Tuesday, March 18, 2014

24 More Studies on the Vaccine - Autism Link

24 More Studies on the Vaccine - Autism Link

61.  Adverse events following 12 and 18 month vaccinations: a population-based, self-controlled case series analysis.

PLoS One. 2011;6(12):e27897. Epub 2011 Dec 12.

Wilson K, Hawken S, Kwong JC, Deeks S, Crowcroft NS, Van Walraven C, Potter BK, Chakraborty P, Keelan J, Pluscauskas M, Manuel D. Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada. kwilson@ohri.ca

Live vaccines have distinct safety profiles, potentially causing systemic reactions one to 2 weeks after administration. In the province of Ontario, Canada, live MMR vaccine is currently recommended at age 12 months and 18 months.

Using the self-controlled case series design we examined 271,495 12 month vaccinations and 184,312 18 month vaccinations to examine the relative incidence of the composite endpoint of emergency room visits or hospital admissions in consecutive one day intervals following vaccination. These were compared to a control period 20 to 28 days later. In a post-hoc analysis we examined the reasons for emergency room visits and the average acuity score at presentation for children during the at-risk period following the 12 month vaccine.

Four to 12 days post 12 month vaccination, children had a 1.33 (1.29-1.38) increased relative incidence of the combined endpoint compared to the control period, or at least one event during the risk interval for every 168 children vaccinated. Ten to 12 days post 18 month vaccination, the relative incidence was 1.25 (95%, 1.17-1.33) which represented at least one excess event for every 730 children vaccinated. The primary reason for increased events was statistically significant elevations in emergency room visits following all vaccinations. There were non-significant increases in hospital admissions. There were an additional 20 febrile seizures for every 100,000 vaccinated at 12 months.

There are significantly elevated risks of primarily emergency room visits approximately one to two weeks following 12 and 18 month vaccination. Future studies should examine whether these events could be predicted or prevented.

62.  Administration of thimerosal to infant rats increases overflow of glutamate and aspartate in the prefrontal cortex: protective role of dehydroepiandrosterone sulfate.

Neurochem Res. 2012 Feb;37(2):436-47. Epub 2011 Oct 21.

Duszczyk-Budhathoki M, 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.

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.

63.  Neonatal Administration of Thimerosal Causes Persistent Changes in Mu Opioid Receptors in the Rat Brain

Neurochem Res. 2010 November; 35(11): 1840–1847.

Mieszko Olczak, Michalina Duszczyk, Pawel Mierzejewski, Teresa Bobrowicz, and Maria Dorota Majewska1, Department of Pharmacology and Physiology of the Nervous System, Institute of Psychiatry and Neurology, Sobieskiego 9 str., 02-957 Warsaw, Poland, Department of Forensic Medicine, Medical University of Warsaw, Oczki 1 str., 02-007 Warsaw, Poland, Department of Neuropathology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland, Department of Biology and Environmental Science, University of Cardinal Stefan Wyszynski, Wóycickiego Str. 1/3, 01-815 Warsaw, Poland

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.

64.  Unanswered Questions: A Review of Compensated Cases of Vaccine-Induced Brain Injury

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

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 vaccine-induced 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.

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.

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.”

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.

65.  Integrating experimental (in vitro and in vivo) neurotoxicity studies of low-dose thimerosal relevant to vaccines.

Neurochem Res. 2011 Jun;36(6):927-38. doi: 10.1007/s11064-011-0427-0. Epub 2011 Feb 25.

Dórea JG, Faculty of Health Sciences, Universidade de Brasília, CP 04322, 70919-970, Brasília, DF, Brazil. dorea@rudah.com.br

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.

66.  Hepatitis B vaccine induces apoptotic death in Hepa1-6 cells

Apoptosis. 2012 Jan 17.  Hamza H, 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, 430070, People's Republic of China, Heyam68_hamza@yahoo.com.

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.

67.  Thimerosal Induces Apoptosis in a Neuroblastoma Model via the cJun N-Terminal Kinase Pathway.

Toxicological Sciences 92 (1). 246-253

ML Herdman, A Marcelo, Y Huang, RM Niles, Dhar  S &  Kiningham KK. (2006).  

Department of Pharmacology, Joan C. Edwards School of Medicine, 1542 Spring Valley Drive, Marshall University, Huntington, WV USA

EXCERPT: In recent years, controversy has surrounded the use of thimerosal in vaccines as mercury is a known neurotoxin and nephrotoxin. Since the controversy began in the late 1990's, much of the thimerosal has been removed from vaccines administered to children in the United States. However, it remains in some, such as the influenza vaccine, and is added to multidose vials used in countries around the world. Studies concentrating on thimerosal-induced neurotoxicity are limited, and exposure guidelines, such as those set by the Food and Drug Administration, are based on research with methylmercury. Interestingly, some in vitro and in vivo studies suggest that ethylmercury may react differently than methylmercury (Aschner and Aschner, 1990; Harry et al., 2004; Magos et al., 1985). Few studies with thimerosal have focused on determining specific signaling pathways involved in neurotoxicity. Establishing these pathways may be an important step in
discovering methods of alleviating toxic outcomes in patients exposed to thimerosal….Our study is the first demonstration that thimerosal can induce the activation of JNK and AP-1 in the SK-N-SH neuroblastoma cell line. We showed that activation of cJun and AP-1 transcriptional activity following thimerosal treatment does not appear to be involved in the induction of apoptosis, as demonstrated with the studies using the cJun dominant negative. Furthermore, we were able to show that JNK is an essential upstream component of this pathway through the use of the JNK inhibitor SP600125. This compound was able to attenuate activation of downstream components of mitochondrial-mediated cell death and subsequently protect the cells from apoptosis. These results are significant because identifying specific signaling pathways activated in response to thimerosal exposure presents pharmacological targets for attenuating potential toxicity in patients exposed to
thimerosal-containing products.  

68.  Maternal thimerosal exposure results in aberrant cerebellar oxidative stress, thyroid hormone metabolism, and motor behavior in rat pups; sex- and strain-dependent effects.

Cerebellum. 2012 Jun;11(2):575-86. doi: 10.1007/s12311-011-0319-5.

Sulkowski ZL, Chen T, Midha S, Zavacki AM, Sajdel-Sulkowska EM, Department of Psychiatry, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

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.

69.  The rise in autism and the role of age at diagnosis.

Epidemiology. 2009 Jan;20(1):84-90. doi: 10.1097/EDE.0b013e3181902d15.

Hertz-Picciotto I, Delwiche L.,  Department of Public Health Sciences, University of California, Davis, California 95616, USA. ihp@ucdavis.edu

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.
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.
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.
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.

70.  Slow CCL2-dependent translocation of biopersistent particles from muscle to brain

Zakir Khan1,2, Christophe Combadière3,4,5, François-Jérôme Authier1,2,6, Valérie Itier1,11,2, François Lux7,8, Christopher Exley9, Meriem Mahrouf-Yorgov1,11,2, Xavier Decrouy1,2, Philippe Moretto10, Olivier Tillement7,8, Romain K Gherardi1,12,2,6*† and Josette Cadusseau1,11,12,2*†

Author Affiliations

1 Inserm, U955, 8 rue du Général Sarrail, Créteil, 94010, France

2 Université Paris Est, Faculté de Médecine, 8 rue du Général Sarrail, Créteil, 94010, France

3 Inserm, UMR-S 945, 91 Boulevard de l’Hôpital, Paris, 75013, France

4 Université Pierre et Marie Curie, Faculté de Médecine, 11 Boulevard de l’Hôpital, Paris, 75013, France

5 AP-HP, Groupe Hospitalier Pitié-Salpétrière, Service d’Immunologie, 11 Boulevard de l’Hôpital, Paris, 75013, France

6 AP-HP, Hôpital H. Mondor - A. Chenevier, Service d’Histologie, Centre de Référence Neuromusculaire GNMH, 51 Avenue du Maréchal de Lattre de Tassigny, Créteil, 94000, France

7 CNRS UMR 5620, Laboratoire de Physico-Chimie des Matériaux Luminescents, 2 rue Victor Grignard, Villeurbanne, 69622, France

8 Université Claude Bernard Lyon 1, 2 rue Victor Grignard, Villeurbanne, 69622, France

9 The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, ST5 5BG, UK

10 CNRS UMR 5797, Centre d'Etudes Nucléaires de Bordeaux Gradignan, Allée du haut Vignaud, Gradignan, 33175, France

11 Faculté des Sciences et Technologie, UPEC, 61 Avenue du Général de Gaulle, Créteil, France

12 IMRB Team 10, Faculté de Médecine, 8 rue du Général Sarrail, Créteil, F-94010, France

BMC Medicine 2013, 11:99 doi:10.1186/1741-7015-11-99, 4 April 2013


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).
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 X-ray emission) (PIXE) Both 500 nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids (Al-Rho) were used.
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.
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.

71.  Thimerosal and autism? A plausible hypothesis that should not be dismissed.

Med Hypotheses. 2004;62(5):788-94.

Blaxill MF, Redwood L, Bernard S.

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.

72.  Autism Spectrum Disorders in Relation to Distribution of Hazardous Air Pollutants in the SF Bay Area

Environmental Health Perspectives – Vol. 114 No. 9, September, 2006

Gayle Windham, Div. of Environmental and Occupational Disease Control, California Department of Health Services

284 ASD children & 657 controls, born in 1994 in Bay Area, were assigned exposure levels by birth tract for 19 chemicals. Risks for autism were elevated by 50% in tracts with the highest chlorinated solvents and heavy metals. The highest risk compounds were mercury, cadmium, nickel, trichloroethylene, and vinyl chloride, and the risk from heavy metals was almost twice as high as solvents.

Excerpt: “Our results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence.”

73.  Inflammatory Responses to Trivalent Influenza Virus Vaccine Among Pregnant Women

Vaccine. 2011 Nov 8;29(48):8982-7. doi: 10.1016/j.vaccine.2011.09.039. Epub 2011 Sep 22.

Christian LM, Iams JD, Porter K, Glaser R.

Department of Psychiatry, The Ohio State University Medical Center, Columbus, OH 

In the U.S., seasonal trivalent influenza vaccination (TIV) is currently universally recommended for all pregnant women. However, data on the maternal inflammatory response to vaccination is lacking and would better delineate the safety and clinical utility of immunization. In addition, for research purposes, vaccination has been used as a mild immune trigger to examine in vivo inflammatory responses in nonpregnant adults. The utility of such a model in pregnancy is unknown. Given the clinical and empirical justifications, the current study examined the magnitude, time course, and variance in inflammatory responses following seasonal influenza virus vaccination among pregnant women.
Women were assessed prior to and at one day (n=15), two days (n=10), or approximately one week (n=21) following TIV. Serum interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP), and macrophage migration inhibitory factor (MIF) were determined by high sensitivity immunoassay.
Significant increases in CRP were seen at one and two days post-vaccination (ps <.05). A similar effect was seen for TNF-α, for which an increase at two days post-vaccination approached statistical significance (p = .06). There was considerable variability in magnitude of response; coefficients of variation for change at two days post-vaccination ranged from 122% to 728%, with the greatest variability in IL-6 responses at this timepoint.
Trivalent influenza virus vaccination elicits a measurable inflammatory response among pregnant women. There is sufficient variability in response for testing associations with clinical outcomes. As adverse perinatal health outcomes including preeclampsia and preterm birth have an inflammatory component, a tendency toward greater inflammatory responding to immune triggers may predict risk of adverse outcomes, providing insight into biological mechanisms underlying risk. The inflammatory response elicited by vaccination is substantially milder and more transient than seen in infectious illness, arguing for the clinical value of vaccination. However, further research is needed to confirm that the mild inflammatory response elicited by vaccination is benign in pregnancy

74.  Elevated maternal C-reactive protein and autism in a national birth cohort.

Mol Psychiatry. 2013 Jan 22. doi: 10.1038/mp.2012.197.

Brown AS, Sourander A, Hinkka-Yli-Salomäki S, McKeague IW, Sundvall J, Surcel HM.

Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, NY, USA, Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA.

Autism is a complex neuropsychiatric syndrome with a largely unknown etiology. Inflammation during pregnancy may represent a common pathway by which infections and other insults increase risk for the disorder. Hence, we investigated the association between early gestational C-reactive protein (CRP), an established inflammatory biomarker, prospectively assayed in maternal sera, and childhood autism in a large national birth cohort with an extensive serum biobank. Other strengths of the cohort included nearly complete ascertainment of pregnancies in Finland (N=1.2 million) over the study period and national psychiatric registries consisting of virtually all treated autism cases in the population. Increasing maternal CRP levels, classified as a continuous variable, were significantly associated with autism in offspring. For maternal CRP levels in the highest quintile, compared with the lowest quintile, there was a significant, 43% elevated risk. This
finding suggests that maternal inflammation may have a significant role in autism, with possible implications for identifying preventive strategies and pathogenic mechanisms in autism and other neurodevelopmental disorders.Molecular Psychiatry advance online publication, 22 January 2013; doi:10.1038/mp.2012.197.

75.  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?

N Am J Med Sci. 2009 July; 1(2): 28–47.

Graham E. Ewing

Montague Healthcare, Nottingham United Kingdom

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.

76.  Neurologic adverse events following vaccination

Prog Health Sci 2012, Vol 2 , No1

Sienkiewicz D.*, Kułak W., Okurowska-Zawada B., Paszko-Patej G.

Department of Pediatric Rehabilitation of the Medical University of Bialystok, Poland

The present review summarizes data on neurological adverse events following vaccination in the relation to intensity, time of onset, taking into account the immunological and non-immunological mechanisms. The authors described the physiological development of the immune system and the possible immune system responses following vaccination. Toxic property of thimerosal - a mercury-containing preservative used in some vaccines was presented. The neurological complications after vaccination were described. The role of vaccination in the natural course of infectious diseases and the current immunizations schedule in Poland was discussed.

77.  Immunological and autoimmune considerations of Autism Spectrum Disorders.

J Autoimmun. 2013 Jul 15. pii: S0896-8411(13)00073-5. doi: 10.1016/j.jaut.2013.05.005.

Gesundheit B, Rosenzweig JP, Naor D, Lerer B, Zachor DA, Procházka V, Melamed M, Kristt DA, Steinberg A, Shulman C, Hwang P, Koren G, Walfisch A, Passweg JR, Snowden JA, Tamouza R, Leboyer M, Farge-Bancel D, Ashwood P.

Jerusalem, Israel.

Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental conditions presenting in early childhood with a prevalence ranging from 0.7% to 2.64%. Social interaction and communication skills are impaired and children often present with unusual repetitive behavior. The condition persists for life with major implications for the individual, the family and the entire health care system. While the etiology of ASD remains unknown, various clues suggest a possible association with altered immune responses and ASD. Inflammation in the brain and CNS has been reported by several groups with notable microglia activation and increased cytokine production in postmortem brain specimens of young and old individuals with ASD. Moreover several laboratories have isolated distinctive brain and CNS reactive antibodies from individuals with ASD. Large population based epidemiological studies have established a correlation between ASD and a family
history of autoimmune diseases, associations with MHC complex haplotypes, and abnormal levels of various inflammatory cytokines and immunological markers in the blood. In addition, there is evidence that antibodies that are only present in some mothers of children with ASD bind to fetal brain proteins and may be a marker or risk factor for ASD. Studies involving the injection of these ASD specific maternal serum antibodies into pregnant mice during gestation, or gestational exposure of Rhesus monkeys to IgG subclass of these antibodies, have consistently elicited behavioral changes in offspring that have relevance to ASD. We will summarize the various types of studies associating ASD with the immune system, critically evaluate the quality of these studies, and attempt to integrate them in a way that clarifies the areas of immune and autoimmune phenomena in ASD research that will be important indicators for future research.

78.  Identification of Unique Gene Expression Profile in Children with Regressive Autism Spectrum Disorder (ASD) and Ileocolitis

PLoS ONE 8(3): e58058. doi:10.1371/journal.pone.0058058

Walker SJ, Fortunato J, Gonzalez LG, Krigsman A

Gastrointestinal symptoms are common in children with autism spectrum disorder (ASD) and are often associated with mucosal inflammatory infiltrates of the small and large intestine. Although distinct histologic and immunohistochemical properties of this inflammatory infiltrate have been previously described in this ASDGI group, molecular characterization of these lesions has not been reported. In this study we utilize transcriptome profiling of gastrointestinal mucosal biopsy tissue from ASDGI children and three non-ASD control groups (Crohn's disease, ulcerative colitis, and histologically normal) in an effort to determine if there is a gene expression profile unique to the ASDGI group. Comparison of differentially expressed transcripts between the groups demonstrated that non-pathologic (normal) tissue segregated almost completely from inflamed tissue in all cases. Gene expression profiles in intestinal biopsy tissue from patients with Crohn's
disease, ulcerative colitis, and ASDGI, while having significant overlap with each other, also showed distinctive features for each group. Taken together, these results demonstrate that ASDGI children have a gastrointestinal mucosal molecular profile that overlaps significantly with known inflammatory bowel disease (IBD), yet has distinctive features that further supports the presence of an ASD-associated IBD variant, or, alternatively, a prodromal phase of typical inflammatory bowel disease. Although we report qPCR confirmation of representative differentially expressed transcripts determined initially by microarray, these findings may be considered preliminary to the extent that they require further confirmation in a validation cohort.

79.  Abnormal immune response to brain tissue antigen in the syndrome of autism.

Am J Psychiatry. 1982 Nov;139(11):1462-5.

Weizman A, Weizman R, Szekely GA, Wijsenbeek H, Livni E.

Cell-mediated immune response to human myelin basic protein was studied by the macrophage migration inhibition factor test in 17 autistic patients and a control group of 11 patients suffering from other mental diseases included in the differential diagnosis of the syndrome of autism. Of the 17 autistic patients, 13 demonstrated inhibition of macrophage migration, whereas none of the nonautistic patients showed such a response. The results indicate the existence of a cell-mediated immune response to brain tissue in the syndrome of autism.

80.  Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism.

Dig Dis Sci. 2000 Apr;45(4):723-9.

Kawashima H, Mori T, Kashiwagi Y, Takekuma K, Hoshika A, Wakefield A.

Department of Paediatrics, Tokyo Medical University, Japan.

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.

81.  Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations

Lupus. 2012 Feb;21(2):223-30. doi: 10.1177/0961203311430221.

L Tomljenovic, CA Shaw

Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada

Departments of Ophthalmology and Visual Sciences and Experimental Medicine and the Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada

Lucija Tomljenovic, Post-doctoral fellow, Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia

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.

82.  Thiol-modulated mechanisms of the cytotoxicity of thimerosal and inhibition of DNA topoisomerase II alpha.

Chem Res Toxicol. 2008 Feb;21(2):483-93.

Wu X, Liang H, O'Hara KA, Yalowich JC, Hasinoff BB.

Faculty of Pharmacy, University of Manitoba, 50 Sifton Road, Winnipeg, Manitoba, R3T 2N2, Canada.

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.

83.  Topoisomerases facilitate transcription of long genes linked to autism

Nature (2013) doi:10.1038/nature12504
Received 17 January 2013 Accepted 24 July 2013 Published online 28 August 2013

Ian F. King,      Chandri N. Yandava, Angela M. Mabb,      Jack S. Hsiao,          Hsien-Sung Huang, Brandon L. Pearson,  J. Mauro Calabrese,  Joshua Starmer,        Joel S. Parker,          Terry Magnuson,            Stormy J. Chamberlain,        Benjamin D. Philpot  & Mark J. Zylka

Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. Our findings suggest that chemicals and genetic mutations
that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.

84.  Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity.

Immunol Res. 2013 Jul;56(2-3):304-16. 

Shaw CA, Tomljenovic L.

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 age-related 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.

Posted by Ginger Taylor  at Thursday, June 14, 2007   

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