake induced by glutamate. Similarly, AlCl3
had no effect on intracellular free Ca2+ levels measured using fluorescent
probe fura-2, but potentiated the increase induced by glutamate. The production
of reactive oxygen species (ROS) was examined using the fluorescent probe
dichlorofluorescin. By itself, AlCl3 had little effect on ROS production.
However, AlCl3 pretreatment potentiated the ROS production induced by 50 microM
Fe2+. These results suggest that aluminum may facilitate increases in
intracellular Ca2+ and ROS, and potentially contribute to neurotoxicity induced
by other neurotoxicants. http://www.ncbi.nlm.nih.gov/pubmed/9437657

“Aluminum is a neurotoxic metal that may be involved in the progression of
neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral
sclerosis ... aluminum may facilitate increases in intracellular Ca2+ and ROS,
and potentially contribute to neurotoxicity induced by other neurotoxicants.”

“Although the mechanisms of aluminum absorption have not been elucidated,
both passive and active transcellular processes and paracellular transport are
believed to occur.” Critical Reviews In Clinical Laboratory Science • 1997

Aluminum exposure and metabolism Author information Greger JL1, Sutherland JE.
Department of Nutritional Sciences University of Wisconsin, Madison 53706, USA
Abstract Aluminum (Al) is a nonessential, toxic metal to which humans are
frequently exposed. Oral exposure to aluminum occurs through ingestion of
aluminum-containing pharmaceuticals and to a lesser extent foods and water.
Parenteral exposure to aluminum can occur via contaminated total parenteral
nutrition (TPN), intravenous (i.v.) solutions, or contaminated dialysates.
Inhalation exposure may be important in some occupational settings. The gut is
the most effective organ in preventing tissue aluminum accumulation after oral
exposure. Typically gastrointestinal absorption of aluminum from diets is < 1%.
Although the mechanisms of aluminum absorption have not been elucidated, both
passive and active transcellular processes and paracellular transport are
believed to occur. Aluminum and calcium may share some absorptive pathways.
Aluminum absorption is also affected by the speciation of aluminum and a
variety of other substances, including citrate, in the gut milieu. Not all
absorbed or parenterally delivered aluminum is excreted in urine. Low
glomerular filtration of aluminum reflects that most aluminum in plasma is
nonfiltrable because of complexation to proteins, predominantly transferrin.
The importance of biliary secretion of aluminum is debatable and the
mechanism(s) is poorly understood and appears to be saturable by fairly low
oral doses of aluminum. http://www.ncbi.nlm.nih.gov/pubmed/?term=9405895

“Metal ions are believed to participate in many neurodegenerative conditions.”
Metal-Based Drugs • 1997

Metal Ions in Neuroscience C. Ian Ragan Department of Biochemistry and
Molecular Biology Neuroscience Research Centre, Merck Sharp and Dohme Research
Laboratories Terlings Park, Harlow CM20 2QR, UK Abstract Metal ions are
believed to participate in many neurodegenerative conditions. In excitotoxic
cell death there is convincing evidence for the participation of Ca 2+ and Zn
2+ ions although the exact molecular mechanisms by which these metals exert
their effects are unclear. Only in one instance has the metal binding site of
metalloenzymes been exploited for therapeutic purposes and this is the use of
Li+ in the treatment of bipolar affective disorder. Again the exact molecular
target is not clear but is likely to involve a Mg2+-dependent enzyme of an
intracellular signalling pathway. In Parkinson’s disease, the selective loss of
dopaminergic neurones in the substantia nigra may be caused by radical-mediated
damage and there is good evidence to suggest that Fe2+ or 3+ is important in
promoting formation of radical species. The evidence that free radicals are
important in mediating other neurodegenerative conditions is less strong but
still substantial enough to suggest that removal of reactive oxygen species or
preventing their formation may be a valid approach to therapy. Full Report
http://www.hindawi.com/archive/1997/532916/abs/

Toxicology And Industrial Health • January 1998

Neurobehavioral alteration in rodents following developmental exposure to
aluminum Author information Alleva E1, Rankin J, Santucci D. Behavioural
Pathophysiology Section Istituto Superiore di Sanità, Roma, Italy alleva@iss.it
Abstract Aluminum (Al) is one of the most abundant metals in the earth’s crust,
and humans can be exposed to it from several sources. It is present in food,
water, pharmaceutical compounds, and in the environment, e.g., as a result of
acid rain leaching it from the soil. Exposure to Al has recently been
implicated in a number of human pathologies, but it has not yet been definitely
proved that it plays a major causal role in any of them. In this paper we
review the effects of developmental exposure of laboratory animals to Al salts
as a model for human pathological conditions. The data presented show
behavioral and neurochemical changes in the offspring of AL-exposed mouse dams
during gestation, which include alterations in the pattern of ultrasonic
vocalizations and a marked reduction in central nervous system (CNS) choline
acetyltransferase activity. Prenatal Al also affects CNS cholinergic functions
under Nerve Growth Factor (NGF) control, as shown by increased central NGF
levels and impaired performances in a maze learning task in young-adult mice.
The need for more detailed studies to evaluate the risks for humans associated
with developmental exposure to Al, as well as the importance of using more than
one strain of laboratory animal in the experimental design, is emphasized.
http://www.ncbi.nlm.nih.gov/pubmed/9460176

“The data presented show behavioral and neurochemical changes in the offspring
of Aluminum-exposed mouse dams during gestation, which include alterations in
the pattern of ultrasonic vocalizations and a marked reduction in central
nervous system choline acetyltransferase activity. Prenatal Al also affects
central nervous system cholinergic functions under Nerve Growth Factor (NGF)
control, as shown by increased central NGF levels and impaired performances in
a maze learning task in young-adult mice.”

Journal Of Inorganic Biochemistry • July 1998

The precipitation of mucin by aluminium Author information Christopher Exley
Birchall Centre for Inorganic Chemistry and Materials Science Department of
Chemistry, Keele University, Staffordshire, UK cha38@keele.ac.uk Abstract The
interactions of Al with a mucin glycopeptide have been studied. A number of
specific reactions were identified the nature of which were dependent upon the
Al chemistry in the hydration environment. In particular, Al was observed to
precipitate mucin and it is suggested that this proceeded via the intercalation
of the hydroxide within the hydrated macroreticular network of the mucin
biopolymer. This precipitation of mucin was visible by eye and abolished the
viscosity of native mucin. Viscometry indicated that Al was bound by mucin at
low pH. At pH > 3 Al formed a low molecular weight complex with mucin which was
hydrolytically stable and was not precipitated at pH up to 8. In an additional
and competitive reaction Al was bound by mucin and the resultant mucin-Al
complex was suggested to be the precursor to selfassembled mucin-Al spheres
identified in solution, by photon correlation spectroscopy, and in precipitate
using selective histochemistry. The majority of these spherical structures were
of sub-micron diameter and, through their interaction with each other, were
probably responsible for the observed pH-dependent peaks of mucin solution
viscosity. The larger spheres, between 20 and 80 microns in diameter, were only
identified in isolated mucin/Al precipitates and, being comparatively rare,
were unlikely to have influenced solution viscosities. These large spheres were
observed to act as possible nucleation sites for the flocculation of mucin/Al
precipitate. Al at concentrations as low as 0.015 mM induced changes in the
rheological properties of mucin. Considering the ubiquitous nature of mucin and
the degree to which it is conserved within biota the interactions of Al with
mucin may have wide ranging implications for biological systems.
http://www.ncbi.nlm.nih.gov/pubmed/9720305

“Aluminum at concentrations as low as 0.015 mM induced changes in the
rheological properties of mucin. Considering the ubiquitous nature of mucin and
the degree to which it is conserved within biota the interactions of Aluminum
with mucin may have wide ranging implications for biological systems.”

Zhongguo Zhong Yao Za Zhi
Chinese Journal Of Chinese Materia Medica • December 1998

Influence of alum on intestinal flora in mice Author information Yan M1, Song
H, Zhang L, Wang Y, Wu Y, Zhou Z. Institute of Chinese Materia Medica China
Academy of Traditional Chinese Medicine Beijing 100700 Abstract OBJECTIVE To
observe the influence of alum on the intestinal microecological balance in
normal microorganisms. METHOD The mice were administered orally with alum of a
small dosage(0.25/ kg) and a large dosage(1 g/kg) for half a month, two months
and three months, and a micro flora analysis of the mice was carried out at
intervals of the above mentioned administrations. RESULT The intestinal flora
in the animals administered with alum was imbalanced. The counts of
bifidobacteria and lactobacilli closely related to human physiological
activities were decreased. The counts of pathogenic E. Coli significantly
increased; and the longer the animals were treated with alum, the stronger the
microecological balance was influenced. CONCLUSION Alum could induce imbalance
of the normal intestinal flora in mice.
http://www.ncbi.nlm.nih.gov/pubmed/12242827

“The counts of pathogenic E. Coli significantly increased; and the longer the
animals were treated with alum, the stronger the microecological balance was
influenced.”

“Aluminum toxicity is well documented and contamination of milk formulas
has been implicated as the source of accumulation in bone and brain tissues.”
Journal Of Pediatric Gastroenterology And Nutrition • March 1999

Aluminum contents of human milk, cow’s milk, and infant formulas Author
information Fernandez-Lorenzo JR1, Cocho JA, Rey-Goldar ML, Couce M, Fraga JM.
Service of Neonatology and Metabolic and Nutritional Laboratory Hospital Xeral
de Galicia, Santiago de Compostela, Spain Abstract BACKGROUND Aluminum toxicity
is well documented and contamination of milk formulas has been implicated as
the source of accumulation in bone and brain tissues. The purpose of the
current study was to evaluate the aluminum contents of human milk, cow’s milk,
and infant formulas. METHODS Aluminum contents were determined by atomic
absorption spectrometry in samples of human milk in the colostrum,
intermediate, and mature stages; infant formulas from eight manufacturers; and
various types and brands of commercially available cow’s milk. RESULTS Mean
aluminum concentration was lowest in human milk (23.4 +/- 9.6 microg/l), and
did not differ significantly between colostrum, intermediate-stage and
mature-stage milk. Mean aluminum concentration was 70 microg/l in cow’s milk,
and 226 microg/l in reconstituted infant formulas. Aluminum concentrations in
infant formulas differed markedly among manufacturers; concentration in milk
from one of the manufacturers was particularly high (mean, 551 microg/l; range,
302-1149 microg/l). These values are for milk reconstituted with aluminum-free
water under laboratory conditions; formulas prepared with tap water in the
University Hospital’s infant-feeding unit had even higher aluminum content.
Experiments showed that aluminum concentration in the high-aluminum milk could
be reduced by more than 70% at the manufacturing stage, by using low aluminum
components. CONCLUSIONS The results of the present study support the
recommendations for infant formula manufacturers to strive to reduce aluminum
concentration in their products.
http://www.ncbi.nlm.nih.gov/pubmed/?term=10067727

Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi
Chinese Journal Of Experimental And Clinical Virology • June 1999

Influence of aluminum adjuvant to experimental rabies vaccine Author
information Lin H1, Perrin P. National Institute for the Control of
Pharmaceutical and Biololgical Products Beijing 100050 Abstract OBJECTIVE To
study whether the rabies vaccine for human use should contain aluminum
adjuvant.

“Aluminum adjuvant to rabies vaccine

METHODS Testing vaccine antibodies and efficacy (ED50), comparing the effect
between aluminum adjuvant contained and non-aluminum adjuvant contained
vaccines in a new animal model which accords with the rabies field practice.

has no advantages, this paper suggests that

RESULTS At fourth and seventh day after immunization, the neutralizing antibody
titres of the rabies vaccine containing aluminium adjuvant were much lower than
that of the vaccine not containing aluminum adjuvant. In the NIH efficacy test
the ED50 of the vaccine containing aluminum adjuvant was 93-132 ng while the
ED50 of the vaccine not containing aluminum adjuvant was 221 ng, but the NIH
test does not accord with the rabies field practice. In that new animal model,
aluminum adjuvant to rabies vaccine had not any promoting effect for preventing
and treating rabies.

adjuvant had better compare in human bodies. If the

CONCLUSION Aluminum adjuvant to rabies vaccine has no advantages, this paper
suggests that the vaccines containing and not-containing aluminium adjuvant had
better compare in human bodies. If the results are the same as our experiments,
the aluminum adjuvant should be eliminated from rabies vaccine for human use.
http://www.ncbi.nlm.nih.gov/pubmed/?term=12569779

the vaccines containing and not-containing aluminium

results are the same as our experiments, the aluminum adjuvant should be
eliminated from rabies vaccine for human use.”

Journal Of Leukocyte Biology • February 2000

Particulate adjuvants can induce macrophage survival, DNA synthesis, and a
synergistic proliferative response to GM-CSF and CSF-1 Author information
Hamilton JA1, Byrne R, Whitty G. Inflammation Research Centre, University of
Melbourne Department of Medicine, The Royal Melbourne Hospital Parkville,
Victoria, Australia j.hamilton@medicine.unimelb.edu.au Abstract The mode of
action of immunological adjuvants is not yet completely understood. Many are
particulate. Certain antigen-presenting (dendritic) cell populations belong to
the monocyte/macrophage lineage and, like other members of the lineage, in some
tissues appear to be short-lived. We report that many poorly degradable,
particulate adjuvants, for example, aluminum hydroxide, oil-in-water emulsions,
calcium phosphate, and silica, enhance murine bone marrow-derived macrophage
survival; induction of DNA synthesis was even observed. No evidence could be
found for a requirement for endogenous granulocyte-macrophage
colony-stimulating factor (GM-CSF) or macrophage-CSF (M-CSF or CSF-1). Synergy
for the proliferative effects was noted in the presence of added GM-CSF or
CSF-1. It is suggested from these in vitro findings that one function of
certain particulate adjuvants may be to increase by enhanced survival or even
proliferation the number of cells available for subsequent antigen presentation
and cytokine production. http://www.ncbi.nlm.nih.gov/pubmed/?term=10670584

“The mode of action of immunological adjuvants is not yet completely
understood.”

Presse Medicale Paris • February 2000

Macrophagic myofasciitis Study and Research Group on Acquired and
Dysimmunity-related muscular diseases (GERMMAD) Author information Chérin P1,
Laforêt P, Ghérardi RK, Authier FJ, Maisonobe T, Coquet M, Mussini JM,
Pellissier JF, Eymard B, Herson S. Service de Médecine Interne Groupe
Hospitalier Pitié-Salpêtrière, Paris patrick.cherin@psl.ap-hop-paris.fr
Abstract Macrophagic Myofasciitis A most unusual inflammatory myopathy, first
described by Germmad had been reported with increasing frequency since 1993 in
the leading French myopathology centers. We present our experience with this
new disease: macrophagic myofasciitis. CLINICAL FEATURES By November 1999, 70
cases of macrophagic myofasciitis had been recorded since our first
description. The first 22 patients (sex ratio M/F = 1:3) referred with the
presumptive diagnosis of polymyositis (n = 11), polymyalgia rheumatica (n = 5),
mitochondrial cytopathy (n = 4), and congenital myopathy or muscle dystrophy (n
= 1 each). Symptoms included myalgia (91%), anthralgia (68%), marked asthenia
(55%), muscle weakness (45%), and fever (32%). LABORATORY FINDINGS Abnormal
laboratory findings included elevated CK levels (50%), markedly increased
erythrocyte sedimentation rate (37%), and myopathic EMG (35%). Muscle biopsy
showed a unique myopathological pattern characterized by: i) centripetal
infiltration of epimysium, perimysium and perifascicular endomysium by sheets
of large cells of the monocyte/macrophage lineage (CD68+, CD1a-, S100-, with a
PAS-positive content; ii) absence of necrosis, of both epithelioid and giant
cells, and of mitotic figures; iii) presence of occasional CD8+ T-cells; iv)
inconspicuous muscle fiber damage. The picture was easily distinguishable from
sarcoid myopathy and fasciitis-panniculitis syndromes. The infectious diseases
know to be associated with reactive histiocytes, including Whippleís disease,
Mycobacterium avium intracellulare infection and malakoplakia, could not be
documented. Patients improved under corticosteroid therapy and/or
immunomodulatory therapeutic. CONCLUSION A new inflammatory muscle disorder,
characterized by a distinctive pathological pattern of macrophagic myofasciitis
is emerging in France. http://www.ncbi.nlm.nih.gov/pubmed/10705901

“A most unusual inflammatory myopathy, first described by Germmad had been
reported with increasing frequency since 1993 in the leading French
myopathology centers. We present our experience with this new disease:
macrophagic myofasciitis.”

Pharmacology And Toxicology • March 2000

Effects of various aluminium compounds given orally to mice on Al tissue
distribution and tissue concentrations of essential elements Author information
Dsugaszek M1, Fiejka MA, Graczyk A, Aleksandrowicz JC, Slowikowska M. Institute
of Optoelectronics Military University of Technology Warsaw, Poland Abstract To
evaluate the risk of gastrointestinal long-term aluminium (Al) exposure,
aluminium distribution and the levels of the following essential elements: Ca,
Mg, Zn, Cu, and Fe in tissue were studied. Aluminium was administered in
drinking water as aluminium chloride, dihydroxyaluminium sodium carbonate or
aluminium hydroxide. Mice (strain Pzh:SFIS) were exposed to a total dose of 700
mg Al in long-term treatment (for each Al compound n = 15). Concentrations of
Al, Ca, Mg, Zn, Cu, and Fe in stomach, kidneys, bone and liver were analyzed by
atomic absorption spectrometry. After AlCl3 treatment, aluminium was found to
accumulate in all tested tissues. A significant decrease in Fe concentration in
liver and Zn in kidneys was observed in comparison to concentrations of these
elements in the control group. In the Al(OH)3-treated group, accumulation of
aluminium was observed in bone only and decline of Fe concentration in stomach
and Cu in liver and kidney. In the NaAl(OH)2CO3-treated group the increase in
Al concentration was significant in bone; there was no change in concentration
of essential elements in the examined tissues. The observed aluminium
accumulation was not accompanied by changes in Ca and Mg concentration except
for bone. This study showed that oral administration as a route of Al exposure
can result in diverging accumulation of aluminium in tissues, the concentration
depending on the chemical form. Full Report
http://onlinelibrary.wiley.com/doi/10.1034/j.1600-0773.2000.pto860308.x/epdf

“This study showed that oral administration as a route of Aluminum exposure can
result in diverging accumulation of aluminium in tissues ...”

“Complaints about ... a mysterious muscle ailment
have prompted researchers to take a fresh look at the use of aluminum adjuvants
... This month, as some 70 scientists gathered here for 2 days of often
vigorous discussion of the findings about the muscle ailment, a larger question
hung over the gathering: Will aluminum be the next battleground in the vaccine
wars?” Science • May 2000

Public health: Aluminum is put on trial as a vaccine booster Malakoff D. SAN
JUAN, PUERTO RICO—Complaints about vaccine safety and debate over a mysterious
muscle ailment have prompted researchers to take a fresh look at the use of
aluminum adjuvants, which are used to cause the immune system to react earlier,
more potently, and more persistently to the antigen contained in the vaccine.
This month, as some 70 scientists gathered here for 2 days of often vigorous
discussion of the findings about the muscle ailment, a larger question hung
over the gathering: Will aluminum be the next battleground in the vaccine wars?
http://www.sciencemag.org/content/288/5470/1323.summary?sid=82b7933f-c912-48c2-b2cf-40874fa78e61

Allergy • September 2000

Aluminium-induced granulomas after inaccurate intradermal hyposensitization
injections of aluminium-adsorbed depot preparations Author information
Vogelbruch M1, Nuss B, Körner M, Kapp A, Kiehl P, Bohm W. Department of
Dermatology and Allergology Hannover Medical University, Germany Abstract
BACKGROUND The development of persistent subcutaneous nodules at the injection
sites of aluminium-adsorbed hyposensitization solutions is rare. These nodules
have been interpreted as a delayed, granulomatous hypersensitivity reaction to
aluminium. We report for the first time a case of persistent intradermal
granulomas that developed at the sites of inaccurate intradermal, instead of
subcutaneous, hyposensitization injections. METHODS An intradermal nodule was
excised and processed for histopathology, scanning electron microscopy, and
X-ray microanalysis. Intradermal and patch tests with aluminium hydroxide were
performed. RESULTS Histologically, the nodule presented a pattern of
granulomatous inflammatory reaction surrounding foci of necrotic tissue.
Scanning electron microscopy and X-ray microanalysis revealed deposits of
aluminium within the granulomas. Patch tests with aluminium hydroxide were
negative, and intradermal tests caused persistent intradermal granulomas.
Subsequent hyposensitization therapy in our department with the usual
subcutaneous injections of aluminium-adsorbed allergen extracts was well
tolerated by the patient. CONCLUSIONS Local toxic effects of aluminium may be
crucial in the development of persistent intradermal injection-site granulomas.
Such intradermal nodules may develop even if the subcutaneous route is well
tolerated. We conclude that inaccurate intradermal injections of
aluminium-containing solutions have to be strictly avoided. Full Report
http://onlinelibrary.wiley.com/doi/10.1034/j.1398-9995.2000.00501.x/full

“We report for the first time a case of persistent intradermal granulomas that
developed at the sites of inaccurate intradermal, instead of subcutaneous,
hyposensitization injections.”

Review of Toxicological Literature Abridged Final Report • October 2000

Aluminum Compounds

Subcutaneous (s.c.) injections of aluminum produced a significant decrease in
iron levels in plasma and the striatum. Significant aluminum accumulation was
induced in the striatum, hippocampus, and cortex, and in the hippocampus, TBARS
production was increased. Reproductive and Teratological Effects

Prepared for Scott Masten, Ph.D., National Institute of Environmental Health
Sciences P.O. Box 12233 Research Triangle Park, North Carolina 27709 Contract
No. N01-ES-65402 Submitted by Bonnie L. Carson, M.S. Integrated Laboratory
Systems, P.O. Box 13501, Research Triangle Park, North Carolina 27709 EXECUTIVE
SUMMARY Human Toxicity The effects of aluminum on humans have been extensively
reviewed. Overall, there is little indication that aluminum is acutely toxic
for the general population; few cases of acute aluminum toxicity during alum
therapy (i.e., alum bladder irrigation) have been reported. Prolonged exposure
to aluminum, however, can cause systemic toxicity, mainly affecting the
gastrointestinal tract and causing neurological and skeletal effects. Aluminum
is a potent neurotoxic agent in humans. The association between aluminum and
characteristics of Alzheimer’s disease have prompted numerous studies of all
sources of intake of aluminum. Epidemiological and case control studies have
examined the potential link between oral exposure to aluminum via drinking
water and the disease. The causal role of aluminum, however, remains
controversial. Some studies have found a significant relationship between the
exposure to aluminum in water and an increased risk of Alzheimer’s disease,
while other studies have not. There is … convincing evidence that aluminum is
the causative agent in dialysis dementia, which is seen in patients undergoing
long-term hemodialysis. Developmental effects such as encephalopathy, bone
disease, microcytic anemia, and rickets have occurred in premature infants with
reduced or failed renal function receiving aluminum-containing treatment (e.g.,
dialysate or aluminum-based phosphate binders) and in nonuremic infants
receiving parenteral nutrition with aluminum-containing fluids or high doses of
aluminum antacids. There are no adequate studies of the long-term effects of
aluminum exposure on brain development and skeletal maturation. No
immunotoxicity studies are available. Few cases, however, report of
hypersensitivity to aluminum following dermal application or parenteral
administration. There have also been no reports of genetic or reproductive
effects in humans. In mice, oral administration of aluminum as aluminum
ammonium sulfate decreased dopamine, dihydroxyphenylacetic acid, and
homovanillic acid levels in the hypothalamus, and aluminum lactate increased
the 2-thiobarbituric acid reactive substances (TBARS) in the brain but
decreased brain stem weight. In rats, oral administration of aluminum as the
sulfate, nitrate, chloride, hydroxide, citrate, and lactate resulted in
aluminum accumulation in bone, brain, spleen, liver, heart, gastrointestinal
tract, and spleen. Significant decreases occurred in body weight, water
consumption, urine volume, plasma glutamic-pyruvic transaminase, serum
triglycerides, serum iron concentration, and alkaline phosphatase, ATP, ADP,
and AMP, as well as in motor activity. Additional health effects include
changes in the cytological and enzymatic content of the lavage fluid,
inhibition of colony-forming units-erythroid (CFU-E), and neurobehavioral
effects.

Reproductive toxicity and teratogenicity from aluminum compounds has been
reported in a number of papers. Reproductive effects observed in male mice,
rats, or dogs given aluminum compounds orally or s.c. included repressed sexual
behavior, decreased spermatogenesis, or other effects on the testes, sperm
duct, and/or epididymis. Reproductive effects from oral administration to
female rats included irregularity of the estrus cycle of female offspring or
effects on the ovaries or fallopian tubes in treated adults. Maternal toxicity
was observed in several studies in which pregnant mice, rats, or rabbits were
administered aluminum compounds orally, i.p., or s.c. during gestation.
Developmental toxicity from oral, i.p., or s.c. aluminum compound
administration was also noted in some rat and mouse studies. Teratogenic
effects induced by oral, i.p., or s.c. administration of aluminum compounds
included skeletal or musculoskeletal variations, cleft palate or other
craniofacial malformations, cardiovascular system abnormalities, and other
unspecified physical effects. Injection of aluminum compounds into the yolk sac
of fertilized chicken eggs induced similar developmental malformations.
Neurotoxic effects were observed when aluminum compounds were given orally to
mice, rats, or rabbits. A number of studies were also found that reported no
reproductive, maternal, developmental toxicity or teratogenicity from oral,
inhalation, i.p., or s.c. administration of aluminum compounds. Genotoxicity In
one acellular assay, aluminum was found to bind to DNA through chelation. It
was also found to reduce 3H-thymidine incorporation in a transformed cell line,
indicating that aluminum compounds may impede cell cycle progression. Aluminum
compounds were not mutagenic in the preponderance of Salmonella typhimurium and
Escherichia coli studies. Only one study reported a positive mutagenic
response, in which aluminum acetylacetonate was tested on S. typhimurium strain
TA104 in the absence of metabolic activation. Effects induced in vitro by
aluminum compounds included crosslinking of chromosomal proteins in rat ascites
hepatoma cells, anaphasic changes in BALB/c mouse 3T3 cells, and formation of
DNA-protein crosslinks, micronuclei, sister chromatic exchanges (SCEs), and
chromosomal aberrations in cultured human lymphocytes. Effects induced in vivo
included SCEs in mice and sheep, delayed mitosis in mice and sheep, and
formation of micronucleated polychromatic lymphocytes in mice, and chromosomal
aberrations in rats and mice. Neurotoxicity Dementia in dialysis patients and
encephalopathy in infants undergoing parenteral nutrition are well known
examples of aluminum intoxication in humans. Numerous in vitro studies and
epidemiological studies have examined the possible role of aluminum in
Alzheimer’s disease, other dementias, and cognitive dysfunction. Numerous
animal studies, particularly orally studies in mice and rats, show that
aluminum compounds are neurotoxic, but species variation exist. The toxicity is
characterized by progressive neurological impairment leading to death
associated with repeated seizures. Morphologically, the progressive
encephalopathy, associated with neurofibrillary pathology in neurons mostly in
the spinal cord, brain stem, and the hippocampus and cingulated gyrus of the
cortex, has been induced by aluminum in susceptible animals such as the rabbit,
cat, guinea pig, and ferret when given as intrathecal, intracerebral, and
subcutaneous injections. For example, in cats and rabbits intracerebral
injections of soluble aluminum compounds resulted in impairment in learning and
memory, and in rabbits repeated subcutaneous injections affected classical
conditioning, while single or repeated intracisternal injection of metallic
aluminum altered motor function. Oral administration of aluminum compounds,
however, produced no encephalopathy or epilepsy but resulted in behavioral
impairment.

http://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/aluminum_508.pdf#search=aluminum%20compounds

Neurotoxicology • February 2001

Differential toxicity of aluminum salts in human cell lines of neural origin:
implications for neurodegeneration Author information Campbell A1, Hamai D,
Bondy SC. Department of Community and Environmental Medicine Center for
Occupational and Environmental Health University of California, Irvine
92697-1820, USA Abstract Aluminum is highly oxophilic and its minerals are
usually found surrounded by six oxygen atoms. A role for the metal has been
established in dialysis encephalopathy and Al-induced osteomalacia. The metal
has been implicated in Alzheimer’s disease but the issue is at present
controversial. Human cell lines of neural origin were utilized to study the
effect of lipophilic aluminum acetylacetonate and non-lipophilic aluminum
sulfate on cell proliferation and viability. Although analysis of Al species in
the cell culture media demonstrated that there are positively charged Al
species present in solutions prepared with both Al salts, only the aluminum
acetylacetonate salt caused changes in cell proliferation and viability.
Therefore, the lipophilic nature of the organic Al salt is a critical
determinant of toxicity. The effect of aluminum acetylacetonate was
dose-dependent and time-dependent. Neuroblastoma (SK-N-SH) cells were more
susceptible to decreased cell proliferation although the lipophilic Al salt was
more toxic to the glioblastoma (T98G) cells. While the toxicity of aluminum
acetylacetonate was inhibited in the T98G cells by the addition of phosphate,
the same treatment did not reverse cell death in the SK-N-SH cells. Thus, the
mechanism of Al toxicity appears to be different in the two cell lines. It is
possible that the principal neurotoxic target of the metal is glial and when
these cells are in a compromised state, this may secondarily impact the
neuronal population and thus eventually lead to neurodegeneration.
http://www.ncbi.nlm.nih.gov/pubmed/11307852

“It is possible that the principal neurotoxic target of the metal is glial and
when these cells are in a compromised state, this may secondarily impact the
neuronal population and thus eventually lead to neurodegeneration.”

“Aluminum is a nonessential metal to which humans are frequently exposed.”
Regulatory Toxicology And Pharmacology • February 2001

Safety evaluation of dietary aluminum Author information Soni MG1, White SM,
Flamm WG, Burdock GA. Burdock and Associates, Inc. 622 Beachland Boulevard
Suite B, Vero Beach, Florida 32963, USA Abstract Aluminum is a nonessential
metal to which humans are frequently exposed. Aluminum in the food supply comes
from natural sources, water used in food preparation, food ingredients, and
utensils used during food preparations. The amount of aluminum in the diet is
small, compared with the amount of aluminum in antacids and some buffered
analgesics. The healthy human body has effective barriers (skin, lungs,
gastrointestinal tract) to reduce the systemic absorption of aluminum ingested
from water, foods, drugs, and air. The small amount of aluminum (<1%) that is
systemically absorbed is excreted principally in the urine and, to a lesser
extent, in the feces. No reports of dietary aluminum toxicity to healthy
individuals exist in the literature. Aluminum can be neurotoxic, when injected
directly into the brains of animals and when accidentally introduced into human
brains (by dialysis or shrapnel). A study from Canada reports cognitive and
other neurological deficits among groups of workers occupationally exposed to
dust containing high levels of aluminum. While the precise pathogenic role of
aluminum in Alzheimer’s disease (AD) remains to be defined, present data do not
support a causative role for aluminum in AD. High intake of aluminum from
antacid for gastrointestinal ailments has not been reported to cause any
adverse effects and has not been correlated with neurotoxicity or AD. Foods and
food ingredients are generally the major dietary sources of aluminum in the
United States. Cooking in aluminum utensils often results in statistically
significant, but relatively small, increases in aluminum content of food.
Common aluminum-containing food ingredients are used mainly as preservatives,
coloring agents, leavening agents, anticaking agents, etc. Safety evaluation
and approval of these ingredients by the Food and Drug Administration indicate
that these aluminumcontaining compounds are safe for use in foods.
http://www.ncbi.nlm.nih.gov/pubmed/11259180

Pharmacology And Toxicology • April 2001

Aluminium toxicokinetics: an updated minireview Author information Yokel RA1,
McNamara PJ. College of Pharmacy and Graduate Center for Toxicology University
of Kentucky Medical Center Lexington 40536-0082, USA ryokell@pop.uky.edu
Abstract This MiniReview updates and expands the MiniReview of aluminium
toxicokinetics by Wilhelm et al. published by this journal in 1990. The use of
26Al, analyzed by accelerator mass spectrometry, now enables determination of
Al toxicokinetics under physiological conditions. There is concern about
aluminium in drinking water. The common sources of aluminium for man are
reviewed. Oral Al bioavailability from water appears to be about 0.3%. Food is
the primary common source. Al bioavailability from food has not been adequately
determined. Industrial and medicinal exposure, and perhaps antiperspirant use,
can significantly increase absorbed aluminium. Inhalation bioavailability of
airborne soluble Al appears to be about 1.5% in the industrial environment. Al
may distribute to the brain from the nasal cavity, but the significance of this
exposure route is unknown. Systemic Al bioavailability after single underarm
antiperspirant application may be up to 0.012%. All intramuscularly injected
Al, e.g. from vaccines, may eventually be absorbed. Al distributes unequally to
all tissues. Distribution and renal excretion appear to be enhanced by citrate.
Brain uptake of Al may be mediated by Al transferrin and Al citrate complexes.
There appears to be carrier-mediated efflux of Al citrate from the brain.
Elimination half-lives of years have been reported in man, probably reflecting
release from bone. Al elimination is primarily renal with < or = 2% excreted in
bile. The contribution of food to absorbed Al needs to be determined to advance
our understanding of the major components of Al toxicokinetics.
http://www.ncbi.nlm.nih.gov/pubmed/11322172

“All intramuscularly injected Aluminum, e.g. from vaccines, may eventually be
absorbed.”

Brain Research Bulletin • May 2001

Aluminium toxicity in the rat brain: histochemical and immunocytochemical
evidence Author information Platt B1, Fiddler G, Riedel G, Henderson Z.
Biomedical Sciences, Aberdeen University Scotland, Aberdeen, UK.
b.platt@abdn.ac.uk Abstract Although the neurotoxic actions of aluminium (Al)
have been well documented, its contribution to neurodegenerative diseases such
as Alzheimer’s disease remains controversial. In the present study, we applied
histochemical techniques to identify changes induced by intracerebroventricular
Al injections (5.4 microg in 5.5 microl, daily over a period of 5 successive
days) in the adult rat brain after survival periods of either 1 or 6 weeks. For
both Al- and saline-infused controls, no major signs of gross histological
changes were evident in cresyl violet-stained sections. Al (as indicated by the
fluorescent Morin staining) was concentrated in white matter of the medial
striatum, corpus callosum, and cingulate bundle. Immunoreactivity of astrocytes
and phagocytic microglia based on glial fibrillary acidic protein and ED1
markers, respectively, revealed a greater inflammatory response in Al-injected
animals compared to controls. Damage of the cingulate bundle in Al-treated
animals led to a severe anterograde degeneration of cholinergic terminals in
cortex and hippocampus, as indicated by acetylcholinesterase labelling. Our
data suggest that the enhancement of inflammation and the interference with
cholinergic projections may be the modes of action through which Al may cause
learning and memory deficits, and contribute to pathological processes in
Alzheimer’s disease. http://www.ncbi.nlm.nih.gov/pubmed/?term=11470325

“Our data suggest that the enhancement of inflammation and the interference
with cholinergic projections may be the modes of action through which Aluminum
may cause learning and memory deficits, and contribute to pathological
processes in Alzheimer’s disease.”

“... these results firmly establish that aluminium hydroxide-containing vaccines
represent the direct cause of the Macrophagic myofasciitis (MMF) lesion.” Brain
• September 2001

Macrophagic myofasciitis lesions assess long-term persistence of
vaccine-derived aluminium hydroxide in muscle Author information Gherardi RK1,
Coquet M, Cherin P, Belec L, Moretto P, Dreyfus PA, Pellissier JF, Chariot P,
Authier FJ. Equipe mixte INSERM E 0011/Université Paris XII, France
romain.gherardi@hmn.ap-hop-paris.fr Abstract Macrophagic myofasciitis (MMF) is
an emerging condition of unknown cause, detected in patients with diffuse
arthromyalgias and fatigue, and characterized by muscle infiltration by
granular periodic acid-Schiff’s reagent-positive macrophages and lymphocytes.
Intracytoplasmic inclusions have been observed in macrophages of some patients.
To assess their significance, electron microscopy was performed in 40
consecutive cases and chemical analysis was done by microanalysis and atomic
absorption spectrometry. Inclusions were constantly detected and corresponded
to aluminium hydroxide, an immunostimulatory compound frequently used as a
vaccine adjuvant. A lymphocytic component was constantly observed in MMF
lesions. Serological tests were compatible with exposure to aluminium
hydroxide-containing vaccines. History analysis revealed that 50 out of 50
patients had received vaccines against hepatitis B virus (86%), hepatitis A
virus (19%) or tetanus toxoid (58%), 3-96 months (median 36 months) before
biopsy. Diffuse myalgias were more frequent in patients with than without an
MMF lesion at deltoid muscle biopsy (P < 0.0001). Myalgia onset was subsequent
to the vaccination (median 11 months) in 94% of patients. MMF lesion was
experimentally reproduced in rats. We conclude that the MMF lesion is secondary
to intramuscular injection of aluminium hydroxide-containing vaccines, shows
both long-term persistence of aluminium hydroxide and an ongoing local immune
reaction, and is detected in patients with systemic symptoms which appeared
subsequently to vaccination. Full Report
http://brain.oxfordjournals.org/content/124/9/1821

Pediatric And Developmental Pathology • March 2002

Aluminum phagocytosis in quadriceps muscle following vaccination in children:
relationship to macrophagic myofasciitis Author information Lacson AG1, D’Cruz
CA, Gilbert-Barness E, Sharer L, Jacinto S, Cuenca R. Departments of Pediatrics
and Pathology University of South Florida at All Children’s Hospital 801 Sixth
Street South 7020, St. Petersburg, FL 33731, USA Abstract Macrophagic
myofasciitis (MMF) is a rare, seemingly emerging entity among adult patients in
France. We encountered two children with the first two cases of MMF in North
America. A 5-year-old male with chronic intestinal pseudo-obstruction required
nighttime parenteral nutrition. Abnormal pupillary reflexes and urinary
retention suggested a diffuse dysautonomia, which prompted a neurological
diagnostic work-up. A 3-year-old child had developmental delay and hypotonia.
Both children received age-appropriate immunizations. Quadriceps muscle biopsy
from each child showed the typical patchy, cohesive centripetal infiltration of
alpha-1-antitrypsin+, alpha-1antichymotrypsin+, CD68+, PAS+, CD1a-, S-100-,
factor XIII- granular macrophages with adjacent myofiber atrophy, dilated blood
vessels, and mild endomysial and perimysial fibrosis. No myonecrosis was
observed and no discrete granulomas were seen. A single aluminum peak was
demonstrated on energy dispersive X-ray microanalysis. The etiology of the
clinical symptoms in these cases and in cases reported as MMF remains
intriguing. Despite numerous stains to demonstrate organisms, most infectious
causes leading to macrophage activation were ruled out. These cases are being
reported to increase awareness of this condition and to encourage a systematic
epidemiologic and clinicopathologic study in North America.
http://www.ncbi.nlm.nih.gov/pubmed/11910509

“Macrophagic myofasciitis (MMF) is a rare, seemingly emerging entity among
adult patients in France. We encountered two children with the first two cases
of MMF in North America.”

Vaccine • May 2002

Mechanisms of stimulation of the immune response by aluminum adjuvants Author
information HogenEsch H. Department of Veterinary Pathobiology Purdue
University, West Lafayette IN 47907-1243, USA hogenesch@purdue.edu Abstract
Aluminum adjuvants are widely used in human and veterinary vaccines. They are
appropriate adjuvants for vaccines that confer protection by inducing
antibodies via the induction of a type 2 immune response, but they do not
induce cytotoxic T cell and cell-mediated immunity. The mechanisms by which
aluminum adjuvants selectively enhance the immune response are poorly
understood. Following exposure to interstitial fluid in vitro and in vivo, most
antigens are rapidly desorbed from aluminum adjuvants, suggesting that
sustained release of antigen from a depot does not significantly contribute to
the adjuvant effect of aluminum compounds. However, the adsorption of antigens
onto aluminum salts may result in a high local concentration of antigen at the
injection site and enhance the uptake by antigen-presenting cells. Aluminum
compounds can further enhance the immune response by direct or indirect
stimulation of dendritic cells, activation of complement and by inducing the
release of chemokines. The relative importance of these mechanisms remains to
be determined. http://www.ncbi.nlm.nih.gov/pubmed/12184362

“Aluminum compounds can further enhance the immune response by direct or
indirect stimulation of dendritic cells, activation of complement and by
inducing the release of chemokines. The relative importance of these mechanisms
remains to be determined.”

“Dr. Gherardi believes that Macrophagic Myofasciitis, a syndrome of ascending myalgias,
fatigue and diffuse musculoskeletal pain, may be related to a chronic immune
response to aluminum granulomas persisting at the sites of prior immunization
with aluminum adjuvated vaccines.” Vaccine • May 2002

Macrophagic myofasciitis: a summary of Dr. Gherardi’s presentations Author
information Brenner A1. Rheumatological Services, Inc. Framington, MA 01702,
USA alanrsi@aol.com Abstract Dr. R.K. Gherardi presented two papers at the
symposium, detailing his researches into a proposed new clinical entity which
he has entitled Macrophagic Myofasciitis (MMF). In his first paper he described
the histopathologic and immunologic characteristics of the condition, and in
the second, the clinical and serologic features. Dr. Gherardi believes that
MMF, a syndrome of ascending myalgias, fatigue and diffuse musculoskeletal
pain, may be related to a chronic immune response to aluminum granulomas
persisting at the sites of prior immunization with aluminum adjuvated vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/?term=12184366

“there is no known physiological role for aluminum within the body ...”
Environmental Research • June 2002

Aluminum: impacts and disease Author information Nayak P. Department of
Physiology Sikkim Manipal Institute of Medical Sciences 5th Mile, Tadong,
Gangtok, 737102, Sikkim, India Abstract Aluminum is the most widely distributed
metal in the environment and is extensively used in modern daily life. Aluminum
enters into the body from the environment and from diet and medication.
However, there is no known physiological role for aluminum within the body and
hence this metal may produce adverse physiological effects. The impact of
aluminum on neural tissues is well reported but studies on extraneural tissues
are not well summarized. In this review, the impacts of aluminum on humans and
its impact on major physiological systems are summarized and discussed. The
neuropathologies associated with high brain aluminum levels, including
structural, biochemical, and neurobehavioral changes, have been summarized. In
addition, the impact of aluminum on the musculoskeletal system, respiratory
system, cardiovascular system, hepatobiliary system, endocrine system, urinary
system, and reproductive system are discussed.
http://www.ncbi.nlm.nih.gov/pubmed/?term=12123643

“The exact mechanism of aluminum toxicity is not known
but accumulating evidence suggests that the metal can potentiate oxidative and
inflammatory events, eventually leading to tissue damage.” Toxicology And
Industrial Health • August 2002

Aluminum as a toxicant Author information Becaria A1, Campbell A, Bondy SC.
Department of Community and Environmental Medicine Center for Occupational and
Environmental Health Sciences Irvine, CA 92697-1820, USA abecaria@uci.edu
Abstract Although aluminum is the most abundant metal in nature, it has no
known biological function. However, it is known that there is a causal role for
aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia.
Aluminum has also been proposed to play a role in the pathogenesis of
Alzheimer’s disease (AD) even though this issue is controversial. The exact
mechanism of aluminum toxicity is not known but accumulating evidence suggests
that the metal can potentiate oxidative and inflammatory events, eventually
leading to tissue damage. This review encompasses the general toxicology of
aluminum with emphasis on the potential mechanisms by which it may accelerate
the progression of chronic age-related neurodegenerative disorders.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15068131

“... even intermittent or low-dose use of aluminium-based phosphate binders adds to the
total load of this toxin in the bone; thus, aluminium use is inadvisable, even
for a ‘rescue indication’.” Nephrology, Dialysis, Transplantation • 2002

Aluminium and bone disease in chronic renal failure Author information Malluche
HH University of Kentucky, Division of Nephrology Bone and Mineral Metabolism
Lexington, 40536-1052, USA hhmall@uky.edu Abstract Aluminium is absorbed by the
intestines and is rapidly transported into bone, where it disrupts
mineralization and bone cell growth and activity. Its toxicities result in or
exacerbate painful forms of renal osteodystrophy, most notably adynamic bone
disease and osteomalacia, but also other forms of the disease. Because
aluminium is sequestered in bone for long periods, its toxic effects are
cumulative. As a result, even intermittent or low-dose use of aluminium-based
phosphate binders adds to the total load of this toxin in the bone; thus,
aluminium use is inadvisable, even for a ‘rescue indication’. Aluminium blood
levels are not a reliable marker of aluminium absorption or organ load in
dialysis patients: only stainable aluminium at the mineralization front
reflects the histopathological changes observed in bone. Therefore, bone
biopsies remain the only approach for definitive diagnosis of aluminium-related
bone disease. Most importantly, lack of correlation between overall organ
concentrations of a toxin, such as aluminium, and pathological changes does not
rule out toxicity. Thus, the specific localization of the toxin is more
important than overall organ concentration. What has been observed with
aluminium during 25 years of research might be reproduced with other metals
that are absorbed, transported and accumulated in bone. What we have learned
about the toxicity of aluminium should inform our interpretation of data from
studies of other metal-based therapeutics for renal patients. This calls for
careful evaluation of any newly introduced therapeutic agents for bone disease
in patients lacking excretory kidney function.
http://www.ncbi.nlm.nih.gov/pubmed/?term=11904354

Vaccine • 2002

Workshop Summary Aluminum In Vaccines Conference report

Theodore C. Eickhoff Division of Infectious Disease University of Colorado
Health Sciences 4200 East 9th Avenue Denver, CO 80262, USA Martin Myers
National Vaccine Program Office 1600 Cligton Road MS 0-66, Atlanta, GA 30333
Abstract On May 11–12 in San Juan, Puerto Rico the National Vaccine Program
Office (NVPO) sponsored a workshop on aluminum in vaccines. The meeting was
attended by a diverse group of vaccinologists, immunologists, experts on
metals, pathologists, rheumatologists, and other interested parties. The
objectives of this meeting were to: (1) establish a better understanding of the
role and need of aluminum as an adjuvant in vaccines; (2) explore the
possibility of adverse events due to the use of aluminum in vaccines; and (3)
develop a research agenda to expand existing knowledge of the impact of
aluminum on the human body. From the Metal Ions in Biology and Medicine
International Symposium held immediately prior to the aluminum workshop, we
learned about “pervasive uncertainty”, a phrase used in this workshop to denote
missing data on pharmocokinetics and toxicities of aluminum injected into
humans. Even with identification of areas needing further study, it was
apparent that aluminum which has been used as a vaccine adjuvant for more than
70 years, has an established safety record with low incidence of reported
adverse events. The first session of the workshop was devoted to important
background about immunologic adjuvants in general and aluminum adjuvants in
particular. Dr. Robert Hunter, University of Texas, provided a broad overview
of the history and development of adjuvants, and the conventional views of
their mechanism of action and uses. Aluminum adjuvants have been thought to
form a repository of antigen in tissue, to produce particulate antigen for
presentation to immune cells, and perhaps to activate complement and other
immune enhancers. The immune response to some, but not all, protein antigens is
enhanced by aluminum salts, however, these salts have little effect on peptide
and polysaccharide antigens. Aluminum adjuvants enhance the primary
immunization series, reducing the amount of antigen needed per dose and the
number of required doses. They increase the proportion of responders, however,
there appears to be little effect of adjuvant in subsequent booster doses. Dr.
Norman Baylor, US Food and Drug Administra- tion, provided a detailed analysis
of aluminum adjuvants, as well as regulatory perspectives. The three general
types of

aluminum-containing adjuvants are: (1) aluminum hydroxide, (2) aluminum
phosphate, and (3) alum, or potassium aluminum sulfate. Each of these types of
formulations has different isoelectric points, and properties; they are not
simply interchangeable. The efficacy of each salt as an adjuvant depends also
on the characteristics of the antigens in the vaccine. FDA regulations limit
the aluminum content of an individual dose of a vaccine to 0.85 mg. of
elemental aluminum. This is equivalent to 15 mg. of alum per dose. The
immunologic advantage conferred by these adjuvants has been well documented,
although most of this documentation is found in studies published before 1970.
In general, these studies showed that aluminum-adjuvanted vaccines resulted in
higher and more prolonged antibody responses than did comparable aqueous
vaccines. This advantage was most apparent during primary immunization; there
seemed to be little advantage to incorporating adjuvant in booster doses. The
US licensed products that contain aluminum adjuvants include DTP, DTaP, some
but not all HIB vaccines, hepatitis B vaccine, and all combination DTaP, HIB,
or HB vaccines. Others containing aluminum include hepatitis A vaccine, lyme
disease vaccine, anthrax vaccine, and rabies vaccine. Inactivated vaccines that
do not contain aluminum salts include IPV and influenza vaccines. Of interest
was the fact that there are substantial differences among manufacturers both in
the specific aluminum adjuvant used, as well as the amount of that adjuvant, in
vaccines such as DTaP and in combination vaccines made by several
manufacturers. Dr. Baylor also pointed out that any alteration of a vaccine,
such as removal of aluminum in booster doses, would necessitate treating the
altered vaccine as a new product requiring the collection of additional
clinical data. Adverse reactions that have been reported with
aluminum-containing vaccines are generally local reactions including sterile
abscesses, erythema, subcutaneous (SC) nodules, granulomatous inflammation, and
contact hypersensitivity. None of these reactions, however, has been
sufficiently frequent to arouse concern.

http://archive.hhs.gov/nvpo/nvac/documents/Aluminumws.pdf

Journal Of Inorganic Biochemistry • September 2003

A biogeochemical cycle for aluminium? Author information Exley C1. Birchall
Centre for Inorganic Chemistry and Materials Science Keele University,
Staffordshire ST5 5BG, UK c.exley@chem.keele.ac.uk Abstract The elaboration of
biogeochemical cycles for elements which are known to be essential for life has
enabled a broad appreciation of the homeostatic mechanisms which underlie
element essentiality. In particular they can be used effectively to identify
any part played by human activities in element cycling and to predict how such
activities might impact upon the lithospheric and biospheric availability of an
element in the future. The same criteria were the driving force behind the
construction of a biogeochemical cycle for aluminium, a non-essential element
which is a known ecotoxicant and a suspected health risk in humans. The purpose
of this exercise was to examine the concept of a biogeochemical cycle for
aluminium and not to review the biogeochemistry of this element. The cycle as
presented is rudimentary and qualitative though, even in this nascent form, it
is informative and predictive and, for these reasons alone, it is deserving of
future quantification. A fully fledged biogeochemical cycle for aluminium
should explain the biospheric abundance of this element and whether we should
expect its (continued) active involvement in biochemical evolution.
http://www.ncbi.nlm.nih.gov/pubmed/14507454

“a non-essential element which is a known ecotoxicant and a suspected health
risk in humans.”

Vaccine • December 2003

Unexpectedly high incidence of persistent itching nodules and delayed
hypersensitivity to aluminium in children after the use of adsorbed vaccines
from a single manufacturer Author information Bergfors E1, Trollfors B, Inerot
A. Department of Primary Health Care, Göteborg University Box 454, S-40530
Göteborg, Sweden elisabet.bergfors@allmed.gu.se Abstract During trials of
aluminium adsorbed diphtheria-tetanus/acellular pertussis vaccines from a
single producer, persistent itching nodules at the vaccination site were
observed in an unexpectedly high frequency. The afflicted children were
followed in a longitudinal observational study, and the presence of aluminium
sensitization was investigated in the children with itching nodules and their
symptomless siblings by patch tests. Itching nodules were found in 645 children
out of about 76,000 vaccinees (0.8%) after both subcutaneous (s.c.) and
intramuscular (i.m.) injection. The itching was intense and long-lasting. So
far, 75% still have symptoms after a median duration of 4 years. Contact
hypersensitivity to aluminium was demonstrated in 77% of the children with
itching nodules and in 8% of the symptomless siblings who had received the same
vaccines (P<0.001). Children with persistent itching nodules and/or aluminium
sensitization should be warned about aluminium containing products (e.g.
vaccines and antiperspirants). The reason for the high incidence of itching
nodules after SSI vaccines is unknown and should be further investigated.
http://www.ncbi.nlm.nih.gov/pubmed/?term=14604572

“Itching nodules were found in 645 children out of about 76,000 vaccinees after
both subcutaneous and intramuscular injection. The itching was intense and
long-lasting. So far, 75% still have symptoms after a median duration of 4
years.”

Journal Of Neuroscience Research • February 2004

Chronic exposure to aluminum in drinking water increases inflammatory
parameters selectively in the brain Author information Campbell A1, Becaria A,
Lahiri DK, Sharman K, Bondy SC. Department of Community and Environmental
Medicine Center for Occupational and Environmental Health Sciences Irvine,
California 92697, USA Abstract A link between aluminum (Al) exposure and
age-related neurological disorders has long been proposed. Although the exact
mechanism by which the metal may influence disease processes is unknown, there
is evidence that exposure to Al causes an increase in both oxidative stress and
inflammatory events. These processes have also been suggested to play a role in
Alzheimer’s disease (AD), and exposure to the metal may contribute to the
disorder by potentiating these events. Al lactate (0.01, 0.1, and 1 mM) in
drinking water for 10 weeks increased inflammatory processes in the brains of
mice. The lowest of these levels is in the range found to increase the
prevalence of AD in regions where the concentrations of the metal are elevated
in residential drinking water (Flaten [2001] Brain Res. Bull. 55:187-196).
Nuclear factor-kappaB as well as tumor necrosis factor-alpha (TNF-alpha) and
interleukin 1alpha (IL-1alpha) levels were increased in the brains of treated
animals. The mRNA for TNF-alpha was also up-regulated following treatment.
Enhancement of glial fibrillary acidic protein levels and reactive microglia
was seen in the striatum of Al-treated animals. The level of amyloid beta
(Abeta40) was not significantly altered in the brains of exposed animals.
Insofar as no parallel changes were observed in the serum or liver of treated
animals, the proinflammatory effects of the metal may be selective to the
brain. Al exposure may not be sufficient to cause abnormal production of the
principal component of senile plaques directly but does exacerbate underlying
events associated with brain aging and thus could contribute to progression of
neurodegeneration. http://www.ncbi.nlm.nih.gov/pubmed/14743440

“Although the exact mechanism by which the metal may influence disease
processes is unknown, there is evidence that exposure to Al causes an increase
in both oxidative stress and inflammatory events. Insofar as no parallel
changes were observed in the serum or liver of treated animals, the
proinflammatory effects of the metal may be selective to the brain.”

“... the more detailed mode of action of these adjuvants is still not completely understood.”
Vaccine • September 2004

Aluminium adjuvants—in retrospect and prospect Author information Lindblad EB.
Adjuvant Dept. Brenntag Biosector DK-3600 Frederikssund, Denmark Abstract
Aluminium compounds have been used as adjuvants in practical vaccination for
more than 60 years to induce an early, an efficient and a long lasting
protective immunity and are at present the most widely used adjuvants in both
veterinary and human vaccines. Although the last two decades of systematic
research into the nature of these adjuvants has contributed significantly to
understanding their nature and their limitations as Th2 stimulators the more
detailed mode of action of these adjuvants is still not completely understood.
We have a comprehensive record of their behaviour and performance in practical
vaccination, but an empirical approach to optimising their use in new vaccine
formulations is still to some extent a necessity. The aim of the present review
is to put the recent findings into a broader perspective to facilitate the
application of these adjuvants in general and experimental vaccinology.
http://www.ncbi.nlm.nih.gov/pubmed/15315845

Archives Of Toxicology • October 2004

Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and
methylmercury in cell lines of neural origin Author information Toimela T1,
Tähti H. Medical School, Cell Research Center University of Tampere 33014
University of Tampere, Finland Tarja.Toimela@uta.fi Abstract Mercury and
aluminum are considered to be neurotoxic metals, and they are often connected
with the onset of neurodegenerative diseases. In this study, mercuric mercury,
methylmercury and aluminum were studied in three different cell lines of neural
origin. To evaluate the effects, mitochondrial cytotoxicity and apoptosis
induced by the metals were measured after various incubation times. SH-SY5Y
neuroblastoma, U 373MG glioblastoma, and RPE D407 retinal pigment epithelial
cells were subcultured to appropriate cell culture plates and 0.01-1,000 microM
concentrations of methylmercury, mercuric and aluminum chloride were added into
the growth medium. In the assay measuring the mitochondrial dehydrogenase
activity, WST-1, the cultures were exposed for 15 min, 24 or 48 h before
measurement. Cells were allowed to recover from the exposure in part of the
study. Apoptosis induced by the metals was measured after 6-, 24- and 48-h
exposure times with the determination of activated caspase 3 enzyme.
Mitochondrial assays showed a clear dose-response and exposure time-response to
the metals. The most toxic was methylmercury (EC50 ~0.8 microM, 48 h), and the
most sensitive cell line was the neuroblastoma cell line SH-SY5Y. Furthermore,
there was marked mitochondrial activation, especially in connection with
aluminum and methylmercury at low concentrations. This activation may be
important during the initiation of cellular processes. All the metals tested
induced apoptosis, but with a different time-course and cell-line specificity.
In microscopic photographs, glioblastoma cells formed fibrillary tangles, and
neuroblastoma cells settled along the fibrilles in cocultures of glial and
neuronal cell lines during aluminum exposure. The study emphasized the toxicity
of methylmercury to neural cells and showed that aluminum alters various
cellular activities. http://www.ncbi.nlm.nih.gov/pubmed/?term=15150681

“Mercury and aluminum are considered to be neurotoxic metals, and they are
often connected with the onset of neurodegenerative diseases. The study
emphasized the toxicity of methylmercury to neural cells and showed that
aluminum alters various cellular activities.”

Journal Of Inorganic Biochemistry • September 2005

Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression
in human brain cells in primary culture Author information Lukiw WJ1, Percy ME,
Kruck TP. Neuroscience Center of Excellence and Department of Ophthalmology
Louisiana State University Health Sciences Center 2020 Gravier Street, Suite
8B8, New Orleans, LA 70112-2272, USA wlukiw@lsuhsc.edu Abstract Aluminum, the
most abundant neurotoxic metal in our biosphere, has been implicated in the
etiology of several neurodegenerative disorders including Alzheimer’s disease
(AD). To further understand aluminum’s influence on gene expression, we
examined total messenger RNA levels in untransformed human neural cells exposed
to 100 nanomolar aluminum sulfate using high density DNA microarrays that
interrogate the expression of every human gene. Preliminary data indicate that
of the most altered gene expression levels, 17/24 (70.8%) of aluminum-affected
genes, and 7/8 (87.5%) of aluminum-induced genes exhibit expression patterns
similar to those observed in AD. The seven genes found to be significantly
up-regulated by aluminum encode pro-inflammatory or pro-apoptotic signaling
elements, including NF-kappaB subunits, interleukin-1beta precursor, cytosolic
phospholipase A2, cyclooxygenase-2, beta-amyloid precursor protein and DAXX, a
regulatory protein known to induce apoptosis and repress transcription. The
promoters of genes upregulated by aluminum are enriched in binding sites for
the stress-inducible transcription factors HIF-1 and NF-kappaB, suggesting a
role for aluminum, HIF-1 and NF-kappaB in driving atypical, pro-inflammatory
and pro-apoptotic gene expression. The effect of aluminum on specific
stress-related gene expression patterns in human brain cells clearly warrant
further investigation. http://www.ncbi.nlm.nih.gov/pubmed/15961160

“The effect of aluminum on specific stress-related gene expression patterns in
human brain cells clearly warrant further investigation.”

Journal Of Alzheimers Disease • November 2005

Synergistic effects of iron and aluminum on stress-related gene expression in
primary human neural cells Author information Alexandrov PN1, Zhao Y, Pogue AI,
Tarr MA, Kruck TP, Percy ME, Cui JG, Lukiw WJ. Russian Academy of Medical
Sciences Moscow 113152, Russia Abstract Disturbances in metal-ion transport,
homeostasis, overload and metal ion-mediated catalysis are implicated in
neurodegenerative conditions such as Alzheimer’s disease (AD). The mechanisms
of metal-ion induced disruption of genetic function, termed genotoxicity, are
not well understood. In these experiments we examined the effects of
non-apoptotic concentrations of magnesium-, ironand aluminum-sulfate on gene
expression patterns in untransformed human neural (HN) cells in primary culture
using high density DNA array profiling and Western immunoassay. Two week old HN
cells were exposed to low micromolar magnesium, iron, or aluminum for 7 days,
representing trace metal exposure over one-third of their lifespan. While total
RNA yield and abundance were not significantly altered, both iron and aluminum
were found to induce HSP27, COX-2, betaAPP and DAXX gene expression. Similarly
up-regulated gene expression for these stress-sensing, pro-inflammatory and
pro-apoptotic elements have been observed in AD brain. The combination of iron
and aluminum together was found to be particularly effective in up-regulating
these genes, and was preceded by the evolution of reactive oxygen intermediates
as measured by 2’,7’-dichlorofluorescein diacetate assay. These data indicate
that physiologically relevant amounts of iron and aluminum are capable of
inducing Fenton chemistry-triggered gene expression programs that may support
downstream pathogenic responses and brain cell dysfunction.
http://www.ncbi.nlm.nih.gov/pubmed/16308480

“These data indicate that physiologically relevant amounts of iron and aluminum
are capable of inducing Fenton chemistry-triggered gene expression programs
that may support downstream pathogenic responses and brain cell dysfunction.”

Food Additives And Contaminants • March 2005

Aluminium content of some foods and food products in the USA, with aluminium
food additives Author information Saiyed SM1, Yokel RA. College of Pharmacy
University of Kentucky Medical Center Lexington, KY, USA Abstract The primary
objective was to determine the aluminium (Al) content of selected foods and
food products in the USA which contain Al as an approved food additive. Intake
of Al from the labeled serving size of each food product was calculated. The
samples were acid or base digested and analysed for Al using electrothermal
atomic absorption spectrometry. Quality control (QC) samples, with matrices
matching the samples, were generated and used to verify the Al determinations.
Food product Al content ranged from <1-27,000 mg kg(-1). Cheese in a serving of
frozen pizzas had up to 14 mg of Al, from basic sodium aluminium phosphate;
whereas the same amount of cheese in a ready-to-eat restaurant pizza provided
0.03-0.09 mg. Many single serving packets of non-dairy creamer had
approximately 50-600 mg Al kg(-1) as sodium aluminosilicate, providing up to
1.5 mg Al per serving. Many single serving packets of salt also had sodium
aluminosilicate as an additive, but the Al content was less than in
single-serving non-dairy creamer packets. Acidic sodium aluminium phosphate was
present in many food products, pancakes and waffles. Baking powder, some
pancake/waffle mixes and frozen products, and ready-to-eat pancakes provided
the most Al of the foods tested; up to 180 mg/serving. Many products provide a
significant amount of Al compared to the typical intake of 3-12 mg/day reported
from dietary Al studies conducted in many countries.
http://www.ncbi.nlm.nih.gov/pubmed/16019791

“The primary objective was to determine the aluminium (Al) content of selected
foods and food products in the USA which contain Al as an approved food
additive. Intake of Al from the labeled serving size of each food product was
calculated.”

“Aluminum has been associated with several neurodegenerative diseases,
such as dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism
dementia in the Kii peninsula and Guam, and in particular, Alzheimer’s
disease.” Journal Of Alzheimers Disease • November 2005

Effects of aluminum on the nervous system and its possible link with
neurodegenerative diseases Author information Kawahara M. Department of
Analytical Chemistry School of Pharmaceutical Sciences Kyushu University of
Health and Welfare Nobeoka-city, Miyazaki, 882-8508, Japan Abstract Aluminum is
environmentally abundant, but not an essential element. Aluminum has been
associated with several neurodegenerative diseases, such as dialysis
encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the
Kii peninsula and Guam, and in particular, Alzheimer’s disease. Although this
association remains controversial, there is increasing evidence which suggests
the implication of metal homeostasis in the pathogenesis of Alzheimer’s
disease. Aluminum, zinc, copper, and iron cause the conformational changes of
Alzheimer’s amyloid-beta protein. Al causes the accumulation of tau protein and
amyloid-beta protein in experimental animals. Aluminum induces neuronal
apoptosis in vivo as well as in vitro. Furthermore, a relationship between
aluminum and the iron-homeostasis or calcium-homeostasis has been suggested.
Based on these findings, the characteristics of aluminum neurotoxicity are
reviewed, and the potential link between aluminum and neurodegenerative
diseases is reconsidered. http://www.ncbi.nlm.nih.gov/pubmed/16308486

Immunology Letters • January 2006

(How) do aluminium adjuvants work? Author information Brewer JM. Division of
Immunology Infection and Inflammation University of Glasgow, Western Infirmary
Glasgow G11 6NT, UK j.m.brewer@clinmed.gla.ac.uk Abstract The aluminium
compounds, originally identified as adjuvants over 70 years ago, remain unique
in their widespread application to human vaccines. Given this history, it is
surprising that the physicochemical interactions between aluminium compounds
and antigens are relatively poorly understood. This has clearly been a
contributing factor to vaccine failures, for example, through inappropriate
selection of aluminium species or buffers. Similarly, the mechanism(s) of
action of aluminium adjuvants are relatively unstudied, although it appears
that these agents fail to fit within the current principles underlying
activation of the immune response. This review aims to examine recent
developments in our understanding of the physicochemical and biological aspects
of research into aluminium adjuvants.
http://www.ncbi.nlm.nih.gov/pubmed/16188325?dopt=Abstract

“The aluminium compounds, originally identified as adjuvants over 70 years ago,
remain unique in their widespread application to human vaccines. Given this
history, it is surprising that the physicochemical interactions between
aluminium compounds and antigens are relatively poorly understood.”

Neuromuscular Disorders • May 2006

AlOH3-adjuvanted vaccine-induced macrophagic myofasciitis in rats is influenced
by the genetic background Author information Authier FJ1, Sauvat S, Christov C,
Chariot P, Raisbeck G, Poron MF, Yiou F, Gherardi R. Centre de Référence Pour
Maladies Neuromusculaires CHU Henri Mondor, AP-HP, Créteil, France
francois-jerome.authier@hmn.aphp.fr Abstract Macrophagic myofasciitis (MMF) is
a specific histopathologic lesion involved in the persistence for years of
aluminum hydroxide [Al(OH)(3)] at the site of previous intramuscular (i.m.)
injection. In order to study mechanisms involved persistence of MMF lesions, we
set up an experimental model of MMF-lesion in Sprague-Dawley and Lewis rat, by
i.m. injections of 10 microL of an Al(OH)(3)-adjuvanted vaccine. An evaluation
carried out over a 12-month period disclosed significant shrinkage of MMF
lesions with time. A radioisotopic study did not show significant aluminium
uptake by Al(OH)(3)-loaded macrophages. A morphometric approach showed that
Lewis rats with Th1-biased immunity had significantly smaller lesions than
Sprague-Dawley rats with balanced Th1/Th2 immunity. Concluding, our results
indicate that genetic determinatives of cytotoxic T-cell responses could
interfere with the clearance process and condition the persistence of
vaccine-induced MMF-lesions. http://www.ncbi.nlm.nih.gov/pubmed/?term=16616846

“Macrophagic myofasciitis (MMF) is ... involved in the persistence for years of
aluminum hydroxide at the site of previous intramuscular injection. Concluding,
our results indicate that genetic determinatives of cytotoxic T-cell responses
could interfere with the clearance process and condition the persistence of
vaccine-induced MMF-lesions.”

Journal Of Alzheimers Disease • November 2006

Blood-brain barrier flux of aluminum, manganese, iron and other metals
suspected to contribute to metal-induced neurodegeneration Author information
Yokel RA. College of Pharmacy and Graduate Center for Toxicology University of
Kentucky Medical Center Lexington, KY 40536-0082, USA ryokel@email.uky.edu
Abstract The etiology of many neurodegenerative diseases has been only partly
attributed to acquired traits, suggesting environmental factors may also
contribute. Metal dyshomeostasis causes or has been implicated in many
neurodegenerative diseases. Metal flux across the bloodbrain barrier (the
primary route of brain metal uptake) and the choroid plexuses as well as
sensory nerve metal uptake from the nasal cavity are reviewed. Transporters
that have been described at the blood-brain barrier are listed to illustrate
the extensive possibilities for moving substances into and out of the brain.
The controversial role of aluminum in Alzheimer’s disease, evidence suggesting
brain aluminum uptake by transferrin-receptor mediated endocytosis and of
aluminum citrate by system Xc;{-} and an organic anion transporter, and results
suggesting transporter-mediated aluminum brain efflux are reviewed. The ability
of manganese to produce a parkinsonism-like syndrome, evidence suggesting
manganese uptake by transferrin- and non-transferrin-dependent mechanisms which
may include storeoperated calcium channels, and the lack of
transporter-mediated manganese brain efflux, are discussed. The evidence for
transferrin-dependent and independent mechanisms of brain iron uptake is
presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes
and Wilson’s diseases, are summarized. Brain zinc uptake is facilitated by L-
and D-histidine, but a transporter, if involved, has not been identified. Brain
lead uptake may involve a non-energy-dependent process, store-operated calcium
channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a
complex with L-cysteine that mimics methionine, enabling its transport by the L
system. The putative roles of zinc transporters, ZnT and Zip, in regulating
brain zinc are discussed. Although brain uptake mechanisms for some metals have
been identified, metal efflux from the brain has received little attention,
preventing integration of all processes that contribute to brain metal
concentrations. http://www.ncbi.nlm.nih.gov/pubmed/17119290

“Although brain uptake mechanisms for some metals have been identified, metal
efflux from the brain has received little attention, preventing integration of
all processes that contribute to brain metal concentrations.”

Archives Of Toxicology • January 2007

The effects of low dose aluminum on hemorheological and hematological
parameters in rats Author information Turgut S1, Bor-Kucukatay M, Emmungil G,
Atsak P, Turgut G. Department of Physiology Medical Faculty, Pamukkale
University 20020 Denizli, Turkey sturgut@pamukkale.edu.tr Abstract Aluminum
(Al) is a nonessential element and humans are constantly exposed to Al as a
result of an increase in industrialization and improving technology practices.
Al toxicity can induce several clinical disorders such as neurotoxicity,
gastrointestinal toxicity, hepatotoxicity, bone diseases, and anemia. This
study aimed at evaluating the possible effects of short term and low dose Al
exposure on hemorheological and hematological parameters in rats. Fourteen
young, male Wistar albino rats were divided into two groups: 1 mg/200 g body
weight of aluminum sulfate (Al(2)(SO(4))(3) was injected intraperitoneally to
the first group for two weeks, three times a week. The animals of the control
group received only physiological saline solution during this period. At the
end of the experimental period, anticoagulated blood samples were collected and
hematological parameters were determined using an electronic hematology
analyzer. Red blood cell (RBC) deformability and aggregation were measured
using an ektacytometer (LORCA) and plasma and whole blood viscosities were
determined with a WellsBrookfield cone-plate rotational viscometer. Significant
decreases in mean corpuscular volume (MCV), red blood cell (RBC) deformability
at low shear stress levels, the aggregation half time (t1/2) and the amplitude
(AMP) of aggregation and significant increments in whole blood viscosity (WBV)
at native and 40% hematocrit (Hct) of Al-treated rats have been observed. In
conclusion, low dose Al(2)(SO(4))(3) exposure for a short-time may be
responsible for alterations in either rheological properties of blood or
hemorheological properties through a remarkable effect on RBC membrane
mechanical properties. These alterations may also play an important role in the
development of anemia in the Al-treated animals.
http://www.ncbi.nlm.nih.gov/pubmed/16721596

“In conclusion, low dose Aluminum exposure for a short-time may be responsible
for alterations in either rheological properties of blood or hemorheological
properties through a remarkable effect on RBC membrane mechanical properties. ”

“It is hypothesized, in the present review, that Aluminum is a potential factor
for induction or maintaining the inflammation in Crohn’s Disease ...” Annals Of
The New York Academy Of Science • June 2007

Aluminum is a potential environmental factor for Crohn’s disease induction:
extended hypothesis Author information Lerner A. Pediatric Gastroenterology and
Nutrition Unit Carmel Medical Center, Pappaport School of Medicine
Technion-Israel Institute of Technology, Haifa, Israel
lerner_aaron@clalit.org.il Abstract Aluminum (Al) is a common environmental
compound with immune-adjuvant activity and granulomatous inflammation inducer.
Al exposure in food, additives, air, pharmaceuticals, and water pollution is
ubiquitous in Western culture. Crohn’s disease (CD) is a chronic relapsing
intestinal inflammation in genetically susceptible individuals and is
influenced by yet unidentified environmental factors. It is hypothesized, in
the present review, that Al is a potential factor for induction or maintaining
the inflammation in CD. Epidemiologically, CD incidence is higher in urban
areas, where microparticle pollution is prevalent. Al immune activities share
many characteristics with the immune pathology of CD: increased antigen
presentation and APCs activation, many luminal bacterial or dietary compounds
can be adsorbed to the metal and induce Th1 profile activity, promotion of
humoral and cellular immune responses, proinflammatory, apoptotic, oxidative
activity, and stress-related molecule expression enhancement, affecting
intestinal bacterial composition and virulence, granuloma formation, colitis
induction in an animal model of CD, and terminal ileum uptake. The Al-bacterial
interaction, the microparticles homing the intestine together with the
extensive immune activity, put Al as a potential environmental candidate for CD
induction and maintenance. http://www.ncbi.nlm.nih.gov/pubmed/?term=17804561

Human Vaccines • July 2007

Effect of alternative aluminum adjuvants on the absorption and immunogenicity
of HPV16 L1 VLPs in mice Author information Caulfield MJ1, Shi L, Wang S, Wang
B, Tobery TW, Mach H, Ahl PL, Cannon JL, Cook JC, Heinrichs JH, Sitrin RD.
Vaccine & Biologics Research Merck Research Laboratories West Point,
Pennsylvania USA michael_caufield@merck.com Abstract Aluminum adjuvants are
commonly used in prophylactic vaccines to enhance antigen immunogenicity
through induction of high-titer antibody responses. Three major forms of
aluminum adjuvants with substantially different physical and chemical
properties have been described: aluminum phosphate (AlPO(4)), aluminum
hydroxide (AlOH) and amorphous aluminum hydroxyphosphate sulfate (AAHS). Here
we describe the effect of these different aluminum adjuvants on the formulation
and subsequent immunogenicity in mice of virus-like particles (VLPs) consisting
of the L1 protein of Human Papillomavirus (HPV) Type 16. Electron microscopy
demonstrated that the physical appearance of the phosphate-containing aluminum
adjuvants was markedly different from that of aluminum hydroxide. All three
aluminum adjuvants were found to display unique surface charge profiles over a
range of pH, while AAHS demonstrated the greatest inherent capacity for
adsorption of L1 VLPs. These differences were associated with differences in
immunogenicity: anti-HPV L1 VLP responses from mice immunized with
AAHS-formulated HPV16 vaccine were substantially greater than those produced by
mice immunized with the same antigen formulated with aluminum hydroxide. In
addition, HPV L1 VLPs formulated on AAHS also induced a substantial
interferon-gamma secreting T cell response to L1 peptides indicating the
potential for an enhanced memory response to this antigen. These results
indicate that the chemical composition of aluminum adjuvants can have a
profound influence on the magnitude and quality of the immune response to HPV
VLP vaccines. http://www.ncbi.nlm.nih.gov/pubmed/17581283

“These results indicate that the chemical composition of aluminum adjuvants can
have a profound influence on the magnitude and quality of the immune response
to HPV VLP vaccines.”

Free Radical Biology & Medicine • October 2007

Aluminum: a potential pro-oxidant in sunscreens/sunblocks? Nicholson S, Exley
C. Scientists at Keele University in Staffordshire have questioned the safety
of aluminium added to sunscreens and sunblocks The researchers, Scott
Nicholson, BSc, and Dr Christopher Exley, PhD, Birchall Centre for Inorganic
Chemistry and Materials Science at Keele, measured the aluminium content of
sunscreens/sunblocks, which either include or do not include an aluminium salt
(for example, aluminium hydroxide, aluminium oxide, aluminium silicate,
aluminium stearate, aluminium starch octenylsuccinate) as an ingredient.
Aluminium was present in all seven products tested and its content was of
particular significance in three products, each of which listed it as an
ingredient. Following numerous enquiries the manufacturers were not forthcoming
as to the role of aluminium in their product, except one manufacturer, who
confirmed that aluminium hydroxide was added to their product to coat the
surface and thereby prevent the agglomeration of another ingredient, titanium
dioxide particles. World Health Organisation guidelines recommend a single
application of at least 35mL of a sunscreen/sunblock to achieve the stated sun
protection factor. For three of the sunscreens/sunblocks investigated a single
application of product would result in 200 mg of aluminium being applied to the
skin surface. In addition, WHO guidelines suggest re-application of product
every two hours which, for example, for an average day on the beach, would
result in up to 1g of aluminium being applied to the skin surface. Skin is
permeable to aluminium salts when, for example, they are topically applied as
antiperspirant formulations. It will accumulate in the skin and be transported
to sites throughout the body. It is highly likely that the everyday use of
sunscreens/sunblocks is an hitherto unrecognised contributor of aluminium to
the human body burden of this non-essential metal. Perhaps of immediate
significance is the potential for aluminium in the skin to act as a
pro-oxidant. Recent research in the journal Free Radical Biology and Medicine
has shown that UV filters in sunscreens promote the formation of reactive
oxygen species (ROS) in the nucleated epidermis of the skin. The authors
speculate upon the role which might be played by anti-oxidants, either already
in the skin or included in sunscreen formulations, in counteracting the
pro-oxidant activities of UV filters though they did not consider how the
presence of additional pro-oxidants might exacerbate such effects. Aluminium is
one such pro-oxidant and could significantly increase the potential for
oxidative damage in the skin. While the relationship between the burgeoning use
of sunscreens/sunblocks and the increased incidence of skin cancers and, in
particular, melanoma, is highly controversial it has not hitherto been
considered that aluminium in these products could be an extremely significant
contributing factor. Of course, aluminium is already in the skin surface and
may not need to be a component of sunscreens/sunblocks to exacerbate oxidative
damage attributed to the application of such products.
http://www.ncbi.nlm.nih.gov/pubmed/17854717

Journal Of Inorganic Biochemistry • October 2007

A systems biology approach to the blood-aluminium problem: the application and
testing of a computational model Author information Beardmore J1, Rugg G, Exley
C. Birchall Centre for Inorganic Chemistry and Materials Science Lennard-Jones
Laboratories, Keele University Staffordshire ST5 5BG, UK Abstract Transport and
distribution of systemic aluminium are influenced by its interaction with
blood. Current understanding is centred upon the role played by the iron
transport protein transferrin which has been shown to bind up to 90% of serum
total aluminium. We have coined what we have called the blood-aluminium problem
which states that the proportion of serum aluminium which, at any one moment in
time, is bound by transferrin is more heavily influenced by kinetic constraints
than thermodynamic equilibria with the result that the role played by
transferrin in the transport and distribution of aluminium is likely to have
been over estimated. To begin to solve the blood-aluminium problem and
therewith provide a numerical solution to the aforementioned kinetic
constraints we have applied and tested a simple computational model of the
time-dependency of a putative transferrin ligand (L) binding aluminium to form
an Al-L complex with a probability of existence, K(E), between 0% (no complex)
and 100% (complex will not dissociate). The model is based upon the principles
of a lattice-gas automaton which when ran for K(E) in the range 0.1-98.0%
demonstrated the emergence of complex behaviour which could be defined in the
terms of a set of parameters (equilibrium value, E(V), equilibrium time, E(T),
peak value, P(V), peak time, P(T), area under curve, AUC) the values of which
varied in a predictable way with K(E). When K(E) was set to 98% the model
predicted that ca. 90% of the total aluminium would be bound by transferrin
within ca. 350 simulation timesteps. We have used a systems biology approach to
develop a simple model of the time-dependency of the binding of aluminium by
transferrin. To use this approach to begin to solve the blood-aluminium problem
we shall need to increase the complexity of the model to better reflect the
heterogeneity of a biological system such as the blood.
http://www.ncbi.nlm.nih.gov/pubmed/17629565

“Aluminum is a metal with known neurotoxic properties
which are linked to encephalopathy and neurodegenerative diseases.”
Neurotoxicology • November 2007

Occupational aluminum exposure: evidence in support of its neurobehavioral
impact Author information Meyer-Baron M1, Schäper M, Knapp G, van Thriel C.
Leibniz Research Centre for Working Environment and Human Factors Ardeystr. 67,
44139 Dortmund, Germany meyerbaron@ifado.de Abstract Aluminum is a metal with
known neurotoxic properties which are linked to encephalopathy and
neurodegenerative diseases. The objectives of the current meta-analysis study
were: (1) to summarize neurobehavioral data obtained by epidemiological studies
in occupational settings and (2) to analyze confounding within these data. The
meta-analysis was based on estimates of effect sizes. Overall effect sizes were
obtained by application of a random effects model. The final sample consisted
of nine studies examining 449 exposed and 315 control subjects. The mean
urinary aluminum concentrations in the exposed groups ranged from 13 to 133
microg/l. Six neuropsychological tests, which yielded 10 performance variables,
were analyzed. Nine overall effect sizes indicated an inferior performance for
the exposed group. A significant overall effect size (d(RE)=-0.43) was obtained
for the digit symbol test measuring speed-related components of cognitive and
motor performance. Moreover, the individual effect sizes obtained for this test
suggested an exposure-response relationship. Results obtained from either raw
or adjusted mean scores revealed that confounding in the data could not be
excluded. The results were compared to studies not included here due to a
shortage of required data. Similarities were discussed in terms of sensitivity
of the tests for detecting aluminum-related changes in brain function. There
was concurring evidence from different studies that urinary Al concentrations
below 135 microg/l have an impact on cognitive performance. The significant
effect for the digit symbol might be related to its multifaceted character
which requires functioning in different components of cognitive and motor
performance. This feature could possibly turn the test into a screening
instrument for neurobehavioral effects. However, additional studies are
necessary to verify and to differentiate the effect of aluminum on cognitive
performance. From a neuropsychological perspective, implicit and explicit
memory, visuo-spatial and central odor processing should be examined. A measure
of verbal intelligence should be included in order to address the influence of
confounding. Internationally standardized exposure measures would enhance the
comparability of studies. http://www.ncbi.nlm.nih.gov/pubmed/?term=17692380

Neuromolecular Medicine • 2007

Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice
Author information Petrik MS1, Wong MC, Tabata RC, Garry RF, Shaw CA.
Department of Ophthalmology and Program in Neuroscience University of British
Columbia, Vancouver British Columbia, Canada mspetrik@interchange.ubc.ca
Abstract Gulf War illness (GWI) affects a significant percentage of veterans of
the 1991 conflict, but its origin remains unknown. Associated with some cases
of GWI are increased incidences of amyotrophic lateral sclerosis and other
neurological disorders. Whereas many environmental factors have been linked to
GWI, the role of the anthrax vaccine has come under increasing scrutiny. Among
the vaccine’s potentially toxic components are the adjuvants aluminum hydroxide
and squalene. To examine whether these compounds might contribute to neuronal
deficits associated with GWI, an animal model for examining the potential
neurological impact of aluminum hydroxide, squalene, or aluminum hydroxide
combined with squalene was developed. Young, male colony CD-1 mice were
injected with the adjuvants at doses equivalent to those given to US military
service personnel. All mice were subjected to a battery of motor and
cognitivebehavioral tests over a 6-mo period postinjections. Following
sacrifice, central nervous system tissues were examined using
immunohistochemistry for evidence of inflammation and cell death. Behavioral
testing showed motor deficits in the aluminum treatment group that expressed as
a progressive decrease in strength measured by the wire-mesh hang test (final
deficit at 24 wk; about 50%). Significant cognitive deficits in water-maze
learning were observed in the combined aluminum and squalene group (4.3 errors
per trial) compared with the controls (0.2 errors per trial) after 20 wk.
Apoptotic neurons were identified in aluminum-injected animals that showed
significantly increased activated caspase-3 labeling in lumbar spinal cord
(255%) and primary motor cortex (192%) compared with the controls.
Aluminum-treated groups also showed significant motor neuron loss (35%) and
increased numbers of astrocytes (350%) in the lumbar spinal cord. The findings
suggest a possible role for the aluminum adjuvant in some neurological features
associated with GWI and possibly an additional role for the combination of
adjuvants. http://www.ncbi.nlm.nih.gov/pubmed/17114826

“Among the vaccine’s potentially toxic components are the adjuvants aluminum
hydroxide and squalene. The findings suggest a possible role for the aluminum
adjuvant in some neurological features associated with Gulf War Illness and
possibly an additional role for the combination of adjuvants.”

Journal Of Toxicology And Environmental Health Part B Critical Reviews • 2007

Human Health Risk Assessment For Aluminum, Aluminum Oxide, And Aluminum
Hydroxide Author Information Daniel Krewski,1,2 Robert A Yokel,3 Evert
Nieboer,4 David Borchelt,5 Joshua Cohen,6 Jean Harry,7 Sam Kacew,2,8 Joan
Lindsay,9 Amal M Mahfouz,10 and Virginie Rondeau11 1. Department of
Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa,
Ottawa, Ontario, Canada 2. McLaughlin Centre for Population Health Risk
Assessment, Institute of Population Health, University of Ottawa, Ottawa,
Ontario, Canada 3. College of Pharmacy and Graduate Center for Toxicology,
University of Kentucky Medical Center, Kentucky, USA 4. Department of
Biochemistry and Biomedical Sciences, McMaster University Hamilton, Ontario,
Canada and Institute of Community Medicine, University of Tromsø, Norway 5.
SantaFe Health Alzheimer’s Disease Research Center, Department of Neuroscience,
McKnight Brain Institute, University of Florida, USA 6. Institute for Clinical
Research and Health Policy Studies, Tufts-New England Medical Center, USA 7.
National Institute of Environmental Health Sciences, NIH, Research Triangle
Park, NC, USA 8. Department of Cellular and Molecular Medicine, University of
Ottawa, Ottawa, Ontario, Canada 9. Aging-Related Diseases Section, Surveillance
Division, Public Health Agency of Canada, Ottawa, Ontario, Canada 10. United
States Environmental Protection Agency, Washington DC, USA 11. INSERM E0338
(Biostatistic), Université Victor Segalen Bordeaux 2, Bordeaux, France

Corresponding Author: Daniel Krewski Professor and Director, McLaughlin Centre
for Population Health Risk Assessment University of Ottawa, Room 320, One
Stewart Street, Ottawa, Ontario Tel: 613-562-5381, Fax: 613-562-5380 Findings
“This report classified the weight of evidence for each exposure pathway and
health effect as strong, modest, limited, or having no clear evidence (see
Table 25). We concluded that there is strong evidence that aluminum can cause
irritation following exposure via either inhalation or injection. Modest
evidence of an effect exists for reproductive toxicity following oral exposure,
for neurological toxicity following either oral or injection exposure, and for
bone toxicity following injection exposure.” Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782734/

“Modest evidence of an effect exists for reproductive toxicity following oral
exposure, for neurological toxicity following either oral or injection
exposure, and for bone toxicity following injection exposure.”

Journal Of Experimental Medicine • April 2008

Alum adjuvant boosts adaptive immunity by inducing uric acid and activating
inflammatory dendritic cells Kool M1, Soullié T, van Nimwegen M, Willart MA,
Muskens F, Jung S, Hoogsteden HC, Hammad H, Lambrecht BN. Department of
Pulmonary Medicine Erasmus University Medical Centre 3015 GD Rotterdam,
Netherlands Abstract Alum (aluminum hydroxide) is the most widely used adjuvant
in human vaccines, but the mechanism of its adjuvanticity remains unknown. In
vitro studies showed no stimulatory effects on dendritic cells (DCs). In the
absence of adjuvant, Ag was taken up by lymph node (LN)-resident DCs that
acquired soluble Ag via afferent lymphatics, whereas after injection of alum,
Ag was taken up, processed, and presented by inflammatory monocytes that
migrated from the peritoneum, thus becoming inflammatory DCs that induced a
persistent Th2 response. The enhancing effects of alum on both cellular and
humoral immunity were completely abolished when CD11c(+) monocytes and DCs were
conditionally depleted during immunization. Mechanistically, DC-driven
responses were abolished in MyD88-deficient mice and after uricase treatment,
implying the induction of uric acid. These findings suggest that alum adjuvant
is immunogenic by exploiting “nature’s adjuvant,” the inflammatory DC through
induction of the endogenous danger signal uric acid.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18362170

“Alum (aluminum hydroxide) is the most widely used adjuvant in human vaccines,
but the mechanism of its adjuvanticity remains unknown.”

Annales de Pathologie • April 2008

Late-onset vaccination-induced subcutaneous pseudolymphoma Author information
Croce S1, Lhermitte B, Tomasetto C, Guillard O, Bellocq JP, Chenard MP.
Département de Pathologie CHU de Strasbourg, hôpital de Hautepierre 1 avenue
Molière, 67098 Strasbourg cedex, France Abstract Persistent subcutaneous
nodules arise on rare occasions at sites of injection of aluminium
hydroxide-adsorbed vaccine. We report a case following a diphtheria, tetanus
and pertussis vaccination. The late onset of the lesion, four years after the
injection, led to an uncertain preoperative diagnosis. Histopathologic
examination showed features of a subcutaneous pseudolymphoma. The demonstration
of aluminium by Morin staining and atomic absorption spectrometry on a
paraffin-embedded tissue probe supported the diagnosis of a vaccination-induced
pseudolymphoma. http://www.ncbi.nlm.nih.gov/pubmed/18675172

“The late onset of the lesion, four years after the injection, led to an
uncertain preoperative diagnosis.”

Experimental Gerontology • April 2008

Effects of aluminium sulphate in the mouse liver: similarities to the aging
process Author information Stacchiotti A1, Lavazza A, Ferroni M, Sberveglieri
G, Bianchi R, Rezzani R, Rodella LF. Department of Biomedical Sciences and
Biotechnologies Brescia University, Brescia, Italy stacchio@med.unibs.it
Abstract Aluminium (Al) is a ubiquitous metal that is potentially toxic to the
brain. Its effects on other fundamental organs are not completely understood.
This morphological in vivo study sought to compare sublethal hepatotoxic
changes and Al deposition in adult mice that orally ingested Al sulphate daily
for 10 months, in age matched control mice that drank tap water and in
senescent mice (24 months old). Livers were examined for collagen deposition
using Sirius red and Masson, for iron accumulation using Perls’ stain. Light,
electron microscopy and morphometry were used to assess fibrosis and vascular
changes. Scanning transmission electron microscopy and EDX microanalysis were
used to detect in situ elemental Al. Iron deposition, transferrin receptor
expression were significantly altered following Al exposure and in the aged
liver but were unaffected in age matched control mice. In Al treated mice as in
senescent mice, endothelial thickness was increased and porosity was decreased
like perisinusoidal actin. Furthermore, Al stimulated the deposition of
collagen and laminin, mainly in acinar zones 1 and 3. Pseudocapillarization and
periportal laminin in senescent mice were similar to Al treated adult liver. In
conclusion, prolonged Al sulphate intake accelerates features of senescence in
the adult mice liver. http://www.ncbi.nlm.nih.gov/pubmed/18337038

“Aluminium (Al) is a ubiquitous metal that is potentially toxic to the brain
... prolonged Al sulphate intake accelerates features of senescence in the
adult mice liver.”

Actas Dermo-Sifiliograficas • April 2008

B-cell pseudolymphoma caused by aluminium hydroxide following hyposensitization
therapy Author information Hernández I1, Sanmartín O, Cardá C, Góme S, Alfaro
A. Servicio de Dermatología Hospital General Básico de la Defensa de Valencia
España Abstract Aluminium hydroxide is used as an adjuvant in vaccines. We
describe the case of a patient who presented a persistent adverse local
reaction to aluminium hydroxide due to hyposensitization therapy to dust mites.
Multiple painful and pruriginous subcutaneous nodules were observed in both
arms, along with hypertrichosis at the injection site. Histology revealed a
pseudolymphomatous B cell reaction predominantly involving cells that were CD20
positive, did not express bcl-2, and did not display the t(14-18)
translocation. The cells also exhibited polyclonal rearrangement of the
immunoglobulin heavy chains. X-ray spectral microanalysis revealed deposits of
inorganic aluminium in the granular histiocytes among the germinal centers. The
patient was diagnosed with cutaneous B-cell pseudolymphoma due to aluminium
hydroxide as a result of immunotherapy.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18358197

“The patient was diagnosed with cutaneous B-cell pseudolymphoma due to
aluminium hydroxide ...”

Vaccine • May 2008

Alum boosts TH2-type antibody responses to whole-inactivated virus influenza
vaccine in mice but does not confer superior protection Author information
Bungener L1, Geeraedts F, Ter Veer W, Medema J, Wilschut J, Huckriede A.
Department of Medical Microbiology, Molecular Virology Section University
Medical Center Groningen and University of Groningen Postbus 30.001, 9700 RB
Groningen, The Netherlands Abstract Clinical trials with pandemic influenza
vaccine candidates have focused on aluminium hydroxide as an adjuvant to boost
humoral immune responses. In this study we investigated the effect of aluminium
hydroxide on the magnitude and type of immune response induced by
whole-inactivated virus (WIV) vaccine. Balb/c mice were immunized once with a
range of antigen doses (0.04-5 microg) of WIV produced from A/PR/8 virus,
either alone or in combination with aluminium hydroxide. The hemagglutination
inhibition (HI) titers of mice receiving WIV+aluminium hydroxide were 4-16-fold
higher than HI titers in mice receiving the same dose of WIV alone, indicating
the boosting effect of aluminium hydroxide. WIV induced a TH1 skewed humoral
and cellular immune response, characterized by strong influenza-specific IgG2a
responses and a high number of IFNgamma-secreting T cells. In contrast,
immunization with WIV adsorbed to aluminium hydroxide resulted in skewing of
this response to a TH2 phenotype (high IgG1 levels and a low number of
IFNgammaproducing T cells). To assess the effect of the observed immune
response skewing on viral clearance from the lungs mice immunized once with 1
microg WIV without or with aluminium hydroxide were challenged with A/PR/8
virus 4 weeks later. The immunized mice showed a significant decrease in viral
lung titers compared to control mice receiving buffer. However, despite higher
antibody titers, mice immunized with WIV adsorbed to aluminium hydroxide
suffered from more severe weight loss and had significantly higher virus loads
in their lung tissue than mice receiving WIV alone. Major difference between
these groups of mice was the type of immune response induced, TH2 instead of
TH1, indicating that a TH1 response plays a major role in viral clearance.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18400340

“despite higher antibody titers, mice immunized with whole-inactivated virus
adsorbed to aluminium hydroxide suffered from more severe weight loss and had
significantly higher virus loads in their lung tissue than mice receiving
whole-inactivated virus alone.”

Food And Chemical Toxicology • June 2008

Aluminum bioavailability from basic sodium aluminum phosphate, an approved food
additive emulsifying agent, incorporated in cheese Author information Yokel
RA1, Hicks CL, Florence RL. Department of Pharmaceutical Sciences College of
Pharmacy University of Kentucky Academic Medical Center 511C Pharmacy Building,
725 Rose Street Lexington, KY 40536-0082, USA ryokel@email.uky.edu Abstract
Oral aluminum (Al) bioavailability from drinking water has been previously
estimated, but there is little information on Al bioavailability from foods. It
was suggested that oral Al bioavailability from drinking water is much greater
than from foods. The objective was to further test this hypothesis. Oral Al
bioavailability was determined in the rat from basic [26Al]-sodium aluminum
phosphate (basic SALP) in a process cheese. Consumption of approximately 1g
cheese containing 1.5% or 3% basic SALP resulted in oral Al bioavailability (F)
of approximately 0.1% and 0.3%, respectively, and time to maximum serum 26Al
concentration (Tmax) of 8-9h. These Al bioavailability results were
intermediate to previously reported results from drinking water (F
approximately 0.3%) and acidic-SALP incorporated into a biscuit (F
approximately 0.1%), using the same methods. Considering the similar oral
bioavailability of Al from food vs. water, and their contribution to the
typical human’s daily Al intake ( approximately 95% and 1.5%, respectively),
these results suggest food contributes much more Al to systemic circulation,
and potential Al body burden, than does drinking water. These results do not
support the hypothesis that drinking water provides a disproportionate
contribution to total Al absorbed from the gastrointestinal tract.
http://www.ncbi.nlm.nih.gov/pubmed/18436363

“these results suggest food contributes much more Al to systemic circulation,
and potential Al body burden, than does drinking water.”

Journal Of Child Neurology • June 2008

Macrophagic myofasciitis in children is a localized reaction to vaccination
Author information Lach B1, Cupler EJ. Department of Pathology and Laboratory
Medicine King Faisal Specialist Hospital and Research Center Riyadh, Saudi
Arabia boleklach2@hotmail.com Abstract Macrophagic myofasciitis is a novel,
“inflammatory myopathy” described after a variety of vaccinations, almost
exclusively in adults. We examined the relevance of histological findings of
this myopathy to the clinical presentation in pediatric patients. Muscle
biopsies from 8 children (7 months to 6 years old) with histological features
of macrophagic myofasciitis were reviewed and correlated with the clinical
manifestations. Patients underwent quadriceps muscle biopsy for suspected
mitochondrial disease (4 patients), spinal muscular atrophy (2 patients),
myoglobinuria (1 patient), and hypotonia with motor delay (1 patient). All
biopsies showed identical granulomas composed of periodic acid-Schiff-positive
and CD68-positive macrophages. Characteristic aluminum hydroxide crystals were
identified by electron microscopy in 2 cases. The biopsy established diagnoses
other than macrophagic myofasciitis in 5 patients: spinal muscular atrophy (2),
Duchenne muscular dystrophy (1), phospho-glycerate kinase deficiency (1), and
cytochrome c oxidase deficiency (1). Three children with manifestations and/or
a family history of mitochondrial disease had otherwise morphologically normal
muscle. All children had routine vaccinations between 2 months and 1 year
before the biopsy, with up to 11 intramuscular injections, including the biopsy
sites. There was no correlation between histological findings of macrophagic
myofasciitis in biopsies and the clinical symptoms. We believe that macrophagic
myofasciitis represents a localized histological hallmark of previous
immunization with the aluminum hydroxide adjuvants contained in vaccines,
rather than a primary or distinct inflammatory muscle disease.
http://www.ncbi.nlm.nih.gov/pubmed/18281624

“We believe that macrophagic myofasciitis represents a localized histological
hallmark of previous immunization with the aluminum hydroxide adjuvants
contained in vaccines, rather than a primary or distinct inflammatory muscle
disease.”

Brain Research • September 2008

Impairment of mitochondrial energy metabolism in different regions of rat brain
following chronic exposure to aluminium Author information Kumar V1, Bal A,
Gill KD. Department of Biochemistry Postgraduate Institute of Medical Education
and Research Chandigarh, 160 012, India Abstract The present study was designed
with an aim to evaluate the effects of chronic aluminium exposure (10 mg/kg
b.wt, intragastrically for 12 weeks) on mitochondrial energy metabolism in
different regions of rat brain in vivo. Mitochondrial preparations from
aluminium treated rats revealed significant decrease in the activity of various
electron transport complexes viz. cytochrome oxidase, NADH cytochrome c
reductase and succinic dehydrogenase as well, in the hippocampus region. The
decrease in the activity of these respiratory complexes was also seen in the
other two regions viz. corpus striatum and cerebral cortex, but to a lesser
extent. This decrease in the activities of electron transport complexes in turn
affected the ATP synthesis and ATP levels adversely in the mitochondria
isolated from aluminium treated rat brain regions. We also studied the spectral
properties of the mitochondrial cytochromes viz. cyt a, cyt b, cyt c1, and cyt
c in both control and treated rat brains. The various cytochrome levels were
found to be decreased following 12 weeks of aluminium exposure. Further, these
impairments in mitochondrial functions may also be responsible for the
production of reactive oxygen species and impaired antioxidant defense system
as observed in our study. The electron micrographs of neuronal cells depicted
morphological changes in mitochondria as well as nucleus only from hippocampus
and corpus striatum regions following 12 weeks exposure to aluminium. The
present study thus highlights the significance of altered mitochondrial energy
metabolism and increased ROS production as a result of chronic aluminium
exposure in different regions of the rat brain.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18691561

“The present study thus highlights the significance of altered mitochondrial
energy metabolism and increased ROS production as a result of chronic aluminium
exposure in different regions of the rat brain.”

“Select human population can be at risk of Aluminum neurotoxicity,
and Aluminum is proposed to be involved in the etiology of neurodegenerative
diseases.” Archives Of Toxicology • November 2008

Aluminium and lead: molecular mechanisms of brain toxicity Author information
Verstraeten SV1, Aimo L, Oteiza PI. Department of Biological Chemistry, IIMHNO
(UBA) and IQUIFIB (UBA-CONICET) School of Pharmacy and Biochemistry, University
of Buenos Aires, Buenos Aires, Argentina Abstract The fact that aluminium (Al)
and lead (Pb) are both toxic metals to living organisms, including human
beings, was discovered a long time ago. Even when Al and Pb can reach and
accumulate in almost every organ in the human body, the central nervous system
is a particular target of the deleterious effects of both metals. Select human
population can be at risk of Al neurotoxicity, and Al is proposed to be
involved in the etiology of neurodegenerative diseases. Pb is a widespread
environmental hazard, and the neurotoxic effects of Pb are a major public
health concern. In spite of the numerous efforts and the accumulating evidence
in this area of research, the mechanisms of Al and Pb neurotoxicity are still
not completely elucidated. This review will particularly address the
involvement of oxidative stress, membrane biophysics alterations, deregulation
of cell signaling, and the impairment of neurotransmission as key aspects
involved Al and Pb neurotoxicity. http://www.ncbi.nlm.nih.gov/pubmed/18668223

“Aluminium has been implicated in various neurodegenerative diseases
but exact mechanism of action is still not known.” Toxicology • January 2009

Susceptibility of mitochondrial superoxide dismutase to aluminium induced
oxidative damage Author information Kumar V1, Bal A, Gill KD. Department of
Biochemistry Postgraduate Institute of Medical Education and Research
Chandigarh 160012, India Abstract Aluminium has been implicated in various
neurodegenerative diseases but exact mechanism of action is still not known.
Mitochondria being a major site of reactive oxygen species production are
considered to be target of oxidative stress and it seems that the oxidative
damage to mitochondrial proteins may underlie the pathogenesis of aluminium
induced neurodegeneration. Thus, the present study was undertaken to reveal the
effects of chronic aluminium exposure (10mg/kg b.wt, intragastrically for 12
weeks) on the oxidative damage to mitochondrial proteins in male albino Wistar
rats. Chronic aluminium exposure resulted in decrease in the activity of
mitochondrial superoxide dismutase (MnSOD) and aconitase in different regions
of rat brain suggesting increased oxidative stress. This decrease in MnSOD
activity in turn might be responsible for the increased protein oxidation as
observed in our study. All these processes taken together may cause increased
oxidative damage to mitochondrial proteins in general. By taking the advantage
of recent immunochemical probe for oxidatively modified proteins, we identified
MnSOD to be susceptible to oxidative damage in aluminium treated animals. The
quantitative RTPCR analysis for Lon protease, a protease involved in the
removal of oxidatively modified proteins from mitochondria, showed decreased
mRNA expression suggesting increased oxidative damage and decreased removal of
mitochondrial proteins. The identification of specific proteins as targets of
oxidative damage may provide new therapeutic measures to reverse the effects of
aluminium induced neurodegeneration.
http://www.ncbi.nlm.nih.gov/pubmed/19010380

Medical Hypotheses • February 2009

A role for the body burden of aluminium in vaccine-associated macrophagic
myofasciitis and chronic fatigue syndrome Author information Exley C1,
Swarbrick L, Gherardi RK, Authier FJ. Birchall Centre for Inorganic Chemistry
and Materials Science Keele University, Staffordshire ST5 5BG, UK
c.exley@chem.keele.ac.uk Abstract Macrophagic myofasciitis and chronic fatigue
syndrome are severely disabling conditions which may be caused by adverse
reactions to aluminiumcontaining adjuvants in vaccines. While a little is known
of disease aetiology both conditions are characterised by an aberrant immune
response, have a number of prominent symptoms in common and are coincident in
many individuals. Herein, we have described a case of vaccine-associated
chronic fatigue syndrome and macrophagic myofasciitis in an individual
demonstrating aluminium overload. This is the first report linking the latter
with either of these two conditions and the possibility is considered that the
coincident aluminium overload contributed significantly to the severity of
these conditions in this individual. This case has highlighted potential
dangers associated with aluminium-containing adjuvants and we have elucidated a
possible mechanism whereby vaccination involving aluminium-containing adjuvants
could trigger the cascade of immunological events which are associated with
autoimmune conditions including chronic fatigue syndrome and macrophagic
myofasciitis. http://www.ncbi.nlm.nih.gov/pubmed/19004564

“This case has highlighted potential dangers associated with
aluminium-containing adjuvants and we have elucidated a possible mechanism
whereby vaccination involving aluminium-containing adjuvants could trigger the
cascade of immunological events which are associated with autoimmune conditions
including chronic fatigue syndrome and macrophagic myofasciitis.”

Journal Of Inorganic Biochemistry • August 2009

Guest editorial ‘The natural history of aluminium: from non-selection to
natural selection’. Author Information Christopher Exley Keele University
Birchall Centre for Inorchanic Chemistry and Materials Science Lennard-Jones
Laboratories, Keele Staffordshire ST5 5BG, UK Abstract “Al accumulates in the
body with age and particularly so when exposure is high and/or protective
gastrointestinal mechanisms are bypassed or renal function is impaired (Kisters
et al., 1999). Al toxicity in humans, even at low levels of exposure (Exley,
2009b), is a well-established fact and the brain is a target organ for Al to
exert its deleterious effects (Exley et al., 1996; Exley, 1999; Yokel et al.,
1999). The molecular mechanisms of Al neurotoxicity are not completely
understood: Al has been reported to alter the blood-brain barrier (Zatta et
al., 2003) and is deposited in the human brain (Exley and House, 2011). “

“Aluminum toxicity in humans, even at low levels of exposure, is a
well-established fact and the brain is a target organ for Aluminum to exert its
deleterious effects. The molecular mechanisms of Al neurotoxicity are not
completely understood: Aluminum has been reported to alter the blood-brain
barrier and is deposited in the human brain ...”

https://www.researchgate.net/publication/26763878_Guest_editorial_%27The_natural_history_of_aluminium_from_non-selection_to_natural_selection%27

“... our findings indicate that fatty acids common in food
increase the paracellular intestinal absorption of Aluminum.”
Chemical-Biological Interactions • October 2009

Fatty acids increase paracellular absorption of aluminium across Caco-2 cell
monolayers Author information Aspenström-Fagerlund B1, Sundström B, Tallkvist
J, Ilbäck NG, Glynn AW. Toxicology Division National Food Administration
Uppsala, Sweden bfas@slv.se Abstract Passive paracellular absorption, regulated
by tight junctions (TJs), is the main route for absorption of poorly absorbed
hydrophilic substances. Surface active substances, such as fatty acids, may
enhance absorption of these substances by affecting the integrity of TJ and
increasing the permeability. It has been suggested that aluminium (Al)
absorption occurs mainly by the paracellular route. Herein, we investigated if
physiologically relevant exposures of fully differentiated Caco-2 cell
monolayers to oleic acid and docosahexaenoic acid (DHA), which are fatty acids
common in food, increase absorption of Al and the paracellular marker mannitol.
In an Al toxicity test, mannitol and Al absorption through Caco-2 cell
monolayers were similarly modulated by Al concentrations between 1 and 30mM,
suggesting that absorption of the two compounds occurred via the same pathways.
Exposure of Caco-2 cell monolayers to non-toxic concentrations of Al (2mM) and
(14)C-mannitol in fatty acid emulsions (15 and 30mM oleic acid, 5 and 10mM DHA)
caused a decreased transepithelial electrical resistance (TEER). Concomitantly,
fractional absorption of Al and mannitol, expressed as percentage of apical Al
and mannitol retrieved at the basolateral side, increased with increasing dose
of fatty acids. Transmission electron microscopy was applied to assess the
effect of oleic acid on the morphology of TJ. It was shown that oleic acid
caused a less structured morphology of TJ in Caco-2 cell monolayers. Taken
together our findings indicate that fatty acids common in food increase the
paracellular intestinal absorption of Al. These findings may influence future
risk assessment of human Al exposure.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19576870

Archives Of Toxicology • November 2009

Aluminium neurotoxicity: neurobehavioural and oxidative aspects

“Aluminium is the most widely distributed

Author information

metal in the environment and is extensively

Kumar V1, Gill KD.

used in daily life that provides easy exposure

Abstract Aluminium is the most widely distributed metal in the environment and
is extensively used in daily life that provides easy exposure to human beings.
The exposure to this toxic metal occurs through air, food and water. However,
there is no known physiological role for aluminium within the body and hence
this metal may produce adverse physiological effects. Chronic exposure of
animals to aluminium is associated with behavioural, neuropathological and
neurochemical changes. Among them, deficits of learning and behavioural
functions are most evident. Some epidemiological studies have shown poor
performance in cognitive tests and a higher abundance of neurological symptoms
for workers occupationally exposed to aluminium. However, in contrast to well
established neurotoxic effects, neurobehavioural studies of aluminium in
rodents have generally not produced consistent results. Current researches show
that any impairment in mitochondrial functions may play a major role in many
human disorders including neurodegenerative disorders. Being involved in the
production of reactive oxygen species, aluminium may cause impairments in
mitochondrial bioenergetics and may lead to the generation of oxidative stress
which may lead to a gradual accumulation of oxidatively modified cellular
proteins. In this review, the neuropathologies associated with aluminium
exposure in terms of neurobehavioural changes have been discussed. In addition,
the impact of aluminium on the mitochondrial functions has also been
highlighted. http://www.ncbi.nlm.nih.gov/pubmed/?term=19568732

to human beings. The exposure to this toxic metal occurs through air, food and
water. However, there is no known physiological role for aluminium within the
body and hence this metal may produce adverse physiological effects. Chronic
exposure of animals to aluminium is associated with behavioural,
neuropathological and neurochemical changes. Among them, deficits of learning
and behavioural functions are most evident.”

Journal Of Inorganic Biochemistry • November 2009

Long-term persistence of vaccine-derived aluminum hydroxide is associated with
chronic cognitive dysfunction Author information Couette M1, Boisse MF, Maison
P, Brugieres P, Cesaro P, Chevalier X, Gherardi RK, Bachoud-Levi AC, Authier
FJ. INSERM, Unite U955, Team 1, Creteil F-94010, France Abstract Macrophagic
myofasciitis (MMF) is an emerging condition, characterized by specific muscle
lesions assessing long-term persistence of aluminum hydroxide within
macrophages at the site of previous immunization. Affected patients mainly
complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We
designed a comprehensive battery of neuropsychological tests to prospectively
delineate MMF-associated cognitive dysfunction (MACD). Compared to control
patients with arthritis and chronic pain, MMF patients had pronounced and
specific cognitive impairment. MACD mainly affected (i) both visual and verbal
memory; (ii) executive functions, including attention, working memory, and
planning; and (iii) left ear extinction at dichotic listening test. Cognitive
deficits did not correlate with pain, fatigue, depression, or disease duration.
Pathophysiological mechanisms underlying MACD remain to be determined. In
conclusion, long-term persistence of vaccine-derived aluminum hydroxide within
the body assessed by MMF is associated with cognitive dysfunction, not solely
due to chronic pain, fatigue and depression.
http://www.ncbi.nlm.nih.gov/pubmed/19748679

“In conclusion, long-term persistence of vaccine-derived aluminum hydroxide
within the body assessed by MMF is associated with cognitive dysfunction, not
solely due to chronic pain, fatigue and depression.”

Journal Of Inorganic Biochemistry • November 2009

Aluminum hydroxide injections ‘ lead to motor deficits and motor neuron
degeneration Author information Shaw CA1, Petrik MS. Departments of
Ophthalmology and Visual Sciences University of British Columbia, Vancouver
British Columbia, Canada cashawlab@gmail.com Abstract Gulf War Syndrome is a
multi-system disorder afflicting many veterans of Western armies in the
1990-1991 Gulf War. A number of those afflicted may show neurological deficits
including various cognitive dysfunctions and motor neuron disease, the latter
expression virtually indistinguishable from classical amyotrophic lateral
sclerosis (ALS) except for the age of onset. This ALS “cluster” represents the
second such ALS cluster described in the literature to date. Possible causes of
GWS include several of the adjuvants in the anthrax vaccine and others. The
most likely culprit appears to be aluminum hydroxide. In an initial series of
experiments, we examined the potential toxicity of aluminum hydroxide in male,
outbred CD-1 mice injected subcutaneously in two equivalent-to-human doses.
After sacrifice, spinal cord and motor cortex samples were examined by
immunohistochemistry. Aluminum-treated mice showed significantly increased
apoptosis of motor neurons and increases in reactive astrocytes and microglial
proliferation within the spinal cord and cortex. Morin stain detected the
presence of aluminum in the cytoplasm of motor neurons with some neurons also
testing positive for the presence of hyper-phosphorylated tau protein, a
pathological hallmark of various neurological diseases, including Alzheimer’s
disease and frontotemporal dementia. A second series of experiments was
conducted on mice injected with six doses of aluminum hydroxide. Behavioural
analyses in these mice revealed significant impairments in a number of motor
functions as well as diminished spatial memory capacity. The demonstrated
neurotoxicity of aluminum hydroxide and its relative ubiquity as an adjuvant
suggest that greater scrutiny by the scientific community is warranted.
http://www.ncbi.nlm.nih.gov/pubmed/19740540

“Possible causes of Gulf War Syndrome include several of the adjuvants in the
anthrax vaccine and others. The most likely culprit appears to be aluminum
hydroxide.”

Nanomedicine • December 2009

Glia activation induced by peripheral administration of aluminum oxide
nanoparticles in rat brains Author information Li XB1, Zheng H, Zhang ZR, Li M,
Huang ZY, Schluesener HJ, Li YY, Xu SQ. MOE Key Lab, Institute of Environmental
Medicine School of Public Health, Tongji Medical College Huazhong University of
Science and Technology Wuhan, China Abstract With the wide application of
nanoscaled particles, the risk of human exposure to these particles has been
markedly increased. However, knowledge about their safety falls far behind the
utility of these nanoparticles. Here we have analyzed the activation of brain
microglia and astrocytes, which are sensitive to changes of brain environment
after peripheral exposure to nanoscaled aluminum oxide suspension.
Sprague-Dawley rats (six rats per treatment) were intraperitoneally injected
once every second day for 30 or 60 days with nanoscaled aluminum oxide (NSAO; 1
mg/kg or 50 mg/kg), non-nanoscaled aluminum oxide (nNSAO, 1 mg/kg), or vehicle
(saline). After 60 days’ exposure the numbers of ED1+, GFAP+, and nestin+ cells
in cortex and hippocampus were significantly higher in NSAO-treated rats than
nNSAO- or vehicle-treated rats; thus, compared with nNSAO, NSAO has potential
effects on the innate immune system of rat brain. This should be considered
when evaluating the toxicological effects of nanosized particles. From The
Clinical Editor Sprague-Dawley rats were intraperitoneally injected with
nanosized aluminum oxide, (NSAO); non-nanoscaled aluminum oxide, or vehicle
(saline). The numbers of ED1+, GFAP+, and nestin+ cells in cortex and
hippocampus were significantly higher in NSAO-treated rats than nNSAO- or
vehicletreated rats; thus, NSAO has potential effects on the innate immune
system of rat brain. http://www.ncbi.nlm.nih.gov/pubmed/19523415

“With the wide application of nanoscaled particles, the risk of human exposure
to these particles has been markedly increased. However, knowledge about their
safety falls far behind the utility of these nanoparticles ... [aluminum] has
potential effects on the innate immune system of rat brain.”

CellPress Nucleus
Mitochondria & Metabolism Volume 34, Issue 12, p589–593, December 2009

Darwin, natural selection and the biological essentiality of aluminium and
silicon by Christopher Exley The Birchall Centre, Lennard-Jones Laboratories,
Keele University, Staffordshire, ST5 5BG, UK Absract If one was asked to
produce a set of ‘Trump Cards™’ based upon ‘Forces of Nature Defining Life on
Earth’ then which card would be ‘Top Trump’? I was recently chastised on the
Darwin Today website for suggesting Darwin and ‘natural selection’ rather than,
for example, Newton and ‘gravity’. Although there is no denying the
significance of gravity, my argument in favour of natural selection is simply
that gravity is just one factor that contributes towards an outcome which
ultimately is defined by natural selection. Both the beauty and the brilliance
of natural selection are reflected in its omnipotence to explain the myriad
observations of life and, as I will affirm herein, its explanation of the
biological essentiality of aluminium and silicon is no exception. Together they
constitute a form of homeostasis with aluminium being retained both physically
and chemically in myriad forms and each form being capable of acting as a sink
or source of labile and potentially biologically reactive aluminium. It is
always important to emphasise that there is no evolutionarily directed or
conserved biology to enable aluminium homeostasis and so this non-essential but
highly biologically reactive metal cation is at the whim of the predominant or
pre-eminent chemistry of any particular environment [8] [9]. This
unpredictability makes biologically available aluminium a concern for all forms
of life on Earth [2]. In this year, 200th anniversary of the birth of Charles
Darwin and the 150th anniversary of the publication of On the Origin of
Species, a UK scientist has used Darwin’s seminal work on Natural Selection in
helping to define the biological essentiality of the second (silicon) and third
(aluminium) most abundant elements of the Earth’s crust.

means that those characteristics which convey fitness in one environment may
not convey fitness in another, perhaps adjacent, environment or niche. This is
both the strength and the beauty of natural selection and it can be applied to
cellular biochemistry as it is applied to speciation of organisms.

“This unpredictability

Aluminium is biologically reactive, while silicon is biologically inert.
Natural selection informs us that the non-essentiality of aluminium is
explained by its non-participation in biochemical evolution due to a complete
lack of its biologically reactive forms.

available aluminium

On the other hand the biologically available form of silicon (silicic acid) has
been extremely abundant throughout biochemical evolution and its biological
essentiality has been dictated by its extremely limited biological reactivity.

makes biologically

a concern for all forms of life on Earth.”

It is no coincidence that one of the very few reactions of silicic acid is that
with aluminium and that this reaction protects against the toxicity of
aluminium. An essential role of silicon throughout biochemical evolution has
been to keep aluminium out of life! However, the activities of humans in
learning how to extract aluminium from its ores and using it in myriad ways in
what is now the Aluminium Age means that Earth’s inherent protection against
the toxicity of aluminium is being compromised and that biologically reactive
aluminium is now an active participant in biochemical (and hence human)
evolution.

The lack of any clear or significant biological essentiality for both of these
elements is a mystery as all other abundant elements of the Earth’s crust are
known to be biologically essential.

Some of the early results of the arrival of biochemically reactive aluminium
have been worryingly obvious, including the death of fish and trees in
geographical regions impacted by acid deposition, whereas others, and perhaps
those which in particular are linked with the human condition, might yet be too
subtle to be directly attributable to the participation of
biologically-reactive aluminium in the natural selection of the elements of
biological essentiality.

Dr Chris Exley, Reader in Bioinorganic Chemistry at Keele University and a
world authority on the ways in which aluminium impacts upon life on Earth, says
natural selection is often interpreted as ‘survival of the fittest’ but what is
often not appreciated is that the selection processes themselves are niche
driven, which

Link: I can’t provide a link for this report and I’m certain that this is not
the complete report. The text above consists of excerpts found in other reports
that reference this one using a variety of internet search terms. The complete
document requires purchase:

http://www.cell.com/trends/biochemical-sciences/abstract/S0968-0004(09)00167-4?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0968000409001674%3Fshowall%3Dtrue

Trends In Immunology • March 2010

The immunobiology of aluminium adjuvants: how do they really work? Author
information Exley C1, Siesjö P, Eriksson H. The Birchall Centre Lennard-Jones
Laboratories Keele University, Staffordshire, ST5 5BG, UK
c.exley@chem.keele.ac.uk Abstract Aluminium adjuvants potentiate the immune
response, thereby ensuring the potency and efficacy of typically sparingly
available antigen. Their concomitant critical importance in mass vaccination
programmes may have prompted recent intense interest in understanding how they
work and their safety. Progress in these areas is stymied, however, by a lack
of accessible knowledge pertaining to the bioinorganic chemistry of aluminium
adjuvants, and, consequently, the inappropriate application and interpretation
of experimental models of their mode of action. The objective herein is,
therefore, to identify the many ways that aluminium chemistry contributes to
the wide and versatile armoury of its adjuvants, such that future research
might be guided towards a fuller understanding of their role in human
vaccinations. http://www.ncbi.nlm.nih.gov/pubmed/20153253

“Progress in these areas [aluminum research] is stymied, however, by a lack of
accessible knowledge pertaining to the bioinorganic chemistry of aluminium
adjuvants, and, consequently, the inappropriate application and interpretation
of experimental models of their mode of action.”

“Preterm neonates receiving parenteral nutrition are at risk of aluminum overload
because of the presence of aluminum as a contaminant in parenteral
formulations. Despite US Food and Drug Administration regulation, commercial
products continue to present Al contamination. Moreover, premature neonates
were receiving, on average, 3 times the amount considered by the Food and Drug
Administration as a safe limit.” Journal Of Pediatric Gastroenterology And
Nutrition • August 2010

Aluminum loading in preterm neonates revisited Author information Bohrer D1,
Oliveira SM, Garcia SC, Nascimento PC, Carvalho LM. Department of Chemistry
Universidade Federal de Santa Maria Santa Maria, RS, Brazil
ndenise@quimica.ufsm.br Abstract Preterm neonates receiving parenteral
nutrition are at risk of aluminum (Al) overload because of the presence of Al
as a contaminant in parenteral formulations. Despite US Food and Drug
Administration regulation, commercial products continue to present Al
contamination. To reassess Al exposure in the premature neonatal population,
the present study evaluated the Al balance (intake vs urinary excretion) in a
group of preterm neonates during the period in which they stayed in the
intensive care unit (NICU) under total parenteral nutrition. For the 10
patients selected, daily infusion solutions (nutrition and medication) were
collected and the level of Al contamination was measured. From the urine
collected daily, an aliquot was taken for Al determination. Blood was also
collected for Al determination on the first and last day in the NICU. The
measurements were carried out by atomic absorption spectrometry. The difference
between Al administered and excreted revealed that 56.2% +/- 22.7% of the Al
intake was not eliminated. The mean serum Al levels from the first to the last
day decreased from 41.2 +/- 23.3 to 23.5 +/- 11.2 microg/L. The resulting mean
Al daily intake of the 10 patients was 15.2 +/- 8.0 microg x kg(-1) x day(-1).
Because Al intake was higher than that excreted and Al in serum decreased to
practically half during the period in the NICU (+/-7.3 days), some amount of Al
deposition occurred. Moreover, premature neonates were receiving, on average, 3
times the amount of 5 microg x kg(-1) x day(-1), considered by the Food and
Drug Administration as a safe limit.
http://www.ncbi.nlm.nih.gov/pubmed/?term=20479688

“... the vulnerability of infants to early exposure to aluminium serves to highlight
an urgent need to reduce the aluminium content of infant formulas ...” BMC
Pediatrics • August 2010

There is (still) too much aluminium in infant formulas Author information
Burrell SA1, Exley C. The Birchall Centre, Lennard-Jones Laboratories, Keele
University, Staffordshire, UK Abstract BACKGROUND Infant formulas are
sophisticated milk-based feeds for infants which are used as a substitute for
breast milk. Historically they are known to be contaminated by aluminium and in
the past this has raised health concerns for exposed infants. We have measured
the aluminium content of a number of widely used infant formulas to determine
if their contamination by aluminium and consequent issues of child health
persists. METHODS Samples of ready-made milks and powders used to make milks
were prepared by microwave digestion of acid/peroxide mixtures and their
aluminium content determined by THGA. RESULTS The concentration of aluminium in
ready-made milks varied from ca 176 to 700 μg/L. The latter concentration was
for a milk for preterm infants. The aluminium content of powders used to make
milks varied from ca 2.4 to 4.3 μg/g. The latter content was for a soya-based
formula and equated to a ready-to-drink milk concentration of 629 μg/L. Using
the manufacturer’s own guidelines of formula consumption the average daily
ingestion of aluminium from infant formulas for a child of 6 months varied from
ca 200 to 600 μg of aluminium. Generally ingestion was higher from powdered as
compared to ready-made formulas. CONCLUSIONS The aluminium content of a range
of well known brands of infant formulas remains high and particularly so for a
product designed for preterm infants and a soya-based product designed for
infants with cow’s milk intolerances and allergies. Recent research
demonstrating the vulnerability of infants to early exposure to aluminium
serves to highlight an urgent need to reduce the aluminium content of infant
formulas to as low a level as is practically possible. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939626/

Neurotoxicology • September 2010

The neurotoxicity of environmental aluminum is still an issue Author
information Bondy SC. Program in Environmental Toxicology Division Occupational
and Environmental Health Department of Medicine, University of California
Irvine, CA 92697-1825, USA scbondy@uci.edu

“Emphasis is given to the potential role of aluminum in

Abstract

acceleration and promotion of

Evidence for the neurotoxicity of extended exposure to low levels of aluminum
salts is described using an animal model treated with aluminum at low levels
reflecting those found in some water supplies. Emphasis is given to the
potential role of aluminum in acceleration and promotion of some indices
characteristic of brain aging. These hallmarks include the appearance of excess
levels of inflammation in specific brain areas. Aluminum salts can increase
levels of glial activation, inflammatory cytokines and amyloid precursor
protein within the brain. Both normal brain aging and to a greater extent,
Alzheimer’s disease are associated with elevated basal levels of markers for
inflammation. These are not attributable to obvious exogenous stimuli and may
reflect the lifespan history of the organism’s immune responses. It is possible
that aluminum salts can act as a subtle promoter of such apparently unprovoked
responses.

some indices characteristic of

http://www.ncbi.nlm.nih.gov/pubmed/?term=20553758

brain aging. These hallmarks include the appearance of excess levels of
inflammation in specific brain areas.”

Journal Of Exposure Science & Environmental Epidemiology • November 2010

Infants’ exposure to aluminum from vaccines and breast milk during the first 6
months Author information Dórea JG1, Marques RC. Department of Nutrition
Universidade de Brasília Brasília, DF, Brazil dorea@rudah.com.br Abstract The
success of vaccination programs in reducing and eliminating infectious diseases
has contributed to an ever-increasing number of vaccines given at earlier ages
(newborns and infants). Exposure to low levels of environmental toxic
substances (including metals) at an early age raises plausible concerns over
increasingly lower neuro-cognitive rates. Current immunization schedules with
vaccines containing aluminum (as adjuvant) are given to infants, but thimerosal
(as preservative) is found mostly in vaccines used in non-industrialized
countries. Exclusively, breastfed infants (in Brazil) receiving a full
recommended schedule of immunizations showed an exceedingly high exposure of Al
(225 to 1750 μg per dose) when compared with estimated levels absorbed from
breast milk (2.0 μg). This study does not dispute the safety of vaccines but
reinforces the need to study long-term effects of early exposure to neuro-toxic
substances on the developing brain. Pragmatic vaccine safety needs to embrace
conventional toxicology, addressing especial characteristics of unborn fetuses,
neonates and infants exposed to low levels of aluminum, and ethylmercury
traditionally considered innocuous to the central nervous system.
http://www.ncbi.nlm.nih.gov/pubmed/20010978

“Exclusively, breastfed infants (in Brazil) receiving a full recommended
schedule of immunizations showed an exceedingly high exposure of Aluminum (225
to 1750 μg per dose) when compared with estimated levels absorbed from breast
milk (2.0 μg).”

Pharmacological Reports • November 2010

Effects of ethylene glycol ethers on cell viability in the human neuroblastoma
SH-SY5Y cell line Author information Regulska M1, Pomierny B, Basta-Kaim A,
Starek A, Filip M, Lason W, Budziszewska B. Department of Experimental
Neuroendocrinology Institute of Pharmacology Polish Academy of Sciences Sm∼tna
12, PL 31-343 Kraków, Poland Abstract Ethylene glycol ethers (EGEs) are a class
of chemicals used extensively in the manufacture of a wide range of domestic
and industrial products, which may result in human exposure and toxicity.
Hematologic and reproductive toxicity of EGEs are well known whereas their
action on neuronal cell viability has not been studied so far. In the present
study, we investigated the effects of some EGEs on cell viability and on the
hydrogen peroxide-induced damage in the human neuroblastoma (SH-SY5Y) cells. It
has been found that 2-phenoxyethanol in a concentration-dependent manner (5-25
mM, 24 h) increased the basal and H(2)O(2)-induced lactate dehydrogenase (LDH)
release and 3-[4,5-dimethylthiazol-2-yl]2,5-diphenyl tetrazolium bromide (MTT)
reduction. 2-Butoxyethanol given alone did not affect LDH release and MTT
reduction but concentration-dependently enhanced the cytotoxic effect of
H(2)O(2). 2-Isopropoxyethanol significantly and concentration-dependently (1-25
mM) increased the basal LDH release and attenuated MTT reduction, but did not
potentiate the cytotoxic effect of H(2)O(2). Contrary to this, 2-methoxyethanol
did not show a cytotoxic effect while 2-ethoxyethanol at high concentrations
intensified the hydrogen peroxide action. This study demonstrated that among
the EGEs studied, 2-phenoxyethanol showed the most consistent cytotoxic effect
on neurons in in vitro conditions and enhanced the hydrogen peroxide action.
2-Isopropoxyethanol had also a potent cytotoxic effect, but it did not enhance
the hydrogen peroxide action, whereas 2-butoxyethanol only potentiated
cytotoxic effect of H(2)O(2). It is concluded that the results of the present
study should be confirmed in in vivo conditions and that some EGEs, especially
2-phenoxyethanol, 2-butoxyethanol and 2-isopropoxyethanol, may be responsible
for initiation or exacerbation of neuronal cell damage.
http://www.ncbi.nlm.nih.gov/pubmed/?term=21273685

“2-phenoxyethanol showed the most consistent cytotoxic effect on neurons in in
vitro conditions and enhanced the hydrogen peroxide action.”

Environmental Health And Preventative Medicine • January 2011

Gene expression in primary cultured astrocytes affected by aluminum: alteration
of chaperons involved in protein folding Author information Aremu DA1, Ezomo
OF, Meshitsuka S. Division of Integrative Bioscience Institute for Regenerative
Medicine and Biofunction Graduate School of Medical Science Tottori University,
Yonago, Tottori, 683-8503, Japan Abstract OBJECTIVES Aluminum is notorious as a
neurotoxic metal. The aim of our study was to determine whether endoplasmic
reticulum (ER) stress is involved in aluminum-induced apoptosis in astrocytes.

“The results of this study

METHODS Mitochondrial RNA (mRNA) was analyzed by reverse transcription (RT)-PCR
following pulse exposure of aluminum glycinate to primary cultured astrocytes.
Tunicamycin was used as a positive control.

apoptosis in astrocytes via ER stress by

RESULTS Gene expression analysis revealed that Ire1∼ was up-regulated in
astrocytes exposed to aluminum while Ire1 was up-regulated by tunicamycin.
Exposure to aluminum glycinate, in contrast to tunicamycin, seemed to
down-regulate mRNA expression of many genes, including the ER resident
molecular chaperone BiP/Grp78 and Ca(2+)-binding chaperones (calnexin and
calreticulin), as well as stanniocalcin 2 and OASIS. The down-regulation or
non-activation of the molecular chaperons, whose expressions are known to be
protective by increasing protein folding, may spell doom for the adaptive
response. Exposure to aluminum did not have any significant effects on the
expression of Bax and Bcl2 in astrocytes. CONCLUSIONS The results of this study
demonstrate that aluminum may induce apoptosis in astrocytes via ER stress by
impairing the protein-folding machinery.
http://www.ncbi.nlm.nih.gov/pubmed/21432213

demonstrate that aluminum may induce

impairing the protein-folding machinery.”

“aluminum (Al), plays a relevant role in affecting Aß aggregation and neurotoxicity.”
PLoS One • January 2011

Microarray Analysis on Human Neuroblastoma Cells Exposed to Aluminum,
ß1–42-Amyloid or the ß1–42-Amyloid Aluminum Complex Valentina Gatta, Denise
Drago, Karina Fincati, Maria Teresa Valenti, Luca Dalle Carbonare, Stefano L.
Sensi, Paolo Zatta Abstract Background A typical pathological feature of
Alzheimer’s disease (AD) is the appearance in the brain of senile plaques made
up of ß-amyloid (Aß) and neurofibrillary tangles. AD is also associated with an
abnormal accumulation of some metal ions, and we have recently shown that one
of these, aluminum (Al), plays a relevant role in affecting Aß aggregation and
neurotoxicity. Methodology In this study, employing a microarray analysis of
35,129 genes, we investigated the effects induced by the exposure to the
Aß1–42-Al (Aß-Al) complex on the gene expression profile of the neuronal-like
cell line, SH-SY5Y. Principal Findings The microarray assay indicated that,
compared to Aß or Al alone, exposure to Aß-Al complex produced selective
changes in gene expression. Some of the genes selectively over or
underexpressed are directly related to AD. A further evaluation performed with
Ingenuity Pathway analysis revealed that these genes are nodes of networks and
pathways that are involved in the modulation of Ca2+ homeostasis as well as in
the regulation of glutamatergic transmission and synaptic plasticity.
Conclusions and Significance Aß-Al appears to be largely involved in the
molecular machinery that regulates neuronal as well as synaptic dysfunction and
loss. Aß-Al seems critical in modulating key AD-related pathways such as
glutamatergic transmission, Ca2+ homeostasis, oxidative stress, inflammation,
and neuronal apoptosis.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015965#authcontrib

Monatshefte für Chemie - Chemical Monthly • April 2011

Aluminium in the human brain Christopher Exley , Emily R. House Abstract An
inevitable consequence of humans living in the Aluminium Age is the presence of
aluminium in the brain. This non-essential, neurotoxic metal gains entry to the
brain throughout all stages of human development, from the foetus through to
old age. Human exposure to myriad forms of this ubiquitous and omnipresent
metal makes its presence in the brain inevitable, while the structure and
physiology of the brain makes it particularly susceptible to the accumulation
of aluminium with age. In spite of aluminium’s complete lack of biological
essentiality, it actually participates avidly in brain biochemistry and
substitutes for essential metals in critical biochemical processes. The degree
to which such substitutions are disruptive and are manifested as biological
effects will depend upon the biological availability of aluminium in any
particular physical or chemical compartment, and will under all circumstances
be exerting an energy load on the brain. In short, the brain must expend energy
in its ‘unconscious’ response to an exposure to biologically available
aluminium. There are many examples where ‘biological effect’ has resulted in
aluminium-induced neurotoxicity and most potently in conditions that have
resulted in an aluminium-associated encephalopathy. However, since aluminium is
non-essential and not required by the brain, its biological availability will
only rarely achieve such levels of acuity, and it is more pertinent to consider
and investigate the brain’s response to much lower though sustained levels of
biologically reactive aluminium. This is the level of exposure that defines the
putative role of aluminium in chronic neurodegenerative disease and, though
thoroughly investigated in numerous animal models, the chronic toxicity of
aluminium has yet to be addressed experimentally in humans. A feasible test of
the ‘aluminium hypothesis’, whereby aluminium in the human brain is implicated
in chronic neurodegenerative disease, would be to reduce the brain’s aluminium
load to the lowest possible level by non-invasive means. The simplest way that
this aim can be fulfilled in a significant and relevant population is by
facilitating the urinary excretion of aluminium through the regular drinking of
a silicic acid-rich mineral water over an extended time period. This will lower
the body and brain burden of aluminium, and by doing so will test whether brain
aluminium contributes significantly to chronic neurodegenerative diseases such
as Alzheimer’s and Parkinson’s.
http://link.springer.com/article/10.1007%2Fs00706-010-0417-y

Vaccine • August 2011
Letter to the Editor

Aluminium-based adjuvants should not be used as placebos in clinical trials by
Christopher Exley The Birchall Centre, Lennard-Jones Laboratories, Keele
University, Staffordshire, UK August 2011 Report available for purchase $39.95
http://www.ncbi.nlm.nih.gov/pubmed/?term=21871940

[Vaccine manufacturers use aluminum-based adjuvants with controls in clinical
trials meaning adverse affects of aluminum will go unnoticed]

“Aluminium ... has no known biological role.
It accumulates in the body when protective gastrointestinal mechanisms are
bypassed ...” [for example, when it’s injected] Proceedings Of The Nutrition
Society • August 2011

Aluminium exposure from parenteral nutrition in preterm infants and later
health outcomes during childhood and adolescence Author information Fewtrell
MS1, Edmonds CJ, Isaacs E, Bishop NJ, Lucas A. Childhood Nutrition Research
Centre, UCL Institute of Child Health 30 Guilford Street, London WC1N 1EH, UK
m.fewtrell@ich.ucl.ac.uk Abstract Aluminium is the most common metallic
element, but has no known biological role. It accumulates in the body when
protective gastrointestinal mechanisms are bypassed, renal function is
impaired, or exposure is high - all of which apply frequently to preterm
infants. Recognised clinical manifestations of aluminium toxicity include
dementia, anaemia and bone disease. Parenteral nutrition (PN) solutions are
liable to contamination with aluminium, particularly from acidic solutions in
glass vials, notably calcium gluconate. When fed parenterally, infants retain
>75% of the aluminium, with high serum, urine and tissue levels. Later health
>effects of neonatal intravenous aluminium exposure were investigated in a
>randomised trial comparing standard PN solutions with solutions specially
sourced for low aluminium content. Preterm infants exposed for >10 d to
standard solutions had impaired neurologic development at 18 months. At 13-15
years, subjects randomised to standard PN had lower lumbar spine bone mass;
and, in non-randomised analyses, those with neonatal aluminium intake above the
median had lower hip bone mass. Given the sizeable number of infants undergoing
intensive care and still exposed to aluminium via PN, these findings have
contemporary relevance. Until recently, little progress had been made on
reducing aluminium exposure, and meeting Food and Drug Administration
recommendations (<5 μg/kg per d) has been impossible in patients <50 kg using
available products. Recent advice from the UK Medicines and Healthcare
regulatory Authority that calcium gluconate in small volume glass containers
should not be used for repeated treatment in children <18 years, including
preparation of PN, is an important step towards addressing this problem.
http://www.ncbi.nlm.nih.gov/pubmed/?term=21781356

Journal Of Inorganic Biochemistry • November 2011

Do aluminum vaccine adjuvants contribute to the rising prevalence of autism?
Author information Tomljenovic L1, Shaw CA. Neural Dynamics Research Group
Department of Ophthalmology and Visual Sciences University of British Columbia
828 W. 10th Ave, Vancouver, BC Canada V5Z 1L8 lucijat77@gmail.com Abstract
Autism spectrum disorders (ASD) are serious multisystem developmental disorders
and an urgent global public health concern. Dysfunctional immunity and impaired
brain function are core deficits in ASD. Aluminum (Al), the most commonly used
vaccine adjuvant, is a demonstrated neurotoxin and a strong immune stimulator.
Hence, adjuvant Al has the potential to induce neuroimmune disorders. When
assessing adjuvant toxicity in children, two key points ought to be considered:
(i) children should not be viewed as “small adults” as their unique physiology
makes them much more vulnerable to toxic insults; and (ii) if exposure to Al
from only few vaccines can lead to cognitive impairment and autoimmunity in
adults, is it unreasonable to question whether the current pediatric schedules,
often containing 18 Al adjuvanted vaccines, are safe for children? By applying
Hill’s criteria for establishing causality between exposure and outcome we
investigated whether exposure to Al from vaccines could be contributing to the
rise in ASD prevalence in the Western world. Our results show that: (i)
children from countries with the highest ASD prevalence appear to have the
highest exposure to Al from vaccines; (ii) the increase in exposure to Al
adjuvants significantly correlates with the increase in ASD prevalence in the
United States observed over the last two decades (Pearson r=0.92, p<0.0001);
and (iii) a significant correlation exists between the amounts of Al
administered to preschool children and the current prevalence of ASD in seven
Western countries, particularly at 3-4 months of age (Pearson r=0.89-0.94,
p=0.0018-0.0248). The application of the Hill’s criteria to these data
indicates that the correlation between Al in vaccines and ASD may be causal.
Because children represent a fraction of the population most at risk for
complications following exposure to Al, a more rigorous evaluation of Al
adjuvant safety seems warranted. http://www.ncbi.nlm.nih.gov/pubmed/22099159

“Our results show that:

(i) children from countries with the highest Autistic Spectrum Disorder
prevalence appear to have the highest exposure to Aluminum from vaccines;

(ii) the increase in exposure to Al adjuvants significantly correlates with the
increase in Autistic Spectrum Disorder prevalence in the United States observed
over the last two decades and

(iii) a significant correlation exists between the amounts of Aluminum
administered to preschool children and the current prevalence of Autistic
Spectrum Disorder in seven Western countries, particularly at 3-4 months of
age.”

Journal Of Inorganic Biochemistry • November 2011

Aluminium and human breast diseases Author information Darbre PD1, Pugazhendhi
D, Mannello F. Biomedical Sciences Section School of Biological Sciences
University of Reading, Reading RG6 6UB, UK p.d.darbre@reading.ac.uk Abstract
The human breast is exposed to aluminium from many sources including diet and
personal care products, but dermal application of aluminium-based
antiperspirant salts provides a local long-term source of exposure. Recent
measurements have shown that aluminium is present in both tissue and fat of the
human breast but at levels which vary both between breasts and between tissue
samples from the same breast. We have recently found increased levels of
aluminium in noninvasively collected nipple aspirate fluids taken from breast
cancer patients (mean 268 ± 28 μg/l) compared with control healthy subjects
(mean 131 ± 10 μg/l) providing evidence of raised aluminium levels in the
breast microenvironment when cancer is present. The measurement of higher
levels of aluminium in type I human breast cyst fluids (median 150 μg/l)
compared with human serum (median 6 μg/l) or human milk (median 25 μg/l)
warrants further investigation into any possible role of aluminium in
development of this benign breast disease. Emerging evidence for aluminium in
several breast structures now requires biomarkers of aluminium action in order
to ascertain whether the presence of aluminium has any biological impact. To
this end, we report raised levels of proteins that modulate iron homeostasis
(ferritin, transferrin) in parallel with raised aluminium in nipple aspirate
fluids in vivo, and we report overexpression of mRNA for several S100 calcium
binding proteins following long-term exposure of MCF-7 human breast cancer
cells in vitro to aluminium chlorhydrate.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22099158

“Recent measurements have shown that aluminium is present in both tissue and
fat of the human breast but at levels which vary both between breasts and
between tissue samples from the same breast. We have recently found increased
levels of aluminium in noninvasively collected nipple aspirate fluids taken
from breast cancer patients (mean 268 ± 28 μg/l) compared with control healthy
subjects (mean 131 ± 10 μg/l) providing evidence of raised aluminium levels in
the breast microenvironment when cancer is present.”

Journal Of Inorganic Biochemistry • November 2011

Long-term follow-up of cognitive dysfunction in patients with aluminum
hydroxide-induced macrophagic myofasciitis (MMF) Author information Passeri E1,
Villa C, Couette M, Itti E, Brugieres P, Cesaro P, Gherardi RK, Bachoud-Levi
AC, Authier FJ. Paris Est-Creteil University & Henri-Mondor University Hospital
(APHP) Reference Center for Neuromuscular Diseases
Garches-Necker-Mondor-Hendaye Creteil, F-94010, France Abstract Macrophagic
myofasciitis (MMF) is characterized by specific muscle lesions assessing
long-term persistence of aluminum hydroxide within macrophages at the site of
previous immunization. Affected patients are middle-aged adults, mainly
presenting with diffuse arthromyalgias, chronic fatigue, and cognitive
dysfunction. Representative features of MMF-associated cognitive dysfunction
(MACD) include (i) dysexecutive syndrome; (i) visual memory; (iii) left ear
extinction at dichotic listening test. In present study we retrospectively
evaluated the progression of MACD in 30 MMF patients. Most patients fulfilled
criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some
cognitive deficits seemed unusually severe. MACD remained stable over time,
although dysexecutive syndrome tended to worsen. Long-term follow-up of a
subset of patients with 3 or 4 consecutive neuropsychological evaluations
confirmed the stability of MACD with time, despite marked fluctuations.
http://www.ncbi.nlm.nih.gov/pubmed/22099155

“Macrophagic myofasciitis (MMF) is characterized by specific muscle lesions
assessing long-term persistence of aluminum hydroxide within macrophages at the
site of previous immunization.”

Journal Of Inorganic Biochemistry • November 2011

Towards the prevention of potential aluminum toxic effects and an effective
treatment for Alzheimer’s disease Author information Percy ME1, Kruck TP, Pogue
AI, Lukiw WJ. Neurogenetics Laboratory Surrey Place Centre, Toronto, ON Canada
M5S 2C2 maire.percy@utoronto.ca Abstract In 1991, treatment with low dose
intramuscular desferrioxamine (DFO), a trivalent chelator that can remove
excessive iron and/or aluminum from the body, was reported to slow the
progression of Alzheimer’s disease (AD) by a factor of two. Twenty years later
this promising trial has not been followed up and why this treatment worked
still is not clear. In this critical interdisciplinary review, we provide an
overview of the complexities of AD and involvement of metal ions, and revisit
the neglected DFO trial. We discuss research done by us and others that is
helping to explain involvement of metal ion catalyzed production of reactive
oxygen species in the pathogenesis of AD, and emerging strategies for
inhibition of metal-ion toxicity. Highlighted are insights to be considered in
the quests to prevent potentially toxic effects of aluminum toxicity and
prevention and intervention in AD.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22099160

“Highlighted are insights to be considered in the quests to prevent potentially
toxic effects of aluminum toxicity and prevention and intervention in AD.”

Journal Of Inorganic Biochemistry • November 2011

Aluminum toxicity and astrocyte dysfunction: a metabolic link to neurological
disorders Author information Lemire J., Appanna VD. Department of Chemistry and
Biochemistry Laurentian University, Sudbury, Ontario Canada P3E 2C6 Abstract
Aluminum (Al) has been implicated in a variety of neurological diseases.
However, the molecular mechanisms that enable Al to be involved in these
disorders have yet to be fully delineated. Using astrocytes as a model of the
cerebral cellular system, we have uncovered the biochemical networks that are
affected by Al toxicity. In this review, we reveal how the inhibitory influence
of Al on ATP production and on mitochondrial functions help generate globular
astrocytes that are fat producing machines. These biological events may be the
contributing factors to Al-triggered brain disorders.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22099161

“Aluminum (Al) has been implicated in a variety of neurological diseases.
However, the molecular mechanisms that enable Al to be involved in these
disorders have yet to be fully delineated. These biological events may be the
contributing factors to Al-triggered brain disorders.”

IOS Press Library • November 2011

Aluminum and Alzheimer’s Disease: After a Century of Controversy, Is there a
Plausible Link? Author Information Tomljenovic, Lucija Neural Dynamics Research
Group Department of Ophthalmology and Visual Sciences University of British
Columbia Vancouver, BC, Canada

“Research, however, reveals that:

1) very small amounts of Al are needed to produce neurotoxicity and this
criterion is satisfied through dietary Al intake

Abstract The brain is a highly compartmentalized organ exceptionally
susceptible to accumulation of metabolic errors. Alzheimer’s disease (AD) is
the most prevalent neurodegenerative disease of the elderly and is
characterized by regional specificity of neural aberrations associated with
higher cognitive functions. Aluminum (Al) is the most abundant neurotoxic metal
on earth, widely bioavailable to humans and repeatedly shown to accumulate in
AD-susceptible neuronal foci. In spite of this, the role of Al in AD has been
heavily disputed based on the following claims: 1) bioavailable Al cannot enter
the brain in sufficient amounts to cause damage, 2) excess Al is efficiently
excreted from the body, and 3) Al accumulation in neurons is a consequence
rather than a cause of neuronal loss. Research, however, reveals that: 1) very
small amounts of Al are needed to produce neurotoxicity and this criterion is
satisfied through dietary Al intake, 2) Al sequesters different transport
mechanisms to actively traverse brain barriers, 3) incremental acquisition of
small amounts of Al over a lifetime favors its selective accumulation in brain
tissues, and 4) since 1911, experimental evidence has repeatedly demonstrated
that chronic Al intoxication reproduces neuropathological hallmarks of AD.
Misconceptions about Al bioavailability may have mislead scientists regarding
the significance of Al in the pathogenesis of AD. The hypothesis that Al
significantly contributes to AD is built upon very solid experimental evidence
and should not be dismissed. Immediate steps should be taken to lessen human
exposure to Al, which may be the single most aggravating and avoidable factor
related to AD.
http://content.iospress.com/articles/journal-of-alzheimers-disease/jad101494

2) Al sequesters different transport mechanisms to actively traverse brain
barriers

3) incremental acquisition of small amounts of Al over a lifetime favors its
selective accumulation in brain tissues

4) since 1911, experimental evidence has repeatedly demonstrated that chronic
Al intoxication reproduces neuropathological hallmarks of AD.”

Biomedical And Environmental Science • December 2011

Effect of aluminum hydroxide adjuvant on the immunogenicity of the 2009
pandemic influenza A/H1N1 vaccine: multi-level modeling of data with repeated
measures Author information Yin da P1, Zhu BP, Wang HQ, Cao L, Wu WD, Jiang KY,
Xia W, Zhang GM, Zheng JS, Cao LS, Liang XF. Chinese Center for Disease Control
and Prevention Beijing 100050, China Abstract OBJECTIVE To evaluate the effect
of the aluminum hydroxide (Al-OH) adjuvant on the 2009 pandemic influenza
A/H1N1 (pH1N1) vaccine. METHODS In a multicenter, double-blind, randomized,
placebo-controlled trial, participants received two doses of split-virion
formulation containing 15 μg hemagglutinin antigen, with or without aluminum
hydroxide (Al-OH). We classified the participants into six age categories (>61
years, 41-60 years, 19-40 years, 13-18 years, 8-12 years, and 3-7 years) and
obtained four blood samples from each participant on days 0, 21, 35, and 42
following the first dose of immunization. We assessed vaccine immunogenicity by
measuring the geometric mean titer (GMT) of hemagglutination inhibiting
antibody. We used a two-level model to evaluate the fixed effect of aluminum
Al-OH and other factors, accounting for repeated measures. RESULTS The
predictions of repeated measurement on GMTs of formulations with or without
Al-OH, were 80.35 and 112.72, respectively. Al-OH significantly reduced
immunogenicity after controlling for time post immunization, age-group and
gender. CONCLUSION The Al-OH adjuvant does not increase but actually reduces
the immunogenicity of the split-virion pH1N1 vaccine.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22365398

“The aluminum hydroxide adjuvant does not increase but actually reduces the
immunogenicity of the split-virion pH1N1 vaccine.”

Current Medicinal Chemistry • 2011

Aluminum Vaccine Adjuvants: Are they Safe? L. Tomljenovic*,1 and C.A. Shaw2
Neural Dynamics Research Group Department of Ophthalmology and Visual Sciences
University of British Columbia 828 W. 10th Ave, Vancouver, BC, V5Z 1L8, Canada
2Departments of Ophthalmology and Visual Sciences and Experimental Medicine and
the Graduate Program in Neuroscience University of British Columbia, Vancouver,
British Columbia 828 W. 10th Ave, Vancouver, BC, V5Z 1L8, Canada Abstract
Aluminum is an experimentally demonstrated neurotoxin and the most commonly
used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum
adjuvants, medical science’s understanding about their mechanisms of action is
still remarkably poor. There is also a concerning scarcity of data on
toxicology and pharmacokinetics of these compounds. In spite of this, the
notion that aluminum in vaccines is safe appears to be widely accepted.
Experimental research, however, clearly shows that aluminum adjuvants have a
potential to induce serious immunological disorders in humans. In particular,
aluminum in adjuvant form carries a risk for autoimmunity, long-term brain
inflammation and associated neurological complications and may thus have
profound and widespread adverse health consequences. In our opinion, the
possibility that vaccine benefits may have been overrated and the risk of
potential adverse effects underestimated, has not been rigorously evaluated in
the medical and scientific community. We hope that the present paper will
provide a framework for a much needed and long overdue assessment of this
highly contentious medical issue.
http://www.meerwetenoverfreek.nl/images/stories/Tomljenovic_Shaw-CMC-published.pdf

“Experimental research, however, clearly shows that aluminum adjuvants have a
potential to induce serious immunological disorders in humans. In particular,
aluminum in adjuvant form carries a risk for autoimmunity, long-term brain
inflammation and associated neurological complications and may thus have
profound and widespread adverse health consequences. In our opinion, the
possibility that vaccine benefits may have been overrated and the risk of
potential adverse effects underestimated, has not been rigorously evaluated in
the medical and scientific community.”

Entropy • 2012
Special Issue Biosemiotic Entropy: Disorder, Disease, and Mortality

Empirical Data Confirm Autism Symptoms Related to Aluminum and Acetaminophen
Exposure

“Using standard log-likelihood ratio techniques, we identify several signs and
symptoms that are significantly more prevalent in vaccine reports after

Author Information

2000, including cellulitis, seizure, depression, fatigue,

Stephanie Seneff 1,* , Robert M. Davidson 2 and Jingjing Liu 1

pain and death, which are also significantly associated

1. Computer Science and Artificial Intelligence Laboratory Massachusetts
Institute of Technology, Cambridge, MA 02139, USA

with aluminum-containing vaccines. We propose that

2. Internal Medicine Group Practice PhyNet, Inc., Longview, TX 75604, USA

children with the autism diagnosis are especially

Abstract

vulnerable to toxic metals such as aluminum and

Autism is a condition characterized by impaired cognitive and social skills,
associated with compromised immune function. The incidence is alarmingly on the
rise, and environmental factors are increasingly suspected to play a role. This
paper investigates word frequency patterns in the U.S. CDC Vaccine Adverse
Events Reporting System (VAERS) database. Our results provide strong evidence
supporting a link between autism and the aluminum in vaccines. A literature
review showing toxicity of aluminum in human physiology offers further support.
Mentions of autism in VAERS increased steadily at the end of the last century,
during a period when mercury was being phased out, while aluminum adjuvant
burden was being increased. Using standard log-likelihood ratio techniques, we
identify several signs and symptoms that are significantly more prevalent in
vaccine reports after 2000, including cellulitis, seizure, depression, fatigue,
pain and death, which are also significantly associated with
aluminum-containing vaccines. We propose that children with the autism
diagnosis are especially vulnerable to toxic metals such as aluminum and
mercury due to insufficient serum sulfate and glutathione. A strong correlation
between autism and the MMR (Measles, Mumps, Rubella) vaccine is also observed,
which may be partially explained via an increased sensitivity to acetaminophen
administered to control fever. http://www.mdpi.com/1099-4300/14/11/2227

mercury due to insufficient serum sulfate and glutathione. A strong correlation
between autism and the MMR (Measles, Mumps, Rubella) vaccine is also observed,
which may be partially explained via an increased sensitivity to acetaminophen
administered to control fever.”

Neurotoxicology And Teratology • January 2012

Multiple toxic heavy metals and neonatal neurobehavior in China require
considering co-exposure to Thimerosal-ethylmercury and adjuvant-aluminum Author
information Dórea JG. Faculty of Health Sciences Universidade de Brasilia
70919-970 Brasilia, DF, Brazil dorea@rudah.com.br
https://www.infona.pl/resource/bwmeta1.element.elsevier-5ea9d498-e159-3496-99a1-2b3c4a568a20

Lupus • February 2012

Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric
populations Author information Tomljenovic L1, Shaw CA. Neural Dynamics
Research Group Department of Ophthalmology and Visual Sciences University of
British Columbia Vancouver, BC, Canada lucijat77@gmail.com Abstract Immune
challenges during early development, including those vaccine-induced, can lead
to permanent detrimental alterations of the brain and immune function.
Experimental evidence also shows that simultaneous administration of as little
as two to three immune adjuvants can overcome genetic resistance to
autoimmunity. In some developed countries, by the time children are 4 to 6
years old, they will have received a total of 126 antigenic compounds along
with high amounts of aluminum (Al) adjuvants through routine vaccinations.
According to the US Food and Drug Administration, safety assessments for
vaccines have often not included appropriate toxicity studies because vaccines
have not been viewed as inherently toxic. Taken together, these observations
raise plausible concerns about the overall safety of current childhood
vaccination programs. When assessing adjuvant toxicity in children, several key
points ought to be considered: (i) infants and children should not be viewed as
“small adults” with regard to toxicological risk as their unique physiology
makes them much more vulnerable to toxic insults; (ii) in adult humans Al
vaccine adjuvants have been linked to a variety of serious autoimmune and
inflammatory conditions (i.e., “ASIA”), yet children are regularly exposed to
much higher amounts of Al from vaccines than adults; (iii) it is often assumed
that peripheral immune responses do not affect brain function. However, it is
now clearly established that there is a bidirectional neuro-immune cross-talk
that plays crucial roles in immunoregulation as well as brain function. In
turn, perturbations of the neuro-immune axis have been demonstrated in many
autoimmune diseases encompassed in “ASIA” and are thought to be driven by a
hyperactive immune response; and (iv) the same components of the neuro-immune
axis that play key roles in brain development and immune function are heavily
targeted by Al adjuvants. In summary, research evidence shows that increasing
concerns about current vaccination practices may indeed be warranted. Because
children may be most at risk of vaccine-induced complications, a rigorous
evaluation of the vaccine-related adverse health impacts in the pediatric
population is urgently needed. http://www.ncbi.nlm.nih.gov/pubmed/22235057

“Immune challenges during early development, including those vaccine-induced,
can lead to permanent detrimental alterations of the brain and immune function.

Experimental evidence also shows that simultaneous administration of as little
as two to three immune adjuvants can overcome genetic resistance to
autoimmunity. In some developed countries, by the time children are 4 to 6
years old, they will have received a total of 126 antigenic compounds along
with high amounts of aluminum (Al) adjuvants through routine vaccinations.

According to the US Food and Drug Administration, safety assessments for
vaccines have often not included appropriate toxicity studies because vaccines
have not been viewed as inherently toxic. Taken together, these observations
raise plausible concerns about the overall safety of current childhood
vaccination programs.”

Immunology Letters • September 2012

Alum increases antigen uptake reduces antigen degradation and sustains antigen
presentation by DCs in vitro Author information Ghimire TR1, Benson RA, Garside
P, Brewer JM. Strathclyde Institute of Pharmacy and Biomedical Sciences
University of Strathclyde, Glasgow, Scotland, United Kingdom Abstract Aluminium
adjuvants (alum) have been the only widely approved adjuvants for use in human
vaccines since the 1920s, however, the mechanism of action of these adjuvants
remains elusive. Due to increasing demand for novel adjuvants, a clearer
understanding of the mechanisms that allow these important agents to affect
adaptive immune responses will make a significant contribution to the rational
design of future vaccines. Using a novel approach to tracking antigen and
antigen presentation, we demonstrate that alum induces higher antigen
accumulation and increased antigen presentation by dendritic cells (DCs) in
vitro. Antigen accumulation was 100-fold higher and antigen presentation
10-fold higher following alum treatment when compared with soluble protein
alone. We also observed that alum causes an initial reduction in presentation
compared with soluble antigen, but eventually increases the magnitude and
duration of antigen presentation. This was associated with reduced protein
degradation in DCs following alum treatment. These studies demonstrate the
dynamic alterations in antigen processing and presentation induced by alum that
underlie enhanced DC function in response to this adjuvant.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22732235

“Aluminium adjuvants (alum) have been the only widely approved adjuvants for
use in human vaccines since the 1920s, however, the mechanism of action of
these adjuvants remains elusive.”

Coordination Chemistry Reviews • October 2012

Metal Ions in Neurodegenerative Diseases The coordination chemistry of
aluminium in neurodegenerative disease by Christopher Exley Abstract The
coordination chemistry of a metal ion defines its optimal association with a
biomolecule such that its binding by specific ligands on that molecule confers
function and biological purpose. Aluminium is a non-essential metal with no
known biological role which means that its coordination neurochemistry defines
aluminium’s putative role in a number of neurodegenerative diseases. In
examining this chemistry it is found that very little is known about the
complexes formed and ligands involved in aluminium’s interactions with
neurochemically-relevant ligands. Aluminium’s action as a pro-oxidant as well
as an excitotoxin are highlighted while the evidence for its interactions with
amyloid beta, tau and DNA are discussed and it is concluded that it is too
early to discount these ligands as targets for the neurotoxicity of aluminium.
Highlights • There are few quantitaive data describing the coordination
chemistry of aluminium in neurodegenerative disease. • One compelling line of
evidence relates to the putative aluminium superoxide semi-reduced radical ion
AlO22+ and its powerful action as a pro-oxidant. • Another important candidate
is aluminium’s complex with ATP and its potential to disrupt neuronal
signalling and induce excitotoxicity. • Though there are no quantitative data
to describe aluminium’s interactions with amyloid beta this does not preclude
their association in the brain. • The biological reactivity of aluminium
supports myriad as yet unidentified interactions with biomolecules associated
with brain function in health and disease.
http://www.sciencedirect.com/science/article/pii/S0010854512000392

“In examining this chemistry it is found that very little is known about the
complexes formed and ligands involved in aluminium’s interactions with
neurochemically-relevant ligands. Aluminium’s action as a pro-oxidant as well
as an excitotoxin are highlighted while the evidence for its interactions with
amyloid beta, tau and DNA are discussed and it is concluded that it is too
early to discount these ligands as targets for the neurotoxicity of aluminium.”

Journal Of Trace Elements In Medicine And Biology • October 2012

Aluminium overload after 5 years in skin biopsy following post-vaccination with
subcutaneous pseudolymphoma Author information Guillard O1, Fauconneau B,
Pineau A, Marrauld A, Bellocq JP, Chenard MP. CHU Poitiers, Department of
Biochemistry Poitiers, France olivier.guillard@univ-poitiers.fr Abstract
Aluminium hydroxide is used as an effective adjuvant in a wide range of
vaccines for enhancing immune response to the antigen. The pathogenic role of
aluminium hydroxide is now recognized by the presence of chronic fatigue
syndrome, macrophagic myofasciitis and subcutaneous pseudolymphoma, linked to
intramuscular injection of aluminium hydroxide-containing vaccines. The aim of
this study is to verify if the subcutaneous pseudolymphoma observed in this
patient in the site of vaccine injection is linked to an aluminium overload.
Many years after vaccination, a subcutaneous nodule was discovered in a
45-year-old woman with subcutaneous pseudolymphoma. In skin biopsy at the
injection site for vaccines, aluminium (Al) deposits are assessed by Morin
stain and quantification of Al is performed by Zeeman Electrothermal Atomic
Absorption Spectrophotometry. Morin stain shows Al deposits in the macrophages,
and Al assays (in μg/g, dry weight) were 768.10±18 for the patient compared
with the two control patients, 5.61±0.59 and 9.13±0.057. Given the pathology of
this patient and the high Al concentration in skin biopsy, the authors wish to
draw attention when using the Al salts known to be particularly effective as
adjuvants in single or repeated vaccinations. The possible release of Al may
induce other pathologies ascribed to the well-known toxicity of this metal.
http://www.ncbi.nlm.nih.gov/pubmed/22425036

“The pathogenic role of aluminium hydroxide is now recognized by the presence
of chronic fatigue syndrome, macrophagic myofasciitis and subcutaneous
pseudolymphoma, linked to intramuscular injection of aluminium
hydroxide-containing vaccines.”

Current Aging Science • December 2012

Aluminum excytotoxicity and neuroautotoimmunity: the role of the brain
expression of CD32+ (FcyRIIa), ICAM-1+ and CD3E in aging Author information
Jovanova-Nesic K1, Shoenfeld Y, Spector NH. Immunology Research Center
Branislav Jankovic Department of Neuroimmunology, Institute of Virology
Vaccines and Sera-Torlak, Belgrade, Serbia Abstract In the central nervous
system (CNS) microglia are crucial for the defense of the brain against
invading microorganisms, formation of tumors, and damage following trauma.
However, uncontrolled activation of these cells may have deleterious outcomes
through activation of Fcy and the complement 3 receptors and the induction of
an adaptive immune reaction. Proteins contributing to this reaction are the
intercellular adhesion molecule-1 (ICAM-1) and CD3 molecules, among others.
Both can be expressed on the glia cells before cytokine release and may
facilitate an autoimmune inflammatory reaction in the brain. Round microglial
cells among the pyramidal cells of the hippocampus with increased expression of
CD32+ (FcyIIa) and near the site of injection of aluminum were detected
immunohistochemically and indicate microglial activation at the site of
aluminum injury. ICAM-1+ immunoreactivity significantly increased in the
hippocampus and in the choroids plexus, indicating increased inflammation in
the brain as well as increased CD3E+ expression in the hippocampus and
non-MHC-restricted T cytotoxicity after aluminum injection. The pattern of
expression of CD32+ (FcyIIa receptor) near the site of aluminum injection
indicates that microglia may play a phagocytic role at the site of
aluminum-induced excitotoxicity in the brain. Significant expression of ICAM-1+
and CD3E+ immunoreactive cells with the clusters of ICAM-1+ in the choroid
plexus suggests a consequently neurotoxic autoimmune reaction induced by
microglial hyperactivation in the injured brain.
http://www.ncbi.nlm.nih.gov/pubmed/23387884

“In the central nervous system (CNS) microglia are crucial for the defense of
the brain against invading microorganisms, formation of tumors, and damage
following trauma. However, uncontrolled activation of these cells may have
deleterious outcomes ...”

“alum has high neurotoxic potential and planning administration of continuously escalating doses of this poorly biodegradable
adjuvant in the population should be carefully evaluated by regulatory agencies
since the compound may be insidiously unsafe.” BMC Medicine • April 2013

Slow CCL2-dependent translocation of biopersistent particles from muscle to
brain Author information Khan Z1, Combadière C, Authier FJ, Itier V, Lux F,
Exley C, Mahrouf-Yorgov M, Decrouy X, Moretto P, Tillement O, Gherardi RK,
Cadusseau J. INSERM, U955, 8 rue du Général Sarrail, Créteil, 94010, France
Abstract BACKGROUND Long-term biodistribution of nanomaterials used in medicine
is largely unknown. This is the case for alum, the most widely used vaccine
adjuvant, which is a nanocrystalline compound spontaneously forming
micron/submicron-sized agglomerates. Although generally well tolerated, alum is
occasionally detected within monocyte-lineage cells long after immunization in
presumably susceptible individuals with systemic/neurologic manifestations or
autoimmune (inflammatory) syndrome induced by adjuvants (ASIA). METHODS On the
grounds of preliminary investigations in 252 patients with alum-associated ASIA
showing both a selective increase of circulating CCL2, the major monocyte
chemoattractant, and a variation in the CCL2 gene, we designed mouse
experiments to assess biodistribution of vaccine-derived aluminum and of
alum-particle fluorescent surrogates injected in muscle. Aluminum was detected
in tissues by Morin stain and particle induced Xray emission) (PIXE) Both 500
nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids
(Al-Rho) were used. RESULTS Intramuscular injection of alum-containing vaccine
was associated with the appearance of aluminum deposits in distant organs, such
as spleen and brain where they were still detected one year after injection.
Both fluorescent materials injected into muscle translocated to draining lymph
nodes

(DLNs) and thereafter were detected associated with phagocytes in blood and
spleen. Particles linearly accumulated in the brain up to the six-month
endpoint; they were first found in perivascular CD11b+ cells and then in
microglia and other neural cells. DLN ablation dramatically reduced the
biodistribution. Cerebral translocation was not observed after direct
intravenous injection, but significantly increased in mice with chronically
altered blood-brain-barrier. Loss/gain-of-function experiments consistently
implicated CCL2 in systemic diffusion of Al-Rho particles captured by
monocyte-lineage cells and in their subsequent neurodelivery. Stereotactic
particle injection pointed out brain retention as a factor of progressive
particle accumulation. CONCLUSION Nanomaterials can be transported by
monocyte-lineage cells to DLNs, blood and spleen, and, similarly to HIV, may
use CCL2-dependent mechanisms to penetrate the brain. This occurs at a very low
rate in normal conditions explaining good overall tolerance of alum despite its
strong neurotoxic potential. However, continuously escalating doses of this
poorly biodegradable adjuvant in the population may become insidiously unsafe,
especially in the case of overimmunization or immature/altered blood brain
barrier or high constitutive CCL-2 production. Full Report:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616851/

“... a form of the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome)
in commercial sheep, linked to the repetitive inoculation of
aluminum-containing adjuvants through vaccination. The syndrome shows an acute
phase that affects less than 0.5% of animals in a given herd ...” [a syndrome
that affects 5,000 individuals per each 1 million] Immunology Research • July
2013

Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in
commercial sheep Author information Luján L1, Pérez M, Salazar E, Álvarez N,
Gimeno M, Pinczowski P, Irusta S, Santamaría J, Insausti N, Cortés Y, Figueras
L, Cuartielles I, Vila M, Fantova E, Chapullé JL. Department of Animal
Pathology Veterinary Faculty, University of Zaragoza 177 Miguel Servet Street,
50013, Saragossa, Spain Lluis.Lujan@unizar.es Abstract We describe a form of
the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome)
in commercial sheep, linked to the repetitive inoculation of
aluminum-containing adjuvants through vaccination. The syndrome shows an acute
phase that affects less than 0.5% of animals in a given herd, it appears 2-6
days after an adjuvant-containing inoculation and it is characterized by an
acute neurological episode with low response to external stimuli and acute
meningoencephalitis, most animals apparently recovering afterward. The chronic
phase is seen in a higher proportion of flocks, it can follow the acute phase,
and it is triggered by external stimuli, mostly low temperatures. The chronic
phase begins with an excitatory phase, followed by weakness, extreme cachexia,
tetraplegia and death. Gross lesions are related to a cachectic process with
muscular atrophy, and microscopic lesions are mostly linked to a
neurodegenerative process in both dorsal and ventral column of the gray matter
of the spinal cord. Experimental reproduction of ovine ASIA in a small group of
repeatedly vaccinated animals was successful. Detection of Al(III) in tissues
indicated the presence of aluminum in the nervous tissue of experimental
animals. The present report is the first description of a new sheep syndrome
(ovine ASIA syndrome) linked to multiple, repetitive vaccination and that can
have devastating consequences as it happened after the compulsory vaccination
against bluetongue in 2008. The ovine ASIA syndrome can be used as a model of
other similar diseases affecting both human and animals. A major research
effort is needed in order to understand its complex pathogenesis.
http://www.ncbi.nlm.nih.gov/pubmed/?term=23579772

Immunology Research • July 2013

Aluminum in the central nervous system (CNS): toxicity in humans and animals,
vaccine adjuvants, and autoimmunity Author information Shaw CA1, Tomljenovic L.
Neural Dynamics Research Group Department of Ophthalmology and Visual Sciences
University of British Columbia (UBC) 828 W. 10th Ave., Vancouver, BC V5Z 1L8,
Canada cashawlab@gmail.com Abstract We have examined the neurotoxicity of
aluminum in humans and animals under various conditions, following different
routes of administration, and provide an overview of the various associated
disease states. The literature demonstrates clearly negative impacts of
aluminum on the nervous system across the age span. In adults, aluminum
exposure can lead to apparently agerelated neurological deficits resembling
Alzheimer’s and has been linked to this disease and to the Guamanian variant,
ALS-PDC. Similar outcomes have been found in animal models. In addition,
injection of aluminum adjuvants in an attempt to model Gulf War syndrome and
associated neurological deficits leads to an ALS phenotype in young male mice.
In young children, a highly significant correlation exists between the number
of pediatric aluminum-adjuvanted vaccines administered and the rate of autism
spectrum disorders. Many of the features of aluminum-induced neurotoxicity may
arise, in part, from autoimmune reactions, as part of the ASIA syndrome.
http://www.ncbi.nlm.nih.gov/pubmed/23609067

“In young children, a highly significant correlation exists between the number
of pediatric aluminum-adjuvanted vaccines administered and the rate of autism
spectrum disorders. Many of the features of aluminum-induced neurotoxicity may
arise, in part, from autoimmune reactions, as part of the ASIA syndrome.”

Journal Of Inorganic Biochemistry • September 2013

Selective accumulation of aluminum in cerebral arteries in Alzheimer’s disease
(AD) Author information Bhattacharjee S1, Zhao Y, Hill JM, Culicchia F, Kruck
TP, Percy ME, Pogue AI, Walton JR, Lukiw WJ. Neuroscience Center Louisiana
State University Health Sciences Center New Orleans, LA 70112, USA Abstract
Once biologically available aluminum bypasses gastrointestinal and blood-brain
barriers, this environmentally-abundant neurotoxin has an exceedingly high
affinity for the large pyramidal neurons of the human brain hippocampus. This
same anatomical region of the brain is also targeted by the earliest evidence
of Alzheimer’s disease (AD) neuropathology. The mechanism for the selective
targeting and transport of aluminum into the hippocampus of the human brain is
not well understood. In an effort to improve our understanding of a
pathological aluminum entry system into the brain, this study examined the
aluminum content of 8 arteries that supply blood to the hippocampus, including
the aorta and several cerebral arteries. In contrast to age-matched controls,
in AD patients we found a gradient of increasing aluminum concentration from
the aorta to the posterior cerebral artery that supplies blood to the
hippocampus. Primary cultures of human brain endothelial cells were found to
have an extremely high affinity for aluminum when compared to other types of
brain cells. Together, these results suggest for the first time that
endothelial cells that line the cerebral vasculature may have biochemical
attributes conducive to binding and targeting aluminum to selective anatomical
regions of the brain, such as the hippocampus, with potential downstream
pro-inflammatory and pathogenic consequences.
http://www.ncbi.nlm.nih.gov/pubmed/23764827

“Once biologically available aluminum bypasses gastrointestinal and blood-brain
barriers, this environmentally-abundant neurotoxin has an exceedingly high
affinity for the large pyramidal neurons of the human brain hippocampus. This
same anatomical region of the brain is also targeted by the earliest evidence
of Alzheimer’s disease (AD) neuropathology. The mechanism for the selective
targeting and transport of aluminum into the hippocampus of the human brain is
not well understood.”

“All 30 infant formulas were contaminated with aluminium.”
BMC Pediatrics • October 2013

The aluminium content of infant formulas remains too high Author information
Chuchu N1, Patel B, Sebastian B, Exley C. The Birchall Centre, Lennard-Jones
Laboratories Keele University, Staffordshire, UK c.exley@keele.ac.uk Abstract
BACKGROUND Recent research published in this journal highlighted the issue of
the high content of aluminium in infant formulas. The expectation was that the
findings would serve as a catalyst for manufacturers to address a significant
problem of these, often necessary, components of infant nutrition. It is
critically important that parents and other users have confidence in the safety
of infant formulas and that they have reliable information to use in choosing a
product with a lower content of aluminium. Herein, we have significantly
extended the scope of the previous research and the aluminium content of 30 of
the most widely available and often used infant formulas has been measured.
METHODS Both ready-to-drink milks and milk powders were subjected to microwave
digestion in the presence of 15.8 M HNO3 and 30% w/v H2O2 and the aluminium
content of the digests was measured by TH GFAAS. RESULTS Both ready-to-drink
milks and milk powders were contaminated with aluminium. The concentration of
aluminium across all milk products ranged from ca 100 to 430 μg/L. The
concentration of aluminium in two soya-based milk products was 656 and 756
μg/L. The intake of aluminium from non-soya-based infant formulas varied from
ca 100 to 300 μg per day. For soya-based milks it could be as high as 700 μg
per day. CONCLUSIONS All 30 infant formulas were contaminated with aluminium.
There was no clear evidence that subsequent to the problem of aluminium being
highlighted in a previous publication in this journal that contamination had
been addressed and reduced. It is the opinion of the authors that regulatory
and other non-voluntary methods are now required to reduce the aluminium
content of infant formulas and thereby protect infants from chronic exposure to
dietary aluminium. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851493/

“... aluminum has the potential to induce damage at a range of levels in the Central Nervous System
leading to neuronal death, circuit malfunction, and ultimately system failure.”
Immunome Research • October 2013

Aluminums Role in CNS-immune System Interactions leading to Neurological
Disorders Shaw CA1,2,3*, Kette SD4, Davidson RM5 and Seneff S6 1. Neural
Dynamics Research Group, Department of Ophthalmology and Visual Sciences 828 W.
10th Ave., Vancouver, British Columbia, V5Z1L8, Canada 2. Program Experimental
Medicine, University of British Columbia, Vancouver, V5Z1L8, Canada 3. Program
in Neurosciences, University of British Columbia, Vancouver, V5Z1L8, Canada 4.
Independent researcher, Hudson, FL 34667, USA 5.Internal Medicine Group
Practice, PhyNet, Inc., 4002 Technology Center, Longview, TX 75605, USA 6. MIT
Computer Science and Artificial Intelligence Laboratory, 32 Vassar Street,
Cambridge, MA 02139, USA

Abstract Multisystem interactions are well established in neurological
disorders, in spite of conventional views that only the central nervous system
(CNS) is impacted. We review evidence for mutual interactions between the
immune and nervous systems and show how these seem to be implicated in the
origin and progression of nervous system disorders. Well-established immune
system triggers leading to autoimmune reactions are considered. Of these,
aluminum, a known neurotoxicant, may be of particular importance. We have
demonstrated elsewhere that aluminum has the potential to induce damage at a
range of levels in the CNS leading to neuronal death, circuit malfunction, and
ultimately system failure. Aluminum is widely used as an adjuvant in various
vaccine formulations and has been implicated in a multisystem disorder termed
autoimmune/inflammatory syndrome induced by adjuvants (ASIA). The implications
of aluminum-induced ASIA in some disorders of the CNS are considered. We
propose a unified theory capturing a progression from a local response to a
systemic response initiated by disruption of water-based interfaces of exposed
cells.
http://www.omicsonline.com/open-access/aluminums-role-in-cnsimmune-system-interactions-leading-to-neurological-disorders-14822-1745-7580-9-069.php?aid=20403

Environmental Science • Processes And Impacts • October 2013

Human exposure to aluminium Author information Christopher Exley The Birchall
Centre Lennard-Jones Laboratories Keele University, Staffordshire, UK
c.exley@keele.ac.uk Abstract Human activities have circumvented the efficient
geochemical cycling of aluminium within the lithosphere and therewith opened a
door, which was previously only ajar, onto the biotic cycle to instigate and
promote the accumulation of aluminium in biota and especially humans. Neither
these relatively recent activities nor the entry of aluminium into the living
cycle are showing any signs of abating and it is thus now imperative that we
understand as fully as possible how humans are exposed to aluminium and the
future consequences of a burgeoning exposure and body burden. The aluminium age
is upon us and there is now an urgent need to understand how to live safely and
effectively with aluminium. http://www.ncbi.nlm.nih.gov/pubmed/23982047

“The aluminium age is upon us and there is now an urgent need to understand how
to live safely and effectively with aluminium.”

Communications In Integrated Biology • November 2013

Aluminum and the human diet revisited Christopher A Shaw and Thomas E Marler
Abstract Concerns about aluminum (Al) exposure in the human diet have persisted
for one century. We suggest that continued research would benefit from better
reporting of environmental factors that are known to influence Al accumulation
in plant organs that are consumed, focusing on subsets of the general public
that exhibit the highest risk for neuropathological responses, increased
evaluation of commercial processing procedures that may concentrate Al or other
toxic substances, and designing studies with low dose, chronic exposure rather
than further study of acute, brief exposure. Neurological Disorders Cognitive
decline and central nervous system (CNS) pathologies that resemble those of
Alzheimer are induced by Al in older rats.20 Soil and water sources of Al were
implicated in the ALS-parkinsonism dementia complex on Guam.21 Additionally,
the acute effects of higher doses of Al-induced dialysis associated
encephalopathy in humans are well documented.22 The route of administration of
Al plays a key role in the type of neurotoxicity exhibited. While most dietary
Al is removed by the kidneys, those lacking mature or patent kidney function
such as pediatric and geriatric subjects may be more likely to accumulate Al in
different organs, including the CNS. Injected Al from Al adjuvants in vaccines
have a very different fate and appear to be picked up from the draining lymph
nodes by circulating macrophages and transported into the CNS.23 Motor neuron
loss following Al hydroxide injections in mice and sheep24-26 and macrophagic
myofasciitis in humans involving cognitive dysfunction in humans.27 Al
adjuvants have also been linked to a series of autoimmune disorders in
humans.28 Developmental neurological disorders such as autism spectrum disorder
(ASD) also have a potential Al link through the accumulative weight of
pediatric vaccines, many of which contain Al as adjuvants.29 Indeed, there is a
highly significant correlation between ASD rates and cumulative Al adjuvant
amount,30 a correlation that satisfies eight of nine Hill criteria for
causality. Similar outcomes are found in new born mice injected with Al
adjuvants.31 A recent review also links Al to ASD.32
http://www.ncbi.nlm.nih.gov/pubmed/24505503

“Developmental neurological disorders such as autism spectrum disorder (ASD)
also have a potential Aluminum link through the accumulative weight of
pediatric vaccines, many of which contain Aluminum as adjuvants.”

Journal Of Inorganic Biochemistry • November 2013

Administration of aluminium to neonatal mice in vaccine-relevant amounts is
associated with adverse long term neurological outcomes Author information Shaw
CA1, Li Y, Tomljenovic L. Dept. of Ophthalmology and Visual Sciences University
of British Columbia, Vancouver, British Columbia, Canada Program in
Experimental Medicine University of British Columbia, Vancouver, British
Columbia, Canada Program in Neuroscience University of British Columbia,
Vancouver, British Columbia, Canada cashawlab@gmail.com Abstract Our previous
ecological studies of autism spectrum disorder (ASD) has demonstrated a
correlation between increasing ASD rates and aluminium (Al) adjuvants in common
use in paediatric vaccines in several Western countries. The correlation
between ASD rate and Al adjuvant amounts appears to be dose-dependent and
satisfies 8 of 9 Hill criteria for causality. We have now sought to provide an
animal model to explore potential behavioural phenotypes and central nervous
system (CNS) alterations using s.c. injections of Al hydroxide in early
postnatal CD-1 mice of both sexes. Injections of a “high” and “low” Al adjuvant
levels were designed to correlate to either the U.S. or Scandinavian paediatric
vaccine schedules vs. control saline-injected mice. Both male and female mice
in the “high Al” group showed significant weight gains following treatment up
to sacrifice at 6 months of age. Male mice in the “high Al” group showed
significant changes in light-dark box tests and in various measures of
behaviour in an open field. Female mice showed significant changes in the
light-dark box at both doses, but no significant changes in open field
behaviours. These current data implicate Al injected in early postnatal life in
some CNS alterations that may be relevant for a better understanding of the
aetiology of ASD. http://www.ncbi.nlm.nih.gov/pubmed/23932735

“Our previous ecological studies of autism spectrum disorder (ASD) has
demonstrated a correlation between increasing Autism Spectrum Disorder rates
and aluminium (Al) adjuvants in common use in paediatric vaccines in several
Western countries.”

Journal Of Inorganic Biochemistry • November 2013

Aluminium based adjuvants and their effects on mitochondria and lysosomes of
phagocytosing cells Author information Ohlsson L1, Exley C, Darabi A, Sandén E,
Siesjö P, Eriksson H. Department of Biomedical Laboratory Science Faculty of
Health and Society Malmö University SE-205 06 Malmö, Sweden Abstract Aluminium
oxyhydroxide, Al(OH)3 is one of few compounds approved as an adjuvant in human
vaccines. However, the mechanism behind its immune stimulating properties is
still poorly understood. In vitro co-culture of an aluminium adjuvant and the
human monocytic cell line THP-1 resulted in reduced cell proliferation.
Inhibition occurred at concentrations of adjuvant several times lower than
would be found at the injection site using a vaccine formulation containing an
aluminium adjuvant. Based on evaluation of the mitochondrial membrane
potential, THP-1 cells showed no mitochondrial rupture after co-culture with
the aluminium adjuvant, instead an increase in mitochondrial activity was seen.
The THP-1 cells are phagocytosing cells and after co-culture with the aluminium
adjuvant the phagosomal pathway was obstructed. Primary or early phagosomes
mature into phagolysosomes with an internal pH of 4.5 - 5 and carry a wide
variety of hydrolysing enzymes. Coculture with the aluminium adjuvant yielded a
reduced level of acidic vesicles and cathepsin L activity, a proteolytic enzyme
of the phagolysosomes, was almost completely inhibited. THP-1 cells are an
appropriate in vitro model in order to investigate the mechanism behind the
induction of a phagocytosing antigen presenting cell into an inflammatory cell
by aluminium adjuvants. Much information will be gained by investigating the
phagosomal pathway and what occurs inside the phagosomes and to elucidate the
ultimate fate of phagocytosed aluminium particles.
http://www.ncbi.nlm.nih.gov/pubmed/23992993

“Much information will be gained by investigating the phagosomal pathway and
what occurs inside the phagosomes and to elucidate the ultimate fate of
phagocytosed aluminium particles.”

Journal Of Inorganic Biochemistry • November 2013

Aluminium and breast cancer: Sources of exposure, tissue measurements and
mechanisms of toxicological actions on breast biology Author information Darbre
PD1, Mannello F, Exley C. School of Biological Sciences, University of Reading
Reading RG6 6UB, UK p.d.darbre@reading.ac.uk Abstract This review examines
recent evidence linking exposure to aluminium with the aetiology of breast
cancer. The human population is exposed to aluminium throughout daily life
including through diet, application of antiperspirants, use of antacids and
vaccination. Aluminium has now been measured in a range of human breast
structures at higher levels than in blood serum and experimental evidence
suggests that the tissue concentrations measured have the potential to
adversely influence breast epithelial cells including generation of genomic
instability, induction of anchorage-independent proliferation and interference
in oestrogen action. The presence of aluminium in the human breast may also
alter the breast microenvironment causing disruption to iron metabolism,
oxidative damage to cellular components, inflammatory responses and alterations
to the motility of cells. The main research need is now to investigate whether
the concentrations of aluminium measured in the human breast can lead in vivo
to any of the effects observed in cells in vitro and this would be aided by the
identification of biomarkers specific for aluminium action.
http://www.ncbi.nlm.nih.gov/pubmed/23899626

“Aluminium has now been measured in a range of human breast structures at
higher levels than in blood serum and experimental evidence suggests that the
tissue concentrations measured have the potential to adversely influence breast
epithelial cells including generation of genomic instability, induction of
anchorage-independent proliferation and interference in oestrogen action.”

Immunome Research • 2013

Aluminum’s Role in CNS-immune System Interactions leading to Neurological
Disorders Shaw CA1,2,3*, Kette SD4, Davidson RM5 and Seneff S6 1. Neural
Dynamics Research Group, Department of Ophthalmology and Visual Sciences 828 W.
10th Ave., Vancouver, British Columbia, V5Z1L8, Canada 2. Program Experimental
Medicine, University of British Columbia, Vancouver, V5Z1L8, Canada 3. Program
in Neurosciences, University of British Columbia, Vancouver, V5Z1L8, Canada 4.
Independent researcher, Hudson, FL 34667, USA 5. Internal Medicine Group
Practice, PhyNet, Inc., 4002 Technology Center, Longview, TX 75605, USA 6. MIT
Computer Science and Arti cial Intelligence Laboratory, 32 Vassar Street,
Cambridge, MA 02139, USA

Abstract Multisystem interactions are well established in neurological
disorders, in spite of conventional views that only the central nervous system
(CNS) is impacted. We review evidence for mutual interactions between the
immune and nervous systems and show how these seem to be implicated in the
origin and progression of nervous system disorders. Well-established immune
system triggers leading to autoimmune reactions are considered. Of these,
aluminum, a known neurotoxicant, may be of particular importance. We have
demonstrated elsewhere that aluminum has the potential to induce damage at a
range of levels in the CNS leading to neuronal death, circuit malfunction and
ultimately, system failure. Aluminum is widely used as an adjuvant in various
vaccine formulations and has been implicated in a multisystem disorder termed
“autoimmune/inflammatory syndrome induced by adjuvants” (ASIA). The
implications of aluminum-induced ASIA in some disorders of the CNS are
considered. We propose a unified theory capturing a progression from a local
response to a systemic response initiated by disruption of water-based
interfaces of exposed cells.
https://people.csail.mit.edu/seneff/Shaw_et_al_Immunome_Res_2013.pdf

“The implications of aluminum-induced ASIA in some disorders of the Central
Nervous System are considered.”

“Unfortunately, despite its favorable safety profile, aluminum hydroxide
can only weakly or moderately potentiate antigen-specific antibody responses.
Simply reducing the particle size of the traditional aluminum hydroxide
adjuvant into nanometers represents a novel and effective approach to improve
its adjuvanticity.” Journal Of Controlled Release • January 2014

Aluminum hydroxide nanoparticles show a stronger vaccine adjuvant activity than
traditional aluminum hydroxide microparticles Author information Li X, Aldayel
AM, Cui Z. The University of Texas at Austin College of Pharmacy, Pharmaceutics
Division Austin, TX 78712, USA Abstract Aluminum hydroxide is used as a vaccine
adjuvant in various human vaccines. Unfortunately, despite its favorable safety
profile, aluminum hydroxide can only weakly or moderately potentiate
antigen-specific antibody responses. When dispersed in an aqueous solution,
aluminum hydroxide forms particulates of 1-20μm. There is increasing evidence
that nanoparticles around or less than 200nm as vaccine or antigen carriers
have a more potent adjuvant activity than large microparticles. In the present
study, we synthesized aluminum hydroxide nanoparticles of 112nm. Using
ovalbumin and Bacillus anthracis protective antigen protein as model antigens,
we showed that protein antigens adsorbed on the aluminum hydroxide
nanoparticles induced a stronger antigen-specific antibody response than the
same protein antigens adsorbed on the traditional aluminum hydroxide
microparticles of around 9.3μm. The potent adjuvant activity of the aluminum
hydroxide nanoparticles was likely related to their ability to more effectively
facilitate the uptake of the antigens adsorbed on them by antigen-presenting
cells. Finally, the local inflammation induced by aluminum hydroxide
nanoparticles in the injection sites was milder than that induced by
microparticles. Simply reducing the particle size of the traditional aluminum
hydroxide adjuvant into nanometers represents a novel and effective approach to
improve its adjuvanticity. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918952/

Bulletin de l’Academie Nationale de Medecine • January 2014

Biopersistence and systemic distribution of intramuscularly injected particles:
what impact on long-term tolerability of alum adjuvants? Gherardi RK, Cadusseau
J, Authier FJ. Abstract Aluminium oxyhydroxide (alum), a nanocrystalline
compound that forms agglomerates, has been widely used as a vaccine adjuvant
since 1927, but the mechanisms by which it stimulates immune responses remain
poorly understood. Although generally well tolerated, alum may occasionally
cause chronic health problems in presumably susceptible individuals. Some
individuals may rarely develop delayed-onset diffuse myalgia, chronic
exhaustion and cognitive dysfunction, associated with long-term persistence (up
to 12 years) of alumloaded macrophages at site of i.m. immunization, defining
so-called macrophagic myofasciitis (MMF). Symptoms are consistent with the
chronic fatigue/myalgic encephalomyelitis (CFS/ME) syndrome, and have been used
as a paradigm of the “autoimmune/inflammatory syndrome induced by adjuvants”
(ASIA). Cognitive dysfunction is reminiscent of that described in workers
exposed to inhaled Al particles. Individual susceptibility may influence both
alum biopersistence and difusion away from injection sites. Biopersistent
particles such as fluorescent alum-coated nanohybrids, when injected into mouse
muscle, are captured by monocyte-lineage cells and then carried to distant
organs, draining lymph nodes and blood, probably via the thoracic duct, with
delayed and accumulative translocation to the brain (microglial cells). Brain
penetration occurs at extremely low levels in normal conditions, possibly
explaining the good tolerance of alum despite its high neurotoxic potential.
However, systemic diffusion is considerably enhanced by the potentiating effect
of MCP-1, the main monocyte chemoattractant factor, the production of which is
subject to marked variations linked to age and to genetic and environmental
factors. Selective MCP-1 elevation is the only known circulating biomarker of
MMF. http://www.ncbi.nlm.nih.gov/pubmed/26259285

“Biopersistent particles such as fluorescent alum-coated nanohybrids, when
injected into mouse muscle, are captured by monocyte-lineage cells and then
carried to distant organs, draining lymph nodes and blood, probably via the
thoracic duct, with delayed and accumulative translocation to the brain
(microglial cells). Brain penetration occurs at extremely low levels in normal
conditions, possibly explaining the good tolerance of alum despite its high
neurotoxic potential.”

Clinical And Experimental Immunology • January 2014

Effects of adjuvants for human use in systemic lupus erythematosus (SLE)-prone
(New Zealand black/New Zealand white) F1 mice Author information Favoino E1,
Favia EI, Digiglio L, Racanelli V, Shoenfeld Y, Perosa F. Department of
Internal Medicine (DIMO) Rheumatologic and Systemic Autoimmune Diseases and
Internal Medicine Section University of Bari Medical School, Bari, Italy
Abstract The safety of four different adjuvants was assessed in lupus-prone New
Zealand black/New Zealand white (BW)F1 mice. Four groups of mice were injected
intraperitoneally with incomplete Freund’s adjuvant (IFA), complete Freund’s
adjuvant (CFA), squalene (SQU) or aluminium hydroxide (ALU). An additional
group received plain phosphate-buffered saline (PBS) (UNT group). Mice were
primed at week 9 and boosted every other week up to week 15. Proteinuria became
detectable at weeks 17 (IFA group), 24 (CFA group), 28 (SQU and ALU groups) and
32 (UNT group). Different mean values were obtained among the groups from weeks
17 to 21 [week 17: one-way analysis of variance (anova) P = 0·016; weeks 18 and
19: P = 0·048; weeks 20 and 21: P = 0·013] being higher in the IFA group than
the others [Tukey’s honestly significant difference (HSD) post-test P < 0·05].
No differences in anti-DNA antibody levels were observed among groups.
Anti-RNP/Sm antibody developed at week 19 in only one CFA-treated mouse. Mean
mouse weight at week 18 was lower in the ALU group than the IFA (Tukey’s HSD
post-test P = 0·04), CFA (P = 0·01) and SQU (P < 0·0001) groups, while the mean
weight in the SQU group was higher than in the IFA (P = 0·009), CFA (P = 0·013)
and UNT (P = 0·005) groups. The ALU group weight decreased by almost half
between weeks 29 and 31, indicating some toxic effect of ALU in the late
post-immunization period. Thus, SQU was the least toxic adjuvant as it did not
(i) accelerate proteinuria onset compared to IFA; (ii) induce toxicity compared
to ALU or (iii) elicit anti-RNP/ Sm autoantibody, as occurred in the CFA group.
http://www.ncbi.nlm.nih.gov/pubmed/24112107

“The aluminum group weight decreased by almost half between weeks 29 and 31,
indicating some toxic effect of aluminum in the late post-immunization period.”

Allergy, Asthma & Clinical Immunology • January 2014

Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy
Christopher Exley The Birchall Centre Lennard-Jones Laboratories Keele
University, Staffordshire, UK c.exley@keele.ac.uk Abstract Sub-cutaneous
immunotherapy is an effective treatment for allergy. It works by helping to
modify or re-balance an individual’s immune response to allergens and its
efficacy is greatly improved by the use of adjuvants, most commonly, aluminium
hydroxide. Aluminium salts have been used in allergy therapy for many decades
and are assumed to be safe with few established side-effects. This assumption
belies their potency as adjuvants and their potential for biological reactivity
both at injection sites and elsewhere in the body. There are very few data
purporting to the safety of aluminium adjuvants in allergy immunotherapy and
particularly so in relation to longer term health effects. There are, if only
few, published reports of adverse events following allergy immunotherapy and
aluminium adjuvants are the prime suspects in the majority of such incidents.
Aluminium adjuvants are clearly capable of initiating unwanted side effects in
recipients of immunotherapy and while there is as yet no evidence that such are
commonplace it is complacent to consider aluminium salts as harmless
constituents of allergy therapies. Future research should establish the safety
of the use of aluminium adjuvants in sub-cutaneous allergy immunotherapy.
http://www.aacijournal.com/content/10/1/4

“Aluminium salts have been used in allergy therapy for many decades and are
assumed to be safe with few established side-effects. This assumption belies
their potency as adjuvants and their potential for biological reactivity both
at injection sites and elsewhere in the body.”

Computational and Structural Biotechnology Journal • March 2014

Aluminium in Biological Environments: A Computational Approach Author
Information Jon I Mujika,a Elixabete Rezabal,b Jose M Mercero,a Fernando
Ruipérez,c Dominique Costa,d Jesus M Ugalde,a and Xabier Lopeza a. Kimika
Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia International
Physics Center (DIPC) P.K. 1072, 20080 Donostia, Euskadi, Spain b. Laboratoire
de Chimie Moleculaire Department of Chemistry, Ecole Polytechnique and CNRS
91128 Palaiseau Cedex, France c. POLYMAT, Euskal Herriko Unibertsitatea UPV/EHU
Joxe Mari Korta zentroa, Tolosa Etorbidea 72 20018 Donostia-San Sebastián,
Euskadi, Spain d. Laboratoire de Physico-Chimie des Surfaces (UMR 7045) ENSCP
Chimie-Paristech, 11 rue P. et M. Curie, 75005 Paris, France Abstract The
increased availability of aluminium in biological environments, due to human
intervention in the last century, raises concerns on the effects that this so
far “excluded from biology” metal might have on living organisms. Consequently,
the bioinorganic chemistry of aluminium has emerged as a very active field of
research. This review will focus on our contributions to this field, based on
computational studies that can yield an understanding of the aluminum
biochemistry at a molecular level. Aluminium can interact and be stabilized in
biological environments by complexing with both low molecular mass chelants and
high molecular mass peptides. The speciation of the metal is, nonetheless,
dictated by the hydrolytic species dominant in each case and which vary
according to the pH condition of the medium. In blood, citrate and serum
transferrin are identified as the main low molecular mass and high molecular
mass molecules interacting with aluminium. The complexation of aluminium to
citrate and the subsequent changes exerted on the deprotonation pathways of its
tritable groups will be discussed along with the mechanisms for the intake and
release of aluminium in serum transferrin at two pH conditions, physiological
neutral and endosomatic acidic. Aluminium can substitute other metals, in
particular magnesium, in protein buried sites and trigger conformational
disorder and alteration of the protonation states of the protein’s sidechains.
A detailed account of the interaction of aluminium with proteic sidechains will
be given. Finally, it will be described how alumnium can exert oxidative stress
by stabilizing superoxide radicals either as mononuclear aluminium or clustered
in boehmite. The possibility of promotion of Fenton reaction, and production of
hydroxyl radicals will also be discussed.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995234/

“The increased availability of aluminium in biological environments, due to
human intervention in the last century, raises concerns on the effects that
this so far “excluded from biology” metal might have on living organisms.”

“There is prolonged retention of a fraction of aluminium that enters the brain ...”

Neurotoxicology • March 2014

Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and
its amelioration: a review Author information Kumar V1, Gill KD2. 1. Department
of Biochemistry, Maharshi Dayanand University, Rohtak, India 2. Department of
Biochemistry, Maharshi Dayanand University, Rohtak, India Department of
Biochemistry, Postgraduate Institute of Medical Education and Research
Chandigarh, India kdgill2002@yahoo.co.in Abstract Aluminium is light weight and
toxic metal present ubiquitously on earth which has gained considerable
attention due to its neurotoxic effects. The widespread use of products made
from or containing aluminium is ensuring its presence in our body. There is
prolonged retention of a fraction of aluminium that enters the brain,
suggesting its potential for accumulation with repeated exposures. There is no
known biological role for aluminium within the body but adverse physiological
effects of this metal have been observed in mammals. The generation of
oxidative stress may be attributed to its toxic consequences in animals and
humans. The oxidative stress has been implicated in pathogenesis of various
neurodegenerative conditions including Alzheimer’s disease and Parkinson’s
disease. Though it remains unclear whether oxidative stress is a major cause or
merely a consequence of cellular dysfunction associated with neurodegenerative
diseases, an accumulating body of evidence implicates that impaired
mitochondrial energy production and increased mitochondrial oxidative damage is
associated with the pathogenesis of neurodegenerative disorders. Being involved
in the production of reactive oxygen species, aluminium may impair
mitochondrial bioenergetics and may lead to the generation of oxidative stress.
In this review, we have discussed the oxidative stress and mitochondrial
dysfunctions occurring in Al neurotoxicity. In addition, the ameliorative
measures undertaken in aluminium induced oxidative stress and mitochondrial
dysfunctions have also been highlighted.
http://www.ncbi.nlm.nih.gov/pubmed/24560992

Journal Of Trace Elements In Medical Biology • April 2014

If exposure to aluminium in antiperspirants presents health risks, its content
should be reduced Author information Pineau A1, Fauconneau B2, Sappino AP3,
Deloncle R4, Guillard O5. 1. Université de Nantes, Faculté de Pharmacie
Laboratoire de Toxicologie, 44035 Nantes, France 2. Université de Poitiers,
Faculté de Médecine et de Pharmacie Service de Pharmacologie clinique, CHU
Poitiers, 86021 Poitiers, France 3. Clinique des Grangettes, Chemin des
Grangettes 7 1224 Chêne-Bougeries, Confédération Helvétique, Switzerland 4.
Université de Tours, Faculté de Pharmacie, Laboratoire de Toxicologie, 37000
Tours, France 5. Université de Poitiers, Faculté de Médecine et Pharmacie 6 rue
de la Milétrie, 86034 Poitiers, France olivier.guillard@univ-poitiers.fr
Abstract Since aluminium (Al) pervades our environment, the scientific
community has for many years raised concerns regarding its safety in humans. Al
is present in numerous cosmetics such as antiperspirants, lipsticks and
sunscreens. Al chlorohydrate is the active antiperspirant agent in underarm
cosmetics and may constitute for Al a key exposure route to the human body and
a potential source of damage. An in vitro study has demonstrated that Al from
antiperspirant can be absorbed through viable human stripped skin. The
potential toxicity of Al has been clearly shown and recent works convincingly
argue that Al could be involved in cancerogenic processes. Nowadays, for
example, Al is suspected of being involved in breast cancer. Recent work in
cells in culture has lent credence to the hypothesis that this metal could
accumulate in the mammary gland and selectively interfere with the biological
properties of breast epithelial cells, thereby promoting a cascade of
alterations reminiscent of the early phases of malignant transformation. In
addition, several studies suggest that the presence of Al in human breast could
influence metastatic process. As a consequence, given that the toxicity of Al
has been widely recognized and that it is not a physiological component in
human tissues, reducing the concentration of this metal in antiperspirants is a
matter of urgency. http://www.ncbi.nlm.nih.gov/pubmed/?term=24418462

“Al chlorohydrate is the active antiperspirant agent in underarm cosmetics and
may constitute for Aluminum a key exposure route to the human body and a
potential source of damage. An in vitro study has demonstrated that Aluminum
from antiperspirant can be absorbed through viable human stripped skin. The
potential toxicity of Aluminum has been clearly shown and recent works
convincingly argue that Aluminum could be involved in cancerogenic processes.”

World Journal Of Pediatrics • May 2014

Aluminum exposure and toxicity in neonates: a practical guide to halt aluminum
overload in the prenatal and perinatal periods Author information Fanni D1,
Ambu R, Gerosa C, Nemolato S, Iacovidou N, Van Eyken P, Fanos V, Zaffanello M,
Faa G. Department of Pathology University Hospital San Giovanni di Dio AOU
Cagliari and University of Cagliari Cagliari, Italy Abstract BACKGROUND During
the last years, human newborns have been overexposed to biologically reactive
aluminum, with possible relevant consequences on their future health and on
their susceptibility to a variety of diseases. Children, newborns and
particularly preterm neonates are at an increased risk of aluminum toxicity
because of their relative immaturity. DATA SOURCES Based on recent original
publications and classical data of the literatures, we reviewed the aluminum
content in mother’s food during the intrauterine life as well as in breast milk
and infant formula during lactation. We also determined the possible role of
aluminum in parenteral nutrition solutions, in adjuvants of vaccines and in
pharmaceutical products. A special focus is placed on the relationship between
aluminum overexposure and the insurgence of bone diseases. RESULTS Practical
points of management and prevention are suggested. Aluminum sources that
infants may receive during the first 6 months of life are presented. In the
context of prevention of possible adverse effects of aluminum overload in fetal
tissues during development, simple suggestions to pregnant women are described.
Finally, practical points of management and prevention are suggested.
CONCLUSIONS Pediatricians and neonatologists must be more concerned about
aluminum content in all products our newborns are exposed to, starting from
monitoring aluminum concentrations in milk- and soy-based formulas in which, on
the basis of recent studies, there is still too much aluminum.
http://www.ncbi.nlm.nih.gov/pubmed/24801228

“Pediatricians and neonatologists must be more concerned about aluminum content
in all products our newborns are exposed to, starting from monitoring aluminum
concentrations in milk and soy based formulas in which, on the basis of recent
studies, there is still too much aluminum.”

Mucosal Immunology • May 2014

Aluminum enhances inflammation and decreases mucosal healing in experimental
colitis in mice Author information Pineton de Chambrun G1, Body-Malapel M2,
Frey-Wagner I3, Djouina M2, Deknuydt F4, Atrott K3, Esquerre N2, Altare F4,
Neut C5, Arrieta MC6, Kanneganti TD7, Rogler G3, Colombel JF1, Cortot A1,
Desreumaux P1, Vignal C2 1. Univ Lille Nord de France, Lille, France [2] Inserm
U995, Lille, France [3] UDSL, Lille, France [4] Hepato-Gastroenterology
Department, CHU Lille, Lille, France 2. Univ Lille Nord de France, Lille,
France [2] Inserm U995, Lille, France [3] UDSL, Lille, France 3. Division of
Gastroenterology and Hepatology, University Hospital Zurich, Zurich,
Switzerland 4. INSERM, UMR892, Nantes, France [2] CNRS, UMR6299, Nantes, France
[3] Université de Nantes, Nantes, France 5. Univ Lille Nord de France, Lille,
France [2] Inserm U995, Lille, France [3] UDSL, Lille, France [4] Clinical
Bacteriology, College of Pharmacy, Lille, France 6. Finlay Lab, Michael Smith
Laboratories, University of British Columbia Vancouver, British Columbia,
Canada 7. Department of Immunology, St Jude Children’s Research Hospital,
Memphis, Tennessee, USA

Abstract The increasing incidence of inflammatory bowel diseases (IBDs) in
developing countries has highlighted the critical role of environmental
pollutants as causative factors in their pathophysiology. Despite its ubiquity
and immune toxicity, the impact of aluminum in the gut is not known. This study
aimed to evaluate the effects of environmentally relevant intoxication with
aluminum in murine models of colitis and to explore the underlying mechanisms.
Oral administration of aluminum worsened intestinal inflammation in mice with
2,4,6-trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis
and chronic colitis in interleukin 10-negative (IL10(-/-)) mice. Aluminum
increased the intensity and duration of macroscopic and histologic
inflammation, colonic myeloperoxidase activity, inflammatory cytokines
expression, and decreased the epithelial cell renewal compared with control
animals. Under basal conditions, aluminum impaired intestinal barrier function.
In vitro, aluminum induced granuloma formation and synergized with
lipopolysaccharide to stimulate inflammatory cytokines expression by epithelial
cells. Deleterious effects of aluminum on intestinal inflammation and mucosal
repair strongly suggest that aluminum might be an environmental IBD risk
factor. http://www.ncbi.nlm.nih.gov/pubmed/24129165

“Deleterious effects of aluminum on intestinal inflammation and mucosal repair
strongly suggest that aluminum might be an environmental Inflammatory Bowel
Disease risk factor.”

Expert Reviews In Neurotherapy • June 2014

What is the risk of aluminium as a neurotoxin? by Christopher Exley The
Birchall Centre Lennard- Jones Laboratories Keele University, Staffordshire, UK
The body burden of aluminium: To understand or even appreciate the risk that
aluminium poses as a neurotoxin, we will need to further our understanding of
the body burden of aluminium and we will need to implement measures to reduce
the body burden to a lowest practical limit. I have recently reformulated the
definition of aluminium’s body burden placing it into the context of what I
have called aluminium’s exposome [13]. We have also been investigating
noninvasive ways to reduce the uptake of aluminium into the body and,
importantly, to facilitate the excretion of aluminium from the body. We were
successful in lowering the body burden of aluminium in individuals with
moderate-to-severe AD and concomitantly we were able to demonstrate clinically
significant improvements in cognitive performance in some individuals [14].
These experiments offer some hope that the aluminium hypothesis of AD, and
indeed other neurodegenerative diseases, might be tested by lowering the body
burden of aluminium in affected individuals. Then we might be able to ascertain
if AD, for example, is the human manifestation of the risk of aluminium as a
known neurotoxin.

“Then we might be able to ascertain if AD, for example, is the human
manifestation of the risk of aluminium as a known neurotoxin.”

https://www.futsci.com/uploads/project/file/da0e1cb2dbea30e405db672eea4290b35a0d6a90.pdf

“There is now sufficient evidence from both human and animal studies
showing that cumulative exposure to aluminium adjuvants is not as benign as
previously assumed.” Autism • Causes & Prevalence • June 2014

Etiology of autism spectrum disorders: Genes, environment, or both? C Shaw1*, S
Sheth1, D Li1, L Tomljenovic1 University of British Columbia, Vancouver,
British Columbia, Canada cashawlab@gmail.com Abstract Thus far, most of the
research on both neurodevelopmental and neurodegenerative disorders has been
focused on finding the presumed underlying genetic causes, while much less
emphasis has been put on potential environmental factors. While some forms of
autism are clearly genetic, the fact remains that heritability factors cannot
adequately explain all reported cases nor their drastic increase over the last
few decades. In particular, studies on twins have now shown that common
environmental factors account for 55% of their risk for developing autism while
genetic susceptibility explains only 37% of cases. Because the prenatal
environment and early postnatal environment are shared between twins and
because overt symptoms of autism emerge around the end of the first year of
life, it is likely that at least some of the environmental factors contributing
to the risk of autism exert their deleterious neurodevelopmental effect during
this early period of life. Indeed, evidence has now emerged showing that autism
may in part result from early-life immune insults induced by environmental
xenobiotics. One of the most common xenobiotic with immuno-stimulating as well
as neurotoxic properties to which infants under two years of age are routinely
exposed worldwide is the aluminum (Al) vaccine adjuvant. In this review we
discuss the mechanisms by which Al can induce adverse neurological and
immunological effects and how these may provide important clues of Al’s
putative role in autism. Because of the tight connection between the
development of the immune and the central nervous system, the possibility that
immune-overstimulation in early infancy via vaccinations may play a role in
neurobehavioural disorders needs to be carefully considered. Conclusion There
is now sufficient evidence from both human and animal studies showing that
cumulative exposure to aluminium adjuvants is not as benign as previously
assumed. Given that vaccines are the only medical intervention that we attempt
to deliver to every living human on earth and that by far the largest target
population for vaccination are healthy children, a better appreciation and
understanding of vaccine adjuvant risks appears warranted.
http://www.oapublishinglondon.com/article/1368

Vaccine • July 2014

Aluminium in allergen-specific subcutaneous immunotherapy— a German perspective
Author information Kramer MF1, Heath MD2. 1. Bencard Allergie GmbH,
Messerschmittstr. 4, 80992 München, Germany. 2. Allergy Therapeutics, Plc.
Dominion Way, Worthing BN14 8SA, United Kingdom
matthew.heath@allergytherapeutics.com Abstract We are living in an “aluminium
age” with increasing bioavailability of the metal for approximately 125 years,
contributing significantly to the aluminium body burden of humans. Over the
course of life, aluminium accumulates and is stored predominantly in the lungs,
bones, liver, kidneys and brain. The toxicity of aluminium in humans is briefly
summarised, highlighting links and possible causal relationships between a high
aluminium body burden and a number of neurological disorders and disease
states. Aluminium salts have been used as depot-adjuvants successfully in
essential prophylactic vaccinations for almost 100 years, with a convincing
positive benefit-risk assessment which remains unchanged. However,
allergen-specific immunotherapy commonly consists of administering a
long-course programme of subcutaneous injections using preparations of relevant
allergens. Regulatory authorities currently set aluminium limits for vaccines
per dose, rather than per treatment course. Unlike prophylactic vaccinations,
numerous injections with higher proportions of aluminium-adjuvant per injection
are applied in subcutaneous immunotherapy (SCIT) and will significantly
contribute to a higher cumulative life dose of aluminium. While the human body
may cope robustly with a daily aluminium overload from the environment,
regulatory cumulative threshold values in immunotherapy need further
addressing. Based on the current literature, predisposing an individual to an
unusually high level of aluminium, such as through subcutaneous immunotherapy,
has the potential to form focal accumulations in the body with the propensity
to exert forms of toxicity. Particularly in relation to longer-term health
effects, the safety of aluminium adjuvants in immunotherapy remains
unchallenged by health authorities - evoking the need for more consideration,
guidance, and transparency on what is known and not known about its safety in
long-course therapy and what measures can be taken to prevent or minimise its
risks. The possibility of providing an effective means of measuring aluminium
accumulation in patients undergoing long-term SCIT treatment as well as
reducing their aluminium body burden is discussed. Full Report
http://www.sciencedirect.com/science/article/pii/S0264410X14007397

“... the safety of aluminium adjuvants in immunotherapy remains unchallenged by
health authorities - evoking the need for more consideration ...”

“... there is only a limited understanding of the response of regulatory T cells
to aluminum adjuvants and the vaccines that contain them.” Vaccine • September
2014

A role for impaired regulatory T cell function in adverse responses to aluminum
adjuvant-containing vaccines in genetically susceptible individuals Author
information Terhune TD, Deth RC. Department of Pharmaceutical Sciences
Northeastern University, Boston, MA, USA toddterhune@comcast.net Abstract
Regulatory T cells play a critical role in the immune response to vaccination,
but there is only a limited understanding of the response of regulatory T cells
to aluminum adjuvants and the vaccines that contain them. Available studies in
animal models show that although induced T regulatory cells may be induced
concomitantly with effector T cells following aluminum-adjuvanted vaccination,
they are unable to protect against sensitization, suggesting that under the Th2
immune-stimulating effects of aluminum adjuvants, Treg cells may be
functionally compromised. Allergic diseases are characterized by immune
dysregulation, with increases in IL-4 and IL-6, both of which exert negative
effects on Treg function. For individuals with a genetic predisposition, the
beneficial influence of adjuvants on immune responsiveness may be accompanied
by immune dysregulation, leading to allergic diseases. This review examines
aspects of the regulatory T cell response to aluminum-adjuvanted immunization
and possible genetic susceptibility factors related to that response.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25066736

Journal Of Toxicology • October 2014

Aluminum-induced entropy in biological systems: implications for neurological
disease Author information Shaw CA1, Seneff S2, Kette SD3, Tomljenovic L4,
Oller JW Jr5, Davidson RM6. 1. Neural Dynamics Research Group, Department of
Ophthalmology and Visual Sciences 828 W. 10th Avenue, Vancouver, British
Columbia, Canada V5Z 1L8; Program Experimental Medicine, University of British
Columbia, Vancouver, Canada V5Z 1L8 Program in Neurosciences, University of
British Columbia, Vancouver, Canada V5Z 1L8 2. MIT Computer Science and
Artificial Intelligence Laboratory 32 Vassar Street, Cambridge, MA 02139, USA
3. Hudson, FL 34667, USA 4. Neural Dynamics Research Group, Department of
Ophthalmology and Visual Sciences, 828 W. 10th Avenue, Vancouver, British
Columbia, Canada V5Z 1L8 5. Department of Communicative Disorders, University
of Louisiana Lafayette, LA 70504-3170, USA 6. Internal Medicine Group Practice,
PhyNet Inc., 4002 Technology Center Longview, TX 75605, USA

Abstract Over the last 200 years, mining, smelting, and refining of aluminum
(Al) in various forms have increasingly exposed living species to this
naturally abundant metal. Because of its prevalence in the earth’s crust, prior
to its recent uses it was regarded as inert and therefore harmless. However, Al
is invariably toxic to living systems and has no known beneficial role in any
biological systems. Humans are increasingly exposed to Al from food, water,
medicinals, vaccines, and cosmetics, as well as from industrial occupational
exposure. Al disrupts biological self-ordering, energy transduction, and
signaling systems, thus increasing biosemiotic entropy. Beginning with the
biophysics of water, disruption progresses through the macromolecules that are
crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It
injures cells, circuits, and subsystems and can cause catastrophic failures
ending in death. Al forms toxic complexes with other elements, such as
fluorine, and interacts negatively with mercury, lead, and glyphosate. Al
negatively impacts the central nervous system in all species that have been
studied, including humans. Because of the global impacts of Al on water
dynamics and biosemiotic systems, CNS disorders in humans are sensitive
indicators of the Al toxicants to which we are being exposed. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202242/

“Beginning with the biophysics of water, disruption progresses through the
macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans,
and proteins). It injures cells, circuits, and subsystems and can cause
catastrophic failures ending in death. Aluminum forms toxic complexes with
other elements, such as fluorine, and interacts negatively with mercury, lead,
and glyphosate.

Aluminum negatively impacts the central nervous system in all species that have
been studied, including humans. Because of the global impacts of Aluminum on
water dynamics and biosemiotic systems, Central Nervous System disorders in
humans are sensitive indicators of the Aluminum toxicants to which we are being
exposed.

... vaccine trials often treat an Aluminum adjuvant-containing injection as a
harmless “ placebo “ (a comparison benchmark or control treatment) or they use
another Al-containing vaccine to treat a “ control group, “ despite evidence
that Aluminum in vaccine-relevant exposures is universally toxic to humans and
animals. Its use in a supposed “ placebo “ or in any “ control “ treatment in
vaccine trials is indefensible.”

Critical Reviews In Toxicology • October 2014

Systematic review of potential health risks posed by pharmaceutical,
occupational and consumer exposures to metallic and nanoscale aluminum,
aluminum oxides, aluminum hydroxide and its soluble salts Author information
Willhite CC1, Karyakina NA, Yokel RA, Yenugadhati N, Wisniewski TM, Arnold IM,
Momoli F, Krewski D. Risk Sciences International, Ottawa, ON , Canada Abstract
Abstract Aluminum (Al) is a ubiquitous substance encountered both naturally (as
the third most abundant element) and intentionally (used in water, foods,
pharmaceuticals, and vaccines); it is also present in ambient and occupational
airborne particulates. Existing data underscore the importance of Al physical
and chemical forms in relation to its uptake, accumulation, and systemic
bioavailability. The present review represents a systematic examination of the
peer-reviewed literature on the adverse health effects of Al materials
published since a previous critical evaluation compiled by Krewski et al.
(2007) . Challenges encountered in carrying out the present review reflected
the experimental use of different physical and chemical Al forms, different
routes of administration, and different target organs in relation to the
magnitude, frequency, and duration of exposure. Wide variations in diet can
result in Al intakes that are often higher than the World Health Organization
provisional tolerable weekly intake (PTWI), which is based on studies with Al
citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes
that gastrointestinal bioavailability for all dietary Al forms is equivalent to
that for Al citrate, an approach that requires validation. Current occupational
exposure limits (OELs) for identical Al substances vary as much as 15-fold. The
toxicity of different Al forms depends in large measure on their physical
behavior and relative solubility in water. The toxicity of soluble Al forms
depends upon the delivered dose of Al(+3) to target tissues. Trivalent Al
reacts with water to produce bidentate superoxide coordination spheres
[Al(O2)(H2O4)(+2) and Al(H2O)6 (+3)] that after complexation with O2(•-),
generate Al superoxides

[Al(O2(•))](H2O5)](+2). Semireduced AlO2(•) radicals deplete mitochondrial Fe
and promote generation of H2O2, O2 (•-) and OH(•). Thus, it is the
Al(+3)-induced formation of oxygen radicals that accounts for the oxidative
damage that leads to intrinsic apoptosis. In contrast, the toxicity of the
insoluble Al oxides depends primarily on their behavior as particulates.
Aluminum has been held responsible for human morbidity and mortality, but there
is no consistent and convincing evidence to associate the Al found in food and
drinking water at the doses and chemical forms presently consumed by people
living in North America and Western Europe with increased risk for Alzheimer’s
disease (AD). Neither is there clear evidence to show use of Al-containing
underarm antiperspirants or cosmetics increases the risk of AD or breast
cancer. Metallic Al, its oxides, and common Al salts have not been shown to be
either genotoxic or carcinogenic. Aluminum exposures during neonatal and
pediatric parenteral nutrition (PN) can impair bone mineralization and delay
neurological development. Adverse effects to vaccines with Al adjuvants have
occurred; however, recent controlled trials found that the immunologic response
to certain vaccines with Al adjuvants was no greater, and in some cases less
than, that after identical vaccination without Al adjuvants. The scientific
literature on the adverse health effects of Al is extensive. Health risk
assessments for Al must take into account individual co-factors (e.g., age,
renal function, diet, gastric pH). Conclusions from the current review point to
the need for refinement of the PTWI, reduction of Al contamination in PN
solutions, justification for routine addition of Al to vaccines, and
harmonization of OELs for Al substances.

http://www.ncbi.nlm.nih.gov/pubmed/25233067

“The scientific literature on the adverse health effects of Al is extensive.
Conclusions from the current review point to the need for refinement of the
provisional tolerable weekly intake (PTWI), reduction of Aluminum contamination
in parenteral nutrition (PN) solutions, justification for routine addition of
Aluminum to vaccines ...”

Frontiers In Neurology • October 2014

Why industry propaganda and political interference cannot disguise the
inevitable role played by human exposure to aluminum in neurodegenerative
diseases, including Alzheimer’s disease Author Information

“Herein, I will make the case

Christopher Exley

that it is inevitable both today and in the

The Birchall Centre, Lennard-Jones Laboratories Keele University,
Stoke-on-Trent, UK Abstract In the aluminum age, it is clearly unpalatable for
aluminum, the globe’s most successful metal, to be implicated in human disease.
It is unpalatable because for approximately 100 years human beings have reaped
the rewards of the most abundant metal of the Earth’s crust without seriously
considering the potential consequences for human health. The aluminum industry
is a pillar of the developed and developing world and irrespective of the
tyranny of human exposure to aluminum it cannot be challenged without
significant consequences for businesses, economies, and governments. However,
no matter how deep the dependency or unthinkable the withdrawal, science
continues to document, if not too slowly, a burgeoning body burden of aluminum
in human beings. Herein, I will make the case that it is inevitable both today
and in the future that an individual’s exposure to aluminum is impacting upon
their health and is already contributing to, if not causing, chronic diseases
such as Alzheimer’s disease. This is the logical, if uncomfortable, consequence
of living in the aluminum age. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209859/

future that an individual’s exposure to aluminum is impacting upon their health
and is already contributing to, if not causing, chronic diseases such as
Alzheimer’s disease. This is the logical, if uncomfortable, consequence of
living in the aluminum age.”

Environmental Science And Pollution Research International • November 2014

Effects of aluminium and bacterial lipopolysaccharide on oxidative stress and
immune parameters in roach, Rutilus rutilus L Author information Jolly S1,
Jaffal A, Delahaut L, Palluel O, Porcher JM, Geffard A, Sanchez W, Betoulle S.
Université de Reims Champagne-Ardenne UMR-I02 SEBIO, BP 1039, 51687 Reims Cedex
2, France sabrina.jolly@univ-reims.fr Abstract Aluminium is used in diverse
anthropogenic processes at the origin of pollution events in aquatic
ecosystems. In the Champagne region (France), high concentrations of aluminium
(Al) are detected due to vine-growing practices. In fish, little is known about
the possible immune-related effects at relevant environmental concentrations.
The present study analyzes the simultaneous effects of aluminium and bacterial
lipopolysaccharide (LPS), alone and in combination, on toxicological biomarkers
in the freshwater fish species Rutilus rutilus. For this purpose, roach treated
or not with LPS were exposed to environmental concentrations of aluminium (100
μg/L) under laboratory-controlled conditions for 2, 7, 14 and 21 days. After
each exposure time, we assessed hepatic lipoperoxidation, catalase activity,
glutathione reductase activity and total glutathione content. We also analyzed
cellular components related to the LPSinduced inflammatory response in possible
target tissues, i.e. head kidney and spleen. Our results revealed a significant
prooxidant effect in the liver cells and head kidney leukocytes of roach
exposed to 100 μg of Al/L for 2 days. In liver, we observed more
lipoperoxidation products and lower endogenous antioxidant activity levels such
as glutathione reductase activity and total glutathione content. These
prooxidant effects were associated with a higher oxidative burst in head kidney
leukocytes, and they were all the more important in fish stimulated by LPS
injection. These findings demonstrate that environmental concentrations of Al
induce oxidative and immunotoxic effects in fish and are associated to an
immunomodulatory process related to the inflammatory response.
http://www.ncbi.nlm.nih.gov/pubmed/24996940

“These findings demonstrate that environmental concentrations of Aluminum
induce oxidative and immunotoxic effects in fish and are associated to an
immunomodulatory process related to the inflammatory response.”

Science Reports • September 2014

Unequivocal identification of intracellular aluminium adjuvant in a monocytic
THP-1 cell line Author information Mold M1, Eriksson H2, Siesjö P3, Darabi A3,
Shardlow E1, Exley C1. 1. The Birchall Centre, Lennard-Jones Laboratories,
Keele University Keele, Staffordshire, ST5 5BG, UK 2. Department of Biomedical
Laboratory Science, Faculty of Health and Society Malmö University, SE-205 06
Malmö, Sweden 3. Glioma Immunotherapy Group, Department of Clinical Sciences
BMC D14, Lund University, SE-221 84 Lund, Sweden Abstract Aluminium-based
adjuvants (ABA) are the predominant adjuvants used in human vaccinations. While
a consensus is yet to be reached on the aetiology of the biological activities
of ABA several studies have identified shape, crystallinity and size as
critical factors affecting their adjuvanticity. In spite of recent advances,
the fate of ABA following their administration remains unclear. Few if any
studies have demonstrated the unequivocal presence of intracellular ABA. Herein
we demonstrate for the first time the unequivocal identification of ABA within
a monocytic T helper 1 (THP-1) cell line, using lumogallion as a fluorescent
molecular probe for aluminium. Use of these new methods revealed that
particulate ABA was only found in the cell cytoplasm. Transmission electron
microscopy revealed that ABA were contained within vesicle-like structures of
approximately 0.5-1 μm in diameter. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155332/

“In spite of recent advances, the fate of Aluminium-based adjuvants following
their administration remains unclear. Herein we demonstrate for the first time
the unequivocal identification of ABA within a monocytic T helper 1 cell line,
using lumogallion as a fluorescent molecular probe for aluminium. Use of these
new methods revealed that particulate Aluminium-based adjuvants was only found
in the cell cytoplasm.”

“This short “Opinion” paper will overview and comment on
the current massive mobilization of aluminum into the earth’s biosphere.”
Frontiers In Neurology • December 2014

The mobilization of aluminum into the biosphere Aileen I. Pogue1 and Walter J.
Lukiw2,3* 1. Alchem Biotech, Toronto, ON, Canada 2. Louisiana State University
Neuroscience Center and Department of Ophthalmology Louisiana State University
School of Medicine, New Orleans, LA, USA 3. Department of Neurology, Louisiana
State University Health Sciences Center New Orleans, LA, USA Abstract Aluminum
is currently the most widely used non-ferrous metal, and its extraction and
purification from geological stores exceeds that of any other metal except iron
(1, 2). In 2013, global primary aluminum production was ~52 million tons (104
billion pounds) or about 15 pounds for very person on the earth (1–4). The
global outlook for aluminum demand from developing countries such as Brazil,
China, India, and Indonesia is rapidly increasing, due to new applications for
aluminum and aluminum alloys in infrastructural support, transportation
including automobiles, aviation and aerospace applications, electrical
transmission, and the generation of energy, including catalytic zeolites in the
petroleum and petrochemical industries (5). Interestingly, the largest
“machine” built by humankind is the domestic and international networks for the
transmission of electricity. Although traditionallyused copper has a higher
electrical conductivity, aluminum is only slightly less so, being lighter, more
ductile, and less expensive; aluminum is now widely used for both high-voltage
tower construction and the electrical transmission wires themselves (2–5). It
has been estimated that within the next 10 years aluminum production will
exceed that of the previous 150 years (1–3). This prolific de novo generation
of aluminum combined with its highly efficient recycling means this metal is
becoming increasingly present in our biosphere, defined as the sum of all
ecosystems and living organisms on the earth. This short “Opinion” paper will
overview and comment on the current massive mobilization of aluminum into the
earth’s biosphere.
http://journal.frontiersin.org/article/10.3389/fneur.2014.00262/full

Immunology Research • December 2014

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): clues and
pitfalls in the pediatric background Author information Esposito S1, Prada E,
Mastrolia MV, Tarantino G, Codecà C, Rigante D. Pediatric Highly Intensive Care
Unit Department of Pathophysiology and Transplantation Fondazione IRCCS Ca’
Granda Ospedale Maggiore Policlinico Università degli Studi di Milano Via
Commenda 9, 20122, Milan, Italy susanna.esposito@unimi.it Abstract The
development and increasing diffusion of new vaccinations and global
immunization protocols have aroused burning debates about safety of adjuvants
and their immunogenicity-enhancing effect in vaccines. Shoenfeld and
Agmon-Levin have grouped under the term “autoimmune/inflammatory syndrome
induced by adjuvants” (ASIA) a complex of variable signs and symptoms that may
occur after a previous exposure to different adjuvants and also external
environmental triggers, even eliciting specific overt immune-mediated
disorders. This entity subsumes five medical conditions: post-vaccination
phenomena, gulf war syndrome, macrophagic myofasciitis syndrome, siliconosis,
and sick building syndrome, but the relevance and magnitude of the syndrome in
the pediatric age is fundamentally limited to post-vaccination autoimmune or
inflammatory disorders. The occurrence of vaccine-triggered phenomena
represents a diagnostic challenge for clinicians and a research conundrum for
many investigators. In this paper, we will analyze the general features of ASIA
and focus on specific post-vaccination events in relation with the pediatric
background. In the presence of a favorable genetic background, many
autoimmune/inflammatory responses can be triggered by adjuvants and external
factors, showing how the man himself might breach immune tolerance and drive
many pathogenetic aspects of human diseases. Nonetheless, the elective
application of ASIA diagnostic criteria to the pediatric population requires
further assessment and evaluations. Additional studies are needed to help
clarify connections between innate or adaptive immunity and pathological and/or
protective autoantibodies mostly in the pediatric age, as children and
adolescents are mainly involved in the immunization agendas related to
vaccine-preventable diseases. http://www.ncbi.nlm.nih.gov/pubmed/25395340

“In the presence of a favorable genetic background, many
autoimmune/inflammatory responses can be triggered by adjuvants and external
factors, showing how the man himself might breach immune tolerance and drive
many pathogenetic aspects of human diseases.”

Reproductive Toxicology • December 2014

Aluminum content of human semen: implications for semen quality Author
information Klein JP1, Mold M2, Mery L3, Cottier M4, Exley C5. 1. Université de
Lyon, F-42023, Saint-Etienne, EA 4624, SFR IFRESIS, France Université Jean
Monnet and CHU de Saint-Etienne, France 2. The Birchall Centre, Lennard Jones
Laboratories Keele University, Staffordshire ST5 5BG, UK 3. Université de Lyon,
F-42023, Saint-Etienne, EA 4624, SFR IFRESIS, France Université Jean Monnet and
CHU de Saint-Etienne, France 4. Université de Lyon, F-42023, Saint-Etienne, EA
4624, SFR IFRESIS, France Université Jean Monnet and CHU de Saint-Etienne,
France 5. The Birchall Centre, Lennard Jones Laboratories Keele University,
Staffordshire ST5 5BG, UK c.exley@keele.ac.uk Abstract A deterioration of human
semen quality has been observed over recent decades. A possible explanation
could be an increased exposure to environmental pollutants, including aluminum.
Our aim was to measure the aluminum concentration in the semen of 62 patients
and to carry out a preliminary evaluation on its impact on specific semen
parameters. For each patient, semen analyses were performed according to WHO
guidelines. A graphite furnace atomic absorption spectrometry method was used
to determine semen aluminum concentration. A cytological analysis using an
aluminum-specific fluor, lumogallion, was also performed. The mean aluminum
concentration in human semen was 339 μg/L. Patients with oligozoospermia had a
statistically higher aluminum concentration than others. No significant
difference was observed for other semen parameters. Cytological analysis showed
the presence of aluminum in spermatozoa. This study provided unequivocal
evidence of high concentrations of aluminum in human semen and suggested
possible implications for spermatogenesis and sperm count.
http://www.ncbi.nlm.nih.gov/pubmed/25461904

“This study provided unequivocal evidence of high concentrations of aluminum in
human semen and suggested possible implications for spermatogenesis and sperm
count.”

Journal of Alzheimer’s Disease • 2014

Chronic aluminum intake causes Alzheimer’s disease: applying Sir Austin
Bradford Hill’s causality criteria Walton JR Faculty of Medicine University of
New South Wales St George Hospital, Sydney, Australia Industrialized societies
produce many convenience foods with aluminum additives that enhance various
food properties and use alum (aluminum sulfate or aluminum potassium sulfate)
in water treatment to enable delivery of large volumes of drinking water to
millions of urban consumers. The present causality analysis evaluates the
extent to which the routine, life-long intake, and metabolism of aluminum
compounds can account for Alzheimer’s disease (AD), using Austin Bradford
Hill’s nine epidemiological and experimental causality criteria, including
strength of the relationship, consistency, specificity, temporality,
dose-dependent response, biological rationale, coherence with existing
knowledge, experimental evidence, and analogy. Mechanisms that underlie the
risk of low concentrations of aluminum relate to (1) aluminum’s absorption
rates, allowing the impression that aluminum is safe to ingest and as an
additive in food and drinking water treatment, (2) aluminum’s slow progressive
uptake into the brain over a long prodromal phase, and (3) aluminum’s
similarity to iron, in terms of ionic size, allows aluminum to use ironevolved
mechanisms to enter the highly-active, iron-dependent cells responsible for
memory processing. Aluminum particularly accumulates in these iron-dependent
cells to toxic levels, dysregulating iron homeostasis and causing microtubule
depletion, eventually producing changes that result in disconnection of
neuronal afferents and efferents, loss of function and regional atrophy
consistent with MRI findings in AD brains. AD is a human form of chronic
aluminum neurotoxicity. The causality analysis demonstrates that chronic
aluminum intake causes AD. http://europepmc.org/abstract/med/24577474

“Aluminum particularly accumulates in these iron-dependent cells to toxic
levels, dysregulating iron homeostasis and causing microtubule depletion,
eventually producing changes that result in disconnection of neuronal afferents
and efferents, loss of function and regional atrophy consistent with MRI
findings in AD brains. AD is a human form of chronic aluminum neurotoxicity.
The causality analysis demonstrates that chronic aluminum intake causes AD.”

Immunotherapy • 2014

Are there negative CNS impacts of aluminum adjuvants used in vaccines and
immunotherapy? Author information Shaw CA1, Li D, Tomljenovic L. Neural
Dynamics Research Group 828 W. 10th Ave, Vancouver BC, V5Z 1L8, Canada Abstract
In spite of a common view that aluminum (Al) salts are inert and therefore
harmless as vaccine adjuvants or in immunotherapy, the reality is quite
different. In the following article we briefly review the literature on Al
neurotoxicity and the use of Al salts as vaccine adjuvants and consider not
only direct toxic actions on the nervous system, but also the potential impact
for triggering autoimmunity. Autoimmune and inflammatory responses affecting
the CNS appear to underlie some forms of neurological disease, including
developmental disorders. Al has been demonstrated to impact the CNS at every
level, including by changing gene expression. These outcomes should raise
concerns about the increasing use of Al salts as vaccine adjuvants and for the
application as more general immune stimulants.
http://www.ncbi.nlm.nih.gov/pubmed/25428645

“Aluminum has been demonstrated to impact the Central Nervous System at every
level, including by changing gene expression. These outcomes should raise
concerns about the increasing use of Aluminum salts as vaccine adjuvants and
for the application as more general immune stimulants.”

“Currently, ethylmercury (EtHg) and adjuvant-Aluminum are the dominating interventional exposures
encountered by fetuses, newborns, and infants due to immunization with
Thimerosal-containing vaccines (TCVs). Despite their long use as active agents
of medicines and fungicides, the safety levels of these substances have never
been determined, either for animals or for adult humans—much less for fetuses,
newborns, infants, and children.” International Journal Of Environmental
Research And Public Health • January 2015

Exposure to mercury and aluminum in early life: developmental vulnerability as
a modifying factor in neurologic and immunologic effects Author information
Dórea JG. Department of Nutrition Faculty of Health Sciences Universidade de
Brasilia 70919-970 DF Brasilia, Brazil jg.dorea@gmail.com Abstract Currently,
ethylmercury (EtHg) and adjuvant-Al are the dominating interventional exposures
encountered by fetuses, newborns, and infants due to immunization with
Thimerosal-containing vaccines (TCVs). Despite their long use as active agents
of medicines and fungicides, the safety levels of these substances have never
been determined, either for animals or for adult humans—much less for fetuses,
newborns, infants, and children. I reviewed the literature for papers reporting
on outcomes associated with (a) multiple exposures and metabolism of EtHg and
Al during early life; (b) physiological and metabolic characteristics of
newborns, neonates, and infants relevant to xenobiotic exposure and effects;
(c) neurobehavioral, immunological, and inflammatory reactions to Thimerosal
and Al-adjuvants resulting from TCV exposure in infancy. Immunological and
neurobehavioral effects of Thimerosal-EtHg and Al-adjuvants are not
extraordinary; rather, these effects are easily detected in high and low income
countries, with co-exposure to methylmercury (MeHg) or other neurotoxicants.
Rigorous and replicable studies (in different animal species) have shown
evidence of EtHg and Al toxicities. More research attention has been given to
EtHg and findings have showed a solid link with neurotoxic effects in humans;
however, the potential synergic effect of both toxic agents has not been
properly studied. Therefore, early life exposure to both EtHg and Al deserves
due consideration. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344667

Frontiers In Neurology • February 2015

Biopersistence and brain translocation of aluminum adjuvants of vaccines Author
information Gherardi RK1, Eidi H1, Crépeaux G1, Authier FJ1, Cadusseau J1.
Faculté de Médecine and Faculté des Sciences et Technologie INSERM U955 Team
10, Université Paris Est-Créteil Créteil, France Abstract Aluminum oxyhydroxide
(alum) is a crystalline compound widely used as an immunological adjuvant of
vaccines. Concerns linked to the use of alum particles emerged following
recognition of their causative role in the so-called macrophagic myofasciitis
(MMF) lesion detected in patients with myalgic encephalomyelitis/chronic
fatigue/syndrome. MMF revealed an unexpectedly long-lasting biopersistence of
alum within immune cells in presumably susceptible individuals, stressing the
previous fundamental misconception of its biodisposition. We previously showed
that poorly biodegradable aluminum-coated particles injected into muscle are
promptly phagocytosed in muscle and the draining lymph nodes, and can
disseminate within phagocytic cells throughout the body and slowly accumulate
in brain. This strongly suggests that long-term adjuvant biopersistence within
phagocytic cells is a prerequisite for slow brain translocation and delayed
neurotoxicity. The understanding of basic mechanisms of particle biopersistence
and brain translocation represents a major health challenge, since it could
help to define susceptibility factors to develop chronic neurotoxic damage.
Biopersistence of alum may be linked to its lysosome-destabilizing effect,
which is likely due to direct crystal-induced rupture of phagolysosomal
membranes. Macrophages that continuously perceive foreign particles in their
cytosol will likely reiterate, with variable interindividual efficiency, a
dedicated form of autophagy (xenophagy) until they dispose of alien materials.
Successful compartmentalization of particles within double membrane
autophagosomes and subsequent fusion with repaired and re-acidified lysosomes
will expose alum to lysosomal acidic pH, the sole factor that can solubilize
alum particles. Brain translocation of alum particles is linked to a Trojan
horse mechanism previously described for infectious particles (HIV, HCV), that
obeys to CCL2, signaling the major inflammatory monocyte chemoattractant. Full
Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318414/

“This strongly suggests that long-term adjuvant biopersistence within
phagocytic cells is a prerequisite for slow brain translocation and delayed
neurotoxicity.”

Biotechnic And Histochemistry • February 2015

A histological study of toxic effects of aluminium sulfate on rat hippocampus
Author information Çabus N1, Oguz EO, Tufan AÇ, Adıgüzel E. Department of
Histology and Embryology Faculty of Medicine, Hacettepe University Sihhiye
Ankara, Turkey Abstract Aluminium has toxic effects on many organ systems of
the human body. Aluminium toxicity also is a factor in many neurodegenerative
diseases. We investigated changes in numbers of hippocampal neurons in rats
exposed to aluminium using an optical fractionator and we investigated
aluminium-induced apoptosis using the transferase mediated dUTP nick end
labeling (TUNEL) assay. Twenty-four female rats were divided equally into
control, sham and aluminium-exposed groups. The control group received no
treatment. The two treatment groups were injected intraperitoneally with 1 ml
0.9% saline without (sham) and with 3 mg/ml aluminium sulfate every day for two
weeks. Following the treatments, the brains were removed, the left hemisphere
was used for hippocampal neuron counting using an optical fractionator and the
right hemisphere was investigated using hippocampal TUNEL assay to determine
the apoptotic index. The number of neurons in the stratum pyramidale of the
hippocampus was significantly less in the aluminium group than in the control
and sham groups; there was no significant difference between the control and
sham groups. The apoptotic index also was significantly higher in the aluminium
group than in the other two groups. We quantified the toxic effects of
aluminium on the rat hippocampus and determined that apoptosis was the
mechanism of aluminium-induced neuron death in the hippocampus.
http://www.ncbi.nlm.nih.gov/pubmed/25314162

“Aluminium has toxic effects on many organ systems of the human body. We
quantified the toxic effects of aluminium on the rat hippocampus and determined
that apoptosis was the mechanism of aluminiuminduced neuron death in the
hippocampus.”

Journal Of Trace Elements In Medicine And Biology • April 2015

The binding, transport and fate of aluminium in biological cells Author
information Exley C1, Mold MJ2. The Birchall Centre, Lennard-Jones Laboratories
Keele University, Staffordshire ST5 5BG, UK c.exley@keele.ac.uk Abstract
Aluminium is the most abundant metal in the Earth’s crust and yet,
paradoxically, it has no known biological function. Aluminium is biochemically
reactive, it is simply that it is not required for any essential process in
extant biota. There is evidence neither of element-specific nor evolutionarily
conserved aluminium biochemistry. This means that there are no ligands or
chaperones which are specific to its transport, there are no transporters or
channels to selectively facilitate its passage across membranes, there are no
intracellular storage proteins to aid its cellular homeostasis and there are no
pathways which evolved to enable the metabolism and excretion of aluminium. Of
course, aluminium is found in every compartment of every cell of every
organism, from virus through to Man. Herein we have investigated each of the
‘silent’ pathways and metabolic events which together constitute a form of
aluminium homeostasis in biota, identifying and evaluating as far as is
possible what is known and, equally importantly, what is unknown about its
uptake, transport, storage and excretion.
http://www.ncbi.nlm.nih.gov/pubmed/25498314

“Of course, aluminium is found in every compartment of every cell of every
organism, from virus through to Man. Herein we have investigated each of the
‘silent’ pathways and metabolic events which together constitute a form of
aluminium homeostasis in biota, identifying and evaluating as far as is
possible what is known and, equally importantly, what is unknown about its
uptake, transport, storage and excretion.”

PLoS One • June 2015

Bumblebee pupae contain high levels of aluminium Author information Exley C1,
Rotheray E2, Goulson D2. 1. The Birchall Centre, Lennard-Jones Laboratories,
Keele University Stoke-on-Trent, Staffordshire, ST5 5BG, United Kingdom 2.
Evolution, Behaviour & Ecology, School of Life Sciences University of Sussex,
Brighton, BN1 9QG, United Kingdom Abstract The causes of declines in bees and
other pollinators remains an on-going debate. While recent attention has
focussed upon pesticides, other environmental pollutants have largely been
ignored. Aluminium is the most significant environmental contaminant of recent
times and we speculated that it could be a factor in pollinator decline. Herein
we have measured the content of aluminium in bumblebee pupae taken from
naturally foraging colonies in the UK. Individual pupae were acid-digested in a
microwave oven and their aluminium content determined using transversely heated
graphite furnace atomic absorption spectrometry. Pupae were heavily
contaminated with aluminium giving values between 13.4 and 193.4 μg/g dry wt.
and a mean (SD) value of 51.0 (33.0) μg/g dry wt. for the 72 pupae tested. Mean
aluminium content was shown to be a significant negative predictor of average
pupal weight in colonies. While no other statistically significant
relationships were found relating aluminium to bee or colony health, the actual
content of aluminium in pupae are extremely high and demonstrate significant
exposure to aluminium. Bees rely heavily on cognitive function and aluminium is
a known neurotoxin with links, for example, to Alzheimer’s disease in humans.
The significant contamination of bumblebee pupae by aluminium raises the
intriguing spectre of cognitive dysfunction playing a role in their population
decline. Full Report: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456414/

“the actual content of aluminium in pupae are extremely high and demonstrate
significant exposure to aluminium.”

Pharmacology Research • October 2015

Vaccines, adjuvants and autoimmunity Author information Guimarães LE1, Baker
B1, Perricone C2, Shoenfeld Y3. 1. The Zabludowicz Center for Autoimmune
Diseases, Chaim Sheba Medical Center, Tel-Hashomer, Israel 2. Reumatologia,
Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di
Roma, Italy 3. Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical
Ctr, Tel-Hashomer, Israel; Incumbentof the Laura Schwarz-kipp chair for
research of autoimmune diseases, Sackler Faculty of Medicine, Tel-Aviv
University, Israel shoenfel@post.tau.ac.il

Abstract Vaccines and autoimmunity are linked fields. Vaccine efficacy is based
on whether host immune response against an antigen can elicit a memory T-cell
response over time. Although the described side effects thus far have been
mostly transient and acute, vaccines are able to elicit the immune system
towards an autoimmune reaction. The diagnosis of a definite autoimmune disease
and the occurrence of fatal outcome post-vaccination have been less frequently
reported. Since vaccines are given to previously healthy hosts, who may have
never developed the disease had they not been immunized, adverse events should
be carefully accessed and evaluated even if they represent a limited number of
occurrences. In this review of the literature, there is evidence of
vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both
experimental models as well as human patients. Adjuvants and infectious agents
may exert their immune-enhancing effects through various functional activities,
encompassed by the adjuvant effect. These mechanisms are shared by different
conditions triggered by adjuvants leading to the autoimmune/inflammatory
syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several
case reports of autoimmune diseases following vaccines, however, due to the
limited number of cases, the different classifications of symptoms and the long
latency period of the diseases, every attempt for an epidemiological study has
so far failed to deliver a connection. Despite this, efforts to unveil the
connection between the triggering of the immune system by adjuvants and the
development of autoimmune conditions should be undertaken. Vaccinomics is a
field that may bring to light novel customized, personalized treatment
approaches in the future. http://www.ncbi.nlm.nih.gov/pubmed/26275795

“In this review of the literature, there is evidence of vaccine-induced
autoimmunity and adjuvant-induced autoimmunity in both experimental models as
well as human patients.”

Journal Of Inorganic Biochemistry • November 2015

Highly delayed systemic translocation of aluminum-based adjuvant in CD1 mice
following intramuscular injections Author information Crépeaux G1, Eidi H2,
David MO3, Tzavara E4, Giros B4, Exley C5, Curmi PA3, Shaw CA6, Gherardi RK7,
Cadusseau J8. 1. INSERM U955 E10, Paris Est University, Créteil,
Franceguillemette.crepeaux@gmail.com. 2. INSERM U955 E10, Paris Est University,
Créteil, France; INSERM U1204, Evry University, Evry, France 3. INSERM U1204,
Evry University, Evry, France 4. INSERM U1130, CNRS UMR 8246, UPMC UM CR18,
Paris, France 5. Birchall Centre, Keele University, Staffordshire, UK 6.
Department of Ophthalmology, University of British Columbia, Vancouver, BC,
Canada 7. INSERM U955 E10, Paris Est University, Créteil, France 8. INSERM U955
E10, Paris Est University, Créteil, France; Faculté des Sciences & Technologie
UPEC, Créteil, France

Abstract Concerns regarding vaccine safety have emerged following reports of
potential adverse events in both humans and animals. In the present study,
alum, alum-containing vaccine and alum adjuvant tagged with fluorescent
nanodiamonds were used to evaluate i) the persistence time at the injection
site, ii) the translocation of alum from the injection site to lymphoid organs,
and iii) the behavior of adult CD1 mice following intramuscular injection of
alum (400μgAl/kg). Results showed for the first time a strikingly delayed
systemic translocation of adjuvant particles. Alum-induced granuloma remained
for a very long time in the injected muscle despite progressive shrinkage from
day 45 to day 270. Concomitantly, a markedly delayed translocation of alum to
the draining lymph nodes, major at day 270 endpoint, was observed.
Translocation to the spleen was similarly delayed (highest number of particles
at day 270). In contrast to C57BL/6J mice, no brain translocation of alum was
observed by day 270 in CD1 mice. Consistently neither increase of Al cerebral
content, nor behavioral changes were observed. On the basis of previous reports
showing alum neurotoxic effects in CD1 mice, an additional experiment was done,
and showed early brain translocation at day 45 of alum injected subcutaneously
at 200μgAl/kg. This study confirms the striking biopersistence of alum. It
points out an unexpectedly delayed diffusion of the adjuvant in lymph nodes and
spleen of CD1 mice, and suggests the importance of mouse strain, route of
administration, and doses, for future studies focusing on the potential toxic
effects of aluminum-based adjuvants.
http://www.ncbi.nlm.nih.gov/pubmed/26384437

“Concerns regarding vaccine safety have emerged following reports of potential
adverse events in both humans and animals. This study confirms the striking
biopersistence of alum. It points out an unexpectedly delayed diffusion of the
adjuvant in lymph nodes and spleen of CD1 mice ...”

“The well-recognized manifestations of systemic aluminum toxicity include
fracturing osteomalacia, dialysis encephalopathy, and microcytic hypochromic
anemia. More recently, aluminum loading has been demonstrated in premature
infants receiving intravenous fluid therapy.” American Academy Of Pediatrics •
December 2015 Committee on Nutrition

Aluminum Toxicity in Infants and Children Abstract During the last 15 years,
accumulating evidence has implicated aluminum in disorders associated with
chronic renal failure.1-6 The well-recognized manifestations of systemic
aluminum toxicity include fracturing osteomalacia, dialysis encephalopathy, and
microcytic hypochromic anemia. More recently, aluminum loading has been
demonstrated in premature infants receiving intravenous fluid therapy.7
Although the clinical importance of this finding is unclear, it warrants
careful attention. The association between aluminum excess and neurologic
dysfunction, which has been reported in patients with chronic renal failure,
suggests the possibility that aluminum overload may contribute to the
pathogenesis of CNS damage in the sick premature infant.7,8 Aluminum Exposure
Aluminum, which is the most abundant metal in the earth’s crust, is ubiquitous
in its distribution.7 There is constant exposure to this element through
ingestion of water and food and exposure to dust particles.10 Because aluminum
sulfate (alum) is used as a flocculating agent in the purification of municipal
water supplies, drinking water may contain high levels of aluminum (up to 1,000
μg/L). Aluminum cans, containers, and cooking utensils, as well as
aluminum-containing medications, are also potential sources of oral intake of
aluminum. Increase in aluminum intake as a result of transfer through the skin
is probably negligible; however, exposure is common due to use of aluminum in
deodorants.10 Some inhaled aluminum is retained in pulmonary tissue and in the
peribronchial lymph nodes, but it is largely excluded from other tissues.
Pulmonary aluminum concentration increases with age; unlike aluminum levels in
other tissues, the concentration in the lung does not correlate with that in
other tissues. http://pediatrics.aappublications.org/content/78/6/1150

Springer Plus • 2015

The mechanisms of action of vaccines containing aluminum adjuvants: an in vitro
vs in vivo paradigm Tirth Raj Ghimire Division of Veterinary and Primate Health
Global Primate Network, Kathmandu, Nepal Department of Zoology, Birendra
Multiple Campus Tribhuvan University, Chitwan, Nepal Abstract Adjuvants such as
the aluminum compounds (alum) have been dominantly used in many vaccines due to
their immunopotentiation and safety records since 1920s. However, how these
mineral agents influence the immune response to vaccination remains elusive.
Many hypotheses exist as to the mode of action of these adjuvants, such as
depot formation, antigen (Ag) targeting, and the induction of inflammation.
These hypotheses are based on many in vitro and few in vivo studies.
Understanding how cells interact with adjuvants in vivo will be crucial to
fully understanding the mechanisms of action of these adjuvants. Interestingly,
how alum influences the target cell at both the cellular and molecular level,
and the consequent innate and adaptive responses, will be critical in the
rational design of effective vaccines against many diseases. Thus, in this
review, mechanisms of action of alum have been discussed based on available in
vitro vs in vivo evidences to date. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406982/

“Adjuvants such as the aluminum compounds (alum) have been dominantly used in
many vaccines due to their immunopotentiation and safety records since 1920s.
However, how these mineral agents influence the immune response to vaccination
remains elusive.”

Chapter Four
The Human Papilloma Virus Vaccine 2008 - 2015 Dr. Harper was the lead scientist
for Mercks Gardasil vaccine. She explained in a presentation at the 4th
International Public Conference on Vaccination in October of 2009 that the
cervical cancer risk in the U.S. is already extremely low, and that
vaccinations are unlikely to have any effect upon the rate of cervical cancer
in the United States. In fact, 70% of all HPV infections resolve themselves
without treatment in a year and the number rises to well over 90% in two years.
Harper also mentioned the safety angle. All trials of the vaccines were done on
children aged 15 and above, despite them currently being marketed for
9-year-olds. So far, 15,037 girls have reported adverse side effects from
Gardasil alone to the Vaccine Adverse Event Reporting System (V.A.E.R.S.), and
this number only reflects parents who underwent the hurdles required for
reporting adverse reactions. At the time of writing, over 100 girls are
officially known to have died from this vaccine. The reported side effects
include Guillian Barré Syndrome (paralysis lasting for years, or permanently —
sometimes eventually causing suffocation), lupus, seizures, blood clots, brain
inflammation and more. Parents are usually not made aware of these risks. Dr.
Harper, the vaccine developer, claimed that she was speaking out, so that she
might finally be able to sleep at night. “About eight in every ten women who
have been sexually active will have H.P.V. at some stage of their life.
Normally there are no symptoms, and in 98 per cent of cases it clears itself.”
- Dr. Diane Harper Spanish attorney Don Manuel Saez Ochoa filed a criminal
  complaint against Merck-Sanofi Pasteur Laboratories and the Spanish National
  Health Authorities in the Spanish courts in June of 2014. The complaint
  alleges that Merck failed to use an inert placebo during clinical trials
  thereby manipulating data and thus Gardasil was marketed under false
  pretences. Merck-Sanofi Pasteur and Spain’s National and Regional (La Rioja)
  health authorities are charged with the following:

• fraudulent marketing and/or administration of an inadequately tested vaccine;
• failure to inform the public about the potential risks of using Gardasil; •
clear infringement of the right to informed consent; • ignoring new medical
conditions in those who used Gardasil despite the similarity of their symptoms
and the relatively short period of time between vaccine administration and the
onset of symptoms; • ignoring established and new scientific evidence
illustrating the potential harmful effects of Gardasil ingredients and
manufacturing methods; • callous disregard for those suffering new medical
conditions post-Gardasil; • failure to inform the public that HPV infections
are simply one of the risk factors involved in the development of cervical
cancer; • failure to inform the public that 90% of all HPV infections clear on
their own without medical intervention; • failure to inform the publlic about
alternative methods of controlling cervical cancer; • and criminal liability
for the injuries resulting from the administration of Gardasil. Thousands of
young women around the world are finding themselves in the same position. They
have gone from being happy, active, and healthy to facing a multitude of
autoimmune problems and neurological disorders. For them, the ‘possible’
adverse effects of Gardasil have become an all too harsh and brutal reality. It
is time for those responsible to be held accountable for their actions.
Criminal prosecution is quite possibly the only way to accomplish that goal.
Perhaps six to twelve years in prison would remind those responsible what it
means to conduct yourself in an ethical manner. Perhaps they would remember
that their first duty is to maintain the public health, not destroy it. On July
30, the Judge decided to open criminal proceedings and an investigation of the
facts. The first criminal case in Spain regarding Gardasil injuries and
potential criminal liability now begins.

Canadian Medical Association Journal • September 2008

The human papillomavirus vaccine and risk of anaphylaxis Neal A. Halsey, MD
From the Institute for Vaccine Safety Johns Hopkins Bloomberg School of Public
Health Baltimore, Md. Abstract In this issue of CMAJ, Brotherton and
colleagues1 report a comprehensive investigation revealing higher than expected
rates of apparent anaphylaxis following vaccination with the quadrivalent human
papillomavirus (HPV) vaccine in Australian children. The cause of these
reactions remains somewhat unclear and needs further investigation. Of note,
rates of anaphylaxis, if confirmed, may not be as high in other populations.
Further investigations may assist in clarifying differences between the
Australian study and other reports. The HPV vaccine is associated with high
rates of fainting in adolescents, which can result in serious head injuries.
These adverse events emphasize the need for recommendations to keep adolescents
and children under close observation (preferably sitting) for at least 15
minutes after vaccination. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527389/

“The HPV vaccine is associated with high rates of fainting in adolescents,
which can result in serious head injuries.”

Pharmacotherapy • September 2008

Development of unilateral cervical and supraclavicular lymphadenopathy after
human papilloma virus vaccination Author information Studdiford J1, Lamb K,
Horvath K, Altshuler M, Stonehouse A. Department of Family and Community
Medicine Jefferson University Hospital Philadelphia Pennsylvania 19107, USA
Abstract A 26-year-old woman developed significant unilateral anterior cervical
and supraclavicular lymphadenopathy 3 days after receiving her first dose (of a
total of three doses) of human papilloma virus (HPV) vaccine. She had no
history of lymphadenopathy after other previous immunizations, and had received
no vaccines other than HPV at that time. The left-sided lymphadenopathy
developed after she was vaccinated in the left deltoid muscle. The spatial and
temporal relationships between the appearance of the lymphadenopathy and
receipt of the vaccine in the absence of other causal agents strongly suggest
that the HPV vaccine was the causal agent. Use of the Naranjo adverse drug
reaction probability scale indicated that the HPV vaccine was a probable (score
of 6) cause of the patient’s adverse reaction. The patient received her second
dose of the HPV vaccine 2 months later without further lymphadenopathy. To
prevent unnecessary lymph node biopsies and patient concern, clinicians should
be aware that lymphadenopathy may occur after HPV vaccination.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18752390

“clinicians should be aware that lymphadenopathy may occur after HPV
vaccination.”

Multiple Sclerosis • January 2009

CNS demyelination and quadrivalent HPV vaccination Author information Sutton
I1, Lahoria R, Tan I, Clouston P, Barnett M. Department of Neurology St
Vincent’s Hospital Darlinghurst, New South Wales Australia Abstract Vaccination
is generally considered safe in patients with multiple sclerosis (MS). We
report five patients who presented with multifocal or atypical demyelinating
syndromes within 21 days of immunization with the quadrivalent human papilloma
virus (HPV) vaccine, Gardasil. Although the target population for vaccination,
young females, has an inherently high risk for MS, the temporal association
with demyelinating events in these cases may be explained by the potent
immuno-stimulatory properties of HPV virus-like particles which comprise the
vaccine. A prospective casecontrol study of patients with MS or clinically
isolated demyelinating syndromes receiving the Gardasil vaccine may provide
relevant safety data in this population.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18805844

“We report five patients who presented with multifocal or atypical
demyelinating syndromes within 21 days of immunization with the quadrivalent
human papilloma virus (HPV) vaccine, Gardasil ... association with
demyelinating events in these cases may be explained by the potent
immuno-stimulatory properties of HPV virus-like particles which comprise the
vaccine.”

Obstetrics & Gynecology • February 2009

Cervical cancers after human papillomavirus vaccination Author information
Beller U1, Abu-Rustum NR. Abstract BACKGROUND Current randomized clinical
trials have shown that the quadrivalent human papillomavirus (HPV) vaccine can
reduce the morbidity of precancerous lesions associated with HPV infection of
vaccine-related subtypes. However, to date, there is no definite evidence
showing the vaccine reduces the incidence of invasive cervical carcinoma. CASES
We present two cases—one young, vaccinated woman who developed cervical
carcinoma that was unrelated to HPV and another who developed cervical
carcinoma secondary to infection with an HPV subtype not covered by the
vaccine. Both patients were treated successfully and remained well without
evidence of cancer. CONCLUSION Long-term follow-up data are needed to evaluate
the prophylactic effectiveness of the current HPV vaccine. These cases could
represent non-vaccine-related HPV infections. Young women must be thoroughly
counseled about the efficacy and limitations of the vaccine and about
continuing lifelong screening even after vaccination.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19155953

“However, to date, there is no definite evidence showing the vaccine reduces
the incidence of invasive cervical carcinoma.”

Vaccine • August 2009

Quadrivalent Human Papillomavirus recombinant vaccine associated lipoatrophy

“Involutional lipoatrophy, a loss of subcutaneous fat, may be

Author information

idiopathic, associated with inflammatory skin conditions, or

Ojaimi S1, Buttery JP, Korman TM. Department of Infectious Diseases Monash
Medical Centre, Clayton, Monash University 246 Clayton Rd, Clayton, Victoria,
Australia samojaimi@yahoo.com.au Abstract Involutional lipoatrophy, a loss of
subcutaneous fat, may be idiopathic, associated with inflammatory skin
conditions, or trauma, and has also been reported following injections of
medications including insulin, corticosteroids and penicillin. There have also
been reports in association with Diptheria Pertussis Tetanus (DPT) vaccine. We
report on two cases of lipoatrophy associated with the new Quadrivalent Human
Papillomavirus (HPV) recombinant vaccine (Gardasil).
http://www.ncbi.nlm.nih.gov/pubmed/19555713

trauma, and has also been reported following injections of medications
including insulin, corticosteroids and penicillin. There have also been reports
in association with Diptheria Pertussis Tetanus (DPT) vaccine. We report on two
cases of lipoatrophy associated with the new Quadrivalent Human Papillomavirus
(HPV) recombinant vaccine (Gardasil).”

4th International Public Conference on Vaccination • October 2nd through 4th, 2009

No actual evidence that the vaccine can prevent any cancer Dr. Diane Harper
Lead Vaccine Researcher Merck Gardasil And Cervarix Vaccines Abstract Dr. Diane
Harper was the lead researcher in the development of the human papilloma virus
vaccines, Gardasil and Cervarix. She is the latest to come forward and question
the safety and effectiveness of these vaccines. She made the surprising
announcement at the 4th International Public Conference on Vaccination, which
took place in Reston, Virginia on Oct. 2nd through 4th, 2009. Her speech was
supposed to promote the Gardasil and Cervarix vaccines, but she instead turned
on her corporate bosses in a very public way. When questioned about the
presentation, audience members remarked that they came away feeling that the
vaccines should not be used. “I came away from the talk with the perception
that the risk of adverse side effects is so much greater than the risk of
cervical cancer, I couldn’t help but question why we need the vaccine at all.”
– Joan Robinson Dr. Harper explained in her presentation that the cervical
cancer risk in the U.S. is already extremely low, and that vaccinations are
unlikely to have any effect upon the rate of cervical cancer in the United
States. In fact, 70% of all H.P.V. infections resolve themselves without
treatment in a year, and the number rises to well over 90% in two years. Harper
also mentioned the safety angle. All trials of the vaccines were done on
children aged 15 and above, despite them currently being marketed for
9-year-olds. So far, 15,037 girls have reported adverse side effects from
Gardasil alone to the Vaccine Adverse Event Reporting System (V.A.E.R.S.), and
this number only reflects parents who underwent the hurdles required for
reporting adverse reactions. At the time of writing, 44 girls are officially
known to have died from these vaccines.

The reported side effects include Guillian Barré Syndrome (paralysis lasting
for years, or permanently — sometimes eventually causing suffocation), lupus,
seizures, blood clots, and brain inflammation. Parents are usually not made
aware of these risks. Dr. Harper, the vaccine developer, claimed that she was
speaking out, so that she might finally be able to sleep at night. “About eight
in every ten women who have been sexually active will have H.P.V. at some stage
of their life. Normally there are no symptoms, and in 98 per cent of cases it
clears itself. But in those cases where it doesn’t, and isn’t treated, it can
lead to pre-cancerous cells which may develop into cervical cancer.” - Dr.
Diane Harper One must understand how the establishment’s word games are played
to truly understand the meaning of the above quote, and one needs to understand
its unique version of “science”. When they report that untreated cases “can”
lead to something that “may” lead to cervical cancer, it really means that the
relationship is merely a hypothetical conjecture that is profitable if people
actually believe it. In other words, there is no demonstrated relationship
between the condition being vaccinated for and the rare cancers that the
vaccine might prevent, but it is marketed to do that nonetheless. In fact,
there is no actual evidence that the vaccine can prevent any cancer. From the
manufacturers own admissions, the vaccine only works on 4 strains out of 40 for
a specific venereal disease that dies on its own in a relatively short period,
so the chance of it actually helping an individual is about about the same as
the chance of him being struck by a meteorite. Why do nine-year-old girls need
vaccinations for extremely rare and symptomless venereal diseases that the
immune system usually kills anyway?

http://www.whydontyoutrythis.com/2013/07/the-lead-vaccine-developer-comes-clean-so-she-can-sleep-at-night.html

Dermatology • July 2010

The quadrivalent human papillomavirus vaccine: erythema multiforme and
cutaneous side effects after administration Author information Pérez-Carmona
L1, Aguayo-Leiva I, González-García C, Jaén-Olasolo P. Ramón y Cajal Hospital
Madrid, Spain lpcarmona@hotmail.com Abstract The quadrivalent human
papillomavirus (qHPV) vaccine, the first vaccine for use in the prevention of
cervical cancer and condyloma acuminatum, was approved in June 2006. In 2008,
the mass media reported suspected links between the qHPV vaccine and serious
adverse events; however, several studies have found that the vaccine is safe
and the main adverse events are mild local reactions. Erythema multiforme (EM)
is an acute self-limited cutaneous or mucocutaneous syndrome characterized by
the abrupt onset of symmetric target lesions. The clinical manifestations and
histological features of EM, Stevens-Johnson syndrome and toxic epidermal
necrolysis show considerable overlap, and they are classically considered to
represent a spectrum of skin disorders. We present a case of EM following qHPV
vaccination to review the cutaneous side effects of this vaccine and the
possibility of more serious side effects with the administration of booster
doses. http://www.ncbi.nlm.nih.gov/pubmed/?term=20861606

“We present a case of Erythema multiforme following qHPV vaccination to review
the cutaneous side effects of this vaccine and the possibility of more serious
side effects with the administration of booster doses.”

Journal Of Vaccines & Vaccination • November 2010

Review of Gardasil Author information Harper DM1, Vierthaler SL, Santee JA.
Professor of Medicine, Director Center of Excellence in Women’s Health
University of Missouri-Kansas City School of Medicine Departments of Biomedical
and Health Informatics Obstetrics and Gynecology and Community and Family
Medicine Abstract Human papillomavirus (HPV) is necessary for the development
of cervical cancer. Cervical cancer is the second most common cancer in women
worldwide but 80% occurs in developing countries, not countries with Pap
screening programs. Pap screening programs in industrialized countries have
reduced the incidence of cervical cancer to 4-8/100,000 women. HPV vaccines may
be a promising strategy for cervical cancer in women without access to
screening programs. In industrialized countries, the benefit of HPV vaccines
focuses on individual abnormal Pap test reduction not cancer prevention. The
focus of this review is to cover the side effects of Gardasil in perspective
with the limited population benefit cervical cancer reduction in countries with
organized Pap screening programs. In addition, information about Gardasil
benefits, risks and unknowns for individual patient decision making for
vaccination is presented. Gardasil offers protection against CIN 2+ lesions
caused by HPV 16/18 and against genital warts caused by HPV 6/11 for at least 5
years. Combining Gardasil with repeated cytology screenings may reduce the
proportion of abnormal cytology screens and hence reduce the associated
morbidity with the subsequent colposcopies and excisional procedures.
http://www.ncbi.nlm.nih.gov/pubmed/23805398

“Pap screening programs in industrialized countries have reduced the incidence
of cervical cancer to 4-8/100,000 women.

HPV vaccines may be a promising strategy for cervical cancer in women without
access to screening programs.”

Dermatology • November 2010

Erythema multiforme following vaccination for human papillomavirus Author
information Katoulis AC1, Liakou A, Bozi E, Theodorakis M, Alevizou A,
Zafeiraki A, Mistidou M, Stavrianeas NG. National and Kapodistrian University
of Athens Medical School, 2nd Department of Dermatology and Venereology Attikon
General University Hospital, Athens, Greece alexanderkatoulis @ yahoo.co.uk
Abstract Erythema multiforme (EM) is an acute self-limited immune-mediated
reaction manifested by target skin lesions with mucous membrane involvement.
The most common causes are infections and drugs. Vaccinations have been
reported as a triggering factor, and they may be a frequent cause of EM in
childhood. A 19-year-old female developed several target lesions of the hands
and feet 10 days after the second dose of human papillomavirus (HPV) vaccine.
Clinico-histologically, a diagnosis of EM minor was made. Treatment with
topical corticosteroids and oral antihistamines resulted in complete clearance
of the rash. Four months later, she received the last booster dose of the
vaccine. A few subtle lesions appeared and disappeared spontaneously after a
few days. Gardasil is a non-infectious vaccine, developed for the prevention of
cervical cancer, precancerous genital lesions and genital warts. It delivers
the major capsid (L1) protein of HPV types 6, 11, 16 and 18. Mild local
reactions are the main adverse events. The only serious events are very rare
cases of anaphylaxis. In our patient, the temporal relationship between the
development of EM and the vaccination suggests that the HPV vaccine probably
was the causal agent. This is the first published case of EM following HPV
vaccination. http://www.ncbi.nlm.nih.gov/pubmed/?term=19887766

“In our patient, the temporal relationship between the development of Erythema
multiforme and the vaccination suggests that the HPV vaccine probably was the
causal agent. This is the first published case of Erythema multiforme following
HPV vaccination.”

Vaccine • January 2011

Guillain-Barré syndrome after Gardasil vaccination: data from Vaccine Adverse
Event Reporting System 2006-2009 Author information Souayah N1, Michas-Martin
PA, Nasar A, Krivitskaya N, Yacoub HA, Khan H, Qureshi AI. Department of
Neurology University of Medicine and Dentistry of New Jersey Newark, NJ 07103,
USA souayani@umdnj.edu

“The estimated weekly reporting rate of post-Gardasil Guillain-Barré Syndrome
within the first 6 weeks (6.6 per 10,000,000) was higher than that of the
general population, and higher than post-Menactra and post-influenza
vaccinations.”

Abstract Using data from Vaccine Adverse Event Reporting System, we identified
69 reports of Guillain-Barré Syndrome (GBS) after Gardasil vaccination that
occurred in the United States between 2006 and 2009. The onset of symptoms was
within 6 weeks after vaccination in 70% of the patients in whom the date of
vaccination was known. The estimated weekly reporting rate of post-Gardasil GBS
within the first 6 weeks (6.6 per 10,000,000) was higher than that of the
general population, and higher than post-Menactra and post-influenza
vaccinations. Further prospective active surveillance for accurate
ascertainment and identification of high-risk groups of GBS after Gardasil
vaccination is warranted. http://www.ncbi.nlm.nih.gov/pubmed/?term=20869467

[for every 100 million women vaccinated it is known and recognized that there
will be an estimated 66 cases of collateral damage in the form of
Guillain-Barré Syndrome]

Vaccine • June 2011

Autoimmune hepatitis type 2 following anti-papillomavirus vaccination in a
11-year-old girl Author information Della Corte C1, Carlucci A, Francalanci P,
Alisi A, Nobili V. Unit of Liver Research Department of Pathology Bambino Gesù
Children’s Hospital IRCCS, P.le S. Onofrio 4, 00165 Rome, Italy
claudia.dellacorte@opbg.net Abstract In the last years numerous reports
describing a possible association between administration of vaccines and
development of autoimmune phenomena and overt autoimmune disease were
published. Possible mechanisms of induction of autoimmune phenomena by vaccines
and their excipients are probably similar to those implicated in induction by
infectious agents. Here we report the case of an 11-year-old girl who developed
autoimmune hepatitis type II after four weeks from vaccination against human
papillomavirus. The possible relationships between the use of adjuvated vaccine
against papillomavirus and autoimmune hepatitis are discussed. Although we do
not provide evidence for a causal link, we suggest that the occurrence of the
autoimmune hepatitis may be related to the stimulation of immune system by
adjuvated-vaccine, that could have triggered the disease in a genetically
predisposed individual. Therefore a monitoring of liver function test following
administration of vaccine against papillomavirus may be useful in adolescent
girl with signs of hepatopathy, as jaundice, dark urine or hepatomegaly, to
early identify and to promptly treat autoimmune liver disorders.
http://www.ncbi.nlm.nih.gov/pubmed/?term=21596082

“In the last years numerous reports describing a possible association between
administration of vaccines and development of autoimmune phenomena and overt
autoimmune disease were published.”

Lupus • February 2012

Systemic lupus erythematosus following HPV immunization or infection? Author
information Soldevilla HF1, Briones SF, Navarra SV. 1University of Santo Tomas,
Manila, Philippines helmar_110576@yahoo.com Abstract BACKGROUND AND PURPOSE The
link between autoimmunity and infectious agents has been strongly suggested by
reports of lupus or lupus-like syndromes following immunization. This report
describes three patients with either newly diagnosed systemic lupus
erythematosus (SLE) or SLE flare, following vaccination for human papilloma
virus (HPV). CASE 1: A 17-year-old female completed two doses of HPV vaccine
uneventfully. Two months later, she developed arthralgias with pruritic rashes
on both lower extremities, later accompanied by livedo reticularis, bipedal
edema with proteinuria, anemia, leucopenia, hypocomplementemia and high titers
of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA).
Kidney biopsy showed International Society of Nephrology/Renal Pathology
Society Class III lupus nephritis. She was started on high dose steroids
followed by pulse cyclophosphamide therapy protocol for lupus nephritis, and
subsequently went into remission. CASE 2: A 45-year-old housewife, previously
managed for 11 years as having rheumatoid arthritis, had been in clinical
remission for a year when she received two doses of HPV immunization. Four
months later, she developed fever accompanied by arthritis, malar rash, oral
ulcers, recurrent ascites with intestinal pseudo-obstruction, and behavioral
changes. Cranial MRI showed vasculitic lesions on the frontal and parietal
lobes. Laboratory tests showed anemia with leucopenia, hypocomplementemia,
proteinuria, ANA positive at 1:320, and antibodies against dsDNA, Ro/SSA,
La/SSB and histone. She improved following pulse methylprednisolone with
subsequent oral prednisone combined with hydroxychloroquine. CASE 3: A
58-year-old housewife diagnosed with SLE had been in clinical remission for 8
years when she received two doses of HPV immunization. Three months later, she
was admitted to emergency because of a 1-week history of fever, malar rash,
easy fatigability, cervical lymph nodes, gross hematuria and pallor. Laboratory
exams showed severe anemia, thrombocytopenia, active urine sediments, and
hypocomplementemia. Despite pulse steroid therapy, blood transfusions,
intravenous immunoglobulin and aggressive resuscitative measures, she expired a
day after hospital admission. SUMMARY These cases narrate instances of the
onset or exacerbation of lupus following HPV immunization suggesting
adjuvant-induced autoimmunity. On the other hand, there are reports of higher
incidence of HPV infection in SLE, with the infection per se possibly
contributing to disease activity. Thus, the benefit of HPV immunization may
still outweigh the risk among these individuals.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22235047

“These cases narrate instances of the onset or exacerbation of lupus following
HPV immunization suggesting adjuvant-induced autoimmunity.”

American Journal Of Public Health • May 2012

Pharmaceutical companies’ role in state vaccination policymaking: the case of
human papillomavirus vaccination Author information Mello MM1, Abiola S,
Colgrove J. Harvard School of Public Health, Boston, MA, USA
mmello@hsph.harvard.edu Abstract OBJECTIVES We sought to investigate roles that
Merck & Co Inc played in state human papillomavirus (HPV) immunization
policymaking, to elicit key stakeholders’ perceptions of the appropriateness of
these activities, and to explore implications for relationships between health
policymakers and industry.

“Most stakeholders

METHODS We used a series of state case studies combining data from key
informant interviews with analysis of media reports and archival materials. We
interviewed 73 key informants in 6 states that were actively engaged in HPV
vaccine policy deliberations.

acceptable in principle,

RESULTS Merck promoted school-entry mandate legislation by serving as an
information resource, lobbying legislators, drafting legislation, mobilizing
female legislators and physician organizations, conducting consumer marketing
campaigns, and filling gaps in access to the vaccine. Legislators relied
heavily on Merck for scientific information. Most stakeholders found lobbying
by vaccine manufacturers acceptable in principle, but perceived that Merck had
acted too aggressively and nontransparently in this case. CONCLUSIONS Although
policymakers acknowledge the utility of manufacturers’ involvement in
vaccination policymaking, industry lobbying that is overly aggressive, not
fully transparent, or not divorced from financial contributions to lawmakers
risks undermining the prospects for legislation to foster uptake of new
vaccines. http://www.ncbi.nlm.nih.gov/pubmed/?term=22420796

found lobbying by vaccine manufacturers

but perceived that Merck had acted too aggressively and nontransparently in
this case.”

American Journal Of Public Health • September 2012

Who Profits From Uncritical Acceptance of Biased Estimates of Vaccine Efficacy
and Safety? Lucija Tomljenovic, PhD and Christopher A. Shaw, PhD At the time of
the writing, Lucija Tomljenovic and Christopher A. Shaw were with the Neural
Dynamics Research Group University of British Columbia, Vancouver, Canada
Abstract We read with great interest the analysis by Mello et al.1 on how Merck
& Co., Inc. (Merck) influenced state human papillomavirus (HPV) vaccination
policymaking. The exclusive reliance on Merck for scientific information on
behalf of the legislators is unfortunate, especially in the light of
independent research which has repeatedly warned that drug companies may
manipulate clinical trial designs and subsequent data analysis and reporting to
make their drugs look better and safer.2–4 Indeed, careful scrutiny of Gardasil
clinical trials shows that their design, as well as data reporting and
interpretation, were largely inadequate.4–6 Given this, the widespread public
optimism regarding Gardasil’s clinical benefits appears to rest on an extremely
weak base built on a number of untested assumptions and significant
misinterpretation of factual evidence. For example, the claim that Gardasil
vaccination will result in approximately 70% reduction of cervical cancers7,8
is made despite the fact that the clinical trial data have not demonstrated to
date that the vaccine has actually prevented a single case of cervical cancer
(let alone cervical cancer death),4 nor that the current overly optimistic
surrogate marker–based extrapolations are justified.6 A second equally
fallacious claim is that lifelong protection arises from three vaccine
doses,7,8 although clinical trial follow-up data do not extend beyond five
years.9 The third claim is that Gardasil may induce only minor side effects of
negligible clinical importance,7,8 although such conclusions are only supported
by highly flawed safety trials design.4,10 Additionally, we note evidence of
biased and selective reporting of results from clinical trials, that is,
exclusion of particular vaccine efficacy figures from peerreviewed
publications, such as those related to study subgroups in which efficacy might
be lower or even negative.4,5 All of the above issues suggest that the
information presented by Merck to the public and the various state legislators
concerning Gardasil safety and true prophylactic value were incomplete and
inaccurate and thus inevitably misleading, particularly in light of data from
various vaccine safety surveillance systems and case reports that continue to
raise significant concerns regarding the safety of Gardasil (Table 1).4 Keeping
in mind that “the primary interest of a pharmaceutical company is developing
and selling pharmaceutical product,”1 one must ask whether rational vaccine
policy decisions should be based on conclusions derived from an uncritical
acceptance of flawed vaccine safety and efficacy estimates provided by the
vaccine manufacturer. Failure to adhere to principles of evidence-based
medicine with respect to Gardasil promotion and vaccination policymaking
inevitably raises the question of whether we have learned anything from the
Vioxx debacle. Full Report with References:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482043/

Age-Adjusted Rate Of Adverse Reactions (ADRs) Related To Gardasil Compared With
All Other Vaccines In The United States Reported To The Vaccine Adverse Event
Reporting System (VAERS) As Of March 25th, 2012. Event

Gardasil

All Vaccines

Gardasil %

All Serious Deaths Life-Threatening Permanently Disabled Prolonged
Hospitalization Emergency Room Visit

14,616 1,272 37 289 468 172 6,892

31,713 2,077 58 444 572 229 12,927

46.1 61.2 63.8 65.1 81.2 75.1 53.3

Note: Compared with all other vaccines, Gardasil alone is associated with >60%
of all serious Adverse Reactions (including 63.8% of all deaths and 81.2% cases
of permanent disability) in females younger than 30 years. In context, while
females in this age group have a near-zero risk of dying from cervical cancer,
they are faced with a risk of dying and a permanently disabling condition from
a vaccine that has not prevented a single case of cervical cancer thus far. For
a vaccine with uncertain benefits designed to prevent a disease that is
preventable through Papanicolaou screening combined with the loop
electrosurgical excision procedure, which together carry no such risks, the
potental for harm to those vaccinated should be negligible. It is not.

“In context. while females in this age group have a near-zero risk of dying
from cervical cancer, they are faced with a risk of dying and a permanently
disabling condition from a vaccine that has not prevented a single case of
cervical cancer thus far. For a vaccine with uncertain benefits designed to
prevent a disease that is preventable through Papanicolaou screening combined
with the loop electrosurgical precision procedure, which together carry no such
risks, the potential for harm to those vaccinated should be negligible.”

BMJ Case Report • September 2012

Premature ovarian failure 3 years after menarche in a 16-year-old girl
following human papillomavirus vaccination Author information Little DT1, Ward
HR. Department of General Practice North Bellingen Medical Services, Bellingen,
Australia dradford@wirefree.net.au Abstract Its occurrence raises important
questions about causation, which may signal other systemic concerns. This
patient presented with amenorrhoea after identifying a change from her regular
cycle to irregular and scant periods following vaccinations against human
papillomavirus. She declined the oral contraceptives initially prescribed for
amenorrhoea. The diagnostic tasks were to determine the reason for her
secondary amenorrhoea and then to investigate for possible causes of the
premature ovarian failure identified. Although the cause is unknown in 90% of
cases, the remaining chief identifiable causes of this condition were excluded.
Premature ovarian failure was then notified as a possible adverse event
following this vaccination. The young woman was counselled regarding
preservation of bone density, reproductive implications and relevant follow-up.
This event could hold potential implications for population health and prompts
further inquiry. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543769/

“Premature ovarian failure in a well adolescent is a rare event. This patient
presented with amenorrhoea after identifying a change from her regular cycle to
irregular and scant periods following vaccinations against human
papillomavirus. This event could hold potential implications for population
health and prompts further inquiry.”

Journal of Internal Medicine
Volume 272, Issue 5, pages 514–515 • November 2012

tion [6]. This outcome suggests that rather than preventing future cases of
cervical cancer, Gardasil, at best, may only be effective in postponing them.

Letter to the Editor

In addition, unlike screening and the loop electrosurgical excision procedure
(LEEP), Gardasil offers no therapeutic benefits as it cannot cause regression
of pre-existing HPV-16/18 infections or associated lesions. On the contrary,
Gardasil may exacerbate cervical cancer disease in women with pre-existing
HPV-6/11/16/18 infections [5]. It thus appears that the current widespread
optimism regarding the putative long-term benefits of HPV vaccination has only
been made possible by invalid and premature extrapolations from such often
inadequate surrogate markers [3, 9, 10]. As recently noted by Gerhardus and
Razum [9], the, ‘unwarranted confidence in the new [HPV] vaccines led to the
impression that there was no need to actually evaluate their effectiveness’.

No autoimmune safety signal after vaccination with quadrivalent HPV vaccine
Gardasil? L. Tomljenovic and C. A. Shaw Dear sir, Recently, the Journal of
Internal Medicine published a study by Chao et al. [1] on autoimmune conditions
following the routine use of Gardasil, which failed to identify any significant
autoimmune safety concerns. This study was conducted in collaboration between
two managed care organizations, Kaiser Permanente Southern California (KPSC)
and Kaiser Permanente Northern California (KPNC), as a postlicensure commitment
to the FDA, the European Medicines Agency (EMA) and other regulatory
authorities to help evaluate the autoimmune safety of the vaccine. In
particular, Chao et al. [1] noted that ‘well-designed postlicensure safety
studies for newly approved vaccines facilitate proper evaluation of their
autoimmune safety’ [emphasis added]. We certainly do agree with the authors
that such studies are needed for determining whether or not new vaccines have
adequate safety profiles. The study population for the autoimmune surveillance
by the Kaiser’s research team thus included 189 629 women of diverse ethnical
and socio-economic background, 99% of whom were in the recommended age range
for HPV vaccination (9–26 years) [1]. Nonetheless, two potential biases might
have influenced the outcome of the safety analysis conducted by the authors.
First, the study included all women who received at least one dose of Gardasil,
thus making this particular population sample less sensitive for the detection
of serious adverse reactions (ADRs), as such events may be expected to occur
less frequently if fewer doses of the vaccine are administered. As the authors
did not report how many women actually completed the recommended three-dose HPV
vaccination regimen, it is impossible to know what proportion of the study
population was actually at high risk from vaccine-related serious ADRs.
Secondly, the Safety Review Committee (SRC) that reviewed all safety data
included a general paediatrician/clinical epidemiologist, a
perinatologist/teratologist, a vaccinologist, a paediatric rheumatologist and a
pharmacoepidemiologist [1]. In view of the fact that the autoimmune conditions
of interest to be examined by this expert Committee included (i)
rheumatologic/autoimmune disorders, (ii) autoimmune endocrine conditions and
(iii) autoimmune neurological/ophthalmic disorders [1]; the question must be
asked about why the Kaiser’s research team failed to recruit an expert panel
with similar expertise if, in fact, the study aimed to facilitate proper
evaluation of autoimmune safety for Gardasil? It is thus surprising to note the
absence of an immunologist/autoimmunologist, neurologist and ophthalmologist
from the SRC especially because such experts were in fact present at a later
stage, in the analysis of case reports selected by the SRC [1]. As demonstrated
repeatedly in the scientific literature, inadequately designed research cannot
be used to reliably evaluate the safety of any drug [2,3]. We have previously
pointed out to existing HPV vaccine-related safety concerns as well as
uncertainties about the efficacy of HPV vaccination against actual cervical
cancer incidence [3, 4]. Whilst results from clinical trials show that Gardasil
can reduce the incidence of a subset of abnormal CIN 2/3+ cytologies (i.e.
those related to HPV-16/18) in women with no pre-existing HPV infections [5],
the vaccine is unlikely to reduce the overall frequency of cervical cancers (at
least not beyond what Pap screening has already accomplished) [6, 7], yet this
is the primary aim for which the vaccine was developed [8]. Furthermore,
current data show that antibodies against HPV-18 after Gardasil fall rapidly,
with 35% of women having no measurable antibody titres by 5 years postinjec-

On the other hand, abundant evidence now exists that HPV vaccines can cause
serious adverse events, including death and long-term disabling autoimmune
conditions [3, 6]. Moreover, because currently there are no active surveillance
programs for monitoring vaccine safety outcomes anywhere in the world, the true
rate of serious ADRs following Gardasil remains unknown. In context, whilst
12-year-old preadolescents are at zero risk of dying from cervical cancer, they
are faced with a risk of death and a permanently disabling lifelong autoimmune
or neurodegenerative condition from a vaccine that thus far has not prevented a
single case of cervical cancer, let alone cervical cancer death. For vaccines
with uncertain benefits designed to prevent a disease that is already
preventable by Pap screening and LEEP, both of which carry no such risks, the
potential for harm to those vaccinated should be negligible [3, 4]. Conflict of
interest statement Authors LT and CAS conducted a histological analysis of
autopsy brain samples from a Gardasil-suspected death case
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2012.02551.x/full

“the vaccine is unlikely to reduce the overall frequency of cervical cancers
(at least not beyond what Pap screening has already accomplished), yet this is
the primary aim for which the vaccine was developed. Furthermore, current data
show that antibodies against HPV-18 after Gardasil fall rapidly, with 35% of
women having no measurable antibody titres by 5 years postinjection. This
outcome suggests that rather than preventing future cases of cervical cancer,
Gardasil, at best, may only be effective in postponing them.”

The Journal Of Law, Medicine & Ethics • Fall 2012

Too fast or not too fast: the FDA’s approval of Merck’s HPV vaccine Gardasil
Author information Tomljenovic L1, Shaw CA. University of British Columbia
Abstract There are not many public health issues where views are as extremely
polarized as those concerning vaccines, and Merck’s HPV vaccine Gardasil is a
case in point. Ever since gaining the FDA’s approval in 2006, Merck has been
heavily criticized for their overly aggressive marketing strategies and
lobbying campaigns aimed at promoting Gardasil as a mandatory vaccine.
Subsequently, questions have been raised as to whether it was appropriate for
vaccine manufacturers to partake in public health policies when their conflicts
of interests are so obvious. Some of their advertising campaign slogans, such
as “cervical cancer kills x women per year” and “your daughter could become one
less life affected by cervical cancer,” seemed more designed to promote fear
rather than evidence-based decision making about the potential benefits of the
vaccine. Although, conflicts of interests do not necessarily mean that the
product itself is faulty, marketing claims should be carefully examined against
factual science data. Currently Gardasil vaccination is strongly recommended by
the U.S. and other health authorities while public concerns about safety and
efficacy of the vaccine appear to be increasing. This discrepancy leads to some
important questions that need to be resolved. The current review examines key
issues of this debate in light of currently available research evidence.
http://www.ncbi.nlm.nih.gov/pubmed/23061593

“Some of their advertising campaign slogans, such as “cervical cancer kills x
women per year” and “your daughter could become one less life affected by
cervical cancer,” seemed more designed to promote fear rather than
evidence-based decision making about the potential benefits of the vaccine.”

Pharmaceutical Regulatory Affairs • 2012

Death after Quadrivalent Human Papillomavirus (HPV) Vaccination: Causal or
Coincidental? Lucija Tomljenovic1* and Christopher A Shaw1,2,3 1. Department of
Ophthalmology and Visual Sciences, University of British Columbia, Canada 2.
Program in Experimental Medicine, University of British Columbia, Canada 3.
Program in Neuroscience, University of British Columbia, Canada Abstract
Background The proper understanding of a true risk from vaccines is crucial for
avoiding unnecessary adverse reactions (ADRs). However, to this date no solid
tests or criteria have been established to determine whether adverse events are
causally linked to vaccinations.

“Our study suggests that HPV vaccines

Objectives This research was carried out to determine whether or not some
serious autoimmune and neurological ADRs following HPV vaccination are causal
or merely coincidental and to validate a biomarker-based immunohistochemical
(IHC) protocol for assessing causality in case of vaccination-suspected serious
adverse neurological outcomes.

inherent risk for triggering potentially fatal

containing HPV-16L1 antigens pose an

autoimmune vasculopathies.”

Results In both cases, the autopsy revealed no anatomical, microbiological nor
toxicological ndings that might have explained the death of the individuals. In
contrast, our IHC analysis showed evidence of an autoimmune vasculitis
potentially triggered by the cross-reactive HPV-16L1 antibodies binding to the
wall of cerebral blood vessels in all examined brain samples. We also detected
the presence of HPV-16L1 particles within the cerebral vasculature with some
HPV-16L1 particles adhering to the blood vessel walls. HPV-18L1 antibodies did
not bind to cerebral blood vessels nor any other neural tissues. IHC also
showed increased T-cell signalling and marked activation of the classical
antibody-dependent complement pathway in cerebral vascular tissues from both
cases. This pattern of complement activation in the absence of an active brain
infection indicates an abnormal triggering of the immune response in which the
immune attack is directed towards self-tissue. Conclusions Our study suggests
that HPV vaccines containing HPV-16L1 antigens pose an inherent risk for
triggering potentially fatal autoimmune vasculopathies. Practice implications
Cerebral vasculitis is a serious disease which typically results in fatal
outcomes when undiagnosed and left untreated. The fact that many of the
symptoms reported to vaccine safety surveillance databases following HPV
vaccination are indicative of cerebral vasculitis, but are unrecognized as such
(i.e., intense persistent migraines, syncope, seizures, tremors and tingling,
myalgia, locomotor abnormalities, psychotic symptoms and cognitive de cits), is
a serious concern in light of the present findings. It thus appears that in
some cases vaccination may be the triggering factor of fatal
autoimmune/neurological events. Physicians should be aware of this association.
Full Report:
http://sanevax.org/wp-content/uploads/2012/10/Tomljenovic-Shaw-Gardasil-Causal-Coincidental-2167-7689-S12-001.pdf

Current Pharmaceutical Design • 2013

Human papillomavirus (HPV) vaccines as an option for preventing cervical
malignancies: (how) effective and safe? Author information Tomljenovic L1,
Spinosa JP, Shaw CA. Neural Dynamics Research Group Department of Ophthalmology
and Visual Sciences University of British Columbia 828 W. 10th Ave, Vancouver,
BC, V5Z 1L8, Canada lucijat77@gmail.com Abstract We carried out a systematic
review of HPV vaccine pre- and post-licensure trials to assess the evidence of
their effectiveness and safety. We find that HPV vaccine clinical trials
design, and data interpretation of both efficacy and safety outcomes, were
largely inadequate. Additionally, we note evidence of selective reporting of
results from clinical trials (i.e., exclusion of vaccine efficacy figures
related to study subgroups in which efficacy might be lower or even negative
from peer-reviewed publications). Given this, the widespread optimism regarding
HPV vaccines long-term benefits appears to rest on a number of unproven
assumptions (or such which are at odd with factual evidence) and significant
misinterpretation of available data. For example, the claim that HPV
vaccination will result in approximately 70% reduction of cervical cancers is
made despite the fact that the clinical trials data have not demonstrated to
date that the vaccines have actually prevented a single case of cervical cancer
(let alone cervical cancer death), nor that the current overly optimistic
surrogate marker-based extrapolations are justified. Likewise, the notion that
HPV vaccines have an impressive safety profile is only supported by highly
flawed design of safety trials and is contrary to accumulating evidence from
vaccine safety surveillance databases and case reports which continue to link
HPV vaccination to serious adverse outcomes (including death and permanent
disabilities). We thus conclude that further reduction of cervical cancers
might be best achieved by optimizing cervical screening (which carries no such
risks) and targeting other factors of the disease rather than by the reliance
on vaccines with questionable efficacy and safety profiles.
http://www.ncbi.nlm.nih.gov/pubmed/23016780

“We carried out a systematic review of HPV vaccine preand post-licensure trials
to assess the evidence of their effectiveness and safety. We find that HPV
vaccine clinical trials design, and data interpretation of both efficacy and
safety outcomes, were largely inadequate. Given this, the widespread optimism
regarding HPV vaccines long-term benefits appears to rest on a number of
unproven assumptions (or such which are at odd with factual evidence) and
significant misinterpretation of available data. Likewise, the notion that HPV
vaccines have an impressive safety profile is only supported by highly flawed
design of safety trials and is contrary to accumulating evidence from vaccine
safety surveillance databases and case reports which continue to link HPV
vaccination to serious adverse outcomes (including death and permanent
disabilities).”

Infectious Agents & Cancer • 2013

HPV vaccines and cancer prevention, science versus activism Lucija
Tomljenovic,1 Judy Wilyman,2 Eva Vanamee,3 Toni Bark,4 and Christopher A Shaw1
1. Neural Dynamics Research Group Vancouver General Hospital Research Pavilion
University of British Columbia, 828 W. 10th Ave Vancouver, BC, V5Z 1L8, Canada
2. School of Social Sciences Media and Communication University of Wollongong,
Wollongong 2522, Australia 3. Department of Structural and Chemical Biology
Mount Sinai School of Medicine, 1425 Madison Ave Rm 1623, New York, NY, 10029,
USA 4. School of Public Health-Healthcare Emergency Management Boston
University, Boston, MA, 02118, USA Abstract The rationale behind current
worldwide human papilloma virus (HPV) vaccination programs starts from two
basic premises, 1) that HPV vaccines will prevent cervical cancers and save
lives and, 2) have no risk of serious side effects. Therefore, efforts should
be made to get as many pre-adolescent girls vaccinated in order to decrease the
burden of cervical cancer. Careful analysis of HPV vaccine pre- and
post-licensure data shows however that both of these premises are at odds with
factual evidence and are largely derived from significant misinterpretation of
available data. Letter The recent Editorial by Silvia de Sanjosé* [1] is
problematic from a variety of perspectives. Mainly, it attempts to portray a
complex issue as a simple dichotomy between supposedly unjustified “anti-HPV
vaccine activism” and alleged absolute science which has presumably provided
indisputable evidence on HPV vaccine safety and efficacy. In spite of much
unwarranted and premature optimism, the fact is however that HPV vaccines have
not thus far prevented a single case of cervical cancer (let alone cervical
cancer death). Instead, what the clinical trials have shown is that HPV
vaccines can prevent some of the pre-cancerous CIN 2/3 lesions associated with
HPV-16 and HPV-18 infection, a large fraction of which would spontaneously
resolve regardless of the vaccination status [24]. For example, in adolescent
women aged 13 to 24 years, 38% of CIN 2 resolve after one year, 63% after two
and 68% after three years [5]. Moreover, the validity of CIN 2 being a cancer
precursor is questionable due to high misclassification rates and poor intra-
and inter-observer reproducibility in diagnosis, as well as high regression
rates [6-9]. According to Castle et al. [7] CIN 2 is the least reproducible of
all histopathologic diagnoses and may in part reflect sampling error. While CIN
3 is a more reliable marker for cancer progression than CIN 2, the use of this
marker is not without caveats [2,10]. Indeed, the optimistic assumption that
HPV vaccination (even if proven effective against cervical cancer as claimed),
will result in 70% reduction of cervical cancers appears to be largely based on
premature, exaggerated

and invalid surrogate marker-based extrapolations [2,11]. Crucially, these
assumptions failed to take into account several important real-world factors
such as: (1) reliability of surrogate-markers (i.e., whether they can
accurately measure what they are purport to measure); (2) efficacy against
oncogenic HPV strains not covered by the vaccine; (3) possibility of increased
frequency of infections with these types; (4) efficacy in women acquiring
multiple HPV types; (5) effects in women with pre-existing HPV infections It is
also noteworthy that Merck’s HPV vaccine Gardasil received priority Fast Track
approval by the U.S. Food and Drug Administration (FDA) after a 6-month review
process, despite the fact that it failed (and still continues to fail) to meet
a single one of the four criteria required by the FDA for Fast Track approval.
Gardasil is demonstrably neither safer nor more effective than Pap screening
combined with the loop electrosurgical excision procedure (LEEP) in preventing
cervical cancers, nor can it improve the diagnosis of serious cervical cancer
outcomes [12]. In this regard, Gerhardus and Razum have recently noted that the
“…unwarranted confidence in the newHPVvaccines led to the impression that there
was no need to actually evaluate their effectiveness” [11]. Similarly, the
notion that HPV vaccines have an impressive safety profile can only be
supported by highly flawed design of safety trials [2,13] and is contrary to
accumulating evidence from vaccine safety surveillance databases and case
reports which continue to link HPV vaccination to serious adverse outcomes
(including death and permanent disabilities) [2,4,14]. For example, compared to
all other vaccines in the U.S. vaccination schedule, Gardasil alone is
associated with 61% of all serious adverse reactions (including 63.8% of all
deaths and 81.2% cases of permanent disability) in females younger than 30
years of age [12]. Although a report to a vaccine safety surveillance system
does not by itself prove that the vaccine caused an adverse reaction, the
unusually high frequency of adverse reactions related to HPV vaccines reported
worldwide, as well as their consistent pattern (i.e. nervous system-related
disorders rank the highest in frequency), points to a potentially causal
relationship [2]. Furthermore, matching the data from vaccine surveillance
databases is an increasing number of case reports documenting similar serious
adverse reactions associated with HPV vaccine administration, with nervous
system and autoimmune disorders being the most frequently reported in the
medical literature [15-24]. In summary, the optimistic claims that HPV vaccines
will prevent cervical cancers and save lives, and that they are extremely safe,
rest on assumptions which are misinterpreted and presented to the public as
factual evidence. We thus conclude that further reduction of cervical cancers
might be best achieved by optimizing cervical screening (which carries no
serious health risks) and targeting other factors of the disease rather than by
the reliance on vaccines with questionable efficacy and safety profiles [2,25].
To those who wish to promote HPV vaccination as a means for reducing cervical
cancer burden, perhaps the following should be asked: 1. HPV vaccines have not
been demonstrated to prevent any cervical cancers so why are they being
promoted as cervical cancer vaccines? 2. If the majority of HPV infections and
a great proportion of pre-cancerous lesions clear spontaneously and without
medical treatment and are thus not a reliable indication of cancer later in
life, then how can these end-points be used as a reliable indicator of the
number of cervical cancer cases that will be prevented by HPV vaccines? 3. How
can the clinical trials make an accurate estimate of the risk associated with
HPV-vaccines if they are methodologically biased to produce type-2 errors
(false negatives [2,4,13])? [continued next page]

4. Can a passive monitoring system such as that used by most vaccine surveillance systems world-wide allow
the medical regulatory agencies to make accurate estimates on the real
frequency of HPV-vaccine related adverse reactions? 5. Can an accurate estimate
of the real frequency of HPV-vaccine related adverse reactions be made if
appropriate follow-up and thorough investigation of suspected vaccine related
ADRs is not conducted but instead, these cases are a-priori dismissed as being
unrelated to the vaccine? 6. Why are women not informed of the fact that in
some circumstances (i.e., prior exposure to vaccine-targeted and non-targeted
HPV types), HPV vaccination may accelerate the progression of cervical
abnormalities [4,2628]?

“ Gardasil is demonstrably neither safer nor more effective than Pap screening

7. How can women make a fully informed decision about whether or not to consent
to vaccination if crucial information regarding HPV vaccine efficacy and safety
is not being disclosed to them?

combined with the loop electrosurgical

8. Should the medical health regulators and authorities rely solely on data
provided by the vaccine manufacturers to make vaccine-policy decisions and
recommendations [12,29]?

excision procedure (LEEP) in preventing

Competing interests The authors declare that they have no conflict of interests
Authors’ contributions LT was involved in choosing the topic and drafting the
initial manuscript. CAS, JW, EV and TB were involved in critically revising the
manuscript and additional content. The authors have read and approved the
manuscript. This work was supported by the Dwoskin and Katlyn Fox Family
Foundations. Full Report with References
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565961/ “As for all vaccines, and
in particular for newly marketed ones, the surveillance of adverse events
represents an essential step in the evaluation of a vaccination programme.”
[because all vaccines are part of a long-term human population-wide medical
experiment]

cervical cancers, nor can it improve the diagnosis of serious cervical cancer
outcomes.”

Annals Of Medicine • March 2013

Human papillomavirus (HPV) vaccine policy and evidence-based medicine: are they
at odds? Author information Tomljenovic L1, Shaw CA. Neural Dynamics Research
Group Department of Ophthalmology and Visual Sciences University of British
Columbia, 828 W. 10th Ave Vancouver, BC, V5Z 1L8, Canada lucijat77@gmail.com
Abstract All drugs are associated with some risks of adverse reactions. Because
vaccines represent a special category of drugs, generally given to healthy
individuals, uncertain benefits mean that only a small level of risk for
adverse reactions is acceptable. Furthermore, medical ethics demand that
vaccination should be carried out with the participant’s full and informed
consent. This necessitates an objective disclosure of the known or foreseeable
vaccination benefits and risks. The way in which HPV vaccines are often
promoted to women indicates that such disclosure is not always given from the
basis of the best available knowledge. For example, while the world’s leading
medical authorities state that HPV vaccines are an important cervical cancer
prevention tool, clinical trials show no evidence that HPV vaccination can
protect against cervical cancer. Similarly, contrary to claims that cervical
cancer is the second most common cancer in women worldwide, existing data show
that this only applies to developing countries. In the Western world cervical
cancer is a rare disease with mortality rates that are several times lower than
the rate of reported serious adverse reactions (including deaths) from HPV
vaccination. Future vaccination policies should adhere more rigorously to
evidence-based medicine and ethical guidelines for informed consent.
http://www.ncbi.nlm.nih.gov/pubmed/22188159

“... while the world’s leading medical authorities state that HPV vaccines are
an important cervical cancer prevention tool, clinical trials show no evidence
that HPV vaccination can protect against cervical cancer. Similarly, contrary
to claims that cervical cancer is the second most common cancer in women
worldwide, existing data show that this only applies to developing countries.
In the Western world cervical cancer is a rare disease with mortality rates
that are several times lower than the rate of reported serious adverse
reactions (including deaths) from HPV vaccination.”

Clinical Rheumatology • September 2013

Human papillomavirus vaccine and systemic lupus erythematosus Author
information Gatto M1, Agmon-Levin N, Soriano A, Manna R, Maoz-Segal R, Kivity
S, Doria A, Shoenfeld Y. Department of Medicine University of Padova, Padova,
Italy Abstract To investigate the association between human papillomavirus
(HPV) vaccination and autoimmune manifestations compatible with systemic lupus
erythematosus (SLE) or SLE-like disease, the medical history of six women who
presented with SLE or SLE-like disease following HPV immunization was
collected. Data regarding type of vaccine, number of immunization, family and
personal, clinical and serological features, as well as response to treatments
were analyzed. In the reported cases, several common features were observed,
such as personal or familial susceptibility to autoimmunity or adverse response
to a prior dose of the vaccine, both of which may be associated with a higher
risk of post-vaccination autoimmunity. Favorable response to immunosuppressant
was observed in all patients. In the current study, a temporal association
between immunization with HPV vaccine and the appearance of a spectrum of
SLE-like conditions is reported. Additionally, among the patients described,
several common features were observed that may enable better identification of
subjects at risk. Further studies are required to assess the safety of
immunization with the HPV vaccine in patients with autoimmune-rheumatic
diseases or in subject at risk of autoimmunity as well as the potential
beneficial effect of preventive immunosuppressants.
http://www.ncbi.nlm.nih.gov/pubmed/23624585

“In the current study, a temporal association between immunization with HPV
vaccine and the appearance of a spectrum of SLE-like conditions is reported.
Additionally, among the patients described, several common features were
observed that may enable better identification of subjects at risk.”

Neuropediatrics • October 2013

Association of acute cerebellar ataxia and human papilloma virus vaccination: a
case report Author information Yonee C1, Toyoshima M, Maegaki Y, Kodama Y,
Hayami H, Takahashi Y, Kusunoki S, Uchibori A, Chiba A, Kawano Y. Department of
Pediatrics Graduate School of Medical and Dental Sciences Kagoshima University,
Kagoshima City Kagoshima, Japan Abstract INTRODUCTION We report the case of a
patient who developed symptoms of acute cerebellar ataxia (ACA) after
administration of the human papilloma virus (HPV)-16/18 vaccine. PATIENT AND
METHOD This patient developed symptoms of ACA, including nausea, vertigo,
severe limb and truncal ataxia, and bilateral spontaneous continuous horizontal
nystagmus with irregular rhythm, 12 days after administration of the HPV-16/18
AS04-adjuvanted cervical cancer vaccine. After this, the patient received
methylprednisolone pulse and intravenous immunoglobulin (IVIG) therapies as
well as immunoadsorption plasmapheresis. RESULTS Severe ACA symptoms did not
improve after methylprednisolone pulse and IVIG therapies, but the patient
recovered completely after immunoadsorption plasmapheresis. CONCLUSION This
temporal association strongly suggests that ACA was induced by the vaccination.
http://www.ncbi.nlm.nih.gov/pubmed/?term=23378179

“This temporal association strongly suggests that acute cerebellar ataxia was
induced by the vaccination.”

American Journal Of Reproductive Immunology • October 2013

Human papilloma virus vaccine and primary ovarian failure: another facet of the
autoimmune/inflammatory syndrome induced by adjuvants Author information
Colafrancesco S1, Perricone C, Tomljenovic L, Shoenfeld Y. Zabludowicz Center
for Autoimmune Diseases Sheba Medical Center, Tel-Hashomer, Israel

“We documented here the evidence

Rheumatology Unit, Department of Internal Medicine and Medical Specialities
Sapienza University of Rome, Rome, Italy

of the potential of the HPV vaccine

Abstract

to trigger a life-disabling autoimmune condition.

PROBLEM Post-vaccination autoimmune phenomena are a major facet of the
autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and different
vaccines, including HPV, have been identified as possible causes.

The increasing number of similar reports of

METHOD OF STUDY The medical history of three young women who presented with
secondary amenorrhea following HPV vaccination was collected. Data regarding
type of vaccine, number of vaccination, personal, clinical and serological
features, as well as response to treatments were analyzed.

uncertainty of long-term clinical benefits of HPV

RESULTS All three patients developed secondary amenorrhea following HPV
vaccinations, which did not resolve upon treatment with hormone replacement
therapies. In all three cases sexual development was normal and genetic screen
revealed no pertinent abnormalities (i.e., Turner’s syndrome, Fragile X test
were all negative). Serological evaluations showed low levels of estradiol and
increased FSH and LH and in two cases, specific auto-antibodies were detected
(antiovarian and anti thyroid), suggesting that the HPV vaccine triggered an
autoimmune response. Pelvic ultrasound did not reveal any abnormalities in any
of the three cases. All three patients experienced a range of common
non-specific post-vaccine symptoms including nausea, headache, sleep
disturbances, arthralgia and a range of cognitive and psychiatric disturbances.
According to these clinical features, a diagnosis of primary ovarian failure
(POF) was determined which also fulfilled the required criteria for the ASIA
syndrome.

warrants further rigorous inquiry.”

CONCLUSION We documented here the evidence of the potential of the HPV vaccine
to trigger a life-disabling autoimmune condition. The increasing number of
similar reports of post HPV vaccine-linked autoimmunity and the uncertainty of
long-term clinical benefits of HPV vaccination are a matter of public health
that warrants further rigorous inquiry.
http://www.ncbi.nlm.nih.gov/pubmed/23902317

post HPV vaccine-linked autoimmunity and the

vaccination are a matter of public health that

Current Drug Safety • March 2014

Human papilloma virus vaccine associated uveitis Author information Holt HD,
Hinkle DM, Falk NS, Fraunfelder FT, Fraunfelder FW1. Lions Eye Institute,
Albany Medical College, Slingerlands, New York, USA hncl1983@gmail.com Abstract
PURPOSE To report a possible association between human papilloma virus (HPV)
vaccination and uveitis. METHODS Spontaneous reports from the National Registry
of Drug-Induced Ocular Side effects, World Health Organization and Food and
Drug Administration were collected on uveitis associated with human papilloma
virus vaccination. A MEDLINE search was performed using keywords “uveitis,”
“iritis,” “iridocyclitis,” “human papilloma virus,” “Cervarix”, and “Gardasil.”
MAIN OUTCOME MEASURES Data garnered from spontaneous reports included the age,
gender, adverse drug reaction (ADR), date of administration, concomitant
administration of other vaccinations, time until onset of ADR, other systemic
reactions, and dechallenge and rechallenge data. RESULTS A total of 24 case
reports of uveitis associated with human papilloma virus vaccination were
identified, all cases were female, and the median age was 17. Median time from
HPV vaccination to reported ADR was 30 days (range 0-476 days). DISCUSSION
According to World Health Organization criteria, the relationship between human
papilloma virus vaccination and uveitis is “possible.” Causality assessments
are based on the time relationship of drug administration, uveitis development
and rechallenge data. CONCLUSIONS Clinicians should be aware of a possible
bilateral uveitis and papillitis following HPV vaccination.
http://www.ncbi.nlm.nih.gov/pubmed/24191906

“A total of 24 case reports of uveitis associated with human papilloma virus
vaccination were identified, all cases were female, and the median age was 17.
According to World Health Organization criteria, the relationship between human
papilloma virus vaccination and uveitis is “possible.”

European Journal Of Neurology • September 2014

Postural tachycardia syndrome following human papillomavirus vaccination Author
information Blitshteyn S. Department of Neurology State University of New York
at Buffalo School of Medicine and Biomedical Sciences Buffalo, NY, USA Abstract
BACKGROUND AND PURPOSE Postural tachycardia syndrome (POTS) is a heterogeneous
disorder of the autonomic nervous system that may have an autoimmune etiology.
METHODS Six patients who developed new onset POTS 6 days to 2 months following
human papillomavirus vaccination are reported. RESULTS Three patients also had
neurocardiogenic syncope, and three patients were diagnosed with possible small
fiber neuropathy. Symptoms in all patients improved over 3 years with
pharmacotherapy and non-pharmacological measures but residual symptoms
persisted. Molecular mimicry with formation of cross-reacting autoantibodies to
the potential targets of the autonomic ganglia, neurons, cardiac proteins or
vascular receptors is considered as a possible pathogenesis of new onset POTS
after immunization. CONCLUSION Correct diagnosis of POTS and awareness that
POTS may occur after vaccination in young women is essential for prompt and
effective management of this condition.
http://www.ncbi.nlm.nih.gov/pubmed/24102827

“Six patients who developed new onset Postural tachycardia syndrome 6 days to 2
months following human papillomavirus vaccination are reported.”

Journal Of Investigative Medicine
High Impact Case Reports • October 2014

Adolescent Premature Ovarian Insufficiency Following Human Papillomavirus
Vaccination: A Case Series Seen in General Practice Author information Little
DT1, Ward HR2. 1. Bellingen District Hospital, Bellingen, New South Wales,
Australia 2. University of New South Wales, Coffs Harbour, New South Wales,
Australia Abstract Three young women who developed premature ovarian
insufficiency following quadrivalent human papillomavirus (HPV) vaccination
presented to a general practitioner in rural New South Wales, Australia. The
unrelated girls were aged 16, 16, and 18 years at diagnosis. Each had received
HPV vaccinations prior to the onset of ovarian decline. Vaccinations had been
administered in different regions of the state of New South Wales and the 3
girls lived in different towns in that state. Each had been prescribed the oral
contraceptive pill to treat menstrual cycle abnormalities prior to
investigation and diagnosis. Vaccine research does not present an ovary
histology report of tested rats but does present a testicular histology report.
Enduring ovarian capacity and duration of function following vaccination is
unresearched in preclinical studies, clinical and postlicensure studies.
Postmarketing surveillance does not accurately represent diagnoses in adverse
event notifications and can neither represent unnotified cases nor compare
incident statistics with vaccine course administration rates. The potential
significance of a case series of adolescents with idiopathic premature ovarian
insufficiency following HPV vaccination presenting to a general practice
warrants further research. Preservation of reproductive health is a primary
concern in the recipient target group. Since this group includes all
prepubertal and pubertal young women, demonstration of ongoing, uncompromised
safety for the ovary is urgently required. This matter needs to be resolved for
the purposes of population health and public vaccine confidence.
http://www.ncbi.nlm.nih.gov/pubmed/26425627

“Three young women who developed premature ovarian insufficiency following
quadrivalent human papillomavirus (HPV) vaccination presented to a general
practitioner in rural New South Wales, Australia. The potential significance of
a case series of adolescents with idiopathic premature ovarian insufficiency
following HPV vaccination presenting to a general practice warrants further
research. This matter needs to be resolved for the purposes of population
health and public vaccine confidence.”

Human Vaccines And Immunotherapeutics • 2014

Comparison of adaptive and innate immune responses induced by licensed vaccines
for Human Papillomavirus Author information Herrin DM1, Coates EE, Costner PJ,
Kemp TJ, Nason MC, Saharia KK, Pan Y, Sarwar UN, Holman L, Yamshchikov G, Koup
RA, Pang YY, Seder RA, Schiller JT, Graham BS, Pinto LA, Ledgerwood JE. 1.
Vaccine Research Center National Institute of Allergy and Infectious Disease
National Institutes of Health; Bethesda, MD USA Abstract Two HPV virus-like
particle (VLP) vaccines, HPV-16/18 (GlaxoSmithKline, Cervarix®) and
HPV-6/11/16/18 (Merck, Gardasil®), are currently licensed in the United States.
Given the similar antigenic content but different adjuvant formulations in the
2 vaccines, they provide an efficient method for evaluating adjuvants and
comparing the kinetics of the innate and adaptive immune responses. We
randomized women to receive either Cervarix® or Gardasil®, followed 6 month
vaccination delivery schedules per manufacturer’s recommendations, and analyzed
the humoral immune response, T cell response, and circulating plasma cytokine
levels in response to vaccination. Cervarix® recipients had higher anti-HPV-16
antibody and neutralization titers at month 7, and elevated anti-HPV-18
antibody and neutralization titers at months 7 and 12. Antibody avidity was
similar for the 2 vaccines. HPV-31 was the only phylogenetically related
non-vaccine HPV type, for which there is evidence of cross-protection, to be
cross-neutralized and only in response to Cervarix®. Comparing CD4+ T cell
cytokine responses at month 12, there was a trend of increased levels of IL-2
and TNF-∼ in the Cervarix® groups versus the Gardasil® groups that was
consistent across all 4 tested HPV types (16/18/33/45). Elevated levels of
circulating plasma cytokine/chemokines were observed post first vaccination in
Gardasil® recipients and proinflammatory cytokines were elevated following 1st
and 3rd Cervarix® vaccinations. Cervarix® and Gardasil® are both highly
immunogenic vaccines. Higher antibody levels and CD4 T cell responses were
achieved with Cervarix® after 3 doses, although similar affinity maturation was
measured for the 2 vaccines. The clinical implications of the differences in
immune responses are unknown. http://www.ncbi.nlm.nih.gov/pubmed/?term=25483691

[proving vaccines are continuous, long-term human experiments]

HPV vaccine is neither safe nor effective

References

The following letter to the editor of the Baltimore Sun, with references, was
written by Emily Tarsell, LCPC, and Dr. William Reichel on August 9, 2015

1. Tomljenovic L, Shaw CA, Spinosa JP: Human Papillomavirus (HPV) Vaccines as
an option for preventing cervical malignancies: (How) effective and safe? Curr
Pharm Des 2012, :CPD-EPUB-20120924-13.Epub ahead of print. 2. Tomljenovic L,
Shaw CA: Who profits from uncritical acceptance of biased estimates of vaccine
efficacy and safety? Am J Public Health 2012, 102(9):e13–e14. 3. Tomljenovic L,
Shaw CA: Human papillomavirus (HPV) vaccine policy and evidence-based medicine:
are they at odds? Ann Med 2011, doi:10.3109/07853890.2 011.645353 4. Slade BA,
Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent
human papillomavirus recombinant vaccine. JAMA. 2009; 302 (7): 750- 757. 5.
Tomljenovic L, Wilyman J, Vanamee E, Bark T,Shaw CA. HPV vaccines and cancer
prevention, science versus activism. Infectious Agents and Cancer 2013,8:6.
http://www.infectagentscancer.com/content/8/1/6. 6. Vactruth. French Medical
Doctors Say, “Delist & Suspend HPV Vaccines. December 28, 2011
http://www.medocean.re/2011/09/legardasil-a-l%E2%80%99as-
semblee-nationale/.Accessed January 2012. 7. Sarojini N B, Sandhya Srinivasan,
Madhavi Y, Srinivasan S, Anjali Shenoifie HPV Vaccine: Science, Ethics and
Regulation. Economic & Political Weekly EPW november 27, 2010 vol xlv no 48. 8.
Erickson N. Japan and the hpv vaccine controversy. www.sanevax.org. Accessed
4/29/2014. 9. Kyodo. Cervarix vaccine issues trigger health notice. Japan
Times. June 15,2013.
http://www.japantimes.co.jp/news/2013/06/15/national/cervix-vaccine-issues-trigger-health-notice/#.VMfXlWjF8fX.
Accessed 4/29/2014. 10. Ministry of Health, Labor and Welfare. Shimbun A.
Analysis: Experts at loss over pain from cervical cancer vaccination. Asia and
Japan Watch. June 18, 2013. http://ajw.asahi.com/article/behind_news/social_a
airs/AJ201306180057. Ac- cessed 1/27/15 11. Archive of proceedings and events
regarding an investigation into hpv vaccines safety and efficacy by the
Japanese Ministry of Health, Labor and Welfare. Medwatcher Japan.
http://www.yakugai.gr.jp/en/activity/index.php?year=2014. Accessed 1/26/15. 12.
Chustecka Z. Safety Profile of HPV Vaccines Under Review in Europe. Med-
scape.July 13. 2015. http://www.medscape.com/ viewarticle/847841src=wnl_edit_
newsal&uac=148182AN&impID=759675&faf=1 Accessed July 20, 2015. 13. Lee, SH.
Detection of human papillomavirus (HPV) L1gene DNA possibly bound to
particulate aluminum adjuvant in the HPVvaccine Gardasil. Journal of Inorganic
Biochemistry.117 (2012) 85-92. www.elsevier.com/locate/jinorgbio. 14. Shoenfeld
Y, Agmon-Levin N. ‘ASIA’ – Autoimmune/in ammatory syndrome induced by
adjuvants. Journal of Autoimmunity (2010), 2010; XXX: 1-5. 15. Tomljenovic L,
Shaw CA. Mechanisms of Aluminum adjuvant toxicity and autoimmunity in pediatric
populations. Lupus 2012; 21:223-230. 16. Shaw CA, Petrik MS. Aluminum hydroxide
injections lead to motor de cits and motor neuron degeneration. J Inorg Biochem
2009; 103: 1555-1562.

Dear Editor: Your recent article in The Baltimore Sun, Medicine Briefs for
August 2, 2015, states that “not enough pediatricians are strongly recommending
HPV vaccine.” It appears there are excellent medical and scientific reasons why
many doctors do not. Since hpv vaccines were introduced seven years ago, it has
been assumed that this vaccine will prevent cervical cancer. Yet it has never
been demonstrated to prevent any cancer, cervical or otherwise (1, 2, 3). It
has also been assumed for 7 years that this vaccine is safe. Yet there have
been thousands of adverse event reports. The CDC itself admits there are 3x as
many adverse events for the hpv vaccine Gardasil as there are for all other
vaccines combined.(4) Compared to all other vaccines in the US schedule,
Gardasil alone is associated with 61% of all serious adverse events including
63.8% of all deaths and 81.2% of all permanent disabilities in females under 30
years of age. (5) In fact, Japan, India and France have removed hpv vaccines
from their recommended list due to safety and ef cacy concerns.(6, 7, 8, 11)
Unethical practices and serious post hpv vaccination injuries and deaths
prompted the Supreme Court of India to initiate an ongoing investigation of the
Bill and Melin- da Gates Foundation. (7) The Health Welfare and Labor Ministry
of Japan conducted a national inves- tigation regarding post hpv vaccine
injuries in their country. The outcome was the removal of funding and removal
of recommendations regarding hpv vaccines. (8, 9, 10, 11) They concluded that
the harm experienced is overwhelmingly greater than the bene t expected.
Prompted by medical reports of post hpv vaccination arrhythmia and motor neuron
disabilities in children in Denmark, the European Medicines Agency is
conducting an investigation of hpv injection adverse events. (12) Law suits for
hpv injuries and deaths have also been led in Spain, France and Columbia. Some
studies have linked serious hpv vaccine adverse events to the aluminum adjuvant
which is a known neurotoxin. (13, 14, 15, 16) Yet the latest version of hpv
vaccine, Gardasil 9, contains double the amount of aluminum adjuvant than its
predecessor. We already have proven, safe and effective ways to prevent
cervical cancer with pap screening which carries no serious health risk. So the
doctors who do not recommend hpv vaccination are the ones who have done their
research. The public should be grateful to those who have taken their oath
seriously. Sincerely,

“Since hpv vaccines were introduced seven years ago, it has been assumed that
this vaccine will prevent cervical cancer. Yet it has never been demonstrated
to prevent any cancer, cervical or otherwise. It has also been assumed for 7
years that this vaccine is safe. Yet there have been thousands of adverse event
reports. The CDC itself admits there are 3x as many adverse events for the hpv
vaccine Gardasil as there are for all

William Reichel, MD Emily Tarsell, LCPC

other vaccines combined.”

Danish Medical Journal • April 2015

Suspected side effects to the quadrivalent human papilloma vaccine Author
information Brinth L1, Theibel AC, Pors K, Mehlsen J. Koordinerende
Forskningsenhed/Synkopecenteret Vej 3, Indgang 4, Frederiksberg Hospital,
Nordre Fasanvej 57 2000 Frederiksberg, Denmark
louise.schouborg.brinth@regionh.dk Abstract Introduction The quadrivalent
vaccine that protects against human papilloma virus types 6, 11, 16 and 18
(Q-HPV vaccine, Gardasil) was included into the Danish childhood vaccination
programme in 2009. During the past years, a collection of symptoms primarily
consistent with sympathetic nervous system dysfunction have been described as
suspected side effects to the Q-HPV vaccine. Methods We present a description
of suspected side effects to the Q-HPV vaccine in 53 patients referred to our
Syncope Unit for tilt table test and evaluation of autonomic nervous system
function. Results All patients had symptoms consistent with pronounced
autonomic dysfunction including different degrees of orthostatic intolerance,
severe non-migraine-like headache, excessive fatigue, cognitive dysfunction,
gastrointestinal discomfort and widespread pain of a neuropathic character.
Conclusion We found consistency in the reported symptoms as well as between our
findings and those described by others. Our findings neither confirm nor
dismiss a causal link to the Q-HPV vaccine, but they suggest that further
research is urgently warranted to clarify the pathophysiology behind the
symptoms experienced in these patients and to evaluate the possibility and the
nature of any causal link and hopefully establish targeted treatment options.
http://www.ncbi.nlm.nih.gov/pubmed/25872549

“During the past years, a collection of symptoms primarily consistent with
sympathetic nervous system dysfunction have been described as suspected side
effects to the Q-HPV vaccine. All patients had symptoms consistent with
pronounced autonomic dysfunction including different degrees of orthostatic
intolerance, severe non-migraine-like headache, excessive fatigue, cognitive
dysfunction, gastrointestinal discomfort and widespread pain of a neuropathic
character.”

Brain And Nerve • July 2015

Neurologic Complications in HPV Vaccination Author information Ikeda S.
Department of Medicine (Neurology and Rheumatology) Shinshu University School
of Medicine Japan Abstract A relatively high incidence of chronic limb pain,
frequently complicated by violent, tremulous involuntary movements, has been
noted in Japanese girls following human papillomavirus vaccination. The average
incubation period after the first dose of the vaccine was 5.47 ± 5.00 months.
Frequent manifestations included headaches, general fatigue, coldness of the
feet, limb pain, and weakness. The skin temperature of the girls with limb
symptoms was slightly lower in the fingers and moderately lower in the toes.
Digital plethysmograms revealed a reduced peak of the waves, especially in the
toes. Limb symptoms of the affected girls were compatible with the diagnostic
criteria for complex regional pain syndrome. The Schellong test identified a
significant number of patients with orthostatic hypotension and a few with
postural orthostatic tachycardia syndrome. Electron-microscopic examinations of
the intradermal nerves showed an abnormal pathology in the unmyelinated fibers
in two of the three girls examined. The symptoms observed in this study can be
explained by abnormal peripheral sympathetic responses. The most common
previous diagnosis in the patients was psychosomatic disease. Recently, delayed
manifestation of cognitive dysfunction in the post-vaccinated girls has
attracted attention. The symptoms include memory loss and difficulty in reading
textbooks and/or calculation. http://www.ncbi.nlm.nih.gov/pubmed/26160812

“A relatively high incidence of chronic limb pain, frequently complicated by
violent, tremulous involuntary movements, has been noted in Japanese girls
following human papillomavirus vaccination.”

Expert Opinion On Drug Safety • July 2015

The safety of human papilloma virus-blockers and the risk of triggering
autoimmune diseases Author information Baker B1, Eça Guimarães L, Tomljenovic
L, Agmon-Levin N, Shoenfeld Y. The Zabludowicz Center for Autoimmune Diseases
Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel +972 3 5302652; +972 3
5352855 shoenfel@post.tau.ac.il Abstract INTRODUCTION With the safety of human
papilloma virus vaccine (HPVv) being questioned, this article aims to assess
the risks and benefits of the commercially available HPVv. Within the last
decade, two vaccines (Gardasil and Cervarix) have been put on the market to
prevent infection with the most oncogenic HPV subtypes. Both vaccines contain
aluminum adjuvants that are meant to cause a hyper stimulated immune response
to prevent HPV infection. AREAS COVERED The purpose of this paper is to
consider the safety of these two vaccines based on the data from the U.S.
Vaccine Adverse Event Reporting System (VAERS) and case reports. EXPERT OPINION
The current HPVv are both effective and generally safe. However, it should be
noted that autoimmune side effects have been reported in several studies.
Further research should be done to understand the relationship between HPVv and
autoimmunity. http://www.ncbi.nlm.nih.gov/pubmed/26216756

“However, it should be noted that autoimmune side effects have been reported in
several studies. Further research should be done to understand the relationship
between HPVv and autoimmunity.”

Human Vaccines & Immunotherapy • October 2015

Compensation programs after withdrawal of the recommendation for HPV vaccine in
Japan Author information Yuji K1, Nakada H2. 1. Project Division of
International Advanced Medical Research The Institute of Medical Science, The
University of Tokyo 4-6-1 Shirokanedai, Minatoku, Tokyo, Japan, 1088639 2.
Research and Development Initiative Center National Cerebral and Cardiovascular
Center Research Institute Suita City, Osaka, Japan nakad@ncvc.go.jp Abstract
HPV vaccinations were recommended with the backing of a Japanese government
subsidy program in 2010, and were included in the National Immunization Program
in April 2013. However, the Ministry of Health, Labour, and Welfare withdrew
the recommendation for the HPV vaccination in June 2013. We investigated HPV
vaccine injury compensation programs for both the national and local
governments. Approximately 3.38 million girls were vaccinated, and 2,584
complained of health problems. The majority of these received the vaccine shot
as a non-routine vaccination. In total, 98 people developed health problems and
applied for assistance from 2011 to 2014, but no cases have been processed
since October 2014. Several local governments are providing their own
compensation program for cases of vaccine adverse reactions, but the number is
extremely low (16 of 1,741 municipalities and 1 of 47 prefectures). The local
governments that are providing compensation are largely those where HPV vaccine
victim support groups are prominent. The confusion regarding the national
program for HPV vaccine injury was caused by the discrepancy between the
compensation programs for those vaccinated under the immunization law and for
those who received voluntary vaccinations. The establishment of a new
compensation program might be key to finding a lasting resolution.
http://www.ncbi.nlm.nih.gov/pubmed/26513303 HPV Vaccination Crisis In Japan
link:
http://www.researchgate.net/publication/279181953_HPV_vaccination_crisis_in_Japan

“the Ministry of Health, Labour, and Welfare withdrew the recommendation for
the HPV vaccination in June 2013.”

Clinical Rheumatology • November 2015

HPV vaccination syndrome A questionnaire-based study Author information
Martínez-Lavín M1, Martínez-Martínez LA2, Reyes-Loyola P2. 1. Departamento de
Reumatología Instituto Nacional de Cardiología Ignacio Chávez Juan Badiano 1,
14080, Mexico City, Mexico drmartinezlavin@gmail.com. 2. Departamento de
Reumatología Instituto Nacional de Cardiología Ignacio Chávez Juan Badiano 1,
14080, Mexico City, Mexico Abstract Isolated cases and small series have
described the development of complex regional pain syndrome, postural
orthostatic tachycardia, and fibromyalgia after human papillomavirus (HPV)
vaccination. These illnesses are difficult to diagnose and have overlapping
clinical features. Small fiber neuropathy and dysautonomia may play a major
role in the pathogenesis of these entities. We used the following validated
questionnaires to appraise the chronic illness that might appear after HPV
vaccination: The 2010 American College of Rheumatology Fibromyalgia Diagnostic
Criteria, COMPASS 31 dysautonomia questionnaire, and S-LANSS neuropathic pain
form. These questionnaires and a “present illness” survey were emailed to
persons who had the onset of a chronic ailment soon after HPV vaccination.
Forty-five filled questionnaires from individuals living in 13 different
countries were collected in a month’s period. Mean (±SD) age at vaccination
time was 14 ± 5 years. Twenty-nine percent of the cases had immediate (within
24 h) post-vaccination illness onset. The most common presenting complaints
were musculoskeletal pain (66 %), fatigue (57 %), headache (57 %),
dizziness/vertigo (43 %), and paresthesias/allodynia (36 %). Fifty-three
percent of affected individuals fulfill the fibromyalgia criteria. COMPASS-31
score was 43 ± 21, implying advanced autonomic dysfunction. Eighty-three
percent of the patients who had ongoing pain displayed S-LANSS values >12,
suggesting a neuropathic component in their pain experience. After a mean
period of 4.2 ± 2.5 years post-vaccination, 93 % of patients continue to have
incapacitating symptoms and remain unable to attend school or work. In
conclusion, a disabling syndrome of chronic neuropathic pain, fatigue, and
autonomic dysfunction may appear after HPV vaccination.
http://www.ncbi.nlm.nih.gov/pubmed/26354426

“Isolated cases and small series have described the development of complex
regional pain syndrome, postural orthostatic tachycardia, and fibromyalgia
after human papillomavirus (HPV) vaccination. In conclusion, a disabling
syndrome of chronic neuropathic pain, fatigue, and autonomic dysfunction may
appear after HPV vaccination.”

Chapter Five
75 Years Of Vaccine Science 1939 - 2016 Both common observation and official
statistics confirm that there have been dramatic increases in chronic physical
and mental illnesses in American children, such as autism, asthma, and
allergies since the introduction of the MMR vaccine in 1978. Government health
officials have denied a relationship with vaccines, but U.S. Congressional
hearings on vaccine safety (1999 to Dec. 2004) revealed a total absence of
vaccine safety tests that would meet current scientific standards, so that it
can be assumed that many vaccine reactions are taking place unrecognized. Prior
to the introduction of vaccines, the Th1 cellular immune system of the
gastrointestinal and respiratory systems served as the primary defense systems
with the Th2 humoral immune system in the bone marrow, serving a secondary
role. There is a school of thought that the “minor childhood diseases” of
earlier times,

including measles, mumps, chicken pox, and rubella, which involved the
epithelial tissues of skin, respiratory, and/or gastrointestinal tracts, served
a necessary purpose in challenging, strengthening, and establishing the
dominance of the Th1 cellular immune system during early childhood. Current
vaccines against these diseases, in contrast, being directed at stimulating
antibody production in the bone marrow, are bypassing the cellular immune
system and thereby tending to reverse the roles of the cellular and humoral
systems, with the former suffering from a lack of challenge. In addition, the
cellular immune system is being further compromised by the powerfully
immunosuppressive effects of the MMR vaccine. The time is overdue to totally
rethink and redirect our current childhood vaccine program. ~ Dr. Harold
Buttram

JAMA • Vol 112, No. 19 • May 13, 1939

Diphtheria immunity in Chicago by Herman N. Bundesen, MD., Sc.D., William I.
Fishbein, MD., John L. White, MD Abstract Although diphtheria mortality and
morbidity have been gradually decreasing in most parts of the United States for
the past twenty-five years, they have not been reduced to the level which it
was hoped would be attained. Antitoxin, control of carriers and the Schick test
were important. The discovery of toxoid added new impetus to the efforts to
control this disease. It was believed that the inoculation of a large
proportion of the child population would result in almost complete eradication
of diphtheria. The results obtained with the use of toxoid did not, however,
approximate expectations. The present study explains to some extent this
failure.
http://jama.jamanetwork.com/article.aspx?articleid=288193&resultClick=3

“It was believed that the inoculation of a large proportion of the child
population would result in almost complete eradication of diphtheria. The
results obtained with the use of toxoid did not, however, approximate
expectations. The present study explains to some extent this failure.”

JAMA • Vol 114, No. 19 • May 11, 1940

Allergy induced by immunization with Tetanus Toxoid by Robert A. Cooke, MD.,
Stanley Hampton, MD., William B. Sherman, MD., Arthur Stull. Ph.D. Abstract A
toxoid for the active immunization of human beings against tetanus infection
has been developed within the past few years and its efficiency as a producer
of tetanus antitoxin has been well established. It has followed directly in the
wake of the development of diphtheria toxoid, and today a refined alum
precipitated formaldehyde detoxified tetanus toxoid standardized under rules of
the National Institute of Health is commercially available. It is not within
the scope of this paper to discuss the aspects of its development or its
antitoxin producing capacity, all of which may be found in such recent papers,
with references, as those of Bergey and Etris,1 Jones and Moss,2 Hall,3 Gold4
and Cowles.5
http://jama.jamanetwork.com/article.aspx?articleid=1160278&resultClick=3

“It has followed directly in the wake of the development of diphtheria toxoid,
and today a refined alum precipitated formaldehyde detoxified tetanus toxoid
standardized under rules of the National Institute of Health is commercially
available.”

Pediatrics • April 1948

Encephalopathies Following Prophylactic Pertussis Vaccine Randolph K. Byers,
Frederic C. Moll Abstract Inspection of the records of the Children’s Hospital
for the past ten years has disclosed 15 instances in which children developed
acute cerebral symptoms within a period of hours after the administration of
pertussis vaccine. The children varied between 5 and 18 months in age and, in
so far as it is possible to judge children of this age range, were developing
normally according to histories supplied by their parents. None had had
convulsions previously. Many different lots of vaccine, made by eight different
manufacturers over a period of eight years, were implicated. The inoculations
were given throughout the usual geographic range of children coming to this
hospital. All but one, at the time of follow-up or death, showed evidence of
impairment of the nervous system, which might still have been in the healing
stage in three or four. During the same period about half as many children were
seen in the hospital suffering from the encephalopathy secondary to smallpox
vaccination, and about twice as many from the encephalopathy complicating
pertussis itself. A variety of etiologic considerations were suggested by
consideration of the reported cases and references to the literature. That
constitutional factors may have been involved was suggested by both the
preponderance of males as opposed to females, and by the high incidence of
abnormalities of the nervous system in the family histories. The clinical
course and cytologic abnormalities of spinal fluids found in acute cases
indicated an encephalopathy. The literature suggested that this process might
have resulted from either the activity of a specific toxin or from an
antigen-antibody response. Against the former of these hypotheses was the
unstable nature of the heretofore recognized toxins which could hardly survive
in properly aged vaccines. The rapid onset of symptoms, occasionally within
minutes of the first injection, seemed strong evidence against the second. The
present study has left these etiologic considerations unanswered, but it has
called attention to a risk of the prophylactic use of pertussis vaccine not
hitherto recognized. In view of the impressive evidence of the effectiveness of
prophylactic pertussis vaccine now accumulating, it seems likely that babies
are safer vaccinated than not. Further studies should be made to prove this
point definitely, for the encephalopathy following pertussis vaccine seems more
devastating than the vast majority of the nervous lesions following the use of
smallpox vaccine.
http://pediatrics.aappublications.org/content/1/4/437?sid=0d16c0ef-0e60-4827-883e-d8993
3f51dfc&variant=abstract&sso=1&sso_redirect_count=5&nfstatus=401&nftoken=000000
00-0000-0000-0000-000000000000&nfstatusdescription=ERROR%3A%20No%20local%
20token&nfstatus=401&nftoken=00000000-0000-0000-0000-000000000000&nfstatusdesc
ription=ERROR%3a+No+local+token

“In view of the impressive evidence of the effectiveness of prophylactic
pertussis vaccine now accumulating, it seems likely that babies are safer
vaccinated than not. Further studies should be made to prove this point
definitely, for the encephalopathy following pertussis vaccine seems more
devastating than the vast majority of the nervous lesions following the use of
smallpox vaccine.”

JAMA • Vol 152, No. 14 • August 1, 1953

Precautions In Pediatric Immunization Procedures by Louis W. Sauer, M.D., Ph.D.
Abstract During the past decade, the simultaneous immunization against
diphtheria, tetanus, and pertussis has become quite well established on
laboratory and clinical evidence. To retard the elimination of antigen (DTP)
from the body and to enhance antitoxin and antibody development, various forms
of aluminum have been used as adjuvant. Most private patients are now
adequately protected by the customary primary series of three or four monthly
doses, and subsequent recall (stimulating or booster) doses. Needless deaths
due to pertussis are still occurring, however, in infants and children from
families with low incomes and orphanages in congested cities and in rural
areas. To reach these children, mass immunization clinics should function at
well baby clinics, primary schools, and mobile units. The diverse difficulties
encountered in the execution of these immunization procedures are problems due
to earlier immunization, febrile reactions, alum cyst, postinoculation
encephalopathy, paralytic poliomyelitis of the injected limb, and unfavorable
results.
http://jama.jamanetwork.com/article.aspx?articleid=287046&resultClick=3

“The diverse difficulties encountered in the execution of these immunization
procedures are problems due to earlier immunization, febrile reactions, alum
cyst, postinoculation encephalopathy, paralytic poliomyelitis of the injected
limb, and unfavorable results.”

“A cell line (MDCK) of dog kidney origin grows
on a glass surface as a mosaic of epithelium with many multicellular
hemispherical vesicles. Science • January 1969

Secretory activity and oncogenicity of a cell line (MDCK) derived from canine
kidneyand A cell line (MDCK) of dog kidney origin grows on a glass surface as a
mosaic of epithelium with many multicellular hemispherical vesicles. The cells
lining the blisters actively secrete into the cyst cavities. Suspensions of
these cells injected intravenously in the chick embryo produce brain metastases
resembling adenocarcinoma.

The cells lining the blisters actively secrete into the cyst cavities.
Suspensions of these cells injected intravenously in the chick embryo produce
brain metastases resembling adenocarcinoma.”

[Editors Note: The MDCK (NBL-2) (ATCC® CCL-34™) cell line has been used since
1958 to produce influenza and other vaccines]
http://www.sciencemag.org/content/163/3866/472.long Information on the MDCK
cell line http://www.atcc.org/products/all/CCL-34.aspx

[In a departure from the use of traditional egg-based vaccines the FDA approved
Flucelvax for Novartis on November 20th, 2012. Flucelvax was the first
mammalian cell-based influenza vaccine in the US. The Madin-Darby canine kidney
cell line is cultured to produce the vaccine. The primary advantage of MDCK
over traditional egg-based manufacturing is rapid growth.]

“The observations of this study as well as those of similar studies
suggest that vaccine failures contributed to the genesis of the epidemic.”
Canadian Medical Association Journal • November 1975

Analysis of a measles epidemic: possible role of vaccine failures W. E. Rawls,
M. L. Rawls, and M. A. Chernesky Abstract A measles epidemic occurred in the
Greensville (Ont.) Unit schools during January and February 1975. There were 47
cases of measles in 403 students: 26 (55%) of the children had a history of
being vaccinated and 18 (38%) had not been vaccinated. Among children known to
have been vaccinated at less than 1 year of age 7 of 13 contracted measles,
while among the 48 children who had not been vaccinated 18 contracted measles.
The attack rate among vaccinees increased with increasing time since
vaccination. The observations of this study as well as those of similar studies
suggest that vaccine failures contributed to the genesis of the epidemic. It is
recommended that all children initially vaccinated at less than 1 year of age
should be revaccinated with live attenuated measles virus vaccine. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1956577/

Journal Of Experimental Medicine • September 1977

Autoimmunity to type II collagen an experimental model of arthritis Trentham
DE, Townes AS, Kang AH. Abstract We have found that intradermal injection of
native type II collagen extracted from human, chick or rat cartilage induces an
inflammatory arthritis in approximately 40% of rats of several strains whether
complete Freund’s adjuvant or incomplete Freund’s adjuvant is used. Type I or
III collagen extracted from skin, cartilage proteoglycans and alpha1(II) chains
were incapable of eliciting arthritis, as was type II collagen injected without
adjuvant. The disease is a chronic proliferative synovitis, resembling adjuvant
arthritis in rats and rheumatoid arthritis in humans. Native type II co-lagen
modified by limited pepsin digestion still produces arthritis, suggesting that
type-specific determinants residing in the helical region of the molecule are
responsible for the induction of disease. Since homologous type II collagen
emulsified in oil without bacterial preparations regularly causes the disease,
this new animal model of arthritis represents a unique example of
experimentally-inducible autoimmunity to a tissue component. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2180804/pdf/je1463857.pdf

“this new animal model of arthritis represents a unique example of
experimentally-inducible autoimmunity to a tissue component.”

Gastroenterology • February 1980

HBe-Antigen in the course and prognosis of hepatitis B infection: a prospective
study Schulman AN, Fagen ND, Brezina M, Silver H, Nitzze A, Morton D, Gitnick
GL. Abstract The prognostic significance of the HBe-antigen (HBeAg) in the
course and outcome of type B hepatitis was studied prospectively in 71
susceptible oncology patients. The patients had been exposed to tumor cell
vaccines inadvertently contaminated with hepatitis B surface antigen
(HBsAg)-containing plasma. Fortyfive patients (63%) were infected. These 45
showed three types of acute seroresponse: HBsAg and HBeAg, 28 patients (62%);
HBsAg alone, 8 patients (18%); and a primary antibody to HBsAg (anti-HBs)
response, 9 patients (20%). There was no significant difference in acute course
and outcome between the two HBsantigenemic groups. All primary anti-HBs
responders had asymptomatic infections. Seventeen patients receiving
chemotherapy during the period of hepatitis B exposure were significantly more
prone to symptomatic infection with acute HBs-antigenemia, and 2 of these
patients developed chronic active hepatitis. The HBeAg is common early in acute
hepatitis B among solid tumor patients and at this stage in disease has no
prognostic significance independent of HBsAg.
http://www.ncbi.nlm.nih.gov/pubmed/?term=7350048

“The patients had been exposed to tumor cell vaccines inadvertently
contaminated with hepatitis B surface antigen-containing plasma. Forty-five
patients (63%) were infected.”

Reviews Of Infectious Diseases • May 1980

Vaccine adjuvants Edelman R. Abstract Nonreplicating, purified subunit or
synthetic viral vaccines of the future are likely to be weak immunogens that
will require immunopotentiation if they are to be effective. These marginal
vaccines could be improved by combination with potent and safe immunologic
adjuvants. The use of adjuvants should also reduce the amount of purified
antigen required for successful immunization, thus making vaccine production
more economical and more feasible. It may be possible to combine the recently
developed relatively nontoxic synthetic immunoregulators of low molecular
weight with antigens in order to modulate preselected compartments of the
immune system. To date, the question of adjuvant safety has not been resolved
and represents the major obstacle to the orderly development of adjuvanted
vaccines. The fear of inducing cancer and other immediate or long-term
perturbations of the immune system must be patently and rationally overcome by
basic and applied experimentation and by the development of appropriate
guidelines for studies in humans.
http://www.ncbi.nlm.nih.gov/pubmed/?term=6997966

“Nonreplicating, purified subunit or synthetic viral vaccines of the future are
likely to be weak immunogens that will require immunopotentiation if they are
to be effective.”

“These data suggest that Tween 80 has an effect on the Central Nervous System
which could lead to misinterpretation of results in toxicology studies that use
this compound as a dosage vehicle.” Life Sciences • June 1982

Effect of Tween 80 on exploratory behavior and locomotor activity in rats
Brubaker CM, Taylor DH, Bull RJ. Abstract Exploratory behavior and locomotor
activity is enhanced in male rat pups (aged 10 to 20 days) whose dams received
a chronic dose (1.25 ml/l) of Tween 80 via their drinking water. This
enhancement manifests itself during the diurnal period of the day. These data
suggest that Tween 80 has an effect on the CNS which could lead to
misinterpretation of results in toxicology studies that use this compound as a
dosage vehicle. http://www.ncbi.nlm.nih.gov/pubmed/7202094

Biochimica et Biophysica Acta • October 1983

Effect of pertussis toxin on the hormonal regulation of cyclic AMP levels in
hamster fat cells by Martínez-Olmedo MA, García-Sáinz JA. Abstract Pertussis
toxin was purified approx. 1800-fold from pertussis vaccine. Administration of
as little as 1 microgram of toxin/100 g body weight to hamsters markedly
decreased the sensitivity of their adipocytes to agents that inhibit adenylate
cyclase through receptor-mediated, GTP-dependent mechanisms such as alpha
2-adrenergic amines, prostaglandins, phenylisopropyladenosine and nicotinic
acid. On the contrary, the inhibitory effect of 2’,5’-dideoxyadenosine on
cyclic AMP accumulation was not affected by the toxin. Activation of adenylate
cyclase by isoproterenol, ACTH or forskolin was not diminished by the toxin but
the maximum cyclic AMP accumulation was consistently increased. Furthermore,
the dose-response curves for ACTH and forskolin were clearly shifted to the
left in adipocytes from toxin-treated hamsters as compared to control
adipocytes. It is concluded that pertussis toxin blocks the transfer of
inhibitory information from the receptors to adenylate cyclase.
http://www.ncbi.nlm.nih.gov/pubmed/6313062

“It is concluded that pertussis toxin blocks the transfer of inhibitory
information from the receptors to adenylate cyclase.”

New England Journal Of Medicine • January 1984

Abnormal T-lymphocyte subpopulations in healthy subjects after tetanus booster
immunization Eibl MM, Mannhalter JW, Zlabinger G. “By way of explanation, a
vaccine safety test is one in which before-and-after vaccine tests are
performed, specifically designed to test for possible adverse effects on the
neurological, immunological, hematologic, genetic, and other systems of the
body, in sufficient numbers of test subjects and controls to be statistically
significant. As an example, in a little noted study from Germany by Eibl et al.
[11], a significant, though temporary, drop of T-Helper lymphocytes was found
in 11 healthy adults following routine tetanus booster vaccinations. Special
concern rests in the fact that, in four of the subjects, T-helper lymphocytes
fell to levels seen in active AIDS patients.” Report available for purchase:
http://www.ncbi.nlm.nih.gov/pubmed/?term=6228737

“As an example, in a little noted study from Germany by Eibl et al. [11], a
significant, though temporary, drop of T-Helper lymphocytes was found in 11
healthy adults following routine tetanus booster vaccinations. Special concern
rests in the fact that, in four of the subjects, T-helper lymphocytes fell to
levels seen in active AIDS patients.”

“This outbreak demonstrates that transmission of measles can occur within a school population with a
documented immunization level of 100%. This level was validated during the
outbreak investigation.” CDC • June 22, 1984

MMWR Weekly From December 9, 1983, to January 13, 1984, 21 cases of measles
occurred in Sangamon County, Illinois.* Nine of the cases were confirmed
serologically. The outbreak involved 16 high school students, all of whom had
histories of measles vaccination after 15 months of age documented in their
school health records. Of the five remaining cases, four occurred in
unvaccinated preschool children, two of whom were under 15 months of age, and
one case occurred in a previously vaccinated college student (Figure 5). The
affected high school had 276 students and was in the same building as a junior
high school with 135 students. A review of health records in the high school
showed that all 411 students had documentation of measles vaccination on or
after the first birthday, in accordance with Illinois law. Measles vaccination
histories were obtained from the school health records of all 276 senior high
school students. Risk of infection was not significantly associated with type
of vaccine, medical provider, age at most recent vaccination, or revaccination.
All the students with measles had received their most recent vaccinations after
15 months of age. However, the measles attack rate increased with increasing
years since most recent vaccination (p = 0.024) (Table 3). The attack rate was
four times greater for students vaccinated 10 or more years before the outbreak
than for students vaccinated more recently (p 0.05). When these data are
corrected for the number of vaccinations, the trend was still observed and
achieved a borderline level of statistical significance (p = 0.07). Age at
first or last vaccination was not a confounding variable. The index patient,
Student A, was a 17-year-old male in the 11th grade; he was present in school
with a productive cough for 3 consecutive days before his onset of rash. The
source of his infection was not identified. Nine students with first-generation
cases developed onset of rash 10-14 days after exposure to Student A (Figure
5). The attack rate was 6% (16/276) for senior high school students and 0%
(0/135) for junior high school students. The highest attack rate was 12% (9/74)
for the 11th grade students (p 0.02).

Repeated and close exposure to Student A was associated with a greater risk of
illness (Table 4). The eight patients with first-generation cases who attended
the high school were used to analyze the degree of exposure to Student A. The
measles attack rate was 3% for students who did have classroom exposure to
Student A versus 2% for those who did not. Moreover, the attack rate was 21%
for students whom Student A identified as “close friends” from the school
enrollment roster, compared with 2% for students not so identified (p 0.001).
Editorial Note This outbreak demonstrates that transmission of measles can
occur within a school population with a documented immunization level of 100%.
This level was validated during the outbreak investigation. Previous
investigations of measles outbreaks among highly immunized populations have
revealed risk factors such as improper storage or handling of vaccine, vaccine
administered to children under 1 year of age, use of globulin with vaccine, and
use of killed virus vaccine (1-5). However, these risk factors did not
adequately explain the occurrence of this outbreak. If waning immunity is not a
problem, this outbreak suggests that measles transmission can occur within the
2%-10% of expected vaccine failures (5,7). However, transmission was not
sustained beyond 36 days in this outbreak, and community spread was principally
among unvaccinated preschool children. The infrequent occurrence of measles
among highly vaccinated persons suggests that this outbreak may have resulted
from chance clustering of otherwise randomly distributed vaccine failures in
the community. That measles transmission can occur among vaccine failures makes
it even more important to ensure persons are adequately vaccinated. Had there
been a substantial number of unvaccinated or inadequately vaccinated students
in the high school and the community, transmission in Sangamon County probably
would have been sustained.

http://www.cdc.gov/mmwr/preview/mmwrhtml/00000359.htm

Acta Paediatrica Scandinavica • July 1984

Bordetella pertussis whole cell vaccines efficacy and toxicity Trollfors B.

“The pertussis-associated mortality is currently very low in the industrialised
countries and no

Abstract The literature concerning efficacy and side effects of pertussis
vaccines is reviewed. With few exceptions, most vaccines induce a protective
immunity lasting for 2 to 5 years. The large-scale use of pertussis vaccines
has markedly contributed to the decrease in pertussis morbidity in small
children but in some countries the incidence has increased in older children.
Not even countries with immunisation rates of 90-95% have managed to eradicate
pertussis or prevent disease in infants below the age of immunisation. The
pertussis-associated mortality is currently very low in the industrialised
countries and no differences can be discerned when countries with high, low and
zero immunisation rates are compared. Local and benign systemic reactions are
commonly seen after immunisation. The vaccines also sometimes cause
convulsions, a shock-like state and, rarely, serious neurological reactions.
http://www.ncbi.nlm.nih.gov/pubmed/6380211

differences can be discerned when countries with high, low and zero
immunisation rates are compared. Local and benign systemic reactions are
commonly seen after immunisation. The vaccines also sometimes cause
convulsions, a shock-like state and, rarely, serious neurological reactions.”

Journal Of Toxicology And Environmental Health • 1984

Formaldehyde and hepatotoxicity: a review Beall JR, Ulsamer AG. Abstract
Exposure to formaldehyde appears to be associated with hepatoxicity in many
species, including humans, following injection, ingestion, or inhalation.
Macroscopic, microscopic, and biochemical manifestations in the liver include
alterations in weight, centrilobular vacuolization, focal cellular necrosis,
and increased alkaline phosphatase concentrations. Time-related changes in the
pattern of the effects are suggested as one goes from acute exposure by
inhalation at greater concentrations to repeated exposure at lesser
concentrations. Although the hepatic changes are generally not extensive and
can be reversible following acute exposure, the potential exists for them to
progressively become more serious with repeated exposures. There are several
possible mechanisms for the toxicity. Depending on the route of exposure could
include direct effects on hepatocytes and/or indirect effects through the
circulatory and immune systems. The catabolism of formaldehyde includes
conversion to CO2 by reactions involving glutathione. Many hepatotoxic
chemicals require glutathione for detoxification. Formaldehyde may then have
the potential to cause additive toxicity with such chemicals in some
circumstances. http://www.ncbi.nlm.nih.gov/pubmed/?term=6389892

“Exposure to formaldehyde appears to be associated with hepatoxicity in many
species, including humans, following injection, ingestion, or inhalation.”

“The results of the present study indicate that polysorbate 80 can neither be used as a solvent
for isolated tissue experiments nor when considered for intravenous
administration.” Arzneimittelforschung • 1985

Polysorbate 80: a pharmacological study Varma RK, Kaushal R, Junnarkar AY,
Thomas GP, Naidu MU, Singh PP, Tripathi RM, Shridhar DR. Abstract
Polyoxyethylene (20) sorbitan monooleate (polysorbate 80, Tween 80), a
surfactant, has been widely used as a solvent for pharmacological experiments.
In the present study, polysorbate 80 was found to have toxicity of a low order
in both the mice and rats when given by i.p. and p.o. routes. It produced mild
to moderate depression of the central nervous system with a marked reduction in
locomotor activity and rectal temperature, exhibited ataxia and paralytic
activity and potentiated the pentobarbital sleeping time. On intravenous
administration in dogs, it had a dose-dependent hypotensive effect. Polysorbate
80 did not have a direct stimulant or relaxant effect on either guinea pig
ileum or rat uterus, however, it antagonised the contractions induced by
acetylcholine, histamine, barium, 5-hydroxytryptamine and carbachol in a
dose-dependent manner. A direct relaxant effect was observed on rabbit jejunum.
A dose-dependent myocardial depressant effect was observed on guinea pig and
rabbit paired atrial preparations. On the electrically-driven guinea pig left
atrial preparation, polysorbate 80 exhibited a dosedependent negative inotropic
action. Polysorbate 80 did not induce diuresis in rats upto a dose of 2.5
ml/kg. The results of the present study indicate that polysorbate 80 can
neither be used as a solvent for isolated tissue experiments nor when
considered for intravenous administration. However, polysorbate 80 can be
employed safely as a vehicle for neuropsychopharmacological experiments in
doses not exceeding 1 ml/kg. http://www.ncbi.nlm.nih.gov/pubmed/4026903

Pediatrics • April 1986

Polysorbate 80 and E-Ferol toxicity Alade SL, Brown RE, Paquet A Jr. Abstract
The relatively recent introduction and use of an intravenous form of a vitamin
E preparation (E-Ferol) has been associated with the development of an unusual
syndrome and fatalities among low birth weight (less than 1,500 g), premature
infants in neonatal intensive care units. We have observed an inhibitory effect
by this vitamin E preparation on the in vitro response of human lymphocytes to
phytohemagglutinin (PHA). E-Ferol suppressed the expected response to low doses
of PHA. However, this suppression was not due to the alpha-tocopherol acetate
(vitamin E) component, because alpha-tocopherol acetate by itself was not
inhibitory; in fact, it often enhanced the PHA response. Because a mixture of
polysorbate 80 and polysorbate 20 is used as a carrier in E-Ferol, these
components were also tested and were found to be responsible for the
suppression, especially the polysorbate 80. Concurrent with this suppression of
PHA-induced mitogenesis was a decrease in the percentage of T11 lymphocytes.
http://www.ncbi.nlm.nih.gov/pubmed/3960626

“The relatively recent introduction and use of an intravenous form of a vitamin
E preparation has been associated with the development of an unusual syndrome
and fatalities among low birth weight (less than 1,500 g), premature infants in
neonatal intensive care units ... polysorbate 80 and polysorbate 20 ... were
found to be responsible for the suppression, especially the polysorbate 80.”

Laboratory Animal Science • March 1989

An evaluation of distress following intraperitoneal immunization with Freund’s
adjuvant in mice Author information Toth LA1, Dunlap AW, Olson GA, Hessler JR.
Department of Comparative Medicine University of Tennessee Memphis 38163
Abstract Intraperitoneal immunization with Freund’s adjuvant is frequently used
to stimulate antibody production in mice. To evaluate the clinical and
pathological effects of this technique, mice were immunized intraperitoneally
with complete Freund’s adjuvant and albumin, and the injection repeated 3-4
weeks later using incomplete Freund’s adjuvant. This regimen induced a mean
antibody titer against albumin of 1:280 within 7 days after booster
immunization and increased the abdominal width, abdominal circumference and
spleen weights of immunized animals. Food intake and body weight decreased
after immunization, but returned to control levels within 1-2 weeks. Openfield
activity was not affected. Neutrophilia, eosinophilia and monocytosis were
present 7 days after immunization and persisted for the duration of the study.
Gross and histopathological lesions included multiple granulomatous abdominal
adhesions and lymphoid hyperplasia. Thus, intraperitoneal immunization with
Freund’s adjuvant and albumin produced some adverse effects in the animal
(weight loss, neutrophilia and granulomatous peritonitis). However, the animals
did not appear to be severely or chronically impaired, since food intake, body
weight and locomotor activity were within normal limits for most of the
post-immunization period. http://www.ncbi.nlm.nih.gov/pubmed/?term=2709800

“intraperitoneal immunization with Freund’s adjuvant and albumin produced some
adverse effects in the animal (weight loss, neutrophilia and granulomatous
peritonitis).”

American Journal Of Public Health • April 1989

The role of secondary vaccine failures in measles outbreaks Author information
Mathias RG1, Meekison WG, Arcand TA, Schechter MT. Department of Health Care
and Epidemiology University of British Columbia, Vancouver Abstract An outbreak
of measles in 1985-86 in a community where measles vaccine trials had been
carried out from 1974-76 allowed the assessment of the role of secondary
vaccine failures in previously immunized children. A total of 188 children from
the vaccine trial were followed. Of these, 175 seroconverted initially while 13
(6 per cent) required re-immunization (primary failure). A total of 13 cases of
measles, eight of which were laboratory and/or physician-confirmed, were
reported in this cohort. Of these, nine cases occurred in the 175 subjects who
had hemagglutination inhibition test (HI) and neutralizing antibody responses
following the initial immunization. These nine cases represent secondary
vaccine failures. An additional four cases occurred in the 13 subjects with
primary vaccine failure. We conclude that secondary vaccine failures occur and
that while primary failures account for most cases, secondary vaccine failures
contribute to the occurrence of measles cases in an epidemic. A booster dose of
measles vaccine may be necessary to reduce susceptibility to a sufficiently low
level to allow the goal of measles elimination to be achieved.
http://www.ncbi.nlm.nih.gov/pubmed/2929807

“These nine cases represent secondary vaccine failures. An additional four
cases occurred in the 13 subjects with primary vaccine failure. We conclude
that secondary vaccine failures occur and that while primary failures account
for most cases, secondary vaccine failures contribute to the occurrence of
measles cases in an epidemic.”

Scope • 1990

Short-term Toxicity Tests for Non-genotoxic Effects Toxicity Tests with
Mammalian Cell Cultures B. Ekwall, V. Silano, A. Paganuzzi-Stammati, F. Zucco
Introduction Cell culture can be used to screen for toxicity both by estimation
of the basal functions of the cell (i.e. those processes common to all types of
cells) or by tests on specialized cell functions (Ekwall, 1983b). General
toxicity tests, aimed mainly at detection of the biological activity of test
substances, can be carried out on many cell types (e.g. fibroblasts, HeLa and
hepatoma cells). A number of parameters including vital staining, cytosolic
enzyme release, cell growth and cloning efficien- cy are used as end-points to
measure toxicity. Organ-specific toxic effects are tested using specialized
cells by measuring alterations in membrane and metabolism integ- rity and/or in
specific cell functions (e.g. glycogen metabolism in primary hepatocyte
cultures, beating rate in mixed myocardial cells or myocytes, and phagocytosis
in macrophages).
http://dge.stanford.edu/SCOPE/SCOPE_41/SCOPE_41_2.02_Chapter_7_75-98.pdf

[shows that as far back as 1990 we could test for non-genotoxic cellular
toxicity]

Neuropediatrics • November 1990

Workshop on neurologic complications of pertussis and pertussis vaccination
Author information Menkes JH1, Kinsbourne M. University of California, Los
Angeles

“1. Vaccines are not standardized between manufacturers.

Abstract A multidisciplinary workshop held from September 29 to October 1,
1989, at Airlie House, Warrenton, Virginia, considered the neurologic
complications of whooping cough and pertussis vaccine. Pertussis mortality in
the U.S. in 2-3/1000 cases. Seizures occur in 1.9% of cases, and encephalopathy
in 0.3%. Reviewing all data, it appears likely that a combination of one or
more bacterial toxins, asphyxia, CO2 retention and loss of cerebral vascular
autoregulation is responsible for neurologic symptoms. The timing of the
encephalopathy suggests that it results from increased lysis of bacteria, and
release of endotoxin. The encephalopathy is not confined to the paroxysmal
phase. In evaluating side-reactions to the vaccine, the following must be kept
in mind: 1. Vaccines are not standardized between manufacturers. 2. For a given
manufacturer, vaccines are not standard from one batch to the next. 3. Unless
the vaccine is properly prepared and refrigerated, its potency and reactivity
varies with shelf life. In fact, the whole question of vaccine detoxification
has never been systematically investigated. Listed in order of increasing
severity, observed adverse reactions include irritability, persistent,
unusually high pitched crying, somnolence, seizures, a shock-like “hypotensive,
hyporesponsive” state, and an encephalopathy. Since the neurologic picture is
not specific for pertussis vaccination, its temporal relationship to the
vaccination is the critical variable for determining causation. Although the
majority of seizures following pertussis vaccination are associated with fever,
it was the consensus of the neurologists attending the workshop, that these do
not represent febrile convulsions, but are non-benign convulsions. The
incidence of post-vaccine encephalopathy is difficult to ascertain. (Abstract
truncated at 250 words) http://www.ncbi.nlm.nih.gov/pubmed/1981251 Full Report
https://www.thieme-connect.com/DOI/DOI?10.1055/s-2008-1071488

2. For a given manufacturer, vaccines are not standard from one batch to the
next.

3. Unless the vaccine is properly prepared and refrigerated, its potency and
reactivity varies with shelf life. In fact, the whole question of vaccine
detoxification has never been systematically investigated.”

Pediatric Infectious Disease Journal • March 1991

Aseptic meningitis as a complication of mumps vaccination Author information
Sugiura A1, Yamada A. Department of Measles Virus National Institute of Health
Tokyo, Japan Abstract In 1989 a nationwide surveillance of neurologic
complications after the administration of mumps vaccine was conducted in Japan,
based on the notification of cases and the testing of mumps viruses isolated
from cerebrospinal fluid for their relatedness to the vaccine by nucleotide
sequence analysis. Among 630,157 recipients of measlesmumps-rubella trivalent
(MMR) vaccine containing the Urabe Am9 mumps vaccine, there were at least 311
meningitis cases suspected to be vaccine-related. In 96 of these 311 cases,
mumps virus related to the vaccine was isolated from cerebrospinal fluid. The
unusually high incidence may have been partly a result of the adverse media
publicity of the problem at the time of surveillance. We analyzed clinical
features of 165 and 27 laboratory-confirmed mumps vaccine-related meningitis
cases that occurred among the recipients of MMR and monovalent mumps vaccines,
respectively, during a 1-year period after the introduction of MMR vaccine. The
incidence of vaccinerelated meningitis was similar among the recipients of MMR
and monovalent Urabe Am9 mumps vaccines. Meningitis was generally mild and
there were no sequelae from the illness. The complication was more frequent
among male than among female children.
http://www.ncbi.nlm.nih.gov/pubmed/2041668

“Among 630,157 recipients of measles-mumps-rubella trivalent (MMR) vaccine
containing the Urabe Am9 mumps vaccine, there were at least 311 meningitis
cases suspected to be vaccine-related. In 96 of these 311 cases, mumps virus
related to the vaccine was isolated from cerebrospinal fluid.”

Lancet • September 1991

Chronic fatigue syndrome: clinical condition associated with immune activation
Author information Landay AL1, Jessop C, Lennette ET, Levy JA. Department of
Immunology/Microbiology Rush-Presbyterian-St. Luke’s Medical Center Chicago,
Illinois Abstract There is much conflicting immunological and viral data about
the causes of chronic fatigue syndrome (CFS); some findings support the notion
that CFS may be due to one or more immune disorders that have resulted from
exposure to an infectious agent. In the present study, flow cytometry and
several different monoclonal antibodies recognising T, B, and natural killer
(NK) cell populations as well as activation and cell adhesion antigens were
used to study 147 individuals with CFS. Compared with healthy controls, a
reduced CD8 suppressor cell population and increased activation markers (CD38,
HLA-DR) on CD8 cells were found. The differences were significant (p = 0.01) in
patient with major symptoms of the disease. These immunological indices were
not observed in 80 healthy individuals, in 22 contacts of CFS patients, or in
43 patients with other diseases. No correlation of these findings in CFS
patients with any known human viruses could be detected by serology. The
findings suggest that immune activation is associated with many cases of CFS.
http://www.ncbi.nlm.nih.gov/pubmed/?term=1679864

“No correlation of these findings in chronic fatigue syndrome (CFS) patients
with any known human viruses could be detected by serology. The findings
suggest that immune activation is associated with many cases of CFS.”

Vaccine • October 1991

Adverse reactions after injection of adsorbed diphtheria-pertussis-tetanus
(DPT) vaccine are not due only to pertussis organisms or pertussis components
in the vaccine Author information Gupta RK1, Relyveld EH. National Institutes
of Health Bethesda, MD 20892 Abstract Reactions to adsorbed
diphtheria-pertussis-tetanus (DPT) vaccine have mostly been attributed to the
pertussis organisms or pertussis components in the vaccine. Nevertheless
reactions may also be due to other factors such as sensitization induced by
aluminium adjuvants and impurities present in crude toxoids that cannot be
removed by purification of toxoids after formalinization. Aluminium compounds
such as aluminium phosphate and aluminium hydroxide are the most commonly used
adjuvants with vaccines for human use. Due to the increasing concern about the
toxicity of aluminium, other adjuvants like calcium phosphate may be evaluated
as an alternative to aluminium adjuvants. To minimize reactions after
immunization with DPT vaccine due to impurities in the toxoids, the use of
toxoided purified toxins is suggested.
http://www.ncbi.nlm.nih.gov/pubmed/?term=1759487

“... reactions may also be due to other factors such as sensitization induced
by aluminium adjuvants and impurities present in crude toxoids that cannot be
removed by purification of toxoids after formalinization.”

Journal Of Autoimmunity • December 1991

Adjuvant oils induce arthritis in the DA rat. I. Characterization of the
disease and evidence for an immunological involvement Author information
Kleinau S1, Erlandsson H, Holmdahl R, Klareskog L. Department of Medical and
Physiological Chemistry Uppsala University, Sweden Abstract An intradermal
injection of Freund’s incomplete adjuvant oil (FIA) without further additives
was shown to induce erosive polyarthritis in dark Agouti (DA) rats, but not in
Lewis rats. Histological examination revealed joint inflammation, first with
polymorphonuclear cells and synovial hyperplasia, and subsequently, with
multinucleated giant cells. Both constituents of FIA, mineral oil and Arlacel
A, as well as Pristane oil were arthritogenic, whereas vegetable oil were not.
Re-administration of adjuvant oil after recovery failed to induce arthritis,
thus making possible a role of specific immunity in this new form of arthritis
in rats. http://www.ncbi.nlm.nih.gov/pubmed/?term=1812893

“Freund’s incomplete adjuvant oil (FIA) was shown to induce erosive
polyarthritis in ... rats ...”

Washington DC National Academies Press (US) 1991
The National Academies Collection Reports funded by National Institutes of
Health Howson CP, Howe CJ, Fineberg HV, editors

Adverse Effects of Pertussis and Rubella Vaccines: A Report of the Committee to
Review the Adverse Consequences of Pertussis and Rubella Vaccines Excerpt
Parents have come to depend on vaccines to protect their children from a
variety of diseases. Some evidence suggests, however, that vaccination against
pertussis (whooping cough) and rubella (German measles) is, in a small number
of cases, associated with increased risk of serious illness. This book examines
the controversy over the evidence and offers a comprehensively documented
assessment of the risk of illness following immunization with vaccines against
pertussis and rubella. Based on extensive review of the evidence from
epidemiologic studies, case histories, studies in animals, and other sources of
information, the book examines: The relation of pertussis vaccines to a number
of serious adverse events, including encephalopathy and other central nervous
system disorders, sudden infant death syndrome, autism, Guillain-Barre
syndrome, learning disabilities, and Reye syndrome. The relation of rubella
vaccines to arthritis, various neuropathies, and thrombocytopenic purpura. The
volume, which includes a description of the committee’s methods for evaluating
evidence and directions for future research, will be important reading for
public health officials, pediatricians, researchers, and concerned parents.
Full Report http://www.ncbi.nlm.nih.gov/pubmed/25121241

“that the evidence is consistent with a causal relation between DPT vaccine and
acute encephalopathy, shock and “unusual shock-like state,” and between RA 27/3
rubella vaccine and chronic arthritis; and that the evidence indicates a causal
relation between DPT vaccine and anaphylaxis, between the pertussis component
of DPT vaccine and protracted, inconsolable crying, and between RA 27/3 rubella
vaccine and acute arthritis.”

[RA 27/3 rubella is still in use today]

JAMA • January 1992

Adverse events following pertussis and rubella vaccines Summary of a report of
the Institute of Medicine Author information Howson CP1, Fineberg HV. Institute
of Medicine National Academy of Sciences Washington, DC 20418 Abstract In
August 1991, the Institute of Medicine released a report entitled Adverse
Effects of Pertussis and Rubella Vaccines, which examined 18 adverse events in
relation to diphtheriatetanus-pertussis (DTP) vaccine and four adverse events
in relation to the currently used rubella vaccine strain, RA 27/3. The
committee spent 20 months reviewing a wide range of information sources,
including case series and individual case reports, both published and
unpublished, epidemiologic studies, studies in animals, and other laboratory
studies. The committee found that the evidence indicates a causal relation
between DTP vaccine and anaphylaxis and between the pertussis component of DTP
vaccine and extended periods of inconsolable crying or screaming. The committee
also reported that the evidence indicates a causal relation between the rubella
vaccine and acute arthritis in adult women. The committee found the available
evidence weaker but still consistent with a causal relation between DTP vaccine
and two conditions--acute encephalopathy and hypotonic, hyporesponsive
episodes--and between rubella vaccine and chronic arthritis in adult women.
Estimated incidence rates of these adverse events following vaccination are
provided, where possible. The committee found that the evidence does not
indicate a causal relation between the DTP vaccine and infantile spasms,
hypsarrhythmia, Reye’s syndrome, and sudden infant death syndrome. The
committee found insufficient evidence to indicate either the presence or
absence of a causal relation between DTP vaccine and chronic neurologic damage,
aseptic meningitis, erythema multiforme or other rash, Guillain-Barré syndrome,
hemolytic anemia, juvenile diabetes, learning disabilities and
attention-deficit disorder, peripheral mononeuropathy, or thrombocytopenia, and
between rubella vaccine and radiculoneuritis and other neuropathies or
thrombocytopenic purpura. The committee’s evaluative methods are briefly
described and a summary of research needs is provided.
http://www.ncbi.nlm.nih.gov/pubmed/1727962

“The committee found that the evidence indicates a causal relation between DTP
vaccine and anaphylaxis and between the pertussis component of DTP vaccine and
extended periods of inconsolable crying or screaming.

The committee also reported that the evidence indicates a causal relation
between the rubella vaccine and acute arthritis in adult women.

The committee found the available evidence weaker but still consistent with a
causal relation between DTP vaccine and two conditions—acute encephalopathy and
hypotonic, hyporesponsive episodes—and between rubella vaccine and chronic
arthritis in adult women.”

National Toxicology Program Technical Report Series • January 1992

NTP Toxicology and Carcinogenesis Studies of Polysorbate 80 (CAS No. 9005-65-6)
in F344/N Rats and B6C3F1 Mice (Feed Studies) Abstract Polysorbate 80 is a
nonionic surfactant used widely as an additive in foods, pharmaceutical
preparations, and cosmetics as an emulsifier, dispersant, or stabilizer.
Toxicity and carcinogenicity studies were conducted by administering
polysorbate 80 (which met all compendial specifications) in feed to groups of
F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years.
Genetic toxicology studies were conducted in Salmonella typhimurium. 14-Day
Studies: Groups of five rats and five mice of each sex received diets
containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm polysorbate 80. All
animals survived to the end of the studies. The mean body weight change of male
rats that received 50,000 ppm was significantly lower than that of the
controls. The mean body weight changes in all other groups of dosed rats and in
all groups of dosed mice were similar to those of the respective controls. No
clinical findings or changes in absolute or relative organ weights in rats or
mice were related to polysorbate 80 administration. 13-Week Studies: Groups of
10 rats and 10 mice of each sex received diets containing 0, 3,100, 6,200,
12,500, 25,000, or 50,000 ppm polysorbate 80. All animals survived to the end
of the studies. The final mean body weights of dosed rats and mice were similar
to those of the controls. No clinical findings, changes in absolute or relative
organ weights, or gross or microscopic lesions in rats or mice were related to
polysorbate 80 administration. 2-Year Studies: Doses for the 2-year studies
were selected based on the lack of observed compound-related effects at the
dose levels used in the 13-week studies. Groups of 60 rats and 60 mice of each
sex received diets containing 0, 25,000, or 50,000 ppm polysorbate 80 for up to
103 weeks. 15-Month Interim Evaluations: Interim evaluations were performed on
7 to 10 rats and mice from each dose group at 15 months. There were no
significant changes in absolute or relative organ weights. Incidences of
hyperplasia and inflammation of the forestomach were increased in female mice
that received 50,000 ppm. No other chemical-related lesions occurred in rats or
male mice evaluated at 15 months. Body Weights, Clinical Findings, and Survival
in the 2-Year Studies: The mean body weights in male and female rats and male
mice administered polysorbate 80 were similar to those of the controls
throughout the studies. The final mean body weight of female mice receiving
50,000 ppm was 11%lower than that of the controls. No clinical findings were
associated with administration of polysorbate 80. The survival of dosed male
rats was lower than that of the controls (0 ppm, 29/50; 25,000 ppm, 18/50;
50,000 ppm, 18/50); the survival of dosed female rats and male and female mice
was similar to that of the respective controls (female rats: 23/50, 25/50,
25/50; male mice: 33/49, 34/50, 32/50; female mice: 30/50, 28/50, 26/50).
Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: The incidence of
adrenal medulla pheochromocytoma was marginally increased in high-dose male
rats (21/50, 19/50, 29/50). The incidence of hyperplasia of the adrenal medulla
was increased in low-dose male rats but not in high-dose male rats (11/50,
22/50, 12/50). No chemical-related increases in the incidences of neoplasms
occurred in male or female mice. The incidences of squamous hyperplasia and
inflammation of the forestomach were significantly increased in high-dose male
and female mice; forestomach ulcers were significantly increased in high-dose
females. Genetic Toxicology: Polysorbate 80 was not mutagenic in Salmonella
typhimurium strains TA100, TA1535, TA1537, and TA98 with or without exogenous
metabolic activation (S9). Conclusions: Under the conditions of these 2-year
feed studies, there was equivocal evidence of carcinogenic activity for
polysorbate 80 in male F344/N rats based on an increased incidence of
pheochromocytomas of the adrenal medulla. There was no evidence of carcinogenic
activity for polysorbate 80 in female F344/N rats or in male or female B6C3F1
mice given 25,000 or 50, or 50,000 ppm. Administration of polysorbate 80 was
associated with inflammation and squamous hyperplasia of the forestomach in
male and female mice, and with ulcers of the forestomach in female mice.
http://www.ncbi.nlm.nih.gov/pubmed/12616296

“Administration of polysorbate 80 was associated with inflammation and squamous
hyperplasia of the forestomach in male and female mice, and with ulcers of the
forestomach in female mice.”

American Journal Of Diseases Of Children • February 1992

Vitamin A levels and severity of measles New York City Author information
Frieden TR1, Sowell AL, Henning KJ, Huff DL, Gunn RA. Division of Field
Epidemiology Centers for Disease Control Abstract Recent studies show that
vitamin A levels decrease during measles and that vitamin A therapy can improve
measles outcome in children in the developing world. Vitamin A levels of
children with measles have not been studied in developed countries. We
therefore measured vitamin A levels in 89 children with measles younger than 2
years and in a reference group in New York City, NY. Vitamin A levels in
children with measles ranged from 0.42 to 3.0 mumol/L; 20 (22%) were low.
Children with low levels were more likely to have fever at a temperature of 40
degrees C or higher (68% vs 44%), to have fever for 7 days or more (54% vs
23%), and to be hospitalized (55% vs 30%). Children with low vitamin A levels
had lower measlesspecific antibody levels. No child in the reference group had
a low vitamin A level. Our data show that many children younger than 2 years in
New York City have low vitamin A levels when ill with measles, and that such
children seem to have lower measles-specific antibody levels and increased
morbidity. Clinicians may wish to consider vitamin A therapy for children
younger than 2 years with severe measles. Additional studies of vitamin A in
measles and other infectious diseases, and in vaccine efficacy trials, should
be done. http://www.ncbi.nlm.nih.gov/pubmed/?term=1285727

“Recent studies show that vitamin A levels decrease during measles and that
vitamin A therapy can improve measles outcome in children in the developing
world. Vitamin A levels of children with measles have not been studied in
developed countries.”

[vitamin A and vaccination will be studied in Africa 20 years from now and
those reports are included herein]

Clinical Infectious Disease • August 1992

Chronic arthritis after rubella vaccination Author information Howson CP1, Katz
M, Johnston RB Jr, Fineberg HV. Division of International Health Institute of
Medicine Washington, D.C. 20418 Abstract In August 1991 the Institute of
Medicine released a report entitled “Adverse Effects of Pertussis and Rubella
Vaccines” that examined, among other relations, the relation between
immunization with the RA 27/3 rubella vaccine strain and chronic arthritis. The
committee spent 20 months reviewing a wide range of information sources
including case series and individual case reports published in peer-reviewed
journals and reported by vaccine manufacturers; unpublished case reports from
physicians, parents, and other concerned persons; epidemiological studies; and
laboratory studies. There were no animal studies available. The committee found
that the evidence is consistent with a causal relation between the RA 27/3
rubella vaccine strain and chronic arthritis in adult women, although the
evidence is limited in scope. Proving that rubella vaccination can cause
chronic arthritis will require a better understanding of pathogenetic
mechanisms and additional well-designed studies. We briefly describe the
committee’s evaluative methods and present the evidence underlying its
conclusion. http://www.ncbi.nlm.nih.gov/pubmed/1520764

“The committee found that the evidence is consistent with a causal relation
between the RA 27/3 rubella vaccine strain and chronic arthritis in adult women
...”

“Tween 80 accelerated maturation, prolonged the oestrus cycle, and induced persistent vaginal oestrus.”
Food And Chemical Toxicology • March 1993

Delayed effects of neonatal exposure to Tween 80 on female reproductive organs
in rats Author information Gajdová M1, Jakubovsky J, Války J. Institute of
Preventive and Clinical Medicine Limbová, Bratislava Abstract Neonatal female
rats were injected ip (0.1 ml/rat) with Tween 80 in 1, 5 or 10% aqueous
solution on days 4-7 after birth. Treatment with Tween 80 accelerated
maturation, prolonged the oestrus cycle, and induced persistent vaginal
oestrus. The relative weight of the uterus and ovaries was decreased relative
to the untreated controls. Squamous cell metaplasia of the epithelial lining of
the uterus and cytological changes in the uterus were indicative of chronic
oestrogenic stimulation. Ovaries were without corpora lutea, and had
degenerative follicles. http://www.ncbi.nlm.nih.gov/pubmed/8473002

Archives of Disease in Childhood • 1994

Ocular contamination with BCG vaccine A j Pollard Department of Paediatrics R H
George Department ofMicrobiology Children’s Hospital Ladywood Middleway
Ladywood, Birmingham B16 8ET Abstract The complications of BCG vaccination in
both the immunocompetent, with local and lymph node ulceration, and in the
immunocompromised, with disseminated infection, are familiar to most
paediatricians. Moreover, the risks to the doctor from needlestick injury are
well known. There are probably few other risks for the vaccinator but we
describe a case of ocular contamination with BCG vaccine. During attempted
intradermal injection of BCG vaccine into a struggling neonate’s upper arm, the
syringe slipped out of the infant’s skin discharging its contents into the
attending doctor’s eye. The doctor had received BCG vaccine in childhood.
Despite lavage of the eye with water, a painful follicular conjunctivitis
developed 24 hours later. There was a rapid response to topical steroids, and
the inflammatory response settled completely over the subsequent week. Although
it was assumed that this was a delayed-type hypersensitivity response, anti-BCG
cover was given with a one month course of oral isoniazid. Full Report:
https://app.box.com/s/ev8bhi6vb3rofhrkavum3v3hpt2xlil9

“During attempted intradermal injection of BCG vaccine into a struggling
neonate’s upper arm, the syringe slipped out of the infant’s skin discharging
its contents into the attending doctor’s eye.”

National Academies Press US • 1994

DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis Institute of
Medicine US Committee to Study New Research on Vaccines Editors Kathleen R.
Stratton, Cynthia J. Howe, and Richard B. Johnston, Jr. Washington, DC
EXECUTIVE SUMMARY

An Institute of Medicine (IOM) committee recently concluded that the evidence
is consistent with a causal relation between vaccination with DPT and acute
encephalopathy (IOM, 1991), and the excess risk was estimated to range from 0
to 10.5 per million DPT immunizations. However, the same IOM committee also
concluded that the evidence was insufficient to indicate a causal relation
between DPT and permanent neurologic damage (IOM, 1991). In fact, the relation
between DPT and chronic nervous system dysfunction had not been studied in a
rigorous scientific manner until recently. Because the evidence has been so
limited, the appearance of a single new report, a 10-year follow-up to the
National Childhood Encephalopathy Study (NCES; Miller et al., 1993), prompted
the U.S. Public Health Service to ask IOM to convene the Committee to Study New
Research on Vaccines with the charge of studying the new data and, if
warranted, reevaluating the causal relation between DPT and chronic nervous
system dysfunction.

serious acute neurologic illness that occurs within 7 days after receiving DPT.
The NCES provides data only on the limited case of a possible relation between
DPT and chronic nervous system dysfunction in those children in whom a serious
acute neurologic illness followed DPT vaccination within 7 days.

The NCES reported that the occurrence of hospitalization for serious neurologic
disorders among 2- to 35-month-old children is very strongly related to the
occurrence of death or nervous system dysfunction (neurologic, behavioral,
educational, motor, sensory, or self-care impairment) up to age 10 years (Madge
et al., 1993; Miller et al., 1993). Children who experienced the rare but
serious acute neurologic disorder within 7 days after receiving DPT were no
more or less likely to experience documented chronic nervous system dysfunction
or to have died within 10 years of the acute disorder than children who had not
received DPT within 7 days prior to the onset of the disorder. There were no
special characteristics associated with the acute or chronic nervous system
illnesses linked to DPT exposure.

2. DPT might trigger (and thereby be an immediate or proximate cause) an acute
neurologic illness and subsequent chronic dysfunction in children with
underlying brain or metabolic abnormalities. Such children might experience
acute neurologic illness and subsequent chronic dysfunction in association with
some trigger other than DPT.

The NCES did not investigate the possibility of a direct relation between DPT
and chronic nervous system dysfunction, that is, in the absence of a

The committee posits three plausible scenarios whereby the acute neurologic
illnesses that follow DPT might be related to chronic nervous system
dysfunction. 1. DPT administration might cause serious acute neurologic illness
and subsequent chronic dysfunction in children who otherwise might not have
experienced either an acute neurologic illness or chronic dysfunction in the
absence of DPT.

3. DPT might cause an acute neurologic illness in children with underlying
brain or metabolic abnormalities that would themselves eventually have led to
chronic dysfunction even in the absence of an acute neurologic illness. The
committee believes its conclusions take into account the fact that the data do
not support any one of these scenarios over the others. Because the NCES did
not (and probably could not) rule out the possibility that onlychildren with
underlying brain or metabolic abnormalities react to stimuli

http://www.ncbi.nlm.nih.gov/books/NBK225452/

such as DPT with acute neurologic illness, and no other studies establish or
rule out such a possibility, the committee concludes that the evidence is
insufficient to indicate whether or not DPT increases the overall risk in
children of chronic nervous system dysfunction. The National Childhood
Encephalopathy Study data are consistent with the possibility that some
children without underlying brain or metabolic abnormalities might experience
serious acute neurologic illness within 7 days after receiving DPT and that
acute neurologic illness will have chronic nervous system sequelae. The NCES
data also are consistent with the possibility that some children with
underlying brain or metabolic abnormalities (which foster a “triggering” by DPT
of an acute neurologic illness) might go on to develop chronic nervous system
dysfunction due to a DPT-triggered acute illness. Therefore, the committee
concludes that the balance of evidence is consistent with a causal relation
between DPT and the forms of chronic nervous system dysfunction described in
the NCES in those children who experience a serious acute neurologic illness
within 7 days after receiving DPT vaccine. This serious acute neurologic
response to DPT is a rare event. The excess risk has been estimated to range
from 0 to 10.5 per million immunizations (IOM, 1991). The evidence does not
“establish” or “prove” a causal relation. The evidence remains insufficient to
indicate the presence or absence of a causal relation between DPT and chronic
nervous system dysfunction under any other circumstances. That is, because the
NCES is the only systematic study of long-term dysfunctions after DPT, the
committee can only comment on the causal relation between DPT and those
long-term dysfunctions under the conditions studied by the NCES. In particular,
it should be noted that the long-term dysfunctions associated with DPT followed
a serious acute neurologic illness that occurred in children within 7 days
after receiving DPT.

Acta Paediatrica • February 1994

Immunosuppression after measles vaccination Author information Smedman L1, Joki
A, da Silva AP, Troye-Blomberg M, Aronsson B, Perlmann P. Department of
Immunology Stockholm University, Sweden Abstract The influence of conventional
live attenuated measles vaccine on cellular immune responsiveness was
investigated in Sweden and Guinea-Bissau. Sixteen children in a residential
area in Bissau and 16 living in southern Stockholm were examined before and
8-10 days after vaccination. Lymphoproliferation was measured to concanavalin A
(con-A), PPD and tetanus toxoid (TT) using a whole-blood 3H-thymidine
incorporation assay. Stimulation indices were significantly lower after
vaccination than before, in the case of con-A (p = 0.03) and TT (p = 0.01) in
the Guinean children and in the case of PPD (p = 0.009) and TT (p = 0.03) in
the Swedish children. Stimulation of lymphocytes from measles-immune children
with measles antigens resulted in weak lymphoproliferative responses. These
observations may be relevant to the increased mortality found in children
immunized with high-titre measles vaccines, as compared to controls, in recent
studies. The study confirms the applicability and usefulness under field
conditions of the whole blood version of the thymidine incorporation assay.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8193495

“These observations may be relevant to the increased mortality found in
children immunized with high-titre measles vaccines, as compared to controls,
in recent studies.”

Journal Of Clinical Pharmacology • February 1994

Adverse drug reactions in neonates Author information Knight M. Department of
Pediatrics, College of Medicine University of Florida Health Science Center,
Gainesville 32610 Abstract Adverse drug reactions (ADR) are uncommon causes of
admission of neonates to the neonatal intensive care unit. The neonate,
however, is potentially at significant risk for adverse drug reactions because
of underdeveloped mechanisms and systems for handling drugs (the Gray Baby
Syndrome with chloramphenicol as a classic example), the fact that infants in
neonatal intensive care units are often critically ill with multiple organ
system dysfunction, that they may be on multiple drugs, and that they may
present with an adverse drug reaction as a result of exposure while still a
fetus. There is also a history of misadventures in the neonatal intensive care
unit and newborn nurseries due to exposure to antibacterial agents that
produced systemic effects from percutaneous absorption. In this review, an
overview of the mechanisms of adverse drug reactions will be presented,
followed by a general review of the experience of adverse drug reactions in
neonates and some specific examples of current adverse drug reactions and a
suggested approach for the prevention and evaluation of adverse drug reactions
in neonates. http://www.ncbi.nlm.nih.gov/pubmed/?term=8163712

“The neonate, however, is potentially at significant risk for adverse drug
reactions because of underdeveloped mechanisms and systems for handling drugs
...”

“Eighty-seven previously vaccinated school-aged children with measles
that met the Advisory Committee on Epidemiology’s clinical case definition for
measles.” Canadian Medical Association Journal • April 1994

Measles outbreak in 31 schools: risk factors for vaccine failure and evaluation
of a selective revaccination strategy Author information Yuan L. Department of
Preventive Medicine and Biostatistics University of Toronto, Ontario, CA
Abstract OBJECTIVE To examine the risk factors for measles vaccine failure and
to evaluate the effectiveness of a selective revaccination strategy during a
measles outbreak. DESIGN Matched case-control study. SETTING Thirty-one schools
in Mississauga, Ont. SUBJECTS Eighty-seven previously vaccinated school-aged
children with measles that met the Advisory Committee on Epidemiology’s
clinical case definition for measles. Two previously vaccinated control
subjects were randomly selected for each case subject from the same homeroom
class.

INTERVENTIONS All susceptible contacts were vaccinated, and contacts who had
been vaccinated before Jan. 1, 1980, were revaccinated. When two or more cases
occurred in a school all children vaccinated before 1980 were revaccinated.
MAIN OUTCOME MEASURES Risk of measles associated with age at vaccination, time
since vaccination, vaccination before 1980 and revaccination. RESULTS Subjects
vaccinated before 12 months of age were at greater risk of measles than those
vaccinated later (adjusted odds ratio [OR] 7.7, 95% confidence interval [CI]
1.6 to 38.3; p = 0.01). Those vaccinated between 12 and 14 months of age were
at no greater risk than those vaccinated at 15 months or over. Subjects
vaccinated before 1980 were at greater risk than those vaccinated after 1980
(adjusted OR 14.5, 95% CI 1.5 to 135.6). Time since vaccination was not a risk
factor. Revaccination was effective in reducing the risk of measles in both
subjects vaccinated before 1980 and those vaccinated after 1980 (adjusted OR
reduced to 0.6 [95% CI 0.1 to 5.3] and 0.3 [95% CI 0.13 to 2.6] respectively).
However, only 18 cases were estimated to have been prevented by this strategy.
CONCLUSIONS Adherence to routine measles vaccination for all eligible children
is important in ensuring appropriate coverage with a single dose. The selective
revaccination strategy’s high labour intensiveness and low measles prevention
rate during the outbreak bring into question the effectiveness of such a
strategy. http://www.ncbi.nlm.nih.gov/pubmed/8137189

Vaccine • April 1994

Adverse reactions after diphtheria-tetanus booster in 10-year-old
schoolchildren in relation to the type of vaccine given for the primary
vaccination Author information Blennow M1, Granström M, Strandell A.
1Department of Pediatrics Sachs’ Children’s Hospital Stockholm, Sweden Abstract
This prospective open study investigated adverse reactions in 527
schoolchildren to a diphtheria-tetanus (DT) booster given within a national
vaccination programme at 10 years of age. Evaluation was based on those whose
immunization records showed that they had received either three doses of an
adsorbed DT vaccine (n = 388) or a non-adsorbed DT-pertussis vaccine (DTP) (n =
69) for primary series vaccination. No differences in systemic reactions to the
booster between the two groups were observed. Local reactions were
significantly (p < 0.001) more common 1 day after vaccination in children who
had received DT for primary series vaccination: redness, 73% compared with 23%;
swelling, 56% versus 15%; and itching, 47% versus 21%. One and 2 weeks after
the booster, itching was still more pronounced in the group who had received DT
for primary series vaccination (p < 0.001 and 0.014, respectively). The study
indicates that there was a real basis for the increase in spontaneous
notifications of local side-effects to the school DT booster in Sweden. The
most likely cause for the increase seems to be the aluminium adjuvant in the
vaccine given for primary vaccination, a late and unexpected consequence of a
change in the infant immunization programme.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8023551

“This prospective open study investigated adverse reactions in 527
schoolchildren to a diphtheria-tetanus (DT) booster ... The most likely cause
for the increase seems to be the aluminium adjuvant in the vaccine given for
primary vaccination, a late and unexpected consequence of a change in the
infant immunization programme.”

JAMA • May 1994

Adverse events associated with childhood vaccines other than pertussis and
rubella. Summary of a report from the Institute of Medicine Author information
Stratton KR1, Howe CJ, Johnston RB Jr. Institute of Medicine, National Academy
of Sciences Washington, DC Abstract In September 1993, the Institute of
Medicine released a report entitled Adverse Events Associated With Childhood
Vaccines: Evidence Bearing on Causality. The report examined putative serious
adverse consequences associated with administration of diphtheria and tetanus
toxoids; measles, mumps, and measles-mumps-rubella vaccines; oral polio vaccine
and inactivated polio vaccine; hepatitis B vaccines; and Haemophilus influenzae
type b (Hib) vaccines. The committee spent 18 months reviewing all available
scientific and medical data, from individual case reports (published and
unpublished) to controlled clinical trials. The committee found that the
evidence favored the rejection of a causal relation between diphtheria and
tetanus toxoids and encephalopathy, infantile spasms, and sudden infant death
syndrome, and between conjugate Hib vaccines and susceptibility to Hib disease.
The committee found that the evidence favored acceptance of a causal relation
between diphtheria and tetanus toxoids and Guillain-Barré syndrome and brachial
neuritis, between measles vaccine and anaphylaxis, between oral polio vaccine
and Guillain-Barré syndrome, and between unconjugated Hib vaccine and
susceptibility to Hib disease. The committee found that the evidence
established causality between diphtheria and tetanus toxoids and anaphylaxis,
between measles vaccine and death from measles vaccine-strain viral infection,
between measles-mumps-rubella vaccine and thrombocytopenia and anaphylaxis,
between oral polio vaccine and poliomyelitis and death from polio
vaccine-strain viral infection, and between hepatitis B vaccine and
anaphylaxis. For five vaccine-related adverse events, there was no evidence
identified. For the remaining 33 vaccine-related adverse events, the evidence
was inadequate to accept or reject a causal relation.
http://www.ncbi.nlm.nih.gov/pubmed/8182813

“The committee found that the evidence favored acceptance of a causal relation
between diphtheria and tetanus toxoids and Guillain-Barré syndrome and brachial
neuritis, between measles vaccine and anaphylaxis, between oral polio vaccine
and Guillain-Barré syndrome, and between unconjugated Hib vaccine and
susceptibility to Hib disease. The committee found that the evidence
established causality between diphtheria and tetanus toxoids and anaphylaxis,
between measles vaccine and death from measles vaccine-strain viral infection,
between measles-mumpsrubella vaccine and thrombocytopenia and anaphylaxis,
between oral polio vaccine and poliomyelitis and death from polio
vaccine-strain viral infection, and between hepatitis B vaccine and
anaphylaxis.”

“In 1993 we found 17 cases of Adverse Events Following Immunization (AEFI)
out of 1440 children between 0 and 2 years of age ...” Przeglad
Epidemiologiczny • 1994

Adverse events following immunization: AEFI in 17 children between 0 and 2
years of age Author information Taraszkiewicz F1, Bogus-Parafieniuk W, Oldak E,
Sulik A. Klinika Chorób Zakaznych Dzieci Akademii Medycznej w Bialymstoku
Abstract Adverse Events Following Immunization (AEFI) are disadvantageous side
effects of preventive vaccination. In 1993 we found 17 cases of AEFI out of
1440 children between 0 and 2 years of age who had received BCG,
diphtheria-tetanus-pertussis, measles or poliomyelitis vaccine. They were
classified as reactions in 14 children (0.9%) or complications in 3 children
(0.2%). Twelve adverse reactions followed DTP vaccination (0.8%), two followed
BCG vaccination (0.14%), another two measles vaccination (0.14%) and one
followed poliomyelitis vaccination (0.07%). Both generalized and local symptoms
were present and they regressed with no further complications. Two children who
had received BCG were noted to have a deeply placed abscess at the injection
site remaining scar as well as axillary, submandibular and cervical lymph nodes
enlargement within 6 months. In a 3 months old child, after the first injection
of DTP vaccine, convulsions and consciousness disorder occurred. Transfontanel
ultrasonography revealed intraventricular haemorrhage. After one year of
intensive neurological care child’s health state was improved. In spite of
using still more and more safe vaccines none of them is the ideal one—the one
with no adverse events following vaccination. Vaccination technics,
distribution and storage of vaccines are to be improved which may result in
decrease number of AEFI. http://www.ncbi.nlm.nih.gov/pubmed/7597191

CDC • MMWR • 1996

Update: Vaccine Side Effects, Adverse Reactions, Contraindications, and
Precautions Recommendations of the Advisory Committee on Immunization Practices
(ACIP) Summary This report provides updated information concerning the
potential adverse events associated with vaccination for hepatitis B,
poliomyelitis, measles, mumps, diphtheria, tetanus, and pertussis. This
information incorporates findings from a series of recent literature reviews,
conducted by an expert committee at the Institute of Medicine (IOM), of all
evidence regarding the possible adverse consequences of vaccines administered
to children. This report contains modifications to the previously published
recommendations of the Advisory Committee on Immunization Practices (ACIP) and
is based on an ACIP review of the IOM findings and new research on vaccine
safety. In addition, this report incorporates information contained in the
“Recommendations of the Advisory Committee on Immunization Practices: Use of
Vaccines and Immune Globulins in Persons with Altered Immunocompetence” (MMWR
1993;42{No. RR-4}) and the “General Recommendations on Immunization:
Recommendations of the Advisory Committee on Immunization Practices (ACIP)”
(MMWR 1994;43{No. RR-1}). Major changes to the previous recommendations are
highlighted within the text, and specific information concerning the following
vaccines and the possible adverse events associated with their administration
are included: hepatitis B vaccine and anaphylaxis; measles vaccine and a)
thrombocytopenia and b) possible risk for death resulting from anaphylaxis or
disseminated disease in immunocompromised persons; diphtheria and tetanus
toxoids and pertussis vaccine (DTP) and chronic encephalopathy; and
tetanus-toxoid-containing vaccines and a) Guillain-Barre syndrome, b) brachial
neuritis, and c) possible risk for death resulting from anaphylaxis. These
modifications will be incorporated into more comprehensive ACIP recommendations
for each vaccine when such statements are revised. Also included in this report
are interim recommendations concerning the use of measles and mumps vaccines
in: a. persons who are infected with human immunodeficiency virus and b.
persons who are allergic to eggs; ACIP is still evaluating these
recommendations.

http://www.cdc.gov/mmwr/preview/mmwrhtml/00046738.htm

Pediatric Infectious Disease Journal • January 1996

Measles outbreaks in the United States, 1987 through 1990 Author information
Hutchins S1, Markowitz L, Atkinson W, Swint E, Hadler S. National Immunization
Program Centers for Disease Control and Prevention Atlanta, GA, USA Abstract

“There were 815 outbreaks, accounting for 94% of the 52,846 cases reported. 3
patterns of measles transmission during

BACKGROUND During 1989 and 1990 reported measles cases in the United States
increased 6- to 9-fold over the annual mean of 3000 between 1985 and 1988. To
evaluate recent epidemiology we summarized measles outbreaks.

outbreaks were identified:

METHODS Confirmed measles cases reported to the National Notifiable Disease
Surveillance System during 1987 through 1990 were analyzed. An outbreak was
defined as > or = 5 epidemiologically linked cases.

(1) predominantly among unvaccinated

RESULTS There were 815 outbreaks, accounting for 94% of the 52,846 cases
reported. Similar to 1985 and 1986, 3 patterns of measles transmission during
outbreaks were identified: (1) predominantly among unvaccinated pre-school age
children < 5 years of age (38% of outbreaks); (2) predominantly among
vaccinated school age children 5 to 17 years of age (40%); and (3)
predominantly among unvaccinated and vaccinated post-school age persons > or =
18 years of age (22%). Most outbreaks were small (median, 12 cases), but very
large outbreaks occurred (maximum size, 10,670). Although school age outbreaks
(58%) predominated during 1987 and 1988, preschool age (40%) and postschool age
(23%) outbreaks were more important during 1989 and 1990. CONCLUSIONS Recent
epidemiology suggests that to achieve elimination of measles, ACIP
recommendations must be fully implemented, including (1) routine administration
of the first dose of measles vaccine from 12 to 15 months of age and (2) use of
a routine two-dose schedule to prevent school age and post-school age
outbreaks. http://www.ncbi.nlm.nih.gov/pubmed/8684873

pre-school age children (38% of outbreaks)

(2) predominantly among vaccinated school age children 5 to 17 years of age
(40%)

(3) predominantly among unvaccinated and vaccinated post-school age persons
(22%) ...”

Carcinogenesis • January 1996

DNA— protein crosslinks, a biomarker of exposure to formaldehyde— in vitro and
in vivo studies Author information Shaham J1, Bomstein Y, Meltzer A, Kaufman Z,
Palma E, Ribak J. Occupational Cancer Unit Occupational Health and
Rehabilitation Institute Raanana, Israel Abstract Formaldehyde (FA) is a widely
produced industrial chemical. Sufficient evidence exists to consider FA as an
animal carcinogen. In humans the evidence is not conclusive. DNA-protein
crosslinks (DPC) may be one of the early lesions in the carcinogenesis process
in cells following exposures to carcinogens. It has been shown in in vitro
tests that FA can form DPC. We examined the amount of DPC formation in human
white blood cells exposed to FA in vitro and in white blood cells taken from 12
workers exposed to FA and eight controls. We found a significant difference (P
= 0.03) in the amount of DPC among exposed (mean +/- SD 28 +/- 5%, minimum 21%,
maximum 38%) than among the unexposed controls (mean +/- SD 22 +/- 6%, minimum
16%, maximum 32%). Of the 12 exposed workers, four (33%) showed crosslink
values above the upper range of controls. We also found a linear relationship
between years of exposure and the amount of DPC. We conclude that our data
indicate a possible mechanism of FA carcinogenicity in humans and that DPC can
be used as a method for biological monitoring of exposure to FA. Full Report
http://carcin.oxfordjournals.org/content/17/1/121.long

“We conclude that our data indicate a possible mechanism of Formaldehyde
carcinogenicity in humans ...”

Acta Paediatrica Japan • June 1996

Adverse events associated with MMR vaccines in Japan Author information Kimura
M1, Kuno-Sakai H, Yamazaki S, Yamada A, Hishiyama M, Kamiya H, Ueda K, Murase
T, Hirayama M, Oya A, Nozaki S, Murata R. School of Medicine Tokai University,
Isehara, Japan Abstract The largest nationwide active surveillance of four
Measles-Mumps-Rubella (MMR) vaccines was conducted in Japan. A total of 1255
pediatricians actively participated in the study, which comprised 8.6% of all
members of the Japanese Pediatric Society. The total number of registered
recipients of MMR vaccines was 38 203. They were arbitrarily given one of the
MMR vaccines produced by three makers (Takeda, Osaka city, Kitasato Minatoku.
Tokyo and Biken Suita city, Japan) or the standard MMR vaccine made of
designated strains (Kitasato’s measles-AIK-C, Biken’s mumps-Urabe Am9 and
Takeda’s rubella-To336) produced by Takeda, Kitasato and Biken and were
observed for 35 days. The rates of virologically confirmed aseptic meningitis
per 10,000 recipients were 16.6, 11.6, 3.2 and 0 for the standard MMR, Takeda
MMR, Kitasato MMR and Biken MMR vaccines, respectively. The incidence of
convulsions between 15 and 35 days was the highest with the standard MMR
vaccine and the incidence of fever associated with vomiting occurring between
15 and 35 days (symptoms relevant to aseptic meningitis) were also the highest
with the standard MMR vaccine. The incidence of parotid swelling was the lowest
with Takeda MMR vaccine. This surveillance revealed that incidences of aseptic
meningitis after administration of the standard MMR vaccine and of Biken MMR
vaccine were different. This posed questions about the manufacturing
consistency of the Urabe Am9 mumps virus vaccines. On the other hand, the
National Institute of Health found that the biological characteristics of the
Urabe Am9 mumps virus contained in the standard MMR vaccine and in the Biken
MMR vaccine were different. The Biken Company reported that the mumps vaccine
in the standard MMR vaccine was a mixture of two Urabe Am9 mumps vaccine bulks;
one identical to that contained in the Biken MMR vaccine and the other produced
by a different manufacturing process.
http://www.ncbi.nlm.nih.gov/pubmed/8741307

“The incidence of convulsions between 15 and 35 days was the highest with the
standard MMR vaccine and the incidence of fever associated with vomiting
occurring between 15 and 35 days (symptoms relevant to aseptic meningitis) were
also the highest with the standard MMR vaccine. The incidence of parotid
swelling was the lowest with Takeda MMR vaccine. This surveillance revealed
that incidences of aseptic meningitis after administration of the standard MMR
vaccine and of Biken MMR vaccine were different. This posed questions about the
manufacturing consistency of the Urabe Am9 mumps virus vaccines.”

Lancet • June 1996

Measles and atopy in Guinea-Bissau Author information Shaheen SO1, Aaby P, Hall
AJ, Barker DJ, Heyes CB, Shiell AW, Goudiaby A. 1Medical Research Council
Environmental Epidemiology Unit University of Southampton, Southhampton General
Hospital, UK Abstract BACKGROUND Epidemiological studies have led to
speculation that infections in early childhood may prevent allergic
sensitisation but evidence to support this hypothesis is lacking. We
investigated whether measles infection protects against the development of
atopy in children of Guinea-Bissau, West Africa. METHODS We conducted a
historical cohort study in Bandim, a semi-rural district of Bissau, the capital
of Guinea-Bissau. 395 young adults, first surveyed in 1978-80 aged 0-6 years,
were followed up in 1994. Our analyses were restricted to 262 individuals still
living in Bandim for whom a measles history, documented in childhood, was
judged to be reliable. We defined atopy as skin-prick test positivity (> or = 3
mm weal) to one or more of seven allergens. FINDINGS 17 (12.8 percent) of 133
participants who had had measles infection were atopic compared with 33 (25.6
percent) of 129 of those who had been vaccinated and not had measles (odds
ratio, adjusted for potential confounding variables 0.36 [95 percent CI
0.17-0.78], p=O.O1). Participants who had been breastfed for more than a year
were less likely to have a positive skin test to housedust mite. After
adjustment for breastfeeding and other variables, measles infection was
associated with a large reduction in the risk of skin-prick test positivity to
housedust mite (odds ratio for Dermatophagoides pteronyssinus 0.20 [0.05-0.81],
p=0.02; D farinae 0.20 [0.06-0.71], p=0.01). INTERPRETATION Measles infection
may prevent the development of atopy in African children.
http://www.ncbi.nlm.nih.gov/pubmed/8667923

“Measles infection may prevent the development of atopy [allergies] in African
children.” [as Dr. Buttram stated, challenge viruses like measles and chicken
pox strengthen the child’s immune system]

“Triton X-100 efficiently induces the apoptotic cell death ...”
Yonsei Medical Journal • February 1997

Triton X-100 induces apoptosis in human hepatoma cell lines Author information
Ahn JM1, Kim SJ, Kim H, Park C, Kim WH, Park JH. Department of Microbiology
Yonsei University College of Medicine Seoul, Korea Abstract The detergent
Triton X-100 was used to establish a model for apoptosis in hepatoma cell
lines. The electrophoresis of DNA extracted from 0.01% Triton X-100 treated
hepatoma cell lines showed DNA ladder formation, a hallmark of apoptosis. The
DNA fragmentation appeared within less than 60 min of the Triton X-100
treatment. Chromatin condensation and apoptotic bodies were observed by
hematoxylin and eosin (H & E) stain, and fragmented nucleosome was detected by
terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling
(TUNEL) test. Apoptosis was semi-quantitated by measuring the lactate
dehydrogenase (LDH) level for cytotoxity. It was found that apoptosis had been
induced in more than 90% of the cells treated with Triton X-100 for 150 min.
These data show that Triton X-100 efficiently induces the apoptotic cell death
in hepatoma cell lines. http://www.ncbi.nlm.nih.gov/pubmed/9100483

Epidemiology • November 1997

Is infant immunization a risk factor for childhood asthma or allergy? Author
information Kemp T1, Pearce N, Fitzharris P, Crane J, Fergusson D, St George I,
Wickens K, Beasley R. 1Department of Medicine Wellington School of Medicine New
Zealand Abstract The Christchurch Health and Development Study comprises 1,265
children born in 1977. The 23 children who received no
diphtheria/pertussis/tetanus (DPT) and polio immunizations had no recorded
asthma episodes or consultations for asthma or other allergic illness before
age 10 years; in the immunized children, 23.1% had asthma episodes, 22.5%
asthma consultations, and 30.0% consultations for other allergic illness.
Similar differences were observed at ages 5 and 16 years. These findings do not
appear to be due to differential use of health services (although this
possibility cannot be excluded) or confounding by ethnicity, socioeconomic
status, parental atopy, or parental smoking.
http://www.ncbi.nlm.nih.gov/pubmed/9345669

“The 23 children who received no diphtheria/pertussis/tetanus (DPT) and polio
immunizations had no recorded asthma episodes or consultations for asthma or
other allergic illness before age 10 years; in the immunized children, 23.1%
had asthma episodes, 22.5% asthma consultations, and 30.0% consultations for
other allergic illness. Similar differences were observed at ages 5 and 16
years.”

Lancet • June 1996

Measles and atopy in Guinea-Bissau Author information Shaheen SO1, Aaby P, Hall
AJ, Barker DJ, Heyes CB, Shiell AW, Goudiaby A. Medical Research Council
Environmental Epidemiology Unit University of Southampton, Southhampton General
Hospital, UK Abstract BACKGROUND Epidemiological studies have led to
speculation that infections in early childhood may prevent allergic
sensitisation but evidence to support this hypothesis is lacking. We
investigated whether measles infection protects against the development of
atopy in children of Guinea-Bissau, West Africa. METHODS We conducted a
historical cohort study in Bandim, a semi-rural district of Bissau, the capital
of Guinea-Bissau. 395 young adults, first surveyed in 1978-80 aged 0-6 years,
were followed up in 1994. Our analyses were restricted to 262 individuals still
living in Bandim for whom a measles history, documented in childhood, was
judged to be reliable. We defined atopy as skin-prick test positivity (> or = 3
mm weal) to one or more of seven allergens. FINDINGS 17 (12.8 percent) of 133
participants who had had measles infection were atopic compared with 33 (25.6
percent) of 129 of those who had been vaccinated and not had measles (odds
ratio, adjusted for potential confounding variables 0.36 [95 percent CI
0.17-0.78], p=O. O1). Participants who had been breastfed for more than a year
were less likely to have a positive skin test to housedust mite. After
adjustment for breastfeeding and other variables, measles infection was
associated with a large reduction in the risk of skin-prick test positivity to
housedust mite (odds ratio for Dermatophagoides pteronyssinus 0.20 [0.05-0.81],
p=0.02; D farinae 0.20 [0.06-0.71], p=0.01). INTERPRETATION Measles infection
may prevent the development of atopy in African children.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8667923

“Measles infection may prevent the development of atopy [allergies] in African
children.”

Lancet • June 1997

Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a
Th2 profile Author information Rook GA1, Zumla A. Department of Bacteriology
University College London Medical School, UK Abstract The symptoms of Gulf War
syndrome are compatible with the hypothesis that the immune system of affected
individuals is biased towards a Th2cytokine pattern. Factors that could lead to
a Th2 shift among Gulf War veterans include exposure to multiple Th2-inducing
vaccinations under stressful circumstances and the way in which such
vaccinations were administered, which would be expected to maximise Th2
immunogenicity. These factors may have led to a long-term systemic shift
towards a Th2cytokine balance and to mood changes related to the
immunoendocrine state. Other vaccines that lead to similar long-term,
non-specific shifts in cytokine balance are well-established. If our hypothesis
is proven, treatment may be possible with regimens that induce a systemic Th1
bias. http://www.ncbi.nlm.nih.gov/pubmed/9269228

“The symptoms of Gulf War syndrome are compatible with the hypothesis that the
immune system of affected individuals is biased towards a Th2-cytokine pattern.
Factors that could lead to a Th2 shift among Gulf War veterans include exposure
to multiple Th2-inducing vaccinations under stressful circumstances and the way
in which such vaccinations were administered, which would be expected to
maximise Th2 immunogenicity.”

“Although the use of adjuvants in veterinary vaccines enhances the immunogenicity of vaccines,
they have been responsible for a number of side effects.” Seminars In
Veterinary Medicine And Surgery (Small Animal) • August 1997

Vaccine adjuvants Author information Macy DW. Department of Clinical Sciences
Colorado State University College of Veterinary Medicine and Biomedical
Sciences Fort Collins 80523, USA Abstract Vaccine adjuvants provide enhanced
immune responses to a variety of antigens. Unlike human vaccines that are
limited to aluminum-based adjuvants, veterinary vaccines may contain a large
number of substances either alone or in combination that act as vaccine
adjuvants. Although the use of adjuvants in veterinary vaccines enhances the
immunogenicity of vaccines, they have been responsible for a number of side
effects. This article explores the rationale of currently used vaccine
adjuvants and some of the adverse events associated with their use in
veterinary medicine. http://www.ncbi.nlm.nih.gov/pubmed/?term=9283246

Journal Of Paediatric Child Health • October 1997

Incidence of apnoea and bradycardia in preterm infants following DTPw and Hib
immunization: a prospective study Author information Botham SJ1, Isaacs D,
Henderson-Smart DJ. Abstract OBJECTIVE To evaluate the incidence and severity
of apnoea and bradycardia in hospitalized preterm infants following
immunization at 2 months of age, and identify risk factors. METHODOLOGY A
prospective study of 98 preterm infants, of gestational age 24-31 weeks,
immunized at approximately 2 months post natal age with
diphtheria-tetanus-whole cell pertussis vaccine (DTPw) in the neonatal
intensive care unit (NICU) at King George V Hospital Sydney. Half the infants
also received Haemophilus influenzae type b conjugate vaccine (Hib)
simultaneously. All infants were monitored for apnoea and bradycardia in the 24
h periods pre- and post immunization. RESULTS Only one infant had apnoea and/or
bradycardia pre-immunization compared with 17 post immunization. For 12 infants
these events were brief, self-limiting and not associated with desaturations
(oxygen saturation < 90%). However, for five infants (30%) these events were
associated with oxygen desaturation and two of these infants required
supplemental oxygen. The group that had apnoea and/or bradycardia and the group
that did not were not significantly different in terms of gestational age,
birth weight and other variables. Infants who received Hib together with DTPw
were less likely to have apnoea and/or bradycardia than those given DTPw alone.
CONCLUSION When considering immunization for preterm infants, the benefits of
early immunization must be balanced against the risk of apnoea and bradycardia.
We recommend that the cardio-respiratory function of hospitalized infants born
at less than 31 weeks gestation be monitored for 48 h post immunization.
http://www.ncbi.nlm.nih.gov/pubmed/?term=9401886

“Only one infant had apnoea and/or bradycardia pre-immunization compared with
17 post immunization. For 12 infants these events were brief, self-limiting and
not associated with desaturations (oxygen saturation < 90%). However, for five
infants (30%) these events were associated with oxygen desaturation and two of
these infants required supplemental oxygen.”

Epidemiology • November 1997

Is infant immunization a risk factor for childhood asthma or allergy? Author
information Kemp T1, Pearce N, Fitzharris P, Crane J, Fergusson D, St George I,
Wickens K, Beasley R. Department of Medicine Wellington School of Medicine New
Zealand Abstract The Christchurch Health and Development Study comprises 1,265
children born in 1977. The 23 children who received no
diphtheria/pertussis/tetanus (DPT) and polio immunizations had no recorded
asthma episodes or consultations for asthma or other allergic illness before
age 10 years; in the immunized children, 23.1% had asthma episodes, 22.5%
asthma consultations, and 30.0% consultations for other allergic illness.
Similar differences were observed at ages 5 and 16 years. These findings do not
appear to be due to differential use of health services (although this
possibility cannot be excluded) or con-founding by ethnicity, socioeconomic
status, parental atopy, or parental smoking.
http://www.ncbi.nlm.nih.gov/pubmed/?term=9345669

“The 23 children who received no diphtheria/pertussis/tetanus (DPT) and polio
immunizations had no recorded asthma episodes or consultations for asthma or
other allergic illness before age 10 years; in the immunized children, 23.1%
had asthma episodes, 22.5% asthma consultations, and 30.0% consultations for
other allergic illness.”

American Journal Of Human Genetics • 1998
Ecogenetics ’98

Variability in Immune Response to Pathogens: Using Measles Vaccine to Probe
Immunogenetic Determinants of Response Gregory A. Poland Mayo Vaccine Research
Group Clinical Pharmacology Unit Mayo Clinic and Foundation Rochester, MN
Abstract “The measles had not prevailed on the Faroes since 1781; they broke
out early in April, 1846. Of the 7,782 inhabitants, about 6,000 were taken with
measles ) 225 persons in all died. Of the many old people still living on the
Faroes who had had the measles in 1781, not one was attacked the second time.”
Quote from P. L. Panum in the report titled “Observations Made during the
Epidemic of Measles on the Faroe Islands in the Year 1846” The Faroe Islands
measles outbreak described above is of interest to geneticists in several
regards: Why did some people survive and some die? Why was the case fatality
rate so high? Why was the protective effect of prior exposure so high?
Understanding the genetic influences on the phenotypes of protective and
nonprotective an- tibody responses provides a unique window to under- stand the
variability in host response to pathogens. Vaccine Response as a Marker of
Disease Susceptibility Postimmunization antibody response can be used as a
marker of disease susceptibility. For example, the level of antibody response
after hepatitis B immunization predicts susceptibility to disease on exposure
(Ellis 1993). In studies of measles, postimmunization measles antibody in the
“low positive” range did not protect against clinical measles when subjects
were exposed to the wild measles virus, whereas high levels were protective
(Chen et al. 1990). Furthermore, nonresponders to a single dose of measles
vaccine who demonstrated an antibody response only after a second immunization
were still six times more likely than were responders to a single dose of
measles vaccine to develop measles on exposure to wild virus (Mathias et al.
1989). Others examined “poor responders,” who were reimmunized and developed
poor or low-level antibody responses only to lose detectable antibody and
develop measles on exposure 2–5 years later. They concluded that there is a
strong correlation between low antibody levels after a single dose of vaccine
and high susceptibility to infection with exposure (Deseda-Tous et al. 1978).
Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1376909/pdf/9463343.pdf

Vaccine Non-Responders And Low Responders

“... nonresponders to a single dose of measles vaccine who demonstrated an
antibody response only after a second immunization were still six times more
likely than were responders to a single dose of measles vaccine to develop
measles on exposure to wild virus (Mathias et al. 1989). Others examined “poor
responders,” who were reimmunized and developed poor or low-level antibody
responses only to lose detectable antibody and develop measles on exposure 2–5
years later. They concluded that there is a strong correlation between low
antibody levels after a single dose of vaccine and high susceptibility to
infection with exposure.” (Deseda-Tous et al. 1978)

Pediatrics Volume 101 • Issue 3 • March 1998

Acute Encephalopathy Followed by Permanent Brain Injury or Death Associated
With Further Attenuated Measles Vaccines: A Review of Claims Submitted to the
National Vaccine Injury Compensation Program by Robert E. Weibel, Vito Caserta,
David E. Benor, Geoffrey Evans Abstract Objective To determine if there is
evidence for a causal relationship between acute encephalopathy followed by
permanent brain injury or death associated with the administration of further
attenuated measles vaccines (Attenuvax or Lirugen, Hoechst Marion Roussel,
Kansas City, MO), mumps vaccine (Mumpsvax, Merck and Co, Inc, West Point, PA),
or rubella vaccines (Meruvax or Meruvax II, Merck and Co, Inc, West Point, PA),
combined measles and rubella vaccine (M-R-Vax or M-R-Vax II, Merck and Co, Inc,
West Point, PA), or combined measles, mumps, and rubella vaccine (M-M-R or
M-M-R II, Merck and Co, Inc, West Point, PA), the lead author reviewed claims
submitted to the National Vaccine Injury Compensation Program. Methods The
medical records of children who met the inclusion criteria of receiving the
first dose of these vaccines between 1970 and 1993 and who developed such an
encephalopathy with no determined cause within 15 days were identified and
analyzed. Results A total of 48 children, ages 10 to 49 months, met the
inclusion criteria after receiving measles vaccine, alone or in combination.
Eight children died, and the remainder had mental regression and retardation,
chronic seizures, motor and sensory deficits, and movement disorders. The onset
of neurologic signs or symptoms occurred with a nonrandom, statistically
significant distribution of cases on days 8 and 9. No cases were identified
after the administration of monovalent mumps or rubella vaccine. Conclusions
This clustering suggests that a causal relationship between measles vaccine and
encephalopathy may exist as a rare complication of measles immunization.
http://www.ncbi.nlm.nih.gov/pubmed/9481001

“A total of 48 children, ages 10 to 49 months, met the inclusion criteria after
receiving measles vaccine, alone or in combination. Eight children died, and
the remainder had mental regression and retardation, chronic seizures, motor
and sensory deficits, and movement disorders. This clustering suggests that a
causal relationship between measles vaccine and encephalopathy may exist as a
rare complication of measles immunization.”

Biomedical And Environmental Science • March 1998

Detection of cytogenetic effects in peripheral lymphocytes of students exposed
to formaldehyde with cytokinesis-blocked micronucleus assay Author information
He JL1, Jin LF, Jin HY. School of Public Health Zhejiang Medical University
Hangzhou, China Abstract Cytokinesis-blocked micronucleus assay was applied as
a biological dosimeter to detect abnormalities in human peripheral lymphocytes
of thirteen students exposed to formaldehyde (FA) during a 12-week (10 h per
week) anatomy class. Breathing-zone air samples collected during dissection
procedures showed a mean concentration of 2.37 ppm (3.17 mg/m3). Ten students
from the same school but without FA exposure served as controls. Chromosome
aberrations (CA) and sister chromatid exchanges (SCE) were detected in both
groups. The micronuclei (MN) rate (6.38 +/- 2.50 /1000) and CA rate (5.92 +/-
2.40%) in the FA-exposed group showed a significant increase (P < 0.01) when
compared with those of the controls (3.15 +/- 1.46 /1000 and 3.40 +/1.57%
respectively). A correlation between MN and CA in individuals was observed. SCE
in the exposed group were also increased (P < 0.05), but not so greatly as MN
or CA. The results indicated that FA might damage the chromosomes of human
lymphocytes. http://www.ncbi.nlm.nih.gov/pubmed/?term=9559107

“The results indicated that FA might damage the chromosomes of human
lymphocytes.”

“The reader will notice an emerging clear picture that the majority (if not all) of these advances
have been achieved from studies funded by independent or charity organizations
rather than by the responsible authorities who are supposed and are duty bound
to take on this task.” Adverse Drug Reactions And Toxicological Reviews • March
1998

Gulf War syndrome— a model for the complexity of biological and environmental
interaction with human health Author information Jamal GA. University
Department of Neurology Southern General Hospital NHS Trust, Glasgow Abstract
Since the end of the Gulf War, tens of thousands of American, Canadian and
British soldiers who participated in that war have claimed to be suffering from
a variety of incapacitating symptoms which are generally termed as Gulf War
Syndrome (GWS). The symptoms are multiple but mainly consist of excessive
tiredness, muscle and joint pain, loss of balance, sensory symptoms,
neurobehavioural manifestations, diarrhoea, bladder dysfunction, sweating
disturbances, and respiratory, gastrointestinal, musculoskeletal and skin
manifestations. These veterans have been exposed to a variety of damaging or
potentially damaging risk factors including environmental adversities,
pesticides such as organophosphate chemicals, skin insect repellents, medical
agents such as pyridostigmine bromide (NAPS), possible low-levels of chemical
warfare agents, multiple vaccinations in combinations, depleted uranium, and
other factors. A large number of basic research findings, clinical
epidemiological studies, and case control studies are reviewed to try and link
them together to produce a coherent picture and to demonstrate the complexity
of the interaction of biological systems, environmental and genetic factors,
combinations of drugs and toxins with human health. The findings of these
studies so far have demonstrated that many of the previous assumptions made
about the ‘safety’ of certain drugs and toxic substances or vaccines must be
radically reviewed. Many of the findings have far reaching implications not
only in terms of explanation of what might have gone wrong during the Gulf War,
but also have wider implications for many occupational groups who are exposed
daily to some of these risk factors. More open-mindedness and much less
prejudice are required concerning the basic biology of interactions of the
above factors and their effects on cell functions and wider intelligent
research is urgently required with high priority. This review highlights the
importance of intelligent research for answers for a new phenomenon, and
demonstrates the necessity for a combination of this approach with high quality
epidemiological research. The reader will notice an emerging clear picture that
the majority (if not all) of these advances have been achieved from studies
funded by independent or charity organizations rather than by the responsible
authorities who are supposed and are duty bound to take on this task.
http://www.ncbi.nlm.nih.gov/pubmed/9638279

Proceedings Of The National Academy Of Science USA • May 1998

Identification of rat susceptibility loci for adjuvant-oil-induced arthritis
Author information Lorentzen JC1, Glaser A, Jacobsson L, Galli J, Fakhrai-rad
H, Klareskog L, Luthman H. Department of Medicine, Rheumatology Unit CMM L8:04,
Karolinska Hospital, S-171 76 Stockholm, Sweden johnny.lorentzen@cmm.ki.se
Abstract One intradermal injection of incomplete Freund’s adjuvant-oil induces
a T cell-mediated inflammatory joint disease in DA rats. Susceptibility genes
for oil-induced arthritis (OIA) are located both within and outside the major
histocompatibility complex (MHC, Oia1). We have searched for disease-linked
non-MHC loci in an F2 intercross between DA rats and MHC-identical but
arthritis-resistant LEW.1AV1 rats. A genome-wide scan with microsatellite
markers revealed two major chromosome regions that control disease incidence
and severity: Oia2 on chromosome 4 (P = 4 x 10(-13)) and Oia3 on chromosome 10
(P = 1 x 10(-6)). All animals homozygous for DA alleles at both loci developed
severe arthritis, whereas all those homozygous for LEW.1AV1 alleles were
resistant. These results have general implications for situations where
nonspecific activation of the immune system (e.g., incomplete Freund’s
adjuvant-oil) causes inflammation and disease, either alone or in conjunction
with specific antigens. They may also provide clues to the etiology of
inflammatory diseases in humans, including rheumatoid arthritis. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27729/

“These results have general implications for situations where nonspecific
activation of the immune system (e.g., incomplete Freund’s adjuvant-oil) causes
inflammation and disease, either alone or in conjunction with specific
antigens. They may also provide clues to the etiology of inflammatory diseases
in humans, including rheumatoid arthritis.”

Acta Virologica • June 1998

Neurologic complications associated with oral poliovirus vaccine and genomic
variability of the vaccine strains after multiplication in humans Author
information Friedrich F. Departamento de Virologia Instituto Oswaldo
Cruz/FIOCRUZ Rio de Janeiro, RJ, Brazil Abstract The oral poliovirus vaccine
(OPV) has been effectively used in the reduction and control of poliomyelitis
cases on the planet. Despite several advantages of using the attenuated OPV
strains, the rare occurrence of vaccine-associated paralytic poliomyelitis
(VAPP) cases in vaccine recipients and their susceptible contacts is a
disadvantage. Molecular biology studies of polioviruses isolated from stool and
central nervous system (CNS) of patients with VAPP have confirmed the vaccine
origin of the isolates and demonstrated genomic modifications known or
suspected to increase the neurovirulence. Similar genomic modifications have
also been identified in OPV-derived strains isolated from healthy vaccinees and
healthy contacts, suggesting that host factors are also involved in the
establishment of poliomyelitis. Other neurologic complications such as
meningitis, encephalitis, convulsions, transverse myelitis and Guillain-Barré
syndrome have also been rarely associated with the use of this vaccine. The
characterization of polioviruses isolated from such cases has demonstrated
their OPV origin. http://www.ncbi.nlm.nih.gov/pubmed/9842449

“Molecular biology studies of polioviruses isolated from stool and central
nervous system (CNS) of patients with VAPP have confirmed the vaccine origin of
the isolates and demonstrated genomic modifications known or suspected to
increase the neurovirulence. Similar genomic modifications have also been
identified in OPV-derived strains isolated from healthy vaccinees and healthy
contacts, suggesting that host factors are also involved in the establishment
of poliomyelitis. Other neurologic complications such as meningitis,
encephalitis, convulsions, transverse myelitis and Guillain-Barré syndrome have
also been rarely associated with the use of this vaccine.”

Lancet • August 1998

Macrophagic myofasciitis: an emerging entity Groupe d’Etudes et Recherche sur
les Maladies Musculaires Acquises et Dysimmunitaires (GERMMAD) de l’Association
Française contre les Myopathies (AFM) Author information Gherardi RK1, Coquet
M, Chérin P, Authier FJ, Laforêt P, Bélec L, Figarella-Branger D, Mussini JM,
Pellissier JF, Fardeau M. Université Paris XII-Val de Marne Département de
Pathologie, Hôpital Henri Mondor Créteil, France gherardi@univ-paris12.fr
Abstract BACKGROUND An unusual inflammatory myopathy characterised by an
infiltration of non-epithelioid histiocytic cells has been recorded with
increasing frequency in the past 5 years in France. We reassessed some of these
cases. METHODS We did a retrospective analysis of 18 such cases seen in five
myopathology centres between May, 1993, and December, 1997. The myopathological
changes were reassessed at a clinopathology seminar. FINDINGS Detailed clinical
information was available for 14 patients. The main presumptive diagnoses were
polymyositis and polymyalgia rheumatica. Symptoms included myalgias in 12
patients, arthralgias in nine, muscle weakness in six, pronounced asthenia in
five, and fever in four. Abnormal laboratory findings were occasionally
observed, and included raised creatine kinase concentrations, increased
erythrocyte sedimentation rate, and myopathic electromyography. Muscle biopsy
showed infiltration of the subcutaneous tissue, epimysium, perimysium, and
perifascicular endomysium by sheets of large macrophages, with a finely
granular PAS-positive content. Also present were occasional CD8 T cells, and
inconspicuous muscle-fibre damage. Epithelioid and giant cells, necrosis, and
mitotic figures were not seen. The images were easily distinguishable from
sarcoid myopathy and fasciitis-panniculitis syndromes. Whipple’s disease,
Mycobacterium avium intracellulare infection, and malakoplakia could not be
confirmed. Ten patients were treated with various combinations of steroids and
antibiotics; symptoms improved in eight patients, and stabilised in two.
INTERPRETATION A new inflammatory muscle disorder of unknown cause,
characterized by a distinctive pathological pattern of macrophagic
myofasciitis, is emerging in France.
http://www.ncbi.nlm.nih.gov/pubmed/?term=9717921

“A new inflammatory muscle disorder of unknown cause, characterised by a
distinctive pathological pattern of macrophagic myofasciitis, is emerging in
France.”

Clinical Immunology And Immunopathology • October 1998

Serological association of measles virus and human herpesvirus-6 with brain
autoantibodies in autism Author information Singh VK1, Lin SX, Yang VC. College
of Pharmacy University of Michigan Ann Arbor, Michigan, 48109-1065, USA
Abstract Considering an autoimmunity and autism connection, brain
autoantibodies to myelin basic protein (anti-MBP) and neuron-axon filament
protein (anti-NAFP) have been found in autistic children. In this current
study, we examined associations between virus serology and autoantibody by
simultaneous analysis of measles virus antibody (measles-IgG), human
herpesvirus-6 antibody (HHV-6-IgG), anti-MBP, and anti-NAFP. We found that
measlesIgG and HHV-6-IgG titers were moderately higher in autistic children but
they did not significantly differ from normal controls. Moreover, we found that
a vast majority of virus serology-positive autistic sera was also positive for
brain autoantibody: (i) 90% of measles-IgG-positive autistic sera was also
positive for anti-MBP; (ii) 73% of measles-IgG-positive autistic sera was also
positive for anti-NAFP; (iii) 84% of HHV-6-IgG-positive autistic sera was also
positive for anti-MBP; and (iv) 72% of HHV-6-IgG-positive autistic sera was
also positive for anti-NAFP. This study is the first to report an association
between virus serology and brain autoantibody in autism; it supports the
hypothesis that a virus-induced autoimmune response may play a causal role in
autism. http://www.ncbi.nlm.nih.gov/pubmed/9756729

“This study is the first to report an association between virus serology and
brain autoantibody in autism; it supports the hypothesis that a virus-induced
autoimmune response may play a causal role in autism.”

Pediatrics • November 1998

Report of a US public health service workshop on hypotonic-hyporesponsive
episode (HHE) after pertussis immunization Author information Braun MM1,
Terracciano G, Salive ME, Blumberg DA, Vermeer-de Bondt PE, Heijbel H, Evans G,
Patriarca PA, Ellenberg SS. Center for Biologics Evaluation and Research, Food
and Drug Administration Rockville, MD 20852, USA Abstract
Hypotonic-hyporesponsive episode (HHE) is a term used to describe a somewhat
heterogenous group of clinical disorders that have been reported primarily in
association with whole-cell pertussis vaccination. A 1991 review by the
Institute of Medicine determined that the evidence available was indeed
consistent with a causal relation between whole-cell
pertussis-diphtheria-tetanus immunization and HHE, but that the evidence was
insufficient to indicate a causal relationship between HHE and the subsequent
development of permanent neurologic damage. More recent data from clinical
trials conducted in Europe suggest that HHE also occurs after vaccination with
acellular pertussis vaccines. The US Food and Drug Administration, in
collaboration with the US Public Health Service, sponsored a workshop on HHE in
Rockville, Maryland, on June 19, 1997. The primary goals of the workshop were
to develop a case definition of HHE and to evaluate the general design and
feasibility of possible studies of HHE using the federal Vaccine Adverse Event
Reporting System (VAERS), a national passive surveillance system. The goals of
such studies would be to understand better the acute HHE event and to evaluate
the possibility of long-term sequelae. Case Definition. There has been no
generally accepted definition of HHE, and a standard definition would be useful
for vaccine safety work and would potentially facilitate interstudy comparisons
of the growing number of licensed vaccines containing acellular pertussis
components. The workshop defined HHE as an event of sudden onset occurring
within 48 hours of immunization, with duration of the episode ranging from 1
minute to 48 hours, in children younger than 10 years of age. All of the
following must be present: 1) limpness or hypotonia, 2) reduced responsiveness
or hyporesponsiveness, and 3) pallor or cyanosis or failure to observe or to
recall skin coloration. HHE is not considered to have occurred if there is a
known cause for

these signs (eg, postictal), if urticaria is present during the event, if
normal skin coloration is observed throughout the episode, or if the child is
simply sleeping. This inclusive (sensitive) case definition will allow
investigators, through the technique of stratification according to certain
characteristics (eg, time from vaccination to onset of HHE), to attempt to hone
the definition and make it more specific. Refinement of the definition of HHE
has been hindered by the lack of information on its pathophysiology and by the
lack of pathognomonic signs, symptoms, and diagnostic tests. Another hindrance
is that by the time the child presents for medical evaluation, the signs of HHE
often have normalized. Moreover, different mechanisms may be involved in
different individuals whose events meet this workshop’s HHE definition.
Probably the most important question about HHE is whether it has any permanent
sequelae. The workshop assessed the possible contribution VAERS-based studies
could make to answering this question and found substantial methodologic
problems; however, ongoing studies in Sweden and The Netherlands have the
potential to provide useful information on this question. The most useful
contribution of VAERS data would be in a descriptive study of HHE, with a
possible case-control study of factors that may affect the risk of HHE after
vaccination, rather than a study of possible permanent sequelae. The workshop
participants felt that a detailed descriptive study of approximately 100 HHE
events reported during a 1- to 2-year period could provide a more in-depth
description of HHE cases in greater numbers than has been published previously,
but the study would not address the issue of long-term sequelae of HHE. Better
descriptive data may lead to new hypotheses concerning risk factors, etiology,
and pathophysiology of HHE that might be evaluated further by studying
subsequent cases and controls from VAERS or from other sources.

http://www.ncbi.nlm.nih.gov/pubmed/9794982

Journal Of Dental Research • November 1998

Toxicity of formaldehyde to human oral fibroblasts and epithelial cells:
influences of culture conditions and role of thiol status Author information
Nilsson JA1, Zheng X, Sundqvist K, Liu Y, Atzori L, Elfwing A, Arvidson K,
Grafström RC. Division of Experimental Carcinogenesis Institute of
Environmental Medicine Karolinska Institutet, Stockholm, Sweden Abstract The
toxicity of formaldehyde, a monomer released from certain polymeric dental
materials, was studied in cultured human oral fibroblasts and epithelial cells.
The influences of growth conditions were evaluated for both cell types, as well
as the role of the internal and external thiol states. A one-hour exposure to
formaldehyde decreased the colonyforming efficiency (CFE) of both cell types in
a concentration-dependent manner, although the toxicity varied up to 100-fold
with the conditions. Clearly, the presence of serum and the thiol cysteine
counteracted the toxicity in fibroblasts. Similarly, pituitary extract and
cysteine, or a mixture of amino acids and ethanolamines, counteracted the
formaldehyde toxicity in serum-free cultures of epithelial cells. In contrast,
a growthpromoting surface matrix of fibronectin and collagen did not influence
the formaldehyde toxicity, as shown by both the CFE assay and a dye reduction
assay. Further, a shortterm change to the various growth media per se with or
without the supplements serum or cysteine did not significantly alter the CFE.
Analysis of the thiol state demonstrated significant differences between
epithelial cells and fibroblasts, i.e., comparatively lower cellular levels of
the free low-molecular-weight thiols glutathione and cysteine in fibroblasts.
This result correlated to significantly higher formaldehyde toxicity in the
fibroblasts than in the epithelial cells. Taken together, the results indicated
the cytoprotective function of both intracellular and extracellular thiols
toward formaldehyde, as well as the usefulness of thiol-free and chemically
defined conditions for toxicity assessments in oral epithelial cells and
fibroblasts. We conclude that the combined use of a controlled external milieu
and the presumed target cell type may be advantageous in evaluations of oral
toxicity mechanisms or the toxic potency of dental materials, particularly
those which, like formaldehyde, may react with thiols or amines.
http://www.ncbi.nlm.nih.gov/pubmed/?term=9823728

“A one-hour exposure to formaldehyde decreased the colony-forming efficiency of
both cell types in a concentration-dependent manner, although the toxicity
varied up to 100-fold with the conditions.”

Scandinavian Journal Of Immunology • January 1999

Identification of arthritogenic adjuvants of self and foreign origin Author
information Lorentzen JC. Department of Medicine, Karolinska Hospital
Karolinska Institute, Stockholm, Sweden Abstract The lack of defined triggers
for human inflammatory joint diseases warrants efforts to identify candidate
molecules. For this task, it may be an important lead that nonspecific
activation of the immune system can precipitate arthritis in rats.
Consequently, arthritis-prone rat strains were used to search for
disease-triggering factors among molecules which initially induce innate
defence reactions rather than specific immune responses. A variety of
immunological adjuvants were investigated by intradermal injection into DA and
LEW.1AV1 rats and monitoring of clinical signs for 30 days. Several
arthritogenic cell-wall structures from yeast and bacteria were identified,
such as beta-glucan, lipopolysaccharide and trehalosedimycolate. The test
procedures also revealed arthritogens of chemical origin, such as
dioctadecyldiammoniumbromide (DDA = C38H80NBr) and heptadecane (C17H36).
Furthermore, it allowed the precise definition of arthritogenic determinants of
lipids, since C16H34 induced arthritis, whereas the closely related linear
hydrocarbons C16H32, C16H33Br and C15H32 did not. The observed pathogenicity of
organic lipids raised the question of whether endogenous lipids can also
precipitate arthritis. Indeed, this was true for the cholesterol precursor
squalene (C30H50). In conclusion, this article describes the rational use of
arthritis-prone rat strains to identify arthritogenic factors of both foreign
and self origin. Although structurally unrelated, the pathogenic molecules
defined here share the feature of being nonspecific triggers of the immune
system. This consolidates a general principle for the induction of adjuvant
arthritis which may provide clues to the aetiology of human arthritides,
including rheumatoid arthritis.
http://www.ncbi.nlm.nih.gov/pubmed/?term=10023856

“The observed pathogenicity of organic lipids raised the question of whether
endogenous lipids can also precipitate arthritis. Indeed, this was true for the
cholesterol precursor squalene ...”

Archives Of Toxicology • February 1999

Effects of 2-phenoxyethanol on N-methyl-D-aspartate (NMDA) receptor-mediated
ion currents Author information Musshoff U1, Madeja M, Binding N, Witting U,
Speckmann EJ. Institut für Physiologie Universität Münster, Germany
mushoff@uni-muenster.de Abstract The actions were examined of 17 frequently
used glycol ether compounds on the glutamate receptor-mediated ion currents.
The receptors were expressed in Xenopus oocytes by injection of rat brain mRNA.
Most of the 17 glycol ethers exerted no effects on the glutamate subreceptors
activated by kainate and N-methyl-D-aspartate (NMDA), whereas 2-phenoxyethanol
(ethylene glycol monophenyl ether) caused a considerable reduction of
NMDA-induced membrane currents in a reversible and concentration-dependent
manner. The threshold concentration of the ethylene glycol monophenyl ether
effect was < 10 mumol/l. The concentration for a 50% inhibition (IC50) was
approximately 360 mumol/l. The results indicate a neurotoxic potential for
2-phenoxyethanol. http://www.ncbi.nlm.nih.gov/pubmed/?term=10207615

“The results indicate a neurotoxic potential for 2-phenoxyethanol.”
[2-phenoxyethanol is a vaccine ingredient]

Epidemiology • May 1999

Hepatitis B vaccine and liver problems in U.S. children less than 6 years old
1993 and 1994 Author information Fisher MA1, Eklund SA. Department of
Epidemiology University of Michigan Ann Arbor 48109, USA Abstract Data to
assess the benefits and risks of hepatitis B vaccine for the general population
of U.S. children are sparse. This study addressed the problem of external
validity found in previous studies of high risk populations by evaluating the
benefit of hepatitis B vaccination for the general population of American
children. We calculated the risk of liver problems among hepatitis B vaccinated
and non-hepatitis B vaccinated children using logistic regression. Hepatitis B
vaccinated children had an unadjusted odds ratio of 2.94 and age-adjusted odds
ratio of 2.35 for liver problems compared with non-hepatitis B vaccinated
children in the 1993 National Health Interview Survey. Hepatitis B vaccinated
children had an unadjusted odds ratio of 2.57 and age-adjusted odds ratio of
1.53 for liver problems compared with non-hepatitis B vaccinated children in
the 1994 National Health Interview Survey dataset.
http://www.ncbi.nlm.nih.gov/pubmed/10230847

“Hepatitis B vaccinated children had an unadjusted odds ratio of 2.94 and
age-adjusted odds ratio of 2.35 for liver problems compared with non-hepatitis
B vaccinated children in the 1993 National Health Interview Survey.”

Vaccine • July 1999

An overview of the vaccine adverse event reporting system (VAERS) as a
surveillance system VAERS Working Group Author information Singleton JA1, Lloyd
JC, Mootrey GT, Salive ME, Chen RT. Vaccine Safety and Development Activity
National Immunization Program Centers for Disease Control and Prevention
Atlanta, GA 30333, USA Abstract We evaluated the Vaccine Adverse Event
Reporting System (VAERS), the spontaneous reporting system for
vaccine-associated adverse events in the United States, as a public health
surveillance system, using evaluation guidelines from the Centers for Disease
Control and Prevention. We found that VAERS is simple for reporters to use,
flexible by design and its data are available in a timely fashion. The
predictive value positive for one severe event is known to be high, but for
most events is unknown. The acceptability, sensitivity and representativeness
of VAERS are unknown. The study of vaccine safety is complicated by
underreporting, erroneous reporting, frequent multiple exposures and multiple
outcomes. http://www.ncbi.nlm.nih.gov/pubmed/?term=10438063

“The acceptability, sensitivity and representativeness of VAERS are unknown.
The study of vaccine safety is complicated by underreporting, erroneous
reporting, frequent multiple exposures and multiple outcomes.”

“... A non specific permeabilization of the Blood Brain Barrier ...”
Pharmaceutical Research • December 1999

Indirect evidence that drug brain targeting using polysorbate 80-coated
polybutylcyanoacrylate nanoparticles is related to toxicity Author information
Olivier JC1, Fenart L, Chauvet R, Pariat C, Cecchelli R, Couet W. Laboratoire
de Pharmacie Galénique et Biopharmacie UPRES EA 1223 34, Poitiers, France
jc.olivier@campus.univ-poitiers.fr Abstract PURPOSE To investigate the
mechanism underlying the entry of the analgesic peptide dalargin into brain
using biodegradable polybutylcyanoacrylate (PBCA) nanoparticles (NP) overcoated
with polysorbate 80. METHODS The investigations were carried out with PBCA NP
and with non biodegradable polystyrene (PS) NP (200 nm diameter). Dalargin
adsorption was assessed by HPLC. Its entry into the CNS in mice was evaluated
using the tail-flick procedure. Locomotor activity measurements were performed
to compare NP toxicities. BBB permeabilization by PBCA NP was studied in vitro
using a coculture of bovine brain capillary endothelial cells and rat
astrocytes. RESULTS Dalargin loading was 11.7 microg/mg on PBCA NP and 16.5
microg/ mg on PS NP. Adding polysorbate 80 to NP led to a complete desorption.
Nevertheless, dalargin associated with PBCA NP and polysorbate 80 induced a
potent and prolonged analgesia, which could not be obtained using PS NP in
place of PBCA NP. Locomotor activity dramatically decreased in mice dosed with
PBCA NP, but not with PS NP. PBCA NP also caused occasional mortality. In
vitro, PBCA NP (10 microg/ml) induced a permeabilization of the BBB model.
CONCLUSIONS A non specific permeabilization of the BBB, probably related to the
toxicity of the carrier, may account for the CNS penetration of dalargin
associated with PBCA NP and polysorbate 80.
http://www.ncbi.nlm.nih.gov/pubmed/10644071

Acta Paediatrica • January 2000

Gait disturbance interpreted as cerebellar ataxia after MMR vaccination at 15
months of age: a follow-up study Author information Plesner AM1, Hansen FJ,
Taudorf K, Nielsen LH, Larsen CB, Pedersen E. Department of Epidemiology
Statens Serum Institute Copenhagen, Denmark Abstract Measles, mumps and rubella
(MMR) vaccination was included in the Danish childhood vaccination programme in
1987. During the following 10-y period, 550 notification records of adverse
events after MMR vaccination at 15 mo of age have been registered, and a total
of 41 notifications have included “gait disturbance”. This corresponds to a
frequency of 8 per 100,000 doses of MMR vaccine used for 15-mo-old children.
The symptoms and signs are characteristic of cerebellar ataxia. In 28
notifications, the descriptions by the doctors included only “gait
disturbance”, while in 13 an additional interpretation was included. Thirty-two
parents (78%) filled in a questionnaire and 26 (63%) agreed to participate in a
clinical follow-up study. The gait disturbance symptoms mainly occurred 7-14 d
after the vaccination, and the duration was median 1-2 wk (range 1 d to more
than 4 mo). One-third of the children had symptoms lasting more than 2 wk.
Significantly more children with long duration of symptoms had some kind of
complaint or clinical signs at the follow-up in 1997. Gait disturbance
registered after MMR vaccination seems to be more frequent than hitherto
reported. Most cases are mild and short-lasting and a longer duration of
symptoms seems to be predictive of late sequelae. A clinical diagnosis of
cerebellar ataxia after MMR and the exact frequency of this adverse event
remains to be tested in prospective studies.
http://www.ncbi.nlm.nih.gov/pubmed/10677059

“Gait disturbance registered after MMR vaccination seems to be more frequent
than hitherto reported. Most cases are mild and short-lasting and a longer
duration of symptoms seems to be predictive of late sequelae.”

Clinical And Experimental Rheumatology • January 2000

Immune-mediated pathology following hepatitis B vaccination. Two cases of
polyarteritis nodosa and one case of pityriasis rosea-like drug eruption Author
information De Keyser F1, Naeyaert JM, Hindryckx P, Elewaut D, Verplancke P,
Peene I, Praet M, Veys E. Department of Rheumatology University Hospital Gent,
Belgium Filip.Dekeyser@rug.ac.be Abstract The association of hepatitis B virus
infection and vasculitis or other immunemediated manifestations is well
documented. Reports on such manifestations in relation to hepatitis B
vaccination are scarce, however. We report 2 patients who developed
polyarteritis nodosa following vaccination against hepatitis B. In one patient
this resulted in an ischemic and necrotic digital ulcus, necessitating surgical
amputation. The other patient presented with typical cutaneous polyarteritis
nodosa which responded well to corticosteroid treatment. A third patient
developed a severe pityrias rosea-like eruption. He was treated with topical
steroids with healing of the lesions, leaving only post-inflammatory
hyperpigmentation. The literature on these associations is reviewed.
http://www.ncbi.nlm.nih.gov/pubmed/10728450

“We report 2 patients who developed polyarteritis nodosa following vaccination
against hepatitis B. In one patient this resulted in an ischemic and necrotic
digital ulcus, necessitating surgical amputation. The other patient presented
with typical cutaneous polyarteritis nodosa which responded well to
corticosteroid treatment. A third patient developed a severe pityrias
rosea-like eruption. He was treated with topical steroids with healing of the
lesions, leaving only post-inflammatory hyperpigmentation.”

Journal Of Autoimmunity • February 2000

Vaccination and autoimmunity’vaccinosis’: a dangerous liaison? Author
information Shoenfeld Y1, Aron-Maor A. Department of Internal Medicine B, Sheba
Medical Center, Tel Hashomer, Israel shoefel@post.tau.ac.il Abstract The
question of a connection between vaccination and autoimmune illness (or
phenomena) is surrounded by controversy. A heated debate is going on regarding
the causality between vaccines, such as measles and anti-hepatitis B virus
(HBV), and multiple sclerosis (MS). Brain antibodies as well as clinical
symptoms have been found in patients vaccinated against those diseases. Other
autoimmune illnesses have been associated with vaccinations. Tetanus toxoid,
influenza vaccines, polio vaccine, and others, have been related to phenomena
ranging from autoantibodies production to full-blown illness (such as
rheumatoid arthritis (RA)). Conflicting data exists regarding also the
connection between autism and vaccination with measles vaccine. So far only one
controlled study of an experimental animal model has been published, in which
the possible causal relation between vaccines and autoimmune findings has been
examined: in healthy puppies immunized with a variety of commonly given
vaccines, a variety of autoantibodies have been documented but no frank
autoimmune illness was recorded. The findings could also represent a polyclonal
activation (adjuvant reaction). The mechanism (or mechanisms) of autoimmune
reactions following immunization has not yet been elucidated. One of the
possibilities is molecular mimicry; when a structural similarity exists between
some viral antigen (or other component of the vaccine) and a self-antigen. This
similarity may be the trigger to the autoimmune reaction. Other possible
mechanisms are discussed. Even though the data regarding the relation between
vaccination and autoimmune disease is conflicting, it seems that some
autoimmune phenomena are clearly related to immunization (e.g. Guillain-Barre
syndrome). The issue of the risk of vaccination remains a philosophical one,
since to date the advantages of this policy have not been refuted, while the
risk for autoimmune disease has not been irrevocably proved. We discuss the
pros and cons of this issue (although the temporal relationship (i.e. always
2-3 months following immunization) is impressive).
http://www.ncbi.nlm.nih.gov/pubmed/10648110

“Even though the data regarding the relation between vaccination and autoimmune
disease is conflicting, it seems that some autoimmune phenomena are clearly
related to immunization (e.g. Guillain-Barre syndrome).”

Journal Of Manipulative And Physiological Therapeutics • February 2000

Effects of diphtheria-tetanus-pertussis or tetanus vaccination on allergies and
allergy-related respiratory symptoms among children and adolescents in the
United States Author information Hurwitz EL1, Morgenstern H. Abstract
BACKGROUND Findings from animal and human studies confirm that diphtheria and
tetanus toxoids and pertussis (DTP) and tetanus vaccinations induce allergic
responses; associations between childhood vaccinations and subsequent allergies
have been reported recently.

“DTP or tetanus vaccination

OBJECTIVE The association of DTP or tetanus vaccination with allergies and
allergy-related respiratory symptoms among children and adolescents in the
United States was assessed.

and related respiratory symptoms

METHODS Data were used from the Third National Health and Nutrition Examination
Survey on infants aged 2 months through adolescents aged 16 years. DTP or
tetanus vaccination, lifetime allergy history, and allergy symptoms in the past
12 months were based on parental or guardian recall. Logistic regression
modeling was performed to estimate the effects of DTP or tetanus vaccination on
each allergy. RESULTS The odds of having a history of asthma was twice as great
among vaccinated subjects than among unvaccinated subjects (adjusted odds
ratio, 2.00; 95% confidence interval, 0.59 to 6.74). The odds of having had any
allergy-related respiratory symptom in the past 12 months was 63% greater among
vaccinated subjects than unvaccinated subjects (adjusted odds ratio, 1.63; 95%
confidence interval, 1.05 to 2.54). The associations between vaccination and
subsequent allergies and symptoms were greatest among children aged 5 through
10 years. CONCLUSIONS DTP or tetanus vaccination appears to increase the risk
of allergies and related respiratory symptoms in children and adolescents.
Although it is unlikely that these results are entirely because of any sources
of bias, the small number of unvaccinated subjects and the study design limit
our ability to make firm causal inferences about the true magnitude of effect.
http://www.ncbi.nlm.nih.gov/pubmed/?term=10714532

appears to increase the risk of allergies

in children and adolescents.”

American Journal Of Epidemiology • March 2000

Outbreak of aseptic meningitis associated with mass vaccination with a
urabe-containing measles-mumps-rubella vaccine: implications for immunization
programs Author information Dourado I1, Cunha S, Teixeira MG, Farrington CP,
Melo A, Lucena R, Barreto ML. Instituto de Saúde Coletiva Universidade Federal
da Bahia Salvador, Brazil Abstract A mass immunization campaign with a
Urabe-containing measles-mumps-rubella vaccine was carried out in 1997 in the
city of Salvador, northeastern Brazil, with a target population of children
aged 1-11 years. There was an outbreak of aseptic meningitis following the mass
campaign. Cases of aseptic meningitis were ascertained through data collected
from the records of children admitted to the local referral hospital for
infectious diseases between March and October of 1997, using previously defined
eligibility criteria. Vaccination histories were obtained through home visits
or telephone calls. Eighty-seven cases fulfilled the study criteria. Of those,
58 cases were diagnosed after the vaccination campaign. An elevated risk of
aseptic meningitis was observed 3 weeks after Brazil’s national vaccination day
compared with the risk in the prevaccination period (relative risk = 14.3; 95%
confidence interval: 7.9, 25.7). This result was confirmed by a case series
analysis (relative risk = 30.4; 95% confidence interval: 11.5, 80.8). The
estimated risk of aseptic meningitis was 1 in 14,000 doses. This study confirms
a link between measles-mumps-rubella vaccination and aseptic meningitis. The
authors discuss the implications of this for the organization and planning of
mass immunization campaigns. http://www.ncbi.nlm.nih.gov/pubmed/10707922 Full
Report: http://aje.oxfordjournals.org/content/151/5/524.long

“An elevated risk of aseptic meningitis was observed 3 weeks after Brazil’s
national vaccination day compared with the risk in the prevaccination period
(relative risk = 14.3; 95% confidence interval: 7.9, 25.7). This result was
confirmed by a case series analysis (relative risk = 30.4; 95% confidence
interval: 11.5, 80.8). The estimated risk of aseptic meningitis was 1 in 14,000
doses. This study confirms a link between measles-mumps-rubella vaccination and
aseptic meningitis.”

The Israel Medical Association Journal • March 2000

Gender differences in the reactogenicity of measles-mumps-rubella vaccine
Author information Shohat T1, Green MS, Nakar O, Ballin A, Duvdevani P, Cohen
A, Shohat M. Israel Center for Disease Control Gertner Institute for Policy
Research Tel-Hashomer, Israel shohat@trendline.co.il Abstract BACKGROUND In
trials comparing different formulations of measles vaccine, excess non-specific
mortality occurred in female children who received high titer vaccine. These
findings suggest a genderspecific effect of measles vaccine. OBJECTIVES To
determine whether gender differences exist in the rates of adverse reactions
and morbidity in the month following immunization with measles-containing
vaccine, and to evaluate whether there is a gender-specific association between
the humoral immune response to measles vaccination and post-vaccination
morbidity. METHODS Parents completed questionnaires on the health status of 755
infants aged 15-20 months, during the month preceding and the month following
the measles-mumps-rubella vaccination. Blood samples were tested for measles
antibody titers in a subsample of 237 infants.

“Our findings demonstrate higher rates of adverse effects in females following
vaccination with MMR vaccine, irrespective of the humoral response. This study

RESULTS After controlling background morbidity in the infants, the relative
risk of fever and rash following vaccination was 2.35 in females and 1.36 in
males. The geometric mean antibody titers against measles were similar in both
sexes and there was no significant association between antibody titer and
post-vaccination morbidity in either sex.

emphasizes the need to consider

CONCLUSIONS Our findings demonstrate higher rates of adverse effects in females
following vaccination with MMR vaccine, irrespective of the humoral response.
This study emphasizes the need to consider possible gender differences when
evaluating new vaccines.

evaluating new vaccines.”

http://www.ncbi.nlm.nih.gov/pubmed/?term=10774264 Full Report:
http://www.ima.org.il/FilesUpload/IMAJ/0/61/30887.pdf

possible gender differences when

Digestive Diseases And Science • April 2000

Detection and sequencing of measles virus from peripheral mononuclear cells
from patients with inflammatory bowel disease and autism Author information
Kawashima H1, Mori T, Kashiwagi Y, Takekuma K, Hoshika A, Wakefield A.
Department of Paediatrics Tokyo Medical University, Japan Abstract It has been
reported that measles virus may be present in the intestine of patients with
Crohn’s disease. Additionally, a new syndrome has been reported in children
with autism who exhibited developmental regression and gastrointestinal
symptoms (autistic enterocolitis), in some cases soon after MMR vaccine. It is
not known whether the virus, if confirmed to be present in these patients,
derives from either wild strains or vaccine strains. In order to characterize
the strains that may be present, we have carried out the detection of measles
genomic RNA in peripheral mononuclear cells (PBMC) in eight patients with
Crohn’s disease, three patients with ulcerative colitis, and nine children with
autistic enterocolitis. As controls, we examined healthy children and patients
with SSPE, SLE, HIV-1 (a total of eight cases). RNA was purified from PBMC by
Ficoll-paque, followed by reverse transcription using AMV; cDNAs were subjected
to nested PCR for detection of specific regions of the hemagglutinin (H) and
fusion (F) gene regions. Positive samples were sequenced directly, in
nucleotides 8393-8676 (H region) or 5325-5465 (from noncoding F to coding F
region). One of eight patients with Crohn disease, one of three patients with
ulcerative colitis, and three of nine children with autism, were positive.
Controls were all negative. The sequences obtained from the patients with
Crohn’s disease shared the characteristics with wild-strain virus. The
sequences obtained from the patients with ulcerative colitis and children with
autism were consistent with being vaccine strains. The results were concordant
with the exposure history of the patients. Persistence of measles virus was
confirmed in PBMC in some patients with chronic intestinal inflammation.
http://www.ncbi.nlm.nih.gov/pubmed/10759242

“The sequences obtained from the patients with ulcerative colitis and children
with autism were consistent with being vaccine strains. The results were
concordant with the exposure history of the patients. Persistence of measles
virus was confirmed in PBMC in some patients with chronic intestinal
inflammation.”

BMJ • May 2000

Role of vaccinations as risk factors for ill health in veterans of the Gulf
war: cross sectional study Author information Hotopf M1, David A, Hull L,
Ismail K, Unwin C, Wessely S. Gulf War Research Unit King’s College and St
Thomas’s School of Medicine King’s College London, London SE5 8AZ
m.hotopf@iop.kcl.ac.uk Abstract OBJECTIVES To explore the relation between ill
health after the Gulf war and vaccines received before or during the conflict.
To test the hypothesis that such ill health is limited to military personnel
who received multiple vaccines during deployment and that pesticide use
modifies any effect. DESIGN Cross sectional study of Gulf war veterans followed
for six to eight years after deployment. SETTING UK armed forces. PARTICIPANTS
Military personnel who served in the Gulf and who still had their vaccine
records. MAIN OUTCOME MEASURES Multisymptom illness as classified by the
Centers for Disease Control and Prevention; fatigue; psychological distress;
post-traumatic stress reaction; health perception; and physical functioning.
RESULTS The response rate for the original survey was 70.4% (n=3284). Of these,
28% (923) had vaccine records. Receipt of multiple vaccines before deployment
was associated with only one of the six health outcomes (post-traumatic stress
reaction). By contrast five of the six outcomes (all but post-traumatic stress
reaction) were associated with multiple vaccines received during deployment.
The strongest association was for the multisymptom illness (odds ratio 5.0; 95%
confidence interval 2.5 to 9.8). CONCLUSION Among veterans of the Gulf war
there is a specific relation between multiple vaccinations given during
deployment and later ill health. Multiple vaccinations in themselves do not
seem to be harmful but combined with the “stress” of deployment they may be
associated with adverse health outcomes. These results imply that every effort
should be made to maintain routine vaccines during peacetime. Full Report:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27378/

“Among veterans of the Gulf war there is a specific relation between multiple
vaccinations given during deployment and later ill health.”

American Journal Of Pathology • June 2000

The Endogenous Adjuvant Squalene Can Induce a Chronic T-Cell-Mediated Arthritis
in Rats Barbro C. Carlson,* Åsa M. Jansson,* Anders Larsson,† Anders Bucht,‡*
and Johnny C. Lorentzen* From the Department of Medicine,* Unit of
Rheumatology, Karolinska Institutet, Stockholm the Department of Medical
Sciences,† University Hospital, Uppsala and the Department of Biomedicine,‡
Division of NBC Defense, Defense Research Establishment Umeå, Sweden Abstract
Squalene is a cholesterol precursor, which stimulates the immune system
nonspecifically. We demonstrate that one intradermal injection of this adjuvant
lipid can induce joint-specific inflammation in arthritis-prone DA rats.
Histopathological and immunohistochemical analyses revealed erosion of bone and
cartilage, and that development of polyarthritis coincided with infiltration of
∼∼+ T cells. Depletion of these cells with anti-∼∼ TcR monoclonal antibody
(R73) resulted in complete recovery, whereas antiCD8 and anti-∼∼ TcR injections
were ineffective. The apparent dependence on CD4+ T cells suggested a role for
genes within the major histocompatibility complex (MHC), and this was concluded
from comparative studies of MHC congenic rat strains, in which DA.1H rats were
less susceptible than DA rats. Furthermore, LEW.1AV1 and PVG.1AV1 rats with MHC
identical to DA rats were arthritis-resistant, demonstrating that non-MHC genes
also determine susceptibility. Some of these genetic influences could be linked
to previously described arthritis susceptibility loci in an F2 intercross
between DA and LEW.1AV1 rats (ie, Cia3, Oia2 and Cia5). Interestingly, some F2
hybrid rats developed chronic arthritis, a phenotype not apparent in the
parental inbred strains. Our demonstration that an autoadjuvant can trigger
chronic, immune-mediated joint-specific inflammation may give clues to the
pathogenesis of rheumatoid arthritis, and it raises new questions concerning
the role of endogenous molecules with adjuvant properties in chronic
inflammatory diseases. In conclusion, arthritis induced with the cholesterol
precursor squalene shares notable similarities with rheumatoid arthritis, and
raises interesting questions concerning the role of endogenous molecules with
adjuvant properties in chronic inflammatory diseases. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850095/

“arthritis induced with the cholesterol precursor squalene shares notable
similarities with rheumatoid arthritis, and raises interesting questions
concerning the role of endogenous molecules with adjuvant properties in chronic
inflammatory diseases.”

First International Conference on Metals & The Brain
September 20-23, 2000 From Neurochemistry to Neurodegeneration University of
Padova, Italy

Aluminum And Health Recommendations Aluminum is an environmentally abundant
element to which we are all exposed. The neurotoxicity of this metal has been
known for more than a century. More recently, it has been implicated as an
etiological factor in some pathologies (including encephalopathy, bone disease,
anemia) related to dialysis treatment . In addition, it has been hypothesized
to be a cofactor in the etiopathogenesis of some neurodegenerative diseases,
including Alzheimer’s disease (AD), although, despite many studies in several
laboratories in different countries, direct evidence is still, so far
controversial. Thus, examples of aluminum neurotoxicity are well recognized-in
experimental animals and in individuals with renal failure (consequent upon
aging, intoxication or renal disease) - and there are grounds to link
neurodegenerative disorders to aluminum exposure. Furthermore, an increased
concentration of Al in infant formulas and in solutions for home parenteral
nutrition has been associated with neurological consequences and metabolic bone
disease, characterized by low-bone formation rate, respectively. For all these
reasons and on the basis of our many years of scientific experience in this
field, we propose the following recommendations as guidelines to avoid risks
due to aluminum accumulation and potential intoxication. These recommendations
are not rigid and will be updated when relevant new scientific data is
available. General Recommendations 1. It would be valuable to define as
completely as possible which patient groups are at risk for iatrogenic aluminum
loading, and under which conditions aluminum represents a health hazard. The
more complete knowledge we have for the clinical, iatrogenic setting, the
better basis we will have to judge whether different types of aluminum exposure
are hazardous to the general population or to susceptible subgroups. 2. A
provisional list of patients groups at risk of iatrogenic aluminum loading
should include, at least, people with impaired renal function,

infants, old people and patients on total home parenteral nutrition. Where such
exposure occurs, serum aluminum concentrations should be less than 30 μg/l and
possibly lower. However, further studies are necessary.

8. It is recommended that acidic food, e.g., acid cabbage, tomato, etc. should
not be cooked or stored in aluminum ware. In this connection, it has been
demonstrated that in the juice of acidic cabbage, cooked in aluminum, the metal
ion content is up to 20 mg/ L.

3. Urinary aluminum is also an indicator of aluminum absorption, the excreted
Al/retained Al ratio depends on the integrity of the renal function.

9. Individual susceptibility to aluminum has been reported by the scientific
literature. Thus, special efforts should be taken to prevent contamination of
food and beverages etc. with aluminum either directly or during preparation,
with special regard to infants, old people or individuals with suboptimal renal
functionality.

4. Al may enter human body by mouth, intravenous infusions and by environment.
Specific controls have to be adopted in order to reduce each risk of exposure.
Oral Exposure 5. Aluminum in drinking water should be less than 50 μg L-1.
Silicon is relevant to aluminum toxicity and, therefore, the water silicon
concentrations should be monitored in parallel. 6. The aluminum content should
be declared in all food preparations and pharmacological products. 7.
Citrate-containing compounds appear to increase the bioavailability of ingested
aluminum. Therefore, particular care should be taken to avoid these compounds
in combination with Al-containing drugs. With citric acid, the enhanced
gastrointestinal absorption may by compensated for by a parallel increase in
urinary Al excretion, where there is good renal function. However, it is
strongly suspected from recent simulation studies that other dietary acids
(e.g., succinic and tartaric acids) also increase Al-bioavailability but do not
cause any compensatory increase in urinary excretion. Ascorbate and lactate
also significantly enhance gastrointestinal absorption of Al, as was recently
demonstrated in animal studies. www.laleva.cc/environment/aluminum_health.html

10. Magnesium depletion is considered a high risk for aluminum accumulation
especially during pregnancy and in the neonate with possible consequent
problems for normal development and growth. Magnesium depletion is also common
with aging. 11. Iron depletion is considered a high risk for aluminium
accumulation, as iron and Al share common carriers. Parenteral Exposure 12.
Aluminum in all intravenous (i.v.) fluids should be controlled monitored and
labeled. There is a general consensus that the aluminum content of i.v. fluids
used in children and adults with renal failure or undergoing dialysis, should
be as low as possible and in any case no higher than 10 μg/L. 13. The use of
parenteral nutrition fluids that are high in aluminum should be eliminated or
significantly reduced. This document will be published in relevant scientific
journals, and will be sent to all Health Ministers of the European Community as
well as to other Public Health Authorities. (FDA, WHO etc.). For further
information, please contact Prof. P. Zatta: zatta@civ.bio.unipd.it

BMJ • December 2000

Routine vaccinations and child survival: follow up study in Guinea-Bissau, West
Africa Ines Kristensen, physician,a Peter Aaby, anthropologist,a and Henrik
Jensen, statisticianb aBandim Health Project, Apartado 861, Bissau
Guinea-Bissau, bDanish Epidemiology Science Centre Statens Serum Institut,
Copenhagen, Denmark Contributors: IK supervised the last year of data
collection and wrote the first draft of the paper. HJ supervised data control
and carried out the statistical analyses. PA initiated the study, supervised
data collection, carried out the first analyses, and wrote the final version of
the paper. HJ and PA will act as guarantors. Abstract

Main Outcome Measures Infant mortality over six months (between age 0-6 months
and 7-13 months for BCG, diphtheria, tetanus, and pertussis, and polio vaccines
and between 7-13 months and 14-20 months for measles vaccine). Results
Mortality was lower in the group vaccinated with any vaccine compared with
those not vaccinated, the mortality ratio being 0.74 (95% confidence interval
0.53 to 1.03). After cluster, age, and other vaccines were adjusted for, BCG
was associated with significantly lower mortality (0.55 (0.36 to 0.85)).
However, recipients of one dose of diphtheria, tetanus, and pertussis or polio
vaccines had higher mortality than children who had received none of these
vaccines (1.84 (1.10 to 3.10) for diphtheria, tetanus, and pertussis).
Recipients of measles vaccine had a mortality ratio of 0.48 (0.27 to 0.87).
When deaths from measles were excluded from the analysis the mortality ratio
was 0.51 (0.28 to 0.95). Estimates were unchanged by controls for background
factors.

Design Follow up study.

Conclusions These trends are unlikely to be explained exclusively by selection
biases since different vaccines were associated with opposite tendencies.
Measles and BCG vaccines may have beneficial effects in addition to protection
against measles and tuberculosis. Diphtheria, tetanus, and pertussis and polio
vaccines were associated with higher infant mortality.

Participants 15 351 women and their children born during 1990 and 1996.

Full Report: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27544/

Objective To examine the association between routine childhood vaccinations and
survival among infants in Guinea-Bissau.

Setting Rural Guinea-Bissau.

“Diphtheria, tetanus, and pertussis and polio vaccines were associated with
higher infant mortality.”

“... in rats, the pertussis component of DTPoP
acts on the cardiovascular system and disturbs its circadian rhythm.”
Laboratory Animals • 2000

Disturbance of cardiovascular circadian rhythms by pertussis vaccine in
freely-moving rats W. Vleeming, A. van de Kuil, J. D. te Biesebeek, J. W. van
der Laan, D. J. de Wildt & J. G. C. van Amsterdam National Institute of Public
Health and the Environment Laboratory of Health Effects Research PO Box 1, NL
3720 BA Bilthoven, The Netherlands Summary Vaccination of young children with
diphtheria, tetanus, poliomyelitis and pertussis (DTPoP) vaccine is effective
in preventing outbreaks of whooping cough but adverse events sometimes occur.
This pilot study shows that in freely-moving rats, multiple treatment with
DTPoP (at day 0 and day 5, 6 ml/kg i.v.) increased heart rate (HR) for 5 days
after the first treatment and decreased diastolic blood pressure (DBP)for at
least 26 days after the first treatment and inhibited the circadian rhythm of
HR and DBP for at least 10 days. DTPo vaccine, containing no pertussis vaccine,
was free of such effects. Thus, in rats, the pertussis component of DTPoP acts
on the cardiovascular system and disturbs its circadian rhythm. The
contribution of these findings to clinical adverse effects is as yet unknown
and needs further research. http://lan.sagepub.com/content/34/4/399.long

Veterinary Pathology • March 2001

Feline vaccine-associated fibrosarcoma: an ultrastructural study of 20 tumors
1996-1999 Author information Madewell BR1, Griffey SM, McEntee MC, Leppert VJ,
Munn RJ. Department of Surgical and Radiological Sciences, School of Veterinary
Medicine University of California, Davis 95616 USA brmadewell@ucdavis.edu
Abstract Twenty feline vaccine-associated sarcomas were examined by
transmission electron microscopy. Tumors contained pleomorphic spindle cells,
histiocytoid cells, and giant cells. Most tumors contained myofibroblasts,
which had morphologic features similar to those of fibroblasts. These cells
were further distinguished by subplasmalemmal dense plaques and thin
cytoplasmic actin myofilaments organized as elongated bundles concentrated at
irregular intervals forming characteristic dense bodies. Intracellular
crystalline particulate material was found in 5 of the 20 tumors. Energy
dispersive X-ray spectroscopy was used to identify the crystalline material
within one tumor as aluminum-based. One tumor from a feline leukemia
virus-infected cat contained budding and immature retroviral particles. In one
of the first reports of feline vaccine-associated sarcomas, dense crystalline
material was recognized by electron microscopy within macrophages surrounding
tumor cells.9 Subsequent electron-probe microanalytical studies demonstrated
aluminum in the cytoplasm of the macrophages within these sarcomas, suggesting
the role of aluminum-containing adjuvant as irritant in the pathogenesis of
vaccine-associated sarcomas.9 The role of vaccine adjuvant in the
etiopathogenesis of these tumors remains unclear. The most prevalent adjuvants
used in licensed veterinary vaccines are aluminum salts and oil emulsions; all
of these formulations are considered to act as depots for injected vaccines.1
Aluminum hydroxide adjuvants are used in many human and veterinary vaccines,
presumably because of their safety and low cost. Aluminum has been detected at
the site of subcutaneous injections for up to 1 year in animals.3 That the
tissues collected in this study represented tumors that developed months to
years after vaccination when the precise site of vaccination was unknown and
that most tumors were several centimeters in diameter or greater at the time of
excision suggest that a large amount of aluminum, indeed, was contained within
these adjuvanted vaccines to allow its detection in randomly selected ultrathin
(60–90 nm thick) tissue sections examined in the electron microscope. The
results of this study support previous morphologic observations of feline
vaccine-associated sarcomas. The role of the myofibroblast in
vaccine-associated sarcomas is unclear but perhaps reflects a continuum of the
inflammatory response that characterizes, in part, these unique neoplasms. The
role of adjuvant, similarly, in these tumors is unknown. Full Report:
http://vet.sagepub.com/content/38/2/196.long

“The results of this study support previous morphologic observations of feline
vaccine-associated sarcomas. The role of the myofibroblast in
vaccine-associated sarcomas is unclear but perhaps reflects a continuum of the
inflammatory response that characterizes, in part, these unique neoplasms. The
role of adjuvant, similarly, in these tumors is unknown.”

Brain • May 2001

Central nervous system disease in patients with macrophagic myofasciitis Author
information Authier FJ1, Cherin P, Creange A, Bonnotte B, Ferrer X, Abdelmoumni
A, Ranoux D, Pelletier J, Figarella-Branger D, Granel B, Maisonobe T, Coquet M,
Degos JD, Gherardi RK. Groupe d’Etudes et de Recherches sur le Muscle et le
Nerf (GERMEN, EA Université Paris XII-Val de Marne) Faculté de Médecine de
Créteil, Département de Pathologie Hôpital Henri Mondor, AP-HP, Créteil, France
authier@univ-paris12.fr Abstract Macrophagic myofasciitis (MMF), a condition
newly recognized in France, is manifested by diffuse myalgias and characterized
by highly specific myopathological alterations which have recently been shown
to represent an unusually persistent local reaction to intramuscular injections
of aluminium-containing vaccines. Among 92 MMF patients recognized so far,
eight of them, which included the seven patients reported here, had a
symptomatic demyelinating CNS disorder. CNS manifestations included hemisensory
or sensorimotor symptoms (four out of seven), bilateral pyramidal signs (six
out of seven), cerebellar signs (four out of seven), visual loss (two out of
seven), cognitive and behavioural disorders (one out of seven) and bladder
dysfunction (one out of seven). Brain T(2)-weighted MRI showed single (two out
of seven) or multiple (four out of seven) supratentorial white matter
hyperintense signals and corpus callosum atrophy (one out of seven). Evoked
potentials were abnormal in four out of six patients and CSF in four out of
seven. According to Poser’s criteria for multiple sclerosis, the diagnosis was
clinically definite (five out of seven) or clinically probable multiple
sclerosis (two out of seven). Six out of seven patients had diffuse myalgias.
Deltoid muscle biopsy showed stereotypical accumulations of PAS (periodic
acid-Schiff)-positive macrophages, sparse CD8+ T cells and minimal myofibre
damage. Aluminium-containing vaccines had been administered 3-78 months (median
= 33 months) before muscle biopsy (hepatitis B virus: four out of seven,
tetanus toxoid: one out of seven, both hepatitis B virus and tetanus toxoid:
two out of seven). The association between MMF and multiple sclerosis-like
disorders may give new insights into the controversial issues surrounding
vaccinations and demyelinating CNS disorders. Deltoid muscle biopsy searching
for myopathological alterations of MMF should be performed in multiple
sclerosis patients with diffuse myalgias. Full Report
http://brain.oxfordjournals.org/content/124/5/974

“Macrophagic myofasciitis (MMF), a condition newly recognized in France, is
manifested by diffuse myalgias and characterized by highly specific
myopathological alterations which have recently been shown to represent an
unusually persistent local reaction to intramuscular injections of
aluminium-containing vaccines. Among 92 MMF patients recognized so far, eight
of them, which included the seven patients reported here, had a symptomatic
demyelinating Central Nervous System disorder.”

Current Atherosclerosis Reports • July 2001

Antiphospholipid syndrome, antiphospholipid antibodies, and atherosclerosis
Author information Sherer Y1, Shoenfeld Y. Department of Medicine ‘B’ Sheba
Medical Center Tel-Hashomer 52621, Israel Abstract The antiphospholipid
syndrome is characterized by arterial and venous thrombosis, as well as
pregnancy morbidity, in the presence of elevated levels of antiphospholipid
antibodies. These autoantibodies have procoagulant activity, as they affect
platelets, humoral coagulation factors, and endothelial cells. In addition,
they are proatherogenic, as demonstrated by animal models and by the increased
prevalence of cardiovascular diseases in patients with systemic lupus
erythematosus and antiphospholipid syndrome. Moreover, antiphospholipid
antibodies, including anticardiolipin, anti-b2-glycoprotein-I, and
anti-oxidized low-density lipoprotein, are associated with atherosclerosis and
its consequences in the general population as well. This autoimmune aspect of
atherosclerosis in the presence or absence of an autoimmune disease suggests
benefit from development of immunomodulating therapies.
http://www.ncbi.nlm.nih.gov/pubmed/?term=11389799

“The antiphospholipid syndrome is characterized by arterial and venous
thrombosis, as well as pregnancy morbidity, in the presence of elevated levels
of antiphospholipid antibodies.”

“Vaccine-related cardiorespiratory events are relatively common in preterm babies.”
Acta Paediatrica • August 2001

Adverse events following vaccination in premature infants S Sen1, Y Cloete2, K
Hassan1 andP Buss1, Department of Paediatrics and Neonatology, Royal Gwent
Hospital, Newport, UK Nevill Hall Hospital, Abergavenny, UK Royal Gwent
Hospital, Cardiff Road, Newport NP9 2UB, UK Abstract The aims of this study
were to study the frequency, severity and types of adverse reactions following
DPT/Hib (diphtheria and tetanus toxoids and pertussisHaemophilus influenzae
type B conjugate) immunization in very preterm infants and to identify possible
risk factors. Case notes of 45 preterm babies vaccinated in the neonatal
intensive care unit between January 1993 and December 1998 were studied
retrospectively. Birthweight, gestational age, duration of ventilation, oxygen
dependency, timing of vaccination, weight, corrected gestation at vaccination
and apparent adverse effects were noted. Apparent adverse events were noted in
17 of 45 (37.8%) babies: 9 (20%) had major events, i.e. apnoea, bradycardia or
desaturations, and 8 (17.8%) had minor events, i.e. increased oxygen
requirements, temperature instability, poor handling and feed intolerance.
Babies with major events were significantly younger (p<0.05), had a lower
postmenstrual age (p < 0.05) and weighed less (p< 0.05) at the time of
vaccination compared with babies without major events. No differences in the
mean birthweight, gestational age, duration of ventilation or oxygen dependency
were found between the two groups. Age at vaccination of 70 days or less was
significantly associated with increased risk (p < 0.01). Of 27 babies
vaccinated at 70 days or less, 9 (33.3%) developed major events compared with
none when vaccinated over 70d. Conclusion Vaccine-related cardiorespiratory
events are relatively common in preterm babies. Problems were much more common
if vaccine is administered at or before 70 d. These babies should therefore be
monitored postvaccination. Further prospective studies are needed to clarify
whether delaying vaccination offers protection against these adverse events.
http://onlinelibrary.wiley.com/doi/10.1111/j.1651-2227.2001.tb02457.x/abstract

Archives Of Virology • August 2001

Comparative analysis of host responses related to immunosuppression between
measles patients and vaccine recipients with live attenuated measles vaccines
Author information Okada H1, Sato TA, Katayama A, Higuchi K, Shichijo K,
Tsuchiya T, Takayama N, Takeuchi Y, Abe T, Okabe N, Tashiro M. Department of
Viral Diseases and Vaccine Control National Institute of Infectious Diseases
Musashi-Murayama, Tokyo, Japan Abstract Measles virus infection induces a
profound immunosuppression. We analyzed in a timedependent manner peripheral
bloods of one to two-year-old children immunized with live attenuated measles
vaccines, compared with age-matched measles patients, for immunosuppression. In
contrast to transient severe lymphopenia with measles patients, primarily due
to extensive apoptosis of a broad spectrum of uninfected lymphocytes, neither
apoptosis nor lymphopenia occurred with measles vaccine recipients. Increase in
number and activation of NK cells, which might compensate for the lymphopenia
in measles patients, were not found with the vaccinees. While cell surface
expression of apoptosis-related molecules such as TNF-related
apoptosis-inducing ligand (TRAIL), TRAIL-receptors, CD95(Fas) and Fas-ligand,
and plasma interferon-gamma were increased for measles patients, they remained
unchanged after vaccination. Plasma interleukin (IL)-18, which is responsible
for inducing apoptosis in several infectious diseases, was increased
predominantly with measles patients, whereas the increase remained marginal
with the vaccinees. IL-10 was elevated transiently in both measles patients and
vaccinees. Decrease in plasma IL-12, which is often correlated with T cell
suppression, was not found for both cases. Serum IgM and IgG antibodies to
measles virus were induced at lower titers in the vaccinees than measles
patients. These results indicate that in contrast to wild-type measles virus,
live measles vaccines hardly provoked host cytokine responses that lead to
apoptotic cytolysis of uninfected lymphocytes, lymphopenia and
immunosuppression, and thereby induced weaker immune responses to the virus.
http://www.ncbi.nlm.nih.gov/pubmed/?term=11448026

“These results indicate that in contrast to wild-type measles virus, live
measles vaccines hardly provoked host cytokine responses that lead to apoptotic
cytolysis of uninfected lymphocytes, lymphopenia and immunosuppression, and
thereby induced weaker immune responses to the virus.”

Acta Paediatrica • August 2001

Adverse events following vaccination in premature infants Author information
Sen S1, Cloete Y, Hassan K, Buss P. Department of Paediatrics and Neonatology
Royal Gwent Hospital, Newport, UK Abstract The aims of this study were to study
the frequency, severity and types of adverse reactions following DPT/Hib
(diphtheria and tetanus toxoids and pertussis/Haemophilus influenzae type B
conjugate) immunization in very preterm infants and to identify possible risk
factors. Case notes of 45 preterm babies vaccinated in the neonatal intensive
care unit between January 1993 and December 1998 were studied retrospectively.
Birthweight, gestational age, duration of ventilation, oxygen dependency,
timing of vaccination, weight, corrected gestation at vaccination and apparent
adverse effects were noted. Apparent adverse events were noted in 17 of 45
(37.8%) babies: 9 (20%) had major events, i.e. apnoea, bradycardia or
desaturations, and 8 (17.8%) had minor events, i.e. increased oxygen
requirements, temperature instability, poor handling and feed intolerance.
Babies with major events were significantly younger (p < 0.05), had a lower
postmenstrual age (p < 0.05) and weighed less (p < 0.05) at the time of
vaccination compared with babies without major events. No differences in the
mean birthweight, gestational age, duration of ventilation or oxygen dependency
were found between the two groups. Age at vaccination of 70 days or less was
significantly associated with increased risk (p < 0.01). Of 27 babies
vaccinated at 70 days or less, 9 (33.3%) developed major events compared with
none when vaccinated over 70 days. CONCLUSION: Vaccine-related
cardiorespiratory events are relatively common in preterm babies. Problems were
much more common if vaccine is administered at or before 70 d. These babies
should therefore be monitored postvaccination. Further prospective studies are
needed to clarify whether delaying vaccination offers protection against these
adverse events. http://www.ncbi.nlm.nih.gov/pubmed/?term=11529542

“Vaccine-related cardiorespiratory events are relatively common in preterm
babies. Problems were much more common if vaccine is administered at or before
70 days.”

Clinical Immunology • September 2001

Infection of human B lymphocytes with MMR vaccine induces IgE class switching
Author information

“Circulating immunoglobulin E (IgE) is one of the characteristics of human
allergic diseases including allergic asthma. We recently showed that infection
of

Imani F1, Kehoe KE.

human B cells with rhinovirus or measles virus could

Division of Clinical Immunology, Department of Medicine The Johns Hopkins
University School of Medicine Asthma and Allergy Center, 5501 Hopkins Bayview
Circle Baltimore, Maryland 21224, USA fimani@mail.jhmi.edu

lead to the initial steps of IgE class switching. Our data

Abstract Circulating immunoglobulin E (IgE) is one of the characteristics of
human allergic diseases including allergic asthma. We recently showed that
infection of human B cells with rhinovirus or measles virus could lead to the
initial steps of IgE class switching. Since many viral vaccines are live
viruses, we speculated that live virus vaccines may also induce IgE class
switching in human B cells. To examine this possibility, we selected the
commonly used live attenuated measles mumps rubella (MMR) vaccine. Here, we
show that infection of a human IgM(+) B cell line with MMR resulted in the
expression of germline epsilon transcript. In addition, infection of freshly
prepared human PBLs with this vaccine resulted in the expression of mature IgE
mRNA transcript. Our data suggest that a potential side effect of vaccination
with live attenuated viruses may be an increase in the expression of IgE.
http://www.ncbi.nlm.nih.gov/pubmed/11513549

suggest that a potential side effect of vaccination with live attenuated
viruses may be an increase in the expression of IgE.”

[Based on these findings, the authors concluded that viral vaccines might be
playing a role in the increasing incidence of asthma and other allergic
diseases]

“From October 1998 to December 1999, 112 cases of intussusception were reported.”
Vaccine • September 2001

Data mining in the US Vaccine Adverse Event Reporting System (VAERS): early
detection of intussusception and other events after rotavirus vaccination
Author Information Manette T. Niu.a, Diane E. Erwin.c, M.Miles Braun.b a.
Vaccine Safety Branch, Division of Epidemiology, Office of Biostatistics and
Epidemiology, Center for Biologic Evaluation and Research, US Food and Drug
Administration, 1401 Rockville Pike, HFM-210, Rockville, MD b. Division of
Epidemiology, Office of Biostatistics and Epidemiology Center for Biologic
Evaluation and Research, US Food and Drug Administration, Rockville, MD c.
Information Management Services, Inc., Rockville, MD, USA

Abstract The Vaccine Adverse Event Reporting System (VAERS) is the US passive
surveillance system monitoring vaccine safety. A major limitation of VAERS is
the lack of denominator data (number of doses of administered vaccine), an
element necessary for calculating reporting rates. Empirical Bayesian data
mining, a data analysis method, utilizes the number of events reported for each
vaccine and statistically screens the database for higher than expected
vaccine-event combinations signaling a potential vaccine-associated event. This
is the first study of data mining in VAERS designed to test the utility of this
method to detect retrospectively a known side effect of
vaccination–intussusception following rotavirus (RV) vaccine. From October 1998
to December 1999, 112 cases of intussusception were reported. The data mining
method was able to detect a signal for RV-intussusception in February 1999 when
only four cases were reported. These results demonstrate the utility of data
mining to detect significant vaccine-associated events at early date. Data
mining appears to be an efficient and effective computer-based program that may
enhance early detection of adverse events in passive surveillance systems.
http://www.sciencedirect.com/science/article/pii/S0264410X01002377

Emerging Infectious Diseases • September 2001

Adaptation of Bordetella pertussis to vaccination: a cause for its reemergence?
Author information Mooi FR1, van Loo IH, King AJ. National Institute for Public
Health and the Environment Bilthoven, the Netherlands fr.mooi@rivm.nl Abstract
In the Netherlands, as in many other western countries, pertussis vaccines have
been used extensively for more than 40 years. Therefore, it is conceivable that
vaccine-induced immunity has affected the evolution of Bordetella pertussis.
Consistent with this notion, pertussis has reemerged in the Netherlands,
despite high vaccination coverage. Further, a notable change in the population
structure of B. pertussis was observed in the Netherlands subsequent to the
introduction of vaccination in the 1950s. Finally, we observed antigenic
divergence between clinical isolates and vaccine strains, in particular with
respect to the surface-associated proteins pertactin and pertussis toxin.
Adaptation may have allowed B. pertussis to remain endemic despite widespread
vaccination and may have contributed to the reemergence of pertussis in the
Netherlands. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631860/

“Adaptation may have allowed B. pertussis to remain endemic despite widespread
vaccination and may have contributed to the reemergence of pertussis in the
Netherlands.”

European Journal Of Immunology • October 2001

Immunization with the adjuvant MF59 induces macrophage trafficking and
apoptosis Author information Dupuis M1, Denis-Mize K, LaBarbara A, Peters W,
Charo IF, McDonald DM, Ott G. Cardiovascular Research Institute and Department
of Anatomy University of California, San Francisco, USA Abstract The mechanisms
associated with the immunostimulatory activity of vaccine adjuvants are still
poorly understood. We have undertaken a study to determine whether
antigen-presenting cell trafficking is modified by administration of the
submicron emulsion adjuvant MF59. We investigated the fate of inflammatory
macrophages after intramuscular injection of the antigen herpes simplex virus
gD2 with fluorescencelabeled MF59. A homogeneous population of macrophages
infiltrated the muscle, internalized adjuvant and expressed markers
characteristic of mature macrophages over a 48-h period. Macrophage influx to
the injection site was reduced by 70% in mice deficient for the chemokine
receptor 2 (CCR2). Two distinct cell populations were shown to contain
fluorescence-labeled MF59 in the draining lymph node at 48 h post injection.
The first population had a round morphology, exhibited bright fluorescence, was
located in the subcapsular sinus, and was apoptotic. The second population had
a dendritic morphology, was weakly fluorescent, and was located in the T cell
area where adjuvantcontaining apoptotic bodies identified by TUNEL labeling
were present. We propose that lymph node-resident dendritic cells can acquire
antigen and MF59 after intramuscular immunization by uptake of the apoptotic
macrophages. http://www.ncbi.nlm.nih.gov/pubmed/11592066

“We propose that lymph node-resident dendritic cells can acquire antigen and
MF59 [squalene] after intramuscular immunization by uptake of the apoptotic
macrophages.”

“There are significantly elevated risks
of febrile seizures after receipt of DTP vaccine or MMR vaccine ...” CDC New
England Journal Of Medicine • 2001

The Risk of Seizures after Receipt of Whole-Cell Pertussis or Measles, Mumps,
and Rubella Vaccine William E. Barlow, Ph.D., Robert L. Davis, M.D., M.P.H.,
John W. Glasser, Ph.D., M.P.H., Phillip H. Rhodes, Ph.D., Robert S. Thompson,
M.D., John P. Mullooly, Ph.D., Steven B. Black, M.D., Henry R. Shinefield,
M.D., Joel I. Ward, M.D., S. Michael Marcy, M.D., Frank DeStefano, M.D.,
Virginia Immanuel, M.P.H., John A. Pearson, M.D., Constance M. Vadheim, Ph.D.,
Viviana Rebolledo, B.S., Dimitri Christakis, M.D., M.P.H., Patti J. Benson,
M.P.H., Ned Lewis, M.P.H., and Robert T. Chen, M.D. for the Centers for Disease
Control and Prevention Vaccine Safety Datalink Working Group BACKGROUND The
administration of the diphtheria and tetanus toxoids and whole-cell pertussis
(DTP) vaccine and measles, mumps, and rubella (MMR) vaccine has been associated
with seizures. We studied the relation between these vaccinations and the risk
of a first seizure, subsequent seizures, and neurodevelopmental disability in
children. METHODS This cohort study was conducted at four large health
maintenance organizations and included reviews of the medical records of
children with seizures. We calculated the relative risks of febrile and
nonfebrile seizures among 679,942 children after 340,386 vaccinations with DTP
vaccine, 137,457 vaccinations with MMR vaccine, or no recent vaccination.
Children who had febrile seizures after vaccination were followed to identify
the risk of subsequent seizures and other neurologic disabilities. RESULTS
Receipt of DTP vaccine was associated with an increased risk of febrile
seizures only on the day of vaccination (adjusted relative risk, 5.70; 95
percent confidence interval, 1.98 to 16.42). Receipt of MMR vaccine was
associated with an increased risk of febrile seizures 8 to 14 days after
vaccination (relative risk, 2.83; 95 percent confidence interval, 1.44 to
5.55). Neither vaccination was associated with an increased risk of nonfebrile
seizures. The number of febrile seizures attributable to the administration of
DTP and MMR vaccines was estimated to be 6 to 9 and 25 to 34 per 100,000
children, respectively. As compared with other children with febrile seizures
that were not associated with vaccination, the children who had febrile
seizures after vaccination were not found to be at higher risk for subsequent
seizures or neurodevelopmental disabilities. CONCLUSIONS There are
significantly elevated risks of febrile seizures after receipt of DTP vaccine
or MMR vaccine, but these risks do not appear to be associated with any
long-term, adverse consequences.
http://www.nejm.org/doi/full/10.1056/NEJMoa003077

Toxicology In Vitro • February 2002

Formaldehyde cytotoxicity in three human cell types assessed in three different
assays Author information Lovschall H1, Eiskjaer M, Arenholt-Bindslev D. Tissue
Culture Laboratory Department of Dental Pathology Royal Dental College, Faculty
of Health Sciences University of Aarhus, DK-8000 Aarhus C, Denmark
loev@odont.au.dk Abstract International standards for preclinical screening of
the cytotoxicity of dental materials so far recommend the use of established
cell lines. The aim of this study was to assess the relative susceptibility of
human dental pulp fibroblasts (HPF), human buccal epithelial cells (HBE) and
HeLa cervix cancer cells exposed to identical cytotoxic challenges.
Formaldehyde, which may be released from dental materials such as dental
composites, glassionomer cements, and endodontic sealers, was used as test
chemical. Cytotoxicity data including dose-response relations and TC(50) values
were assessed in three different assays: BrdU incorporation, neutral red uptake
and MTT assays. HBE and HPF demonstrated statistically significant lower TC(50)
values in both the neutral red and the BrdU assay in comparison to HeLa cells.
In the MTT assay no statistically significant differences were observed between
the cell types. In the two target-tissue cell types (HPF and HBE) the Neutral
Red assay revealed lower TC(50) values in comparison to the BrdU assay. In HeLa
cells no statistically significant differences were observed between the
assays. In conclusion, the present study confirms that cytotoxicity data
obtained by cell culture studies are influenced by both cell culture model and
choice of assay. Under identical experimental conditions, human target tissue
cells appeared to be more sensitive to formaldehyde toxicity than human HeLa
cancer cells. http://www.ncbi.nlm.nih.gov/pubmed/?term=11812641

“Under identical experimental conditions, human target tissue cells appeared to
be more sensitive to formaldehyde toxicity than human HeLa cancer cells.”

“antivaccination activists use: highly emotive content,
conspiratorial claims and privately published material and newspapers articles
...” [the reason for the publication of this eBook] Archives Of Disease In
Childhood • March 2002

Antivaccination activists on the world wide web Author Information P Davies1, S
Chapman1, J Leask2 1. Department of Public Health and Community Medicine,
University of Sydney A27, NSW 2006, Australia 2. National Centre for
Immunisation Research and Surveillance Simonc@health.usyd.edu.au Abstract Aims
To determine the likelihood of finding an antivaccination site on the world
wide web and to characterise their explicit claims and rhetorical appeals.
Methods Using “vaccination” and “immunisation”, examining the first 10 sites
displayed on seven leading search engines. Detailed examination of content of
100 antivaccination sites found on Google. Results 43% of websites were
antivaccination (all of the first 10 on Google). Main rhetorical appeals
involve themes of the scientific veracity of antivaccination argument; rapport
with parents seeking to protect their children from harm; and alleged collusion
between doctors, the pharmaceutical industry, and government to deny vaccine
harm. Conclusions There is a high probability that parents will encounter
elaborate antivaccination material on the world wide web. Factual refutational
strategies alone are unlikely to counter the highly rhetorical appeals that
shape these sites.Campaigns by those opposed to immunisation have been followed
by falling immunisation rates and outbreaks of vaccine preventable disease.1
The internet has provided antivaccinationists with unprecedented opportunities
for exposure. In the USA, 55% of adults with internet access use it to seek
health related information.2 For all its benefits, the internet has great
potential to disseminate health information that is incorrect and potentially
dangerous.3 To date, all studies on health information on the internet have
assessed content against

a priori standards of evidence, and have not considered the rhetorical subtexts
and wider social discourses in which this information is embedded.4,5 We
examined the content of 100 antivaccination websites, considering not only the
explicit claims made about vaccination, but also the ways these claims are
framed to maximise their appeal and influence. Response to the problem To
defuse conspiratorial claims the public should be made aware of efforts to
address the issue of vaccine safety through more active surveillance of adverse
events and studies investigating hypothesised links between vaccination and
serious chronic diseases.9,10 Since antivaccination websites share many of the
characteristics we have described, the themes identified in this article might
act as a tool for parents to discern whether the source is trustworthy. The
checklist might include: • Highly emotive content • Conspiratorial claims •
Privately published material, newspapers articles, etc., given as sources of
information • Claims to have privileged information unknown to medical
authorities Where refuting antivaccination arguments on the basis of fact alone
is insufficient, it may be possible to use similarly emotive tactics to promote
immunisation. Emphasis could be given to images and stories of children harmed
by vaccine preventable illnesses (see, for example,
http://www.immunize.org/stories/unprot.htm).

Full Report: http://adc.bmj.com/content/87/1/22.full

“Several recent epidemiological studies have shown that vaccinations against biological warfare
using pertussis as an adjuvant were associated with the Gulf war syndrome.”
Medical Hypotheses • April 2002

Gulf war syndrome: could it be triggered by biological warfare-vaccines using
pertussis as an adjuvant? Author information Tournier JN1, Jouan A, Mathieu J,
Drouet E. Département de biologie des agents transmissibles CRSSA, La Tronche,
France j.tournier@eudoramail.com Abstract Several recent epidemiological
studies have shown that vaccinations against biological warfare using pertussis
as an adjuvant were associated with the Gulf war syndrome. If such
epidemiological findings are confirmed, we propose that the use of pertussis as
an adjuvant could trigger neurodegeneration through induction of
interleukin1beta secretion in the brain. In turn, neuronal lesions may be
sustained by stress or neurotoxic chemical combinations. Particular
susceptibility for IL-1beta secretion and potential distant neuronal damage
could provide an explanation for the diversity of the symptoms observed on
veterans. http://www.ncbi.nlm.nih.gov/pubmed/12027522

The Journal of Infection • May 2002

The effect of vaccination on the epidemiology of varicella zoster virus Author
information Edmunds WJ1, Brisson M. Immunisation Division Colindale, London NW9
5EQ, UK jedmunds@phls.org.uk Abstract Varicella zoster virus (VZV) causes
chickenpox (varicella) on primary exposure and can reactivate later in life to
cause shingles (zoster). As primary infection is more serious in adults than
children, and exposure to the virus might boost the immune response to both
chickenpox and shingles, there are two main concerns regarding infant VZV
vaccination: that it could lead to an increase in adult disease; and/or that it
could lead to a temporary increase in the incidence of shingles. This paper
reviews the evidence for such outcomes. The consensus view of mathematical
modelling studies is that the overall varicella associated burden is likely to
decrease in the long term, regardless of the level of vaccine coverage. On the
other hand, recent evidence suggests that an increase in zoster incidence
appears likely, and the more effective vaccination is at preventing varicella,
the larger the increase in zoster incidence. Targeted vaccination of
susceptible adolescents and/or the contacts of high-risk individuals can be
effective at preventing disease in these individuals with minimal risk to the
community. However, targeted strategies would not prevent most disease
(including most severe disease), and will not lead to a long-term reduction in
the incidence of zoster. Understanding the mechanisms for maintaining immunity
against varicella and zoster is critical for predicting the long-term effects
of vaccination. Meanwhile sensitive surveillance of both chickenpox and
shingles is essential in countries that have implemented, or are about to
implement, varicella vaccination. http://www.ncbi.nlm.nih.gov/pubmed/12099726

“... recent evidence suggests that an increase in zoster [shingles] incidence
appears likely, and the more effective vaccination is at preventing varicella,
the larger the increase in zoster incidence.”

[varicella is chicken pox]

Current Opinions In Neurology • June 2002

Neurological adverse events associated with vaccination Author information

“These complications include autism (measles vaccine), multiple sclerosis
(hepatitis B vaccine), meningoencephalitis (Japanese encephalitis vaccine),

Piyasirisilp S1, Hemachudha T. Division of Neurology, Department of Medicine
Chiang Mai University, Chiang Mai 50200, Thailand spiyasir@mail.med.cmu.ac.th
Abstract Public tolerance to adverse reactions is minimal. Several reporting
systems have been established to monitor adverse events following immunization.
The present review summarizes data on neurologic complications following
vaccination, and provides evidence that indicates whether they were directly
associated with the vaccines. These complications include autism (measles
vaccine), multiple sclerosis (hepatitis B vaccine), meningoencephalitis
(Japanese encephalitis vaccine), Guillain-Barré syndrome and giant cell
arteritis (influenza vaccine), and reactions after exposure to animal rabies
vaccine. Seizures and hypotonic/hyporesponsive episodes following pertussis
vaccination and potential risks associated with varicella vaccination, as well
as vaccine-associated paralytic poliomyelitis following oral poliovirus
vaccination, are also described. In addition, claims that complications are
caused by adjuvants, preservatives and contaminants [i.e. macrophagic
myofasciitis (aluminium), neurotoxicity (thimerosal), and new variant
Creutzfeldt-Jakob disease (bovine-derived materials)] are discussed.
http://www.ncbi.nlm.nih.gov/pubmed/?term=12045734

Guillain-Barré syndrome and giant cell arteritis (influenza vaccine), and
reactions after exposure to animal rabies vaccine. Seizures and
hypotonic/hyporesponsive episodes following pertussis vaccination and potential
risks associated with varicella vaccination, as well as vaccine-associated
paralytic poliomyelitis following oral poliovirus vaccination, are also
described.”

“The present review summarizes data on neurologic complications following vaccination ...”
Current Opinion in Neurology • June 2002

Neurological adverse events associated with vaccination Piyasirisilp, Sucheepa;
Hemachudha, Thiravatb Abstract Public tolerance to adverse reactions is
minimal. Several reporting systems have been established to monitor adverse
events following immunization. The present review summarizes data on neurologic
complications following vaccination, and provides evidence that indicates
whether they were directly associated with the vaccines. These complications
include autism (measles vaccine), multiple sclerosis (hepatitis B vaccine),
meningoencephalitis (Japanese encephalitis vaccine), Guillain-Barré syndrome
and giant cell arteritis (influenza vaccine), and reactions after exposure to
animal rabies vaccine. Seizures and hypotonic/hyporesponsive episodes following
pertussis vaccination and potential risks associated with varicella
vaccination, as well as vaccine-associated paralytic poliomyelitis following
oral poliovirus vaccination, are also described. In addition, claims that
complications are caused by adjuvants, preservatives and contaminants [i.e.
macrophagic myofasciitis (aluminium), neurotoxicity (thimerosal), and new
variant Creutzfeldt-Jakob disease (bovine-derived materials)] are discussed.
http://www.ncbi.nlm.nih.gov/pubmed/12045734

Journal Of Biomedical Science • July 2002

Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with
autism Author information Singh VK1, Lin SX, Newell E, Nelson C. Department of
Biology and Biotechnology Center Utah State University, Logan, Utah 84322, USA
singhvk@cc.usu.edu Abstract Autoimmunity to the central nervous system (CNS),
especially to myelin basic protein (MBP), may play a causal role in autism, a
neurodevelopmental disorder. Because many autistic children harbor elevated
levels of measles antibodies, we conducted a serological study of
measles-mumpsrubella (MMR) and MBP autoantibodies. Using serum samples of 125
autistic children and 92 control children, antibodies were assayed by ELISA or
immunoblotting methods. ELISA analysis showed a significant increase in the
level of MMR antibodies in autistic children. Immunoblotting analysis revealed
the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but
not in control sera. This antibody specifically detected a protein of 73-75 kD
of MMR. This protein band, as analyzed with monoclonal antibodies, was
immunopositive for measles hemagglutinin (HA) protein but not for measles
nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in
autistic sera detected measles HA protein, which is unique to the measles
subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic
sera were also positive for MBP autoantibodies, suggesting a strong association
between MMR and CNS autoimmunity in autism. Stemming from this evidence, we
suggest that an inappropriate antibody response to MMR, specifically the
measles component thereof, might be related to pathogenesis of autism.
http://www.ncbi.nlm.nih.gov/pubmed/12145534

“... over 90% of MMR antibody-positive autistic sera were also positive for MBP
autoantibodies, suggesting a strong association between MMR and CNS
autoimmunity in autism. Stemming from this evidence, we suggest that an
inappropriate antibody response to MMR, specifically the measles component
thereof, might be related to pathogenesis of autism.”

“The results indicated that whole-cell DTP vaccine contained high levels of endotoxin
and was statistically significantly more reactogenic than acellular DTaP
vaccine.” Pediatric Rehabilitation • July 2002

Serious neurological conditions following pertussis immunization: an analysis
of endotoxin levels, the vaccine adverse events reporting system (VAERS)
database and literature review Author information Geier DA1, Geier MR. MedCon,
Inc., Silver Spring, MD, USA Abstract The purpose of this study was to
determine the potential risks for the development and outcome of serious
neurological illnesses following whole-cell DTP vaccination and also to
determine if the switch to using acellular DTaP vaccine in the US has had any
effect on the incidence rate of serious neurological illnesses following
vaccination. This study used the Limulus amebocyte lysate (LAL) endotoxin assay
to determine the levels of endotoxin in various commercially available
whole-cell and acellular DTaP vaccines, analysed the Vaccine Adverse Events
Reporting System (VAERS) database to determine the clinical effects of the use
of whole-cell DTP and acellular DTaP vaccines in the US and reviewed recently
published pertinent studies that analysed the incidence rates of serious
neurological illness following whole-cell DTP and acellular DTaP vaccines. The
results indicated that whole-cell DTP vaccine contained high levels of
endotoxin and was statistically significantly more reactogenic than acellular
DTaP vaccine. The presence of bias in the VAERS database was not borne-out. The
recommendation by the American Academy of Paediatrics to use acellular DTaP
vaccine for the entire childhood vaccination schedule beginning in 1996 and the
absence of the availability of whole-cell DTP in the US beginning in 2001 seems
well justified based upon the results of this study.
http://www.ncbi.nlm.nih.gov/pubmed/12587565

Experimental And Molecular Pathology • August 2002

Antibodies to squalene in recipients of anthrax vaccine Author information Asa
PB1, Wilson RB, Garry RF. Department of Microbiology Tulane University Medical
School New Orleans, Louisiana 70112, USA Abstract We previously reported that
antibodies to squalene, an experimental vaccine adjuvant, are present in
persons with symptoms consistent with Gulf War Syndrome (GWS) (P. B. Asa et
al., Exp. Mol. Pathol 68, 196-197, 2000). The United States Department of
Defense initiated the Anthrax Vaccine Immunization Program (AVIP) in 1997 to
immunize 2.4 million military personnel. Because adverse reactions in
vaccinated personnel were similar to symptoms of GWS, we tested AVIP
participants for antisqualene antibodies (ASA). In a pilot study, 6 of 6
vaccine recipients with GWS-like symptoms were positive for ASA. In a larger
blinded study, only 32% (8/25) of AVIP personnel compared to 15.7% (3/19) of
controls were positive (P > 0.05). Further analysis revealed that ASA were
associated with specific lots of vaccine. The incidence of ASA in personnel in
the blinded study receiving these lots was 47% (8/17) compared to an incidence
of 0% (0/8; P < 0.025) of the AVIP participants receiving other lots of
vaccine. Analysis of additional personnel revealed that in all but one case
(19/20; 95%), ASA were restricted to personnel immunized with lots of vaccine
known to contain squalene. Except for one symptomatic individual, positive
clinical findings in 17 ASA-negative personnel were restricted to 4 individuals
receiving vaccine from lots containing squalene. ASA were not present prior to
vaccination in preimmunization sera available from 4 AVIP personnel. Three of
these individuals became ASA positive after vaccination. These results suggest
that the production of ASA in GWS patients is linked to the presence of
squalene in certain lots of anthrax vaccine.
http://www.ncbi.nlm.nih.gov/pubmed/12127050

“Three of these individuals became anti-squalene antibody positive after
vaccination. These results suggest that the production of anti-squalene
antibody in Gulf War Syndrome patients is linked to the presence of squalene in
certain lots of anthrax vaccine.”

Laboratory Medicine • September 2002

Vaccines and Autism

“Vaccinations may be one of the triggers for autism.

by Bernard Rimland, PhD, Woody McGinnis, MD

Substantial data demonstrate immune abnormality

Autism Research Institute, San Diego, CA

in many autistic children consistent with impaired

Abstract Autism research is characterized by diverse findings. There is no
consensus about the biological determinants of autism. This paper examines the
autistic immune profile and the possible role of vaccines in autism.
Vaccinations may be one of the triggers for autism. Substantial data
demonstrate immune abnormality in many autistic children consistent with
impaired resistance to infection, activation of inflammatory response, and
autoimmunity. Impaired resistance may predispose to vaccine injury in autism. A
mercurial preservative in childhood vaccines, thimerosal, may cause direct
neurotoxic, immunodepressive, and autoimmune injury and contribute to
early-onset and regressed autism. Live viruses in measles, mumps, and rubella
(MMR) may result in chronic infection of the gut and trigger regressed autism.
Thimerosal injection may potentiate MMR injury. Consideration of vaccine
etiology must include recognition of compromised gut and nutrition in most
autistic children. An integrated view of the underlying biological problems in
autistic children serves our understanding of the possible role of vaccines.
Development of screening methods for deferral of vaccines in at-risk children
is a worthy goal.
http://labmed.oxfordjournals.org/content/labmed/33/9/708.full.pdf

resistance to infection, activation of inflammatory response, and autoimmunity.
Impaired resistance may predispose to vaccine injury in autism.

A mercurial preservative in childhood vaccines, thimerosal, may cause direct
neurotoxic, immunodepressive, and autoimmune injury and contribute to
early-onset and regressed autism. Live viruses in measles, mumps, and rubella
(MMR) may result in chronic infection of the gut and trigger regressed autism.
Thimerosal injection may potentiate MMR injury.”

Journal Of Pharmaceutical Sciences • October 2002

Peroxide formation in polysorbate 80 and protein stability Author information
Ha E1, Wang W, Wang YJ. Analytics & Formulation Department Process Sciences,
Bayer Biotechnology 800 Dwight Way, Berkeley, California 94701, USA Abstract
Nonionic surfactants are widely used in the development of protein
pharmaceuticals. However, the low level of residual peroxides in surfactants
can potentially affect the stability of oxidation-sensitive proteins. In this
report, we examined the peroxide formation in polysorbate 80 under a variety of
storage conditions and tested the potential of peroxides in polysorbate 80 to
oxidize a model protein, IL-2 mutein. For the first time, we demonstrated that
peroxides can be easily generated in neat polysorbate 80 in the presence of air
during incubation at elevated temperatures. Polysorbate 80 in aqueous solution
exhibited a faster rate of peroxide formation and a greater amount of peroxides
during incubation, which is further promoted/catalyzed by light. Peroxide
formation can be greatly inhibited by preventing any contact with air/oxygen
during storage. IL-2 mutein can be easily oxidized both in liquid and solid
states. A lower level of peroxides in polysorbate 80 did not change the rate of
IL-2 mutein oxidation in liquid state but significantly accelerated its
oxidation in solid state under air. A higher level of peroxides in polysorbate
80 caused a significant increase in IL-2 mutein oxidation both in liquid and
solid states, and glutathione can significantly inhibit the peroxide-induced
oxidation of IL-2 mutein in a lyophilized formulation. In addition, a higher
level of peroxides in polysorbate 80 caused immediate IL-2 mutein oxidation
during annealing in lyophilization, suggesting that implementation of an
annealing step needs to be carefully evaluated in the development of a
lyophilization process for oxidation-sensitive proteins in the presence of
polysorbate. http://www.ncbi.nlm.nih.gov/pubmed/?term=12226852

“For the first time, we demonstrated that peroxides can be easily generated in
neat polysorbate 80 ...”

Vaccine • November 2002

Routine vaccinations and child survival in a war situation with high mortality:
effect of gender Author information Aaby P1, Jensen H, Garly ML, Balé C,
Martins C, Lisse I. Bandim Health Project, Apartado 861Bissau Guinea-Bissau and
Danish Epidemiology Science Centre Artillerivej 5, 2300 Copenhagen S, Denmark
psb@sol.gtelecom.gw Abstract Non-specific effects of vaccination may be
different for boys and girls. Due to the sequential administration of vaccines,
it is difficult to separate the effect of different vaccines. We tested
sex-specific effects of diphtheria, tetanus, pertussis (DTP) and polio vaccines
and measles vaccines during the recent war (1998) in Guinea-Bissau when there
was no functioning immunisation programme in the country. The study included
1491 children aged 1-17 months in four urban districts in Bissau. Vaccination
status had been assessed in the study area in the 3 months before the war. The
effect of DTP and polio vaccines was assessed for children who had not received
measles vaccine. The effect of measles vaccine was evaluated for children aged
6-17 months. Compared with measles-unvaccinated children, measles-vaccinated
children had lower mortality (mortality ratio (MR)=0.44 (95% CI 0.20-1.00)),
the difference being marked for girls (0.25 (0.09-0.71)) but not for boys (0.84
(0.26-2.75)) (test of homogeneity, P=0.095). If measles cases were censored in
the analysis, the mortality ratio for vaccinated and unvaccinated children was
0.38 (0.16-0.89). DTP and polio-vaccinated children did not have lower
mortality than unvaccinated children. The female-male mortality ratio for DTP
and polio-vaccinated children was 3.08 (1.11-8.56) and 0.63 (0.28-1.40) for
measles-vaccinated children, a significant inversion of the ratios (test of
homogeneity, P=0.013). The divergent female-male mortality ratios are unlikely
to be explained by a selection bias going in different directions for different
vaccines. The reduction associated with measles vaccination was unrelated to
prevention against measles infection. Non-specific effects of vaccination
should be assessed separately for boys and girls. Taking these effects into
consideration may have implications for child mortality patterns in developing
countries. http://www.ncbi.nlm.nih.gov/pubmed/12443658

“The divergent female-male mortality ratios are unlikely to be explained by a
selection bias going in different directions for different vaccines.
Non-specific effects of vaccination should be assessed separately for boys and
girls.”

Diabetes • December 2002

The rise of childhood type 1 diabetes in the 20th century Author information
Gale EA Department of Diabetes and Metabolism Division of Medicine, University
of Bristol Medical School Unit, Southmead Hospital Bristol BS10 5NB, U.K.
Abstract The incidence of childhood type 1 diabetes increased worldwide in the
closing decades of the 20th century, but the origins of this increase are
poorly documented. A search through the early literature revealed a number of
useful but neglected sources, particularly in Scandinavia. While these do not
meet the exacting standards of more recent surveys, tentative conclusions can
be drawn concerning long-term changes in the demography of the disease.
Childhood type 1 diabetes was rare but well recognized before the introduction
of insulin. Low incidence and prevalence rates were recorded in several
countries over the period 1920-1950, and one carefully performed study showed
no change in childhood incidence over the period 1925-1955. An almost
simultaneous upturn was documented in several countries around the mid-century.
The overall pattern since then is one of linear increase, with evidence of a
plateau in some high-incidence populations and of a catch-up phenomenon in some
low-incidence areas. Steep rises in the age-group under 5 years have been
recorded recently. The disease process underlying type 1 diabetes has changed
over time and continues to evolve. Understanding why and how this produced the
pandemic of childhood diabetes would be an important step toward reversing it.
http://www.ncbi.nlm.nih.gov/pubmed/12453886

“Understanding why and how this produced the pandemic of childhood diabetes
would be an important step toward reversing it.”

“... probably because the pertussis component of most currently available acellular DPT vaccines
contains toxoided pertussis toxin that has a significant rate of reversion to
active toxin.” Toxicology Mechanisms And Methods • 2002

An analysis of the occurrence of convulsions and death after childhood
vaccination Author information Geier DA1, Geier MR. MedCon, Inc., Silver
Spring, Maryland USA Abstract The association between the whole-cell
diphtheria, tetanus, and pertussis (DTP) vaccine and the occurrence of
convulsions and death has long been debated by the medical and scientific
communities. A certified copy of the Vaccine Adverse Events Reporting System
database was obtained from the Centers for Disease Control, and the data were
analyzed using the Microsoft Access program. The results of this analysis
reveal a statistically (p < .01) higher rate of occurrence of convulsions and
death after whole-cell DTP vaccination than after acellular DTP and DT
vaccination, showing, as do the previous findings of many other scientists,
that acellular DTP vaccine is much less reactogenic than is whole-cell DTP
vaccine. This study helps to validate the decision by American vaccine
manufactures and the Food and Drug Administration to use only acellular DTP for
the American childhood vaccination schedule. However, acellular DTP vaccine is
still more reactogenic than is DT vaccine, probably because the pertussis
component of most currently available acellular DPT vaccines contains toxoided
pertussis toxin that has a significant rate of reversion to active toxin. This
suggests the need to use the newer acellular pertussis vaccines, which are of
higher purity and in which the reversion of the pertussis toxin is prevented.
http://www.ncbi.nlm.nih.gov/pubmed/20597817

“DTP and MMR vaccine are associated with a transiently increased risk of febrile seizures ...”
Paediatric Drugs • 2003

Placing the risk of seizures with pediatric vaccines in a clinical context
Author information Davis RL1, Barlow W. Departments of Pediatrics and
Epidemiology University of Washington, Seattle, Washington 98101, USA
rdavis@u.washington.edu Abstract In this review we discuss the relationship
between commonly administered childhood vaccines such as
diphtheria-tetanus-whole cell pertussis (DTP) and measles-mumps-rubella (MMR),
and the risk of nonfebrile and febrile seizure. We summarize data from the
Vaccine Safety Datalink Study and other studies that suggest that DTP and MMR
vaccine are associated with a transiently increased risk of febrile seizures,
and cause between 5-9 and 2534 additional extra febrile seizures per 100 000
immunized children, respectively. DTP and MMR do not appear to increase the
risk of nonfebrile seizures. We discuss some methodologic challenges in studies
of vaccines and seizures. Because there is no adequate comparison group that
would allow for the study of seizures long after vaccination, studies of
seizures are limited to acute events shortly following vaccination.
Additionally, while seizures following vaccination are worrisome to parents and
physicians alike, observational studies of the neurodevelopmental outcomes of
these children are particularly problematic. We discuss how such studies are
confounded by the natural history of predisposition to febrile seizures and by
the increased diagnostic scrutiny that children with febrile seizures might
undergo. Nevertheless, current data suggest that children with febrile seizures
do not experience long-term negative effects. Finally, we discuss the creation
of new clinics designed specifically to assist physicians in managing the
vaccination of children with a personal or family history of seizures. Data
from these clinics suggest that vaccination is safe for children with a
personal or family history of seizures, but statistical power has been limited.
We conclude by discussing the introduction of new vaccines, and note that, even
with widespread use, it will take many years before we can be knowledgeable
about the risk of rare events with these newly licensed products.
http://www.ncbi.nlm.nih.gov/pubmed/?term=14580221

International Pediatrics • Vol. 18 • No. 2 • 2003
by Mark R. Geier, MD, PhD; David A Geier

Pediatric MMR Vaccination Safety Abstract Measles, mumps and rubella are viral
infections that have the potential to result in globally destructive disorders.
Measles, mumps and rubella (MMR) vaccine has helped to dramatically reduce the
number of cases of measles, mumps and rubella infection, as well as to reduce
the amount of pain and suffering associated with each of these natural
infections. The purpose of this study was to analyze the incidence of serious
neurologic disorders in a comparative examination between MMR vaccine and a
vaccine control group. The Vaccine Adverse Events Reporting System (VAERS)
database was analyzed for the incidence rate of permanent brain damage,
cerebellar ataxia, autism and mental retardation reported following MMR vaccine
and diphtheria, tetanus and whole-cell pertussis (DTwcP) containing-vaccines
from 1994 through 2000 in the US. Statistically significant increases in the
incidence of serious neurologic disorders following pediatric MMR vaccine in
comparison to DTwcP vaccine were found. The potentially globally destructive
effects of natural measles, mumps and rubella infections means that continued
vaccination is necessary, but improvements in MMR vaccines are needed to
improve its safety. These results show that primary pediatric MMR vaccination
in children is associated with a marked increase in serious neurologic
disorders in comparison to DTwcP vaccination. The increase is statistically
significant for cerebellar ataxia, autism, mental retardation and permanent
brain damage following primary pediatric MMR vaccination in comparison to DTwcP
vaccination. These results are remarkable considering that DTwcP vaccination
has been found by the scientific and medical communities to be responsible for
permanent neurologic sequellae in children. Another study found 18 cases of
neurological complications following live measles vaccine administered between
1971 to 1978 in Hamburg, Germany. A causal connection was assumed by the author
in 14 of the cases, resulting in an incidence of 1 per 2,500 vaccinees. The
author observed an incidence of 1 per 17,650 vaccinees of abortive
encephalopathy following live measles vaccination. In conclusion, this study
showed a highly statistically significant increase in serious neurologic
conditions following primary pediatric MMR vaccination in comparison to a DTwcP
vaccine control group. This finding confirms and extends a number of previous
studies showing that patients are at increased risk for developing serious
neurologic disorders for about 5-10 days following pediatric MMR vaccination.
The pathogenesis of these reactions appears to follow a similar course as in
the natural viral infections. In order to alleviate the potential for serious
neurologic disorders following primary pediatric MMR vaccination, we recommend
that killed MMR vaccine be made available. If live MMR vaccine is to be used,
parents should have the option to have each viral component of MMR vaccine
administered separately. http://www.tested.net/vaccine/MMRresearch.pdf

“These results show that primary pediatric MMR vaccination in children is
associated with a marked increase in serious neurologic disorders in comparison
to DTwcP vaccination. The increase is statistically significant for cerebellar
ataxia, autism, mental retardation and permanent brain damage following primary
pediatric MMR vaccination in comparison to DTwcP vaccination. These results are
remarkable considering that DTwcP vaccination has been found by the scientific
and medical communities to be responsible for permanent neurologic sequellae in
children.”

Revue Neurologique, Paris • February 2003

Lessons from macrophagic myofasciitis: towards definition of a vaccine
adjuvant-related syndrome Author information Gherardi RK. Groupe Nerf-Muscle,
Département de Pathologie Hôpital Henri Mondor, Créteil
romain.gherardi@hmn.ap-hop-paris.fr Abstract Macrophagic myofasciitis is a
condition first reported in 1998, which cause remained obscure until 2001. Over
200 definite cases have been identified in France, and isolated cases have been
recorded in other countries. The condition manifests by diffuse myalgias and
chronic fatigue, forming a syndrome that meets both Center for Disease Control
and Oxford criteria for the so-called chronic fatigue syndrome in about half of
patients. One third of patients develop an autoimmune disease, such as multiple
sclerosis. Even in the absence of overt autoimmune disease they commonly show
subtle signs of chronic immune stimulation, and most of them are of the
HLADRB1*01 group, a phenotype at risk to develop polymyalgia rheumatica and
rheumatoid arthritis. Macrophagic myofasciitis is characterized by a
stereotyped and immunologically active lesion at deltoid muscle biopsy.
Electron microscopy, microanalytical studies, experimental procedures, and an
epidemiological study recently demonstrated that the lesion is due to
persistence for years at site of injection of an aluminum adjuvant used in
vaccines against hepatitis B virus, hepatitis A virus, and tetanus toxoid.
Aluminum hydroxide is known to potently stimulate the immune system and to
shift immune responses towards a Th-2 profile. It is plausible that persistent
systemic immune activation that fails to switch off represents the
pathophysiologic basis of chronic fatigue syndrome associated with macrophagic
myofasciitis, similarly to what happens in patients with post-infectious
chronic fatigue and possibly idiopathic chronic fatigue syndrome. Therefore,
the WHO recommended an epidemiological survey, currently conducted by the
French agency AFSSAPS, aimed at substantiating the possible link between the
focal macrophagic myofasciitis lesion (or previous immunization with
aluminium-containing vaccines) and systemic symptoms. Interestingly, special
emphasis has been put on Th-2 biased immune responses as a possible explanation
of chronic fatigue and associated manifestations known as the Gulf war
syndrome. Results concerning macrophagic myofasciitis may well open new avenues
for etiologic investigation of this syndrome. Indeed, both type and structure
of symptoms are strikingly similar in Gulf war veterans and patients with
macrophagic myofasciitis. Multiple vaccinations performed over a short period
of time in the Persian gulf area have been recognized as the main risk factor
for Gulf War syndrome. Moreover, the war vaccine against anthrax, which is
administered in a 6shot regimen and seems to be crucially involved, is
adjuvanted by aluminium hydroxide and, possibly, squalene, another Th-2
adjuvant. If safety concerns about long-term effects of aluminium hydroxide are
confirmed it will become mandatory to propose novel and alternative vaccine
adjuvants to rescue vaccine-based strategies and the enormous benefit for
public health they provide worldwide.
http://www.ncbi.nlm.nih.gov/pubmed/12660567

“Macrophagic myofasciitis is a condition first reported in 1998, which cause
remained obscure until 2001. Over 200 definite cases have been identified in
France, and isolated cases have been recorded in other countries [many
thousands of cases have since been identified]. Electron microscopy,
microanalytical studies, experimental procedures, and an epidemiological study
recently demonstrated that the lesion is due to persistence for years at site
of injection of an aluminum adjuvant used in vaccines against hepatitis B
virus, hepatitis A virus, and tetanus toxoid ... If safety concerns about
long-term effects of aluminium hydroxide are confirmed it will become mandatory
to propose novel and alternative vaccine adjuvants to rescue vaccine-based
strategies ...”

Arthritis & Rheumatism • February 2003

Chronic fatigue syndrome in patients with macrophagic myofasciitis
François-Jérôme Authier MD, PhD, Stéphane Sauvat MD, Julien Champey MD, Irène
Drogou MD, Michèle Coquet MD andRomain K. Gherardi MD Abstract Macrophagic
myofasciitis (MMF), a condition first reported in France in 1998, is defined by
the presence of a stereotyped and immunologically active lesion at deltoid
muscle biopsy (1, 2). It was recently demonstrated that this lesion is an
indicator of long-term persistence of the immunologic adjuvant aluminum
hydroxide within the cytoplasm of macrophages at the site of previous
intramuscular (IM) injection (2). MMF is typically detected in patients with
diffuse arthromyalgias that have appeared subsequent to aluminum hydroxide
administration in the absence of a clearly defined anatomic substratum (2).
Patients also report unexplained chronic fatigue (1). These manifestations are
reminiscent of the so-called chronic fatigue syndrome (CFS), a poorly
understood condition manifesting as disabling fatigue, musculoskeletal pain,
sleep disturbance, impaired concentration, and headaches (3). The present study
was conducted to determine the proportion of MMF patients fulfilling
international criteria for CFS. Thirty unselected consecutive patients with
biopsy-proven MMF identified in Créteil and Bordeaux were retrospectively
included, regardless of symptoms that led to indication of muscle biopsy. As
previously described (2), MMF was assessed by 1) well-circumscribed sheets of
denselypacked, large, nonepithelioid macrophages with a finely granular,
periodic acid–Schiff–positive content, in the connective structures of deltoid
muscle; 2) lymphocytic infiltrates intermingled with macrophages and forming
microvascular cuffs; and 3) absence of significant muscle fiber injury (see
Figure 1). In each patient, we determined, through both chart review and either
direct patient questioning or telephone interview, 1) the presence of chronic
fatigue of >6 months’ duration, 2) the alleged severity of fatigue, and 3) the
presence of CFS according to Centers for Disease Control and Prevention (CDC)
criteria (1994) (4) or Oxford criteria (1991) (5). In addition, in 20 patients,
we retrospectively evaluated history of immunization as well as prevalence of
fever and neurologic features suggestive of central nervous system
demyelinating disease; laboratory findings, including erythrocyte sedimentation
rate, creatine kinase levels, and 67Ga scintigraphy; and responsiveness to
steroids. Figure 1. Deltoid muscle biopsy samples from patients with
macrophagic myofasciitis (MMF). A, Tightly packed, large, basophilic
macrophages intermingled with lymphocytes in perifascicular endomysium (frozen
section, hematoxylin and eosin stained; original magnification ×400). B, MMF
lesion in perimuscular adipose tissue showing immunolocalization of the
macrophage marker CD68 (paraffin section, immunoperoxidase procedure; original
magnification ×400). C, Adjacent section of the same biopsy sample showing
immunolocalization of the T cell marker CD3 (paraffin section, immunoperoxidase
procedure; original magnification ×400).

The male:female ratio was 1:2. The mean age of patients was 52 years (range
12–78 years). Chronic fatigue was found in 28 of 30 patients (93%) and was
considered disabling in 26 of 30 patients (87%). Sixteen patients (53%)
fulfilled CFS criteria from either the CDC (14 of 30 patients, 47%) or Oxford
(12 of 30 patients, 40%), 11 of 30 patients (37%) fulfilled both CDC and Oxford
criteria. Other symptoms, laboratory findings, and steroid responsiveness are
detailed in Table 1. 67Ga scintigraphy was performed in 5 patients and showed
increased levels of 67Ga uptake in muscle and para-articular areas, mainly in
lower limbs. A history of vaccination was available for 19 of 20 patients. All
19 patients had received IM administration of aluminum-containing vaccine prior
to the onset of CFS symptoms, and the delay from the last vaccination to the
first manifestations ranged from 1 month to 72 months (median 12 months). We
have previously determined that myalgias are a major symptom in patients with
MMF. The prevalence of myalgias was much higher in such patients than in other
patients who had undergone deltoid muscle biopsies at the same time in the same
centers (85% versus 45%; P < 0.0001 by Fisher’s exact test) (2). We show now
that chronic disabling fatigue is a symptom as frequent as diffuse myalgias in
patients with MMF (87%), a finding also noted in the French Institut de Veille
Sanitaire exploratory investigation report (6). More than half of the patients
also reported other manifestations of CFS. Therefore, MMF should be
alternatively considered as a cause of CFS or as an additional exclusion
criterion, along with rheumatoid arthritis, lupus, and other diseases, for the
diagnosis of idiopathic CFS (4). Consequently, we suggest that patients with
CFS should be carefully checked for a history of IM administration of aluminum
hydroxide, and, if there is consistent chronology, a muscle biopsy to search
for MMF at the site of injection should be considered, even many years after
onset of symptoms. Pathophysiology of CFS is still fiercely debated by
psychologists, neuroendocrinologists, and immunologists. Chronic immune
stimulation that fails to switch off has been previously reported as a possible
cause of CFS (7–9), and such a situation may very well result from persistence
of the immunologic adjuvant aluminum hydroxide within antigen-presenting cells
(2, 10). Therefore, MMF may well represent a paradigm for CFS of immunologic
origin. We believe that clarification of MMF pathophysiology would
significantly contribute to the understanding of the whole spectrum of chronic
fatigue and its syndromes.

Full Report: http://onlinelibrary.wiley.com/doi/10.1002/art.10740/full PDF:
http://onlinelibrary.wiley.com/doi/10.1002/art.10740/epdf

Expert Opinion On Drug Safety • March 2003

A review of hepatitis B vaccination Author information Geier MR1, Geier DA,
Zahalsky AC. The Genetic Centers of America 14 Redgate Ct, Silver Spring, MD
20905, USA mgeier@erols.com Abstract Hepatitis B is one of the most important
infectious causes of acute and chronic liver disease both in the US and
worldwide. In order to combat the life-threatening effects of hepatitis B
infection, recombinant hepatitis B vaccines have been developed. The medical
and scientific communities have generally accepted that recombinant hepatitis B
vaccine - a highly purified, genetically engineered, single antigen vaccine -
is a safe vaccine. Information is presented showing that hepatitis B vaccine
contains yeast, aluminium, thimerosal and hepatitis B surface antigen epitopes,
which may result in hepatitis B vaccine being associated with autoimmune
diseases among susceptible adult vaccine recipients. There is little doubt that
the benefits of this vaccine overall far outweigh its risks. Physicians and
patients should evaluate the risks and benefits of hepatitis B vaccination and,
together, make an informed consent decision as to whether to undergo
vaccination. Individuals who experience an adverse reaction to hepatitis B
vaccination should report it to the Vaccine Adverse Event Reporting System
database and be advised that they may be eligible for compensation from the
no-fault National Vaccine Injury Compensation Program, administered by the US
Court of Claims. The authors strongly urge that additional research be
conducted into the molecular basis of adverse events following hepatitis B
vaccine administration, so that further recommendations may be made on how to
improve their safety profiles. http://www.ncbi.nlm.nih.gov/pubmed/12904111

“Information is presented showing that hepatitis B vaccine contains yeast,
aluminium, thimerosal and hepatitis B surface antigen epitopes, which may
result in hepatitis B vaccine being associated with autoimmune diseases among
susceptible adult vaccine recipients.”

Pediatric Neurology • April 2003

Elevated levels of measles antibodies in children with autism Author
information Singh VK1, Jensen RL. Department of Biology and Biotechnology
Center Utah State University, Logan, Utah, USA Abstract Virus-induced
autoimmunity may play a causal role in autism. To examine the etiologic link of
viruses in this brain disorder, we conducted a serologic study of measles
virus, mumps virus, and rubella virus. Viral antibodies were measured by
enzyme-linked immunosorbent assay in the serum of autistic children, normal
children, and siblings of autistic children. The level of measles antibody, but
not mumps or rubella antibodies, was significantly higher in autistic children
as compared with normal children (P = 0.003) or siblings of autistic children
(P <or= 0.0001). Furthermore, immunoblotting of measles vaccine virus revealed
that the antibody was directed against a protein of approximately 74 kd
molecular weight. The antibody to this antigen was found in 83% of autistic
children but not in normal children or siblings of autistic children. Thus
autistic children have a hyperimmune response to measles virus, which in the
absence of a wild type of measles infection might be a sign of an abnormal
immune reaction to the vaccine strain or virus reactivation.
http://www.ncbi.nlm.nih.gov/pubmed/?term=12849883

“Thus autistic children have a hyperimmune response to measles virus, which in
the absence of a wild type of measles infection might be a sign of an abnormal
immune reaction to the vaccine strain or virus reactivation.”

Clinical Immunology • May 2003

Influenza vaccination and Guillain Barre syndrome Author information Geier MR1,
Geier DA, Zahalsky AC. The Genetic Centers of America 14 Redgate Court, Silver
Spring, MD 20905, USA mgeier@erols.com Abstract Acute and severe Guillain Barre
Syndrome (GBS) cases reported following influenza vaccine to the Vaccine
Adverse Events Reporting System (VAERS) database from 1991 through 1999 were
examined. Endotoxin concentrations were measured using the Limulus amebocyte
lysate assay in influenza vaccines. There were a total of 382 cases of GBS
reported to the VAERS database following influenza vaccination (male/female
ratio, 1.2). The median onset of GBS following influenza vaccine was 12 days
(interquartile range, 7 days to 21 days). There was an increased risk of acute
GBS (relative risk, 4.3; 95% confidence interval, 3.0 to 6.4) and severe GBS
(relative risk, 8.5; 95% confidence interval, 3.7 to 18.9) in comparison to an
adult tetanus-diphtheria (Td) vaccine control group. There were maximums in the
incidence of GBS following influenza vaccine that occurred approximately every
third year (1993, 1996, and 1998) and statistically significant variation in
the incidence of GBS among different influenza manufacturers. Influenza
vaccines contained from a 125- to a 1250fold increase in endotoxin
concentrations in comparison to an adult Td vaccine control and endotoxin
concentrations varied up to 10-fold among different lots and manufacturers of
influenza vaccine. The biologic mechanism for GBS following influenza vaccine
may involve the synergistic effects of endotoxin and vaccine-induced
autoimmunity. There were minimal potential reporting biases in the data
reported to the VAERS database in this study. Patients should make an informed
consent decision on whether to take this optional vaccine based upon its safety
and efficacy and physicians should vigilantly report GBS following influenza
vaccination to the VAERS in the United States so that continued evaluation of
the safety of influenza vaccine may be undertaken.
http://www.ncbi.nlm.nih.gov/pubmed/?term=12763480

“from 1991 through 1999 ... There were a total of 382 cases of Guillain-Barre
Syndrome reported to the VAERS database following influenza vaccination ...”

Mediators Of Inflammation • August 2003

Cytokine profile after rubella vaccine inoculation: evidence of the
immunosuppressive effect of vaccination Author information Pukhalsky AL1,
Shmarina GV, Bliacher MS, Fedorova IM, Toptygina AP, Fisenko JJ, Alioshkin VA
Research Centre for Medical Genetics 1 Moskvorechie Street Moscow 11547 Russia
Abstract BACKGROUND AND AIM: Immunization with live virus vaccines may cause an
immunosuppression with lymphopaenia, impaired cytokine production and defective
lymphocyte response to mitogenes. These abnormalities were described in
subjects vaccinated against measles. This study was performed to analyse the
host immune response related to immunosuppression in subjects vaccinated with
live attenuated rubella vaccine. METHODS: Eighteen schoolgirls, aged 11-13
years, were vaccinated with live attenuated rubella vaccine Rudivax. Before
immunization, and 7 and 30 days after, peripheral blood was collected. Cellular
fractions were subjected to flow cytometric analysis, and the lymphocyte
response to phytohaemagglutinin was investigated. Plasma samples were analysed
for cytokines (interleukin (IL)-4, IL-10, tumour necrosis factor-alpha, and
interferon-gamma) by enzyme-linked immunosorbent assay techniques. RESULTS: On
day 7 after vaccination, the number of each lymphocyte subset was decreased;
however, only for CD3 and CD4 lymphocytes has a significant reduction been
shown. On the contrary, tumour necrosis factor-alpha and IL-10 levels markedly
increased and amounted to its maximum on day 30. Simultaneously, a significant
reduction in plasma interferongamma and a profound decrease of the lymphocyte
response to phytohaemagglutinin were shown. The changes were accompanied with
marked elevation of plasma IL-4. CONCLUSIONS: Our data indicate that the
vaccination with live attenuated rubella vaccine results in moderate but
sustained immune disturbance. The signs of immunosuppression, including
defective lymphocyte response to mitogene and impaired cytokine production, may
persist for at least 1 month after vaccination.
http://www.ncbi.nlm.nih.gov/pubmed/?term=14514470

“Immunization with live virus vaccines may cause an immunosuppression with
lymphopaenia, impaired cytokine production and defective lymphocyte response to
mitogenes. These abnormalities were described in subjects vaccinated against
measles. Our data indicate that the vaccination with live attenuated rubella
vaccine results in moderate but sustained immune disturbance.”

“The potential to induce autoimmunity may complicate the use of
oil adjuvants in human and veterinary vaccines.” Journal Of Autoimmunity •
August 2003

Induction of lupus autoantibodies by adjuvants Author information Satoh M1,
Kuroda Y, Yoshida H, Behney KM, Mizutani A, Akaogi J, Nacionales DC, Lorenson
TD, Rosenbauer RJ, Reeves WH. Division of Rheumatology and Clinical Immunology
Department of Medicine, University of Florida P.O. Box 100221, 1600 SW Archer
Road Gainesville, FL 32610-0221, USA satohm@medicine.ufl.edu Abstract Exposure
to the hydrocarbon oil pristane induces lupus specific autoantibodies in
non-autoimmune mice. We investigated whether the capacity to induce lupus-like
autoimmunity is a unique property of pristane or is shared by other adjuvant
oils. Seven groups of 3-month-old female BALB/cJ mice received a single
intraperitoneal injection of pristane, squalene (used in the adjuvant MF59),
incomplete Freund’s adjuvant (IFA), three different medicinal mineral oils, or
saline, respectively. Serum autoantibodies and peritoneal cytokine production
were measured. In addition to pristane, the mineral oil Bayol F (IFA) and the
endogenous hydrocarbon squalene both induced anti-nRNP/Sm and -Su
autoantibodies (20% and 25% of mice, respectively). All of these hydrocarbons
had prolonged effects on cytokine production by peritoneal APCs. However, high
levels of IL-6, IL-12, and TNFalpha production 2-3 months after intraperitoneal
injection appeared to be associated with the ability to induce lupus
autoantibodies. The ability to induce lupus autoantibodies is shared by several
hydrocarbons and is not unique to pristane. It correlates with stimulation of
the production of IL-12 and other cytokines, suggesting a relationship with a
hydrocarbon’s adjuvanticity. The potential to induce autoimmunity may
complicate the use of oil adjuvants in human and veterinary vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/?term=12892730

Neurology • September 2003

Excess incidence of ALS in young Gulf War veterans Author information Haley RW.
Epidemiology Division Department of Internal Medicine University of Texas
Southwestern Medical Center Dallas, TX 75390-8874, USA
Robert.Haley@UTSouthwestern.edu Abstract BACKGROUND Reported cases of ALS in
young veterans of the 1991 Gulf War have suggested excess incidence. OBJECTIVE
To compare observed and expected incidence of ALS in Gulf War veterans
diagnosed before age 45 years (young veterans). METHODS Cases of ALS diagnosed
from 1991 through 1998 were collected from military registries and a publicity
campaign in late 1998. Diagnoses were established from neurologists’ medical
records using El Escorial criteria. Expected incidence was estimated from the
age distribution of the Gulf War veteran population, weighted by age-specific
death rates of the US population. Secular changes in nationwide ALS rates were
assessed using calculations of the age-specific US population death rates from
vital statistics data of 1979 to 1998. RESULTS During 8 postwar years, 20 ALS
cases were confirmed in approximately 690,000 Gulf War veterans, and 17 were
diagnosed before age 45 years. All developed bulbar and spinal involvement, and
11 have died. In young veterans, the expected incidence increased from 0.93
cases/year in 1991 to 1.57 cases/year in 1998, but the observed incidence
increased from 1 to 5 cases/year. The observed incidence was 0.94 (95% CI, 0.26
to 2.41) times that expected in the baseline period from 1991 to 1994 (4 vs
4.25 cases; p = 0.6); it increased to 2.27 (95% CI, 1.27 to 3.88) times that
expected during the 4-year period from 1995 to 1998 (13 vs 5.72 cases; p =
0.006); and it peaked at 3.19 (95% CI, 1.03 to 7.43) times that expected in
1998 (5 vs 1.57 cases; p = 0.02). The magnitude of the excess of ALS cases over
the expected incidence increased during the 8-year period (Poisson trend test,
p = 0.05), and the increase was not explained by a change in the interval from
onset to diagnosis or by a change in the US population death rate of ALS in
those aged <45 years. CONCLUSIONS The observed incidence of ALS in young Gulf
War veterans exceeded the expected, suggesting a war-related environmental
trigger. http://www.ncbi.nlm.nih.gov/pubmed/?term=14504316

“The observed incidence of Amyotrophic Lateral Sclerosis in young Gulf War
veterans exceeded the expected ...”

Neuroscience And Biobehavioral Reviews • October 2003

Analysis of neurological disease in four dimensions: insight from ALS-PDC
epidemiology and animal models Author information Shaw CA1, Wilson JM. Program
in Neuroscience University of British Columbia Vancouver, BC, Canada
cshaw@interchange.ubc.ca Abstract The causal factor(s) responsible for sporadic
neurological diseases are unknown and the stages of disease progression remain
undefined and poorly understood. We have developed an animal model of
amyotrophic lateral sclerosis-parkinsonism dementia complex which mimics all
the essential features of the disease with the initial neurological insult
arising from neurotoxins contained in washed cycad seeds. Animals fed washed
cycad develop deficits in motor, cognitive, and sensory behaviors that
correlate with the loss of neurons in specific regions of the central nervous
system. The ability to recreate the disease by exposure to cycad allows us to
extend the model in multiple dimensions by analyzing behavioral, cellular, and
biochemical changes over time. In addition, the ability to induce toxin-based
neurodegeneration allows us to probe the interactions between genetic and
epigenetic factors. Our results show that the impact of both genetic causal and
susceptibility factors with the cycad neurotoxins are complex. The article
describes the features of the model and suggests ways that our understanding of
cycad-induced neurodegeneration can be used to decipher and identify the early
events in various human neurological diseases.
http://www.ncbi.nlm.nih.gov/pubmed/?term=14599431

“... causal factor(s) responsible for sporadic neurological diseases are
unknown and the stages of disease progression remain undefined and poorly
understood.”

Immunology And Allergy Clinics Of North America • November 2003

Aluminum inclusion macrophagic myofasciitis: a recently identified condition
Author information Gherardi RK1, Authier FJ. Muscle and Nerve Group Henri
Mondor University Hospital Créteil, France lauret@univ-paris12.fr Abstract The
authors conclude that the persistence of aluminum hydroxide at the site of
intramuscular injection is a novel finding which has an exact significance that
remains to be established fully. It seems mandatory to evaluate possible
long-term adverse effects induced by this compound, because this issue has not
been addressed (in the past, aluminum hydroxide was believed to be cleared
quickly from the body). If safety concerns about the long-term effects of
aluminum hydroxide are confirmed, novel and alternative vaccine adjuvants to
rescue vaccine-based strategies should be proposed to ensure the enormous
benefit for public health that these vaccines provide worldwide.
http://www.ncbi.nlm.nih.gov/pubmed/?term=14753387

“The authors conclude that the persistence of aluminum hydroxide at the site of
intramuscular injection is a novel finding which has an exact significance that
remains to be established fully.”

“... it has become apparent over the past 20 years, and most notably during the past 10 years,
that an array of metabolic machinery is also expressed in this organ ...” Drug
Metabolism & Disposition • December 2003

The Small Intestine As A Xenobiotic-Metabolizing Organ Author Information
Laurence S. Kaminsky and Qing-Yu Zhang Wadsworth Center, New York State
Department of Health Albany, New York (L.S.K., Q-Y.Z.) Department of
Environmental Health and Toxicology School of Public Health, University at
Albany State University of New York, Albany, New York (L.S.K.) Address
correspondence to: Dr. Laurence Kaminsky, New York State Department of Health
Wadsworth Center, P.O. Box 509, Albany, NY 12201-0509 kaminsky@wadsworth.org
Abstract The mammalian small intestine serves principally as the site for
absorption of nutrients, water, and both beneficial and potentially harmful
xenobiotics. However, it has become apparent over the past 20 years, and most
notably during the past 10 years, that an array of metabolic machinery is also
expressed in this organ (Kaminsky and Fasco, 1992; Lin et al., 1999; Doherty
and Charman, 2002; Ding and Kaminsky, 2003). Both phase I and phase II
metabolic enzymes are expressed, together with associated transporters. In this
minireview we discuss some of the most prominent phase I and II enzymes in the
metabolic systems in the small intestine. The transporters, despite their
importance for the fate of enterocyte- absorbed xenobiotics, are beyond the
scope of this minireview (Suzuki and Sugiyama, 2000).
http://dmd.aspetjournals.org/content/31/12/1520.long

[vaccines are xenobiotics]

Pediatrics • December 2003

Addressing parents’ concerns: do vaccines contain harmful preservatives,
adjuvants, additives, or residuals? Author information Offit PA1, Jew RK.
Division of Infectious Diseases Children’s Hospital of Philadelphia University
of Pennsylvania School of Medicine and Wistar Institute of Anatomy and Biology
Philadelphia, Pennsylvania 19104, USA offit@email.chop.edu Abstract Vaccines
often contain preservatives, adjuvants, additives, or manufacturing residuals
in addition to pathogen-specific immunogens. Some parents, alerted by stories
in the news media or information contained on the World Wide Web, are concerned
that some of the substances contained in vaccines might harm their children. We
reviewed data on thimerosal, aluminum, gelatin, human serum albumin,
formaldehyde, antibiotics, egg proteins, and yeast proteins. Both gelatin and
egg proteins are contained in vaccines in quantities sufficient to induce rare
instances of severe, immediate-type hypersensitivity reactions. However,
quantities of mercury, aluminum, formaldehyde, human serum albumin,
antibiotics, and yeast proteins in vaccines have not been found to be harmful
in humans or experimental animals. http://www.ncbi.nlm.nih.gov/pubmed/14654615

[Dr. Offit, pro-vaccine media pundit, discusses vaccine safety with parents]

Alternative Medicine Reviews • 2003

Th1/Th2 Balance: The Hypothesis, its Limitations, and Implications for Health
and Disease Parris Kidd, PhD Abstract One theory of immune regulation involves
homeostasis between T-helper 1 (Th1) and T- helper 2 (Th2) activity. The
Th1/Th2 hypothesis arose from 1986 research suggesting mouse T-helper cells
expressed differing cytokine patterns. This hypothesis was adapted to human
immunity, with Th1- and Th2-helper cells directing different immune response
pathways. Th1 cells drive the type-1 pathway (“cellular immunity”) to fight
viruses and other intracellular pathogens, eliminate cancerous cells, and
stimulate delayed-type hypersensitivity (DTH) skin reactions. Th2 cells drive
the type-2 pathway (“humoral immunity”) and up-regulate antibody production to
fight extracellular organisms; type 2 dominance is credited with tolerance of
xenografts and of the fetus during pregnancy. Overactivation of either pattern
can cause disease, and either pathway can down-regulate the other. But the
hypothesis has major inconsistencies; human cytokine activities rarely fall
into exclusive pro- Th1 or -Th2 patterns. The non-helper regulatory T cells, or
the antigen-presenting cells (APC), likely influence immunity in a manner
comparable to Th1 and Th2 cells. Many diseases previously classified as Th1 or
Th2 dominant fail to meet the set criteria. Experimentally, Th1 polarization is
readily transformed to Th2 dominance through depletion of intracellular
glutathione, and vice versa. Mercury depletes glutathione and polarizes toward
Th2 dominance. Several nutrients and hormones measurably influence Th1/Th2
balance, including plant sterols/sterolins, melatonin, probiotics,
progesterone, and the minerals selenium and zinc. The long- chain omega-3 fatty
acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) significantly
benefit diverse inflammatory and autoimmune conditions without any specific
Th1/Th2 effect. Th1/Th2-based immunotherapies, e.g., T-cell receptor (TCR)
peptides and interleukin-4 (IL- 4) injections, have produced mixed results to
date. Conclusion In managing immune hypofunction or other dysfunction, it is
crucial to manage all forms of stress. Rooks reported diverse stressors,
includ- ing sleep deprivation, calorie restriction, excessive exercise,
examination stress, and cardiopul- monary bypass surgery, down-regulate Th1 and
up-regulate Th2 activity.95 These effects are mediated mainly by
glucocorticoids, but also by the catecholamine hormones epinephrine and norepi-
nephrine.92 As heroic efforts to tailor technological immune therapies go
forward, the best immune intervention tools continue to be lifestyle
modification, vitamins, minerals, orthomolecules, and selected nontoxic
phytotherapies. http://www.altmedrev.com/publications/8/3/223.pdf

“As heroic efforts to tailor technological immune therapies go forward, the
best immune intervention tools continue to be lifestyle modification, vitamins,
minerals, orthomolecules, and selected nontoxic phytotherapies.”

Brain Pathology • January 2004

The July 2003 Case of the Month (COM) 62-year-old female with progressive
muscular weakness Author information Bornemann A1, Bohl J, Schneider HM, Goebel
HH, Schmidt PF, Gherardi RK. Institute of Brain Research Eberhard-Karls
University Tübingen, Germany Abstract The July 2003 Case of the Month (COM). A
62-year-old female patient experienced progressive muscular weakness over the
last ten years, involving shoulder and pelvic girdle muscles, paraspinal and
facial muscles. A biopsy was taken from the left deltoid muscle where hepatitis
vaccination had taken place 4 weeks previously. The specimen revealed
macrophagic myofasciitis due to the injection of aluminium-bound vaccines. The
finding can be reproduced experimentally by injecting vaccines in rats. The
pathomechanism is supposed to involve immune stimulation due to long term
persistence of the adjuvant. Macrophagic myofasciitis has been suggested to
occasionally cause myopathy but is supposed to be unrelated to the underlying
myopathy in our patient. http://www.ncbi.nlm.nih.gov/pubmed/?term=14997943

“The specimen revealed macrophagic myofasciitis due to the injection of
aluminium-bound vaccines.”

“When mass vaccination programs encompass billions of lives, even relatively rare toxicity events cannot be tolerated.”
Presentation to the Vaccine Safety Committee of the Institute of Medicine The
National Academies of Science • February 9, 2004 Jeff Bradstreet MD, ICDRC
321-953-0278

Biological Evidence of Significant Vaccine Related Side-effects Resulting in
Neurodevelopmental Disorders Hypothesis Evident for many individuals
experienced with these issues, is the data supporting unprecedented levels of
neurodevelopmental and immune disorders within the last two decades. The
prevalence has risen to the point that many believe it has reached epidemic
proportions. Our group of researchers and clinicians, have hypothesized that a
subset of neurodevelopmental and medical disorders including: encephalopathy
with autistic features, a unique inflammatory bowel disease, along with speech,
learning and sensorimotor dysfunction, represent the manifestations of injuries
related to vaccine components, especially mercury in the form of Thimerosal and
measles virus from the MMR. Part of this hypothesis has been the existence of
specific genetic vulnerability or environmental susceptibility cofactors. Our
group represents researchers and clinicians with heterogeneous experience and
expertise, that when taken together, provide the substance for a broad
understanding of this phenomena.

Vaccine Contribution to Public Health The well-accepted benefits of
vaccinations to prevention of many childhood and serious illnesses are without
question. All the data presented herein are intended to improve vaccine safety
and long-term public confidence in vaccines. When mass vaccination programs
encompass billions of lives, even relatively rare toxicity events cannot be
tolerated. While others may debate the frequency of specific adverse events and
the appropriate detection and surveillance methodologies, medicine remains
governed by the foundational tenet, primum non nocere. Where options exist, as
is the case with Thimerosal, there is no acceptable rationale for continued use
of a known, suspected or plausible neurotoxin in vaccines for developing
children. Safe vaccine policy can now completely eliminate any concern of
mercury for every age-group. This way, none of us need to fear even subtle
potential effects of mercury.

Thesis It must be recognized I am defining the data of a subgroup of children
and in no way making estimates about autism or autism spectrum disorders in
general. These terms will be discussed further in a moment. For what is often
referred to as the broader autism phenotype, numerous candidate genes have been
presented in the literature which I will not discuss here. To my knowledge,
none of these genes would serve as susceptibility genes for measles viral
persistence, mercury toxicity or autoimmunity of the type we will describe in
this presentation, with the exception of the haplotype B44-SC30-DR4. Within
this population, specific vulnerability factors, i.e. single nucleotide
polymorphisms (SNP) within genes for enzymes regulating the methionine
transulfuration and glutathione systems, occur at statistically significant
greater frequency than within the general or control populations. The
biochemical defects predicted by these SNP are all present as well. These
include: low methionine, thiol deficiencies, heavy metal (particularly mercury)
accumulation, immunological disorders including autoimmunity and
neurotransmitter malregulation, and the probability of viral persistence.
Proteomic studies are presently underway and will help to further define and
confirm these associations. Other environmental factors include oxidative
stress, which has broad implications on chemistry, and in utero exposure to
mercury (methylmercury from fish and Thimerosal in anti-Rho immunoglobulin
preparations). In all endpoint issues, the findings have been reproduced by at
least two independent laboratories, and as in the case of SNP identification
and low thiols, by multiple laboratories using various methodologies. These
data will be presented in summary form to the committee during the brief time
allotted, but will be presented in toto in written form with supporting
literature.

The sixth month cut-off, which seems to be in practice (whereby children over 6
months are routinely advised to take vaccines with 25 mcg of ethylmercury, e.g.
influenza vaccine) is equally untenable. As has been eloquently demonstrated by
Landing et al, (full paper submitted: Pediatric Pathology and Molecular
Medicine 21: 321^342, 2002) the organization of the six layers of the human
neocortex undergoes repeated and dynamic changes during the exact time when a
known neurotoxicant (ethylmercury) has been and is continuing to be
administered. Strides to reduce Thimerosal in vaccines have been partially
successful in the youngest children, but incompletely understood potential
risks remain in older children who are still being exposed through Diptheria
Tetanus boosters, Influenza and other vaccines. Since no market-ready
alternative for MMR exists in the US, this is a more challenging issue until
new options emerge. I did receive notice from Secretary Tommy Thompson that a
nasal measles vaccine was in development and expected within 2-3 years. No
safety data is available, nor will be available for some time. Researchers at
Johns Hopkins are working on a DNA MV vaccine. The concept is designed to
further improve safety, but I have serious reservation regarding those within
the population at risk for DNA hypomethylation, i.e. the same individuals with
deficient methionine production secondary to folate deficiency, MTHFR defects
or other factors. Methylation of viral DNA is a critical pathway to viral
replication regulation/ suppression. A discussion of this is beyond the scope
of this paper. Below are two graphs from the Landing paper, presented here to
allow easier understanding of the timing issue on neocortical development.
http://www.vaccinationnews.org/DailyNews/2004/February/IOMBradstreet14.htm Full
Report:
http://iom.nationalacademies.org/~/media/4B8DAC4AD18F432283E67D91DB81F49B.ashx

Neuromuscular Disorders • February 2004

Macrophagic myofasciitis: an infantile Italian case Author information Di Muzio
A1, Capasso M, Verrotti A, Trotta D, Lupo S, Pappalepore N, Manzoli C,
Chiarelli F, Uncini A. Center for Neuromuscular Diseases University ‘G.
d’Annunzio’, Chieti, Italy Abstract Macrophagic myofasciitis is a recently
identified inflammatory myopathy mostly described in adult French patients
complaining of arthro-myalgias and fatigue. It is probably due to intramuscular
injection of aluminium-containing vaccines and is characterized by a typical
muscular infiltrate of large macrophages with aluminium inclusions. We report a
1-year-old Italian child presenting irritability, delayed motor development,
hyperCKemia (up to 10 times the normal value), and typical features of
macrophagic myofasciitis on muscle biopsy. The child recovered fully after
steroid therapy. Macrophagic myofasciitis is a new treatable cause of motor
retardation and hyperCKemia in children, and is probably more common than
reported. Diagnosis requires a high index of suspicion and can be missed if
biopsy is performed outside the vaccination site.
http://www.ncbi.nlm.nih.gov/pubmed/?term=14733966

“It is probably due to intramuscular injection of aluminium-containing vaccines
and is characterized by a typical muscular infiltrate of large macrophages with
aluminium inclusions.”

Pediatrics • April 2004

An analysis of rotavirus vaccine reports to the vaccine adverse event reporting
system: more than intussusception alone? Author information Haber P1, Chen RT,
Zanardi LR, Mootrey GT, English R, Braun MM; VAERS Working Group. National
Immunization Program Centers for Disease Control and Prevention Atlanta,
Georgia 30333, USA phaber@cdc.gov Abstract BACKGROUND The rhesus-human
rotavirus reassortant-tetravalent vaccine (RRV-TV) was licensed on August, 31,
1998, and subsequently recommended for routine infant immunizations in the
United States. After approximately 1 million doses had been administered, an
increase in acute risk of intussusception in vaccinees led to the suspension of
the use of RRV-TV and its withdrawal from the market. These postmarketing
safety studies focused on a single adverse event (intussusception) and, to
minimize the risk of a false-positive finding, accepted only cases that met a
strict case definition. Safer rotavirus vaccines are needed to prevent the
substantial global morbidity and mortality caused by rotavirus infections;
their development and future use may benefit from a better understanding of the
postmarketing safety profile of RRV-TV beyond intussusception. OBJECTIVE To
characterize more completely the postmarketing surveillance safety profile of
RRV-TV more completely by review and analysis of Vaccine Adverse Event
Reporting System (VAERS) case reports to better understand 1) whether severe
adverse events other than intussusception may have occurred after RRV-TV and 2)
the likely scope of gastrointestinal illnesses, of which the previously
identified, highly specific intussusception cases may account for just a
fraction. SETTING AND PARTICIPANTS Infants vaccinated with RRV-TV and other
vaccines in the United States and for whom a report was submitted to VAERS
during September 1, 1998, to December 31, 1999. METHODOLOGY To detect adverse
events of interest other than intussusception, we used proportional morbidity
analysis to compare the adverse event profile of VAERS reports among infants
who received routine vaccines including RRV-TV

(after excluding confirmed and suspected intussusception reports) with infants
who received identical vaccine combinations but without RRV-TV. Next, to better
capture all described diagnoses, signs, and symptoms associated with the
suspected adverse events, a set of new codes was developed and assigned to each
VAERS report. All 448 nonfatal RRV-TV-associated reports (including
intussusception) were recoded manually from the clinical description on the
VAERS report and categorized into clinical groups to better describe a spectrum
of reported illnesses after the vaccine. Each report was assigned to one of the
following hierarchical and mutually exclusive clinical groups: 1) diagnosed
intussusception; 2) suspected intussusception; 3) illness consistent with
either gastroenteritis or intussusception; 4) gastroenteritis; 5) other
gastrointestinal diagnoses (ie, not consistent with intussusception or
rotavirus-like gastroenteritis); and 6) nongastrointestinal diagnoses. RESULTS
Even after excluding intussusception cases, a higher proportion of RRV-TV
reports than non-RRV-TV reports included fever and various gastrointestinal
symptoms, most notably bloody stool but also vomiting, diarrhea, abdominal
pain, gastroenteritis, abnormal stool, and dehydration. Distribution of RRV-TV
reports by clinical groups was as follows: diagnosed intussusception (109
[24%], suspected intussusception (36 [8%]), and illness consistent with
gastroenteritis or intussusception (33 [7%]), gastroenteritis (101 [22%]),
other gastrointestinal diagnoses (10 [2%]), and nongastrointestinal outcomes
(159 [35%]). The median time interval between vaccination and illness onset
decreased incrementally among the first 4 clinical groups: from 7 days for
diagnosed intussusceptions to 3 days for gastroenteritis. CONCLUSIONS
Intussusception and gastroenteritis were the most commonly reported outcomes;
however, a substantial number of reports indicate signs and symptoms consistent
with either illness, possibly suggestive of a spectrum of gastrointestinal
illness(es) related to RRV-TV. Although VAERS data have recognized limitations
such as underreporting (that may differ by vaccine) and are nearly always
insufficient to prove causality between a vaccine and an adverse event, this
safety profile of RRV-TV may aid better understanding of the pathophysiology of
intussusception as well as development of future safer rotavirus vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/15060267

“Intussusception and gastroenteritis were the most commonly reported outcomes;
however, a substantial number of reports indicate signs and symptoms consistent
with either illness, possibly suggestive of a spectrum of gastrointestinal
illness(es) related to RRV-TV.”

“Induction of autoantibodies by mineral oils considered nontoxic
also may have pathogenetic implications in human autoimmune diseases.”
Toxicology Science • April 2004

Distinctive patterns of autoimmune response induced by different types of
mineral oil Author information Kuroda Y1, Akaogi J, Nacionales DC, Wasdo SC,
Szabo NJ, Reeves WH, Satoh M. Division of Rheumatology and Clinical Immunology
Department of Medicine, University of Florida Gainesville, Florida 32610-0221,
USA Abstract Although mineral oils are generally considered nontoxic and have a
long history of use in humans, the mineral oil Bayol F (incomplete Freund’s
adjuvant, IFA) and certain mineral oil components (squalene and n-hexadecane)
induce lupus-related anti-nRNP/Sm or -Su autoantibodies in nonautoimmune mice.
In the present study, we investigated whether medicinal mineral oils can induce
other types of autoantibodies and whether structural features of hydrocarbons
influence autoantibody specificity. Female 3-month-old BALB/c (16-45/group)
mice each received an i.p. injection of pristane (C19), squalene (C30), IFA,
three medicinal mineral oils (MO-F, MO-HT, MO-S), or PBS. Sera were tested for
autoantibodies and immunoglobulin levels. Hydrocarbons were analyzed by gas
chromatography/mass spectrometry. IFA contained mainly C15-C25 hydrocarbons,
whereas MO-HT and MO-S contained C20-C40, and MO-F contained C15-C40. Pristane
and n-hexadecane were found in IFA (0.17% and 0.10% w/v, respectively) and MOs
(0.0026-0.027%). At 3 months, pristane and IFA induced mainly IgG2a, squalene
IgG1, and MOs IgG3 and IgM in sera. Anti-cytoplasmic antibodies were common in
mice treated with MO-F, as well as those treated with pristane, squalene, and
IFA. Anti-ssDNA and -chromatin antibodies were higher in MO-F and MO-S than in
untreated/PBS, squalene-, or IFA-treated mice, suggesting that there is
variability in the induction of anti-nRNP/Sm versus -chromatin/DNA antibodies.
The preferential induction of anti-chromatin/ssDNA antibodies without
antinRNP/Sm/Su by MO-S and MO-F is consistent with the idea that different
types of autoantibodies are regulated differently. Induction of autoantibodies
by mineral oils considered nontoxic also may have pathogenetic implications in
human autoimmune diseases. Full Report
http://toxsci.oxfordjournals.org/content/78/2/222.long

Journal Of American Physicians And Surgeons • Summer 2004

Chronic Microglial Activation and Excitotoxicity Secondary to Excessive Immune
Stimulation: Possible Factors in Gulf War Syndrome and Autism Russell L.
Blaylock, M.D. Abstract There is considerable and growing evidence that chronic
microglial activation plays a major role in numerous neurological conditions
including Alzheimer’s dementia, Parkinson’s disease, ALS, strokes, and
inflammatory brain diseases. The release of toxic elements from activated
microglia, such as cytokines and excitotoxins, is known to produce
neurodegeneration. Peripheral immune stimulation has been shown to activate CNS
microglia, and when excessive can lead to neurodegeneration and cognitive
defects commonly associated with both the Gulf War Syndrome (GWS) and autism.
This paper summarizes the mechanism linking these two disorders with excessive
immune stimulation secondary to overvaccination. The Role of Vaccines As stated
above, peripheral immune stimulation readily activates the brain’s immune
system. In most instances this is short- lived, and neuron damage is minimal.
Chronic activation of microglia, however, can lead to substantial disruption of
neuronal function and even neurodegeneration. Two basic processes seem to be
responsible for the chronic stimulation of brain immunity: repeated, closely
spaced inoculation without allowing brain recovery, and inoculation with live
viruses or contaminant organisms that persist in the brain. Gulf War veterans
were given some 17 inoculations very close together. Children are often given
as many as five to seven inoculations during one visit to the pediatrician’s
office, several as combined vaccines, such as measles-mumps-rubella (MMR). Of
particular concern is the use of live organisms and contaminant organisms.
Garth Nicolson and co-workers have demonstrated polymerase chain reaction (PCR)
evidence of mycoplasma species in the blood samples of Gulf War veterans
suffering from ALS, the incidence of which was found to be increased by 200
percent in this population.40 Nicolson et al. found that 83 percent of veterans
with ALS had positive tests, whereas positives were rarely seen in controls. It
is hypothesized that the vaccines were contaminated primarily with Mycoplasma
fermentens. Numerous activated microglia are found in the spinal cord of
affected veterans. The involvement of live M. fermentens could also explain the
appearance of similar illnesses in other household members. Excitotoxins
contribute to the damage in central nervous system infections. Cerebrospinal
fluid glutamate levels rise in bacterial meningitis, and levels are directly
correlated with prognosis. Extracellular glutamate levels are elevated in all
cases of viral encephalopathies, including that of the acquired
immunodeficiency

syndrome (AIDS). Glutamate and aspartate levels in the plasma were also found
to be elevated in 11 of 14 autistic children.41 There is also evidence that
viruses can enhance the toxicity of glutamate.42 Injection of the immune
adjuvant lipopolysaccharide (LPS) closely resembles the vaccination process. In
one study, it was shown for the first time that peripherally administered LPS
decreased learning in mice.43 The dose used did not produce observable injury
to the neurons, but significantly impaired the animals’ completing the Morris
water maze and spontaneous alternation Y-maze, which tests spatial learning
requiring a functional hippocampus. Associative learning was affected most.
Memory retention was spared. LPS injection, by elevating IL-1 levels, has been
shown to alter hippocampal norepinephrine and serotonin levels, as well as
increasing glutamate levels.44 Elevated serotonin levels have been described in
autism.45 Long-term persistent immune activation and low-grade brain
inflammation have been described in three children who recovered from Herpex
simplex encephalitis before age two.46 The children all demonstrated abundant
activated microglia at brain biopsy and continued to deteriorate after viral
treatment, indicating continued microgial activation. Viral fragments, without
active infection, can produce this phenomenon. Not all persistent viral
infections are associated with obvious inflammatory responses. Using a hamster
neurotrophic strain of measles, it was found that a noninflammatory
encephalopathy could occur with destruction of the CA1 and CA3 segments of the
hippocampus.47 This could more closely resemble the situation in autistic child
and some cases of GWS, since obvious clinical and laboratory signs of
inflammation would be absent. Neurodegeneration caused by this neurotrophic
measles virus was blocked using the NMDA receptor antagonist, MK-801,
indicating an excitotoxic mechanism. (The NMDA receptor is the postsynaptic
receptor for L- glutamate that can be activated by the drug
N-methyl-D-aspartate.) The smallpox vaccine is associated with postvaccinal
encephalitis at a rate of 1 in 110,000 vaccinations. This includes only obvious
cases of encephalitis; more chronic, subtle cases involving ill-defined
neurological symptoms remote from the vaccination would be overlooked. Most
vaccine follow-up studies do not extend beyond two weeks. It is obvious from
the above studies that this follow-up period is far too short. More persistent
neurotropic viruses now being discovered appear to be related to chronic
neurodegeneration. These include HSV-1, coronavirus, measles virus, and human
herpes viruses 6 and 7 (HHV-6 and HHV- 7). A postvaccinal encephalopathy has
been described in children under age two years following the smallpox
vaccine.48 Most of these occur as chronic conditions.

http://www.jpands.org/vol9no2/blaylock.pdf

Toxicology • July 2004

Flow-cytometric analysis on adverse effects of polysorbate 80 in rat thymocytes
Author information Hirama S1, Tatsuishi T, Iwase K, Nakao H, Umebayashi C,
Nishizaki Y, Kobayashi M, Ishida S, Okano Y, Oyama Y. Department of
Pharmaceutical Care and Clinical Pharmacy Faculty of Pharmaceutical Sciences,
Tokushima Bunri University Tokushima 770-8514, Japan Abstract The effects of
polysorbate 80, a non-ionic surfactant widely used in pharmaceutical products,
on rat thymocytes were examined to reveal its toxic property at the cellular
level. Polysorbate 80 at concentrations of 1-100 microg/ml did not
significantly affect the cell viability. This surfactant at 30 microg/ml or
more augmented the intensity of fluo-3 fluorescence, indicating the increase in
intracellular Ca(2+) concentration. Such an augmentation of fluo-3 fluorescence
by polysorbate 80 was not seen under the Ca(2+)-free condition, suggesting that
polysorbate 80 increased membrane Ca(2+) permeability. The
concentration-dependent polysorbate 80 at 10 microg/ ml or more attenuated the
intensity of 5-chloromethylfluorescein, indicating a decrease in cellular
content of glutathione by polysorbate 80. Furthermore, the agent at 1 microg/ml
or more attenuated the intensity of bis-(1,3-dibutylbarbituric acid) trimethine
oxonol fluorescence, being independent from the changes in membrane potential.
This phenomenon indicates that polysorbate 80 at 1 microg/ ml or more may
attenuate the incorporation of anionic compounds into the membranes. It can be
suggested that polysorbate 80 modifies some of membranes and intracellular
physiological parameters without affecting the cell viability.
http://www.ncbi.nlm.nih.gov/pubmed/15147788

“ It can be suggested that polysorbate 80 modifies some of membranes and
intracellular physiological parameters without affecting the cell viability.”

JAMA • July 2004

MMR vaccination and febrile seizures: evaluation of susceptible subgroups and
long-term prognosis Author information Vestergaard M1, Hviid A, Madsen KM,
Wohlfahrt J, Thorsen P, Schendel D, Melbye M, Olsen J. The Danish Epidemiology
Science Centre Department of Epidemiology and Social Medicine Aarhus
University, Aarhus, Denmark mv@soci.au.dk Abstract CONTEXT The rate of febrile
seizures increases following measles, mumps, and rubella (MMR) vaccination but
it is unknown whether the rate varies according to personal or family history
of seizures, perinatal factors, or socioeconomic status. Furthermore, little is
known about the long-term outcome of febrile seizures following vaccination.
OBJECTIVES To estimate incidence rate ratios (RRs) and risk differences of
febrile seizures following MMR vaccination within subgroups of children and to
evaluate the clinical outcome of febrile seizures following vaccination.
DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study of all
children born in Denmark between January 1, 1991, and December 31, 1998, who
were alive at 3 months; 537,171 children were followed up until December 31,
1999, by using data from the Danish Civil Registration System and 4 other
national registries. MAIN OUTCOME MEASURES Incidence of first febrile seizure,
recurrent febrile seizures, and subsequent epilepsy. RESULTS A total of 439,251
children (82%) received MMR vaccination and 17,986 children developed febrile
seizures at least once; 973 of these febrile seizures occurred within 2 weeks
of MMR vaccination. The RR of febrile seizures increased during the 2 weeks
following MMR vaccination (2.75; 95% confidence interval [CI], 2.55-2.97), and
thereafter was close to the observed RR for nonvaccinated children. The RR did
not vary significantly in the subgroups of children that had been defined by
their family history of seizures, perinatal factors, or socioeconomic status.
At 15 to 17 months, the risk difference of febrile seizures within 2 weeks
following MMR vaccination was 1.56 per 1000 children overall (95% CI,
1.44-1.68), 3.97 per 1000 (95% CI, 2.90-5.40) for siblings of children with a
history of febrile seizures, and 19.47 per 1000 (95% CI, 16.05-23.55) for
children with a personal history of febrile seizures. Children with febrile
seizures following MMR vaccinations had a slightly increased rate of recurrent
febrile seizures (RR, 1.19; 95% CI, 1.01-1.41) but no increased rate of
epilepsy (RR, 0.70; 95% CI, 0.33-1.50) compared with children who were
nonvaccinated at the time of their first febrile seizure. CONCLUSIONS MMR
vaccination was associated with a transient increased rate of febrile seizures
but the risk difference was small even in high-risk children. The long-term
rate of epilepsy was not increased in children who had febrile seizures
following vaccination compared with children who had febrile seizures of a
different etiology. http://www.ncbi.nlm.nih.gov/pubmed/15265850

“439,251 children received MMR vaccination and 17,986 children developed
febrile seizures at least once ...”

Brain Development • August 2004

An evaluation of serious neurological disorders following immunization: a
comparison of whole-cell pertussis and acellular pertussis vaccines Author
information Geier DA1, Geier MR. MedCon, Inc., Silver Spring, MD 20905, USA
Abstract Serious neurological disorders reported following whole-cell pertussis
in comparison to acellular pertussis vaccines were evaluated. The Vaccine
Adverse Events Reporting System (VAERS) was analyzed for Emergency Department
(ED) visits, life-threatening reactions, hospitalizations, disabilities,
deaths, seizures, infantile spasms, encephalitis/encephalopathy, autism, Sudden
Infant Death Syndrome (SIDS) and speech disorders reported with an initial
onset of symptoms within 3 days following whole-cell pertussis and acellular
pertussis vaccines among those residing in the US from 1997 to 1999. Controls
were employed to evaluate potential biases in VAERS. Evaluations as to whether
whole-cell and acellular vaccines were administered to populations of similar
age and sex were undertaken because these factors might influence the study’s
results. Statistical increases were observed for all events examined following
whole-cell pertussis vaccination in comparison to acellular pertussis
vaccination, excepting cerebellar ataxia. Reporting biases were minimal in
VAERS, and whole-cell and acellular pertussis vaccines were administered to
populations of similar age and sex. Biologic mechanisms for the increased
reactogenicity of whole-cell pertussis vaccines may stem from the fact that
whole-cell pertussis vaccines contain 3,000 different proteins, whereas DTaP
contains two to five proteins. Whole-cell pertussis vaccine contains known
neurotoxins including: endotoxin, pertussis toxin and adenylate cyclase. Our
results, and conclusions by the US Institute of Medicine, suggest an
association between serious neurological disorders and whole-cell pertussis
immunization. In light of the presence of a safer and at least equally
efficacious acellular pertussis vaccine alternative, the Japanese and US switch
to using acellular pertussis vaccine seems well justified. Other countries
using whole-cell pertussis-containing vaccines should consider following suite
in the near future. http://www.ncbi.nlm.nih.gov/pubmed/15165669

“... results, and conclusions by the US Institute of Medicine, suggest an
association between serious neurological disorders and whole-cell pertussis
immunization.”

Annals Of Dermatology And Venereology • August 2004

Granuloma with lymphocytic hyperplasia following vaccination: 10 cases Presence
of aluminium in the biopsies Author information Lafaye S1, Authier FJ, Fraitag
S, Rethers L, Bagot M, Wechsler J. Département de Pathologie, Hôpital Henri
Mondor, 51 avenue du Maréchal de Lattre de Tassigny 94010 Créteil, France
Abstract BACKGROUND Few cases of cutaneous lymphocytic hyperplasia secondary to
vaccination have been published, although such lesions are not rare. PATIENTS
AND METHODS We report a series of 10 cases registered between 1993 and 2003.
RESULTS Mean age was 25. The clinical aspect was solitary or multiple
subcutaneous nodules, located on the arm, developing after a delay of 1 to 18
months after vaccination. Histologic examination showed a lymphocytic
infiltration of the subcutaneous fat, with diffuse and/or follicular pattern,
without nuclear atypia, the morphological and immunohistochemical analysis of
which revealed the benign nature. In all cases, there was fibrosis and
granuloma composed of lymphocytes, plasma cells, eosinophils and macrophages
with basophilic cytoplasm. Morin stain showed intralesional aluminium in the 6
investigated cases. Evolution was always benign, with no relapse following
exeresis. DISCUSSION Cutaneous lymphocytic hyperplasia secondary to vaccination
has to be suspected in a young patient with subcutaneous nodules appearing at a
vaccination site. Evidence of aluminium in the lesions supports the diagnosis
and the hypothesis that aluminium in the vaccine excipient might have a role in
the onset of such lesions. http://www.ncbi.nlm.nih.gov/pubmed/?term=15505542

“Cutaneous lymphocytic hyperplasia secondary to vaccination has to be suspected
in a young patient with subcutaneous nodules appearing at a vaccination site.
Evidence of aluminium in the lesions supports the diagnosis ...”

American Journal Of Therapeutics • September 2004

Urinary tract diseases revealed after DTP vaccination in infants and young
children: cytokine irregularities and down-regulation of cytochrome P-450
enzymes induced by the vaccine may uncover latent diseases in genetically
predisposed subjects Author information Prandota J. Faculty of Medicine and
Dentistry, University Medical School, Wroclaw, Poland
Jzef.854735@pharmanet.com.pl Abstract Prophylactic vaccinations may sometimes
shorten the incubation period of some illnesses and/or convert a latent
infection/inflammation into a clinically apparent disease. Cytokines play a
major role in mediating the inflammatory process in various clinical entities
and represent a potential source of tissue damage if their production is not
sufficiently well controlled. It seems that irregularities in production of
proinflammatory cytokines may be responsible for the abnormalities associated
with full-blown clinical symptoms of various urinary tract diseases observed
after DTP vaccination in 13 infants and young children hospitalized over the
past 24 years. On admission, upper respiratory tract diseases, atopic
dermatitis, and/or latent urinary tract infection/inflammation were found in
these children. It is suggested that the whole-cell pertussis present in DTP
vaccine, acting as an excessive stimulus in these patients, produced symptoms
reminiscent of biologic responses to circulating proinflammatory monokines such
as IL-1beta, TNF-alpha, and IL-6 because earlier it was reported that in vitro
the whole-cell vaccine induced significantly more such cytokine production than
did the acellular pertussis or diphtheria-tetanus-only vaccine. Analysis of the
cellular immune disturbances previously reported in urinary tract
infection/inflammation (increased serum and/or urinary IL-1alpha, IL-1 receptor
antagonist, IL-6 and IL-8), steroid-sensitive nephrotic syndrome (increased
IL-2, IFN-gamma, TNF-alpha, and decreased or increased IL-4, depending on the
cells studied), and atopic dermatitis (decreased IFN-gamma and increased IL-4
production), may suggest that similar subclinical chronic cytokine-mediated
abnormalities produced in the course of latent diseases revealed in our
patients, combined with those caused by DTP vaccination stimulus, were
responsible for the pathomechanism of these clinical entities. This speculation
is in agreement with the reports on the long-lasting induction of cytokine
release and down-regulation of hepatic cytochrome P-450 isoenzyme activities
after administration of DTP vaccine to mice and may be supported by the fact
that TH1 phenotype is associated with the up-regulation of intercellular
adhesion molecule-1 and RANTES, whereas TH2 phenotype is associated with the
up-regulation of the vascular cell adhesion molecule and P-selectin, which are
key players in the migration into inflamed tissues and localization of
lymphocytes and other allergic effector and inflammatory cells. Because several
inflammatory cytokines down-regulate gene expression of major cytochrome P-450
and/or other enzymes with the specific effects on mRNA levels, protein
expression, and enzyme activity, thus affecting the metabolism of several
endogenous lipophilic substances such as steroids, lipid-soluble vitamins,
prostaglandins, leukotrienes, thromboxanes, and exogenous substances, their
irregularities in the body may eventually lead to the flare of latent diseases
in some predisposed subjects. Also, interleukin genetic polymorphisms,
especially the constellation of TNF-alpha and IL-6 genetic variants, might
predispose some infants with infection to a more than usually intense
inflammatory response in the kidneys after vaccination. It seems that the
aforementioned pathomechanism may also be responsible for some cases of sudden
infant death syndrome, which is often preceded by infection/inflammation.
http://www.ncbi.nlm.nih.gov/pubmed/15356430

“It seems that the aforementioned pathomechanism may also be responsible for
some cases of sudden infant death syndrome, which is often preceded by
infection/inflammation.”

Neurology • September 2004

Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a
prospective study Author information Hernán MA1, Jick SS, Olek MJ, Jick H.
Department of Epidemiology Harvard School of Public Health 677 Huntington
Avenue, Boston, MA 02115, USA miguel_hernan@post.harvard.edu Abstract
BACKGROUND A potential link between the recombinant hepatitis B vaccine and an
increased risk of multiple sclerosis (MS) has been evaluated in several
studies, but some of them have substantial methodologic limitations.

“These findings

METHODS The authors conducted a nested case-control study within the General
Practice Research Database (GPRD) in the United Kingdom. The authors identified
patients who had a first MS diagnosis recorded in the GPRD between January 1993
and December 2000. Cases were patients with a diagnosis of MS confirmed through
examination of medical records, and with at least 3 years of continuous
recording in the GPRD before their date of first symptoms (index date). Up to
10 controls per case were randomly selected, matched on age, sex, practice, and
date of joining the practice. Information on receipt of immunizations was
obtained from the computer records.

the hypothesis that

RESULTS The analyses include 163 cases of MS and 1,604 controls. The OR of MS
for vaccination within 3 years before the index date compared to no vaccination
was 3.1 (95% CI 1.5, 6.3). No increased risk of MS was associated with tetanus
and influenza vaccinations. CONCLUSIONS These findings are consistent with the
hypothesis that immunization with the recombinant hepatitis B vaccine is
associated with an increased risk of MS, and challenge the idea that the
relation between hepatitis B vaccination and risk of MS is well understood.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15365133

are consistent with

immunization with the recombinant hepatitis B vaccine is associated with an
increased risk of MS, and challenge the idea that the relation between
hepatitis B vaccination and risk of MS is well understood.”

“In this review, we discuss recent articles and controversies pertaining to vaccine-associated adverse events.”
Current Allergy And Asthma Reports • November 2004

Update on side effects from common vaccines Author information Song BJ1, Katial
RK. Division of Adult Allergy and Immunology National Jewish Medical and
Research Center 1400 Jackson Street, Denver, CO 80206, USA Abstract Vaccines
have had a tremendous impact on public health by reducing morbidity and
mortality from a variety of virulent pathogens. However, unintended side
effects continue to pose a potential risk that may outweigh the vaccine’s
protective attributes. In this review, we discuss recent articles and
controversies pertaining to vaccine-associated adverse events. Included in the
discussion are influenza, hepatitis B, measles-mumps-rubella,
diphtheria-tetanus-pertussis, polio, Haemophilus influenzae type b, and
rotavirus vaccines. The importance and contribution of vaccine constituents
(such as thimerosal) to side effects is also reviewed.
http://www.ncbi.nlm.nih.gov/pubmed/15462710

JAMA • November 2004

Guillain-Barré syndrome following influenza vaccination Author information
Haber P1, DeStefano F, Angulo FJ, Iskander J, Shadomy SV, Weintraub E, Chen RT.
Immunization Safety Branch Epidemiology and Surveillance Division National
Immunization Program Centers for Disease Control and Prevention Atlanta, Ga
30333, USA PHaber@cdc.gov Abstract CONTEXT An unexplained increase in the risk
of Guillain-Barre syndrome (GBS) occurred among recipients of the swine
influenza vaccine in 1976-1977. Guillain-Barre syndrome remains the most
frequent neurological condition reported after influenza vaccination to the
Vaccine Adverse Events Reporting System (VAERS) since its inception in 1990.
OBJECTIVE To evaluate trends of reports to VAERS of GBS following influenza
vaccination in adults. DESIGN, SETTING, AND PARTICIPANTS VAERS is the US
national spontaneous reporting system for adverse events following vaccination.
Reports of GBS in persons 18 years or older following influenza vaccination
were evaluated for each influenza season from July 1, 1990, through June 30,
2003. The number of people vaccinated was estimated from the National Health
Interview Survey and US census data. Beginning in 1994, active follow-up was
conducted to verify GBS diagnosis and obtain other clinical details. MAIN
OUTCOME MEASURE Reporting rates of GBS following influenza vaccination over
time. RESULTS From July 1990 through June 2003, VAERS received 501 reports of
GBS following influenza vaccination in adults. The median onset interval (13
days) was longer than that of non-GBS reports of adverse events after influenza
vaccine (1 day) (P<.001). The annual reporting rate decreased 4-fold from a
high of 0.17 per 100,000 vaccinees in 1993-1994 to 0.04 in 2002-2003 (P<.001).
A GBS diagnosis was confirmed in 82% of reports. Preceding illness within 4
weeks of vaccination was identified in 24% of reported cases. CONCLUSIONS From
1990 to 2003, VAERS reporting rates of GBS after influenza vaccination
decreased. The long onset interval and low prevalence of other preexisting
illnesses are consistent with a possible causal association between GBS and
influenza vaccine. These findings require additional research, which can lead
to a fuller understanding of the causes of GBS and its possible relationship
with influenza vaccine. http://www.ncbi.nlm.nih.gov/pubmed/?term=15562126

“An unexplained increase in the risk of Guillain-Barre syndrome (GBS) occurred
among recipients of the swine influenza vaccine in 1976-1977. Guillain-Barre
syndrome remains the most frequent neurological condition reported after
influenza vaccination to the Vaccine Adverse Events Reporting System (VAERS)
since its inception in 1990.”

“... the whole cell vaccine may lead to the acute encephalopathy, fever seizures,
hypotonic-hyporeactive episodes, inconsolable crying or anaphylactic
reactions.” Przeglad Epidemiologiczny • 2004

Prevention of pertussis and high expectations concerning vaccines Author
information Wysocki J. Katedra Profilaktyki Zdrowotnej Akademia Medyczna im
Karola Marcinkowskiego w Poznaniu Abstract The basic vaccine used in the
prevention of pertussis is the combined vaccine including a whole cell
pertussis component and tetanus and diphtheria toxoids. Although this type of
vaccine has been used more than 50 years in USA and more than 40 years in
Poland it is still effective what can be evidenced by the decreased number of
pertussis cases since the vaccine has been implemented. There are however some
evidences that the whole cell vaccine may lead to the acute encephalopathy,
fever seizures, hypotonic-hyporeactive episodes, inconsolable crying or
anaphylactic reactions. But still is a lack of convincing evidences that the
vaccine may be a cause of persistent brain damage. It was also shown that the
longer is the period after the last dose of the vaccine the lower effectiveness
was observed. Improving the safety of the pertussis vaccine was the reason of
introducing the acellular vaccines in the eightieth. All these products contain
pertussis toxoid and some of them contain also filamentous hemagglutinin,
pertactin and fimbrial agglutinogens. Some published studies have shown that
the effectiveness of these vaccines is similar to the whole cells vaccines and
that the incidence of some adverse events especially seizures,
hypotonic-hyporeactive episodes and inconsolable crying is lower.
http://www.ncbi.nlm.nih.gov/pubmed/15807156

Archives de Pediatrie • January 2005

Vaccine adjuvants and macrophagic myofasciitis Author information Siegrist CA.
Département de pathologie centre de vaccinologie, université de Genève CMU,
Suisse claire-anne.siegrist@medecine.unige.ch Abstract Aluminium-based
adjuvants have been used throughout the world since 1926, and their safety
profile is such that they have long been the sole adjuvants registered for
clinical use. Their safety has nevertheless been questioned in France over the
last few years following the demonstration that aluminium could persist for
prolonged periods at the injection site, within macrophages gathered around the
muscular fibres and forming a microscopic histological lesion called
“macrophagic myofasciitis (MMF)”. This image has been observed in patients
undergoing a deltoid muscular biopsy for diagnostic purposes of various
symptoms essentially including muscular pain and fatigue, in association with a
large panel of various symptoms and diseases, including those of an autoimmune
nature. Studies of the clinical, biological and epidemiological characteristics
undertaken to identify a possible association between the MMF histological
image and a systematic disease have remained negative. As of today, available
evidence indicates that although vaccine aluminium may persist at the site of
injection for years (“vaccine tattoo”), this does not reflect the existence of
a diffuse inflammatory muscular disease and is not associated with a specific
clinical disease. The existence of sampling bias inherent to the complexity of
the clinical and pathological diagnoses remains the most likely hypothesis.
http://www.ncbi.nlm.nih.gov/pubmed/15653065

“Aluminium-based adjuvants have been used throughout the world since 1926, and
their safety profile is such that they have long been the sole adjuvants
registered for clinical use. Their safety has nevertheless been questioned in
France over the last few years following the demonstration that aluminium could
persist for prolonged periods at the injection site, within macrophages
gathered around the muscular fibres and forming a microscopic histological
lesion called “macrophagic myofasciitis (MMF)”.”

Danish Medical Journal • January 2005

Combining vitamin A and vaccines: convenience or conflict? Author information
Benn CS1. Bandim Health Project, Statens Serum Institut, Copenhagen S, Denmark
cb@ssi.dk Abstract The present thesis is based on 11 papers from 1995-2010. The
studies have mainly taken place at the Bandim Health Project in Guinea-Bissau,
West Africa, but a reanalysis of a randomised trial from Ghana is also
included. My research has explored the consequences of combining high-dose
vitamin A supplementation and childhood vaccines. Vitamin A deficiency is
associated with increased mortality. To protect against the consequences of
vitamin A deficiency the World Health Organization recommends that high-dose
vitamin A supplements be given together with routine vaccines to children
between 6 months and 5 years of age in more than 100 low-income countries. The
recommendation is based on logistical considerations. The consequences of
combining vitamin A and vaccines were not investigated in randomised trials
prior to the implementation of this policy - it was assumed that the
interventions were independent. My first project aimed to study the effect on
the immune response to measles of providing vitamin A together with measles
vaccine. We found that the two interventions were not independent. Vitamin A
enhanced the antibody response to measles vaccine given at 9 months of age
significantly, especially in boys. The effects were sustained over time; the
children who had received vitamin A with their measles vaccine were more
protected against measles at 6-8 years of age. Though vitamin A supplementation
had a beneficial effect on the immune response to measles vaccine, it intrigued
me that the effect of vitamin A supplementation on overall mortality was not
always beneficial. While vitamin A was beneficial when given after 6 months of
age, and two studies had shown a beneficial effect when given at birth, all
studies testing the effect between 1-5 months of age had found no effect. These
time windows are dominated by three different childhood vaccines: BCG vaccine
given at birth, diphtheria-tetanus-pertussis (DTP) vaccine given between 1-5
months of age, and measles vaccine given at 9 months of age. These vaccines
have been shown to have strong effects on mortality from infectious diseases in
general, so-called non-specific effects. The live BCG and measles vaccine
protects against more mortality than can be ascribed to the prevention of
tuberculosis and measles, respectively. The inactivated DTP vaccine worryingly
has been associated with increased mortality from other infectious diseases.
Both positive and negative effects are strongest for girls. I proposed the
hypothesis that vitamin A amplifies not only the specific vaccine effects, as
we saw for measles vaccine, but also the non-specific effects of vaccines on
mortality from other infectious diseases. According to my hypothesis, vitamin A
would enhance the non-specific beneficial effects on mortality of BCG and
measles vaccine, but also the negative effects of DTP vaccine. Hence, the
hypothesis offered an explanation for the mortality-age pattern after vitamin A
supplementation. Since it was formulated, I have aimed to test this hypothesis.
Since it is associated with ethical problems to randomise

children above 6 months of age to vitamin A supplementation, and to randomise
children in general to recommended vaccines, we have had to be pragmatic when
designing the trials. Hence, our studies have taken many different forms. We
conducted an observational study during a vitamin A campaign in which missing
vaccines were also provided, and a randomised trial testing the effect of two
different doses of vitamin A during another campaign; we tested the effect of
providing vitamin A with BCG at birth in two randomised trials, and we
reanalysed data from one of the original randomised trials of vitamin A
supplementation from the perspective of vaccination status. In all studies the
main outcome was mortality. The results document that vitamin A supplements do
more than protect against vitamin A deficiency. They support the hypothesis
that vitamin A supplements interact with vaccines with important consequences
for mortality. First, a smaller dose of vitamin A was more beneficial than a
larger dose for girls. Second, the effect of vitamin A given with DTP vaccine
was significantly different from the effect of vitamin A given with measles
vaccine, and children, who received vitamin A with DTP vaccine, had higher
mortality than children, who had received vitamin A alone, or who did not
receive anything. Third, vitamin A given with BCG at birth interacted
negatively with subsequent DTP vaccines in girls. Fourth, the effect of vitamin
A to older children in Ghana depended on vaccination status, being beneficial
in boys, but harmful in girls who received DTP vaccine during follow-up. The
results also show that boys and girls respond differently to vitamin A and
vaccines. It is a common assumption within public health in low-income
countries that interventions can be combined without producing unexpected
consequences. The work presented in this thesis confronts this assumption; the
results show that vitamin A and vaccines should be seen not only as specific
interventions with specific and independent effects, but as immuno-modulators,
which can interact with important consequences for overall mortality. Combining
interventions can be convenient and lead to synergistic health benefits, but we
documented several examples, where it also leads to unexpectedly increased
mortality. Thus, to optimise the child health intervention policy in low-income
countries a shift in paradigm is needed. Health interventions should no longer
be seen as merely specific and independent, and the policy should probably not
be the same for boys and girls. Though more complex, it is necessary to
evaluate all health interventions in terms of their effect on overall mortality
- and their potential interactions with other health interventions and
potential sex-differential effects should always be investigated. Only in this
way can we assure that the children in the poorest countries get the best
possible treatment and avoid using large amounts of money and resources on
interventions which may, in worst case, kill them.

http://www.ncbi.nlm.nih.gov/pubmed/22239846

“In all studies the main outcome was mortality. The results document that
vitamin A supplements do more than protect against vitamin A deficiency. They
support the hypothesis that vitamin A supplements interact with vaccines with
important consequences for mortality. First, a smaller dose of vitamin A was
more beneficial than a larger dose for girls. Second, the effect of vitamin A
given with DTP vaccine was significantly different from the effect of vitamin A
given with measles vaccine, and children, who received vitamin A with DTP
vaccine, had higher mortality than children, who had received vitamin A alone,
or who did not receive anything. Third, vitamin A given with BCG at birth
interacted negatively with subsequent DTP vaccines in girls. Fourth, the effect
of vitamin A to older children in Ghana depended on vaccination status, being
beneficial in boys, but harmful in girls who received DTP vaccine during
follow-up. The results also show that boys and girls respond differently to
vitamin A and vaccines. It is a common assumption within public health in
low-income countries that interventions can be combined without producing
unexpected consequences. The work presented in this thesis confronts this
assumption; the results show that vitamin A and vaccines should be seen not
only as specific interventions with specific and independent effects, but as
immuno-modulators, which can interact with important consequences for overall
mortality. Combining interventions can be convenient and lead to synergistic
health benefits, but we documented several examples, where it also leads to
unexpectedly increased mortality.”

Vaccine • January 2005

Routine vaccinations associated with divergent effects on female and male
mortality at the paediatric ward in Bissau, Guinea-Bissau Author information
Veirum JE1, Sodemann M, Biai S, Jakobsen M, Garly ML, Hedegaard K, Jensen H,
Aaby P. Projecto de Saúde de Bandim, Apartado 861 Bissau, Guinea-Bissau
Abstract Several studies have suggested that routine childhood immunisations
may have non-specific effects on mortality. To examine which disease categories
might be affected, we investigated whether immunisation status had an impact on
the case fatality for hospitalised children. Between 1990 and 1996, the Bandim
Health Project maintained a register of all children from the study area
hospitalised at the paediatric ward of the central hospital in Bissau,
Guinea-Bissau. The study included 2079 hospitalised children aged 1.5-17 months
coming from the Bandim study area. Among children whose vaccination card had
been seen at admission, the case fatality ratio for measles-vaccinated children
versus measles-unvaccinated children was 0.51 (0.27-0.98), the beneficial
effect being significantly stronger for girls than for boys (test of
interaction, p=0.050). The protective effect of measles vaccine remained
unchanged when hospitalised measles cases were excluded from the analysis (0.49
(0.26-0.94)). The effect of measles vaccine was strongest for children with
pneumonia (MR=0.28 (0.07-0.91)) and presumptive malaria (MR=0.40 (0.13-1.18)).
For measlesvaccinated children, the female to male case fatality ratio was 0.54
(0.28-0.97). Among children having received diphtheria-tetanus-pertussis (DTP)
and oral polio (OPV) as the last vaccines, girls had higher case fatality than
boys, the mortality ratio being 1.63 (1.03-2.59). The female to male ratios
were significantly inversed for DTP and OPV versus measles vaccine (test of
interaction, p=0.003). These results remained unchanged if 1-month
post-discharge deaths were included in the analysis, and in multivariate
analyses controlling for determinants of mortality. In conclusion, measles
vaccine was associated with reduced mortality from diseases other than measles,
the beneficial effect being stronger for girls than for boys. On the other
hand, DTP and OPV vaccine were associated with higher case fatality for girls
than for boys. Understanding the divergent non-specific effects of common
vaccines may contribute to better child survival in developing countries.
http://www.ncbi.nlm.nih.gov/pubmed/15629363

“Diphtheria-Tetanus-Pertussis and Oral Polio Vaccine were associated with
higher case fatality for girls than for boys.”

Reviews In Medical Virology • January 2005

Viruses as adjuvants for autoimmunity: evidence from Coxsackievirus-induced
myocarditis Author information Fairweather D1, Frisancho-Kiss S, Rose NR. The
Department of Pathology Johns Hopkins School of Medicine Baltimore, MD 21205,
USA Abstract Adjuvants historically are considered to stimulate immune
responses ‘non-specifically’. Recently, a renewed understanding of the critical
role of innate immunity in influencing the development of an adaptive immune
response has led researchers to a better understanding of ‘the adjuvant
effect’. Although innate immune cells do not respond to specific antigenic
epitopes on pathogens, they do produce restricted responses to particular
classes of pathogens via pattern recognition receptors such as Toll-like
receptors (TLR). Coxsackievirus infection was found to upregulate TLR4 on mast
cells and macrophages immediately following infection. Although both
susceptible and resistant mice produce a mixture of Th1 and Th2 cytokines,
susceptible mice have increased levels of key proinflammatory cytokines,
increased numbers of mast cells, and go on to develop chronic autoimmune heart
disease. TLR4 signalling also increases acute myocarditis and proinflammatory
cytokines in the heart. Many similarities are described in the pathogenesis of
Coxsackievirus and the adjuvant-induced model of myocarditis including
upregulation of particular TLRs and cytokines soon after inoculation. Recent
findings suggest that mast cell activation by viruses or adjuvants may be
important in initiating autoimmune disease.
http://www.ncbi.nlm.nih.gov/pubmed/15386590

“... mast cell activation by viruses or adjuvants may be important in
initiating autoimmune disease.”

Autoimmunity Reviews • February 2005

Autoimmune hazards of hepatitis B vaccine Author information Girard M1. 1 bd de
la République 78000-Versailles, France agosgirard@aol.com Abstract According to
Hippocratic tradition, the safety level of a preventive medicine must be very
high, as it is aimed at protecting people against diseases that they may not
contract. This paper points out that information on the safety of hepatitis B
vaccine (HBV) is biased as compared to classical requirements of evidence-based
medicine (EBM), as exemplified by a documented selectivity in the presentation
or even publication of available clinical or epidemiological data. Then, a
review is made of data suggesting that HBV is remarkable by the frequency, the
severity and the variety of its complications, some of them probably related to
a mechanism of molecular mimicry leading to demyelinating diseases, and the
others reproducing the spectrum of non-hepatic manifestations of natural
hepatitis B. To be explained, this unusual spectrum of toxicity requires
additional investigations based upon complete release of available data.
http://www.ncbi.nlm.nih.gov/pubmed/15722255

“... a review is made of data suggesting that Hepatitus B Vaccine is remarkable
by the frequency, the severity and the variety of its complications, some of
them probably related to a mechanism of molecular mimicry leading to
demyelinating diseases, and the others reproducing the spectrum of non-hepatic
manifestations of natural hepatitis B.”

“Result suggests that polysorbate 80 (at clinically-relevant concentrations)
may increase the susceptibility of cells to oxidative stress.” Toxicology •
February 2005

Polysorbate 80 increases the susceptibility to oxidative stress in rat
thymocytes Author information Tatsuishi T1, Oyama Y, Iwase K, Yamaguchi JY,
Kobayashi M, Nishimura Y, Kanada A, Hirama S. Laboratory of Cellular Signaling
Faculty of Integrated Arts and Sciences The University of Tokushima Tokushima
770-8502, Japan Abstract Effect of simultaneous application of polysorbate 80,
a nonionic surfactant widely used in pharmaceutical products, and hydrogen
peroxide on rat thymocytes was examined to see if polysorbate 80 increases the
susceptibility to oxidative stress because this surfactant decreases the
cellular content of glutathione. Polysorbate 80 at clinically-relevant
concentrations increases the cytotoxicity of hydrogen peroxide under the in
vitro condition. Result suggests that polysorbate 80 may increase the
susceptibility of cells to oxidative stress.
http://www.ncbi.nlm.nih.gov/pubmed/15590117

Journal Of The American Academy Of Dermatology • April 2005

Vaccination-induced cutaneous pseudolymphoma Author information Maubec E1,
Pinquier L, Viguier M, Caux F, Amsler E, Aractingi S, Chafi H, Janin A, Cayuela
JM, Dubertret L, Authier FJ, Bachelez H. Institut de Recherche sur la Peau
Université Paris 7, Paris, France Abstract BACKGROUND Although mild early
cutaneous transient reactions to vaccinations are common, late-onset chronic
lesions have been scarcely reported. We report herein a series of 9 patients
presenting with cutaneous and subcutaneous pseudolymphoma. OBSERVATIONS Nine
patients presenting with late-onset, chronic skin lesions occurring at the site
of antihepatitis B (8 cases) and antihepatitis A (one case) vaccination were
reported. Histopathologic and immunohistochemic studies, and molecular analysis
of clonality of skin biopsy specimens, were performed. Furthermore, the
presence of vaccine products was investigated in skin lesions by using
histochemical, microanalytic, and electronic microscopy techniques. RESULTS
Histopathologic studies showed dermal and hypodermal lymphocytic follicular
infiltrates with germinal center formation. The center of follicles was mostly
composed of B cells without atypia, whereas CD4+ T cells were predominant at
the periphery. Molecular analysis of clonality revealed a polyclonal pattern of
B-cell and T-cell subsets. Aluminium deposits were evidenced in all cases by
using histochemical staining in all cases, and by microanalysis and
ultrastructural studies in one case. Associated manifestations were vitiligo
(one case) and chronic fatigue with myalgia (two cases). CONCLUSION Cutaneous
lymphoid hyperplasia is a potential adverse effect of vaccinations including
aluminium hydroxide as an adjuvant. Further prospective studies are warranted
to evaluate the incidence of this complication in the immunized population.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15793512

“Cutaneous lymphoid hyperplasia is a potential adverse effect of vaccinations
including aluminium hydroxide as an adjuvant.”

Autoimmunity • May 2005

Infection, vaccines and other environmental triggers of autoimmunity Author
information Molina V1, Shoenfeld Y. Department of Medicine B and The Center for
Autoimmune Diseases Sheba Medical Center, Tel-Hashomer, Israel Abstract The
etiology of autoimmune diseases is still not clear but genetic, immunological,
hormonal and environmental factors are considered to be important triggers.
Most often autoimmunity is not followed by clinical symptoms unless an
additional event such as an environmental factor favors an overt expression.
Many environmental factors are known to affect the immune system and may play a
role as triggers of the autoimmune mosaic.Infections: bacterial, viral and
parasitic infections are known to induce and exacerbate autoimmune diseases,
mainly by the mechanism of molecular mimicry. This was studied for some
syndromes as for the association between SLE and EBV infection, pediatric
autoimmune neuropsychiatric disorders associated with streptococcal infection
and more. Vaccines, in several reports were found to be temporally followed by
a new onset of autoimmune diseases. The same mechanisms that act in infectious
invasion of the host, apply equally to the host response to vaccination. It has
been accepted for diphtheria and tetanus toxoid, polio and measles vaccines and
GBS. Also this theory has been accepted for MMR vaccination and development of
autoimmune thrombocytopenia, MS has been associated with HBV vaccination.
Occupational and other chemical exposures are considered as triggers for
autoimmunity. A debate still exists about the role of silicone implants in
induction of scleroderma like disease.Not only foreign chemicals and agents
have been associated with induction of autoimmunity, but also an intrinsic
hormonal exposure, such as estrogens. This might explain the sexual dimorphism
in autoimmunity. Better understanding of these environmental risk factors will
likely lead to explanation of the mechanisms of onset and progression of
autoimmune diseases and may lead to effective preventive involvement in
specific high-risk groups. So by diagnosing a new patient with autoimmune
disease a wide anamnesis work should be done.
http://www.ncbi.nlm.nih.gov/pubmed/16126512

“The same mechanisms that act in infectious invasion of the host, apply equally
to the host response to vaccination.

It has been accepted for diphtheria and tetanus toxoid, polio and measles
vaccines and Guillain Barre Syndrome.

Also this theory has been accepted for MMR vaccination and development of
autoimmune thrombocytopenia, Multiple Sclerosis has been associated with HBV
vaccination.”

Neurologic Clinics • May 2005

Neurodegenerative memory disorders: a potential role of environmental toxins
Author information Caban-Holt A1, Mattingly M, Cooper G, Schmitt FA.
Sanders-Brown Center on Aging University of Kentucky Medical Center Lexington,
KY 40536, USA Abstract The hypothesis that neurotoxins may play a role in
neurodegenerative disorders remains an elusive one, given that epidemiologic
studies often provide conflicting results. Although these conflicting results
may result from methodological differences within and between studies, the
complexity of chemical disruption of the central nervous system cannot be
ignored in attempts to evaluate this hypothesis in different neurodegenerative
disorders. Spencer provides a detailed review of the complex processes involved
in defining the neurotoxic potential of naturally occurring and synthetic
agents. Even concepts such as exposure and dose, as often reported in studies
attempting to evaluate the risk imparted by a potential compound, can be
deceptive. For example, although dose reflects “that amount of chemical
transferred to the exposed subject”, factors such as time and concentration in
the organism, the ability to access the central nervous system, and how a
compound reaches the central nervous system (routes of administration) or
secondarily affects other organ systems leading to central nervous system
disruption are clearly important to the concept of neurotoxic risk in
neurodegenerative disorders. These factors would appear to explain the observed
disagreements between studies using animal or neuronal models of neurotoxicity
and population-based studies in humans. The importance of these factors and how
a potential neurotoxin is investigated are clearly seen in the data on AD and
aluminum. In contrast, the impact of MTPT on the central nervous system is more
direct and compelling. Added complexity in the study of neurotoxins in human
neurodegeneration is derived from data showing that agents may have additive,
potentiating, synergistic, or antagonistic effects. Therefore, data from
studies evaluating EMF risks could be readily confounded by the presence or
absence of heavy metals (eg, arc welding). Other factors that may conceal
neurotoxic causes for a given disorder focus on additional features such as
genetic predispositions, physiologic changes that occur in aging, and even
nutritional status that can support or hinder the affect of a given agent on
the central nervous system. Finally, many studies that investigate exposure
risk do not readily incorporate the five criteria proposed by Schaumburg for
establishing causation. For example, if we apply Schaumburg’s first criterion,
epidemiologic studies often determines the presence of an agent through
history, yet they cannot readily confirm exposure based on environmental or
clinical chemical analyses to fulfill this criterion for causation. Additional
limitations in research design along with the populations and methods that are
sued to study neurotoxins in human neurodegenerative disorders often fail to
meet other criteria such as linking the severity and onset with duration and
exposure level. Therefore, although studies of agents such as MTPT provide
compelling models of neurotoxins and neurodegeneration in humans, disorders
such as ALS, PD, and particularly AD will require additional effort if research
is to determine the contribution (presence or absence) of neurotoxins to these
neurologic disorders. http://www.ncbi.nlm.nih.gov/pubmed/15757794

“Added complexity in the study of neurotoxins in human neurodegeneration is
derived from data showing that agents may have additive, potentiating,
synergistic, or antagonistic effects.”

Journal Of Neurochemistry • May 2005

Vaccination alone or in combination with pyridostigmine promotes and prolongs
activation of stress-activated kinases induced by stress in the mouse brain
Author information Wang D1, Perides G, Liu YF. Department of Pharmacology
Boston University School of Medicine Massachusetts 02118, USA Abstract Gulf war
illnesses (GWI) are currently affecting thousands of veterans. To date, the
molecular mechanisms underlying the pathogenesis of these illnesses remain
unknown. During Gulf war I, military personnel were exposed to multiple
stressors, one or more vaccines, pyridostigmine (PY), and other chemicals. In
our previous studies, we found that stress induces activation of mitogen
activated proteinkinase kinase 4 (MKK4) and c-Jun-N-terminal kinase (JNK) in
the mouse brain (Liu et al. 2004). Our working hypothesis is that stress,
vaccination, and PY may synergistically induce activation of MKK4 and JNK in
the brain, leading to overactivation of these kinases and neurological
injuries. To test our hypothesis, we examined the effect of keyhole limpet
hemocyanin (KLH) immunization alone or in combination with PY on activation of
MKK4 and JNK induced by stress. We found that KLH immunization alone had a
small effect on MKK4 or JNK activity but it significantly enhanced and
prolonged activation of these kinases induced by stress, from a few hours to
several days. Additionally, KLH immunization caused activation of p38MAPK. PY
treatment further enhanced and prolonged activation of these kinases induced by
stress in combination with KLH immunization and triggered activation of
caspase-3. Our current studies suggest that stress, vaccination, and PY may
synergistically act on multiple stress-activated kinases in the brain to cause
neurological impairments in GWI.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15857404

“Our current studies suggest that stress, vaccination, and pyridostigmine may
synergistically act on multiple stress-activated kinases in the brain to cause
neurological impairments in Gulf War Illness.”

Journal Of Hygiene Research • May 2005

Effect of formaldehyde on energy metabolism in postnatal rat cortex neurons in
culture Author information Liu T1, Bai XT. Department of Toxicology Institute
of Environment Health and Related Product Safety China CDC, Beijing 100021,
China Abstract OBJECTIVE: The mechanism of the effect of formaldehyde on CNS
which is much concerned to formaldehyde poisoning was studied. METHODS: In the
present study, incubation of postnatal rat cortex neurons in culture with
formaldehyde at 1, 2, 4, 8 mg/L (medium) was carried out to evaluate the effect
of formaldehyde on energy metabolism. RESULTS: The result of cytochemistry
showed a significant down-regulation of cytochrome oxidase activity after
consecutive formaldehyde treatment for 4 hours compared with the control (P <
0.01), the significant dosage-response relationship was also observed (R value
is - 0.92, P < 0.01). CONCLUSION: The result demonstrates that excessive
exposure of formaldehyde can decrease cytochrome oxidase activity in cortex
neurons which indicates energy metabolism will be decreased and therefore
normal physiology function would be damaged.
http://www.ncbi.nlm.nih.gov/pubmed/?term=16111027

“The result demonstrates that excessive exposure of formaldehyde can decrease
cytochrome oxidase activity in cortex neurons which indicates energy metabolism
will be decreased and therefore normal physiology function would be damaged.”

Autoimmunity • June 2005

A case-control study of serious autoimmune adverse events following hepatitis B
immunization Author information Geier DA1, Geier MR. MedCon, Inc., Silver
Spring, MD 20905, USA Abstract Hepatitis B infection is one of the most
important causes of acute and chronic liver disease. During the 1980s,
genetically engineered hepatitis B vaccines (HBVs) were introduced in the
United States. A large-series of serious autoimmune conditions have been
reported following HBVs, despite the fact that HBVs have been reported to be
“generally well-tolerated.” A case-control epidemiological study was conducted
to evaluate serious autoimmune adverse events prospectively reported to the
vaccine adverse events reporting system (VAERS) database following HBVs, in
comparison to an age, sex, and vaccine year matched unexposed tetanuscontaining
vaccine (TCV) group for conditions that have been previously identified on an a
priori basis from case-reports. Adults receiving HBV had significantly
increased odds ratios (OR) for multiple sclerosis (OR = 5.2, p < 0.0003, 95%
Confidence Interval (CI) = 1.9 - 20), optic neuritis (OR = 14, p < 0.0002, 95%
CI = 2.3 - 560), vasculitis (OR = 2.6, p < 0.04, 95% CI = 1.03 - 8.7),
arthritis (OR = 2.01, p < 0.0003, 95% CI = 1.3 - 3.1), alopecia (OR = 7.2, p <
0.0001, 95% CI = 3.2 - 20), lupus erythematosus (OR = 9.1, p < 0.0001, 95% CI =
2.3 - 76), rheumatoid arthritis (OR = 18, p < 0.0001, 95% CI = 3.1 - 740), and
thrombocytopenia (OR = 2.3, p < 0.04, 95% CI = 1.02 - 6.2) in comparison to the
TCV group. Minimal confounding or systematic error was observed. Despite the
negative findings of the present study regarding the rare serious adverse
effects of HBVs, it is clear that HBV does, indeed, offer significant benefits,
but it is also clear that chances of exposure to hepatitis B virus in adults is
largely life-style dependent. Adults should make an informed consent decision,
weighing the risks and benefits of HBV, as to whether or not to be immunized.
http://www.ncbi.nlm.nih.gov/pubmed/?term=16206512

“Adults receiving Hepatitus B Vaccine had significantly increased odds ratios
(OR) for multiple sclerosis ... optic neuritis ... vasculitis ... arthritis ...
alopecia ... lupus erythematosus ... rheumatoid arthritis and thrombocytopenia”

Environmental Health Perspectives • September 2005

Meeting report: summary of IARC monographs on formaldehyde, 2-butoxyethanol,
and 1-tert-butoxy-2-propanol Author information Cogliano VJ1, Grosse Y, Baan
RA, Straif K, Secretan MB, El Ghissassi F; Working Group for Volume 88
International Agency for Research on Cancer Lyon, France Abstract An
international, interdisciplinary working group of expert scientists met in June
2004 to develop IARC Monographs on the Evaluation of the Carcinogenic Risk of
Chemicals to Humans (IARC Monographs) on formaldehyde, 2-butoxyethanol, and
1-tert-butoxy-2-propanol. Each IARC Monograph includes a critical review of the
pertinent scientific literature and an evaluation of an agent’s potential to
cause cancer in humans. After a thorough discussion of the epidemiologic,
experimental, and other relevant data, the working group concluded that
formaldehyde is carcinogenic to humans, based on sufficient evidence in humans
and in experimental animals. In the epidemiologic studies, there was sufficient
evidence that formaldehyde causes nasopharyngeal cancer, “strong but not
sufficient” evidence of leukemia, and limited evidence of sinonasal cancer. The
working group also concluded that 2-butoxyethanol and 1-tert-butoxy-2-propanol
are not classifiable as to their carcinogenicity to humans, each having limited
evidence in experimental animals and inadequate evidence in humans. These three
evaluations and the supporting data will be published as Volume 88 of the IARC
Monographs. http://www.ncbi.nlm.nih.gov/pubmed/?term=16140628

“there was sufficient evidence that formaldehyde causes nasopharyngeal cancer,
“strong but not sufficient” evidence of leukemia, and limited evidence of
sinonasal cancer.”

Cochrane Database Systematic Review • October 2005

Vaccines for measles, mumps and rubella in children Author information
Demicheli V1, Jefferson T, Rivetti A, Price D. Servizo Sovrazonale di
Epidemiologia, ASL 20 Via Venezia 6, Alessandria, Piemonte, Italy 15100
demichelivittorio@asl20.piemonte.it Abstract BACKGROUND Public debate over the
safety of the trivalent measles, mumps and rubella (MMR) vaccine, and the
resultant drop in vaccination rates in several countries, persists despite its
almost universal use and accepted effectiveness. OBJECTIVES We carried out a
systematic review to assess the evidence of effectiveness and unintended
effects associated with MMR. SEARCH STRATEGY We searched the Cochrane Central
Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2004),
MEDLINE (1966 to December 2004), EMBASE (1974 to December 2004), Biological
Abstracts (from 1985 to December 2004), and Science Citation Index (from 1980
to December 2004). Results from reviews, handsearching and from the
consultation of manufacturers and authors were also used.

SELECTION CRITERIA Eligible studies were comparative prospective or
retrospective trials testing the effects of MMR compared to placebo, do-nothing
or a combination of measles, mumps and rubella antigens on healthy individuals
up to 15 years of age. These studies were carried out or published by 2004.
DATA COLLECTION AND ANALYSIS We identified 139 articles possibly satisfying our
inclusion criteria and included 31 in the review. MAIN RESULTS MMR was
associated with a lower incidence of upper respiratory tract infections, a
higher incidence of irritability, and similar incidence of other adverse
effects compared to placebo. The vaccine was likely to be associated with
benign thrombocytopenic purpura, parotitis, joint and limb complaints, febrile
convulsions within two weeks of vaccination and aseptic meningitis (mumps)
(Urabe strain-containing MMR). Exposure to MMR was unlikely to be associated
with Crohn’s disease, ulcerative colitis, autism or aseptic meningitis (mumps)
(Jeryl-Lynn strain-containing MMR). We could not identify studies assessing the
effectiveness of MMR that fulfilled our inclusion criteria even though the
impact of mass immunisation on the elimination of the diseases has been largely
demonstrated. AUTHORS’ CONCLUSIONS The design and reporting of safety outcomes
in MMR vaccine studies, both pre- and post-marketing, are largely inadequate.
The evidence of adverse events following immunisation with MMR cannot be
separated from its role in preventing the target diseases.
http://www.ncbi.nlm.nih.gov/pubmed/16235361

“The design and reporting of safety outcomes in MMR vaccine studies, both pre-
and post-marketing, are largely inadequate. The evidence of adverse events
following immunisation with MMR cannot be separated from its role in preventing
the target diseases.”

Clinical And Experimental Immunology • November 2005

Anti-phospholipid antibodies following vaccination with recombinant hepatitis B
vaccine Author information Martinuc Porobic J1, Avcin T, Bozic B, Kuhar M,
Cucnik S, Zupancic M, Prosenc K, Kveder T, Rozman B.

“ In genetically susceptible individuals or together with some other triggers
such combination might confer the risk of developing a continuous autoimmune
response in an individual.”

Department of Allergology Rheumatology and Clinical Immunology University
Children’s Hospital Ljubljana, Slovenia Abstract This study was undertaken to
evaluate the possible role of hepatitis B recombinant vaccine inducing the
synthesis of IgG and IgM anti-cardiolipin antibodies (aCL), antibodies against
beta(2)GPI (anti-beta(2)GPI), lupus anti-coagulant (LA), antinuclear antibodies
and antibodies against extractable nuclear antigens (anti-ENA). The study
population consisted of 85 healthy students (63 female, 22 male; mean age 20.8
years), vaccinated with three doses of recombinant DNA hepatitis B vaccine. One
month after vaccination with the first dose of hepatitis B vaccine a minority
of vaccinated individuals showed changes in IgG or IgM aCL or anti-beta(2)GPI
or LA activity (P < 0.001). Among subjects in whom changes of IgG
anti-beta(2)GPI were observed, a significantly higher number of increased
(8/85) than decreased (2/85) values were found (P < 0.01). Analyses of paired
data showed that differences in aCL or anti-beta(2)GPI levels before
vaccination or 1 month later did not reach statistical significance. In two
people aCL transitorily reached medium positivity after the first dose of
hepatitis B vaccine with a drop 5 months later. Similar evident anti-beta(2)GPI
fluctuation was also observed in one person. Another participant was initially
low positive for IgG anti-beta2GPI and the levels were increasing after
vaccination. Two participants became positive for anti-nuclear antibodies
during 6 months’ follow-up. There were no sex-dependent differences in tested
antibodies observed and no associations between levels of aPL and levels of
anti-HBV antibodies. We conclude that HBV can induce aPL, although rarely. In
genetically susceptible individuals or together with some other triggers such
combination might confer the risk of developing a continuous autoimmune
response in an individual. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1809502/

Editors Note: aPL or Antiphospholipid Syndrome Antiphospholipid syndrome or
antiphospholipid antibody syndrome (APS or APLS), or often also Hughes
syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid
antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as
well as pregnancy-related complications such as miscarriage, stillbirth,
preterm delivery, and severe preeclampsia. Antiphospholipid syndrome can be
primary or secondary. Primary antiphospholipid syndrome occurs in the absence
of any other related disease. Secondary antiphospholipid syndrome occurs with
other autoimmune diseases, such as systemic lupus erythematosus (SLE). In rare
cases, APS leads to rapid organ failure due to generalised thrombosis; this is
termed “catastrophic antiphospholipid syndrome” (CAPS) and is associated with a
high risk of death. Antiphospholipid syndrome often requires treatment with
anticoagulant medication such as heparin to reduce the risk of further episodes
of thrombosis and improve the prognosis of pregnancy. Warfarin/Coumadin is not
used during pregnancy because it can cross the placenta, unlike heparin, and is
teratogenic.

Pediatrics And Neurology • November 2005

Macrophagic myofasciitis in childhood: a controversial entity Author
information Rivas E1, Gómez-Arnáiz M, Ricoy JR, Mateos F, Simón R, García-Peñas
JJ, Garcia-Silva MT, Martín E, Vázquez M, Ferreiro A, Cabello A. Department of
Pathology, Neuropathology Section Hospital Universitario 12 de Octubre, Madrid,
Spain Abstract Macrophagic myofasciitis is an unusual inflammatory myopathy,
which has been almost exclusively reported in French adults with diffuse
arthromyalgias and asthenia. It is characterized by an infiltrate of densely
packed macrophages, with granular periodicacid-Schiff positive content, on
muscle biopsies at the site of vaccination. The presence of aluminum inclusions
in these macrophages points to an inappropriate reaction to aluminum used as an
adjuvant in some vaccines. Although in adults this entity is well defined, less
than 15 cases have been reported in children. This study describes seven
children, younger than 3 years of age, with typical lesions of macrophagic
myofasciitis on quadriceps muscle biopsy. In five cases, biopsies were
performed to exclude mitochondrial pathology. All the children developed
hypotonia and motor or psychomotor delay, associated with others symptoms.
Abnormal neuroimaging was evident in six cases. Spectrometry studies detected
elevated levels of aluminum in muscle in three of four cases tested. Despite
the wide use of vaccines in childhood, macrophagic myofasciitis was rarely
observed in children and its characteristic histologic pattern could not be
correlated with a distinctive clinical syndrome.
http://www.ncbi.nlm.nih.gov/pubmed/?term=16243223

“Although in adults this entity is well defined, less than 15 cases have been
reported in children. This study describes seven children, younger than 3 years
of age, with typical lesions of macrophagic myofasciitis on quadriceps muscle
biopsy.”

European Journal Of Pediatrics • November 2005

Nineteen cases of persistent pruritic nodules and contact allergy to aluminium
after injection of commonly used aluminium-adsorbed vaccines Author information
Bergfors E1, Björkelund C, Trollfors B. Department of Primary Health Care
Göteborg University, Box 454 40530 Gothenburg, Sweden
elisabet.bergfors@allmed.gu.se Abstract Rare cases of persistent pruritic
nodules, sometimes associated with aluminium (Al) allergy, have been reported
after the use of several Al adsorbed vaccines. During vaccine trials in the
1990s a high incidence of pruritic nodules (645 cases/76,000 recipients), in
77% associated with Al allergy, was observed after the administration of
diphtheria-tetanus / acellular pertussis (DT/aP) vaccines from a single
producer. In the present report 19 children with pruritic nodules after
vaccination with Al hydroxide-adsorbed DTaP/polio+Hib (Infanrix, Pentavac) are
described. The children had intensely itching nodules at the injection site,
often aggravated during upper respiratory tract infections, and local skin
alterations. So far, the symptoms have persisted for up to 7 years. The median
time between vaccination and onset of symptoms was 1 month. 16 children were
epicutaneously tested for Al, all with positive reactions indicating delayed
hypersensitivity to Al. The condition is not commonly known but is important to
recognise, as the child and the family may suffer considerably. Future
vaccinations with Al-adsorbed vaccines may cause aggravation of the symptoms
and the Al allergy. Al-containing skin products, such as antiperspirants, may
cause contact dermatitis. Nodules may be mistaken for tumours. Even though the
incidence of itching nodules and Al allergy after administration of Infanrix,
Pentavac and other Al-adsorbed vaccines is probably low, research to replace Al
adjuvants seems appropriate. We conclude that intensely itching subcutaneous
nodules, lasting for many years, and hypersensitivity to aluminium may occur
after DTaP/ polio+Hib vaccination of infants.
http://www.ncbi.nlm.nih.gov/pubmed/?term=16044278

“... intensely itching subcutaneous nodules, lasting for many years, and
hypersensitivity to aluminium may occur after DTaP/polio + Hib vaccination of
infants.”

Medical Hypotheses • 2005

Do cytosine guanine dinucleotide (CpG) fragments induce vasoactive neuropeptide
mediated fatigue-related autoimmune disorders? Author information Staines DR.
Gold Coast Public Health Unit 10-12 Young Street, Southport 4215 Qld.,
Australia don_staines@health.qld.gov.au Abstract Autoimmune dysfunction of
certain vasoactive neuropeptides (e.g., vasoactive intestinal peptide,
pituitary adenylate cyclase activating polypeptide) may be implicated in a
range of disorders associated with fatigue-like states (chronic fatigue
syndrome, Gulf War syndrome) and even sudden infant death syndrome (SIDS). The
important roles of these vasoactive neuropeptides make them a vulnerable target
for autoimmune dysfunction. They are known to be associated with heat shock
proteins for intracellular functioning with which they may form
immunostimulating complexes. Cytosine guanine dinucleotide (CpG) fragments are
potently immunogenic DNA fragments which serve as friend or foe recognition
systems between bacterial (hypomethylated) and mammalian (methylated) DNA and
are being assessed for suitability for use in human vaccines as adjuvants.
Interactions between CpG fragments, heat shock proteins and vasoactive
neuropeptides may be associated with fatigue-related autoimmune conditions.
http://www.ncbi.nlm.nih.gov/pubmed/15922114

“Interactions between CpG fragments, heat shock proteins and vasoactive
neuropeptides may be associated with fatigue-related autoimmune conditions.”

“In this study, 24.5% of asymptomatic children from 6 months to 5 years of age
were sensitized to one or more contact allergens, and thimerosal was the second
most prevalent allergen ...” Dermatitis • 2005

Hypersensitivity Reactions to Vaccine Components Noushin Heidary; David E.
Cohen Department of Dermatology and Allergic, Occupational and Environmental
Dermatology New York University School of Medicine, New York, NY Excerpt This
article will review adverse cutaneous events consistent with hypersensitivity
reactions to the following ingredients in vaccines: aluminum, thimerosal,
2-phenoxyethanol, formaldehyde, and neomycin. Despite the low clinical
relevance of thimerosal allergy, the rate of thimerosal sensitivity has
increased during the last decade, probably because of the increase in vaccines
administered during infancy. With the initiation of a mass vaccination campaign
in Austria in 1981, the administration of thimerosal-containing vaccines for
tick-borne encephalitis (TBE) increased from 6% in 1980 to 86% in 2001. The
growing number of people immunized to TBE has been concomitant with an increase
in thimerosalsensitized individuals in Austria.[14,20] Bruckner and colleagues
investigated the prevalence of positive patch-test results using the TRUE Test
system (Mekos Laboratories A/S, Hillerød, Denmark) on children under 5 years of
age to determine whether sensitization to contact allergens was common in
infancy.[21] In this study, 24.5% of asymptomatic children from 6 months to 5
years of age were sensitized to one or more contact allergens, and thimerosal
was the second most prevalent allergen (after nickel). Vaccines thus appear to
sensitize children to thimerosal at a younger age than expected, given the
unlikeliness of contact exposure in this age group to other
thimerosal-containing products. Osawa and colleagues also demonstrated this
phenomenon by associating DTP vaccination with thimerosal sensitivity in a
guinea pig model.[22] To determine whether patients with thimerosal allergy
could tolerate vaccination, Audicana and colleagues evaluated tolerance to
thimerosal-containing vaccines in 125 patients sensitized to mercury
derivatives and/or thimerosal.[23] Patch-test results in this patient
population revealed that 45% of patients had positive reactions to thimerosal
(0.05% in petrolatum), 74% had positive reactions to metallic mercury (0.5% in
petrolatum), and 70% had positive reactions to mercury chloride (0.1% in
water). In 10 cases, of all mercury derivatives tested, thimerosal yielded the
only positive patch-test result. A questionnaire revealed that the likely
source of sensitization in the 57 thimerosal patch-test-positive patients was
vaccination. Full Report http://www.medscape.com/viewarticle/516045

Virchows Archives • January 2006

Sudden infant death syndrome (SIDS) shortly after hexavalent vaccination:
another pathology in suspected SIDS? Author information Ottaviani G1, Lavezzi
AM, Matturri L. Institute of Pathology, University of Milan Via della Commenda
19, Milan 20122, Italy Abstract Experts from panels of the European Agency for
the Evaluation of Medical Products have investigated whether there might be a
link between hexavalent vaccines and some cases of deaths that occurred.
Participants included pathologists with experience in the field of vaccines and
sudden infant death syndrome who conducted autopsies. However, to the best of
our knowledge, little, if any, attention was paid to examination of the
brainstem and the cardiac conduction systems on serial sections, nor was the
possibility of a triggering role of the vaccine in these deaths considered.
Herein we report the case of a 3-month-old female infant dying suddenly and
unexpectedly shortly after being given a hexavalent vaccination. Examination of
the brainstem on serial sections revealed bilateral hypoplasia of the arcuate
nucleus. The cardiac conduction system presented persistent fetal dispersion
and resorptive degeneration. This case offers a unique insight into the
possible role of hexavalent vaccine in triggering a lethal outcome in a
vulnerable baby. Any case of sudden unexpected death occurring perinatally and
in infancy, especially soon after a vaccination, should always undergo a full
necropsy study according to our guidelines.
http://www.ncbi.nlm.nih.gov/pubmed/16231176

“This case offers a unique insight into the possible role of hexavalent vaccine
in triggering a lethal outcome in a vulnerable baby. Any case of sudden
unexpected death occurring perinatally and in infancy, especially soon after a
vaccination, should always undergo a full necropsy study according to our
guidelines.”

Vaccine • April 2006

Low-dose intraperitoneal Freund’s adjuvant: toxicity and immunogenicity in mice
using an immunogen targeting amyloid-beta peptide Author information Oscherwitz
J1, Hankenson FC, Yu F, Cease KB. Division of Hematology-Oncology, Department
of Internal Medicine University of Michigan Medical School, Ann Arbor, MI
48105, USA joscher@umich.edu Abstract Complete Freund’s adjuvant (CFA) is
effective for potentiating immune responses in mice when administered
subcutaneously, and is often more potent when given intraperitoneally (i.p.).
However, the the potential toxicity of i.p. administration in mice has led
investigators and Institutional Animal Care and Use committees to increasingly
view the use of CFA i.p. with reservation. We evaluated whether an 80%
reduction in the dose of CFA administered i.p. to mice, compared to the i.p.
doses used in a previous analysis, could abrogate the untoward effects
associated with its use, while still maintaining adjuvanticity. Using a novel
immunogen targeting the N-terminus of the 42-amino acid amyloid-beta peptide,
we compared low dose CFA administered i.p., with three other commonly used
adjuvants given i.p.: alum, incomplete Freunds adjuvant (IFA) and monophoshoryl
lipid A + trehalose dicorynomycolate (MPL + TDM). The results of the study
showed that, though the reduction in intraperitoneal dose of CFA mitigated
transient weight loss and leukocytosis observed previously with higher doses of
i.p. CFA, all mice administered CFA or IFA i.p. developed abdominal adhesions
and granulomatous peritonitis. Mice from all adjuvant groups, however, appeared
to tolerate the respective adjuvants well and excellent comparative
immunogenicity was observed in mice immunized with the Freunds and MPL + TDM
adjuvants. Consequently, we conclude that though a high-titered, humoral
response may be generated using low dose CFA administered i.p., the
accompanying toxicity remains significant, and thus alternative adjuvants
and/or routes should be considered.
http://www.ncbi.nlm.nih.gov/pubmed/?term=16307832

“Consequently, we conclude that though a high-titered, humoral response may be
generated using low dose CFA [still used in several vaccines today]
administered i.p., the accompanying toxicity remains significant, and thus
alternative adjuvants and/or routes should be considered.”

“Adverse cardiorespiratory events including apnea, bradycardia, and desaturations have been described
following administration of the first diphtheria-tetanus-pertussis-inactivated
polio-Haemophilus influenzae type B (DTP-IPV-Hib) immunization to preterm
infants.” BMC Pediatrics • June 2006

Frequency of apnea, bradycardia, and desaturations following first
diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B
immunization in hospitalized preterm infants Jackie Lee,1 Joan L Robinson,1 and
Donald W Spady1 Stollery Children’s Hospital and Department of Pediatrics
University of Alberta, Edmonton, Alberta, Canada jr3@ualberta.ca Abstract
Background Adverse cardiorespiratory events including apnea, bradycardia, and
desaturations have been described following administration of the first
diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B
(DTPIPV-Hib) immunization to preterm infants. The effect of the recent
substitution of acellular pertussis vaccine for whole cell pertussis vaccine on
the frequency of these events requires further study.
http://www.ncbi.nlm.nih.gov/pubmed/16784533

“... the outbreak lasted for approximately 2 months, suggesting that varicella in vaccinated persons
was contagious and that 99% varicella vaccination coverage was not sufficient
to prevent the outbreak.” Pediatrics • June 2006

One dose of varicella vaccine does not prevent school outbreaks: is it time for
a second dose? Author information Lopez AS1, Guris D, Zimmerman L, Gladden L,
Moore T, Haselow DT, Loparev VN, Schmid DS, Jumaan AO, Snow SL. Centers for
Disease Control and Prevention, Atlanta, GA 30333, USA alopez@cdc.gov
OBJECTIVES The implementation of a routine childhood varicella vaccination
program in the United States in 1995 has resulted in a dramatic decline in
varicella morbidity and mortality. Although disease incidence has decreased,
outbreaks of varicella continue to be reported, increasingly in highly
vaccinated populations. In 2000, a varicella vaccination requirement was
introduced for kindergarten entry in Arkansas. In October 2003, large numbers
of varicella cases were reported in a school with high vaccination coverage. We
investigated this outbreak to examine transmission patterns of varicella in
this highly vaccinated population, to estimate the effectiveness of 1 dose of
varicella vaccine, to identify risk factors for vaccine failure, and to
implement outbreak control measures. METHODS A retrospective cohort study
involving students attending an elementary school was conducted. A
questionnaire was distributed to parents of all of the students in the school
to collect varicella disease and vaccination history; parents of varicella case
patients were interviewed by telephone. A case of varicella was defined as an
acute, generalized, maculopapulovesicular rash without other apparent cause in
a student or staff member in the school from September 1 to November 20, 2003.
Varicella among vaccinated persons was defined as varicella-like rash that
developed >42 days after vaccination. In vaccinated persons, the rash may be
atypical, maculopapular with few or no vesicles. Cases were laboratory
confirmed by polymerase chain reaction, and genotyping was performed to
identify the strain associated with the outbreak. RESULTS Of the 545 students
who attended the school, 88% returned the questionnaire. Overall varicella
vaccination coverage was 96%. Forty-nine varicella cases were identified; 43
were vaccinated. Three of 6 specimens tested were positive by polymerase chain
reaction. The median age at vaccination of vaccinated students in the school
was 18 months, and the median time since vaccination was 59 months. Forty-four
cases occurred in the East Wing, where 275 students in grades kindergarten
through 2 were located, and vaccination coverage was 99%. In this wing,
varicella attack rates among unvaccinated and vaccinated students were 100% and
18%, respectively. Vaccine effectiveness against varicella of any severity was
82% and 97% for moderate/severe varicella. Vaccinated cases were significantly
milder compared with unvaccinated cases. Among the case patients in the East
Wing, the median age at vaccination was 18.5 and 14 months among non-case
patients. Four cases in the West Wing did not result in further transmission in
that wing. The Arkansas strains were the same as the common varicella-zoster
virus strain circulating in the United States (European varicella-zoster virus
strain).

CONCLUSIONS Although disease was mostly mild, the outbreak lasted for
approximately 2 months, suggesting that varicella in vaccinated persons was
contagious and that 99% varicella vaccination coverage was not sufficient to
prevent the outbreak. This investigation highlights several challenges related
to the prevention and control of varicella outbreaks with the 1-dose varicella
vaccination program and the need for further prevention of varicella through
improved vaccine-induced immunity with a routine 2-dose vaccination program.
The challenges include: 1-dose varicella vaccination not providing sufficient
herd immunity levels to prevent outbreaks in school settings where exposure can
be intense, the effective transmission of varicella among vaccinated children,
and the difficulty in the diagnosis of mild cases in vaccinated persons and
early recognition of outbreaks for implementing control measures. The efficacy
of 2 doses of varicella vaccine compared with 1 dose was assessed in a trial
conducted among healthy children who were followed for 10 years. The efficacy
for 2 doses was significantly higher than for 1 dose of varicella vaccine. This
higher efficacy translated into a 3.3-fold lower risk of developing varicella
>42 days after vaccination in 2- vs 1-dose recipients. Of the children
>receiving 2 doses, 99% achieved a glycoproteinbased enzyme-linked
>immunosorbent assay level of > or =5 units (considered a correlate of
>protection) 6 weeks after vaccination compared with 86% of children who
>received 1 dose. The 6-week glycoprotein-based enzyme-linked immunosorbent
>assay level of > or =5 units has been shown to be a good surrogate for
>protection from natural disease. Ten years after the implementation of the
>varicella vaccination program, disease incidence has declined dramatically,
>and vaccination coverage has increased greatly. However, varicella outbreaks
>continue to occur among vaccinated persons. Although varicella disease among
>vaccinated persons is mild, they are contagious and able to sustain
>transmission. As a step toward better control of varicella outbreaks and to
>reduce the impact on schools and public health officials, in June 2005, the
>Advisory Committee on Immunization Practices recommended the use of a second
>dose of varicella vaccine in outbreak settings. Early recognition of outbreaks
>is important to effectively implement a 2-dose vaccination response and to
>prevent more cases. Although the current recommendation of providing a second
>dose of varicella vaccine during an outbreak offers a tool for controlling
>outbreaks, a routine 2-dose recommendation would be more effective at
>preventing cases. Based on published data on immunogenicity and efficacy of 2
>doses of varicella vaccine, routine 2-dose vaccination will provide improved
>protection against disease and further reduce morbidity and mortality from
>varicella. http://www.ncbi.nlm.nih.gov/pubmed/16740809

Health & Place • June 2006

Environmental mercury release, special education rates, and autism disorder: an
ecological study of Texas Author information Palmer RF1, Blanchard S, Stein Z,
Mandell D, Miller C. University of Texas Health Science Center San Antonio
Department of Family and Community Medicine 7703 Floyd Curl Drive, San Antonio,
Texas 78229-3900, USA palmer@uthscsa.edu Abstract The association between
environmentally released mercury, special education and autism rates in Texas
was investigated using data from the Texas Education Department and the United
States Environmental Protection Agency. A Poisson regression analysis adjusted
for school district population size, economic and demographic factors was used.
There was a significant increase in the rates of special education students and
autism rates associated with increases in environmentally released mercury. On
average, for each 1,000 lb of environmentally released mercury, there was a 43%
increase in the rate of special education services and a 61% increase in the
rate of autism. The association between environmentally released mercury and
special education rates were fully mediated by increased autism rates. This
ecological study suggests the need for further research regarding the
association between environmentally released mercury and developmental
disorders such as autism. These results have implications for policy planning
and cost analysis. http://www.ncbi.nlm.nih.gov/pubmed/16338635

“On average, for each 1,000 lb of environmentally released mercury, there was a
43% increase in the rate of special education services and a 61% increase in
the rate of autism.”

Vaccine • Volume 24, Issues 31–32 • July 2006

Unexplained cases of sudden infant death shortly after hexavalent vaccination
Author Information Zinka B, Rauch E, Buettner A, Ruëff F, Penning R. Report
available for purchase:
http://www.sciencedirect.com/science/article/pii/S0264410X05004688

CMAJ • August 2006

Two successive outbreaks of mumps in Nova Scotia among vaccinated adolescents
and young adults Author Information Gaynor Watson-Creed, Andrea Saunders,
Jeffrey Scott, Luis Lowe, Janice Pettipas, and Todd F. Hatchette From Nova
Scotia Health Promotion and Protection (Watson-Creed, Saunders, Scott) the
Departments of Community Health and Epidemiology (Watson-Creed, Scott),
Pediatrics (Scott) and Pathology (Hatchette) Dalhousie University, and the
Department of Pathology and Laboratory Medicine (Pettipas, Hatchette) QEII
Health Science Centre, Halifax, NS; the Canadian Field Epidemiology Program
(Saunders), Public Health Agency of Canada, Ottawa, Ontario and the Respiratory
and Enteric Virus Branch (Lowe), Centers for Disease Control and Prevention,
Atlanta, GA Abstract Background Before the widespread use of vaccine, mumps was
the most common cause of viral meningitis (up to 10% of mumps infections).
Vaccination programs have resulted in a drop of more than 99% in the number of
reported mumps cases in the United States and Canada. Although rare in Canada,
outbreaks have recently occurred throughout the world, including a large
outbreak in the United Kingdom, where more than 56,000 cases were reported in
2004–2005. Methods Two recent outbreaks in Nova Scotia were investigated by
public health officials. Cases were defined by laboratory confirmation of
infection (i.e., isolation of mumps virus by culture) or clinical diagnosis in
people epidemiologically linked to a laboratory-confirmed case. The people
infected were interviewed to determine possible links and to identify contacts.
Mumps virus was cultured from urine and throat specimens, identified via
reversetranscriptase polymerase chain reaction (RT-PCR) and subjected to
phylogenetic analysis to identify the origin of the strain.

Results The first outbreak involved 13 high-school students (median age 14 yr):
9 who had previously received 2 doses of measles–mumps–rubella vaccine (MMR)
and 4 who received a single dose. The second outbreak comprised 19 cases of
mumps among students and some staff at a local university (median age 23 yr),
of whom 18 had received only 1 dose of MMR (the other received a second dose).
The viruses identified in the outbreaks were phylogenetically similar and
belonged to a genotype commonly reported in the UK. The virus from the second
outbreak is identical to the strain currently circulating in the UK and United
States. Interpretation The predominance in these outbreaks of infected people
of university age not only highlights an environment with potential for
increased transmission but also raises questions about the efficacy of the MMR
vaccine. The people affected may represent a “lost cohort” who do not have
immunity from natural mumps infection and were not offered a 2-dose schedule.
Given the current level of mumps activity around the world, clinicians should
remain vigilant for symptoms of mumps.

Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1550754

“... studies especially on neurotoxicity, genotoxicity,
or carcinogenicity, are previously published in numerous articles.” Biometals •
August 2006

Occurrence, use and potential toxic effects of metals and metal compounds
Ana-Maria Florea, Dietrich Büsselberg Abstract Metals and metal compounds are
constituents of our natural environment. Their distribution depends on the
existence of natural sources (e.g. volcanoes or erosion) and their use in
human’s activity. They are transformed naturally (e.g. by bacterial activity)
with formation of organic species that influence their mobility and
accumulation in abiotic as well as biotic systems. Up to date metal species are
released into the environment questioning their influence on human health. Due
to their widespread use in human activities such as industry, agriculture and
even as medicine (e.g. As, Se, Pt), numerous health risks may be associated
with exposure to these substances. Different reports on metal intoxication are
documented and studies especially on neurotoxicity, genotoxicity, or
carcinogenicity, are previously published in numerous articles. This
mini-review gives an overview on the use and the actions of selected metal
species of actual scientific concern, with a focus on neuronal cells.
http://link.springer.com/article/10.1007%2Fs10534-005-4451-x

Pediatric Neurology • August 2006

Acute metabolic crisis induced by vaccination in seven Chinese patients Author
information Yang Y1, Sujan S, Sun F, Zhang Y, Jiang Y, Song J, Qin J, Wu X.
Department of Pediatrics, Peking University First Hospital Beijing, China
yanlingy@vip.sina.com Abstract Seven Chinese patients (5 males and 2 females)
with vaccination-induced acute metabolic crisis were reported. Only one male
with 21-hydroxylase deficiency had been diagnosed before vaccination. In the
remaining six patients, the preexisting diagnoses were not confirmed before the
vaccination. Acute metabolic crisis occurred in seven patients between 3 and 12
hours after the administration of Japanese encephalitis, diphtheria, and
tetanus toxoids and acellular pertussis, hepatitis B, or measles vaccines.
Patients 1 and 2 displayed acute adrenal insufficiencies at the ages of 5 years
and 3 months, respectively. Patient 3 had presented with mild motor retardation
previously. Patients 4 to 7 were previously healthy, but suffered from fever,
seizures, coma, acidosis, and hypoglycemia after being vaccinated. Glutaric
aciduria type 1 was evident in case 4. Leigh syndromes were present in Patients
5, 6, and 7. They all died from respiratory failure before 2 years of age.
Symmetric foci, cystic cavitations with neuronal loss, and vascular
proliferation were observed by postmortem examination. Among the seven
patients, although the vaccines were not the primary cause of the acute
metabolic crisis, the severe acute episodes occurred coincidentally.
http://www.ncbi.nlm.nih.gov/pubmed/16876007

“Seven Chinese patients with vaccination-induced acute metabolic crisis were
reported.”

“The first rotavirus vaccine ... left instead the unfortunate legacy that
live oral rotavirus vaccines may be associated with a serious but rare adverse
event: intussusception.” Pediatrics • August 2006

Rotavirus Vaccination and Intussusception: Can We Decrease Temporally
Associated Background Cases of Intussusception by Restricting the Vaccination
Schedule? Author Information Jennifer H. Tai, MDa, Aaron T. Curns, MPHb, Umesh
D. Parashar, MBBS, MPHa, Joseph S. Bresee, MDa, Roger I. Glass, MD, PhDa a.
Viral Gastroenteritis Section b. Office of the Director, Division of Viral and
Rickettsial Diseases Centers for Disease Control and Prevention, Atlanta,
Georgia Abstract OBJECTIVE The first rotavirus vaccine that was licensed in the
United States, RotaShield, could have prevented the enormous burden of
rotavirus diarrhea in American children but left instead the unfortunate legacy
that live oral rotavirus vaccines may be associated with a serious but rare
adverse event: intussusception. Although large trials indicate that the next
generation of rotavirus vaccines is not associated with this complication, many
children likely will develop intussusception by chance alone in the 2-week
window after immunization, raising concerns about whether these cases might be
“caused” by the vaccine. Our objective for this study was to model and compare
the number of temporally associated intussusception events that are expected by
chance alone under 2 rotavirus vaccination strategies. CONCLUSIONS Although an
age-restricted vaccination schedule substantially reduced the number of
intussusception events that were observed in the 2-week postvaccination window
when compared with a schedule with fewer restrictions, this decrease was
attributable to a lower rate of vaccine coverage rather than a safer schedule
of vaccination. The risk for intussusception did not differ significantly
between vaccination strategies. Public health policy and education messages for
physicians and parents should be developed to anticipate intussusception events
that will occur by chance alone but are temporally related to rotavirus
vaccination. http://pediatrics.aappublications.org/content/118/2/e258

Multiple Sclerosis • October 2006

Elevated urinary excretion of aluminium and iron in multiple sclerosis Author
information Exley C1, Mamutse G, Korchazhkina O, Pye E, Strekopytov S, Polwart
A, Hawkins C. Birchall Centre for Inorganic Chemistry and Materials Science
Lennard-Jones Laboratories, Keele University, Staffordshire, UK
c.exley@chem.keele.ac.uk Abstract Multiple sclerosis (MS) is a chronic,
immune-mediated, demyelinating disease of the central nervous system of as yet
unknown aetiology. A consensus of opinion has suggested that the disorder is
the result of an interplay between environmental factors and susceptibility
genes. We have used a battery of analytical techniques to determine if the
urinary excretion of i) markers of oxidative damage; ii) iron and iii) the
environmental toxin aluminium and its antagonist, silicon, are altered in
relapsing-remitting (RRMS) and secondary progressive MS (SPMS). Urinary
concentrations of oxidative biomarkers, MDA and TBARS, were not found to be
useful indicators of inflammatory disease in MS. However, urinary
concentrations of another potential marker for inflammation and oxidative
stress, iron, were significantly increased in SPMS (P<0.01) and insignificantly
increased in RRMS (P>0.05). Urinary concentrations of aluminium were also
significantly increased in RRMS (P<0.001) and SPMS (P <0.05) such that the
levels of aluminium excretion in the former were similar to those observed in
individuals undergoing metal chelation therapy. The excretion of silicon was
lower in MS and significantly so in SPMS (P<0.05). Increased excretion of iron
in urine supported a role for iron dysmetabolism in MS. Levels of urinary
aluminium excretion similar to those seen in aluminium intoxication suggested
that aluminium may be a hitherto unrecognized environmental factor associated
with the aetiology of MS. If aluminium is involved in MS then an increased
dietary intake of its natural antagonist, silicon, might be a therapeutic
option. http://www.ncbi.nlm.nih.gov/pubmed/?term=17086897

“Levels of urinary aluminium excretion similar to those seen in aluminium
intoxication suggested that aluminium may be a hitherto unrecognized
environmental factor associated with the aetiology of Multiple Sclerosis.”

Journal Of Autoimmunity • November 2006

Fibromyalgia, infection and vaccination: two more parts in the etiological
puzzle Author information Ablin JN1, Shoenfeld Y, Buskila D. Department of
Rheumatology Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine
Tel-Aviv University, Tel-Aviv, Israel ajacob@post.tau.ac.il Abstract As the
pathogenesis of fibromyalgia continues to raise debate, multiple putative
triggers have been implicated. The current review summarizes the available data
linking fibromyalgia to either infection or vaccination. Multiple infectious
agents have been associated with the development of either full-blown
fibromyalgia (e.g. hepatits C), or with symptom complexes extensively
overlapping with that syndrome (e.g. chronic Lyme disease). The cases of Lyme
disease, mycoplasma, hepatits C and HIV are detailed. Despite the described
associations, no evidence is available demonstrating the utility of antibiotic
or anti-viral treatment in the management of fibromyalgia. Possible mechanistic
links between fibromyalgia and HIV are reviewed. Associations have been
described between various vaccinations and symptom complexes including
fibromyalgia and chronic fatigue syndrome. The case of Gulf War syndrome, a
functional multisystem entity sharing many clinical characteristics with
fibromyalgia is discussed, with emphasis on the possibility of association with
administration of multiple vaccinations during deployment in the Persian Gulf
and the interaction with stress and trauma. Based on this example a model is
proposed, wherein vaccinations function as co-triggers for the development of
functional disorders including fibromyalgia, in conjunction with additional
contributing factors. http://www.ncbi.nlm.nih.gov/pubmed/17071055

“Based on this example a model is proposed, wherein vaccinations function as
co-triggers for the development of functional disorders including fibromyalgia,
in conjunction with additional contributing factors.”

Egyptian Journal Of Immunology • 2006

Possible immunological disorders in autism: concomitant autoimmunity and immune
tolerance Author information Kawashti MI1, Amin OR, Rowehy NG. Microbiology
Department Faculty of Medicine For Women Al Azhar University, Cairo, Egypt
Abstract Autism is a pervasive developmental disorder that affect children
early in their life. Immunological disorders is one of several contributing
factors that have been suggested to cause autism. Thirty autistic children aged
36 years and thirty non-autistic psychologically-free siblings were studied.
Circulating IgA and IgG autoantibodies to casein and gluten dietary proteins
were detected by enzyme-immunoassays (EIA). Circulating IgG antibodies to
measles, mumps and rubella vaccine (M.M.R) and cytomeglovirus were investigated
by EIA. Results revealed high seropositivity for autoantibodies to casein and
gluten: 83.3% and 50% respectively in autistic children as compared to 10% and
6.7% positivity in the control group. Surprisingly, circulating anti-measles,
anti-mumps and anti-rubella IgG were positive in only 50%, 73.3% and 53.3%
respectively as compared to 100% positivity in the control group. Anti-CMV IgG
was positive in 43.3% of the autistic children as compared to 7% in the control
group. It is concluded that, autoimmune response to dietary proteins and
deficient immune response to measles, mumps and rubella vaccine antigens might
be associated with autism, as a leading cause or a resulting event. Further
research is needed to confirm these findings.
http://www.ncbi.nlm.nih.gov/pubmed/17974154

“It is concluded that, autoimmune response to dietary proteins and deficient
immune response to measles, mumps and rubella vaccine antigens might be
associated with autism, as a leading cause or a resulting event.”

Vaccine • January 2007

DTP with or after measles vaccination is associated with increased in-hospital
mortality in Guinea-Bissau Author information Aaby P1, Biai S, Veirum JE,
Sodemann M, Lisse I, Garly ML, Ravn H, Benn CS, Rodrigues A. Projecto de Saúde
de Bandim, Apartado 861 Bissau, Guinea-Bissau p.aaby@bandim.org Abstract
BACKGROUND The sequence of routine immunisations may be important for childhood
mortality. Three doses of diphtheria-tetanus-pertussis vaccine (DTP) should be
given at 6, 10, and 14 weeks and measles vaccine (MV) at 9 months of age. The
sequence is not always respected. We examined inhospital mortality of children
having received DTP with or after measles vaccine. SETTING The only paediatric
ward in Bissau, Guinea-Bissau. PARTICIPANTS Children hospitalised during two
periods in 1990-1996 and 2001-2002 who had received MV prior to
hospitalisation. MAIN OUTCOME MEASURE The all-cause case fatality at the
hospital for children aged 6-17 months. RESULT The case fatality was increased
for children who had received DTP with or after measles vaccine compared with
children who had received measles vaccine as the most recent vaccine, the ratio
being 2.53 (1.37-4.67) and 1.77 (0.92-3.41) in the two periods, respectively.
The combined estimate was 2.10 (1.34-3.28). These results were not explained by
differences in nutritional status, number of doses of DTP or discharge policy.
CONCLUSION Administration of DTP with, or after MV, may reduce the beneficial
effect of MV. http://www.ncbi.nlm.nih.gov/pubmed/17092614

“The case fatality was increased for children who had received DTP with or
after measles vaccine compared with children who had received measles vaccine
as the most recent vaccine, the ratio being 2.53 (1.37-4.67) and 1.77
(0.92-3.41) in the two periods, respectively.”

Brain Research • May 2007

Effects of postnatal formaldehyde exposure on pyramidal cell number, volume of
cell layer in hippocampus and hemisphere in the rat: a stereological study
Author information Sarsilmaz M1, Kaplan S, Songur A, Colakoglu S, Aslan H, Tunc
AT, Ozen OA, Turgut M, Bas O. Department of Anatomy Firat University School of
Medicine Elazig, Turkey Abstract The purpose of the present study was to
determine whether exposure of neonatal rats to formaldehyde (FA) had either
early or delayed effects on the numbers of pyramidal cells in the cornu ammonis
(CA) of the hippocampus. Neonatal Wistar rats were exposed to 0 ppm (control
group), 6 ppm and 12 ppm (high concentration group) of FA concentrations
throughout the 30-day period following the birth by placing them for 6 h/day in
a glass chamber containing FA vapor. Then, some of the animals from each
FA-treated group were anesthetized and decapitated at the day 30, and the
remaining ones were killed at the day 90. The brains were removed immediately
and fixed in 10% neutral-buffered FA solution. The Cavalieri principle was used
to determine the volumes of the CA and the entire cerebral hemisphere. The
optical fractionator counting method was used to estimate the total number of
pyramidal cells in the CA. The appearance of pyramidal cells was normal under
light microscopy at both postnatal day (PND) 30 and PND 90 in all groups. There
were concentration-related volume changes of CA at PND 30 and PND 90; low
concentration of FA significantly increased, whereas high concentration
decreased the volume of CA in comparison of the control at PND 30. Importantly,
high concentration of FA at PND 90 increased the volume of CA in comparison of
the low concentration but not with the control. Furthermore, low and high
concentrations of FA decreased the volume of hemisphere at PND 30, whereas a
reverse effect of these concentrations was observed at the hemisphere of PND 90
in comparison of the control. In both CA and cerebral hemisphere, an
age-related volume decrease in both control and low/high concentration groups
were found. On the other hand, there were significant age-related reductions in
the total number of pyramidal cells at 90 days of age irrespective of the
groups examined. Rats treated with high concentration FA were seen to have
significantly fewer pyramidal cell neurons than either the animals treated with
low concentration FA or control groups (p<0.01). These observations indicate
that pyramidal cells in the hippocampus may be vulnerable to FA exposure during
the early period of life. http://www.ncbi.nlm.nih.gov/pubmed/?term=17346681

“These observations indicate that pyramidal cells in the hippocampus may be
vulnerable to Formaldehyde exposure during the early period of life.”

Journal Of Pediatrics • August 2007

Primary immunization of premature infants with gestational age <35 weeks:
cardiorespiratory complications and C-reactive protein responses associated
with administration of single and multiple separate vaccines simultaneously
Author information Pourcyrous M1, Korones SB, Arheart KL, Bada HS. Department
of Pediatrics The University of Tennessee Health Science Center Memphis,
Tennessee 38163, USA mpourcyrous@utmem.edu Abstract OBJECTIVE To determine the
incidence of cardiorespiratory events and abnormal C-reactive protein (CRP)
level associated with administration of a single vaccine or multiple separate
vaccines simultaneously. STUDY DESIGN Prospective observational study on 239
preterm infants at > or =2 months of age in the neonatal intensive care unit
(NICU). Each infant received either a single vaccine or multiple vaccines on
one day. CRP levels and cardiorespiratory manifestations were monitored for 3
days following immunization. RESULTS Abnormal elevation of CRP level occurred
in 85% of infants administered multiple vaccines and up to 70% of those given a
single vaccine. Overall, 16% of infants had vaccine-associated
cardiorespiratory events within 48 hours postimmunization. In logistic
regression analysis, abnormal CRP values were associated with multiple vaccines
(OR, 15.77; 95% CI 5.10-48.77) and severe intraventricular hemorrhage (IVH)
(OR, 2.28; 95% CI 1.02-5.13). Cardiorespiratory events were associated
marginally with receipt of multiple injections (OR, 3.62; 95% CI 0.99-13.25)
and significantly with gastroesophageal reflux (GER) (OR, 4.76; 95% CI
1.22-18.52). CONCLUSION CRP level is expected to be elevated in the 48 hours
following immunization. In a minority of infants immunized, cardiorespiratory
events were associated with presumed need for intervention. Underlying medical
conditions and possibly multiple injections are associated with
cardiorespiratory events. Precautionary monitoring following immunizations is
warranted. http://www.ncbi.nlm.nih.gov/pubmed/?term=17643770

“In a minority of infants immunized [16%], cardiorespiratory events were
associated with presumed need for intervention.”

Pediatrics • August 2007

Risk of Serious Neurologic Disease After Immunization of Young Children in
Britain and Ireland Author Information Katherine N. Ward, MA, MB, BChir, PhD,
FRCPatha, Naomi J. Bryant, MSca, Nick J. Andrews, MScb, Jennifer S. Bowley,
BSca, Anu Ohrling, MDa, Christopher M. Verity, MA, BM, BCh, FRCP, FRCPCH, DCHc,
Euan M. Ross, MD, FRCP, FRCPCH, FFPH, DCHd, Elizabeth Miller, BSc, MB, BS,
FRCPath, FFPHb a. Centre for Virology (UCL Campus), Division of Infection and
Immunity Royal Free and University College Medical School, Windeyer Institute
of Medical Sciences, London, UK b. Centre for Infections, Health Protection
Agency, London, United Kingdom c. Child Development Centre, Addenbrooke’s
Hospital, Cambridge, United Kingdom d. Child Studies Department, King’s
College, Strand, London, United Kingdom Abstract OBJECTIVE We sought to
investigate the risk of serious neurologic disease after immunization in early
childhood. METHODS The results of a 3-year prospective study of children (2–35
months old) in Britain and Ireland with encephalitis and/or severe illness with
convulsions and fever were linked to each child’s vaccine history. Cases were
reported via the British Paediatric Surveillance Unit’s network. The
self-controlled case-series method was used to investigate associations between
immunization and acute potential adverse events. The risk periods investigated
were 0 to 3 and 0 to 7 days post–diphtheria, tetanus, whole cell pertussis,
Haemophilus influenzae type b or meningococcal C conjugate vaccine and 6 to 11
and 15 to 35 days post–measles, mumps, rubella vaccine. RESULTS A total of 157
disease episodes from 155 children met the analytical case definition. There
were 11 cases of herpes simplex encephalitis and 23 cases of primary human
herpesvirus 6 and/or 7 infection. There was no evidence of a raised relative
incidence of serious neurologic disease in any of the specified risk periods
with the exception of a raised relative incidence of 5.68 in the 6–11 days
after measles, mumps, rubella vaccine. Based on this relative incidence,
between 3 and 6 of the 6 cases in this period were estimated to be attributable
to the vaccine with a best estimate of 5. The 6 cases all had fever with
convulsions lasting >30 minutes; in all but 1, there was complete recovery by
discharge from hospital. Of the 5 patients who recovered, 1 had a concurrent
primary human herpesvirus 6 infection and one a primary human herpesvirus 7.
CONCLUSIONS Six to 11 days after measles, mumps, rubella vaccine there is an
increased risk of fever and convulsions lasting
>30 minutes. All 6 of the episodes temporally related to immunization met the
>criteria for complex febrile convulsions. The estimated attributable risk of
>serious neurological disease was similar to that previously found for
measles vaccine. http://pediatrics.aappublications.org/content/120/2/314

“All 6 of the episodes temporally related to immunization met the criteria for
complex febrile convulsions.”

Journal Of Inorganic Biochemistry • September 2007

Induction of specific micro RNA (miRNA) species by ROS-generating metal
sulfates in primary human brain cells Author information Lukiw WJ1, Pogue AI.
Neuroscience Center and Department of Ophthalmology Louisiana State University
Health Sciences Center New Orleans, LA 70112, USA wlukiu@lsuhsc.edu Abstract
Iron- and aluminum-sulfate together, at nanomolar concentrations, trigger the
production of reactive oxygen species (ROS) in cultures of human brain cells.
Previous studies have shown that following ROS induction, a family of
pathogenic brain genes that promote inflammatory signalling, cellular apoptosis
and brain cell death is significantly over-expressed. Notably, iron- and
aluminum-sulfate induce genes in cultured human brain cells that exhibit
expression patterns similar to those observed to be up-regulated in moderate-
to late-stage Alzheimer’s disease (AD). In this study we have extended our
investigations to analyze the expression of micro RNA (miRNA) populations in
iron- and aluminum-sulfate treated human neural cells in primary culture. The
main finding was that these ROS-generating neurotoxic metal sulfates also
up-regulate a specific set of miRNAs that includes miR-9, miR-125b and miR-128.
Notably, these same miRNAs are up-regulated in AD brain. These findings further
support the idea that ironand aluminum-sulfates induce genotoxicity via a
ROS-mediated up-regulation of specific regulatory elements and pathogenic genes
that redirect brain cell fate towards progressive dysfunction and apoptotic
cell death. http://www.ncbi.nlm.nih.gov/pubmed/?term=17629564

“Iron- and aluminum-sulfate together, at nanomolar concentrations, trigger the
production of reactive oxygen species (ROS) in cultures of human brain cells.
Previous studies have shown that following reactive oxygen species (ROS)
induction, a family of pathogenic brain genes that promote inflammatory
signalling, cellular apoptosis and brain cell death is significantly
over-expressed.”

Archives Of Neurology • November 2007

Optic Neuritis and Vaccination Investigation: Failure to Consider Significant
Sex Differences and Multiple Vaccine Combinations Renata J. M. Engler, MD; Mary
Klote, MD; Michael R. Nelson, MD, PhD Abstract In follow-up to recent
correspondence related to the study of vaccinations and subsequent optic
neuritis by the Centers for Disease Control and Prevention (CDC),1,2 we are
deeply concerned regarding the lack of consideration of sex differences in
incidence of disease for the ICD-9 code 377.3, a common finding for autoimmune
disorders, particularly in young adults aged 18 to 39 years. The Defense
Medical Surveillance System (DMSS) demonstrates that in the population of
service members of greatest concern, there is a consistent pattern, regardless
of year for review, of increased disease incidence by first visit in women
compared with men. This sex difference is also independent of race. The Figure
was extracted from the remote access program to data contained within the DMSS
offered by the Army Medical Surveillance Activity.3 Similar sex differences
were identified for ICD-9 codes for optic neuritis, unspecified (377.30); optic
papillitis (377.31); retrobulbar neuritis, acute (377.32); and optic neuritis,
other (377.39) during the period between January 1, 1998, and December 31,
2003. It is of increasing concern in the context of medical evidence and
research that sex differences are not adequately considered in both research
design and data analysis. Given the mandatory nature of immunizations in the
military health system and the fact that most visits involve complex and
sometimes new mixtures, concern for sex-based risk differences is not a minor
question and merits far more attention on the agenda of vaccine safety
surveillance.
http://archneur.jamanetwork.com/article.aspx?articleid=794738&resultClick=3

“we are deeply concerned regarding the lack of consideration of sex differences
in incidence of disease ... there is a consistent pattern, regardless of year
for review, of increased disease incidence by first visit in women compared
with men ...”

Report of the Subcommittee on Science and Technology • November 2007

FDA Science and Mission at Risk FDA Mission Statement “The FDA is responsible
for protecting the public health by assuring the safety, efficacy, and security
of human and veterinary drugs, biological products, medical devices, our
nation’s food supply, cosmetics, and products that emit radiation. The FDA is
also responsible for advancing the public health by helping to speed
innovations that make medicines and foods more effective, safer, and more
affordable; and helping the public get the accurate, science-based information
they need to use medicines and foods to improve their health.” FINDINGS OF THE
SUBCOMMITTEE The FDA cannot fulfill its mission because its scientific base has
eroded and its scientific organizational structure is weak. The FDA cannot
fulfill its mission because its scientific workforce does not have sufficient
capacity and capability. The FDA cannot fulfill its mission because its
information technology (IT) infrastructure is inadequate. FDA does not have the
capacity to ensure the safety of food for the nation. The development of
medical products based on “new science” cannot be adequately regulated by the
FDA. The FDA cannot provide the information infrastructure support to regulate
products based on new science. The FDA IT infrastructure is obsolete, unstable,
and lacks sufficient controls to ensure continuity of operations or to provide
effective disaster recovery services. There is insufficient capacity in
modeling, risk assessment and analysis. The FDA has experienced decreasing
resources in the face of increasing responsibilities. The FDA science agenda
lacks a coherent structure and vision, as well as effective coordination and
prioritization. The IT workforce is insufficient and suboptimally organized.
The FDA has an inadequate and ineffective program for scientist performance.
Recommendations of excellent FDA reviews are seldom followed. The FDA has
inadequate funding for professional development. The FDA has not taken
sufficient advantage of external and internal collaborations. The FDA lacks the
information science capability and information infrastructure to fulfill its
regulatory mandate.

The nation’s food supply is at risk. Crisis management in FDA’s two food safety
centers, Center for Food Safety and Applied Nutrition (CFSAN) and Center for
Veterinary Medicine (CVM), has drawn attention and resources away from FDA’s
ability to develop the science base and infrastructure needed to efficiently
support innovation in the food industry, provide effective routine
surveillance, and conduct emergency outbreak investigation activities to
protect the food supply. FDA’s inability to keep up with scientific advances
means that American lives are at risk. While the world of drug discovery and
development has undergone revolutionary change — shifting from cellular to
molecular and gene-based approaches — FDA’s evaluation methods have remained
largely unchanged over the last half century. Likewise, evaluation methods have
not kept pace with major advances in medical devices and use of products in
combination. The turnover rate in FDA science staff in key scientific areas is
twice that of other government agencies. There are insufficient programs of
measurement to determine worker performance. There is insufficient investment
in professional development, which means that the workforce does not keep up
with scientific advances. Finally, for various reasons, the FDA does not have
sufficiently extensive collaboration with external scientists, thus limiting
infusion of new knowledge and missing opportunities to leverage resources.
FDA’s failure to retain and motivate its workforce puts FDA’s mission at risk.
Inadequately trained scientists are generally risk-averse, and tend to give no
decision, a slow decision or, even worse, the wrong decision on regulatory
approval or disapproval. During our encounters with staff and center
leadership, we were struck by the near unanimity that the shortage of science
staff (due to lack of resources to hire) and the inability to recruit and
retain needed expertise are serious, longstanding challenges. Internal
expertise and experience to provide the science capability and capacity needed
in highly specialized and fast-evolving areas is disturbingly limited. The lack
of a trained workforce means that the FDA is ineffective in responding to
emerging fields that require individuals and work teams with multidisciplinary
skills built on very complex, highly specialized, often esoteric bodies of
knowledge. The Subcommittee was extremely disturbed at the state of the FDA IT
infrastructure .. the IT workforce is insufficient. The IT situation at FDA is
problematic at best — and at worst it is dangerous. Many of the FDA systems
reside on technology that has been in service beyond the usual life cycle.
Systems fail frequently, and even email systems are unstable — most recently
during an E.coli food contamination investigation. More importantly, reports of
product dangers are not rapidly compared and analyzed, inspectors’ reports are
still hand written and slow to work their way through the compliance system,
and the system for managing imported products cannot communicate with Customs
and other government systems (and often miss significant product arrivals
because the system cannot even distinguish, for example, between road salt and
table salt). There are inadequate emergency backup systems in place: recent
system failures have resulted in loss of FDA data. Critical data reside in
large warehouses sequestered in piles and piles of paper documents. There is no
backup of these records, which include valuable clinical trial data. The FDA
has inadequate extramural funding programs and collaborations to accelerate the
development of critical health information exchanges in order to support
clinical trials and pharmacovigilance activities. In contrast to previous
reviews that warned crises would arise if funding issues were not addressed,
recent events and our findings indicate that some of those crises are now
realities and American lives are at risk.

http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4329b_02_01_FDA%20Report%20on%20Science%20and%20Technology.pdf

Medical Veritas • 2008

Current childhood vaccine programs: An overview with emphasis on the
Measles-Mumps-Rubella (MMR) vaccine and of its compromising of the mucosal
immune system Harold E. Buttram, MD Email: hbuttram1304@comcast.net Abstract
Both common observation and official statistics confirm that there have been
dramatic increases in chronic physical and mental illnesses in American
children, such as autism, asthma, and allergies since the introduction of the
MMR vaccine in 1978. Government health officials have denied a relationship
with vaccines, but U.S. Congressional hearings on vaccine safety (1999 to Dec.
2004) revealed a total absence of vaccine safety tests that would meet current
scientific standards, so that it can be assumed that many vaccine reactions are
taking place unrecognized. Prior to the introduction of vaccines, the Th1
cellular immune system of the gastrointestinal and respiratory systems served
as the primary defense systems with the Th2 hu- moral immune system in the bone
marrow, serving a secondary role. There is a school of thought that the “minor
childhood diseases” of earlier times, including measles, mumps, chicken pox,
and rubella, which involved the epithelial tissues of skin, respiratory, and/or
gastrointestinal tracts, served a necessary purpose in challenging,
strengthening, and estab- lishing the dominance of Th1 cellular immune system
during early childhood. Current vaccines against these diseases, in contrast,
being directed at stimulating antibody production in the bone marrow, are
bypassing the cellular immune system and thereby tending to reverse the roles
of the cellular and humoral systems, with the former suffering from a lack of
challenge. In addition, the cellular immune system is being further compromised
by the powerfully immunosuppressive effects of the MMR vaccine. The time is
overdue to totally rethink and redirect our current childhood vaccine program.
http://www.vacinfo.org/buttram.pdf

“Both common observation and official statistics confirm that there have been
dramatic increases in chronic physical and mental illnesses in American
children, such as autism, asthma, and allergies since the introduction of the
MMR vaccine in 1978. Government health officials have denied a relationship
with vaccines, but U.S. Congressional hearings on vaccine safety (1999 to Dec.
2004) revealed a total absence of vaccine safety tests that would meet current
scientific standards, so that it can be assumed that many vaccine reactions are
taking place unrecognized.”

Medical Veritas 2008

“This paper demonstrates

Vaccines, depression, and neurodegeneration after age 50 years: another reason
to avoid the recommended vaccines

the known links between:

by Russell L. Blaylock, MD, CCN There is growing evidence that a number of the
psychiatric disorders are strongly related to glutamate excess. Likewise,
recent studies have shown a connection between chronic inflammation and these
same disorders. A compelling body of research links these two observations,
glutamate excess (an excitotoxicity marker) and chronic inflammation (immune
over-reactivity). It is known that systemic activation of the immune system
also activates the brain’s special immune system, which is regulated by the
microglia. Based on results of studies of the sickness behavior response to
natural infections, neuroscientists have deciphered much of the mechanism
responsible for the behavioral effects associated with intense systemic immune
activation, including social isolation, depression, anxiety, and a loss of
appetite. Most of these symptoms are shared by the major depressive disorders.
Other studies have linked neurodegeneration and a worsening of
neurodegenerative diseases to systemic immune activation. This paper
demonstrates the known links between: systemic immune activation, brain
microglial activation, and both major depressive disorder and a worsening of
neurodegenerative diseases. Because a number of vaccines are being recommended
to adults, the risk of precipitating or worsening these disorders is quite
real. The mechanism for this process is discussed.
http://www.vacinfo.org/man1742_1747.pdf

systemic immune activation, brain microglial activation, and both major
depressive disorder and a worsening of neurodegenerative diseases. Because a
number of vaccines are being recommended to adults, the risk of precipitating
or worsening these disorders is quite real.”

“Adjuvants ... are challenging to develop and license because
adjuvant compounds that stimulate strong protective immunity also frequently
induce significant toxicity.” Frontiers In Bioscience • January 2008

Rationally-designed vaccine adjuvants: separating efficacy from toxicity Author
information Hauguel TM1, Hackett CJ. Division of Allergy, Immunology, and
Transplantation National Institute of Allergy and Infectious Diseases National
Institutes of Health, Bethesda, Maryland 20892, USA Abstract Adjuvants,
substances included in many vaccines in order to improve immune responses, are
challenging to develop and license because adjuvant compounds that stimulate
strong protective immunity also frequently induce significant toxicity.
Adjuvant design and development has until recently been largely empirical; but
with the current knowledge that most adjuvants act via receptors of the innate
immune system, molecular-based approaches are rapidly advancing the field. Data
support the concept that proinflammatory pathways induced by innate immune
receptor triggering underlie many of the observed toxic effects. Importantly,
the cellular signaling pathways that lead to inflammation are known, for a
number of innate immune receptors, to be distinct from those that are involved
in the costimulation of protective adaptive immune responses, leading to
approaches for attenuating inflammatory signaling that should lead to safer and
more effective vaccine adjuvants. This article addresses whether there is a
clear rationale for the separation of toxicity from efficacy in the function of
adjuvants based upon innate immune receptor ligands.
http://www.ncbi.nlm.nih.gov/pubmed/?term=17981755

“Maternal body weight was lowered at 7.5%. Number of pups born was lowered at 7.5%.
Lowered body weight was observed in male and female offspring ...” Reproductive
Toxicology • January 2008

Evaluation of developmental neurotoxicity of polysorbate 80 in rats Author
information Ema M1, Hara H, Matsumoto M, Hirata-Koizumi M, Hirose A, Kamata E.
Division of Risk Assessment, Biological Safety Research Center National
Institute of Health Sciences, Tokyo, Japan ema@nihs.go.jp Abstract The
developmental neurotoxicity of polysorbate 80 (PS80) was evaluated in rats.
Crl:CD(SD) rats were given drinking water containing PS80 at 0, 0.018, 0.13,
1.0, or 7.5% (0, 0.035, 0.245, 1.864, or 16.783ml/kgbw/day) on day 0 of
pregnancy through day 21 after delivery. Pregnant rats were allowed to deliver
spontaneously. Potential adverse effects of pre- and post-natal exposure on the
development and function of the nervous system in offspring of rats given PS80
were examined. Maternal body weight was lowered at 7.5%. Number of pups born
was lowered at 7.5%. There were no compound-related effects on locomotor
activity of offspring on postnatal days (PNDs) 14-15, 17-18, 20-21 and 33-37.
No compound-related changes were found in developmental landmarks, sexual
maturation, or reflex responses. Although decreased rate of avoidance responses
was noted on PNDs 23-27 in male and female offspring at 7.5%, no
compound-related changes were found in performance in the conditioned avoidance
response on PNDs 60-67. Histopathological examinations of the brain revealed no
toxicological changes. Lowered body weight was observed in male and female
offspring at 7.5%. The NOAEL in this study was considered to be 1.0%
(1.864ml/mg/kgbw/day). http://www.ncbi.nlm.nih.gov/pubmed/17961976

Vaccine • March 2008

Kinetics of asthma- and allergy-associated immune response gene expression in
peripheral blood mononuclear cells from vaccinated infants after in vitro
re-stimulation with vaccine antigen Author information Lahdenperä AI1, Nilsson
LJ, Regnström K. Division of Paediatrics Department of Clinical and
Experimental Medicine Faculty of Health Sciences, Linköping University, 5818
Linköping, Sweden Abstract The global expression of immune response genes in
infants after vaccination and their role in asthma and allergy is not clearly
understood. Pharmacogenomics is ideally suited to study the involved cellular
responses, since the expression of thousands of genes can be assessed
simultaneously. Here, array technology was used to assess the expression
kinetics of immune response genes with association to asthma and allergy in
peripheral blood mononuclear cells (PBMC) of five healthy infants after
vaccination with Infanrix-Polio+Hib. At 12h after in vitro restimulation of the
PBMC with pertussis toxin (PT) antigen, 14 immune response pathways, 33
allergy-related and 66 asthma-related genes were found activated.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18336961

“At 12h after in vitro re-stimulation of the peripheral blood mononuclear cells
with pertussis toxin antigen, 14 immune response pathways, 33 allergy-related
and 66 asthma-related genes were found activated.”

“... Triton X-100-induced apoptosis ...”
Leukemia Research • March 2008

Release of cytochrome c from mitochondria precedes Bax translocation/activation
in Triton X-100-induced apoptosis Author information Sawai H1, Domae N.
Department of Internal Medicine, Osaka Dental University 8-1 Kuzuhahanazonocho,
Hirakata, Osaka 573-1121, Japan sawai@cc.osaka-dent.ac.jp Abstract The precise
mechanisms by which sublytic concentrations of detergents induce apoptosis
remain unclear. Recent studies reported the ability of nonionic detergents such
as Triton X-100 to induce conformational change of Bax to the active form in
vitro. Here we investigated whether activation of Bax might play a role in
Triton X-100-induced apoptosis in cells. Although Bax translocation/activation
was inhibited by caspase inhibitors, cytochrome c release from mitochondria was
not affected in Triton X-100-induced apoptosis in U-937 cells. These results
demonstrate that translocation/activation of Bax occurs downstream of
cytochrome c release and caspase activation in Triton X-100-induced apoptosis.
http://www.ncbi.nlm.nih.gov/pubmed/17689609

Clinical Vaccine Immunology • March 2008

Considerable Differences in Vaccine Immunogenicities and Efficacies Related to
the Diluent Used for Aluminum Hydroxide Adjuvant Author Information Lin Lin,1
Ashraf S. Ibrahim,1,2 Valentina Avanesian,1 John E. Edwards, Jr.,1,2 Yue Fu,1,2
Beverlie Baquir,1 Rebecca Taub,1 and Brad Spellberg1,2,* 1. Division of
Infectious Diseases Los Angeles Biomedical Research Institute at Harbor-UCLA
Medical Center Torrance, California 2. The David Geffen School of Medicine at
UCLA Los Angeles, California Abstract We are developing an anticandidal vaccine
using the recombinant N terminus of Als3p (rAls3p-N). We report that although
more rAls3p-N was bound by aluminum hydroxide diluted in saline than by
aluminum hydroxide diluted in phosphate-buffered saline (PBS), its
immunogenicity and efficacy were superior in PBS. Thus, protein binding, by
itself, may not predict the efficacy of some vaccines with aluminum adjuvants.
Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268268/

“Thus, protein binding, by itself, may not predict the efficacy of some
vaccines with aluminum adjuvants.”

Oxford Journal • Toxicology Science • March 2008

Modeling Neurodevelopment Outcomes and Ethylmercury Exposure from
Thimerosal-Containing Vaccines José G. Dórea*,1 and Rejane C. Marques†

	
Universidade de Brasília, Brasília, DF, Brazil †Fundação Universidade Federal

de Rondônia, Porto Velho, RO, Brazil dorea@rudah.com.br Dear Editor, The
neurotoxic effects of ethylmercury (EtHg) accidentally consumed in Iraq were
sufficient to withdraw ethylmercury-containing fungicides as seed dressing.
Despite that, not only did thimerosal continue to be used in pharmaceutical
preparations but also toxicological interest in EtHg-derived substances
diminished considerably and was never addressed with regard to the small
quantities used as a vaccine preservative. Thimerosal-containing vaccines (TCV)
have no record of overt clinical neurological consequences due to EtHg, and the
plausibility of subtle neurotoxic effects in children has been recognized only
recently by the United States and other industrialized countries. In this
context, we welcome the interesting work of Berman et al. (2008); it is clear
that this assiduous study (in immunologically susceptible mice) took into
consideration doses and schedules of TCV-Hg concentrations that had been used
in infants in the United States. Their mice model does not, however, cover the
full extent of modifying factors associated with TCV-Hg exposure in the
majority of immature and newborns around the world that still have to depend on
TCV. According to Berman et al. (2008), the United States vaccination scheduled
exposed a total of 125 μgHg distributed at 2, 2, and 6 months through TCV
(hepatitis B and DTP). This type of vaccine is no longer used in industrialized
countries but it is still used all over the world. We know that thimerosal
concentrations vary among brands of vaccines and also that immunization
schedules vary depending on a country’s health policy; not only that but new
outbreaks of disease introduce additional new vaccines (which may contain
thimerosal) during the first year of life. As an example, the public health
services of Brazil, like other countries, still uses several brands of
hepatitis B vaccine (containing thimerosal as preservative) with concentrations
ranging from 12.5 to 50 μgHg per 0.5 ml shot. Another salient difference
between countries that use TCV (like Brazil) and the United States is that in
the former country hepatitis B inoculation starts within the first 12–24 h
after birth (Marques et al., 2007) and is administered to low-birth weight
≥2000 g (Ministério, da Saúde, 2006 and premature babies who are also
recommended a fourth shot as an additional booster (DI/ DH/CVE, 2006). In such
situations, not only toxicokinetics (TK) but especially toxicodynamics (TD) of
EtHg are entirely different between a 1-day-old (with different stages of
immaturity and birth weight) and a 60-day-old child (as modeled). The newborn
presents several physiological degrees of immaturity in the excretory system
(kidneys and bile formation) and target organ (central nervous system, CNS)
that are important modi-

fiers of EtHg TK and TD. These features are inversely accentuated by
gestational age and birth weight. Under such circumstances, unbound circulating
EtHg in a newborn (and immature) may not be eliminated as fast as in a
2-month-old baby and thus will be readier to cross the more vulnerable
blood-brain barrier (BBB). The newborn BBB increases in effectiveness with age;
therefore, the free EtHg can more easily penetrate the immature CNS (Dorea,
2007). As a consequence, the smaller the body size and blood volume, the more
altered the TD and TK of EtHg. Indeed, Stajich et al. (2000) showed that
preterm infants do not metabolize Hg efficiently. Collectively, studies show
that larger babies have significantly higher mean liver metallothionein than
smaller babies (Dorea, 2007). Factors associated with protein-binding capacity,
excretion mechanisms, and enzyme activities are immature in the neonate and
modulate differences in adverse effects between newborns and infants exposed to
neurotoxic substances. During the period of immaturity, not only plasma albumin
but also total protein concentrations decrease (Dorea, 2007). The best example
in differences between neurotoxic effects is the type of albumin and
competition for binding sites (due to increased circulatory concentrations of
bilirubin). Albumin binding (to bilirubin) is less effective during the first
postnatal days and, as a consequence, excess free bilirubin can cross the BBB
at early stages of the postnatal CNS immaturity and cause brainstem
abnormalities; albumin priming can be effective in attenuating effects caused
by unbound bilirubin (Dorea, 2007). We do not dispute the conclusions drawn by
Berman et al. regarding Hg and the neurobiology of autism; however, we think it
is possible to take their findings one step further in regards to thimerosal
neurotoxicity. We contend that these findings are appropriate for U.S.-like
scenarios (as intended by the authors) but are not sufficient to address the
current TCV schedules in the majority of newborns and infants around the world.
TCV are used worldwide in vaccination schedules that include more of these
vaccines at an earlier age. Unfortunately, the differences that set newborns
(especially low-birth-weights and prematures) apart from 2-month-old infants
have not yet been modeled in experimental studies and remain neglected in TK
and TD knowledge of TCV-EtHg exposure. We hope that studies like Berman et al.
(2008) can inspire conventional toxicology to address uncertainties regarding
current serial EtHg exposure in newborns and infants that have to take TCV.

Full Report http://toxsci.oxfordjournals.org/content/103/2/414.long

Rheumatology International • April 2008

HBV vaccine and dermatomyositis: is there an association? Author information
Altman A1, Szyper-Kravitz M, Shoenfeld Y. Center for Autoimmune Diseases and
Department of Medicine Beth Sheba Tel-Hashomer, Sackler Faculty of Medicine Tel
Aviv University, Tel Aviv, Israel Abstract The etiology of dermatomyositis is
unknown, but immune mechanisms play an important role. Several dermatological
manifestations have been reported among carriers of hepatitis B surface
antigen, and after vaccination with the HBV vaccine. Almost all the skin
reactions described were peculiar skin eruptions suggestive of an immune
complex reaction. Some authors described the occurrence of dermatomyositis
after BCG and influenza vaccination. We report a case of a 6-year-old child,
who was vaccinated for hepatitis B virus and developed a flu-like disease
accompanied by a skin rash, which had the typical features of dermatomyositis.
The association of vaccination with autoimmunity is discussed.
http://www.ncbi.nlm.nih.gov/pubmed/18034245

“Several dermatological manifestations have been reported among carriers of
hepatitis B surface antigen, and after vaccination with the HBV vaccine. Some
authors described the occurrence of dermatomyositis after BCG and influenza
vaccination. The association of vaccination with autoimmunity is discussed.”

Clinical Rheumatology • May 2008

Polyglandular autoimmunity with macrophagic myofasciitis Author information
Theeler BJ1, Simper NB, Ney JP. Department of Neurology Madigan Army Medical
Center 9040A Fitzsimmons Dr., Tacoma WA 98431, USA btheeler@hotmail.com

“This rare and recently described muscle disorder

Abstract

is seen in patients exposed to

We report a man with chronic fatigue, multiple autoimmune disorders, and a
muscle biopsy consistent with macrophagic myofasciitis. This rare and recently
described muscle disorder is seen in patients exposed to vaccinations with
aluminum hydroxide adjuvant. This case highlights the relationship between
macrophagic myofasciitis and autoimmunity.

vaccinations with aluminum

http://www.ncbi.nlm.nih.gov/pubmed/?term=18180978

hydroxide adjuvant.”

Toxicological & Environmental Chemistry • June 2008

Hepatitis B triple series vaccine and developmental disability in US children
aged 1–9 years Author Information Carolyn Gallaghera & Melody Goodmana Abstract
This study investigated the association between vaccination with the Hepatitis
B triple series vaccine prior to 2000 and developmental disability in children
aged 1–9 years (n = 1824), proxied by parental report that their child receives
early intervention or special education services (EIS). National Health and
Nutrition Examination Survey 1999–2000 data were analyzed and adjusted for
survey design by Taylor Linearization using SAS version 9.1 software, with SAS
callable SUDAAN version 9.0.1. The odds of receiving EIS were approximately
nine times as great for vaccinated boys (n = 46) as for unvaccinated boys (n =
7), after adjustment for confounders. This study found statistically
significant evidence to suggest that boys in United States who were vaccinated
with the triple series Hepatitis B vaccine, during the time period in which
vaccines were manufactured with thimerosal, were more susceptible to
developmental disability than were unvaccinated boys.
http://www.fourteenstudies.com/pdf/hep_b.pdf This report is also referenced
[17] in 2008 United Nations Environmental Program (UNEP) report under the
subheading ‘New Evidence’

“The odds of receiving special education services were approximately nine times
as great for vaccinated boys (n = 46) as for unvaccinated boys (n = 7), after
adjustment for confounders. This study found statistically significant evidence
to suggest that boys in United States who were vaccinated with the triple
series Hepatitis B vaccine, during the time period in which vaccines were
manufactured with thimerosal, were more susceptible to developmental disability
than were unvaccinated boys.”

United Nations Report:
http://www.who.int/immunization/sage/meetings/2012/april/Pichichero_Update_on_safety.pdf

BMJ • June 2008

Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in
Guinea-Bissau: randomised placebo controlled trial Author information Benn CS1,
Diness BR, Roth A, Nante E, Fisker AB, Lisse IM, Yazdanbakhsh M, Whittle H,
Rodrigues A, Aaby P. Bandim Health Project, Statens Serum Institut Artillerivej
5, 2300 Copenhagen S, Denmark cb@ssi.dk Abstract OBJECTIVE To investigate the
effect of high dose vitamin A supplementation given with BCG vaccine at birth
in an African setting with high infant mortality. DESIGN Randomised placebo
controlled trial. Setting Bandim Health Project’s demographic surveillance
system in Guinea-Bissau, covering approximately 90,000 inhabitants.
Participants 4345 infants due to receive BCG. INTERVENTION Infants were
randomised to 50,000 IU vitamin A or placebo and followed until age 12 months.
MAIN OUTCOME MEASURE Mortality rate ratios. RESULTS 174 children died during
follow-up (mortality=47/1000 person-years). Vitamin A supplementation was not
significantly associated with mortality; the mortality rate ratio was 1.07 (95%
confidence interval 0.79 to 1.44). The effect was 1.00 (0.65 to 1.56) during
the first four months and 1.13 (0.75 to 1.68) from 4 to 12 months of age. The
mortality rate ratio in boys was 0.84 (0.55 to 1.27) compared with 1.39 (0.90
to 2.14) in girls (P for interaction=0.10). An explorative analysis revealed a
strong interaction between vitamin A and season of administration. CONCLUSIONS
Vitamin A supplementation given with BCG vaccine at birth had no significant
benefit in this African setting. Although little doubt exists that vitamin A
supplementation reduces mortality in older children, a global recommendation of
supplementation for all newborn infants may not contribute to better survival.
TRIAL REGISTRATION Clinical trials NCT00168597. Full Report:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2432170/

“Vitamin A supplementation given with BCG vaccine at birth had no significant
benefit in this African setting.”

European Journal Of Internal Medicine • July 2008

“A 12 year-old girl, without a relevant previous history,

Status epilepticus and lymphocytic pneumonitis following hepatitis B
vaccination

taking no drugs, developed a seizure attack followed by

Author information de Carvalho JF1, Shoenfeld Y. Rheumatology Division São
Paulo University School of Medicine São Paulo, Brazil Abstract The case
reported refers to a patient who developed status epilepticus in the day of her
third dose of hepatitis B vaccination and we review the literature on this
subject. A 12 year-old girl, without a relevant previous history, taking no
drugs, developed a seizure attack followed by unconsciousness, and eventually
died after three days of her third dose of hepatitis B (HB) vaccination.
Autopsy study revealed cerebral edema with congestion and herniation and
diffuse interstitial type pneumonitis. There seem to be a straight forward time
relationship between the third HB vaccine, the event of convulsion and the
sudden death of the patient. We suggest that, in some cases, vaccination may be
the triggering factor for autoimmune and neurological disturbances in
genetically predisposed individuals and physicians should be aware of this
possible association. http://www.ncbi.nlm.nih.gov/pubmed/18549949

unconsciousness, and eventually died after three days of her third dose of
hepatitis B (HB) vaccination. Autopsy study revealed cerebral edema with
congestion and herniation and diffuse interstitial type pneumonitis. There seem
to be a straight forward time relationship between the third HB vaccine, the
event of convulsion and the sudden death of the patient. We suggest that, in
some cases, vaccination may be the triggering factor for autoimmune and
neurological disturbances in genetically predisposed individuals ...”

Forensic Science International • August 2008

Beta-tryptase and quantitative mast-cell increase in a sudden infant death
following hexavalent immunization Author information D’Errico S1, Neri M,
Riezzo I, Rossi G, Pomara C, Turillazzi E, Fineschi V.

“A fatal case of a 3-month-old female infant, who died

Department of Forensic Pathology, University of Foggia Ospedale Colonnello
D’Avanzo Via degli Aviatori 1, 71100 Foggia, Italy

within 24 h of vaccination with hexavalent vaccine is

Abstract The association between sudden infant death syndrome and immunization
is frequently discussed. Serious adverse events following vaccination have
generally been defined as those adverse events that result in permanent
disability, hospitalization or prolongation of hospitalization, life
threatening illness, congenital anomaly or death. They are generally referred
to the inherent properties of the vaccine (vaccine reaction) or some error in
the immunization process (programme error). The event could also be totally
unrelated but only temporally linked to immunization (coincidental event). A
fatal case of a 3-month-old female infant, who died within 24 h of vaccination
with hexavalent vaccine is presented. Clinical data, post-mortem findings
(acute pulmonary oedema, acute pulmonary emphysema), quali-quantitative data
collected from immunohistochemical staining (degranulating mast cells) and
laboratory analysis with a high level of beta-tryptase in serum, 43.3 microg/l,
allows us to conclude that acute respiratory failure likely due to post
hexavalent immunization-related shock was the cause of death.
http://www.ncbi.nlm.nih.gov/pubmed/18538957

presented. Clinical data, post-mortem findings (acute pulmonary oedema, acute
pulmonary emphysema), quali-quantitative data collected from
immunohistochemical staining (degranulating mast cells) and laboratory analysis
with a high level of beta-tryptase in serum, 43.3 microg/l, allows us to
conclude that acute respiratory failure likely due to post hexavalent
immunization-related shock was the cause of death.”

The Journal of Immunology • April 15, 2008

The Adjuvants Aluminum Hydroxide and MF59 Induce Monocyte and Granulocyte
Chemoattractants and Enhance Monocyte Differentiation toward Dendritic Cells
Author Information Anja Seubert, Elisabetta Monaci, Mariagrazia Pizza, Derek T.
O’Hagan and Andreas Wack Novartis Vaccines, Siena, Italy Abstract Aluminum
hydroxide (alum) and the oil-in-water emulsion MF59 are widely used, safe and
effective adjuvants, yet their mechanism of action is poorly understood. We
assessed the effects of alum and MF59 on human immune cells and found that both
induce secretion of chemokines, such as CCL2 (MCP-1), CCL3 (MIP-1∼), CCL4
(MIP-1∼), and CXCL8 (IL-8), all involved in cell recruitment from blood into
peripheral tissue. Alum appears to act mainly on macrophages and monocytes,
whereas MF59 additionally targets granulocytes. Accordingly, monocytes and
granulocytes migrate toward MF59-conditioned culture supernatants. In
monocytes, both adjuvants lead to increased endocytosis, enhanced surface
expression of MHC class II and CD86, and down-regulation of the monocyte marker
CD14, which are all phenotypic changes consistent with a differentiation toward
dendritic cells (DCs). When monocyte differentiation into DCs is induced by
addition of cytokines, these adjuvants enhanced the acquisition of a mature DC
phenotype and lead to an earlier and higher expression of MHC class II and
CD86. In addition, MF59 induces further up-regulation of the maturation marker
CD83 and the lymph node-homing receptor CCR7 on differentiating monocytes. Alum
induces a similar but not identical pattern that clearly differs from the
response to LPS. This model suggests a common adjuvant mechanism that is
distinct from that mediated by danger signals. We conclude that during
vaccination, adjuvants such as MF59 may increase recruitment of immune cells
into the injection site, accelerate and enhance monocyte differentiation into
DCs, augment Ag uptake, and facilitate migration of DCs into tissue-draining
lymph nodes to prime adaptive immune responses. Full Report:
http://www.jimmunol.org/content/180/8/5402.full

“Aluminum hydroxide (alum) and the oil-in-water emulsion MF59 [squalene] are
widely used, safe and effective adjuvants, yet their mechanism of action is
poorly understood.”

Autoimmunity Review • October 2008

Chronic fatigue syndrome with autoantibodies— the result of an augmented
adjuvant effect of hepatitis-B vaccine and silicone implant

“... the changes induced by MF59 and alum share common features …”

Author information Nancy AL1, Shoenfeld Y. Center for Autoimmune Diseases
Department of Medicine Beth Sheba Medical Center Tel-Hashomer, Israel Abstract
Background Chronic fatigue syndrome (CFS) that defines by prolonged fatigue and
other manifestations, was recently integrated into a spectrum of central
sensitivity syndromes including several diseases as fibromylagia. CFS etiology
is multi-factorial commonly triggered by infectious agents. Vaccines, induce an
immune response similarly to infections, and may trigger just like infections
autoimmune diseases, CFS and fibromyalgia. Furthermore vaccines contain an
adjuvant which enhances their immune stimulation. Case Presentation A
56-year-old woman was diagnosed with CFS accompanied by fibromyalgia,
demyelination and autoantibodies. Her illness begun following the 2nd dose of
hepatitis-B vaccine, and was aggravated by the 3rd vaccination. She underwent
silicone breast implantation 6 years before vaccination with no adverse events.
However, between the 2nd and 3rd vaccination she suffered a breast injury with
local inflammation. Upon explanation of her breast implants silicone leak was
observed. Discussion Vaccines have been reported to precede CFS mainly
following exposure to multiple vaccinations (e.g. the Gulf war syndrome), or as
an adverse response to the vaccine adjuvant (e.g. the macrophagic myofasciitis
syndrome). Silicone is considered an adjuvant to the immune system, and may
induce “the adjuvant disease”. Silicone implant, especially silicone leak
relationship with autoimmunity and CFS has been the focus of considerable
debates. Conclusion Our patient illness started following hepatitis-B vaccine,
suggesting that it was caused or accelerated by vaccination. In parallel to
vaccination our patient suffered from breast injury, which might represent the
time of silicone leak. The exposure to the adjuvant, silicone, might have
augmented her immune response to the vaccine. To the best of our knowledge this
is the first case of combined adverse effect to vaccine and silicone. Vaccine
safety in individuals with silicone implants requires further studies.
http://www.ncbi.nlm.nih.gov/pubmed/18725327

“Vaccines have been reported to precede Chronic Fatigue Syndrome mainly
following exposure to multiple vaccinations (e.g. the Gulf war syndrome), or as
an adverse response to the vaccine adjuvant (e.g. the macrophagic myofasciitis
syndrome).”

Pediatric Infectious Disease Journal • October 2008

Mumps epidemiology and immunity: the anatomy of a modern epidemic Author
information Anderson LJ1, Seward JF. Division of Viral Diseases National Center
for Immunization and Respiratory Diseases Centers for Disease Control and
Prevention Atlanta, GA 30333, USA lja2@cdc.gov Abstract The success of the
measles, mumps, and rubella 2-dose vaccination program led public health
officials in 1998 to set a goal to eliminate endemic transmission of mumps
virus by 2010 in the United States. The large outbreak of mumps in the spring
of 2006 has led public health officials to re-evaluate this goal and to
recognize that the transmission and epidemiology of mumps in highly vaccinated
populations may be different than anticipated. During 2006, a total of 6584
confirmed and probable cases of mumps were reported to the Centers for Disease
Control and Prevention and most of these, 5865, occurred between January 1 and
July 31. The peak of the outbreak was in April and seemed to be focused on
college campuses in 9 midwestern states with Iowa having the highest attack
rate. College campuses with mumps outbreaks included ones with 77% to 97% of
students having had 2 doses of a mumps vaccine. Diagnosing mumps proved to be
problematic in vaccinated persons (ie, laboratory tests seemed to be
insensitive and some apparent mumps cases had mild nonclassic illness). The
outbreak demonstrated that mumps can sometimes transmit efficiently in highly
vaccinated populations and the clinical and laboratory diagnosis of mumps in
vaccinated persons is more difficult than in naive persons. The reason for this
mumps outbreak is not clear but probably results from multiple factors
contributing to an overall increase in susceptibility and/or transmission.
http://www.ncbi.nlm.nih.gov/pubmed/18820583

“The outbreak demonstrated that mumps can sometimes transmit efficiently in
highly vaccinated populations and the clinical and laboratory diagnosis of
mumps in vaccinated persons is more difficult than in naive persons.”

Vaccine • November 2008

Vaccine immunogenetics: bedside to bench to population Author information
Poland GA1, Ovsyannikova IG, Jacobson RM. Mayo Vaccine Research Group The
Program in Translational Immunovirology and Biodefense Mayo Clinic College of
Medicine, Rochester, MN 55905, USA poland.gregory@mayo.edu Abstract The
immunogenetic basis for variations in immune response to vaccines in humans
remains largely unknown. Many factors can contribute to the heterogeneity of
vaccine-induced immune responses, including polymorphisms of immune response
genes. It is important to identify those genes involved directly or indirectly
in the generation of the immune response to vaccines. Our previous work with
measles reveals the impact of immune response gene polymorphisms on measles
vaccine-induced humoral and cellular immune responses. We demonstrate
associations between genetic variations (single nucleotide polymorphisms, SNPs)
in HLA class I and class II genes, cytokine, cell surface receptor, and
toll-like receptor genes and variations in immune responses to measles vaccine.
Such information may provide further understanding of genetic restrictions that
influence the generation of protective immune responses to vaccines, and
eventually the development of new vaccines.
http://www.ncbi.nlm.nih.gov/pubmed/18598732

“The immunogenetic basis for variations in immune response to vaccines in
humans remains largely unknown.”

Alternative Therapies In Health And Medicine • November 2008

The history of vaccinations in the light of the autism epidemic Author
information Cave SF Cypress Integrative Medicine Baton Rouge, Louisiana, USA
Abstract Autism has been characterized as a behavioral disorder since it was
first described by Leo Kanner in 1943. The number of autistic children has
increased over the last decade. The incidence of autism was 1 in 10000 before
the 1970s and has steadily increased to 1 in 150 in 2008 with a male:female
predominance of 4:1. The cause of this epidemic has remained unknown, but
several hypotheses have been studied. Many of these suggest an environmental
trigger, such as the ethyl mercury contained in the preservative thimerosal,
which has been used in vaccines since 1931. Other possible triggers associated
with vaccinations are chemical toxins and live viruses. James has published
studies suggesting a genetic predisposition in the families of autistic
children, exposing them to a deficiency in glutathione and an inability to
detoxify heavy metals. Vargas has shown autism to encompass ongoing
inflammation in the brains of autistic children. The Hannah Poling vaccine
decision was a landmark case. Poling’s family was awarded funds for ongoing
medical care of an autistic child who was found to have mitochondrial
dysfunction exacerbated by vaccines that left her with autistic behavior and
seizures. Several studies have emerged supporting the fact that a significant
number of autistic children do have mitochondrial dysfunction. The impact that
the Poling case will have on the ability of parents of autistic children to
gain access to funds to enable them to properly care for their children remains
to be seen. http://www.ncbi.nlm.nih.gov/pubmed/19043939

“Poling’s family was awarded funds for ongoing medical care of an autistic
child who was found to have mitochondrial dysfunction exacerbated by vaccines
that left her with autistic behavior and seizures. Several studies have emerged
supporting the fact that a significant number of autistic children do have
mitochondrial dysfunction. The impact that the Poling case will have on the
ability of parents of autistic children to gain access to funds to enable them
to properly care for their children remains to be seen.”

European Journal Of Internal Medicine • December 2008

Systemic polyarteritis nodosa following hepatitis B vaccination Author
information de Carvalho JF1, Pereira RM, Shoenfeld Y. Rheumatology Division São
Paulo University School of Medicine São Paulo, Brazil Abstract The authors
report a patient who developed systemic polyarteritis nodosa two months after
hepatitis B vaccination and review the literature concerning this vaccination
and the development of autoimmune conditions, mainly vasculitis. A 14-year-old
boy who had no relevant previous history and who was not taking any drugs
presented with a livedo reticularis, fever, loss of weight, testicular pain,
and paresthesias two months after receiving the third dose of a hepatitis B
vaccination. Inflammatory parameters (ESR and CRP) were high. The patient met
the ACR diagnostic criteria for polyarteritis nodosa. He received
corticosteroids and immunosuppressants and showed improvement. After reviewing
the 27 cases of vasculitis after hepatitis B vaccination reported in the
current literature, the authors suggest that, in some cases, vaccination may be
the triggering factor for vasculitis in individuals with a genetic
predisposition. Physicians should be aware of this possible association.
http://www.ncbi.nlm.nih.gov/pubmed/19046721

“After reviewing the 27 cases of vasculitis after hepatitis B vaccination
reported in the current literature, the authors suggest that, in some cases,
vaccination may be the triggering factor for vasculitis in individuals with a
genetic predisposition.”

“There are currently over 100 human diseases
that are considered to be autoimmune or chronic inflammatory affecting 5-10% of
the world population and spanning through all medical specialties.” Journal Of
Autoimmunity • December 2008

The autoimmunologist: geoepidemiology, a new center of gravity, and prime time
for autoimmunity Author information Shoenfeld Y1, Selmi C, Zimlichman E,
Gershwin ME. Department of Medicine B, Center for Autoimmune Diseases, Sheba
Medical Center Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv,
Israel shoenfel@post.tau.ac.il Abstract There are currently over 100 human
diseases that are considered to be autoimmune or chronic inflammatory affecting
5-10% of the world population and spanning through all medical specialties. As
a result, health care costs are enormous and the clinical management is often
challenging, particularly considering the comorbidity rates and the multi-organ
involvement of each condition. We herein propose the creation of a new
specialist, coined the autoimmunologist, to overcome the current limitations in
the diagnostic process and clinical follow-up of patients with autoimmune
diseases. More importantly, we also propose the creation of regional centers of
excellence in autoimmunity where clinical research and management, as well as
basic research may be united and interact in ideal synergy to ultimately create
real translational research and provide better health care.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18838248

“In our study Oral Polio Virus at birth
had a sex-differential effect on mortality.”

PLoS ONE • 2008

Sex-Differential Effect on Infant Mortality of Oral Polio Vaccine Administered
with BCG at Birth in Guinea-Bissau—A Natural Experiment Christine Stabell
Benn,1,* Ane Bærent Fisker,2 Amabelia Rodrigues,2 Henrik Ravn,1 Erliyani
Sartono,3 Hilton Whittle,4 Maria Yazdanbakhsh,3 and Peter Aaby2 1. Bandim
Health Project, Statens Serum Institut, Copenhagen, Denmark 2. Bandim Health
Project, Indepth Network, Bissau, Guinea-Bissau 3. Department of
Immunoparasitology, Leiden University Medical Centre 4. The MRC Laboratories,
Fajara, The Gambia Beverley J. Shea, Editor Abstract Background The policy to
provide oral polio vaccine (OPV) at birth was introduced in low-income
countries to increase coverage. The effect of OPV at birth on overall child
mortality was never studied. During a trial of vitamin A supplementation (VAS)
at birth in Guinea-Bissau, OPV was not available during several periods. We
took advantage of this “natural experiment” to test the effect on mortality of
receiving OPV at birth.

Methodology Between 2002 and 2004, the VAS trial randomised normal-birth-weight
infants to 50,000 IU VAS or placebo administered with BCG. Provision of OPV at
birth was not part of the trial, but we noted whether the infants received OPV
or not. OPV was missing during several periods in 2004. We used Cox
proportional hazards models to compute mortality rate ratios (MRR) of children
who had received or not received OPV at birth. Principal Findings A total of
962 (22.1%) of the 4345 enrolled children did not receive OPV at birth; 179
children died within the first year of life. Missing OPV at birth was
associated with a tendency for decreased mortality (adjusted MRR = 0.69 (95% CI
= 0.46–1.03)), the effect being similar among recipients of VAS and placebo.
There was a highly significant interaction between OPV at birth and sex (p =
0.006). Not receiving OPV at birth was associated with a weak tendency for
increased mortality in girls (1.14 (0.70–1.89)) but significantly decreased
mortality in boys (0.35 (0.18–0.71)). Conclusions In our study OPV at birth had
a sex-differential effect on mortality. Poliovirus is almost eradicated and OPV
at birth contributes little to herd immunity. A randomised study of the effect
of OPV at birth on overall mortality in both sexes is warranted.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605256/

Medical Veritas • 2008

Current childhood vaccine programs: An overview with emphasis on the
Measles-Mumps-Rubella (MMR) vaccine and of its compromising of the mucosal
immune system Harold E. Buttram, MD hbuttram1304@comcast.net Abstract Both
common observation and official statistics confirm that there have been
dramatic increases in chronic physical and mental illnesses in American
children, such as autism, asthma, and allergies since the introduction of the
MMR vaccine in 1978. Government health officials have denied a relationship
with vaccines, but U.S. Congressional hearings on vaccine safety (1999 to Dec.
2004) revealed a total absence of vaccine safety tests that would meet current
scientific standards, so that it can be assumed that many vaccine reactions are
taking place unrecognized. Prior to the introduction of vaccines, the Th1
cellular immune system of the gastrointestinal and respiratory systems served
as the primary defense systems with the Th2 humoral immune system in the bone
marrow, serving a secondary role. There is a school of thought that the “minor
childhood diseases” of earlier times, including measles, mumps, chicken pox,
and rubella, which involved the epithelial tissues of skin, respiratory, and/or
gastrointestinal tracts, served a necessary purpose in challenging,
strengthening, and establishing the dominance of Th1 cellular immune system
during early childhood. Current vaccines against these diseases, in contrast,
being directed at stimulating antibody production in the bone marrow, are
bypassing the cellular immune system and thereby tending to reverse the roles
of the cellular and humoral systems, with the former suffering from a lack of
challenge. In addition, the cellular immune system is being further compromised
by the powerfully immunosuppressive effects of the MMR vaccine. The time is
overdue to totally rethink and redirect our current childhood vaccine program.
Concerns about increasing incidence of childhood autism and related disorders
Many years ago in our medical practice we began asking teachers if, during
their teaching careers, they had observed a change in children. Without
exception, they replied that there had been a dramatic change, most notably
since the early 1980s. Steadily increasing numbers of children, they reported,
were showing autistic-like behaviors, were restless, impulsive, less focused,
less able to concentrate, and therefore less able to learn. It has been
documented that a sharp and persisting rise in the incidence of childhood
autism commenced following the 1978 introduction of the MMR vaccine in the
U.S.A. [1-2], a time when mercury-laced Hepatitis B and Hemophilus influenza
type b vaccines were also introduced. For a number of years previously the live
measles, mumps, and rubella vaccines had been administered separately with
negligible increases in autism. It was only after they were combined that the
incidence of autism began soaring with 1 in 150 children up to eight years age,
according to U.S. multisite study in 2000 [3], as compared with 1 in 10,000
several generations ago. According to more recent information, the incidence of
autism may be even higher, with 1 in 88 military children in U.S.A. having
autism [4], and according to the Vaccine Autoimmune Project (VAP), one in 67 in
U.S.A. and 1 in 86 in the United Kingdom having autism [5]. Considering that
the incidence of autism in boys is approximately four times greater than in
girls, the relative incidence of autism in boys would be even greater. Finally,
as estimated by VAP, the average lifetime cost of caring for autistic children
will be about $3.2 million dollars per child.

In addition to the autism epidemic, in 2004 almost five million children were
classified as learning disabled [6], which represents a three-fold increase
since 1976-7 according to the Digest of Education Statistics [7]. Comparable
increases have taken place in attention deficit hyperactive disorder (ADHD),
with four and one half million children between ages 3 and 17 being diagnosed
with this condition in 2004 [8]. In a bulletin sponsored by the American
Academy of Pediatrics, January, 2004, entitled “AUTISM A.L.A.R.M.”, in addition
to an announcement of the increasing prevalence of autism at that time, it was
announced that 1 in 6 American children were diagnosed with a developmental
disorder and/or behavioral disorder. In a similar fashion the incidence of
asthma has increased from roughly two and a half million children, ages 0-17
years in 1979 [8] to nine million children 0-17 years in 2004 [8], (roughly 12%
of that age group), a time period in which this age-group population increased
114% compared to a 360% increase in asthma. Autoimmune diseases are also
increasing, including juvenile diabetes, multiple sclerosis, Guillain-Barre
Syndrome, and Crohn’s inflammatory bowel disease. Based on the work of Vijendra
Singh, who demonstrated marked elevations of brain antibodies in the form of
myelin basic protein antibodies in autistic children [9-10], autism itself can
be considered an autoimmune disorder. Current studies implicating vaccines as
primary causal agents of autism and related disorders In what may be the most
comprehensive publication to date on the pathophysiology of adverse vaccine
reactions, Russell Blaylock has compiled a mass of evidence that repeated
stimulation of the systemic immune system results in first priming of microglia
of the developing brain, following by intense microglial reaction with each
successive series of vaccinations [16] In explanation, microglia and astrocytes
are first-line-immunological responder cells located in the brain which defend
against foreign infectious invaders. Normally this response, such as to a viral
infection, is of limited duration and harmless to the brain. However, when the
microcytes and astrocytes are overstimulated for prolonged periods, which
vaccines are designed to bring about, this extended activation can be very
destructive to the brain. Because of the critical dependence of the developing
brain on a timed sequence of cytokine and excitatory amino acid fluctuation,
according to Blaylock, sequential vaccinations can result in alterations of
this critical process that will not only result in synaptic and dendritic loss,
but abnormal (nerve) pathway development. When microglia are excessively
activated by vaccines, especially chronically, they secrete a number of
inflammatory cytokines, free radicals, lipid peroxidation products, and the two
excitotoxins, glutamate and quinolenic acid, which may become highly
destructive to the brain when these cells are excessively stimulated for
prolonged periods. This process was suggested as the central mechanism
resulting in the pathological as well as clinical features of autism [16].
Since the U.S. Congressional Hearings on issues of vaccine safety ended in
December, 2004, credible and statistically significant studies have begun
appearing that: a) meet the established criteria for effective safety tests and
b) without exception in my opinion, have implicated vaccines as central causal
factors in today’s epidemic of autism and related disorders. Several are listed
below: • As published in the Annals of Neurology [17], Diana Vargas and
colleagues examined the brains from autopsies of 11 autistic patients, ranging
in ages from 5 to 44 years, in which they found the presence of extensively
activated microglia and astrocytes along with elevations of cytokines and
chemokines, which are immune system proteins involved in inflammatory
processes. As the first study of its kind, it tends to support Blaylock’s
theory

that overstimulation of the brain’s microglia and astrocytes for excessively prolonged periods resulting from current vaccine programs plays a central causal role in today’s epidemic of childhood autism.

include albumin, several forms of aluminum, formaldehyde, various amino acids,
DNA residues, egg protein, gelatin, surfactants, monosodium glutamate(MSG),
Thimerosal (50% ethyl mercury), and various antibiotics.

• Surveys from four widely separated geographic areas have shown higher rates
of asthma in fully vaccinated children as compared with those with limited or
no vaccines [18-21].

• Contrary to public avowals as to the removal of mercury from vaccines, at
time of this writing it is still present in the USA as a preservative in the
multi-dose vials of tetanus-toxoid booster vaccines, the Menomune vaccine, the
JE-Vax, and the inactivated influenza vaccines, including the “bird-flu”
vaccine. Also it’s used in the manufacturing process of many vaccines to remove
contaminants, which currently leaves trace residues of mercury in seven other
vaccine formulations. Even these trace amounts are potentially toxic because of
the universally recognized principle of toxicology, that combinations of toxins
will increase toxicity exponentially; that is, two heavy metals will increase
toxicity 10-fold, or three heavy metals increase toxicity 100-fold. In
vaccines, the combinations would be mercury and aluminum. The same principle
applies in other forms of toxic chemicals [26-28].

• A study on primary immunization of 239 premature infants with gestational
ages of less that 35 weeks was conducted by M. Pourcyrous et al. (Journal of
Pediatrics [22], to determine the incidence of cardiorespiratory events and
abnormal C-reactive protein (CRP) levels associated with administration of a
single vaccine or multiple vaccines simultaneously at or about two months age.
(CRP is a standard blood test to measure body inflammation.) CRP levels and
cardiorespiratory events were monitored for three days following immunizations
in a neonatal intensive care unit sponsored by the University of Tennessee.
Elevations of CRP levels occurred in 70% of infants administered single
vaccines and in 85% of those given multiple vaccines, 43% of which reached
abnormal levels. Overall, 16% of infants had vaccine-associated
cardiorespiratory events with episodes of apnea (cessation of breathing) and
bradycardia. Most important, 17% of those receiving single vaccines had
intraventricular brain hemorrhages, with an incidence of 24% of those receiving
multiple vaccines. (This is the first study of its kind, showing that brain
hemorrhages can commonly take place in vulnerable infants, now being
misdiagnosed as Shaken Baby Syndrome in hospital emergency rooms.) It should be
noted that each and every one of the preceding adverse manifestations could be
attributed to vaccine-induced brain inflammation. • Though long denied by
health officials, the action of mercury in causing brain inflammation in
autistic children tends to be confirmed by Sajdel, Sulkowska, et al. [23]. Also
the first of its kind, this study compared the cerebellar levels of the
oxidative stress marker, 3-nitrotyrosine (3-NT), mercury (Hg), and the
antioxidant, selenium (Se) between autistic and normal children. Average
cerebellar 3-NT levels were statistically elevated by 68% in autistic children,
cerebellar Hg by 68%, and mercury levels relative to protective selenium by 75%
in autistic cases in comparison to controls. • In a study along similar lines
to the S. Sulkowska study above, X. Ming et al. [24] reviewed their animal
model of autism, showing that oxidative stress from methylmercury or valproic
acid exposures in early postnatal life of mice resulted in aberrant social,
cognitive, and motor behavior. They also found that Trolox, a water-soluble
vitamin E derivative, was capable of attenuating a number of these adverse
neurobehavioral side effects. • A telephone survey commissioned by the
nonprofit group, Generation Rescue, compared vaccinated with unvaccinated boys
in nine counties of Oregon and California [25]. The survey included nearly
12,000 households with children ranging in age from 4 to 17 years, including
more than 17,000 boys among whom 991 were described as being completely
unvaccinated. The survey found that, compared to unvaccinated boys, vaccinated
boys were 155% more likely to have a neurological disorder, 224% more likely to
have ADHD, and 61% more likely to have autism. For older vaccinated boys in the
11-17 age bracket, the results were even more pronounced, with 158% more likely
to have neurological disorders, 317% more likely to have ADHD, and 112% more
likely to have autism. • In October, 1998 the French government abandoned its
mandatory hepatitis B vaccine program for school children after more than
15,000 law suits were filed for brain damage and autoimmune reactions including
arthritis, multiple sclerosis, and lupus. Vaccine adjuvants—their role in
inducing prolonged immune response to vaccines and their potentially adverse
consequences • As reviewed by Blaylock [16], adjuvants are substances added to
vaccine formulations during manufacturing that are designed to boost the
overall immune system response when the vaccine is injected. These substances

• A study that was conducted in Lima, Peru by J. Laurente and colleagues [29]
should remove all doubts about the potential dangers of mercury-containing
thimerosal as a vaccine additive: To determine if thimerosal administration in
amounts equivalent to vaccine content produces neurotoxic effects on the
encephalon in postnatal hamsters and on the experimentation animals’
development, three serial thimerosal injections were given on birth days 7, 9,
and 11, with controls receiving only saline injection. Test animals
subsequently showed statistically significant reduction in both weight and
stature compared with controls. Neurotoxic effects were also produced at
encephalic (brain) level at the hippocampus, cerebral cortex, and cerebellum.
On tissue slides there was decrease in neuronal density, neuronal necrosis, and
axonal demyelinization in test animals. • In vaccines, virtually insoluble
polymeric aluminum hydroxy compounds serve to dramatically boost and prolong
the immune reaction to the vaccination by prolonged activation of the
macrophagic immune sub-system in some people [30-35]. Ongoing mass (herd)
immunizations – are they necessary? • Vaccine proponents would have us believe
that mass vaccine programs have been largely responsible for controlling
virtually all of the former epidemics of killer childhood diseases in
industrialized nations, In my opinion, with the exception of small-pox and the
possible exception of the polio vaccine, the facts do not bear this out.
According to the Metropolitan Life Insurance Company, from 1911 to 1935 the
four leading causes of child- hood deaths from infectious diseases in the USA
were diphtheria, pertussis (whooping cough), scarlet fever, and measles. Yet,
by 1945 the combined death rates from these causes had declined by 95%, before
implementation of mass vaccine programs [39]. Other sources provided much the
same pattern of information [40-41]. Furthermore, according to a report in
Morbidity and Mortality Weekly Report, July 30, 1999, improvements in
sanitation, water quality, hygiene, and the introduction of antibiotics have
been the most important factors in control of infectious disease in the past
century. Although vaccines were mentioned, they were not included among the
major factors [42]. The MMR vaccine and childhood autism: a hypothetical model
• As mentioned earlier, it was only after the combination of the measles,
mumps, and rubella live viruses into a single vaccine in the USA in 1978 that
the incidence of childhood autism showed a sharp and dramatic increase 1-2].
Prior to that time the three viral vaccines had been in use a number of years,
but given separately without significant increases in autism. • In addition to
the Blaylock model of microglial overstimulation, also undoubtedly playing a
major role [16], there are two plausible explanations for increases in autism
following the MMR vaccine: First, protein sequences in the measles virus have
been found to have similarities to those in brain tissues [43], so that by
process of mimicry, the formation of antibodies against the measles virus would
tend to cross react adversely with the brain.

Second, and probably far more important, viruses are inherently immunosuppressive, in contrast to bacterial infections which stimulate the immune system, as reflected in the fact that viral infections generally lower white blood
counts in contrast to bacterial infections, which raise white counts. The
measles virus is exceptionally potent in this regard, being powerfully
suppressive to cellular immunity [44-46], with the suppressive action of
measles largely attributed to its suppression of interleukin 12, on which
cellular immunity is dependent [45]. Consequently the combining of three viral
vaccines into a single combination may substantially increase the
immunosuppressive vital effect, bringing about, in varying degrees, an immune
paralysis in the infant. Under these circumstances the measles virus may spread
into various tissues of the body. As with combinations of toxic chemicals that
bring exponential increases in toxicities [26-28], combinations in viral
vaccines may bring exponential increases in their toxic, immunosuppressive
effects. • In support of this hypothesis, Wakefield et al. have demonstrated
live measles virus in the small intestinal lymph nodes in children with the
autistic-colitis syndrome, with the only possible source being from the live
virus in the MMR vaccine [47]. • In his various lectures in this country,
Wakefield stressed that it was only following the introduction of the MMR
vaccine in the United Kingdom in 1987 that the rapid increase in childhood the
colitis/autistic syndrome began to be seen. This pattern was further confirmed
by checking back into the records of public health departments of the United
Kingdom and finding reports of autism occurring among children contracting two
such childhood diseases simultaneously, such as chicken pox and measles, or
mumps and measles. • As reviewed by Blaylock [16], a number of studies have
shown that live viruses used in vaccines can enter the brain and reside there
for a lifetime. One study, in which autopsied tissues from the elderly were
examined for the presence of the measles virus, found that 20% of brains had
live measles virus and that 45% of other organs were infested as well [48]. •
As another study suggesting that active brain invasion by the measles virus in
autistic children from the MMR vaccination, Bradstreet et al. [49] examined
cerebrospinal fluid from three autistic children, which revealed the presence
of measles virus genomic RNA. • As to other viral vaccines, as reported by
Bernard Rimland, the chicken pox vaccine is also playing a role in these cases.

John B. Classen, M.D., and epidemiologic studies concerning a suspected causal
relationship between vaccines and the rising incidence of Insulin-Dependent
Diabetes mellitus (IDDM) • In 1998 John Classen, M.D. gave a presentation at a
conference held by the American College of Medicine in which he reviewed 32
published articles, five authored by himself, indicating a causal relationship
between vaccines and the rising incidence of IDDM. Nations represented in the
papers included New Zealand, Canada, the United Kingdom, Denmark, Finland,
Sweden, the U.S., and Holland. Single vaccines were used including haemophilus,
hepatitis B, pertussis, BCG, and smallpox. • A prototype was one conducted in
Finland by Classen and reported in the British Medical Journal [58]. In this
study, from all children born in Finland between October 1, 1985 and August 31,
1987, approximately 116,000 were randomized as test subjects to receive four
doses of haemophilus vaccine starting at three months of age, or one dose
starting at 24 months. 125,500 unvaccinated children served as controls. Each
group was followed until age 10 years for development of IDDM. The incidence at
seven years for those receiving four doses, those receiving one dose, and those
receiving none was 261, 237, and 207 respectively with relative risks of 1.2,
1.14, and 1 for those receiving no vaccine. • In virtually all of the reports
from other countries the results were very similar, indicating a slight but
consistent increase in IDDM following each of the single vaccines listed above.
Classen interpreted these results as indicating that it was not the type of
vaccination that mattered so much as the immunologic impact of vaccination
itself. Typically there was a delay of 3 to 5 years between vaccines and onset
of IDDM. Quotations by Classen during the 1998 conference included:
“Vaccinating every child against every disease is fundamentally unsound.”
“There is a 3.78-fold increased risk of insulin-dependent diabetes mellitus in
children from today’s vaccines.” “All autoimmune diseases are increasing in
incidence. General immune (over) stimulation from vaccines is a cause of
autoimmunity.” Summary and conclusions

• “The federal government’s Vaccine Adverse Event Reporting System (VAERS),
which supposedly documents adverse reactions to vaccines, received nearly
10,000 reports involving the chickenpox vaccine between March, 1995 and
December, 1999. Some of these reactions included brain inflammation,
neurological damage, immune system abnormalities, seizures, and death. It is
important to note, by the way, that since reporting adverse events is not
mandatory, only an estimated 1 to 10% of adverse events are reported to
VAERS.”[50] • In addition, articles by Gary Goldman seriously question the
efficacy and advisability of universal varicella vaccination [51,52]. •
Immunosuppressive effects have also been reported from the rubella vaccine. In
a study of eighteen school girls, ages 11 to 13 years by Pukhalsky et al.,
profound depression of interferon gamma (a key mediator of cellular immunity)
was found 30 days following rubella vaccine [53]. Returning to the MMR vaccine,
F. Imani and K. Kehoe found a previously unrecognized side effect by incubating
the MMR vaccine with a line of human plasma cells, which resulted in increase
in the expression of allergy-related IgE antibodies, and secondarily a decrease
in protective IgG antibodies. Based on these findings, the authors concluded
that viral vaccines may be playing a role in the increasing incidence of asthma
and other allergic diseases [54].

• Over eons of time nature has evolved two major branches of the immune system,
the Th1 cellular system located in the mucous membranes of the gastrointestinal
and respiratory systems, and the Th2 humoral system, which involves the
production of antigen-specific antibodies by plasma cells in bone marrow. Both
systems are incredibly complex both in the timing of their developments and
their functions. Since a large majority of infectious microorganisms enter the
body through the mucous membranes, the cellular immune system has evolved as
the primary immune defense system of the body, with the humoral system serving
as a secondary or backup role. For these reasons, evolutionary challenges have
required the cellular immune system to become more effective in dealing with
infectious micro-organisms, especially intracellular viral infections [57].
This is undoubtedly the reason that vaccine-induced immunities to measles,
mumps, chicken pox, and rubella, which bypass the cellular immune system, are
of limited duration requiring repeated vaccinations. The natural diseases of
former times, in contrast, were dealt with much more effectively by the
cellular immune system, almost always conferring permanent immunity. • The
reader may well question that we have innumerable viruses passing around in the
population today. Would they not serve the same purposes as measles, chicken
pox, mumps, and rubella? Perhaps, except that chicken pox, mumps, rubella, and
especially measles affect and challenge the epithelial tissues of the skin,
respiratory (rubella),

and gastrointestinal tracts (measles, chicken pox, and mumps) in ways that few if any other viruses do.
• As reviewed above, a newborn infant comes into the world with a rudimentary
immune system which requires a series of challenges to bring it to full
functional capacity, a process requiring approximately three years. In earlier
times these challenges were largely in the forms of the “minor childhood
diseases” listed above. With time and experience it is becoming evident that,
in addition to those already mentioned, another flaw in today’s vaccine
programs is that the injectable vaccines, directed at stimulating antibody
production in the bone marrow, are bypassing the cellular immune system,
leaving it relatively unchallenged and therefore relatively weak and stunted
during the critical infant/childhood period. In addition, there are the
powerfully immunosuppressive effects of the MMR vaccine and other viral
vaccines, to which the cellular immune system is uniquely vulnerable. These
processes appear to be progressively undermining and eroding the cellular
immune system, and unless discontinued or changed, may lead to an immunological
collapses. Perhaps it already has for some children. • It is or should be
manifestly apparent that the humoral antibody-producing system of the bone
marrow can never functionally replace the far more efficient cellular immune
system. • For this reason, in my opinion, any children’s vaccine program which
does not allow the cellular (mucosal) immune system to develop unhampered in a
natural way from natural challenges will be self-defeating. This would
necessarily require a delay of childhood vaccines until two or three years of
age. With this delay, the minor childhood viral diseases might well return, but
would this be a bad thing? The dangers of chicken pox and mumps have been
greatly exaggerated. Because of concerns for congenital rubella, the rubella
vaccine could be delayed to later years, as the infection itself is very mild.
Historically, measles did have some serious consequences including
encephalitis, blindness or death in about 1 in 150 cases. However, there are
other answers. Nutrition has been one of the missing links all along. In third
world countries where measles has resulted in high mortality, this has usually
been associated with malnutrition. One example of nutritional intervention is
vitamin A therapy, authorized by the World Health Organization in developing
nations, which has significantly reduced both mortality and morbidity from
measles. • A study in Afghanistan which showed significantly greater morbidity
and mortality from measles in children administered aspirin and Tylenol than
those not given these medications [62], so that these should be avoided with
measles.

• Then too, we now have antibiotics for secondary infections associated with
measles, which they did not have in the days when measles carried a small but
significant rate of morbidities and mortality, much of which was from secondary
infections. • All of the above lies in the future. For today’s parents the
Autism Research Institute with headquarters in San Diego, California
(www.AutismResearchInstitute.com) has made the following safety recommendations
in childhood vaccines: • Never vaccinate a sick child, even if he or she just
has a runny nose. • Never give more than two vaccines simultaneously. • Rather
than the MMR vaccine, request that these viral vaccines be given separately,
preferably six months apart; give measles last; and do not give any other
vaccines for at least 1 year after measles. Some compounding pharmacies do
provide these individual vaccines. • Administer vitamins A, D and C before and
after vaccines. • Never allow a vaccine containing any level of the mercurial
compound, Thimerosal. At time of this writing in late 2008, 50 micrograms of
Thimerosal is still present in each 0.5- mL dose of vaccine from multi-dose
vials of influenza vaccines and multi-dose vials of tetanus booster vaccines,
but not in single dose vials of these vaccines. A total of 17 vaccines
formulations are still approved and available for use that contain some level
of Thimerosal; 10 of these 17 vaccine formulations contain a preservative level
of Thimerosal. • Any overview on vaccines would be incomplete without mention
of the work of the highly published immunologist, H. H. Fudenberg, and his work
in developing clinical applications of transfer factor, which is a low
molecular weight extract of lymphocytes, capable of enhancing or inducing
cell-mediated immunity de novo (without immunizations) in an antigen specific
fashion [63-64]. • Finally, in view of gross deficiencies of vaccine safety
testings, as documented by the U.S. Congressional Hearings on issues of vaccine
safety (1999-December, 2004), the time is long overdue for a total rethinking
and redirecting of current childhood vaccine programs. Until the safety of such
programs can be assured by thorough and dependable safety testing, any further
mandating of childhood vaccines will remain morally and ethically untenable.
http://www.know-vaccines.org/PDF/MMRmucosalIS.pdf

Journal Of Infectious Disease • 2008

The Safety Profile of Varicella Vaccine: A 10-Year Review Susan A. Galea1, Ann
Sweet1, Paul Beninger1, Sharon P. Steinberg2, Philip S. LaRussa2, Anne A.
Gershon2 and Robert G. Sharrar1 1. Merck Research Laboratories, Clinical Risk
Management and Safety Surveillance, North Wales, PA 2. Columbia University
College of Physicians and Surgeons, New York, NY Abstract Excerpts Reports of
breakthrough varicella There were 5054 reports of breakthrough varicella, for a
reporting rate of 0.9 reports/ 10,000 doses of vaccine distributed. Fifty-one
reports (1%) met the regulatory definition of “serious.” Secondary transmission
The VZVIP confirmed 3 cases of secondary transmission of Oka VZV. The Oka VZV
was present in a 30-year-old pregnant woman who developed 100 vesicular lesions
16 days after her 1-year-old son developed ∼30 vesicular lesions 24 days after
varicella vaccination. She elected to have a therapeutic abortion, and the
products of conception were negative for VZV by PCR analysis [5]. In the second
report, the Oka VZV strain was also present in a 4-month-old boy who developed
25 lesions 19 days after his 1-year-old sibling developed 2 vesicular lesions
14 days after vaccination. The third case in which Oka VZV was identified
occurred in a 35-year-old father who developed >100 lesions 17 days after his
1-year-old son developed 12 vesicular lesions 17 days after vaccination. In
each of the 3 confirmed secondary-transmission cases, the vaccine recipient had
a postvaccination rash and had close, household contact with the susceptible
individual. Additionally, there were 2 reported cases of possible secondary
transmission, in which it was reported that the presence of Oka VZV was
identified by an outside laboratory [6, 7]. The specimens for these cases were
not analyzed through or confirmed by the VZVIP. Neurologic AEs Neurologic
syndromes, such as encephalitis, aseptic meningitis, and cerebellar ataxia,
have been reported in the postmarketing environment after administration of
Varivax. There were 30 (CSF) specimens analyzed by PCR (table 1) from patients
with reports of such syndromes. The reported AEs associated with these reports
included encephalitis (12 patients), meningitis (5 patients), ataxia (5
patients), transverse myelitis (3 patients), seizures (3 patients),
demyelinating disorder (1 patient), and hemiparesis (1 patient). The 5
meningitis reports associated with HZ listed in the “HZ” subsection above are
different

from the cases of meningitis listed in this subsection and are not included
here. None of the CSF specimens from these neurologic reports had Oka VZV
identified by PCR analysis. Several of these reports have been described
elsewhere [1, 4]. Herpes Zoster There were 697 reports of HZ occurring 1-3509
days (median, 362 days) after vaccination in patients 13 months to 68 years of
age (median age, 3.4 years). Four hundred patients (65%) for whom age was
reported were <5 years of age. Table 2 compares the HZ reports in which PCR
analysis identified Oka VZV and wild-type VZV strains. The site of HZ was more
likely to correlate with the site of vaccine injection in reports in which Oka
VZV was identified. PCR was more likely to identify wild-type VZV than Oka VZV
if the time to onset was within 42 days of vaccination. However, 2 reports in
which HZ was diagnosed within 42 days of vaccination had specimens in which Oka
VZV was identified. One of these reports was of a child with acute lymphocytic
leukemia diagnosed 10 days after vaccination with Varivax. The child eventually
developed HZ on 3 occasions: 23, 47, and 116 days after vaccination. PCR
analysis of a specimen from the last episode of HZ identified Oka VZV. In the
second report, Oka VZV was present in a girl 5 years of age who developed an
HZ-like rash in the distribution of the second division of the trigeminal nerve
(right side of face and right eye) 25 days after receiving Varivax. Five
patients developed meningitis in association with HZ. Cerebrospinal fluid (CSF)
specimens from these patients were negative for VZV. The HZ rash specimens from
2 of the patients had Oka VZV identified; however, in 1 of these reports,
enterovirus was identified in the CSF analyzed at the Centers for Disease
Control and Prevention (CDC). A third patient had wild-type VZV identified from
an HZ rash specimen. Additionally, 1 child who received Varivax at 2-3 years of
age had acute lymphocytic leukemia diagnosed at 4 years of age. After treatment
with 6-mercaptopurine weekly and methotrexate monthly, he was hospitalized for
HZ and mild meningeal signs. A CSF specimen had Oka VZV identified. The child
recovered.

Potential conflicts of interest S.A.G., A.S., P.B., and R.G.S. are salaried
employees of Merck and possess stock and stock options in the company. A.A.G.
lectures and consults on varicella-zoster virus vaccines for Merck and
GlaxoSmithKline when invited and receives research support from Merck. A
dditionally, P.S.L., S.P.S., and A.A.G. are in a contractual relationship with
Merck through the Varicella Zoster Virus Identification Program. Full Report:
http://jid.oxfordjournals.org/content/197/Supplement_2/S165.full

Simpsonwood Retreat Center • June 7-8, 2000

Simpsonwood • Scientific Review of Vaccine Safety Datalink Information
Norcross, Georgia Quotes from and link to transcript with a Discussion on the
following page “…the number of dose related relationships [between mercury and
autism] are linear and statistically significant. You can play with this all
you want. They are linear. They are statistically significant.” —Dr. William
Weil, American Academy of Pediatrics. Simpsonwood, GA, June 7, 2000 “Forgive
this personal comment, but I got called out at eight o’clock for an emergency
call and my daughter-inlaw delivered a son by c-section. Our first male in the
line of the next generation and I do not want that grandson to get a Thimerosal
containing vaccine until we know better what is going on. It will probably take
a long time. In the meantime, and I know there are probably implications for
this internationally, but in the meanwhile I think I want that grandson to only
be given Thimerosal-free vaccines.” —Dr. Robert Johnson, Immunologist,
University of Colorado, Simpsonwood, GA, June 7, 2000 “But there is now the
point at which the research results have to be handled, and even if this
committee decides that there is no association and that information gets out,
the work has been done and through the freedom of information that will be
taken by others and will be used in other ways beyond the control of this
group. And I am very concerned about that as I suspect that it is already too
late to do anything regardless of any professional body and what they say ...
My mandate as I sit here in this group is to make sure at the end of the day
that 100,000,000 are immunized with DTP, Hepatitis B and if possible Hib, this
year, next year and for many years to come, and that will have to be with
thimerosal containing vaccines unless a miracle occurs and an alternative is
found quickly and is tried and found to be safe.” —Dr. John Clements, World
Health Organization, Simpsonwood, GA, June 7, 2000 “We are in a bad position
from the standpoint of defending any lawsuits, this will be a resource to our
very busy plaintiff attorneys in this country.” —Dr. Robert Brent, a
pediatrician at the Alfred I. duPont Hospital for Children in Delaware. “
“given the sensitivity of the information, we have been able to keep it out of
the hands of, let’s say, less responsible hands.” —Dr. Bob Chen, head of
vaccine safety for the CDC the study “should not have been done at all” the
results “will be taken by others and will be used in ways beyond the control of
this group. The research results have to be handled.” — Dr. John Clements,
vaccines advisor at the World Health Organization Link to Simpsonwood Document:
http://thinktwice.com/simpsonwood.pdf

Medical Veritas • 2008

The truth behind the vaccine cover-up Russell L. Blaylock, MD
www.russellblaylockmd.com Abstract On June 7-8, 2000 a secret conference was
held at the Simpsonwood Conference Center in Norcross, Georgia to discuss a
study examining the link between increasing doses of Thimerosal and
neurodevelopmental disorders. The study was done using the Vaccine Safety
Datalink (VSD) data-base, an official governmental data bank collecting patient
vaccination information on the children from the health maintenance
organizations (HMOs) being paid to participate. Attending were 51 scientists,
representatives of pharmaceutical vaccine manufacturing companies and a
representative of the World Health Organization; the public and the media were
unlawfully excluded. The conclusions of this meeting were quite startling,
since it confirmed a dose-response link between Thimerosal and
neurodevelopmental disorders that held up to rigorous statistical analyses. In
their discussion, they make plain why the meeting was held in secret: the
conclusions would have destroyed the public’s confidence in the vaccine
program, and more importantly, their faith in vaccine authorities. When the
results of this study were published three years later in the journal
Pediatrics, the “problem” had been fixed, in that by adding another set of data
from a third HMO, reorganizing the criteria for inclusion and restructuring the
patient groupings, a less than statistically significant link was demonstrated.
In my analysis I discuss the more outrageous statements made during the meeting
and how accepted experts in the field of mercury neurotoxicity were excluded
from the meeting. I was asked to write a paper on some of the newer mechanisms
of vaccine damage to the nervous system, but in the interim I came across an
incredible document that should blow the lid off the cover-up being engineered
by the pharmaceutical companies in conjunction with powerful governmental
agencies. It all started when a friend of mine sent me a copy of a letter from
Congressman David Weldon, M.D. to the director of the CDC, Dr Julie L.
Gerberding, in which Congressman Weldon alludes to a study by a Doctor Thomas
Verstraeten, then representing the CDC, on the connection between infant
exposure to Thimerosal-containing vaccines and neurodevelopmental injury. In
this shocking letter, Congressman Weldon refers to Dr. Verstraeten’s study,
which looked at the data from the Vaccine Safety Datalink and found a
statistically significant correlation between Thimerosal exposure via vaccines
and several neurodevelopmental disorders including tics, speech and language
delays, and possibly ADD. Congressman Weldon questions the CDC director as to
why, following this meeting, Dr. Verstraeten published his results almost four
years later in the journal Pediatrics to show just the opposite, that is, that
except for tics, there was no statistically significant correlation to any
neurodevelopmental problems related to Thimerosal exposure in infants. In this
letter, Congressman Weldon refers to a report of the minutes of this meeting
held in 2000, which exposes some incredible statements by the “experts” making
up this study group. The group’s purpose was to evaluate and discuss Dr.
Verstraeten’s interim results and data and make recommendations that would
eventually lead to possible alterations in existing vaccine policy. I contacted
Congressman Weldon’s legislative assistant and he kindly sent me a complete
copy of this report. Now, as usual in these cases, the government did not give
up this report willingly; it required a Freedom of Information Act lawsuit to
pry it loose. Having read the report twice and having carefully analyzed it, I
can see why

they did not want any outsiders to see it. It is a bombshell, as you shall see.
To help the reader understand the importance of this report, in this analysis I
will not only describe and discuss this report, but also will frequently quote
their words directly and supply the exact page number so others can see for
themselves. The official title of the meeting was the “Scientific Review of
Vaccine Safety Datalink Information.” This conference, held on June 7-8, 2000,
at Simpsonwood Retreat Center in Norcross, Georgia, assembled 51 scientists and
physicians, five of whom represented vaccine manufacturers. These included
Smith Kline Beecham, Merck, Wyeth, North American Vaccine and Aventis Pasteur.
During this conference, these scientists focused on the study of the Datalink
material, whose main author was Dr. Thomas Verstraesten and who identified
himself as working at the National Immunization Program of the CDC. It was
discovered by Congressman Weldon that Dr. Verstraeten left the CDC shortly
after this conference to work for the Belgian operations of the pharmaceutical
maker GlaxoSmithKline—a recurring regulated agency/regulated-industry pattern
that has been given the name “a revolving door”. It is also interesting to note
that GlaxoSmithKline was involved in several lawsuits over complications
secondary to their vaccines. To start off the meeting, Dr. Roger Bernier,
Associate Director for Science in the National Immunization Program (CDC),
related some pertinent history. He stated that Congressional action in 1997
required that the FDA review mercury being used in drugs and biologics
(vaccines). To meet this mandate, the FDA called for all the registered
manufacturers of drugs, including vaccines, to submit the mercury information
about their drug products. He notes that a group of European regulators and
manufacturers met on April 1999 and acknowledged the situation but made no
recommendations or changes. In other words, it was all for show. At this point
Dr. Bernier makes an incredible statement (page 12). He says, “In the United
States there was a growing recognition that cumulative exposure may exceed some
of the guidelines.” By guidelines, he is referring to guidelines for mercury
exposure safety levels set by several regulatory agencies. The three guidelines
were set by the ATSDR (The Agency for Toxic Substances and Disease Registry),
the FDA (Food and Drug Administration), and the EPA (Environmental Protection
Agency). The most consistently violated safety guideline was the
mercury-in-food limit set by the EPA. He further explains that he is referring
to children being exposed to Thimerosal in vaccines. Based on this realization
that they were violating safety guidelines, he says that this then “resulted in
a joint statement of the Public Health Service (PHS) and the American Academy
of Pediatrics (AAP) in July of last year (1999), which stated that as a long
term goal, it was desirable to remove mercury from vaccines because it was a
potentially preventable source of exposure.” (Page 12) As an aside, one has to
wonder, where was the Public Health Service and American Academy of Pediatrics
during all the years of mercury use in vaccines and why didn’t they know that,
number one, they were exceeding regulatory safety levels and secondly, why
weren’t they aware of the extensive literature showing deleterious effects on
the developing nervous system of babies? As we shall see, even these “experts”
seem to be cloudy on the mercury literature. Dr. Bernier notes that in August
1999 a public workshop was held in the Lister Auditorium in Bethesda by the
National Vaccine Advisory Group and the Interagency Working Group on Vaccines
to consider Thimerosal risk in vaccine use. And based on what was discussed in
that conference, Merck, one manufacturer of a U.S.-licensed hepatitis B vaccine
(HepB) moved to license a “no Thimerosal” formulation for young children but
kept making and distributing its Thimerosal-preserved HepB formulation into the
mid 2000s while GlaxoS- mithKline,

the other U.S.-licensed HepB maker apparently moved to license a reduced-Thimerosal formulation; apparently,
neither firm moved to recall the existing Thimerosal-preserved doses. It is
interesting to note that the media took very little interest in what was
learned at that meeting and it may have been a secret meeting—probably because
it was also a meeting that was not, as required by law, announced publicly. As
we shall see, there is a reason why they struggle to keep the contents of all
these meetings secret from the public. Dr. Bernier then notes on page 13 that
on October 1999 the Advisory Committee on Immunization Practices (ACIP) “looked
this situation over again and did not express a preference for any of the
vaccines that were Thimerosal free.” In this discussion he further notes that
the ACIP concluded that the Thimerosal-containing vaccines could be used but
the “long-term goal” is to try to remove Thimerosal as soon as possible. Now,
we need to stop and think about what has transpired. We have an important group
here, the ACIP that essentially plays a role in vaccine policy affecting tens
of millions of children every year. And, we have evidence from the Thimerosal
meeting in 1999 that the potential for serious injury to the infant’s brain is
so serious that a recommendation for removal becomes policy. In addition, they
are all fully aware that tiny babies are receiving mercury doses that exceed
even EPA safety limits for adults, yet all they can say is that we must “try to
remove Thimerosal as soon as possible.” Do they not worry about the tens of
millions of babies who will continue receiving Thimerosal-containing vaccines
until they can get around to stopping the use of Thimerosal? It should also be
noted that it is a misnomer to say “removal of Thimerosal” since they are not
removing anything. They just plan to stop adding it to future vaccines once
they use up existing stocks, which entails millions of doses. And incredibly,
the government allows them to do it. Even more incredibly, the American Academy
of Pediatrics and the American Academy of Family Practice similarly endorse
this insane policy. In fact, they specifically state that children should
continue to receive the Thimerosal-containing vaccines until new
Thimerosal-free vaccines can be manufactured at the will of the manufacturers.
It was disclosed that Thimerosal was in all influenza, HepB and DPT vaccines,
as well as most DtaP vaccines . Had vaccine safety been their primary concern,
as it should be, the most obvious solution was to recommend only single-dose
vials, which require no preservative, coupled with a ban on the use of any
mercury compound in the manufacture of all drugs. So, why didn’t they make this
or at least a “no Thimerosal” recommendation? “Oh,” they exclaim, “it would add
to the cost of the vaccine.” Of course, we are only talking about a few dollars
per vaccine at most, certainly worth the health of your child’s brain and
future. They could use some of the hundreds of millions of dollars they waste
on vaccine promotion every year to cover the cost for the poor. Yet, that would
cut into some fat-cat’s profit and we can’t have that. As they begin to
concentrate on the problem at hand we first begin to learn that the greatest
problem with the meeting is that they know virtually nothing about what they
are doing. On page 15, for example, they admit that there is very little
pharmacokinetic data on ethylmercury, the form of mercury in Thimerosal. In
fact, they say there is no data on excretion and the data on toxicity is
sparse; yet it is recognized to cause hypersensitivity, neurological problems,
and even death, and it is known to easily pass the blood-brain barrier and the
placental barrier. Therefore, what they are admitting is that we have a form of
mercury that has been used in vaccines since the 1930s and no one has bothered
to study the effects on biological systems, especially the brains of infants.
Their defense throughout this conference is “we just don’t know the effects of
ethylmercury.” As a solution, they resort to studies on methylmercury because
there are thousands of studies on this form of mercury. The major source of
this form is seafood consumption. It takes them awhile to get the two forms of
mercury straight, since for several pages of the report they say methylmercury
is in Thimerosal rather than ethylmercury. They can be forgiven for this. On
page 16, Dr. Johnson, an immunologist and pediatrician at the University of
Colorado School of Medicine and the National Jewish Center

for Immunology and Respiratory Medicine, notes that he would like to see the
incorporation of wide margins of safety, that is 3 to 10-fold margins of safety
to “account for data uncertainties.” What he means is that there are so many
things we do not know about this toxin that we had better use very wide margins
of safety. For most substances the FDA uses a 100-fold margin of safety. The
reason for this, which they do not mention, is that in a society of hundreds of
millions of people, there are groups of people who are much more sensitive to
the toxin than others. For instance, the elderly, the chronically ill, the
nutritionally deficient, small babies, premature babies, those on certain
medications and those with inborn defects in detoxification, just to name a
few. In fact, premature babies and low birth weight babies were excluded from
the main study since (1) some had the highest mercury levels, (2) these would
be hard to study, and (3) they had the most developmental problems possibly
related to the mercury. In other words, including these babies might endanger
their claims of safety. It should also be noted that all participants at this
conference ignored the differences in total mercury exposure among infants and
small children living in different geographical areas. For example, a child’s
mother who had dental amalgams, who regularly eats high-methymercury-containing
seafood and lives in an area with high atmospheric mercury levels will have
much higher total mercury exposure than one exposed to little dietary, dental,
and environmental mercury. Also on page 16, Dr. Johnson makes an incredible
statement, one that defines the problem we have in this country with the
promoters of these vaccines. He states, “As an aside, we found a cultural
difference between vaccinologist and environmental health people in that many
of us in the vaccine arena have never thought about uncertainty factors before.
We tend to be relatively concrete in our thinking.” Then he says, “One of the
big cultural events in that meeting ... was when Dr. Clarkson repetitively
pointed out to us that we just didn’t get it about uncertainty, and he was
actually quite right.” This is an incredible admission. First, what is a
“vaccinologist”? Do you go to school to learn to be one? How many years of
residency training are required to be a “vaccinologist”? Are there board exams?
It’s an ill-defined term used to describe people who are obsessed with
vaccines, not that they actually study the effects of the vaccines, as we shall
see throughout this meeting. Most important is the admission by Dr. Johnson
that he and his fellow “vaccinologists” are so blinded by their obsession with
forcing vaccines on society that they never even considered that there might be
factors involved that could greatly affect human health, the so-called
“uncertainties”. Further, he admits that he and his fellow “vaccinologists”
like to think in concrete terms; that is, they are very narrow in their
thinking and wear blinders that prevent them from seeing the numerous problems
occurring with large numbers of vaccinations in infants and children. Their
goal in life is to vaccinate as many people as possible with an ever-growing
number of vaccines. On page 17 his “concrete thinking” once again takes over.
He refers to the Bethesda meeting on Thimerosal safety issues and says, “there
was no evidence of a problem, only a theoretical concern that young infants’
developing brains were being exposed to an organomercurial.” Of course, as I
shall point out later, it is a lot more than a “theoretical concern”. He then
continues by saying, “We agree that while there was no evidence of a problem,
the increasing number of vaccine injections given to infants, was increasing
the theoretical mercury exposure risk.” It’s hard to conceive of a true
scientist not seeing the incredible irony of these statements. The medical
literature abounds with studies on the deleterious effects of mercury on
numerous enzymes, mitochondrial energy production, synaptic function, dendritic
function, neurotubule dissolution and excitotoxicity—yet he sees only a
“theoretical risk” associated with an ever increasing addition of
Thimerosal-containing vaccines. It is also important to note that these
geniuses never even saw a problem in the first place, it was pressure from
outside scientists, parents of affected children, and groups representing them
that pointed out the problem. They were, in essence, reacting to pressure from
outside the “vaccinologist club” and, therefore, had not discovered internally
that a problem even “might” exist.

In fact, if these outside groups had not become involved, these “vaccinologists” would have continued to add
more and more mercury-containing vaccines to the list of required vaccines.
Only when the problem became so obvious, that is of epidemic proportion and the
legal profession became involved, would they have even noticed there was a
problem. This is a recurring theme in the government’s regulatory agencies, as
witnessed with fluoride, aspartame, MSG, dioxin and pesticides issues.

In fact, this statement is not based on any risk to U.S. children at all and he
makes that plain when he states, “that the potential impact on countries that
have 10% to 15% newborn hepatitis B exposure risk was very distressing to
consider.” (page 18) In other words the risk is not to normal U.S. children but
to children in developing countries. In fact, hepatitis B is not a risk until
the teenage years and after in this country. The only at-risk children are
those born to drug abusing parents, to mothers infected with hepatitis B, or to
HIV infected parents.

It is also interesting that Dr. Johnson did admit that the greatest risk was
among low birth weight infants and premature infants. Now why would that be if
there existed such a large margin of safety with mercury used in vaccines?
Could just a few pounds of body weight make such a dramatic difference? In
fact, it does, but it also means that normal birth weight children, especially
those near the low range of normal birth weight, are also in greater danger. It
also would mean that children receiving doses of mercury higher than the 75 ug
in this study would be at high risk as well because their dose, based on body
weight, would be comparable to that of the low birth weight child receiving the
lower dose. This is never even considered by these “vaccinologist” experts who
decide policy for your children.

Infectious disease authorities know that 90% of people infected with this virus
either have a mild infection and recover or have no symptoms at all. Even
pregnant women infected with the virus have only a 20% chance of transmitting
the virus to their babies. According to statistics, the United States has one
of the lowest rates of hepatitis B infection in the world, with only 53 cases
of the infection being reported in children among 3.9 million births. In fact,
there were three times as many serious complications from the vaccine as there
were children who contracted the disease. The real reason for vaccinating the
newborns is to capture them before they can escape the vaccinologists’ vaccine
program.

Now this next statement should shock everyone, but especially the poor who
might believe that these “vaccinologist” experts have their best interest in
mind. Dr. Johnson says on page 17, “We agree that it would be desirable to
remove mercury from U.S. licensed vaccines, but we did not agree that this was
a universal recommendation that we would make because of the issue concerning
preservatives for delivering vaccines to other countries, particularly
developing countries, in the absence of hard data that implied that there was
in fact a problem.” So, here you have it. The data is convincing enough that
the American Academy of Pediatrics and the American Academy of Family Practice,
as well as the regulatory agencies and the CDC, all recommend its removal as
quickly as possible because of concerns of adverse effects of mercury on brain
development, but not for the children in the developing countries. I thought
the whole idea of child health programs in the United States directed toward
the developing world was to give poor children a better chance in an
increasingly competitive world. This policy being advocated would increase the
neurodevelopmental problems seen in poor children of developing countries and
of this country, impairing their ability to learn and develop competitive
minds. Remember, there was a representative of the World Health Organization
(WHO), Dr. John Clements, serving on this panel of “experts” who apparently
never challenged this statement made by Dr. Johnson. It also needs to be
appreciated that children in developing countries are at a much greater risk of
complications from vaccinations and from mercury toxicity than children in
developed countries. This is because of poor nutrition, concomitant parasitic
and bacterial infections, and a high incidence of low birth weight in these
children. We are now witnessing a disaster in African countries caused by the
use of older live virus polio vaccines that has now produced an epidemic of
vaccine related polio, that is, polio caused by the vaccine itself. In, fact,
in some African countries, polio was not seen until the vaccine was introduced.
The WHO and the “vaccinologist experts” from this country now justify a
continued polio vaccination program with this dangerous vaccine on the basis
that now that they have created the epidemic of polio, they cannot stop the
program. In a recent article it was pointed out that this is the most deranged
reasoning, since more vaccines will mean more vaccine-related cases of polio.
But then, “vaccinologists” have difficulty with these “uncertainties”. (Jacob
JT. A developing country perspective on vaccine-associated paralytic
poliomyelitis. Bulletin WHO 2004; 82:53-58. See commentary by D.M. Salisbury at
the end of the article.) Then Dr. Johnson again emphasizes the philosophy that
the health of children is secondary to “the program” when he says, “We saw some
compelling data that delaying the birth dose of HepB vaccine would lead to
significant disease burden as a consequence of missed opportunity to immunize.”
This implies that our children would be endangered from the risk of hepatitis B
should the vaccine program stop vaccinating newborns with the HepB vaccine.

This is a tactic often used to scare mothers into having their children
vaccinated. For example, vaccinologists say that if children are not vaccinated
against measles, millions of children could die during a measles epidemic. They
know this is nonsense. What they are using are examples taken from developing
countries with poor nutrition and poor immune function in which such epidemic
death can occur. In the United States we would not see this because of better
nutrition, better health facilities and better sanitation. In fact, most deaths
seen during measles outbreaks in the United States occur in children in whom
vaccination was contraindicated, when the vaccine did not work or in children
with chronic, immune-suppressing diseases. In fact, most studies show that
children catching the measles or other childhood diseases have been either
fully immunized or partially immunized. The big secret among “vaccinologists”
is that anywhere from 20 to 50% of children are not resistant to the diseases
for which they have been vaccinated. Also on page 18, Dr. Johnson tells the
committee that it was Dr. Walter Orenstein who “asked the most provocative
question which introduced a great deal of discussion. That was, should we try
to seek neurodevelopmental outcomes from children exposed to varying doses of
mercury by utilizing the Vaccine Safety Datalink data from one or more sites.”
(page 18) I take from this no one had ever even thought of looking at the data
that had just been sitting there all these years unreviewed. Children could
have been dropping like flies or suffering from terrible neurodevelopmental
defects caused by the vaccine program and no one in the government would have
known. In fact, that is exactly what the data suggested was happening, at least
as regards neurodevelopmental delays. We should also appreciate that the
government sponsored two conferences on the possible role of metals, aluminum
and mercury, being use in vaccines, without any change in vaccine policy
occurring after the meetings. These meetings were held a year before this
year’s 2000 meeting and before any examination of the data which was being held
tightly by the CDC (which was denied to other independent, highly qualified
researchers). I will talk more about what was discussed in the aluminum
conference later. It is very important and is only briefly referred to in this
conference for a very good reason. If the public knew what was discussed at the
aluminum meeting no one would ever get a vaccination using the presently
manufactured types of vaccines again. Despite what was discussed in the
aluminum meeting and the scientific literature on the neurotoxicity of
aluminum, Dr. Johnson makes the following remark; “Aluminum salts have a very
wide margin of safety. Aluminum and mercury are often simultaneously
administered to infants, both at the same site and at different sites.” Also on
page 20, he states, “However, we also learned that there is absolutely no data,
including animal data, about the potential for synergy, additively or
antagonism, all of which can occur in binary metal mixtures...”

It is important here to appreciate a frequently used deception by those who are trying to defend an indefensible
practice. They use the very same language just quoted, that is, that there is
no data to show, etc., etc. They intend it to convey the idea that the issue
has been looked at and studied thoroughly and no toxicity was found. In truth,
it means that no one has looked at this possibility and there have been no
studies that would give us an answer one way or the other. In fact, we know
that aluminum is a significant neurotoxin and that it shares many common
mechanisms with mercury as a neurotoxin. For example, they are both toxic to
neuronal neurotubules, interfere with antioxidant enzymes, poison DNA repair
enzymes, interfere with mitochondrial energy production, block the glutamate
reuptake proteins (GLT-1 and GLAST), bind to DNA and interfere with neuronal
membrane function. Toxins that share toxic mechanisms are almost always
additive and frequently synergistic in their toxicity. So, Dr. Johnson’s
statement is sheer nonsense. A significant number of studies have shown that
both of these metals play a significant role in all of the neurodegenerative
disorders. It is also important to remember, both of these metals accumulate in
the brain and spinal cord. This makes them accumulative toxins and therefore
much more dangerous than rapidly excreted toxins. To jump ahead, on page 23 Dr.
Tom Sinks, Associate Director for Science at the National Center for
Environmental Health at the CDC and the Acting Division Director for Division
of Birth Defects, Developmental Disabilities and Health, asks, “I wonder is
there a particular health outcome that is related to aluminum salts that may
have anything that we are looking at today?” Dr. Martin Meyers, Acting Director
of the National Vaccine Program Office, answers, “No, I don’t believe there are
any particular health concerns that were raised.” This is after an aluminum
conference held the previous year that did, indeed, find significant health
concerns and extensive scientific literature showing aluminum to be of great
concern. On page 24 Dr. William Weil, a pediatrician representing the Committee
on Environmental Health of the American Academy of Pediatrics, brings some
sense to the discussion by reminding them that, “there are just a host of
neurodevelopmental data that would suggest that we’ve got a serious problem.
The earlier we go, the more serious the problem.” Here he means that the
further back you go during the child’s brain development, the more likely the
damage to the infant. I must give him credit; at least he briefly recognized
that a significant amount of brain development does take place later—that is
after birth. He also reminds his colleagues that aluminum produced severe
dementia and death in dialysis cases. He concludes by saying, “To think there
isn’t some possible problem here is unreal.” (page 25) Not to let it end there,
Dr. Meyers adds, “We held the aluminum meeting in conjunction with the metal
ions in biology and medicine meeting, we were quick to point out that in the
absence of data we didn’t know about additive or inhibitory activities.” Once
again we see the “no data” ploy. There is abundant data on the deleterious
effects of aluminum on the brain, a significant portion of which came out in
that very meeting. Dr. Johnson also quotes Dr. Thomas Clarkson, who identifies
himself as associated with the mercury program at the University of Rochester,
as saying that delaying the HepB vaccine for 6 months or so would not affect
the mercury burden (page 20). He makes the correct conclusion when he says, “I
would have thought that the difference was in the timing. That is you are
protecting the first six months of the developing central nervous system.”
Hallelujah, for a brief moment I thought that they had stumbled on one of the
most basic concepts in neurotoxicology. Then Dr. Meyers dashed my hopes by
saying that single, separated doses would not affect blood levels at all. At
this juncture, we need a little enlightenment. It is important to appreciate
that mercury is a fat soluble metal. That is, it is stored in the body’s fat.
The brain contains 60% fat and therefore is a common site for mercury storage.
Now, they establish in this discussion that about half of methylmercury is
excreted over several months when ingested. A recent study found that
ethylmercury has a half-life of 7 days.

A significant proportion of the mercury will enter the brain (it has been shown
to easily pass through the bloodbrain barrier) where it is stored in the
phospholipids (fats). It should also be appreciated that when cleared from the
blood, the ethylmercury enters the bowel, where it is re-circulated many times
over—each time depositing more mercury in the child’s brain. With each new
vaccine dose, and remember, at the time of this conference, these children were
receiving as many as 36 doses of these vaccines by age 2 years, many of which
contained mercury—another increment of mercury is added to the brain storage
depot. This is why we call mercury an accumulative poison. They never once, not
once, mention this vital fact throughout the entire conference. Not once.
Moreover, they do so for a good reason; it gives the unwary, those not trained
in neuroscience, assurance that all that matters here is blood levels. In fact,
on page 163, Dr. Robert Brent, a developmental biologist and pediatrician at
Thomas Jefferson University and Dupont Hospital for Children, says that we
don’t have data showing accumulation and “that with the multiple exposures you
get an increasing level, and we don’t know whether that is true or not.” He
redeems himself somewhat by pointing out that some of the damage is
irreversible and with each dose more irreversible damage occurs and in that way
it is accumulative. On page 21 Dr. Thomas Clarkson makes the incredible
statement implying that he knows of no studies that show exposure to mercury
after birth or at six months would have deleterious effects. Dr. Isabelle
Rapin, a neurologist for children at Albert Einstein College of Medicine,
follows up by saying that “I am not an expert on mercury in infancy” but she
knows it can affect the nerves (peripheral nervous system). So, here is one of
our experts admitting that she knows little about the effects of mercury on the
infant. My question is: Why is she here? Dr. Rapin is a neurologist for
children at Albert Einstein College of Medicine who stated that she has a keen
interest in developmental disorders, in particular those involving language and
autism, yet she knows little about the effects of mercury on the infant brain.
This conference is concerned with the effects of mercury in the form of
Thimerosal on infant brain development, yet throughout this conference our
experts, especially the “vaccinologists”, seem to know little about mercury
except limited literature that shows no toxic effects except at very high
levels. None of the well known experts were invited, such as Dr. Michael
Aschner from Bowman Grey School of Medicine or Dr. Boyd Haley, who has done
extensive work on the toxic effects of low concentrations of mercury on the CNS
(Central Nervous System). They were not invited because they would be harmful
to the true objective of this meeting, and that was to exonerate mercury in
vaccines. Several times throughout this conference, Dr. Brent reminds everyone
that the most sensitive period for the developing brain is during the early
stages of pregnancy. In fact, he pinpoints the 8th to 18th week as the period
of neuromaturation. In fact, the most rapid period of brain maturation,
synaptic development and brain pathway development, is during the last three
months of pregnancy continuing until two years after birth. This is often
referred to as the “brain growth spurt”. This is also not mentioned once in
this conference, again because if mothers knew that their child’s brain was
busy developing for up to two years after birth, they would be less likely to
accept this safety of mercury nonsense these “vaccinologists” proclaim. The
brain develops over 100 trillion synaptic connections and tens of trillions of
dendritic connections during this highly sensitive period. Both dendrites and
synapses are very sensitive, even to very low doses of mercury and other
toxins. It has also been shown that subtoxic doses of mercury can block the
glutamate transport proteins that play such a vital role in protecting the
brain against excitotoxicity. Compelling studies indicate that damage to this
protective system plays a major role in most of the neurodegenerative diseases
and abnormal brain development as well.

Recent studies have shown that glutamate accumulates in the brains of autistic children, yet these experts seem to
be unconcerned about a substance (mercury) that is very powerful in triggering
brain excitotoxicity. It is also interesting to see how many times Dr. Brent
emphasizes that we do not know the threshold for mercury toxicity for the
developing brain. Again, that is not true. We do know and the Journal of
Neurotoxicology states that anything above 10μg (micrograms) is neurotoxic. The
WHO in fact states that there is no safe level of mercury. On page 164 Dr.
Robert Davis, Associate Professor of Pediatrics and Epidemiology at the
University of Washington, makes a very important observation. He points out
that in a population like the United States you have individuals with varying
levels of mercury from other causes (diet, living near coal-burning facilities,
etc.) and by vaccinating everyone you raise those with the highest levels even
higher and bring those with median levels into a category of higher levels. The
“vaccinologists” with their problem of “concrete thinking” cannot seem to
appreciate the fact that not everyone is the same. That is, they fail to see
these “uncertainties”. To further emphasize this point, let’s consider a
farming family that lives within three miles of a coal-burning electrical
plant. Since they also live near the ocean they eat seafood daily. The
fertilizers, pesticides and herbicides used on the crops contain appreciable
levels of mercury. The coal-burning electrical plant emits high levels of
mercury in the air they breathe daily and the seafood they consume has levels
of mercury higher than EPA safety standards. This means that any babies born to
these people will have very high mercury levels. Once born, they are given
numerous vaccines containing even more mercury, thereby adding significantly to
their already high mercury burden. Are these “vaccinologists” trying to
convince us that these children don’t matter and that they are to be sacrificed
at the alter of “vaccine policy”? Recent studies by neurotoxicologists have
observed that as our ability to detect subtle toxic effects improves,
especially on behavior and other neurological functions, we lower the level of
acceptable exposure. In fact, Dr. Sinks brings up that exact point, using lead
as an example. He notes that as our neurobehavioral testing improved, we
lowered the acceptable dose considerably and continue to do so. Dr. Johnson had
the audacity to add, “The smarter we get, the lower the threshold.” Yet,
neither he, nor the other participants seem to be getting any smarter
concerning this issue. Dr. Robert Chen, Chief of Vaccine Safety and Development
at the National Immunization Program at the CDC, then reveals why they refuse
to act on this issue. He says, “the issue is that it is impossible, unethical
to leave kids unimmunized, so you will never, ever resolve that issue. So then
we have to refer back from that.” (page 169) In essence, immunization of the
kids takes precedence over safety concerns with the vaccines. If the problem of
vaccine toxicity cannot be solved, he seems to be saying, then we must accept
that some kids will be harmed by the vaccines. In fact, we are now seeing that
the harm from the vaccines exceeds the benefit of disease prevention. Dr. Brent
makes the statement that he knows of no known genetic susceptibility data on
mercury and therefore assumes there is a fixed threshold of toxicity. That is,
that everyone is susceptible to the same dose of mercury and there are no
genetically hypersensitive groups of people. In fact, a recent study found just
such a genetic susceptibility in mice. In this study researchers found that
mice susceptible to autoimmunity developed neurotoxic effects to their
hippocampus, including excitotoxicity, not seen in other strains of mice. They
even hypothesize that the same may be true in humans, since familial
autoimmunity increases the likelihood of autism in offspring. (Hornig M, Chian
D, Lipkin WI. Neurotoxic effects of postnatal Thimerosal are mouse strain
dependent. Mol Psychiatry 2004 Sep.;9(9):833–45). For the next quotation you
need a little discussion to be able to appreciate the meaning. They are
discussing the fact that in Dr. Verstraeten’s study frightening correlations
were found between the higher doses of Thimerosal

and problems with neurodevelopment, including ADD and autism. The problem with
the study was that there were so few children that had been administered
Thimerosal-free vaccines, that a true control group could not be used. Instead
they had to use children getting 12.5μg of mercury as the control and some even
wanted to use the control dose as 37.5μg. So the controls had mercury levels
that could indeed cause neurodevelopmental problems. Even with this basic flaw,
a strong positive correlation was found between the dose of mercury given and
these neurodevelopmental problems. It was proposed that a group of children
receiving non-Thimerosal vaccines be compared to those who had Thimerosal. In
fact, we later learn that a large group of children could have been used as a
Thimerosal-free control. It seems that for two years before this conference,
the Bethesda Naval Hospital had been using unlicensed reducedThimerosal
vaccines in place of the U.S.-licensed Thimerosal-preserved vaccines to
immunize their outpatient children. Unfortunately, in general, these children
were too young for the symptoms of neurodevelopmental-regressive autism to be
manifest when Verstraten began his studies in the late 1990s. So, now to the
quote: Dr. Braun responds to the idea of starting a new study using such
Thimerosal-free controls by saying, “Sure we will have the answer in five
years. The question is what can we do now with the data we have?” (page 170)
Well, we have the answer to that, they simply covered this study up, declared
that Thimerosal is of no concern and continued the unaltered policy. That is,
they can suggest that the pharmaceutical manufacturers of vaccines remove the
Thimerosal but not make it mandatory or examine the vaccines to make sure they
have removed it. Let us take a small peek at just how much we can trust the
pharmaceutical manufacturers to do the right thing. Several reports of major
violations of vaccine manufacturing policy have been cited by the regulatory
agencies. This includes obtaining plasma donations without taking adequate
histories on donors as to disease exposures and previous health problems, poor
record keeping on these donors, improper procedures, and improper handing of
specimens. That these are not minor violations is emphasized by the discovery
that a woman with variant Mad Cow Disease was allowed to give plasma to be used
in vaccines in England. In fact, it was learned only after the contaminated
plasma was pooled and used to make millions of doses of vaccines that her
disease was discovered. British health officials told the millions of
vaccinated not to worry, since the “experts” have no idea if it will really
spread the disease. Contamination of vaccines is a major concern in this
country as well, as these regulatory violations make plain. It is also
important to note that no fines were given, just warnings. Conclusions by the
study group At the end of the conference, a poll was taken asking two
questions. One was, Do you think that there is sufficient data to make a causal
connection between the use of Thimerosal-containing vaccines and
neurodevelopmental delays? Second, do you think further study is called for
based on this study? First, let us see some of the comments on the question of
doing further studies. Dr. Paul Stehr-Green, Associate Professor of
Epidemiology at the University of Washington School of Public Health and
Community Medicine, who voted yes, gave as his reason, “The implications are so
profound these should be examined further.” (page 180) Meanwhile, Dr. Brent
interjects his concern that the lawyers will get hold of this information and
begin filing lawsuits. He says, “They want business and this could potentially
be a lot of business.” (page 191) Dr. Loren Koller, Pathologist and
Immunotoxicologist at the College of Veterinary Medicine, Oregon State
University, is to be congratulated for recognizing more is involved in the
vaccine effects than just ethylmercury (page

192). He mentions aluminum and even the viral agents beings used as other possibilities. This is especially important in the face of Dr. R. K. Gherardi’s identification of macrophagic myofascitis, a condition causing profound
weakness and multiple neurological syndromes, one of which closely resembled
multiple sclerosis. Both human studies and animal studies have shown a strong
causal relationship to the aluminum hydroxide or aluminum phosphate used as
vaccine adjuvants. More than 200 cases have been identified [1000s across the
globe since this report was written] in European countries and the United
States and have been described as an “emerging condition”. Here are some of the
neurological problems seen with the use of aluminum hydroxide and aluminum
phosphate in vaccines. In two children aged 3 and 5 years, doctors at the All
Children’s Hospital in St. Petersburg, Florida described chronic intestinal
pseudo-obstruction, urinary retention, and other findings indicative of a
generalized loss of autonomic nervous system function (diffuse dysautonomia).
The 3-year old had developmental delay and hypotonia (loss of muscle tone). A
biopsy of the children’s vaccine injection site disclosed elevated aluminum
levels. In a study of some 92 patients suffering from this emerging syndrome,
eight developed a full-blown demyelinating Central Nervous System disorder
(i.e., multiple sclerosis) [Authier FJ, Cherin P, et al. Central nervous system
disease in patients with macrophagic myofasciitis. Brain 2001;124:974–83]. This
included sensory and motor symptoms, visual loss, bladder dysfunction,
cerebellar signs (loss of balance and coordination) and cognitive (thinking)
and behavioral disorders. Dr. Gherardi, the French physician who first
described the condition in 1998, has collected over 200 proven cases. One third
of these developed an autoimmune disease such as multiple sclerosis. Of
critical importance is his finding that even in the absence of obvious
autoimmune disease there is evidence of chronic immune stimulation caused by
the injected aluminum, known to be a very powerful immune adjuvant. The reason
this is so important is that there is overwhelming evidence that chronic immune
activation in the brain (activation of microglial cells in the brain) is a
major cause of damage in numerous degenerative brain disorders, from multiple
sclerosis to the classic neurodegenerative diseases (Alzheimer’s disease,
Parkinson’s and ALS). In fact, I have presented evidence that chronic immune
activation of CNS microglia is a major cause of autism, attention deficit
disorder and Gulf War Syndrome. Dr. Gherardi emphasizes that once the aluminum
is injected into the muscle, the immune activation persists for years. In
addition, we must consider the effect of the aluminum that travels to the brain
itself. Numerous studies have shown harmful effects when aluminum accumulates
in the brain. A growing amount of evidence points to high brain aluminum levels
as a major contributor to Alzheimer’s disease and possibly Parkinson’s disease
and ALS (Lou Geherig’s disease). This may also explain the 10X increase in
Alzheimer’s disease in those receiving the flu vaccine 5 years in a row. (Dr.
Hugh Fudenberg, in press, Journal of Clinical Investigation). It is also
interesting to note that a recent study found that aluminum phosphate produced
a 3X elevation in blood levels of aluminum, as did aluminum hydroxide (Flarend
RE, Hem SL, et al. In vivo absorption of aluminum-containing vaccine adjuvants
using 26Al. Vaccine 1997 Aug.-Sept.;15:1314–8). Of course, in this conference,
our illustrious experts tell us that there is “no data showing an additive or
synergistic effect between mercury and aluminum.” Dr. Rapin expressed her
concern over public opinion when this information eventually gets out. She says
(page 197), they are going to be captured by the public and we had better make
sure that “(a) we counsel them carefully and (b) that we pursue this because of
the very important public health and public implications of the data.” Dr.
Johnson adds, “the stakes are very high...” From this, how can one conclude
anything other than the fact

that at least these scientists were extremely concerned by what was discovered
by this study examining the Vaccine Safety Datalink material? They were
obviously terrified that the information would leak out to the public. Stamped
in bold letters at the top of each page of the study were the words: “DO NOT
COPY OR RELEASE” and “CONFIDENTIAL”. This is not the wording one would expect
on a clinical study of vaccine safety; rather you would expect it on topsecret
NSA or CIA files. Why was this information being kept secret? The answer is
obvious—it might endanger the vaccine program and indict the federal regulatory
agencies for ignoring this danger for so many years. Our society is littered
with millions of children who have been harmed in one degree or another by this
vaccine policy. In addition, let us not forget the millions of parents who have
had to watch helplessly as their children have been destroyed by this
devastating vaccine program. Dr. Bernier on page 198 says, “the negative
findings need to be pinned down and published.” Why was he so insistent that
the “negative findings” be published? Because he said, “other less responsible
parties will treat this as a signal.” By that he means, a signal of a problem
with Thimerosal-containing vaccines. From this, I assume he wants a paper that
says only that nothing was found by the study. As we shall see, he gets his
wish. In addition, on page 198, Dr. Rapin notes that a study in California
found a 300X increase in autism following the introduction of certain vaccines.
She quickly attributes this to better physician recognition. Two things are
critical to note at this point. She makes this assertion on better physician
recognition without any data at all, just her wishful thinking. If someone
pointing out the dangers of vaccines were to do that, she would scream “junk
science”. Second, Dr. Weil on page 207, attacks this reasoning when he says,
“the number of dose related relationships are linear and statistically
significant. You can play with this all you want. They are linear. They are
statistically significant.” In other words, how can you argue with results that
show a strong dose/response relationship between the dose of mercury and
neurodevelopmental outcomes? The higher the mercury levels in the children the
greater the number of neurological problems. He continues by saying that the
increase in neurobehavioral problems is probably real. He tells them that he
works in a school system with special education programs and “I have to say the
number of kids getting help in special education is growing nationally and
state by state at a rate not seen before. So there is some kind of increase. We
can argue about what it is due to.” (page 207) Dr. Johnson seems to be
impressed by the findings as well. He says on page 199, “This association leads
me to favor a recommendation that infants up to two years old not be immunized
with Thimerosal-containing vaccines if suitable alternative preparations are
available.” Incredibly, he quickly adds, “I do not believe the diagnosis
justifies compensation in the Vaccine Compensation Program at this point.” It
is interesting to note that one of our experts in attendance is Dr. Vito
Caserta, the Chief Officer for the Vaccine Injury Compensation Program. At this
point Dr. Johnson tells the group of his concerns for his own grandchild. He
says, (page 200) “Forgive this personal comment, but I got called out at eight
o’clock for an emergency call and my daughter-in-law delivered a son by
C-section. Our first male in the line of the next generation and I do not want
that grandson to get a Thimerosal-containing vaccine until we know better what
is going on. It will probably take a long time. In the meantime, and I know
there are probably implications for this internationally, but in the meanwhile
I think I want that grandson to only be given Thimerosal-free vaccines.” So, we
have a scientist sitting on this panel which will eventually make policy
concerning all of the children in this country, as well as other countries, who
is terrified about his new grandson getting a Thimerosal-containing vaccine but
he is not concerned enough about your child to speak out and try to stop this
insanity. He allows a cover-up to take place after this meeting adjourns and
remains silent. It is also interesting to note that he feels the answers will
be a long time coming, but in the mean time, his grandson will be protected.
The American Academy of Pediatrics, The American Academy of Family Practice,
the AMA,

CDC and every other organization will endorse these vaccines and proclaim them to be safe as spring water, but
Dr. Johnson and some of the others will keep their silence. It is only during
the last day of the conference that we learn that most of the objections
concerning the positive relationship between Thimerosal-containing vaccines and
ADD and ADHD were bogus. For example, Dr. Rapin on page 200 notes that all
children in the study were below age 6 and that ADD and ADHD are very difficult
to diagnose in pre-schoolers. She also notes that some children were followed
for only a short period. Dr. Stein adds that in fact the average age for
diagnosis of ADHD was 4 years and 1 month, a very difficult diagnosis to make
with the guidelines, as published by the American Academy of Pediatrics,
limiting diagnosis to 6 to 12 year olds. Of course, he was implying that too
many were diagnosed as ADHD. Yet, a recent study found that the famous Denmark
study that led to the announcement by the Institute of Medicine that there was
no relationship between autism and the MMR vaccine, used the same tactic. They
cut off the age of follow-up at age six. It is known that many cases appear
after this age group, especially with ADD and ADHD. In fact, most learning
problems appear as the child is called on to handle more involved intellectual
material. Therefore, the chances are that they failed to diagnose a number of
cases by stopping the study too early. Several of the participants tried to
imply that autism was a genetic disorder and therefore could have nothing to do
with vaccines. Dr. Weil put that to rest with this comment, “We don’t see that
kind of genetic change in 30 years.” In other words, how can we suddenly see a
300% increase in a genetically related disorder over such a short period? It is
also known that there are two forms of autism, one that is apparent at birth
and one that develops later in childhood. The former has not changed in
incidence since statistics have been kept; the other is epidemic. One
interesting exchange, which involves two studies in children born to mothers
consuming high intakes of mercury-contaminated fish, ends up providing their
justification for the view that mercury is of no danger to children vaccinated
with vaccines containing Thimerosal. One study in the journal Neurotoxicology,
examined children living in the Republic of Seychelles. This study examined the
effect of prenatal exposure to mercury through the mother’s consumption of fish
high in methylmercury. A battery of developmental milestone tests were done and
no adverse effects were reported in the study done by Dr. Clarkson and
co-workers, the very same person in this conference. He never mentions that a
follow-up study of these same children did find a positive correlation between
methylmercury exposure and poor performance on a memory test. In a subsequent
study of children living on the Faroe Islands exposed to methylmercury,
researchers also found impairments of neurodevelopment. This experiment was
done by scientists from Japan. Throughout the remainder of this discussion, Dr.
Clarkson and others refer to these two studies. When they are reminded that the
Faroe study did find neurological injury to the children, they counter by
saying that this was prenatal exposure to mercury and not exposure following
birth as would be seen with vaccination. The idea being that prenatally the
brain is undergoing neural formation and development making it more vulnerable.
As I have mentioned, this rapid brain growth and development continues for two
years after birth and even at age 6 years the brain is only 80% formed. Dr.
Clarkson keeps referring to the Seychelles study which demonstrated that the
children reached normal neurodevelopmental milestones as shown by a number of
tests. Dr Weil points out on page 216 that this tells us little about these
children’s future brain function. He says, “I have taken a lot of histories of
kids who are in trouble in school. The history is that developmental milestones
were normal or advanced and they can’t read at second grade, they can’t write
at third grade, they can’t do math in the fourth grade and it has no
relationship as far as I can tell to the history we get of the developmental
milestones. So I think this is a very crude measure of neurodevelopment.”

In other words, both of these studies tell us nothing about the actual
development of these children’s brain function except that they reached the
most basic of milestones. To put this another way, your child may be able to
stack blocks, recognize shapes and have basic language skills, but later in
life she/he could be significantly impaired when it came to higher math, more
advanced language skills (comprehension) and ability to compete in a very
competitive intellectual environment, like college or advanced schooling. The
future of such children would be limited to the more mundane and intellectually
limited jobs. Postnatal brain development, that is from birth to age six or
seven, involves the fine tuning of synaptic connections, dendritic development
and pathway refinement, all of which prepare the brain for more complex
thinking. These brain elements are very sensitive to toxins and excessive
immune stimulation during this period. This fact is never mentioned at the
conference. In addition, it must be remembered that the children in these two
studies were exposed only to methylmercury and not the combined neurotoxic
effect of mercury, aluminum and excessive and chronic activation of the brain’s
immune system (microgia). This is what makes it so incredible, that several of
these “vaccinologists” and so-called experts would express doubt about the
“biological plausibility” of Thimerosal or any vaccine component causing
neurodevelopmental problems. The medical literature is exploding with such
studies. The biological plausibility is very powerful. Mercury, for example,
even in low concentrations, is known to impair energy production by
mitochondrial enzymes. The brain has one of the highest metabolic rates of any
organ and impairment of its energy supply, especially during development, can
have devastating consequences. In addition, mercury, even in lower
concentrations, is known to damage DNA and impair DNA repair enzymes, which
again plays a vital role in brain development. Mercury is known to impair
neurotubule stability, even in very low concentrations. Neurotubules are
absolutely essential to normal brain cell function. Mercury activates
microglial cells, which increases excitotoxicity and brain free radical
production as well as lipid peroxidation, central mechanisms in brain injury.
In addition, even in doses below that which can cause obvious cell injury,
mercury impairs the glutamate transport system, which in turn triggers
excitotoxicity, a central mechanism in autism and other neurological disorders.
Ironically, aluminum also paralyzes this system. On page 228, we see another
admission that the government has had no interest in demonstrating the safety
of Thimerosal-containing vaccines despite over 2000 articles showing harmful
effects of mercury. Here we see a reference to the fact that the FDA “has a
wonderful facility in Arkansas with hundreds of thousands of animals” available
for any study needed to supply these answers on safety. The big question to be
asked is – So, why has the government ignored the need for research to answer
these questions concerning Thimerosal safety? You will recall in the beginning
the participants of this conference complained that there were just so few
studies or no studies concerning this “problem”. Again, on page 229 Dr, Brent
rails about the lawsuit problem. He tells the others that he has been involved
in three lawsuits related to vaccine injuries leading to birth defects and
concluded, “If you want to see junk science, look at those cases...” He then
complains about the type of scientists testifying in these cases. He adds, “But
the fact is those scientist are out there in the United States.” In essence, he
labels anyone who opposes the “official policy” on vaccines as a junk
scientists. We have seen in the discussion who the “junk scientists” really
are. Knowing that what they have found can cause them a great deal of problems
he adds, “The medical/legal findings in this study, causal or not, are
horrendous.... If an allegation was made that a child’s neurobehavioral
findings were caused by Thimerosal-containing vaccines, you could readily find
a junk scientist who will support the claim with a reasonable degree of
certainty.” On page 229 he then admits that they are in a bad position because
they have no data for their defense. Now, who are the junk scientists?

Is a “real scientist” one who has no data, just wishful thinking and a “feeling” that everything will be all right?
Are real scientists the ones who omit recognized experts on the problem in
question during a conference because it might endanger the “program”? Are they
the ones who make statements that they don’t want their grandson to get
Thimerosal-containing vaccines until the problem is worked out, but then tell
millions of parents that the vaccines are perfectly safe for their children and
grandchildren? Dr. Meyers on page 231 put it this way, “My own concern, and a
couple of you said it, there is an association between vaccines and outcomes
that worries both parents and pediatricians.” He sites other possible
connections to vaccine-related neurobehavioral and neurodevelopmental problems
including the number of vaccines being given, the types of antigens being used,
and other vaccine additives. Dr. Caserta tells the group that he attended the
aluminum conference the previous year and learned that metals could often act
differently in biological systems when existing as an ion. This is interesting
in the face of the finding that fluoride when combined to aluminum forms a
compound that can destroy numerous hippocampal neurons at a concentration of
0.5 ppm in drinking water. It seems that aluminum readily combines with
fluoride to form this toxic compound. With over 60% of communities having
fluoridated drinking water this becomes a major concern. It has also been
learned that fluoroaluminum compounds mimic the phosphate and can activate
G-proteins. Gproteins play a major role in numerous biological systems,
including endocrine, neurotransmitters, and as cellular second messengers. Some
of the glutamate receptors are operated by a G- protein mechanism. Over the
next ten to fifteen pages, they discuss how to control this information so that
it will not get out and if it does how to control the damage. On page 248 Dr.
Clements has this to say: “But there is now the point at which the research
results have to be handled, and even if this committee decides that there is no
association and that information gets out, the work has been done and through
the freedom of information that will be taken by others and will be used in
other ways beyond the control of this group. And I am very concerned about that
as I suspect that it is already too late to do anything regardless of any
professional body and what they say.” In other words, he wants this information
kept not only from the public but also from other scientists and pediatricians
until they can be properly counseled. In the next statement he spills the beans
as to why he is determined that no outsider get hold of this damaging
information. He says, “My mandate as I sit here in this group is to make sure
at the end of the day that 100,000,000 are immunized with DTP, Hepatitis B and
if possible Hib, this year, next year, and for many years to come, and that
will have to be with Thimerosal-containing vaccines unless a miracle occurs and
an alternative is found quickly and is tried and found to be safe.” This is one
of the most shocking statements I have ever heard. In essence, he is saying, I
don’t care if the vaccines are found to be harmful and destroying the
development of children’s brains, these vaccines will be given now and forever.
His only concern, by his own admission, is to protect the vaccine program even
if it is not safe. Dr. Brent refers to this as an “eloquent statement.” On page
253, we again see that these scientists have a double standard when it comes to
their children and grandchildren. Dr. Rapin raises the point about a loss of an
IQ point caused by Thimerosal exposure. She says, “Can we measure the IQ that
accurately, that this one little point is relevant?” Then she answers her own
question by saying, “Even in my grandchildren, one IQ point I am going to fight
about.” Yet, they are saying in unison, in essence—“To hell with your
children”—to the rest of America. It is also interesting that they bring up the
history of lead as a neurobehavioral toxin. Dr. Weil noted that the
neurotoxicologists and regulatory agencies have lowered the acceptable level
from 10 to 5μg. In fact, some feel that even lower levels are neurotoxic to the
developing brain. Before the toxicologists began to look at lead as a brain

toxin in children most “experts” assumed it was not toxic even at very high
levels. Again, it shows that “experts” can be wrong and it is the public who
pays the price. Dr. Chen on page 256 expresses his concern about this
information reaching the public. He remarks, “We have been privileged so far
that given the sensitivity of information, we have been able to manage to keep
it out of, let’s say, less responsible hands...” Dr. Bernier agrees and notes,
“This information has been held fairly tightly.” Later he calls it “embargoed
information” and “very highly protected information.” That they knew the
implications of what they had discovered was illustrated by Dr. Chen’s
statement on page 258. He says, “I think overall there was this aura that we
were engaged in something as important as anything else we have ever done. So I
think that this was another element to this that made this a special meeting.”
You may remember, Dr. Weil emphasized that the data analysis left no doubt that
there was a strong correlation between neurodevelopmental problems and exposure
to Thimerosal-containing vaccines. So if they understood the importance of this
finding and this was the most important thing they have ever dealt with, why
was this being kept from the public? In fact, it gets even worse. Just so you
will not doubt my statement that this audience of experts was not objective, I
give you the words of Dr. Walter Orenstein, Director of the National
Immunization Program at the CDC, on page 259. He tells the group, “I have seen
him (Verstraeten) in audience after audience deal with exceedingly skeptical
individuals...” “Exceedingly skeptical individuals” does that sound like
objective scientists who wanted to look at the data with a clear mind, or were
they scientists who were convinced before the meeting was held that there was
no danger to children from Thimerosal or any other vaccine component? In one of
the closing remarks (page 257) Dr. Bernier says, “the other thing I was struck
by was the science,” meaning the science expressed by the attendees of the
meeting. Then Dr, Orenstein adds, “I would also like to thank Roger Bernier who
pulled off this meeting in rather short notice...” Here is a meeting that has
been called one of the most important they have ever dealt with and we learn
that it was “pulled off” on short notice. In addition, we were told that the
results of this meeting would lead to eventual vaccine policy. He then has the
nerve to add: “In a sense this meeting addresses some of the concerns we had
last summer when we were trying to make policy in the absence of a careful
scientific review. I think this time we have gotten it straight.” Well, I hate
to be the one to break the news, but he didn’t get it straight. There was
little or no science in this meeting; rather it was composed of a lot of
haggling and nit picking over epidemiological methodology and statistical
minutia in an effort to discredit the data, all without success. In fact, the
so-called mercury experts admitted they had to do some quick homework to
refresh their memories and learn something about the subject. Conclusions This
top secret meeting was held to discuss a study done by Dr. Thomas Verstraeten
and his co-workers using Vaccine Safety Datalink data as a project
collaboration between the CDC’s National Immunization Program (NIP) and four
HMOs. The study examined the records of 110,000 children. Within the limits of
the data, they did a very thorough study and found the following: 1. Exposure
to Thimerosal-containing vaccines at one month was associated significantly
with the misery and unhappiness disorder that was dose related. That is, the
higher the child’s exposure to Thimerosal the higher the incidence of the
disorder. This disorder is characterized by a baby that cries uncontrollably
and is fretful more so than that seen in normal babies. 2. A nearly significant
increased risk of ADD with 12.5μg exposure at one month.

3. With exposure at 3 months, they found an increasing risk of neurodevelopmental disorders, including speech
disorders, with increasing exposure to Thimerosal. This was statistically
significant. It is important to remember that the control group was not
children without Thimerosal exposure but, rather, those at 12.5μg exposure.
This means that there is a significant likelihood that even more
neurodevelopmental problems would have been seen had they used a real control
population. No one disagreed that these findings were significant and
troubling. Yet, when the final study was published in the journal Pediatrics,
Dr. Verstraeten and co-workers reported that no consistent associations were
found between Thimerosal-containing vaccine exposure and neurodevelopmental
problems. In addition, he lists himself as an employee of the CDC, not
disclosing the fact that at the time the article was accepted, he worked for
GlaxoSmithKline, a vaccine manufacturing company. So how did they do this bit
of prestidigitation? They simply added another HMO to the data: the Harvard
Pilgrimage. (Additionally there were other manipulations, e.g., altering
inclusion criteria, discarding children receiving the highest total dose,
splitting children into separate groups, using only one HMO’s data in some
cases, expressing effects ratios in terms of per dose of mercury.) Congressman
Dave Weldon noted in his letter to the CDC Director that this HMO had been in
receivership by the state of Massachusetts because its records were in
shambles. Yet, this study was able to make the embarrassing data from Dr.
Verstraeten’s previous study disappear. Attempts by Congressman Weldon to force
the CDC to release the data to an independent researcher, Dr. Mark Geier, a
researcher with impeccable credentials and widely published in peer-reviewed
journals, have failed and the CDC now claims that the original data-sets
Verstraeten et al. used have been “lost”. It is obvious that a massive cover-up
is in progress, as we have seen with so many other scandals, such as fluoride,
food-based excitotoxins, pesticides, aluminum, and now vaccines. I would
caution those critical of the present vaccine policy not to put all their eggs
in one basket, that is, with Thimerosal as being the main culprit. There is no
question that it plays a significant role, but there are other factors that are
also critical, including aluminum, fluoroaluminum complexes, and chronic immune
activation of brain microglia. I believe that repeated, closely spaced,
sequential vaccinations given during the most active period of brain
development is the major cause of autism. In fact, excessive, chronic
microglial activation can explain many of the effects of excessive vaccine
exposure as I point out in two recently published articles. One property of
both aluminum and mercury is microglial activation. With chronic microglial
activation, large concentrations of excitotoxins are released as well as
neurotoxic cytokines. These have been shown to destroy synaptic connections,
dendrites and cause abnormal pathway development in the developing brain as
well as in the adult brain. In essence, too many vaccines are being given to
children during the brain’s most rapid growth period. Known toxic metals are
being used in vaccines, interfering with brain metabolism and antioxidant
enzymes, damaging DNA and DNA repair enzymes and triggering excitotoxicity.
Removing the mercury will help but will not solve the problem because
overactivation of the brain’s immune system will cause varying degrees of
neurological damage to the highly-vulnerable developing brain. Full Report With
References: www.vacinfo.org/man1714_1726.pdf

DNA Repair Amsterdam • January 2009

DNA Repair Modulates The Vulnerability Of The Developing Brain To Alkylating
Agents Author Information G.E. Kisby,*,1 A. Olivas,1 T. Park,1 M. Churchwell,2
D. Doerge,2 L. D. Samson,3 S.L. Gerson,4 and M.S. Turker1 1. Center for
Research on Occupational and Environmental Toxicology (CROET) Oregon Health
Sciences University, Portland, OR 97201 2. NCTR, Jefferson, AR 3. Biological
Engineering Division, Center for Environmental Health Sciences Massachusetts
Institute of Technology, Cambridge, MA 02139 4. Case Western Reserve
University, Case Comprehensive Cancer Center 10900 Euclid Avenue, Cleveland, OH
44106 Abstract Neurons of the developing brain are especially vulnerable to
environmental agents that damage DNA (i.e., genotoxicants), but the mechanism
is poorly understood. The focus of the present study is to demonstrate that DNA
damage plays a key role in disrupting neurodevelopment. To examine this
hypothesis, we compared the cytotoxic and DNA damaging properties of the
methylating agents methylazoxymethanol (MAM) and dimethyl sulfate (DMS) and the
mono- and bifunctional alkylating agents chloroethylamine (CEA) and nitrogen
mustard (HN2), in granule cell neurons derived from the cerebellum of neonatal
wild type mice and three transgenic DNA repair strains. Wild type cerebellar
neurons were significantly more sensitive to the alkylating agents DMS and HN2
than neuronal cultures treated with MAM or the half-mustard CEA. Parallel
studies with neuronal cultures from mice deficient in alkylguanine DNA
glycosylase (Aag-/-) or O6-methylguanine methyltransferase (Mgmt-/-), revealed
significant differences in the sensitivity of neurons to all four
genotoxicants. Mgmt-/- neurons were more sensitive to MAM and HN2 than the
other genotoxicants and wild type neurons treated with either alkylating agent.
In contrast, Aag/- neurons were for the most part significantly less sensitive
than wild type or Mgmt-/- neurons to MAM and HN2. Aag-/- neurons were also
significantly less sensitive than wild type neurons treated with either DMS or
CEA. Granule cell development and motor function were also more severely
disturbed by MAM and HN2 in Mgmt-/- mice than in comparably treated wild type
mice. In contrast, cerebellar development and motor function were well
preserved in MAM treated Aag-/- or MGMT overexpressing (MgmtTg+) mice, even as
compared with wild type mice suggesting that AAG protein increases MAM
toxicity, whereas MGMT protein decreases toxicity. Surprisingly, neuronal
development and motor function were severely disturbed in MgmtTg+ mice treated
with HN2. Collectively, these in vitro and in vivo studies demonstrate that the
type of DNA lesion and the efficiency of DNA repair are two important factors
that determine the vulnerability of the developing brain to long-term injury by
a genotoxicant. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692311/

“Neurons of the developing brain are especially vulnerable to environmental
agents that damage DNA (i.e., genotoxicants), but the mechanism is poorly
understood. Collectively, these in vitro and in vivo studies demonstrate that
the type of DNA lesion and the efficiency of DNA repair are two important
factors that determine the vulnerability of the developing brain to long-term
injury by a genotoxicant.”

“Of these 1162 cases, 1105 were considered to be related to the vaccination ...”
European Journal of Pediatrics • January 2009

Discolored leg syndrome after vaccination—descriptive epidemiology Jeanet M.
Kemmeren , Patricia E. Vermeer-de Bondt, Nicoline A. T. van der Maas Abstract
Discoloration of the leg following vaccination is a relatively unknown entity.
We carried out a study of discolored leg syndrome (DLS) during a 10-year
consecutive period with the objective of characterizing DLS in infants
following vaccination received in the Dutch National Vaccination Program as
well as its occurrence and association with different vaccines. Discolored leg
syndrome was defined as an even or patchy red, blue or purple discoloration of
the leg(s) and/or leg petechiae with or without swelling. All reports of
adverse events following immunization that were made to the passive
surveillance system between 1994 and 2003 were included—a total of 1162
identified cases. Red, blue, purple discoloration and isolated petechiae were
reported in 39, 19, 27 and 14% of these cases, respectively. Of these 1162
cases, 1105 were considered to be related to the vaccination, based on a
predefined risk window with symptom onset after vaccination (48 h for
discolorations and 2 weeks for petechiae). Of the 1105 cases, about 50%
occurred after DTP-IPV+Hib1 vaccinations, and 30% occurred after DTP-IPV+Hib2
vaccinations. Discolored leg syndrome was frequently accompanied by fierce
crying (78%). The median time interval between vaccination and the occurrence
of DLS was 3.8 ± 46.7 h, and the median duration was short (2 ± 61.7 h).
Advancing the vaccination schedule from 3 to 2 months of age caused a small
increase in DLS. Discolored leg syndrome manifested mainly after the first
and/or second vaccination. In addition to dose, the occurrence of DLS may be
slightly age-dependent and self-limiting. The pathophysiology is unknown but
may be the result of a vasomotor reaction. Future studies should elucidate the
recurrence rate, identify risk factors and assess late outcomes.
http://link.springer.com/article/10.1007%2Fs00431-008-0707-0

“... Triton X-100 (TX)-induced apoptosis.”
Biochemical And Biophysical Research Communications • January 2009

Differential roles for Bak in Triton X-100and deoxycholate-induced apoptosis
Author information Sawai H1, Domae N. Department of Internal Medicine, Osaka
Dental University 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan
Abstract We recently reported that Bax activation occurs downstream of caspase
activation in Triton X-100 (TX)-induced apoptosis. Here, Bak was found to be
activated in TX-induced apoptosis. Although z-VAD-fmk completely suppressed Bax
activation, it only partially attenuated TX-induced Bak activation. Moreover,
activation of both Bak and Bax was detected in apoptosis induced by
deoxycholate, a physiological detergent in bile. z-VAD-fmk completely
suppressed deoxycholate-induced Bak as well as Bax activation. Furthermore, Bak
siRNA attenuated TX- but not deoxycholate-induced caspase activation. These
results suggest that Bak activation may occur upstream of caspase activation in
TX- but not deoxycholate-induced apoptosis and that the mechanism of TX-induced
apoptosis may differ from that of deoxycholate-induced apoptosis at least with
regard to the role for Bak. http://www.ncbi.nlm.nih.gov/pubmed/19041633

Journal Of Neuroimmunology • February 2009

Elevated immune response in the brain of autistic patients Author information
Li X1, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M.
Abstract This study determined immune activities in the brain of ASD patients
and matched normal subjects by examining cytokines in the brain tissue. Our
results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1
cytokine (IFN-gamma) and chemokine (IL8) were significantly increased in the
brains of ASD patients compared with the controls. However the Th2 cytokines
(IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was
also significantly increased in ASD patients. Conclusion ASD patients displayed
an increased innate and adaptive immune response through the Th1 pathway,
suggesting that localized brain inflammation and autoimmune disorder may be
involved in the pathogenesis of ASD.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770268/

“ASD patients displayed an increased innate and adaptive immune response
through the Th1 pathway, suggesting that localized brain inflammation and
autoimmune disorder may be involved in the pathogenesis of ASD.”

“... these occurrences support an association between
receipt of aluminium adjuvant and sterile abscesses in susceptible patients.”
BMJ Case Reports • March 2009 Findings that shed new light on the possible
pathogenesis of a disease or an adverse effect

Recurrent sterile abscesses following aluminium adjuvant-containing vaccines
Author Information Nicola P Klein1, Kathryn M Edwards3, Robert C Sparks3,
Cornelia L Dekker2, on behalf of the Clinical Immunization Safety Assessment
(CISA) Network 1. Kaiser PermanenteVaccine Study Center, 16th Floor, One Kaiser
Plaza, Oakland, California 94612, USA 2. Stanford University School of
Medicine, Division of Pediatric Infectious Diseases, 300 Pasteur Drive,
Stanford, California, USA 3. Vanderbilt University Medical Center, Vanderbilt
Vaccine Research Program, Department of Pediatrics 1211 Medical Center Drive,
Nashville, Tennessee 37232, USA

Nicola Klein, Nicola.Klein@kp.org Summary Abscess formation following
immunisation is a previously reported complication, generally associated with
microbial contamination of the vaccine. Less commonly, such abscesses have been
sterile. Here we describe two children evaluated in the Center for Disease
Control and Prevention (CDC)-funded Clinical Immunization Safety Assessment
(CISA) network who developed recurrent sterile abscesses after administration
of vaccines containing aluminium adjuvant, either individually or in
combination. Although the abscesses healed without sequelae, these occurrences
support an association between receipt of aluminium adjuvant and sterile
abscesses in susceptible patients. For patients with similar symptoms,
clinicians may wish to choose a vaccine formulation containing the least amount
of aluminium adjuvant.
http://casereports.bmj.com/content/2009/bcr.09.2008.0951.long

Mutation Research • March 2009

Formaldehyde exposure and leukemia: a new meta-analysis and potential
mechanisms Author information Zhang L1, Steinmaus C, Eastmond DA, Xin XK, Smith
MT. School of Public Health 50 University Hall University of California
Berkeley, CA 94720-7356, USA luoping@berkeley.edu Abstract Formaldehyde is an
economically important chemical, to which more than 2 million U.S. workers are
occupationally exposed. Substantially more people are exposed to formaldehyde
environmentally, as it is generated by automobile engines, is a component of
tobacco smoke and is released from household products, including furniture,
particleboard, plywood, and carpeting. The International Agency for Research on
Cancer (IARC) recently classified formaldehyde as a human carcinogen that
causes nasopharyngeal cancer and also concluded that there is “strong but not
sufficient evidence for a causal association between leukemia and occupational
exposure to formaldehyde”. Here, we review the epidemiological studies
published to date on formaldehyde-exposed workers and professionals in relation
to lymphohematopoietic malignances. In a new meta-analysis of these studies,
focusing on occupations known to have high formaldehyde exposure, we show that
summary relative risks (RRs) were elevated in 15 studies of leukemia (RR=1.54;
confidence interval (CI), 1.182.00) with the highest relative risks seen in the
six studies of myeloid leukemia (RR=1.90; 95% CI, 1.31-2.76). The biological
plausibility of this observed association is discussed and potential mechanisms
proposed. We hypothesize that formaldehyde may act on bone marrow directly or,
alternatively, may cause leukemia by damaging the hematopoietic stem or early
progenitor cells that are located in the circulating blood or nasal passages,
which then travel to the bone marrow and become leukemic stem cells. To test
these hypotheses, we recommend that future studies apply biomarkers validated
for other chemical leukemogens to the study of formaldehyde.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18674636

“formaldehyde may act on bone marrow directly or, alternatively, may cause
leukemia by damaging the hematopoietic stem or early progenitor cells that are
located in the circulating blood or nasal passages, which then travel to the
bone marrow and become leukemic stem cells.”

Journal Of Neurochemistry • March 2009

Vaccination alone or in combination with pyridostigmine promotes and prolongs
activation of stress-activated kinases induced by s tress in the mouse brain
Author information Wang D1, Perides G, Liu YF. 1Department of Pharmacology
Boston University School of Medicine Massachusetts 02118, USA Abstract Gulf war
illnesses (GWI) are currently affecting thousands of veterans. To date, the
molecular mechanisms underlying the pathogenesis of these illnesses remain
unknown. During Gulf war I, military personnel were exposed to multiple
stressors, one or more vaccines, pyridostigmine (PY), and other chemicals. In
our previous studies, we found that stress induces activation of mitogen
activated protein-kinase kinase 4 (MKK4) and c-Jun-N-terminal kinase (JNK) in
the mouse brain (Liu et al. 2004). Our working hypothesis is that stress,
vaccination, and PY may synergistically induce activation of MKK4 and JNK in
the brain, leading to over-activation of these kinases and neurological
injuries. To test our hypothesis, we examined the effect of keyhole limpet
hemocyanin (KLH) immunization alone or in combination with PY on activation of
MKK4 and JNK induced by stress. We found that KLH immunization alone had a
small effect on MKK4 or JNK activity but it significantly enhanced and
prolonged activation of these kinases induced by stress, from a few hours to
several days. Additionally, KLH immunization caused activation of p38MAPK. PY
treatment further enhanced and prolonged activation of these kinases induced by
stress in combination with KLH immunization and triggered activation of
caspase-3. Our current studies suggest that stress, vaccination, and PY may
synergistically act on multiple stress-activated kinases in the brain to cause
neurological impairments in GWI.
http://www.ncbi.nlm.nih.gov/pubmed/?term=15857404 Full Report:
http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2005.03093.x/full

“Gulf war illnesses (GWI) are currently affecting thousands of veterans. Our
current studies suggest that stress, vaccination, and pyridostigmine may
synergistically act on multiple stress-activated kinases in the brain to cause
neurological impairments in Gulf war illnesses.”

Deutsches Arzteblatt International • April 2009

Correspondence (letter to the editor): Long Term Side Effects Due to
Vaccination And Pharmacovigilance Maurice Pich,* Arno Köster,* and Andreas
Klement, Dr. Institut für Allgemeinmedizin Martin-Luther-Universität
Halle-Wittenberg 06112 Halle/Saale, Germany We thank the authors for their
clear overview of vaccine sceptics’ common objections, which are helpful for
everyday clinical practice. Most vaccinations and vaccination advice in Germany
are given by general practitioners and pediatricians. Appropriate and
responsible advice includes providing information to those about to receive the
vaccine and their parents, about rare but possible side effects. These include
the possible occurrence of Guillain-Barré syndromes after flu vaccinations (1),
for example; the possible association between recombinant hepatitis B vaccine
and multiple sclerosis (2), which is still under discussion in current
publications; and the unexplained possible association of multiple vaccinations
with neurodegenerative disorders in connection with aluminum hydroxide, which
to date is the most common vaccine adjuvant in use (3). Long term side effects
due to vaccination can be detected to a sufficiently high quality standard only
by means of long term, active pharmacovigilance conducted through independent
and sufficiently equipped monitoring systems. To assess the long term safety of
vaccines, passive post-vaccination observation by notification of vaccination
complications by primary care physicians is not enough: possible causal
associations with developing disorders—for example, neurodegenerative
disorders—are difficult to state in individual cases years after the vaccine
was given. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689587/

“... the possible occurrence of Guillain-Barré syndromes after flu
vaccinations, for example; the possible association between recombinant
hepatitis B vaccine and multiple sclerosis, which is still under discussion in
current publications; and the unexplained possible association of multiple
vaccinations with neurodegenerative disorders in connection with aluminum
hydroxide, which to date is the most common vaccine adjuvant in use ...”

Journal Of Environmental Monitoring • May 2009

JEM spotlight: metal speciation related to neurotoxicity in humans Author
information Michalke B1, Halbach S, Nischwitz V. Helmholtz Zentrum München
Institute of Ecological Chemistry, 85764 Neuherberg, Germany
bernhard.michalke@helmholtz-muenchen.de Abstract Improved living conditions
have led to a steady increase in the life expectancy of humans in most
countries. However, this is accompanied by an increased probability of
suffering from neurodegenerative diseases like Alzheimer’s disease or
Parkinson’s disease. Unfortunately, the therapeutic possibilities for curing
these diseases are very limited up to now. Many studies indicate that a variety
of environmental factors contribute to the initiation and promotion of
neurodegenerative diseases. For example, the role of metal exposure and
disturbance of metal homeostasis in the brain is discussed in this respect.
However, most studies focus on the neurological and toxicological aspects but
not on a detailed characterisation of the species of the involved metals.
Therefore, this review summarizes the neurotoxic effects of selected metals on
humans and focuses on contributions from trace element speciation analysis with
relevance to neuroscientific research. In spite of the advance in
instrumentation and methodology of speciation analysis there are few
applications for matrices like cerebrospinal fluid which is due to limited
access to these samples and analytical challenges caused by matrix
interferences, low concentrations and limited stability of many trace element
species of interest. The most relevant neurotoxic metals aluminium, lead,
manganese and mercury are reviewed in detail while further metals like cadmium,
arsenic, bismuth and tin are briefly discussed. Current results indicate that
knowledge on trace element speciation can contribute to a better understanding
of the transport of metals across the neural barriers and potentially of their
role in diseased human brains. http://www.ncbi.nlm.nih.gov/pubmed/19436852

“The most relevant neurotoxic metals aluminium, lead, manganese and mercury are
reviewed in detail while further metals like cadmium, arsenic, bismuth and tin
are briefly discussed. Current results indicate that knowledge on trace element
speciation can contribute to a better understanding of the transport of metals
across the neural barriers and potentially of their role in diseased human
brains.”

American Journal of Epidemiology • May 2009

Re: Determinants Of The Incidence Of Childhood Asthma: A Two-Stage Case-Control
Study Author Information José G. Dórea Faculty of Health Sciences Universidade
de Brasilia 70919-970 Brasilia, Brazil dorea@rudah.com.br Abstract In a recent
article, Martel et al. (1) took into consideration 47 variables that could
influence children’s asthma incidence but missed one that has been
significantly researched—vaccines. The Quebec, Canada, children enrolled in the
study were born between 1990 and 2002. During this time, Canada underwent major
changes in types of vaccines and the calendar of immunization for infants and
children: Thimerosal was withdrawn from infants’ vaccines, some of the vaccines
were combined, some new vaccines were introduced, and still others underwent
changes in their starting date and subsequent calendar; this without counting
parental preference for administration of multiple shots at a single clinical
visit. Some vaccines can contain thimerosal, which is a recognized sensitizer
in children (2); additionally, a polymorphism in the glutathione S-transferase
gene can alter its metabolism in children. Indeed, glutathione Stransferase M1
deficiency was found to be significantly more frequent among patients who had
been sensitized to thimerosal (3). Thyssen et al. (4) speculated that the
decrease in allergy in the general population of Denmark could be due to
thimerosal’s no longer being used as a vaccine preservative in that country.
Although contact allergy due to thimerosal is not a contraindication for
receipt of vaccines, these reactions are expected to be fewer in the future
because of changes in current vaccine formulations (5). Fombonne et al. (6)
have described changes in vaccine formulations and schedules taking place in
Canada from 1985 to 2006. The measlesmumps-rubella vaccines were officially
incorporated in 1976 and were recommended for use at age 1 year in Quebec; as
of 1996, 2 doses of measles-mumps-rubella vaccine were being given at ages 12
and 18 months. A combined diphtheria-tetanus-pertussis vaccine was recommended
at ages 2, 4, 6, and 18 months and ages 4–6 years; this vaccine contained 50 μg
of thimerosal and was used from 1985 to 1987. In 1988, a Haemophilus influenzae
type b vaccine (which also contained thimerosal) was added to the schedule at
18 months of age. As of 1992,

the H. influenzae type b vaccines were also administered at ages 2, 4, 6, and
18 months. The poliomyelitis vaccine was administered separately at ages 2, 4,
and 18 months and ages 4–6 years from 1987 to 1995. With the exception of the
measles-mumps-rubella and poliomyelitis vaccines, all of the vaccines contained
50 μg of thimerosal. Estimated cumulative exposure to thimerosal was 200 μg by
age 2 years until 1988; it then increased to 250 μg by 1990. Therefore, as of
1992, cumulative exposure to thimerosal by age 2 years reached 400 μg (6).
Because of mass immunization against meningococcal disease (occurring in 1993),
there was additional exposure to thimerosal. Following Fombonne et al.’s (6)
reasoning, there could have been different cumulative thimerosal exposures of
300 μg in children born between March 1990 and December 1991 and 450 μg in
children born between January 1992 and September 1992. However, both the
poliomyelitis and H. influenzae type b vaccines were combined with the
diphtheria-pertussis (cellular)-tetanus vaccine in a thimerosal-free
formulation in 1996; this pentavaccine was administered at ages 2, 4, 6, and 18
months, with a poliomyelitis-pertussis (cellular)-tetanus booster
(thimerosal-free) being given at ages 4–6 years. In 1998, the cellular
pertussis vaccine was replaced by the acellular vaccine in the pentavaccine.
From 1996 onward, all immunizations were thimerosal-free. Nevertheless, there
is 1 additional challenge that has been overlooked (or is difficult to track)
by almost all epidemiologic studies that have addressed the issue of vaccines
and asthma: multiple applications of different vaccines at a single
immunization visit (7). A study carried out in Canada indicated a negative
association between delay in administration of the first dose of
diphtheria-pertussis-tetanus vaccine and the development of asthma; a greater
association was shown with delays in the first 3 doses (8). De Serres et al.
(9) also reported oculorespiratory syndrome as an adverse event that occurred
with influenza vaccines used in Canada (2000–2003).

http://aje.oxfordjournals.org/content/169/12/1532.long

“Thyssen et al. speculated that the decrease in allergy in the general
population of Denmark could be due to thimerosal’s no longer being used as a
vaccine preservative in that country.”

Archives Of Diseases In Childhood • Fetal & Neonatal Edition • July 2009

Toxic additives in medication for preterm infants Author information Whittaker
A1, Currie AE, Turner MA, Field DJ, Mulla H, Pandya HC. Department of Infection
Immunity & Inflammation, University of Leicester Robert Kilpatrick Clinical
Sciences Building Leicester Royal Infirmary, Leicester LE2 7LX, UK
hp28@le.ac.uk Abstract BACKGROUND Little is known about exposure of preterm
infants to excipients during routine clinical care. OBJECTIVE To document
excipient exposure in vulnerable preterm babies in a single centre, taking into
account chronic lung disease (CLD) as a marker of illness severity. DESIGN
Excipient exposure after treatment with eight oral liquid medications was
determined by retrospectively analysing the drug charts of infants admitted to
a neonatal unit. SETTING The Leicester Neonatal Service. PARTICIPANTS 38
infants born between June 2005 and July 2006 who were less than 30 weeks’
gestation and 1500 g in weight at birth and managed in Leicester to discharge.
RESULTS The 38 infants represented 53% of the eligible target group; 7/38
infants had CLD. During their in-patient stay, infants were exposed to over 20
excipients including ethanol and propylene glycol, chemicals associated with
neurotoxicity. Infants with CLD were exposed to higher concentrations of these
toxins. Infants were also exposed to high concentrations of sorbitol, with some
infants being exposed to concentrations in excess of recommended guidelines for
maximum exposure in adults. CONCLUSIONS Preterm infants are commonly exposed to
excipients, some of which are potentially toxic. Strategies aimed at reducing
excipient load in preterm infants are urgently required.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19158148

“Preterm infants are commonly exposed to excipients, some of which are
potentially toxic.”

North American Journal Of Medical Science • July 2009

What is regressive autism and why does it occur? Is it the consequence of
multi-systemic dysfunction affecting the elimination of heavy metals and the
ability to regulate neural temperature? Graham E. Ewing, Director Montague
Healthcare Mulberry House, 6 Vine Farm Close Cotgrave, Nottingham NG12 3TU,
United Kingdom Abstract There is a compelling argument that the occurrence of
regressive autism is attributable to genetic and chromosomal abnormalities,
arising from the overuse of vaccines, which subsequently affects the stability
and function of the autonomic nervous system and physiological systems. That
sense perception is linked to the autonomic nervous system and the function of
the physiological systems enables us to examine the significance of autistic
symptoms from a systemic perspective. Failure of the excretory system
influences elimination of heavy metals and facilitates their accumulation and
subsequent manifestation as neurotoxins: the long-term consequences of which
would lead to neurodegeneration, cognitive and developmental problems. It may
also influence regulation of neural hyperthermia. This article explores the
issues and concludes that sensory dysfunction and systemic failure, manifested
as autism, is the inevitable consequence arising from subtle DNA alteration and
consequently from the overuse of vaccines.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364648/

“This article explores the issues and concludes that sensory dysfunction and
systemic failure, manifested as autism, is the inevitable consequence arising
from subtle DNA alteration and consequently from the overuse of vaccines.”

Neuropediatrics • August 2009

Macrophagic myofasciitis plus (distinct types of muscular dystrophy) Author
information Müller HD1, Landeghem FK, Schmidt PF, Sommer C, Goebel HH.
Department of Neuropathology University Medical Center of the Johannes
Gutenberg University Mainz Mainz, Germany
mueller@neuropatho.klinik.uni-mainz.de Abstract Macrophagic myofasciitis (MMF)
is a well-known lesion following vaccination with aluminium-containing
vaccines. It has abundantly been reported in adults and several times in
children, often in single patients or in rather small cohorts. Only few of
these published reports on children have shown distinct myopathology of another
neuromuscular disease except for MMF. Indications for biopsy often were
nondescript clinical features in children, such as hypotonia or delay in motor
development but, apparently, never that of suspected MMF. Thus, in previous
reports as well as in our two patients, encountering MMF in the biopsied tissue
specimens was coincidental. Our two unrelated patients with MMF also had two
separate types of muscular dystrophy, a merosinopathy and dystrophinopathy,
showing a combination of myopathologically well-defined neuromuscular diseases,
muscular dystrophies and MMF. Detecting such a combination of two separate
conditions may, in the future, be rare when non-invasive techniques, e. g.,
genetic, will have replaced muscle biopsy in ascertaining hereditary
neuromuscular conditions, especially in children.
http://www.ncbi.nlm.nih.gov/pubmed/20135575

“Macrophagic myofasciitis (MMF) is a well-known lesion following vaccination
with aluminium-containing vaccines. It has abundantly been reported in adults
and several times in children, often in single patients or in rather small
cohorts. Our two unrelated patients with MMF also had two separate types of
muscular dystrophy, a merosinopathy and dystrophinopathy, showing a combination
of myopathologically well-defined neuromuscular diseases, muscular dystrophies
and MMF.”

Emerging Infectious Diseases • August 2009

Bordetella pertussis strains with increased toxin production associated with
pertussis resurgence Author information Mooi FR1, van Loo IH, van Gent M, He Q,
Bart MJ, Heuvelman KJ, de Greeff SC, Diavatopoulos D, Teunis P, Nagelkerke N,
Mertsola J. National Institute for Public Health and the Environment Bilthoven,
the Netherlands frits.mooi@rivm.nl Abstract Before childhood vaccination was
introduced in the 1940s, pertussis was a major cause of infant death worldwide.
Widespread vaccination of children succeeded in reducing illness and death. In
the 1990s, a resurgence of pertussis was observed in a number of countries with
highly vaccinated populations, and pertussis has become the most prevalent
vaccine-preventable disease in industrialized countries. We present evidence
that in the Netherlands the dramatic increase in pertussis is temporally
associated with the emergence of Bordetella pertussis strains carrying a novel
allele for the pertussis toxin promoter, which confers increased pertussis
toxin (Ptx) production. Epidemiologic data suggest that these strains are more
virulent in humans. We discuss changes in the ecology of B. pertussis that may
have driven this adaptation. Our results underline the importance of Ptx in
transmission, suggest that vaccination may select for increased virulence, and
indicate ways to control pertussis more effectively.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19751581

“We present evidence that in the Netherlands the dramatic increase in pertussis
is temporally associated with the emergence of Bordetella pertussis strains
carrying a novel allele for the pertussis toxin promoter, which confers
increased pertussis toxin (Ptx) production. Epidemiologic data suggest that
these strains are more virulent in humans.”

Acta Paediatrica • August 2009

Breastfeeding is an essential complement to vaccination Author information
Dòrea JG. Department of Nutrition Universidade de Brasília 70919-970 Brasília,
DF, Brazil dorea@rudah.com.br Abstract AIM: This article explores the role of
breastfeeding in different aspects of vaccination in the first 6 months when
infants are still developing: (1) pain management; (2) immunomodulation of
infants’ vaccine responses; (3) metabolism of thimerosal. METHODS: Major
databases were searched for studies that addressed outcomes of related issues.
RESULTS: Studies reveal that breastfeeding can: (1) help mothers and infants to
cope with the stressful situations that accompany parenteral vaccines; (2)
improve response to vaccines in the still maturing immunologic and
enterohepatic systems of infants; (3) influence physiologic parameters that can
change metabolism of ethylmercury derived from some vaccines. CONCLUSION:
Health promotion that supports vaccinations should also emphasize early
initiation and maintenance of exclusive breastfeeding up until 6 months for
maximum protection of the infants with a possible beneficial effect on the
vaccine response. Paediatric professionals should inform mothers of the proven
benefits of breastfeeding and its importance in complementing vaccination and
lowering stress and the risk of untoward reactions on susceptible infants.
http://www.ncbi.nlm.nih.gov/pubmed/19594471

“Health promotion that supports vaccinations should also emphasize early
initiation and maintenance of exclusive breastfeeding up until 6 months for
maximum protection of the infants with a possible beneficial effect on the
vaccine response.”

“This study demonstrates
a significant positive association between the severity of autism and the
relative body burden of toxic metals.”

Journal Of Toxicology • August 2009

The Severity of Autism Is Associated with Toxic Metal Body Burden and Red Blood
Cell Glutathione Levels J. B. Adams,1,* M. Baral,2 E. Geis,3 J. Mitchell,1 J.
Ingram,3 A. Hensley,3 I. Zappia,3 S. Newmark,4 E. Gehn,3 R. A. Rubin,5 K.
Mitchell,3 J. Bradstreet,2, 6 and J. M. El-Dahr7 1. Division of Basic Medical
Sciences, Southwest College of Naturopathic Medicine, Tempe, AZ 85282, USA 2.
Department of Pediatric Medicine, Southwest College of Naturopathic Medicine,
Tempe, AZ 85282, USA 3. Autism Research Institute, San Diego, CA 92116-2599,
USA 4. Center for Integrative Pediatric Medicine, Tucson, AZ 85711, USA 5.
Department of Mathematics, Whittier College, Whittier, CA 90601-4413, USA 6.
International Child Development Resource Center, Phoenix, AZ, USA 7. Department
of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA

	
J. B. Adams: Email: ∼ude.usa@smada.mij Abstract This study investigated the

relationship of children’s autism symptoms with their toxic metal body burden
and red blood cell (RBC) glutathione levels. In children ages 3–8 years, the
severity of autism was assessed using four tools: ADOS, PDD-BI, ATEC, and SAS.
Toxic metal body burden was assessed by measuring urinary excretion of toxic
metals, both before and after oral dimercaptosuccinic acid (DMSA). Multiple
positive correlations were found between the severity of autism and the urinary
excretion of toxic metals. Variations in the severity of autism measurements
could be explained, in part, by regression analyses of urinary excretion of
toxic metals before and after DMSA and the level of RBC glutathione (adjusted
R2 of 0.22–0.45, P < .005 in all cases). This study demonstrates a significant
positive association between the severity of autism and the relative body
burden of toxic metals. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809421/

“... vaccination is depicted as playing an important role in Chronic Fatigue Syndrome onset.”
Annals Of The New York Academy Of Science • September 2009

Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause
or coincidence? Author information Ortega-Hernandez OD1, Shoenfeld Y.
Department of Internal Medicine B and Research for Autoimmune Diseases Sheba
Medical Center, Tel Hashomer, Israel Abstract Chronic fatigue syndrome (CFS) is
a heterogeneous syndrome of unknown etiology and physiopathology. CFS patients
complain about disabling fatigue, depression, difficulty with memory, and
concomitant skeletal and muscular pain. Interestingly enough, there is certain
overlap between CFS symptoms, autoimmune rheumatic disease, and infectious
diseases. Certain neuroendocrine-immune abnormalities have also been described,
and autoantibodies commonly described in some autoimmune diseases have been
found in CFS patients as well. An increasing number of autoantibodies, mainly
directed against other nuclear cell components, have been illustrated.
Likewise, an association between some infectious agents, antibody production,
and later CFS onset has been reported. Similarly, vaccination is depicted as
playing an important role in CFS onset. Recently, a case report pointed toward
a causal association between silicone breast linkage, hepatitis B virus
vaccination, and CFS onset in a previous healthy woman. Such findings suggest
that there is a likely deregulation of the immune system influenced by specific
agents (infections, vaccination, and products, such as silicone). Evidence
suggests that CFS is a complex disease in which several risk factors might
interact to cause its full expression. Thus, although different alterations
have been found in CFS patients, undoubtedly the main feature is central
nervous system involvement with immunological alterations. Therefore, a new
term neuro-psycho-immunology must be quoted. New studies based on this concept
are needed in order to investigate syndromes, such as CFS, in which
immunological alterations are thought to be associated with concomitant
psychological and health disturbances.
http://www.ncbi.nlm.nih.gov/pubmed/19758205

Lupus • November 2009

Transverse myelitis and vaccines: a multi-analysis Author information
Agmon-Levin N1, Kivity S, Szyper-Kravitz M, Shoenfeld Y. Center for Autoimmune
Diseases Sheba Medical Center Tel-Hashomer, Israel

“We have disclosed 37 reported cases of transverse myelitis associated with
different vaccines including those against hepatitis B virus,
measles-mumps-rubella, diphtheria-tetanus-pertussis and others, given to
infants, children and adults. Although vaccines harbor a major

Abstract Transverse myelitis is a rare clinical syndrome in which an
immune-mediated process causes neural injury to the spinal cord. The
pathogenesis of transverse myelitis is mostly of an autoimmune nature,
triggered by various environmental factors, including vaccination. Our aim here
was to search for and analyze reported cases of transverse myelitis following
vaccination. A systematic review of PubMed, EMBASE and DynaMed for all
English-language journals published between 1970 and 2009 was preformed,
utilizing the key words transverse myelitis, myelitis, vaccines,
post-vaccination, vaccination and autoimmunity. We have disclosed 37 reported
cases of transverse myelitis associated with different vaccines including those
against hepatitis B virus, measles-mumps-rubella, diphtheria-tetanus-pertussis
and others, given to infants, children and adults. In most of these reported
cases the temporal association was between several days and 3 months, although
a longer time frame of up to several years was also suggested. Although
vaccines harbor a major contribution to public health in the modern era, in
rare cases they may be associated with autoimmune phenomena such as transverse
myelitis. The associations of different vaccines with a single autoimmune
phenomenon allude to the idea that a common denominator of these vaccines, such
as an adjuvant, might trigger this syndrome.
http://www.ncbi.nlm.nih.gov/pubmed/19880568

contribution to public health in the modern era, in rare cases they may be
associated with autoimmune phenomena such as transverse myelitis. The
associations of different vaccines with a single autoimmune phenomenon allude
to the idea that a common denominator of these vaccines, such as an adjuvant,
might trigger this syndrome.”

Lupus • November 2009

Ten cases of systemic lupus erythematosus related to hepatitis B vaccine Author
information Agmon-Levin N1, Zafrir Y, Paz Z, Shilton T, Zandman-Goddard G,
Shoenfeld Y. Center for Autoimmune Diseases Sheba Medical Center, Tel-Hashomer,
Israel Abstract The objective of this article is to identify common and
atypical features of systemic lupus erythematosus diagnosed following hepatitis
B vaccination. We analyzed retrospectively the medical records of 10 systemic
lupus erythematosus patients from different centers, who developed the disease
following hepatitis B vaccination and determined the prevalence of different
manifestations and the time association to vaccination. In this case series,
80% of the patients were female, mean age 35 +/- 9 years, of which 20% received
one inoculation, 20% received two doses and 60% received all three
inoculations. The mean latency period from the first hepatitis B virus
immunization and onset of autoimmune symptoms was 56.3 days. All patients were
diagnosed with systemic lupus erythematosus, according to the American College
of Rheumatology revised criteria within 1 year. The prevalence of some systemic
lupus erythematosus manifestations was typical and included involvement of the
joints (100%), skin (80%), muscles (60%) and photosensitivity (30%). Other
symptoms differed in this unique group of systemic lupus erythematosus patients
such as low rate of kidney and hematologic involvement, and a relatively high
rate of hepatitis (20%). Neurological (80%) and pulmonary (70%) symptoms were
also common in this group. Data from this case-series, and previously
documented cases in the literature could only show a temporal relation between
hepatitis B vaccination and the appearance of systemic lupus erythematosus.
Systemic lupus erythematosus related to vaccine may differ from idiopathic
systemic lupus erythematosus in its clinical presentation and may resemble
drug-induced systemic lupus erythematosus. Thus, physicians should be alerted
to this potential association, its possible long latency period and unique
presentations, and be encouraged to report and analyze these cases.
http://www.ncbi.nlm.nih.gov/pubmed/19880567

“Other symptoms differed in this unique group of systemic lupus erythematosus
patients such as low rate of kidney and hematologic involvement, and a
relatively high rate of hepatitis (20%). Neurological (80%) and pulmonary (70%)
symptoms were also common in this group. Systemic lupus erythematosus related
to vaccine may differ from idiopathic systemic lupus erythematosus in its
clinical presentation and may resemble drug-induced systemic lupus
erythematosus.”

“Owing to the adverse effects exerted by adjuvants, there is no doubt that safer adjuvants
need to be developed and incorporated into future vaccines.” Lupus • November
2009

Adjuvants and autoimmunity Author information Israeli E1, Agmon-Levin N, Blank
M, Shoenfeld Y. Center for Autoimmune Diseases Sheba Medical Center
Tel-Hashomer, Israel Abstract Some adjuvants may exert adverse effects upon
injection or, on the other hand, may not trigger a full immunological reaction.
The mechanisms underlying adjuvant adverse effects are under renewed scrutiny
because of the enormous implications for vaccine development. In the search for
new and safer adjuvants, several new adjuvants were developed by pharmaceutical
companies utilizing new immunological and chemical innovations. The ability of
the immune system to recognize molecules that are broadly shared by pathogens
is, in part, due to the presence of special immune receptors called toll-like
receptors (TLRs) that are expressed on leukocyte membranes. The very fact that
TLR activation leads to adaptive immune responses to foreign entities explains
why so many adjuvants used today in vaccinations are developed to mimic TLR
ligands. Alongside their supportive role, adjuvants were found to inflict by
themselves an illness of autoimmune nature, defined as ‘the adjuvant diseases’.
The debatable question of silicone as an adjuvant and connective tissue
diseases, as well as the Gulf War syndrome and macrophagic myofaciitis which
followed multiple injections of aluminium-based vaccines, are presented here.
Owing to the adverse effects exerted by adjuvants, there is no doubt that safer
adjuvants need to be developed and incorporated into future vaccines. Other
needs in light of new vaccine technologies are adjuvants suitable for use with
mucosally delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines.
In particular, there is demand for safe and non-toxic adjuvants able to
stimulate cellular (Th1) immunity. More adjuvants were approved to date besides
alum for human vaccines, including MF59 in some viral vaccines, MPL, AS04,
AS01B and AS02A against viral and parasitic infections, virosomes for HBV, HPV
and HAV, and cholera toxin for cholera. Perhaps future adjuvants occupying
other putative receptors will be employed to bypass the TLR signaling pathway
completely in order to circumvent common side effects of adjuvant-activated
TLRs such as local inflammation and the general malaise felt because of the
costly whole-body immune response to antigen.
http://www.ncbi.nlm.nih.gov/pubmed/19880572

National Reviews In Rheumatology • November 2009

Vaccines and autoimmunity Author information Agmon-Levin N1, Paz Z, Israeli E,
Shoenfeld Y. Center for Autoimmune Diseases and Department of Medicine B Sheba
Medical Center, Sheba Medical Center, Tel-Hashomer 52621, Israel Abstract
Vaccines have been used for over 200 years and are the most effective way of
preventing the morbidity and mortality associated with infections. Like other
drugs, vaccines can cause adverse events, but unlike conventional medicines,
which are prescribed to people who are ill, vaccines are administered to
healthy individuals, thus increasing the concern over adverse reactions. Most
side effects attributed to vaccines are mild, acute and transient; however,
rare reactions such as hypersensitivity, induction of infection, and
autoimmunity do occur and can be severe and even fatal. The rarity and subacute
presentation of post-vaccination autoimmune phenomena means that ascertaining
causality between these events can be difficult. Moreover, the latency period
between vaccination and autoimmunity ranges from days to years. In this
article, on the basis of published evidence and our own experience, we discuss
the various aspects of the causal and temporal interactions between vaccines
and autoimmune phenomena, as well as the possible mechanisms by which different
components of vaccines might induce autoimmunity.
http://www.ncbi.nlm.nih.gov/pubmed/19865091

“Most side effects attributed to vaccines are mild, acute and transient;
however, rare reactions such as hypersensitivity, induction of infection, and
autoimmunity do occur and can be severe and even fatal. Moreover, the latency
period between vaccination and autoimmunity ranges from days to years.”

Lupus • November 2009

Vaccination of healthy subjects and autoantibodies: from mice through dogs to
humans Author information Toplak N1, Avcin T. 1. Department of Allergology
Rheumatology and Clinical Immunology University Children’s Hospital University
Medical Centre Ljubljana, Slovenia natasa.toplak@kclj.si Abstract Vaccination
against pathogenic microorganisms is one of the major achievements of modern
medicine, but due to an increasing number of reports of adverse reactions the
vaccination procedure has induced also considerable debate. It is well known
that certain infections are involved in triggering the production of
autoantibodies, which could lead to autoimmune adverse reactions in genetically
predisposed subjects. Based on these findings it was assumed that vaccinations
might induce similar autoimmune reactions. At present there is no clear-cut
evidence that vaccinations are associated with overt autoimmune diseases but it
has been demonstrated that in genetically predisposed persons vaccination can
trigger the production of autoantibodies and autoimmune adverse reactions. The
first studies investigating the production of autoantibodies following
vaccination were done in dogs and mice. Several studies investigated the
production of autoantibodies following vaccination in patients with autoimmune
diseases, but there are only limited data on the autoimmune responses after
vaccinations in apparently healthy humans. This review summarizes current
evidence on the vaccination-induced autoantibodies in apparently healthy
subjects including studies in animals and humans.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19880566

“due to an increasing number of reports of adverse reactions the vaccination
procedure has induced also considerable debate ... it has been demonstrated
that in genetically predisposed persons vaccination can trigger the production
of autoantibodies and autoimmune adverse reactions.”

Lupus • November 2009

Vaccines as a trigger for myopathies Author information Orbach H1, Tanay A.
Department of Medicine B Wolfson Medical Center, Holon, Israel
orbach@wolfson.health.gov.il Abstract Vaccines are considered to be among the
greatest medical discoveries, credited with the virtual eradication of some
diseases and the consequent improved survival and quality of life of the
at-risk population. With that, vaccines are among the environmental factors
implicated as triggers for the development of inflammatory myopathies. The
sporadic reports on vaccine-induced inflammatory myopathies include cases of
hepatitis B virus, bacillus Calmette-Guérin, tetanus, influenza, smallpox,
polio, diphtheria, diphtheria-pertussis-tetanus, combination of diphtheria with
scarlet fever and diphtheria-pertussis-tetanus with polio vaccines. However, a
significant increase in the incidence of dermatomyositis or polymyositis after
any massive vaccination campaign has not been reported in the literature. In
study patients with inflammatory myopathies, no recent immunization was
recorded in any of the patients. Moreover, after the 1976 mass flu vaccination,
no increase in the incidence of inflammatory myopathies was observed. Although
rare, macrophagic myofasciitis has been reported following vaccination and is
attributed to the aluminium hydroxide used as an adjuvant in some vaccines.
Prospective multicenter studies are needed to identify potential environmental
factors, including vaccines, as potential triggers for inflammatory myopathies.
http://www.ncbi.nlm.nih.gov/pubmed/19880571

“... macrophagic myofasciitis has been reported following vaccination and is
attributed to the aluminium hydroxide used as an adjuvant in some vaccines.”

PLoS One • December 2009

Self-organized criticality theory of autoimmunity Author information Tsumiyama
K1, Miyazaki Y, Shiozawa S. Department of Biophysics Kobe University Graduate
School of Health Science Kobe, Japan Abstract BACKGROUND The cause of
autoimmunity, which is unknown, is investigated from a different angle, i.e.,
the defect in immune ‘system’, to explain the cause of autoimmunity.
METHODOLOGY/PRINCIPAL FINDINGS Repeated immunization with antigen causes
systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune
diseases. Overstimulation of CD4(+) T cells led to the development of
autoantibody-inducing CD4(+) T (aiCD4(+) T) cell which had undergone T cell
receptor (TCR) revision and was capable of inducing autoantibodies. The
aiCD4(+) T cell was induced by de novo TCR revision but not by cross-reaction,
and subsequently overstimulated CD8(+) T cells, driving them to become
antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further
matured by antigen cross-presentation, after which they caused autoimmune
tissue injury akin to systemic lupus erythematosus (SLE).
CONCLUSIONS/SIGNIFICANCE Systemic autoimmunity appears to be the inevitable
consequence of overstimulating the host’s immune ‘system’ by repeated
immunization with antigen, to the levels that surpass system’s self-organized
criticality. http://www.ncbi.nlm.nih.gov/pubmed/20046868

“Systemic autoimmunity appears to be the inevitable consequence of
over-stimulating the host’s immune ‘system’ by repeated immunization with
antigen, to the levels that surpass system’s self-organized criticality.”

Infection, Genetics And Evolution • January 2010

Bordetella pertussis and vaccination: the persistence of a genetically
monomorphic pathogen Author information Mooi FR. Lab for Infectious Diseases
and Screening Netherlands Centre for Infectious Diseases Control Natl Institute
for Public Health and the Environment RIVM, PO Box 1, 3720 BA Bilthoven,
Netherlands frits.mooi@rivm.nl Abstract Before childhood vaccination was
introduced in the 1950s, pertussis or whooping cough was a major cause of
infant death worldwide. Widespread vaccination of children was successful in
significantly reducing morbidity and mortality. However, despite vaccination,
pertussis has persisted and, in the 1990s, resurged in a number of countries
with highly vaccinated populations. Indeed, pertussis has become the most
prevalent vaccinepreventable disease in developed countries with estimated
infection frequencies of 1-6%. Recently vaccinated children are well protected
against pertussis disease and its increase is mainly seen in adolescents and
adults in which disease symptoms are often mild. The etiologic agent of
pertussis, Bordetella pertussis, is extremely monomorphic and its ability to
persist in the face of intensive vaccination is intriguing. Numerous studies
have shown that B. pertussis populations changed after the introduction of
vaccination suggesting adaptation. These adaptations did not involve the
acquisition of novel genes but small genetic changes, mainly SNPs, and occurred
in successive steps in a period of 40 years. The earliest adaptations resulted
in antigenic divergence with vaccine strains. More recently, strains emerged
with increased pertussis toxin (Ptx) production. Here I argue that the
resurgence of pertussis is the compound effect of pathogen adaptation and
waning immunity. I propose that the removal by vaccination of naïve infants as
the major source for transmission was the crucial event which has driven the
changes in B. pertussis populations. This has selected for strains which are
more efficiently transmitted by primed hosts in which immunity has waned. The
adaptation of B. pertussis to primed hosts involved delaying an effective
immune response by antigenic divergence with vaccine strains and by increasing
immune suppression through higher levels of Ptx production. Higher levels of
Ptx may also benefit transmission by enhancing clinical symptoms. The study of
B. pertussis populations has not only increased our understanding of pathogen
evolution, but also suggests way to improve pertussis vaccines, underlining the
public health significance of population-based studies of pathogens.
http://www.ncbi.nlm.nih.gov/pubmed/19879977

“despite vaccination, pertussis has persisted and, in the 1990s, resurged in a
number of countries with highly vaccinated populations. Here I argue that the
resurgence of pertussis is the compound effect of pathogen adaptation and
waning immunity.”

[resurgence is not a result of the unvaccinated]

Medical Hypotheses • January 2010

Revisiting the possibility of serious adverse events from the whole cell
pertussis vaccine: were metabolically vulnerable children at risk? Author
information Wilson K1, Potter B, Manuel D, Keelan J, Chakraborty P. Department
of Medicine, Ottawa Hospital Research Institute University of Ottawa, Ottawa,
Canada kwilson@ohri.ca Abstract In the early 1980’s concerns about the safety
of the whole cell pertussis vaccine in the United States resulted in declining
vaccination rates and the withdrawal of multiple vaccine providers from the
market. While the possibility of inflammation and febrile reactions to the
vaccine were acknowledged by public health authorities, parents also claimed
the vaccine was associated with sudden infant death syndrome and
encephalopathy. Epidemiological studies examining this question, however,
consistently failed to identify an association. We argue that these reactions
may have occurred in metabolically vulnerable children, specifically those with
defects in fatty acid oxidation. In these children the combination of anorexia
and fever that could be caused by the vaccine may have resulted in hypoglycemic
episodes and possibly death. We believe that this association was not detected
because these conditions were not recognized at the time and because these
conditions are uncommon. Nevertheless, at a population level, enough events
could have occurred to cause concern amongst parents.
http://www.ncbi.nlm.nih.gov/pubmed/19660877

“We argue that these reactions may have occurred in metabolically vulnerable
children, specifically those with defects in fatty acid oxidation. In these
children the combination of anorexia and fever that could be caused by the
vaccine may have resulted in hypoglycemic episodes and possibly death. We
believe that this association was not detected because these conditions were
not recognized at the time and because these conditions are uncommon.
Nevertheless, at a population level, enough events could have occurred to cause
concern amongst parents.”

Pediatrics, Volume 125 / Issue 2 • February 2010

Sibling Transmission of Vaccine-Derived Rotavirus (RotaTeq) Associated With
Rotavirus Gastroenteritis Daniel C. Payne, Kathryn M. Edwards, Michael D.
Bowen, Erin Keckley, Jody Peters, Mathew D. Esona, Elizabeth N. Teel, Diane
Kent, Umesh D. Parashar, Jon R. Gentsch

“Although rotavirus vaccines are known to be shed in stools, transmission of
vaccine-derived virus to unvaccinated contacts resulting in symptomatic
rotavirus gastroenteritis has not been reported to our knowledge.

Abstract Although rotavirus vaccines are known to be shed in stools,
transmission of vaccine-derived virus to unvaccinated contacts resulting in
symptomatic rotavirus gastroenteritis has not been reported to our knowledge.
We document here the occurrence of vaccine-derived rotavirus (RotaTeq [Merck
and Co, Whitehouse Station, NJ]) transmission from a vaccinated infant to an
older, unvaccinated sibling, resulting in symptomatic rotavirus gastroenteritis
that required emergency department care. Results of our investigation suggest
that reassortment between vaccine component strains of genotypes P7[5]G1 and
P1A[8]G6 occurred during replication either in the vaccinated infant or in the
older sibling, raising the possibility that this reassortment may have
increased the virulence of the vaccine-derived virus. Both children remain
healthy 11 months after this event and are without underlying medical
conditions. http://pediatrics.aappublications.org/content/125/2/e438

We document here the occurrence of vaccine-derived rotavirus (RotaTeq, Merck
and Co, Whitehouse Station, NJ) transmission from a vaccinated infant to an
older, unvaccinated sibling, resulting in symptomatic rotavirus gastroenteritis
that required emergency department care.”

Discovery Medicine • February 2010

Vaccines and autoimmune diseases of the adult Author information Orbach H1,
Agmon-Levin N, Zandman-Goddard G. Department of Medicine B Wolfson Medical
Center Holon, Israel Abstract Infectious agents contribute to the environmental
factors involved in the development of autoimmune diseases possibly through
molecular mimicry mechanisms. Hence, it is feasible that vaccinations may also
contribute to the mosaic of autoimmunity. Evidence for the association of
vaccinations and the development of these diseases is presented in this review.
Infrequently reported post-vaccination autoimmune diseases include systemic
lupus erythematosus, rheumatoid arthritis, inflammatory myopathies, multiple
sclerosis, Guillain-Barré syndrome, and vasculitis. In addition, we will
discuss macrophagic myofasciitis, aluminum containing vaccines, and the recent
evidence for autoimmunity following the use of human papillomavirus vaccine.

“Hence, it is feasible that vaccinations may also contribute to the mosaic of
autoimmunity. Evidence for the association of vaccinations and the development
of these diseases is presented in this review. In addition, we will discuss
macrophagic myofasciitis, aluminum containing vaccines, and the recent evidence
for autoimmunity following the use of human papillomavirus vaccine.”

http://www.ncbi.nlm.nih.gov/pubmed/20193633 Full Report
http://www.discoverymedicine.com/Hedi-Orbach/2010/02/04/vaccines-and-autoimmune-diseases-of-the-adult/

Discovery Medicine • February 2010

Vaccines and Autoimmune Diseases of the Adult Author: Hedi Orbach Specialty:
Immunology, Rheumatology, Microbiology, Infectious Diseases Institution:
Department of Medicine B, Wolfson Medical Center Author: Nancy Agmon-Levin
Specialty: Immunology, Rheumatology, Microbiology, Infectious Diseases
Institution: Center for Autoimmune Diseases. Sheba Medical Center Author:
Gisele Zandman-Goddard Specialty: Immunology, Rheumatology, Microbiology,
Infectious Diseases Institution: Department of Medicine C, Wolfson Medical
Center

Abstract Infectious agents contribute to the environmental factors involved in
the development of autoimmune diseases possibly through molecular mimicry
mechanisms. Hence, it is feasible that vaccinations may also contribute to the
mosaic of autoimmunity. Evidence for the association of vaccinations and the
development of these diseases is presented in this review. Infrequently
reported post-vaccination autoimmune diseases include systemic lupus
erythematosus, rheumatoid arthritis, inflammatory myopathies, multiple
sclerosis, Guillain-Barré syndrome, and vasculitis. In addition, we will
discuss macrophagic myofasciitis, aluminum containing vaccines, and the recent
evidence for autoimmunity following human papilloma virus vaccine. Introduction
Systemic and organ-specific autoimmune diseases are known to develop following
infectious triggers. Recently we have suggested that certain autoimmune
diseases like systemic lupus erythematosus (SLE) may result due to specific
viral agents. Furthermore, the spectrum of disease may be influenced by a
certain microbial agent in the genetically predisposed individual
(Zandman-Goddard et al., 2009). Vaccines are a prototypic source for natural
immune stimulation, but may be involved in pathogenic disease in the setting of
aberrant immune system function. Possibly, the burden on the immune system
resulting from simultaneous multiple vaccines and even the different types of
vaccines may also be an overwhelming challenge in the autoimmune prone
individual (Shoenfeld et al., 2008). In this review, we discuss the evidence
for the development of autoimmune diseases following infections and
vaccinations. While vaccinations are generally safe, warranted and have
virtually eradicated endemic diseases and probably lessened morbidity and
mortality, a question arises regarding the evaluation of possible autoimmune
phenomena in vaccinated individuals. Reported post-vaccination autoimmune
diseases in the adult include SLE, rheumatoid arthritis (RA), inflammatory
myopathies, multiple sclerosis (MS), Guillain-Barré syndrome (GBS), and
vasculitis. Evidence for the association of vaccinations and the development of
these diseases is presented in this review. In addition, we will discuss
macrophagic myofasciitis, post aluminum containing vaccines and the recent
support for autoimmunity following human papilloma virus vaccine.
http://www.discoverymedicine.com/Hedi-Orbach/2010/02/04/vaccines-and-autoimmune-diseases-of-the-adult/

“Vaccines are a prototypic source for natural immune stimulation, but may be
involved in pathogenic disease in the setting of aberrant immune system
function. Possibly, the burden on the immune system resulting from simultaneous
multiple vaccines and even the different types of vaccines may also be an
overwhelming challenge in the autoimmune prone individual (Shoenfeld et al.,
2008).

Reported post-vaccination autoimmune diseases in the adult include SLE,
rheumatoid arthritis (RA), inflammatory myopathies, multiple sclerosis (MS),
Guillain-Barré syndrome (GBS), and vasculitis. Evidence for the association of
vaccinations and the development of these diseases is presented in this review.
In addition, we will discuss macrophagic myofasciitis, post aluminum containing
vaccines and the recent support for autoimmunity following human papilloma
virus vaccine.”

BMJ • March 2010

Effect of revaccination with BCG in early childhood on mortality: randomised
trial in Guinea-Bissau Adam Edvin Roth, clinician,1,2 Christine Stabell Benn,
senior researcher,3 Henrik Ravn, senior statistician,3 Amabelia Rodrigues,
research director,1 Ida Maria Lisse, senior registrar,4 Maria Yazdanbakhsh,
professor,5 Hilton Whittle, professor,6 and Peter Aaby, professor1,3 1. Bandim
Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau 2.
Department of Medical Microbiology, Lund University, 205 02 Malmö, Sweden 3.
Bandim Health Project, Danish Epidemiology Science Centre, Statens Serum
Institut, Artillerivej 5, 2300 Copenhagen S, Denmark 4. Department of
Pathology, Herlev University Hospital, 2730 Herlev, Denmark 5. Department of
Parasitology, Leiden University, Netherlands 6. MRC Laboratories, Fajara, POB
273, Gambia

Abstract Objective To determine whether BCG revaccination at 19 months of age
reduces overall child mortality. Design Randomised trial, with follow-up to age
5. Setting A health project in Bissau, Guinea-Bissau, which maintains a health
and demographic surveillance system in an urban area with 90,000 inhabitants.

Participants 2871 children aged 19 months to 5 years with low or no reactivity
to tuberculin and who were not severely sick on the day of enrolment.
Intervention BCG vaccination or no vaccination (control). Main outcome measure
Hazard ratios for mortality. Results 77 children died during follow-up.
Compared with controls, the BCG revaccinated children had a hazard ratio of
1.20 (95% confidence interval 0.77 to 1.89). Two hundred and fifty children
were admitted to hospital for the first time between enrolment and the end of
the study, with an incidence rate ratio for BCG revaccinated children versus
controls of 1.04 (0.81 to 1.33). The trial was stopped prematurely because of a
cluster of deaths in the BCG arm of the study. This increase in mortality
occurred at a time when many children had received missing vaccinations or
vitamin A or iron supplementation; the hazard ratio for BCG revaccinated
children compared with controls was 2.69 (1.05 to 6.88) in the period after
these campaigns. Throughout the trial, the effect of BCG revaccination on
mortality was significantly different (P=0.006) in children who had received
diphtheria-tetanus-pertussis (DTP) booster vaccination before enrolment (hazard
ratio 0.36, 0.13 to 0.99) and children who had not received the booster before
enrolment (1.78, 1.04 to 3.04). Conclusions There was no overall beneficial
effect of being revaccinated with BCG. The effect of BCG revaccination on
mortality might depend on other health interventions. “77 of 2871 children died
during follow-up” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839082/

“77 children died during follow-up. Two hundred and fifty children were
admitted to hospital for the first time. There was no overall beneficial effect
of being revaccinated with BCG. ”

Cutaneous And Ocular Toxicology • March 2010

Hepatitis B vaccine and uveitis: an emerging hypothesis suggested by review of
32 case reports Author information Fraunfelder FW1, Suhler EB, Fraunfelder FT.
Casey Eye Institute Portland, Oregon 97239, USA fraunfel@ohsu.edu Abstract
OBJECTIVE To report a possible association between hepatitis B vaccine and
uveitis. METHODS Spontaneous reports from the National Registry of Drug-Induced
Ocular Side Effects, the World Health Organization, and the Food and Drug
Administration were collected on hepatitis B vaccine associated with uveitis
between 1982 and 2009. In addition, we performed a Medline literature search
using the keywords of uveitis, iritis, or vitritis, in combination with
vaccines and hepatitis B vaccine. Data garnered from the spontaneous reports
included age, gender, adverse drug reaction, temporal association of uveitis
with vaccine doses, concomitant drugs, other systemic disease, recovery, and
recurrence after repeat dosage. RESULTS Thirty-two case reports of uveitis
occurring after hepatitis B vaccine were reported to the spontaneous reporting
databases. The mean age of the patients was 29 years (1-57 years), with 8 male
and 24 female patients. The mean number of days until uveitis was reported
after vaccination was 3 days (1-15 days). The uveitis was reported to occur
after the first vaccination in 15 patients, after the second vaccination in 3
patients, and after the third vaccination in 3 patients; the duration of time
to occurrence of uveitis was not reported for 9 patients. One patient had
recurrent uveitis after both the second and third doses of vaccine. One patient
had recurrent uveitis after the first and second doses of vaccine. CONCLUSION
Hepatitis B vaccine may have a possible association with the development of
uveitis in some patients. Immune complex deposition and adjuvant effects are
potential pathogenic mechanisms.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19947819

“Hepatitis B vaccine may have a possible association with the development of
uveitis in some patients. Immune complex deposition and adjuvant effects are
potential pathogenic mechanisms.”

Cell Biology And Toxicology • April 2010

Induction of metallothionein in mouse cerebellum and cerebrum with low-dose
thimerosal injection Author information Minami T1, Miyata E, Sakamoto Y,
Yamazaki H, Ichida S. Department of Life Sciences Kinki University,
Higashi-osaka Osaka, Japan minamita@life.kindai.ac.jp Abstract Thimerosal, an
ethyl mercury compound, is used worldwide as a vaccine preservative. We
previously observed that the mercury concentration in mouse brains did not
increase with the clinical dose of thimerosal injection, but the concentration
increased in the brain after the injection of thimerosal with
lipopolysaccharide, even if a low dose of thimerosal was administered.
Thimerosal may penetrate the brain, but is undetectable when a clinical dose of
thimerosal is injected; therefore, the induction of metallothionein (MT)
messenger RNA (mRNA) and protein was observed in the cerebellum and cerebrum of
mice after thimerosal injection, as MT is an inducible protein. MT-1 mRNA was
expressed at 6 and 9 h in both the cerebrum and cerebellum, but MT-1 mRNA
expression in the cerebellum was three times higher than that in the cerebrum
after the injection of 12 microg/kg thimerosal. MT2 mRNA was not expressed
until 24 h in both organs. MT-3 mRNA was expressed in the cerebellum from 6 to
15 h after the injection, but not in the cerebrum until 24 h. MT-1 and MT-3
mRNAs were expressed in the cerebellum in a dose-dependent manner. Furthermore,
MT-1 protein was detected from 6 to 72 h in the cerebellum after 12 microg/kg
of thimerosal was injected and peaked at 10 h. MT-2 was detected in the
cerebellum only at 10 h. In the cerebrum, little MT-1 protein was detected at
10 and 24 h, and there were no peaks of MT-2 protein in the cerebrum. In
conclusion, MT-1 and MT-3 mRNAs but not MT-2 mRNA are easily expressed in the
cerebellum rather than in the cerebrum by the injection of low-dose thimerosal.
It is thought that the cerebellum is a sensitive organ against thimerosal. As a
result of the present findings, in combination with the brain pathology
observed in patients diagnosed with autism, the present study helps to support
the possible biological plausibility for how low-dose exposure to mercury from
thimerosal-containing vaccines may be associated with autism.
http://www.ncbi.nlm.nih.gov/pubmed/19357975

“It is thought that the cerebellum is a sensitive organ against thimerosal. As
a result of the present findings, in combination with the brain pathology
observed in patients diagnosed with autism, the present study helps to support
the possible biological plausibility for how low-dose exposure to mercury from
thimerosal containing vaccines may be associated with autism.”

Disability & Health Journal • April 2010

Sex differences in the evaluation and diagnosis of autism spectrum disorders
among children Author information Giarelli E1, Wiggins LD, Rice CE, Levy SE,
Kirby RS, Pinto-Martin J, Mandell D. University of Pennsylvania School of
Nursing, Philadelphia, 19104, USA giarelli@nursing.upenn.edu Abstract
BACKGROUND One of the most consistent features of the autism spectrum disorders
(ASDs) is the predominance among males, with approximately four males to every
female. We sought to examine sex differences among children who met case
definition for ASD in a large, population-based cohort with respect to age at
first developmental evaluation, age of diagnosis, influence of cognitive
impairment on these outcomes, and sex-specific behavioral characteristics.
METHODS We conducted a secondary analysis of data collected for a
population-based study of the prevalence of ASD. The sample comprised 2,568
children born in 1994 who met the case definition of ASD as established by the
Autism and Developmental Disabilities Monitoring (ADDM) Network for ASD
surveillance. Children who had a history of developmental disability and
behavioral features consistent with the DSM-IV-TR criteria for autistic
disorder, Asperger’s disorder, and Pervasive Developmental Disorder-Not
Otherwise Specified in existing evaluation records were classified as ASD cases
via two paths: streamlined and nonstreamlined. Streamlined reviews were
conducted if there was an ASD diagnosis documented in the records. Data were
collected in 13 sites across the United States through the ADDM Network, funded
by the Centers for Disease Control and Prevention. RESULTS Males constituted
81% of the sample. There were no differences by sex in average age at first
evaluation or average age of diagnosis among those with an existing documented
chart diagnosis of an ASD. Girls were less likely than boys to have a
documented diagnosis (odds ratio [OR] = 0.76, p = .004). This analysis was
adjusted for cognitive impairment status. In the logistic model, with the
interaction term for sex and cognitive impairment, girls with IQ of 70 or less
were less likely than boys with IQ of 70 or less to have a documented diagnosis
(OR = 0.70, 95% confidence interval [CI] = 0.50-0.97, p = .035). Boys with IQ
greater than 70 were less likely than boys with IQ of 70 or less to have a
documented diagnosis (OR = 0.60, 95% CI = 0.49-0.74, p < .001). This finding
(less likely to have a documented diagnosis) was also true for girls with IQ
greater than 70 (OR = 0.45, 95% CI = 0.32-0.66, p < .001). Girls were more
likely to have notations of seizure-like behavior (p < .001). Boys were more
likely to have notations of hyperactivity or a short attention span and
aggressive behavior (p < .01). CONCLUSIONS Girls, especially those without
cognitive impairment, may be formally identified at a later age than boys. This
may delay referral for early intervention. Community education efforts should
alert clinicians and parents to the potential of ASDs in boys and girls.
http://www.ncbi.nlm.nih.gov/pubmed/?term=21122776

“One of the most consistent features of the autism spectrum disorders (ASDs) is
the predominance among males, with approximately four males to every female. We
sought to examine sex differences among children who met case definition for
ASD ...”

PLoS One • May 2010

Oral polio vaccine influences the immune response to BCG vaccination A natural
experiment Author information Sartono E1, Lisse IM, Terveer EM, van de Sande
PJ, Whittle H, Fisker AB, Roth A, Aaby P, Yazdanbakhsh M, Benn CS. Department
of Parasitology, Leiden University Medical Center Leiden, The Netherlands
E.Sartono@lumc.nl Abstract BACKGROUND Oral polio vaccine (OPV) is recommended
to be given at birth together with BCG vaccine. While we were conducting two
trials including low-birth-weight (LBW) and normal-birth-weight (NBW) infants
in Guinea-Bissau, OPV was not available during some periods and therefore some
infants did not receive OPV at birth, but only BCG. We investigated the effect
of OPV given simultaneously with BCG at birth on the immune response to BCG
vaccine.

“Worryingly, the results indicate that

METHODS AND FINDINGS We compared the in vitro and the in vivo response to PPD
in the infants who received OPV and BCG with that of infants who received BCG
only. At age 6 weeks, the in vitro cytokine response to purified protein
derivate (PPD) of M. Tuberculosis was reduced in LBW and NBW infants who had
received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was
associated with significantly lower IL-13 (p = 0.041) and IFN-gamma (p = 0.004)
and a tendency for lower IL-10 (p = 0.054) in response to PPD. Furthermore, OPV
was associated with reduced in vivo response to PPD at age 2 months, the
prevalence ratio (PR) of having a PPD reaction being 0.75 (0.58-0.98), p =
0.033, and with a tendency for reduced likelihood of having a BCG scar (0.95
(0.91-1.00), p = 0.057)). Among children with a scar, OPV was associated with
reduced scar size, the regression coefficient being -0.24 (-0.43-0.05), p =
0.012.

Bacille Calmette-Guerin [BCG - tuberculosis] vaccine

CONCLUSIONS This study is the first to address the consequences for the immune
response to BCG of simultaneous administration with OPV. Worryingly, the
results indicate that the common practice in low-income countries of
administering OPV together with BCG at birth may down-regulate the response to
BCG vaccine. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873948/

the common practice in low-income countries of administering Oral polio vaccine
together with

at birth may down-regulate the response to Bacille Calmette-Guerin [BCG -
tuberculosis] vaccine.”

Medical Science Monitor • May 2010

The relative toxicity of compounds used as preservatives in vaccines and
biologics Author information Geier DA1, Jordan SK, Geier MR. CoMeD, Inc.,
Silver Spring, MD, USA Abstract BACKGROUND In vaccines/biologics, preservatives
are used to prevent microbial growth. MATERIAL/METHODS The present study
examined: (1) the comparative toxicities of commonly used preservatives in US
licensed vaccines to human neurons; and (2) the relative toxicity index of
these compounds to human neurons in comparison to bacterial cells. RESULTS
Using human neuroblastoma cells, the relative cytotoxicity of the levels of the
compounds commonly used as preservative in US licensed vaccines was found to be
phenol <2-phenoxyethanol < benzethonium chloride < Thimerosal. The observed
relative toxicity indices (human neuroblastoma cells/bacterial cells) were
2-phenoxyethanol (4.6-fold) < phenol (12.2-fold) < Thimerosal (>330-fold). In
addition, for the compounds tested, except for 2-phenoxyethanol, the
concentrations necessary to induce significant killing of bacterial cells were
significantly higher than those routinely present in US licensed
vaccine/biological preparations. CONCLUSIONS None of the compounds commonly
used as preservatives in US licensed vaccine/biological preparations can be
considered an ideal preservative, and their ability to fully comply with the
requirements of the US Code of Federal Regulations (CFR) for preservatives is
in doubt. Future formulations of US licensed vaccines/biologics should be
produced in aseptic manufacturing plants as single dose preparations,
eliminating the need for preservatives and an unnecessary risk to patients.
http://www.ncbi.nlm.nih.gov/pubmed/?term=20424565

“None of the compounds commonly used as preservatives in US licensed
vaccine/biological preparations can be considered an ideal preservative, and
their ability to fully comply with the requirements of the US Code of Federal
Regulations (CFR) for preservatives is in doubt.”

BMJ • June 2010

Ramifications of adverse events in children in Australia Author information
Peter Collignon, infectious diseases physician and microbiologist1 Peter Doshi,
program in history, anthropology, science, technology and society2 Tom
Jefferson, coordinator3 1. School of Clinical Medicine, Australian National
University PO Box 11, Woden, ACT 2607, Australia 2. Massachusetts Institute of
Technology Cambridge, MA 02139, USA 3. Cochrane Vaccines Field, Rome, Italy
peter.collignon@act.gov.au Many serious adverse reactions to this year’s
seasonal influenza vaccine have occurred across Australia, and its use remains
suspended in children aged 5 years and under.1 2 3 Data released on 1 June 2010
show that 1 in every 110 young children vaccinated with the CSL vaccine had a
febrile seizure.3 A previous H1N1 vaccine study published earlier this year
showed that a large proportion of children developed fevers after vaccination:
between three and six in every 10 children under 3 years, depending on dose.4
The study was, however, underpowered to detect febrile convulsions at the
current rates in Australia because it included only 162 children under 3 years.
Fever is the most important risk factor for febrile convulsions. The vaccine
manufacturer CSL, which sponsored the trial, and Australia’s regulatory body,
the Therapeutic Goods Administration, which used these data in approving the
vaccine for children, were presumably aware of these important findings.4 But
the authors did not discuss the high incidence of fever associated with
vaccination,4 and most data were reported without comment in the online only
supplementary tables.4 The many children with adverse effects and the
subsequent suspension of the vaccine challenge the assumption that regulators
are ensuring the safety and efficacy of all marketed therapeutics. Influenza
vaccine is said to have “an established record of safety in all age groups.”2
However, published data on the effects of vaccinating young children against
influenza are comparatively few.5 Some manufacturers have even withheld data
from public scrutiny amid general indifference.2 5 Last winter the likelihood
that a child without risk factors would die from swine flu was less than one in
a million.2 When such a high proportion of children develop moderate to severe
febrile reactions to the influenza vaccine, more harm than good seems likely
from vaccinating them. Report available for purchase. I accessed this report
using a 14-day free trial: http://www.bmj.com/content/340/bmj.c2994.long

“... the likelihood that a child without risk factors would die from swine flu
was less than one in a million. When such a high proportion of children develop
moderate to severe febrile reactions to the influenza vaccine, more harm than
good seems likely from vaccinating them.”

BMJ • June 2010

Australian government says healthy under 5s should not be given seasonal flu
jab Moynihan R. http://www.ncbi.nlm.nih.gov/pubmed/20530085

Discovery Medicine • July 2010

Prophylactic HPV vaccines: current knowledge of impact on gynecologic
premalignancies Author information Harper DM1, Williams KB. University of
Missouri-Kansas City School of Medicine 7900 Lee’s Summit Road, Kansas City,
Missouri 64139, USA diane.m.harper@gmail.com

“Screening still remains the

Abstract Approaches for cervical cancer prevention are changing. Screening
still remains the most effective method for cervical cancer prevention.
Guidelines are moving to an older group of women to be screened less frequently
with combinations of technologies that include biomarkers and cytology. HPV
vaccination is an appropriate option for this older group of women as well,
should the woman not wish to make her decision about vaccination until 21 years
of age, the age of screening. Parents making decisions about HPV vaccination
for their young adolescent daughters need to be fully informed that only
continued screening prevents cervical cancer. HPV vaccination reduces the
possibility of their daughter having an abnormal Pap test by 10% if the
vaccines have not waned by the time the young adolescent becomes sexually
active. HPV vaccine efficacy must last at least 15 years to contribute to the
prevention of cervical cancers. At this time, protection against cervical
intraepithelial neoplasia grade 2/3 (CIN 2/3) is 5 years for Gardasil and 8.4
years for Cervarix. The value of the current protection HPV vaccines offer will
be viewed differently by different women. Physicians’ ethical duties are to
provide full explanation of the risks and benefits of adding HPV vaccination to
the ongoing screening programs, and to support women in their personal choice
for cervical cancer prevention. http://www.ncbi.nlm.nih.gov/pubmed/20670593

most effective method for cervical cancer prevention. HPV vaccination reduces
the possibility of their daughter having an abnormal Pap test by 10% if the
vaccines have not waned by the time the young adolescent becomes sexually
active.”

Reviews Of Environmental Contamination And Toxicology • July 2010
.

The toxic effects of formaldehyde on the nervous system Author information
Songur A1, Ozen OA, Sarsilmaz M. Department of Anatomy, School of Medicine
University of Kocatepe, Afyonkarahisar, Turkey asongur55@yahoo.com Abstract
Formaldehyde (FA) is found in the polluted atmosphere of cities, domestic air
(e.g., paint, insulating materials, chipboard and plywood, fabrics, furniture,
paper), and cigarette smoke, etc.; therefore, everyone and particularly
susceptible children may be exposed to FA. FA is also widely used in industrial
and medical settings and as a sterilizing agent, disinfectant, and
preservative. Therefore, employees may be highly exposed to it in there
settings. Of particular concern to the authors are anatomists and medical
students, who can be highly exposed to formaldehyde vapor during dissection
sessions. Formaldehyde is toxic over a range of doses; chances of exposure and
subsequent harmful effects are increased as (room) temperature increases,
because of FA’s volatility. Many studies have been conducted to evaluate the
effects of FA during systemic and respiratory exposures in rats. This review
compiles that literature and emphasizes the neurotoxic effects of FA on
neuronal morphology, behavior, and biochemical parameters. The review includes
the results of some of the authors’ work related to FA neurotoxicity, and such
neurotoxic effects from FA exposure were experimentally demonstrated. Moreover,
the effectiveness of some antioxidants such as melatonin, fish omega-3, and
CAPE was observed in the treatment of the harmful effects of FA. Despite the
harmful effects from FA exposure, it is commonly used in Turkey and elsewhere
in dissection laboratories. Consequently, all anatomists must know and
understand the effects of this toxic agent on organisms and the environment,
and take precautions to avoid unnecessary exposure. The reviewed studies have
indicated that FA has neurotoxic characteristics and systemic toxic effects. It
is hypothesized that inhalation of FA, during the early postnatal period, is
linked to some neurological diseases that occur in adults. Although complete
prevention is impossible for laboratory workers and members of industries
utilizing FA, certain precautions can be taken to decrease and/or prevent the
toxic effects of FA. http://www.ncbi.nlm.nih.gov/pubmed/?term=19957118

“The reviewed studies have indicated that Formaldehyde has neurotoxic
characteristics and systemic toxic effects.”

Journal Of Toxicology And Environmental Health Part A • 2010

Hepatitis B vaccination of male neonates and autism diagnosis NHIS 1997-2002
Author information Gallagher CM1, Goodman MS. PhD Program in Population Health
and Clinical Outcomes Research Stony Brook University Medical Center State
University of New York at Stony Brook Stony Brook, New York, USA
cmgallagher@notes.cc.sunysb.edu Abstract Universal hepatitis B vaccination was
recommended for U.S. newborns in 1991; however, safety findings are mixed. The
association between hepatitis B vaccination of male neonates and parental
report of autism diagnosis was determined. This cross-sectional study used
weighted probability samples obtained from National Health Interview Survey
1997-2002 data sets. Vaccination status was determined from the vaccination
record. Logistic regression was used to estimate the odds for autism diagnosis
associated with neonatal hepatitis B vaccination among boys age 3-17 years,
born before 1999, adjusted for race, maternal education, and two-parent
household. Boys vaccinated as neonates had threefold greater odds for autism
diagnosis compared to boys never vaccinated or vaccinated after the first month
of life. Non-Hispanic white boys were 64% less likely to have autism diagnosis
relative to nonwhite boys. Findings suggest that U.S. male neonates vaccinated
with the hepatitis B vaccine prior to 1999 (from vaccination record) had a
threefold higher risk for parental report of autism diagnosis compared to boys
not vaccinated as neonates during that same time period. Nonwhite boys bore a
greater risk. http://www.ncbi.nlm.nih.gov/pubmed/?term=21058170

“Findings suggest that U.S. male neonates vaccinated with the hepatitis B
vaccine prior to 1999 (from vaccination record) had a threefold higher risk for
parental report of autism diagnosis compared to boys not vaccinated as neonates
during that same time period. Nonwhite boys bore a greater risk.”

Acta Neurobiologiea Experimentalis • 2010

Influence of pediatric vaccines on amygdala growth and opioid ligand binding in
rhesus macaque infants: A pilot study Author information Hewitson L1, Lopresti
BJ, Stott C, Mason NS, Tomko J. 1Department of Obstetrics and Gynecology
University of Pittsburgh School of Medicine Pittsburgh, PA, USA lch1@pitt.edu
Abstract This longitudinal, case-control pilot study examined amygdala growth
in rhesus macaque infants receiving the complete US childhood vaccine schedule
(1994-1999). Longitudinal structural and functional neuroimaging was undertaken
to examine central effects of the vaccine regimen on the developing brain.
Vaccine-exposed and saline-injected control infants underwent MRI and PET
imaging at approximately 4 and 6 months of age, representing two specific
timeframes within the vaccination schedule. Volumetric analyses showed that
exposed animals did not undergo the maturational changes over time in amygdala
volume that was observed in unexposed animals. After controlling for left
amygdala volume, the binding of the opioid antagonist [(11)C]diprenorphine
(DPN) in exposed animals remained relatively constant over time, compared with
unexposed animals, in which a significant decrease in [(11)C]DPN binding
occurred. These results suggest that maturational changes in amygdala volume
and the binding capacity of [(11)C]DPN in the amygdala was significantly
altered in infant macaques receiving the vaccine schedule. The macaque infant
is a relevant animal model in which to investigate specific environmental
exposures and structural/functional neuroimaging during neurodevelopment.
http://www.ncbi.nlm.nih.gov/pubmed/?term=20628439

“This longitudinal, case-control pilot study examined amygdala growth in rhesus
macaque infants receiving the complete US childhood vaccine schedule
(1994-1999). These results suggest that maturational changes in amygdala volume
and the binding capacity of [(11)C]DPN in the amygdala was significantly
altered in infant macaques receiving the vaccine schedule.”

“The decrease in the collapse pressure of the monolayer film caused by coated nanoparticles,
in vitro, was associated with an acute pulmonary toxicity in vivo.” American
Association Of Pharmaceutical Sciences • September 2010

Pulmonary Toxicity of Polysorbate-80-coated Inhalable Nanoparticles; In vitro
and In vivo Evaluation M. H. D. Kamal Al-Hallak, Shirzad Azarmi, Chris Sun,
Patrick Lai, Elmar J. Prenner, Wilson H. Roa, and Raimar Löbenberg Faculty of
Pharmacy and Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre University
of Alberta, Edmonton, Alberta T6G 2N8 Canada Faculty of Pharmacy and
Pharmaceutical Sciences, Damascus University, Damascus, Syria Faculty of
Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Department of
Biological Sciences, University of Calgary, Calgary, Alberta Canada Cross
Cancer Institute, University of Alberta, Edmonton, Alberta Canada CONCLUSION
The presented in vitro model for studying the surface pressure-area isotherms
is an early screening tool to assess the biophysical compatibility of selected
drug carriers with lung surfactant films. The decrease in the collapse pressure
of the monolayer film caused by coated NPs, in vitro, was associated with an
acute pulmonary toxicity in vivo. This in vivo toxicity was not observed when
uncoated nanoparticles were used. Therefore, the dosage from toxicity of
colloidal carriers intended for pulmonary delivery is mainly determined by
their final composition rather than their individual components. More
investigations are required to set different cut-off points for the collapse
pressure to correlate them with different stages of pulomary toxicity in vivo.
The outcomes of this study should not be generalized for all surfactants or
bi-block polymers. Other surfactants with different hydrophilic-lipophilic
properties might interact differently with lung surfactant films. This method
may be useful to establish upper deposition limits for inhalable dry powders.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895437/

Proceedings Of The National Academy Of Sciences Of The USA • September 2010

Triton X-100 concentration effects on membrane permeability of a single HeLa
cell by scanning electrochemical microscopy (SECM) Author information Koley D1,
Bard AJ. Center for Electrochemistry Department of Chemistry and Biochemistry
University of Texas at Austin 1 University Station, A5300 Austin, TX
78712-0165, USA

“Permeability of the cell membrane to the otherwise impermeable, highly charged

Abstract Changes in HeLa cell morphology, membrane permeability, and viability
caused by the presence of Triton X-100 (TX100), a nonionic surfactant, were
studied by scanning electrochemical microscopy (SECM). No change in membrane
permeability was found at concentrations of 0.15 mM or lower during an
experimental period of 30 to 60 min. Permeability of the cell membrane to the
otherwise impermeable, highly charged hydrophilic molecule ferrocyanide was
seen starting at concentrations of TX100 of about 0.17 mM. This concentration
level of TX100 did not affect cell viability. Based on a simulation model, the
membrane permeability for ferrocyanide molecules passing though the live cell
membrane was 6.5 ± 2.0 × 10(-6) m/s. Cells underwent irreversible
permeabilization of the membrane and structural collapse when the TX100
concentration reached the critical micelle concentration (CMC), in the range of
0.19 to 0.20 mM. The impermeability of ferrocyanide molecules in the absence of
surfactant was also used to determine the height and diameter of a single
living cell with the aid of the approach curve and probe scan methods in SECM.
http://www.ncbi.nlm.nih.gov/pubmed/?term=20837548

hydrophilic molecule ferrocyanide was seen starting at concentrations of TX100
of about 0.17 mM. Cells underwent irreversible permeabilization of the membrane
and structural collapse when the TX100 concentration reached the critical
micelle concentration (CMC), in the range of 0.19 to 0.20 mM.”

Proceedings Of The National Academy Of Science • September 2010

Triton X-100 concentration effects on membrane permeability of a single HeLa
cell by scanning electrochemical microscopy (SECM) Dipankar Koley and Allen J.
Bard1 Center for Electrochemistry Department of Chemistry and Biochemistry
University of Texas at Austin, 1 University Station A5300, Austin, TX
78712-0165 ABSTRACT Changes in HeLa cell morphology, membrane permeability, and
viability caused by the presence of Triton X-100 (TX100), a nonionic
surfactant, were studied by scanning electrochemical microscopy (SECM). No
change in membrane permeability was found at concentrations of 0.15 mM or lower
during an experimental period of 30 to 60 min. Permeability of the cell
membrane to the otherwise impermeable, highly charged hydrophilic molecule
ferrocyanide was seen starting at concentrations of TX100 of about 0.17 mM.
This concentration level of TX100 did not affect cell viability. Based on a
simulation model, the membrane permeability for ferrocyanide molecules passing
though the live cell membrane was 6.5 ± 2.0 × 10-6 m/ s. Cells underwent
irreversible permeabilization of the membrane and structural collapse when the
TX100 concentration reached the critical micelle concentration (CMC), in the
range of 0.19 to 0.20 mM. The impermeability of ferrocyanide molecules in the
absence of surfactant was also used to determine the height and diameter of a
single living cell with the aid of the approach curve and probe scan methods in
SECM. DISCUSSION When the concentration of TX100 is below the CMC range (i.e.
0.17 mM and less) the surfactant may act as a permeabilizing agent depending on
the dose and duration of exposure to cells. This is a good range for
transfection of the cell with an added agent, but prolonged exposure to cells
even at these low concentrations can lead to some cell death. When
concentrations of TX100 in the CMC range,
> 0.18 mM, are used, the cell membrane disintegrated causing a collapse of the
entire cell structure and cell death within a few minutes. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947864/

“When concentrations of TX100 in the CMC range, > 0.18 mM, are used, the cell
membrane disintegrated causing a collapse of the entire cell structure and cell
death within a few minutes.”

Yao Xue Xue Bao • Acta Pharmaceutica Sinica • October 2010

Polysorbate-80 modified neurotoxin nanoparticle with its transport and
cytotoxicity against blood-brain barrier Author information Zhao YM1, Xia AX,
Wei YH, Ruan YP, Li FZ. College of Pharmaceutical Science Zhejiang Chinese
Medical University Hangzhou 310053, China Abstract This study was aimed at the
transport across blood-brain barrier (BBB) of polysorbate-80 modified
neurotoxin loaded polybutylcyanoacrylate nanoparticle (P-80-NT-NP) and its
cytotoxicity. An in vitro model of BBB using rat brain microvascular
endothelial cells (rBMECs) was established. The cytotoxicity of P-80-NTNP was
measured by the MTT assays, where neurotoxin (NT), nanoparticle (NP),
neurotoxin nanoparticle (NT-NP) as control, and the permeability of P-80-NT-NP
was determined by using of Millicell insert coculture with rBMECs and
fluorescence spectrophotometry. MTT results showed that NT, NP, NT-NP and
P80-NT-NP were avirulent to rBMECs when the concentration of NT was lower than
200 ng x mL(-1). But the cytotoxicity of NP, NT-NP and P-80-NT-NP would be
augmented accordingly as concentration increased (P < 0.01), causing obvious
reductions of cell survival rate, with no significant difference between them
(P > 0.05). When the concentration of NT was 150 ng x mL(-1), the permeability
on rBMECs of P-80-NT-NP and NT-NP were both significantly higher than that of
NT (P < 0.01), and the permeability of P-80-NT-NP was greater than that of
NT-NP (P < 0.05). In conclusion, polysorbate-80 modified neurotoxin
nanoparticles can transport across the BBB, while concentration of NT is
greater than 200 ng x mL(-1), P-80-NT-NP has a little cytotoxicity against
rBMECs. http://www.ncbi.nlm.nih.gov/pubmed/21348312

“... polysorbate-80 modified neurotoxin nanoparticles can transport across the
Blood Brain Barrier ...”

Vaccine • January 2011

Diphtheria-tetanus-pertussis vaccine administered simultaneously with measles
vaccine is associated with increased morbidity and poor growth in girls A
randomised trial from Guinea-Bissau Author information Agergaard J1, Nante E,
Poulstrup G, Nielsen J, Flanagan KL, Østergaard L, Benn CS, Aaby P. Bandim
Health Project, Indepth Network, Apartado 861, 1004 Bissau Codex, Guinea-Bissau
heja@dadlnet.dk Abstract BACKGROUND Combined vaccination with
diphtheria-tetanus-pertussis (DTP) and measles vaccine (MV) has been associated
with increased mortality in observational studies. Among children missing MV
and a dose of DTP and oral polio vaccine (OPV), we conducted a randomised trial
of providing MV+DTP+OPV simultaneously, as currently recommended, or MV+OPV
only, and examined the effect on morbidity and growth. We hypothesised that the
MV+OPV group would experience less morbidity and grow better. Due to previous
observations of sex differences in the non-specific effects of vaccinations, we
analysed all data stratified by sex. METHODS At the Bandim Health Project in
Guinea-Bissau, 568 children who were due to receive MV and who were missing
either DTP3 or DTP booster were enrolled in the study. A subgroup of 332
children was followed intensively to register adverse events and infections in
the first month after vaccination. A subgroup of 276 children was followed
every third month for a year to monitor growth. All children were followed for
one year for infectious diseases, consultations, and hospitalisations. RESULTS
As expected, adverse events were more common in the MV+DTP+OPV group; diarrhoea
and use of medication

were increased among girls but not among boys (both p=0.02, test of interaction
between DTP and sex). Febrile disease with vesicular rash, as well as
consultations and hospitalisations tended to be more common in the MV+DTP+OPV
group than in the MV+OPV group; the hazard ratio (HR) for febrile disease with
vesicular rash was 1.86 (1.00; 3.47). The strongest tendencies for more febrile
diseases and hospitalisations in the MV+DTP+OPV group were found in girls.
Overall, growth did not differ by randomisation group. However, results
differed by sex. Girls in the MV+DTP+OPV group had a consistent pattern of
worse z-scores for weight, height, and mid-upper-arm-circumference (MUAC) than
girls in the MV+OPV group. The effect was opposite for boys, with boys in the
MV+OPV group faring worse than those in the MV+DTP+OPV group, the interaction
test for sex and DTP being significant for weight at 6 and 9 months, for MUAC
at 12 months and for weight-forheight at 3 and 9 months after randomisation.
CONCLUSION This is the first randomised trial of the non-specific effects of
DTP and supports that these effects may be sexdifferential and of clinical and
anthropometric importance. Combined vaccination with DTP+MV+OPV may be
detrimental for girls. http://www.ncbi.nlm.nih.gov/pubmed/21093496

“This is the first randomised trial of the non-specific effects of DTP and
supports that these effects may be sex-differential and of clinical and
anthropometric importance. Combined vaccination with DTP+MV+OPV may be
detrimental for girls.”

Nucleic Acids Research • January 2011

Protegen: a web-based protective antigen database and analysis system Author
information Yang B1, Sayers S, Xiang Z, He Y. Unit for Laboratory Animal
Medicine University of Michigan Medical School Center for Computational
Medicine and Bioinformatics University of Michigan, Ann Arbor, MI 48109
Abstract Protective antigens are specifically targeted by the acquired immune
response of the host and are able to induce protection in the host against
infectious and non-infectious diseases. Protective antigens play important
roles in vaccine development, as biological markers for disease diagnosis, and
for analysis of fundamental host immunity against diseases. Protegen is a
webbased central database and analysis system that curates, stores and analyzes
protective antigens. Basic antigen information and experimental evidence are
curated from peer-reviewed articles. More detailed gene/protein information
(e.g. DNA and protein sequences, and COG classification) are automatically
extracted from existing databases using internally developed scripts.
Bioinformatics programs are also applied to compute different antigen features,
such as protein weight and pI, and subcellular localizations of bacterial
proteins. Presently, 590 protective antigens have been curated against over 100
infectious diseases caused by pathogens and non-infectious diseases (including
cancers and allergies). A user-friendly web query and visualization interface
is developed for interactive protective antigen search. A customized BLAST
sequence similarity search is also developed for analysis of new sequences
provided by the users. To support data exchange, the information of protective
antigens is stored in the Vaccine Ontology (VO) in OWL format and can also be
exported to FASTA and Excel files. Protegen is publically available at
http://www.violinet.org/protegen. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013795/

“Protegen is a web-based central database and analysis system that curates,
stores and analyzes protective antigens. Presently, 590 protective antigens
have been curated against over 100 infectious diseases caused by pathogens and
non-infectious diseases (including cancers and allergies).”

Journal Of Autoimmunity • February 2011

Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old
truths and a new syndrome? Author information Meroni PL1. Division of
Rheumatology, Istituto G. Pini, Milan, Italy pierluigi.meroni@unimi.it Abstract
There has been considerable interest in the role of environmental factors and
the induction of autoimmunity and the ways by which they facilitate loss of
tolerance. Clearly both genetic and environmental factors are incriminated, as
evidenced by the lack of concordance in identical twins and the relatively
recent identification of the shared epitope in rheumatoid arthritis. In this
issue a new syndrome called ‘Asia’-autoimmune/auto-inflammatory syndrome
induced by adjuvants has been proposed. It is an intriguing issue and one that
is likely to be provocative and lead to further biologic and molecular
investigations. http://www.ncbi.nlm.nih.gov/pubmed/21051205

“In this issue a new syndrome called ‘Asia’-autoimmune/auto-inflammatory
syndrome induced by adjuvants has been proposed. It is an intriguing issue and
one that is likely to be provocative and lead to further biologic and molecular
investigations.”

Journal Of Autoimmunity • February 2011

‘ASIA’ autoimmune/inflammatory syndrome induced by adjuvants Author information
Shoenfeld Y1, Agmon-Levin N. The Zabludowicz Center for Autoimmune Diseases
Department of Medicine B’ Sheba Medical Center Tel-Hashomer, Israel
shoenfel@post.tau.ac.il Abstract The role of various environmental factors in
the pathogenesis of immune mediated diseases is well established. Of which,
factors entailing an immune adjuvant activity such as infectious agents,
silicone, aluminium salts and others were associated with defined and
non-defined immune mediated diseases both in animal models and in humans. In
recent years, four conditions: siliconosis, the Gulf war syndrome (GWS), the
macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena were
linked with previous exposure to an adjuvant. Furthermore, these four diseases
share a similar complex of signs and symptoms which further support a common
denominator. Thus, we review herein the current data regarding the role of
adjuvants in the pathogenesis of immune mediated diseases as well as the
amassed data regarding each of these four conditions. Relating to the current
knowledge we would like to suggest to include these comparable conditions under
a common syndrome entitled ASIA, “Autoimmune (Auto-inflammatory) Syndrome
Induced by Adjuvants”. http://www.ncbi.nlm.nih.gov/pubmed/20708902

“Relating to the current knowledge we would like to suggest to include these
comparable conditions under a common syndrome entitled ASIA, “Autoimmune
(Auto-inflammatory) Syndrome Induced by Adjuvants”.”

“By means of a study including 300 unexplained sudden unexpected deaths (uSUD),
a 16-fold risk increase [in death] after the 4th dose could be detected with a
power of at least 90 per cent. A general 2-fold risk increase after vaccination
could be detected with a power of 80 per cent.” Statistics In Medicine • March
2011

A modified self-controlled case series method to examine association between
multidose vaccinations and death Author information Kuhnert R1, Hecker H,
Poethko-Müller C, Schlaud M, Vennemann M, Whitaker HJ, Farrington CP. Robert
Koch-Institute Division for Health of Children and Adolescents Prevention
Concepts, Postfach 650261 13353 Berlin, Germany KuhnertR@rki.de Abstract The
self-controlled case series method (SCCS) was developed to analyze the
association between a time-varying exposure and an outcome event. We consider
penta- or hexavalent vaccination as the exposure and unexplained sudden
unexpected death (uSUD) as the event. The special situation of multiple
exposures and a terminal event requires adaptation of the standard SCCS method.
This paper proposes a new adaptation, in which observation periods are
truncated according to the vaccination schedule. The new method exploits known
minimum spacings between successive vaccine doses. Its advantage is that it is
very much simpler to apply than the method for censored, perturbed or curtailed
post-event exposures recently introduced. This paper presents a comparison of
these two SCCS methods by simulation studies and an application to a real data
set. In the simulation studies, the age distribution and the assumed
vaccination schedule were based on real data. Only small differences between
the two SCCS methods were observed, although 50 per cent of cases could not be
included in the analysis with the SCCS method with truncated observation
periods. By means of a study including 300 uSUD, a 16-fold risk increase after
the 4th dose could be detected with a power of at least 90 per cent. A general
2-fold risk increase after vaccination could be detected with a power of 80 per
cent. Reanalysis of data from cases of the German case-control study on sudden
infant death (GeSID) resulted in slightly higher point estimates using the SCCS
methods than the odds ratio obtained by the case-control analysis.
http://www.ncbi.nlm.nih.gov/pubmed/21337361

Mutation Research • March 2011

Genotoxicity biomarkers in occupational exposure to formaldehyde the case of
histopathology laboratories Author information Ladeira C1, Viegas S, Carolino
E, Prista J, Gomes MC, Brito M. Escola Superior de Tecnologia da Saúde de
Lisboa Instituto Politécnico de Lisboa, Portugal carina.ladeira@estesl.ipl.pt
Abstract Formaldehyde, classified by the IARC as carcinogenic in humans and
experimental animals, is a chemical agent that is widely used in histopathology
laboratories. The exposure to this substance is epidemiologically linked to
cancer and to nuclear changes detected by the cytokinesis-block micronucleus
test (CBMN). This method is extensively used in molecular epidemiology, since
it provides information on several biomarkers of genotoxicity, such as
micronuclei (MN), which are biomarkers of chromosomes breakage or loss,
nucleoplasmic bridges (NPB), common biomarkers of chromosome rearrangement,
poor repair and/or telomere fusion, and nuclear buds (NBUD), biomarkers of
elimination of amplified DNA. The aim of this study is to compare the frequency
of genotoxicity biomarkers, provided by the CBMN assay in peripheral
lymphocytes and the MN test in buccal cells, between individuals occupationally
exposed and non-exposed to formaldehyde and other environmental factors, namely
tobacco and alcohol consumption. The sample comprised two groups: 56
individuals occupationally exposed to formaldehyde (cases) and 85 unexposed
individuals (controls), from whom both peripheral blood and exfoliated
epithelial cells of the oral mucosa were collected in order to measure the
genetic endpoints proposed in this study. The mean level of TWA(8h) was
0.16±0.11 ppm (<detection limit until 0.51 ppm) and the mean of ceiling values
was 1.14±0.74 ppm (0.18-2.93 ppm). All genotoxicity biomarkers showed
significant increases in exposed workers in comparison with controls
(Mann-Whitney test, p<0.002) and the analysis of confounding factors showed
that there were no differences between genders. As for age, only the mean MN
frequency in lymphocytes was found significantly higher in elderly people among
the exposed groups (p=0.006), and there was also evidence of an interaction
between age and gender with regards to that biomarker in those exposed. Smoking
habits did not influence the frequency of the biomarkers, whereas alcohol
consumption only influenced the MN frequency in lymphocytes in controls
(p=0.011), with drinkers showing higher mean values. These results provide
evidence of the association between occupational exposure to formaldehyde and
the presence of genotoxicity biomarkers.
http://www.ncbi.nlm.nih.gov/pubmed/?term=21256246

“These results provide evidence of the association between occupational
exposure to formaldehyde and the presence of genotoxicity biomarkers.”

Medical Journal of Australia • April 2011
Medicine and the law

Vaccination, consent and multidose vials Mark R Diamond, PhD, Research
Psychologist Angela O’Brien-Malone, PhD, Research Psychologist School of
Psychology, University of Tasmania, Hobart, TAS Correspondence:
diamondm@utas.edu.au Abstract • Multidose vials (MDVs) for injectable
therapeutic agents, including vaccines, pose a risk of infection to injected
patients as a result of contamination of the vials. • The Australian Government
Department of Health and Ageing (DoHA) distributed the vaccine against pandemic
(H1N1) 2009 influenza in MDVs. The distribution was accompanied by consent
forms. • The consent forms provided an inadequate basis for a discussion with
patients about the risks associated with the use of MDVs. • The High Court of
Australia has previously held that medical practitioners who fail to explain
the material risks of medical procedures to their patients might be held liable
in negligence for any adverse sequelae of the procedures, even if the risks are
very low. • Medical practitioners, nurses, medical indemnity insurers and the
DoHA should prepare now for the probable future use of MDVs by developing a
consent form that would provide a solid foundation for a discussion of material
risks with patients seeking vaccination. Full Report
https://www.mja.com.au/system/files/issues/194_08_180411/dia10882_fm.pdf

“The consent forms provided an inadequate basis for a discussion with patients
about the risks associated with the use of Multi-dose Vials.”

Evidence Based Complementary Alternative Medicine • April 2011

Revisiting the Sham: Is It all Smoke and Mirrors? Author information Horn B1,
Balk J, Gold JI. Eastern Center for Complementary Medicine, PC Los Angeles,
California, USA Abstract The misuse of sham controls in examining the efficacy
or effectiveness of Complementary and Alternative Medicine has created numerous
problems. The theoretical justification for incorporating a sham is
questionable. The sham does not improve our control of bias and leads to
relativistic data that, in most instances, has no appropriate interpretation
with regards to treatment efficacy. Even the concept of a sham or placebo
control in an efficacy trial is inherently paradoxical. Therefore, it is
prudent to re-examine how we view sham controls in the context of medical
research. Extreme caution should be used in giving weight to any
sham-controlled study claiming to establish efficacy or safety. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137704/

Clinical And Experimental Pharmacology And Physiology • April 2011

Formaldehyde induces neurotoxicity to PC12 cells involving inhibition of
paraoxonase-1 expression and activity Tang XQ1, Ren YK, Chen RQ, Zhuang YY,
Fang HR, Xu JH, Wang CY, Hu B. Author information Department of Physiology,
Medical College University of South China, Hengyang, Hunan, China Abstract 1.
Formaldehyde (FA) has been found to cause toxicity to neurons. However, its
neurotoxic mechanisms have not yet been clarified. Increasing evidence has
shown that oxidative damage is one of the most critical effects of formaldehyde
exposure. Paraoxonase-1 (PON-1) is a pivotal endogenous anti-oxidant. Thus, we
hypothesized that FA-mediated downregulation of PON1 is associated with its
neurotoxicity. 2. In the present work, we used PC12 cells to study the
neurotoxicity of FA and explore whether PON-1 is implicated in FA-induced
neurotoxicity. 3. We found that FA has potent cytotoxic and apoptotic effects
on PC12 cells. FA induces an accumulation of intracellular reactive oxygen
species along with downregulation of Bcl-2 expression, as well as increased
cytochrome c release. FA significantly suppressed the expression and activity
of PON-1 in PC12 cells. Furthermore, H(2)S, an endogenous anti-oxidant gas,
antagonizes FA-induced cytotoxicity as well as 2-hydroxyquinoline, a specific
inhibitor of PON-1, which also induces cytotoxicity to PC12 cells. 4. The
results of the present study provide, for the first time, evidence that the
inhibitory effect on PON-1 expression and activity is involved in the
neurotoxicity of FA, and suggest a promising role of PON-1 as a novel
therapeutic strategy for FA-mediated toxicity.
http://www.ncbi.nlm.nih.gov/pubmed/21261675

“The results of the present study provide, for the first time, evidence that
the inhibitory effect on Paraoxonase-1 expression and activity is involved in
the neurotoxicity of Formaldehyde ...”

British Journal of Dermatology • May 2011

Biologic-induced urticaria due to polysorbate 80: usefulness of prick test L.
Pérez-Pérez, J. García-Gavín, B. Piñeiro andA. Zulaica Department of
Dermatology University Complex Hospital of Vigo C/ Porriño 5, 36209 Vigo
(Pontevedra), Spain Report Available For Purchase Only:
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2133.2011.10220.x/abstract

Virology Journal • June 2011

Genetic drift evolution under vaccination pressure among H5N1 Egyptian isolates
Author information Abdel-Moneim AS1, Afifi MA, El-Kady MF. Department of
Virology Faculty of Veterinary Medicine Beni-Suef University, Beni-Suef, Egypt
asa@bsu.edu.eg Abstract Background The highly pathogenic H5N1 is a major avian
pathogen that intensively affects the poultry industry in Egypt even in spite
of the adoption of vaccination strategy. Antigenic drift is among the
strategies the influenza virus uses to escape the immune system that might
develop due to the pressure of extensive vaccination. H5N1 mutates in an
intensified manner and is considered a potential candidate for the possible
next pandemic with all the catastrophic consequences such an eventuality will
entail. Methods H5N1 was isolated from the pooled organ samples of four
different affected flocks in specific pathogen free embryonated chicken eggs
(SPF-ECE). A reverse transcriptase polymerase chain reaction (RT-PCR) was
performed to the haemagglutingin and neuraminidase. Sequencing of the full
length haemagglutingin was performed. Sequence analyses of the isolated strains
were performed and compared to all available H5N1 from Egyptian human and avian
strains in the flu database. Changes in the different amino acid that may be
related to virus virulence, receptor affinity and epitope configuration were
assigned and matched with all available Egyptian strains in the flu database.
Results One out of the four strains was found to be related to the B2 Egyptian
lineage, 2 were related to A1 lineage and the 4th was related to A2 lineage.
Comparing data obtained from the current study by other available Egyptian H5N1
sequences remarkably demonstrates that amino acid changes in the immune escape
variants are remarkably restricted to a limited number of locations on the HA
molecule during antigenic drift. Molecular diversity in the HA gene, in
relevance to different epitopes, were not found to follow a regular trend,
suggesting abrupt cumulative sequence mutations. However a number of amino
acids were found to be subjected to high mutation pressure. Conclusion The
current data provides a comprehensive view of HA gene evolution among H5N1
subtype viruses in Egypt. Egyptian H5N1-AIVs are constantly undergoing genetic
changes and reveal a complex pattern of drifts. These findings raise the
concerns about the value of using influenza vaccines in correlation with the
development of antigenic drift in influenza epidemics. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146449/

“The current data provides a comprehensive view of HA gene evolution among H5N1
subtype viruses in Egypt. Egyptian H5N1-AIVs are constantly undergoing genetic
changes and reveal a complex pattern of drifts. These findings raise the
concerns about the value of using influenza vaccines in correlation with the
development of antigenic drift in influenza epidemics.”

Surgery Neurology International • July 2011

Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy
—A unifying hypothesis Russell L. Blaylock* and Joseph Maroon1 Theoretical
Neurosciences, LLC Visiting Professor of Biology Belhaven University, Jackson,
MS 315 Rolling Meadows Rd Ridgeland, MS 39157, USA 2. Department of
Neurosurgery, Heindl Scholar in Neuroscience University of Pittsburgh Medical
Center Team Neurosurgeon, The Pittsburgh Steelers, USA Abstract Some
individuals suffering from mild traumatic brain injuries, especially repetitive
mild concussions, are thought to develop a slowly progressive encephalopathy
characterized by a number of the neuropathological elements shared with various
neurodegenerative diseases. A central pathological mechanism explaining the
development of progressive neurodegeneration in this subset of individuals has
not been elucidated. Yet, a large number of studies indicate that a process
called immunoexcitotoxicity may be playing a central role in many
neurodegenerative diseases including chronic traumatic encephalopathy (CTE).
The term immunoexcitotoxicity was first coined by the lead author to explain
the evolving pathological and neurodevelopmental changes in autism and the Gulf
War Syndrome, but it can be applied to a number of neurodegenerative disorders.
The interaction between immune receptors within the central nervous system
(CNS) and excitatory glutamate receptors trigger a series of events, such as
extensive reactive oxygen species/reactive nitrogen species generation,
accumulation of lipid peroxidation products, and prostaglandin activation,
which then leads to dendritic retraction, synaptic injury, damage to
microtubules, and mitochondrial suppression. In this paper, we discuss the
mechanism of immunoexcitotoxicity and its link to each of the
pathophysiological and neurochemical events previously described with CTE, with
special emphasis on the observed accumulation of hyperphosphorylated tau.
[Although this report discusses traumatic brain injury the data discussed fits
in perfectly with and coincides with vaccine-induced brain injury and is
included for that reason] Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157093/

Vaccine • August 2011

Pandemic influenza H1N1 2009 infection in Victoria, Australia: no evidence for
harm or benefit following receipt of seasonal influenza vaccine in 2009 Author
information Kelly HA1, Grant KA, Fielding JE, Carville KS, Looker CO, Tran T,
Jacoby P. Victorian Infectious Diseases Reference Laboratory Melbourne,
Victoria, Australia heath.kelly@mh.org.au Abstract Conflicting findings
regarding the level of protection offered by seasonal influenza vaccination
against pandemic influenza H1N1 have been reported. We performed a testnegative
case control study using sentinel patients from general practices in Victoria
to estimate seasonal influenza vaccine effectiveness against laboratory proven
infection with pandemic influenza. Cases were defined as patients with an
influenza-like illness who tested positive for influenza while controls had an
influenza-like illness but tested negative. We found no evidence of significant
protection from seasonal vaccine against pandemic influenza virus infection in
any age group. Age-stratified point estimates, adjusted for pandemic phase,
ranged from 44% in persons aged less than 5 years to -103% (odds ratio=2.03) in
persons aged 50-64 years. Vaccine effectiveness, adjusted for age group and
pandemic phase, was 3% (95% CI -48 to 37) for all patients. Our study confirms
the results from our previous interim report, and other studies, that failed to
demonstrate benefit or harm from receipt of seasonal influenza vaccine in
patients with confirmed infection with pandemic influenza H1N1 2009.
http://www.ncbi.nlm.nih.gov/pubmed/?term=21473950

“Our study confirms the results from our previous interim report, and other
studies, that failed to demonstrate benefit or harm from receipt of seasonal
influenza vaccine ...”

Pharmazie • September 2011

Stability of the non-ionic surfactant polysorbate 80 investigated by HPLC-MS
and charged aerosol detector Author information Christiansen A1, Backensfeld T,
Kühn S, Weitschies W. Analytical Development Bayer Schering Pharma AG Berlin,
Germany Abstract An analytical method using HPLC coupled with a charged aerosol
detector (CAD) and a mass selective detector (MSD) was developed to
characterize the non-ionic surfactant polysorbate 80 (PS 80). The molecular
structure and heterogeneous composition due to isomers and various lengths of
PEG-chains make it difficult to develop sensitive and specific analytical
methods. Hence, there is only limited knowledge about the stability and purity
of this compound. Polysorbate 80 does not possess any chromophore, thus UV
detection is not applicable. Therefore, CAD and MSD have been used for
determination. The aim of this study was to characterize polysorbate 80 and to
examine its stability at pH 1.0 and 37 degrees C simulating harsh gastric
conditions. It was shown that this surfactant is liable to degradation under
these conditions. Within 8 h monoesters of PS 80 were hydrolyzed to an extent
of 9.5% (+/- 3.0%), whereas incubation in water did not result in any
detectable degradation. Furthermore, we demonstrated that HPLC-MS is a suitable
technique to investigate ethoxylated compounds like polysorbates.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22026121

“The aim of this study was to characterize polysorbate 80 and to examine its
stability at pH 1.0 and 37 degrees C simulating harsh gastric conditions. It
was shown that this surfactant is liable to degradation under these
conditions.”

Human And Experimental Toxicology • September 2011

Infant mortality rates regressed against number of vaccine doses routinely
given: Is there a biochemical or synergistic toxicity? Neil Z Miller and Gary S
Goldman Neil Z Miller PO Box 9638, Santa Fe, NM 87504, USA
neilzmiller@gmail.com Abstract The infant mortality rate (IMR) is one of the
most important indicators of the socio-economic well-being and public health
conditions of a country. The US childhood immunization schedule specifies 26
vaccine doses for infants aged less than 1 year—the most in the world—yet 33
nations have lower IMRs. Using linear regression, the immunization schedules of
these 34 nations were examined and a correlation coefficient of r = 0.70 (p <
0.0001) was found between IMRs and the number of vaccine doses routinely given
to infants. Nations were also grouped into five different vaccine dose ranges:
12–14, 15–17, 18–20, 21–23, and 24–26. The mean IMRs of all nations within each
group were then calculated. Linear regression analysis of unweighted mean IMRs
showed a high statistically significant correlation between increasing number
of vaccine doses and increasing infant mortality rates, with r = 0.992 (p =
0.0009). Using the Tukey-Kramer test, statistically significant differences in
mean IMRs were found between nations giving 12–14 vaccine doses and those
giving 21–23, and 24–26 doses. A closer inspection of correlations between
vaccine doses, biochemical or synergistic toxicity, and IMRs is essential.
Conclusion The US childhood immunization schedule requires 26 vaccine doses for
infants aged less than 1 year, the most in the world, yet 33 nations have
better IMRs. Using linear regression, the immunization schedules of these 34
nations were examined and a correlation coefficient of 0.70 (p < 0.0001) was
found between IMRs and the number of vaccine doses routinely given to infants.
When nations were grouped into five different vaccine dose ranges (12–14,
15–17, 18���20, 21–23, and 24–26), 98.3% of the total variance in IMR was
explained by the unweighted linear regression model. These findings demonstrate
a counter-intuitive relationship: nations that require more vaccine doses tend
to have higher infant mortality rates. Efforts to reduce the relatively high US
IMR have been elusive. Finding ways to lower preterm birth rates should be a
high priority. However, preventing premature births is just a partial solution
to reduce infant deaths. A closer inspection of correlations between vaccine
doses, biochemical or synergistic toxicity, and IMRs, is essential. All
nations—rich and poor, advanced and developing—have an obligation to determine
whether their immunization schedules are achieving their desired goals.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170075/

“These findings demonstrate a counter-intuitive relationship: nations that
require more vaccine doses tend to have higher infant mortality rates.”

BMC Immunology • October 2011

Immune enhancement by novel vaccine adjuvants in autoimmune-prone NZB/W F1
mice: relative efficacy and safety Author information Aachoui Y1, Ghosh SK.
Department of Biology Indiana State University Terre Haute, IN 47809, USA
Abstract BACKGROUND Vaccines have profoundly impacted global health although
concerns persist about their potential role in autoimmune or other adverse
reactions. To address these concerns, vaccine components like immunogens and
adjuvants require critical evaluation not only in healthy subjects but also in
those genetically averse to vaccine constituents. Evaluation in
autoimmune-prone animal models of adjuvants is therefore important in vaccine
development. The objective here was to assess the effectiveness of experimental
adjuvants: two phytol-derived immunostimulants PHIS-01 (phytanol) and PHIS-03
(phytanyl mannose), and a new commercial adjuvant from porcine small intestinal
submucosa (SIS-H), relative to a standard adjuvant alum. Phytol derivatives are
hydrophobic, oil-in water diterpenoids, while alum is hydrophilic, and SIS is
essentially a biodegradable and collagenous protein cocktail derived from
extracellular matrices. RESULTS We studied phthalate -specific and
cross-reactive anti-DNA antibody responses, and parameters associated with the
onset of autoimmune disorders. We determined antibody isotype and
cytokine/chemokine milieu induced by the above experimental adjuvants relative
to alum. Our results indicated that the phytol-derived adjuvant PHIS-01
exceeded alum in enhancing anti-phthalate antibody without much cross
reactivity with ds-DNA. Relatively, SIS and PHIS-03 proved less robust, but
they were also less inflammatory. Interestingly, these adjuvants facilitated
isotype switching of anti-hapten, but not of antiDNA response. The current
study reaffirms our earlier reports on adjuvanticity of phytol compounds and
SIS-H in non autoimmune-prone BALB/c and C57BL/6 mice. These adjuvants are as
effective as alum also in autoimmune-prone NZB/WF1 mice, and they have little
deleterious effects. CONCLUSION Although all adjuvants tested impacted
cytokine/chemokine milieu in favor of Th1/Th2 balance, the phytol compounds
fared better in reducing the onset of autoimmune syndromes. However, SIS is
least inflammatory among the adjuvants evaluated.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22024358

“Evaluation in autoimmune-prone animal models of adjuvants is therefore
important in vaccine development.”

Archives In Neurology • October 2011

Postvaccination Miller Fisher Syndrome Ashkan Shoamanesh, MD; Kristine Chapman,
MD; Anthony Traboulsee, MD Abstract Background Although postvaccination
Guillain-Barré syndrome is commonly reported, there have only been 2 previously
reported cases of postvaccination Miller Fisher syndrome, and none in
association with the novel influenza A(H1N1) vaccine. Objective To describe a
case of Miller Fisher syndrome following receipt of the seasonal influenza and
novel influenza A(H1N1) vaccine. Design Case report and literature review.
Setting Vancouver General Hospital. Patient A 77-year-old Chinese woman.
Results The patient presented with ophthalmoplegia, ataxia, areflexia, and a
sensory neuropathy within 2 weeks of immunization. Findings of parainfectious
evaluation were unremarkable. Treatment with 2 courses of intravenous
immunoglobulin led to clinical improvement. Her presentation and natural
history of disease were similar to the 2 previously published cases.
Conclusions We present the third case of postvaccination Miller Fisher syndrome
in the literature and the first associated with the novel influenza A(H1N1)
vaccine. The benefits of the development of vaccines and the ensuing modern
immunization programs are overwhelmingly without question. Nevertheless, there
is a growing public concern surrounding the potential for postvaccination
adverse events, a sentiment that has dwelled since their nascence.1 In view of
the recent novel influenza A(H1N1) pandemic and scramble toward developing new
vaccines for mass worldwide immunization campaigns, a better understanding of
these potential adverse events is vital. We present a case of Miller Fisher
syndrome (MFS) following seasonal influenza and novel influenza A(H1N1)
vaccination, as well as a review of the literature on postvaccination MFS.
http://archneur.jamanetwork.com/article.aspx?articleid=1107885&resultClick=3

“We present the third case of postvaccination Miller Fisher syndrome in the
literature and the first associated with the novel influenza A(H1N1) vaccine.”

Clinical Reviews In Allergy And Immunology • October 2011

Macrophagic myofaciitis a vaccine (alum) autoimmune-related disease Author
information Israeli E1, Agmon-Levin N, Blank M, Shoenfeld Y. Center for
Autoimmune Diseases Sheba Medical Center Tel-Hashomer, Israel Abstract
Macrophagic myofasciitis (MMF) is an immune-mediated condition first reported
in 1998. MMF is characterized by post-vaccination systemic manifestations as
well as local-stereotyped and immunologically active lesion in the site of
inoculation (deltoid muscle). MMF systemic symptoms included myalgias,
arthralgias, marked asthenia, muscle weakness, chronic fatigue, and fever.
Recently, studies demonstrated that the local lesion is due to persistence for
years at site of injection of an aluminum (Al(OH)3) adjuvant commonly used in
human vaccines. Time elapsed from last immunization with an Al(OH)3-containing
vaccine to muscle biopsy range from 3 months to 8 years; in rare cases, MMF may
be diagnosed even 10 years post-vaccination. The discrepancy between the wide
applications of aluminum hydroxidecontaining vaccines and the very limited
number of MMF cases reported may be resolved by observations suggesting that
aluminum-containing vaccinations may trigger MMF in genetically susceptible
subjects carrying the HLADRB1*01. Thus, MMF may be defined as an emerging novel
condition that may be triggered by exposure to alum-containing vaccines, in
patients with a specific genetic background, and this temporal association may
be exhibited from a few months up to 10 years.
http://www.ncbi.nlm.nih.gov/pubmed/?term=20882368

“MMF may be defined as an emerging novel condition that may be triggered by
exposure to alum-containing vaccines ... and this temporal association may be
exhibited from a few months up to 10 years.”

Infectious Disease Clinics Of North America • December 2011

The common immunogenic etiology of chronic fatigue syndrome: from infections to
vaccines via adjuvants to the ASIA syndrome Author information Rosenblum H1,
Shoenfeld Y, Amital H. Department of Medicine B Sheba Medical Center Sackler
Faculty of Medicine Tel Aviv University, Ramat Aviv Tel-Hashomer 52621, Israel
Abstract Chronic fatigue syndrome (CFS) is characterized by unexplained fatigue
that lasts for at least 6 months with a constellation of other symptoms. Most
cases start suddenly, and are usually accompanied by a flu-like illness. It is
a symptom-based diagnosis of exclusion, the pathogenesis of which is unknown.
Studies have examined and hypothesized about the possible biomedical and
epidemiologic characteristics of the disease, including genetic predisposition,
infections, endocrine abnormalities, and immune dysfunction and psychological
and psychosocial factors. Recently, the AISA (autoimmune/inflammatory syndrome
induced by adjuvants) syndrome was recognized, indicating the possible
contribution of adjuvants and vaccines to the development of autoimmunity.
http://www.ncbi.nlm.nih.gov/pubmed/22054760

“Recently, the AISA (autoimmune/inflammatory syndrome induced by adjuvants)
syndrome was recognized, indicating the possible contribution of adjuvants and
vaccines to the development of autoimmunity.”

Medical Hypotheses • December 2011

Hypothesis: conjugate vaccines may predispose children to autism spectrum
disorders Author information Richmand BJ1. brichmand@gmail.com Abstract The
first conjugate vaccine was approved for use in the US in 1988 to protect
infants and young children against the capsular bacteria Haemophilus influenzae
type b (Hib). Since its introduction in the US, this vaccine has been approved
in most developed countries, including Denmark and Israel where the vaccine was
added to their national vaccine programs in 1993 and 1994, respectively. There
have been marked increases in the reported prevalence of autism spectrum
disorders (ASDs) among children in the US beginning with birth cohorts in the
late 1980s and in Denmark and Israel starting approximately 4-5 years later.
Although these increases may partly reflect ascertainment biases, an exogenous
trigger could explain a significant portion of the reported increases in ASDs.
It is hypothesized here that the introduction of the Hib conjugate vaccine in
the US in 1988 and its subsequent introduction in Denmark and Israel could
explain a substantial portion of the initial increases in ASDs in those
countries. The continuation of the trend toward increased rates of ASDs could
be further explained by increased usage of the vaccine, a change in 1990 in the
recommended age of vaccination in the US from 15 to 2 months, increased
immunogenicity of the vaccine through changes in its carrier protein, and the
subsequent introduction of the conjugate vaccine for Streptococcus pneumoniae.
Although conjugate vaccines have been highly effective in protecting infants
and young children from the significant morbidity and mortality caused by Hib
and S. pneumoniae, the potential effects of conjugate vaccines on neural
development merit close examination. Conjugate vaccines fundamentally change
the manner in which the immune systems of infants and young children function
by deviating their immune responses to the targeted carbohydrate antigens from
a state of hypo-responsiveness to a robust B2 B cell mediated response. This
period of hypo-responsiveness to carbohydrate antigens coincides with the
intense myelination process in infants and young children, and conjugate
vaccines may have disrupted evolutionary forces that favored early brain
development over the need to protect infants and young children from capsular
bacteria. http://www.ncbi.nlm.nih.gov/pubmed/?term=21993250

“This period of hypo-responsiveness to carbohydrate antigens coincides with the
intense myelination process in infants and young children, and conjugate
vaccines may have disrupted evolutionary forces that favored early brain
development over the need to protect infants and young children from capsular
bacteria.”

Reumatismo • 2011

‘ASIA’ Autoimmune/inflammatory syndrome induced by adjuvants: even and odd
Author information Perricone C1, Alessandri C, Valesini G. Reumatologia
Dipartimento di Medicina Interna e Specialità Mediche Sapienza Università di
Roma, Viale del Policlinico 155 Rome, Italy carlo.perricone@gmail.com Abstract
Recently, Shoenfeld and Agmon-Levin described a potential new syndrome, namely
ASIA - autoimmune/inflammatory syndrome induced by adjuvants, that comprises
four medical conditions: siliconosis, the Gulf war syndrome, the macrophagic
myofasciitis syndrome and post-vaccination phenomena, characterized by
hyperactive immune responses accompanied by a similar complex of signs and
symptoms. Most relevantly, these conditions share a linkage represented by
adjuvants. This common soil may possibly induce autoimmune or auto-inflammatory
diseases in humans as it was demonstrated in different animal models.
Reconsidering under a unified umbrella this apparently detached condition is
not only intriguing, but also provocative, and may help in unraveling novel
pathogenetic mechanisms, preventive measures, and therapeutic targets.
http://www.ncbi.nlm.nih.gov/pubmed/21776441

“This common soil may possibly induce autoimmune or auto-inflammatory diseases
in humans as it was demonstrated in different animal models.”

Public Health Report • 2011

Highlights of Historical Events Leading to National Surveillance of Vaccination
Coverage in the United States Author Information Philip J. Smith, PhD,a David
Wood, MD, MPH,b and Paul M. Darden, MDc aCenters for Disease Control and
Prevention National Center for Immunization and Respiratory Diseases, Atlanta,
GA bUniversity of Florida, College of Medicine Community Pediatrics,
Jacksonville, FL cUniversity of Oklahoma Health Sciences Center General &
Community Pediatrics, Oklahoma City, OK Abstract The articles published in this
special supplement of Public Health Reports provide examples of only some of
the current efforts in the United States for evaluating vaccination coverage.
So, how did we get here? The history of vaccination and assessment of
vaccination coverage in the U.S. has its roots in the pre-Revolutionary War
era. In many cases, development of vaccines, and attention devoted to the
assessment of vaccination coverage, has grown from the impact of infectious
disease on major world events such as wars. The purpose of this commentary is
to provide a brief overview of the key historical events in the U.S. that
influenced the development of vaccines and the efforts to track vaccination
coverage, which laid the foundation for contemporary vaccination assessment
efforts. Full Report • Recommended Reading
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113425/

“The history of vaccination and assessment of vaccination coverage in the U.S.
has its roots in the pre-Revolutionary War era.”

JAMA • January 2012

Serum Vaccine Antibody Concentrations in Children Exposed to Perfluorinated
Compounds Philippe Grandjean, MD, DMSc; Elisabeth Wreford Andersen, PhD; Esben
Budtz-Jørgensen, PhD; Flemming Nielsen, PhD; Kåre Mølbak, MD, DMSc; Pal Weihe,
MD; Carsten Heilmann, MD, DMSc Abstract Context Perfluorinated compounds (PFCs)
have emerged as important food contaminants. They cause immune suppression in a
rodent model at serum concentrations similar to those occurring in the US
population, but adverse health effects of PFC exposure are poorly understood.
Objective To determine whether PFC exposure is associated with antibody
response to childhood vaccinations. Design, Setting, and Participants
Prospective study of a birth cohort from the National Hospital in the Faroe
Islands. A total of 656 consecutive singleton births were recruited during
1997-2000, and 587 participated in follow-up through 2008. Main Outcome
Measures Serum antibody concentrations against tetanus and diphtheria toxoids
at ages 5 and 7 years. Results Similar to results of prior studies in the
United States, the PFCs with the highest serum concentrations were
perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Among
PFCs in maternal pregnancy serum, PFOS showed the strongest negative
correlations with antibody concentrations at age 5 years, for which a 2-fold
greater concentration of exposure was associated with a difference of ∼39% (95%
CI, ∼55% to ∼17%) in the diphtheria antibody concentration. PFCs in the child’s
serum at age 5 years showed uniformly negative associations with antibody
levels, especially at age 7 years, except that the tetanus antibody level
following PFOS exposure was not statistically significant. In a structural
equation model, a 2-fold greater concentration of major PFCs in child serum was
associated with a difference of ∼49% (95% CI, ∼67% to ∼23%) in the overall
antibody concentration. A 2-fold increase in PFOS and PFOA concentrations at
age 5 years was associated with odds ratios between 2.38 (95% CI, 0.89 to 6.35)
and 4.20 (95% CI, 1.54 to 11.44) for falling below a clinically protective
level of 0.1 IU/mL for tetanus and diphtheria antibodies at age 7 years.
Conclusion Elevated exposures to PFCs were associated with reduced humoral
immune response to routine childhood immunizations in children aged 5 and 7
years. http://jama.jamanetwork.com/article.aspx?articleid=1104903&resultClick=3

“Elevated exposures to PFCs were associated with reduced humoral immune
response to routine childhood immunizations in children aged 5 and 7 years.”

Journal Of Pharmacology And Pharmacotherapeutics • January 2012

Diphtheria, pertussis (whooping cough), and tetanus vaccine induced recurrent
seizures and acute encephalopathy in a pediatric patient: Possibly due to
pertussis fraction Author information Patel MK1, Patel TK, Tripathi CB.
Department of Pharmacology Government Medical College Bhavnagar, Gujarat, India
Abstract A 5-month-old male patient developed recurrent seizures and acute
encephalopathy possibly due to first dose of diphtheria, pertussis (whooping
cough), and tetanus (DPT) vaccine used for routine immunization. Postreaction
computed tomography (CT) scan of brain, magnetic resonance imaging (MRI) of
brain, and electroencephalogram were normal. Pertussis fraction of DPT vaccine
is responsible for this reaction. It is suggested that acellular pertussis
vaccine should be used instead of whole cell vaccine because it is associated
with lower frequency of neurological complications, such as seizures,
encephalopathy, and hypotensive episodes. However, acellular
pertussis-containing vaccines are currently not affordable in most developing
countries. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3284047/

“It is suggested that acellular pertussis vaccine should be used instead of
whole cell vaccine because it is associated with lower frequency of
neurological complications, such as seizures, encephalopathy, and hypotensive
episodes.”

Lupus • February 2012

Influenza vaccination can induce new-onset anticardiolipins but not
B2-glycoprotein-I antibodies among patients with systemic lupus erythematosus
Author information Vista ES1, Crowe SR, Thompson LF, Air GM, Robertson JM,
Guthridge JM, James JA. 1. Oklahoma Medical Research Foundation, Oklahoma City,
OK 73104, USA Abstract BACKGROUND Antiphospholipid syndrome is characterized by
autoantibodies against cardiolipins (aCL), lupus anticoagulant, and independent
B2-glycoprotein (B2GPI). Controversy exists as to whether vaccination triggers
the development of antiphospholipid antibodies (aPL) in patients with systemic
lupus erythematosus (SLE). METHODS Patients with SLE (101) and matched controls
(101) were enrolled from 20052009 and received seasonal influenza vaccinations.
Sera were tested by ELISA for aCL at baseline, 2, 6, and 12 weeks after
vaccination. Vaccine responses were ranked according to an overall
anti-influenza antibody response index. Individuals with positive aCL were
further tested for B2GPI antibodies. RESULTS Patients with SLE and healthy
controls can develop new-onset aCL post vaccination, although at rates which do
not differ between patients and controls (12/101 cases and 7/101 controls, OR
1.81, p = 0.34). New-onset moderate aCL are slightly enriched in African
American SLE patients (5/36 cases; p = 0.094). The optical density measurements
for aCL reactivity in patients were significantly higher than baseline at 2
weeks (p < 0.05), 6 weeks (p < 0.05), and 12 weeks (p < 0.05) post vaccination.
No new B2GPI antibodies were detected among patients with new aCL reactivity.
Vaccine response was not different between patients with and without new-onset
aCL reactivity (p = 0.43). CONCLUSIONS This study shows transient increases in
aCL, but not anti-B2GPI responses, after influenza vaccination.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22235049

“Controversy exists as to whether vaccination triggers the development of
antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus
(SLE). This study shows transient increases in aCL, but not anti-B2GPI
responses, after influenza vaccination.”

Lupus • February 2012

Autoimmune response following influenza vaccination in patients with autoimmune
inflammatory rheumatic disease Author information Perdan-Pirkmajer K1,
Thallinger GG, Snoj N, 1. University Medical Centre Ljubljana Department of
Rheumatology Ljubljana, Slovenia Abstract Vaccines have undoubtedly brought
overwhelming benefits to mankind and are considered safe and effective.
Nevertheless, they can occasionally stimulate autoantibody production or even a
recently defined syndrome known as autoimmune/inflammatory syndrome induced by
adjuvants (ASIA). There is scarce data regarding autoimmune response after
seasonal/influenza A (H1N1) vaccine in patients with autoimmune inflammatory
rheumatic disease (AIRD). The objective of our study was therefore to determine
autoimmune response in a large group of AIRD patients vaccinated against
seasonal and/or H1N1 influenza. We conducted a prospective cohort study with a
6-month follow-up. Two-hundred and eighteen patients with AIRD (50 vaccinated
against seasonal influenza, six against H1N1, 104 against both, 58
non-vaccinated controls) and 41 apparently healthy controls (nine vaccinated
against seasonal influenza, three against H1N1, 18 against both, 11
nonvaccinated controls) were included. Blood samples were taken and screened
for autoantibodies [antinuclear antibody (ANA), anti-extractable nuclear
antigen (antiENA), anticardiolipin (aCL) IgG/IgM antibodies, anti-beta
2-glycoprotein I (anti∼2GPI)] at inclusion in the study, before each
vaccination, 1 month after the last vaccination and 6 months after inclusion.
For non-vaccinated participants (patients and healthy controls) blood samples
were taken at the time of inclusion in the study and 6 months later. We report
that after the administration of seasonal/H1N1 vaccine there were mostly
transient changes in autoantibody production in AIRD patients and in healthy
participants. However, a small subset of patients, especially ANA-positive
patients, had a tendency towards anti-ENA development. Although no convincing
differences between the seasonal and H1N1 vaccines were observed, our results
imply that there might be a slight tendency of the H1N1 vaccine towards aCL
induction. Although seasonal and H1N1 vaccines are safe and effective, they
also have the potential to induce autoantibodies in selected AIRD patients and
healthy adults. Follow-up of such individuals is proposed and further research
is needed. http://www.ncbi.nlm.nih.gov/pubmed/?term=22235050

“they [vaccines] can occasionally stimulate autoantibody production or even a
recently defined syndrome known as autoimmune/inflammatory syndrome induced by
adjuvants (ASIA).”

Lupus • February 2012

Aluminum as an adjuvant in Crohn’s disease induction Author information Lerner
A. Pediatric Gastroenterology and Nutrition Unit Carmel Medical Center, Haifa,
Israel lerner_aaron@clalit.org.il Abstract Alum (AlK(SO(4))(2)) is an adjuvant
commonly utilized in vaccines, and is a ubiquitous element used extensively in
contemporary life. Food, air, water, waste, the earth’s surface, and
pharmaceuticals all represent pathways of aluminum (Al) exposure. Crohn’s
disease (CD) is a chronic relapsing intestinal inflammation in genetically
susceptible individuals and is caused by yet unidentified environmental
factors. Al is a potential factor for the induction of inflammation in CD, and
its immune activities share many characteristics with the immune pathology of
CD: many luminal bacterial or dietary compounds can be adsorbed to the metal
surface and induce Th1 profile cytokines, shared cytokines/ chemokines,
co-stimulatory molecules, and intracellular pathways and stress-related
molecular expression enhancement, affecting intestinal macrobiota, trans-mural
granuloma formation, and colitis induction in an animal CD model. The
inflammasome plays a central role in Al mode of action and in CD
pathophysiology. It is suggested that Al adjuvant activity can fit between the
aberrations of innate and adaptive immune responses occurring in CD. The CD
mucosa is confronted with numerous inappropriate bacterial components adsorbed
on the Al compound surface, constituting a pro-inflammatory supra-adjuvant. Al
fits the diagnostic criteria of the newly described autoimmune/inflammatory
syndrome induced by adjuvants. If a cause and effect relationship can be
established, the consequences will greatly impact public health and CD
prevention and management. http://www.ncbi.nlm.nih.gov/pubmed/22235058

“The inflammasome plays a central role in Aluminum mode of action and in
Crohn’s Disease (CD) pathophysiology. It is suggested that Aluminum adjuvant
activity can fit between the aberrations of innate and adaptive immune
responses occurring in Crohn’s Disease. The CD mucosa is confronted with
numerous inappropriate bacterial components adsorbed on the Aluminum compound
surface, constituting a pro-inflammatory supra-adjuvant. Aluminum fits the
diagnostic criteria ...”

Lupus • February 2012

Adjuvant immunization induces high levels of pathogenic antiphospholipid
antibodies in genetically prone mice: another facet of the ASIA syndrome Author
information Katzav A1, Kivity S, Blank M, Shoenfeld Y, Chapman J. Department of
Neurology and Sagol Center for Neurosciences Sheba Medical Center, affiliated
to the Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel
avivakatzav@gmail.com Abstract Adjuvants may induce autoimmune diseases in
susceptible individuals, a phenomenon recently defined as
autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Patients with
both antiphospholipid antibodies (aPL) and the genetic coagulopathy factor V
Leiden (FVL) are frequently found. We therefore evaluated whether adjuvant can
induce aPL in heterozygous FVL mice. aPL were measured in naïve mice and at 1
and 5 months after immunization with either complete or incomplete Freund’s
adjuvant (CFA, IFA) in FVL and control C57/B6 background mice. We defined
antibody levels 3 SD above the mean of C57/B6 mice immunized with adjuvant as
positive (specificity of 99%). For B(2)GPI-dependent aPL, 28.6% (6/21) of FVL
mice 5 months after immunization with adjuvant (both IFA and CFA) were positive
compared with 4.8% (1/22) of FVL mice 1 month after adjuvant and 0% of naïve
FVL and C57/B6 mice (0/16, p < 0.001). aPL levels correlated with behavioral
hyperactivity in the staircase test. FVL mice immunized with adjuvant did not
develop B(2)GPI-independent aPL. We hypothesize that the FVL aPL association is
not a coincidence, but that chronic coagulation defects combined with external
inflammatory stimuli analogous to adjuvant may induce aPL and also
antiphospholipid syndrome, thus supporting the notion of ASIA.
http://www.ncbi.nlm.nih.gov/pubmed/22235055

“Adjuvants may induce autoimmune diseases in susceptible individuals, a
phenomenon recently defined as autoimmune/ inflammatory syndrome induced by
adjuvants (ASIA).”

Lupus • February 2012

Autoimmunity following hepatitis B vaccine as part of the spectrum of
‘Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants’ (ASIA): analysis
of 93 cases Author information Zafrir Y1, Agmon-Levin N, Paz Z, Shilton T,
Shoenfeld Y. The Zabludowicz Center for Autoimmune Diseases, Sheba Medical
Center, Tel-Hashomer, Israel Abstract OBJECTIVES In this study we analyzed the
clinical and demographic manifestations among patients diagnosed with immune/
autoimmune-mediated diseases post-hepatitis B vaccination. We aimed to find
common denominators for all patients, regardless of different diagnosed
diseases, as well as the correlation to the criteria of Autoimmune
(Autoinflammatory) Syndrome induced by Adjuvants (ASIA).

“Manifestations that were commonly reported

PATIENTS AND METHODS We have retrospectively analyzed the medical records of
114 patients, from different centers in the USA, diagnosed with immune-mediated
diseases following immunization with hepatitis-B vaccine (HBVv). All patients
in this cohort sought legal consultation. Of these, 93/114 patients diagnosed
with disease before applying for legal consultation were included in the study.
All medical records were evaluated for demographics, medical history, number of
vaccine doses, peri-immunization adverse events and clinical manifestations of
diseases. In addition, available blood tests, imaging results, treatments and
outcomes were recorded. Signs and symptoms of the different immune-mediated
diseases were grouped according to the organ or system involved. ASIA criteria
were applied to all patients.

included neuro-psychiatric (70%),

RESULTS The mean age of 93 patients was 26.5 ± 15 years; 69.2% were female and
21% were considered autoimmune susceptible. The mean latency period from the
last dose of HBVv and onset of symptoms was 43.2 days. Of note, 47% of patients
continued with the immunization program despite experiencing adverse events.
Manifestations that were commonly reported included neuro-psychiatric (70%),
fatigue (42%) mucocutaneous (30%), musculoskeletal (59%) and gastrointestinal
(50%) complaints. Elevated titers of autoantibodies were documented in 80% of
sera tested. In this cohort 80/93 patients (86%), comprising 57/59 (96%) adults
and 23/34 (68%) children, fulfilled the required criteria for ASIA.

gastrointestinal (50%) complaints.”

CONCLUSIONS Common clinical characteristics were observed among 93 patients
diagnosed with immune-mediated conditions post-HBVv, suggesting a common
denominator in these diseases. In addition, risk factors such as history of
autoimmune diseases and the appearance of adverse event(s) during immunization
may serve to predict the risk of post-immunization diseases. The ASIA criteria
were found to be very useful among adults with post-vaccination events. The
application of the ASIA criteria to pediatric populations requires further
study. http://www.ncbi.nlm.nih.gov/pubmed/22235045

fatigue (42%) mucocutaneous (30%), musculoskeletal (59%) and

Lupus • February 2012

Macrophagic myofasciitis: characterization and pathophysiology Author
information Gherardi RK1, Authier FJ. 1. AP-HP, Hôpital H. Mondor, France
Abstract Aluminium oxyhydroxide (alum), a nanocrystalline compound forming
agglomerates, has been used in vaccines for its immunological adjuvant effect
since 1927. Alum is the most commonly used adjuvant in human and veterinary
vaccines, but the mechanisms by which it stimulates immune responses remain
incompletely understood. Although generally well tolerated, alum may
occasionally cause disabling health problems in presumably susceptible
individuals. A small proportion of vaccinated people present with delayed onset
of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very
long-term persistence of alum-loaded macrophages at the site of previous
intramuscular (i.m.) immunization, forming a granulomatous lesion called
macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are
paradigmatic of the recently delineated ‘autoimmune/inflammatory syndrome
induced by adjuvants’ (ASIA). The stereotyped cognitive dysfunction is
reminiscent of cognitive deficits described in foundry workers exposed to
inhaled Al particles. Alum safety concerns will largely depend on whether the
compound remains localized at the site of injection or diffuses and accumulates
in distant organs. Animal experiments indicate that biopersistent nanomaterials
taken up by monocyte-lineage cells in tissues, such as fluorescent alum
surrogates, can first translocate to draining lymph nodes, and thereafter
circulate in blood within phagocytes and reach the spleen, and, eventually,
slowly accumulate in the brain.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22235051

“Animal experiments indicate that biopersistent nanomaterials taken up by
monocyte-lineage cells in tissues, such as fluorescent alum surrogates, can
first translocate to draining lymph nodes, and thereafter circulate in blood
within phagocytes and reach the spleen, and, eventually, slowly accumulate in
the brain.”

Lupus • February 2012

Gulf War syndrome as a part of the autoimmune (autoinflammatory) syndrome
induced by adjuvant (ASIA) Author information Israeli E. 1. The Zabludowicz
Center for Autoimmune Diseases Chaim Sheba Medical Center, Tel-Hashomer, Israel
eitanister@gmail.com Abstract Gulf War syndrome (GWS) is a multi-symptom
condition comprising a variety of signs and symptoms described in the
literature, which not been fully resolved. The various symptoms of the
condition include muscle fatigue and tiredness, malaise, myalgia, impaired
cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances,
headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep
disturbances. In addition, excessive chemical sensitivity and odour intolerance
is reported. The aetiology of the condition is unclear, but many reviews and
epidemiological analyses suggest association with pyridostigmine bromide (PB),
certain vaccination regimes, a variety of possible chemical exposures,
including smoke from oil-well fires or depleted uranium from shells, as well as
physical and psychological stress. Recently, Shoenfeld et al. suggested that
four conditions--siliconosis, macrophagic myofaciitis (MMF), GWS and
post-vaccination phenomena--that share clinical and pathogenic resemblances,
may be incorporated into common syndrome called ‘Autoimmune (Autoinflammatory)
Syndrome induced by Adjuvants’ (ASIA). Symptoms and signs of the four
conditions described by Shoenfeld et al. show that at least eight out of ten
main symptoms are in correlation in all four conditions. Namely, myalgia,
arthralgias, chronic fatigue, neurological cognitive impairment,
gastrointestinal symptoms, respiratory symptoms, skin manifestations and
appearance of autoantibodies. Regardless of the aetiology of GWS, be it
exposure to environmental factors or chemical drugs, vaccinations or the
adjuvants in them, GWS fits well with the definition of ASIA and is included as
part of ‘Shoenfeld’s syndrome’.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22235052

“Recently, Shoenfeld et al. suggested that four conditions—siliconosis,
macrophagic myofaciitis (MMF), GWS and post-vaccination phenomena—that share
clinical and pathogenic resemblances, may be incorporated into common syndrome
called ‘Autoimmune (Autoinflammatory) Syndrome induced by Adjuvants’ (ASIA).
Symptoms and signs of the four conditions described by Shoenfeld et al. show
that at least eight out of ten main symptoms are in correlation in all four
conditions. Namely, myalgia, arthralgias, chronic fatigue, neurological
cognitive impairment, gastrointestinal symptoms, respiratory symptoms, skin
manifestations and appearance of autoantibodies.”

Lupus • February 2012

Vaccine model of antiphospholipid syndrome induced by tetanus vaccine Institute
of Virology, Vaccines and Sera-Torlak Department of Research and Development,
Belgrade, Serbia ljiljana.dimitrijevic@gmail.com Abstract Successful induction
of antiphospholipid syndrome (APS) in two different non-autoimmune prone mouse
strains, BALB/c and C57BL/6, was achieved by tetanus toxoid (TTd)
hyperimmunization using different adjuvants (glycerol or aluminium hydroxide),
and different adjuvant pretreatments (glycerol or Complete Freund’s Adjuvant
(CFA)). APS had different manifestations of reproductive pathology in BALB/c
and C57BL/6 mice: fetal resorption (as a consequence of extreme T-cell
activation obtained in the course of pretreatment), and lowering of fecundity
(as a consequence of polyclonal B-cell stimulation), respectively. In BALB/c
mice fetal resorption coincided with glycerol and CFA pretreatments, while in
C57BL/6 mice lowering of fecundity was most obvious in CFA-pretreated mice
immunized with TTd in aluminium hydroxide. Both molecular mimicry and
polyclonal B-cell activation occur in APS induction, with molecular mimicry
effects being dominant in BALB/c mice, and polyclonal cell activation being
dominant in C57BL/6 mice. Confirmation of molecular mimicry effects, which in
the condition of T-cell stimulation generated fetal resorptions in the BALB/c
strain, was achieved by passive infusion of monoclonal antibody (MoAb) T-26
specific for TTd and anti-∼(2)-glycoprotein I obtained after TTd
hyperimunization. High polyclonal B-cell activation in C57BL/6 mice prevented
fetal resorption but induced fecundity lowering, as was the case in passive
administration of MoAb T-26 in this mouse strain. Passive infusion of
anti-idiotypic MoAb Y7 into C57BL/6 mice induced fetal resorptions and
confirmed the above suggestion on the protective role of polyclonal B-cell
stimulation in fetal resorptions.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22235053

“Successful induction of antiphospholipid syndrome (APS) in two different
non-autoimmune prone mouse strains ... was achieved by tetanus toxoid (TTd)
hyperimmunization using different adjuvants (glycerol or aluminium hydroxide),
and different adjuvant pretreatments (glycerol or Complete Freund’s Adjuvant
(CFA).”

Lupus • February 2012

Oily adjuvants and autoimmunity: now time for reconsideration? Author
information Whitehouse M. School of Medicine, Griffith University Gold Coast,
Queensland, Australia whitehousemd@spin.net.au Abstract Immunologists have
relied heavily on oil-based adjuvants to generate antibodies or induce
auto-allergic responses in experimental animals. These are rarely used today
for human vaccination because of their persistent irritancies and propensity to
cause ulcers at sites of injection. However oily materials with adjuvant
properties abound in our modern environment, both personal and extraneous.
Their inadvertent impact as cryptotoxins may contribute to the rising incidence
of auto-allergic diseases in recent times. Experimentally, the potential
adjuvanticity of various oils, fats and other lipids can be evaluated by their
ability (or otherwise) to induce auto-allergic disease(s) in rats and mice
with, or even without, the addition of a mycobacterial immunostimulant. Genetic
factors have been recognized that determine an animal’s susceptibility or
resistance to these oil-induced immunopathies. So it may be profitable to
further characterize these factors, first in animals and then perhaps in human
populations, to help find ways to enhance natural resistance to those
adjuvant-active oils that may be widely distributed in the personal
environment, notably mineral oil(s). (The six tables in this article summarize
some relevant facts and a few conjectures.) A caveat: This review is restricted
to the adjuvant properties of some oils in the personal environment. It does
not cover the mechanisms of adjuvanticity.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22235056

“Immunologists have relied heavily on oil-based adjuvants to generate
antibodies or induce auto-allergic responses in experimental animals. These are
rarely used today for human vaccination because of their persistent irritancies
and propensity to cause ulcers at sites of injection. However oily materials
with adjuvant properties abound in our modern environment, both personal and
extraneous. Their inadvertent impact as cryptotoxins may contribute to the
rising incidence of auto-allergic diseases in recent times.”

Lupus • February 2012

Induction of the ‘ASIA’ syndrome in NZB/NZWF1 mice after injection of complete
Freund’s adjuvant (CFA) Author information Bassi N1, Luisetto R, Del Prete D,
Ghirardello A, Ceol M, Rizzo S, Iaccarino L, Gatto M, Valente ML, Punzi L,
Doria A. Division of Rheumatology Department of Clinical and Experimental
Medicine University of Padova, Italy Abstract Adjuvants, commonly used in
vaccines, may be responsible for inducing autoimmunity and autoimmune diseases,
both in humans and mice. The so-called ‘ASIA’ (Autoimmune/inflammatory Syndrome
Induced by Adjuvants) syndrome has been recently described, which is caused by
the exposure to a component reproducing the effect of adjuvants. The aim of our
study was to evaluate the effect of injection of complete Freund’s adjuvant
(CFA) in NZB/NZWF1 mice, a lupus-prone murine model. We injected 10 NZB/NZWF1
mice with CFA/PBS and 10 with PBS, three times, 3 weeks apart, and followed-up
until natural death. CFA-injected mice developed both anti-double-stranded DNA
and proteinuria earlier and at higher levels than the control group.
Proteinuria-free survival rate and survival rate were significantly lower in
CFA-treated mice than in the control mice (p = 0.002 and p = 0.001,
respectively). Histological analyses showed a more severe glomerulonephritis in
CFA-injected mice compared with the control mice. In addition, lymphoid
hyperplasia in spleen and lungs, myocarditis, and vasculitis were observed in
the former, but not in the latter group. In conclusion, the injection of CFA in
NZB/NZWF1 mice accelerated autoimmune manifestations resembling ‘ASIA’ syndrome
in humans. http://www.ncbi.nlm.nih.gov/pubmed/22235054

“... lymphoid hyperplasia in spleen and lungs, myocarditis, and vasculitis were
observed in the former, but not in the latter group. In conclusion, the
injection of Complete Freund’s Adjuvant (CFA) [a vaccine ingredient] in
NZB/NZWF1 mice accelerated autoimmune manifestations resembling ‘ASIA’ syndrome
in humans.”

[complete Freund’s adjuvant is used in some vaccines]

“The design and reporting of safety outcomes in MMR vaccine studies,
both pre- and post-marketing, are largely inadequate. The evidence of adverse
events following immunisation with the MMR vaccine cannot be separated from its
role in preventing the target diseases.”

Cochrane Database Of Systematic Reviews • February 2012

Vaccines for measles, mumps and rubella in children Author information
Demicheli V1, Rivetti A, Debalini MG, Di Pietrantonj C. Servizio Regionale di
Riferimento per l’Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field,
Azienda Sanitaria Locale ASL AL,Alessandria, Italy vdemicheli@aslal.it Abstract
BACKGROUND Mumps, measles and rubella (MMR) are serious diseases that can lead
to potentially fatal illness, disability and death. However, public debate over
the safety of the trivalent MMR vaccine and the resultant drop in vaccination
coverage in several countries persists, despite its almost universal use and
accepted effectiveness. OBJECTIVES To assess the effectiveness and adverse
effects associated with the MMR vaccine in children up to 15 years of age.
SEARCH METHODS For this update we searched the Cochrane Central Register of
Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), which
includes the Cochrane Acute Respiratory Infections Group’s Specialised
Register, PubMed (July 2004 to May week 2, 2011) and Embase.com (July 2004 to
May 2011). SELECTION CRITERIA We used comparative prospective or retrospective
trials assessing the effects of the MMR vaccine compared to placebo, do nothing
or a combination of measles, mumps and rubella antigens on healthy individuals
up to 15 years of age. DATA COLLECTION AND ANALYSIS Two review authors
independently extracted data and assessed methodological quality of the
included studies. One review author arbitrated in case of disagreement.

MAIN RESULTS We included five randomised controlled trials (RCTs), one
controlled clinical trial (CCT), 27 cohort studies, 17 case-control studies,
five time-series trials, one case cross-over trial, two ecological studies, six
self controlled case series studies involving in all about 14,700,000 children
and assessing effectiveness and safety of MMR vaccine. Based on the available
evidence, one MMR vaccine dose is at least 95% effective in preventing clinical
measles and 92% effective in preventing secondary cases among household
contacts.Effectiveness of at least one dose of MMR in preventing clinical mumps
in children is estimated to be between 69% and 81% for the vaccine prepared
with Jeryl Lynn mumps strain and between 70% and 75% for the vaccine containing
the Urabe strain. Vaccination with MMR containing the Urabe strain has
demonstrated to be 73% effective in preventing secondary mumps cases.
Effectiveness of Jeryl Lynn containing MMR in preventing laboratory-confirmed
mumps cases in children and adolescents was estimated to be between 64% to 66%
for one dose and 83% to 88% for two vaccine doses. We did not identify any
studies assessing the effectiveness of MMR in preventing rubella.The highest
risk of association with aseptic meningitis was observed within the third week
after immunisation with Urabe-containing MMR (risk ratio (RR) 14.28; 95%
confidence interval (CI) from 7.93 to 25.71) and within the third (RR 22.5; 95%
CI 11.8 to 42.9) or fifth (RR 15.6; 95% CI 10.3 to 24.2) weeks after
immunisation with the vaccine prepared with the Leningrad-Zagreb strain. A
significant risk of association with febrile seizures and MMR exposure during
the two previous weeks (RR 1.10; 95% CI 1.05 to 1.15) was assessed in one large
person-time cohort study involving 537,171 children aged between three months
and five year of age. Increased risk of febrile seizure has also been observed
in children aged between 12 to 23 months (relative incidence (RI) 4.09; 95% CI
3.1 to 5.33) and children aged 12 to 35 months (RI 5.68; 95% CI 2.31 to 13.97)
within six to 11 days after exposure to MMR vaccine. An increased risk of
thrombocytopenic purpura within six weeks after MMR immunisation in children
aged 12 to 23 months was assessed in one case-control study (RR 6.3; 95% CI 1.3
to 30.1) and in one small self controlled case series (incidence rate ratio
(IRR) 5.38; 95% CI 2.72 to 10.62). Increased risk of thrombocytopenic purpura
within six weeks after MMR exposure was also assessed in one other case-control
study involving 2311 children and adolescents between one month and 18 years
(odds ratio (OR) 2.4; 95% CI 1.2 to 4.7). Exposure to the MMR vaccine was
unlikely to be associated with autism, asthma, leukaemia, hay fever, type 1
diabetes, gait disturbance, Crohn’s disease, demyelinating diseases, bacterial
or viral infections. AUTHORS’ CONCLUSIONS The design and reporting of safety
outcomes in MMR vaccine studies, both pre- and post-marketing, are largely
inadequate. The evidence of adverse events following immunisation with the MMR
vaccine cannot be separated from its role in preventing the target diseases.
http://www.ncbi.nlm.nih.gov/pubmed/22336803

“Herein, we report 10 cases of previously healthy subjects who developed GCA/PMR
within 3 months of influenza vaccination (Inf-V). A Medline search uncovered an
additional 11 isolated cases of GCA/PMR occurring after influenza vaccination
Inf-V.”

[GCA stands for giant cell arteritis and PMR stands for polymyalgia rheumatica]
Lupus • February 2012

Giant cell arteritis and polymyalgia rheumatica after influenza vaccination:
report of 10 cases and review of the literature Author information Soriano A1,
Verrecchia E, Marinaro A, Giovinale M, Fonnesu C, Landolfi R, Manna R. Clinical
Autoimmunity Unit Catholic University of the Sacred Heart Rome, Italy Abstract
Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory
rheumatic diseases common in people over the age of 50 years. Herein, we report
10 cases of previously healthy subjects who developed GCA/ PMR within 3 months
of influenza vaccination (Inf-V). A Medline search uncovered additional 11
isolated cases of GCA/PMR occurring after Inf-V. We discuss the role of
individual susceptibility, the potential function of immune adjuvants as
triggers of autoimmunity post-vaccination, and the correlation of our
observation with the ‘ASIA’ syndrome, i.e. autoimmune/inflammatory syndrome
induced by adjuvants and including post-vaccination phenomena.
http://www.ncbi.nlm.nih.gov/pubmed/22235046

Lupus • February 2012

The spectrum of ASIA: ‘Autoimmune (Auto-inflammatory) Syndrome induced by
Adjuvants’ N Agmon-Levin, GRV Hughes, Y Shoenfeld1 1.The Zabludowicz Center for
Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel 2. Head, Lupus
Research Unit, The Rayne Institute, St. Thomas’ Hospital, London, UK 3. Sackler
Faculty of Medicine, Incumbent of the Laura Schwarz-Kip, Chair for Research of
Autoimmune Diseases, Tel-Aviv University, Israel Yehuda Shoenfeld, MD, FRCP,
Zabludowicz Center for Autoimmune Diseases Chaim Sheba Medical Center,
Tel-Hashomer 52621, Israel shoenfel@post.tau.ac.il

Abstract Physicians are often puzzled by enigmatic medical conditions or the
abrupt appearance of an immune-mediated disease. Such a story was recently
presented to us by a young Sheikh. A Saudi Sheikh, who suffered at the age of
27 from joints pains, rash and serological evidence of anti-Ro antibodies, was
diagnosed with probable systemic lupus erythematosus (SLE) at that time. He was
treated with Plaquenil for a year, but as no signs of SLE were apparent,
treatment was stopped and he remained disease free for the next 12 years. At
the age of 39 years, 2 weeks after immunization with the flu vaccine, his
disease reemerged. This time he presented with severe arthritis and
pericarditis, which required treatment with high doses of steroids. This
patient’s story illustrates the acceleration of an autoimmune or
immune-mediated condition following exposure to external stimuli. During the
past year a new syndrome was introduced and termed ASIA, ‘Autoimmune
(Auto-inflammatory) Syndrome induced by Adjuvants’.1 This syndrome assembles a
spectrum of immune-mediated diseases triggered by an adjuvant stimulus.2 – 4
The use of medical adjuvants has become common practice and substances such as
aluminum adjuvant are added to most human and animal vaccines, while the
adjuvant silicone is extensively used for breast implants and cosmetic
procedures. Furthermore, ‘hidden adjuvants’ such as infectious material or
house molds have also been associated with different immune mediated
conditions.1,5 The adjuvant effect has been recognized for years, and is
broadly utilized to enhance desired antigen-specific immune responses.6 This
effect is accomplished via mechanisms that impinge on both the innate and
adaptive immune systems.6 – 9 Formerly, adjuvants were thought to pose little
or no independent threat. Alas, studies of animal models and humans
demonstrated the ability of some of them to inflict autoimmunity and
immune-mediated diseases by themselves.2,10,11 Intriguingly, although exposure
is common, adjuvant disease is relatively rare. It has been suggested that for
a clinically overt adjuvant disease additional risk factors are required such
as genetic susceptibilities or the co-exposure to other environmental factors.1
http://lup.sagepub.com/content/21/2/118.full

This special issue of Lupus is dedicated to ASIA and contains diverse articles
from different geographical areas which provide a broad view of the clinical
manifestations as well as the mechanisms related to the adjuvant effect.

Autism Research • April 2012

Disordered porphyrin metabolism: a potential biological marker for autism risk
assessment Author information Heyer NJ1, Echeverria D, Woods JS. Battelle
Centers for Public Health Research and Evaluation Seattle, Washington, USA
Abstract Autism (AUT) is a complex neurodevelopmental disorder that, together
with Asperger’s syndrome and Pervasive Developmental Disorder-Not Otherwise
Specified (PDD-NOS), comprises the expanded classification of autistic spectrum
disorder (ASD). The heterogeneity of ASD underlies the need to identify
biomarkers or clinical features that can be employed to identify meaningful
subtypes of ASD, define specific etiologies, and inform intervention and
treatment options. Previous studies have shown that disordered porphyrin
metabolism, manifested principally as significantly elevated urinary
concentrations of pentacarboxyl (penta) and coproporphyrins, is commonly
observed among some children with ASD. Here, we extend these observations by
specifically evaluating penta and coproporphyrins as biological indicators of
ASD among 76 male children comprising 30 with validated AUT, 14 with PDD-NOS,
and 32 neurotypical (NT) controls. ASD children (AUT and PDD-NOS) had higher
mean urinary penta (P < 0.006) and copro (P < 0.006) concentrations compared
with same-aged NT children, each characterized by a number of extreme values.
Using Receiver Operating Characteristic curve analysis, we evaluated the
sensitivity and specificity of penta, copro, and their combined Z-scores in ASD
detection. The penta sensitivity was 30% for AUT and 36% for PDD-NOS, with 94%
specificity. The copro sensitivity was 33% and 14%, respectively, with 94%
specificity. The combined Z-score measure had 33% and 21% sensitivity for AUT
and PDDNOS, respectively, with 100% specificity. These findings demonstrate
that porphyrin measures are strong predictors of both AUT and PDD-NOS, and
support the potential clinical utility of urinary porphyrin measures for
identifying a subgroup of ASD subjects in whom disordered porphyrin metabolism
may be a salient characteristic. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329579/

“These findings demonstrate that porphyrin measures are strong predictors of
both AUT and PDD-NOS, and support the potential clinical utility of urinary
porphyrin measures for identifying a subgroup of ASD subjects in whom
disordered porphyrin metabolism may be a salient characteristic.”

“Given all this, supporting the ‘one-size fits all’ vaccination program is neither reasonable nor ethical.”
Vaccine • March 2012

Vaccination: Why the ‘one size fits all’ vaccination argument does not fit all!
By Lucija Tomljenovic, PhD Imagine the next time you went to Walmart, Target or
Sears that due to scientific research and government regulation your retailer
only stocked one size of clothing – regardless of whether you are male or
female, child or adult, and with no sensitivity to your cultural or ethnic
background. Would you be happy? Would you accept it? Would you wear the
clothes? The answer is clearly NO! What if the clothing manufacturer used a
highly toxic dye in the clothing fabric and knew this dye could cause serious
skin reactions in some people but they failed to declare this? Would that be
acceptable to you? Yet that is exactly what the current approach to vaccines
worldwide is – one size fits all and some “collateral damage” is acceptable for
the sake of the alleged “greater good”. In the case of vaccines, the good news
is that even those in the scientific community who are strong proponents of
vaccinations, are coming to question the scientific legitimacy of “one-size
fits all” vaccination practices. [1] For example, Gregory Poland MD, Editor in
Chief of the journal Vaccine and co-author of “The age-old struggle against the
anti-vaccinationists” [2] and colleagues rightly ask whether: ...with the
advances coming from the new biology of the 2st century. It is time to consider
how might new genetic and molecular biology information inform vaccinology
practices of the future? [1] In light of this question Poland et al. conclude
that “one-size fits all” approach for all vaccines and all persons should be
abandoned. According to Poland, this conclusion applies to both vaccine
efficacy, as well as safety.[1]

Regarding the safety, the widely held view that serious vaccine-related adverse
reactions are rare needs revision, as current worldwide vaccination policies
indeed operate on a “one-size fits all” assumption. This assumption persists
despite the fact that historically, vaccine trials routinely exclude vulnerable
individuals with a variety of pre-existing conditions (i.e., premature birth,
personal or family history of developmental delay or neurologic disorders
including epilepsy/seizures, hypersensitivity to vaccine constituents etc...).
[3-7] Because of such selection bias at the very base level of research, the
occurrence of serious adverse reactions resulting from vaccinations is
considerably underestimated. Worse yet, such an outcome should be of concern to
all who vaccinate in view of the documented scientific evidence describing
cases of permanent neurodevelopmental disabilities and deaths following
vaccination in children with underlying genetic/mitochondrial disorders and
other susceptibilities, such as a family history of auto-immune diseases (i.e.,
asthma, diabetes, multiple sclerosis, etc...), allergies, or a compromised
immune system. [8-10] Poland’s along with the other scientists’ current data
therefore have far broader implications for understanding vaccines, not only in
terms of efficacy and the desired immune response, but also in terms of safety
for those susceptible to adverse health outcomes and excluded from clinical
trials --- but not from receipt! Vulnerable individuals, both male and female,
will neither have the same antibody response nor the same level of tolerance to
serious adverse reactions as non-vulnerable individuals. [1, 11] Before one
considers vaccinating their child according to the current ‘one size fits all’
vaccination program, one should think about the fact that we all have a
different genetic history, personal health history, current health status,
nutritional status and exposures to level of environmental toxins – all of
which may impact how an individual, or their child will respond to a vaccine.
Given all this, supporting the ‘one-size fits all’ vaccination program is
neither reasonable nor ethical.

References: 1. Poland, G.A., I.G. Ovsyannikova, and R.M. Jacobson, Vaccine
immunogenetics: bedside to bench to population. Vaccine, 2008. 26(49): p.
6183-8. 2. Poland, G.A. and R.M. Jacobson, The age-old struggle against the
antivaccinationists. N Engl J Med, 2011. 364(2): p. 97-9. 3. Kovel, A., et al.,
Safety and immunogenicity of acellular diphtheria-tetanus-pertussis and
Haemophilus conjugate vaccines given in combination or at separate injection
sites. J Pediatr, 1992. 120(1): p. 84-7. 4. Kaplan, S.L., et al.,
Immunogenicity and safety of Haemophilus influenzae type b-tetanus protein
conjugate vaccine alone or mixed with diphtheria-tetanus-pertussis vaccine in
infants. J Pediatr, 1994. 124(2): p. 323-7. 5. Li, G., et al., Safety and
immunogenicity of a diphtheria, tetanus, acellular pertussis and Haemophilus
influenzae Type b combination vaccine compared with separate administration of
licensed equivalent vaccines in Chinese infants and toddlers for primary and
booster immunization. Vaccine, 2010. 28(25): p. 4215-23. 6. Shinefield, H., et
al., Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine
in healthy children. Pediatr Infect Dis J, 2005. 24(8): p. 665-9. 7. Velu, V.,
et al., Comparative efficacy of two dosages of recombinant hepatitis B vaccine
in healthy adolescents in India. Pediatr Infect Dis J, 2007. 26(11): p.
1038-41. 8. Poling, J.S., et al., Developmental regression and mitochondrial
dysfunction in a child with autism. J Child Neurol, 2006. 21(2): p. 170-2.
9.Yang, Y., et al., Acute metabolic crisis induced by vaccination in seven
Chinese patients. Pediatr Neurol, 2006. 35(2): p. 114-8. 10. Ottaviani, G.,
A.M. Lavezzi, and L. Matturri, Sudden infant death syndrome (SIDS) shortly
after hexavalent vaccination: another pathology in suspected SIDS? Virchows
Arch, 2006. 448(1): p. 100-4. 11. Thomas, C. and M. Moridani, Interindividual
variations in the efficacy and toxicity of vaccines. Toxicology, 2009. 278(2):
p. 204-10.

http://sanevax.org/wp-content/uploads/2015/05/Vaccination-does-one-size-fit-all.pdf

http://www.ncbi.nlm.nih.gov/pubmed/22119595

“103 vaccine adjuvants have been curated in Vaxjo.
Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN
against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants
are categorized and analyzed based on adjuvant types, pathogens used, and
vaccine types.” Journal Of Biomedicine & Biotechnology • March 2012

Vaxjo: a web-based vaccine adjuvant database and its application for analysis
of vaccine adjuvants and their uses in vaccine development Sayers S., Ulysses
G., Xiang Z., He Y. Unit for Laboratory Animal Medicine University of Michigan
Medical School Ann Arbor, MI 48109 USA Abstract Vaccine adjuvants are compounds
that enhance host immune responses to co-administered antigens in vaccines.
Vaxjo is a web-based central database and analysis system that curates, stores,
and analyzes vaccine adjuvants and their usages in vaccine development. Basic
information of a vaccine adjuvant stored in Vaxjo includes adjuvant name,
components, structure, appearance, storage, preparation, function, safety, and
vaccines that use this adjuvant. Reliable references are curated and cited.
Bioinformatics scripts are developed and used to link vaccine adjuvants to
different adjuvanted vaccines stored in the general VIOLIN vaccine database.
Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these
adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81
pathogens, cancers, or allergies. All these vaccine adjuvants are categorized
and analyzed based on adjuvant types, pathogens used, and vaccine types. As a
use case study of vaccine adjuvants in infectious disease vaccines, the
adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly
web query and visualization interface is developed for interactive vaccine
adjuvant search. To support data exchange, the information of vaccine adjuvants
is stored in the Vaccine Ontology (VO) in the Web Ontology Language (OWL)
format. http://www.ncbi.nlm.nih.gov/pubmed/?term=22505817

PLoS One • March 2012

AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the
incidence of childhood narcolepsy in Finland Author information Nohynek H1,
Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, Himanen SL, Hublin
C, Julkunen I, Olsén P, Saarenpää-Heikkilä O, Kilpi T. Department of Vaccines
and Immune Protection National Institute for Health and Welfare, Helsinki,
Finland hanna.nohynek@thl.fi Abstract BACKGROUND Narcolepsy is a chronic sleep
disorder with strong genetic predisposition causing excessive daytime
sleepiness and cataplexy. A sudden increase in childhood narcolepsy was
observed in Finland soon after pandemic influenza epidemic and vaccination with
ASO3-adjuvanted Pandemrix. No increase was observed in other age groups.
METHODS Retrospective cohort study. From January 1, 2009 to December 31, 2010
we retrospectively followed the cohort of all children living in Finland and
born from January 1991 through December 2005. Vaccination data of the whole
population was obtained from primary health care databases. All new cases with
assigned ICD-10 code of narcolepsy were identified and the medical records
reviewed by two experts to classify the diagnosis of narcolepsy according to
the Brighton collaboration criteria. Onset of narcolepsy was defined as the
first documented contact to health care because of excessive daytime
sleepiness. The primary follow-up period was restricted to August 15, 2010, the
day before media attention on post-vaccination narcolepsy started. FINDINGS
Vaccination coverage in the cohort was 75%. Of the 67 confirmed cases of
narcolepsy, 46 vaccinated and 7 unvaccinated were included in the primary
analysis. The incidence of narcolepsy was 9.0 in the vaccinated as compared to
0.7/100,000 person years in the unvaccinated individuals, the rate ratio being
12.7 (95% confidence interval 6.1-30.8). The vaccine-attributable risk of
developing narcolepsy was 1:16,000 vaccinated 4 to 19-year-olds (95% confidence
interval 1:13,000-1:21,000). CONCLUSIONS Pandemrix vaccine contributed to the
onset of narcolepsy among those 4 to 19 years old during the pandemic influenza
in 2009-2010 in Finland. Further studies are needed to determine whether this
observation exists in other populations and to elucidate potential underlying
immunological mechanism. The role of the adjuvant in particular warrants
further research before drawing conclusions about the use of adjuvanted
pandemic vaccines in the future. http://www.ncbi.nlm.nih.gov/pubmed/22470453
Full Report: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314666/

“Pandemrix vaccine contributed to the onset of narcolepsy among those 4 to 19
years old during the pandemic influenza in 2009-2010 in Finland. The role of
the adjuvant in particular warrants further research before drawing conclusions
about the use of adjuvanted pandemic vaccines in the future.”

Clinical Reviews In Allergy & Immunology • April 2012

Guillain-Barré syndrome a classical autoimmune disease triggered by infection
or vaccination Author information Israeli E1, Agmon-Levin N, Blank M, Chapman
J, Shoenfeld Y. The Chaim Zabludowicz Center for Autoimmune Diseases Sheba
Medical Center, Tel-Hashomer, Tel-Aviv, Israel Abstract Guillain-Barré syndrome
(GBS) is a rare autoimmune disorder, the incidence of which is estimated to be
0.6-4/100,000 person/ year worldwide. Often, GBS occurs a few days or weeks
after the patient has had symptoms of a respiratory or gastrointestinal
microbial infection. The disorder is sub-acute developing over the course of
hours or days up to 3 to 4 weeks. About a third of all cases of Guillain-Barré
syndrome are preceded by Campylobacter jejuni infection. C. jejuni strains
isolated from GBS patients have a lipooligosaccharide (LOS) with a GM1-like
structure. Molecular mimicry between LOS and the peripheral nerves as a cause
of GBS was demonstrated in animal models of human GBS. Following the “swine
flu” virus vaccine program in the USA in 1976, an increase in incidence of GBS
was observed and the calculated relative risk was 6.2. Later studies have found
that influenza vaccines contained structures that can induce antiGM1
(ganglioside) antibodies after inoculation into mice. More recent information
has suggested that the occurrence of GBS after currently used influenza and
other vaccines is rare. GBS involves genetic and environmental factors, may be
triggered by infections or vaccinations, and predisposition can be predicted by
analyzing some of these factors. http://www.ncbi.nlm.nih.gov/pubmed/20890797

“ Guillain-Barré syndrome involves genetic and environmental factors, may be
triggered by infections or vaccinations, and predisposition can be predicted by
analyzing some of these factors.”

International Journal Of Cosmetic Science • April 2012

In vitro induction of apoptosis, necrosis and genotoxicity by cosmetic
preservatives: application of flow cytometry as a complementary analysis by NRU
Author information Carvalho CM1, Menezes PF, Letenski GC, Praes CE, Feferman
IH, Lorencini M. Grupo Boticário Research and Innovation Department
Biomolecular Research Laboratory Av. Rui Barbosa no. 3450, 83.065-260 São José
dos Pinhais, PR- Brazil camilamc@grupoboticario.com.br Abstract Preservatives
are used in cosmetics to prevent microbial contamination; however, some
preservatives are not free of allergenic and cytotoxic potential. Allergenicity
and cytotoxicity potential values are major aspects of preservative safety,
which determine limitations and maximum concentration dose in a cosmetic
product. The purpose of this study was to investigate and compare the in vitro
apoptosis, necrosis and genotoxicity-inducing potential of five different types
of preservatives: Phenoxyethanol (PE), Propylparaben (PP), Methylparaben (MP),
Benzyl Alcohol (BA) and Ethylhexyl Glycerine (EG). In vitro experiments were
carried out on human dermal fibroblasts by a quantitative flow cytometry
method, using specific cell markers (Annexin V, Propidium Iodide and H2AX). We
compared the resulting cell viability by means of neutral red uptake (NRU) and
established the IC(50) . Our results showed that PE, PP, MP and BA have similar
cytotoxic mechanisms (high apoptosis and necrosis levels only at the test
concentration of 1%), whereas EG showed only an apoptosis pathway. For
genotoxicity, both parabens yielded the highest values. Results obtained by
flow cytometry for necrosis were comparable to those produced by NRU; however,
NRU does not distinguish apoptosis from necrosis. We propose that flow
cytometry is a more sophisticated methodology for understanding the cytotoxic
mechanisms of cosmetic preservatives and can be used to complement the NRU.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22118339

“Our results showed that Phenoxyethanol [a vaccine ingredient] ... have similar
cytotoxic mechanisms (high apoptosis and necrosis levels only at the test
concentration of 1%) ...”

Dermatitis • May 2012

Hypersensitivity reactions to vaccine constituents: a case series and review of
the literature Author information Leventhal JS1, Berger EM, Brauer JA, Cohen
DE. Ronald O. Perelman Department of Dermatology New York University School of
Medicine, NY, USA Abstract Vaccines are composed of immunogens, preservatives,
adjuvants, antibiotics, and manufacturing by-products. Components of vaccines
may rarely elicit adverse reactions in susceptible individuals, thus raising
concerns regarding vaccine safety. In this report, we add to the medical
literature 3 cases of cutaneous delayed-type hypersensitivity to the vaccine
preservative aluminum. We provide a review of major constituents in vaccines
that have elicited immediate-type or delayed-type hypersensitivity reactions
and describe their clinical manifestations. We include a table of the Food and
Drug Administration-approved vaccines, which lists the quantities of major
components including ovalbumin (egg protein), gelatin, aluminum, neomycin,
2-phenoxyethanol, thimerosal, and formaldehyde. Our goals were to inform
physicians on the variety of hypersensitivity reactions to common vaccines and
to provide information on the choice of vaccines in patients with suspected
hypersensitivity. http://www.ncbi.nlm.nih.gov/pubmed/22653170

“Our goals were to inform physicians on the variety of hypersensitivity
reactions to common vaccines and to provide information on the choice of
vaccines in patients with suspected hypersensitivity.”

BMJ Case Report • May 2012

Hypersensitivity reaction to human papillomavirus vaccine due to polysorbate 80
Author information Badiu I1, Geuna M, Heffler E, Rolla G. Allergy and Clinical
Immunology University of Torino and AO Ordine Mauriziano Torino, Italy Abstract
A 17-year-old girl reported generalised urticaria, eyelid angioedema,
rhino-conjunctivitis, dyspnoea and wheezing 1 h after third intramuscular
administration of quadrivalent human papilloma virus vaccine (Gardasil). She
was treated with antihistamine, and corticosteroids with prompt relief of
rhinitis and dyspnoea, while urticaria and angioedema lasted 24 h. Intradermal
test with Gardasil, which contains polysorbate 80 (PS80), resulted positive,
while skin tests with the bivalent vaccine were negative. Prick test performed
with PS80 resulted positive in the patient and negative in ten healthy
controls. The CD203 basophil activation test result was negative for PS80 at
all the tested dilutions and specific IgE was not found. As flu vaccine was
recommended, the authors skin tested two flu vaccine, one containing PS80
(Fluarix, GSK), which resulted positive and another flu vaccine with no
adjuvant or preservative (Vaxigrip, Sanofi Pasteur MSD), which gave negative
results. The patient then received Vaxigrip without adverse reactions. Full
Report: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351639/

“... the authors skin tested two flu vaccine, one containing PS80 (Fluarix,
GSK), which resulted positive and another flu vaccine with no adjuvant or
preservative (Vaxigrip, Sanofi Pasteur MSD), which gave negative results.”

“With herd immunity to whooping cough,
DTP is associated with higher mortality for girls.” BMJ Open • May 2012

Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative
non-specific and sex-differential effects on child survival in high-mortality
countries Author Information Peter Aaby,1,2 Christine Benn,1,2 Jens Nielsen,1,2
Ida Maria Lisse,1,2 Amabelia Rodrigues,1,2 and Henrik Ravn1,2 1. Bandim Health
Project, INDEPTH Network, Statens Serum Institut, Bissau, Guinea-Bissau 2.
Research Centre for Vitamins and Vaccines (CVIVA), Bandim Health Project,
Statens Serum Institut, Copenhagen, Denmark Abstract Background Measles
vaccines (MV) have sex-differential effects on mortality not explained by
protection against measles infection. Objective The authors examined whether
whole-cell diphtheria–tetanus–pertussis (DTP) vaccine has sex-differential and
non-specific effects. Data sources and eligibility Following previous reviews
and a new search, the effect of DTP on mortality up to the next vaccination was
assessed in all studies where DTP was given after BCG or DTP was given after MV
and there was prospective follow-up after ascertainment of vaccination status.

Setting High-mortality countries in Africa and Asia. Methods The initial
observation of negative effect of DTP generated six hypotheses, which were
examined in all available studies and two randomised trials reducing the time
of exposure to DTP. Main outcome Consistency between studies. Results In the
first study, DTP had negative effects on survival in contrast to the beneficial
effects of BCG and MV. This pattern was repeated in the six other studies
available. Second, the two ‘natural experiments’ found significantly higher
mortality for DTP-vaccinated compared with DTP-unvaccinated children. Third,
the female–male mortality ratio was increased after DTP in all nine studies; in
contrast, the ratio was decreased after BCG and MV in all studies. Fourth, the
increased female mortality associated with high-titre measles vaccine was found
only among children who had received DTP after high-titre measles vaccine.
Fifth, in six randomised trials of early MV, female but not male mortality was
increased if DTP was likely to be given after MV. Sixth, the mortality rate
declined markedly for girls but not for boys when DTP-vaccinated children
received MV. The authors reduced exposure to DTP as most recent vaccination by
administering a live vaccine (MV and BCG) shortly after DTP. Both trials
reduced child mortality. Conclusions These observations are incompatible with
DTP merely protecting against the targeted diseases. With herd immunity to
whooping cough, DTP is associated with higher mortality for girls. Randomised
studies of DTP are warranted to measure the true impact on survival. Full
Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364456/

Apoptosis • May 2012

Hepatitis B vaccine induces apoptotic death in Hepa1-6 cells Author information
Hamza H1, Cao J, Li X, Li C, Zhu M, Zhao S. Key Lab of Agricultural Animal
Genetics Breeding, and Reproduction of Ministry of Education College of Animal
Science and Technology Huazhong Agricultural University, Wuhan People’s
Republic of China Heyam68_hamza@yahoo.com Abstract Vaccines can have adverse
side-effects, and these are predominantly associated with the inclusion of
chemical additives such as aluminum hydroxide adjuvant. The objective of this
study was to establish an in vitro model system amenable to mechanistic
investigations of cytotoxicity induced by hepatitis B vaccine, and to
investigate the mechanisms of vaccine-induced cell death. The mouse liver
hepatoma cell line Hepa1-6 was treated with two doses of adjuvanted (aluminium
hydroxide) hepatitis B vaccine (0.5 and 1 μg protein per ml) and cell integrity
was measured after 24, 48 and 72 h. Hepatitis B vaccine exposure increased cell
apoptosis as detected by flow cytometry and TUNEL assay. Vaccine exposure was
accompanied by significant increases in the levels of activated caspase 3, a
key effector caspase in the apoptosis cascade. Early transcriptional events
were detected by qRT-PCR. We report that hepatitis B vaccine exposure resulted
in significant upregulation of the key genes encoding caspase 7, caspase 9,
Inhibitor caspase-activated DNase (ICAD), Rho-associated coiled-coil containing
protein kinase 1 (ROCK-1), and Apoptotic protease activating factor 1 (Apaf-1).
Upregulation of cleaved caspase 3,7 were detected by western blot in addition
to Apaf-1 and caspase 9 expressions argues that cell death takes place via the
intrinsic apoptotic pathway in which release of cytochrome c from the
mitochondria triggers the assembly of a caspase activation complex. We conclude
that exposure of Hepa1-6 cells to a low dose of adjuvanted hepatitis B vaccine
leads to loss of mitochondrial integrity, apoptosis induction, and cell death,
apoptosis effect was observed also in C2C12 mouse myoblast cell line after
treated with low dose of vaccine (0.3, 0.1, 0.05 μg/ml). In addition In vivo
apoptotic effect of hepatitis B vaccine was observed in mouse liver.
http://www.ncbi.nlm.nih.gov/pubmed/22249285

“We conclude that exposure of Hepa1-6 cells to a low dose of adjuvanted
hepatitis B vaccine leads to loss of mitochondrial integrity, apoptosis
induction, and cell death, apoptosis effect was observed also in C2C12 mouse
myoblast cell line after treated with low dose of vaccine (0.3, 0.1, 0.05
μg/ml). In addition In vivo apoptotic effect of hepatitis B vaccine was
observed in mouse liver.”

“We will discuss the possible mechanisms which pertain to ASIA (Shoenfeld syndrome).”
Lupus • June 2012

When APS (Hughes syndrome) met the autoimmune/inflammatory syndrome induced by
adjuvants (ASIA) Blank M1, Israeli E, Shoenfeld Y. Zabludowitz Center for
Autoimmune Diseases Sheba Medical Center affiliated to Sackler Faculty of
Medicine Tel-Aviv University, Israel Abstract Vaccination of healthy
individuals is the most effective approach to protect the public from
infections and prevent the spread of many infectious diseases all over the
globe. Licensed vaccines are mostly safe, but in rare cases they may be
associated with humoral response to self-antigens due to molecular mimicry,
epitope spread, bystander activation or polyclonal triggering. Moreover, the
clinical picture of autoimmune conditions following post-vaccination is rarer.
Nevertheless, anecdotal case reports on the flare of autoimmune response with
clinical manifestations were reported. Herein, we discuss this topic in
relation to post-vaccination-induced antiphospholipid antibodies following
tetanus toxoid vaccine, HBV and influenza associated in rare cases with
antiphospholipid syndrome clinical manifestations. We will discuss the possible
mechanisms which pertain to ASIA (Shoenfeld syndrome). Therefore, these all
strengthen the importance of ASIA and should be kept in mind during clinical
work and research. Full Report http://lup.sagepub.com/content/21/7/711.long

Environmental Health Perspectives • June 2012

Neurotoxic metal coexposures and neurodevelopment José G. Dórea Faculty of
Health Sciences, Universidade de Brasilia, Brasilia, Brazil E-mail:
dorea@rudah.com.br Abstract Claus Henn et al. (2012) addressed a “real world
scenario” of exposure to multiple neurotoxic metals in their unique and
interesting study. They investigated manganese–lead coexposure and its
association with neurodevelopmental deficiencies in Mexican children. Their
rationale was that neurodevelopmental deficiencies of both metals together
could be more severe than expected based on effects of exposure to each metal
alone. Indeed, they observed a synergism between manganese and lead. Given the
early age of the subjects (12 and 24 months of age), I suggest that some
confounders not included in their model deserve consideration in regard to this
study. Claus Henn et al. (2012) collected information on duration of
breast-feeding, but it seems that in their statistical analyses, they adjusted
only for sex, gestational age, hemoglobin, maternal IQ (intelligence quotient),
and maternal education. Other confounders, such as thimerosal (a compound
containing ethylmercury that is used as a preservative in some vaccines) and
breast-feeding, may influence neurodevelopment outcomes. In countries such as
Mexico, children 12–24 months of age may be immunized with
thimerosal-containing vaccines (TCVs) (WHO 2011). Because of opposite effects
on the central nervous system, the combination of breast-feeding and
ethylmercury may influence neurodevelopmental outcomes. Kramer et al. (2008)
showed that children who were exclusively breast-fed had improved cognitive
development. Indeed, Kostial et al. (1978) demonstrated that infant rats fed
cow’s milk diets absorbed more lead and manganese, which are associated with a
higher relative retention of mercury in the brain. Blood levels of lead and
manganese are indicators of ongoing exposure; however, ethylmercury has a short
half-life and thus is unlikely to be concurrently measured

in blood (Dórea et al. 2011). Nevertheless we can ascertain exposure from
vaccination cards (Dórea et al. 2012; Marques et al. 2009). Following
participants in the National Immunization Program of Mexico, the amount of
ethylmercury from routine immunizations against hepatitis B (three doses), DTP
(diphtheria, tetanus, and pertussis, three doses), and influenza can be
estimated from records on vaccination cards. Additionally, during pregnancy,
Mexican mothers may receive tetanus toxoid (TT) vaccines and other products,
such as anti-RhoD immune globulins (given to Rh-negative mothers) that may
contain thimerosal (Marques et al. 2009). These sources of prenatal and
postnatal ethylmercury exposure should be considered significant sources of an
additional neurotoxic coexposure—organic mercury. Claus Henn et al. (2012)
realized that information on the association of neurodevelopment and coexposure
to multiple chemicals is limited; the scientific literature is even more scarce
for the specific exposure to small amounts of ethylmercury derived from TCVs
(Oken and Bellinger 2008), which are largely used in nonindustrialized
countries. However, recent work has suggested that when studies with young
children are properly adjusted for exposure to TCVs, subtle neurodevelopmental
effects can be demonstrated (Dórea et al. 2012; Marques et al. 2009;
Mrozek-Budzyn 2011a, 2011b). Therefore, the potential for interaction of
ethylmercury, manganese, and lead provides an opportunity to expand our
knowledge. Factors related to maternal neurotoxic exposure and neurodevelopment
(e.g., breastfeeding) are significant in studies of children’s exposure to
ethylmercury (Marques et al. 2009). The study design used by Claus Henn et al.
(2012) could provide further information on this timely issue and also provide
direction for future studies of contaminants and confounders that affect
neurodevelopment.

Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385458/

“Claus Henn et al. (2012) realized that information on the association of
neurodevelopment and coexposure to multiple chemicals is limited; the
scientific literature is even more scarce for the specific exposure to small
amounts of ethyl mercury derived from Thimerosal containing vaccines, which are
largely used in nonindustrialized countries.”

Biometals • June 2012

A case of multiple sclerosis improvement following removal of heavy metal
intoxication: lessons learnt from Matteo’s case Author information Fulgenzi A1,
Zanella SG, Mariani MM, Vietti D, Ferrero ME. Dipartimento di Morfologia Umana
e Scienze Biomediche Città Studi Università degli Studi di Milano, Via L.
Mangiagalli, 31, 20133 Milan, Italy alessandro.fulgenzi@unimi.it Abstract
Multiple sclerosis (MS) is a chronic progressive disease of the central nervous
system (CNS) provoking disability and neurological symptoms. The exact causes
of MS are unknown, even if it is characterized by focal inflammatory lesions in
CNS accompanied by autoimmune reaction against myelin. Indeed, many drugs able
to modulate the immune response of patients have been used to treat MS. More
recently, toxic metals have been proposed as possible causes of
neurodegenerative diseases. The objective of this study is to investigate in
vivo the impact of heavy metal intoxication in MS progression. We studied the
case of a patient affected by MS, who has been unsuccessfully treated for some
years with current therapies. We examined his levels of toxic heavy metals in
the urine, following intravenous “challenge” with the chelating agent calcium
disodium ethylene diamine tetraacetic acid (EDTA).The patient displayed
elevated levels of aluminium, lead and mercury in the urine. Indeed, he was
subjected to treatment with EDTA twice a month. Under treatment, the patient
revealed in time improved symptoms suggestive of MS remission. The clinical
data correlated with the reduction of heavy metal levels in the urine to normal
range values. Our case report suggests that levels of toxic metals can be
tested in patients affected by neurodegenerative diseases as MS.
http://www.ncbi.nlm.nih.gov/pubmed/22438029/

“More recently, toxic metals have been proposed as possible causes of
neurodegenerative diseases.”

“Being protected against influenza, trivalent inactivated influenza vaccine recipients
may lack temporary non-specific immunity that protected against other
respiratory viruses.” Clinical Infectious Disease • June 2012

Increased risk of noninfluenza respiratory virus infections associated with
receipt of inactivated influenza vaccine Author information Cowling BJ1, Fang
VJ, Nishiura H, Chan KH, Ng S, Ip DK, Chiu SS, Leung GM, Peiris JS. School of
Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong,
Pokfulam, Hong Kong SAR, China bcowling@hku.hk Abstract We randomized 115
children to trivalent inactivated influenza vaccine (TIV) or placebo. Over the
following 9 months, TIV recipients had an increased risk of
virologically-confirmed non-influenza infections (relative risk: 4.40; 95%
confidence interval: 1.31-14.8). Being protected against influenza, TIV
recipients may lack temporary non-specific immunity that protected against
other respiratory viruses. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404712/

Zhongguo Zhong Yao Za Zhi
Chinese Journal Of Chinese Materia Medica • July 2012

Comparative study on pseudoanaphylactoid reactions induced by medicinal tween
80 and injectable tween 80 Author information Wang Y1, Li C, Yi Y, Qin L, Zhao
Y, Li G, Cong X, Cao S, Liang A. Capital Medical University School of
Traditional Chinese Medicine Beijing 100069, China wangyunting0@sina.com
Abstract OBJECTIVE To investigate the safety of different level of tween 80 by
comparing the degree of pseudoanaphylactoid reactions (PR) induced by medicinal
tween 80 and injectable tween 80. METHOD The analysis of vascular permeability
of the mice ears: ICR mouse were divided into different test groups, the mice
were intravenously injected with solutions of medicinal tween 80 and injectable
tween 80 with 0.2%, 1% and 5% concentration, positive control Compound 48/80
and 5% glucose injection. All test substances were mixed with 0.4% Evans blue.
The reaction and vascular permeability of the ears were observed and measured
30 min after injection. The analysis of vascular permeability of the rat’s
skin: the rats were intravenous injected with 0. 6% Evans blue normal saline
solution first, 10 minutes later, the same substances were intradermal
administrated into the back of rats. The rats were sacrificed and the diameter
of locus ceruleus and the content of Evans blue leak out were measured 20 min
after injection. RESULT Medicinal tween 80 and injectable tween 80 with 5%
concentration caused obvious vascular hyper permeability in ICR mice, but the
degree of vascular hyperpermeability caused by injectable tween 80 was lighter
than by medicinal tween 80. Other tween 80 didn’t cause obvious vascular hyper
permeability in the ears of mouse. The solution of different concentration of
tween 80 caused obvious locus ceruleus reaction in rat’s back. As for the
content Evans blue leak out, there was no statistical significance between each
group except positive control Compound 48/80 group. CONCLUSION Tween 80 can
cause obvious vascular hyper permeability and the effect is dose dependent,
which indicated that tween 80 can cause PR. On the other hand, injectable tween
80 is more security than medicinal tween 80, the dosage of tween 80 should be
still controlled strictly so that to decrease the incidence of PR.
http://www.ncbi.nlm.nih.gov/pubmed/23019864

“Tween 80 can cause obvious vascular hyper permeability and the effect is dose
dependent, which indicated that Tween 80 can cause PR [pseudoanaphylactoid
reactions].

Current Opinion In Rheumatology • July 2012

Infections and vaccines in the etiology of antiphospholipid syndrome Author
information Cruz-Tapias P1, Blank M, Anaya JM, Shoenfeld Y. Zabludowitz Center
for Autoimmune Diseases Sheba Medical Center affiliated to Sackler Faculty of
Medicine Tel-Aviv University, Israel Abstract PURPOSE OF REVIEW To present
scientific evidence supporting the infectious origin for the antiphospholipid
syndrome (APS) by molecular mimicry between pathogens, infection and
vaccination with ß2-glycoprotein I (ß2-GPI) molecule. RECENT FINDINGS APS is
characterized by the presence of pathogenic autoantibodies against ß2-GPI. The
infection etiology of APS was well established. Likewise, a link between
vaccination such as tetanus toxoid may trigger antibodies targeting tetanus
toxoid and ß2-GPI, due to molecular mimicry between the two molecules. During
the years, the pathogenic potential of anti-tetanus toxoid antibodies cross
reactive with ß2-GPI were found to be pathogenic in animal models, inducing
experimental APS. SUMMARY Accumulated evidence supports that the presence of
anti-ß2-GPI antibodies is associated with a history of infections and the main
mechanism to explain this correlation is molecular mimicry. The relationship
between tetanus toxoid vaccination and APS reveals a novel view on the
autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA).
http://www.ncbi.nlm.nih.gov/pubmed/?term=22617823

“The relationship between tetanus toxoid vaccination and Anti-Phospholipid
Syndrome reveals a novel view on the autoimmune/autoinflammatory syndrome
induced by adjuvants (ASIA).

Blood • July 2012

The significance of autoantibodies against ß2-glycoprotein I Author information
de Groot PG1, Urbanus RT. Department of Clinical Chemistry and Haematology
University Medical Center, Heidelberglaan 100 Utrecht, The Netherlands
ph.g.degroot@umcutrecht.nl Abstract The antiphospholipid syndrome (APS) is
defined by the persistent presence of antiphospholipid antibodies in patients
with a history of thrombosis and/or pregnancy morbidity, including fetal loss.
APS is an autoimmune disease with a confusing name because the pathologic
auto-antibodies are shown to be directed against the plasma protein
ß(2)-glycoprotein I and not against phospholipids. In fact, auto-antibodies
that recognize phospholipids themselves are not associated with thrombosis but
with infectious diseases. One of the intriguing questions is why autoantibodies
against ß(2)-glycoprotein I are so commonly found in both patients and the
healthy. Several potential mechanisms have been suggested to explain the
increased thrombotic risk in patients with these autoantibodies. In this
overview, we will summarize our knowledge on the etiology of the
autoantibodies, and we will discuss the evidence that identify autoantibodies
against ß(2)-glycoprotein I as the culprit of APS.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22553312

“... we will summarize our knowledge on the etiology of the autoantibodies, and
we will discuss the evidence that identify autoantibodies against
ß(2)-glycoprotein I as the culprit of Antiphospholipid Syndrome.”

Food And Chemical Toxicology • September 2012

Fragrance material review on 2-phenoxyethanol Author information Scognamiglio
J1, Jones L, Letizia CS, Api AM. Research Institute for Fragrance Materials
Inc. 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA jscognamiglio@rifm.org
Abstract A toxicologic and dermatologic review of 2-phenoxyethanol when used as
a fragrance ingredient is presented. 2-Phenoxyethanol is a member of the
fragrance structural group Aryl Alkyl Alcohols and is a primary alcohol. The
AAAs are a structurally diverse class of fragrance ingredients that includes
primary, secondary, and tertiary alkyl alcohols covalently bonded to an aryl
(Ar) group, which may be either a substituted or unsubstituted benzene ring.
The common structural element for the AAA fragrance ingredients is an alcohol
group -C-(R1)(R2)OH and generically the AAA fragrances can be represented as an
Ar-C-(R1)(R2)OH or Ar-Alkyl-C-(R1)(R2)OH group. This review contains a detailed
summary of all available toxicology and dermatology papers that are related to
this individual fragrance ingredient and is not intended as a stand-alone
document. Available data for 2-phenoxyethanol were evaluated then summarized
and includes physical properties, acute toxicity, skin irritation, mucous
membrane (eye) irritation, skin sensitization, elicitation, phototoxicity,
photoallergy, toxicokinetics, repeated dose, and reproductive toxicity data. A
safety assessment of the entire Aryl Alkyl Alcohols will be published
simultaneously with this document; please refer to Belsito et al. (2012) for an
overall assessment of the safe use of this material and all Aryl Alkyl Alcohols
in fragrances. http://www.ncbi.nlm.nih.gov/pubmed/?term=22036980 Editors Note:
2-Phenoxyethanol MSDS States: This substance is toxic to kidneys, nervous
system, liver. Link for 2-Phenoxyethanol MSDS
http://www.sciencelab.com/msds.php?msdsid=9926486

“Available data for 2-phenoxyethanol [a vaccine ingredient used in some
vaccines] were evaluated then summarized and includes physical properties,
acute toxicity, skin irritation, mucous membrane (eye) irritation, skin
sensitization, elicitation, phototoxicity, photoallergy, toxicokinetics,
repeated dose, and reproductive toxicity data.”

Human Experimental Toxicology • October 2012

Relative trends in hospitalizations and mortality among infants by the number
of vaccine doses and age, based on the Vaccine Adverse Event Reporting System
(VAERS) 1990-2010 Author information Goldman GS1, Miller NZ. Computer Scientist
Pearblossom, CA 93553, USA gsgoldman@roadrunner.com Abstract In this study, the
Vaccine Adverse Event Reporting System (VAERS) database, 19902010, was
investigated; cases that specified either hospitalization or death were
identified among 38,801 reports of infants. Based on the types of vaccines
reported, the actual number of vaccine doses administered, from 1 to 8, was
summed for each case. Linear regression analysis of hospitalization rates as a
function of (a) the number of reported vaccine doses and (b) patient age
yielded a linear relationship with r(2) = 0.91 and r(2) = 0.95, respectively.
The hospitalization rate increased linearly from 11.0% (107 of 969) for 2 doses
to 23.5% (661 of 2817) for 8 doses and decreased linearly from 20.1% (154 of
765) for children aged <0.1 year to 10.7% (86 of 801) for children aged 0.9
year. The rate ratio (RR) of the mortality rate for 5-8 vaccine doses to 1-4
vaccine doses is 1.5 (95% confidence interval (CI), 1.4-1.7), indicating a
statistically significant increase from 3.6% (95% CI, 3.2-3.9%) deaths
associated with 1-4 vaccine doses to 5.5% (95% CI, 5.2-5.7%) associated with
5-8 vaccine doses. The male-to-female mortality RR was 1.4 (95% CI, 1.3-1.5).
Our findings show a positive correlation between the number of vaccine doses
administered and the percentage of hospitalizations and deaths. Since vaccines
are given to millions of infants annually, it is imperative that health
authorities have scientific data from synergistic toxicity studies on all
combinations of vaccines that infants might receive. Finding ways to increase
vaccine safety should be the highest priority. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547435/

“Our findings show a positive correlation between the number of vaccine doses
administered and the percentage of hospitalizations and deaths.

Since vaccines are given to millions of infants annually, it is imperative that
health authorities have scientific data from synergistic toxicity studies on
all combinations of vaccines that infants might receive.”

[complex and unknown synergies]

“Despite widespread pertussis immunization in childhood,
there are an estimated 50 million cases and 300,000 deaths due to pertussis
globally each year.” Expert Review Of Vaccines • November 2012

Re-emergence of pertussis: what are the solutions? Author information Libster
R1, Edwards KM. Vanderbilt University School of Medicine Department of
Pediatrics, Vanderbilt Vaccine Research Program Nashville, TN, USA Abstract
Whooping cough, due to Bordetella pertussis and Bordetella parapertussis, is an
important cause of childhood morbidity and mortality. Despite widespread
pertussis immunization in childhood, there are an estimated 50 million cases
and 300,000 deaths due to pertussis globally each year. Infants who are too
young to be vaccinated, children who are partially vaccinated and
fully-vaccinated persons with waning immunity are especially vulnerable to
disease. Since pertussis is one of the vaccine-preventable diseases on the
rise, additional vaccine approaches are needed. These approaches include
vaccination of newborns, additional booster doses for older adolescents and
adults, and immunization of pregnant women with existing vaccines. Innovative
new vaccines are also being studied. Each of these options will be discussed
and their potential impact on pertussis control assessed.
http://www.ncbi.nlm.nih.gov/pubmed/23249233

American Journal Of Perinatology • November 2012

Breast-feeding and responses to infant vaccines: constitutional and
environmental factors Author information Dórea JG Department of Nutrition
Universidade de Brasília Brasília, Brazil dorea@rudah.com.br Abstract Neonates
and nursing infants are special with regard to immune development and
vulnerability to infectious diseases. Although breast-feeding is essential to
modulate and prime immune defenses, vaccines (an interventional prophylaxis)
are crucial to prevent and control infectious diseases. During nursing, the
type of feeding influences infants’ natural defenses (including gut
colonization) and their response to vaccines, both through cell-mediated
immunity and specific antibody production. Given the variety and combination of
vaccine components (antigens and excipients, preservative thimerosal, and
aluminum adjuvants) and route of administration, there is a need to examine the
role of infant feeding practices in intended and nonintended outcomes of
vaccination. Maternal factors related to milk constituents (nutrients and
pollutants) and feeding practices can affect response to vaccines.
Collectively, studies that compared type of feeding (or used
breast-feeding-adjusted statistical models) showed significant influence on
some vaccines taken during infancy. Nurslings deprived of the full benefit of
breast-feeding could have altered immune responses affecting vaccine outcome.
In the absence of studies elucidating neurodevelopment (including excitoxicity)
and immunotoxicity issues, vaccination practices should promote and support
breast-feeding. http://www.ncbi.nlm.nih.gov/pubmed/22773284

“Maternal factors related to milk constituents (nutrients and pollutants) and
feeding practices can affect response to vaccines. Collectively, studies that
compared type of feeding (or used breast-feedingadjusted statistical models)
showed significant influence on some vaccines taken during infancy. Nurslings
deprived of the full benefit of breast-feeding could have altered immune
responses affecting vaccine outcome.”

PLoS One • December 2012

Comparison of Shedding Characteristics of Seasonal Influenza Virus (Sub)Types
and Influenza A(H1N1)pdm09 Germany, 2007–2011 Conclusion
Asymptomatic/subclinical infections occur infrequently, but may be associated
with substantial amounts of viral shedding. Presymptomatic shedding may arise
in one third of cases, and shedding characteristics appear to be independent of
(seasonal or pandemic) (sub)type, age, antiviral therapy or vaccination;
however the power to find moderate differences was limited. In summary, our
study addresses several important questions on clinical manifestation, duration
of infectiousness, viral shedding patterns, including shedding before symptom
onset and in asymptomatic/subclinical patients, as well as the effect of
vaccination and antiviral therapy on viral shedding. Important single results
include the finding that children do not seem to be infected asymptomatically,
that shedding one day before symptom onset may occur in one third of influenza
patients, that asymptomatic/subclinical influenza patients occur rarely, but
viral load (and probably infectiousness) may be substantial, and vaccinated
influenza patients do not show different shedding patterns compared to
non-vaccinated cases with ILI. Overall results do not show marked differences
between seasonal influenza (sub)types and influenza A(H1N1)pdm09. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519848/

“Asymptomatic/subclinical infections occur infrequently, but may be associated
with substantial amounts of viral shedding. Presymptomatic shedding may arise
in one third of cases, and shedding characteristics appear to be independent of
(seasonal or pandemic) (sub)type, age, antiviral therapy or vaccination...”

“The effectiveness of influenza vaccines is still controversial ...”
Vaccine • December 2012

Adjuvants in influenza vaccines Author information Tetsutani K1, Ishii KJ.
Laboratory of Adjuvant Innovation National Institute of Biomedical Innovation
Japan Abstract The effectiveness of influenza vaccines is still controversial,
and the role of adjuvants in such vaccines is briefly reviewed in this paper.
Inactivated whole virus vaccines may include components that function as
adjuvants, meaning that additive adjuvants are often not required. MF59 and
AS03 showed higher adjuvanticity than aluminum salts in several clinical
studies. Recent research has suggested that immune cell recruitment is the main
mechanism underlying adjuvant actions in general, and that aluminum salts
induce this recruitment via inflammation at the injected site. The aspect of
how oil-based adjuvants, such as MF59 and AS03, recruit immune cells remains to
be clarified. http://www.ncbi.nlm.nih.gov/pubmed/?term=23084848

Journal Of Inorganic Biochemistry • December 2012

Detection of human papillomavirus (HPV) L1 gene DNA possibly bound to
particulate aluminum adjuvant in the HPV vaccine Gardasil Author information
Lee SH1. Milford Hospital and Milford Molecular Laboratory 2044 Bridgeport
Avenue, Milford, CT 06460, USA shlee01@snet.net Abstract Medical practitioners
in nine countries submitted samples of Gardasil (Merck & Co.) to be tested for
the presence of human papillomavirus (HPV) DNA because they suspected that
residual recombinant HPV DNA left in the vaccine might have been a contributing
factor leading to some of the unexplained post-vaccination side effects. A
total of 16 packages of Gardasil were received from Australia, Bulgaria,
France, India, New Zealand, Poland, Russia, Spain and the United States. A
nested polymerase chain reaction (PCR) method using the MY09/MY11 degenerate
primers for initial amplification and the GP5/GP6based nested PCR primers for
the second amplification were used to prepare the template for direct automated
cycle DNA sequencing of a hypervariable segment of the HPV L1 gene which is
used for manufacturing of the HPV L1 capsid protein by a DNA recombinant
technology in vaccine production. Detection of HPV DNA and HPV genotyping of
all positive samples were finally validated by BLAST (Basic Local Alignment
Search Tool) analysis of a 45-60 bases sequence of the computer-generated
electropherogram. The results showed that all 16 Gardasil samples, each with a
different lot number, contained fragments of HPV-11 DNA, or HPV-18 DNA, or a
DNA fragment mixture from both genotypes. The detected HPV DNA was found to be
firmly bound to the insoluble, proteinase-resistant fraction, presumably of
amorphous aluminum hydroxyphosphate sulfate (AAHS) nanoparticles used as
adjuvant. The clinical significance of these residual HPV DNA fragments bound
to a particulate mineral-based adjuvant is uncertain after intramuscular
injection, and requires further investigation for vaccination safety.
http://www.ncbi.nlm.nih.gov/pubmed/23078778

“Medical practitioners in nine countries submitted samples of Gardasil (Merck &
Co.) to be tested for the presence of human papillomavirus (HPV) DNA because
they suspected that residual recombinant HPV DNA left in the vaccine might have
been a contributing factor leading to some of the unexplained post-vaccination
side effects. A total of 16 packages of Gardasil were received from Australia,
Bulgaria, France, India, New Zealand, Poland, Russia, Spain and the United
States.

The results showed that all 16 Gardasil samples, each with a different lot
number, contained fragments of HPV-11 DNA, or HPV-18 DNA, or a DNA fragment
mixture from both genotypes. The detected HPV DNA was found to be firmly bound
to the insoluble, proteinase-resistant fraction, presumably of amorphous
aluminum hydroxyphosphate sulfate (AAHS) nanoparticles used as adjuvant. The
clinical significance of these residual HPV DNA fragments bound to a
particulate mineral-based adjuvant is uncertain after intramuscular injection
...”

Auto-Immunity Highlights • December 2012

Autoimmunity in connection with a metal implant: a case of
autoimmune/autoinflammatory syndrome induced by adjuvants Author information
Loyo E1, Jara LJ2, López PD3, Puig AC3. 1. Director, Rheumatology and Clinical
Immunology Department Hospital Regional Universitario José Ma. Cabral y Báez
Santiago, Dominican Republic 2. Hospital de Especialidades “Dr. Antonio Fraga
Mouret” Centro Médico Nacional La Raza, IMSS, Mexico, DF Mexico 3. Pontificia
Universidad Católica Madre y Maestra Santiago, Dominican Republic Abstract
Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) has been
recently proposed by Shoenfeld and Agmon-Levin as a new entity that comprises
several conditions: the macrophagic-myofasciitis syndrome, the Gulf War
syndrome, silicosis and post-vaccination phenomena, autoimmunity related to
infectious fragments, hormones, aluminum, silicone, squalene oil, and pristane.
We report the case of a 23-year-old woman who developed serial episodes of high
fever, extreme fatigue, transient thrombocytopenia, multiple cervical
adenopathies, hepatosplenomegaly, anemia, neutropenia, severe proteinuria and
urine sediment abnormalities, elevated serum ferritin levels, and transient low
positive antinuclear antibodies 1 year after she had a nickel-titanium chin
implant for cosmetic reasons. The clinical picture simulated a variety of
probable diseases: systemic lupus erythematosus, Kikuchi-Fujimoto syndrome,
adult onset Still’s disease, antiphospholipid syndrome, and hemophagocytic
syndrome, among others, so she underwent an extensive medical investigation
including two lymph node biopsies. She received treatment accordingly with
steroids, methotrexate, and mofetil mycophenolate, with initial improvement of
her symptoms, which recurred every time the dose was reduced. Two and a half
years later the patient decided to retire the chin implant and afterwards all
her systemic symptoms have disappeared. She remains in good health, without
recurrence of any symptom and off medications until today. Albeit this patient
fulfills proposed major ASIA criteria, to our knowledge it would be the first
description of systemic features of autoinflammation in connection with a metal
implant. http://www.ncbi.nlm.nih.gov/pubmed/26000140

“We report the case of a 23-year-old woman who developed serial episodes of
high fever, extreme fatigue, transient thrombocytopenia, multiple cervical
adenopathies, hepatosplenomegaly, anemia, neutropenia, severe proteinuria and
urine sediment abnormalities, elevated serum ferritin levels, and transient low
positive antinuclear antibodies 1 year after she had a nickel-titanium chin
implant for cosmetic reasons.

Two and a half years later the patient decided to retire the chin implant and
afterwards all her systemic symptoms have disappeared.”

PLoS One • December 2012

Comparison of Shedding Characteristics of Seasonal Influenza Virus (Sub)Types
and Influenza A(H1N1) Germany, 2007–2011 Thorsten Suess, Cornelius Remschmidt,
Susanne B. Schink, Brunhilde Schweiger, Alla Heider, Jeanette Milde, Andreas
Nitsche, Kati Schroeder, Joerg Doellinger, Christian Braun, Walter Haas, Gérard
Krause, Udo Buchhol Abstract Background Influenza viral shedding studies
provide fundamental information for preventive strategies and modelling
exercises. We conducted a prospective household study to investigate viral
shedding in seasonal and pandemic influenza between 2007 and 2011 in Berlin and
Munich, Germany. Methods Study physicians recruited index patients and their
household members. Serial nasal specimens were obtained from all household
members over at least eight days and tested quantitatively by qRT-PCR for the
influenza virus (sub)type of the index patient. A subset of samples was also
tested by viral culture. Symptoms were recorded daily. Results We recruited 122
index patients and 320 household contacts, of which 67 became secondary
household cases. Among all 189 influenza cases, 12 were infected with
seasonal/prepandemic influenza A(H1N1), 19 with A(H3N2), 60 with influenza B,
and 98 with A(H1N1)pdm09. Nine (14%) of 65 non-vaccinated secondary cases were
asymptomatic/subclinical (0 (0%) of 21 children, 9 (21%) of 44 adults; p =
0.03). Viral load among patients with influenza-like illness (ILI) peaked on
illness days 1, 2 or 3 for all (sub)types and declined steadily until days 7–9.
Clinical symptom scores roughly paralleled viral shedding dynamics. On the
first day prior to symptom onset 30% (12/40) of specimens were positive. Viral
load in 6 asymptomatic/subclinical patients was similar to that in
ILI-patients. Duration of infectiousness as measured by viral culture lasted
approximately until illness days 4–6. Viral load did not seem to be influenced
by antiviral therapy, age or vaccination status. Conclusion
Asymptomatic/subclinical infections occur infrequently, but may be associated
with substantial amounts of viral shedding. Presymptomatic shedding may arise
in one third of cases, and shedding characteristics appear to be independent of
(seasonal or pandemic) (sub)type, age, antiviral therapy or vaccination;
however the power to find moderate differences was limited. Full Report
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051653

“Asymptomatic/subclinical infections occur infrequently, but may be associated
with substantial amounts of viral shedding. Presymptomatic shedding may arise
in one third of cases, and shedding characteristics appear to be independent of
(seasonal or pandemic) (sub)type, age, antiviral therapy or vaccination ...”

Der Unfallchirurg • December 2012

Persistent swelling after flushing of an abscess with Octenisept Author
information Bauer B1, Majic M, Rauthe S, Bröcker EB, Kerstan A. Klinik und
Poliklinik für Dermatologie Venerologie und Allergologie Universitätsklinkum
Würzburg Josef-Schneider-Straße 2, 97080 Würzburg, Deutschland
Bauer_B1@klinik.uni-wuerzburg.de Abstract We report the case of a long-lasting
cutaneous side effect after inappropriate use of Octenisept® solution
(containing octenidine and phenoxyethanol). Following lavage of an abscess in
the inguinal region, a painful erythematous induration mimicking cellulitis
persisted for several months. Manual lymphatic drainage considerably improved
the symptoms. Octenisept® shows considerable tissue toxicity in vivo including
- but not restricted to - blood vessel damage. Deterioration of endothelial
cells followed by oedema and continued tissue damage can be seen
histologically. Despite the fact that there is a circular letter issued by the
manufacturer as well as a boxed warning on the bottles, the awareness to avoid
this misuse of Octenisept® is still lacking.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22101779

“Octenisept® solution (containing octenidine and phenoxyethanol) ... shows
considerable tissue toxicity in vivo including but not restricted to - blood
vessel damage. Deterioration of endothelial cells followed by oedema and
continued tissue damage can be seen histologically.”

[phenoxyethanol is a vaccine ingredient]

American Journal Of Perinatology • 2012

Breast-Feeding and Responses to Infant Vaccines: Constitutional and
Environmental Factors José G. Dórea Department of Nutrition Universidade de
Brasília Brasília, Brazil Abstract Neonates and nursing infants are special
with regard to immune development and vulnerability to infectious diseases.
Although breast-feeding is essential to modulate and prime immune defenses,
vaccines (an interventional prophylaxis) are crucial to prevent and control
infectious diseases. During nursing, the type of feeding influences infants’
natural defenses (including gut colonization) and their response to vaccines,
both through cell-mediated immunity and specific antibody production. Given the
variety and combination of vaccine components (antigens and excipients,
preservative thimerosal, and aluminum adjuvants) and route of administration,
there is a need to examine the role of infant feeding practices in intended and
nonintended outcomes of vaccination. Maternal factors related to milk
constituents (nutrients and pollutants) and feeding practices can affect
response to vaccines. Collectively, studies that compared type of feeding (or
used breast-feeding-adjusted statistical models) showed significant influence
on some vaccines taken during infancy. Nurslings deprived of the full benefit
of breast-feeding could have altered immune responses affecting vaccine
outcome. In the absence of studies elucidating neurodevelopment (including
excitoxicity) and immunotoxicity issues, vaccination practices should promote
and support breast-feeding.
https://www.thieme-connect.com/DOI/DOI?10.1055/s-0032-1316442

“Nurslings deprived of the full benefit of breast-feeding could have altered
immune responses affecting vaccine outcome.”

Journal of Autoimmunity • January 2013

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling
the pathogenic, clinical and diagnostic aspects Carlo Perricone a, b, Serena
Colafrancesco a, b, Roei D. Mazor a, Alessandra Soriano a, c, Nancy
Agmon-Levina, Yehuda Shoenfelda,d,* a. The Zabludowicz Center for Autoimmune
Diseases, Sheba Medical Center, Tel-Hashomer, Israel b. Reumatologia,
Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di
Roma, Rome, Italy c. Department of Clinical Medicine and Rheumatology,
University Campus Bio-Medico of Rome, Italy d. Incumbent of the Laura
Schwarz-Kipp Chair for Research of Autoimmune Diseases, Sackler Faculty of
MedicineTel-Aviv University

Abstract In 2011 a new syndrome termed ‘ASIA Autoimmune/Inflammatory Syndrome
Induced by Adjuvants’ was defined pointing to summarize for the first time the
spectrum of immune-mediated diseases triggered by an adjuvant stimulus such as
chronic exposure to silicone, tetramethylpentadecane, pristane, aluminum and
other adjuvants, as well as infectious components, that also may have an
adjuvant effect. All these environmental factors have been found to induce
autoimmunity by themselves both in animal models and in humans: for instance,
silicone was associated with siliconosis, aluminum hydroxide with post-
vaccination phenomena and macrophagic myofasciitis syndrome. Several mechanisms
have been hy- pothesized to be involved in the onset of adjuvant-induced
autoimmunity; a genetic favorable back- ground plays a key role in the
appearance on such vaccine-related diseases and also justifies the rarity of
these phenomena. This paper will focus on protean facets which are part of
ASIA, focusing on the roles and mechanisms of action of different adjuvants
which lead to the autoimmune/inflammatory response. The data herein illustrate
the critical role of environmental factors in the induction of autoimmunity.
Indeed, it is the interplay of genetic susceptibility and environment that is
the major player for the initiation of breach of tolerance. Final remarks
Despite the huge amount of money invested in studying vaccines, there are few
observational studies and virtually no randomized clinical trials documenting
the effect on mortality of any of the existing vaccines. One recent paper found
an increased hospitalization rate with the increase of the number of vaccine
doses and a mortality rate ratio for 5e8 vaccine doses to 1e4 vaccine doses of
1.5, indicating a statistically significant increase of deaths associated with
higher vaccine doses. Since vaccines are given to millions of infants annually,
it is imperative that health authorities have scientific data from synergistic
toxicity studies on all combinations of vaccines that infants might receive to
improve vaccine safety [194]. Moreover, from one side the non-specific
beneficial effects of vaccines on survival can be underestimated, on the other
side the negative effect of other vaccines may not be captured by current
studies [195]. As a matter of fact, in case of vaccine-associated autoimmune
phenomena latency periods between the vaccine administration and the appearance
of clinical symptoms can be longer (months or years after vaccination) than the
time interval commonly established in most vaccine risk assessment studies
[196]. Full Report http://www.2ndchance.info/onesize4all-Perricone2013.pdf

“Despite the huge amount of money invested in studying vaccines, there are few
observational studies and virtually no randomized clinical trials documenting
the effect on mortality of any of the existing vaccines.

One recent paper found an increased hospitalization rate with the increase of
the number of vaccine doses and a mortality rate ratio for 5e8 vaccine doses to
1e4 vaccine doses of 1.5, indicating a statistically significant increase of
deaths associated with higher vaccine doses.”

PLoS One • January 2013

A novel mechanism of formaldehyde neurotoxicity: inhibition of hydrogen sulfide
generation by promoting overproduction of nitric oxide Author information Tang
XQ1, Fang HR, Zhou CF, Zhuang YY, Zhang P, Gu HF, Hu B. Department of
Physiology, Medical College University of South China, Hengyang Hunan, PR China
txq01001@gmail.com Abstract BACKGROUND Formaldehyde (FA) induces neurotoxicity
by overproduction of intracellular reactive oxygen species (ROS). Increasing
studies have shown that hydrogen sulfide (H(2)S), an endogenous gastransmitter,
protects nerve cells against oxidative stress by its antioxidant effect. It has
been shown that overproduction of nitric oxide (NO) inhibits the activity of
cystathionine-beta-synthase (CBS), the predominant H(2)S-generating enzyme in
the central nervous system. OBJECTIVE We hypothesize that FA-caused
neurotoxicity involves the deficiency of this endogenous protective antioxidant
gas, which results from excessive generation of NO. The aim of this study is to
evaluate whether FA disturbs H(2)S synthesis in PC12 cells, and whether this
disturbance is associated with overproduction of NO. PRINCIPAL FINDINGS We
showed that exposure of PC12 cells to FA causes reduction of viability,
inhibition of CBS expression, decrease of endogenous H(2)S production, and NO
production. CBS silencing deteriorates FA-induced decreases in endogenous H(2)S
generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells;
while ADMA, a specific inhibitor of NOS significantly attenuates FA-induced
decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS
accumulation in PC12 cells. CONCLUSION/SIGNIFICANCE Our data indicate that FA
induces neurotoxicity by inhibiting the generation of H(2)S through excess of
NO and suggest that strategies to manipulate endogenous H(2)S could open a
suitable novel therapeutic avenue for FA-induced neurotoxicity. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554621/

“Our data indicate that Formaldehyde induces neurotoxicity by inhibiting the
generation of hydrogen sulfide through excess of nitric oxide ...”

Brain, Behavior And Immunity • February 2013

Altered immune pathway activity under exercise challenge in Gulf War Illness:
an exploratory analysis Author information Broderick G1, Ben-Hamo R, Vashishtha
S, Efroni S, Nathanson L, Barnes Z, Fletcher MA, Klimas N. Department of
Medicine, University of Alberta Edmonton, Canada gordon.broderick@ualberta.ca
Abstract Though potentially linked to the basic physiology of stress response
we still have no clear understanding of Gulf War Illness (GWI), a debilitating
illness presenting with a complex constellation of immune, endocrine and
neurological symptoms. Here we compared male GWI (n=20) with healthy veterans
(n=22) and subjects with chronic fatigue syndrome/myalgic encephalomyelitis
(CFS/ME) (n=7). Blood was drawn during a Graded eXercise Test (GXT) prior to
exercise, at peak effort (VO2 max) and 4-h post exercise. Affymetrix HG U133
plus 2.0 microarray gene expression profiling in peripheral blood mononuclear
cells (PBMCs) was used to estimate activation of over 500 documented pathways.
This was cast against ELISA-based measurement of 16 cytokines in plasma and
flow cytometric assessment of lymphocyte populations and cytotoxicity. A 2-way
ANOVA corrected for multiple comparisons (q statistic <0.05) indicated
significant increases in neuroendocrine-immune signaling and inflammatory
activity in GWI, with decreased apoptotic signaling. Conversely, cell cycle
progression and immune signaling were broadly subdued in CFS. Partial
correlation networks linking pathways with symptom severity via changes in
immune cell abundance, function and signaling were constructed. Central to
these were changes in IL-10 and CD2+ cell abundance and their link to two
pathway clusters. The first consisted of pathways supporting neuronal
development and migration whereas the second was related to androgen-mediated
activation of NF-∼B. These exploratory results suggest an over-expression of
known exercise response mechanisms as well as illness-specific changes that may
involve an overlapping stresspotentiated neuro-inflammatory response.
http://www.ncbi.nlm.nih.gov/pubmed/23201588

“These exploratory results suggest an over-expression of known exercise
response mechanisms as well as illness-specific changes that may involve an
overlapping stress-potentiated neuro-inflammatory response.”

Biomedical Research International • February 2013

Vaccine adverse events reported during the first ten years (1998-2008) after
introduction in the state of Rondonia, Brazil Author information Cunha MP1,
Dórea JG, Marques RC, Leão RS. Department of Nursing Fundação Universidade
Federal de Rondônia 76801-974 Porto Velho, RO, Brazil Abstract Despite good
safety records, vaccines given to young children can cause adverse events. We
investigated the reported adverse events following immunization (AEFI) of
vaccines given to children of less than seven years of age during the first ten
years (1998 to 2008) in the state of Rondonia, Brazil. We worked with the
events related to BCG (Bacillus Calmett-Guérin), HB (hepatitis B), DTwP/Hib
(diphtheria-tetanus-pertussis+Hemophillus influenza b), DTP
(diphtheria-tetanus-pertussis), MMR (mumps, measles, rubella), and YF (yellow
fever) vaccines because they were part of the recommended scheme. The number of
doses of vaccines given was 3,231,567 with an average of AEFI of 57.2/year
during the studied period. DTwP/Hib was responsible for 298 (57.8%), DTP 114
(22.9%), HB 31 (6%), MMR 28 (5.4%), BCG 24 (4.7%), and YF 20 (3.9%) of the
reported AEFI. The combination of the AEFI for DTwP/Hib vaccines showed the
highest number of systemic (61.4%) and local events (33.8%). Young children
(≤1-year old) were more susceptible to AEFI occurring in the 6 hours (54.2%)
following vaccine uptake. This study suggests significant differences in
reactogenicity of vaccines and that despite limitations of the AEFI Brazilian
registry system we cannot ignore underreporting and should use the system to
expand our understanding of adverse events and effects.
http://www.ncbi.nlm.nih.gov/pubmed/23509790

“This study suggests significant differences in reactogenicity of vaccines ...”

Biomolecular Concepts • February 2013

The meaning of aluminium exposure on human health and aluminium-related
diseases Crisponi G, Fanni D, Gerosa C, Nemolato S, Nurchi VM, Crespo-Alonso M,
Lachowicz JI, Faa G. Abstract The aim of this review is to attempt to answer
extremely important questions related to aluminium-related diseases. Starting
from an overview on the main sources of aluminium exposure in everyday life,
the principal aspects of aluminium metabolism in humans have been taken into
consideration in an attempt to enlighten the main metabolic pathways utilised
by trivalent metal ions in different organs. The second part of this review is
focused on the available evidence concerning the pathogenetic consequences of
aluminium overload in human health, with particular attention to its putative
role in bone and neurodegenerative human diseases.
http://www.ncbi.nlm.nih.gov/pubmed/25436567

“ The second part of this review is focused on the available evidence
concerning the pathogenetic consequences of aluminium overload in human health,
with particular attention to its putative role in bone and neurodegenerative
human diseases.”

Biomedical Research International • February 2013

Vaccine Adverse Events Reported during the First Ten Years (1998–2008) after
Introduction in the State of Rondonia, Brazil Author Information Mônica P. L.
Cunha, 1 José G. Dórea, 2 ,* Rejane C. Marques, 3 and Renata S. Leão 4
1Department of Nursing, Fundação Universidade Federal de Rondônia 76801-974
Porto Velho, RO, Brazil 2Faculty of Health Sciences, Universidade de Brasília
70919-970 Brasilia, DF, Brazil 3Universidade Federal do Rio de Janeiro, Campus
Macaé 27971-550 Rio de Janeiro, RJ, Brazil 4Instituto de Biofísica Carlos
Chagas Filho, Universidade Federal do Rio de Janeiro 21941-902 Rio de Janeiro,
RJ, Brazil Abstract Despite good safety records, vaccines given to young
children can cause adverse events. We investigated the reported adverse events
following immunization (AEFI) of vaccines given to children of less than seven
years of age during the first ten years (1998 to 2008) in the state of
Rondonia, Brazil. We worked with the events related to BCG (Bacillus
CalmettGuérin), HB (hepatitis B), DTwP/Hib
(diphtheria-tetanus-pertussis+Hemophillus influenza b), DTP
(diphtheria-tetanus-pertussis), MMR (mumps, measles, rubella), and YF (yellow
fever) vaccines because they were part of the recommended scheme. The number of
doses of vaccines given was 3,231,567 with an average of AEFI of 57.2/year
during the studied period. DTwP/Hib was responsible for 298 (57.8%), DTP 114
(22.9%), HB 31 (6%), MMR 28 (5.4%), BCG 24 (4.7%), and YF 20 (3.9%) of the
reported AEFI. The combination of the AEFI for DTwP/Hib vaccines showed the
highest number of systemic (61.4%) and local events (33.8%). Young children
(≤1-year old) were more susceptible to AEFI occurring in the 6 hours (54.2%)
following vaccine uptake. This study suggests significant differences in
reactogenicity of vaccines and that despite limitations of the AEFI Brazilian
registry system we cannot ignore underreporting and should use the system to
expand our understanding of adverse events and effects.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586457/

“... despite limitations of the AEFI Brazilian registry system we cannot ignore
underreporting ...”

Annals Of Medical & Health Sciences Research • July 2013

Are the Currently Existing Anti-Human Papillomavirus Vaccines Appropriate for
the Developing World? Author Information LJ van Bogaert Department Of
Histopathology National Health Laboratory, Service and University of Limpopo
Polokwane, South Africa Abstract Cervical cancer prevention is expected to be
achieved by vaccination of girls 2-3 years before sexual debut, and cervical
smear cytology follow-up. The existing human papillomavirus (HPV) vaccines
target the low-risk 6 and 11, and the high-risk 16 and 18 subtypes, the most
common agents of ano-genital pre-invasive and invasive lesions. We conducted
the review by searching PubMed using the terms “HPV,” “HPV subtypes,”
“developing world,” and “HPV-vaccine” to retrieve articles published between
2000 and 2011. We focused on studies that were relevant to the developing
world. The proposed vaccination policy is currently unachievable in the
developing world because of the cost of the vaccine, the lack of adequate
cytology and follow-up infrastructures. Moreover, the subtypes of HPV involved
in cervical pathology, their associations, and natural history (clearance and
persistence rates) differ from the industrialized world. Therefore, the current
bivalent and quadrivalent anti-HPV vaccines are unlikely to achieve their
target in the developing world. It follows from published data that there is an
obligation of the pharmaceutical industry and of the public-health policy
makers not to embark on mass vaccination campaigns without thorough information
and investigation of the local relevance. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793430/

“The proposed vaccination policy is currently unachievable in the developing
world because of the cost of the vaccine, the lack of adequate cytology and
follow-up infrastructures. Moreover, the subtypes of HPV involved in cervical
pathology, their associations, and natural history (clearance and persistence
rates) differ from the industrialized world.”

EMBO Reports • March 2013

Scientific dissent and public policy. Is targeting dissent a reasonable way to
protect sound policy decisions? Author information de Melo-Martín I1, Intemann
K. Division of Medical Ethics Department of Public Health Weill Cornell Medical
College, New York, USA imd2001@med.cornell.edu The temptation to silence
dissenters whose non-mainstream views negatively affect public policies is
powerful. However, silencing dissent, no matter how scientifically unsound it
might be, can cause the public to mistrust science in general. Dissent is
crucial for the advancement of science. Disagreement is at the heart of peer
review and is important for uncovering unjustified assumptions, flawed
methodologies and problematic reasoning. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589084

“Dissent is crucial for the advancement of science. Disagreement is at the
heart of peer review and is important for uncovering unjustified assumptions,
flawed methodologies and problematic reasoning.”

Vaccine • March 2013

Review of the United States universal varicella vaccination program: Herpes
zoster incidence rates, cost-effectiveness, and vaccine efficacy based
primarily on the Antelope Valley Varicella Active Surveillance Project data
Author information Goldman GS1, King PG. Abstract In a cooperative agreement
starting January 1995, prior to the FDA’s licensure of the varicella vaccine on
March 17, the Centers for Disease Control and Prevention (CDC) funded the Los
Angeles Department of Health Services’ Antelope Valley Varicella Active
Surveillance Project (AV-VASP). Since only varicella case reports were
gathered, baseline incidence data for herpes zoster (HZ) or shingles was
lacking. Varicella case reports decreased 72%, from 2834 in 1995 to 836 in 2000
at which time approximately 50% of children under 10 years of age had been
vaccinated. Starting in 2000, HZ surveillance was added to the project. By
2002, notable increases in HZ incidence rates were reported among both children
and adults with a prior history of natural varicella. However, CDC authorities
still claimed that no increase in HZ had occurred in any US surveillance site.
The basic assumptions inherent to the varicella cost-benefit analysis ignored
the significance of exogenous boosting caused by those shedding wild-type VZV.
Also ignored was the morbidity associated with even rare serious events
following varicella vaccination as well as the morbidity from increasing cases
of HZ among adults. Vaccine efficacy declined below 80% in 2001. By 2006,
because 20% of vaccinees were experiencing breakthrough varicella and
vaccine-induced protection was waning, the CDC recommended a booster dose for
children and, in 2007, a shingles vaccination was approved for adults aged 60
years and older. In the prelicensure era, 95% of adults experienced natural
chickenpox (usually as children)-these cases were usually benign and resulted
in long-term immunity. Varicella vaccination is less effective than the natural
immunity that existed in prevaccine communities. Universal varicella
vaccination has not proven to be cost-effective as increased HZ morbidity has
disproportionately offset cost savings associated with reductions in varicella
disease. Universal varicella vaccination has failed to provide long-term
protection from VZV disease. http://www.ncbi.nlm.nih.gov/pubmed/22659447

“In the prelicensure era, 95% of adults experienced natural chickenpox (usually
as children)-these cases were usually benign and resulted in long-term
immunity. Varicella vaccination is less effective than the natural immunity
that existed in prevaccine communities. Universal varicella vaccination has not
proven to be cost-effective as increased HZ morbidity has disproportionately
offset cost savings associated with reductions in varicella disease. Universal
varicella vaccination has failed to provide long-term protection from VZV
disease.”

Frontiers In Cellular And Infection Microbiology • March 2013

Vaccine delivery using nanoparticles Anthony E. Gregory,1,* Richard Titball,1
and Diane Williamson2 1. College of Life and Environmental Sciences, University
of Exeter, Exeter, UK 2. DSTL Porton Down, Salisbury, Wiltsire, SP4 0QJ, UK
Abstract Vaccination has had a major impact on the control of infectious
diseases. However, there are still many infectious diseases for which the
development of an effective vaccine has been elusive. In many cases the failure
to devise vaccines is a consequence of the inability of vaccine candidates to
evoke appropriate immune responses. This is especially true where cellular
immunity is required for protective immunity and this problem is compounded by
the move toward devising sub-unit vaccines. Over the past decade nanoscale size
(<1000 nm) materials such as virus-like particles, liposomes, ISCOMs,
polymeric, and non-degradable nanospheres have received attention as potential
delivery vehicles for vaccine antigens which can both stabilize vaccine
antigens and act as adjuvants. Importantly, some of these nanoparticles (NPs)
are able to enter antigen-presenting cells by different pathways, thereby
modulating the immune response to the antigen. This may be critical for the
induction of protective Th1-type immune responses to intracellular pathogens.
Their properties also make them suitable for the delivery of antigens at
mucosal surfaces and for intradermal administration. In this review we compare
the utilities of different NP systems for the delivery of sub-unit vaccines and
evaluate the potential of these delivery systems for the development of new
vaccines against a range of pathogens. Many of the NP delivery systems
mentioned in this review are capable of eliciting both cellular and humoral
immune responses. However, an efficient and protective vaccine is likely to
induce a combination of both responses and should be tailored to the pathogen
in question accordingly. Whilst these delivery vehicles may present as an
exciting prospect for future vaccination strategies, it is also worth noting
their potential drawbacks, particulary those associated with cytotoxicity.
Since NPs have a relatively short history in medicine they do not have a
longstanding safety profile in human use. It is therefore essential that
further research is carried out in NP toxicity to fully address these questions
if they are to be accepted as an alternative method for the delivery of novel
vaccines and are licensed more widely for human use. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607064/

“Whilst these delivery vehicles may present as an exciting prospect for future
vaccination strategies, it is also worth noting their potential drawbacks,
particulary those associated with cytotoxicity.”

“This is the new wind blowing within the branches of autoimmunity ...”
BMC Medicine • April 2013

Novel pebbles in the mosaic of autoimmunity Perricone C, Agmon-Levin N,
Shoenfeld Y. Abstract Almost 25 years ago, the concept of the ‘mosaic of
autoimmunity’ was introduced to the scientific community, and since then this
concept has continuously evolved, with new pebbles being added regularly. We
are now looking at an era in which the players of autoimmunity have changed
names and roles. In this issue of BMC Medicine, several aspects of autoimmunity
have been addressed, suggesting that we are now at the forefront of
autoimmunity science. Within the environmental factors generating autoimmunity
are now included unsuspected molecules such as vitamin D and aluminum. Some
adjuvants such as aluminum are recognized as causal factors in the development
of the autoimmune response. An entirely new syndrome, the
autoimmune/inflammatory syndrome induced by adjuvants (ASIA), has been recently
described. This is the new wind blowing within the branches of autoimmunity,
adding knowledge to physicians for helping patients with autoimmune disease.
http://www.ncbi.nlm.nih.gov/pubmed/23557479

Virus Genes • April 2013

Genetic characterization of HA gene of low pathogenic H9N2 influenza viruses
isolated in Israel during 2006-2012 periods Author information Davidson I1,
Shkoda I, Golender N, Perk S, Lapin K, Khinich Y, Panshin A. Kimron Veterinary
Institute P.O. Box 12, 50250 Beit Dagan, Israel davidsoni@int.gov.il Abstract
H9N2 influenza viruses are isolated in Israel since 2000 and became endemic.
From November 2006 to the beginning of 2012, many H9N2 viruses were identified,
all belonged to the Asian G1like lineage represented by A/qu/Hong Kong/G1/97
(H9N2). In the present study, 66 isolates were selected for their hemagglutinin
gene characterization. Most H9N2 isolates were distributed between two main
groups, identified as the 4th and 5th introductions. The 5th introduction, was
represented by a compact cluster containing viruses isolated in 2011-2012; the
4th introduction was subdivided into two subgroups, A and B, each containing at
least two clusters, which can be identified as A-1, A-2, B-1, and B2,
respectively. Genetic analysis of the deduced HA proteins of viruses, belonging
to the 4th and 5th introductions, revealed amino acid variations in 79 out of
542 positions. All isolates had typical low pathogenicity motifs at the
hemagglutinin (HA) cleavage site. Most viruses had leucine at position 216 in a
receptor binding pocket that enables the virus to bind successfully with the
cellular receptors intrinsic to mammals, including humans. It was shown that
the differences between the HA proteins of viruses used for vaccine production
and local field isolates increased in parallel with the duration and intensity
of vaccine use, illustrating the genetic diversity of the H9N2 viruses in
Israel. http://www.ncbi.nlm.nih.gov/pubmed/23271448

“... the differences between the HA proteins of viruses used for vaccine
production and local field isolates increased in parallel with the duration and
intensity of vaccine use, illustrating the genetic diversity of the H9N2
viruses in Israel.”

Cell Biology And Toxicology • April 2013

How aluminum, an intracellular ROS generator promotes hepatic and neurological
diseases: the metabolic tale Author information Han S1, Lemire J, Appanna VP,
Auger C, Castonguay Z, Appanna VD. Department of Chemistry and Biochemistry
Laurentian University, Sudbury Ontario, P3E 2C6, Canada Abstract Metal
pollutants are a global health risk due to their ability to contribute to a
variety of diseases. Aluminum (Al), a ubiquitous environmental contaminant is
implicated in anemia, osteomalacia, hepatic disorder, and neurological
disorder. In this review, we outline how this intracellular generator of
reactive oxygen species (ROS) triggers a metabolic shift towards lipogenesis in
astrocytes and hepatocytes. This Al-evoked phenomenon is coupled to diminished
mitochondrial activity, anerobiosis, and the channeling of a-ketoacids towards
anti-oxidant defense. The resulting metabolic reconfiguration leads to fat
accumulation and a reduction in ATP synthesis, characteristics that are common
to numerous medical disorders. Hence, the ability of Al toxicity to create an
oxidative environment promotes dysfunctional metabolic processes in astrocytes
and hepatocytes. These molecular events triggered by Al-induced ROS production
are the potential mediators of brain and liver disorders.
http://www.ncbi.nlm.nih.gov/pubmed/23463459

“The resulting metabolic reconfiguration leads to fat accumulation and a
reduction in ATP synthesis, characteristics that are common to numerous medical
disorders.

Hence, the ability of Al toxicity to create an oxidative environment promotes
dysfunctional metabolic processes in astrocytes and hepatocytes. These
molecular events triggered by Al-induced ROS production are the potential
mediators of brain and liver disorders.”

“The incidence of narcolepsy was 25 times higher after the vaccination
compared with the time period before. The children in the postvaccination group
had a lower age at onset and a more sudden onset than that generally seen.”
Neurology • April 2013

Increased childhood incidence of narcolepsy in western Sweden after H1N1
influenza vaccination Author information Szakács A1, Darin N, Hallböök T.
Department of Children County Hospital, Halmstad, Sweden Abstract OBJECTIVES To
assess the incidence of narcolepsy between January 2000 and December 2010 in
children in western Sweden and its relationship to the Pandemrix vaccination,
and to compare the clinical and laboratory features of these children. METHODS
The children were identified from all local and regional pediatric hospitals,
child rehabilitation centers, outpatient pediatric clinics, and regional
departments of neurophysiology. Data collection was performed with the aid of a
standardized data collection form, from medical records and telephone
interviews with patients and parents. The laboratory and investigational data
were carefully scrutinized. RESULTS We identified 37 children with narcolepsy.
Nine of them had onset of symptoms before the H1N1 vaccination and 28 had onset
of symptoms in relationship to the vaccination. The median age at onset was 10
years. All patients in the postvaccination group were positive for human
leukocyte antigen (HLA)-DQB1*0602. Nineteen patients in the postvaccination
group, compared with one in the prevaccination group, had a clinical onset that
could be dated within 12 weeks. CONCLUSION Pandemrix vaccination is a
precipitating factor for narcolepsy, especially in combination with
HLA-DQB1*0602. The incidence of narcolepsy was 25 times higher after the
vaccination compared with the time period before. The children in the
postvaccination group had a lower age at onset and a more sudden onset than
that generally seen. http://www.ncbi.nlm.nih.gov/pubmed/?term=23486871

Expert Reviews Of Clinical Immunology • April 2013

Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld’s syndrome):
clinical and immunological spectrum Author information Vera-Lastra O1, Medina
G, Cruz-Dominguez Mdel P, Jara LJ, Shoenfeld Y. Hospital de Especialidades
Centro Médico La Raza Instituto Mexicano del Seguro Social Mexico City, Mexico
Abstract An adjuvant is a substance that enhances the antigen-specific immune
response, induces the release of inflammatory cytokines, and interacts with
Toll-like receptors and the NALP3 inflammasome. The immunological consequence
of these actions is to stimulate the innate and adaptive immune response. The
activation of the immune system by adjuvants, a desirable effect, could trigger
manifestations of autoimmunity or autoimmune disease. Recently, a new syndrome
was introduced, autoimmune/inflammatory syndrome induced by adjuvants (ASIA),
that includes postvaccination phenomena, macrophagic myofasciitis, Gulf War
syndrome and siliconosis. This syndrome is characterized by nonspecific and
specific manifestations of autoimmune disease. The main substances associated
with ASIA are squalene (Gulf War syndrome), aluminum hydroxide (postvaccination
phenomena, macrophagic myofasciitis) and silicone with siliconosis. Mineral
oil, guaiacol and iodine gadital are also associated with ASIA. The following
review describes the wide clinical spectrum and pathogenesis of ASIA including
defined autoimmune diseases and nonspecific autoimmune manifestations, as well
as the outlook of future research in this field.
http://www.ncbi.nlm.nih.gov/pubmed/23557271

“The activation of the immune system by adjuvants, a desirable effect, could
trigger manifestations of autoimmunity or autoimmune disease. Recently, a new
syndrome was introduced, autoimmune/inflammatory syndrome induced by adjuvants
(ASIA), that includes postvaccination phenomena, macrophagic myofasciitis, Gulf
War syndrome and siliconosis.”

PLoS One • April 2013

Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single
blinded randomized controlled trial Author information Bischoff AL1, Følsgaard
NV, Carson CG, Stokholm J, Pedersen L, Holmberg M, Bisgaard A, Birch S, Tsai
TF, Bisgaard H. Copenhagen Prospective Studies on Asthma in Childhood (COPSAC)
Health Sciences, University of Copenhagen, Copenhagen University Hospital
Gentofte, Denmark Abstract BACKGROUND Pregnant women were suspected to be at
particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary
objective was to compare the immune responses conferred by MF59®-adjuvanted
vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The
secondary aims were to compare influences of dose and adjuvant on the immune
response. METHODS The study was nested in the Copenhagen Prospective Studies on
Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as
a single-blinded blockrandomised [1∼1∼1] controlled clinical trial in pregnant
women after gestational week 20: (1) 7.5 μg H1N1pnd09 antigen with
MF59-adjuvant (Pa7.5 μg); (2) 3.75 μg antigen half MF59-adjuvanted (Pa3.75 μg);
(3) 15 μg antigen unadjuvanted (P15 μg); and in non-pregnant women receiving
(4) 7.5 μg antigen full adjuvanted (NPa7.5 μg). Blood samples were collected at
baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were
recorded prospectively. RESULTS 58 pregnant women were allocated to Pa7.5 μg
and 149 non-pregnant women were recruited to NPa7.5 μg. The sero-conversion
rate was significantly increased in non-pregnant (NPa7.5 μg) compared with
pregnant (Pa7.5 μg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean
titers trended towards being higher, but this difference was not statistically
significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase
rate showed no difference between pregnant (Pa7.5 μg) and non-pregnant (NPa7.5
μg) groups (OR = 0.49 [0.13-1.85], p = 0.29). CONCLUSION Our study suggests the
immune response to the 7.5 μg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in
pregnant women may be diminished compared with non-pregnant women.
http://www.ncbi.nlm.nih.gov/pubmed/23637733

“Our study suggests the immune response to the 7.5 μg MF59-adjuvanted Focetria®
H1N1pnd09 vaccine in pregnant women may be diminished compared with
non-pregnant women.”

“Prevalence of CD and UC increased 2-fold to 3-fold among VA users between 1998 and 2009.”
Inflammatory Bowel Diseases • April 2013

The incidence and prevalence of inflammatory bowel disease among U.S. veterans:
A national cohort study Hou, J.K.ab, Kramer, J.R.ab, Richardson, P.ab, Mei,
M.ab, El-Serag, H.B.ab a. Houston VA HSR and D Center of Excellence, Houston,
TX, United States b. Department of Medicine, Baylor College of Medicine,
Houston, TX, United States Abstract Background: Temporal trends in incidence
and prevalence of Crohn’s disease (CD) and ulcerative colitis (UC) in the
United States have been reported only in regional populations. The Veterans
Affairs (VA) health care system encompasses a national network of clinical care
facilities. The aim of this study was to identify temporal trends in the
incidence and prevalence of CD and UC among VA users using national VA data
sets. Methods: Veterans with CD and UC were identified during fiscal years 1998
to 2009 in the national VA outpatient and inpatient files. Incident and
prevalent cases were identified by diagnosis code, and age-standardized and
gender-standardized annual prevalence and incidence rates were estimated using
the VA 1998 population as the standard population. Results: The total of unique
incident cases were 16,842 and 26,272 for CD and UC, respectively; 94% were
men. The average annual age-standardized and gender-standardized incidence rate
of CD was 33 per 100,000 VA users (range, 27-40), whereas the average for UC
was 50 per 100,000 VA users (range, 36-65). In 2009, the age-standardized and
gender-standardized point prevalence rate of CD was 287 per 100,000 VA users,
whereas the point prevalence of UC was 413 per 100,000 VA users. Conclusions:
Prevalence of CD and UC increased 2-fold to 3-fold among VA users between 1998
and 2009. The incidence of UC decreased among VA users from 1998 to 2004 but
has remained stable from 2005 to 2009. The incidence of CD has remained stable
during the observed time period. http://www.ncbi.nim.nih.gov/pubmed/23448789

Clinical Infectious Disease • May 2013

Influenza vaccine effectiveness in the community and the household Author
information Ohmit SE1, Petrie JG, Malosh RE Cowling BJ, Thompson MG, Shay DK,
Monto AS. Department of Epidemiology University of Michigan School of Public
Health Ann Arbor, MI, USA sohmit@umich.edu Abstract Background There is a
recognized need to determine influenza vaccine effectiveness on an annual basis
and a long history of studying respiratory illnesses in households. Methods We
recruited 328 households with 1441 members, including 839 children, and
followed them during the 2010-2011 influenza season. Specimens were collected
from subjects with reported acute respiratory illnesses and tested by real-time
reverse transcriptase polymerase chain reaction. Receipt of influenza vaccine
was defined based on documented evidence of vaccination in medical records or
an immunization registry. The effectiveness of 2010-2011 influenza vaccination
in preventing laboratory-confirmed influenza was estimated using Cox
proportional hazards models adjusted for age and presence of high-risk
condition, and stratified by prior season (2009-2010) vaccination status.
Results Influenza was identified in 78 (24%) households and 125 (9%)
individuals; the infection risk was 8.5% in the vaccinated and 8.9% in the
unvaccinated (P = .83). Adjusted vaccine effectiveness in preventing
community-acquired influenza was 31% (95% confidence interval [CI], -7% to
55%). In vaccinated subjects with no evidence of prior season vaccination,
significant protection (62% [95%

CI, 17%-82%]) against community-acquired influenza was demonstrated.
Substantially lower effectiveness was noted among subjects who were vaccinated
in both the current and prior season. There was no evidence that vaccination
prevented household transmission once influenza was introduced; adults were at
particular risk despite vaccination. Influenza Vaccine Effectiveness (From Full
Report Linked Below) Adjusted vaccine effectiveness in preventing
community-acquired influenza was 31% (95% confidence interval [CI], ∼7 to 55);
point estimates were lowest in young children and modestly higher in adults.
Stratified analyses indicated substantial differences in vaccine effectiveness
based on whether or not seasonal influenza vaccine had been received the prior
season (interaction term: P = .014). Among subjects with documented evidence of
prior season vaccination, estimates of current season vaccine effectiveness
were low overall and in each of the age groups examined. In contrast, for those
subjects without evidence of prior season vaccine receipt, effectiveness
estimates were higher for all age groups and statistically significant overall
(62% [95% CI, 17%–82%]). In adjusted analyses for all ages combined,
effectiveness estimates were highest against influenza type B (48% [95% CI, ∼5%
to 75%]), and lower for A (pH1N1) (26% [95% CI, ∼68% to 67%]) and A (H3N2) (10%
[95% CI, ∼74% to 54%]). In analyses stratified by prior season vaccination
status, estimates were substantially higher for those subjects without evidence
of prior season vaccine receipt. Conclusions Vaccine effectiveness estimates
were lower than those demonstrated in other observational studies carried out
during the same season. The unexpected findings of lower effectiveness with
repeated vaccination and no protection given household exposure require further
study. http://www.ncbi.nlm.nih.gov/pubmed/?term=23413420 Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693492/

“Influenza was identified in 78 (24%) households and 125 (9%) individuals; the
infection risk was 8.5% in the vaccinated and 8.9% in the unvaccinated (P =
.83). Adjusted vaccine effectiveness in preventing community-acquired influenza
was 31% (95% confidence interval [CI], -7% to 55%). In vaccinated subjects with
no evidence of prior season vaccination, significant protection (62% [95% CI,
17%82%]) against communityacquired influenza was demonstrated. Substantially
lower effectiveness was noted among subjects who were vaccinated in both the
current and prior season. There was no evidence that vaccination prevented
household transmission once influenza was introduced; adults were at particular
risk despite vaccination.”

Human And Experimental Toxicology • May 2013

Comparison of VAERS fetal-loss reports during three consecutive influenza
seasons: was there a synergistic fetal toxicity associated with the two-vaccine
2009/2010 season? Author information Goldman GS Independent Computer Scientist
Pearblossom, CA 93553, USA gsgoldman@roadrunner.com Abstract The aim of this
study was to compare the number of inactivated-influenza vaccine-related
spontaneous abortion and stillbirth (SB) reports in the Vaccine Adverse Event
Reporting System (VAERS) database during three consecutive flu seasons
beginning 2008/2009 and assess the relative fetal death reports associated with
the two-vaccine 2009/2010 season. The VAERS database was searched for reports
of fetal demise following administration of the influenza vaccine/vaccines to
pregnant women. Utilization of an independent surveillance survey and VAERS,
two-source capture-recapture analysis estimated the reporting completeness in
the 2009/2010 flu season. Capture-recapture demonstrated that the VAERS
database captured about 13.2% of the total 1321 (95% confidence interval (CI):
815-2795) estimated reports, yielding an ascertainment-corrected rate of 590
fetal-loss reports per million pregnant women vaccinated (or 1 per 1695). The
unadjusted fetal-loss report rates for the three consecutive influenza seasons
beginning 2008/2009 were 6.8 (95% CI: 0.1-13.1), 77.8 (95% CI: 66.3-89.4), and
12.6 (95% CI: 7.2-18.0) cases per million pregnant women vaccinated,
respectively. The observed reporting bias was too low to explain the magnitude
increase in fetal-demise reporting rates in the VAERS database relative to the
reported annual trends. Thus, a synergistic fetal toxicity likely resulted from
the administration of both the pandemic (A-H1N1) and seasonal influenza
vaccines during the 2009/2010 season. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888271/

“Thus, a synergistic fetal toxicity likely resulted from the administration of
both the pandemic (A-H1N1) and seasonal influenza vaccines during the 2009/2010
season.”

“While young infants represent the major target population for vaccination,
effective immunization in this age group remains a challenge. Many parameters
of innate immune responses differ quantitatively and qualitatively from
newborns to infants and adults, revealing a highly regulated developmental
program.” Vaccine • May 2013

Immune response to vaccine adjuvants during the first year of life Ofer Levya,
Stanislas Gorielyb, Tobias R. Kollmannc Abstract Subunit vaccine formulations
often include adjuvants that primarily stimulate innate immune cells. While
young infants represent the major target population for vaccination, effective
immunization in this age group remains a challenge. Many parameters of innate
immune responses differ quantitatively and qualitatively from newborns to
infants and adults, revealing a highly regulated developmental program. Herein,
we discuss the potential implications of innate immune ontogeny for the
activity of adjuvants contained in licensed infant vaccines, as well as future
directions for rational design of adjuvanted vaccines for this age group. • We
comprehensively reviewed mechanisms of action of licensed adjuvants. • We
examined the changes of adjuvant responses with age in early life. • We
juxtaposed the current knowledge with safety considerations. • We point to the
need for targeted investigations of adjuvant activity early in life.
http://www.sciencedirect.com/science/article/pii/S0264410X12014624

Scandinavian Journal Of Clinical And Laboratory Investigations • May 2013

Leukocyte transcript alterations in West-African girls following a booster
vaccination with diphtheria-tetanus-pertussis vaccine Author information
Orntoft NW1, Thorsen K, Benn CS, Lemvik G, Nanque JR, Aaby P, Ostergaard L,
Agergaard J. Department of Medicine V (Hepatology and Gastroenterology) Aarhus
University Hospital, Aarhus, Denmark Abstract Background. Observational studies
from low-income countries have shown that the vaccination against diphtheria,
tetanus and pertussis (DTP) is associated with excess female mortality due to
infectious diseases. Methods. To investigate possible changes in gene
expression after DTP vaccination, we identified a group of nine comparable West
African girls, from a biobank of 356 children, who were due to receive DTP
booster vaccine at age 18 months. As a pilot experiment we extracted RNA from
blood samples before, and 6 weeks after, vaccination to analyze the coding
transcriptome in leukocytes using expression microarrays, and ended up with
information from eight girls. The data was further analyzed using dedicated
array pathway and network software. We aimed to study whether DTP vaccination
introduced a systematic alteration in the immune system in girls. Results. We
found very few transcripts to alter systematically. Those that did mainly
belonged to the Interferon (IFN) signalling pathway. We scrutinized this
pathway as well as the Interleukin (IL) pathways. Two out of eight showed a
down-regulated IFN pathway and two showed an up-regulated IFN pathway. The two
with down-regulated IFN pathway had also down-regulated IL-6 pathway. In the
study of networks, two of the girls stood out as not having the inflammatory
response as top altered network. Conclusion. The transcriptome changes
following DTP booster vaccination were subtle, but although the material was
small, it was possible to identify sub groups that deviate from each other,
mainly in the IFN response. http://www.ncbi.nlm.nih.gov/pubmed/?term=23668887

“Two out of eight showed a down-regulated IFN [Interferon] pathway and two
showed an up-regulated IFN [Interferon] pathway.”

BMC Medicine • May 2013

Video Q&A: what is ASIA? An interview with Yehuda Shoenfeld Yehuda Shoenfeld
Zabludowicz Center for Autoimmune Diseases Sheba Medical Center, Tel-Aviv
University Tel-Hashomer 52621, Israel Introduction Professor Yehuda Shoenfeld
is the founder and head of the Zabludowicz Center for Autoimmune Diseases at
the Sheba Medical Center, which is affiliated to the Sackler Faculty of
Medicine at Tel-Aviv University, Israel. He is also the Incumbent of the Laura
Schwarz-Kipp Chair for Research of Autoimmune Diseases at Tel-Aviv University.
His clinical and scientific works focus on autoimmune and rheumatic diseases,
and he has been the recipient of multiple awards, including a Life Contribution
Prize in Internal Medicine in Israel, 2012. In recent years, Professor
Shoenfeld noted that four conditions: siliconosis, Gulf War syndrome (GWS),
macrophagicmyofasciitis syndrome (MMF) and post-vaccination phenomena were
linked with previous exposure to an adjuvant, and that the patients also
presented with similar clinical symptoms. In 2011, this led Professor Shoenfeld
to suggest these comparable conditions should be grouped under a common
syndrome entitled ‘ASIA’, for ‘Autoimmune (Autoinflammatory) Syndrome Induced
by Adjuvants’. In this Q&A we talk to Professor Shoenfeld about ASIA, and
discuss his recommendations regarding further research in the field. Full
Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662178/ Video Interview
https://www.youtube.com/watch?v=0n12pWMfHhs

“In this Q&A we talk to Professor Shoenfeld about ASIA, and discuss his
recommendations regarding further research in the field.”

PLoS One • June 2013

Exercise challenge in Gulf War Illness reveals two subgroups with altered brain
structure and function Author information Rayhan RU1, Stevens BW, Raksit MP,
Ripple JA, Timbol CR, Adewuyi O, VanMeter JW, Baraniuk JN. Division of
Rheumatology, Immunology and Allergy Department of Medicine, Georgetown
University Medical Center Washington, District of Columbia, United States of
America rur@georgetown.edu Abstract Nearly 30% of the approximately 700,000
military personnel who served in Operation Desert Storm (1990-1991) have
developed Gulf War Illness, a condition that presents with symptoms such as
cognitive impairment, autonomic dysfunction, debilitating fatigue and chronic
widespread pain that implicate the central nervous system. A hallmark complaint
of subjects with Gulf War Illness is post-exertional malaise; defined as an
exacerbation of symptoms following physical and/ or mental effort. To study the
causal relationship between exercise, the brain, and changes in symptoms, 28
Gulf War veterans and 10 controls completed an fMRI scan before and after two
exercise stress tests to investigate serial changes in pain, autonomic
function, and working memory. Exercise induced two clinical Gulf War Illness
subgroups. One subgroup presented with orthostatic tachycardia (n = 10). This
phenotype correlated with brainstem atrophy, baseline working memory
compensation in the cerebellar vermis, and subsequent loss of compensation
after exercise. The other subgroup developed exercise induced hyperalgesia (n =
18) that was associated with cortical atrophy and baseline working memory
compensation in the basal ganglia. Alterations in cognition, brain structure,
and symptoms were absent in controls. Our novel findings may provide an
understanding of the relationship between the brain and post-exertional malaise
in Gulf War Illness. http://www.ncbi.nlm.nih.gov/pubmed/23798990

“Nearly 30% of the approximately 700,000 military personnel who served in
Operation Desert Storm (1990-1991) have developed Gulf War Illness, a condition
that presents with symptoms such as cognitive impairment, autonomic
dysfunction, debilitating fatigue and chronic widespread pain that implicate
the central nervous system.”

Methods In Molecular Biology • June 2013

Databases and in silico tools for vaccine design Author information He Y1,
Xiang Z. Department of Microbiology and Immunology Center for Computational
Medicine and Bioinformatics University of Michigan Medical School, Ann Arbor,
MI, USA Abstract In vaccine design, databases and in silico tools play
different but complementary roles. Databases collect experimentally verified
vaccines and vaccine components, and in silico tools provide computational
methods to predict and design new vaccines and vaccine components.
Vaccine-related databases include databases of vaccines and vaccine components.
In the USA, the Food and Drug Administration (FDA) maintains a database of
licensed human vaccines, and the US Department of Agriculture keeps a database
of licensed animal vaccines. Databases of vaccine clinical trials and vaccines
in research also exist. The important vaccine components include vaccine
antigens, vaccine adjuvants, vaccine vectors, and -vaccine preservatives. The
vaccine antigens can be whole proteins or immune epitopes. Various in silico
vaccine design tools are also available. The Vaccine Investigation and Online
Information Network (VIOLIN; http://www.violinet.org ) is a comprehensive
vaccine database and analysis system. The VIOLIN database includes various
types of vaccines and vaccine components. VIOLIN also includes Vaxign, a
Web-based in silico vaccine design program based on the reverse vaccinology
strategy. Vaccine information and resources can be integrated with Vaccine
Ontology (VO). This chapter introduces databases and in silico tools that
facilitate vaccine design, especially those in the VIOLIN system.
http://www.ncbi.nlm.nih.gov/pubmed/23568467

“Vaxign, a Web-based in silico vaccine design program based on the reverse
vaccinology strategy.”

Romanian Journal Of Internal Medicine • July 2013

ASIA or Shoenfeld’s syndrome— an autoimmune syndrome induced by adjuvants
Cojocaru M, Chico∼ B. Abstract Recently, reports have suggested grouping
different autoimmune conditions that are triggered by external stimuli as a
single syndrome called autoimmune syndrome induced by adjuvants (ASIA). This
syndrome is characterized by the appearance of myalgia, myositis, muscle
weakness, arthralgia, arthritis, chronic fatigue, sleep disturbances, cognitive
impairment and memory loss, and the possible emergence of a demyelinating
autoimmune disease caused by systemic exposure after vaccines and adjuvants. As
there are no markers for ASIA, the authors intend to present ASIA, or
Shoenfeld’s syndrome, as an autoimmune syndrome induced by adjuvants.
http://www.ncbi.nlm.nih.gov/pubmed/24620624

“This syndrome is characterized by the appearance of myalgia, myositis, muscle
weakness, arthralgia, arthritis, chronic fatigue, sleep disturbances, cognitive
impairment and memory loss, and the possible emergence of a demyelinating
autoimmune disease caused by systemic exposure after vaccines and adjuvants.”

Immunology Research • July 2013

Adverse events following immunization with vaccines containing adjuvants Author
information Cerpa-Cruz S1, Paredes-Casillas P, Landeros Navarro E,
Bernard-Medina AG, Martínez-Bonilla G, Gutiérrez-Ureña S. Rheumatology and
Immunology Department Hospital Civil de Guadalajara Fray Antonio Alcalde
Hospital 278, SH, Colonia El Retiro, 44280 Guadalajara, Jalisco, Mexico
sacer04@prodigy.net.mx Abstract A traditional infectious disease vaccine is a
preparation of live attenuated, inactivated or killed pathogen that stimulates
immunity. Vaccine immunologic adjuvants are compounds incorporated into
vaccines to enhance immunogenicity. Adjuvants have recently been implicated in
the new syndrome named ASIA autoimmune/inflammatory syndrome induced by
adjuvants. The objective describes the frequencies of postvaccination clinical
syndrome induced by adjuvants. We performed a cross-sectional study; adverse
event following immunization was defined as any untoward medical occurrence
that follows immunization 54 days prior to the event. Data on vaccinations and
other risk factors were obtained from daily epidemiologic surveillance.
Descriptive statistics were done using means and standard deviation, and odds
ratio adjusted for potential confounding variables was calculated with SPSS 17
software. Forty-three out of 120 patients with moderate or severe
manifestations following immunization were hospitalized from 2008 to 2011. All
patients fulfilled at least 2 major and 1 minor criteria suggested by Shoenfeld
and Agmon-Levin for ASIA diagnosis. The most frequent clinical findings were
pyrexia 68%, arthralgias 47%, cutaneous disorders 33%, muscle weakness 16% and
myalgias 14%. Three patients had diagnosis of Guillain-Barre syndrome, one
patient had Adult-Still’s disease 3 days after vaccination. A total of 76% of
the events occurred in the first 3 days postvaccination. Two patients with
previous autoimmune disease showed severe adverse reactions with the
reactivation of their illness. Minor local reactions were present in 49% of
patients. Vaccines containing adjuvants may be associated with an increased
risk of autoimmune/inflammatory adverse events following immunization.
http://www.ncbi.nlm.nih.gov/pubmed/23576057

“Vaccines containing adjuvants may be associated with an increased risk of
autoimmune/inflammatory adverse events following immunization.”

“... a form of the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome)
in commercial sheep, linked to the repetitive inoculation of
aluminum-containing adjuvants through vaccination. The syndrome shows an acute
phase that affects less than 0.5% of animals in a given herd ...” [a syndrome
that affects 5,000 per each 1 million] Immunology Research • July 2013

Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in
commercial sheep Author information Luján L1, Pérez M, Salazar E, Álvarez N,
Gimeno M, Pinczowski P, Irusta S, Santamaría J, Insausti N, Cortés Y, Figueras
L, Cuartielles I, Vila M, Fantova E, Chapullé JL. Department of Animal
Pathology Veterinary Faculty, University of Zaragoza 177 Miguel Servet Street,
50013, Saragossa, Spain Lluis.Lujan@unizar.es Abstract We describe a form of
the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome)
in commercial sheep, linked to the repetitive inoculation of
aluminum-containing adjuvants through vaccination. The syndrome shows an acute
phase that affects less than 0.5% of animals in a given herd, it appears 2-6
days after an adjuvant-containing inoculation and it is characterized by an
acute neurological episode with low response to external stimuli and acute
meningoencephalitis, most animals apparently recovering afterward. The chronic
phase is seen in a higher proportion of flocks, it can follow the acute phase,
and it is triggered by external stimuli, mostly low temperatures. The chronic
phase begins with an excitatory phase, followed by weakness, extreme cachexia,
tetraplegia and death. Gross lesions are related to a cachectic process with
muscular atrophy, and microscopic lesions are mostly linked to a
neurodegenerative process in both dorsal and ventral column of the gray matter
of the spinal cord. Experimental reproduction of ovine ASIA in a small group of
repeatedly vaccinated animals was successful. Detection of Al(III) in tissues
indicated the presence of aluminum in the nervous tissue of experimental
animals. The present report is the first description of a new sheep syndrome
(ovine ASIA syndrome) linked to multiple, repetitive vaccination and that can
have devastating consequences as it happened after the compulsory vaccination
against bluetongue in 2008. The ovine ASIA syndrome can be used as a model of
other similar diseases affecting both human and animals. A major research
effort is needed in order to understand its complex pathogenesis.
http://www.ncbi.nlm.nih.gov/pubmed/?term=23579772

American Journal of Homeopathic Medicine • Autumn 2013

Hidden in Plain Sight: Vaccines as a Major Risk Factor for Chronic Disease
Richard Moskowitz, MD Abstract The science and politics of vaccination in this
country are examined, with a careful look at the rationale for mandatory
vaccination, benefits, and harms, and illustrated by case examples showing
injury, yet problematic medical-legal recognition. Thirty-five years of medical
practice have convinced me that all vaccines carry a significant risk of
chronic disease that is inherent in the vaccination process and in fact central
to how they work. Yet the growing concerns of parents and legislators and the
media reports about them seldom elicit anything beyond automatic, scornful
denials by medical and public health authorities alike. Reflecting on this
discrepancy, the focal point of this essay, has also helped me appreciate how
much the invisibility actually heightens the risk, and how intimately these
phenomena are connected, like mirror-images of the same reality, so that it is
wisest to study them together. Since I am mainly a clinician, I will begin with
a story. It concerns a twelve-year-old boy whom I know of solely from his
mother’s letter, but her words are so heartfelt and so congruent with the rest
of my experience that I cannot doubt their veracity: My son Adam was healthy
until his first MMR shot at 15 months. Within 2 weeks he had flu and cold
symptoms, which persisted for 6 weeks. Then his eyes became puffy, and he was
hospitalized with nephrotic syndrome. A renal biopsy showed “focal sclerosing
glomerulonephritis,” but the illness didn’t respond to steroids. I asked if it
could be related to the vaccine, but they told me it couldn’t, and we accepted
that. Over the next 4 years he was hospitalized repeatedly, and missed many
months of school, but finally went into remission, seeming normal and healthy
and staying off all medications for about 5 years. When he turned 10, his
pediatrician recommended a booster, saying that a rise in measles cases made it
dangerous for him not to be protected. I checked the PDR and other sources but
found no

contraindication for kidney disease and no listing of nephrosis as a possible
adverse reaction, so I agreed to it. In less than 2 weeks he relapsed, with 4+
protein in his urine, swelling, and weight gain, signs that we recognized
immediately. He got worse even on Prednisone, and was admitted in hypertensive
crisis, with blood in his urine, fluid in his lungs,*and massive weight gain.
On Cytoxan, massive doses of Prednisone, and three other drugs, he slowly
improved, but missed another 7 months of school. It’s been 2 years since that
horrible episode, and he still needs Captopril daily for high blood pressure,
and spills 4+ protein every day. The doctor says he sustained major kidney
damage, will always need medication to control his blood pressure, and will
worsen as he grows older, necessitating a transplant eventually. This time I
was convinced that his condition was related to the vaccine, but still the
doctors didn’t take me seriously, and told me it was a coincidence. I began
searching for information, and even contacted the manufacturer of the vaccine.
Finally they sent me two case reports of nephrotic syndrome following the MMR
vaccine. It’s very difficult for lay people to get information, or even ask
questions, since we don’t use the correct medical terms and are made to feel
stupid. Please tell me if my ideas are reasonable. I don’t think my son could
tolerate another episode, and I think he’d have normal blood pressure and
kidney function today if not for that second vaccination. I also have a great
concern for other children who develop nephritic syndrome some weeks after
receiving MMR and whose doctors never make the connection. They could all be at
great risk if revaccinated. I realize that this letter has taken up a great
deal of your time, and I’d appreciate any help you can give me. If we were
closer, I’d make an appointment to see you in person, so please feel free to
charge me. Thank you. Full Text http://www.whale.to/vaccine/moskowitz.html

Advisory Commission on Childhood Vaccines • September 2013

Updating the Vaccine Injury Table: Guillain-Barré Syndrome (GBS) and Seasonal
Influenza Vaccines Ahmed Calvo, M.D., M.P.H. Medical Officer National Vaccine
Injury Compensation Program (VICP) Summary

The report leaves us understanding that the strength of evidence and
association is high between (2009) H1N1 vaccines and Guillain Barre Syndrome.
Full Report
http://www.hrsa.gov/vaccinecompensation/updatevaccineinjurytable2013.pdf

Current Alzheimer Research • November 2013

Military risk factors for cognitive decline, dementia and Alzheimer’s disease
Author information Veitch DP1, Friedl KE, Weiner MW. Center for Imaging of
Neurodegenerative Diseases Veterans Medical Center and Departments of
Radiology, Medicine, Psychiatry and Neurology University of California, San
Francisco San Francisco, CA, USA michael.weiner@ucsf.edu Abstract Delayed
neurological health consequences of environmental exposures during military
service have been generally underappreciated. The rapidly expanding
understanding of Alzheimer’s disease (AD) pathogenesis now makes it possible to
quantitate some of the likely long-term health risks associated with military
service. Military risk factors for AD include both factors elevated in military
personnel such as tobacco use, traumatic brain injury (TBI), depression, and
post-traumatic stress disorder (PTSD) and other nonspecific risk factors for AD
including, vascular risk factors such as obesity and obesity-related diseases
(e.g., metabolic syndrome), education and physical fitness. The degree of
combat exposure, Vietnam era Agent Orange exposure and Gulf War Illness may
also influence risk for AD. Using available data on the association of AD and
specific exposures and risk factors, the authors have conservatively estimated
423,000 new cases of AD in veterans by 2020, including 140,000 excess cases
associated with specific military exposures. The cost associated with these
excess cases is approximately $5.8 billion to $7.8 billion. Mitigation of the
potential impact of military exposures on the cognitive function of veterans
and management of modifiable risk factors through specifically designed
programs will be instrumental in minimizing the impact of AD in veterans in the
future decades. http://www.ncbi.nlm.nih.gov/pubmed/23906002

“... the authors have conservatively estimated 423,000 new cases of AD in
veterans by 2020, including 140,000 excess cases associated with specific
military exposures. The cost associated with these excess cases is
approximately $5.8 billion to $7.8 billion.”

Journal Of Inorganic Biochemistry • November 2013

Distinctive clinical features in arthro-myalgic patients with and without
aluminum hydroxyde-induced macrophagic myofasciitis: an exploratory study
Author information Ragunathan-Thangarajah N1, Le Beller C, Boutouyrie P, Bassez
G, Gherardi RK, Laurent S, Authier FJ. INSERM U955-Equipe 10 Université Paris
Est-Créteil, Créteil, France Abstract Macrophagic myofasciitis (MMF) is a
specific histological lesion assessing the persistence of vaccine-derived
aluminum oxyhydroxide in muscle tissue, at a site of previous immunization.
Long-lasting MMF is usually detected in patients with arthromyalgias, chronic
fatigue, and stereotyped cognitive dysfunction. MMF diagnosis requires muscle
biopsy, an invasive procedure not suitable for the routine investigation of all
patients with musculoskeletal pain. To help decision making in routine
practice, we designed a retrospective analysis of 130 consecutive
arthro-myalgic patients, previously immunized with aluminum-containing
vaccines, in whom deltoid muscle biopsy was performed for diagnostic purposes.
According to biopsy results, the patients were ascribed to either the MMF or
the non-MMF group. MMF was diagnosed in 32.3% of the patients. MMF and non-MMF
groups were similar according to both the injected vaccines and the delay
between vaccination and biopsy. MMF patients had less frequent fibromyalgia
than nonMMF patients (≥11 fibromyalgic tender points in 16.6 vs 55.5%, p <
0.04), and more often abnormal evoked potentials suggestive of CNS
demyelination (38.5 vs 5.7%, p < 0.01). Predictive bioclinical scores based on
simple variables such as the number of fibromyalgic tender points, arthralgias,
and spinal pain, had sensitivity ranging from 50 to 88.1% and specificity from
36.4 to 76.1%. In Conclusion (i) most aluminum-containing vaccine receivers do
not have long-lasting MMF in their muscle, but the prevalence of MMF among
patients with arthromyalgia following immunization is substantial; (ii)
patients with MMF have more CNS dysfunction and less fibromyalgic tender points
than non-MMF patients; (iii) predictive scores may help to identify patients at
high vs low risk of MMF. http://www.ncbi.nlm.nih.gov/pubmed/?term=23921285

“most aluminum-containing vaccine receivers do not have long-lasting MMF in
their muscle, but the prevalence of MMF among patients with arthromyalgia
following immunization is substantial ... patients with MMF have more CNS
dysfunction ...”

Deutsches Arzteblatt International • November 2013

Targeted vaccine selection in influenza vaccination Author information Wutzler
P1, Hardt R, Knuf M, Wahle K. Institute of Virology and Antiviral Therapy -
University Hospital Jena Catholic Clinic Mainz, St. Hildegardis Hospital
Department of Child and Adolescent Medicine Dr. Horst Schmidt Clinic GmbH,
Wiesbaden German Association of General Practitioners, Münster Abstract
BACKGROUND The main target groups for influenza vaccination are the elderly,
the chronically ill, infants, and toddlers. Influenza vaccines are needed that
suit the immunological particularities of each of these age and risk groups.
Recent years have seen the approval of influenza vaccines that are more
immunogenic than before, but whose use in Germany is limited by the restriction
of reimbursement to a small number of vaccines. METHODS The Medline database
was selectively searched for pertinent literature. RESULTS The suboptimal
immunogenicity of conventional influenza vaccines that contain inactivated
viral cleavage products and subunits can be markedly improved by the use of
squalene-based adjuvant systems, by the integration of viral antigens in
virosomal particles, or by intradermal administration. The vaccination of
elderly persons with a vaccine containing the adjuvant MF59 was found to lower
the risk of hospitalization for influenza or pneumonia by 25% compared to
vaccination with a trivalent inactivated vaccine (TIV). On the other hand, the
adjuvant ASO3 was found to be associated with an up to 17-fold increase in the
frequency of narcolepsy among 4- to 18-year-olds. In a prospective study, a
virosomal vaccine lowered the frequency of laboratory-confirmed influenza in
vaccinated children by 88% compared to unvaccinated children (2 versus 18 cases
per 1000 individuals). A live, attenuated influenza vaccine lowered the rate of
disease in children up to age 7 by 48% compared to a TIV (4.2% versus 8.1%).
CONCLUSION The newer vaccines possess improved efficacy when used for primary
and booster immunization in certain age and risk groups, and they are superior
in this respect to conventional vaccines based on viral cleavage products and
subunits. The risk/benefit profiles of all currently available vaccines vary
depending on the age group or risk group in which they are used.
http://www.ncbi.nlm.nih.gov/pubmed/24314622

From the full report:

“... the adjuvant ASO3 [squalene] was found to be associated with an up to
17-fold increase in the frequency of narcolepsy among 4- to 18-year-olds.”

Eurosurveillance, Volume 18 • December 2013
Rapid communications

routine 30 days post-MMR immunisation period used by the Canadian adverse event
following immunization (AEFI) surveillance system.

Case Of Vaccine-Associated Measles Five Weeks Post-Immunization, British
Columbia, Canada, October 2013 Author Information M Murti ()1, M Krajden2, M
Petric2 J Hiebert3, F Hemming1, B Hefford4 M Bigham1, P Van Buynder1 1. Fraser
Health Authority Surrey, British Columbia, Canada 2. Public Health Microbiology
and Reference Laboratory British Columbia Centre for Disease Control Vancouver,
British Columbia, Canada 3. National Microbiology Laboratory Public Health
Agency of Canada Winnipeg, Manitoba, Canada 4. 1-1400 George St., White Rock
British Columbia, Canada We describe a case of vaccine-associated measles in a
two-year-old patient from British Columbia, Canada, in October 2013, who
received her first dose of measlescontaining vaccine 37 days prior to onset of
prodromal symptoms. Identification of this delayed vaccine-associated case
occurred in the context of an outbreak investigation of a measles cluster.
Based on our review of the literature, this report documents the first case of
MMR vaccine-associated measles, 37 days post-immunisation, well beyond 21 days
and the

Measles-containing vaccines are used globally, have been part of the British
Columbia immunisation schedule since 1969, and have an impressive record of
safety validated by careful, ongoing AEFI surveillance. Rash and/or mild
clinical illness following MMR vaccine are not uncommon [7]. Clinically
significant vaccine-associated illness is rare, but when it occurs it is
indistinguishable from wild-type measles, except by genotyping [8]. Detection
of vaccine virus has been documented up to 14 days post-immunisation by RT-PCR,
and up to 16 days by immunofluorescence microscopy of urine sediment [9-12].
Complications from vaccine-associated measles have been documented in both
immune-competent and compromised individuals [13,14]. Of note, only one case
report of transmission from vaccine-associated measles has been identified
[15,16]. Possible explanations for this prolonged shedding of measles vaccine
virus include interference with the immune response by host or vaccine factors.
Immunoglobulin administration early in the incubation period has been reported
to extend the time to onset of symptoms, but in this child there was no such
history and no known immunosuppressive illness [5]. The two-fold rise between
acute and convalescent measles-specific IgG suggests the vaccine-mediated
immune response had been underway prior to the onset of symptoms.
Investigations clarified that there were no shipping, handling or coldchain
deviations for the specific vaccine used, and that it was administered by a
public health nurse trained in immunisations. The potential immunological
impact of the older age of the child at the time of receiving the first dose of
MMR vaccine, 33 months versus the typical 1215 months of age, and the
co-administration of meningococcal C and pneumococcal conjugate vaccines are
areas for future investigation.

Full Report http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20649

“We describe a case of vaccine-associated measles in a two-year-old patient
from British Columbia, Canada, in October 2013, who received her first dose of
measlescontaining vaccine 37 days prior to onset of prodromal symptoms.
Identification of this delayed vaccine-associated case occurred in the context
of an outbreak investigation of a measles cluster. Possible explanations for
this prolonged shedding of measles vaccine virus include interference with the
immune response by host or vaccine factors.”

American Journal Of Obstetrics & Gynecology • December 2013

The fetal inflammatory response syndrome is a risk factor for morbidity in
preterm neonates Author information Hofer N1, Kothari R, Morris N, Müller W,
Resch B. Research Unit for Neonatal Infectious Diseases and Epidemiology
Medical University of Graz, Graz, Austria Abstract OBJECTIVE The aim of this
study was to show and discuss an association between fetal inflammatory
response syndrome (FIRS) and an adverse neonatal outcome defined as combined
severe neonatal morbidity and mortality in preterm neonates hospitalized in our
neonatal intensive care unit. STUDY DESIGN This was an observational study
including all preterm neonates hospitalized in our neonatal intensive care unit
over a 21 month period. FIRS was defined as cord blood interleukin (IL)-6
greater than 11 pg/mL. Main outcome parameter was an adverse neonatal outcome
defined as hospital mortality and/or the presence of any of 5 prespecified
morbidities (bronchopulmonary dysplasia, periventricular leukomalacia,
intraventricular hemorrhage, and early- or late-onset sepsis). RESULTS
Fifty-seven of 176 preterm infants hospitalized during the study period (32%)
had an adverse neonatal outcome and 62 of these 176 infants (35%) had FIRS with
median IL-6 values of 51.8 pg/mL (range, 11.2 to >1000 pg/mL). In a regression
analysis, FIRS was significantly associated with adverse neonatal outcome (P <
.001) and with the single outcome parameters, intraventricular hemorrhage and
early-onset sepsis (P = .006 and P = .018, respectively). In the bivariate
analysis, FIRS was associated with death and bronchopulmonary dysplasia (P =
.004 and P < .001, respectively). IL-6 correlated with adverse neonatal outcome
(r = 0.411, P < .001). When comparing the correlation in neonates less than 32
weeks’ gestational age (r = 0.481, P < .001) with neonates 32 weeks or longer
(r = 0.233, P = .019), the difference was nearly significant (P = .065).
CONCLUSION FIRS is a risk factor for adverse neonatal outcome in preterm
infants. In particular, the combination of IL-6 greater than 11 pg/mL and low
gestational age increased the risk for severe neonatal morbidity or death.
http://www.ncbi.nlm.nih.gov/pubmed/?term=23994220

[hospitals do not routinely check interleukin (IL)-6 cord blood prior to
vaccination, although they could]

Journal Of Autoimmunity • December 2013

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling
the pathogenic, clinical and diagnostic aspects Author information Perricone
C1, Colafrancesco S, Mazor RD, Soriano A, Agmon-Levin N, Shoenfeld Y. The
Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Israel
Reumatologia, Dipartimento di Medicina Interna e Specialità Mediche Sapienza
Università di Roma, Rome, Italy Abstract In 2011 a new syndrome termed ‘ASIA
Autoimmune/Inflammatory Syndrome Induced by Adjuvants’ was defined pointing to
summarize for the first time the spectrum of immunemediated diseases triggered
by an adjuvant stimulus such as chronic exposure to silicone,
tetramethylpentadecane, pristane, aluminum and other adjuvants, as well as
infectious components, that also may have an adjuvant effect. All these
environmental factors have been found to induce autoimmunity by themselves both
in animal models and in humans: for instance, silicone was associated with
siliconosis, aluminum hydroxide with post-vaccination phenomena and macrophagic
myofasciitis syndrome. Several mechanisms have been hypothesized to be involved
in the onset of adjuvant-induced autoimmunity; a genetic favorable background
plays a key role in the appearance on such vaccine-related diseases and also
justifies the rarity of these phenomena. This paper will focus on protean
facets which are part of ASIA, focusing on the roles and mechanisms of action
of different adjuvants which lead to the autoimmune/inflammatory response. The
data herein illustrate the critical role of environmental factors in the
induction of autoimmunity. Indeed, it is the interplay of genetic
susceptibility and environment that is the major player for the initiation of
breach of tolerance. http://www.ncbi.nlm.nih.gov/pubmed/24238833

“In 2011 a new syndrome termed ‘ASIA Autoimmune/Inflammatory Syndrome Induced
by Adjuvants’ was defined pointing to summarize for the first time the spectrum
of immune-mediated diseases triggered by an adjuvant stimulus such as chronic
exposure to silicone, tetramethylpentadecane, pristane, aluminum and other
adjuvants, as well as infectious components, that also may have an adjuvant
effect.”

Current Medicinal Chemistry • 2013

Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)— animal
models as a proof of concept Author information Cruz-Tapias P1, Agmon-Levin N,
Israeli E, Anaya JM, Shoenfeld Y. Head of Zabludowitz Center for Autoimmune
Diseases Sheba Medical Center, Tel Hashomer 52621, Israel
shoenfel@post.tau.ac.il Abstract ASIA syndrome, “Autoimmune (Auto-inflammatory)
Syndromes Induced by Adjuvants” includes at least four conditions which share a
similar complex of signs and symptoms and have been defined by hyperactive
immune responses: siliconosis, macrophagic myofasciitis syndrome, Gulf war
syndrome and post-vaccination phenomena. Exposure to adjuvants has been
documented in these four medical conditions, suggesting that the common
denominator to these syndromes is a trigger entailing adjuvant activity. An
important role of animal models in proving the ASIA concept has been
established. Experimentally animal models of autoimmune diseases induced by
adjuvants are currently widely used to understand the mechanisms and etiology
and pathogenesis of these diseases and might thus promote the development of
new diagnostic, predictive and therapeutic methods. In the current review we
wish to unveil the variety of ASIA animal models associated with systemic and
organ specific autoimmune diseases induced by adjuvants. We included in this
review animal models for rheumatoid arthritis-like disease, for systemic lupus
erythematosus-like disease, autoimmune thyroid disease-like disease,
antiphospholipid syndrome, myocarditis and others. All these models support the
concept of ASIA, as the Autoimmune (Auto-inflammatory) Syndrome Induced by
Adjuvants. http://www.ncbi.nlm.nih.gov/pubmed/23992328

“We included in this review animal models for rheumatoid arthritis-like
disease, for systemic lupus erythematosus-like disease, autoimmune thyroid
disease-like disease, antiphospholipid syndrome, myocarditis and others. All
these models support the concept of ASIA, as the Autoimmune (Auto-inflammatory)
Syndrome Induced by Adjuvants.”

“... vaccine-induced Febrile Seizures could be a problem, particularly in genetically predisposed children.”
Expert Review of Vaccines • 2013

Vaccines and febrile seizures Abstract Vaccine administration is the second
leading cause of febrile seizures (FS). FS occurrence in children is a serious
concern because it leads to public apprehension of vaccinations. This review
discusses the clinical implications of FS, its potential link to vaccinations
and its impact on official recommendations for vaccinations in children.
Vaccines such as the pertussis antigen-containing vaccine, the
measles-containing vaccine and the influenza vaccine have been linked to FS.
However, FS events are very rare and are not usually associated with downstream
complications or severe neurologic diseases. Considering their significant
health benefits, vaccinations have not been restricted in the pediatric
population. Nevertheless, vaccine-induced FS could be a problem, particularly
in genetically predisposed children. Therefore, post-marketing surveillance
studies are required to accurately assess the incidence of FS and identify
individuals who are particularly susceptible to FS after vaccination.
http://www.tandfonline.com/doi/abs/10.1586/14760584.2013.814781

Human Vaccines And Immunotherapeutics • 2014

Mortality among recipients of the Merck V710 Staphylococcus aureus vaccine
after postoperative S. aureus infections: an analysis of possible contributing
host factors Author information McNeely TB1, Shah NA, Fridman A, Joshi A,
Hartzel JS, Keshari RS, Lupu F, DiNubile MJ. Merck Research Laboratories, West
Point, PA USA Abstract In a blinded randomized trial, preoperative receipt of
the Merck V710 Staphylococcus aureus vaccine was associated with a higher
mortality rate than placebo in patients who later developed postoperative S.
aureus infections. Of the tested patients, all 12 V710 recipients (but only 1
of 13 placebo recipients) with undetectable serum IL2 levels prior to
vaccination and surgery died after postoperative S. aureus infection. The
coincidence of 3 factors (low prevaccination IL-2 levels, receipt of V710, and
postoperative S. aureus infection) appeared to substantially increase mortality
in our study population after major cardiothoracic surgery. Furthermore, 9 of
the 10 V710 recipients with undetectable preoperative IL17a levels and
postoperative S. aureus infections died. Although the current study is
hypothesis-generating and the exact pathophysiology remains speculative, these
findings raise concern that immune predispositions may adversely impact the
safety and efficacy of staphylococcal vaccines actively under development. The
potential benefits of an effective vaccine against S. aureus justify continued
but cautious pursuit of this elusive goal.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25483690

“In a blinded randomized trial, preoperative receipt of the Merck V710
Staphylococcus aureus vaccine was associated with a higher mortality rate than
placebo in patients who later developed postoperative S. aureus infections. Of
the tested patients, all 12 V710 recipients (but only 1 of 13 placebo
recipients) with undetectable serum IL2 levels prior to vaccination and surgery
died after postoperative S. aureus infection.”

Human Vaccines & Immunotherapeutics • 2014

Hepatitis B vaccine adverse events in China: risk control and regulation Author
information Meina L1, Xiaodong L, Lulu Z. 1. The Second Military Medical
University Faculty of Health Service; Institute of Military Health Management
PLA; Shanghai, China Abstract The death of 17 children raised public fears over
infant hepatitis B vaccination in China. Though the relation between hepatitis
B and children’s death was denied after prudent investigation, the negative
impact remained. In order to prevent or minimize adverse events after
vaccination, special strategy including regulation and reimbursement should be
developed. http://www.ncbi.nlm.nih.gov/pubmed/25483642

“The death of 17 children raised public fears over infant hepatitis B
vaccination in China.”

Current Medical Chemistry • 2014

Selective elevation of circulating CCL2/MCP1 levels in patients with
longstanding post-vaccinal macrophagic myofasciitis and ASIA Author information
Cadusseau J, Ragunathan-Thangarajah N, Surenaud M, Hue S, Authier FJ, Gherardi
RK1. Université Paris Est, Faculté de Sciences et Technologie Créteil, 94000,
France romain.gherardi@hmn.aphp.fr Abstract Several medical conditions sharing
similar signs and symptoms may be related to immune adjuvants. These conditions
described as ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants),
include a condition characterized by macrophagic myofasciitis (MMF) assessing
long-term persistence of vaccine derived-alum adjuvants into macrophages at
sites of previous immunization. Despite increasing data describing clinical
manifestations of ASIA have been reported, biological markers are particularly
lacking for their characterization and follow up. We report an extensive
cytokine screening performed in serum from 44 MMF patients compared both to sex
and age matched healthy controls and to patients with various types of
inflammatory neuromuscular diseases. Thirty cytokines were quantified using
combination of Luminex® technology and ELISA. There was significant mean
increase of serum levels of the monocytechemoattractant protein 1 (CCL2/MCP-1)
in MMF patients compared to healthy subjects. MMF patients showed no elevation
of other cytokines. This contrasted with inflammatory patients in whom
CCL2/MCP-1 serum levels were unchanged, whereas several other inflammatory
cytokines were elevated (IL1∼, IL5 and CCL3/MIP1∼). These results suggest that
CCL2 may represent a biological marker relevant to the pathophysiology of MMF
rather than a non specific inflammatory marker and that it should be checked in
the other syndromes constitutive of ASIA.
http://www.ncbi.nlm.nih.gov/pubmed/?term=24083602

“These conditions described as ASIA, include a condition characterized by
macrophagic myofasciitis (MMF) assessing long-term persistence of vaccine
derived-alum adjuvants into macrophages at sites of previous immunization.”

Human Vaccines And Immunotherapeutics • 2014

Immunological persistence in 5 year olds previously vaccinated with hexavalent
DTPa-HBV-IPV/Hib at 3, 5, and 11 months of age Author information Silfverdal
SA1, Assudani D, Kuriyakose S, Van Der Meeren O. 1. Department of Clinical
Sciences Pediatrics; Umeå University Umeå, Sweden Abstract The combined
diphtheria-tetanus-acellular pertussis-hepatitis B-poliomyelitis/Haemophilus
influenza vaccine (DTPa-HBV-IPV/Hib: Infanrix™ hexa, GlaxoSmithKline Vaccines)
is used for primary vaccination of infants in a range of schedules world-wide.
Antibody persistence after 4 DTPa-HBV-IPV/Hib doses in the first 2 y of life
has been documented, but long-term persistence data following the 3, 5, 11-12
months (3-5-11) infant vaccination schedule, employed for example in Nordic
countries, are limited. We assessed antibody persistence in 57 5-year-old
children who had received either DTPaHBV-IPV/Hib or DTPa-IPV/Hib
(Infanrix™-IPV/Hib, GlaxoSmithKline Vaccines) in the 3-5-11 schedule. Among
DTPa-HBV-IPV/Hib recipients, 7/12 retained seroprotective antibody
concentrations for diphtheria, 10/12 for tetanus, 5/12 for hepatitis and 10/12
for Hib. Detectable antibodies were observed for 0/12 children for pertussis
toxin (PT), 12/12 for filamentous haemagglutinin (FHA) and 8/12 for pertactin
(PRN). Among DTPa-IPV/Hib recipients, 28/45 retained seroprotective
anti-diphtheria concentrations, 34/44 for tetanus and 40/45 for Hib. Detectable
antibodies were observed for 9/45 children for PT, 41/45 for FHA and 34/45 for
PRN. Antibody persistence in DTPa-HBV-IPV/Hib and DTPa-IPV/Hib-vaccinees
appeared similar in 5 y olds to that previously observed in children of a
similar age who had received 4 prior doses of DTPa-HBV-IPV/Hib (or DTPa-IPV/
Hib). As in subjects primed with 4 prior doses, we observed that antibodies
markedly declined by 5 y of age, calling for the administration of a pre-school
booster dose in order to ensure continued protection against pertussis.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25483640

[regarding vaccine non-responders and low-responders:

In this study 7 of 12 five year old children retained seroprotective antibody
concentrations for diphtheria, 10 of 12 for tetanus, 5 of 12 for hepatitis and
10 of 12 for Hib. The pro-vaccine lobby never discusses non-responders and low
responders and the large variance in human response to vaccination. Even
vaccinated people can be fully non-responsive or so low-responsive that they
can communicate diseases as easily as non-vaccinated people making vaccination
an entirely uncertain medical procedure and adding substance and support to the
position that vaccination is not always effective]

Human Vaccines And Immunotherapeutics • 2014

Consumer reporting of adverse events following immunization Author information
Clothier HJ1, Selvaraj G, Easton ML, Lewis G, Crawford NW, Buttery JP. 1.
SAEFVIC; Murdoch Childrens Research Institute Melbourne; School of Population &
Global Health University of Melbourne; Melbourne, Victoria, Australia Abstract
Surveillance of adverse events following immunisation (AEFI) is an essential
component of vaccine safety monitoring. The most commonly utilized passive
surveillance systems rely predominantly on reporting by health care providers
(HCP). We reviewed adverse event reports received in Victoria, Australia since
surveillance commencement in July 2007, to June 2013 (6 years) to ascertain the
contribution of consumer (vaccinee or their parent/guardian) reporting to
vaccine safety monitoring and to inform future surveillance system development
directions. Categorical data included were: reporter type; serious and
non-serious AEFI category; and, vaccinee age group. Chi-square test and
2-sample test of proportions were used to compare categories; trend changes
were assessed using linear regression. Consumer reporting increased over the 6
years, reaching 21% of reports received in 2013 (P<0.001), most commonly for
children aged less than 7 years. Consumer reports were 5% more likely to
describe serious AEFI than HCP (P=0.018) and 10% more likely to result in
specialist clinic attendance (P<0.001). Although online reporting increased to
32% of all report since its introduction in 2010, 85% of consumers continued to
report by phone. Consumer reporting of AEFI is a valuable component of vaccine
safety surveillance in addition to HCP reporting. Changes are required to AEFI
reporting systems to implement efficient consumer AEFI reporting, but may be
justified for their potential impact on signal detection sensitivity.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25483686

“Consumer reporting increased over the 6 years, reaching 21% of reports
received in 2013 (P<0.001), most commonly for children aged less than 7 years.”

Human Vaccines And Immunotherapeutics • 2014

Immunocompetent mouse models to evaluate intrahepatic T cell responses to HCV
vaccines Author information Yu W1, Grubor-Bauk B, Mullick R, Das S, Gowans EJ.
1. Discipline of Surgery University of Adelaide Basil Hetzel Institute
Adelaide, SA, Australia Abstract Despite considerable progress in the
development of immunocompetent mouse models using different high end
technologies, most available small animal models for HCV study are unsuitable
for challenge experiments, which are vital for vaccine development, as they
fail to measure the T cell response in liver. A recently developed
intra-hepatic challenge model results in HCV antigen expression in mouse
hepatocytes and through the detection of the surrogate marker, SEAP, in serum,
the effect of prior vaccination can be monitored longitudinally.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25483684

[vaccination is inherently experimental. There are so many unknowns that this
is indisputable]

Human Vaccines And Immunotherapeutics • 2014

The persistence of anti-HBs antibody and anamnestic response 20 years after
primary vaccination with recombinant hepatitis B vaccine at infancy Author
information Bagheri-Jamebozorgi M1, Keshavarz J, Nemati M,
Mohammadi-Hossainabad S, Rezayati MT, Nejad-Ghaderi M, Jamalizadeh A, Shokri F,
Jafarzadeh A. Molecular Medicine Research Center Rafsanjan University of
Medical Sciences Rafsanjan, Iran Abstract Hepatitis B (HB) vaccine induces
protective levels of antibody response (anti-HBs≥10 mIU/ mL) in 90-99% of
vaccinees. The levels of anti-HBs antibody decline after vaccination. The aim
of this study was to evaluate the persistence of anti-HBs antibodies and
immunologic memory in healthy adults at 20 years after primary vaccination with
recombinant HB vaccine. Blood samples were collected from 300 adults at 20
years after primary HB vaccination and their sera were tested for anti-HBs
antibody by ELISA technique. A single booster dose of HB vaccine was
administered to a total of 138 subjects, whose anti-HBs antibody titer was <10
mIU/mL. The sera of subjects were re-tested for the anti-HBs antibody levels at
4 weeks after booster vaccination. At 20 years after primary vaccination 37.0%
of participants had protective levels of antibody with geometric mean titer
(GMT) of 55.44±77.01 mIU/mL. After booster vaccination, 97.1% of vaccinees
developed protective levels of antibody and the GMT rose from 2.35±6.49 mIU/mL
to 176.28±161.78 mIU/mL. 125/138 (90.6%) of revaccinated subjects also showed
an anamnestic response to booster vaccination. At 20 years after primary
vaccination with HB vaccine, low proportion of the subjects had protective
levels of antibody. However, the majority of the re-vaccinated subjects
developed protective levels of anti-HBs and showed an anamnestic response after
booster vaccination. Additional follow-up studies are necessary to determine
the duration of immunological memory.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25483689

“At 20 years after primary vaccination 37.0% of participants had protective
levels of antibody ...”

Human Vaccines And Immunotherapeutics • 2014

Serum and mucosal antibody responses to inactivated polio vaccine after
sublingual immunization using a thermoresponsive gel delivery system Author
information White JA1, Blum JS, Hosken NA, Marshak JO, Duncan L, Zhu C, Norton
EB, Clements JD, Koelle DM, Chen D, Weldon WC, Oberste MS, Lal M. Abstract
Administering vaccines directly to mucosal surfaces can induce both serum and
mucosal immune responses. Mucosal responses may prevent establishment of
initial infection at the port of entry and subsequent dissemination to other
sites. The sublingual route is attractive for mucosal vaccination, but both a
safe, potent adjuvant and a novel formulation are needed to achieve an adequate
immune response. We report the use of a thermoresponsive gel (TRG) combined
with a double mutant of a bacterial heat-labile toxin (dmLT) for sublingual
immunization with a trivalent inactivated poliovirus vaccine (IPV) in mice.
This TRG delivery system, which changes from aqueous solution to viscous gel
upon contact with the mucosa at body temperature, helps to retain the
formulation at the site of delivery and has functional adjuvant activity from
the inclusion of dmLT. IPV was administered to mice either sublingually in the
TRG delivery system or intramuscularly in phosphate-buffered saline. We
measured poliovirus type-specific serum neutralizing antibodies as well as
polio-specific serum Ig and IgA antibodies in serum, saliva, and fecal samples
using enzyme-linked immunosorbent assays. Mice receiving sublingual vaccination
via the TRG delivery system produced both mucosal and serum antibodies,
including IgA. Intramuscularly immunized animals produced only serum
neutralizing and binding Ig but no detectable IgA. This study provides proof of
concept for sublingual immunization using the TRG delivery system, comprising a
thermoresponsive gel and dmLT adjuvant.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25483682

“This study provides proof of concept for sublingual immunization ...”

Vaccine • January 2014

Nanoparticle vaccines Liang Zhaoa, 1, Arjun Setha, 1, Nani Wibowoa, Chun-Xia
Zhaoa, Neena Mitterb, Chengzhong Yua, Anton P.J. Middelberga a. The University
of Queensland Australian Institute for Bioengineering and Nanotechnology St.
Lucia QLD 4072, Australia b. The University of Queensland Queensland Alliance
for Agriculture and Food Innovation St. Lucia QLD 4072, Australia Abstract
Nanotechnology increasingly plays a significant role in vaccine development. As
vaccine development orientates toward less immunogenic “minimalist”
compositions, formulations that boost antigen effectiveness are increasingly
needed. The use of nanoparticles in vaccine formulations allows not only
improved antigen stability and immunogenicity, but also targeted delivery and
slow release. A number of nanoparticle vaccines varying in composition, size,
shape, and surface properties have been approved for human use and the number
of candidates is increasing. However, challenges remain due to a lack of
fundamental understanding regarding the in vivo behavior of nanoparticles,
which can operate as either a delivery system to enhance antigen processing
and/or as an immunostimulant adjuvant to activate or enhance immunity. This
review provides a broad overview of recent advances in prophylactic
nanovaccinology. Types of nanoparticles used are outlined and their interaction
with immune cells and the biosystem are discussed. Increased knowledge and
fundamental understanding of nanoparticle mechanism of action in both
immunostimulatory and delivery modes, and better understanding of in vivo
biodistribution and fate, are urgently required, and will accelerate the
rational design of nanoparticle-containing vaccines.
http://www.sciencedirect.com/science/article/pii/S0264410X13016319

“As vaccine development orientates toward less immunogenic “minimalist”
compositions, formulations that boost antigen effectiveness are increasingly
needed. The use of nanoparticles in vaccine formulations allows not only
improved antigen stability and immunogenicity, but also targeted delivery and
slow release. A number of nanoparticle vaccines varying in composition, size,
shape, and surface properties have been approved for human use and the number
of candidates is increasing.”

Nucleic Acids Research • January 2014

Updates on the web-based VIOLIN vaccine database and analysis system Author
information He Y1, Racz R, Sayers S, Lin Y, Todd T, Hur J, Li X, Patel M, Zhao
B, Chung M, Ostrow J, Sylora A, Dungarani P, Ulysse G, Kochhar K, Vidri B,
Strait K, Jourdian GW, Xiang Z. Unit for Laboratory Animal Medicine, University
of Michigan Department of Microbiology and Immunology, University of Michigan
Center for Computational Medicine and Biology, University of Michigan
Comprehensive Cancer Center, University of Michigan College of Pharmacy,
University of Michigan School of Public Health, University of Michigan Division
of Comparative Medicine, University of South Florida Department of Neurology,
University of Michigan College of Literature, Science, and the Arts, University
of Michigan Department of Biomedical Engineering, University of Michigan
Department of Internal Medicine, University of Michigan Medical School
Department of Biological Chemistry, University of Michigan Medical School
Abstract The integrative Vaccine Investigation and Online Information Network
(VIOLIN) vaccine research database and analysis system
(http://www.violinet.org) curates, stores, analyses and integrates various
vaccine-associated research data. Since its first publication in NAR in 2008,
significant updates have been made. Starting from 211 vaccines annotated at the
end of 2007, VIOLIN now includes over 3240 vaccines for 192 infectious diseases
and eight noninfectious diseases (e.g. cancers and allergies). Under the
umbrella of VIOLIN, >10 relatively independent programs are developed. For
example, Protegen stores over 800 protective antigens experimentally proven
valid for vaccine development. VirmugenDB annotated over 200 ‘virmugens’, a
term coined by us to represent those virulence factor genes that can be mutated
to generate successful live attenuated vaccines. Specific patterns were
identified from the genes collected in Protegen and VirmugenDB. VIOLIN also
includes Vaxign, the first web-based vaccine candidate prediction program based
on reverse vaccinology. VIOLIN collects and analyzes different vaccine
components including vaccine adjuvants (Vaxjo) and DNA vaccine plasmids
(DNAVaxDB). VIOLIN includes licensed human vaccines (Huvax) and veterinary
vaccines (Vevax). The Vaccine Ontology is applied to standardize and integrate
various data in VIOLIN. VIOLIN also hosts the Ontology of Vaccine Adverse
Events (OVAE) that logically represents adverse events associated with licensed
human vaccines. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964998/

“The integrative Vaccine Investigation and Online Information Network (VIOLIN)
vaccine research database and analysis system curates, stores, analyses and
integrates various vaccine-associated research data. Starting from 211 vaccines
annotated at the end of 2007, VIOLIN now includes over 3,240 vaccines for 192
infectious diseases and eight noninfectious diseases ...”

Vaccine • January 2014

Co-administration of live measles and yellow fever vaccines and inactivated
pentavalent vaccines is associated with increased mortality compared with
measles and yellow fever vaccines only An observational study from
Guinea-Bissau Author information Fisker AB1, Ravn H2, Rodrigues A3, Østergaard
MD4, Bale C5, Benn CS6, Aaby P7. 1. Bandim Health Project, INDEPTH Network,
Apartado 861, Bissau, Guinea-Bissau; Research Center for Vitamins and Vaccines
(CVIVA), Bandim Health Project, Statens Serum Institut, Artillerivej 5, 2300
Copenhagen S, Denmark. Electronic address: a.fisker@bandim.org. 2. Bandim
Health Project, INDEPTH Network, Apartado 861, Bissau, Guinea-Bissau; Research
Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum
Institut, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address:
hjn@ssi.dk. 3. Bandim Health Project, INDEPTH Network, Apartado 861, Bissau,
Guinea-Bissau. Electronic address: a.rodrigues@bandim.org. 4. Bandim Health
Project, INDEPTH Network, Apartado 861, Bissau, Guinea-Bissau. Electronic
address: mariedrivsholm@gmail.com. 5. Bandim Health Project, INDEPTH Network,
Apartado 861, Bissau, Guinea-Bissau. Electronic address: c.bale@bandim.org. 6.
Bandim Health Project, INDEPTH Network, Apartado 861, Bissau, Guinea-Bissau;
Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project,
Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic
address: cb@ssi.dk. 7. Bandim Health Project, INDEPTH Network, Apartado 861,
Bissau, Guinea-Bissau; Research Center for Vitamins and Vaccines (CVIVA),
Bandim Health Project, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen
S, Denmark. Electronic address: p.aaby@bandim.org

Abstract BACKGROUND Studies from low-income countries indicate that
co-administration of inactivated diphtheria-tetanus-pertussis (DTP) vaccine and
live attenuated measles vaccine (MV) is associated with increased mortality
compared with receiving MV only. Pentavalent (DTP-H. Influenza type B-Hepatitis
B) vaccine is replacing DTP in many low-income countries and yellow fever
vaccine (YF) has been introduced to be given together with MV. Pentavalent and
YF vaccines were introduced in Guinea-Bissau in 2008. We investigated whether
co-administration of pentavalent vaccine with MV and yellow fever vaccine has
similar negative effects. METHODS In 2007-2011, we conducted a randomised
placebo-controlled trial of vitamin A at routine vaccination contacts among
children aged 6-23 months in urban and rural Guinea-Bissau. In the present
study, we included 2331 children randomised to placebo who received live
vaccines only (MV or MV+YF) or a combination of live and inactivated vaccines
(MV+DTP or MV+YF+pentavalent). Mortality was compared in Cox proportional
hazards models stratified for urban/rural enrolment adjusted for age and
unevenly distributed baseline factors. RESULTS While DTP was still used 685
children received MV only and 358 MV+DTP; following the change in programme,
940 received MV+YF only and 348 MV+YF+pentavalent. During 6 months of
follow-up, the adjusted mortality rate ratio (MRR) for coadministered live and
inactivated vaccines compared with live vaccines only was 3.24 (1.20-8.73). For
MV+YF+pentavalent compared with MV+YF only, the adjusted MRR was 7.73
(1.79-33.4). CONCLUSION In line with previous studies of DTP, the present
results indicate that pentavalent vaccine co-administered with MV and YF is
associated with increased mortality.
http://www.ncbi.nlm.nih.gov/pubmed/24325827

“In line with previous studies of DTP, the present results indicate that
pentavalent vaccine co-administered with MV and YF is associated with increased
mortality.”

Autoimmunity Review • January 2014

A review on the association between inflammatory myopathies and vaccination
Author information Stübgen JP. Department of Neurology Weill Cornell Medical
College/New York Presbyterian Hospital 525 East 68th Street, New York, NY
10065-4885, USA pstuebge@med.cornell.edu Abstract Several viruses and vaccines
are among the environmental factors implicated as triggers of autoimmune
inflammatory myopathies. Case histories report on the onset of
dermatomyositis/polymyositis after immunization with various vaccines of
patients with probable genetic predisposition. However, retrospective and
epidemiological studies failed to ascertain an association between DM/PM and
vaccines: no significant increase in the incidence of DM/PM was reported after
large vaccination campaigns. The risk for vaccine-induced adverse events may be
enhanced by adjuvants. Macrophagic myofasciitis is a novel inflammatory
myopathy ascribed to an ongoing local immune reaction to a vaccine adjuvant.
Isolated prospective studies showed that the administration of unadjuvanted,
non-live vaccine to patients with DM/PM caused no short-term harmful effects to
DM/PM immune processes. However, more research is warranted to clarify the
incidence of vaccine-preventable infections, harmful effects of vaccination,
and the influence of any immunomodulating agents on vaccination efficacy.
Vaccination is an important disease prevention tool in modern medicine. This
review does not address risk-benefit or cost-benefit analyses, and does not
advocate the use of specific vaccines or vaccination programs. Despite a great
deal of scientific uncertainty, the concept of a possible causal link between
immunization and inflammatory myopathies should not be totally rejected.
http://www.ncbi.nlm.nih.gov/pubmed/24001753

“Macrophagic myofasciitis is a novel inflammatory myopathy ascribed to an
ongoing local immune reaction to a vaccine adjuvant ... more research is
warranted to clarify the incidence of vaccine-preventable infections, harmful
effects of vaccination, and the influence of any immunomodulating agents on
vaccination efficacy. Despite a great deal of scientific uncertainty, the
concept of a possible causal link between immunization and inflammatory
myopathies should not be totally rejected.”

Journal Of Autoimmunity • January 2014

Sjögren’s syndrome: another facet of the autoimmune/inflammatory syndrome
induced by adjuvants (ASIA) Author information Colafrancesco S1, Perricone C1,
Priori R2, Valesini G2, Shoenfeld Y3. 1. Department of Internal Medicine and
Medical Specialities, Rheumatology Unit, Sapienza University of Rome, Italy The
Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer,
Israel 2. Department of Internal Medicine and Medical Specialities,
Rheumatology Unit, Sapienza University of Rome, Italy 3. The Zabludowicz Center
for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel Incumbent
of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases Sackler
Faculty of Medicine, Tel Aviv University, Israel shoenfel@post.tau.ac.il

Abstract Recently, a new syndrome, namely the “Autoimmune/inflammatory syndrome
induced by adjuvants” (ASIA) has been defined. In this syndrome different
conditions characterized by common signs and symptoms and induced by the
presence of an adjuvant are included. The adjuvant is a substance capable of
boosting the immune response and of acting as a trigger in the development of
autoimmune diseases. Post-vaccination autoimmune phenomena represent a major
issue of ASIA. Indeed, despite vaccines represent a mainstay in the improvement
of human health, several of these have been implicated as a potential trigger
for autoimmune diseases. Sjogren’s Syndrome (SjS) is a systemic chronic
autoimmune inflammatory disease characterized by the presence of an
inflammatory involvement of exocrine glands accompanied by systemic
manifestations. Own to the straight association between infectious agents
exposure (mainly viruses) and sicca syndrome development, the possible link
between vaccine and SjS is not surprising. Indeed, a few cases of SjS following
vaccine delivery have been reported. At the same extent, the induction of SjS
following silicone exposure has been described too. Thus, the aim of this
review was to focus on SjS and its possible development following vaccine or
silicone exposure in order to define another possible facet of the ASIA
syndrome. http://www.ncbi.nlm.nih.gov/pubmed/24774584

“despite vaccines represent a mainstay in the improvement of human health,
several of these have been implicated as a potential trigger for autoimmune
diseases. Sjogren’s Syndrome (SjS) is a systemic chronic autoimmune
inflammatory disease characterized by the presence of an inflammatory
involvement of exocrine glands accompanied by systemic manifestations.”

New England Journal Of Medicine • February 2014

Risk of intussusception after monovalent rotavirus vaccination Author
information Weintraub ES1, Baggs J, Duffy J, Vellozzi C, Belongia EA, Irving S,
Klein NP, Glanz JM, Jacobsen SJ, Naleway A, Jackson LA, DeStefano F. From the
Centers for Disease Control and Prevention Immunization Safety Office, Atlanta
(E.S.W., J.B., J.D., C.V., F.D.) Marshfield Clinic Research Foundation,
Marshfield, WI (E.A.B.) Center for Health Research, Kaiser Permanente
Northwest, Portland, OR (S.I., A.N.) Vaccine Study Center, Kaiser Permanente
Northern California, Oakland (N.P.K.) Kaiser Permanente Colorado, Aurora
(J.M.G.) Kaiser Permanente Southern California, Pasadena (S.J.J.) Group Health
Research Institute, Seattle (L.A.J.) Abstract BACKGROUND Although current
rotavirus vaccines were not associated with an increased risk of
intussusception in large trials before licensure, recent postlicensure data
from international settings suggest the possibility of a small increase in risk
of intussusception after monovalent rotavirus vaccination. We examined this
risk in a population in the United States. METHODS Participants were infants
between the ages of 4 and 34 weeks who were enrolled in six integrated health
care organizations in the Vaccine Safety Datalink (VSD) project. We reviewed
medical records and visits for intussusception within 7 days after monovalent
rotavirus vaccination from April 2008 through March 2013. Using sequential
analyses, we then compared the risk of intussusception among children receiving
monovalent rotavirus vaccine with historical background rates. We further
compared the risk after monovalent rotavirus vaccination with the risk in a
concurrent cohort of infants who received the pentavalent rotavirus vaccine.
RESULTS During the study period, 207,955 doses of monovalent rotavirus vaccine
(including 115,908 first doses and 92,047 second doses) were administered in
the VSD population. We identified 6 cases of intussusception within 7 days
after the administration of either dose of vaccine. For the two doses combined,
the expected number of intussusception cases was 0.72, resulting in a
significant relative risk of 8.4. For the pentavalent rotavirus vaccine,
1,301,810 doses were administered during the study period, with 8 observed
intussusception cases (7.11 expected), for a nonsignificant relative risk of
1.1. The relative risk of chart-confirmed intussusception within 7 days after
monovalent rotavirus vaccination, as compared with the risk after pentavalent
rotavirus vaccination, was 9.4 (95% confidence interval, 1.4 to 103.8). The
attributable risk of intussusception after the administration of two doses of
monovalent rotavirus vaccine was estimated to be 5.3 per 100,000 infants
vaccinated. CONCLUSIONS In this prospective postlicensure study of more than
200,000 doses of monovalent rotavirus vaccine, we observed a significant
increase in the rate of intussusception after vaccination, a risk that must be
weighed against the benefits of preventing rotavirus-associated illness.
http://www.ncbi.nlm.nih.gov/pubmed/?term=24422678

“In this prospective postlicensure study of more than 200,000 doses of
monovalent rotavirus vaccine, we observed a significant increase in the rate of
intussusception after vaccination, a risk that must be weighed against the
benefits of preventing rotavirus-associated illness.”

Trends In Microbiology • February 2014

Do we need a new vaccine to control the re-emergence of pertussis? Author
information Mills KH, Ross PJ, Allen AC, Wilk MM. School of Biochemistry and
Immunology Trinity Biomedical Sciences Institute Trinity College Dublin,
Dublin, Ireland kingston.mills@tcd.ie Abstract Bordetella pertussis causes
whooping cough and is re-emerging in developed countries despite widespread
immunization with acellular pertussis vaccines (Pa), which are less effective
than the whole cell vaccines that they replaced. Efficacy of Pa could be
improved by switching from alum to alternative adjuvants that generate more
potent cell mediated immunity. http://www.ncbi.nlm.nih.gov/pubmed/24485284

“Bordetella pertussis causes whooping cough and is re-emerging in developed
countries despite widespread immunization with acellular pertussis vaccines
...”

Immunology Research • February 2014

Evolution of multiple sclerosis in France since the beginning of hepatitis B
vaccination Author information Le Houézec D REVAHB (“Réseau Vaccin Hépatite B”
in French) 32 rue du Clos Herbert, 14000, Caen, France
dominique.le.houezec@freesbee.fr Abstract Since the implementation of the mass
vaccination campaign against hepatitis B in France, the appearance of multiple
sclerosis, sometimes occurring in the aftermath of vaccinations, led to the
publication of epidemiological international studies. This was also justified
by the sharp increase in the annual incidence of multiple sclerosis reported to
the French health insurance in the mid-1990s. Almost 20 years later, a
retrospective reflection can be sketched from these official data and also from
the national pharmacovigilance agency. Statistical data from these latter
sources seem to show a significant correlation between the number of hepatitis
B vaccinations performed and the declaration to the pharmacovigilance of
multiple sclerosis occurring between 1 and 2 years later. The application of
the Hill’s criteria to these data indicates that the correlation between
hepatitis B vaccine and multiple sclerosis may be causal.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25395338

“The application of the Hill’s criteria to these data indicates that the
correlation between hepatitis B vaccine and multiple sclerosis may be causal.”

Human Vaccines & Immunotherapeutics content • February 2014

Toward a mechanism-based in vitro safety test for pertussis toxin Stefan FC
Vaessena, Martijn WP Bruystersb, Rob J Vandebrielb*, Saertje Verkoeijena,
Rogier Bosc, Cyrille AM Krula & Arnoud M Akkermansb Research Centre Technology
& innovation innovative testing in Life sciences and Chemistry University of
Applied Sciences; Utrecht, the Netherlands Center for Health Protection
National institute for Public Health and the environment Bilthoven, the
Netherlands Central Committee on Research involving Human Subjects Den Haag,
the Netherlands Abstract Pertussis vaccines are routinely administered to
infants to protect them from whooping cough. Still, an adequate safety test for
pertussis toxin (PT), one of the main antigens in these vaccines, is not
available. The histamine sensitization test is currently the only assay
accepted by regulatory authorities to test for the absence of active PT in
vaccines. This is however, a lethal animal test with poor reproducibility. In
addition, it is not clear whether the assumed underlying mechanism, i.e.,
ADP-ribosylation of G proteins, is the only effect that should be considered in
safety evaluation of PT. The in vitro safety test for PT that we developed is
based on the clinical effects of PT in humans. For this, human cell lines were
chosen based on the cell types involved in the clinical effects of PT. These
cell lines were exposed to PT and analyzed by microarray. In this review, we
discuss the clinical effects of PT and the mechanisms that underlie them. The
approach taken may provide as an example for other situations in which an in
vitro assay based on clinical effects in humans is required. Full Report
http://www.tandfonline.com/doi/pdf/10.4161/hv.28001

From the full report: “Taken together, the main clinical effects in humans
where Pertussis Toxin is involved are increased insulin secretion with
resulting hypoglycemia, leukocytosis, lung edema and inflammatory responses,
together resulting in pulmonary hypertension and pneumonia. Moreover, PT can
induce systemic hypotension, and is possibly involved in inducing neurological
problems.”

BMC Bioinformatics • March 2014

DNAVaxDB: the first web-based DNA vaccine database and its data analysis Racz
R, Li X, Patel M, Xiang Z, He Y. Abstract Since the first DNA vaccine studies
were done in the 1990s, thousands more studies have followed. Here we report
the development and analysis of DNAVaxDB (http://www.violinet.org/ dnavaxdb),
the first publically available web-based DNA vaccine database that curates,
stores, and analyzes experimentally verified DNA vaccines, DNA vaccine plasmid
vectors, and protective antigens used in DNA vaccines. All data in DNAVaxDB are
annotated from reliable resources, particularly peer-reviewed articles. Among
over 140 DNA vaccine plasmids, some plasmids were more frequently used in one
type of pathogen than others; for example, pCMVi-UB for G-bacterial DNA
vaccines, and pCAGGS for viral DNA vaccines. Presently, over 400 DNA vaccines
containing over 370 protective antigens from over 90 infectious and
non-infectious diseases have been curated in DNAVaxDB. While extracellular and
bacterial cell surface proteins and adhesin proteins were frequently used for
DNA vaccine development, the majority of protective antigens used in
Chlamydophila DNA vaccines are localized to the inner portion of the cell. The
DNA vaccine priming, other vaccine boosting vaccination regimen has been widely
used to induce protection against infection of different pathogens such as HIV.
Parasitic and cancer DNA vaccines were also systematically analyzed.
User-friendly web query and visualization interfaces are available in DNAVaxDB
for interactive data search. To support data exchange, the information of DNA
vaccines, plasmids, and protective antigens is stored in the Vaccine Ontology
(VO). DNAVaxDB is targeted to become a timely and vital source of DNA vaccines
and related data and facilitate advanced DNA vaccine research and development.
Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094999/

“... the first publically available web-based DNA vaccine database that
curates, stores, and analyzes experimentally verified DNA vaccines, DNA vaccine
plasmid vectors, and protective antigens used in DNA vaccines. Presently, over
400 DNA vaccines containing over 370 protective antigens from over 90
infectious and non-infectious diseases have been curated in DNAVaxDB.”

Current Medicinal Chemistry • March 2014

Sudden infant death following hexavalent vaccination: a neuropathologic study
Author information Matturri L, Del Corno G, Lavezzi AM1 . “Lino Rossi” Research
Center Department of Biomedical Surgical and Dental Sciences University of
Milan, Italy Via della Commenda, 19 - 20122 Milan, Italy anna.lavezzi@unimi.it
Abstract We examined a large number of sudden infant death syndrome victims in
order to point out a possible causal relationship between a previous hexavalent
vaccination and the sudden infant death. We selected 110 cases submitted to
in-depth histological examination of the autonomic nervous system and provided
with detailed clinical and environmental information. In 13 cases (11.8%) the
death occurred in temporal association with administration of the hexavalent
vaccine (from 1 to 7 days). In none of these victims congenital developmental
alterations of the main nervous structures regulating the vital functions were
observed. Only the hypoplasia of the arcuate nucleus was present in 5 cases. In
one case in particular an acquired hyperacute encephalitis of the tractus
solitarii nucleus was diagnosed in the brainstem. This study does not prove a
causal relationship between the hexavalent vaccination and SIDS. However, we
hypothesize that vaccine components could have a direct role in sparking off a
lethal outcome in vulnerable babies. In conclusion, we sustain the need that
deaths occurring in a short space of time after hexavalent vaccination are
appropriately investigated and submitted to a post-mortem examination
particularly of the autonomic nervous system by an expert pathologist to
objectively evaluate the possible causative role of the vaccine in SIDS.
http://www.ncbi.nlm.nih.gov/pubmed/24083600

“we hypothesize that vaccine components could have a direct role in sparking
off a lethal outcome in vulnerable babies.”

Journal Of Investigative Medicine • High Impact Case Reports • March 2014

Postural Orthostatic Tachycardia With Chronic Fatigue After HPV Vaccination as
Part of the “Autoimmune/Auto-inflammatory Syndrome Induced by Adjuvants”: Case
Report and Literature Review Author information Tomljenovic L1, Colafrancesco
S2, Perricone C2, Shoenfeld Y3. 1. Sheba Medical Center, Tel-Hashomer, Israel
University of British Columbia, Vancouver, British Columbia, Canada 2. Sheba
Medical Center, Tel-Hashomer, Israel Sapienza University of Rome, Rome, Italy
3. Sheba Medical Center, Tel-Hashomer, Israel Tel Aviv University, Tel Aviv,
Israel Abstract We report the case of a 14-year-old girl who developed postural
orthostatic tachycardia syndrome (POTS) with chronic fatigue 2 months following
Gardasil vaccination. The patient suffered from persistent headaches,
dizziness, recurrent syncope, poor motor coordination, weakness, fatigue,
myalgias, numbness, tachycardia, dyspnea, visual disturbances, phonophobia,
cognitive impairment, insomnia, gastrointestinal disturbances, and a weight
loss of 20 pounds. The psychiatric evaluation ruled out the possibility that
her symptoms were psychogenic or related to anxiety disorders. Furthermore, the
patient tested positive for ANA (1:1280), lupus anticoagulant, and
antiphospholipid. On clinical examination she presented livedo reticularis and
was diagnosed with Raynaud’s syndrome. This case fulfills the criteria for the
autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA). Because
human papillomavirus vaccination is universally recommended to teenagers and
because POTS frequently results in long-term disabilities (as was the case in
our patient), a thorough follow-up of patients who present with relevant
complaints after vaccination is strongly recommended.
http://www.ncbi.nlm.nih.gov/pubmed/26425598

“The patient suffered from persistent headaches, dizziness, recurrent syncope,
poor motor coordination, weakness, fatigue, myalgias, numbness, tachycardia,
dyspnea, visual disturbances, phonophobia, cognitive impairment, insomnia,
gastrointestinal disturbances, and a weight loss of 20 pounds.”

PLoS One • March 2014

Mitochondrial dysfunction in Gulf War illness revealed by 31Phosphorus Magnetic
Resonance Spectroscopy: a case-control study Author information Koslik HJ1,
Hamilton G2, Golomb BA3. 1. Department of Medicine, University of California
San Diego, La Jolla, California, USA 2. Department of Radiology, University of
California San Diego, La Jolla, California, USA 3. Department of Medicine,
University of California San Diego, La Jolla, California, USA; Department of
Family and Preventive Medicine, University of California San Diego, La Jolla,
California, USA

Abstract BACKGROUND Approximately 1/3 of 1990-1 Gulf War veterans developed
chronic multisymptom health problems. Implicated exposures bear mechanisms that
adversely affect mitochondria. Symptoms emphasize fatigue, cognition and muscle
(brain and muscle are aerobically demanding); with protean additional domains
affected, compatible with mitochondrial impairment. Recent evidence supports
treatments targeting cell bioenergetics (coenzyme10) to benefit Gulf War
illness symptoms. However, no evidence has directly documented mitochondrial or
bioenergetic impairment in Gulf War illness. OBJECTIVE We sought to objectively
assess for mitochondrial dysfunction, examining post-exercise
phosphocreatine-recovery time constant (PCr-R) using (31)Phosphorus Magnetic
Resonance Spectroscopy ((31)P-MRS), in Gulf War veterans with Gulf War illness
compared to matched healthy controls. PCr-R has been described as a “robust and
practical” index of mitochondrial status. DESIGN AND PARTICIPANTS Case-control
study from 2012-2013. Fourteen community-dwelling Gulf War veterans and matched
controls from the San Diego area comprised 7 men meeting CDC and Kansas
criteria for Gulf War illness, and 7 non-deployed healthy controls matched 1:1
to cases on age, sex, and ethnicity. OUTCOME MEASURE Calf muscle
phosphocreatine was evaluated by (31)P-MRS at rest, through 5 minutes of foot
pedal depression exercise, and in recovery, to assess PCr-R. Paired t-tests
compared cases to matched controls. RESULTS PCr-R was significantly prolonged
in Gulf War illness cases vs their matched controls: control values, mean ± SD,
29.0 ± 8.7 seconds; case values 46.1 ± 18.0 seconds; difference 17.1 ± 14.9
seconds; p = 0.023. PCr-R was longer for cases relative to their matched
controls for all but one pair; moreover while values clustered under 31 seconds
for all but one control, they exceeded 35 seconds (with a spread up to 70
seconds) for all but one case. DISCUSSION These data provide the first direct
evidence supporting mitochondrial dysfunction in Gulf War illness. Findings
merit replication in a larger study and/or corroboration with additional
mitochondrial assessment tools. http://www.ncbi.nlm.nih.gov/pubmed/24675771

“These data provide the first direct evidence supporting mitochondrial
dysfunction in Gulf War illness.”

Journal Of Investigative Medicine
High Impact Case Reports • March 2014

Postural Orthostatic Tachycardia With Chronic Fatigue After HPV Vaccination as
Part of the “Autoimmune/Auto-inflammatory Syndrome Induced by Adjuvants” Lucija
Tomljenovic, PhD1,2, Serena Colafrancesco, MD1,3, Carlo Perricone, MD1,3,
Yehuda Shoenfeld, MD, FRCP (Hon), MaACR1,4 1. Sheba Medical Center,
Tel-Hashomer, Israel 2. University of British Columbia, Vancouver, British
Columbia, Canada 3. Sapienza University of Rome, Rome, Italy 4. Tel Aviv
University, Tel Aviv, Israel Shoenfel@post.tau.ac.il Abstract We report the
case of a 14-year-old girl who developed postural orthostatic tachycardia
syndrome (POTS) with chronic fatigue 2 months following Gardasil vaccination.
The patient suffered from persistent headaches, dizziness, recurrent syncope,
poor motor coordination, weakness, fatigue, myalgias, numbness, tachycardia,
dyspnea, visual disturbances, phonophobia, cognitive impairment, insomnia,
gastrointestinal disturbances, and a weight loss of 20 pounds. The psychiatric
evaluation ruled out the possibility that her symptoms were psychogenic or
related to anxiety disorders. Furthermore, the patient tested positive for ANA
(1:1280), lupus anticoagulant, and antiphospholipid. On clinical examination
she presented livedo reticularis and was diagnosed with Raynaud’s syndrome.
This case fulfills the criteria for the autoimmune/auto-inflammatory syndrome
induced by adjuvants (ASIA). Because human papillomavirus vaccination is
universally recommended to teenagers and because POTS frequently results in
long-term disabilities (as was the case in our patient), a thorough follow-up
of patients who present with relevant complaints after vaccination is strongly
recommended. http://hic.sagepub.com/content/2/1/2324709614527812.abstract

“We report the case of a 14-year-old girl who developed postural orthostatic
tachycardia syndrome (POTS) with chronic fatigue 2 months following Gardasil
vaccination. The patient suffered from persistent headaches, dizziness,
recurrent syncope, poor motor coordination, weakness, fatigue, myalgias,
numbness, tachycardia, dyspnea, visual disturbances, phonophobia, cognitive
impairment, insomnia, gastrointestinal disturbances, and a weight loss of 20
pounds. This case fulfills the criteria for the autoimmune/auto-inflammatory
syndrome induced by adjuvants (ASIA).”

Clinical And Experimental Rheumatology • March 2014

Alum, an aluminum-based adjuvant, induces Sjögren’s syndrome-like disorder in
mice Author information Bagavant H1, Nandula SR, Kaplonek P, Rybakowska PD,
Deshmukh US. Division of Nephrology, University of Virginia, Charlottesville VA
and Arthritis and Clinical Immunology Program Oklahoma Medical Research
Foundation, Oklahoma City, OK, USA harini-bagavant@omrf.org Abstract OBJECTIVES
Adjuvant-induced innate immune responses have been suspected to play a role in
the initiation of certain autoimmune disorders. This study investigates the
role of alum, an aluminum-based adjuvant in the induction of Sjögren’s
syndrome-like disorder in mice. METHODS Inbred, female New Zealand Mixed (NZM)
2758 strain of mice were injected with alum. Control mice were treated
similarly with PBS. The mice were monitored for salivary gland dysfunction by
measuring pilocarpine-induced salivation. Presence of lymphocytic infiltrates
within the submandibular glands was studied by histopathology. Autoantibodies
to Ro and La proteins were analysed by ELISA and the presence of anti-nuclear
antibodies (ANA) was analysed by indirect immunofluorescence. RESULTS By eight
weeks after treatment, the saliva production in the alum-treated mice was
significantly decreased in comparison to the PBS-treated mice. This functional
loss persisted till the termination of experiments at 20 wks. The incidence and
severity of sialoadenitis was significantly higher in the alum-treated mice.
Although there were no differences in the levels of anti-Ro/La autoantibodies
in sera of alum and PBS-treated groups, the alum group showed higher ANA
reactivity. CONCLUSIONS In the NZM2758 mice, alum induces a Sjögren’s
syndrome-like disorder that is characterised by chronic salivary gland
dysfunction and the presence of lymphocytic infiltrates within the salivary
glands. Thus, the potential of aluminum-based adjuvants for induction of
autoimmunity should be closely monitored in individuals genetically susceptible
to developing autoimmune disorders. http://www.ncbi.nlm.nih.gov/pubmed/24739520

“Adjuvant-induced innate immune responses have been suspected to play a role in
the initiation of certain autoimmune disorders. This study investigates the
role of alum, an aluminum-based adjuvant in the induction of Sjögren’s
syndrome-like disorder in mice.”

Behavioral And Brain Functions • April 2014

A key role for an impaired detoxification mechanism in the etiology and
severity of autism spectrum disorders Author information Alabdali A, Al-Ayadhi
L, El-Ansary A1. Biochemistry Department, Science College King Saud University,
P,O box 22452, Zip code 11495 Riyadh, Saudi Arabia elansary@ksu.edu.sa Abstract
BACKGROUND Autism Spectrum Disorders (ASD) is a syndrome with a number of
etiologies and different mechanisms that lead to abnormal development. The
identification of autism biomarkers in patients with different degrees of
clinical presentation (i.e., mild, moderate and severe) will give greater
insight into the pathogenesis of this disease and will enable effective early
diagnostic strategies and treatments for this disorder. METHODS In this study,
the concentration of two toxic heavy metals, lead (Pb) and mercury (Hg), were
measured in red blood cells, while glutathione-s-transferase (GST) and vitamin
E, as enzymatic and non-enzymatic antioxidants, respectively, were measured in
the plasma of subgroups of autistic patients with different Social
Responsiveness Scale (SRS) and Childhood Autism Rating Scale (CARS) scores. The
results were compared to age- and gender-matched healthy controls. RESULTS The
obtained data showed that the patients with autism spectrum disorder had
significantly higher Pb and Hg levels and lower GST activity and vitamin E
concentrations compared with the controls. The levels of heavy metals (Hg and
Pb), GST and vitamin E were correlated with the severity of the social and
cognitive impairment measures (SRS and CARS). Receiver Operating
Characteristics (ROC) analysis and predictiveness curves indicated that the
four parameters show satisfactory sensitivity, very high specificity and
excellent predictiveness. Multiple regression analyses confirmed that higher
levels of Hg and Pb, together with lower levels of GST and vitamin E, can be
used to predict social and cognitive impairment in patients with autism
spectrum disorders. CONCLUSION This study confirms earlier studies that
implicate toxic metal accumulation as a consequence of impaired detoxification
in autism and provides insight into the etiological mechanism of autism. Full
Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017810/

“This study confirms earlier studies that implicate toxic metal accumulation as
a consequence of impaired detoxification in autism and provides insight into
the etiological mechanism of autism.”

Epidemiology And Infection • April 2014

Pertussis resurgence: waning immunity and pathogen adaptation— two sides of the
same coin Author information Mooi FR1, Van Der Maas NA2, De Melker HE2. 1.
Laboratory for Infectious Disease Centre for Infectious Disease Control
National Institute for Public Health and the Environment Bilthoven, The
Netherlands 2. Epidemiology and Surveillance Centre for Infectious Disease
Control National Institute for Public Health and the Environment Bilthoven, The
Netherlands Abstract Pertussis or whooping cough has persisted and resurged in
the face of vaccination and has become one of the most prevalent
vaccine-preventable diseases in Western countries. The high circulation rate of
Bordetella pertussis poses a threat to infants that have not been (completely)
vaccinated and for whom pertussis is a severe, life-threatening, disease. The
increase in pertussis is mainly found in age groups in which immunity has waned
and this has resulted in the perception that waning immunity is the main or
exclusive cause for the resurgence of pertussis. However, significant changes
in B. pertussis populations have been observed after the introduction of
vaccinations, suggesting a role for pathogen adaptation in the persistence and
resurgence of pertussis. These changes include antigenic divergence with
vaccine strains and increased production of pertussis toxin. Antigenic
divergence will affect both memory recall and the efficacy of antibodies, while
higher levels of pertussis toxin may increase suppression of the innate and
acquired immune system. We propose these adaptations of B. pertussis have
decreased the period in which pertussis vaccines are effective and thus
enhanced the waning of immunity. We plead for a more integrated approach to the
pertussis problem which includes the characteristics of the vaccines, the B.
pertussis populations and the interaction between the two.
http://www.ncbi.nlm.nih.gov/pubmed/23406868

“We propose these adaptations of B. pertussis have decreased the period in
which pertussis vaccines are effective and thus enhanced the waning of
immunity.”

Environmental Pollution • April 2014

Perinatal multiple exposure to neurotoxic (lead, methylmercury, ethylmercury,
and aluminum) substances and neurodevelopment at six and 24 months of age
Author information Marques RC1, Bernardi JV2, Dórea JG3, de Fatima R Moreira
M4, Malm O5. 1. Federal University of Rio de Janeiro, Campus Macaé, CEP
27930-560 RJ, Brazil 2. University of Brasília, Brasília, 70919-970 DF, Brasil
3. University of Brasília, Brasília, 70919-970 DF, Brasil 4. Escola Nacional de
Saúde Pública, Fundação Oswaldo Cruz, RJ, Brazil 5. Institute of Biophysics
Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil
jg.dorea@gmail.com Abstract We studied neurodevelopment in infants from two
communities. Children living in the vicinity of tin-ore kilns and smelters -
TOKS; n = 51) were compared to children from a fishing village (Itapuã; n =
45). Mean hair-Hg (HHg) concentrations were significantly higher in Itapuã
children which received significantly (p = 0.0000001) less mean ethylmercury
(88.6 μg) from Thimerosal-containing vaccines (TCV) than the TOKS children (120
μg). Breast-milk Pb concentrations were significantly higher in the TOKS
mothers (p = 0.000017; 10.04 vs. 3.9 μg L(-1)). Bayley mental development index
(MDI) and psychomotor development index (PDI) were statistically significant
(respectively p < 0.0000001, p = 0.000007) lower for the TOKS children only at
24 months of age. Multivariate regression analysis showed that MDI was
negatively affected by breast-milk Pb and by HHg. PDI was positively affected
by breastfeeding and negatively affected by ethylmercury. Milestone
achievements were negatively affected by breast-milk Pb (age of walking) and by
HHg (age of talking). http://www.ncbi.nlm.nih.gov/pubmed/24486466

“Milestone achievements were negatively affected by breast-milk lead (age of
walking) and by Mean hair-mercury (age of talking).”

International Journal Of Epidemiology • May 2014

The non-specific effects of vaccines and other childhood interventions: the
contribution of INDEPTH Health and Demographic Surveillance Systems Author
Information Osman Sankoh,1,2,3,* Paul Welaga,1,4 Cornelius Debpuur,1,4 Charles
Zandoh,1,5 Stephney Gyaase,1,5 Mary Atta Poma,1,6 Martin Kavao Mutua,1,7 SM
Manzoor Ahmed Hanifi,1,8 Cesario Martins,1,9 Eric Nebie,1,10 Moubassira
Kagoné,1,10 Jacques BO Emina,1 and Peter Aaby1,9 1. INDEPTH Network, Accra,
Ghana 2. School of Public Health, University of the Witwatersrand,
Johannesburg, South Africa 3. Faculty of Public Health, Hanoi Medical
University, Hanoi, Viet Nam 4. Navrongo Health Research Centre, Ghana Health
Service, Navrongo, Ghana 5. Kintampo Health Research Centre, Ghana Health
Service, Kintampo, Ghana 6. Dodowa Health Research Centre, Ghana Health
Service, Dodowa, Ghana 7. African Population and Health Research Centre,
Nairobi, Kenya 8. Chakaria Community Health Project Community Health Division,
ICDDRB, Mohakhali, Dhaka, Bangladesh 9. Bandim Health Project, Bandim,
Guiné-Bissau 10. Centre de Recherche en Santé de Nouna (CRSN), Nouna, Burkina
Faso Abstract Most childhood interventions (vaccines, micronutrients) in
low-income countries are justified by their assumed effect on child survival.
However, usually the interventions have only been studied with respect to their
disease/deficiency-specific effects and not for their overall effects on
morbidity and mortality. In many situations, the population-based effects have
been very different from the anticipated effects; for example, the
measles-preventive high-titre measles vaccine was associated with 2-fold
increased female mortality; BCG reduces neonatal mortality although children do
not die of tuberculosis in the neonatal period; vitamin A may be associated
with increased or reduced child mortality in different situations; effects of
interventions may differ for boys and girls. The reasons for these and other
contrasts between expectations and observations are likely to be that the
immune system learns more than specific prevention from an intervention; such
training may enhance or reduce susceptibility to unrelated infections. INDEPTH
member centres have been in an ideal position to document such additional
non-specific effects of interventions because they follow the total population
long term. It is proposed that more INDEPTH member centres extend their routine
data collection platform to better measure the use and effects of childhood
interventions. In a longer perspective, INDEPTH may come to play a stronger
role in defining health research issues of relevance to low-income countries.
Conclusion Existing studies suggest a general pattern, namely that the live
vaccines (BCG, measles vaccine, OPV and vaccinia) are associated with
beneficial non-specific effects, leading to reduced all-cause mortality,
whereas the inactivated, alum-adjuvated DTP vaccine is associated with
increased susceptibility to other unrelated infections, particularly in
females. Full Report: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052142/

“... the inactivated, alum-adjuvated DTP vaccine is associated with increased
susceptibility to other unrelated infections, particularly in females.”

Parasitology Research • May 2014

Cytotoxic effect of organic solvents and surfactant agents on Acanthamoeba
castellanii cysts Author information Ezz Eldin HM1, Sarhan RM. Medical
Parasitology Department, Faculty of Medicine Ain Shams University, Cairo, Egypt
hayamezz@hotmail.com Abstract Acanthamoeba castellanii is a protozoan parasite
that may cause sight-threatening keratitis in some individuals. Its eradication
is difficult because the trophozoites encyst making organisms highly resistant
to anti-amoebic drugs. To test new anti-Acanthamoeba agents, usually having low
water solubility, organic solvents and surfactant agents should be used.
Therefore, the lethal effect of different concentrations of the solvents
acetone, methanol, ethanol, and DMSO and surfactant agents Tween 20, Tween 80,
and Triton X-100 was tested. The minimal inhibitory concentrations (MIC) were
determined against Acanthamoeba cysts. Results of the present study showed that
the MIC for ethanol, methanol, acetone and DMSO was 25, 12.5, 12.5, and 10%,
respectively and for Tween 20, Tween 80, and Triton X-100 was 0.25, 0.06, and
0.03%, respectively. There was no significant inhibitory effect on the
multiplication of Acanthamoeba cysts as compared to parasite control when using
the concentrations 3.12% for ethanol, 1.6% for methanol and acetone, 1.25% for
DMSO, and 0.016% for Tween 20. On the other hand, both Tween 80 and Triton
X-100 showed highly significant difference in comparison to parasite control
almost among all the range of concentrations used in this study, and both
showed lethal effect of 19 and 27.2%, respectively at their least
concentration. http://www.ncbi.nlm.nih.gov/pubmed/24638907

“... both Tween 80 and Triton X-100 showed ... lethal effect of 19 and 27.2%,
respectively at their least concentration.”

“Adjuvants are necessary components to warrant the efficacy of vaccines,
however the overstimulation of the immune system is also associated with
adverse effects.” International Immunopharmacology • May 2014

Systemic immunotoxicity reactions induced by adjuvanted vaccines Author
information Batista-Duharte A1, Portuondo D2, Pérez O3, Carlos IZ2. 1.
Immunotoxicology Laboratory, Toxicology and Biomedicine Center (TOXIMED),
Medical Science University Autopista Nacional Km. 1 1/2, CP 90400 Santiago de
Cuba, Cuba; Faculty of Pharmaceutical Sciences Universidade Estadual Paulista
Julio Mesquita Filho (UNESP), Rua Expedicionarios do Brasil 1621 CEP 14801-902
Araraquara, SP, Brazil; CAPES-PVE/Brasil Grant, Foreigner Visiting Professor
Program, Brazil 2. Faculty of Pharmaceutical Sciences, Universidade Estadual
Paulista Julio Mesquita Filho (UNESP) Rua Expedicionarios do Brasil 1621, CEP
14801-902 Araraquara, SP, Brazil 3. Immunology Department, Institute of
Preclinical and Basic Sciences (ICBP) “Victoria de Girón” University of Medical
Sciences of Havana. 146 No. 2504. e/ 25 Ave and 31 Ave, Playa, Havana, Cuba

Abstract Vaccine safety is a topic of concern for the treated individual, the
family, the health care personnel, and the others involved in vaccination
programs as recipients or providers. Adjuvants are necessary components to
warrant the efficacy of vaccines, however the overstimulation of the immune
system is also associated with adverse effects. Local reactions are the most
frequent manifestation of toxicity induced by adjuvanted vaccines and, with the
exception of the acute phase response (APR), much less is known about the
systemic reactions that follow vaccination. Their low frequency or subclinical
expression meant that this matter has been neglected. In this review, various
systemic reactions associated with immune stimulation will be addressed,
including: APR, hypersensitivity, induction or worsening of autoimmune
diseases, modification of hepatic metabolism and vascular leak syndrome (VLS),
with an emphasis on the mechanism involved. Finally, the authors analyze the
current focus of discussion about vaccine safety and opportunities to improve
the design of new adjuvanted vaccines in the future.
http://www.ncbi.nlm.nih.gov/pubmed/?term=24607449

Autism • Causes & Prevalence • June 2014

Etiology of autism spectrum disorders: Genes, environment, or both? C Shaw1*, S
Sheth1, D Li1, L Tomljenovic1 (1) University of British Columbia Vancouver,
British Columbia, Canada cashawlab@gmail.com Abstract Thus far, most of the
research on both neurodevelopmental and neurodegenerative disorders has been
focused on finding the presumed underlying genetic causes, while much less
emphasis has been put on potential environmental factors. While some forms of
autism are clearly genetic, the fact remains that heritability factors cannot
adequately explain all reported cases nor their drastic increase over the last
few decades. In particular, studies on twins have now shown that common
environmental factors account for 55% of their risk for developing autism while
genetic susceptibility explains only 37% of cases. Because the prenatal
environment and early postnatal environment are shared between twins and
because overt symptoms of autism emerge around the end of the first year of
life, it is likely that at least some of the environmental factors contributing
to the risk of autism exert their deleterious neurodevelopmental effect during
this early period of life. Indeed, evidence has now emerged showing that autism
may in part result from early-life immune insults induced by environmental
xenobiotics. One of the most common xenobiotic with immuno-stimulating as well
as neurotoxic properties to which infants under two years of age are routinely
exposed worldwide is the aluminum (Al) vaccine adjuvant. In this review we
discuss the mechanisms by which Al can induce adverse neurological and
immunological effects and how these may provide important clues of Al’s
putative role in autism. Because of the tight connection between the
development of the immune and the central nervous system, the possibility that
immune-overstimulation in early infancy via vaccinations may play a role in
neurobehavioural disorders needs to be carefully considered. Conclusion There
is now sufficient evidence from both human and animal studies showing that
cumulative exposure to aluminium adjuvants is not as benign as previously
assumed. Given that vaccines are the only medical intervention that we attempt
to deliver to every living human on earth and that by far the largest target
population for vaccination are healthy children, a better appreciation and
understanding of vaccine adjuvant risks appears warranted.
http://www.oapublishinglondon.com/article/1368

“Indeed, evidence has now emerged showing that autism may in part result from
early-life immune insults induced by environmental xenobiotics. One of the most
common xenobiotic with immuno-stimulating as well as neurotoxic properties to
which infants under two years of age are routinely exposed worldwide is the
aluminum (Al) vaccine adjuvant. In this review we discuss the mechanisms by
which Al can induce adverse neurological and immunological effects and how
these may provide important clues of Aluminum’s putative role in autism.”

“… the United States Centers for Disease Control and Prevention states that Thimerosal is safe
and there is no relationship between [T]himerosal[-]containing vaccines and
autism rates in children. This is puzzling because, in a study conducted
directly by CDC epidemiologists, a 7.6-fold increased risk of autism from
exposure to Thimerosal during infancy was found.” Biomedical Research
International • June 2014

Methodological issues and evidence of malfeasance in research purporting to
show thimerosal in vaccines is safe Author information Hooker B1, Kern J2,
Geier D3, Haley B4, Sykes L5, King P5, Geier M3. 1. Simpson University, 2211
College View Drive, Redding, CA 96001 2. Institute of Chronic Illness, Inc., 14
Redgate Court, Silver Spring, MD 20905 University of Texas Southwestern Medical
Center at Dallas, Dallas, TX 75235 3. Institute of Chronic Illness, Inc., 14
Redgate Court, Silver Spring, MD 20905 4. University of Kentucky, Lexington, KY
40506 5. CoMeD, Inc., Silver Spring, MD, USA Abstract There are over 165
studies that have focused on Thimerosal, an organic-mercury (Hg) based
compound, used as a preservative in many childhood vaccines, and found it to be
harmful. Of these, 16 were conducted to specifically examine the effects of
Thimerosal on human infants or children with reported outcomes of death;
acrodynia; poisoning; allergic reaction; malformations; auto-immune reaction;
Well’s syndrome; developmental delay; and neurodevelopmental disorders,
including tics, speech delay, language delay, attention deficit disorder, and
autism. In contrast, the United States Centers for Disease Control and
Prevention states that Thimerosal is safe and there is “no relationship between
[T]himerosal[-]containing vaccines and autism rates in children.” This is
puzzling because, in a study conducted directly by CDC epidemiologists, a
7.6-fold increased risk of autism from exposure to Thimerosal during infancy
was found. The CDC’s current stance that Thimerosal is safe and that there is
no relationship between Thimerosal and autism is based on six specific
published epidemiological studies coauthored and sponsored by the CDC. The
purpose of this review is to examine these six publications and analyze
possible reasons why their published outcomes are so different from the results
of investigations by multiple independent research groups over the past 75+
years. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065774/

International Journal Of Epidemiology • June 2014

The non-specific effects of vaccines and other childhood interventions: the
contribution of INDEPTH Health and Demographic Surveillance Systems Author
information Sankoh O1, Welaga P2, Debpuur C2, Zandoh C2, Gyaase S2, Poma MA2,
Mutua MK2, Hanifi SM2, Martins C2, Nebie E2, Kagoné M2, Emina JB3, Aaby P2.
INDEPTH Network, Accra, Ghana, School of Public Health University of the
Witwatersrand, Johannesburg, South Africa Abstract Most childhood interventions
(vaccines, micronutrients) in low-income countries are justified by their
assumed effect on child survival. However, usually the interventions have only
been studied with respect to their disease/deficiency-specific effects and not
for their overall effects on morbidity and mortality. In many situations, the
population-based effects have been very different from the anticipated effects;
for example, the measles-preventive high-titre measles vaccine was associated
with 2-fold increased female mortality; BCG reduces neonatal mortality although
children do not die of tuberculosis in the neonatal period; vitamin A may be
associated with increased or reduced child mortality in different situations;
effects of interventions may differ for boys and girls. The reasons for these
and other contrasts between expectations and observations are likely to be that
the immune system learns more than specific prevention from an intervention;
such training may enhance or reduce susceptibility to unrelated infections.
INDEPTH member centres have been in an ideal position to document such
additional non-specific effects of interventions because they follow the total
population long term. It is proposed that more INDEPTH member centres extend
their routine data collection platform to better measure the use and effects of
childhood interventions. In a longer perspective, INDEPTH may come to play a
stronger role in defining health research issues of relevance to low-income
countries. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052142/

“In many situations, the population-based effects have been very different from
the anticipated effects; for example, the measles-preventive high-titre measles
vaccine was associated with 2-fold increased female mortality ...”

“Our results indicated that food emulsifier applied in relatively high concentrations
in even the most frequently consumed foods can increase the absorption of DEHP,
and its role may be related to the structure and function damages of
mitochondria in enterocytes.” Toxicology Science • June 2014

Food emulsifier polysorbate 80 increases intestinal absorption of
di-(2-ethylhexyl) phthalate in rats Author information Lu Y1, Wang YY, Yang N,
Zhang D, Zhang FY, Gao HT, Rong WT, Yu SQ, Xu Q. Jiangsu Key Laboratory for
Supramolecular Medicinal Materials and Applications College of Life Sciences,
Nanjing Normal University Nanjing 210046, The People’s Republic of China
Abstract The aim of the present research was to explore whether food emulsifier
polysorbate 80 can enhance the absorption of di-(2-ethylhexyl) phthalate (DEHP)
and its possible mechanism. We established the high-performance liquid
chromatography (HPLC) method for detecting DEHP and its major metabolite,
mono-ethylhexyl phthalate (MEHP) in rat plasma, and then examined the
toxicokinetic and bioavailability of DEHP with or without polysorbate 80 in
rats. The study of its mechanism to increase the absorption of phthalates
demonstrated that polysorbate 80 can induce mitochondrial dysfunction in time-
and concentration-dependence manners in Caco-2 cells by reducing mitochondrial
membrane potential, diminishing the production of the adenosine triphosphate,
and decreasing the activity of electron transport chain. Our results indicated
that food emulsifier applied in relatively high concentrations in even the most
frequently consumed foods can increase the absorption of DEHP, and its role may
be related to the structure and function damages of mitochondria in
enterocytes. Full Report
http://toxsci.oxfordjournals.org/content/139/2/317.long

Journal Of Infectious Disease • July 2014

Sex-based biology and the rational design of influenza vaccination strategies
Author information Klein SL1, Pekosz A1. W. Harry Feinstone Department of
Molecular Microbiology and Immunology Johns Hopkins Bloomberg School of Public
Health, Baltimore, Maryland Abstract Biological (ie, sex) differences as well
as cultural (ie, gender) norms influence the acceptance and efficacy of
vaccines for males and females. These differences are often overlooked in the
design and implementation of vaccination strategies. Using seasonal and
pandemic influenza vaccines, we document profound differences between the sexes
in the acceptance, correlates of protection, and adverse reactions following
vaccination in both young and older adults. Females develop higher antibody
responses, experience more adverse reactions to influenza vaccines, and show
greater vaccine efficacy than males. Despite greater vaccine efficacy in
females, both young and older females are often less likely to accept influenza
vaccines than their male counterparts. Identification of the biological
mechanisms, including the hormones and genes, that underlie differential
responses to vaccination is necessary. We propose that vaccines should be
matched to an individual’s biological sex, which could involve systematically
tailoring diverse types of FDA-approved influenza vaccines separately for males
and females. One goal for vaccines designed to protect against influenza and
even other infectious diseases should be to increase the correlates of
protection in males and reduce adverse reactions in females in an effort to
increase acceptance and vaccine-induced protection in both sexes. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157517/

“Biological (ie, sex) differences as well as cultural (ie, gender) norms
influence the acceptance and efficacy of vaccines for males and females. These
differences are often [always] overlooked in the design and implementation of
vaccination strategies.”

“Seventy-nine infants received a total of 1,303 prescriptions comprising 77 formulations and 70 active drugs.
Eighty-six excipients were identified, of which, 9 were harmful excipients (HE)
and 48 were potentially harmful excipients (PHE).” European Journal Of
Pediatrics • July 2014

Toxic excipients in medications for neonates in Brazil Author information Souza
A Jr1, Santos D, Fonseca S, Medeiros M, Batista L, Turner M, Coelho H. Mother
and Child Hospital of Brasilia, SGAS, Av. L2 Sul, Quadra 608 Módulo A Asa Sul,
Brasília, Federal District, Brazil alcidesiojr@gmail.com Abstract The aim was
to describe the exposure to excipients among neonates hospitalised in the
neonatal intensive care unit (NICU) of a public hospital in Brasilia, Brazil.
This was a retrospective study based on medicines that were prescribed
electronically to neonates (≤28 days) who were admitted to the NICU of a
hospital in Brasilia between January 1 and March 31, 2012. Excipients were
identified from the medicine package leaflets and were classified according to
toxicity. Seventy-nine infants received a total of 1,303 prescriptions
comprising 77 formulations and 70 active drugs. Eighty-six excipients were
identified, of which, 9 were harmful excipients (HE) and 48 were potentially
harmful excipients (PHE). Almost all the neonates (98.7 %) were exposed to at
least one HE and PHE. Preterm neonates (n = 64; 1,502 neonate days) presented
high risk of exposure to polysorbate 80 (3.26/100 neonate days), sodium
hydroxide (3.39), PG (3.19) and propylparaben (3.06). Full-term neonates (n =
15; 289 neonate days) presented risks in relation to phenol (4.84), ethanol
(3.8) and sodium citrate (3.46). CONCLUSION Neonates in NICUs in Brazil are
exposed to a wide variety of HE and PHE with unpredictable results.
http://www.ncbi.nlm.nih.gov/pubmed/24500397

Translational Neurodegeneration • August 2014

Measles-mumps-rubella vaccination timing and autism among young African
American boys: a reanalysis of CDC data Author information Hooker BS. Simpson
University, Redding, CA, USA. Abstract BACKGROUND A significant number of
children diagnosed with autism spectrum disorder suffer a loss of
previously-acquired skills, suggesting neurodegeneration or a type of
progressive encephalopathy with an etiological basis occurring after birth. The
purpose of this study is to investigate the effectof the age at which children
got their first Measles-Mumps-Rubella (MMR) vaccine on autism incidence. This
is a reanalysis of the data set, obtained from the U.S. Centers for Disease
Control and Protection (CDC), used for the Destefano et al. 2004 publication on
the timing of the first MMR vaccine and autism diagnoses. METHODS The author
embarked on the present study to evaluate whether a relationship exists between
child age when the first MMR vaccine was administered among cases diagnosed
with autism and controls born between 1986 through 1993 among school children
in metropolitan Atlanta. The Pearson’s chi-squared method was used to assess
relative risks of receiving an autism diagnosis within the total cohort as well
as among different race and gender categories. RESULTS When comparing cases and
controls receiving their first MMR vaccine before and after 36 months of age,
there was a statistically significant increase in autism cases specifically
among African American males who received the first MMR prior to 36 months of
age. Relative risks for males in general and African American males were 1.69
(p=0.0138) and 3.36 (p=0.0019), respectively. Additionally, African American
males showed an odds ratio of 1.73 (p=0.0200) for autism cases in children
receiving their first MMR vaccine prior to 24 months of age versus 24 months of
age and thereafter. CONCLUSIONS The present study provides new epidemiologic
evidence showing that African American males receiving the MMR vaccine prior to
24 months of age or 36 months of age are more likely to receive an autism
diagnosis. http://www.ncbi.nlm.nih.gov/pubmed/25114790

“The present study provides new epidemiologic evidence showing that African
American males receiving the MMR vaccine prior to 24 months of age or 36 months
of age are more likely to receive an autism diagnosis.”

Vaccine • September 2014

Abstract

Interaction between neonatal vitamin A supplementation and timing of measles
vaccination: a retrospective analysis of three randomized trials from
Guinea-Bissau

BACKGROUND In Guinea-Bissau we conducted three trials of neonatal vitamin A
supplementation (NVAS) from 2002 to 2008. None of the trials found a beneficial
effect on mortality. From 2003 to 2007, an early measles vaccine (MV) trial was
ongoing, randomizing children 1:2 to early MV at 4.5 months or no early MV, in
addition to the usual MV at 9 months. We have previously found interactions
between vitamin A and vaccines.

Author information

OBJECTIVE We investigated whether there were interactions between NVAS and
early MV.

Benn CS1, Martins CL2, Fisker AB3, Diness BR3, Garly ML3, Balde I2, Rodrigues
A2, Whittle H4, Aaby P5. 1. Research Center for Vitamins and Vaccines (CVIVA)
Bandim Health Project, Artillerivej 5, 2300 Copenhagen S, Denmark Institute of
Clinical Research University of Southern Denmark/Odense University Hospital,
Denmark cb@ssi.dk. 2. Bandim Health Project, Indepth Network, Bissau,
Guinea-Bissau 3. Research Center for Vitamins and Vaccines (CVIVA) Bandim
Health Project, Artillerivej 5, 2300 Copenhagen S, Denmark 4. The London School
of Hygiene and Tropical Medicine, Keppel Street, London, UK 5. Research Center
for Vitamins and Vaccines (CVIVA) Bandim Health Project, Artillerivej 5, 2300
Copenhagen S, Denmark Bandim Health Project, Indepth Network, Bissau,
Guinea-Bissau

DESIGN We compared the mortality of NVAS and placebo recipients: first, from
4.5 to 8 months for children randomized to early MV or no early MV; and second,
from 9 to 17 months in children who had received two MV or one MV. Mortality
rates (MR) were compared in Cox models producing mortality rate ratios (MRR).
RESULTS A total of 5141 children were randomized to NVAS (N=3015) or placebo
(N=2126) and were later randomized to early MV (N=1700) or no early MV
(N=3441). Between 4.5 and 8 months, NVAS compared with placebo was associated
with higher mortality in early MV recipients (MR=30 versus MR=0, p=0.01), but
not in children who did not receive early MV (p for interaction between NVAS
and early MV=0.03). From 9 to 17 months NVAS was not associated with mortality.
Overall, from 4.5 to 17 months NVAS was associated with increased mortality in
early MV recipients (Mortality rate ratio=5.39 (95% confidence interval: 1.62,
17.99)). CONCLUSIONS These observations indicate that NVAS may interact with
vaccines given several months later. This may have implications for the
planning of future child intervention programs.
http://www.ncbi.nlm.nih.gov/pubmed/25131735

“These observations indicate that neonatal vitamin A supplementation may
interact with vaccines given several months later.”

BMC Pediatrics • August 2014

Neonatal vitamin A supplementation associated with a cluster of deaths and poor
early growth in a randomised trial among low-birth-weight boys of vitamin A
versus oral polio vaccine at birth Najaaraq Lund,1,2,3 Sofie Biering-Sørensen,1
Andreas Andersen,1 Ivan Monteiro,3 Luis Camala,4 Mathias Jul Jørgensen,3 Peter
Aaby,1,3 and Christine Stabell Benn1,5 1Research Center for Vitamins and
Vaccines (CVIVA), Bandim Health Project Statens Serum Institut, Copenhagen,
Denmark 2Department of Infectious Diseases, Aarhus University Hospital, Aarhus,
Denmark 3Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau
4Maternidade, Hospital Nacional Simão Mendes, Bissau, Guinea-Bissau 5OPEN,
Institute of Clinical Research, University of Southern Denmark/Odense
University Hospital Odense, Denmark Abstract Background The effect of oral
polio vaccine administered already at birth (OPV0) on child survival was not
examined before being recommended in 1985. Observational data suggested that
OPV0 was harmful for boys, and trials have shown that neonatal vitamin A
supplementation (NVAS) at birth may be beneficial for boys. We set out to test
this research question in a randomised trial. Methods The trial was carried out
at the Bandim Health Project, Guinea-Bissau. We planned to enrol 900 low-birth
weight (LBW) boys in a randomised trial to investigate whether NVAS instead of
OPV0 could lower infant mortality for LBW boys. At birth, the children were
randomised to OPV (usual treatment) or VAS (intervention treatment) and
followed for 6 months for growth and 12 months for survival. Hazard Ratios (HR)
for mortality were calculated using Cox regression. We compared the individual
anthropometry measurements to the 2006 WHO growth reference. We compared
differences in z-scores by linear regression. Relative risks (RR) of being
stunted or underweight were calculated in Poisson regression models with robust
standard errors. Results In the rainy season we detected a cluster of deaths in
the VAS group and the trial was halted immediately with 232 boys enrolled. The
VAS group had significantly higher mortality than the OPV group in the rainy
season (HR: 9.91 (1.23 – 80)). All deaths had had contact with the neonatal
nursery; of seven VAS boys enrolled during one week in September, six died
within two months of age, whereas only one died among the six boys receiving
OPV (p = 0.05). Growth (weight and arm-circumference) in the VAS group was
significantly worse until age 3 months. Conclusion VAS at birth instead of OPV
was not beneficial for the LBW boys in this study. With the premature closure
of the trial it was not possible to answer the research question. However, the
results of this study call for extra caution when testing the effect of NVAS in
the future. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236664/

[example of the experimental nature of vaccination. This test using Vitamin A
Supplementation versus Oral Polio Vaccine resulted in the deaths of 6 African
boys]

Human & Experimental Toxicology • August 2014

Vaccination to prevent varicella: Goldman and King’s response to Myers’
interpretation of Varicella Active Surveillance Project data Author information
Goldman GS1, King PG2. 1. Independent Computer Scientist, Pearblossom, CA, USA
gsgoldman@roadrunner.com 2. Facility Automation Management Engineering (FAME)
Systems, Lake Hiawatha, NJ, USA Abstract BACKGROUND There is increasing
evidence that herpes zoster (HZ) incidence rates among children and adults
(aged <60 years) with a history of natural varicella are influenced primarily
by the frequency of exogenous exposures, while asymptomatic endogenous
reactivations help to cap the rate at approximately 550 cases/100,000
person-years when exogenous boosting becomes rare. The Antelope Valley
Varicella Active Surveillance Project was funded by the Centers for Disease
Control and Prevention in 1995 to monitor the effects of varicella vaccination
in one of the three representative regions of the United States. The stability
in the data collection and number of reporting sites under varicella
surveillance from 1995-2002 and HZ surveillance during 2000-2001 and 2006-2007
contributed to the robustness of the discerned trends. DISCUSSION Varicella
vaccination may be useful for leukemic children; however, the target population
in the United States is all children. Since the varicella vaccine inoculates
its recipients with live, attenuated varicella-zoster virus (VZV), clinical
varicella cases have dramatically declined. Declining exogenous exposures
(boosts) from children shedding natural VZV have caused waning cell-mediated
immunity. Thus, the protection provided by varicella vaccination is neither
lifelong nor complete. Moreover, dramatic increases in the incidence of adult
shingles cases have been observed since HZ was added to the surveillance in
2000. In 2013, this topic is still debated and remains controversial in the
United States. SUMMARY When the costs of the booster dose for varicella and the
increased shingles recurrences are included, the universal varicella
vaccination program is neither effective nor cost-effective.
http://www.ncbi.nlm.nih.gov/pubmed/24275643

“When the costs of the booster dose for varicella and the increased shingles
recurrences are included, the universal varicella vaccination program is
neither effective nor cost-effective.”

Vaccine • September 2014

Interaction between neonatal vitamin A supplementation and timing of measles
vaccination: a retrospective analysis of three randomized trials from
Guinea-Bissau Author information Benn CS1, Martins CL2, Fisker AB3, Diness BR3,
Garly ML3, Balde I2, Rodrigues A2, Whittle H4, Aaby P5. 1. Research Center for
Vitamins and Vaccines (CVIVA), Bandim Health Project 2300 Copenhagen S,
Denmark; OPEN, Institute of Clinical Research,University of Southern
Denmark/Odense University Hospital, Denmark 2. Bandim Health Project, Indepth
Network, Bissau, Guinea-Bissau. 3. Research Center for Vitamins and Vaccines
(CVIVA), Bandim Health Project, Artillerivej 5, 2300 Copenhagen S, Denmark. 4.
The London School of Hygiene and Tropical Medicine, Keppel Street, London, UK.
5. Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project,
Artillerivej 5 2300 Copenhagen S, Denmark; Bandim Health Project, Indepth
Network, Bissau, Guinea-Bissau

“These observations indicate that neonatal vitamin A

Abstract BACKGROUND In Guinea-Bissau we conducted three trials of neonatal
vitamin A supplementation (NVAS) from 2002 to 2008. None of the trials found a
beneficial effect on mortality. From 2003 to 2007, an early measles vaccine
(MV) trial was ongoing, randomizing children 1:2 to early MV at 4.5 months or
no early MV, in addition to the usual MV at 9 months. We have previously found
interactions between vitamin A and vaccines. OBJECTIVE We investigated whether
there were interactions between NVAS and early MV. DESIGN We compared the
mortality of NVAS and placebo recipients: first, from 4.5 to 8 months for
children randomized to early MV or no early MV; and second, from 9 to 17 months
in children who had received two MV or one MV. Mortality rates (MR) were
compared in Cox models producing mortality rate ratios (MRR). RESULTS A total
of 5141 children were randomized to NVAS (N=3015) or placebo (N=2126) and were
later randomized to early MV (N=1700) or no early MV (N=3441). Between 4.5 and
8 months, NVAS compared with placebo was associated with higher mortality in
early MV recipients (MR=30 versus MR=0, p=0.01), but not in children who did
not receive early MV (p for interaction between NVAS and early MV=0.03). From 9
to 17 months NVAS was not associated with mortality. Overall, from 4.5 to 17
months NVAS was associated with increased mortality in early MV recipients
(Mortality rate ratio=5.39 (95% confidence interval: 1.62, 17.99)). CONCLUSIONS
These observations indicate that NVAS may interact with vaccines given several
months later. This may have implications for the planning of future child
intervention programs. http://www.ncbi.nlm.nih.gov/pubmed/25131735

supplementation may interact with vaccines given several months later.”

“This is the first report of measles transmission from a twice vaccinated individual.”
Oxford Journals Clinical Infectious Diseases • October 2014

Outbreak of Measles Among Persons With Prior Evidence of Immunity New York
City, 2011 Author Information Jennifer B. Rosen1, Jennifer S. Rota2, Carole J.
Hickman2, Sun Sowers2, Sara Mercader2, Paul A. Rota2, William J. Bellini2, Ada
J. Huang3, Margaret K. Doll1, Jane R. Zucker1,2, and Christopher M. Zimmerman1
1. Bureau of ImmunizationNew York City Department of Health and Mental Hygiene
New York City, New York 2. National Center for Immunization and Respiratory
Diseases, Centers for Disease Control and Prevention (CDC) Atlanta, GA 3.
Westchester County Department of Health, New Rochelle, New York Abstract
Background Measles was eliminated in the United States through high vaccination
coverage and a public health system able to rapidly respond to measles. Measles
may occur among vaccinated individuals, but secondary transmission from such
individuals has not been documented. Methods Suspected cases and contacts
exposed during a measles outbreak in New York City in 2011 were investigated.
Medical histories and immunization records were obtained. Cases were confirmed
by detection of measlesspecific IgM and/or RNA. Tests for measles IgG, IgG
avidity, measurement of measles neutralizing antibody titers, and genotyping
were performed to characterize the cases. Results The index case had two doses
of measles-containing vaccine. Of 88 contacts, four secondary cases were
confirmed that had either two doses of measles-containing

vaccine or a past positive measles IgG antibody. All cases had laboratory
confirmation of measles infection, clinical symptoms consistent with measles,
and high avidity IgG antibody characteristic of a secondary immune response.
Neutralizing antibody titers of secondary cases reached >80,000 mIU/mL 3-4 days
post-rash onset while that of the index was <500 mIU/mL 9 days post-rash onset.
No additional cases occurred among 231 contacts of secondary cases. Conclusions
This is the first report of measles transmission from a twice vaccinated
individual. The clinical presentation and laboratory data of the index were
typical of measles in a naïve individual. Secondary cases had robust anamnestic
antibody responses. No tertiary cases occurred despite numerous contacts. This
outbreak underscores the need for thorough epidemiologic and laboratory
investigation of suspected measles cases regardless of vaccination status.

http://cid.oxfordjournals.org/content/early/2014/02/27/cid.ciu105

Indian Journal Of Medical Ethics • October 2014

Thimerosal as discrimination: vaccine disparity in the UN Minamata Convention
on mercury Sykes LK1, Geier DA2, King PG1, Kern JK3, Haley BE1, Chaigneau CG1,
Megson MN4, Love JM5, Reeves RE1, Geier MR2. Author information 1. CoMeD, Inc,
Silver Spring, MD United States 2. CoMeD, Inc, Silver Spring, MD; Institute of
Chronic Illnesses, Inc, Silver Spring, MD 3. Institute of Chronic Illnesses,
Inc, Silver Spring, MD United States 4. Pediatric and Adolescent Ability
Center, Richmond, VA United States 5. CoMeD, Inc, Silver Spring, MD Abstract
When addressing toxins, one unmistakable parallel exists between biology and
politics: developing children and developing nations are those most vulnerable
to toxic exposures. This disturbing parallel is the subject of this critical
review, which examines the use and distribution of the mercury (Hg)-based
compound, thimerosal, in vaccines. Developed in 1927, thimerosal is 49.55% Hg
by weight and breaks down in the body into ethyl-Hg chloride, ethyl-Hg
hydroxide and sodium thiosalicylate. Since the early 1930s, there has been
evidence indicating that thimerosal poses a hazard to the health of human
beings and is ineffective as an antimicrobial agent. While children in the
developed and predominantly western nations receive doses of mostly
no-thimerosal and reduced-thimerosal vaccines, children in the developing
nations receive many doses of several unreduced thimerosal-containing vaccines
(TCVs). Thus, thimerosal has continued to be a part of the global vaccine
supply and its acceptability as a component of vaccine formulations remained
unchallenged until 2010, when the United Nations (UN), through the UN
Environment Programme, began negotiations to write the global, legally binding
Minamata Convention on Hg. During the negotiations, TCVs were dropped from the
list of Hg-containing products to be regulated. Consequently, a double standard
in vaccine safety, which previously existed due to ignorance and economic
reasons, has now been institutionalised as global policy. Ultimately, the
Minamata Convention on Hg has sanctioned the inequitable distribution of
thimerosal by specifically exempting TCVs from regulation, condoning a two-tier
standard of vaccine safety: a predominantly no-thimerosal and
reduced-thimerosal standard for developed nations and a predominantly
thimerosal-containing one for developing nations. This disparity must now be
evaluated urgently as a potential form of institutionalised discrimination.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25101548

“the Minamata Convention on Mercury has sanctioned the inequitable distribution
of thimerosal by specifically exempting TCVs from regulation, condoning a
two-tier standard of vaccine safety; a predominantly no-thimerosal and
reduced-thimerosal standard for developed nations and a predominantly
thimerosal-containing one for developing nations. This disparity must now be
evaluated urgently as a potential form of institutionalized discrimination.”

Annals Of Medical And Health Sciences Research • November 2014

Hepatitis B vaccination and associated oral manifestations: a non-systematic
review of literature and case reports Author information Tarakji B1, Ashok N1,
Alakeel R2, Azzeghaibi S1, Umair A1, Darwish S1, Mahmoud R3, Elkhatat E3.

“A total of 82 articles were identified which included 58 case series or case
reports, 15 review articles, 4 cross sectional studies, 3 prospective cohort
studies, one retrospective cohort study and a case control study. After

Abstract Hepatitis B vaccine has been administered in children and adults
routinely to reduce the incidence of the disease. Even though, hepatitis B
vaccine is considered as highly safe, some adverse reactions have been
reported. A literature search was carried out in PubMed, accessed via the
National Library of Medicine PubMed interface, searching used the following
keywords: Hepatitis B vaccine and complications from 1980 to 2014. A total of
1147 articles were obtained out of which articles, which discuss the
complications occurring orally or occurring elsewhere in the body, which have
the potential to manifest orally after hepatitis B vaccination were selected. A
total of 82 articles were identified which included 58 case series or case
reports, 15 review articles, 4 cross sectional studies, 3 prospective cohort
studies, one retrospective cohort study and a case control study. After
reviewing the literature, we observed that complications seen after Hepatitis B
vaccination are sudden infant death syndrome, multiple sclerosis, chronic
fatigue syndrome, idiopathic thrombocytopenic purpura, vasculititis optic
neuritis, anaphylaxis, systemic lupus erytymatosus, lichen planus and
neuro-muscular disorder. Of these complications, some are manifested orally or
have the potential to manifest orally. Although, most of the complications are
self-limiting, some are very serious conditions, which require hospitalization
with immediate medical attention. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250977/

reviewing the literature, we observed that complications seen after Hepatitis B
vaccination are sudden infant death syndrome, multiple sclerosis, chronic
fatigue syndrome, idiopathic thrombocytopenic purpura, vasculititis optic
neuritis, anaphylaxis, systemic lupus erytymatosus, lichen planus and
neuro-muscular disorder. Of these complications, some are manifested orally or
have the potential to manifest orally.”

Environmental Health • November 2014

Longitudinal analysis of the association between removal of dental amalgam,
urine mercury and 14 self-reported health symptoms Author information Zwicker
JD1, Dutton DJ, Emery JC. Abstract BACKGROUND Mercury vapor poses a known
health risk with no clearly established safe level of exposure. Consequently
there is debate over whether the level of prolonged exposure to mercury vapor
from dental amalgam fillings, combining approximately 50% mercury with other
metals, is sufficiently high to represent a risk to health. The objective of
our study is to determine if mercury exposure from amalgam fillings is
associated with risk of adverse health effects. METHODS In a large longitudinal
non-blind sample of participants from a preventative health program in Calgary,
Canada we compared number of amalgam fillings, urine mercury measures and
changes in 14 self-reported health symptoms, proposed to be mercury dependent
sub-clinical measures of mental and physical health. The likelihood of change
over one year in a sample of persons who had their fillings removed was
compared to a sample of persons who had not had their fillings removed. We use
non-parametric statistical tests to determine if differences in urine mercury
were statistically significant between sample groups. Logistic regression
models were used to estimate the likelihood of observing symptom improvement or
worsening in the sample groups. RESULTS At baseline, individuals with dental
amalgam fillings have double the measured urine mercury compared to a control
group of persons who have never had amalgam fillings. Removal of amalgam
fillings decreases measured urine mercury to levels in persons without amalgam
fillings. Although urine mercury levels in our sample are considered by Health
Canada to be too low to pose health risks, removal of amalgam fillings reduced
the likelihood of self-reported symptom deterioration and increased the
likelihood of symptom improvement in comparison to people who retained their
amalgam fillings. CONCLUSIONS Our findings suggest that mercury exposure from
amalgam fillings adversely impact health and therefore are a health risk. The
use of safer alternative materials for dental fillings should be encouraged to
avoid the increased risk of health deterioration associated with unnecessary
exposure to mercury. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273453/

“Our findings suggest that mercury exposure from amalgam fillings adversely
impact health and therefore are a health risk.”

Journal Of Autoimmunity • November 2014

Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine
model Author information Agmon-Levin N1, Arango MT2, Kivity S3, Katzav A4,
Gilburd B5, Blank M5, Tomer N5, Volkov A6, Barshack I6, Chapman J4, Shoenfeld
Y7 1. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center,
Tel-Hashomer 52621 Israel; Sackler Medical School, Tel Aviv University, Israel
2. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center,
Tel-Hashomer 52621 Israel; Doctoral Program in Biomedical Sciences Universidad
del Rosario, Bogota 111221, Colombia Center for Autoimmune Diseases Research -
CREA, Universidad del Rosario, Bogota 111221, Colombia 3. Zabludowicz Center
for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 52621 Israel;
Sackler Medical School, Tel Aviv University, Israel The Dr. Pinchas Borenstein
Talpiot Medical Leadership Program 2013, Sheba Medical Center, Tel-Hashomer
52621, Israel 4. Department of Neurology and Sagol Neuroscience Center, Sheba
Medical Center, Tel-Hashomer 52621, Israel 5. Zabludowicz Center for Autoimmune
Diseases, Sheba Medical Center, Tel-Hashomer 52621, Israel 6. Institute of
Pathology, Sheba Medical Center, Tel Hashomer 52621, Israel 7. Zabludowicz
Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 52621,
Israel Incumbent of the Laura Schwarz-Kip Chair for Autoimmunity, Tel-Aviv
University, Israel shoenfel@post.tau.ac.il

Abstract Hepatitis-B vaccine (HBVv) can prevent HBV-infection and associated
liver diseases. However, concerns regarding its safety, particularly among
patients with autoimmune diseases (i.e. SLE) were raised. Moreover, the
aluminum adjuvant in HBVv was related to immune mediated adverse events.
Therefore, we examined the effects of immunization with HBVv or alum on
SLE-like disease in a murine model. NZBWF1 mice were immunized with HBVv
(Engerix), or aluminum hydroxide (alum) or phosphate buffered saline (PBS) at 8
and 12 weeks of age. Mice were followed for weight, autoantibodies titers,
blood counts, proteinuria, kidney histology, neurocognitive functions (novel
object recognition, staircase, Y-maze and the forced swimming tests) and brain
histology. Immunization with HBVv induced acceleration of kidney disease
manifested by high anti-dsDNA antibodies (p < 0.01), early onset of proteinuria
(p < 0.05), histological damage and deposition of HBs antigen in the kidney.
Mice immunized with HBVv and/or alum had decreased cells counts mainly of the
red cell lineage (p < 0.001), memory deficits (p < 0.01), and increased
activated microglia in different areas of the brain compare with mice immunized
with PBS. Anxiety-like behavior was more pronounced among mice immunized with
alum. In conclusion, herein we report that immunization with the HBVv
aggravated kidney disease in an animal model of SLE. Immunization with either
HBVv or alum affected blood counts, neurocognitive functions and brain gliosis.
Our data support the concept that different component of vaccines may be linked
with immune and autoimmune mediated adverse events.
http://www.ncbi.nlm.nih.gov/pubmed/25042822

“... concerns regarding its safety, [hepatitis B vaccine] particularly among
patients with autoimmune diseases (i.e. SLE) were raised. Moreover, the
aluminum adjuvant in HBVv was related to immune mediated adverse events. Our
data support the concept that different component of vaccines may be linked
with immune and autoimmune mediated adverse events.”

Frontiers In Neurology • November 2014

Clinical features in patients with long-lasting macrophagic myofasciitis Author
information Rigolet M1, Aouizerate J2, Couette M3, Ragunathan-Thangarajah N2,
Aoun-Sebaiti M3, Gherardi RK4, Cadusseau J5, Authier FJ4. 1. Faculty of
Medicine, INSERM U955-Team 10, Créteil, France 2. Faculty of Medicine, INSERM
U955-Team 10, Créteil, France Reference Center for Neuromuscular Diseases
Garches-Necker-Mondor-Hendaye 3. Neurology Department, Henri Mondor University
Hospital, Créteil, France 4. Faculty of Medicine, INSERM U955-Team 10, Créteil,
France Reference Center for Neuromuscular Diseases
Garches-Necker-Mondor-Hendaye Créteil, France; Paris Est-Créteil University,
Créteil, France 5. Reference Center for Neuromuscular Diseases
Garches-Necker-Mondor-Hendaye Créteil, France; Paris Est-Créteil University,
Créteil, France Abstract Macrophagic myofasciitis (MMF) is an emerging
condition characterized by specific muscle lesions assessing abnormal long-term
persistence of aluminum hydroxide within macrophages at the site of previous
immunization. Affected patients usually are middle-aged adults, mainly
presenting with diffuse arthromyalgias, chronic fatigue, and marked cognitive
deficits, not related to pain, fatigue, or depression. Clinical features
usually correspond to that observed in chronic fatigue syndrome/myalgic
encephalomyelitis. Representative features of MMF-associated cognitive
dysfunction include dysexecutive syndrome, visual memory impairment, and left
ear extinction at dichotic listening test. Most patients fulfill criteria for
non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive
deficits appear unusually severe. Cognitive dysfunction seems stable over time
despite marked fluctuations. Evoked potentials may show abnormalities in
keeping with central nervous system involvement, with a neurophysiological
pattern suggestive of demyelination. Brain perfusion SPECT shows a pattern of
diffuse cortical and subcortical abnormalities, with hypoperfusions correlating
with cognitive deficiencies. The combination of musculoskeletal pain, chronic
fatigue, and cognitive disturbance generates chronic disability with possible
social exclusion. Classical therapeutic approaches are usually unsatisfactory
making patient care difficult. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246686/

“The combination of musculoskeletal pain, chronic fatigue, and cognitive
disturbance generates chronic disability with possible social exclusion.
Classical therapeutic approaches are usually unsatisfactory making patient care
difficult.”

Environmental Health • November 2014

Longitudinal analysis of the association between removal of dental amalgam,
urine mercury and 14 self-reported health symptoms Author information Zwicker
JD1, Dutton DJ, Emery JC. School of Public Policy, University of Calgary
Calgary, AB T2P 1H9, Canada zwicker1@ucalgary.ca Abstract BACKGROUND Mercury
vapor poses a known health risk with no clearly established safe level of
exposure. Consequently there is debate over whether the level of prolonged
exposure to mercury vapor from dental amalgam fillings, combining approximately
50% mercury with other metals, is sufficiently high to represent a risk to
health. The objective of our study is to determine if mercury exposure from
amalgam fillings is associated with risk of adverse health effects. METHODS In
a large longitudinal non-blind sample of participants from a preventative
health program in Calgary, Canada we compared number of amalgam fillings, urine
mercury measures and changes in 14 self-reported health symptoms, proposed to
be mercury dependent sub-clinical measures of mental and physical health. The
likelihood of change over one year in a sample of persons who had their
fillings removed was compared to a sample of persons who had not had their
fillings removed. We use non-parametric statistical tests to determine if
differences in urine mercury were statistically significant between sample
groups. Logistic regression models were used to estimate the likelihood of
observing symptom improvement or worsening in the sample groups. RESULTS At
baseline, individuals with dental amalgam fillings have double the measured
urine mercury compared to a control group of persons who have never had amalgam
fillings. Removal of amalgam fillings decreases measured urine mercury to
levels in persons without amalgam fillings. Although urine mercury levels in
our sample are considered by Health Canada to be too low to pose health risks,
removal of amalgam fillings reduced the likelihood of self-reported symptom
deterioration and increased the likelihood of symptom improvement in comparison
to people who retained their amalgam fillings. CONCLUSIONS Our findings suggest
that mercury exposure from amalgam fillings adversely impact health and
therefore are a health risk. The use of safer alternative materials for dental
fillings should be encouraged to avoid the increased risk of health
deterioration associated with unnecessary exposure to mercury. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273453/

“Our findings suggest that mercury exposure from amalgam fillings adversely
impact health and therefore are a health risk.”

Clinical And Experimental Immunology • December 2014

Vaccine-associated varicella and rubella infections in severe combined
immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R
detected by tandem whole exome sequencing and chromosomal microarray Author
information Bayer DK1, Martinez CA, Sorte HS, Forbes LR, Demmler-Harrison GJ,
Hanson IC, Pearson NM, Noroski LM, Zaki SR, Bellini WJ, Leduc MS, Yang Y, Eng
CM, Patel A, Rodningen OK, Muzny DM, Gibbs RA, Campbell IM, Shaw CA, Baker MW,
Zhang V, Lupski JR, Orange JS, Seeborg FO, Stray-Pedersen A. Department of
Pediatrics Section of Immunology, Allergy, and Rheumatology Baylor College of
Medicine and Texas Children’s Hospital Houston, TX, USA Abstract In areas
without newborn screening for severe combined immunodeficiency (SCID),
diseasedefining infections may lead to diagnosis, and in some cases, may not be
identified prior to the first year of life. We describe a female infant who
presented with disseminated vaccineacquired varicella (VZV) and
vaccine-acquired rubella infections at 13 months of age. Immunological
evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the
presence of CD8(+) T cells, poor lymphocyte proliferation,
hypergammaglobulinaemia and poor specific antibody production to VZV infection
and routine immunizations. A combination of whole exome sequencing and
custom-designed chromosomal microarray with exon coverage of primary
immunodeficiency genes detected compound heterozygous mutations (one single
nucleotide variant and one intragenic copy number variant involving one exon)
within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in
pretransplant blood and buccal DNA and maternal engraftment (5-10%)
demonstrated in pretransplant blood DNA. This may be responsible for the
patient’s unusual immunological phenotype compared to classical interleukin
(IL)-7R∼ deficiency. Disseminated VZV was controlled with anti-viral and
immune-based therapy, and umbilical cord blood stem cell transplantation was
successful. Retrospectively performed T cell receptor excision circle (TREC)
analyses completed on neonatal Guthrie cards identified absent TREC. This case
emphasizes the danger of live viral vaccination in severe combined
immunodeficiency (SCID) patients and the importance of newborn screening to
identify patients prior to high-risk exposures. It also illustrates the value
of aggressive pathogen identification and treatment, the influence newborn
screening can have on morbidity and mortality and the significant impact of
newer genomic diagnostic tools in identifying the underlying genetic aetiology
for SCID patients. http://www.ncbi.nlm.nih.gov/pubmed/25046553

“This case emphasizes the danger of live viral vaccination in severe combined
immunodeficiency (SCID) patients and the importance of newborn screening to
identify patients prior to high-risk exposures.”

Yale Journal Of Biology And Medicine • December 2014

‘Poisonous, Filthy, Loathsome, Damnable Stuff’: The Rhetorical Ecology of
Vaccination Concern Author Information Bernice L. Hausman, PhD, Mecal
Ghebremichael, BS, Philip Hayek, MA, and Erin Mack, BS Department Of English,
Virginia Tech, Blacksburg, VA Mailman School of Public Health, Columbia
University, New York, NY Abstract In this article, we analyze newspaper
articles and advertisements mentioning vaccination from 1915 to 1922 and refer
to historical studies of vaccination practices and attitudes in the early 20th
century in order to assess historical continuities and discontinuities in
vaccination concern. In the Progressive Era period, there were a number of
themes or features that resonated with contemporary issues and circumstances:
1) fears of vaccine contamination; 2) distrust of medical professionals; 3)
resistance to compulsory vaccination; and 4) the local nature of vaccination
concern. Such observations help scholars and practitioners understand vaccine
skepticism as longstanding, locally situated, and linked to the sociocultural
contexts in which vaccination occurs and is mandated for particular segments of
the population. A rhetorical approach offers a way to understand how discourses
are engaged and mobilized for particular purposes in historical contexts.
Historically situating vaccine hesitancy and addressing its articulation with a
particular rhetorical ecology offers scholars and practitioners a robust
understanding of vaccination concerns that can, and should, influence current
approaches to vaccination skepticism. Introduction On June 26, 2014, Eric
Kodish, MD, a medical ethicist at the Cleveland Clinic, wrote in the Washington
Post that “The anti-vaccination movement is a relatively new one that has taken
hold over the past decade. Started by a small community of parents, it is based
on myths that have been perpetuated by the power of the Internet and
endorsements from celebrities such as actress Jenny McCarthy, who has suggested
that vaccinations may have caused her son’s autism” [1]. This statement
encapsulates mainstream public health attitudes toward vaccine skepticism in
the early 21st century — that it constitutes a unified national movement, that
the movement is relatively new, and that it has gained authority due to the
power of the Internet and celebrity endorsements.

Indeed, it does seem as if the medical and public health consensus concerning
the value of vaccination is unraveling culturally in the United States. Medical
researchers routinely study health messaging about vaccination, finding most
recently that popular public health promotion programs do not convince
committed non-vaccinators to change their minds [2]. A discourse of crisis
pervades media reporting on outbreaks of infectious disease, and every flu
season brings with it a series of escalating media exhortations to be
vaccinated. Physicians report increasing frustrations with parents who refuse
to vaccinate their children or who seek a different vaccination schedule [3,4].
The American Academy of Pediatrics (AAP) has had to state unequivocally that it
is against firing patients as a result of their vaccination status [5]; and, as
with Erik Kodish, medical ethicists accuse parents who do not vaccinate their
children of negligence [1,6]. Yet national vaccination rates for most routine
infectious diseases of childhood in the United States remain high, suggesting
that ongoing concerns about vaccination occur in tandem with the general
success of public health efforts to vaccinate children against what were once
routine childhood diseases. National immunization rates suggest that there is
no widespread refusal to vaccinate (see Table 1). Kodish repeats a common
statistic indicating “1 in 10 parents in the United States now forgo or delay
vaccinations for their kids,” yet without more information about what those
parents eventually do, it is difficult to accept that statement as a threat to
national public health [1]. After all, in those families are children whose
parents simply delay vaccinations due to child illness at the time of the
doctors’ visit or due to a specific decision to slow the pace of vaccination
during infancy. In either case, Table 1 suggests that by 36 months, most
children are caught up with individual vaccines and many of the national rates
for those vaccines are at herd immunity levels.

www.ncbi.nim.nih.gov/pmc/articles/PMC4257028/

Immunology Research • December 2014

Evolution of multiple sclerosis in France since the beginning of hepatitis B
vaccination Author information Le Houézec D1. REVAHB (“Réseau Vaccin Hépatite
B” in French) 32 rue du Clos Herbert, 14000 Caen, France
dominique.le.houezec@freesbee.fr Abstract Since the implementation of the mass
vaccination campaign against hepatitis B in France, the appearance of multiple
sclerosis, sometimes occurring in the aftermath of vaccinations, led to the
publication of epidemiological international studies. This was also justified
by the sharp increase in the annual incidence of multiple sclerosis reported to
the French health insurance in the mid-1990s. Almost 20 years later, a
retrospective reflection can be sketched from these official data and also from
the national pharmacovigilance agency. Statistical data from these latter
sources seem to show a significant correlation between the number of hepatitis
B vaccinations performed and the declaration to the pharmacovigilance of
multiple sclerosis occurring between 1 and 2 years later. The application of
the Hill’s criteria to these data indicates that the correlation between
hepatitis B vaccine and multiple sclerosis may be causal.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25395338

“The application of the Hill’s criteria to these data indicates that the
correlation between hepatitis B vaccine and multiple sclerosis may be causal.”

Immunology Research • December 2014

Chronic fatigue syndrome and fibromyalgia following immunization with the
hepatitis B vaccine: another angle of the ‘autoimmune (auto-inflammatory)
syndrome induced by adjuvants’

(ASIA) Author information Agmon-Levin N1, Zafrir Y, Kivity S, Balofsky A,
Amital H, Shoenfeld Y. The Zabludowicz Center for Autoimmune Diseases Chaim
Sheba Medical Center, 52621, Tel-Hashomer, Israel Abstract The objectives of
this study were to gather information regarding demographic and clinical
characteristics of patients diagnosed with either fibromyalgia (FM) or chronic
fatigue (CFS) following hepatitis B vaccination (HBVv) and furthermore to apply
the recently suggested criteria of autoimmune (auto-inflammatory) syndromes
induced by adjuvants (ASIA), in the aim of identifying common characteristics
that may suggest an association between fibromyalgia, chronic fatigue and HBV
vaccination. Medical records of 19 patients with CFS and/or fibromyalgia
following HBVv immunization were analyzed. All of which were immunized during
1990-2008 in different centers in the USA. All medical records were evaluated
for demographics, medical history, the number of vaccine doses, as well as
immediate and long term post-immunization adverse events and clinical
manifestations. In addition, available blood tests, imaging results, treatments
and outcomes were analyzed. ASIA criteria were applied to all patients. The
mean age of patients was 28.6 ± 11 years, of which 68.4 % were females. 21.05 %
had either personal or familial background of autoimmune disease. The mean
latency period from the last dose of HBVv to onset of symptoms was 38.6 ± 79.4
days, ranging from days to a year. Eight (42.1 %) patients continued with the
immunization program despite experiencing adverse events. Manifestations that
were commonly reported included neurological manifestations (84.2 %),
musculoskeletal (78.9 %), psychiatric (63.1 %), fatigue (63.1 %),
gastrointestinal complains (58 %) and mucocutaneous manifestations (36.8 %).
Autoantibodies were detected in 71 % of patients tested. All patients fulfilled
the ASIA criteria. This study suggests that in some cases CFS and FM can be
temporally related to immunization, as part of ASIA syndrome. The appearance of
adverse event during immunization, the presence of autoimmune susceptibility
and higher titers of autoantibodies all can be suggested as risk factors. ASIA
criteria were fulfilled in all patients eluding the plausible link between ASIA
and CFS/FM. http://www.ncbi.nlm.nih.gov/pubmed/25427994

“This study suggests that in some cases Chronic Fatigue Syndrome (CFS) and
fibromyalgia (FM) can be temporally related to immunization, as part of ASIA
syndrome.”

“... a causal link with vaccine cannot be excluded in some individuals.”
Immunology Research • December 2014

A sudden onset of a pseudo-neurological syndrome after HPV-16/18 AS04-adjuvated
vaccine: might it be an autoimmune/inflammatory syndrome induced by adjuvants
(ASIA) presenting as a somatoform disorder? Author information Poddighe D1,
Castelli L, Marseglia GL, Bruni P. Department of Pediatrics, Azienda
Ospedaliera di Melegnano, Milan, Italy dimimedpv@yahoo.it Abstract In last
centuries, vaccines reduced the incidence of several infectious diseases. In
last decades, some vaccines aimed at preventing also some cancers, where
viruses play a causative role. However, several adverse events have been
described after vaccines, but a causal relationship has been established only
in a minority of cases. Here, we describe a pseudo-neurological syndrome
occurred shortly after the administration of the bivalent HPV vaccine. Some
autoimmune disorders, including neurological demyelinating diseases, have been
reported after HPV vaccines, but the patient showed no organic lesions. The
patient was diagnosed as having a functional somatoform syndrome, which was
supposed to be autoimmune/inflammatory syndrome induced by adjuvants (ASIA),
seen the temporal link with vaccination and the presence of anti-phospholipid
autoantibodies. Immunological mechanisms of vaccines-and of adjuvants-have not
been completely elucidated yet, and although there is no evidence of
statistical association with many post-vaccination events, a causal link with
vaccine cannot be excluded in some individuals.
http://www.ncbi.nlm.nih.gov/pubmed/25388965

Psychoneuroendocrinology • January 2015

Altered inflammatory activity associated with reduced hippocampal volume and
more severe posttraumatic stress symptoms in Gulf War veterans Author
information O’Donovan A1, Chao LL2, Paulson J3, Samuelson KW4, Shigenaga JK2,
Grunfeld C2, Weiner MW2, Neylan TC2. Abstract BACKGROUND Inflammation may
reduce hippocampal volume by blocking neurogenesis and promoting
neurodegeneration. Posttraumatic stress disorder (PTSD) has been linked with
both elevated inflammation and reduced hippocampal volume. However, few studies
have examined associations between inflammatory markers and hippocampal volume,
and none have examined these associations in the context of PTSD. METHODS We
measured levels of the inflammatory markers interleukin-6 (IL-6) and soluble
receptor II for tumor necrosis factor (sTNF-RII) as well as hippocampal volume
in 246 Gulf War veterans with and without current and past PTSD as assessed
with the Clinician Administered PTSD Scale (CAPS). Enzyme-linked immunosorbent
assays were used to measure inflammatory markers, and 1.5Tesla magnetic
resonance imaging (MRI) and Freesurfer version 4.5 were used to quantify
hippocampal volume. Hierarchical linear regression and analysis of covariance
models were used to examine if hippocampal volume and PTSD status would be
associated with elevated levels of IL-6 and sTNF-RII. RESULTS Increased
sTNF-RII, but not IL-6, was significantly associated with reduced hippocampal
volume (∼=-0.14, p=0.01). The relationship between sTNF-RII and hippocampal
volume was independent of potential confounds and covariates, including PTSD
status. Although we observed no PTSD diagnosis-related differences in either
IL-6 or sTNF-RII, higher PTSD severity was associated with significantly
increased sTNF-RII (∼=0.24, p=0.04) and reduced IL-6 levels (∼=-0.24, p=0.04).
CONCLUSIONS Our results indicate that specific inflammatory proteins may be
associated with brain structure and function as indexed by hippocampal volume
and PTSD symptoms. http://www.ncbi.nlm.nih.gov/pubmed/25465168

“Our results indicate that specific inflammatory proteins may be associated
with brain structure and function as indexed by hippocampal volume and PTSD
symptoms.”

“Macrophagic myofasciitis (MMF) characterized by specific muscle lesions assessing long-term persistence
of aluminum hydroxide within macrophages at the site of previous immunization
has been reported with increasing frequency in the past 10 years. The vaccines
containing this adjuvant may trigger MMF in some patients.” Rheumatology
International • January 2015

Macrophagic myofasciitis and vaccination: consequence or coincidence? Author
information Santiago T1, Rebelo O, Negrão L, Matos A. Rheumatology Unit Centro
Hospitalar e Universitário de Coimbra Praceta Prof. Mota Pinto, 3000-075
Coimbra, Portugal tlousasantiago@hotmail.com Abstract Macrophagic myofasciitis
(MMF) characterized by specific muscle lesions assessing long-term persistence
of aluminum hydroxide within macrophages at the site of previous immunization
has been reported with increasing frequency in the past 10 years. We describe
clinical and laboratory findings in patients with MMF. We did a retrospective
analysis of 16 cases observed in our Neuropathology Laboratory, between January
2000 and July 2013. The mean age of the 16 patients was 48.8 ± 18.0 years; 80.0
% were female. Chronic fatigue syndrome was found in 8 of 16 patients. Half of
the patients had elevated creatinine kinase levels, and 25.0 % had a myopathic
electromyogram. Thirteen patients received intramuscular administration of
aluminum-containing vaccine prior to the onset of symptoms. MMF may mirror a
distinctive pattern of an inflammatory myopathy. The vaccines containing this
adjuvant may trigger MMF in some patients.
http://www.ncbi.nlm.nih.gov/pubmed/24923906

Harefuah • February 2015

The sick building syndrome as a part of ‘ASIA’

(autoimmune/auto-inflammatory syndrome induced by adjuvants) by Maoz-Segal R,
Agmon-Levin N, Israeli E, Shoenfeld Y. Abstract The entity ‘sick building
syndrome’ is poorly defined and comprises of a set of symptoms resulting from
environmental exposure to a work or a living environment. The symptoms are
mainly “allergic”-like and include nasal, eye, and mucous membrane irritation,
dry skin as well as respiratory symptoms and general symptoms such as fatigue,
lethargy, headaches and fever. The Autoimmune [Auto-inflammatory] Syndrome
Induced by Adjuvants (ASIA) is a wider term which describes the role of various
environmental factors in the pathogenesis of immune mediated diseases. Factors
entailing an immune adjuvant activity such as infectious agents, silicone,
aluminium salts and others were found in association with defined and
non-defined immune mediated diseases. The sick building syndrome and ASIA share
a similar complex of signs and symptoms and probably the same immunological
mechanisms which further support a common denominator.
http://www.ncbi.nlm.nih.gov/pubmed/25856869

“Factors entailing an immune adjuvant activity such as infectious agents,
silicone, aluminium salts and others were found in association with defined and
non-defined immune mediated diseases.”

“... 2,207 cases were considered probably or possibly related to vaccination.
These represent the largest ASIA cohort ever reported ...” Immunology Research
• February 2015

The epidemiological profile of ASIA syndrome after HPV vaccination: an
evaluation based on the Vaccine Adverse Event Reporting Systems Author
information Pellegrino P1, Perrone V, Pozzi M, Carnovale C, Perrotta C,
Clementi E, Radice S. Unit of Clinical Pharmacology Department of Biomedical
and Clinical Sciences University Hospital “Luigi Sacco”, University of Milan
Via GB Grassi 74, 20157, Milan, Italy Abstract The term
“ASIA-Autoimmune/inflammatory Syndrome Induced by Adjuvants” describes an
umbrella of clinical conditions sharing similar signs or symptoms, including
post-vaccination phenomena. No information is available on the epidemiology of
the ASIA syndrome, especially following HPV vaccination. We carried out an
analysis of the VAERS database to retrieve all cases of suspected ASIA syndrome
according to the Shoenfeld and AgmonLevin’s guideline for the diagnosis. After
causality assessment and case validation, 2,207 cases were considered probably
or possibly related to vaccination. These represent the largest ASIA cohort
ever reported and allowed us to estimate epidemiological and clinical
characteristic of this syndrome. The commonest clinical manifestation observed
were pyrexia (58%), myalgia (27%) and arthralgia or arthritis (19%), and the
estimated reporting rate was of 3.6 cases per 100,000 doses of HPV vaccine
distributed (95% CI 3.4-3.7). This study presents the first systematic
estimation of ASIA incidence and expands the knowledge on this pathology.
Further analyses are needed to identify genetic and non-genetic risk factors
for ASIA syndrome. http://www.ncbi.nlm.nih.gov/pubmed/25381482

BMC Infectious Disease • February 2015

Pertussis outbreak in university students and evaluation of acellular pertussis
vaccine effectiveness in Japan Author information Hara M1, Fukuoka M2, Tashiro
K3, Ozaki I4, Ohfuji S5, Okada K6, Nakano T7, Fukushima W8, Hirota Y9,10.
Abstract BACKGROUND Recent studies worldwide have reported increasing numbers
of adults diagnosed with Bordetella pertussis despite receiving childhood
vaccinations. This study describes a pertussis outbreak at a university medical
faculty campus and examines the effectiveness of diphtheria, tetanus, and
pertussis (DTaP) vaccination completed during infancy in Japan. METHODS After
the outbreak, self-administered questionnaires and serum samples were collected
from students on campus to determine the incidence of pertussis and underlying
diseases. Pertussis was diagnosed on the basis of clinical criteria and serum
anti-pertussis toxin antibody levels. Using data collected from 248 first and
second grade students who had submitted copies of their vaccination records, we
evaluated the effectiveness of DTaP vaccination in infancy against adult
pertussis. RESULTS Questionnaire responses were obtained from 636 students (of
671 registered students; 95% response rate). Of 245 students who reported a
continuous cough during the outbreak period, 84 (attack rate: 13.2%) were
considered “probable” pertussis cases that met clinical criteria. The outbreak
occurred mainly in first and second grade students in the Faculty of Medicine.
Of 248 students who provided vaccination records, 225 had received 4 DTaP doses
(coverage: 90.7%); the relative risk of the complete vaccination series
compared to those with fewer than 4 doses or no doses for probable cases was
0.48 (95% confidence interval: 0.24-0.97). CONCLUSIONS Waning protection was
suspected due to over time. Booster vaccination for teenagers and development
of highly efficacious pertussis vaccines are needed.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25656486

“Waning protection was suspected ...”

“The emerging epidemic of Hodgkin and non-Hodgkin lymphomas worldwide
continues to defy our understanding ...” Immunology Research • February 2015

Adjuvants and lymphoma risk as part of the ASIA spectrum Author information
Butnaru D1, Shoenfeld Y. The Zabludowicz Center for Autoimmune Diseases Sheba
Medical Center, Tel Hashomer, Israel dana_medis@iberserv.es Abstract The
emerging epidemic of Hodgkin and non-Hodgkin lymphomas worldwide continues to
defy our understanding and forces the search for the causative factors.
Adjuvants are known to act as triggers of immune and inflammatory responses.
Animal experiments have demonstrated that long-term inflammation is related to
aggravation of the immune network resulting in cellular and humoral responses
leading to autoimmunity and lymphoma development. Chronic stimulation of the
immune system is thought to be the key mechanism through which infectious
diseases as well as autoimmune diseases can lead to lymphomagenesis. Many
adjuvants can act similarly perturbing immune system’s function, inducing a
state of prolonged immune activation related to chronic lymphatic drainage.
Several mechanisms were proposed by which adjuvants induce inflammation, and
they are discussed herein. Some of them are triggering inflammasome; others
bind DNA, lipid moieties in cells, induce uric acid production or act as
lipophilic and/or hydrophobic substances. The sustained inflammation increases
the risk of genetic aberrations, where the initial polyclonal activation ends
in monoclonality. The latter is the hallmark of malignant lymphoma. Thus,
chronic adjuvant stimulation may lead to lymphoma.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25582758

Archives Of Toxicology • February 2015

Ethylmercury and Hg2+ induce the formation of neutrophil extracellular traps
(NETs) by human neutrophil granulocytes Author information Haase H1,2, Hebel
S3, Engelhardt G3, Rink L4. Department of Food Chemistry and Toxicology Berlin
Institute of Technology Gustav-Meyer-Allee 25 13355, Berlin, Germany Medical
Faculty, Institute of Immunology RWTH Aachen University Hospital,
Pauwelsstrasse 30 52074, Aachen, Germany haase@tu-berlin.de. Abstract Humans
are exposed to different mercurial compounds from various sources, most
frequently from dental fillings, preservatives in vaccines, or consumption of
fish. Among other toxic effects, these substances interact with the immune
system. In high doses, mercurials are immunosuppressive. However, lower doses
of some mercurials stimulate the immune system, inducing different forms of
autoimmunity, autoantibodies, and glomerulonephritis in rodents. Furthermore,
some studies suggest a connection between mercury exposure and the occurrence
of autoantibodies against nuclear components and granulocyte cytoplasmic
proteins in humans. Still, the underlying mechanisms need to be clarified. The
present study investigates the formation of neutrophil extracellular traps
(NETs) in response to thimerosal and its metabolites ethyl mercury (EtHg),
thiosalicylic acid, and mercuric ions (Hg2+). Only EtHg and Hg2+ triggered
NETosis. It was independent of PKC, ERK1/2, p38, and zinc signals and not
affected by the NADPH oxidase inhibitor DPI. Instead, EtHg and Hg2+ triggered
NADPH oxidase-independent production of ROS, which are likely to be involved in
mercurial-induced NET formation. This finding might help understanding the
autoimmune potential of mercurial compounds. Some diseases, to which a
connection with mercurials has been shown, such as Wegener’s granulomatosis and
systemic lupus erythematosus, are characterized by high prevalence of
autoantibodies against neutrophil-specific auto-antigens. Externalization in
the form of NETs may be a source for exposure to these self-antigens. In
genetically susceptible individuals, this could be one step in the series of
events leading to autoimmunity.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25701957

“lower doses of some mercurials stimulate the immune system, inducing different
forms of autoimmunity, autoantibodies, and glomerulonephritis in rodents.
Furthermore, some studies suggest a connection between mercury exposure and the
occurrence of autoantibodies ... This finding might help understanding the
autoimmune potential of mercurial compounds.”

Journal Of Applied Toxicology • March 2015

Tween-80 and impurity induce anaphylactoid reaction in zebrafish Author
information Yang R1, Lao QC, Yu HP, Zhang Y, Liu HC, Luan L, Sun HM, Li CQ.
National Institutes for Food and Drug Control China Food and Drug
Administration (CFDA) No. 2 Tiantan Xili, Dongcheng District Beijing, 100050,
China

“A number of recent reports suspected

Abstract

that Tween-80 in injectable medicines,

A number of recent reports suspected that Tween-80 in injectable medicines,
including traditional Chinese medicine injections could cause life-threatening
anaphylactoid reaction, but no sound conclusion was drawn. A drug-induced
anaphylactoid reaction is hard to be assayed in vitro and in conventional
animal models. In this study, we developed a microplate-based quantitative in
vivo zebrafish assay for assessing anaphylactoid reaction and live whole
zebrafish mast cell tryptase activity was quantitatively measured at a
wavelength of 405 nm using N-benzoyl-dl-arginine p-nitroanilide as a substrate.
We assessed 10 batches of Tween-80 solutions from various national and
international suppliers and three Tween80 impurities (ethylene glycol,
2-chloroethanol and hydrogen peroxide) in this model and found that three
batches of Tween80 (nos 2, 20080709 and 20080616) and one Tween-80 impurity,
hydrogen peroxide (H2 O2 ), induced anaphylactoid reactions in zebrafish.
Furthermore, we found that H2 O2 residue and peroxide value were much higher in
Tween-80 samples 2, 20080709 and 20080616. These findings suggest that H2 O2
residue in combination with oxidized fatty acid residues (measured as peroxide
value) or more likely the oxidized fatty acid residues in Tween-80 samples, but
not Tween-80 itself, may induce anaphylactoid reaction. High-throughput
zebrafish tryptase assay developed in this report could be used for assessing
safety of Tween-80-containing injectable medicines and potentially for
screening novel mast cellmodulating drugs.

including traditional Chinese medicine

http://www.ncbi.nlm.nih.gov/pubmed/25345596

injections could cause life-threatening anaphylactoid reaction, but no sound
conclusion was drawn. These findings suggest that H2 O2 residue in combination
with oxidized fatty acid residues (measured as peroxide value) or more likely
the oxidized fatty acid residues in Tween-80 samples, but not Tween-80 itself,
may induce anaphylactoid reaction.”

Journal Of Pediatrics • April 2015

Adverse events following Haemophilus influenzae type b vaccines in the Vaccine
Adverse Event Reporting System 1990-2013 Author information Moro PL1, Jankosky
C2, Menschik D2, Lewis P3, Duffy J3, Stewart B3, Shimabukuro TT3. 1.
Immunization Safety Office Centers for Disease Control and Prevention, Atlanta,
GA pmoro@cdc.gov 2. Center for Biologics Evaluation and Research US Food and
Drug Administration, Silver Spring, MD 3. Immunization Safety Office Centers
for Disease Control and Prevention, Atlanta, GA Abstract Objective To
characterize adverse events (AEs) after Haemophilus influenzae type b (Hib)
vaccines reported to the US Vaccine Adverse Event Reporting System (VAERS), a
spontaneous reporting surveillance system. Study Design We searched VAERS for
US reports after Hib vaccines among reports received from January 1, 1990, to
December 1, 2013. We reviewed a random sample of reports and accompanying
medical records for reports classified as serious. All reports of death were
reviewed. Physicians assigned a primary clinical category to each reviewed
report. We used empirical Bayesian data mining to identify AEs that were
disproportionally reported after Hib vaccines. Results VAERS received 29,747
reports after Hib vaccines; 5179 (17%) were serious, including 896 reports of
deaths. Median age was 6 months (range 0-1022 months). Sudden infant death
syndrome was the stated cause of death in 384 (51%) of 749 death reports with
autopsy/death certificate records. The most common nondeath serious AE
categories were neurologic (80; 37%), other noninfectious (46; 22%) (comprising
mainly constitutional signs and symptoms); and gastrointestinal (39; 18%)
conditions. No new safety concerns were identified after clinical review of
reports of AEs that exceeded the data mining statistical threshold. Conclusion
Review of VAERS reports did not identify any new or unexpected safety concerns
for Hib vaccines. http://www.ncbi.nlm.nih.gov/pubmed/25598306

“VAERS received 29,747 reports after Hib vaccines; 5179 (17%) were serious,
including 896 reports of deaths.

Median age was 6 months (range 0-1022 months). Sudden infant death syndrome was
the stated cause of death in 384 (51%) of 749 death reports with autopsy/death
certificate records.

The most common nondeath serious AE categories were neurologic (80; 37%), other
noninfectious (46; 22%) (comprising mainly constitutional signs and symptoms);
and gastrointestinal (39; 18%) conditions.”

The Pediatric Infectious Disease Journal • April 2015

Seroprevalence of pertussis in the Gambia: evidence for continued circulation
of bordetella pertussis despite high vaccination rates Author information Scott
S1, van der Sande M, Faye-Joof T, Mendy M, Sanneh B, Barry Jallow F, de Melker
H, van der Klis F, van Gageldonk P, Mooi F, Kampmann B. From the *Medical
Research Council (MRC) Unit, The Gambia, Fajara, The Gambia, West Africa;
†Department of Infectious Disease Epidemiology, London School of Hygiene &
Tropical Medicine, London, United Kingdom; ‡National Institute of Public Health
and the Environment (RIVM), Centre for Infectious Diseases Control (CIb),
Bilthoven, The Netherlands; §Julius Centre for Health Sciences and Primary
Care, Utrecht University, Utrecht, The Netherlands; ¶International Agency for
Research on Cancer, Lyon, France; and Department of Paediatrics, Imperial
College, London, United Kingdom Abstract BACKGROUND Bordetella pertussis can
cause severe respiratory disease and death in children. In recent years, large
outbreaks have occurred in high-income countries; however, little is known
about pertussis incidence in sub-Saharan Africa. METHODS We evaluated antibody
responses to pertussis toxin (Ptx) from individuals aged between 2 and 90 years
in rural Gambia. IgG-Ptx was measured using luminex xMAP technology. IgG-Ptx
geometric mean concentrations (GMC) and their 95% confidence intervals were
calculated. The proportion seropositive (>20 EU/mL or ≥62.5 EU/mL) and GMCs
were compared by age, sex, ethnic group, vaccination status, birth order and
number of siblings per household using logistic and linear regression. RESULTS
76.3% had anti-Ptx levels <20 EU/mL, 17.5% had concentrations between 20 and
62.5 EU/mL, 4.4% had concentrations between 62.5 and 125 EU/mL and 1.8% had
concentrations ≥125 EU/mL. The overall Ptx antibody GMC was 6.4 EU/mL (95%
confidence interval: 5.8-6.9). Higher antibody concentrations were observed in
older populations with evidence for an increase in infection risk with
increasing age (1.9% yearly increase, 95% confidence interval: 1.3-2.5). No
child under 6 years of age had GMC above 62.5 EU/mL but 29.5% had
concentrations between 20 and 62.5 EU/mL. CONCLUSIONS These data provide
evidence that B. pertussis is being transmitted within this population despite
high vaccination coverage. Re-infection may occur implying that immunity from
childhood vaccination may not be lifelong. In the absence of data on actual
clinical cases of pertussis, seroprevalence studies remain valuable tools to
assess the transmission dynamics of B. pertussis.
http://www.ncbi.nlm.nih.gov/pubmed/25764094

“These data provide evidence that B. pertussis is being transmitted within this
population despite high vaccination coverage. Re-infection may occur implying
that immunity from childhood vaccination may not be lifelong.”

Springerplus • April 2015

The mechanisms of action of vaccines containing aluminum adjuvants: an in vitro
vs in vivo paradigm Tirth Raj Ghimire Division of Veterinary and Primate Health
Global Primate Network, Kathmandu, Nepal Department of Zoology, Birendra
Multiple Campus Tribhuvan University, Chitwan, Nepal The theory of
‘inflammation’ The use of adjuvants in vaccination is usually associated with
some degree of injection site inflammation, and this process is considered an
essential part of adjuvant function (Qin et al. 2009). This is consistent with
the ‘Danger Theory’ of immune activation as proposed by Polly Matzinger in 1994
(Matzinger 1994). According to this theory, initiation of the immune response
is not dependent on microbial recognition, but rather on the ability of
pathogens or other agents such as adjuvants to cause tissue damage. The danger
signals released from damaged tissues then have the capacity to drive
inflammation and initiate an adaptive immune response (Matzinger 1994). This
provides an important mechanistic theory for alum adjuvants with many reports
of inflammatory effects at the injection site and the induction of danger
signals from cells following alum interaction. For example, nodule or granuloma
formation in humans and animals following alum injection has been reported from
the 1930s to present day (Glenny 1931; Harrison 1935; Farago 1940; Holt 1950;
White et al. 1955; Munks et al. 2010; Lu and Hogenesch 2013; Vogelbruch et al.
2000; Bordet et al. 2001; Chong et al. 2006; Rock et al. 2010; Marsee et al.
2008). The development of alum granuloma is independent of the route of
immunization and occurs from a few days to several years (e.g., up to >12
years) following immunization, supporting the hypothesis that vaccines
containing alum lead to a short-term inflammatory effect in a normal
environment as well as long-term inflammatory effects in a pathological
environment, at the site of injection (Gherardi et al. 2001; Kool et al.
2008a). It has been shown that alum induces uric acid or monosodium urate (MSU)
crystal as a danger signal (Kool et al. 2008a). Subsequently, other signals
such as heat shock protein 70 (HSP70) (Wang et al. 2012), and deoxyribonucleic
acid (DNA) (Marichal et al. 2011; McKee et al. 2013) have been illustrated as
inducers of alum-mediated immune responses, indicating that the mechanisms by
which alum particles induce inflammation is central to understanding its
adjuvant properties. A clear causal association of alum in triggering immune
responses via cellular death and or enhancing the quality, duration, and
magnitude of T- and B- cell responses will make a significant contribution to
the rational design of effective and safe vaccines and development of new
adjuvants for future use. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406982/

“The use of adjuvants in vaccination is usually associated with some degree of
injection site inflammation, and this process is considered an essential part
of adjuvant function. This is consistent with the ‘Danger Theory’ of immune
activation as proposed by Polly Matzinger in 1994. According to this theory,
initiation of the immune response is not dependent on microbial recognition,
but rather on the ability of pathogens or other agents such as adjuvants to
cause tissue damage.”

Ugeskrift For Laeger • April 2015

Aluminium allergy and granulomas induced by vaccinations for children Author
information Andersen RM1, Zachariae C, Johansen JD. Videncenter for Allergi
Hud- og Allergiafdelingen Gentofte Hospital Niels Andersens vej 65 2900
Hellerup jeanne.Duus.Johansen@regionh.dk Abstract Vaccination with
aluminium-adsorbed vaccines can induce aluminium allergy with persistent
itching subcutaneous nodules at the injection site - vaccination granulomas. In
this article we give an overview of childhood aluminium-adsorbed vaccines
available in Denmark. Through literature studies we examine the incidence, the
symptoms and the prognosis for the vaccination granulomas and the allergy.
Finally we discuss the status in Denmark.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25350883

“Vaccination with aluminium-adsorbed vaccines can induce aluminium allergy with
persistent itching subcutaneous nodules at the injection site - vaccination
granulomas.”

Prescrire International • May 2015

Efficacy of the HPV vaccine in late 2014 [No authors listed] Abstract Initial
evaluation of the HPV 6, 11, 16, 18 vaccine showed about a 40% reduction in
high-grade cervical dysplasia due to all virus genotypes among young women aged
16 to 23 years who were not yet sexually active. These results were obtained
after 4 years of follow-up and were confirmed after an additional 3 years.
Clinical assessment of the HPV 16, 18 vaccine yielded similar results. The
interval between initial HPV infection and diagnosis of cervical cancer seems
to be at least 20 years. Comparisons of vaccinated and unvaccinated cohorts are
consistent with the results of clinical trials, but follow-up is still too
short because most of the women studied have not reached the age at which the
incidence of high-grade dysplasia peaks. The available evidence shows no
replacement of HPV vaccine genotypes by other highly oncogenic genotypes but,
once again, follow-up is relatively short. In late 2014, follow-up is still too
short to show whether HPV vaccination prevents cervical cancer in young women
before they become sexually active. Earlier clinical trials showing efficacy in
preventing high-grade dysplasia have not been challenged by epidemiological
data. Overall, it will be several more years before conclusive evidence is
obtained. In 2015, screening remains the cornerstone for reducing the incidence
of invasive cervical cancer. http://www.ncbi.nlm.nih.gov/pubmed/26034805

“ In late 2014, follow-up is still too short to show whether HPV vaccination
prevents cervical cancer in young women before they become sexually active.
Earlier clinical trials showing efficacy in preventing high-grade dysplasia
have not been challenged by epidemiological data. Overall, it will be several
more years before conclusive evidence is obtained. In 2015, screening remains
the cornerstone for reducing the incidence of invasive cervical cancer.”

Clinics In Dermatology • May 2015

Cutaneous reactions to vaccinations Author information Rosenblatt AE1, Stein
SL2. 1. Department of Medicine, Section of Dermatology University of Chicago,
Pritzker School of Medicine 5841 S. Maryland Ave MC 5067, Chicago, IL 60637 2.
Department of Medicine, Section of Dermatology University of Chicago, Pritzker
School of Medicine 5841 S. Maryland Ave MC 5067, Chicago, IL 60637 Department
of Pediatrics University of Chicago Pritzker School of Medicine 5841 S.
Maryland Ave MC, 5067 Chicago, IL 60637 Abstract Vaccinations are important for
infectious disease prevention; however, there are adverse effects of vaccines,
many of which are cutaneous. Some of these reactions are due to nonspecific
inflammation and irritation at the injection site, whereas other reactions are
directly related to the live attenuated virus. Rarely, vaccinations have been
associated with generalized hypersensitivity reactions, such as erythema
multiforme, Stevens-Johnson syndrome, urticaria, acute generalized
exanthematous pustulosis, and drug hypersensitivity syndrome. The onset of
certain inflammatory dermatologic conditions, such as lichen planus, granuloma
annulare, and pemphigoid, were reported to occur shortly after vaccine
administration. Allergic contact dermatitis can develop at the injection site,
typically due to adjuvant ingredients in the vaccine, such as thimerosal and
aluminum. Vaccinations are important to promote development of both individual
and herd immunity. Although most vaccinations are considered relatively safe,
there may be adverse effects associated with any vaccine. Cutaneous
manifestations make up a large portion of the types of reactions associated
with vaccines. There are many different reasons for the development of a
cutaneous reaction to a vaccination. Some are directly related to the injection
of a live attenuated virus, such as varicella or vaccinia (for immunity to
smallpox), whereas others cause more nonspecific erythema and swelling at the
injection site, as a result of local inflammation or irritation. Vaccinations
have also been associated in rare reports with generalized hypersensitivity
reactions, such as erythema multiforme, Stevens-Johnson syndrome, urticaria,
acute generalized exanthematous pustulosis, and drug hypersensitivity syndrome.
There have been case reports associating the administration of a vaccine with
the new onset of a dermatologic condition, such as lichen planus, granuloma
annulare, and Sweet syndrome. Finally, allergic contact dermatitis can develop
at the injection site, typically due to adjuvant ingredients in the vaccine,
such as thimerosal and aluminum. http://www.ncbi.nlm.nih.gov/pubmed/25889134

“there are adverse effects of vaccines, many of which are cutaneous ...
vaccinations have been associated with generalized hypersensitivity reactions,
such as erythema multiforme, Stevens-Johnson syndrome, urticaria, acute
generalized exanthematous pustulosis, and drug hypersensitivity syndrome.

The onset of certain inflammatory dermatologic conditions, such as lichen
planus, granuloma annulare, and pemphigoid, were reported to occur shortly
after vaccine administration.”

Expert Review Of Vaccines • June 2015

The avian influenza vaccine Emerflu Why did it fail? Author information Young
BE1, Sadarangani SP, Leo YS. Communicable Diseases Centre Institute of
Infectious Diseases and Epidemiology Communicable Diseases Centre, 144 Moulmein
Road, Singapore Abstract Emerflu is an inactivated, split-virion pandemic
preparedness vaccine, containing 30 μg of hemagglutinin (HA) and 600 μg of
aluminum hydroxide adjuvant. It is administered in two doses, 3 weeks apart.
Only moderate immunogenicity was evident from clinical studies with the vaccine
in adults, and HA antibody responses were below the criteria established by the
EMA and US FDA for licensure. With the exception of Australia, the vaccine
remains unlicensed. Further clinical development appears to have been
suspended, and newer adjuvants such as MF59 and AS03 have since demonstrated
safety and superior immunogenicity with lower HA doses. Emerflu is symbolic of
the failure of aluminum salts as an adjuvant for influenza vaccines. Reasons
for this failure are unclear, and may reflect problems with the
adjuvant-antigen complex or interference in the immune response by
heterosubtypic immunity. http://www.ncbi.nlm.nih.gov/pubmed/26098721

“Emerflu is symbolic of the failure of aluminum salts as an adjuvant for
influenza vaccines.”

“These results provide a neurobiological substrate for brain dysfunction
in aluminum hydroxide adjuvant-induced MMF patients.” PLoS One • June 2015

Neuropsychological Correlates of Brain Perfusion SPECT in Patients with
Macrophagic Myofasciitis Author information Van Der Gucht A1, Aoun Sebaiti M2,
Itti E1, Aouizerate J3, Evangelista E1, Chalaye J1, Gherardi RK3,
Ragunathan-Thangarajah N4, Bachoud-Levi AC5, Authier FJ3. 1. Department of
Nuclear Medicine, H. Mondor Hospital Assistance Publique-Hôpitaux de
Paris/Paris-Est University, Créteil, F-94010, France 2. Department of
Neurology, H. Mondor Hospital Assistance Publique-Hôpitaux de Paris/Paris-Est
University, Créteil, F-94010, France 3. Department of Pathology, H. Mondor
Hospital Assistance Publique-Hôpitaux de Paris/Paris-Est University Créteil,
F-94010, France; Reference Center for Neuromuscular Disorders H. Mondor
Hospital, Assistance Publique-Hôpitaux de Paris, Créteil, F-94010, France
INSERM U955-Team 10, Créteil, F-94010, France 4. Reference Center for
Neuromuscular Disorders, H. Mondor Hospital Assistance Publique-Hôpitaux de
Paris, Créteil, F-94010, France INSERM U955-Team 10, Créteil, F-94010, France
5. Department of Neurology, H. Mondor Hospital, Assistance Publique-Hôpitaux de
Paris/Paris-Est University Créteil, F-94010, France; INSERM U955-Team 1,
Créteil, F-94010, France

Abstract BACKGROUND Patients with aluminum hydroxide adjuvant-induced
macrophagic myofasciitis (MMF) complain of arthromyalgias, chronic fatigue and
cognitive deficits. This study aimed to characterize brain perfusion in these
patients.

METHODS Brain perfusion SPECT was performed in 76 consecutive patients (aged
49±10 y) followed in the Garches-Necker-Mondor-Hendaye reference center for
rare neuromuscular diseases. Images were acquired 30 min after intravenous
injection of 925 MBq 99mTc-ethylcysteinate dimer (ECD) at rest. All patients
also underwent a comprehensive battery of neuropsychological tests, within
1.3±5.5 mo from SPECT. Statistical parametric maps (SPM12) were obtained for
each test using linear regressions between each performance score and brain
perfusion, with adjustment for age, sex, socio-cultural level and time delay
between brain SPECT and neuropsychological testing. RESULTS SPM analysis
revealed positive correlation between neuropsychological scores (mostly
exploring executive functions) and brain perfusion in the posterior associative
cortex, including cuneus/precuneus/occipital lingual areas, the periventricular
white matter/corpus callosum, and the cerebellum, while negative correlation
was found with amygdalo-hippocampal/entorhinal complexes. A positive
correlation was also observed between brain perfusion and the posterior
associative cortex when the time elapsed since last vaccine injection was
investigated. CONCLUSIONS Brain perfusion SPECT showed a pattern of cortical
and subcortical changes in accordance with the MMF-associated cognitive
disorder previously described. These results provide a neurobiological
substrate for brain dysfunction in aluminum hydroxide adjuvant-induced MMF
patients. Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451975/

“The fluorescent nanodiamond technology is able to overcome the limitations of previously used
organic fluorophores, thus appearing as a choice methodology for studying
distribution, persistence and long-term neurotoxicity of alum adjuvants and
beyond ...” BMC Medicine • June 2015

Fluorescent nanodiamonds as a relevant tag for the assessment of alum adjuvant
particle biodisposition Author information Eidi H1,2, David MO3, Crépeaux G4,
Henry L5, Joshi V6, Berger MH7, Sennour M8, Cadusseau J9,10, Gherardi RK11,
Curmi PA12. 1. Institut National de la Santé et de la Recherche Médicale
(INSERM) - UMR 1204 Université Evry-Val d’Essonne, Laboratoire
Structure-Activité des Biomolécules Normales et Pathologiques, Evry, France 2.
Inserm - U955, Université Paris Est, Faculté de Médecine, Créteil, France -
housam.eidi@gmail.com 3. Institut National de la Santé et de la Recherche
Médicale (INSERM) - UMR 1204, Université Evry-Val d’Essonne Laboratoire
Structure-Activité des Biomolécules Normales et Pathologiques, Evry, France -
MO.David@iut.univ-evry.fr 4. Inserm - U955, Université Paris Est, Faculté de
Médecine, Créteil, France - guillemette.crepeaux@gmail.com 5. Institut National
de la Santé et de la Recherche Médicale (INSERM) - UMR 1204, Université
Evry-Val d’Essonne Laboratoire Structure-Activité des Biomolécules Normales et
Pathologiques, Evry, France. laetitia.henry@wanadoo.fr 6. Institut National de
la Santé et de la Recherche Médicale (INSERM) - UMR 1204, Université Evry-Val
d’Essonne Laboratoire Structure-Activité des Biomolécules Normales et
Pathologiques, Evry, France. vandana.joshi@univ-evry.fr 7. Laboratoire
Pierre-Marie Fourt, Centre des Matériaux de l’Ecole des Mines de Paris and CNRS
UMR 7633 Evry, France. marie-helene.berger@mines-paristech.fr 8. Laboratoire
Pierre-Marie Fourt, Centre des Matériaux de l’Ecole des Mines de Paris and CNRS
UMR 7633 Evry, France. mohamed.sennour@ensmp.fr 9. Inserm - U955, Université
Paris Est, Faculté de Médecine, Créteil, France. josette.cadusseau@inserm.fr
10. Faculté des Sciences et Technologie UPEC, Créteil, France.
josette.cadusseau@inserm.fr 11. Inserm - U955, Université Paris Est, Faculté de
Médecine, Créteil, France. romain.gherardi@hmn.aphp.fr 12. Institut National de
la Santé et de la Recherche Médicale (INSERM) - UMR 1204, Université Evry-Val
d’Essonne, Laboratoire Structure-Activité des Biomolécules Normales et
Pathologiques, Evry, France. pcurmi@univ-evry.fr

Abstract BACKGROUND Aluminum oxyhydroxide (alum) is a crystalline compound
widely used as an immunologic adjuvant of vaccines. Concerns linked to alum
particles have emerged following recognition of their causative role in the
so-called macrophagic myofasciitis (MMF) lesion in patients

with myalgic encephalomyelitis, revealing an unexpectedly long-lasting
biopersistence of alum within immune cells and a fundamental misconception of
its biodisposition. Evidence that aluminum-coated particles phagocytozed in the
injected muscle and its draining lymph nodes can disseminate within phagocytes
throughout the body and slowly accumulate in the brain further suggested that
alum safety should be evaluated in the long term. However, lack of specific
staining makes difficult the assessment of low quantities of bona fide alum
adjuvant particles in tissues. METHODS We explored the feasibility of using
fluorescent functionalized nanodiamonds (mfNDs) as a permanent label of alum
(Alhydrogel(®)). mfNDs have a specific and perfectly photostable fluorescence
based on the presence within the diamond lattice of nitrogen-vacancy centers
(NV centers). As the NV center does not bleach, it allows the
microspectrometric detection of mfNDs at very low levels and in the long-term.
We thus developed fluorescent nanodiamonds functionalized by hyperbranched
polyglycerol (mfNDs) allowing good coupling and stability of alum:mfNDs
(AluDia) complexes. Specificities of AluDia complexes were comparable to the
whole reference vaccine (anti-hepatitis B vaccine) in terms of particle size
and zeta potential. RESULTS In vivo, AluDia injection was followed by prompt
phagocytosis and AluDia particles remained easily detectable by the specific
signal of the fND particles in the injected muscle, draining lymph nodes,
spleen, liver and brain. In vitro, mfNDs had low toxicity on THP-1 cells and
AluDia showed cell toxicity similar to alum alone. Expectedly, AluDia elicited
autophagy, and allowed highly specific detection of small amounts of alum in
autophagosomes. CONCLUSIONS The fluorescent nanodiamond technology is able to
overcome the limitations of previously used organic fluorophores, thus
appearing as a choice methodology for studying distribution, persistence and
long-term neurotoxicity of alum adjuvants and beyond of other types of
nanoparticles. http://www.ncbi.nlm.nih.gov/pubmed/26082187

International Journal Of Epidemiology • June 2015

An enigma: why vitamin A supplementation does not always reduce mortality even
though vitamin A deficiency is associated with increased mortality Author
information Benn CS1, Aaby P2, Arts RJ3, Jensen KJ4, Netea MG3, Fisker AB2. 1.
Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project,
Statens Serum Institut Copenhagen, Denmark, OPEN, Institute of Clinical
Research, University of Southern Denmark Odense University Hospital, Odense,
Denmark 2. Research Center for Vitamins and Vaccines (CVIVA), Bandim Health
ProjectStatens Serum Institut Copenhagen, Denmark, Bandim Health Project,
INDEPTH Network, Bissau, Guinea-Bissau 3. Department of Internal Medicine,
Radboud University Medical Center, Nijmegen, The Netherlands 4. Research Center
for Vitamins and Vaccines (CVIVA), Bandim Health Project Statens Serum
Institut, Copenhagen, Denmark

“To prevent Vitamin A deficiency, WHO recommends high-dose vitamin A
supplementation every 4-6 months for children aged between 6 months and 5 years
of age

Abstract BACKGROUND Vitamin A deficiency (VAD) is associated with increased
mortality. To prevent VAD, WHO recommends high-dose vitamin A supplementation
(VAS) every 4-6 months for children aged between 6 months and 5 years of age in
countries at risk of VAD. The policy is based on randomized clinical trials
(RCTs) conducted in the late 1980s and early 1990s. Recent RCTs indicate that
the policy may have ceased to be beneficial. In addition, RCTs attempting to
extend the benefits to younger children have yielded conflicting results.
Stratified analyses suggest that whereas some subgroups benefit more than
expected from VAS, other subgroups may experience negative effects. METHODS AND
RESULTS We reviewed the potential modifiers of the effect of VAS. The variable
effect of VAS was not explained by underlying differences in VAD. Rather, the
effect may depend on the sex of the child, the vaccine status and previous
supplementation with vitamin A. Vitamin A is known to affect the Th1/Th2
balance and, in addition, recent evidence suggests that vitamin A may also
induce epigenetic changes leading to down-regulation of the innate immune
response. Thus VAS protects against VAD but has also important and long-lasting
immunological effects, and the effect of providing VAS may vary depending on
the state of the immune system. CONCLUSIONS To design optimal VAS programmes
which target those who benefit and avoid those harmed, more studies are needed.
Work is ongoing to define whether neonatal VAS should be considered in
subgroups. In the most recent RCT in older children, VAS doubled the mortality
for males but halved mortality for females. Hence, we urgently need to
re-assess the effect of VAS on older children in large-scale RCTs powered to
study effect modification by sex and other potential effect modifiers, and with
nested immunological studies. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521135/

in countries at risk of Vitamin A deficiency. The policy is based on randomized
clinical trials conducted in the late 1980s and early 1990s. Recent RCTs
indicate that the policy may have ceased to be beneficial.”

Clinical Rheumatology • July 2015

Hypothesis: Human papillomavirus vaccination syndromesmall fiber neuropathy and
dysautonomia could be its underlying pathogenesis Author information
Martínez-Lavín M. Rheumatology Department Instituto Nacional de Cardiología
Ignacio Chávez Juan Badiano 1, 14080, Mexico City, Mexico
drmartinezlavin@gmail.com Abstract Vaccination has been one of the most
effective public health measures in the history of medicine. However, seemingly
inexplicit adverse reactions have been described after the injection of the
newer vaccines vs. human papillomavirus (HPV). The symptoms more often reported
are chronic pain with paresthesias, headaches, fatigue, and orthostatic
intolerance. Adverse reactions appear to be more frequent after HPV vaccination
when compared to other type of immunizations. Different isolated cases and
small series have described the development of complex regional pain syndrome
(CRPS), postural orthostatic tachycardia syndrome (POTS), and fibromyalgia
after HPV vaccination. These are illnesses often difficult to diagnose that
have overlapping clinical features. Sympathetic nervous system dysfunction
seems to play a major role in the pathogenesis of these syndromes. Also, small
fiber neuropathy has been recently recognized in CRPS, POTS, and fibromyalgia.
This article forwards the hypothesis that small fiber neuropathy and
dysautonomia could be the common underlying pathogenesis to the group of rare,
but severe reactions that follow HPV vaccination. Clinicians should be aware of
the possible association between HPV vaccination and the development of these
difficult to diagnose painful dysautonomic syndromes.
http://www.ncbi.nlm.nih.gov/pubmed/25990003

“Different isolated cases and small series have described the development of
complex regional pain syndrome (CRPS), postural orthostatic tachycardia
syndrome (POTS), and fibromyalgia after HPV vaccination. These are illnesses
often difficult to diagnose that have overlapping clinical features.
Sympathetic nervous system dysfunction seems to play a major role in the
pathogenesis of these syndromes. Also, small fiber neuropathy has been recently
recognized in CRPS, POTS, and fibromyalgia.”

Archives Of Diseases In Childhood • July 2015

Potentially harmful excipients in neonatal medicines: a pan-European
observational study Nellis G1, Metsvaht T2, Varendi H3, Toompere K4, Lass J5,
Mesek I6, Nunn AJ7, Turner MA8, Lutsar I6; ESNEE consortium with Collaborators
(31) Author information 1. Institute of Microbiology, Tartu University, Tartu,
Tartumaa, Estonia Neonatal Unit, Tartu University Hospital, Childrens Clinic,
Tartu, Tartumaa, Estonia 2. Institute of Microbiology, Tartu University, Tartu,
Tartumaa, Estonia Paediatric Intensive Care Unit, Tartu University Hospital,
Clinic of Anaesthesiology and Intensive Care, Tartu, Tartumaa, Estonia 3.
Neonatal Unit, Tartu University Hospital, Childre∼s Clinic, Tartu, Tartumaa,
Estonia 4. Department of Public Health, Tartu University, Tartu, Tartumaa,
Estonia 5. Institute of Microbiology, Tartu University, Tartu, Tartumaa,
Estonia Pharmacy Department, Tartu University Hospital, Estonia 6. Institute of
Microbiology, Tartu University, Tartu, Tartumaa, Estonia 7. Alder Hey
Children’s NHS Foundation Trust, Liverpool, UK 8. Neonatal Unit, Liverpool
Women’s Hospital, Liverpool, UK Institute of Translational Medicine, University
of Liverpool, UK

Abstract OBJECTIVES We aimed to describe administration of eight potentially
harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene
glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium
chloride-to hospitalised neonates in Europe and to identify risk factors for
exposure. METHODS All medicines administered to neonates during 1 day with
individual prescription and demographic data were registered in a web-based
point prevalence study. Excipients were identified from the Summaries of
Product Characteristics. Determinants of EOI administration (geographical
region, gestational age (GA), active pharmaceutical ingredient, unit level and
hospital teaching status) were identified using multivariable logistical
regression analysis. RESULTS Overall 89 neonatal units from 21 countries
participated. Altogether 2095 prescriptions for 530 products administered to
726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were
administered to 456 (63%) neonates through a relatively small number of
products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313
(43%) neonates, were used most frequently. EOI administration varied by
geographical region, GA and route of administration. Geographical region
remained a significant determinant of the use of parabens, polysorbate 80,
propylene glycol and saccharin sodium after adjustment for the potential
covariates including anatomical therapeutic chemical class of the active
ingredient. CONCLUSIONS European neonates receive a number of potentially
harmful pharmaceutical excipients. Regional differences in EOI administration
suggest that EOI-free products are available and provide the potential for
substitution to avoid side effects of some excipients.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25854872

“We aimed to describe administration of eight potentially harmful excipients of
interest— (EOI)parabens, polysorbate 80, propylene glycol, benzoates, saccharin
sodium, sorbitol, ethanol and benzalkonium chloride—to hospitalised neonates in
Europe and to identify risk factors for exposure.”

Expert Review Of Vaccines • July 2015

Are we entering a new age for human vaccine adjuvants? Author information
O’Hagan DT1, Fox CB. Novartis Vaccines, Cambridge, MA, USA Abstract Major
advances in adjuvant development for human vaccines have been reported recently
for a range of indications, including malaria, influenza and varicella zoster
virus. Furthermore, there is an increased understanding of adjuvant mechanisms
of action and a greater emphasis on the importance of formulation and
characterization. This progress may signify a new golden age of vaccine
adjuvant discovery and development. http://www.ncbi.nlm.nih.gov/pubmed/25947042

Brain & Cognition • August 2015

Word-finding impairment in veterans of the 1991 Persian Gulf War Author
information Moffett K1, Crosson B2, Spence JS3, Case K4, Levy I5, Gopinath K6,
Shah P7, Goyal A8, Fang Y9, Briggs RW10, Hart J Jr11, Moore A12, Haley RW13. 1.
Department of Clinical and Health Psychology, University of Florida, 1225
Center Drive, Room 3151, Gainesville, FL 32611, USA. Electronic address:
kmoffett@phhp.ufl.edu. 2. Department of Veterans Affairs Rehabilitation
Research and Development, Brain Rehabilitation Research Center of Excellence,
Malcolm Randall VA Medical Center, 1601 S.W. Archer Road, Gainesville, FL
32608-1197, USA; Department of Veterans Affairs Rehabilitation Research and
Development, Center of Excellence for Visual and Neurocognitive Rehabilitation,
1670 Clairmont Rd., Decatur, GA 30033, USA; Departments of Neurology and
Radiology, Emory University, 101 Woodruff Circle, Suite 6000, Atlanta, GA
30322, USA; Department of Psychology, Georgia State University, PO Box 5010,
Atlanta, GA 303025010, USA. Electronic address: bruce.crosson@emory.edu. 3.
Departments of Internal Medicine (Epidemiology Division) and Radiology,
University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.,
Dallas, TX 75390-8874, USA. Electronic address: jss130230@utdallas.edu. 4.
Department of Clinical and Health Psychology, University of Florida, 1225
Center Drive, Room 3151, Gainesville, FL 32611, USA. Electronic address:
kim.case@ufl.edu. 5. Department of Clinical and Health Psychology, University
of Florida, 1225 Center Drive, Room 3151, Gainesville, FL 32611, USA.
Electronic address: ilana.f.levy@gmail.com. 6. Departments of Internal Medicine
(Epidemiology Division) and Radiology, University of Texas Southwestern Medical
Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA. Electronic address:
Kaundinya.s.gopinath@emory.edu. 7. Departments of Internal Medicine
(Epidemiology Division) and Radiology, University of Texas Southwestern Medical
Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA. Electronic address:
parina. shah30@yahoo.com. 8. Departments of Internal Medicine (Epidemiology
Division) and Radiology, University of Texas Southwestern Medical Center, 5323
Harry Hines Blvd., Dallas, TX 75390-8874, USA. Electronic address:
goyala@yorku.ca. 9. Departments of Internal Medicine (Epidemiology Division)
and Radiology, University of Texas Southwestern Medical Center, 5323 Harry
Hines Blvd., Dallas, TX 75390-8874, USA. Electronic address:
fangyan331@gmail.com. 10. Departments of Internal Medicine (Epidemiology
Division) and Radiology, University of Texas Southwestern Medical Center, 5323
Harry Hines Blvd., Dallas, TX 75390-8874, USA; Department of Physics &
Astronomy, Georgia State University, Atlanta, GA 30302-5060, USA. Electronic
address: rbriggs1@gsu.edu.

11. Departments of Internal Medicine (Epidemiology Division) and Radiology,
University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.,
Dallas, TX 75390-8874, USA. Electronic address: jhart@utdallas.edu. 12. Center
for Rehabilitation Medicine, Emory University, 101 Woodruff Circle, Suite 6000,
Atlanta, GA 30322, USA. Electronic address: annabmoore@gmail.com. 13.
Departments of Internal Medicine (Epidemiology Division) and Radiology,
University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.,
Dallas, TX 75390-8874, USA. Electronic address: Robert.
Haley@UTSouthwestern.edu.

Abstract Approximately one quarter of 1991 Persian Gulf War Veterans experience
cognitive and physiological sequelae that continue to be unexplained by known
medical or psychological conditions. Difficulty coming up with words and names,
familiar before the war, is a hallmark of the illness. Three Gulf War Syndrome
subtypes have been identified and linked to specific war-time chemical
exposures. The most functionally impaired veterans belong to the Gulf War
Syndrome 2 (Syndrome 2) group, for which subcortical damage due to toxic nerve
gas exposure is the suspected cause. Subcortical damage is often associated
with specific complex language impairments, and Syndrome 2 veterans have
demonstrated poorer vocabulary relative to controls. 11 Syndrome 1, 16 Syndrome
2, 9 Syndrome 3, and 14 age-matched veteran controls from the Seabees Naval
Construction Battalion were compared across three measures of complex language.
Additionally, functional magnetic resonance imaging (fMRI) was collected during
a covert category generation task, and whole-brain functional activity was
compared between groups. Results demonstrated that Syndrome 2 veterans
performed significantly worse on letter and category fluency relative to
Syndrome 1 veterans and controls. They also exhibited reduced activity in the
thalamus, putamen, and amygdala, and increased activity in the right
hippocampus relative to controls. Syndrome 1 and Syndrome 3 groups tended to
show similar, although smaller, differences than the Syndrome 2 group. Hence,
these results further demonstrate specific impairments in complex language as
well as subcortical and hippocampal involvement in Syndrome 2 veterans. Further
research is required to determine the extent of language impairments in this
population and the significance of altered neurologic activity in the
aforementioned brain regions with the purpose of better characterizing the Gulf
War Syndromes. http://www.ncbi.nlm.nih.gov/pubmed/26114921

“Results demonstrated that Syndrome 2 veterans performed significantly worse on
letter and category fluency relative to Syndrome 1 veterans and controls. They
also exhibited reduced activity in the thalamus, putamen, and amygdala, and
increased activity in the right hippocampus relative to controls. Hence, these
results further demonstrate specific impairments in complex language as well as
subcortical and hippocampal involvement in Syndrome 2 veterans.”

Brain Connectivity • August 2015

Shared Brain Connectivity Issues, Symptoms, and Comorbidities in Autism
Spectrum Disorder, Attention Deficit/Hyperactivity Disorder, and Tourette
Syndrome Author information Kern JK1, Geier DA1, King PG2, Sykes LK2, Mehta
JA3, Geier MR1. 1. Institute of Chronic Illnesses, Inc., Silver Spring,
Maryland 2. CoMeD, Inc. , Silver Spring, Maryland 3. Communication Sciences &
Disorders Texas Woman’s University, Denton, Texas Abstract The prevalence of
neurodevelopmental disorders, including autism spectrum disorder (ASD),
attention deficit/ hyperactivity disorder (ADHD), and Tourette syndrome (TS),
has increased over the past two decades. Currently, about one in six children
in the United States is diagnosed as having a neurodevelopmental disorder.
Evidence suggests that ASD, ADHD, and TS have similar neuropathology, which
includes long-range underconnectivity and short-range overconnectivity. They
also share similar symptomatology with considerable overlap in their core and
associated symptoms and a frequent overlap in their comorbid conditions.
Consequently, it is apparent that ASD, ADHD, and TS diagnoses belong to a
broader spectrum of neurodevelopmental illness. Biologically, long-range
underconnectivity and short-range overconnectivity are plausibly related to
neuronal insult (e.g., neurotoxicity, neuroinflammation, excitotoxicity,
sustained microglial activation, proinflammatory cytokines, toxic exposure, and
oxidative stress). Therefore, these disorders may a share a similar etiology.
The main purpose of this review is to critically examine the evidence that ASD,
ADHD, and TS belong to a broader spectrum of neurodevelopmental illness, an
abnormal connectivity spectrum disorder, which results from neural long-range
underconnectivity and short-range overconnectivity. The review also discusses
the possible reasons for these neuropathological connectivity findings. In
addition, this review examines the role and issue of axonal injury and
regeneration in order to better understand the neuropathophysiological
interplay between short- and long-range axons in connectivity issues.
http://www.ncbi.nlm.nih.gov/pubmed/25602622

“The prevalence of neurodevelopmental disorders, including autism spectrum
disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and Tourette
syndrome (TS), has increased over the past two decades. Currently, about one in
six children in the United States is diagnosed as having a neurodevelopmental
disorder.”

[this defines a pandemic of neurological disorders]

Clinical And Experimental Rheumatology • August 2015

Autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA) after
quadrivalent human papillomavirus vaccination in Colombians: a call for
personalised medicine Author information Anaya JM1, Reyes B1,
Perdomo-Arciniegas AM2, Camacho-Rodríguez B2, Rojas-Villarraga A1. 1. Centre
for Autoimmune Diseases Research (CREA) Universidad del Rosario; and Mederi
Hospital Universitario Mayor Bogota, Colombia 2. Banco de Sangre, Tejidos y
Células Hemocentro Distrital, Secretaría de Salud de Bogota Bogota, Colombia
Abstract This was a case study in which 3 patients with
autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA) after
quadrivalent human papillomavirus vaccination (HPV) were evaluated and
described. All the patients were women. Diagnosis consisted of HLA-B27
enthesitis related arthritis, rheumatoid arthritis and systemic lupus
erythematous, respectively. Our results highlight the risk of developing ASIA
after HPV vaccination and may serve to increase the awareness of such a
complication. Factors that are predictive of developing autoimmune diseases
should be examined at the population level in order to establish preventive
measures in at-risk individuals for whom healthcare should be personalized and
participatory. http://www.ncbi.nlm.nih.gov/pubmed/25962455

“This was a case study in which 3 patients with autoimmune/auto-inflammatory
syndrome induced by adjuvants (ASIA) after quadrivalent human papillomavirus
vaccination (HPV) were evaluated and described. All the patients were women.”

Vaccine • September 2015

Spontaneous reports of vasculitis as an adverse event following immunization: A
descriptive analysis across three international databases

CONCLUSION Similar reporting patterns of vasculitides were observed in
different databases. Implementation of standardized case definitions for
specific vasculitides could improve overall data quality and comparability of
reports. http://www.ncbi.nlm.nih.gov/pubmed/26392009

Felicetti P1, Trotta F2, Bonetto C2, Santuccio C2, Brauchli Pernus Y3, Burgner
D4, Chandler R5, Girolomoni G6, Hadden RD7, Kochar S8, Kucuku M9, Monaco G10,
Ozen S11, Pahud B12, Phuong L13, Bachtiar NS14, Teeba A15, Top K16, Varricchio
F17, Wise RP18, Zanoni G19, ∼ivkovic S20, Bonhoeffer J21; Brighton
Collaboration Vasculitis Working Group

Author information 1. Italian Medicines Agency, Rome, Italy. Electronic
address: contact@brightoncollaboration.org 2. Italian Medicines Agency, Rome,
Italy 3. Brighton Collaboration Foundation, Basel, Switzerland 4. Monash
Children’s Hospital-Clayton, Melbourne, Australia; Murdoch Children’s Research
Institute (MCRI) Department of Paediatrics, Melbourne University, Australia 5.
Uppsala Monitoring Centre, Uppsala, Sweden 6. University of Verona, Department
of Medicine, Section of Dermatology and Venereology, Verona, Italy 7. King’s
College Hospital, London, UK 8. USAID, Deliver Project, JSIPL, New Delhi, India
9. Department of Vaccines Control, National Agency for Medicine & Medical
Devices, Tirana, Albania 10. Centre for Pharmacovigilance, The Lombardy Region,
Milan, Italy 11. Hacettepe University, Department of Pediatric Rheumatology,
Ankara, Turkey 12. Children’s Mercy Hospital, Kansas City, MO, USA 13. Monash
Children’s and Royal Children’s Hospitals, Melbourne, Australia 14. Bio Farma
Vaccine Institute, Bandung, West Java, Indonesia 15. Centre National Anti
Poison et de Pharmacovigilance, Rabat, Morocco 16. Department of Pediatrics,
Dalhousie University, Halifax, NS, Canada 17. Independent Consultant
Vaccinologist, Wakefield, RI, USA 18. MedImmune/AstraZeneca, Gaithersburg, MD,
USA 19. Immunology Unit, Azienda Ospedaliera Universitaria Integrata Verona,
Verona, Italy 20. University of Pittsburgh Medical Center and Neurology
service, MSL, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA 21.
University of Basel Children’s Hospital, Basel, Switzerland; Brighton
Collaboration Foundation, Basel, Switzerland

Abstract

“We retrieved 1797 reports of vasculitis in EV, 1171 in VAERS, and 2606 in
VigiBase®. Vasculitis was predominantly reported in children aged 1-17 years,
and less frequently in the elderly (>65 years). The generic term “vasculitis”
was the most frequently reported AEFI in this category across the three
databases (range 21.9% to 27.5% of all reported vasculitis for vaccines). For
the more specific terms, Henoch-Schoenlein Purpura (HSP) was most frequently
reported, (19.1% on average), followed by Kawasaki disease (KD) (16.1% on
average) and polymyalgia rheumatica (PMR) (9.2% on average). Less frequently
reported subtypes were cutaneous vasculitis (CuV), vasculitis of the central
nervous system (CNS-V), and Behcet’s

BACKGROUND Vasculitides have been reported as adverse events following
immunization (AEFI) following various vaccines. We describe reports of
vasculitis to three international spontaneous reporting systems.

syndrome (BS). HSP, PMR and CuV were more frequently

RESULTS We retrieved 1797 reports of vasculitis in EV, 1171 in VAERS, and 2606
in VigiBase®. Vasculitis was predominantly reported in children aged 1-17
years, and less frequently in the elderly (>65 years). The generic term
“vasculitis” was the most frequently reported AEFI in this category across the
three databases (range 21.9% to 27.5% of all reported vasculitis for vaccines).
For the more specific terms, Henoch-Schoenlein Purpura (HSP) was most
frequently reported, (19.1% on average), followed by Kawasaki disease (KD)
(16.1% on average) and polymyalgia rheumatica (PMR) (9.2% on average). Less
frequently reported subtypes were cutaneous vasculitis (CuV), vasculitis of the
central nervous system (CNSV), and Behcet’s syndrome (BS). HSP, PMR and CuV
were more frequently reported with influenza vaccines: on average in 29.3% for
HSP reports, 61.5% for PMR reports and in 39.2% for CuV reports. KD was
reported with pneumococcal vaccines in 32.0% of KD reports and with rotavirus
vaccines in more than 20% of KD reports. BS was most frequently reported after
hepatitis and HPV vaccines and CNS-V after HPV vaccines.

reports, 61.5% for PMR reports and in 39.2% for CuV reports.

reported with influenza vaccines: on average in 29.3% for HSP KD was reported
with pneumococcal vaccines in 32.0% of KD reports and with rotavirus vaccines
in more than 20% of KD reports. BS was most frequently reported after hepatitis
and HPV vaccines and CNS-V after HPV vaccines.”

Epidemiologie Mikrobiologie Imunology • September 2015

Antigenic variability of Bordetella pertussis strains isolated in 1967-2010 in
the Czech Republic— possible explanation for the rise in cases of pertussis? by
Zavadilová J, Lzicarová D, Musílek M, Krízová P, Fabiánová K. Abstract
OBJECTIVE Comparison of antigenic structures of Bordetella pertussis (B.
pertussis) strains isolated from 1967 to 2010 in the Czech Republic. MATERIAL
AND METHODS Seventy strains of B. pertussis were referred to the National
Reference Laboratory (NRL) for Pertussis and Diphtheria within the surveillance
of pertussis from all over the Czech Republic (CR) between 1967 and 2010. To
study the strains, the analysis was performed of the genome sequences encoding
the surface immunogenic structures--the pertussis toxin S1 subunit gene (ptxA),
pertactin gene region 1 (prnA), type 3 fimbriae gene (fim3)-and pertussis toxin
promoter (ptxP) responsible for the regulation of the production of pertussis
toxin. RESULTS For the study set of B. pertussis strains, the sequencing
analysis revealed changes in all genomic regions studied. The isolates from
three periods differ in the allelic profile. In period I (19671978) with the
use of whole cell pertussis vaccine (wP), the following two profiles were the
most common: ptxP(1), ptxA(2), prnA(1), fim3(1) and ptxP(1), ptxA(1), prnA(3),
fim3(1). In period 2 (19902007) with the switch to acellular pertussis vaccine
(aP), the most common profile was: ptxP(3), ptxA(1), prnA(2), fim3(2). Period 3
(20082010) with the use of aP was characterized by the predominance of the
following two profiles which had never been found in period 1: ptxP(3),
ptxA(1), prnA(2), fim3(2) and ptxP(3) ptxA(1), prnA(2), fim3(1). CONCLUSIONS
Sequencing of the genomic regions ptxP, ptxA, prnA, and fim3 of B. pertussis
strains isolated in the CR between 1967 and 2010 confirmed changes in the
allelic variants of these regions. The incidence of strains carrying the new
allelic variants was increasing after 1995 at the expense of those carrying the
original variants. The study results can be interpreted as a partial genetic
escape of pathogenic strains of B. pertussis beyond the reach of the pertussis
vaccines. http://www.ncbi.nlm.nih.gov/pubmed/26448300

“The study results can be interpreted as a partial genetic escape of pathogenic
strains of B. pertussis beyond the reach of the pertussis vaccines.”

“Since then [1964], the literature has been flooded with case reports and case series
of granulomatous and systemic autoimmune disorders related to vaccines ...”
Lupus • September 2015

Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by
adjuvants. Where have we come from? Where are we going? A proposal for new
diagnostic criteria Author information Alijotas J.-Reig J. Systemic Autoimmune
Disease Unit, Department of Internal Medicine I Vall d’Hebron
UniversityHospital, Barcelona, Spain Faculty of Medicine,Universitat Autonoma,
Barcelona, Spain 16297jar@comb.es jalijotas@vhebron.net Abstract In 1964,
Miyoshi reported a series of patients with diverse symptoms after receiving
treatment with silicone or paraffin fillers. Miyoshi named this condition
‘human adjuvant disease’. Since then, the literature has been flooded with case
reports and case series of granulomatous and systemic autoimmune disorders
related to vaccines, infection or other adjuvants such as silicone and other
biomaterials. A new term -autoimmune/inflammatory syndrome induced by
adjuvants--has recently been coined for a process that includes several
clinical features previously described by Miyoshi plus other clinical and
laboratory parameters related to exposure to diverse external stimuli.
Disorders such as siliconosis, Gulf War syndrome, macrophagic myofasciitis
syndrome, sick building syndrome and post-vaccination syndrome have been
included in autoimmune/inflammatory syndrome induced by adjuvants. Disorders
such as Spanish toxic oil syndrome and Ardystil syndrome could also be
included. Furthermore, biomaterials other than silicone should also be
considered as triggering factors for these adjuvant-related syndromes. New
diagnostic criteria in this field have been proposed. Nevertheless, many of
these criteria are too subjective, leading to some patients being diagnosed
with chronic fatigue syndrome or other ‘central sensitization syndromes’.
Diagnostic criteria based only on objective clinical and laboratory data to be
further discussed and validated are proposed herein.
http://www.ncbi.nlm.nih.gov/pubmed/25813870

Journal Of Vaccines & Vaccination • September 2015

Vaccines and Drug-induced Lung Injury Yamamoto Y* Respiratory Center Asahikawa
Medical University Asahikawa, Hokkaido, Japan Abstract The corresponding author
has no conflict of interest to declare. The author is invited to submit this
manuscript in the Short Communication section. Drug-induced lung injuries
(DLIs) are adverse drug reactions that specifically occur in the pulmonary
system. The main causative agents include cytotoxic drugs, antibiotics,
interferon, and anti-rheumatic drugs. More recently, biological reaction
modifiers and molecular targeted drugs have emerged as causes of DLIs.
Interstitial lung diseases are the most common form of DLIs [1]. Vaccines have
rarely been associated with DLIs. One possible reason is that the causal
relationship is difficult to prove. This problem is true for vaccines against
human papilloma virus (HPV). The author has recently reported a case of
interstitial pneumonia that occurred after the vaccination with HPV16/18
adjuvant system 04 (AS04) vaccines (Cervarix) [2]. Detailed information of this
case is available on the respiratory medicine case reports website
(http://www.dx.doi.org/ 10.1016/j.rmcr.2015.06.003). A middle-aged woman, who
had no pre-existing pulmonary diseases, completed three doses of Cervarix.
Non-specific interstitial pneumonia developed three months after the last
vaccination. A lung biopsy specimen showed lymphocytic alveolitis, providing
evidence that cell-mediated immunity likely contributed to the occurrence. The
patient had increased levels of serum biomarkers specific to interstitial
pneumonias such as Krebs von der Lungen (KL)-6 and surfactant protein (SP)-D.
Other causes except

the vaccination were eliminated. Of note was that the interstitial pneumonia
spontaneously resolved with complete remission of chest radiographic findings
and serum biomarkers. The self-limiting course suggested that the interstitial
pneumonia occurred with a temporal association with the vaccination. A
re-challenge test to Cervarix was not conducted for safety reasons. The
interstitial pneumonia was finally diagnosed as a DLI according to the clinical
course, chest images, pathological findings, and specific use of Cervarix.
Assuming that all drugs are capable of causing a lung injury is the first step
for diagnosing DLIs [1]. Vaccines are not exceptions in that DLIs can develop
even after the treatment has been completed [1]. Most cases of
vaccine-associated DLIs have been diagnosed by clinical judgments [3-5]. Gold
standard tests have not been established for the diagnosis of DLIs; however the
likelihood of an adverse reaction can be semi-quantified using the Naranjo
algoris. Such algorisms can reduce inter- and intra-individual variations with
regard to the assessment [6]. Chest imaging findings are non-specific but
useful for early diagnosis.[1] Measurements of KL-6 and SP-D may play a
supplementary role in the diagnosis of DLIs [1,7]. An exvivo drug stimulation
test using peripheral lymphocytes has a quite limited diagnostic value [7].
Further studies are required to develop diagnostic procedures, which are more
sensitive and specific to a drug adverse reaction. Influenza vaccines can cause
several types of DLIs, including acute respiratory distress syndrome [3-5].
Watanabe et al. reviewed 7 cases (4 males and 3 females) of DLIs secondary to
the influenza vaccination [5]. The median age of onset was relatively high (59
years). Previous pulmonary diseases

were present in four cases. All patients had acute symptoms. The time to onset
was 1 to 10 days. They all had severe clinical manifestations, but recovered
after receiving corticosteroid therapy. Of note, 6 of the 7 cases were Asians
[5]. Genetic and environmental factors may affect difference in the
susceptibility to DLIs [7]. Unlike influenza vaccines, Cervarix caused a mild
and subclinical form of DLI. How did Cervarix affect the pulmonary system? In
the disease process of DLIs, drugs can act as a hapten, interact with immune
receptors, and trigger danger signals [7]. These actions probably underlie the
onset of immune-mediated DLIs [1,7]. These processes were probably attributed
to the Cervarix-associated DLI. As a reason, the pathologically proven
lymphocytic alveolitis was suggestive of cell-mediated immune responses [2]. Of
the constituents of Cervarix, the AS04 adjuvant appeared to be most responsible
owing to its strong immunogenicity [8]. Large-scale analyses have not shown
that AS04-adjuvanted vaccines increase risks for developing autoimmune
disorders [9,10]. This trend still remains significant when the subjects are
stratified by age [10]. However, the immune-mediated diseases assessed are
confined to gastrointestinal, metabolic, musculoskeletal, neuroinflammatory,
and skin disorders [10]. Any lung disorders including interstitial pneumonia
are not listed. Further studies are needed to clarify the prevalence, outcomes,
and risk factors for the Cervarix-associated DLI.

Full Report With References
http://www.omicsonline.org/open-access/vaccines-and-druginduced-lung-injury-2157-7560-1000291.pdf

Journal Of Biological Chemistry • October 2015

Formaldehyde Crosslinking: A Tool for the Study of Chromatin Complexes Author
information Hoffman EA1, Frey BL2, Smith LM2, Auble DT3. 1. The Department of
Biochemistry and Molecular Genetics University of Virginia Health System,
Charlottesville, Virginia 22908 and 2. The Department of Chemistry and Genome
Center of Wisconsin University of Wisconsin, Madison, Wisconsin 53706 and 3.
The Department of Biochemistry and Molecular Genetics University of Virginia
Health System, Charlottesville, Virginia 22908 auble@virginia.edu Abstract
Formaldehyde has been used for decades to probe macromolecular structure and
function and to trap complexes, cells, and tissues for further analysis.
Formaldehyde crosslinking is routinely employed for detection and
quantification of protein-DNA interactions, interactions between chromatin
proteins, and interactions between distal segments of the chromatin fiber.
Despite widespread use and a rich biochemical literature, important aspects of
formaldehyde behavior in cells have not been well described. Here, we highlight
features of formaldehyde chemistry relevant to its use in analyses of chromatin
complexes, focusing on how its properties may influence studies of chromatin
structure and function. http://www.ncbi.nlm.nih.gov/pubmed/?term=26354429

“ Formaldehyde [a vaccine ingredient] has been used for decades to probe
macromolecular structure and function and to trap complexes, cells, and tissues
for further analysis. Despite widespread use and a rich biochemical literature,
important aspects of formaldehyde behavior in cells have not been well
described.”

International Journal Of General Medicine • October 2015

A case of polymyalgia rheumatica following influenza B infection Kentaro Iwata1
and Yasushi Mizuno2 1Division of Infectious Diseases Kobe University Hospital,
Kobe, Japan 2Department of General Medicine Kobe City Medical Center General
Hospital Kobe, Japan Abstract Polymyalgia rheumatica (PMR) is relatively common
among the elderly, and is characterized by multiple body aches with an elevated
erythrocyte sedimentation rate. Even though the etiology of PMR remains
unknown, a number of infectious agents have been suggested to cause PMR. Also,
there are reports of PMR after influenza vaccination. The exact role of
influenza vaccination on the development of PMR remains unknown, but may be
associated with specific human leukocyte antigens (HLAs), such as HLA-DRB1 and
HLA-DQB1. Whether postvaccination PMR is caused by influenza virus antigen or
adjuvants in the vaccine is another unanswered question. We herein report a
case of an 85-year-old woman who developed PMR shortly after contracting
influenza virus B. Even though infections are hypothesized to be one of the
causes of PMR, this is the first-ever case of PMR following influenza virus
infection. Further studies may elucidate the exact role of influenza virus
infection on the etiology and pathogenesis of PMR.
http://www.ncbi.nlm.nih.gov/pubmed/26527896

“this is the first-ever case of Polymyalgia rheumatica following influenza
virus infection. Further studies may elucidate the exact role of influenza
virus infection on the etiology and pathogenesis of Polymyalgia rheumatica.”

Frontiers In Pediatrics • October 2015

A Prospective Longitudinal Assessment of Medical Records for Diagnostic
Substitution among Subjects Diagnosed with a Pervasive Developmental Disorder
in the United States Author information Geier DA1, Kern JK1, Hooker BS2, Sykes
LK3, Geier MR1. 1. The Institute of Chronic Illnesses, Inc , Silver Spring, MD
, USA. 2. Simpson University , Redding, CA , USA. 3. CoMeD, Inc , Silver
Spring, MD , USA. Abstract BACKGROUND Previously, investigators suggested that
diagnostic substitution from other diagnoses, e.g., mental retardation (MR)
and/or cerebral palsy (CP) to pervasive developmental disorder (PDD) is a
driving factor behind increases in autism. This study evaluated potential
diagnostic substitution among subjects diagnosed with PDD vs. MR or CP by
examining birth characteristic overlap. METHODS SAS(®) and StatsDirect software
examined medical records for subjects within the Vaccine Safety Datalink
database who were Health Maintenance Organization-enrolled from birth until
diagnosed with an International Classification of Disease, 9th revision (ICD-9)
outcome of PDD (299.xx, n = 84), CP (343.xx, n = 300), or MR (317.xx, 318.xx,
or 319.xx, n = 51). RESULTS Subjects with PDD had significantly (p < 0.01)
increased: male/female ratio (PDD = 5.5 vs. CP = 1.5 or MR = 1.3), mean age of
initial diagnosis in years (PDD = 3.13 vs. CP = 1.09 or MR = 1.62), mean
gestational age in weeks at birth (PDD = 38.73 vs. CP = 36.20 or MR = 34.84),
mean birth weight in grams (PDD = 3,368 vs. CP = 2,767 or MR = 2,406), and mean
Appearance-Pulse-Grimace-Activity-Respiration scores at 1 min (PDD = 7.82 vs.
CP = 6.37 or MR = 6.76) and 5 min (PDD = 8.77 vs. CP = 7.92 or MR = 8.04), as
compared to subjects diagnosed with CP or MR. CONCLUSION This study suggests
diagnostic substitution cannot fully explain increased PDD prevalence during
the 1990s within the United States. http://www.ncbi.nlm.nih.gov/pubmed/26528457

“This study suggests diagnostic substitution cannot fully explain increased
pervasive developmental disorder (PDD) prevalence during the 1990s within the
United States.”

Autoimmunity Review • October 2015

On vaccine’s adjuvants and autoimmunity: Current evidence and future
perspectives Author information Pellegrino P1, Clementi E2, Radice S1. 1. Unit
of Clinical Pharmacology Department of Biomedical and Clinical Sciences
University Hospital “Luigi Sacco”, Università di Milano 20157 Milan, Italy 2.
Scientific Institute IRCCS E. Medea 23842 Bosisio Parini, Lecco, Italy Unit of
Clinical Pharmacology Department of Biomedical and Clinical Sciences Consiglio
Nazionale delle Ricerche Institute of Neuroscience University Hospital “Luigi
Sacco”, Università di Milano 20157 Milan, Italy emilio.clementi@unimi.it
Abstract Adjuvants are compounds incorporated into vaccines to enhance
immunogenicity and the development of these molecules has become an expanding
field of research in the last decades. Adding an adjuvant to a vaccine antigen
leads to several advantages, including dose sparing and the induction of a more
rapid, broader and strong immune response. Several of these molecules have been
approved, including aluminium salts, oil-in-water emulsions (MF59, AS03 and
AF03), virosomes and AS04. Adjuvants have recently been implicated in the new
syndrome named “ASIA-Autoimmune/inflammatory Syndrome Induced by Adjuvants”,
which describes an umbrella of clinical conditions including post-vaccination
adverse reactions. Recent studies implicate a web of mechanisms in the
development of vaccine adjuvant-induced autoimmune diseases, in particular, in
those associated with aluminium-based compounds. Fewer and unsystematised data
are instead available about other adjuvants, despite recent evidence indicating
that vaccines with different adjuvants may also cause specific autoimmune
adverse reactions possible towards different pathogenic mechanisms. This topic
is of importance as the specific mechanism of action of each single adjuvant
may have different effects on the course of different diseases. Herein, we
review the current evidence about the mechanism of action of currently employed
adjuvants and discuss the mechanisms by which such components may trigger
autoimmunity. http://www.ncbi.nlm.nih.gov/pubmed/26031899

“Adding an adjuvant to a vaccine antigen leads to several advantages, including
dose sparing and the induction of a more rapid, broader and strong immune
response. Adjuvants have recently been implicated in the new syndrome named
“ASIA-Autoimmune/inflammatory Syndrome Induced by Adjuvants”, which describes
an umbrella of clinical conditions including post-vaccination adverse
reactions. Recent studies implicate a web of mechanisms in the development of
vaccine adjuvant-induced autoimmune diseases, in particular, in those
associated with aluminium-based compounds.”

Future Microbiology • October 2015

Investigating pertussis toxin and its impact on vaccination Author information
Coutte L1, Locht C. Center for Infection & Immunity of Lille Institut Pasteur
de Lille 1 rue du Prof. Calmette, F-59019 Lille Cedex, France Abstract Whooping
cough, caused by Bordetella pertussis, remains a major global health problem.
Each year around 40 million of pertussis cases resulting in 200,000400,000
annual deaths occur worldwide. Pertussis toxin is a major virulence factor of
B. pertussis. Murine studies have shown its importance in bacterial
colonization and in immunomodulation to evade innate or adaptive immunity. The
toxin is composed of an A protomer expressing ADP-ribosyltransferase activity
and a B oligomer, responsible for toxin binding to target cells. The toxin is
also a major protective antigen in all currently available vaccines. However,
vaccine escape mutants with altered toxin expression have recently been
isolated in countries with high vaccination coverage illustrating the need for
improved pertussis vaccines. http://www.ncbi.nlm.nih.gov/pubmed/25689536

“[pertussis toxin] is also a major protective antigen in all currently
available vaccines. However, vaccine escape mutants with altered toxin
expression have recently been isolated in countries with high vaccination
coverage illustrating the need for improved pertussis vaccines.”

Journal Of Biological Chemistry • October 2015

Pertussis Toxin Exploits Specific Host Cell Signaling Pathways for Promoting
Invasion and Translocation of Escherichia coli K1 RS218 in Human Brain-derived
Microvascular Endothelial Cells Author information Karassek S1, Starost L1,
Solbach J1, Greune L1, Sano Y2, Kanda T2, Kim K3, Schmidt MA4. 1. From the
Institute of Infectiology, Center for Molecular Biology of Inflammation,
Westfälische Wilhelms-Universität Münster 2. the Department of Neurology and
Clinical Neuroscience, Yamaguchi University Graduate School of Medicine,
Yamaguchi, Japan 3. the Pediatric Infectious Diseases Division, The Johns
Hopkins University School of Medicine, Baltimore, Maryland 21287 4. From the
Institute of Infectiology, Center for Molecular Biology of Inflammation,
Westfälische Wilhelms-Universität Münster infekt@uni-muenster.de

Abstract Pertussis toxin (PTx), an AB5 toxin and major virulence factor of the
whooping cough-causing pathogen Bordetella pertussis, has been shown to affect
the blood-brain barrier. Dysfunction of the blood-brain barrier may facilitate
penetration of bacterial pathogens into the brain, such as Escherichia coli K1
(RS218). In this study, we investigated the influence of PTx on blood-brain
barrier permissiveness to E. coli infection using human brainderived
endothelial HBMEC and TY10 cells as in vitro models. Our results indicate that
PTx acts at several key points of host cell intracellular signaling pathways,
which are also affected by E. coli K1 RS218 infection. Application of PTx
increased the expression of the pathogen binding receptor gp96. Further, we
found an activation of STAT3 and of the small GTPase Rac1, which have been
described as being essential for bacterial invasion involving host cell actin
cytoskeleton rearrangements at the bacterial entry site. In addition, we showed
that PTx induces a remarkable relocation of VE-cadherin and ∼-catenin from
intercellular junctions. The observed changes in host cell signaling molecules
were accompanied by differences in intracellular calcium levels, which might
act as a second messenger system for PTx. In summary, PTx not only facilitates
invasion of E. coli K1 RS218 by activating essential signaling cascades; it
also affects intercellular barriers to increase paracellular translocation.
http://www.ncbi.nlm.nih.gov/pubmed/?term=26324705

“Pertussis toxin (PTx), [an ingredient in several vaccines] an AB5 toxin and
major virulence factor of the whooping cough-causing pathogen Bordetella
pertussis, has been shown to affect the blood-brain barrier. Dysfunction of the
blood-brain barrier may facilitate penetration of bacterial pathogens into the
brain, such as Escherichia coli K1 (RS218).”

Vaccine • November 2015

Genetic diversity and population dynamics of Bordetella pertussis in China
between 1950-2007 Author information Xu Y1, Zhang L1, Tan Y1, Wang L1, Zhang
S1, Wang J2. 1. Key Laboratory of the Ministry of Health for Research on
Quality and Standardization of Biotech Products, National Institutes for Food
and Drug Control, No. 2, Tiantan Xili, Beijing 100050, PR China 2. Key
Laboratory of the Ministry of Health for Research on Quality and
Standardization of Biotech Products, National Institutes for Food and Drug
Control, No. 2, Tiantan Xili, Beijing 100050, PR China wangjz@nifdc.org.cn
Abstract Pertussis is an acute respiratory infectious disease caused by the
bacterium Bordetella pertussis. Although pertussis vaccination was introduced
in the 1960s, pertussis is still an endemic disease in China. To better
understand the genetic diversity of the Chinese B. pertussis population, we
characterized 115 clinical isolates obtained in China during 1950-2007 using
multilocus variable-number tandem repeat analysis (MLVA). Forty-six different
B. pertussis MLVA profiles (MTs) were identified, of which 13 were new MTs.
Analysis using a minimum-spanning tree showed that distinct MTs were prevalent
during different periods, suggesting that a dynamic change in B. pertussis MTs
occurred over time in China. The predominant MTs in recent isolates from China
were different from those of many developed countries. A decreasing trend in
genetic diversity of the B. pertussis population was observed following the
introduction of pertussis vaccines. Similar to the pertactin 2 (prn2) allele,
the novel pertussis toxin promoter (ptxP3) allele first emerged in 2000, but
unlike trends elsewhere, ptxP1 remained predominant among the isolates, further
reflecting the unique temporal trends in the B. pertussis population in China.
Our results suggest that temporal changes in the B. pertussis population may be
closely associated with vaccination coverage and the vaccine types used. These
data may lead to an improved understanding of the virulence mechanism of B.
pertussis and facilitate new strategies for controlling this infectious
disease. http://www.ncbi.nlm.nih.gov/pubmed/26409140

“Although pertussis vaccination was introduced in the 1960s, pertussis is still
an endemic disease in China. Our results suggest that temporal changes in the
B. pertussis population may be closely associated with vaccination coverage
...”

[viral mutation or ‘drift’]

Drug Safety • November 2015

Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and
Future Needs Author information Petrovsky N. Department of Endocrinology and
Diabetes Flinders University, Adelaide, SA, 5042, Australia
nikolai.petrovsky@flinders.edu.au Vaxine Pty Ltd, Adelaide, SA, Australia
nikolai.petrovsky@flinders.edu.au Abstract Use of highly pure antigens to
improve vaccine safety has led to reduced vaccine immunogenicity and efficacy.
This has led to the need to use adjuvants to improve vaccine immunogenicity.
The ideal adjuvant should maximize vaccine immunogenicity without compromising
tolerability or safety. Unfortunately, adjuvant research has lagged behind
other vaccine areas such as antigen discovery, with the consequence that only a
very limited number of adjuvants based on aluminium salts, monophosphoryl lipid
A and oil emulsions are currently approved for human use. Recent strategic
initiatives to support adjuvant development by the National Institutes of
Health should translate into greater adjuvant choices in the future.
Mechanistic studies have been valuable for better understanding of adjuvant
action, but mechanisms of adjuvant toxicity are less well understood. The
inflammatory or danger-signal model of adjuvant action implies that increased
vaccine reactogenicity is the inevitable price for improved immunogenicity.
Hence, adjuvant reactogenicity may be avoidable only if it is possible to
separate inflammation from adjuvant action. The biggest remaining challenge in
the adjuvant field is to decipher the potential relationship between adjuvants
and rare vaccine adverse reactions, such as narcolepsy, macrophagic
myofasciitis or Alzheimer’s disease. While existing adjuvants based on
aluminium salts have a strong safety record, there are ongoing needs for new
adjuvants and more intensive research into adjuvants and their effects.
http://www.ncbi.nlm.nih.gov/pubmed/26446142

“Use of highly pure antigens to improve vaccine safety has led to reduced
vaccine immunogenicity and efficacy. The biggest remaining challenge in the
adjuvant field is to decipher the potential relationship between adjuvants and
rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or
Alzheimer’s disease.”

Vaccine • November 2015

A measles outbreak in a middle school with high vaccination coverage and
evidence of prior immunity among cases, Beijing, P.R. China Author information
Ma R1, Lu L2, Zhangzhu J1, Chen M1, Yu X1, Wang F3, Peng X3, Wu J1. 1. EPI
Department, Beijing Center for Disease Control and Prevention, Beijing 100013,
PR China 2. EPI Department, Beijing Center for Disease Control and Prevention,
Beijing 100013, PR China 3. EPI Department, Shunyi District Center for Disease
Control and Prevention, Beijing 101300, PR China Abstract BACKGROUND
Age-appropriate receipt of ≥2 measles-containing vaccine (MCV) doses has been
considered evidence of immunity against measles. Transmission of measles is
rarely reported among such persons. METHODS We report a measles outbreak in a
middle school in Beijing that has high coverage with≥2 documented MCV doses.
History of previous measles and documentation of MCV receipt were collected for
all individuals. Cases were identified by active surveillance and confirmed by
laboratory tests. Measles immunoglobulin G (IgG) titers and clinical
presentations were obtained for each case. RESULTS Of 1331 individuals without
a prior history of measles, 1172 (88.1% [95%CI:86.4-91.5%]) and 1078 (81.0%
[95%CI:78.9-83.1%]) had age-appropriate receipt of ≥2 MCV doses by domestic and
U.S. CDC/ACIP criteria, respectively. Thirteen measles cases occurred in the
outbreak. The index case and 3 secondary cases were students. The 9 tertiary
cases included 2 teachers and 7 students. All 11 student cases received ≥2
age-appropriate MCV doses by Chinese domestic criteria; 8 were
age-appropriately vaccinated by U.S. CDC/ACIP criteria. Measles IgG was
detected during the acute phase of measles for all but 2 cases -the first case
and 1 tertiary case. Among students with age-appropriate receipt of ≥2 MCV
doses, the length of time since the last MCV was significantly associated with
risk of measles: for the 1172 students, the risk was 4.6 [OR5.6;95%CI:1.4-22.9]
and 5.5 [OR6.5;95%CI:1.4-29.8] times higher when the last MCV dose was 5-9
years and ≥10 years prior, respectively, compared with <5 years prior; for the
1078 students, the risk was 4.1 [OR5.1;95%CI:1.3-20.7] times higher when the
last MCV dose was 5-9 years prior compared with <5 years prior. CONCLUSIONS
This is the first report from China showing measles transmission among persons
with prior evidence of immunity. Secondary vaccine failure may have played an
important role in measles transmission. Further laboratory surveillance is
needed to assess the persistence of vaccine-induced immunity of
domestically-produced MCV in China. http://www.ncbi.nlm.nih.gov/pubmed/26589518

“This is the first report from China showing measles transmission among persons
with prior evidence of immunity. Secondary vaccine failure may have played an
important role in measles transmission.”

Vaccine • November 2015

Risk of spontaneous abortion and other pregnancy outcomes in 15-25 year old
women exposed to human papillomavirus-16/18 AS04adjuvanted vaccine in the
United Kingdom Author information Baril L1, Rosillon D2, Willame C2, Angelo
MG2, Zima J2, van den Bosch JH3, Van Staa T4, Boggon R4, Bunge EM3,
Hernandez-Diaz S5, Chambers CD6 1. GSK Vaccines, 20, Avenue Fleming, B-1300
Wavre, Belgium laurence.x.baril@gsk.com 2. GSK Vaccines, 20, Avenue Fleming,
B-1300 Wavre, Belgium 3. Pallas, Health Research and Consultancy, Rotterdam,
The Netherlands 4. CPRD Research Group, London, United Kingdom 5. Harvard
School of Public Health, Cambridge, USA 6. University of California San Diego
School of Medicine, USA

Abstract BACKGROUND We assessed the risk of spontaneous abortion (SA) after
inadvertent exposure to HPV-16/18-vaccine during pregnancy using an
observational cohort design. METHODS The study population included women aged
15-25 years registered with the Clinical Practice Research Datalink General
Practice OnLine Database in the United Kingdom (UK), who received at least one
HPV-16/18-vaccine dose between 1st September 2008 and 30th June 2011. Exposed
women had the first day of gestation between 30 days before and 45 days (90
days for the extended exposure period) after any HPV-16/18-vaccine dose.
Nonexposed women had the first day of gestation 120 days-18 months after the
last dose. SA defined as foetal loss between weeks 1 and 23 of gestation (UK
definition). RESULTS The frequency of SA was 11.6% (among 207 exposed) and 9.0%
(632 non-exposed), women: hazard ratio (HR) adjusted for age at first day of
gestation 1.30 (95% confidence interval: 0.79-2.12). Sensitivity analysis per
number of doses administered (-30 to +45-day risk period) showed a HR for SA of
1.11 (0.64-1.91) for 18/178 women with one dose during the risk period versus
2.55 (1.09-5.93) in 6/29 women with two doses within a 4-5 weeks period. The
proportion of pre-term/full-term/postterm deliveries, small/large for
gestational age infants, and birth defects was not significantly different
between exposed and non-exposed women. Results were consistent using a (United
States) SA definition of foetal loss between weeks 1-19 and/or the extended
risk period. CONCLUSION There was no evidence of an increased risk of SA and
other adverse pregnancy outcomes in young women inadvertently
HPV-16/18-vaccinated around gestation. Nevertheless, women who are pregnant or
trying to become pregnant are advised to postpone vaccination until completion
of pregnancy. http://www.ncbi.nlm.nih.gov/pubmed/26206268 Full Report:
http://www.sciencedirect.com/science/article/pii/S0264410X15009688

“The frequency of SA was 11.6% (among 207 exposed) and 9.0% (632 non-exposed)
... Results were consistent using a (United States) SA definition of foetal
loss between weeks 1-19 and/or the extended risk period ... women who are
pregnant or trying to become pregnant are advised to postpone vaccination until
completion of pregnancy.”

Journal Of Maternal, Fetal & Neonatal Medicine • November 2015

The prevalence and pattern of pharmaceutical and excipient exposure in a
neonatal unit in Slovenia Author information Fister P1, Urh S2, Karner A1,
Krzan M3, Paro-Panjan D1. 1. Department of Neonatology, Division of Pediatrics
University Medical Centre Ljubljana, Ljubljana, Slovenia 2. Department of
Pharmacy, University Medical Centre Ljubljana Ljubljana, Slovenia 3. Faculty of
Medicine, Institute of Pharmacology and Experimental Toxicology University of
Ljubljana, Ljubljana , Slovenia. Abstract OBJECTIVE Because of the restraints
on conducting studies on pharmaceutical use in sick newborns, many drugs are
used off-label in this population. Moreover, industrially manufactured
pharmaceuticals may contain different excipients, which may be either untested
or not licensed for use in neonates. The aim of our study was to determine the
prevalence and pattern of pharmaceutical and excipient exposure in newborns
hospitalized at the Department of Neonatology, Ljubljana, Slovenia. METHODS A
longitudinal prospective cross-sectional study was performed during a one-month
period and included all hospitalized neonates. Route of administration, site of
action, type of manufacture, licensing status, type and concentrations of
excipients for all pharmaceuticals given to the neonates were determined.
RESULTS Twenty seven different pharmaceutical preparations were prescribed to a
total of 48 hospitalized newborns. In most cases, newborns were prescribed
various pharmaceuticals that were not approved for use in this population.
Newborns were exposed to 60 different excipients in industrially manufactured
pharmaceutical preparations. More than half of the received pharmaceuticals
contained potentially harmful and harmful excipients. CONCLUSIONS Two-thirds of
pharmaceutical preparations for neonates were used off-label. Newborns receive
more auxiliary substances, which may be unsuitable for this age group and may
even be toxic to them, via industrially manufactured pharmaceuticals.
http://www.ncbi.nlm.nih.gov/pubmed/?term=25316561

“Newborns receive more auxiliary substances, which may be unsuitable for this
age group and may even be toxic to them, via industrially manufactured
pharmaceuticals.”

Vaccine • December 2015

A sera-epidemiological study on pertussis immunity levels among community
populations and an analysis of the underlying factors in Tianjin China Author
information Zhang Y1, Huang H2, Gao Z2, Liu Y2, Liu P2, Ding Y2, Wang L3, Chen
D4, Wu S5. 1. Tianjin Centers for Disease Control and Prevention, Tianjin,
300011, China 2. Tianjin Centers for Disease Control and Prevention, Tianjin,
300011, China 3. Hangu Centers for Disease Control and Prevention, Tianjin,
300480, China 4. Hongqiao Centers for Disease Control and Prevention, Tianjin,
300132, China 5. Beichen Centers for Disease Control and Prevention, Tianjin,
300400, China cdczhangying@sina.com Abstract BACKGROUND The aim of this study
is to characterize the sera-epidemiology of pertussis immunity levels among
community populations and to identify the underlying factors. Moreover, our
study will help resolve new issues encountered during the control and
prevention of pertussis reemergence. METHODS The anti-pertussis antibody levels
among community populations were examined using enzyme linked immunosorbent
assays (ELISA) over three years. Comparative studies were carried out to assess
the efficacy of different types of vaccines. Meanwhile, the duration of
protection provided by DTaP within the under-7 age group was subjected to
further analysis. RESULTS The average positive rate for anti-pertussis antibody
was 49.15% across all community populations, among which the 4-12 age group
showed a rate substantially lower than those of other groups (P<0.001). There
was no statistically significant difference in anti-pertussis antibody levels
(P=0.977) between people receiving three and four doses of the vaccine. The
surveillance results showed that the positive antibody response rate elicited
by component pertussis combo (DTcP) vaccines (84.44%) was strikingly higher
than that elicited by acellular pertussis combo (DTaP) vaccines (37.22%,
P<0.001). More specifically, when given 4 doses of DTcP vaccines, 66.67% of the
people showed positive anti-pertussis toxin (PT) antibody levels, which was
higher than the ratio of 9.87% (P<0.001) in the case of DTaP vaccines. The
positive anti-pertussis antibody levels peaked at 73% within the first five
months following vaccination and then gradually decreased to below 20% in four
years. The positive rate was inversely correlated with the length of time after
vaccination (r=-0.929, P=0.003). CONCLUSIONS The anti-pertussis antibody levels
were not only relatively low among community populations, but also dropped
excessively rapidly among vaccinated populations. Natural infection is an
important contributor to the high pertussis immunity levels seen in adolescents
and adults. The efficacy of DTaP remains to be improved.
http://www.ncbi.nlm.nih.gov/pubmed/26562317

“The anti-pertussis antibody levels were not only relatively low among
community populations, but also dropped excessively rapidly among vaccinated
populations. Natural infection is an important contributor to the high
pertussis immunity levels seen in adolescents and adults. The efficacy of DTaP
remains to be improved.”

Journal Of Infectious Disease • December 2015

The Decline of Pertussis-Specific Antibodies After Tetanus, Diphtheria, and
Acellular Pertussis Immunization in Late Pregnancy Author information Abu Raya
B1, Srugo I2, Kessel A3, Peterman M4, Vaknin A5, Bamberger E6. 1. Department of
Pediatrics The Ruth and Bruce Rappaport Faculty of Medicine Technion-Israel
Institute of Technology, Haifa 2. Department of Pediatrics Clinical
Microbiology Laboratory The Ruth and Bruce Rappaport Faculty of Medicine,
Technion-Israel Institute of Technology, Haifa 3. Division of Allergy and
Clinical Immunology, Bnai Zion Medical Center The Ruth and Bruce Rappaport
Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 4. Clinical
Microbiology Laboratory 5. The Ruth and Bruce Rappaport Faculty of Medicine
Technion-Israel Institute of Technology, Haifa 6. Clinical Microbiology
Laboratory The Ruth and Bruce Rappaport Faculty of Medicine Technion-Israel
Institute of Technology, Haifa

Abstract We prospectively measured pertussis-specific antibodies 9-15 months
after delivery in women immunized with tetanus, diphtheria, and acellular
pertussis (Tdap) after the 20th week of their recent pregnancy. The
Tdap-immunized women (n = 38) exhibited a decline in geometric mean
concentrations between their peripartum and follow-up levels for immunoglobulin
G to pertussis toxin (21.48 [95% confidence interval, 12.51-36.89] vs 11.72
[7.09-19.37] IU/mL];); filamentous hemagglutinin (185.95 [157.93-218.94] vs
140.33 IU/mL [113.46-173.57] IU/mL); and pertactin (171.52 [120.73243.67] vs
83.74 [60.58-115.75] IU/mL) (all P < .001). For women immunized with Tdap
during late pregnancy, pertussis-specific immunoglobulin G levels decreased
significantly 9-15 months after delivery.
http://www.ncbi.nlm.nih.gov/pubmed/26160743

“For women immunized with Tdap during late pregnancy, pertussis-specific
immunoglobulin G levels decreased significantly 9-15 months after delivery.”

Current Pharmaceutical Design • 2015

Why are Excipients Important to Neonates? Author information Turner MA1, Shah
U. Department of Women’s and Children’s Health Institute of Translational
Medicine, University of Liverpool Liverpool Women’s Hospital, Crown Street,
Liverpool, L8 7SS, UK mark.turner@liverpool.ac.uk Abstract Neonates are given
many medicines. A significant proportion of these medicines contain excipients.
Excipients are used to facilitate the manufacture and use of medicines. Without
excipients, it would not be feasible to formulate some drugs into appropriate
medicinal products. For others the removal of excipients would reduce the shelf
life and make them uneconomic to produce or too expensive for users to
purchase. Excipients are also important because some of them can cause harm.
Accordingly, it is important to minimize excipient exposure when possible and
to only use them when there is a clear pharmaceutical requirement. On balance
it is generally safe to use medicines containing excipients. This review
introduces physicians and nurses to the functions of excipients in medicines
and describes some potential adverse effects of excipients in neonates. The
review also provides pharmaceutical scientists with an insight to issues that
arise when excipients are administered to neonates. The review answers some key
questions about excipients, addresses some case studies of excipient use,
proposes approaches for clinicians who prescribe and administer medicines
containing excipients and identifies areas for research that seeks to establish
the safety profiles of excipients in neonates.”
http://www.ncbi.nlm.nih.gov/pubmed/?term=26323411

“Accordingly, it is important to minimize excipient exposure when possible and
to only use them when there is a clear pharmaceutical requirement.”

Current Pharmaceutical Design • 2015

Neonatal Formulations: The Need for a Tailored, Knowledge Driven Approach
Author information Allegaert K1, Cosaert K, van den Anker JN. Neonatal
Intensive Care Unit, University Hospital Herestraat 49, 3000 Leuven, Belgium
karel.allegaert@uzleuven.be Abstract To attain effective and safe
pharmacotherapy in neonates, caregivers have to consider both the clinical
characteristics of the newborn and the pharmacokinetic estimates of a given
compound during prescription and administration. Overall, clearance in neonates
is low when compared to other pediatric subpopulations. Despite this overall
low clearance, there is already extensive between individual variability in
clearance in early life. As a consequence, neonates are in urgent need of
tailored drug product development that considers the need for both low and
flexible dosing to maintain dose accuracy. During the development of such
formulations tailored for neonates, there is also a need for guidance on
excipient exposure. The available knowledge on the safety or toxicity of
excipients is limited and difficult to retrieve, but there are initiatives
(e.g. Safety and Toxicity of Excipients for Pediatrics [STEP] database
initiative) to improve the present situation. In addition, population focussed
studies on aspects of clinical pharmacology of excipients in neonates should be
conducted. The propylene glycol research project and the European Study for
Neonatal Excipient Exposure (ESNEE) initiative illustrate its feasibility.
Finally, until tailored formulations make it to the market, compounding
practices for drug formulations in neonates should be evaluated to guarantee
correct dosing, product stability, safety and to support pharmacists in their
daily practice. http://www.ncbi.nlm.nih.gov/pubmed/?term=26323412

“Overall, clearance in neonates is low when compared to other pediatric
subpopulations.”

Current Pharmaceutical Design • 2015

Development of a Physiologically-Based Pharmacokinetic Model for Preterm
Neonates: Evaluation with In Vivo Data Author information Claassen K, Thelen K,
Coboeken K, Gaub T, Lippert J, Allegaert K, Willmann S1. Bayer Pharma AG,
Clinical Pharmacometrics 42113 Wuppertal, Germany stefan.willmann@bayer.com
Abstract Among pediatric patients, preterm neonates and newborns are the most
vulnerable subpopulation. Rapid developmental changes of physiological factors
affecting the pharmacokinetics of drug substances in newborns require extreme
care in dose and dose regimen decisions. These decisions could be supported by
in silico methods such as physiologically-based pharmacokinetic (PBPK)
modeling. In a comprehensive literature search, the physiological information
of preterm neonates that is required to establish a PBPK model has been
summarized and implemented into the database of a generic PBPK software.
Physiological parameters include the organ weights and blood flow rates, tissue
composition, as well as ontogeny information about metabolic and elimination
processes in the liver and kidney. The aim of this work is to evaluate the
model’s accuracy in predicting the pharmacokinetics following intravenous
administration of two model drugs with distinct physicochemical properties and
elimination pathways based on earlier reported in vivo data. To this end, PBPK
models of amikacin and paracetamol have been set up to predict their plasma
levels in preterm neonates. Predicted plasma concentration-time profiles were
compared to experimentally obtained in vivo data. For both drugs, plasma
concentrationtime profiles following single and multiple dosing were
appropriately predicted for a large range gestational and postnatal ages. In
summary, PBPK simulations in preterm neonates appear feasible and might become
a useful tool in the future to support dosing decisions in this special patient
population. http://www.ncbi.nlm.nih.gov/pubmed/?term=26323410

“Among pediatric patients, preterm neonates and newborns are the most
vulnerable subpopulation. Rapid developmental changes of physiological factors
affecting the pharmacokinetics of drug substances in newborns require extreme
care in dose and dose regimen decisions.”

Vaccine • December 2015

Needle-free and adjuvant-free epicutaneous boosting of pertussis immunity:
Preclinical proof of concept Author information Gavillet BM1, Mondoulet L2,
Dhelft V2, Eberhardt CS3, Auderset F3, Pham HT4, Petre J4, Lambert PH3,
Benhamou PH2, Siegrist CA3. 1. World Health Organization Collaborating Center
for Vaccine Immunology Departments of Pathology-Immunology, University of
Geneva, 1211 Geneva, Switzerland 2. DBV Technologies, Green Square, 80/84 rue
des Meuniers, 92220 Bagneux, France 3. World Health Organization Collaborating
Center for Vaccine Immunology Departments of Pathology-Immunology, University
of Geneva, 1211 Geneva, Switzerland 4. BioNet-Asia Co., Ltd., 19 Udomsuk 37,
Sukhumvit 103 Bangjak, Prakanong, Bangkok 10260, Thailand Abstract The limited
durability of pertussis vaccine-induced protection requires novel approaches to
reactivate immunity and limit pertussis resurgence in older children and
adults. We propose that periodic boosters could be delivered using a novel
epicutaneous delivery system (Viaskin) to deliver optimized pertussis antigens
such as genetically-detoxified pertussis toxin (rPT). To best mimic the human
situation in which vaccine-induced memory cells persist, whereas antibodies
wane, we developed a novel adoptive transfer murine model of pertussis
immunity. This allowed demonstrating that a single application of Viaskin
delivering rPT and/or pertactin and filamentous hemagglutinin effectively
reactivates vaccine-induced pertussis immunity and protects against Bordetella
pertussis challenge. Recalling pertussis immunity without needles nor adjuvant
may considerably facilitate the acceptance and application of periodic
boosters. http://www.ncbi.nlm.nih.gov/pubmed/?term=26067183

“Recalling pertussis immunity without needles nor adjuvant may considerably
facilitate the acceptance and application of periodic boosters.”

Example Of A Current Research Study In Progress • January 2016
NIHJ Research Portfolio Online Reporting Tools RePORT Project Number:
1R15ES012209-01 Contact PI / Project Leader: Kiningham, Kinsley K. Title:

Mechanism Of Thimerosal Induced Neurotoxicity Awardee Organization: Marshall
University Abstract Text: DESCRIPTION (provided by applicant): Mercurials are
potent neurotoxins, which localize to both neurons and glia within the central
nervous system and elicit a range of deleterious actions. Sodium
ethylmercurithiosalicylate (thimerosal) is a widely used ethyl mercury
containing preservative used in over-the-counter medications, cleaners and
cosmetics. Recent concern has been raised on the use of thimerosal in over 30
vaccines licensed in the United States. With the addition of several important
vaccines over the last few years, exposure to mercury has increased among
infants, leading some investigators to suggest an association between
thimerosal exposure and autism. There is limited toxicological information
regarding ethyl mercury; therefore, estimates of health risks from thimerosal
exposure have been based on mechanistic studies of methyl mercury, a close
chemical relative about which much is known. These estimates may actually
underestimate the toxicity of ethyl mercury containing agents. The wide use of
thimerosal makes understanding the mechanism(s) of its toxicity a significant
human health issue. The overall goal of this project is to investigate the
mechanism by which thimerosal causes neuronal cell death. The hypothesis to be
tested is that thimerosal results in dose-dependent activation of specific
signaling molecules and redox-sensitive transcription factors known to activate
pro-death genes in neurons. If this hypothesis is correct then pharmacological
intervention should attenuate toxicity as a result of thimerosal exposure.
Using a human neuroblastoma cell line, SK-N-SH, this project will test the
hypothesis in four specific aims. Aim 1 will identify in a dose-dependent
manner the predominant cell death pathway (apoptotic versus necrotic)
associated with thimerosal exposure and to determine if it is associated with
an increase in reactive oxygen species and caspase-3 dependent. Aim 2 will
determine if cell death is mediated through an AP-1-dependent pathway. In
addition, this specific aim will establish the role of c-Jun-N-terminal kinase;
an enzyme, which phosphorylates and activates AP-1, in thimerosalmediated
neuronal death. Aim 3 will determine if the cell death pathway is mediated
through an NFkappaB-dependent mechanism. Aim 4 will determine if thimerosal
toxicity can be attenuated by the administration of S-adenosylmethionine, an
enzyme which increases endogenous levels of glutathione. This project will
generate mechanistic data on thimerosal neurotoxicity and potentially identify
specific targets for pharmacological intervention.
https://projectreporter.nih.gov/project_info_description.cfm?projectnumber=1R15ES012209-01

“This project will generate mechanistic data on thimerosal neurotoxicity and
potentially identify specific targets for pharmacological intervention.”

Chapter Six
Autism 1987 - 2015 In 1976, children received 10 vaccines before attending
school. Today they will receive over 36 injections. The American Academy of
Pediatrics and the Center for Disease Control assured parents that it was safe
to not only give these vaccines, but that they could be given at one time with
complete safety. Is this true? Or are we being lied to on a grand scale? The
medical establishment has created a set of terms, which they use constantly to
boost their egos and firm up their authority as the unique holders of medical
wisdom–the mantra is “evidence-based medicine”, as if everything outside their
anointing touch is bogus and suspect. A careful examination of many of the
accepted treatments reveals that most have little or no scientific
“evidence-based” data to support it. One often repeated study found that almost
80% of medical practice had no scientific backing. Most men of medicine
recognize that some things are obvious without a placebo controlled,
double-blind, randomized study. For example, there has never been such a study
to see if smashing your finger with a hammer will be painful, but we accept it
without such pristine evidence. The same is true with removing brain tumors or
sewing up severe lacerations. I find it interesting that there exist an
incredible double standard when it comes to our evidence versus theirs. The
proponents of vaccination safety can just say they are safe, without any
supporting evidence what-so-ever, and it is to be accepted without question.
They can announce that mercury is not only safe, but that it seems to actually
increase the IQ, and we are to accept it. They can proclaim thimerosal safe to
use in vaccines without their having ever been a single study on its safety in
over 60 years of use, and we are to accept it. Yet, let me, or anyone else,
suggest that excessive vaccination can increase the risk of not only autism,
but also schizophrenia and neurodegenerative diseases, and they will scream
like banshees –Where is the evidence? Where is the evidence? When we produce
study after study, they always proclaim them to be insufficient evidence or
unacceptable studies. More often than not, they just completely ignore the
evidence. This is despite the fact that we produce dozens or even hundreds of
studies that not only demonstrate the link clinically and scientifically, but
also clearly show the mechanism by which the damage is being done —even on a
molecular level. These include cell culture studies, mixed cell cultures,
organotypic tissue studies, in vivo animal studies using multiple species and
even human studies. To the defenders of vaccine safety—our evidence is never
sufficient and, if we face reality—never will be. ~ Dr. Russell Blaylock

The Vaccine Court
The United States federal court has presided over landmark cases for the autism
community, filing official court decisions that have linked vaccinations as an
environmental trigger of autism. The court in which all of these decisions are
rendered is the Office of Special Masters of the United States Courts of
Federal Claims, otherwise known as “Vaccine Court.” The U.S. government created
this specific court in 1986 to protect pharmaceutical companies from the direct
lawsuits that were arising due to the preponderance of illnesses and injuries
that were stemming from the company’s vaccination products. By establishing the
Vaccine Court, the government now protects the pharmaceutical industry by
trying the cases and awarding damages from a federal excise tax added to the
cost of each dosage of a vaccine. In the “Vaccine Court,” the burden of proof
lays squarely on the claimant. In other words, a family must show a clear
causal connection between a vaccination and its adverse effects. For the autism
community, this standard is made more challenging because the “Vaccine Court”
does not accept “autism” as a legal determination. This is because autism is a
clinical diagnosis, labeled on the basis of a collection of clinical features
and created by causes that are still unknown. But the autism community has
still persevered, and compelled the court to acknowledge the link between their
children’s autism diagnoses and vaccinations’ environmental triggers.

Vaccine Injury Court

Vaccine Injury Court

The Bailey Banks Case

The Richelle Oxley Case

The judge rules that the Banks family successfully demonstrates that “the MMR
vaccine at issue actually caused the conditions from which Bailey suffered and
continues to suffer.” This includes Bailey’s diagnosis of Pervasive
Developmental Disorder-Not Otherwise Specified, which has long been recognized
as an autism spectrum disorder by the CDC and other federal health agencies.

The Oxley family presents their case that Richelle’s disabilities, including
encephalopathy and autistic behaviors, are a result of the pertussis vaccine.
The judge rules in their favor, stating that their “claim is strongly
supported” by the presented evidence, and that there is “not a preponderance of
the evidence that Richelle’s condition is due to factors unrelated to the
administration of the vaccine.”

BOX LINK

BOX LINK

Vaccine Injury Court

Vaccine Injury Court

The Eric Lassiter Case

The Hannah Poling Case

The Lassiter family presents Eric’s diptheria-pertusis-tetanus vaccination as
the cause of his injuries, a diagnosis described as “static encepalopathy with
autistic tendencies in addition to delayed development.” The judge rules that
the Department of Health & Human Services’ “respondent’s evidence and proffered
explanations are weak, unconvincing and insufficient” and that the Lassiter
family “has presented a better case in support of. . . injury. The Court
concludes that a preponderance of the evidence requires a finding for the
petitioner.”

The Division of Vaccine Injury Compensation, Department of Health and Human
Services concedes that Hannah’s vaccinations aggravated her mitochondrial
disorder, resulting in “features of autism spectrum disorder.”

BOX LINK

BOX LINK

Journal Of The American Academy Of Child And Adolescent Psychiatry • May 1987

Reduced natural killer cell activity in autism Warren RP, Foster A, Margaretten
NC. Dr. Warren is Associate Professor of Biology and the Developmental Center
for Handicapped Persons Utah State University, Logan, Utah. Ms. Foster is
Nursing Supervisor, Inpalient Psychiatric Unit, Primary Children’s Medical
Center Salt Lake City, Utah. Dr. Margaretten is currently a Postdoctoral Fellow
Oakridge National Laboratory, Oakridge, Tennessee. Abstract Natural killer (NK)
cells arc believed to afford protection against malignancy and viral
infections. In addition, these cells may be involved in regulating the immune
response because altered NK activity is often associated with autoimmune
disorders. An investigation of the natural cytotoxic potential of peripheral
blood mononuclear cells from 31 patients with autism has been carried out using
K562 tumor cells as target cells. Cells of 12 of the patients induced
significantly reduced levels of cytotoxicity; this was not correlated with a
quantitative alteration in patient NK cells as determined by use of the Leu-11
monoclonal antibody. This observation of altered NK cell activity, and
previously reported findings of other immune abnormalities in autism, suggest
that immune changes may be directly related to underlying biological processes
of autism or that these changes may be an indirect reflection of the actual
pathological mechanism.
http://www.jaacap.com/article/S0890-8567(09)65685-9/abstract

“This observation of altered NK cell activity, and previously reported findings
of other immune abnormalities in autism, suggest that immune changes may be
directly related to underlying biological processes of autism or that these
changes may be an indirect reflection of the actual pathological mechanism.”

Alternative Medicine Review • October 2001

Trace element analysis in hair: factors determining accuracy, precision, and
reliability Author information Bass DA1, Hickock D, Quig D, Urek K. Doctors
Data Inc., St. Charles, IL 60174, USA dbass@doctorsdata.com Abstract Trace
element analysis in biological samples has improved significantly over the last
40 years. Improvements in instrumentation such as inductively coupled
plasma-mass spectrometry and microwave digestion have resulted in improved
precision, accuracy, reliability, and detection limits. The analysis of human
scalp hair has benefited significantly from these improvements. A recent
article in the Journal of the American Medical Association found significant
inter-laboratory variation amongst several laboratories performing trace metal
hair testing. It concluded that standardization was necessary to improve
inter-laboratory comparability, and an accompanying commentary described the
characteristics of a laboratory that should be used in performing hair
analysis. The objective of this study is to demonstrate that good laboratory
practices will generate precise, accurate, and reliable results. A method for
establishing reference ranges and specific data on an analytical method will
also be presented. The use of prescribed clinical quality control, including
method validation, proficiency testing, split sampling, and good laboratory
practices clearly demonstrates that measuring trace elements in hair can be
analytically valid. http://www.ncbi.nlm.nih.gov/pubmed/?term=11703167

“The use of prescribed clinical quality control, including method validation,
proficiency testing, split sampling, and good laboratory practices clearly
demonstrates that measuring trace elements in hair can be analytically valid.”

Laboratory Medicine • September 2002

Vaccines and Autism Author Information Bernard Rimland, PhD, Woody McGinnis, MD
Autism Research Institute, San Diego, CA Abstract Autism research is
characterized by diverse findings. There is no consensus about the biological
determinants of autism. This paper examines the autistic immune profile and the
possible role of vaccines in autism. Vaccinations may be one of the triggers
for autism. Substantial data demonstrate immune abnormality in many autistic
children consistent with impaired resistance to infection, activation of
inflammatory response, and autoimmunity. Impaired resistance may predispose to
vaccine injury in autism.

“Vaccinations may be one of the triggers for autism.

A mercurial preservative in childhood vaccines, thimerosal, may cause direct
neurotoxic, immunodepressive, and au- toimmune injury and contribute to
early-onset and regressed autism. Live viruses in measles, mumps, and rubella
(MMR) may result in chronic infection of the gut and trigger regressed autism.
Thimerosal injection may potentiate MMR injury.

of vaccines in at-risk children is a worthy goal.”

Consideration of vaccine etiology must include recognition of compromised gut
and nutrition in most autistic children. An integrated view of the underlying
biological problems in autistic children serves our understanding of the
possible role of vaccines. Development of screening methods for deferral of
vaccines in at-risk children is a worthy goal.
http://labmed.oxfordjournals.org/content/labmed/33/9/708.full.pdf

Development of screening methods for deferral

“In this study, we postulated that infectious agent antigens such as streptokinase,
dietary peptides (gliadin and casein) and ethyl mercury (xenobiotic) bind to
different lymphocyte receptors and tissue enzyme ...” International Journal Of
Immunopathology And Pharmacology • September 2003

Infections, toxic chemicals and dietary peptides binding to lymphocyte
receptors and tissue enzymes are major instigators of autoimmunity in autism
Author information Vojdani A1, Pangborn JB, Vojdani E, Cooper EL. Laboratory Of
Comparative Immunology, Department Of Neurobiology UCLA Medical Center, Los
Angeles, CA, USA DrAri@msn.com Abstract Similar to many complex autoimmune
diseases, genetic and environmental factors including diet, infection and
xenobiotics play a critical role in the development of autism. In this study,
we postulated that infectious agent antigens such as streptokinase, dietary
peptides (gliadin and casein) and ethyl mercury (xenobiotic) bind to different
lymphocyte receptors and tissue enzyme (DPP IV or CD26). We assessed this
hypothesis first by measuring IgG, IgM and IgA antibodies against CD26, CD69,
streptokinase (SK), gliadin and casein peptides and against ethyl mercury bound
to human serum albumin in patients with autism. A significant percentage of
children with autism developed anti-SK, anti-gliadin and casein peptides and
anti-ethyl mercury antibodies, concomitant with the appearance of anti-CD26 and
anti-CD69 autoantibodies. These antibodies are synthesized as a result of SK,
gliadin, casein and ethyl mercury binding to CD26 and CD69, indicating that
they are specific. Immune absorption demonstrated that only specific antigens,
like CD26, were capable of significantly reducing serum anti-CD26 levels.
However, for direct demonstration of SK, gliadin, casein and ethyl mercury to
CD26 or CD69, microtiter wells were coated with CD26 or CD69 alone or in
combination with SK, gliadin, casein or ethyl mercury and then reacted with
enzyme labeled rabbit anti-CD26 or anti-CD69. Adding these molecules to CD26 or
CD69 resulted in 28-86% inhibition of CD26 or CD69 binding to anti-CD26 or
anti-CD69 antibodies. The highest % binding of these antigens or peptides to
CD26 or CD69 was attributed to SK and the lowest to casein peptides. We,
therefore, propose that bacterial antigens (SK), dietary peptides (gliadin,
casein) and Thimerosal (ethyl mercury) in individuals with pre-disposing HLA
molecules, bind to CD26 or CD69 and induce antibodies against these molecules.
In conclusion, this study is apparently the first to demonstrate that dietary
peptides, bacterial toxins and xenobiotics bind to lymphocyte receptors and/or
tissue enzymes, resulting in autoimmune reaction in children with autism.
http://www.ncbi.nlm.nih.gov/pubmed/14611720

Annals Of Neurology • January 2005

Neuroglial activation and neuroinflammation in the brain of patients with
autism Author information Vargas DL1, Nascimbene C, Krishnan C, Zimmerman AW,
Pardo CA. Department of Neurology Johns Hopkins University School of Medicine
600 North Wolfe Street, Baltimore, MD 21287, USA Abstract Autism is a
neurodevelopmental disorder characterized by impaired communication and social
interaction and may be accompanied by mental retardation and epilepsy. Its
cause remains unknown, despite evidence that genetic, environmental, and
immunological factors may play a role in its pathogenesis. To investigate
whether immune-mediated mechanisms are involved in the pathogenesis of autism,
we used immunocytochemistry, cytokine protein arrays, and enzyme-linked
immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from
autistic patients and determined the magnitude of neuroglial and inflammatory
reactions and their cytokine expression profiles. Brain tissues from
cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11
patients with autism were used for morphological studies. Fresh-frozen tissues
available from seven patients and CSF from six living autistic patients were
used for cytokine protein profiling. We demonstrate an active neuroinflammatory
process in the cerebral cortex, white matter, and notably in cerebellum of
autistic patients. Immunocytochemical studies showed marked activation of
microglia and astroglia, and cytokine profiling indicated that macrophage
chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from
neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a
unique proinflammatory profile of cytokines, including a marked increase in
MCP-1. Our findings indicate that innate neuroimmune reactions play a
pathogenic role in an undefined proportion of autistic patients, suggesting
that future therapies might involve modifying neuroglial responses in the
brain. http://www.ncbi.nlm.nih.gov/pubmed/15546155

International Review Of Neurobiology • March 2005

Immunological findings in autism Author information Cohly HH1, Panja A.
Department of Biology, Jackson State University, Mississippi 39217, USA
Abstract The immunopathogenesis of autism is presented schematically in Fig. 1.
Two main immune dysfunctions in autism are immune regulation involving
pro-inflammatory cytokines and autoimmunity. Mercury and an infectious agent
like the measles virus are currently two main candidate environmental triggers
for immune dysfunction in autism. Genetically immune dysfunction in autism
involves the MHC region, as this is an immunologic gene cluster whose gene
products are Class I, II, and III molecules. Class I and II molecules are
associated with antigen presentation. The antigen in virus infection initiated
by the virus particle itself while the cytokine production and inflammatory
mediators are due to the response to the putative antigen in question. The
cell-mediated immunity is impaired as evidenced by low numbers of CD4 cells and
a concomitant T-cell polarity with an imbalance of Th1/Th2 subsets toward Th2.
Impaired humoral immunity on the other hand is evidenced by decreased IgA
causing poor gut protection. Studies showing elevated brain specific antibodies
in autism support an autoimmune mechanism. Viruses may initiate the process but
the subsequent activation of cytokines is the damaging factor associated with
autism. Virus specific antibodies associated with measles virus have been
demonstrated in autistic subjects. Environmental exposure to mercury is
believed to harm human health possibly through modulation of immune
homeostasis. A mercury link with the immune system has been postulated due to
the involvement of postnatal exposure to thimerosal, a preservative added in
the MMR vaccines. The occupational hazard exposure to mercury causes edema in
astrocytes and, at the molecular level, the CD95/Fas apoptotic signaling
pathway is disrupted by Hg2+. Inflammatory mediators in autism usually involve
activation of astrocytes and microglial cells. Proinflammatory chemokines
(MCP-1 and TARC), and an anti-inflammatory and modulatory cytokine, TGFbeta1,
are consistently elevated in autistic brains. In measles virus infection, it
has been postulated that there is immune suppression by inhibiting T-cell
proliferation and maturation and downregulation MHC class II expression.
Cytokine alteration of TNF-alpha is increased in autistic populations.
Tolllike-receptors are also involved in autistic development. High NO levels
are associated with autism. Maternal antibodies may trigger autism as a
mechanism of autoimmunity. MMR vaccination may increase risk for autism via an
autoimmune mechanism in autism. MMR antibodies are significantly higher in
autistic children as compared to normal children, supporting a role of MMR in
autism. Autoantibodies (IgG isotype) to neuron-axon filament protein (NAFP) and
glial fibrillary acidic protein (GFAP) are significantly increased in autistic
patients (Singh et al., 1997). Increase in Th2 may explain the increased
autoimmunity, such as the findings of antibodies to MBP and neuronal axonal
filaments in the brain. There is further evidence that there are other
participants in the autoimmune phenomenon. (Kozlovskaia et al., 2000). The
possibility of its involvement in autism cannot be ruled out. Further
investigations at immunological, cellular, molecular, and genetic levels will
allow researchers to continue to unravel the immunopathogenic mechanisms’
associated with autistic processes in the developing brain. This may open up
new avenues for prevention and/or cure of this devastating neurodevelopmental
disorder. http://www.ncbi.nlm.nih.gov/pubmed/16512356

“Mercury and an infectious agent like the measles virus are currently two main
candidate environmental triggers for immune dysfunction in autism. Studies
showing elevated brain specific antibodies in autism support an autoimmune
mechanism. Viruses may initiate the process but the subsequent activation of
cytokines is the damaging factor associated with autism. Virus specific
antibodies associated with measles virus have been demonstrated in autistic
subjects.”

The Neuroscientist • October 2005

Large brains in autism: the challenge of pervasive abnormality Author
information Herbert MR1. Pediatric Neurology Center for Morphometric Analysis
Massachusetts General Hospital Charleston, MA 02129, USA mherbert1@partners.org
Abstract The most replicated finding in autism neuroanatomy-a tendency to
unusually large brains-has seemed paradoxical in relation to the specificity of
the abnormalities in three behavioral domains that define autism. We now know a
range of things about this phenomenon, including that brains in autism have a
growth spurt shortly after birth and then slow in growth a few short years
afterward, that only younger but not older brains are larger in autism than in
controls, that white matter contributes disproportionately to this volume
increase and in a nonuniform pattern suggesting postnatal pathology, that
functional connectivity among regions of autistic brains is diminished, and
that neuroinflammation (including microgliosis and astrogliosis) appears to be
present in autistic brain tissue from childhood through adulthood. Alongside
these pervasive brain tissue and functional abnormalities, there have arisen
theories of pervasive or widespread neural information processing or signal
coordination abnormalities (such as weak central coherence, impaired complex
processing, and underconnectivity), which are argued to underlie the specific
observable behavioral features of autism. This convergence of findings and
models suggests that a systemsand chronic disease-based reformulation of
function and pathophysiology in autism needs to be considered, and it opens the
possibility for new treatment targets.
http://www.ncbi.nlm.nih.gov/pubmed/16151044

“This convergence of findings and models suggests that a systems- and chronic
disease-based reformulation of function and pathophysiology in autism needs to
be considered ...”

“Although the etiology of autism is unknown,
data suggest that autism results from multiple etiologies with both genetic and
environmental contributions, which may explain the spectrum of behaviors seen
in this disorder.” Journal of NeuroVirology • November 2005

Autistic disorder and viral infections Jane E Libbey,1 Thayne L Sweeten,1
William M McMahon,2 and Robert S Fujinami1 Departments of 1Neurology and
2Psychiatry University of Utah, Salt Lake City, Utah, USA Autistic disorder
(autism) is a behaviorally defined developmental disorder with a wide range of
behaviors. Although the etiology of autism is unknown, data suggest that autism
results from multiple etiologies with both genetic and environmental
contributions, which may explain the spectrum of behaviors seen in this
disorder. One proposed etiology for autism is viral infection very early in
development. The mechanism, by which viral infection may lead to autism, be it
through direct infection of the central nervous system (CNS), through infection
elsewhere in the body acting as a trigger for disease in the CNS, through
alteration of the immune response of the mother or offspring, or through a
combination of these, is not yet known. Animal models in which early viral
infection results in behavioral changes later in life include the influenza
virus model in pregnant mice and the Borna disease virus model in newborn Lewis
rats. Many studies over the years have presented evidence both for and against
the association of autism with various viral infections. The best association
to date has been made between congenital rubella and autism; however, members
of the herpes virus family may also have a role in autism. Recently,
controversy has arisen as to the involvement of measles virus and/or the
measles, mumps, rubella (MMR) vaccine in the development of autism. Biological
assays lend support to the association between measles virus or MMR and autism
whereas epidemiologic studies show no association between MMR and autism.
Further research is needed to clarify both the mechanisms whereby viral
infection early in development may lead to autism and the possible involvement
of the MMR vaccine in the development of autism.
http://www.jneurovirol.com/o_pdf/11(1)/001-010.pdf

Journal Of Child Neurology • February 2006

Developmental Regression and Mitochondrial Dysfunction in a Child With Autism
Author Information Jon S. Poling, MD, PhD, Richard E. Frye, MD, PhD, John
Shoffner, MD, and Andrew W. Zimmerman, MD Department of Neurology and
Neurosurgery, Johns Hopkins Hospital, Baltimore, MD Case Report A 19-month-old
girl was born after a normal full-term pregnancy. There was no family history
of autism or affective, neuromuscular, or hearing disorders. Her development
was progressing well, with normal receptive and expressive language and use of
prelinguistic gestures, such as pointing for joint attention. Imaginary play
and social reciprocity were typical for age. She used at least 20 words and
could point to five body parts on command. Several immunizations were delayed
owing to frequent bouts of otitis media with fever. Within 48 hours after
immunizations to diphtheria, tetanus, and pertussis; Haemophilus influenzae B;
measles, mumps, and rubella; polio; and varicella (Varivax), the patient
developed a fever to 38.9°C, inconsolable crying, irritability, and lethargy
and refused to walk. Four days later, the patient was waking up multiple times
in the night, having episodes of opistho-tonus, and could no longer normally
climb stairs. Instead, she crawled up and down the stairs. Low-grade
intermittent fever was noted for the next 12 days. Ten days following
immunization, the patient developed a generalized erythematous macular rash
beginning in the abdomen. The patient’s pediatrician diagnosed this as due to
varicella vaccination. For 3 months, the patient was irritable and increasingly
less responsive verbally, after which the patient’s family noted clear autistic
behaviors, such as spinning, gaze avoidance, disrupted sleep/wake cycle, and
perseveration on specific television programs. All expressive language was lost
by 22 months. The patient continued to have chronic yellow watery diarrhea
intermittently for 6 months, which was evaluated with negative testing for
Clostridium difficile, ova/parasites, and culture. Four months later, an
evaluation with the Infant and Toddlers Early Intervention program for possible
autism was initiated. Along with the regression, her appetite remained poor for
6 months and her body weight did not increase. This resulted in a decline on a
standard growth chart for weight from the 97th to the 75th percentile.
Evaluation at 23 months showed atopic dermatitis, slow hair growth, generalized
mild hypotonia, toe walking, and normal tendon reflexes. The Childhood Autism
Rating Scale (CARS) score was 33 (mild autism range), and she also met
Diagnostic and Statistical Manual for Mental Disorders-IV criteria for autism.
Laboratory findings included repeated measurements of aspartate
aminotransferase 40 IU/L (normal < 31 IU/L), serum bicarbonate 20 mmol/L
(normal 21–31 mmol/L), serum creatine kinase level 203 IU/L (normal < 170
IU/L), and fasting lactic acid 3.3 mmol/L (normal 0.5–2.2 mmol/ L).
Quantitative urinary organic acid analyses showed trace amounts of dicarboxylic
acids (adipic, suberic, octenedioic acids) and small amounts of ethylmalonic
and methylsuccinic acids, consistent

with a fatty acid oxidation dysfunction. Quantitative plasma amino acids were
all within the normal range; however, the alanine to lysine ratio (a surrogate
marker for pyruvate; Dr Richard Kelley, personal communication, 2001) was
elevated at 3.2 (normal 1.5–2.5). Cranial magnetic resonance imaging,
otoacoustic emission testing, overnight electroencephalography with slow-wave
sleep, serum lead, chromosomes, and fragile X by DNA testing were all normal.
The patient was referred for muscle biopsy (J.S.) because of persistent mild
lactic acidosis, elevated serum creatine kinase level, and increased aspartate
aminotransferase. A fresh vastus lateralis biopsy was performed and examined as
described previously.7,8 The biopsy showed abnormal histology with type I
myofiber atrophy, increased myofiber lipid content, and reduced cytochrome c
oxidase activity. Oxidative phosphorylation enzymology showed markedly reduced
complex I, I + III, and III activity. Complex IV activity was near the 5%
confidence limit of the control group (Table 1). Mitochondrial DNA sequencing
of the skeletal muscle was normal. Now 6 years old, our patient has been
treated with vitamin supplements since 2½ years of age. Even before starting
supplementation, the patient began speaking again at 23 months old and had a
fourword vocabulary of “bubbles,” “ball,” “drink,” and “cracker.” Levocarnitine
250 mg and thiamine 50 mg three times per day were initiated when the patient
was 29 months old. Coenzyme Q10 was added at age 33 months. Although she still
exhibits mild autistic behaviors, our patient has continued to improve in
language functions and sociability such that she now attends a regular
kindergarten with an aide. There have been slow yet steady improvements in
muscle tone, motor coordination, and gastrointestinal symptoms with
occupational therapy, applied behavioral analysis interventions, and
mitochondrial enzyme cofactor supplements. After the age of 2 years, growth
trajectory has continued along the 75th percentile for both height and weight.
Laboratory tests were repeated at ages 2 years and 10 months (aspartate
aminotransferase 47 IU/L, normal < 38 IU/L; alanine transferase 20 IU/L, normal
< 40 IU/L; serum creatine kinase level 105 IU/L, normal < 194 IU/L), 4 years
old (aspartate aminotransferase 36 IU/L; alanine transferase 19 IU/L; serum
creatine kinase level 169 IU/L), and 6 years old (aspartate aminotransferase 36
IU/L; alanine transferase 21 IU/L; alanine to lysine ratio 1.58, normal < 1.5
to 2.5). During an acute illness owing to C difficile, the aspartate
aminotransferase was on one occasion elevated to 50 IU/L; however, the serum
creatine kinase level remained normal at 169 IU/L. Urine organic acids and
serum amino acids have been normal at ages 3 and 6 years. Childhood Autism
Rating Scale scores since beginning kindergarten have been under 30.

Full Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2536523/

Toxicology And Applied Pharmacology • July 2006

Porphyrinuria in childhood autistic disorder: implications for environmental
toxicity Author information Nataf R1, Skorupka C, Amet L, Lam A, Springbett A,
Lathe R. Laboratoire Philippe Auguste, Paris, France Abstract To address a
possible environmental contribution to autism, we carried out a retrospective
study on urinary porphyrin levels, a biomarker of environmental toxicity, in
269 children with neurodevelopmental and related disorders referred to a Paris
clinic (2002-2004), including 106 with autistic disorder. Urinary porphyrin
levels determined by high-performance liquid chromatography were compared
between diagnostic groups including internal and external control groups.
Coproporphyrin levels were elevated in children with autistic disorder relative
to control groups. Elevation was maintained on normalization for age or to a
control heme pathway metabolite (uroporphyrin) in the same samples. The
elevation was significant (P < 0.001). Porphyrin levels were unchanged in
Asperger’s disorder, distinguishing it from autistic disorder. The atypical
molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was
also elevated in autistic disorder (P < 0.001) but not significantly in
Asperger’s. A subgroup with autistic disorder was treated with oral
dimercaptosuccinic acid (DMSA) with a view to heavy metal removal. Following
DMSA there was a significant (P = 0.002) drop in urinary porphyrin excretion.
These data implicate environmental toxicity in childhood autistic disorder.
http://www.ncbi.nlm.nih.gov/pubmed/?term=16782144

“These data implicate environmental toxicity in childhood autistic disorder.”

[note: in the medical literature vaccination is considered an environmental
toxicant]

Lancet • July 2006

Prevalence of disorders of the autism spectrum in a population cohort of
children in South Thames: the Special Needs and Autism Project (SNAP) Author
information Baird G1, Simonoff E, Pickles A, Chandler S, Loucas T, Meldrum D,
Charman T. Newcomen Centre Guy’s and St Thomas’ NHS Foundation Trust London, UK
gillian.baird@gstt.nhs.uk Abstract BACKGROUND Recent reports have suggested
that the prevalence of autism and related spectrum disorders (ASDs) is
substantially higher than previously recognised. We sought to quantify
prevalence of ASDs in children in South Thames, UK. METHODS Within a total
population cohort of 56 946 children aged 9-10 years, we screened all those
with a current clinical diagnosis of ASD (n=255) or those judged to be at risk
for being an undetected case (n=1515). A stratified subsample (n=255) received
a comprehensive diagnostic assessment, including standardised clinical
observation, and parent interview assessments of autistic symptoms, language,
and intelligence quotient (IQ). Clinical consensus diagnoses of childhood
autism and other ASDs were derived. We used a sample weighting procedure to
estimate prevalence. FINDINGS The prevalence of childhood autism was 38.9 per
10,000 (95% CI 29.9-47.8) and that of other ASDs was 77.2 per 10,000
(52.1-102.3), making the total prevalence of all ASDs 116.1 per 10,000
(90.4-141.8). A narrower definition of childhood autism, which combined
clinical consensus with instrument criteria for past and current presentation,
provided a prevalence of 24.8 per 10,000 (17.6-32.0). The rate of previous
local identification was lowest for children of less educated parents.
INTERPRETATION Prevalence of autism and related ASDs is substantially greater
than previously recognised. Whether the increase is due to better
ascertainment, broadening diagnostic criteria, or increased incidence is
unclear. Services in health, education, and social care will need to recognise
the needs of children with some form of ASD, who constitute 1% of the child
population. http://www.ncbi.nlm.nih.gov/pubmed/?term=16844490

“Prevalence of autism and related ASDs is substantially greater than previously
recognised.”

Journal Of Leukocyte Biology • July 2006

The immune response in autism: a new frontier for autism research Author
information Ashwood P1, Wills S, Van de Water J. Medical Microbiology and
Immunology and the M.I.N.D Institute, University of California Davis
Sacramento, CA 95817, USA pashwood@ucdavis.edu Abstract Autism spectrum
disorders (ASD) are part of a broad spectrum of neurodevelopmental disorders
known as pervasive developmental disorders, which occur in childhood. They are
characterized by impairments in social interaction, verbal and nonverbal
communication and the presence of restricted and repetitive stereotyped
behaviors. At the present time, the etiology of ASD is largely unknown, but
genetic, environmental, immunological, and neurological factors are thought to
play a role in the development of ASD. Recently, increasing research has
focused on the connections between the immune system and the nervous system,
including its possible role in the development of ASD. These neuroimmune
interactions begin early during embryogenesis and persist throughout an
individual’s lifetime, with successful neurodevelopment contingent upon a
normal balanced immune response. Immune aberrations consistent with a
dysregulated immune response, which so far, have been reported in autistic
children, include abnormal or skewed T helper cell type 1 (T(H)1)/T(H)2
cytokine profiles, decreased lymphocyte numbers, decreased T cell mitogen
response, and the imbalance of serum immunoglobulin levels. In addition, autism
has been linked with autoimmunity and an association with immune-based genes
including human leukocyte antigen (HLA)-DRB1 and complement C4 alleles
described. There is potential that such aberrant immune activity during
vulnerable and critical periods of neurodevelopment could participate in the
generation of neurological dysfunction characteristic of ASD. This review will
examine the status of the research linking the immune response with ASD.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/?term=16698940 Full Report:
http://www.jleukbio.org/content/80/1/1.long

“There is potential that such aberrant immune activity during vulnerable and
critical periods of neurodevelopment could participate in the generation of
neurological dysfunction characteristic of ASD. This review will examine the
status of the research linking the immune response with ASD.”

Pathophysiology • August 2006

Oxidative stress in autism Author information Chauhan A1, Chauhan V. NYS
Institute for Basic Research in Developmental Disabilities 1050 Forest Hill
Road, Staten Island, NY 10314, USA Abstract Autism is a severe developmental
disorder with poorly understood etiology. Oxidative stress in autism has been
studied at the membrane level and also by measuring products of lipid
peroxidation, detoxifying agents (such as glutathione), and antioxidants
involved in the defense system against reactive oxygen species (ROS). Lipid
peroxidation markers are elevated in autism, indicating that oxidative stress
is increased in this disease. Levels of major antioxidant serum proteins,
namely transferrin (iron-binding protein) and ceruloplasmin (copper-binding
protein), are decreased in children with autism. There is a positive
correlation between reduced levels of these proteins and loss of previously
acquired language skills in children with autism. The alterations in
ceruloplasmin and transferrin levels may lead to abnormal iron and copper
metabolism in autism. The membrane phospholipids, the prime target of ROS, are
also altered in autism. The levels of phosphatidylethanolamine (PE) are
decreased, and phosphatidylserine (PS) levels are increased in the erythrocyte
membrane of children with autism as compared to their unaffected siblings.
Several studies have suggested alterations in the activities of antioxidant
enzymes such as superoxide dismutase, glutathione peroxidase, and catalase in
autism. Additionally, altered glutathione levels and homocysteine/methionine
metabolism, increased inflammation, excitotoxicity, as well as mitochondrial
and immune dysfunction have been suggested in autism. Furthermore,
environmental and genetic factors may increase vulnerability to oxidative
stress in autism. Taken together, these studies suggest increased oxidative
stress in autism that may contribute to the development of this disease. A
mechanism linking oxidative stress with membrane lipid abnormalities,
inflammation, aberrant immune response, impaired energy metabolism and
excitotoxicity, leading to clinical symptoms and pathogenesis of autism is
proposed. http://www.ncbi.nlm.nih.gov/pubmed/16766163

“According to the Autism Society of America, autism is now considered to be an epidemic.”
Journal Of Toxicology And Environmental Health Part B, Critical Review •
November 2006

Evidence of toxicity, oxidative stress, and neuronal insult in autism Author
information Kern JK1, Jones AM. Department of Psychiatry, University of Texas
Southwestern Medical Center at Dallas Dallas, Texas 75390-9119, USA
janet.kern@UTSouthwestern.edu Abstract According to the Autism Society of
America, autism is now considered to be an epidemic. The increase in the rate
of autism revealed by epidemiological studies and government reports implicates
the importance of external or environmental factors that may be changing. This
article discusses the evidence for the case that some children with autism may
become autistic from neuronal cell death or brain damage sometime after birth
as result of insult; and addresses the hypotheses that toxicity and oxidative
stress may be a cause of neuronal insult in autism. The article first describes
the Purkinje cell loss found in autism, Purkinje cell physiology and
vulnerability, and the evidence for postnatal cell loss. Second, the article
describes the increased brain volume in autism and how it may be related to the
Purkinje cell loss. Third, the evidence for toxicity and oxidative stress is
covered and the possible involvement of glutathione is discussed. Finally, the
article discusses what may be happening over the course of development and the
multiple factors that may interplay and make these children more vulnerable to
toxicity, oxidative stress, and neuronal insult.
http://www.ncbi.nlm.nih.gov/pubmed/17090484

Neurotoxicology • May 2008

Immunologic and neurodevelopmental susceptibilities of autism Author
information Pessah IN1, Seegal RF, Lein PJ, LaSalle J, Yee BK, Van De Water J,
Berman RF. School of Veterinary Medicine, University of California, Davis, CA
95616, USA inpessah@ucdavis.edu Abstract Symposium 5 focused on research
approaches that are aimed at understanding common patterns of immunological and
neurological dysfunction contributing to neurodevelopmental disorders such as
autism and ADHD. The session focused on genetic, epigenetic, and environmental
factors that might act in concert to influence autism risk, severity and
co-morbidities, and immunological and neurobiological targets as etiologic
contributors. The immune system of children at risk of autism may be therefore
especially susceptible to psychological stressors, exposure to chemical
triggers, and infectious agents. Identifying early biomarkers of risk provides
tangible approaches toward designing studies in animals and humans that yield a
better understanding of environmental risk factors, and can help identify
rational intervention strategies to mitigate these risks. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475601/

Alternative Therapies In Health And Medicine • November 2008

The history of vaccinations in the light of the autism epidemic Author
information Cave SF. Cypress Integrative Medicine Baton Rouge, Louisiana, USA
Abstract Autism has been characterized as a behavioral disorder since it was
first described by Leo Kanner in 1943. The number of autistic children has
increased over the last decade. The incidence of autism was 1 in 10000 before
the 1970s and has steadily increased to 1 in 150 in 2008 with a male:female
predominance of 4:1. The cause of this epidemic has remained unknown, but
several hypotheses have been studied. Many of these suggest an environmental
trigger, such as the ethyl mercury contained in the preservative thimerosal,
which has been used in vaccines since 1931. Other possible triggers associated
with vaccinations are chemical toxins and live viruses. James has published
studies suggesting a genetic predisposition in the families of autistic
children, exposing them to a deficiency in glutathione and an inability to
detoxify heavy metals. Vargas has shown autism to encompass ongoing
inflammation in the brains of autistic children. The Hannah Poling vaccine
decision was a landmark case. Poling’s family was awarded funds for ongoing
medical care of an autistic child who was found to have mitochondrial
dysfunction exacerbated by vaccines that left her with autistic behavior and
seizures. Several studies have emerged supporting the fact that a significant
number of autistic children do have mitochondrial dysfunction. The impact that
the Poling case will have on the ability of parents of autistic children to
gain access to funds to enable them to properly care for their children remains
to be seen. http://www.ncbi.nlm.nih.gov/pubmed/19043939

“The Hannah Poling vaccine decision was a landmark case. Poling’s family was
awarded funds for ongoing medical care of an autistic child who was found to
have mitochondrial dysfunction exacerbated by vaccines that left her with
autistic behavior and seizures. Several studies have emerged supporting the
fact that a significant number of autistic children do have mitochondrial
dysfunction. The impact that the Poling case will have on the ability of
parents of autistic children to gain access to funds to enable them to properly
care for their children remains to be seen.”

Alternative Therapies In Health And Medicine • November 2008

A possible central mechanism in autism spectrum disorders Part 1 Author
information Blaylock RL. Belhaven College Jackson, Mississippi, USA Abstract
The autism spectrum disorders (ASD) are a group of related neurodevelopmental
disorders that have been increasing in incidence since the 1980s. Despite a
considerable amount of data being collected from cases, a central mechanism has
not been offered. A careful review of ASD cases discloses a number of events
that adhere to an immunoexcitotoxic mechanism. This mechanism explains the link
between excessive vaccination, use of aluminum and ethylmercury as vaccine
adjuvants, food allergies, gut dysbiosis, and abnormal formation of the
developing brain. It has now been shown that chronic microglial activation is
present in autistic brains from age 5 years to age 44 years. A considerable
amount of evidence, both experimental and clinical, indicates that repeated
microglial activation can initiate priming of the microglia and that subsequent
stimulation can produce an exaggerated microglial response that can be
prolonged. It is also known that one phenotypic form of microglia activation
can result in an outpouring of neurotoxic levels of the excitotoxins, glutamate
and quinolinic acid. Studies have shown that careful control of brain glutamate
levels is essential to brain pathway development and that excesses can result
in arrest of neural migration, as well as dendritic and synaptic loss. It has
also been shown that certain cytokines, such as TNF-alpha, can, via its
receptor, interact with glutamate receptors to enhance the neurotoxic reaction.
To describe this interaction I have coined the term immunoexcitotoxicity, which
is described in this article. http://www.ncbi.nlm.nih.gov/pubmed/?term=19043938

“This mechanism explains the link between excessive vaccination, use of
aluminum and ethylmercury as vaccine adjuvants, food allergies, gut dysbiosis,
and abnormal formation of the developing brain.”

Alternative Therapies In Health And Medicine • January 2009

A possible central mechanism in autism spectrum disorders, Part 2
immunoexcitotoxicity Author information Blaylock RL. Belhaven College Jackson,
Mississippi, USA Abstract In this section, I explore the effects of mercury and
inflammation on transsulfuration reactions, which can lead to elevations in
androgens, and how this might relate to the male preponderance of autism
spectrum disorders (ASD). It is known that mercury interferes with these
biochemical reactions and that chronically elevated androgen levels also
enhance the neurodevelopmental effects of excitotoxins. Both androgens and
glutamate alter neuronal and glial calcium oscillations, which are known to
regulate cell migration, maturation, and final brain cytoarchitectural
structure. Studies have also shown high levels of DHEA and low levels of DHEA-S
in ASD, which can result from both mercury toxicity and chronic inflammation.
Chronic microglial activation appears to be a hallmark of ASD. Peripheral
immune stimulation, mercury, and elevated levels of androgens can all stimulate
microglial activation. Linked to both transsulfuration problems and chronic
mercury toxicity are elevations in homocysteine levels in ASD patients.
Homocysteine and especially its metabolic products are powerful excitotoxins.
Intimately linked to elevations in DHEA, excitotoxicity and mercury toxicity
are abnormalities in mitochondrial function. A number of studies have shown
that reduced energy production by mitochondria greatly enhances excitotoxicity.
Finally, I discuss the effects of chronic inflammation and elevated mercury
levels on glutathione and metallothionein.
http://www.ncbi.nlm.nih.gov/pubmed/19161050

“In this section, I explore the effects of mercury and inflammation on
transsulfuration reactions, which can lead to elevations in androgens, and how
this might relate to the male preponderance of autism spectrum disorders
(ASD).”

Alternative Therapies In Health And Medicine • March 2009

A possible central mechanism in autism spectrum disorders Part 3 the role of
excitotoxin food additives and the synergistic effects of other environmental
toxins Author information Blaylock RL. Belhaven College, Jackson, Mississippi,
USA. Abstract There is compelling evidence from a multitude of studies of
various design indicating that foodborne excitotoxin additives can elevate
blood and brain glutamate to levels known to cause neurodegeneration and in the
developing brain, abnormal connectivity. Excitotoxins are also secreted by
microglial activation when they are in an activated state. Recent studies,
discussed in part 1 of this article, indicate that chronic microglial
activation is common in the autistic brain. The interaction between
excitotoxins, free radicals, lipid peroxidation products, inflammatory
cytokines, and disruption of neuronal calcium homeostasis can result in brain
changes suggestive of the pathological findings in cases of autism spectrum
disorders. In addition, a number of environmental neurotoxins, such as
fluoride, lead, cadmium, and aluminum, can result in these pathological and
biochemical changes. http://www.ncbi.nlm.nih.gov/pubmed/19284184

“There is compelling evidence from a multitude of studies of various design
indicating that foodborne excitotoxin additives can elevate blood and brain
glutamate to levels known to cause neurodegeneration and in the developing
brain, abnormal connectivity.”

New England Journal Of Medicine • 2008

Dr. Paul Offit and Dr. Jon Poling: New England Journal of Medicine

We have the most heated controversy in medicine today over vaccines and Healy
addressed it by saying, “It is the job of the public health community and of
physicians to be out there and to say yes, we can make it safer because we are
able to say, this is a subset. We’re going to deliver it in a way we think is
safer.” Sharyl Attkisson then brought up the fact that health officials will
deny there is a link between vaccines and autism. They say there’s no evidence.

By Anne Dachel Healy, shaking her head, firmly stated twice, “You can’t say
that.” On August 7, the New England Journal of Medicine published the opposing
opinions of Dr. Jon Poling, father of Hannah Poling, and Dr. Paul Offit,
Infectious Disease Specialist from Children’s Hospital of Philadelphia, on the
Vaccine Court case in which the federal government conceded that vaccines were
a factor in the development of autism in Hannah. Titled, Vaccines and Autism
Revisited, the letters run in the “Correspondance” section of NEJM. In the May
15 NEJM Perspective section, Offit split every hair he could to try and lessen
the impact of the Poling case. He tried to convince the public that there was
no scientific basis for the concession. Offit’s remarks led to the August 7
response by Dr. Poling. In his August 7 piece, Poling went after Offit’s
opinion about his daughter’s case using phrases like “Offit misrepresents my
position,” “Offit confuses issues,” and “His opinion is unsupported by clinical
trials.” Poling also said that he agreed with the remarks made by former head
of the National Institutes of Health, Dr. Bernadine Healy, on CBS News, who
said, “I don’t think you should ever turn your back on any scientific
hypothesis because you’re afraid of what it might show. . . . If you know that
susceptible group, you can save those children. If you turn your back on the
notion there is a susceptible group . . . what can I say?”

Why? Because they haven’t studied “the population that got sick.” Healy said
that she hasn’t seen “major studies that focus on 300 kids who got autistic
symptoms within a period of a few weeks of getting a vaccine.” Healy noted the
primate and mouse studies that have been too quickly dismissed. She challenged
the conclusions of the IOM Report of 2004 where we were told not to “pursue
susceptibility groups.” Healy said, “I really take issue with that conclusion.
The reason they didn’t want to look for those susceptibility groups was because
if they found them, . . . that would scare the public away.” Offit might think
that the endless epidemiological studies have settled the question, but Healy
made it clear, “Populations do not test causality, they test associations. You
have to go into the laboratory.” Healy chided the medical community by saying,
“The fact that there is concern that you don’t want to know that susceptible
group is a real disappointment to me.” She ended a chilling comment about
vaccines and the link to autism: “The question has not been answered.”

The fair and balanced NEJM then allowed Offit to respond to Poling at the
bottom of the article. Offit defended his remarks by claiming that the science
is on his side and the facts support his view. He made one stunning comment. He
brought up Healy’s remarks about the need for further study of a subgroup of
children who might be damaged by vaccines. Offit wrote, “Now, Poling and Healy
are standard-bearers for the poorly conceived hypothesis that children receive
too many vaccines too early. As a consequence, some parents are choosing to
delay, withhold, or separate vaccines.” That was really a low blow. To claim
that one of the top doctors in the U.S. was promoting a “poorly conceived
hypothesis” and that “the public airing of that hypothesis caused thousands of
parents to avoid the MMR; many children were hospitalized and several died from
measles as a result,” was really pitting doctor against doctor in the vaccine
war. (Amanda Peet just told us on Good Morning America, “Please don’t listen to
me. . . . Go to the experts.” Well, here they are and they don’t agree!) I had
to go back to the remarks made by Healy on CBS Evening News (Click HERE) on May
12 to figure out what exactly she said that could be described as a “poorly
conceived hypothesis.” Soft-spoken and reasonable in her conversation with CBS
reporter Sharyl Attkisson, Healy called for more studies on vaccines and
autism. She said that we need to do the studies to find out if there is a
subgroup of children who are susceptible to a particular vaccine, to vaccines
plural, or to components in vaccines. She urged scientists “to take another
look at that hypothesis, not deny it.” Healy said nothing to undermine that
vaccine program. She told the public, “A susceptible group does not mean that
vaccines aren’t good.” She firmly stated that she didn’t believe “the public
would lose faith in vaccines.”

From his remarks, it’s pretty obvious that Offit is opposed to any open
scientific inquiry. Healy didn’t say that all children were receiving too many
too soon, as Offit claimed. She said we need to find that subgroup of children.
The CDC studies that are always being promoted in the press haven’t settled a
thing. The public is growing increasingly skeptical of health officials and
their claims. They don’t want to risk the health of their children by giving
them vaccines with possibly damaging side effects. Healy’s was the refreshing
voice of reason in this debate. Too bad Offit refused to listen. Perhaps the
ending of the Poling/Offit pieces said it all. After Poling’s remarks, he
listed his conflicts from the lecturing and consulting fees he had received
from different pharmaceutical companies. At the end of Offit’s, all we see is
“Children’s Hospital of Philadelphia.” Here’s the body copy from NEJM: Vaccines
and Autism Revisited Related Article by Offit, P. A. To the Editor: In his
Perspective article on a possible connection between vaccines and autism, Offit
(May 15 issue)1 speculates about my daughter, Hannah, and repeats inaccuracies
from a March New York Times opinion piece that was officially corrected by the
Times and our April 5 letter. By omitting critical information from my March 6,
2008, statement, Offit misrepresents my position. I said, “Many in the autism
community and their champions believe that the result in this case may well
signify a land-

show. . . . If you know that susceptible group, you can save those children. If
you turn your back on the notion there is a susceptible group . . . what can I
say?”4 Also commendable is the new 5-year research plan of the National Vaccine
Advisory Committee, which will entail the study of minority subpopulations,
including patients with mitochondrial disorders.5

mark decision as it pertains to children developing autism following
vaccinations. This still remains to be seen, but currently there are almost
5,000 other cases pending.” Offit’s remarks about Hannah’s case are not
evidence-based. He has no access to my daughter’s personal medical records,
legal documents, or affidavits. In contrast, physicians from the Department of
Health and Human Services (DHHS) who studied this information recommended that
the government concede Hannah’s case. The clinical history Offit presents
contains significant inaccuracies, and the resulting conclusions are
consequently flawed. Offit confuses issues by comparing Hannah’s case with
unrelated decisions in “vaccine court.” The Office of the Secretary of DHHS,
through the Department of Justice, conceded Hannah’s case. There was no
courtroom hearing and no decision from the “unusual vaccine court.” Offit is
frequently cited regarding the “biologically plausible” theory that
simultaneous administration of multiple vaccines is safe. His opinion is
unsupported by clinical trials, much less investigations in potentially
susceptible subpopulations. Despite the high frequency of mitochondrial
dysfunction in autistic children,2 studies have not established primary or
secondary roles. To explore this question, we need an immunization database for
children with metabolic disorders to establish safety guidelines3 and improve
vaccine safety for minority subgroups of children. I agree with the statement
of Bernadine Healy, former director of the National Institutes of Health, who
said, “I don’t think you should ever turn your back on any scientific
hypothesis because you’re afraid of what it might

A strong, safe vaccination program is a cornerstone of public health.
Misrepresenting Hannah Poling v. HHS to the medical profession does not improve
confidence in the immunization program or advance science toward an
understanding of how and why regressive encephalopathy with autistic features
follows vaccination in susceptible children. Jon S. Poling, M.D., Ph.D. Athens
Neurological Associates Athens, GA 30606 Dr. Poling is the father of Hannah
Poling and reports receiving consulting or lecture fees from Pfizer, Eisai,
Ortho-McNeil, Biogen, Teva, Immunex, and Allergan. No other potential conflict
of interest relevant to this letter was reported. References 1. Offit PA.
Vaccines and autism revisited -- the Hannah Poling case. N Engl J Med
2008;358:2089-2091. [Free Full Text] 2. Oliveira G, Ataíde A, Marques C, et al.
Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical
characterization, and medical conditions. Dev Med Child Neurol 2007;49:726-733.
[ISI][Medline] 3. Brady MT. Immunization recommendations for children with
metabolic disorders: more data would help. Pediatrics 2006;118:810-813. [Free
Full Text] 4. CBS News. The “open question” on vaccines and autism. May 2008.
(Accessed July 18, 2008, at http://www.cbsnews.com/blogs/2008/05/12/
couricandco/entry4090144.shtml.) 5. Draft ISO Scientific Agenda for NVAC
Vaccine Safety Working Group. Centers for Disease Control and Prevention’s
Immunization Safety Office scientific agenda: draft recommendations. April 4,
2008. In: Scientific review. Washington, DC: National Vaccine Advisory
Committee Vaccine Safety Working Group, April 11, 2008:30. (Accessed July 18,
2008, at
http://www.cdc.gov/vaccinesafety/00_pdf/draft_agenda_recommendations_080404.pdf.)
__________________________________________________ The author replies: Poling
implies that by omitting his phrase “many in the autism community and their
champions,” I unfairly attributed the notion that vaccines might cause autism
to him alone. However, Dr. Poling’s public announcement of the DHHS concession
to the press and his subsequent appearances on national television and at
autism conferences suggest that he is, at the very least, a vocal centerpiece
of that community. www.ageofautism.com/2008/08/dr-paul-offit-a.html

Poling claims that I didn’t have access to his daughter’s medical records. My
information was based on a verbatim transcript of the DHHS concession, which
stated that his daughter had had frequent ear infections and a series of viral
infections early in life. These infections, which are a far greater immunologic
challenge than attenuated or inactivated vaccines, are not in dispute. Poling
states that my assertion that the administration of multiple vaccines is safe
is an “opinion . . . unsupported by clinical trials.” But studies of
concomitant use, which are required by the Food and Drug Administration before
licensure to show that new vaccines do not affect the safety or immunogenicity
of existing vaccines or vice versa, have clearly shown that multiple vaccines
can be administered safely. Poling agrees with Healy that “you should [n]ever
turn your back on any scientific hypothesis because you’re afraid of what it
might show.” However, scientists have not been afraid to test the hypothesis
that vaccines might cause autism. Far from it: the ill-founded notion that the
measles–mumps– rubella (MMR) vaccine caused autism was tested in 10
epidemiologic studies. Unfortunately, the public airing of that hypothesis
caused thousands of parents to avoid the MMR; many children were hospitalized
and several died from measles as a result.1,2,3,4 Now, Poling and Healy are
standardbearers for the poorly conceived hypothesis that children receive too
many vaccines too early. As a consequence, some parents are choosing to delay,
withhold, or separate vaccines. The problem here is not a failure of scientists
to consider hypotheses; rather, it is a failure of the media and the public to
distinguish hypotheses from scientific evidence. Paul A. Offit, M.D. Children’s
Hospital of Philadelphia Philadelphia, PA 19104

“Younger ages at diagnosis, differential migration, changes in diagnostic criteria,
and inclusion of milder cases do not fully explain the observed increases.”
Epidemiology • January 2009

The Rise in Autism and the Role of Age at Diagnosis Hertz-Picciotto, Irvaa,b;
Delwiche, Loraa Abstract Background Autism prevalence in California, based on
individuals eligible for state-funded services, rose throughout the 1990s. The
extent to which this trend is explained by changes in age at diagnosis or
inclusion of milder cases has not been previously evaluated. Methods Autism
cases were identified from 1990 through 2006 in databases of the California
Department of Developmental Services, which coordinates services for
individuals with specific developmental disorders. The main outcomes were
population incident cases younger than age 10 years for each quarter,
cumulative incidence by age and birth year, age-specific incidence rates
stratified by birth year, and proportions of diagnoses by age across birth
years. Results Autism incidence in children rose throughout the period.
Cumulative incidence to 5 years of age per 10,000 births rose consistently from
6.2 for 1990 births to 42.5 for 2001 births. Age-specific incidence rates
increased most steeply for 2- and 3-year olds. The proportion diagnosed by age
5 years increased only slightly, from 54% for 1990 births to 61% for 1996
births. Changing age at diagnosis can explain a 12% increase, and inclusion of
milder cases, a 56% increase. Conclusions Autism incidence in California shows
no sign yet of plateauing. Younger ages at diagnosis, differential migration,
changes in diagnostic criteria, and inclusion of milder cases do not fully
explain the observed increases. Other artifacts have yet to be quantified, and
as a result, the extent to which the continued rise represents a true increase
in the occurrence of autism remains unclear.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113600/

Journal Of Neuroimmunology • February 2009

Elevated immune response in the brain of autistic patients Author information
Li X1, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M.
Department of Neurochemistry NY State Institute for Basic Research in
Developmental Disabilities NY 10314, New York, USA xiaohong.li@mssm.edu
Abstract This study determined immune activities in the brain of ASD patients
and matched normal subjects by examining cytokines in the brain tissue. Our
results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1
cytokine (IFN-gamma) and chemokine (IL-8) were significantly increased in the
brains of ASD patients compared with the controls. However the Th2 cytokines
(IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was
also significantly increased in ASD patients. CONCLUSION ASD patients displayed
an increased innate and adaptive immune response through the Th1 pathway,
suggesting that localized brain inflammation and autoimmune disorder may be
involved in the pathogenesis of ASD. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770268/

“ASD patients displayed an increased innate and adaptive immune response
through the Th1 pathway, suggesting that localized brain inflammation and
autoimmune disorder may be involved in the pathogenesis of ASD.”

Current Medicinal Chemistry • July 2009

Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum
disorders Author information Blaylock RL1, Strunecka A. Belhaven College
Jackson, Mississippi, USA Abstract Despite the great number of observations
being made concerning cellular and the molecular dysfunctions associated with
autism spectrum disorders (ASD), the basic central mechanism of these disorders
has not been proposed in the major scientific literature. Our review brings
evidence that most heterogeneous symptoms of ASD have a common set of events
closely connected with dysregulation of glutamatergic neurotransmission in the
brain with enhancement of excitatory receptor function by pro-inflammatory
immune cytokines as the underlying mechanism. We suggest that environmental and
dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the
pathological and clinical problems by worsening excitotoxicity and by
microglial priming. In addition, each has effects on cell signaling that can
affect neurodevelopment and neuronal function. Our hypothesis opens the door to
a number of new treatment modes, including the nutritional factors that
naturally reduce excitotoxicity and brain inflammation.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19149568

“... environmental and dietary excitotoxins, mercury, fluoride, and aluminum
can exacerbate the pathological and clinical problems by worsening
excitotoxicity and by microglial priming. In addition, each has effects on cell
signaling that can affect neurodevelopment and neuronal function.”

Journal Of Toxicology • August 2009

The severity of autism is associated with toxic metal body burden and red blood
cell glutathione levels Author information Adams JB1, Baral M, Geis E, Mitchell
J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K,
Bradstreet J, El-Dahr JM. Division of Basic Medical Sciences Southwest College
of Naturopathic Medicine Tempe, AZ 85282, USA Abstract This study investigated
the relationship of children’s autism symptoms with their toxic metal body
burden and red blood cell (RBC) glutathione levels. In children ages 3-8 years,
the severity of autism was assessed using four tools: ADOS, PDD-BI, ATEC, and
SAS. Toxic metal body burden was assessed by measuring urinary excretion of
toxic metals, both before and after oral dimercaptosuccinic acid (DMSA).
Multiple positive correlations were found between the severity of autism and
the urinary excretion of toxic metals. Variations in the severity of autism
measurements could be explained, in part, by regression analyses of urinary
excretion of toxic metals before and after DMSA and the level of RBC
glutathione (adjusted R(2) of 0.22-0.45, P < .005 in all cases). This study
demonstrates a significant positive association between the severity of autism
and the relative body burden of toxic metals.
http://www.ncbi.nlm.nih.gov/pubmed/?term=20107587

“Multiple positive correlations were found between the severity of autism and
the urinary excretion of toxic metals.”

Journal Of Cellular And Molecular Medicine • October 2009

One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in
children with autism spectrum disorders Author information Paca SP1, Dronca E,
Kaucsár T, Craciun EC, Endreffy E, Ferencz BK, Iftene F, Benga I, Cornean R,
Banerjee R, Dronca M. Department of Medical Biochemistry Faculty of Medicine,
Iuliu HaTieganu University of Medicine and Pharmacy Cluj-Napoca, Romania
Abstract Autism spectrum disorders (ASDs), which include the prototypic
autistic disorder (AD), Asperger’s syndrome (AS) and pervasive developmental
disorders not otherwise specified (PDD-NOS), are complex neurodevelopmental
conditions of unknown aetiology. The current study investigated the metabolites
in the methionine cycle, the transsulphuration pathway, folate, vitamin B(12)
and the C677T polymorphism of the MTHFR gene in three groups of children
diagnosed with AD (n= 15), AS (n= 5) and PDD-NOS (n= 19) and their age- and
sex-matched controls (n= 25). No metabolic disturbances were seen in the AS
patients, while in the AD and PDD-NOS groups, lower plasma levels of methionine
(P= 0.01 and P= 0.03, respectively) and alpha-aminobutyrate were observed (P=
0.01 and P= 0.001, respectively). Only in the AD group, plasma cysteine (P=
0.02) and total blood glutathione (P= 0.02) were found to be reduced. Although
there was a trend towards lower levels of serine, glycine, N, N-dimethylglycine
in AD patients, the plasma levels of these metabolites as well as the levels of
homocysteine and cystathionine were not statistically different in any of the
ASDs groups. The serum levels of vitamin B(12) and folate were in the normal
range. The results of the MTHFR gene analysis showed a normal distribution of
the C677T polymorphism in children with ASDs, but the frequency of the 677T
allele was slightly more prevalent in AD patients. Our study indicates a
possible role for the alterations in one carbon metabolism in the
pathophysiology of ASDs and provides, for the first time, preliminary evidence
for metabolic and genetic differences between clinical subtypes of ASDs. Full
Report http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496129/

“Our study indicates a possible role for the alterations in one carbon
metabolism in the pathophysiology of ASDs and provides, for the first time,
preliminary evidence for metabolic and genetic differences between clinical
subtypes of ASDs.”

Current Medicinal Chemistry • 2009

Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum
disorders Author information Blaylock RL1, Strunecka A. Belhaven College
Jackson, Mississippi, USA Abstract Despite the great number of observations
being made concerning cellular and the molecular dysfunctions associated with
autism spectrum disorders (ASD), the basic central mechanism of these disorders
has not been proposed in the major scientific literature. Our review brings
evidence that most heterogeneous symptoms of ASD have a common set of events
closely connected with dysregulation of glutamatergic neurotransmission in the
brain with enhancement of excitatory receptor function by pro-inflammatory
immune cytokines as the underlying mechanism. We suggest that environmental and
dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the
pathological and clinical problems by worsening excitotoxicity and by
microglial priming. In addition, each has effects on cell signaling that can
affect neurodevelopment and neuronal function. Our hypothesis opens the door to
a number of new treatment modes, including the nutritional factors that
naturally reduce excitotoxicity and brain inflammation.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19149568

“We suggest that environmental and dietary excitotoxins, mercury, fluoride, and
aluminum can exacerbate the pathological and clinical problems by worsening
excitotoxicity and by microglial priming. In addition, each has effects on cell
signaling that can affect neurodevelopment and neuronal function.”

Acta Neurobiologiea Experimentalis • 2010

The review of most frequently occurring medical disorders related to aetiology
of autism and the methods of treatment Author information Cubala-Kucharska M.
Foundation for the Development of Integrative Medicine Piaseczno, Poland
info@drcubala.com Abstract The medical understanding of autism has changed
since it was first defined by Kanner. Nowadays medicine identifies many medical
abnormalities and diseases, which may underline or aggravate the cognitive
aspect, behavioural issues and general health in autists. This includes chronic
inflammation of gastrointestinal tract, dysbiosis, maldigestion, malabsorption,
malnutrition, food intolerance, allergies, chronic viral, fungal and bacterial
infections, impaired kidney function, impaired detoxification of endo- and
exotoxins, disorders of metal ion transportation. Treatment of the above
mentioned conditions combined with improving detoxification mechanisms,
followed by a special diet and individually customized supplementation of
nutritional deficiencies may lead to the improvement of the functioning of
these patients, changing their level of functioning and self-dependence. The
aim of this paper is to present medical problems of children with autism which
may be identified and treated by general practitioners as a review of current
medical papers related to Autism Spectrum Disorder, in the context of author’s
professional experience, based on the medical cases from author’s practice.
http://www.ncbi.nlm.nih.gov/pubmed/?term=20628438

“This includes chronic inflammation of gastrointestinal tract, dysbiosis,
maldigestion, malabsorption, malnutrition, food intolerance, allergies, chronic
viral, fungal and bacterial infections, impaired kidney function, impaired
detoxification of endo- and exotoxins, disorders of metal ion transportation.”

Neurobiologiae Experimentalis • 2010

Age-dependent lower or higher levels of hair mercury in autistic children than
in healthy controls Maria Dorota Majewska1*, Ewa Urbanowicz3, Paulina
Rok-Bujko3, Irena Namyslowska3, Pawel Mierzejewski2 1. Marie Curie Chair,
Department of Pharmacology and Physiology of the Nervous System Institute of
Psychiatry and Neurology, Warsaw, Poland majewska@ipin.edu.pl 2. Department of
Pharmacology and Physiology of the Nervous System Institute of Psychiatry and
Neurology, Warsaw, Poland 3. Department of Child and Adolescent Psychiatry
Institute of Psychiatry and Neurology, Warsaw, Poland Abstract An association
between autism and early life exposure to mercury is a hotly debated issue. In
this study, 91 autistic Polish children, male and female, 3-4 and 7-9 years
old, were compared to 75 age- and sex-matched healthy children with respect to:
demographic, perinatal, clinical and developmental measures, parental age,
birth order, morphometric measures, vaccination history, and hair mercury
content. In demographic and perinatal measures there were no consistent
differences between the autistic and control groups. Autistic children had a
significantly greater prevalence of adverse reactions after vaccinations and
abnormal development than controls. Between 45 and 80% of autistic children
experienced developmental regress. Autistic children significantly differed
from healthy peers in the concentrations of mercury in hair: younger autistics
had lower levels, while older - higher levels than their respective controls.
The results suggest that autistic children differ from healthy children in
metabolism of mercury, which seems to change with age.
https://app.box.com/s/938bs6e55098v78c4tnuyca38p2xnnqu

“The results suggest that autistic children differ from healthy children in
metabolism of mercury ...”

Neurobiologiae Experimentalis • 2010

Sorting out the spinning of autism: heavy metals and the question of incidence
Mary Catherine DeSoto* and Robert T. Hitlan Department of Psychology,
University of Northern Iowa Cedar Falls, Iowa USA cathy.desoto@uni.edu Abstract
The reasons for the rise in autism prevalence are a subject of heated
professional debate. Featuring a critical appraisal of some research used to
question whether rising levels of autism are related to environmental exposure
to toxins (Soden et al. 2007, Barbaresi et al. 2009, Thompson et al. 2007) we
aim to evaluate the actual state of scientific knowledge. In addition, we
surveyed the empirical research on the topic of autism and heavy metal toxins.
In our opinion empirical investigations are finding support for a link with
heavy metal toxins. The various causes that have led to the increase in autism
diagnosis are likely multi-faceted, and understanding the causes is one of the
most important health topics today. We argue that scientific research does not
support rejecting the link between the neurodevelopmental disorder of autism
and toxic exposures. https://app.box.com/s/rs4j52jgdbjvj0a7qroo8sgxv7t06ly9

“We argue that scientific research does not support rejecting the link between
the neurodevelopmental disorder of autism and toxic exposures.”

Journal Of Neurovirology • March 2010

Association of autism with polyomavirus infection in postmortem brains Author
information Lintas C1, Altieri L, Lombardi F, Sacco R, Persico AM. Laboratory
of Molecular Psychiatry and Neurogenetics University Campus Bio-Medico, Rome,
Italy Abstract Autism is a highly heritable behavioral disorder. Yet, two
decades of genetic investigation have unveiled extremely few cases that can be
solely explained on the basis of de novo mutations or cytogenetic
abnormalities. Vertical viral transmission represents a nongenetic mechanism of
disease compatible with high parent-to-offspring transmission and with low
rates of disease-specific genetic abnormalities. Vertically transmitted viruses
should be found more frequently in the affected tissues of autistic individuals
compared to controls. Our initial step was thus to assess by nested polymerase
chain reaction (PCR) and DNA sequence analysis the presence of cytomegalovirus
(CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1 (HSV1), herpes
simplex virus type 2 (HSV2), human herpes virus 6 (HHV6), BK virus (BKV), JC
virus (JCV), and simian virus 40 (SV40) in genomic DNA extracted from
postmortem temporocortical tissue (Brodmann areas 41/42) belonging to 15
autistic patients and 13 controls. BKV, JCV, and SV40 combined are
significantly more frequent among autistic patients compared to controls (67%
versus 23%, respectively; P < .05). The majority of positives yielded
archetypal sequences, whereas six patients and two controls unveiled
single-base pair changes in two or more sequenced clones. No association is
present with the remaining viruses, which are found in relatively few
individuals (N <or= 3). Also polyviral infections tend to occur more frequently
in the brains of autistic patients compared to controls (40% versus 7.7%,
respectively; P = .08). Follow-up studies exploring vertical viral transmission
as a possible pathogenetic mechanism in autistic disorder should focus on, but
not be limited to, the role of polyomaviruses.
http://www.ncbi.nlm.nih.gov/pubmed/20345322

“BKV, JCV, and SV40 [viruses] combined are significantly more frequent among
autistic patients compared to controls (67% versus 23%, respectively; P <
.05).”

Journal Of Pediatrics • April 2010

Autism spectrum disorders in extremely preterm children Author information
Johnson S1, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N. Institute for
Women’s Health University College, London United Kingdom Abstract OBJECTIVES To
investigate the prevalence, correlates, and antecedents of autism spectrum
disorders (ASD) in extremely preterm children. STUDY DESIGN We conducted a
prospective study of all births <26 weeks gestation in the United Kingdom and
Ireland in 1995. Of 307 survivors at 11 years, 219 (71%) were assessed and
compared with 153 term-born classmates. Parents completed the Social
Communication Questionnaire (SCQ) to assess autism spectrum symptoms, and ASD
were diagnosed by using a psychiatric evaluation. An IQ test and clinical
evaluation were also administered. Longitudinal outcome data were available for
extremely preterm children. RESULTS Extremely preterm children had
significantly higher SCQ scores than classmates (mean difference, 4.6 points;
95% CI, 3.4-5.8). Sixteen extremely preterm children (8%) were assigned an ASD
diagnosis, compared with none of the classmates. By hospital discharge, male
sex, lower gestation, vaginal breech delivery, abnormal cerebral ultrasound
scanning results, and not having had breast milk were independently associated
with autism spectrum symptoms. By 6 years, independent associates were
cognitive impairment, inattention and peer problems, withdrawn behavior at 2.5
years, and not having had breast milk. CONCLUSIONS Extremely preterm children
are at increased risk for autism spectrum symptoms and ASD in middle childhood.
These symptoms and disorders were associated with neurocognitive outcomes,
suggesting that ASD may result from abnormal brain development in this
population. http://www.ncbi.nlm.nih.gov/pubmed/?term=20056232

“Extremely preterm children are at increased risk for autism spectrum symptoms
and ASD in middle childhood.”

Journal Of Pediatrics • April 2010

Autism spectrum disorders in extremely preterm children Author information
Johnson S1, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N. Institute for
Women’s Health University College, London United Kingdom s.j.johnson@ucl.ac.uk
Abstract OBJECTIVES To investigate the prevalence, correlates, and antecedents
of autism spectrum disorders (ASD) in extremely preterm children. STUDY DESIGN
We conducted a prospective study of all births <26 weeks gestation in the
United Kingdom and Ireland in 1995. Of 307 survivors at 11 years, 219 (71%)
were assessed and compared with 153 term-born classmates. Parents completed the
Social Communication Questionnaire (SCQ) to assess autism spectrum symptoms,
and ASD were diagnosed by using a psychiatric evaluation. An IQ test and
clinical evaluation were also administered. Longitudinal outcome data were
available for extremely preterm children. RESULTS Extremely preterm children
had significantly higher SCQ scores than classmates (mean difference, 4.6
points; 95% CI, 3.4-5.8). Sixteen extremely preterm children (8%) were assigned
an ASD diagnosis, compared with none of the classmates. By hospital discharge,
male sex, lower gestation, vaginal breech delivery, abnormal cerebral
ultrasound scanning results, and not having had breast milk were independently
associated with autism spectrum symptoms. By 6 years, independent associates
were cognitive impairment, inattention and peer problems, withdrawn behavior at
2.5 years, and not having had breast milk. CONCLUSIONS Extremely preterm
children are at increased risk for autism spectrum symptoms and ASD in middle
childhood. These symptoms and disorders were associated with neurocognitive
outcomes, suggesting that ASD may result from abnormal brain development in
this population. http://www.ncbi.nlm.nih.gov/pubmed/?term=20056232

Journal Of Toxicology And Environmental Health Part A • June 2010

Porphyrinuria in Korean children with autism: correlation with oxidative stress
Author information

“Autism spectrum disorder (ASD)

Youn SI1, Jin SH, Kim SH, Lim S.

is a neurodevelopmental disorder

Department of Basic Eastern Medical Science Graduate School, KyungHee
University Seoul, Republic of Korea Abstract Autism spectrum disorder (ASD) is
a neurodevelopmental disorder believed to be associated with heavy metal
exposure, especially mercury (Hg), and is characterized by disturbances in
metal elimination. Various studies correlated elevated heavy metal body burden
with ASD diagnoses as evidenced by increased urinary porphyrin levels in
patients. Urinary porphyrins were also determined in Korean patients diagnosed
with ASD (n = 65) who visited AK Eastern Medicinal Clinic in Kangnam-gu, Seoul,
from June 2007 to September 2008, compared to controls (n = 9) residing in the
same area, by means of Metametrix (CLIA-approved) laboratory testing. Further,
urinary organic acids as indicators of hepatic detoxification/oxidative stress
were also analyzed among patients diagnosed with ASD. Significant increases
were found in patients diagnosed with ASD for proporphyrins,
pentacarboxyporphyrin, precoproporphyrin, coproporphyrins, and total
porphyrins. Significant correlations were observed between hepatic
detoxification/ oxidative stress markers and urinary porphyrins. In agreement
with published data, the present results demonstrated that measurement of
porphyrins serves as a reliable tool for diagnosis of heavy metal involvement
in ASD. http://www.ncbi.nlm.nih.gov/pubmed/?term=20391113

believed to be associated with heavy metal exposure, especially mercury (Hg),
and is characterized by disturbances in metal elimination. Significant
correlations were observed between hepatic detoxification/oxidative stress
markers and urinary porphyrins. In agreement with published data, the present
results demonstrated that measurement of porphyrins serves as a reliable tool
for diagnosis of heavy metal involvement in Autistic Spectrum Disorder.”

Acta Neurobiologiea Experimentalis • 2010

The biological basis of autism spectrum disorders: Understanding causation and
treatment by clinical geneticists Geier DA1, Kern JK, Geier MR. Author
information The Institute of Chronic Illnesses, Inc. Silver Spring, Maryland,
USA Abstract Autism spectrum disorders (ASDs) also known as pervasive
developmental disorders (PDD) are a behaviorally defined group of
neurodevelopmental disorders that are usually diagnosed in early childhood.
ASDs disproportionately affect male children. Mercury (Hg) a heavy metal, is
widespread and persistent in the environment. Mercury is a ubiquitous source of
danger in fish, drugs, fungicides/herbicides, dental fillings, thermometers,
and many other products. Elevated Hg concentrations may remain in the brain
from several years to decades following exposure. This is important because
investigators have long recognized that Hg is a neurodevelopmental poison; it
can cause problems in neuronal cell migration and division, and can ultimately
cause cell degeneration and death. Case-reports of patients have described
developmental regressions with ASD symptoms following fetal and/or early
childhood Hg exposure, and epidemiological studies have linked exposure to Hg
with an elevated risk of a patient being diagnosed with an ASD. Immune,
sensory, neurological, motor, and behavioral dysfunctions similar to traits
defining or associated with ASDs were reported following Hg intoxication with
similarities extending to neuroanatomy, neurotransmitters, and biochemistry.
The sexual dimorphism of ASDs may result from synergistic neurotoxicity caused
by the interaction of testosterone and Hg; in contrast, estrogen is protective,
mitigating the toxicity of Hg. Mercury exposure may significantly increase
androgen levels, and as a result, patients diagnosed with an ASD may
significantly benefit from anti-androgen therapy. Finally, the clinical
geneticist has a wealth of biomarkers to evaluate and treat patients diagnosed
with an ASD. http://www.ncbi.nlm.nih.gov/pubmed/20628444

Journal Of Immunotoxicology • January 2011

Theoretical aspects of autism: causes—a review Author information Ratajczak
HV1. hratajcz@comcast.net Abstract Autism, a member of the pervasive
developmental disorders (PDDs), has been increasing dramatically since its
description by Leo Kanner in 1943. First estimated to occur in 4 to 5 per
10,000 children, the incidence of autism is now 1 per 110 in the United States,
and 1 per 64 in the United Kingdom, with similar incidences throughout the
world. Searching information from 1943 to the present in PubMed and Ovid
Medline databases, this review summarizes results that correlate the timing of
changes in incidence with environmental changes. Autism could result from more
than one cause, with different manifestations in different individuals that
share common symptoms. Documented causes of autism include genetic mutations
and/or deletions, viral infections, and encephalitis following vaccination.
Therefore, autism is the result of genetic defects and/or inflammation of the
brain. The inflammation could be caused by a defective placenta, immature
blood-brain barrier, the immune response of the mother to infection while
pregnant, a premature birth, encephalitis in the child after birth, or a toxic
environment. http://www.ncbi.nlm.nih.gov/pubmed/21299355

Pediatrics • June 2011

Trends in the prevalence of developmental disabilities in US children,
1997-2008 Author information Boyle CA1, Boulet S, Schieve LA, Cohen RA,
Blumberg SJ, Yeargin-Allsopp M, Visser S, Kogan MD. National Center on Birth
Defects and Developmental Disabilities Centers for Disease Control and
Prevention, Atlanta, GA 30333, USA cboyle@cdc.gov Abstract OBJECTIVE To fill
gaps in crucial data needed for health and educational planning, we determined
the prevalence of developmental disabilities in US children and in selected
populations for a recent 12-year period. PARTICIPANTS AND METHODS We used data
on children aged 3 to 17 years from the 1997-2008 National Health Interview
Surveys, which are ongoing nationally representative samples of US households.
Parent-reported diagnoses of the following were included: attention deficit
hyperactivity disorder; intellectual disability; cerebral palsy; autism;
seizures; stuttering or stammering; moderate to profound hearing loss;
blindness; learning disorders; and/or other developmental delays. RESULTS Boys
had a higher prevalence overall and for a number of select disabilities
compared with girls. Hispanic children had the lowest prevalence for a number
of disabilities compared with non-Hispanic white and black children. Low income
and public health insurance were associated with a higher prevalence of many
disabilities. Prevalence of any developmental disability increased from 12.84%
to 15.04% over 12 years. Autism, attention deficit hyperactivity disorder, and
other developmental delays increased, whereas hearing loss showed a significant
decline. These trends were found in all of the sociodemographic subgroups,
except for autism in non-Hispanic black children. CONCLUSIONS Developmental
disabilities are common and were reported in ~1 in 6 children in the United
States in 2006-2008. The number of children with select developmental
disabilities (autism, attention deficit hyperactivity disorder, and other
developmental delays) has increased, requiring more health and education
services. Additional study of the influence of risk-factor shifts, changes in
acceptance, and benefits of early services is needed.
http://www.ncbi.nlm.nih.gov/pubmed/21606152

“Developmental disabilities are common and were reported in 1 in 6 children in
the United States in 2006-2008. The number of children with select
developmental disabilities (autism, attention deficit hyperactivity disorder,
and other developmental delays) has increased, requiring more health and
education services.”

Surveillance Summaries • March 30, 2012

Prevalence of Autism Spectrum Disorders Autism and Developmental Disabilities
Monitoring Network • 14 Sites USA Autism and Developmental Disabilities
Monitoring Network Surveillance Year 2008 Corresponding author: Jon Baio, EdS,
National Center on Birth Defects and Developmental Disabilities CDC, 1600
Clifton Road, MS E-86, Atlanta, GA 30333 Telephone: 404-498-3873; Fax:
404-498-3550 jbaio@cdc.gov. Abstract Problem/Condition Autism spectrum
disorders (ASDs) are a group of developmental disabilities characterized by
impairments in social interaction and communication and by restricted,
repetitive, and stereotyped patterns of behavior. Symptoms typically are
apparent before age 3 years. The complex nature of these disorders, coupled
with a lack of biologic markers for diagnosis and changes in clinical
definitions over time, creates challenges in monitoring the prevalence of ASDs.
Accurate reporting of data is essential to understand the prevalence of ASDs in
the population and can help direct research. Period Covered 2008 Description of
System The Autism and Developmental Disabilities Monitoring (ADDM) Network is
an active surveillance system that estimates the prevalence of ASDs and
describes other characteristics among children aged 8 years whose parents or
guardians reside within 14 ADDM sites in the United States. ADDM does not rely
on professional or family reporting of an existing ASD diagnosis or
classification to ascertain case status. Instead, information is obtained from
children’s evaluation records to determine the presence of ASD symptoms at any
time from birth through the end of the year when the child reaches age 8 years.
ADDM focuses on children aged 8 years because a baseline study conducted by CDC
demonstrated that this is the age of identified peak prevalence. A child is
included as meeting the surveillance case definition for an ASD if he or she
displays behaviors (as described on a comprehensive evaluation completed by a
qualified professional) consistent with the American Psychiatric Association’s
Diagnostic and Statistical Manual-IV, Text Revision (DSM-IV-TR) diagnostic
criteria for any of the following conditions: Autistic Disorder; Pervasive
Developmental Disorder–Not Otherwise Specified (PDD-NOS, including Atypical
Autism); or Asperger Disorder. The first phase of the ADDM methodology involves
screening and abstraction of

comprehensive evaluations completed by professional providers at multiple data
sources in the community. Multiple data sources are included, ranging from
general pediatric health clinics to specialized programs for children with
developmental disabilities. In addition, many ADDM sites also review and
abstract records of children receiving special education services in public
schools. In the second phase of the study, all abstracted evaluations are
reviewed by trained clinicians to determine ASD case status. Because the case
definition and surveillance methods have remained consistent across all ADDM
surveillance years to date, comparisons to results for earlier surveillance
years can be made. This report provides updated ASD prevalence estimates from
the 2008 surveillance year, representing 14 ADDM areas in the United States. In
addition to prevalence estimates, characteristics of the population of children
with ASDs are described, as well as detailed comparisons of the 2008
surveillance year findings with those for the 2002 and 2006 surveillance years.
Results For 2008, the overall estimated prevalence of ASDs among the 14 ADDM
sites was 11.3 per 1,000 (one in 88) children aged 8 years who were living in
these communities during 2008. Overall ASD prevalence estimates varied widely
across all sites (range: 4.8–21.2 per 1,000 children aged 8 years). ASD
prevalence estimates also varied widely by sex and by racial/ethnic group.
Approximately one in 54 boys and one in 252 girls living in the ADDM Network
communities were identified as having ASDs. Comparison of 2008 findings with
those for earlier surveillance years indicated an increase in estimated ASD
prevalence of 23% when the 2008 data were compared with the data for 2006 (from
9.0 per 1,000 children aged 8 years in 2006 to 11.0 in 2008 for the 11 sites
that provided data for both surveillance years) and an estimated increase of
78% when the 2008 data were compared with the data for 2002 (from 6.4 per 1,000
children aged 8 years in 2002 to 11.4 in 2008 for the 13 sites that provided
data for both surveillance years). Because the ADDM Network sites do not make
up a nationally representative sample, these combined prevalence estimates
should not be generalized to the United States as a whole.

http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6103a1.htm

“For 2008, the overall estimated prevalence of Autistic Spectrum Disorder among
the 14 ADDM sites was 11.3 per 1,000 (one in 88) ...”

Molecular Psychiatry • April 2012

A review of research trends in physiological abnormalities in autism spectrum
disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial
dysfunction and environmental toxicant exposures Author information Rossignol
DA1, Frye RE. International Child Development Resource Center Melbourne, FL
32934, USA rossignolmd@gmail.com Abstract Recent studies have implicated
physiological and metabolic abnormalities in autism spectrum disorders (ASD)
and other psychiatric disorders, particularly immune dysregulation or
inflammation, oxidative stress, mitochondrial dysfunction and environmental
toxicant exposures (‘four major areas’). The aim of this study was to determine
trends in the literature on these topics with respect to ASD. A comprehensive
literature search from 1971 to 2010 was performed in these four major areas in
ASD with three objectives. First, publications were divided by several
criteria, including whether or not they implicated an association between the
physiological abnormality and ASD. A large percentage of publications
implicated an association between ASD and immune dysregulation/ inflammation
(416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial
dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second,
the strength of evidence for publications in each area was computed using a
validated scale. The strongest evidence was for immune
dysregulation/inflammation and oxidative stress, followed by toxicant exposures
and mitochondrial dysfunction. In all areas, at least 45% of the publications
were rated as providing strong evidence for an association between the
physiological abnormalities and ASD. Third, the time trends in the four major
areas were compared with trends in neuroimaging, neuropathology, theory of mind
and genetics (‘four comparison areas’). The number of publications per 5-year
block in all eight areas was calculated in order to identify significant
changes in trends. Prior to 1986, only 12 publications were identified in the
four major areas and 51 in the four comparison areas (42 for genetics). For
each 5-year period, the total number of publications in the eight combined
areas increased progressively. Most publications (552 of 895, 62%) in the four
major areas were published in the last 5 years (2006-2010). Evaluation of
trends between the four major areas and the four comparison areas demonstrated
that the largest relative growth was in immune dysregulation/inflammation,
oxidative stress, toxicant exposures, genetics and neuroimaging. Research on
mitochondrial dysfunction started growing in the last 5 years. Theory of mind
and neuropathology research has declined in recent years. Although most
publications implicated an association between the four major areas and ASD,
publication bias may have led to an overestimation of this association. Further
research into these physiological areas may provide insight into general or
subset-specific processes that could contribute to the development of ASD and
other psychiatric disorders. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317062/

[the state of autism research]

PLoS One • April 2012

The co-morbidity burden of children and young adults with autism spectrum
disorders Author information Kohane IS1, McMurry A, Weber G, MacFadden D,
Rappaport L, Kunkel L, Bickel J, Wattanasin N, Spence S, Murphy S, Churchill S.
1Center for Biomedical Informatics Harvard Medical School, Boston,
Massachusetts, USA Isaac_kohane@harvard.edu Abstract OBJECTIVES Use electronic
health records Autism Spectrum Disorder (ASD) to assess the comorbidity burden
of ASD in children and young adults. STUDY DESIGN A retrospective prevalence
study was performed using a distributed query system across three general
hospitals and one pediatric hospital. Over 14,000 individuals under age 35 with
ASD were characterized by their co-morbidities and conversely, the prevalence
of ASD within these comorbidities was measured. The comorbidity prevalence of
the younger (Age<18 years) and older (Age 18-34 years) individuals with ASD was
compared. RESULTS 19.44% of ASD patients had epilepsy as compared to 2.19% in
the overall hospital population (95% confidence interval for difference in
percentages 13.58-14.69%), 2.43% of ASD with schizophrenia vs. 0.24% in the
hospital population (95% CI 1.89-2.39%), inflammatory bowel disease (IBD) 0.83%
vs. 0.54% (95% CI 0.13-0.43%), bowel disorders (without IBD) 11.74% vs. 4.5%
(95% CI 5.726.68%), CNS/cranial anomalies 12.45% vs. 1.19% (95% CI
9.41-10.38%), diabetes mellitus type I (DM1) 0.79% vs. 0.34% (95% CI 0.3-0.6%),
muscular dystrophy 0.47% vs 0.05% (95% CI 0.260.49%), sleep disorders 1.12% vs.
0.14% (95% CI 0.79-1.14%). Autoimmune disorders (excluding DM1 and IBD) were
not significantly different at 0.67% vs. 0.68% (95% CI -0.14-0.13%). Three of
the studied comorbidities increased significantly when comparing ages 0-17 vs
18-34 with p<0.001: Schizophrenia (1.43% vs. 8.76%), diabetes mellitus type I
(0.67% vs. 2.08%), IBD (0.68% vs. 1.99%) whereas sleeping disorders, bowel
disorders (without IBD) and epilepsy did not change significantly. CONCLUSIONS
The comorbidities of ASD encompass disease states that are significantly
overrepresented in ASD with respect to even the patient populations of tertiary
health centers. This burden of comorbidities goes well beyond those routinely
managed in developmental medicine centers and requires broad multidisciplinary
management that payors and providers will have to plan for. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325235/

[autism encompasses far more than just neurological disorders. Autism includes
epilepsy, schizophrenia, inflammatory bowel disease, bowel disorders, cranial
anomalies, diabetes mellitus type 1, muscular dystrophy, sleep disorders,
autoimmune disorders and more... ]

European Journal Of Paediatric Neurology • November 2012

Observed prevalence of autism spectrum disorders in two Norwegian counties
Author information Isaksen J1, Diseth TH, Schjølberg S, Skjeldal OH. Department
of Habilitation Innlandet Hospital Trust, Maihaugveien 4 2609 Lillehammer,
Norway jorn.isaksen@sykehuset-innlandet.no Abstract BACKGROUND The prevalence
of autism spectrum disorders (ASD) has previously been reported to be
increasing dramatically in European and non-European countries. No similar
increase in prevalence rates has been documented in Norway to date. The current
study reports on ASD prevalence rates in two Norwegian counties.

“there has been almost a fourfold increase

METHODS The population comprised 31,015 children, ages six to 12. Information
about special needs services was provided by the school authorities and the
public health service. Multiple search strategies were applied to identify
children at risk of ASD or diagnosed with ASD. Hospital registers were searched
and a mapping tool was used in all local schools.

in the occurrence of

RESULTS The total number of patients with ASD found in the population was 158.
This gives a prevalence of 51 per 10,000 (95% CI, 0.43-0.59).

occurrence of all ASD groups.”

CONCLUSION Compared with the previously reported prevalence of ASD in Norway,
there has been almost a fourfold increase in the occurrence of childhood autism
and a tenfold increase in the occurrence of all ASD groups. These findings have
significant implications for designing and dimensioning appropriate
intervention programmes for children with ASD and their families.
http://www.ncbi.nlm.nih.gov/pubmed/?term=22342070

childhood autism and a tenfold increase in the

International Journal Of Environmental Research And Public Health • December 2012

Hair toxic metal concentrations and autism spectrum disorder severity in young
children Author information Geier DA1, Kern JK, King PG, Sykes LK, Geier MR.
Institute of Chronic Illnesses, Silver Spring, MD 20905, USA
davidallengeier@comcast.net.net Abstract Previous studies have found a higher
body-burden of toxic metals, particularly mercury (Hg), among subjects
diagnosed with an autism spectrum disorder (ASD) in comparison to neurotypical
controls. Moreover, Hg body-burden was associated with ASD severity. This
cross-sectional study examined the potential correlation between hair toxic
metal concentrations and ASD severity in a prospective cohort of participants
diagnosed with moderate to severe ASD. The Institutional Review Board at the
University of Texas Southwestern Medical Center at Dallas (Dallas, TX) approved
the present study. Qualifying study participants (n = 18) were evaluated for
ASD severity using the Childhood Autism Rating Scale (CARS) and quantitatively
for arsenic, Hg, cadmium, lead, chromium, cobalt, nickel, aluminum, tin,
uranium, and manganese using hair toxic element testing by Doctor’s Data (a
CLIA-approved laboratory). CARS scoring and hair toxic element testing were
blinded to one another. Increasing hair Hg concentrations significantly
correlated with increased ASD severity. In contrast, no significant
correlations were observed between any other of the hair toxic metals examined
and ASD severity. This study helps to provide additional mechanistic support
for Hg in the etiology of ASD severity, and is supported by an increasing
number of recent critical reviews that provide biological plausibility for the
role of Hg exposure in the pathogenesis of ASDs. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546773/

“This study helps to provide additional mechanistic support for Hg [ethyl
mercury or thimerosal] in the etiology of Autistic Spectrum Disorder [ASD]
severity, and is supported by an increasing number of recent critical reviews
that provide biological plausibility for the role of ethyl mercuty [Hg]
exposure in the pathogenesis of Autistic Spectrum Disorder”

Acta Neurobiologia Experimentalis • 2012

Evidence of parallels between mercury intoxication and the brain pathology in
autism Author information Kern JK1, Geier DA, Audhya T, King PG, Sykes LK,
Geier MR. Institute of Chronic Illnesses, Inc., Silver Spring, MD, USA
jkern@dfwair.net Abstract The purpose of this review is to examine the
parallels between the effects mercury intoxication on the brain and the brain
pathology found in autism spectrum disorder (ASD). This review finds evidence
of many parallels between the two, including: (1) microtubule degeneration,
specifically large, long-range axon degeneration with subsequent abortive
axonal sprouting (short, thin axons); (2) dentritic overgrowth; (3)
neuroinflammation; (4) microglial/astrocytic activation; (5) brain immune
response activation; (6) elevated glial fibrillary acidic protein; (7)
oxidative stress and lipid peroxidation; (8) decreased reduced glutathione
levels and elevated oxidized glutathione; (9) mitochondrial dysfunction; (10)
disruption in calcium homeostasis and signaling; (11) inhibition of glutamic
acid decarboxylase (GAD) activity; (12) disruption of GABAergic and
glutamatergic homeostasis; (13) inhibition of IGF-1 and methionine synthase
activity; (14) impairment in methylation; (15) vascular endothelial cell
dysfunction and pathological changes of the blood vessels; (16) decreased
cerebral/cerebellar blood flow; (17) increased amyloid precursor protein; (18)
loss of granule and Purkinje neurons in the cerebellum; (19) increased
pro-inflammatory cytokine levels in the brain (TNF-∼, IFN-∼, IL-1∼, IL-8); and
(20) aberrant nuclear factor kappalight-chain-enhancer of activated B cells
(NF-kappaB). This review also discusses the ability of mercury to potentiate
and work synergistically with other toxins and pathogens in a way that may
contribute to the brain pathology in ASD. The evidence suggests that mercury
may be either causal or contributory in the brain pathology in ASD, possibly
working synergistically with other toxic compounds or pathogens to produce the
brain pathology observed in those diagnosed with an ASD. Full Report
http://www.ncbi.nlm.nih.gov/pubmed/22810216

“The evidence suggests that mercury may be either causal or contributory in the
brain pathology in Autistic Spectrum Disorder, possibly working synergistically
with other toxic compounds or pathogens to produce the brain pathology observed
in those diagnosed with an Autistic Spectrum Disorder”

Translational Neurodegeneration • August 2013

Evidence of neurodegeneration in autism spectrum disorder Author information
Kern JK1, Geier DA, Sykes LK, Geier MR. Institute of Chronic Illnesses,
Incorporation, Silver Spring, MD, USA jkern@dfwair.net

“Evidence of neurodegeneration in the brain in ASD [autistic spectrum disorder]
includes:

Abstract Autism spectrum disorder (ASD) is a neurological disorder in which a
significant number of children experience a developmental regression
characterized by a loss of previously-acquired skills and abilities. Loss of
neurological function in ASD, as observed in affected children who have
regressed, can be explained as neurodegeneration. Although there is research
evidence of neurodegeneration or progressive encephalopathy in ASD, the issue
of neurodegeneration in ASD is still under debate. Evidence of
neurodegeneration in the brain in ASD includes: (1) neuronal cell loss, (2)
activated microglia and astrocytes, (3) proinflammatory cytokines, (4)
oxidative stress, and (5) elevated 8-oxo-guanosine levels. The evidence from
this review suggests that neurodegeneration underlies the loss of neurological
function in children with ASD who have experienced regression and loss of
previously acquired skills and abilities, and that research into treatments to
address the issue of neurodegeneration in ASD are warranted.
http://www.ncbi.nlm.nih.gov/pubmed/23925007

(1) neuronal cell loss, (2) activated microglia and astrocytes, (3)
proinflammatory cytokines, (4) oxidative stress, and (5) elevated
8-oxo-guanosine levels.”

Journal on Developmental Disabilities • 2012

Autism Author Information Tomljenovic, Lucija; Dórea, José G.; Shaw,
Christopher A. Abstract Autism is a multisystem developmental disorder
characterized by dysfunctional immunity and impaired brain function. Although
autism is partly determined by genetic susceptibility factors, reported
dramatic increases in the prevalence of autism in developed countries have
intensified scientific focus on environmental exposures. Pre- and perinatal
immunotoxic insults are now strongly suspected as contributors to this
increase. Mercury (Hg) is both a neuro- and an immunotoxin and continues to be
used in some pediatric vaccines in the form of the preservative thimerosal.
Although currently there are no direct human studies on the risks of Hg
exposure from thimerosal-containing vaccines (TCVs), animal studies show that
doses relevant to human TCV exposure can result in adverse neurodevelopmental
outcomes. To date, TCVs continue to be administered on a regular basis to
potentially the most vulnerable populations: pregnant women and children. In
light of existing experimental evidence, the rationale for using this known
immunotoxic and neurotoxic substance in human vaccines should be reconsidered.

http://connection.ebscohost.com/c/articles/79268607/commentary-link-between-mercury-exposure-autism-spectrum-disorder-other-neurodevelopmental-disorders-implications-thimerosal-containing-vaccines

Brain • September 2013

Early brain enlargement and elevated extra-axial fluid in infants who develop
autism spectrum disorder Shen MD1, Nordahl CW, Young GS, Wootton-Gorges SL, Lee
A, Liston SE, Harrington KR, Ozonoff S, Amaral DG. Abstract Prospective studies
of infants at risk for autism spectrum disorder have provided important clues
about the early behavioural symptoms of autism spectrum disorder. Diagnosis of
autism spectrum disorder, however, is not currently made until at least 18
months of age. There is substantially less research on potential brain-based
differences in the period between 6 and 12 months of age. Our objective in the
current study was to use magnetic resonance imaging to identify any
consistently observable brain anomalies in 6-9 month old infants who would
later develop autism spectrum disorder. We conducted a prospective infant
sibling study with longitudinal magnetic resonance imaging scans at three time
points (6-9, 12-15, and 18-24 months of age), in conjunction with intensive
behavioural assessments. Fifty-five infants (33 ‘high-risk’ infants having an
older sibling with autism spectrum disorder and 22 ‘low-risk’ infants having no
relatives with autism spectrum disorder) were imaged at 6-9 months; 43 of these
(27 high-risk and 16 low-risk) were imaged at 12-15 months; and 42 (26
high-risk and 16 low-risk) were imaged again at 18-24 months. Infants were
classified as meeting criteria for autism spectrum disorder, other
developmental delays, or typical development at 24 months or later (mean age at
outcome: 32.5 months). Compared with the other two groups, infants who
developed autism spectrum disorder (n = 10) had significantly greater
extra-axial fluid at 6-9 months, which persisted and remained elevated at 12-15
and 18-24 months. Extra-axial fluid is characterized by excessive cerebrospinal
fluid in the subarachnoid space, particularly over the frontal lobes. The
amount of extra-axial fluid detected as early as 6 months was predictive of
more severe autism spectrum disorder symptoms at the time of outcome. Infants
who developed autism spectrum disorder also had significantly larger total
cerebral volumes at both 12-15 and 18-24 months of age. This is the first
magnetic resonance imaging study to prospectively evaluate brain growth
trajectories from infancy in children who develop autism spectrum disorder. The
presence of excessive extra-axial fluid detected as early as 6 months and the
lack of resolution by 24 months is a hitherto unreported brain anomaly in
infants who later develop autism spectrum disorder. This is also the first
magnetic resonance imaging evidence of brain enlargement in autism before age
2. These findings raise the potential for the use of structural magnetic
resonance imaging to aid in the early detection of children at risk for autism
spectrum disorder or other neurodevelopmental disorders. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754460/

Journal Of Mental Health Research And Intellectual Disability • October 2013

A Comparison of the Autism Treatment Evaluation Checklist (ATEC) and the
Childhood Autism Rating Scale (CARS) for the Quantitative Evaluation of Autism
Author information Geier DA1, Kern JK, Geier MR. Institute of Chronic
Illnesses, Inc. Silver Spring, Maryland Abstract The purpose of this study was
to evaluate scores generated from the Autism Treatment Evaluation Checklist
(ATEC), a parent-rated measure, and those derived from professionally completed
Childhood Autism Rating Scale (CARS) evaluations. A cohort of 56 participants
diagnosed with an autism spectrum disorder was used for the study, and each
child was evaluated independently by the parent using the ATEC and a health
care professional using the CARS. The Spearman’s rank correlation statistic ∼
was used to evaluate the correlation between ATEC and CARS scores. It was
observed that there was a significant correlation between total ATEC and CARS
scores (∼ = .71). Specific domains in the ATEC evaluation significantly
correlated with CARS scores. Sensitivity, specificity, and receiver operating
characteristic confirmed the association between CARS and ATEC domains. The
results help to validate the utility of the parentally completed ATEC in
comparison with an established, professional-related measure of autism.
http://www.ncbi.nlm.nih.gov/pubmed/23914277

“The results help to validate the utility of the parentally completed ATEC in
comparison with an established, professional-related measure of autism.”

Current Neuropharmacology • March 2014

Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites,
Immuno-inflammation, Autoimmunity and the Amygdala George Anderson1,* and
Michael Maes2,3 1. CRC, Rm:30, 57 Laurel Street, Glasgow, Scotland 2.
Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand 3.
Department of Psychiatry, Deakin University, Geelong, Australia Abstract The
autistic spectrum disorders (ASD) form a set of multi-faceted disorders with
significant genetic, epigenetic and environmental determinants. Oxidative and
nitrosative stress (O&NS), immuno-inflammatory pathways, mitochondrial
dysfunction and dysregulation of the tryptophan catabolite (TRYCATs) pathway
play significant interactive roles in driving the early developmental etiology
and course of ASD. O&NS interactions with immuno-inflammatory pathways mediate
their effects centrally via the regulation of astrocyte and microglia
responses, including regional variations in TRYCATs produced. Here we review
the nature of these interactions and propose an early developmental model
whereby different ASD genetic susceptibilities interact with environmental and
epigenetic processes, resulting in glia biasing the patterning of central
interarea interactions. A role for decreased local melatonin and
Nacetylserotonin production by immune and glia cells may be a significant
treatment target. Full Report
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964746/

Pediatrics • May 2014

Parental obesity and risk of autism spectrum disorder Author information Surén
P1, Gunnes N2, Roth C2, Bresnahan M3, Hornig M4, Hirtz D5, Lie KK6, Lipkin WI4,
Magnus P6, Reichborn-Kjennerud T7, Schjølberg S6, Susser E3, Oyen AS8, Smith
GD9, Stoltenberg C10. 1. Norwegian Institute of Public Health, Oslo, Norway;
Centre for Paediatric Epidemiology and Biostatistics UCL Institute of Child
Health, London, United Kingdom 2. Norwegian Institute of Public Health, Oslo,
Norway; Mailman School of Public Health, Columbia University, New York, New
York 3. Mailman School of Public Health, Columbia University, New York, New
York; New York State Psychiatric Institute, New York, New York 4. Mailman
School of Public Health, Columbia University, New York, New York 5. National
Institute of Neurologic Disorders and Stroke, Bethesda, Maryland 6. Norwegian
Institute of Public Health, Oslo, Norway 7. Norwegian Institute of Public
Health, Oslo, Norway; Institute of Psychiatry, University of Oslo, Oslo, Norway
8. Norwegian Institute of Public Health, Oslo, Norway; Nic Waals Institute,
Lovisenberg Hospital, Oslo, Norway 9. MRC Centre for Causal Analysis in
Translational Epidemiology, University of Bristol, Bristol, United Kingdom and
10. Norwegian Institute of Public Health, Oslo, Norway; Department of Public
Health and Primary Health Care University of Bergen, Bergen, Norway

Abstract OBJECTIVES The objective of the study was to investigate the
associations among maternal prepregnancy BMI, paternal BMI, and the risk of
autism spectrum disorders (ASDs) in children. METHODS The study sample of 92
909 children was derived from the population-based, prospective Norwegian
Mother and Child Cohort Study. The age range was 4.0 through 13.1 (mean 7.4)
years. Relative risks of ASDs were estimated by odds ratios (ORs) and 95%
confidence intervals (CIs) from logistic regression models. RESULTS At the end
of follow-up on December 31, 2012, 419 children in the study sample had been
diagnosed with ASDs: 162 with autistic disorder, 103 with Asperger disorder,
and 154 with pervasive developmental disorder not otherwise specified. Maternal
obesity (BMI ≥30) was only weakly associated with ASD risk, whereas paternal
obesity was associated with an increased risk of autistic disorder and Asperger
disorder. The risk of autistic disorder was 0.27% (25 of 9267) in children of
obese fathers and 0.14% (59 of 41 603) in children of fathers with normal
weight (BMI <25), generating an adjusted OR of 1.73 (95% CI: 1.07-2.82). For
Asperger disorder, analyses were limited to children aged ≥7 years (n = 50
116). The risk was 0.38% (18 of 4761) in children of obese fathers and 0.18%
(42 of 22 736) in children of normal-weight fathers, and the adjusted OR was
2.01 (95% CI: 1.13-3.57). No associations were found for pervasive
developmental disorder not otherwise specified. CONCLUSIONS Paternal obesity is
an independent risk factor for ASDs in children. The associations should be
investigated further in genetic and epigenetic studies.
http://www.ncbi.nlm.nih.gov/pubmed/24709932

“Several of these influences, including polybrominated diphenyl ethers, aluminum adjuvants,
the herbicide glyphosate, and obesity among U.S. women, have increasing trends
that are positively correlated to the rise in autism. However, most of the
toxins surveyed, including lead, PCBs, organochlorine pesticides, vehicular
emissions and air pollution, have flat or declining trends, making it less
likely that they can be driving the increase in diagnosed autism seen over the
35-year period of the composite data set.” Environmental Health • September
2014

A comparison of temporal trends in United States autism prevalence to trends in
suspected environmental factors Cynthia D Nevison Abstract Background The
prevalence of diagnosed autism has increased rapidly over the last several
decades among U.S. children. Environmental factors are thought to be driving
this increase and a list of the top ten suspected environmental toxins was
published recently. Methods Temporal trends in autism for birth years 1970–2005
were derived from a combination of data from the California Department of
Developmental Services (CDDS) and the United States Individuals with
Disabilities Education Act (IDEA). Temporal trends in suspected toxins were
derived from data compiled during an extensive literature survey. Toxin and
autism trends were compared by visual inspection and computed correlation
coefficients. Using IDEA data, autism prevalence vs. birth year trends were
calculated independently from snapshots of data from the most recent annual
report, and by tracking prevalence at a constant age over many years of
reports. The ratio of the snapshot:tracking trend slopes was used to estimate
the “real” fraction of the increase in autism. Results The CDDS and IDEA data
sets are qualitatively consistent in suggesting a strong increase in autism
prevalence over recent decades. The quantitative comparison of IDEA snapshot
and constant-age tracking trend slopes suggests that ~75-80% of the tracked
increase in autism since 1988 is due to an actual increase in the disorder
rather than to changing diagnostic criteria. Most of the suspected
environmental toxins examined have flat or decreasing

temporal trends that correlate poorly to the rise in autism. Some, including
lead, organochlorine pesticides and vehicular emissions, have strongly
decreasing trends. Among the suspected toxins surveyed, polybrominated diphenyl
ethers, aluminum adjuvants, and the herbicide glyphosate have increasing trends
that correlate positively to the rise in autism. Conclusions Diagnosed autism
prevalence has risen dramatically in the U.S over the last several decades and
continued to trend upward as of birth year 2005. The increase is mainly real
and has occurred mostly since the late 1980s. In contrast, children’s exposure
to most of the top ten toxic compounds has remained flat or decreased over this
same time frame. Environmental factors with increasing temporal trends can help
suggest hypotheses for drivers of autism that merit further investigation.
Summary Temporal trends in autism were constructed both by tracking prevalence
at a constant age in a series of historical IDEA reports and by computing
prevalence from age-resolved snapshots in individual, recent IDEA reports. Both
the snapshot and tracking approaches suggest a strong increase in autism that
took off in the late 1980s and was ongoing as of birth year 2005. The ratio of
the snapshot:tracking slopes suggests that among states with the most reliable
data, about 75 to 80% of the tracked increase in IDEA autism since 1988 is due
to a real increase in the disorder rather than just to better or expanded
diagnosis. The trend in California IDEA autism prevalence was shown to be
broadly representative of the mean United States trend and was extended to span
birth years 1970–2005 using a composite CDDS plus IDEA dataset. The composite
dataset, which shows that a more gradual increase in autism had begun already
by 1980, was compared to the corresponding trends in a list of suspected toxins
and environmental influences. Several of these influences, including
polybrominated diphenyl ethers, aluminum adjuvants, the herbicide glyphosate,
and obesity among U.S. women, have increasing trends that are positively
correlated to the rise in autism. However, most of the toxins surveyed,
including lead, PCBs, organochlorine pesticides, vehicular emissions and air
pollution, have flat or declining trends, making it less likely that they can
be driving the increase in diagnosed autism seen over the 35-year period of the
composite data set. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177682/

Molecular Autism • September 2014

Dysregulation of estrogen receptor beta (ERß), aromatase (CYP19A1), and ER
co-activators in the middle frontal gyrus of autism spectrum disorder subjects
Author information Crider A1, Thakkar R2, Ahmed AO1, Pillai A1. 1. Department
of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents
University, 997 St. Sebastian Way, Augusta, GA 30912 USA 2. Department of
Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia
Regents University, 997 St. Sebastian Way, Augusta, GA 30912 USA Abstract
BACKGROUND Autism spectrum disorders (ASD) are much more common in males than
in females. Molecular alterations within the estrogen receptor (ER) signaling
pathway may contribute to the sex difference in ASD, but the extent of such
abnormalities in the brain is not known. METHODS Postmortem middle frontal
gyrus tissues (13 ASD and 13 control subjects) were used. The protein levels
were examined by western blotting. The gene expression was determined by
qRT-PCR. RESULTS Gene expression analysis identified a 35% decrease in ER∼ mRNA
expression in the middle frontal gyrus of ASD subjects. In addition, a 38%
reduction in aromatase (CYP19A1) mRNA expression was observed in ASD subjects.
We also found significant decreases in ER co-activators that included a 34%
decrease in SRC-1, a 77% decrease in CBP, and a 52% decrease in P/CAF mRNA
levels in ASD subjects relative to controls. There were no differences in the
mRNA levels of TIF-2, AIB-1 (ER co-activators), ER co-repressors (SMRT and
nCoR) and ERß in the middle frontal gyrus of ASD subjects as compared to
controls. We observed significant correlations between ERß, CYP19A1, and
co-activators in the study subjects. Immunoblot analysis further confirmed the
changes in ERß and aromatase at the protein level in the control and ASD
subjects. http://www.ncbi.nlm.nih.gov/pubmed/25221668

Journal of Public Health and Epidemiology • September 2014

Impact of environmental factors on the prevalence of autistic disorder after
1979 Author Information Theresa A. Deisher*, Ngoc V. Doan, Angelica Omaiye,
Kumiko Koyama and Sarah Bwabye Sound Choice Pharmaceutical Institute 1749
Dexter Ave N, Seattle, WA 98109, USA Abstract The aim of this study was to
investigate a previously overlooked, universally introduced environmental
factor, fetal and retroviral contaminants in childhood vaccines, absent prior
to change points (CPs) in autistic disorder (AD) prevalence with subsequent
dose-effect evidence and known pathologic mechanisms of action. Worldwide
population based cohort study was used for the design of this study. The United
States, Western Australia, United Kingdom and Denmark settings were used. All
live born infants who later developed autistic disorder delivered after 1
January 1970, whose redacted vaccination and autistic disorder diagnosis
information is publicly available in databases maintained by the US Federal
Government, Western Australia, UK, and Denmark. The live births, grouped by
father’s age, were from the US and Australia. The children vaccinated with
MMRII, Varicella and Hepatitis A vaccines varied from 19 to 35 months of age at
the time of vaccination. Autistic disorder birth year change points were
identified as 1980.9, 1988.4 and 1996 for the US, 1987 for UK, 1990.4 for
Western Australia, and 1987.5 for Denmark. Change points in these countries
corresponded to introduction of or increased doses of human fetal cell
line-manufactured vaccines, while no relationship was found between paternal
age or Diagnostic and Statistical Manual (DSM) revisions and autistic disorder
diagnosis. Further, linear regression revealed that Varicella and Hepatitis A
immunization coverage was significantly correlated to autistic disorder cases.
R software was used to calculate change points. Autistic disorder change points
years are coincident with introduction of vaccines manufactured using human
fetal cell lines, containing fetal and retroviral contaminants, into childhood
vaccine regimens. This pattern was repeated in the US, UK, Western Australia
and Denmark. Thus, rising autistic disorder prevalence is directly related to
vaccines manufactured utilizing human fetal cells. Increased paternal age and
DSM revisions were not related to rising autistic disorder prevalence.
http://soundchoice.org/scpiJournalPubHealthEpidem092014.pdf

“R software was used to calculate change points. Autistic disorder change
points years are coincident with introduction of vaccines manufactured using
human fetal cell lines, containing fetal and retroviral contaminants, into
childhood vaccine regimens ... rising autistic disorder prevalence is directly
related to vaccines manufactured utilizing human fetal cells.”

Environmental Toxicology And Pharmacology • November 2014

Autism: a form of lead and mercury toxicity Author information Yassa HA
Forensic Medicine and Clinical Toxicology Department Faculty of Medicine,
Assiut University, Egypt heba612@hotmail.com Abstract AIM Autism is a
developmental disability characterized by severe deficits in social interaction
and communication. The definite cause of autism is still unknown. The aim of
this study is to find out the relation between exposure to Lead and/or mercury
as heavy metals and autistic symptoms, dealing with the heavy metals with
chelating agents can improve the autististic symptoms. METHOD Blood and hair
samples were obtained from 45 children from Upper Egypt with autism between the
ages of 2 and 10 years and 45 children served as controls in the same age
range, after taken an informed consent and fill a questionnaire to assess the
risk factors. The samples were analyzed blindly for lead and mercury by using
atomic absorption and ICP-MS. Data from the two groups were compared, then
follow up of the autistic children after treatment with chelating agents were
done. RESULTS The results obtained showed significant difference among the two
groups, there was high level of mercury and lead among those kids with autism.
Significant decline in the blood level of lead and mercury with the use of DMSA
as a chelating agent. In addition, there was decline in the autistic symptoms
with the decrease in the lead and mercury level in blood. CONCLUSION Lead and
mercury considered as one of the main causes of autism. Environmental exposure
as well as defect in heavy metal metabolism is responsible for the high level
of heavy metals. Detoxification by chelating agents had great role in
improvement of those kids. http://www.ncbi.nlm.nih.gov/pubmed/25461563

“Lead and mercury considered as one of the main causes of autism. Environmental
exposure as well as defect in heavy metal metabolism is responsible for the
high level of heavy metals.”

Current Problems In Pediatric And Adolescent Health Care • November 2014

Environmental chemical exposures and autism spectrum disorders: a review of the
epidemiological evidence Author information Kalkbrenner AE1, Schmidt RJ2,
Penlesky AC1. 1. Zilber School of Public Health, University of
Wisconsin-Milwaukee, Milwaukee, WI 2. Department of Public Health Sciences,
University of California Davis School of Medicine, Davis, CA Medical
Investigation of Neurodevelopmental Disorders (MIND) Institute University of
California Davis, Sacramento, CA Abstract In the past decade, the number of
epidemiological publications addressing environmental chemical exposures and
autism has grown tremendously. These studies are important because it is now
understood that environmental factors play a larger role in causing autism than
previously thought and because they address modifiable risk factors that may
open up avenues for the primary prevention of the disability associated with
autism. In this review, we covered studies of autism and estimates of exposure
to tobacco, air pollutants, volatile organic compounds and solvents, metals
(from air, occupation, diet, dental amalgams, and thimerosal-containing
vaccines), pesticides, and organic endocrine-disrupting compounds such as flame
retardants, non-stick chemicals, phthalates, and bisphenol A. We included
studies that had individual-level data on autism, exposure measures pertaining
to pregnancy or the 1st year of life, valid comparison groups, control for
confounders, and adequate sample sizes. Despite the inherent error in the
measurement of many of these environmental exposures, which is likely to
attenuate observed associations, some environmental exposures showed
associations with autism, especially traffic-related air pollutants, some
metals, and several pesticides, with suggestive trends for some volatile
organic compounds (e.g., methylene chloride, trichloroethylene, and styrene)
and phthalates. Whether any of these play a causal role requires further study.
Given the limited scope of these publications, other environmental chemicals
cannot be ruled out, but have not yet been adequately studied. Future research
that addresses these and additional environmental chemicals, including their
most common routes of exposures, with accurate exposure measurement pertaining
to several developmental windows, is essential to guide efforts for the
prevention of the neurodevelopmental damage that manifests in autism symptoms.
http://www.ncbi.nlm.nih.gov/pubmed/25199954

Journal Of Developmental Physical Disability • February 2015

A Review of the Differences in Developmental, Psychiatric, and Medical
Endophenotypes Between Males and Females with Autism Spectrum Disorder Eric
Rubenstein, Lisa D. Wiggins, and Li-Ching Lee Department of Epidemiology Johns
Hopkins Bloomberg School of Public Health 615 N. Wolfe Street, Room E6032
Baltimore, MD 21205, USA Abstract Autism spectrum disorder (ASD) is over four
times more prevalent in males compared to females. Increased understanding of
sex differences in ASD endophenotypes could add insight into possible
etiologies and the assessment and management of the disorder. Consequently, the
purpose of this review is to describe current literature regarding sex
differences in the developmental, psychiatric, and medical endophenotypes of
ASD in order to illustrate current knowledge and areas in need of further
research. Our review found that repetitive behaviors and restricted interests
are more common in males than females with ASD. Intellectual disability is more
common in females than males with ASD. Attention to detail may be more common
in males than females with ASD and epilepsy may be more common in females than
males with ASD, although limited research in these areas prevent definitive
conclusions from being drawn. There does not appear to be a sex difference in
other developmental, psychiatric, and medical symptoms associated with ASD, or
the research was contradictory or too sparse to establish a sex difference. Our
review is unique in that it offers detailed discussion of sex differences in
three major endophenotypes of ASD. Further research is needed to better
understand why sex differences exist in certain ASD traits and to evaluate
whether phenotypic sex differences are related to different pathways of
development, assessment, and treatment of the disorder.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490156/

“Further research is needed to better understand why sex differences exist in
certain ASD traits and to evaluate whether phenotypic sex differences are
related to different pathways of development, assessment, and treatment of the
disorder.”

Journal Of Attention Disorders • September 2015

Are ASD and ADHD a Continuum? A Comparison of Pathophysiological Similarities
Between the Disorders Author information Kern JK1, Geier DA2, Sykes LK3, Geier
MR4, Deth RC5. 1. Institute of Chronic Illnesses, Inc., Silver Spring, MD, USA
University of Texas Southwestern Medical Center at Dallas, TX. USA 2. Institute
of Chronic Illnesses, Inc., Silver Spring, MD, USA 3. CoMeD, Inc., Silver
Spring, MD, USA 4. ASD Centers, LLC, Silver Spring, MD, USA 5. Northeastern
University, Boston, MA, USA jkern@dfwair.net Abstract OBJECTIVE The objective
of this study was to review and compare the similarities between autism
spectrum disorder (ASD) and ADHD with regard to symptomatology, neurological
deficits, metabolic and endocrine-related conditions, and brain pathology.
METHOD A comprehensive review of the relevant research literature was carried
out. RESULTS A number of important similarities between ASD and ADHD were
identified, including recent increases in prevalence, male-biased incidence,
shared involvement of sensory processing, motor and impulse control, abnormal
patterns of neural connectivity, and sleep disturbances. Studies suggest
involvement of androgen metabolism, impaired methylation, and heavy metal
toxicity as possible contributing factors for both disorders. CONCLUSION ASD
and ADHD share a number of features and pathophysiological conditions, which
suggests that the two disorders may be a continuum and have a common origin.
http://www.ncbi.nlm.nih.gov/pubmed/23074304

“ASD and ADHD share a number of features and pathophysiological conditions,
which suggests that the two disorders may be a continuum and have a common
origin.”

International Journal of Emergency Mental Health and Human Resilience • September 2015

Autism Spectrum Disorder in the Emergency Department: Looking Beyond Behavior
Richard E Frye Autism Research Program, Arkansas Children’s Hospital Research
Institute, Little Rock, AR, USA Department of Pediatrics, University of
Arkansas for Medical Sciences, Little Rock, AR, USA Corresponding Author :
E-mail: REFrye@uams.edu Abstract Autism spectrum disorder (ASD) is a complex
neurodevelopmental condition that is behaviorally defined by its
well-recognized impairments in verbal and non-verbal communication and social
interactions in addition to distinctive restrictive and repetitive behaviors
(APA, 1994). Over the past decades the incidence of this disorder has
dramatically increased. Although the reason or reasons for this increase is
still up for debate, the fact remains that ASD is now estimated to affect 1 in
68 children in the United States (Developmental Disabilities Monitoring Network
Surveillance Year Principal, Centers for Disease, & Prevention, 2014). ASD is
defined by behavioral manifestations, yet children with ASD have a high
prevalence of many medical conditions including recurrent infections
(Doshi-Velez, Ge, & Kohane, 2014), gastrointestinal (GI) disturbances (Chaidez,
Hansen, & Hertz-Picciotto, 2013), seizures and epilepsy (Frye et al., 2013),
anxiety (Sukhodolsky, Bloch, Panza, & Reichow, 2013), allergies (Angelidou et
al., 2011) and metabolic disorders (Frye & James, 2014; Frye & Rossignol, 2012)
including mitochondrial disease (Frye & Rossignol, 2011; Rossignol & Frye,
2012). With the increase in prevalence and the significant co-morbidity of
medical problems, it is likely that medical professionals in the emergency and
urgent care facilities will have increasing exposure to individuals with ASD
for urgent medical management, particularly acute behavioral dysregulation.
When this occurs it will be important to consider their special needs and
understand the unique manner in which common medical problem may present in
individuals with ASD. Indeed, children without typical communication skills,
aberrant behaviors may be the manner in which the child is communicating the
need for medical attention (Buie et al., 2010).

ASD is associated with a wide spectrum of behavioral manifestations. Some of
the most disruptive behaviors, referred to as aberrant behaviors, can cause
significant disability and distress to the patient and caregiver (Baghdadli,
Pry, Michelon, & Rattaz, 2014). Aberrant behavior is divided into subcategories
by the Aberrant Behavior Checklist (Slosson Educational Publications Inc, East
Aurora, NY). These categories include Irritability, Social Withdrawal,
Stereotypy, Hyperactivity and Inappropriate Speech. Irritability, which
includes severe tantrums, aggression, and self-injury, is one of the major and
most disruptive aberrant behaviors (Stigler, 2014). Irritability is commonly
treated with antipsychotic medication with or without behavior therapy (Aman et
al., 2009). Treating with a medication to suppression symptoms rather than
understanding if there is an underlying medical cause for such behaviors can be
problematic for several reasons. First, treating symptoms instead of
identifying a cause can lead to increased morbidity and mortality from an
undiagnosed disorder. Second, antipsychotic medications can detrimentally
affect glucose, cholesterol and lipids and weight, even in the shortterm
(Correll et al., 2009; Wink et al., 2014) and long-term anti-psychotic use
increases the risk for type II diabetes (Bobo et al., 2013) and can result in
tardive dyskinesia, a potentially permanent movement disorder (Correll & Kane,
2007). Thus, it may be best to look beyond the obvious of controlling behavior
and understanding what the behavior means in order to solve potentially
important medical conditions to improve the long-term health of a child with
ASD. Several examples are given below of the medical condition that can present
as behavioral dysregulation in children with ASD.

GI disturbances have been reported to occur in 9% to 70% of children with ASD,
with high quality studies suggesting that GI symptoms are very prevalent. GI
symptoms commonly manifest as behavioral manifestations in children with ASD
(Buie et al., 2010). For example, abdominal pain, gastroesophageal reflux
disease and/ or constipation can manifest as vocal symptoms such as frequent
repetitive throat clearing or swallowing and/or screaming, crying, whining or
sobbing for no reason; motor behaviors such as facial grimacing, teeth
grinding, chewing on clothes or other objects, applying pressure to the abdomen
or aggressive or self-injurious behavior; and/or general behaviors such sleep
disturbance or irritability (Buie et al., 2010). Thus, it is important to
obtain a GI history, including symptoms of gastroesophageal reflux, stool
frequency and consistency, and perform a careful GI examination to look for
abdominal distention and/or impaction. Many of the GI symptoms may drive
aberrant behavior through causing pain. When a child cannot communicate
verbally, aberrant and unusual behaviors may be the only manner in which the
child can communicate that pain exists. Thus, the clinician needs to have a
high index of suspicion for obvious and non-obvious sources of pain. For
example, head banging is sometimes associated with headache. Other sources of
pain not uncommon in childhood such as pharyngitis, sinusitis, otitis media and
dental caries, just to name a few, must also be considered. A trial of
analgesics might be appropriate if pain is believed to be driving the behavior.
Interestingly celecoxib has been shown to be an effective adjunctive treatment
to risperidone for irritability in a double-blind placebo-controlled trial.
(Asadabadi et al., 2013).

Full Report With References
http://www.omicsonline.com/open-access/autism-spectrum-disorder-in-the-emergency-department-looking-beyond-behavior-1522-4821-1000253.php?aid=61163

Sleep disruption is estimated to affect from 44% to 83% of individuals with
ASD, with delayed sleep onset and nighttime wakening being the most predominant
symptoms (Krakowiak et al., 2008). Several studies have demonstrated that
disruption in sleep patterns is associated with problem behaviors during the
day, particularly in low-functioning ASD individuals (Cohen et al., 2014), and
lower overall functioning in several measures of development including greater
problems with language and communication (Taylor, Schreck, & Mulick, 2012).
Melatonin is a safe and effective treatment sleep duration and sleep onset
latency but is less effective for night time wakening (Rossignol & Frye, 2011)
and has been shown to improve daytime behavior and parenting stress (Malow et
al., 2012). In addition, a case series reported that the selective melatonin
receptor agonist ramelteon can also be effective for improving sleep and
daytime behavior (Kawabe, Horiuchi, Oka, & Ueno, 2014). Thus, a careful focused
sleep history may provide important information which can lead to appropriate
evaluation and treatment. Anxiety is very common in ASD (Vasa & Mazurek, 2015),
particularly in high-functioning ASD children (Chandler et al., 2015). Anxiety
is related to aggressive behavior (Pugliese, White, White, & Ollendick, 2013),
more severe repetitive behaviors and lower overall development (Magiati et al.,
2015) and sleep disruption (Mazurek & Petroski, 2015). A wide variety of
treatments for anxiety have been studied in individuals with ASD. The best
studied treatments for anxiety in ASD include intranasal oxytocin (Hofmann,
Fang, & Brager, 2015) and cognitive-behavioral therapy (Ung, Selles, Small, &
Storch, 2015). Although selective serotonin reuptake inhibitors were previously
considered useful in the ASD population, such medications may increase the risk
of behavioral activation (Vasa & Mazurek, 2015) and may be best suited for
treating repetitive behavior (Hollander et al., 2012). Thus, it is important to
screen for symptoms of anxiety as such a significant psychiatric comorbidity
could be driving disruptive behavior. There appears to be a wide range of
behavioral manifestations that are related to immune dysregulation, although
the treatments for these disorders are not well studied. Pediatric Autoimmune
Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS), a
disorder which can result in sudden onset obsessive compulsive behavior, tics
and Tourette like behavior (Martino, Defazio, & Giovannoni, 2009), is
associated with ASD (Libbey & Fujinami, 2010). Recently PANDAS has been brought
in under the umbrella of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)

and recommendation for diagnostic workup have been outlined in a consensus
conference (Chang et al., 2015). The recent recognition of the association of
PANDAS/PANS with specific antibodies titers to basal ganglia has provided a
medical test to help with diagnosis of these patients (Cox et al., 2015). Other
immune abnormalities, which are less well-studied, have been reported. These
include the associated between depressed plasma immunoglobulin concentrations
with aberrant behavior (Heuer et al., 2008) and the recognition of a subset of
children with ASD with behavioral dysregulation following episodes of immune
activation (Jyonouchi, Geng, Streck, & Toruner, 2012). Although treatments for
immune abnormalities are not well studied, identifying immune abnormalities can
result in appropriate referral and treatment. A disorder related to depressed
folate concentration in the brain appears to be rather common is ASD and may be
related to behavioral dysregulation. The folate receptor alpha autoantibody is
prevalent in ASD with up to 75% of ASD patients being positive for the blocking
or binding autoantibody (Frye et al., 2013). Autoantibody titers are directly
correlated with increased aggressive behavior (Ramaekers et al., 2007). Titers
are increased by the ingestion of milk and behavior can be improved with the
treatment of a milk free diet (Ramaekers, Sequeira, Blau, & Quadros, 2008).
Since this autoantibody blocks the ability of folate from crossing the
blood-brain barrier, an alternative form of folate, high-dose folinic acid, can
improve behavior in ASD patient with folate receptor alpha autoantibodies (Frye
et al., 2013; Moretti et al., 2005). These medical conditions which are
associated with behavioral dysregulation are under recognized across many
medical settings, but it is of the upmost importance for medical professional
in the emergency and urgent care departments to recognize these potential
medical conditions since many children with ASD will arrive in the emergency
department when behavior suddenly escalates. Unfortunately, the evaluation of
children with ASD and behavioral dysregulation has not been standardized and
many of the medical abnormalities associated with behavioral dysregulation have
not been well studied, especially in regards to treatment. Recognition of these
conditions can lead to appropriate management and referrals. With the rising
number of children with ASD it is important for front line medical professional
to be comfortable with evaluating children with ASD and to consider the medical
complexities associated with ASD.

Behavioral Neurology • October 2015

Assessment of Hair Aluminum, Lead, and Mercury in a Sample of Autistic Egyptian
Children: Environmental Risk Factors of Heavy Metals in Autism Author
information Mohamed Fel B1, Zaky EA1, El-Sayed AB2, Elhossieny RM1, Zahra SS1,
Salah Eldin W3, Youssef WY1, Khaled RA1, Youssef AM1 1. Pediatrics Department,
Faculty of Medicine, Ain Shams University, Cairo, Egypt 2. National Institute
of Standards, Giza, Egypt 3. Community Medicine Department, Ain Shams
University, Cairo, Egypt Abstract Background and Aims. The etiological factors
involved in the etiology of autism remain elusive and controversial, but both
genetic and environmental factors have been implicated. The aim of this study
was to assess the levels and possible environmental risk factors and sources of
exposure to mercury, lead, and aluminum in children with autism spectrum
disorder (ASD) as compared to their matched controls. Methods. One hundred ASD
children were studied in comparison to 100 controls. All participants were
subjected to clinical evaluation and measurement of mercury, lead, and aluminum
through hair analysis which reflects past exposure. Results. The mean Levels of
mercury, lead, and aluminum in hair of the autistic patients were significantly
higher than controls. Mercury, lead, and aluminum levels were positively
correlated with maternal fish consumptions, living nearby gasoline stations,
and the usage of aluminum pans, respectively. Conclusion. Levels of mercury,
lead, and aluminum in the hair of autistic children are higher than controls.
Environmental exposure to these toxic heavy metals, at key times in
development, may play a causal role in autism.
http://www.ncbi.nlm.nih.gov/pubmed/?term=26508811

“Levels of mercury, lead, and aluminum in the hair of autistic children are
higher than controls. Environmental exposure to these toxic heavy metals, at
key times in development, may play a causal role in autism.”

Chapter Seven
Short Essays On Vaccination

Herd Immunity:
Can Infectious Diseases be Prevented by High Vaccination Coverage? By Lucija
Tomljenovic, PhD The frequent statement that high levels of vaccination prevent
disease outbreaks is not accurate as infectious diseases do in fact occur even
in fully vaccinated populations [1] as well as individuals. [2] (See Table 1
for more examples) The likely reason for this is that vaccines primarily
stimulate humoral immunity (antibody-based or Th2 responses) while they have
little or no effect on cellular immunity (cytotoxic T-cells, Th1 responses),
which is absolutely crucial for protection against viral as well as some
bacterial pathogens. [3] This may be the reason why vaccine-induced immunities
are transient, requiring booster shots; while naturally acquired immunity
conferred by the cellular immune system tends to be permanent in the absence of
vaccination. Taken together, these observations may explain why outbreaks of
allegedly vaccine-preventable diseases do occur in fully vaccinated populations
and why, immunity (or its absence) cannot be reliably determined by measuring
antibody levels, [4] which is the most common measure of vaccine efficacy in
clinical trials. [5-7] It should be noted that there is an instance where
vaccinations can induce T-cell (Th1) responses. This is possible in the case of
repetitive immunizations with the same antigen (i.e., closely spaced “booster
shoots”). However, the induction of such immune responses is deleterious as
demonstrated by Tsumiyama et al. [8] who showed that CD4+ T cells from
repeatedly-immunized mice acquire the ability to induce autoantibodies which
result in autoimmune tissue injury akin to that seen in human autoimmune
diseases. From these experiments Tsumiyama et al. [8] concluded that systemic
autoimmunity appears to be the inevitable consequence of over-stimulating the
host’s immune ‘system’ by repeated immunization with antigen. Full Report
http://sanevax.org/wp-content/uploads/2015/05/Herd-Immunity-.pdf

Forced Vaccinations: For the Greater Good?
by Lucija Tomljenovic, PhD Full Report
http://vaccinechoicecanada.com/wp-content/uploads/Forced-Vaccinations-For-the-Greater-Good-Tomljenovic.pdf

Dr. Lucija Tomljenovic was awarded a PhD in 2009 in Biochemistry from the
Comparative Genomics Centre at James Cook University in Townsville, Australia.
In 2010, she joined the Neural Dynamics Research Group at the University of
British Columbia (Chris Shaw’s lab) and is currently researching the neurotoxic
effects of aluminium vaccine adjuvants.

Lawsuits claiming Merck lied
about mumps vaccine efficacy headed to trial September 9, 2014 by Carly Helfand
Two lawsuits claiming Merck ($MRK) lied about the efficacy of its mumps vaccine
won’t be going away anytime soon. A federal judge in Pennsylvania refused to
dismiss the suits, filed by a pair of whistleblowers and a group of doctors and
payers, and now, they’re on their way to trial. On Thursday, U.S. District
Judge C. Darnell Jones II ruled that the whistleblowers--two former Merck
virologists-had sufficiently showed that the company may have misstated the
vaccine’s efficacy to the government, Law360 reports. And the direct purchasers
produced enough evidence to establish that those false statements could have
helped give Merck a monopoly, the judge said. Now, the plaintiffs will have to
prove their cases at trial. Merck has been the sole manufacturer with an FDA
license to produce mumps vaccine since 1967, the news service points out, and
the company has long touted a 95% efficacy rate for the shot. The drugmaker
brought in $621 million on mumps vaccine sales last year, between its M-M-R II
vaccine and ProQuad, a pediatric combo jab. But rather than using the “gold
standard” approach and testing the vaccine against a wild-type mumps virus,
Merck tested it against the attenuated virus strain that had created the
vaccine in the 1960s--likely overstating the vaccine’s effectiveness, the
whistleblowers claim, according to the judge’s memorandum. And if Merck
“fraudulently misled the government and omitted, concealed, and adulterated
material information regarding the efficacy of its mumps vaccine” in violation
of the False Claims Act, as they allege, it may have discouraged competition.
“As with the market for any product, a potential competitor’s decision to enter
a market hinges on whether its product can compete with those products already
being sold in the market,” the complaint reads, as quoted by Law360. “If an
existing vaccine is represented as safe and at least 95% effective, as Merck
has falsely represented its vaccine to be, it would be economically irrational
for a potential competitor to bring a new mumps vaccine to the relevant
market,” the suit claims. The way Merck sees it, whether it misstated the
vaccine’s efficacy is a matter for the FDA to investigate. The company argued
that the whistleblowers’ claims “rest on a finding that the vaccine label is
misbranded, a determination which should fall squarely under the ‘scientific
expertise’ and ‘regulatory discretion’” of the agency, the memorandum says. But
Jones didn’t agree, and now it’ll be up to the courts to decide--a prospect
that pleases Constantine Cannon, which is representing the whistleblowers, and
Robins Kaplan Miller & Ciresi, representing the direct purchasers. “This
decision brings us one step closer to shining a light on Merck’s deceptive
business practices so that new and more effective vaccines will ultimately be
developed in the future,” Robins Kaplan Miller & Ciresi lawyer Kellie Lerner
said in a statement. Read the judges Memorandum
http://assets.fiercemarkets.net/public/merckmemo.pdf

CDC Responds to Allegation it Omitted Vaccine-Autism Study Link
by Sharyl Attkisson • August 28, 2014 The Centers for Disease Control and
Prevention (CDC) is responding to a charge from one of its own senior
scientists that it omitted key data in a 2004 study that would have revealed a
link between autism and a commonlyrequired childhood vaccine, MMR (Measles,
Mumps, Rubella). The allegation was made by CDC epidemiologist William Thompson
in a statement this week issued through his attorney. It states: “I regret that
my coauthors and I omitted statistically significant information in our 2004
article published in the journal Pediatrics. The omitted data suggested that
African American males who received the MMR vaccine before age 36 months were
at increased risk for autism.” It is highly unusual, if not unprecedented, for
a sitting CDC senior scientist to blow the whistle on alleged scientific
misconduct involving a study article that he co-authored. In this instance, the
impact of the charge is magnified by more than a decade of allegations from
autism advocates who say the federal government and pharmaceutical interests
have worked to downplay or hide associations between vaccines and autism.

“[Vaccine] exposure around [three years of age] is just not biologically
plausible to have a causal association with autism,” DeStefano says. “I mean
autism would’ve already started by then…it probably starts in the womb. So I
think from a biological argument, it’s implausible this was a causal
association.” Highly-Charged Issue The issue is highly-charged for several
reasons: public health officials fear that the public will panic and stop
vaccinating if they believe there are links between vaccines and autism. That
could lead to resurgence in serious infectious diseases. Also, vaccination is a
multi-billion dollar global industry that employs law firms and public
relations agents to engage in a variety of high-powered PR efforts. These
efforts include: lobbying members of Congress to prevent hearings exploring
vaccine safety, holding private meetings with news executives to discourage
reporting on vaccines and autism, and financing nonprofits which take favorable
positions on vaccine safety issues. Because pharmaceutical companies that
produce vaccines spend millions of dollars each year buying advertising on
television, print and online, critics argue they may be given undue influence
over content of the reporting media.

Dr. Frank DeStefano, CDC Director of Immunization Safety

Pharmaceutical interests and their surrogates routinely falsely portray
scientists and journalists who investigate vaccine safety as “anti-vaccine.” In
his statement, Thompson emphasizes his safety concerns do not reflect an
“anti-vaccine” mentality.

A spokesman for the journal Pediatrics today said the publication stands by the
study despite the news. “There’s a standard process that journals follow when
an article is questioned,” said the spokesman. “Those discussions took place
between the editors of Pediatrics and the authors of this study, and the
editors concluded the research was appropriately conducted.” Pediatrics is
published by the American Academy of Pediatrics, which accepts vaccine industry
funding.

“I want to be absolutely clear that I believe vaccines have saved and continue
to save countless lives,” Thompson states. “I would never suggest that any
parent avoid vaccinating children of any race. Vaccines prevent serious
diseases, and the risks associated with their administration are vastly
outweighed by their individual and societal benefits.

The Director of the CDC Immunization Safety Office, Dr. Frank DeStefano, is a
co-author of the now-questioned study which has been widely-cited to dispel an
MMR-autism link. DeStefano is frequently quoted as an expert who debunks
vaccine-autism ties.

“My concern has been the decision to omit relevant findings in a particular
study for a particular sub group for a particular vaccine. There have always
been recognized risks for vaccination and I believe it is the responsibility of
the CDC to properly convey the risks associated with receipt of those
vaccines.”

“I stand by the research and the conclusions in our 2004 paper, and I’ll
reiterate that the evidence, thus far, the weight of the evidence, is against a
causal association between vaccines and autism,” DeStefano told me in a
telephone interview this week.

Subgroup Susceptibility?

“Lowest Point in my Career” Thompson is a PhD who works in the National
Immunization Program at the CDC where he has been employed for 16 years. His
revelations were first made public after he reportedly made wide-ranging claims
and confessions in a series of telephone conversations with autism advocate and
researcher Brian Hooker of Focus Autism. Hooker, also a PhD, is an assistant
professor of biology and the parent of an autistic teenager. Because of the
significance of Thompson’s allegations, Hooker began recording some of the
conversations without Thompson’s knowledge. “It’s the lowest point in my career
that I went along with that paper,” Thompson tells Hooker in a recording played
on the online Autism Media Channel. “I went along with this, we didn’t report
significant findings.” The CDC’s DeStefano acknowledges that he and his study
co-authors changed their study analysis plan midstream, which resulted in
reducing the statistical vaccine-autism link among black boys. But he says they
did so for good scientific reason.

Former National Institutes of Health Director Dr. Bernadine Healy broke ranks
with her Institute of Medicine colleagues in 2008 in saying that public health
officials have intentionally avoided researching whether subsets of children
are “susceptible” to vaccine side effects because they are afraid that the
answer will scare the public. “What we’re seeing in the bulk of the population:
vaccines are safe,” said Healy. “But there may be this susceptible group. The
fact that there is concern, that you don’t want to know that susceptible group
is a real disappointment to me. If you know that susceptible group, you can
save those children. If you turn your back on the notion that there is a
susceptible group… what can I say?” “You’re saying that public health officials
have turned their back on a viable area of research largely because they’re
afraid of what might be found?” I asked Healy, at the time. Healy answered,
“There is a completely expressed concern that they don’t want to pursue a
hypothesis because that hypothesis could be damaging to the public health
community at large by scaring people. “First of all,” Healy said, “I think the
public’s smarter than that. The public values vaccines. But more importantly, I
don’t think you should ever turn your back on any scientific hypothesis because
you’re afraid of what it might show.” To date, the only vaccine that carries an
explicit autism warning under “Adverse Reactions” on its label is Tripe-

dia’s DTaP (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) vaccine. The label states
that “autism” is included, along with SIDS, encephalopathy (brain damage) among
other adverse events “because of the seriousness or frequency of reporting.”
The label states, “Because these events are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate
their frequencies or to establish a causal relationship to components of
Tripedia vaccine.” The CDC’s MMR vaccine information page cites the following
“very rare” severe problems: “deafness, longterm seizures, coma, or lowered
consciousness and permanent brain damage.” This week, in response to a query,
the CDC stated that it is not currently investigating the relation between
vaccines and autism spectrum disorders (ASD). “Further, CDC does not have any
planned research addressing vaccines and autism,” said a CDC spokesman. “CDC
believes that this topic has been thoroughly studied and no causal links have
been found. Current CDC ASD related research focuses on determining how many
people have ASD and understanding risk factors and causes for ASD.”–CDC
spokesman In his statement, Thompson says that his colleagues and supervisors
at the CDC have been entirely professional since his allegations became public.
“In fact, I received a performance-based award” after the news came out, he
says. Further responding to Thompson’s allegations, the CDC says, “Additional
studies and a more recent rigorous review by the Institute of Medicine have
found that MMR vaccine does not increase the risk

CDC: “Possibility” that vaccines rarely trigger autism

the Kennedy Krieger Institute, stated that he had “personally witnessed
[Hannah’s] developmental regression” following “vaccine-induced fever and
immune stimulation.”

September 2014

CDC’s immunization safety director says it’s a “possibility” that vaccines
rarely trigger autism but “it’s hard to predict who those children might be.”
(They’re not even trying.)

Zimmerman concluded that Hannah was vulnerable to vaccine injury because she
had a metabolic disorder called mitochondrial dysfunction. While vaccines are
safe for most children, in Hannah, they triggered a brain injury, according to
Zimmerman. Whether vaccines “caused” or “triggered” Hannah’s autism, the result
was the same: but for her vaccinations, Zimmerman said, “Hannah may have led a
normal full productive life.” Instead, she suffers “significant lifelong
disability.”

A CDC senior epidemiologist stepped forward last week to say that he and his
CDC colleagues omitted data that linked MMR vaccine to autism in a 2004 study.
The scientist, William Thompson, said “I regret that my coauthors and I omitted
statistically significant information.” A coauthor of the questioned study is
Dr. Frank DeStefano, Director of the CDC Immunization Safety Office. In a
telephone interview last week, DeStefano defended the study and reiterated the
commonly accepted position that there’s no “causal” link between vaccines and
autism. But he acknowledged the prospect that vaccines might rarely trigger
autism.

A second underlying condition that was aggravated by vaccines, resulting in
mental retardation and autism, is tuberous sclerosis or “TS,” according to a
1986 vaccine court case. According to the National Institutes of Health, TS
affects 1 in every 6,000 newborns. Not all children who developed autism as a
result of vaccine injuries, as determined by vaccine court, had identifiable
pre-existing conditions. But I asked the CDC’s DeStefano whether it was worth
trying to figure out what underlying conditions put kids at risk so they can be
tested in advance and, if vulnerable, spared.

“I guess, that, that is a possibility,” said DeStefano. “It’s hard to predict
who those children might be, but certainly, individual cases can be studied to
look at those possibilities.”

“That’s very difficult to do,” DeStefano told me. He said the CDC’s priorities
are gaining a better understanding of the pathogenesis, genetics and biology of
autism. “And then, I think… it’d be more feasible to try to establish if
vaccines in an individual case, say a person with a certain set of genes…if we
ever get to that point, then that kind of research might be fruitful.”

by Sharyl Attkisson

It is a significant admission from a leading health official at an agency that
has worked for nearly 15 years to dispel the public of any notion of a tie
between vaccines and autism. Vaccines are among the most heralded medical
inventions of our time. Billions of people have been vaccinated worldwide,
countless lives have been saved and debilitating injuries prevented. The
possibility that vaccines may also partly be responsible for autism, in
individual cases, is not something public health officials are typically eager
to address. One such individual case is that of Hannah Poling. Hannah Poling
Hannah Poling was considered normal, happy and precocious until 19 months of
age when she was vaccinated against nine diseases in one doctor’s visit:
measles, mumps, rubella, polio, varicella, diphtheria, pertussis, tetanus, and
Haemophilus influenzae. Afterward, she developed high fevers, had screaming
fits, stopped eating, didn’t respond when spoken to and began showing signs of
autism. As vaccination has grown into a multi-billion dollar industry, children
have gone from being inoculated against four diseases in 1953 to today’s
recommended schedule of shots for 16 diseases requiring 49 doses by age 6. The
government and pharmaceutical industry have said evidence shows babies’ systems
can easily handle the immune boost. In federal “vaccine court,” the U.S.
government defends injury claims on behalf of vaccine makers In 2002, Hannah’s
parents—her father a neurologist, her mother a nurse and attorney—filed a claim
in a specially-created federal vaccine court in which the U.S. Department of
Justice defends vaccine interests. Hannah was to serve as a test case to help
decide the outcome of thousands of vaccine-autism claims. The case was strong.
In 2007, contemplating Hannah would win her claim, sources say the vaccine
court analyzed what the broader financial impact might be. It found that a
flood of similar vaccine-autism claims would quickly deplete the government’s
vaccine injury compensation fund, which is supported by a small fee patients
pay on each dose of vaccine. But instead of allowing Hannah’s case to publicly
serve as a precedent for other possible victims, the government took another
course: it quietly settled the case and sealed the results. Other families with
autistic children were never to know. Hannah’s family petitioned the court to
be allowed to reveal the findings but the government fought to keep the case
sealed—and prevailed. Still, news of Hannah’s case leaked out in 2008—along
with the medical explanation for her vaccine-related “autistic encephalopathy
[brain damage].” Vaccines prevent many diseases that once routinely killed or
harmed. But can vaccines trigger autism in a small subset of vulnerable
children? In a court-submitted opinion, neurologist Dr. Andrew Zimmerman,
Director of Medical Research at

Not worthy of study? But it turns out the CDC has ruled out that sort of
research. A CDC spokesman told me that the agency is not “currently
investigating the relation between vaccines and autism spectrum disorders
(ASD). Further, CDC does not have any planned research addressing vaccines and
autism.” As of May, 2010 the government had compensated 1,296 vaccine brain
damage (encephalopathy/encephalitis and seizure cases) but was not tracking how
many of the brain-injured children specifically ended up with autism. “CDC
believes that this topic has been thoroughly studied and no causal links have
been found,” said the spokesman in an email. “Current CDC ASD related research
focuses on determining how many people have ASD and understanding risk factors
and causes for ASD,” said the CDC. Seven years after Hannah’s case settled,
twentyeight years after the TS case, it’s impossible to know how many similar
children, if any, are out there. And the government isn’t trying to find out.
Attkisson: And is, is the pos—the current position that any potential link
between vaccines and autism, secondary, any kind at all, has been entirely
ruled out 100%? DeStefano: I re, you know, I re—uh, I think every hypothesis
that’s been looked at has been, uh, ruled out. Attkisson: But, I mean, are you,
are you, can I say the CDC’s position is that if anybody thinks there’s
anything anymore, it’s a myth? It’s all been disproven? DeStefano: Wouldn’t say
it’s a myth, I’d say, you know, all the evidence, thus far, points to that
there’s not a causal association between vaccines and autism. Attkisson: What
about secondary? DeStefano: Sec—I don’t understand what do you mean
“secondary”? Attkisson: What about not “causal,” but “as a result of” vaccines,
as in the Poling case? The medical expert found, you know, as a result of the
damages she had from the vaccines, she ended up with autism. And the distinc-

tion was made in the medical expert, ‘well, that’s not ‘causal’, it’s sort of a ‘but for’ but it’s not a ‘causal.’
DeStefano: Yeah, I mean, I mean in that case, you know, she had a, I mean, you
know, she had an underlying uh biological illness that uh either vaccination,
or it could’ve been an infection that that would trigger some physiological
stress in her, uh, seems to have, you know, could’ve, could’ve caused uh, um,
manifestations that, characteristics of autism which, you, you know, appears to
be what happened in her case. Attkisson: But I mean doesn’t that, is—isn’t that
a “link”? It’s not a “causal” link, but isn’t that a potential link between
vaccination and autism if certain children with a “underyling biological
illness” can have a “trigger” through vaccination? DeStefano: [Unintell] as you
call it, a secondary link if you wanna call it that way, w– in certain
children, I mean ri—I mean, I, maybe that, but, you know, then I guess, that,
that is a possibility. Attkisson: Do you think that’s an important area of
study so we could figure out which kids might have that predisposition?
DeStefano: uh, [phone noise] Yeah, I mean, I think um…You know, I think it’s
something that, uh, well I mean, you know, in terms of uh… I mean, It’s hard,
it’s hard to say, you know, I mean it’s like, um…I mean how how important that
is. I mean, it’s a theoretical possibility, I guess the, the Poling case maybe
suggested it could happen. Uh, but [unintell] cause it’s hard to predict who
those children might be, but certainly, um individual cases, uh, can be studied
to try to, uh, to look at those, uh, those possibilities. Attkisson: Well I
would just think—and then, then I’ll let you go in a few minutes unless you
have more time— but as a parent, if my kid had whatever Poling had and we could
figure that out, that would be one kid you would cull out [from vaccination]
versus not worry about other kids if they don’t have that predisposition. But
maybe you could identify the ones that would be vulnerable. But I haven’t seen
that there’s any—is there an area of study trying to do such a thing within CDC
or funded by CDC? Or NIH? DeStefano: Well, in terms of like, you know, the area
at CDC that’s that’s studying autism and possible causal relationships of
autism, uh, you know, whatever they may be, uh, is in the Center the National
Center for Birth Defects and Developmental Disability, and they, they do
monitoring for autism prevalence and they do have, uh, studies trying to go on,
you know, going on to, to look at, uh, a number of factors that could be, uh,
related to, uh, increasing the risk of autism or causing autism. Attkisson: I
mean I think to sum up, you’re you’re saying what I, what I think is also the
case just based on my own research: that while the government has ruled out any
known “causal” link between autism and vaccines, it hasn’t ruled out the
possibility, and in fact there seems to be at least one case where it’s
acknowledged what I called a “secondary” link, meaning not “causal” but uh
“triggered.” And the result for the parent, you know, may–to them it may be one
and the same. And they may be trying to figure out which kids, you know, might
have that predisposition. DeStefano: Yeah, but you know, that’s very difficult
to do. That’s almost circular reasoning, say, you know, kind of, you can’t, I
mean, you know, the, the useful thing for parents who are clinically would be
able to identify the kids who are gonna have, I mean, this way we’re
identifying one certain child after the fact and say, you know, maybe in that
one child, it was this or that that happened to him. But uh, it’s very
difficult to make a causal link in in just one case. Attkisson: Well, but isn’t
that what you guys are supposed to do, figure it out? That’s a, as you know,
autism is such a huge problem, even if a teeny percentage is perhaps triggered
by vaccination, I would think that’d be very, very important to, to learn and
try to figure out. You guys are the best at it, I’m sure somebody there can do
it over time. DeStefano: Yeah…[unintell] I think…[unintell] have a better
understanding of uh of the pathogenesis of autism and the genetics and the
biology and then, I think, I mean, and then, and then, with these individual
cases, it’d be, you know, more feasible to try to establish if, uh, if, if
vaccines in an individual case, say a person with a certain, certain set of
genes or something, you know, if we ever get to that point, then that kind of
research, uh, might be fruitful, you know.
https://sharylattkisson.com/cdc-possibility-that-vaccines-rarely-trigger-autism/

June 2011

Basics of the Human Immune System Prior to Introduction of Vaccines: Are
Vaccines Turning Our Children’s Immune Systems Inside Out? Harold E Buttram, MD
and Catherine J Frompovich There is a universal principle referred to as
“atrophy of disuse” which, as far as can be determined, applies to all
physiologic processes of the human body. Although a normal full-term infant
comes into the world with virtually all of the brain cells (neurons) that it
will ever have, the brain continues to grow from increasing numbers of glial
(connective tissue) cells and dendrite branching extensions that continue
throughout life with mental activity. As an example, the story is told of two
sisters who were identical twins and entered a nunnery, one gravitating into
administrative work, the other into menial labor. With the passage of years the
former remained mentally alert and bright, while the latter lapsed into
Alzheimer’s disease from brain atrophy. As a brief review of Part 1, the human
newborn comes into the world with temporary protection from residual maternal
antibodies. Otherwise the infant’s immune system is rudimentary, requiring a
series of challenges to become fully functional, which is around three years of
age. Although the so-called minor childhood diseases of earlier times were
looked upon as nuisances (chickenpox and mumps) or potentially dangerous
(measles and rubella), they may have evolved as friends-in-disguise by
challenging and therefore uniquely activating and strengthening both epithelial
and endothelial tissues, their respective organs, and lymph nodes. Those
natural diseases also had the advantage of conferring permanent immunity, which
is not necessarily the case with vaccines as attested to with revaccination
every few years and higher percentages of infectious disease among those
vaccinated. Concerning the dangers of measles, aside from hygiene and
sanitation, this largely involves personal disciplines in terms of diet,
nutrition, and other health habits in which restriction/avoidance of sugar
plays a prominent role along with abundant dietary sources (fresh fruits and
vegetables) containing vitamins C and A. Nutrient deficiency may be an
underlying reason that flu epidemics tend to occur over holidays, when people
are inclined to overindulge in sweet treats and alcoholic beverages, which
metabolize like sugar in the body. There is an experimental basis for
demonstrating sugar’s paralyzing effects on the immune system. As demonstrated
by Professor Emanuel Cheraskin at the Alabama University Medical School, blood
samples were drawn from students before and after drinking a single soft drink
(soda). White cells were siphoned from the blood samples and the white cells
inoculated with staphylococcus microorganisms. After a period of incubation,
the number of staphylococcus phagocytized (engulfed) by the white cells were
counted under a microscope. The numbers of engulfed staphylococcus were reduced
by more than half following consumption of the soft drink, indicating that the
white cells were significantly paralyzed and crippled by that sugar-containing
beverage. [1] Also pertinent was a study conducted in Afghanistan in which 200
children with measles were divided into two groups, one of which received
aspirin and Tylenol® to lower fever, the other not receiving aspirin or
Tylenol®. The children receiving antipyretics had more prolonged illnesses,
more diarrhea, ear infections, respiratory complications such as pneumonia and
bronchitis, and higher death rates. [2]

Concerning the chickenpox (varicella) vaccine, articles by Gary Goldman
seriously question the advisability of universal varicella vaccination as
related to increasing subsequent occurrences of herpes zoster (shingles or
zona). [3-4] The differing functions of the Th1 cellular and Th2 humoral immune
systems were summarized in a review article by P. Kidd: “The Th1 cells are
hypothesized to lead the attack against intracellular pathogens such as
viruses, raise the classic delayed-type to viral and bacterial antigens, and
fight cancer cells. The Th2 cells are believed to emphasize protection against
extracellular pathogens. On the negative side, the Th1 pathway is often
portrayed as being the more aggressive of the two, and when it is overreactive,
can generate organ-specific autoimmune disease (e.g. arthritis, multiple
sclerosis, type 1 diabetes). The Th2 pathway is seen as underlying allergy and
related IgE disease.” [5] Regarding vaccines and their propensity toward
fostering allergies, Imani and Kehoe found a previously unrecognized side
effect of the MMR vaccine by incubating it with a line of human plasma cells,
which resulted in increased expression of allergy-related IgE antibodies
accompanied by a corresponding decrease in protective IgG antibodies. Based on
these findings, the authors concluded that viral vaccines might be playing a
role in the increasing incidence of asthma and other allergic diseases. [6]
Much the same also holds true for a causal relationship between vaccines and
the rising incidence of juvenile diabetes. In 1998 John Classen, MD, gave a
presentation at a conference held by the American College of Medicine in which
he reviewed 32 published articles, five authored by himself, indicating a
causal relationship between vaccines and the rising incidence of
insulin-dependant diabetes mellitus (IDDM). Nations represented in the papers
included New Zealand, Canada, the United Kingdom, Denmark, Finland, Sweden, the
USA, and Holland. Single vaccines were used including haemophilus influenza,
hepatitis B, pertussis, BCG, and smallpox. A prototype study was conducted in
Finland by Classen and reported in the British Medical Journal. [7] In this
study, from all children born in Finland between October 1, 1985 and August 31,
1987, approximately 116,000 were randomized as test subjects to receive four
doses of haemophilus vaccine starting at three months of age, or one dose
starting at 24 months. Additionally, 125,000 unvaccinated children served as
controls. Each group was followed until age 10 years for development of IDDM.
The incidence at seven years for those receiving four doses, those receiving
one dose, and those receiving none was 261, 237, and 207 respectively with
relative risks of 1.2, 1.14, and 1 for those children receiving no vaccine. In
virtually all of the reports from other countries the results were very
similar, indicating a slight but consistent increase in IDDM following each of
the five single vaccines listed above. Classen interpreted these results as
indicating that it was not the type of vaccination that mattered so much as the
immunologic impact of vaccination itself. Typically there was a 3 to 5 year
delay between vaccines and onset of IDDM. Quotations by Classen during the 1998
conference included: “Vaccinating every child against every disease is
fundamentally unsound.” “There is a 3.78-fold increased risk of
insulin-dependent diabetes mellitus in children from today’s vaccines.” “All
autoimmune diseases are increasing in incidence. General immune (over)
stimulation from vaccines is a cause of autoimmunity.“

Genetic Exchanges in the World Around Us
Barbara McClintock, the 1983 Nobel Laureate “Corn Lady,” was the first to
discover genetic mobility in the socalled jumping genes in the 1930s. For over
50 years she pursued solitary research with corn, uncovering some of nature’s
innermost secrets about life. McClintock studied maize, a form of Indian corn,
where distribution of red kernels and yellow kernels is genetically determined.
What she first perceived was that some of the genes were moving from one place
to another on the cell’s chromosomes (the floating threads on which genes are
lined like beads on a string). She then saw patterns in the movements, with
sharply differing results in the colored kernels, and realized that some genes,
once moved into position, switched other genes on or off. It followed that
while most genes were workers, others were controllers or managers of genes.
According to an article in World Medicine [8] scientists at the University of
Geneva made the startling discovery that biological substances entering
directly into the bloodstream may truly become a part of us, even a part of our
genetic material. The article stated in part: “When Japanese bacteriologists
discovered that bacteria of one species transferred their own highly specific
antibiotic resistance to bacteria of an entirely different species, they seemed
to hit on a unique if not startling phenomenon. Dr. Maurice Stroun and Dr.
Phillippe Anker, with colleagues in the Plant Physiology Department at the
University of Geneva, have now accumulated a wealth of evidence that the
transfer of genetic information is not confined to bacteria but also can occur
between bacteria and higher plants and animals. “Dr. Stroun and colleagues did
most of their research in plants but have now turned to animals. In their
latest experiments they used the isolated auricles of frogs’ hearts, [9] from
which they dipped RNA extracted from the frog auricles into a bacterial
suspension, resulting in a high percentage interlinkage of frog RNA with
bacterial DNA.” The article concluded that the implications of this work on
“transcession” are enormous and reflect something that may be commonly taking
place in human bodies. From the standpoint of future generations, the
possibility that vaccines may be bringing about genetic hybridization in our
children may represent far and away the greatest hazard of today’s childhood
vaccine programs. A Case On Point During June 2011 a great number of German
E.coli infections (3,406) and 39 deaths have occurred with suspicions that
organically grown bean sprouts are the source of contamination. The findings
have vacillated from yes, it was the sprouts to no, it was not the sprouts to
now as of this writing, it IS the sprouts. However, the real issue may be more
than bean sprouts, if they truly are the source of contamination and not a
scapegoat. It seems the medical profession did not recognize that they were
dealing with a rare strain of E.coli, O104:H4. “What most predominantly
differentiates O104 from O157 is its adoption of numerous traits not typically
found congregated in one strain: Not only does it produce the noxious Shiga
toxin of the virulent enterohemorrhagic strains, it also possesses defensive
enteroaggregative traits –a combined mouthful of properties much more difficult
to tolerate physically than verbally.” “When people come into a hospital with
bloody diarrhea, they would normally assume it’s O157 and not give antibiotics
to the patients,” he said. “In this case, because it wasn’t O157, the
physicians might have thought it was okay to give antibiotics, not knowing that
O104 would produce the Shiga toxin.”

“This potential misunderstanding over antibiotics might at least partially
explain the high rate of HUS [hemolytic-uremic syndrome] among the ill. Girón
[Jorge Girón, Ph.D., E. coli researcher and associate professor of microbiology
at the University of Florida’s Emerging Pathogens Institute] said this outbreak
may necessitate new screening procedures at hospitals to account for O104
alongside O157, ensuring patients don’t receive antibiotics that could
exacerbate their illness or kill them.” [Emphasis added] [11] The above may be
the classic example needed to illustrate the unknowns involved in vaccine
pharmacology and morphology, and medicine’s inability or unwillingness to
address that aspect of vaccinology. Are Vaccines Sowing the Seeds of Genetic
Change? As reviewed above, the first six months of an infant’s life is a period
of heightened vulnerability because of the infant’s immature and rapidly
growing nervous system and highly immature immune system. It is during this
time-period that 19 or 20 vaccines are routinely administered, according to
officially recommended schedules, irrespective of whether the infant was born
prematurely, a condition that apparently predisposes preterm infants to a
series of vaccine adverse reactions. [12] A very revealing study reported in
Virus Research tends to support the hypothesis of genetic exchange associated
with viral vaccines. In the study of 24 passages of a nuclear polyhedrosis
virus through cell cultures, there were both insertions and deletions in the
virus, [10] suggesting that the virus freely exchanged genetic material with
the tissues in which it was cultured [similar to transcession discussed above].
Considering that today’s vaccines have been incubated in cell cultures of
aborted fetuses, monkey kidneys, and other animal tissues, this should give any
thinking person pause to consider the possible implications involved in
manufacturing, injecting, and receiving vaccines. Dr. Buttram discusses the
immune system and the impact that vaccines have upon it in his book, A
Commentary on Current Childhood Vaccine Programs, ISBN: 1-891485-30-X),
published in 2010 by Philosophical Publishing Co., PO Box 77, Quakertown, PA
18951, phone 215-538-5300. Catherine J Frompovich is the author of Our Chemical
Lives And The Hijacking Of Our DNA available on Amazon.com here. References: 1.
Information presented at a lecture by Dr. Cheraskin in the 1970s. 2. Ahmady, AS
et al. The adverse effects of antipyretics in measles. Indian Pediatrics. Jan.
1981; 49-52. 3. Goldman, GS. Universal varicella vaccination: Efficacy trends
and effect on herpes zoster. Intern Journ Toxicol. 2005; 24: 205-213. 4.
Goldman, GS. The case against universal varicella vaccination. Intern J
Toxicol, 2006; 25:313-317. 5. Kidd, P. TH1/TH2 balance: The hypothesis, its
limitations and implications in health and disease. Altern Med Rev. 2003;
8:223-246. 6. Imani, E and Kehoe, KE. Infection of human B-lymphocytes with MMR
vaccine induces IgE class switching. Journ Clin Immunol. 2001; 100(3):355361.
7. Classen, JB and Classen, DC. Association between type 1 diabetes and Hib
vaccine, causal relation likely, British Med Journ. 1999; 319: 1133. 8. World
Medicine (Scientific News Report): Mobility of genetic material between life
forms, 1971, Sept. 22nd, London: Clareville House, Oxendon St: 69-72. 9. Anker,
P and Stroun, M. Transcription of spontaneously released bacterial
deoxyribonucleic acid in frog auricles, Journal of Bacteriology, 1973; 114:
114-120. 10. Kumar, S and Miller, IK. Effects of serial passage of Autographa
californica nuclear polyhydrosis virus to cell culture. Virus Research. 1987;
7: 335-349. 11. Food Safety News, 0104:H4 May Change How We Deal With E. coli
http://www.foodsafetynews.com/2011/06/e-coli-expert-weighs-in-with-factsabout-o104h4/
Accessed June 16, 2011. 12. Pourcyrous M, Korones SB, Kristopher LA, Bada HS.
Primary immunization of premature infants with gestational age <35 weeks:
Cardiorespiratory complications and C-reactive protein responses associated
with administration of single and multiple separate vaccines simultaneously. J
Pediatrics. 2007:151, p. 171.
- See more at:
  http://www.vaccinationcouncil.org/2011/06/21/risks-damage-basics-of-the-human-immune-system-prior-to-introduction-of-vaccinesare-vaccines-turning-our-childrens-immune-systems-inside-out-part-2/#sthash.SG9xMVCU.dpuf

Government Wipes Recent Vaccine Injury Data From Website

Older Data Doesn’t Reflect Uptick in Awards to Vaccine Victims

December 30, 2015 • Sharyl Attkisson

HRSA says vaccine makers had no influence over the decision to revert to older
data. The agency said it did so to synch up with a statistic the Centers for
Disease Control (CDC) provides for the same chart that is only current through
2013: the number of vaccine doses distributed in US. “An internal decision was
made to ensure that all internal data was consistent…and to update [the chart]
only when all relevant data was available,” said HRSA in a statement.

In March, the federal government removed the latest vaccine injury court
statistics—more than a year’s worth of data—from one of its publicly reported
charts. It was an abrupt departure from the normal practice of updating the
figures monthly. Wiping the latest data means the “adjudication categories by
alleged vaccine” chart on a government website no longer reflects the recent,
sharp rise in court victories for plaintiffs who claimed their children were
seriously injured or killed by one or more vaccines. Since January of 2014, the
number of flu vaccine cases conceded by the government is more than double the
previous eight years combined. The adjudication chart only reflects half of the
current number. Concessions Won by Flu Shot Victims since 2006 Chart shows
(through 2013): 42 Actual number (through April 2015): 88 Total Flu Shot
Victims Compensated Since 2006 Chart shows (through 2013): 1091 Actual number
(through April 2015): 1271 Also on the rise is the number of vaccine injury
cases the government has ‘conceded:’ up 55% in a little over one year. As a
result of the recent website changes, neither of these trends is reflected on
the current ‘adjudication’ chart.” Since its inception in 2013, the
“adjudication categories by alleged vaccine” chart included monthly, updated
totals. But shortly after publishing the March 2015 chart, the government
removed the 2015 and 2014 data, reverting back to outdated statistics from
2013. The chart appears on the government vaccine court website, which falls
under Health Resources and Services Administration, an agency of the Department
of Health and Human Services (HHS). In the unusual vaccine court, the
government acts on behalf of pharmaceutical companies rather than the public,
defending vaccine makers against alleged victims. Money damages are not paid by
vaccine companies, but through fees collected from patients on every dose of
vaccine.

Court Decisions Won By Vaccine Victims Since 2006 Chart Shows (through 2013):
159 Actual Number (through April 2015): 165 Concessions Won By Vaccine Victims
Since 2006 Chart Shows (through 2013): 127 Actual Number (through April 2015):
198 Vaccine Victims Paid After Settlements Since 2006 Chart Shows (through
2013): 1388 Actual Number (through April 2015): 1488 Only about one injury case
for every million doses of vaccines is compensated in vaccine court. Adverse
events occur more frequently, according to vaccine warning labels, but rarely
end up in the little-known vaccine court. Still, vaccine court statistics can
be useful in reflecting trends. Another recent change made vaccine injury data
harder to find. The “adjudication categories by alleged vaccine” chart used to
be the first item that showed up on the statistics page, but that has been
replaced by language stating vaccines are safe and effective. “Being awarded
compensation for your claim does not necessarily mean that the vaccine caused
the alleged injury,” adds the government to the statement where the
adjudication chart used to be. Readers are directed to click a link to view the
actual vaccine injury statistics. But clicking it only leads back to the
statement that vaccines are safe and effective. To find the statistics, instead
of clicking the link, readers must scroll down past it. According to the
government, from 2006 to 2013, over 2.2 billion doses of vaccines were
distributed in the U.S. For every 1 million doses, 1 alleged victim was
compensated in vaccine court. Since 1998, over 15,916 claims have been filed in
vaccine court. 4,121 were compensated, 9,904 were dismissed. The total amount
paid to victims is approximately $3.1 billion.
https://sharylattkisson.com/govt-wipes-recent-vaccine-injury-data-from-website/

More Free Jeff Prager Books Using Peer Reviewed Reports And Studies

Injected • Vaccines and Genetic Mutation

Bulletproof • An Expose On Glyphosate

ASIA • Autoimmune And Inflammatory Disorders Caused By Vaccines

Water Water • Peer Review And Fluoridated Drinking Water

Download for free or read them online: http://jprager9.wix.com/jeffpragerbooks

The End