Maybe It's 'Genetics' OR Maybe It's a VACCINE INJURY - A Compilation Of Historical Vaccine Injury Studies

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Vaccine Injury is nothing new... it's just rarely talked about...

Vaccine injuries are more common than most people know. 


 This post will include the following sections below:
  • Vaccination as Contamination
  • Aseptic Meningitis and the MMR
  • Vaccinations and Leukemia/Lymphomas
  • Vaccines and Chromosome Changes Leading to Mutations
  • Vaccines and Autoimmunity
  • Vaccinations and Diabetes
  • Other Articles Linking Diabetes to Vaccines
  • Vaccines and Nervous System Changes
  • Vaccines and Demyelination
  • Vaccinations and Seizures
  • Vaccines and Brain Swelling
  • Vaccines and Neurological Damage
  • Vaccinations and Unexplained Diseases
  • Vaccines and Metabolism
  • Vaccines and Skin Disorders
  • The Polio Vaccine And Cancer
  • Vaccinations and Autism
  • Resolving and Reversing Vaccine Injury

Vaccination as Contamination

  • “Our findings indicate that vaccinal immunity might facilitate an evolutional event through antigenic selection, genetic mutation among virulent virus populations shed from vaccinated flocks, or both.” http://www.ncbi.nlm.nih.gov/pubmed/24689191
  • “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.” (something else inside them is…) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC264050/
  • “The novel human retrovirus xenotropic murine leukemia virus-related virus (XMRV) is arguably the most controversial virus of this moment. After its original discovery in prostate cancer tissue from North American patients, it was subsequently detected in individuals with chronic fatigue syndrome from the same continent. However, most other research groups, mainly from Europe, reported negative results. The positive results could possibly be attributed to contamination with mouse products in a number of cases, as XMRV is nearly identical in nucleotide sequence to endogenous retroviruses in the mouse genome. But the detection of integrated XMRV proviruses in prostate cancer tissue proves it to be a genuine virus that replicates in human cells, leaving the question: how did XMRV enter the human population? We will discuss two possible routes: either via direct virus transmission from mouse to human, as repeatedly seen for, e.g., Hantaviruses, or via the use of mouse-related products by humans, including vaccines. We hypothesize that mouse cells or human cell lines used for vaccine production could have been contaminated with a replicating variant of the XMRV precursors encoded by the mouse genome.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109487/
  • “This overview describes the problems and risks associated with viral contaminations in animal cell culture, describes the origins of these contaminations as well as the most important viruses associated with viral contaminations in cell culture.” (cell cultures used in vaccines) “….contaminations are a serious threat for animal cell cultures and may lead to false results in research, development, and virus screening, to viral contaminations in the biologicals derived from the contaminated cultures and finally to an infection of the treated patient.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463984/
  • “Current U.S. requirements for testing cell substrates used in production of human biological products (*VACCINES*) for contamination with bovine and porcine viruses are U.S. Department of Agriculture (USDA) 9CFR tests for bovine serum or porcine trypsin. 9CFR requires testing of bovine serum for seven specific viruses in six families (immunofluorescence) and at least 2 additional families non-specifically (cytopathicity and hemadsorption). 9CFR testing of porcine trypsin is for porcine parvovirus. Recent contaminations suggest these tests may not be sufficient. Assay sensitivity was not the issue for these contaminations that were caused by viruses/virus families not represented in the 9CFR screen. A detailed literature search was undertaken to determine which viruses that infect cattle or swine or bovine or porcine cells in culture also have human host range [ability to infect humans or human cells in culture] and to predict their detection by the currently used 9CFR procedures. There are more viruses of potential risk to biological products manufactured using bovine or porcine raw materials than are likely to be detected by 9CFR testing procedures; even within families, not all members would necessarily be detected……..Cell-culture derived vaccines for human use were developed in the 1950’s. Since fetal calf serum and bovine or porcine trypsin were used in cell culture, the 9CFR tests developed for veterinary use to screen for viruses that can infect cattle and swine were implemented by the authorities regulating human vaccines. However, many viruses not of significant concern to the cattle and swine industry are not addressed by the 9CFR testing. Today, over half a century after cell culture-derived vaccines were initially developed, the human biologics industry is still using the methods specified in the 9CFR regulations for testing FBS and porcine trypsin.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206158/
  • “Mycoplasmas in frozen bovine serum were effectively inactivated by gamma-irradiation at 25-40 kGy. The larger viruses tested, respiratory enteric orphan (REO) and Cache Valley virus (CVV), were inactivated completely, while the smaller virus, simian virus type 40, was not inactivated. Gamma-irradiation of bovine-sourced serum is therefore useful for mitigating the risk of introduction of mycoplasmas and many of the viral contaminants found in biologics unprocessed bulk (e.g., CVV, REO virus, epizootic hemorrhagic disease virus). This mitigation strategy is not useful for the smaller viruses (e.g., polyomaviruses, parvoviruses, picornaviruses, caliciviruses).” 2010 http://www.ncbi.nlm.nih.gov/pubmed/21502047
  • “All currently licensed yellow fever (YF) vaccines are propagated in chicken embryos. Recent studies of chick cell-derived measles and mumps vaccines show evidence of two types of retrovirus particles, the endogenous avian retrovirus (EAV) and the endogenous avian leukosis virus (ALV-E), which originate from the chicken embryonic fibroblast substrates. In this study, we investigated substrate-derived avian retrovirus contamination in YF vaccines currently produced by three manufacturers (YF-vax [Connaught Laboratories], Stamaril [Aventis], and YF-FIOCRUZ [FIOCRUZ-Bio-Manguinhos]). Testing for reverse transcriptase (RT) activity was not possible because of assay inhibition. However, Western blot analysis of virus pellets with anti-ALV RT antiserum detected three distinct RT proteins in all vaccines, indicating that more than one source is responsible for the RTs present in the vaccines.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC140796/
  • “Additionally, a baboon endogenous virus strain M7 was detected, likely due to the monkey cell line in which RotaTeq was produced from.”….. “ The sample of RotaTeq vaccine tested positive for rotavirus A and baboon endogenous virus, as previously reported by Victoria and colleagues [17]. The origin of the baboon endogenous virus is assumed to be related to the African green monkey-derived Vero cell line used in its manufacture and cross-hybridization of its endogenous retroviruses to the baboon endogenous retrovirus probes [17]…….Microarray analysis did not detect PCV from the RotaTeq vaccine, which confirmed the previous results from Victoria et al. that LLMDA detected PCV from Rotarix but did not detect PCV from the RotaTeq vaccine [17]. However, PCV2 in RotaTeq vaccine was detected by PCR assays. RotaTeq contained small PCV-1 and PCV-2 genome fragments but did not contain detectable larger portions of PCV genomes [30]. Studies have shown that the amount of PCV in RotaTeq was about 4000 times lower than the PCV in Rotarix, with the PCV in RotaTeq being barely detectable [25, 31, 32]. A case study by Ranucci et al. has reported that the concentration of PCV-2 DNA fragment in clinical consistency lots was in the range of below limit of detection to 6.4 × 103 copies/mL when measured by QPCR, and that PCV1 was below limit of detection (0.1–0.8 × 103 copies/mL) [30]. ” 2014 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980782/
  • Investigations of porcine circovirus type 1 (PCV1) in vaccine-related and other cell lines. “Porcine circovirus type 1 (PCV1) is highly prevalent in swine and was recently reported in some rotavirus vaccines.” 011 Oct 26;29(46):8429-37. Epub 2011 Aug 9. http://www.ncbi.nlm.nih.gov/pubmed/21835219?dopt=Abstract
  • ABORTED FETAL CELL LINES- “In some cases the cell lines that are used might be tumorigenic, that is, they form tumors when injected into rodents. Some of these tumor-forming cell lines may contain cancer-causing viruses that are not actively reproducing. Such viruses are hard to detect using standard methods. These latent, or “quiet,” viruses pose a potential threat, since they might become active under vaccine manufacturing conditions.” http://www.fda.gov/…/biologicsresearchareas/ucm127327.htm
  • ‘Xenotropic murine leukemia virus-related virus (XMRV) is a recently discovered human retrovirus that has been found in both chronic fatigue syndrome & prostate cancer patients. There is a potential safety concern regarding XMRV in cell substrates used in vaccines…’ http://www.fda.gov/…/biologicsresearchareas/ucm127327.htm
  • “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. “ http://www.ncbi.nlm.nih.gov/pubmed/1981251
  • “However, since vaccine preparation involves the use of materials of biological origin, vaccines are subject to contamination by micro-organisms. In fact, vaccine contamination has occurred; a historical example of vaccine contamination, for example, can be found in the early days of development of the smallpox vaccine. The introduction of new techniques of vaccine virus production on cell cultures has lead to safer vaccines, but has not completely removed the risk of virus contamination. There are several examples of vaccine contamination, for example, contamination of human vaccines against poliomyelitis by SV40 virus from the use of monkey primary renal cells. Several veterinary vaccines have been contaminated by pestiviruses from foetal calf serum.These incidents have lead industry to change certain practices and regulatory authorities to develop more stringent and detailed requirements. But the increasing number of target species for vaccines, the diversity of the origin of biological materials and the extremely high number of known and unknown viruses and their constant evolution represent a challenge to vaccine producers and regulatory authorities.” http://www.ncbi.nlm.nih.gov/pubmed/20456974
  • “Although there is no information regarding the duration of acceptable observation period, 1–3 months may not be long enough for the purpose, considering that it takes 2–6 months for adjuvant oils to induce lupus autoantibodies in mice [8,9,34] and that the oil-induced granulomatous inflammation can last for years.”…….”An important factor to consider in vaccine-induced autoimmunity is the fact that vaccines contain a microbial component (or other type of antigens) and adjuvant [75]. Differentiating adverse reactions caused by these two factors is often difficult, or it can even be a result of the combination of both. Nevertheless, the microbial components are generally considered responsible for adverse reactions and minimum attention has been paid to the potential effects of the adjuvant component. Molecular mimicry of a microbial antigen in a vaccine and a host tissue self-antigen is often considered important [61]. Immune complexes also may be formed following vaccination [61,76], deposit in vascular endothelium and induce vasculitis. Induction of cytokines or shifting cytokine balance may also play an important role.” http://www.ncbi.nlm.nih.gov/pubmed/15194169
  • ‘Xenotropic murine leukemia virus-related virus (XMRV) is a recently discovered human retrovirus that has been found in both chronic fatigue syndrome & prostate cancer patients. There is a potential safety concern regarding XMRV in cell substrates used in vaccines…’ http://www.fda.gov/…/biologicsresearchareas/ucm127327.htm
  • “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.” “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.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795160/
  • “Clustering of cases of insulin dependent diabetes (IDDM) occurring three years after hemophilus influenza B (HiB) immunization support causal relationship between immunization and IDDM (insulin dependent diabetes).” http://www.ncbi.nlm.nih.gov/pubmed/12911277
  • Immune complexes also may be formed following vaccination, deposit in vascular endothelium and induce vasculitis. Induction of cytokines or shifting cytokine balance may also play an important role.” http://www.ncbi.nlm.nih.gov/pubmed/15194169
  • “We initiated and funded a collaborative study with Tuomilehto on the effect of the Haemophilus influenzae type b vaccine on type 1 diabetes and found that the data support a causal relation (paper submitted for publication). Furthermore, the potential risk of the vaccine exceeds the potential benefit. We compared a group that received four doses of the vaccine, a group that received one dose, and a group that was not vaccinated. The cumulative incidence of diabetes per 100000 in the three groups receiving four, one, and no doses of the vaccine was 261, 237, and 207 at age 7 and 398, 376, and 340 at age 10 respectively.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1116914/
  • “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 aluminum 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 stimu/lation), 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-A pretreated mice immunized with TTd in aluminum 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-β(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/22235053
  • “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.” Lupus (2012) 21, 223–230 http://www.ncbi.nlm.nih.gov/pubmed/22235057
  • “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.neurology.org/content/63/5/838.abstract
  • “Hepatitis B vaccination does not “generally” increase the risk of CNS inflammatory demyelination in childhood. However, the Engerix B vaccine appears to increase this risk, particularly for confirmed multiple sclerosis, in the longer term.” http://www.ncbi.nlm.nih.gov/pubmed/18843097
  • “Acquired autoimmunity syndromes occur after viral vaccinations. Molecular mimicry is involved in these phenomena as is the necessity for the presence of two chemically complimentary antigens and an immunologic adjuvant. The HLA pattern of the host is also an important factor. The example used to explain these phenomena is demyelinating disease that follows hepatitis B vaccination. The somatic antigen of the hepatitis B virus in the vaccine has chemical complimentarity with the Epstein-Barr virus antigen in the vaccine recipient. The Epstein-Barr virus shows molecular mimicry with human myelin. The immunologic adjuvant is either present in the vaccine or muramyl peptides in the individual who is vaccinated. Why more than one type of autoimmune disease occurs is explained by the fact that specific autoimmune T-cells have been shown to develop clones that attack multiple human tissues.” http://www.ncbi.nlm.nih.gov/pubmed/17630224
  • “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
  • “Although the exact pathogenesis of the development of KFD following immunization remains unknown, this (IMMUNIZATION) should be added to the list of potential triggers or factors associated with the development of KFD” http://www.ncbi.nlm.nih.gov/pubmed/22476507
  • “Vaccination against 2 avian viruses, the Marek disease virus, and the infectious bursal disease virus, were associated with the emergence of more virulent strains (33). An important role of host immunity in selecting for virulence is also suggested by the co-evolution of the myxomatosis virus and rabbits (34). Furthermore, immune pressure was shown to select for more virulent Plasmodium chabaudi parasites in mice (35). Based on mathematical modeling, vaccines designed to reduce pathogen growth rate and/or toxicity may result in the evolution of pathogens with higher levels of virulence.” http://wwwnc.cdc.gov/eid/article/15/8/08-1511_article.htm
  • “Together, our data suggest that the high level of vaccine failure in Nicaraguan is probably not due to antigenic drift of commonly circulating virus strains nor the emergence of new antigenetically distinct virus strains. Furthermore, our data suggest that the widespread use of the RotaTeq vaccine has led to the introduction of vaccine genes into circulating human RotaViruses” Infect Genet Evol. 2012 Aug;12 http://www.ncbi.nlm.nih.gov/pubmed/22487061
  • “Furthermore, while India has been polio-free for a year, there has been a huge increase in non-polio acute flaccid paralysis (NPAFP). In 2011, there were an extra 47,500 new cases of NPAFP. Clinically indistinguishable from polio paralysis but twice as deadly, the incidence of NPAFP was directly proportional to doses of oral polio received. Though this data was collected within the polio surveillance system, it was not investigated.” http://www.ncbi.nlm.nih.gov/pubmed/22591873
  • “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.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815961/
  • “The biological properties of poxvirus isolates from skin lesions on dairy cows and milkers during recent exanthem episodes in Cantagalo County, Rio de Janeiro State, Brazil, were more like vaccinia virus (VV) than cowpox virus. PCR amplification of the hemagglutinin (HA) gene substantiated the isolate classification as an Old World orthopoxvirus, and alignment of the HA sequences with those of other orthopoxviruses indicated that all the isolates represented a single strain of VV, which we have designated Cantagalo virus (CTGV). HA sequences of the Brazilian smallpox vaccine strain (VV-IOC), used over 20 years ago, and CTGV showed 98.2% identity; phylogeny inference of CTGV, VV-IOC, and 12 VV strains placed VV-IOC and CTGV together in a distinct clade. Viral DNA restriction patterns and protein profiles showed a few differences between VV-IOC and CTGV. Together, the data suggested that CTGV may have derived from VV-IOC by persisting in an indigenous animal(s), accumulating polymorphisms, and now emerging in cattle and milkers as CTGV. CTGV may represent the first case of long-term persistence of vaccinia in the New World.” http://www.ncbi.nlm.nih.gov/pubmed/11080491
  • “Vaccines are not subject to double blind clinical trials despite the evidence of vaccine-drug interactions and perhaps also of vaccine-vaccine interactions.”“Where is the proof that vaccines are safe? The argument has never been that they are completely safe but that the consequences are less than having the disease. Now it is illustrated that the consequences of intensive vaccination schedules pose a greater risk than could ever have been imagined. This leads to the evolution of new viral strains, an unsurprising development when the environment to which it is exposed is being altered by new proteins, structural variants and ALTERED DNA.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364648/
  • “Thus, we conclude that aP (whooping cough) vaccination interferes with the optimal clearance of B. parapertussis and *enhances the *performance of this *pathogen. Our data raise the possibility that *widespread aP vaccination *can *create *hosts *more *susceptible to B. parapertussis infection.” http://www.ncbi.nlm.nih.gov/pubmed/20200027
  • “Although persons often use vaccination and immunization interchangeably in reference to active immunization (VACCINES), the terms are not synonomous because the administration of an immunobiologic CANNOT be automatically equated with the development of adequate immunity.” http://www.cdc.gov/mmwr/PDF/rr/rr4301.pdf 
  • Annual influenza vaccination affects the development of heterosubtypic immunity. 2012- Annual vaccination of healthy children >6 months of age against seasonal influenza has been recommended by public health authorities of some countries. However, currently used seasonal vaccines provide only limited protection against (potentially) pandemic influenza viruses. Furthermore, we recently hypothesized that annual vaccination may hamper the development of cross-reactive immunity against influenza A viruses of novel subtypes, that would otherwise be induced by natural infection. Here we summarize our findings in animal models in which we demonstrated that vaccination against influenza A/H3N2 virus reduced the induction of heterosubtypic immunity against highly pathogenic avian influenza A/H5N1 virus, otherwise induced by a prior infection with influenza A/H3N2 virus. The reduction of heterosubtypic immunity correlated with reduced virus-specific CD8+ T cell responses. An additional study was performed in humans, in which we collected peripheral blood mononuclear cells from annually vaccinated children with cystic fibrosis (CF) and age-matched unvaccinated healthy control children to study the virus-specific T cell response. An age-related increase of the virus-specific CD8+ T cell response was observed in unvaccinated children that was absent in vaccinated children with CF. These findings highlight the importance of the development of vaccines that provide protection against influenza A viruses of all subtypes. (of course the answer is MORE and BETTER vaccines) http://www.ncbi.nlm.nih.gov/pubmed/22643217 
  • “The combined measles, mumps, and rubella (MMR) vaccine has been successfully administered for >20 years. Because of this, protection by maternal antibodies in infants born to vaccinated mothers might be negatively affected…..Conclusions. “Children of mothers vaccinated against measles and, possibly, rubella have lower concentrations of maternal antibodies and lose protection by maternal antibodies at an earlier age than children of mothers in communities that oppose vaccination. This increases the risk of disease transmission in highly vaccinated populations. ” http://www.ncbi.nlm.nih.gov/pubmed/23661802
  • “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 (Herpes Zoster {Shingles increased because of vaccine}) 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.” 2013 PMID: 20642419 http://www.ncbi.nlm.nih.gov/pubmed/22659447


Aseptic Meningitis and the MMR

Vaccines and Leukemia/Lymphomas

Vaccines and Chromosome Changes Leading to Mutations

Vaccines and Autoimmunity

Vaccinations and Diabetes


Other Articles Linking Diabetes to Vaccines

Vaccines and Nervous System Changes

Vaccines and Demyelination

  • Herroelen, L et al, “Central-Nervous-System Demyelination After Immunization with Recombinant Hepatitis B Vaccine”, Lancet, Nov 9, 1991, 338(8776):1174-1175.
  • Kaplanski G, Retornaz F, Durand J, Soubeyrand J, “Central nervous system demyelination after vaccination against hepatitis B and HLA haplotype.” J Neurol Neurosurg Psychiatry 1995 Jun; 58(6):758-759.
  • Matyszak MK, Perry VH, “Demyelination in the central nervous system following a delayed-type hypersensitivity response to bacillus Calmette-Guerin.” Neuroscience 1995 Feb;64(4):967-977.
  • Tornatore CS, Richert JR, “CNS demyelination associated with diploid cell rabies vaccine.” Lancet 1990 Jun 2;335(8701):1346-1347.
  • Adams, JM et al, “Neuromyelitis Optica: Severe Demyelination Occurring Years After Primary Smallpox Vaccinations”, Rev Roum Neurol, 1973, 10:227-231.
  • In 1988, Dietrich used MRI to show that developmentally delayed children had alterations in their myelin. Coulter described that central nervous system damage can be exhibited as abnormal behavior of the child. In 1935, Thomas Rivers, experimental allergic encephalitis (EAE) can be the result of a viral or bacterial infection of the nervous system. “The fact of the matter is that it is a matter of record that it was known that vaccination produced encephalitis since 1926.” The authors stated, “In regions in which there is no organized vaccination of the population, general paralysis is rare. … It is impossible to deny a connection between vaccinations and the encephalitis (brain damage) which follows it.” Vaccines have been linked to seizures, convulsions and epilepsy.

Vaccines and Seizures

  • Hirtz DG, Nelson KB, Ellenberg J H, “Seizures following childhood immunizations”, Pediatr 1983 Jan; 102(1):14-18.
  • Cherry JD, Holtzman AE, Shields WD, Buch D, Nielsen, “Pertussis immunization and characteristics related to first seizures in infants and children,”J Pediatr 1993 Jun;122(6):900-903.
  • Coplan J, “Seizures following immunizations,” J Pediatr 1983 Sep;103(3):496.
  • Barkin RM, Jabhour JT, Samuelson J S, “Immunizations, seizures, and subsequent evaluation,” JAMA 1987 Jul 10;258(2):201.
  • Griffin MR, et al, “Risk of seizures after measles-mumps-rubella immunization,” Pediatrics 1991 Nov;88(5):881-885.
  • Griffin MR, et al, “Risk of seizures and encephalopathy after immunization with the diphtheria-tetanus-pertussis vaccine,” JAMA 1990 Mar 23-30;263(12):1641-1645.
  • Cizewska S, Huber Z, Sluzewski W, “[Prophylactic inoculations and seizure activity in the EEG],” Neurol Neurochir Pol 1981 Sep-Dec;15(5-6):553-557. [Article in Polish]
  • Huttenlocher PR, Hapke RJ, “A follow-up study of intractable seizures in childhood.” Ann Neurol 1990 Nov; 28(5):699-705.
  • Blumberg DA, “Severe reactions associated with diphtheria-tetanus-pertussis vaccine: detailed study of children with seizures, hypotonic-hypo-responsive episodes, high fevers, and persistent crying.”Pediatrics 1993 Jun; 91(6):1158-1165. Vaccinations and Convulsions Citations:
  • Prensky AL, et al, “History of convulsions and use of pertussis vaccine,” J Pediatr 1985 Aug; 107(2):244-255.
  • Baraff LJ, “Infants and children with convulsions and hypotonic-hypo-responsive episodes following diphtheria-tetanus-pertussis immunization: follow-up evaluation,” Pediatrics 1988 Jun; 81(6):789-794.
  • Jacobson V, “Relationship of pertussis immunization to the onset of epilepsy, febrile convulsions and central nervous system infections: a retrospective epidemiologic study,” Tokai J Exp Clin Med 1988;13 Suppl: 137-142.
  • Cupic V,et al, “[Role of DTP vaccine in the convulsive syndromes in children],” Lijec Vjesn 1978 Jun; 100(6):345-348. [Article in Serbo-Croatian (Roman)]
  • Pokrovskaia NIa, “[Convulsive syndrome in DPT vaccination (a clinico-experimental study)],” Pediatriia 1983 May;(5):37-39. [Article in Russian] Vaccinations and Epilepsy Citations:
  • Ballerini, Ricci, B, et al, “On Neurological Complications of Vaccination, With Special Reference to Epileptic Syndromes,” Riv Neurol, Jul-Aug 1973, 43:254-258.
  • Wolf SM, Forsythe A, “Epilepsy and mental retardation following febrile seizures in childhood,” Acta Paediatr Scand 1989 Mar;78(2):291-295.

Vaccines and Brain Swelling

  • Iwasa, S et al, “Swelling of the Brain in Mice Caused by Pertussis … Quantitative Determination and the Responsibility of the Vaccine”, Jpn J Med Sci Biol, 1985 , 38(2):53-65.
  • Mathur R, Kumari S, “Bulging fontanel following triple vaccine.” Indian Pediatr 1981 Jun;18(6):417-418.
  • Barry W, Lenney W, Hatcher G, “Bulging fontanelles in infants without meningitis.” Arch Dis Child 1989 Apr;64(4):635-636.
  • Shendurnikar N, “Bulging fontanel following DPT” Indian Pediatr 1986 Nov;23(11):960.
  • Gross TP, Milstien JB, Kuritsky JN, “Bulging fontanelle after immunization with diphtheria-tetanus-pertussis vaccine and diphtheria-tetanus vaccine.” J Pediatr 1989 Mar;114(3):423-425.
  • Jacob J, Mannino F, “Increased intracranial pressure after diphtheria, tetanus, and pertussis immunization.” Am J Dis Child 1979 Feb;133(2):217-218.
  • Dugmore, WN, “Bilateral Oedema at the Posterior Pole. Hypersensitivity Reaction to Alavac P injection.” Br J Ophthalmol, Dec 1972, 55:848-849.

Vaccines and Neurological Damage

  • Nedar P R, and Warren, R J, “Reported Neurological Disorders Following Live Measles Vaccine”, 1968, Ped, 41:997-1001.
  • Paradiso, G et al, “Multifocal Demyelinating Neuropathy after Tetanus Vaccine”, Medicina (B Aires), 1990, 50(1):52-54.
  • Landrigan, PJ, Whitte, J, “Neurologic Disorders Following Live Measles-virus Vaccination”, JAMA, Mar 26, 1973, v223(13):1459-1462.
  • Turnbull, H M, “Encephalomyelitis Following Vaccination”, Brit Jour Exper Path, 7:181, 1926.
  • Kulenkampff, M et al, “Neurological Complications of Pertussis Inoculation”, Arch Dis Child, 1974, 49:46.
  • Strom, J, “Further Experience of Reactions, Especially of a Cerebral Nature in Conjunction with Triple Vaccination”, Brit Med Jour, 1967, 4:320-323.
  • Berg, J M, “Neurological Complications of Pertussis Immunization,” Brit Med Jour, July 5,1958; p 24.
  • Bondarev, VN et al, “The Changes of the Nervous System in Children After Vaccination”, Pediatria, Jun 1969; 48:20-24.
  • Badalian, LO, “Vaccinal Lesions of the Nervous System in Children,” Vop Okhr Materin Dets, Dec 1959, 13:54-59
  • Lorentz, IT, et al, “Post-Vaccinal Sensory Polyneuropathy with Myoclonus”, Proc Aust Ass Neurol, 1969, 6:81-86.
  • Trump, R C, White, T R, “Cerebellar Ataxia Presumed Due To Live Attenuated Measles Virus Vaccine,” JAMA, 1967, 199:165-166.
  • Allerdist, H, “Neurological Complications Following Measles Vaccination”, Inter Symp, Brussels, 1978, Development Biol Std, Vol 43, 259-264.
  • Finley, K H, “Pathogenesis of Encephalitis Occurring With Vaccination, Variola and Measles, Arch Neur and Psychologist, 1938; 39:1047-1054.
  • Froissart, M et al, “Acute Meningoencephalitis Immediately after an Influenza Vaccination”, Lille Med, Oct 1978, 23(8):548-551.
  • Pokrovskaia, Nia, et al, “Neurological Complications in Children From Smallpox Vaccination”, Pediatriia, Dec 1978, (12):45-49.
  • Allerdist, H, “Neurological Complications Following Measles Virus Vaccination. Evaluation of the Cases seen Between 1971-1977″, Monatsschr Kinderheilkd, Jan 1979, 127(1): 23-28.
  • Ehrengut, W et al, “On Convulsive Reactions Following Oral vaccination Against Polio”, Klin Paediatr, May 1979, 191(3):261-270.
  • Naumova, R P, et al, “Encephalitis Developing After Vaccination without a Local Skin Reaction”, Vrach Delo, Jul 1979, (7):114-115.
  • Goswamy, BM, “Neurological Complications After Smallpox Vaccination”, J Ass Phys India, Jan 1969, 17:41-43.
  • Schchelkunov, SN et al, “The Role of Viruses in the Induction of Allergic Encephalomyelitis,” Dokl Akad Nauk SSSR, 1990,315(1):252-255. [Vaccines contain viruses, too]
  • Walker AM, “Neurologic events following diphtheria-tetanus-pertussis immunization,” Pediatrics 1988 Mar;81(3):345-349.
  • Shields WD, et al, “Relationship of pertussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study,” J Pediatr 1988 Nov; 113(5):801-805.
  • Wilson J, “Proceedings: Neurological complications of DPT inoculation in infancy,” Arch Dis Child 1973 Oct; 48(10):829-830.
  • Iakunin IuA, “[Nervous system complications in children after preventive vaccinations],” Pediatriia 1968 Nov; 47(11):19-26. [Article in Russian]
  • Greco D, et al, “Case-control study on encephalopathy associated with diphtheria-tetanus immunization in Campania, Italy,” Bull World Health Organ 1985;63(5):919-925.
  • Ehrengut W at Institute of Vaccinology and Virology, Hamburg, Germany states, “Bias in the evaluation of CNS complications following pertussis immunization are the following: 1) Notifications of post-immunization adverse events, 2) Publications by vaccine producers on the frequency of adverse reactions, 3) Comparison of permanent brain damage after DPT and DT immunization, 4) Pro-immunization, 5) Immunization associated viral encephalitis, 6) Accuracy of statistics, 7) Personal. A review of these points indicates an underestimation of CNS complications after pertussis immunization.”
  • Reference: Ehrengut W, “Bias in evaluating CNS complications following pertussis immunization.” Acta Paediatr Jpn, 1991 Aug; 33(4):421-427.
  • Sienkiewicz D.*, Kułak W., Okurowska-Zawada B., Paszko-Patej G. “Neurologic adverse events following vaccination,” Prog Health Sci 2012, Vol 2 , No1.  FULL TEXT

Vaccinations and Unexplained Diseases

  • Hiner, E E, Frasch, C E, “Spectrum of Disease Due to Haemophilus Influenza Type B Occurring in Vaccinated Children”, J Infect Disorder, 1988 Aug; 158(2): 343-348.
  • Olin P, Romanus, V, Storsaeter, J, “Invasive Bacterial Infections During an Efficiacy Trial of Acellular Pertussis Vaccines — Implications For Future Surveilance In Pertussis Vaccine Programmes”, Tokai J Exp Clin Med, 1988; 13 Suppl: 143-144.
  • Storsaeter, J, et al, “Mortality and Morbidity From Invasive Bacterial Infections During a Clinical Trial of Acellular Pertussis Vaccines in Sweden”, Pediatr Infect Disorder J, 1988 Sept; 7(9):637-645.
  • Vadheim, CM, et al, “Effectiveness and Safety of an Haemophilus Influenzae type b Conjugate Vaccine (PRP-T) in Young Infants. Kaiser-UCLA Vaccine Study Group,” Pediartics, 1993 Aug; 92(2):272-279. [The vaccines caused fevers, irritability, crying, and seizures, but were declared to be “safe and … effective … “.]
  • Stickl, H, “Estimation of Vaccination Damage”, Med Welt, Oct 14, 1972, 23:1495-1497.
  • Waters, VV, et al, “Risk Factors for Measles in a Vaccinated Population”, JAMA, Mar 27, 1991, 265(12): 1527.
  • Stickl, H, “Iatrogenic Immuno-suppression as a Result of Vaccination”, Fortschr Med, Mar 5, 1981, 99(9);289-292. Vaccine Citations Linking the Vaccine to the “prevented” Disease:
  • Nkowane, et al, “Vaccine-Associated Paralytic Poliomyelitis, US 1973 through 1984, JAMA, 1987, Vol 257:1335-1340.
  • Quast, et al, “Vaccine Induced Mumps-like Diseases”, nd, Int Symp on Immun, Development Bio Stand, Vol 43, p269-272.
  • Green, C et al, “A Case of Hepatitis Related to Etretinate Therapy and Hepatitis B Vaccine”, Dermatologica, 1991, 182(2):119-120.
  • Shasby, DM, et al, “Epidemic Measles in Highly Vaccinated Population”, NEJM, Mar 1977, 296(11): 585-589.
  • Tesovic, G et al, “Aseptic Meningitis after Measles, Mumps and Rubella Vaccine”, Lancet, Jun 12, 1993, 341(8859):1541.
  • Johnson, RH, et al, “Nosocomial Vaccinia Infection”, West J Med, Oct 1976, 125(4):266-270.
  • Malengreau, M, “Reappearance of Post-Vaccination Infection of Measles, Rubella, and Mumps. Should Adolescents be re-vaccinated?” Pedaitric, 1992;47(9):597-601 (25 ref)
  • Basa, SN, “Paralytic Poliomyelitis Following Inoculation With Combined DTP Prophylactic. A review of Sixteen cases with Special Reference to Immunization Schedules in Infancy”, J Indian Med Assoc, Feb 1, 1973, 60:97-99.
  • Landrigan, PJ et al, “Measles in Previously Vaccinated Children in Illinois”, Ill Med J, Arp 1974, 141:367-372.
  • NA, “Vaccine-Associated Poliomyelitis”, Med J Aust, Oct 1973, 2:795-796. Vaccine Failures Citations:
  • Hardy, GE, Jr, et al, “The Failure of a School Immunization Campaign to Terminate an Urban Epidemic of Measles,” Amer J Epidem, Mar 1970; 91:286-293.
  • Cherry, JD, et al, “A Clinical and Serologic Study of 103 Children With Measles Vaccine Failure”, J Pediatr, May 1973; 82:801-808.
  • Jilg, W, et al, “Inoculation Failure Following Hepatitis B Vaccination”, Dtsch Med wochenschr, 1990 Oct 12; 115(41):1514-1548.
  • Plotkin, SA, “Failures of Protection by Measles Vaccine,” J Pediatr, May 1973; 82:798-801.
  • Bolotovskii, V, et al, “Measles Incidence Among Children Properly Vaccinated Against This Infection”, ZH Mikrobiol Epidemiol Immunobiol, 1974; 00(5):32-35.
  • Landrigan, PJ, et al, “Measles in Previously Vaccinated Children in Illinois”, Ill Med J, Apr 1974; 141:367-372.
  • Strebel, P et al, “An Outbreak of Whooping Cough in a Highly Vaccinated Urban Community”, J Trop Pediatr, Mar 1991, 37(2): 71-76.
  • Forrest, JM, et al, “Failure of Rubella Vaccination to Prevent Congenital Rubella,”Med J Aust, 1977 Jan 15; 1(3): 77.
  • Jilg, W, “Unsuccessful Vaccination against Hepatitis B”, Dtsch Med Wochenschr, Nov 16, 1990, 115(46):1773.
  • Coles, FB, et al, “An Outbreak of Influenza A (H3N2) in a Well-Immunized Nursing home Population,” J Am ger Sociologist, Jun 1992, 40(6):589-592.
  • Jilg, W, et al, “Inoculation Failure following Hepatitis B Vaccination,” Dtsch Med Wochenschr, Oct 12, 1990, 115(41):1545-1548.
  • Hartmann, G et al, “Unsuccessful Inoculation against Hepatitis B,” Dtsch Med Wochenschr, May 17, 1991, 116(20): 797.
  • Buddle, BM et al, “Contagious Ecthyma Virus-Vaccination Failures”, Am J Vet Research, Feb 1984, 45(2):263-266.
  • Mathias, R G, “Whooping Cough In Spite of Immunization”, Can J Pub Health, 1978 Mar/Apr; 69(2):130-132.
  • Osterholm, MT, et al, “Lack of Efficacy of Haemophilus b Polysacharide Vaccine in Minnesota”, JAMA, 1988 Sept 9; 260(10:1423-1428.
  • Johnson, RH, et al, “Nosocomial Vaccinia Infection”, West J Med, Oct 1976, 125(4):266-270. Vaccines Causing Another Vaccinal Disease:
  • Basa, SN, “Paralytic Poliomyelitis Following Inoculation With Combined DTP Prophylactic. A review of Sixteen cases with Special Reference to Immunization Schedules in Infancy”, J Indian Med Assoc, Feb 1, 1973, 60:97-99.
  • Pathel, JC, et al, “Tetanus Following Vaccination Against Small-pox”, J Pediatr, Jul 1960; 27:251-263.
  • Favez, G, “Tuberculous Superinfection Following a Smallpox Re-Vaccination”, Praxis, July 21, 1960; 49:698-699.
  • Quast, Ute, and Hennessen, “Vaccine-Induced Mumps-like Diseases”, Intern Symp on Immunizations , Development Bio Stand, Vol 43, p 269-272.
  • Forrest, J M, et al, “Clinical Rubella Eleven months after Vaccination,” Lancet, Aug 26, 1972, 2:399-400.
  • Dittman, S, “Atypical Measles after Vaccination”, Beitr Hyg Epidemiol, 19891, 25:1-274 (939 ref)
  • Sen S, et al, “Poliomyelitis in Vaccinated Children”, Indian Pediatr, May 1989, 26(5): 423-429.
  • Arya, SC, “Putative Failure of Recombinant DNA Hepatitis B Vaccines”, Vaccine, Apr 1989, 7(2): 164-165.
  • Lawrence, R et al, “The Risk of Zoster after Varicella Vaccination in Children with Leukemia”, NEJM, Mar 3, 1988, 318(9): 543-548. Vaccination Citations and Death
  • Na, “DPT Vaccination and Sudden Infant Death – Tennessee, US Dept HEW, MMWR Report, Mar 23, 1979, vol 28(11): 132.
  • Arevalo, “Vaccinia Necrosum. Report on a Fatal Case”, Bol Ofoc Sanit Panamer, Aug 1967, 63:106-110.
  • Connolly, J H, Dick, G W, Field, CM, “A Case of Fatal Progressive Vaccinia”, Brit Med Jour, 12 May 1962; 5288:1315-1317.
  • Aragona, F, “Fatal Acute Adrenal Insufficiency Caused by Bilateral Apoplexy of the Adrenal Glands (WFS) following Anti-poliomyelitis Vaccination”, Minerva Medicolegale, Aug 1960; 80:167-173.
  • Moblus, G et al, “Pathological-Anatomical Findings in Cases of Death Following Poliomyelitis and DPT Vaccination”, Dtsch Gesundheitsw, Jul 20, 1972, 27:1382-1386.
  • NA, “Immunizations and Cot Deaths”, Lancet, Sept 25, 1982, np.
  • Goetzeler, A, “Fatal Encephalitis after Poliomyelitis Vaccination”, 22 Jun 1961, Muenchen Med Wschr, 102:1419-1422.
  • Fulginiti, V, “Sudden Infant Death Syndrome, Diphtheria-Tetanus Toxoid-Pertussis Vaccination and Visits to the Doctor: Chance Association or Cause and Effect?”, Pediatr Infect Disorder, Jan-Feb 1983, 2(1): 7-11.
  • Baraff, LJ, et al, “Possible Temporal Association Between Diphtheria-tetanus toxoid-Pertussis Vaccination and Sudden Infant Death Syndrome”, Pediatr Infect Disorder, Jan-Feb 1983, 2(1): 5-6.
  • Reynolds, E, “Fatal Outcome of a Case of Eczema Vaccinatum”, Lancet, 24 Sept 1960, 2:684-686.
  • Apostolov. et al, “Death of an Infant in Hyperthermia After Vaccination”, J Clin Path, Mar 1961, 14:196-197.
  • Bouvier-Colle, MH, “Sex-Specific Differences in Mortality After High-Titre Measles Vaccination”, Rev Epidemiol Sante Publique, 1995; 43(1): 97.
  • Stewart GT, “Deaths of infants after triple vaccine.”, Lancet 1979 Aug 18;2(8138):354-355.
  • Flahault A, “Sudden infant death syndrome and diphtheria/tetanus toxoid/pertussis/poliomyelitis immunisation.”, Lancet 1988 Mar 12;1(8585):582-583.
  • Larbre, F et al, “Fatal Acute Myocarditis After Smallpox Vaccination”, Pediatrie, Apr-May 1966, 21:345-350.
  • Mortimer EA Jr, “DTP and SIDS: when data differ”, Am J Public Health 1987 Aug; 77(8):925-926.

Vaccines and Metabolism

  • Deutsch J, ” [Temperature changes after triple-immunization in infant age],” Padiatr Grenzgeb 1976;15(1):3-6. [Article in German]
  • NA, “[Temperature changes after triple immunization in childhood],” Padiatr Grenzgeb 1976;15(1):7-10. [Article in German]
  • [Considering that the thyroid controls our Basal Metabolism, it would appear that vaccines altered (depressed) thyroid activity.] Vaccines Altering Resistance to Disease:
  • Burmistrova AL, “[Change in the non-specific resistance of the body to influenza and acute respiratory diseases following immunization diphtheria-tetanus vaccine],” Zh Mikrobiol Epidemiol Immunobiol 1976; (3):89-91. [Article in Russian] Vaccinations and Deafness Citations: So I did a background check to see if there was any scientific evidence linking vaccines to deafness and hearing loss. Here are some of the articles I found:
  • Kaga, “Unilateral Total Loss of Auditory and Vestibular Function as a Complication of Mumps Vaccination”, Int J Ped Oto, Feb 1998, 43(1):73-73
  • Nabe-Nielsen, Walter, “Unilateral Total Deafness as a Complication of the Measles- Mumps- Rubella Vaccination”, Scan Audio Suppl, 1988, 30:69-70
  • Hulbert, et al, “Bilateral Hearing Loss after Measles and Rubella Vaccination in an Adult”, NEJM, 1991 July, 11;325(2):134
  • Healy, “Mumps Vaccine and Nerve Deafness”, Am J Disorder Child, 1972 Jun; 123(6):612
  • Jayarajan, Sedler, “Hearing Loss Following Measles Vaccination”, J Infect, 1995 Mar; 30(2):184-185
  • Pialoux, P et al, “Vaccinations and Deafness”, Ann Otolaryng (Paris), Dec 1963, 80:1012-1013.
  • Angerstein, W, et al, “Solitary Hearing and Equilibrium Damage After Vaccinations”, Gesundheitswesen, May 1995, 57(5): 264-268.
  • Brodsky, Stanievich, “Sensorineural Hearing Loss Following Live Measles Virus Vaccination”, Int J Ped Oto, 1985 Nov; 10(2):159-163
  • Koga, et al, “Bilateral Acute Profound Deafness After MMR Vaccination- Report of a Case”, Nippon Jibiin Gakkai Kai, 1991 Aug;94(8):1142-5
  • Seiferth, LB, “Deafness after Oral Poliomyelitis Vaccination – a Case Report and Review”, HNO, 1977 Aug; 25(8): 297-300
  • Pantazopoulos, PE, “Perceptive Deafness Following Prophylactic use of Tetanus anittoxin”, Laryngoscope, Dec 1965, 75:1832-1836.
  • Zimmerman, W, “Observation of a case of Acute Bilateral Hearing Impairment Following Preventive Poliomyelitis Vaccination (type 3)”, Arch Ohr Nas Kehlkopfheilk, 1965, 185:723-725. Vaccinations and Kidney Disorders Citations:
  • Jacquot, C et al, “Renal Risk in Vaccination”, Nouv Presse Med, Nov 6, 1982, 11(44):3237-3238.
  • Giudicelli, et al, “Renal Risk in Vaccination”, Presse Med, Jun 11, 1982, 12(25):1587-1590.
  • Tan, SY, et al, “Vaccine Related Glomerulonephritis”, BMJ, Jan 23, 1993, 306(6872):248.
  • Pillai, JJ, et al, “Renal Involvement in Association with Post-vaccination Varicella”, Clin Infect Disorder, Dec 1993, 17(6): 1079-1080.
  • Eisinger, AJ et al, “Acute Renal Failure after TAB and Cholera Vaccination”, B Med J, Feb 10, 1979, 1(6160):381-382.
  • Silina, ZM, et al, “Causes of Postvaccinal Complications in the Kidneys in Young Infants”, Pediatria, Dec 1978, (12):59-61.
  • Na, “Albuminurias”, Concours Med, Mar 1964, 85:5095-5098. [vaccination adverse reactions]
  • Oyrl, A, et al, “Can Vaccinations Harm the Kidney?”, Clin Nephrol, 1975, 3(5):204-205.
  • Mel’man Nia, “[Renal lesions after use of vaccines and sera].” Vrach Delo 1978 Oct;(10):67-9, [Article in Russian]
  • Silina ZM, Galaktionova TIa, Shabunina NR, “[Causes of postvaccinal complications in the kidneys in young infants].” Pediatriia 1978 Dec;(12):59-61, [Article in Russian]
  • Silina EM, et al, “[Some diseases of the kidneys in children during the 1st year of life, following primary smallpox vaccination and administration of pertusis-diphtheria-tetanus vaccine].” Vopr Okhr Materin Det 1968 Mar; 13(3):79-80, [Article in Russian]

Vaccines and Skin Disorders 

  • Illingsworth R, Skin rashes after triple vaccine,” Arch Dis Child 1987 Sep; 62(9):979.
  • Lupton GP, “Discoid lupus erythematosus occurring in a smallpox vaccination scar,” J Am Acad Dermatol, 1987 Oct; 17(4):688-690.
  • Kompier, A J, “Some Skin Diseases caused by Vaccinia Virus [Smallpox],” Ned Milt Geneesk T, 15:149-157, May 1962.
  • Weber, G et al, “Skin Lesions Following Vaccinations,” Deutsch Med Wschr, 88:1878-1886, S7 Sept 1963.
  • Copeman, P W, “Skin Complications of Smallpox Vaccination,” Practitioner, 197:793-800, Dec 1966.
  • Denning, DW, et al, “Skin Rashes After Triple Vaccine,” Arch Disorder Child, May 1987, 62(5): 510-511. Vaccinations and Abcesses:
  • Sterler, HC, et al, “Outbreaks of Group A Steptococcal Abcesses Following DTP Vaccination”, Pediatrics, Feb 1985, 75(2):299-303.
  • DiPiramo, D, et al, “Abcess Formation at the Site of Inoculation of Calmette-Guerin Bacillus (BCG),” Riv Med Aeronaut Spaz, Jul-Dec 1981, 46(3-4):190-199. Vaccinations and Shock:
  • Caileba, A et al, “Shock associated with Disseminated Intravascular Coagulation Syndrome following Injection of DT.TAB Vaccine, Prese Med, Sept 15, 1984, 13(3):1900. Vaccines: The Weird, The Wild and The Hilarious Citations: Sometimes there are articles published about the strangest facts related to vaccines that defies our imagination and ability to understand them. They were written seriously by well-meaning scientific persons, but their titles can be seen differently. Some are funny, some are sad and some are purely scientific folly. See if you can figure these out:
  • Pathel, JC, et al, “Tetanus Following Vaccination Against Small-pox”, J Pediatr, Jul 1960; 27:251-263. [Now you need a tetanus vaccination!]
  • Favez, G, “Tuberculous Superinfection Following a Smallpox Re-Vaccination”, Praxis, July 21, 1960; 49:698-699. [Super means large/big/great!]
  • Bonifacio, A et al, “Traffic Accidents as an expression of “Iatrogenic damage”, Minerva Med, Feb 24, 1971, 62:735-740. [But officer I was just vaccinated!]
  • Baker, J et al, “Accidental Vaccinia: Primary Inoculation of a Scrotum”, Clin Pediatr (Phila), Apr 1972, 11:244-245. [Ooops, the needle slipped.]
  • Edwards, K, “Danger of Sunburn Following Vaccination”, Papua New Guinea Med J, Dec 1977, 20(4):203. [Are vaccines phototoxic?]
  • Stroder, J, “Incorrect Therapy in Children”, Folia Clin Int (Barc), Feb 1966, 16:82-90. [Agreed.]
  • Wehrle PF, “Injury associated with the use of vaccines,” Clin Ther 1985;7(3):282-284. [Dah!]
  • Alberts ME, “When and where will it stop”, Iowa Med 1986 Sep; 76(9):424. [When!]
  • Breiman RF, Zanca JA, “Of floors and ceilings — defining, assuring, and communicating vaccine safety”, Am J Public Health 1997 Dec;87(12):1919-1920. [What is in between floors and ceilings?]
  • Stewart, AM, et al, “Aetiology of Childhood Leukaemia”, Lancet, 16 Oct, 1965, 2:789-790.
  • Nelson, ST, “John Hutchinson On Vaccination Syphilis (Hutchinson, J)”, Arch Derm, (Chic), May 1969, 99:529-535. [Vaccinations and STDs!]
  • Mather, C, “Cotton Mather Anguishes Over the Consequences of His Son’s Inoculation Against Smallpox”, Pediatrics, May 1974; 53:756. [Is it for or against?]
  • Thoman M, “The Toxic Shot Syndrome”, Vet Hum Toxicol, Apr 1986, 28(2):163-166. [Animals are not exempt from vaccination damage either!]
  • Johnson, RH, et al, “Nosocomial Vaccinia Infection”, West J Med, Oct 1976, 125(4):266-270. [Nosocomial means a disease acquired in a doctor’s office or hospital.]
  • Heed, JR, “Human Immunization With Rabies Vaccine in Suckling Mice Brain,” Salud Publica, May-Jun 1974, 16(3): 469-480. [Have you had your suckling mice brains today?]
  • Tesovic, G et al, “Aseptic Meningitis after Measles, Mumps and Rubella Vaccine”, Lancet, Jun 12, 1993, 341(8859):1541. [AM has same symptoms as poliomyelitis!]
  • Buddle, BM et al, “Contagious Ecthyma Virus-Vaccination Failures”, Am J Vet Research, Feb 1984, 45(2):263-266.
  • Freter, R et al, “Oral Immunization And Production of Coproantibody in Human Volunteers”, J Immunol, Dec 1963, 91:724-729. [Guess what copro- means …. Feces.]
  • NA, “Vaccination, For and Against”, 1964, Belg T Geneesk, 20:125-130. [Is it for or against?]
  • Sahadevan, MG et al, “Post-vaccinal Myelitis”, J Indian Med Ass, Feb 16, 1966, 46:205-206. [Did I mention myelitis?]
  • Castan, P et al, “Coma Revealing an acute Leukosis in a child, 15 days after an Oral Anti-poliomyelitis Vaccination,” Acta Neurol Bekg, May 1965, 65:349-367. [Coma from vaccines!]
  • Stickl, H, et al, “Purulent [pus] meningitides Following Smallpox Vaccination. On the Problem of Post- Vaccinal Decrease of Resistance”, Deutsch Med Wschr, Jul 22, 1966, 91:1307-1310. [Vaccines are the injection of viruses cultured from pus …]

The Polio Vaccine And Cancer 

  •  Shah, K and Nathanson, N. “Human exposure to SV40.” American Journal of Epidemiology, 1976; 103: 1-12.
  • Innis, M.D. “Oncogenesis and poliomyelitis vaccine.” Nature, 1968; 219:972-73.
  • Soriano, F., et al. “Simian virus 40 in a human cancer.” Nature, 1974; 249:421-24.
  • Weiss, A.F., et a;. “Simian virus 40-related antigens in three human meningiomas with defined chromosome loss.” Proceedings of the National Academy of Science 1975; 72(2):609-13.
  • Scherneck, S., et al. “Isolation of a SV-40-like papovavirus from a human glioblastoma.” International Journal of Cancer 1979; 24:523-31.
  • Stoian, M., et al. “Possible relation between viruses and oromaxillofacial tumors. II. Research on the presence of SV40 antigen and specific antibodies in patients with oromaxillofacial tumors.” Virologie, 1987; 38:35-40.
  • Stoian, M., et al. “Possible relation between viruses and oromaxillofacial tumors. II. Detection of SV40 antigen and of anti-SV40 antibodies in patients with parotid gland tumors.” Virologie, 1987; 38:41-46.
  • Bravo, M.P., et al. “Association between the occurrence of antibodies to simian vacuolating virus 40 and bladder cancer in male smokers.” Neoplasma, 1988; 35:285-88.
  • O’Connell, K., et al. “Endothelial cells transformed by SV40 T-antigen cause Kaposi’s sarcoma-like tumors in nude mice.” American Journal of Pathology,1991; 139(4):743-49.
  • Weiner, L.P., et al. “Isolation of virus related to SV40 from patients with progressive multifocal leukoencephalopathy.” New England Journal of Medicine, 1972; 286:385-90.
  • Tabuchi, K. “Screening of human brain tumors for SV-40-related T-antigen.” International Journal of Cancer 1978; 21:12-17.
  • Meinke, W., et al. “Simian virus 40-related DNA sequences in a human brain tumor.” Neurology 1979; 29:1590-94.
  • Krieg, P., et al. “Episomal simian virus 40 genomes in human brain tumors.” Proceedings of the National Academy of Science 1981; 78:6446-50.
  • Krieg, P., et al. “Episomal Simian Virus 40 Genomes in Human Brain Tumors.” Proceedings of the National Academy of Sciences of the USA, 1981, 78(10):6446-6450.
  • Krieg, P., et al. “Cloning of SV40 genomes from human brain tumors.” Virology 1984; 138:336-40.
  • Geissler, E. “SV40 in human intracranial tumors: passenger virus or oncogenic ‘hit-and-run’ agent?” Z Klin Med, 1986; 41:493-95.
  • Geissler, E. “SV40 and Human Brain Tumors.” Progress in Medical Virology, 1990; 37:211-222.
  • Bergsagel, D.J., et al. “DNA sequences similar to those of simian virus 40 in ependymomas and choroid plexus tumors of childhood.” New England Journal of Medicine, 1992; 326:988-93.
  • Martini, M., et al. “Human Brain Tumors and Simian Virus 40.” Journal of the National Cancer Institute, 1995, 87(17):1331.
  • Lednicky, JA., et al. “Natural Simian Virus 40 Strains are Present in Human Choroid Plexus and Ependymoma Tumors.” Virology, 1995, 212(2):710-17.
  • Tognon, M., et al. “Large T Antigen Coding Sequence of Two DNA Tumor Viruses, BK and SV-40, and Nonrandom Chromosome Changes in Two Gioblastoma Cell Lines.” Cancer Genetics and Cytogenics, 1996, 90(1): 17-23.
  • Carbone, M., et al. “SV-40 Like Sequences in Human Bone Tumors.” Oncogene, 1996, 13(3):527-35.
  • Pass, HI, Carbone, M., et al. “Evidence For and Implications of SV-40 Like Sequences in Human Mesotheliomas.” Important Advances in Oncology, 1996, pp. 89-108.
  • Rock, Andrea. “The Lethal Dangers of the Billion Dollar Vaccine Business,” Money, (December 1996), p. 161. [Article]
  • Carlsen, William. “Rogue virus in the vaccine: Early polio vaccine harbored virus now feared to cause cancer in humans.” San Francisco Chronicle (July 15, 2001), p. 7. [Article: Research by Susan Fisher, epidemiologist, Loyola University Medical Center.]
  • Bookchin, D. and Schumacher J. “Tainted polio vaccine still carries its threat 40 years later.” The Boston Globe (January 26, 1997). [Article]
  • Rosa, FW., et al. “Absence of antibody response to simian virus 40 after inoculation with killed-poliovirus vaccine of mothers offspring with neurological tumors.” New England Journal of Medicine, 1988; 318:1469.
  • Rosa, FW., et al. Response to: “Neurological tumors in offspring after inoculation of mothers with killed poliovirus vaccine.” New England Journal of Medicine,1988, 319:1226.
  • Martini, F., et al. “SV-40 Early Region and Large T Antigen in Human Brain Tumors, Peripheral Blood Cells, and Sperm Fluids from Healthy Individuals.”Cancer Research, 1996, 56(20):4820-4825.

Vaccinations and Autism

  • Eggers, C, “Autistic Syndrome (Kanner) And Vaccinations against Smallpox”, Klin Paediatr, Mar 1976, 188(2):172-180.
  • Kiln MR, “Autism, inflammatory bowel disease, and MMR vaccine.” Lancet 1998 May 2;351(9112):1358.
  • Selway, “MMR vaccination and autism 1998. Medical practitioners need to give more than reassurance.” BMJ 1998 Jun 13;316(7147):1824.
  • Nicoll A, Elliman D, Ross E, “MMR vaccination and autism 1998,” MJ 1998 Mar 7;316(7133):715-716.
  • Lindley K J, Milla PJ, “Autism, inflammatory bowel disease, and MMR vaccine.”Lancet 1998 Mar 21;351(9106):907-908.
  • Bedford H, et al, “Autism, inflammatory bowel disease, and MMR vaccine.” Lancet 1998 Mar 21;351(9106):907.
  • Vijendra K. Singh, Sheren X. Lin, and Victor C. Yang, “Serological Association of Measles Virus and Human Herpesvirus-6 with Brain Autoantibodies in Autism,” Clinical Immunology and Immunopathology, Oct 1998, Vol. 89, No. 1, p 105-108. [“None of the autistic children in the study had measles in the past, but all had the MMR” stated David Whalgren.

160 Research Papers Supporting Vaccine/Autism Causation


Mainstream research has found that vaccines and their ingredients can cause the  underlying medical conditions that committed physicians and researchers are commonly  finding in children who have been given an autism diagnosis. These conditions include  gastrointestinal damage, immune system impairment, chronic infections, mitochondrial  disorders, autoimmune conditions, neurological regression, glial cell activation,  interleukin-6 secretion dysregulation, brain inflammation, loss of integrity of the blood– brain barrier, seizures, synaptic dysfunction, dendritic cell dysfunction, mercury  poisoning, aluminum toxicity, gene activation and alteration, glutathione depletion,  impaired methylation, oxidative stress, impaired thioredoxin regulation, mineral  deficiencies, impairment of the opioid system, endocrine dysfunction, cellular apoptosis,  and other disorders. 

1. Increased risk of developmental neurologic impairment after high exposure to  thimerosal-containing vaccine in first month of life.  

Division of Epidemiology and Surveillance, Vaccine Safety and Development  Branch, National Immunization Program, Centers for Disease Control and  Prevention. 1999.  

Thomas M. Verstraeten, Robert Davis, David Gu, Frank DeStefano  

Background: Concern has risen on the presence of the ethylmercury containing  preservative thimerosal in vaccines. We assessed the risk for neurologic and  renal impairment associated with past exposure to thimerosal-containing vaccine  using automated data from the Vaccine Safety Data link (VSD). VSD is a large  linked database from four health maintenance organizations in Washington,  Oregon and California, containing immunization, medical visit and demographic  data on over 400,000 infants born between '91 and '97.  

Methods: We categorized the cumulative ethylmercury exposure from Thimerosal containing vaccines after one month of life and assessed the subsequent risk of  degenerative and developmental neurologic disorders and renal disorders before the age of six. We applied proportional hazard models adjusting for HMO, year of birth, and gender, excluding premature babies. 

Results: We identified 286 children with degenerative and 3702 with  developmental neurologic disorders, and 310 with renal disorders. The relative  risk (RR) of developing a neurologic development disorder was 1.8 ( 95%  confidence intervals [CI] =1.1-2.8) when comparing the highest exposure group  at 1 month of age (cumulative dose> 25 ug) to the unexposed group. Within this group we also found an elevated risk for the following disorders: autism  (RR 7.6, 95% Cl = 1.8-31.5), non organic sleep disorders (RR 5.0, 95% Cl = 1.6- 15.9}, and speech disorders (RR 2.1, 95% (1=1.1-4.0). For the neurologic  degenerative and renal disorders group we found no significantly increased risk  or a decreased risk. 

Conclusion: This analysis suggests that high exposure to ethyl mercury  from thimerosal-containing vaccines in the first month of life increases the  risk of subsequent development of neurologic development impairment,  but not of neurologic degenerative or renal impairment. Further confirmatory  studies are needed.  

2. Pilot comparative study on the health of vaccinated and unvaccinated 6- to 12-  year old U.S. children 

J Transl Sci 3: DOI: 10.15761/JTS.1000186, April 24, 2017 

Anthony R Mawson, Azad R Bhuiyan, Brian D Ray, Binu Jacob 

Department of Epidemiology and Biostatistics, School of Public Health, Jackson  State University, Jackson, MS 39213, USA 

National Home Education Research Institute, PO Box 13939, Salem, OR 97309,  USA 

Abstract 

Vaccinations have prevented millions of infectious illnesses, hospitalizations and  deaths among U.S. children, yet the long-term health outcomes of the  vaccination schedule remain uncertain. Studies have been recommended by the  U.S. Institute of Medicine to address this question. This study aimed 1) to  compare vaccinated and unvaccinated children on a broad range of health  outcomes, and 2) to determine whether an association found between  vaccination and neurodevelopmental disorders (NDD), if any, remained  significant after adjustment for other measured factors. A cross-sectional study of mothers of children educated at home was carried out in collaboration with  homeschool organizations in four U.S. states: Florida, Louisiana, Mississippi and  Oregon. Mothers were asked to complete an anonymous online questionnaire on their 6- to 12-year-old biological children with respect to pregnancy-related  factors, birth history, vaccinations, physician-diagnosed illnesses, medications  used, and health services. NDD, a derived diagnostic measure, was defined as  having one or more of the following three closely-related diagnoses: a learning  disability, Attention Deficient Hyperactivity Disorder, and Autism Spectrum  Disorder. A convenience sample of 666 children was obtained, of which 261  (39%) were unvaccinated. The vaccinated were less likely than the unvaccinated  to have been diagnosed with chickenpox and pertussis, but more likely to have  been diagnosed with pneumonia, otitis media, allergies and NDD. After  adjustment, vaccination, male gender, and preterm birth remained significantly  associated with NDD. However, in a final adjusted model with interaction,  vaccination but not preterm birth remained associated with NDD, while the  interaction of preterm birth and vaccination was associated with a 6.6-fold  increased odds of NDD (95% CI: 2.8, 15.5). In conclusion, vaccinated  homeschool children were found to have a higher rate of allergies and NDD than unvaccinated homeschool children. While vaccination remained  significantly associated with NDD after controlling for other factors, preterm birth  coupled with vaccination was associated with an apparent synergistic increase in the odds of NDD. Further research involving larger, independent samples and 

stronger research designs is needed to verify and understand these unexpected  findings in order to optimize the impact of vaccines on children’s health. 

Exerpts 

"NDD, a derived diagnostic measure, was defined as having one or more of  the following three closely-related diagnoses: a learning disability,  Attention Deficient Hyperactivity Disorder, and Autism Spectrum Disorder." 

"Chronic illness 

Vaccinated children were significantly more likely than the unvaccinated to  have been diagnosed with the following: allergic rhinitis (10.4% vs. 0.4%, p  <0.001; OR 30.1, 95% CI: 4.1, 219.3), other allergies (22.2% vs. 6.9%, p <0.001;  OR 3.9, 95% CI: 2.3, 6.6), eczema/atopic dermatitis (9.5% vs. 3.6%, p = 0.035;  OR 2.9, 95% CI: 1.4, 6.1), a learning disability (5.7% vs. 1.2%, p = 0.003; OR  5.2, 95% CI: 1.6, 17.4), ADHD (4.7% vs. 1.0%, p = 0.013; OR 4.2, 95% CI: 1.2,  14.5), ASD (4.7% vs. 1.0%, p = 0.013; OR 4.2, 95% CI: 1.2, 14.5), any  neurodevelopmental disorder (i.e., learning disability, ADHD or ASD) (10.5% vs.  3.1%, p <0.001; OR 3.7, 95% CI: 1.7, 7.9) and any chronic illness (44.0% vs.  25.0%, p <0.001; OR 2.4, 95% CI: 1.7, 3.3)." 

3. Hepatitis B vaccination of male neonates and autism diagnosis, NHIS 1997- 2002. 

Gallagher CM, Goodman MS. 

J Toxicol Environ Health A. 2010;73(24):1665-77. doi:  

10.1080/15287394.2010.519317. 

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.


4. Associations of prenatal and early childhood mercury exposure with autistic  behaviors at 5 years of age: The Mothers and Children's Environmental Health  (MOCEH) study 

Science of The Total Environment 

Volumes 605–606, 15 December 2017, Pages 251-257 

JiaRyua. , Eun-HeeHaa, Boong-NyunKimb, MinaHac, YanghoKimd,  HyesookParke, Yun-ChulHongf, Kyoung-NamKim 

Department of Occupational and Environmental Medicine, School of Medicine,  Ewha Womans University, Seoul, Republic of Korea 

Division of Child & Adolescent Psychiatry, Department of Psychiatry and Institute  of Human Behavioral Medicine, College of Medicine, Seoul National University,  Seoul, Republic of Korea 

Department of Preventive Medicine, College of Medicine, Dankook University,  Cheonan, Republic of Korea 

Department of Occupational and Environmental Medicine, Ulsan University  Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea 

Department of Preventive Medicine, School of Medicine, Ewha Womans  University, Seoul, Republic of Korea 

Department of Preventive Medicine, Seoul National University College of  Medicine, Seoul, Republic of Korea 

Institute of Public Health and Medical Service, Seoul National University Hospital, Seoul, Republic of Korea 

Received 26 April 2017, Revised 24 June 2017, Accepted 26 June 2017,  Available online 28 June 2017. 

Abstract 

Background 

Although mercury is an established neurotoxin, only few longitudinal studies have investigated the association between prenatal and early childhood mercury  exposure and autistic behaviors. 

Methods 

We conducted a longitudinal cohort study using an ongoing prospective birth  cohort initiated in 2006, wherein blood mercury levels were measured at early  and late pregnancy; in cord blood; and at 2 and 3 years of age. We analyzed 458 mother-child pairs. Autistic behaviors were assessed using the Social  Responsiveness Scale (SRS) at 5 years of age. Both continuous SRS T-scores  and T-scores dichotomized by a score of ≥ 60 or < 60 were used as outcomes.

Results 

The geometric mean of mercury concentrations in cord blood was 5.52 μg/L. In  adjusted models, a doubling of blood mercury levels at late pregnancy (β = 1.84,  95% confidence interval [CI]: 0.39, 3.29), in cord blood (β = 2.24, 95% CI: 0.22,  4.27), and at 2 years (β = 2.12, 95% CI: 0.54, 3.70) and 3 years (β = 2.80, 95%  CI: 0.89, 4.72) of age was positively associated with the SRS T-scores. When the SRS T-scores were dichotomized, we observed positive associations with  mercury levels at late pregnancy (relative risk [RR] = 1.31, 95% CI: 1.08, 1.60)  and in cord blood (RR = 1.28, 95% CI: 1.01, 1.63). 

Conclusion 

We found that blood mercury levels at late pregnancy and early childhood  were associated with more autistic behaviors in children at 5 years of age.  Further study on the long-term effects of mercury exposure is recommended. 

5. The association between mercury levels and autism spectrum disorders: A  systematic review and meta-analysis 

Journal of Trace Elements in Medicine and Biology 

Volume 44, December 2017, Pages 289-297 

Tina Jafari, Noushin Rostampour, Aziz A.Fallah, Afshin Hesamia 

Clinical Biochemistry Research Center, Shahrekord University of Medical  Sciences, Sharhekord, Iran 

Department of Biochemistry and Nutrition, Faculty of Medicine, Shahrekord  University of Medical Sciences, Shahrekord, Iran 

Department of Internal Medicine, Shahrekord University of Medical Sciences,  Shahrekord, Iran 

Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord 34141, Iran 

Abstract 

Background & aims 

The relationship between mercury and autism spectrum disorders (ASD) has  always been a topic of controversy among researchers. This study aimed to  assess the relationship between ASD and mercury levels in hair, urine, blood, red blood cells (RBC), and brain through a meta-analysis. 

Methods 

A systematic search was performed in several databases including PubMed, ISI  Web of Science, Cochrane register of controlled trials, Google Scholar, Scopus,  and MagIran until June 2017. Case-control studies evaluating concentration of  total mercury in different tissues of ASD patients and comparing them to the  healthy subjects (control group) were identified. Necessary data were extracted  and random effects model was used to calculate overall effect and its 95%  corresponding confidence interval (CI) from the effect sizes.

Results 

A total of 44 studies were identified that met the necessary criteria for meta analysis. The mercury level in whole blood (Hedges = 0.43, 95% CI: 0.12, 0.74, P = 0.007), RBC (Hedges = 1.61, 95% CI: 0.83, 2.38, P < 0.001), and brain (0.61  ng/g, 95% CI, 0.02, 1.19, P = 0.043) was significantly higher in ASD patients than healthy subjects, whereas mercury level in hair (−0.14 mg/g, 95% CI: −0.28,  −0.01, P = 0.039) was significantly lower in ASD patients than healthy subjects.  The mercury level in urine was not significantly different between ASD patients  and healthy subjects (0.51 mg/g creatinine, 95% CI: −0.14, 1.16, P = 0.121). 

Conclusions 

Results of the current meta-analysis revealed that mercury is an important  causal factor in the etiology of ASD. It seems that the detoxification and  excretory mechanisms are impaired in ASD patients which lead to  accumulation of mercury in the body. Future additional studies on mercury  levels in different tissues of ASD patients should be undertaken. 

6. The Relationship Between the Level of Copper, Lead, Mercury and Autism  Disorders: A Meta-Analysis 

  

Authors Jafari Mohammadabadi H, Rahmatian A, Sayehmiri F, Rafiei M Published 21 September 2020 Volume 2020:11 Pages 369—378 

1School of Medicine, Shiraz University of Medical Sciences, Shiraz, Fars, Iran;  2Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran;  3Student Research Committee, School of Medicine, Shahid Beheshti University  of Medical Sciences, Tehran, Iran;  

4Department of Biostatistics and Epidemiology, Arak University of Medical  Sciences, Arak, Iran 

Background and Objectives: There is a likelihood of a possible relationship  between the concentrations of copper, lead, and mercury and autism. The  present review was carried out to determine the relationship between the  concentrations of these elements and autism by meta-analysis. 

Methods: In this study, searching Scopus, PubMed, and Science Direct  databases, 18 articles conducted in different countries from 1982 to 2019 were  collected. Studies’ heterogeneity was investigated using the I2 index. The data  were analyzed using R and STATA software. 

Results: In these 18 studies, 1797 patients (981 cases and 816 controls) aged 2  to 16 years were examined. Concentration of the samples (blood, hair, and nails)  for both case and control groups was evaluated. There was no significant  relationship between copper concentration and autism (SMD (95% CI): 0.02 (−  1.16,1.20); I2=97.7%; P=0.972); there was a significant relationship between  mercury concentration and autism (SMD (95% CI): 1.96 (0.56,3.35); I2=98.6%; 

P=0.006); there was also a significant relationship between lead concentration  and autism (SMD (95% CI): 2.81 (1.64,3.98); I2=97.8%; P=0.000). 

Conclusion: There is, nevertheless, a significant relationship between  mercury concentration and autism. Thus, the concentration of mercury can be listed as a pathogenic cause (disease-causing) for autism. 

7. The Putative Role of Environmental Mercury in the Pathogenesis and  Pathophysiology of Autism Spectrum Disorders and Subtypes 

Molecular Neurobiology, First Online: 22 July 2017 

G. Morris, K. Puri, R. E. Frye, M. Maes 

1.Tir Na NogLlanelliUK 

2.Department of Medicine, Hammersmith Hospital Imperial College London,  LondonUK 

3.Division of Child and Adolescent Neurology and Children’s Learning Institute,  Department of PediatricsUniversity of Texas, Austin USA 

4.Department of PsychiatryChulalongkorn University Bangkok, Thailand 

Abstract 

Exposure to organic forms of mercury has the theoretical capacity to generate a  range of immune abnormalities coupled with chronic nitro-oxidative stress seen  in children with autism spectrum disorder (ASD). The paper discusses possible  

mechanisms explaining the neurotoxic effects of mercury and possible  associations between mercury exposure and ASD subtypes. Environmental  mercury is neurotoxic at doses well below the current reference levels  considered to be safe, with evidence of neurotoxicity in children exposed  to environmental sources including fish consumption and ethylmercury containing vaccines. Possible neurotoxic mechanisms of mercury include  direct effects on sulfhydryl groups, pericytes and cerebral endothelial cells, accumulation within astrocytes, microglial activation, induction of chronic  oxidative stress, activation of immune-inflammatory pathways and  impairment of mitochondrial functioning. (Epi-)genetic factors which may  increase susceptibility to the toxic effects of mercury in ASD include the  following: a greater propensity of males to the long-term neurotoxic effects of postnatal exposure and genetic polymorphisms in glutathione  transferases and other glutathione-related genes and in selenoproteins.  Furthermore, immune and inflammatory responses to immunisations with  mercury-containing adjuvants are strongly influenced by polymorphisms in the human leukocyte antigen (HLA) region and by genes encoding effector  proteins such as cytokines and pattern recognition receptors. Some  epidemiological studies investigating a possible relationship between high  environmental exposure to methylmercury and impaired neurodevelopment have reported a positive dose-dependent effect. Retrospective studies, on the other hand, reported no relationship between a range of ethylmercury-containing  vaccines and chronic neuropathology or ASD. On the basis of these results, we  would argue that more clinically relevant research is required to examine whether

environmental mercury is associated with ASD or subtypes. Specific  recommendations for future research are discussed. 

8. Blood Mercury, Arsenic, Cadmium, and Lead in Children with Autism Spectrum  Disorder. 

Biol Trace Elem Res. 2017 May 8. doi: 10.1007/s12011-017-1002-6. Li H, Li H, Li Y, Liu Y, Zhao Z 

Children's Hospital of Zhejiang University School of Medicine, Hangzhou,  People's Republic of China. 

Laboratory of Neuroinflammation, StVincent's Centre for Applied Medical  Research and University of New South Wales, Sydney, NSW, Australia. 

Children's Hospital of Zhejiang University School of Medicine, Hangzhou,  People's Republic of China. zhaozy@zju.edu.cn. 

Department of Pediatric Health Care, Children's Hospital of Zhejiang University  School of Medicine, 57 Zhuganxiang Road, Hangzhou, People's Republic of  China 

Abstract 

Environmental factors have been implicated in the etiology of autism spectrum  disorder (ASD); however, the role of heavy metals has not been fully defined.  This study investigated whether blood levels of mercury, arsenic, cadmium, and  lead of children with ASD significantly differ from those of age- and sex-matched  controls. One hundred eighty unrelated children with ASD and 184 healthy  controls were recruited. Data showed that the children with ASD had  significantly (p < 0.001) higher levels of mercury and arsenic and a lower  level of cadmium. The levels of lead did not differ significantly between the  groups. The results of this study are consistent with numerous previous  studies, supporting an important role for heavy metal exposure,  particularly mercury, in the etiology of ASD. It is desirable to continue future  research into the relationship between ASD and heavy metal exposure. 

9. Protective role of alpha-lipoic acid in impairments of social and stereotyped  behaviors induced by early postnatal administration of thimerosal in male rat. 

Neurotoxicol Teratol. 2018 Feb 23. pii: S0892-0362(17)30086-7. doi:  10.1016/j.ntt.2018.02.002.  

Namvarpour Z, Nasehi M, Amini A, Zarrindast MR.

Institute for Cognitive Science Studies (ICSS), Tehran, Iran. 

Institute for Cognitive Science Studies (ICSS), Tehran, Iran; Cognitive and  Neuroscience Research Center (CNRC), Tehran Medical Sciences Branch,  Islamic Azad University, Tehran, Iran.  

Department of Biology and Anatomy, School of Medicine, Shahid Beheshti  University of Medical Sciences, Tehran, Iran. 

Institute for Cognitive Science Studies (ICSS), Tehran, Iran; Department of  Pharmacology, School of Medicine, Tehran University of Medical Sciences,  Tehran, Iran.  

Abstract 

Aim Thimerosal, a mercury-containing preservative has been widely used in a  number of biological and drug products, including many vaccines, and has been  studied as a possible etiological factor for some neurodevelopmental disabilities.  Here, the protective effects of Alpha Lipoic Acid (ALA), an organosulfur  compound derived from Octanoic Acid, on Thimerosal-induced behavioral  abnormalities in rat were examined. 

METHODS: 

108 male Wistar rats were divided into three cohorts and treated as follows: 1)  Thimerosal at different doses (30, 300, or 3000 μg Hg/kg) in four i.m. injections  on 7, 9, 11, 15postnatal days. 2) ALA (at doses of 5, 10 and 20 mg/kg), following  the same order; 3) single dose of Thimerosal (3000 μg Hg/kg) plus ALA at  different doses (5, 10 or 20 mg/kg), by the previously described method. A saline  treated control group and a ALA vehicle control (0.1% NaOH) were also included. At 5 and 8 weeks after birth, rats were evaluated with behavioral tests, to assess  locomotor activity, social interactions and stereotyped behaviors, respectively. 

RESULTS: 

The data showed that Thimerosal at all doses (30, 300 and 3000 μg Hg/kg)  significantly impacted locomotor activity. Thimerosal at doses of 300 and 3000  but not 30 μg Hg/kg impaired social and stereotyped behaviors. In contrast, ALA  (at doses of 5, 10 and 20 mg/kg) did not alter behaviors by itself, at doses of  20 mg/kg, it reduced social interaction deficits induced by the highest dose of  Thimerosal (3000 μg Hg/kg). Moreover, ALA, at all doses prevented the adverse  effects of Thimerosal on stereotyped behaviors. 

CONCLUSIONS: 

the results of this preclinical study, consistent with previous studies on mice and  rats, reveals that neonatal dose-dependent exposure to Thimerosal  mimicking the childhood vaccine schedule can induce abnormal social  interactions and stereotyped behaviors similar to those observed in  neurodevelopmental disorders such as autism, and, for the first time,  revealed that these abnormalities may be ameliorated by ALA. This indicates that ALA may protect against mercurial-induced abnormal behaviors.


10. Gender-selective toxicity of thimerosal. 

Exp Toxicol Pathol. 2009 Mar;61(2):133-6. doi: 10.1016/j.etp.2008.07.002. Epub  2008 Sep 3. 

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. 

11. Mercury toxicokinetics--dependency on strain and gender. 

Toxicol Appl Pharmacol. 2010 Mar 15;243(3):283-91. doi:  

10.1016/j.taap.2009.08.026. Epub 2009 Sep 2. 

Ekstrand J1, Nielsen JB, Havarinasab S, Zalups RK, Söderkvist P, Hultman P. Molecular and Immunological Pathology, Department of Clinical and  Experimental Medicine, Linköping University, 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 F2-hybrids 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. 

12. A Review of the Differences in Developmental, Psychiatric, and Medical  Endophenotypes Between Males and Females with Autism Spectrum Disorder 

J Dev Phys Disabil. 2015 Feb; 27(1): 119–139. 

Eric Rubenstein, Department of Epidemiology, Johns Hopkins Bloomberg School  of Public Health, Lisa D. Wiggins, and Li-Ching Lee 

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.

13. Mercury toxicity: Genetic susceptibility and synergistic effects Medical Veritas 2 (2005) 535–542 

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 Prevention. 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 ethylmercury 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.  

Excerpt 

"4. Hormonal effects: Testosterone and Estrogen 

Testosterone and estrogen-like compounds give vastly different 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 system  (data not plotted). However, testosterone which appeared protective at very  low levels (0.01 to 0.1 micromolar), dramatically increased neuron death at  higher levels (0.5 to 1.0 micromolar). 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. 

These testosterone results, while not conclusive because of the in vitro  neuron culture type of testing, clearly demonstrated that male versus  female hormones may play a major role in autism risk and may explain the  high ratio of boys to girls in autism (4 to 1) and autism related disorders." 

14. Autism: a form of lead and mercury toxicity 

Environ Toxicol Pharmacol. 2014 Nov;38(3):1016-24. doi:  

10.1016/j.etap.2014.10.005. Epub 2014 Nov 6.

Yassa HA 

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 autistic 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. 

15. Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? 

J Inorg Biochem. 2011 Nov;105(11):1489-99. Epub 2011 Aug 23. Tomljenovic L, 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. 

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 3-4months 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. 

16. The putative role of environmental aluminium in the development of chronic  neuropathology in adults and children. How strong is the evidence and what  could be the mechanisms involved? 

Metabolic Brain Disease, October 2017, Volume 32, Issue 5, pp 1335–1355 

Gerwyn Morris, Basant K. Puri, Richard E. Frye 

Tir Na Nog, Llanelli, UK, Department of MedicineImperial College London,  Hammersmith Hospital, London UK, College of Medicine, Department of  PediatricsUniversity of Arkansas for Medical Sciences, Arkansas Children’s  Hospital Research Institute, Little Rock 

Abstract 

The conceptualisation of autistic spectrum disorder and Alzheimer’s disease  has undergone something of a paradigm shift in recent years and rather than  being viewed as single illnesses with a unitary pathogenesis and  pathophysiology they are increasingly considered to be heterogeneous  syndromes with a complex multifactorial aetiopathogenesis, involving a highly  complex and diverse combination of genetic, epigenetic and environmental  factors. One such environmental factor implicated as a potential cause in  both syndromes is aluminium, as an element or as part of a salt, received, for  example, in oral form or as an adjuvant. Such administration has the potential to  induce pathology via several routes such as provoking dysfunction and/or  activation of glial cells which play an indispensable role in the regulation of  central nervous system homeostasis and neurodevelopment. Other routes  include the generation of oxidative stress, depletion of reduced glutathione, direct and indirect reductions in mitochondrial performance and integrity, and increasing the production of proinflammatory cytokines in both the brain and peripherally.  The mechanisms whereby environmental aluminium could contribute to the 

development of the highly specific pattern of neuropathology seentransulfuration  in Alzheimer’s disease are described. Also detailed are several mechanisms  whereby significant quantities of aluminium introduced via immunisation could  produce chronic neuropathology in genetically susceptible children. Accordingly, it is recommended that the use of aluminium salts in immunisations should be discontinued and that adults should take steps to minimise their  exposure to environmental aluminium. 

17. Administration of aluminium to neonatal mice in vaccine-relevant amounts is  associated with adverse long term neurological outcomes. 

J Inorg Biochem. 2013 Nov;128:237-44. doi: 10.1016/j.jinorgbio.2013.07.022.  Epub 2013 Jul 19. 

Shaw CA, 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. Electronic address: 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. 

Repetitive administration of aluminium to neonatal mice in amounts comparable  to those to children receive via routine vaccinations significantly increases  anxiety and reduces exploratory behaviour and locomotor activities. The  neurodisruptive effects of aluminium are long-lasting and persist for 6 months  following injection.


18. Aluminum-Induced Entropy in Biological Systems: Implications for Neurological  Disease 

Journal of Toxicology, Volume 2014 (2014), Article ID 491316, 27 pages 

Christopher A. Shaw,1,2,3 Stephanie Seneff,4 Stephen D. Kette,5 Lucija  Tomljenovic,1 John W. Oller Jr.,6 and Robert M. Davidson7 

1Neural Dynamics Research Group, Department of Ophthalmology and Visual  Sciences, 828 W. 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L8 2Program Experimental Medicine, University of British Columbia, Vancouver,  Canada V5Z 1L8 

3Program in Neurosciences, University of British Columbia, Vancouver, Canada  V5Z 1L8 

4MIT Computer Science and Artificial Intelligence Laboratory, 32 Vassar Street,  Cambridge, MA 02139, USA 

5Hudson, FL 34667, USA 

6Department of Communicative Disorders, University of Louisiana, Lafayette, LA  70504-3170, USA 

7Internal Medicine Group Practice, PhyNet Inc., 4002 Technology Center,  Longview, TX 75605, USA 

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. 

Exerpts: "Animal models of neurological disease plainly suggest that the  ubiquitous presence of Al in human beings implicates Al toxicants as  causally involved in Lou Gehrig’s disease (ALS), Alzheimer’s disease and  autism spectrum disorders." 

"All these findings plausibly implicate Al adjuvants in pediatric vaccines as causal factors contributing to increased rates of autism spectrum 

disorders in countries where multiple doses are almost universally  administered." 

19. Clinical clues for autoimmunity and neuroinflammation in patients with autistic  regression. 

Dev Med Child Neurol. 2017 Apr 6. doi: 10.1111/dmcn.13432.  

Scott O, Shi D, Andriashek D, Clark B, Goez HR. 

Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada. Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. Department of Pediatrics, Glenrose Rehabilitation Hospital, Edmonton, AB,  Canada. 

Division of Pediatric Neurology, University of Alberta, Edmonton, AB, Canada 

Abstract 

AIM: 

Autistic regression is a unique variant within the autism spectrum disorders  (ASDs), with recent reports raising the possibility of immune aetiology. This  study explores clinical clues for an association between autistic regression and  autoimmunity. 

METHOD: 

Single-centre charts of children diagnosed with ASD in 2014 were reviewed. We  compared the rates of: (1) familial autoimmunity in first-degree and second degree relatives; (2) febrile illness preceding initial parental concern, as a  potential precipitant of immune activation; and (3) possible non-immune  precipitants such as pregnancy and postnatal complications. 

RESULTS: 

The charts of 206 children with ASD and 33 diagnosed with autistic regression  variant were reviewed. The incidence of febrile illness in the 6 months prior  to initial parental concern was significantly higher in the children with autistic  regression compared with those with ASD (30% vs 0%; p<0.001). The overall  prevalence of familial autoimmunity was also higher in children with autistic  regression compared with those with ASD (33% vs 12%; p<0.001). Type 1  diabetes and autoimmune thyroiditis were both more common in families with  children with autistic regression. Other non-immune risk factors did not differ  between the two groups. 

INTERPRETATION: 

Our findings suggest that predisposition to autoimmunity, and  immune/inflammatory activation, may be associated with autistic  regression. 

20. Biological plausibility of the gut-brain axis in autism.

Ann N Y Acad Sci. 2017 Nov;1408(1):5-6. doi: 10.1111/nyas.13516. Epub 2017  Nov 1. 

Vasquez A 

Abstract 

Organic abnormalities with neuroinflammatory and psychiatric consequences  involving abnormal kynurenine and purine metabolism, neurotransmitter and  cytokine imbalances, and altered levels of nutrients and metabolites are noted in  autism, and many of these abnormalities-specifically including increased  intestinal permeability, microbial metabolites, and heightened serum levels of  endotoxin-originate from the gut.  

21. A comparison of temporal trends in United States autism prevalence to trends in  suspected environmental factors 

Environ Health. 2014; 13: 73. 

Cynthia D Nevison 

Institute for Arctic and Alpine Research, University of Colorado, Boulder, Boulder, CO 80309-0450 USA 

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. 

22. Toxic Metals and Essential Elements in Hair and Severity of Symptoms among  Children with Autism 

Maedica (Buchar). 2012 Jan; 7(1): 38–48. 

Eleonor BLAUROCK-BUSCH,a Omnia R. AMIN,b Hani H. DESSOKI,c and  Thanaa RABAH d 

aLecturer and Advisor, International Board of Clinical Metal Toxicology & German Medical Association of Clinical Metal Toxicology, Hersbruck, Germany bAssociate Professor of Psychiatry, Cairo University, Egypt 

cAssociate Professor of Psychiatry, Beni-Suef University, Egypt - Beni-Suef  University 

dResearcher of Public Health and Biostatistics, National Research Center, Egypt Address for correspondence: Eleonor Blaurock-Busch, Laboratory for Clinical  and Environmental Analyses. Robenstr 20, D-912217, Hersbruck, Germania.  Phone: +0049 91514332 ; Email: ed.ecartorcim@bbew 

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. 

23. Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Heterogeneous Genetic Predisposition 

Volume 8 • Issue 1 • 1000224 

Autism Open Access, an open access journal, ISSN: 2165-7890 DOI: 10.4172/2165-7890.1000224 

James Lyons-Weiler* 

Institute for Pure and Applied Knowledge, USA 

Abstract 

Neurodevelopmental disorders, including autism spectrum disorders, have a  complex biological and medical basis involving diverse genetic risk and myriad  environmental exposures. Teasing apart the role of specific stressors is made  challenging due to the large number of apparently contributing associations,  gene x environment interactions and phenomimicry. Historically, these conditions  have been rare, making causality assessment at the population level infeasible.  Only a few vaccines have been tested for association with autism, and it has  been shown that improved diagnosis only explains a percentage of the increase  in diagnosis. Now the rates are so high in some countries that public school  programs cannot handle to large numbers of special needs students, and  professionals are quitting their jobs due to security concerns. Here, I present a  mechanistic biomedical process model (theory) of the pathophysiology of autism  that reconciles the apparent paradox between the high degree of causal  heterogeneity in environmental toxins, the absence of common "autism genes"  and the high degree of genetic concordance (heritability) of ASD and ASD-like  traits. In brief, the environmental toxin sampling liability for ASD varies among  families involving different local exposures following injury to normal cellular  endoplasmic detoxification and mitochondrial processes from toxic metals. The  literature strongly supports that autism is most accurately seen as an acquired  cellular detoxification deficiency syndrome with heterogeneous genetic  predisposition that manifests pathophysiologic consequences of accumulated,  run-away cellular toxicity. At a more general level, it is a form of a toxicant induced loss of tolerance of toxins, and of chronic and sustained ER overload 

(“ER hyperstress”), contributing to neuronal and glial apoptosis via the unfolded  protein response (UPR). Inherited risk of impaired cellular detoxification and  circulating metal re-toxification in neurons and glial cells accompanied by chronic UPR is key. This model explains the aberrant protein disorder observed in ASD;  the great diversity of genes that are found to have low, but real contributions to  ASD risk and the sensitivity of individuals with ASD to environmental toxins. The  hindrance of detoxification and loss of cellular energetics leads to apoptosis,  release of cytokines and chronic neuroinflammation and microglial activation, all  observed hallmarks of ASD. Interference with the development of normal  complex (redundant) synapses leads to a pathological variation in neuronal  differentiation, axon and dendrite outgrowth, and synaptic protein expression.  The most general outcomes are overall simplification of gross synaptic anatomy  and, neurofunctionally, a loss of inhibitory feedback and aberrations in long-term  connections between distant regions of the brain. Failed resolution of the ER  stress response leads to re-distribution of neurotoxic metals, and the impaired  neurocellular processes lead to subsequent accumulation of a variety of  additional types of toxins with secondary, sometime life-threatening comorbidities such as seizures, with overlapping (not mutually exclusive) causality. Reduction  of exposure to toxins known to cause mitopathy (mercury) and endoplasmic  reticulum dysfunction (mercury and aluminum) during pregnancy and during the  early years of development will reduce the risk of ER overload and ER  hyperstress, and of ASD diagnosis. This knowledge has immediate clinical  translational relevance: Post-vaccination symptoms should be heeded as a sign  of susceptibility to toxin; Vitamin D can be increased to drive the healthy early  phases of the unfolded protein response (UPR), and mutations in ASD genes  encoding proteins with high intrinsic disorder may contraindicate the use of  aluminum and mercury for carriers of risk alleles. Clinicians should be alert to a  patient’s Vitamin D receptor (BSM) mutational status prior to recommending  increased doses. Approaches to improving overall brain health in autistics must  be de-stigmatized and given high priority. Reduction of lifetime exposures of  industrial and agricultural toxins will improve brain health for the entire human  population. Purely genetic studies of ASD, and studies that do not include  vaccination as an environmental exposure with potential liability and interactions  with genes, are unethical. To qualify as science, studies must test plausible  hypotheses, and the absence of association from poorly designed, unethically  executed, and underpowered and unsound whole-population association studies  have been harmful distractions in the quest for understanding. Skilled  pediatricians and ob/gyns will seek evidence of genetic predisposition to  environmental susceptibility in the form of non-synonymous substitutions in brain  proteins that require ER-folding, and they will provide informed cautions on  exposures (from all sources) to environmental toxins to patients and parents of  patients with signs of metal and chemical sensitivity. To aid in this, a list of ASD  environmental susceptibility protein-encoded genes is presented. A clinical  exome sequence test, followed by loss-of-function prediction analysis, would  point to individuals most susceptible to vaccine metal-induced ER hyper stress. 

24. Assessment of infantile mineral imbalances in autism spectrum disorders  (ASDs).

Int J Environ Res Public Health. 2013 Nov 11;10(11):6027-43. doi:  10.3390/ijerph10116027. 

Yasuda H1, Tsutsui T. 

La Belle Vie Research Laboratory, 8-4 Nihonbashi-Tomizawacho, Chuo-ku,  Tokyo 103-0006, Japan. yasuda@lbv.co.jp 

Abstract 

The interactions between genes and the environment are now regarded as the  most probable explanation for autism. In this review, we summarize the results of a metallomics study in which scalp hair concentrations of 26 trace elements were examined for 1,967 autistic children (1,553 males and 414 females aged 0-15  years-old), and discuss recent advances in our understanding of epigenetic roles  of infantile mineral imbalances in the pathogenesis of autism. In the 1,967  subjects, 584 (29.7%) and 347 (17.6%) were found deficient in zinc and  magnesium, respectively, and the incidence rate of zinc deficiency was estimated at 43.5% in male and 52.5% in female infantile subjects aged 0-3 years-old. In  contrast, 339 (17.2%), 168 (8.5%) and 94 (4.8%) individuals were found to suffer  from high burdens of aluminum, cadmium and lead, respectively, and 2.8% or  less from mercury and arsenic. High toxic metal burdens were more frequently  observed in the infants aged 0-3 years-old, whose incidence rates were 20.6%,  12.1%, 7.5%, 3.2% and 2.3% for aluminum, cadmium, lead, arsenic and mercury, respectively. These findings suggest that infantile zinc- and magnesium deficiency and/or toxic metal burdens may be critical and induce epigenetic alterations in the genes and genetic regulation mechanisms of  neurodevelopment in the autistic children, and demonstrate that a time  factor "infantile window" is also critical for neurodevelopment and  probably for therapy. Thus, early metallomics analysis may lead to early  screening/estimation and treatment/prevention for the autistic  neurodevelopment disorders. 

25. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children  with autism. 

J Biomed Sci. 2002 Jul-Aug;9(4):359-64. 

Singh VK, 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-mumps-rubella (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. 

26. Infection, vaccines and other environmental triggers of autoimmunity. Autoimmunity. 2005 May;38(3):235-45. 

Molina V, 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 anamnes is work should be done.

27. Impact of environmental factors on the prevalence of autistic disorder after 1979 

Journal of Public Health and Epidemiology, Vol.6(9), pp. 271-284, September  2014 

Theresa A. Deisher, Ngoc V. Doan, Angelica Omaiye, Kumiko Koyama, Sarah  Bwabye  

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. 

28. A Positive Association found between Autism Prevalence and Childhood  Vaccination uptake across the U.S. Population 

Journal of Toxicology and Environmental Health, Part A: Current Issues Volume 74, Issue 14, 2011, Pages 903 - 916 

Author: Gayle DeLonga

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.  

29. Neonatal administration of a vaccine preservative, thimerosal, produces lasting  impairment of nociception and apparent activation of opioid system in rats. 

Brain Res. 2009 Dec 8;1301:143-51. Epub 2009 Sep 9. 

Olczak M, 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. 

30. Effect of thimerosal on the neurodevelopment of premature rats. 

World J Pediatr. 2013 Nov;9(4):356-60. doi: 10.1007/s12519-013-0443-z. Epub  2013 Nov 14. 

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 post injection 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 thimerosal containing vaccines to infants. 

31. Transcriptomic analyses of neurotoxic effects in mouse brain after intermittent  neonatal administration of thimerosal.

Toxicol Sci. 2014 Jun;139(2):452-65. doi: 10.1093/toxsci/kfu049. Epub 2014 Mar  27. 

State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of  Zoology, Chinese Academy of Sciences, Beijing 100101, China.Li X1, Qu F, Xie  W, Wang F, Liu H, Song S, Chen T, Zhang Y, Zhu S, Wang Y, Guo C, Tang TS. 

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.  

32. Lasting neuropathological changes in rat brain after intermittent neonatal  administration of thimerosal. 

Folia Neuropathol. 2010;48(4):258-69. Olczak M, 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. 

33. Persistent behavioral impairments and alterations of brain dopamine system after early postnatal administration of thimerosal in rats. 

Behav Brain Res. 2011 Sep 30;223(1):107-18. doi: 10.1016/j.bbr.2011.04.026.  Epub 2011 Apr 28. 

Olczak M, 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.

34. B-Lymphocytes from a Population of Children with Autism Spectrum Disorder and Their Unaffected Siblings Exhibit Hypersensitivity to Thimerosal 

J Toxicol. 2013;2013:801517. Epub 2013 Jun 9. 

Sharpe MA, Gist TL, Baskin DS. 

Department of Neurosurgery, The Methodist Neurological Institute, Houston, TX. 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. 

35. Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes:  Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA 

J Toxicol. 2012; 2012: 373678. Published online Jun 28, 2012. doi:  10.1155/2012/373678 

Martyn A. Sharpe, * Andrew D. Livingston, and David S. Baskin 

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. 

36. Thioredoxin: A novel, independent diagnosis marker in children with autism. 

Int J Dev Neurosci. 2014 Nov 26. pii: S0736-5748(14)00191-9. doi:  10.1016/j.ijdevneu.2014.11.007. 

Zhang QB1, Gao SJ1, Zhao HX2. 

Abstract 

BACKGROUND: 

Oxidative stress increases serum thioredoxin (TRX), a redox-regulating protein  with antioxidant activity recognized as an oxidative-stress marker. The aim of this study was to assess the clinical significance of serum TRX levels in Autism  spectrum disorders (ASD). 

METHODS: 

Eighty patients diagnosed with ASD and 100 sex and age matched typically  developing children were assessed for serum TRX content at admission. TRX  were assayed with solid-phase sandwich ELISA, and severity of ASD was  evaluated with the Childhood Autism Rating Scale (CARS) Score. RESULTS: 

The results indicated that the median serum TRX levels were significantly  (P<0.0001) higher in children with ASD as compared to typically developing  children [17.9(IQR: 10.7-25.8)ng/ml and 5.5(3.6-9.2)ng/ml, respectively]. Levels  of TRX increased with increasing severity of ASD as defined by the CARS score.  After adjusting for all other possible covariates, TRX still was an independent  diagnosis marker of ASD with an adjusted OR of 1.454 (95% CI, 1.232-1.892;  P<0.0001). Based on the receiver operating characteristic (ROC) curve, the  optimal cut-off value of serum TRX levels as an indicator for auxiliary diagnosis of autism was projected to be 10.6ng/ml. Further, we found that an increased  diagnosis of ASD was associated with TRX levels ≥10.6ng/ml (adjusted OR  15.31, 95% CI: 7.36-31.85) after adjusting for possible confounders. CONCLUSIONS: 

Our study demonstrated that serum TRX levels were associated with ASD,  and elevated levels could be considered as a novel, independent diagnosis  indicator of ASD. 

37. Inhibition of the human thioredoxin system. A molecular mechanism of mercury  toxicity.

J Biol Chem. 2008 May 2;283(18):11913-23. doi: 10.1074/jbc.M710133200. Epub 2008 Mar 4. 

Carvalho CM1, Chew EH, Hashemy SI, Lu J, Holmgren A. 

Abstract 

Mercury toxicity mediated by different forms of mercury is a major health  problem; however, the molecular mechanisms underlying toxicity remain elusive.  We analyzed the effects of mercuric chloride (HgCl(2)) and monomethylmercury  (MeHg) on the proteins of the mammalian thioredoxin system, thioredoxin  reductase (TrxR) and thioredoxin (Trx), and of the glutaredoxin system,  glutathione reductase (GR) and glutaredoxin (Grx). HgCl(2) and MeHg inhibited  recombinant rat TrxR with IC(50) values of 7.2 and 19.7 nm, respectively. Fully  reduced human Trx1 bound mercury and lost all five free thiols and activity after  incubation with HgCl(2) or MeHg, but only HgCl(2) generated dimers. Mass  spectra analysis demonstrated binding of 2.5 mol of Hg(2+) and 5 mol of  MeHg(+)/mol of Trx1 with the very strong Hg(2+) complexes involving active site  and structural disulfides. Inhibition of both TrxR and Trx activity was observed in  HeLa and HEK 293 cells treated with HgCl(2) or MeHg. GR was inhibited by  HgCl(2) and MeHg in vitro, but no decrease in GR activity was detected in cell  extracts treated with mercurials. Human Grx1 showed similar reactivity as Trx1  with both mercurial compounds, with the loss of all free thiols and Grx  dimerization in the presence of HgCl(2), but no inhibition of Grx activity was  observed in lysates of HeLa cells exposed to mercury. Overall, mercury inhibition  was selective toward the thioredoxin system. In particular, the remarkable  potency of the mercury compounds to bind to the selenol-thiol in the active site of TrxR should be a major molecular mechanism of mercury toxicity. 

38. Effects of selenite and chelating agents on mammalian thioredoxin reductase  inhibited by mercury: implications for treatment of mercury poisoning. 

FASEB J. 2011 Jan;25(1):370-81. doi: 10.1096/fj.10-157594. Epub 2010 Sep 1. Carvalho CM1, Lu J, Zhang X, Arnér ES, Holmgren A. 

Abstract 

Mercury toxicity is a highly interesting topic in biomedicine due to the severe  endpoints and treatment limitations. Selenite serves as an antagonist of mercury  toxicity, but the molecular mechanism of detoxification is not clear. Inhibition of  the selenoenzyme thioredoxin reductase (TrxR) is a suggested mechanism of  toxicity. Here, we demonstrated enhanced inhibition of activity by inorganic and  organic mercury compounds in NADPH-reduced TrxR, consistent with binding of  mercury also to the active site selenolthiol. On treatment with 5 μM selenite and  NADPH, TrxR inactivated by HgCl(2) displayed almost full recovery of activity.  Structural analysis indicated that mercury was complexed with TrxR, but enzyme generated selenide removed mercury as mercury selenide, regenerating the  active site selenocysteine and cysteine residues required for activity. The  antagonistic effects on TrxR inhibition were extended to endogenous 

antioxidants, such as GSH, and clinically used exogenous chelating agents BAL,  DMPS, DMSA, and α-lipoic acid. Consistent with the in vitro results, recovery of  TrxR activity and cell viability by selenite was observed in HgCl(2)-treated HEK  293 cells. These results stress the role of TrxR as a target of mercurials and  provide the mechanism of selenite as a detoxification agent for mercury  poisoning. 

39. Serological association of measles virus and human herpesvirus-6 with brain  autoantibodies in autism. 

Clin Immunol Immunopathol. 1998 Oct;89(1):105-8. 

Singh VK, 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 measles-IgG 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. 

40. Metabolic biomarkers of increased oxidative stress and impaired methylation  capacity in children with autism 

American Journal of Clinical Nutrition, Vol. 80, No. 6, 1611-1617, December 2004 

Department of Pediatrics, University of Arkansas for Medical Sciences, and the  Arkansas Children's Hospital Research Institute 

Abstract 

Background: Autism is a complex neurodevelopmental disorder that usually  presents in early childhood and that is thought to be influenced by genetic and 

environmental factors. Although abnormal metabolism of methionine and  homocysteine has been associated with other neurologic diseases, these  pathways have not been evaluated in persons with autism. 

Objective: The purpose of this study was to evaluate plasma concentrations of  metabolites in the methionine transmethylation and transsulfuration pathways in  children diagnosed with autism. 

Design: Plasma concentrations of methionine, S-adenosylmethionine (SAM), S adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were measured in 20 children with autism  and in 33 control children. On the basis of the abnormal metabolic profile, a  targeted nutritional intervention trial with folinic acid, betaine, and  methylcobalamin was initiated in a subset of the autistic children. 

Results: Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine,  cystathionine, cysteine, and total glutathione and significantly higher  concentrations of SAH, adenosine, and oxidized glutathione. This metabolic  profile is consistent with impaired capacity for methylation (significantly lower  ratio of SAM to SAH) and increased oxidative stress (significantly lower redox  ratio of reduced glutathione to oxidized glutathione) in children with autism. The  intervention trial was effective in normalizing the metabolic imbalance in the  autistic children. 

Conclusions: An increased vulnerability to oxidative stress and a decreased  capacity for methylation may contribute to the development and clinical  manifestation of autism. 

41. Classification and adaptive behavior prediction of children with autism spectrum  disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation 

Daniel P. Howsmon, Uwe Kruger, Stepan Melnyk, S. Jill James, Juergen Hahn  Published: March 16, 2017, https://doi.org/10.1371/journal.pcbi.1005385 

Daniel P. Howsmon 

Affiliations Department of Chemical and Biological Engineering, Rensselaer  Polytechnic Institute, Troy, New York, United States of America, Center for  Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute,  Troy, New York, United States of America 

 ORCID logo http://orcid.org/0000-0002-7177-1342 

Uwe Kruger 

Affiliation Department of Biomedical Engineering, Rensselaer Polytechnic  Institute, Troy, New York, United States of America

 ORCID logo http://orcid.org/0000-0001-5664-9499 

Stepan Melnyk 

Affiliation Department of Pediatrics, University of Arkansas for Medical Sciences,  Little Rock, Arkansas, United States of America 

S. Jill James 

Affiliation Department of Pediatrics, University of Arkansas for Medical Sciences,  Little Rock, Arkansas, United States of America 

Juergen Hahn 

 E-mail: hahnj@rpi.edu 

Affiliations Department of Chemical and Biological Engineering, Rensselaer  Polytechnic Institute, Troy, New York, United States of America, Center for  Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute,  Troy, New York, United States of America, Department of Biomedical  Engineering, Rensselaer Polytechnic Institute, Troy, New York, United States of  America 

Abstract 

The number of diagnosed cases of Autism Spectrum Disorders (ASD) has  increased dramatically over the last four decades; however, there is still  considerable debate regarding the underlying pathophysiology of ASD. This lack  of biological knowledge restricts diagnoses to be made based on behavioral  observations and psychometric tools. However, physiological measurements  should support these behavioral diagnoses in the future in order to enable earlier  and more accurate diagnoses. Stepping towards this goal of incorporating  biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism  and transulfuration pathways taken from blood samples of 83 participants  with ASD and 76 age-matched neurotypical peers. Fisher Discriminant  Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being  correctly identified as such while still correctly identifying 97.6% of the  ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score,  where measurement of five metabolites of the pathways was sufficient to predict  the Vineland score with an R2 of 0.45 after cross-validation. This level of  accuracy for classification as well as severity prediction far exceeds any other  approach in this field and is a strong indicator that the metabolites under  consideration are strongly correlated with an ASD diagnosis but also that the  statistical analysis used here offers tremendous potential for extracting important  information from complex biochemical data sets. 

42. Newborn screening for autism: in search of candidate biomarkers. Biomark Med. 2013 Apr;7(2):247-60. doi: 10.2217/bmm.12.108.

Mizejewski GJ1, Lindau-Shepard B, Pass KA. 

Division of Translational Medicine, Wadsworth Center, NYS Department of  Health, PO Box 509, Albany, NY 12201 0509, USA.  

Abstract 

BACKGROUND: 

Autism spectrum disorder (ASD) represents a wide range of neurodevelopmental disorders characterized by impairments in social interaction, language,  communication and range of interests. Autism is usually diagnosed in children 3- 5 years of age using behavioral characteristics; thus, diagnosis shortly after birth  would be beneficial for early initiation of treatment. 

AIM: 

This retrospective study sought to identify newborns at risk for ASD utilizing  bloodspot specimens in an immunoassay. 

MATERIALS & METHODS: 

The present study utilized stored frozen specimens from ASD children already  diagnosed at 15-36 months of age. The newborn specimens and controls were  analyzed by immunoassay in a multiplex system that included 90 serum  biomarkers and subjected to statisical analysis. 

RESULTS: 

Three sets of five biomarkers associated with ASD were found that differed from  control groups. The 15 candidate biomarkers were then discussed regarding their association with ASD. 

CONCLUSION: 

This study determined that a statistically selected panel of 15 biomarkers  successfully discriminated presumptive newborns at risk for ASD from those of  nonaffected controls. 

Exerpt: 

"GST [Glutathione S-transferase] is a metabolic biomarker directly  associated with ASD. The human gene product for GST constitutes a  candidate susceptibility protein due to its tissue distribution and role in  oxidative stress and methionine metabolism, which results in neuronal  injury and death." 

“Results of a recent study further demonstrated that glutathione, total  glutathione and activity levels of GST were significantly lower in autistic  patients as compared with control subjects; however, homocysteine,  thioredoxin reductase and perioxidoxin levels were remarkably higher.” 

“Autistic children with metabolic disturbances are known to display  reduced metabolic activities of GST, cysteine, glutathione and methionine,  which are associated with methionine transmethylation and trans sulfation.”

43. Altered urinary porphyrins and mercury exposure as biomarkers for autism  severity in Egyptian children with autism spectrum disorder 

Metabolic Brain Disease 

Eman M. KhaledNagwa A. MeguidGeir BjørklundEmail authorAmr  GoudaMohamed H. BaharyAdel HashishNermin M. SallamSalvatore  ChirumboloMona A. El-Bana 

Abstract 

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that  affects social, communication, and behavioral development. Recent evidence  supported but also questioned the hypothetical role of compounds containing  mercury (Hg) as contributors to the development of ASD. Specific alterations in  the urinary excretion of porphyrin-containing ring catabolites have been  associated with exposure to Hg in ASD patients. In the present study, the level of  urinary porphyrins, as biomarkers of Hg toxicity in children with ASD, was  evaluated, and its correlation with severity of the autistic behavior further  explored. A total of 100 children was enrolled in the present study. They were  classified into three groups: children with ASD (40), healthy controls (40), and  healthy siblings of the ASD children (20). Children with ASD were diagnosed  using DSM-IV-TR, ADI-R, and CARS tests. Urinary porphyrins were evaluated  within the three groups using high-performance liquid chromatography (HPLC),  after plasma evaluation of mercury (Hg) and lead (Pb) in the same groups.  Results showed that children with ASD had significantly higher levels of  Hg, Pb, and the porphyrins pentacarboxyporphyrin, coproporphyrin,  precoproporphyrin, uroporphyrins, and hexacarboxyporphyrin compared to  healthy controls and healthy siblings of the ASD children. However, there was no  significant statistical difference in the level of heptacarboxyporphyrin among the  three groups, while a significant positive correlation between the levels of  coproporphyrin and precoproporphyrin and autism severity was observed.  Mothers of ASD children showed a higher percentage of dental amalgam  restorations compared to the mothers of healthy controls suggesting that  high Hg levels in children with ASD may relate to the increased exposure to Hg from maternal dental amalgam during pregnancy and lactation. The  results showed that the ASD children in the present study had increased blood  Hg and Pb levels compared with healthy control children indicating that  disordered porphyrin metabolism might interfere with the pathology associated  with the autistic neurologic phenotype. The present study indicates that  coproporphyrin and precoproporhyrin may be utilized as possible  biomarkers for heavy metal exposure and autism severity in children with  ASD.

44. Porphyrinuria in childhood autistic disorder: Implications for environmental  toxicity 

Toxicology and Applied Pharmacology, 2006 

Robert Natafa, Corinne Skorupkab, Lorene Ametb, Alain Lama, Anthea  Springbettc and Richard Lathed, aLaboratoire Philippe Auguste, Paris, France,  Association ARIANE, Clichy, France, Department of Statistics, Roslin Institute,  Roslin, UK, Pieta Research, 

This new study from France utilizes a new and sophisticated measurement for  environmental toxicity by assessing porphyrin levels in autistic children. It  provides clear and unequivocal evidence that children with autism spectrum  disorders are more toxic than their neurotypical peers. 

Excerpt: "Coproporphyrin levels were elevated in children with autistic disorder  relative to control groups...the elevation was significant. These data implicate  environmental toxicity in childhood autistic disorder." 

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. 

45. An investigation of porphyrinuria in Australian children with autism. 

J Toxicol Environ Health A. 2008;71(20):1349-51. doi:  

10.1080/15287390802271723. 

Austin DW, 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. 

46. Porphyrinuria in Korean children with autism: correlation with oxidative stress. 

J Toxicol Environ Health A. 2010;73(10):701-10. doi:  

10.1080/15287391003614000. 

Youn SI1, Jin SH, Kim SH, Lim S. 

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.

47. Uncoupling of ATP-mediated Calcium Signaling and Dysregulated IL-6 Secretion  in Dendritic Cells by Nanomolar Thimerosal 

Environmental Health Perspectives, July 2006. 

Samuel R. Goth, Ruth A. Chu Jeffrey P. Gregg 

1 National Institute of Environmental Health Sciences Center for Children’s  Environmental Health 

2 Department of Veterinary Molecular Biosciences and 

3 Department of Medical Pathology, University of California–Davis, Davis,  California, USA 

4 MIND (Medical Investigation of Neurodevelopmental Disorders) Institute,  University of California–Davis, Sacramento, California, USA 

Address correspondence to I.N. Pessah, Department of Veterinary Medicine,  Molecular Biosciences, 1311 Haring Hall, One Shields Ave., University of  California, Davis, CA 

Abstract 

Dendritic cells (DCs), a rare cell type widely distributed in the soma, are potent  antigen-presenting cells that initiate primary immune responses. DCs rely on  intracellular redox state and calcium (Ca2+) signals for proper development and  function, but the relationship between these two signaling systems is unclear.  Thimerosal (THI) is a mercurial used to preserve vaccines and consumer  products, and is used experimentally to induce Ca2+ release from microsomal  stores. We tested adenosine triphosphate (ATP)-mediated Ca2+ responses of  DCs transiently exposed to nanomolar THI. Transcriptional and  

immunocytochemical analyses show that murine myeloid immature DCs (IDCs)  and mature DCs (MDCs) express inositol 1,4,5-trisphosphate receptor (IP3R)  and ryanodine receptor (RyR) Ca2+ channels, known targets of THI. IDCs  express the RyR1 isoform in a punctate distribution that is densest near plasma  membranes and within dendritic processes, whereas IP3Rs are more generally  distributed. RyR1 positively and negatively regulates purinergic signaling  because ryanodine (Ry) blockade a) recruited 80% more ATP responders, b)  shortened ATP-mediated Ca2+ transients > 2-fold, and c) produced a delayed  and persistent rise (≥ 2-fold) in baseline Ca2+. THI (100 nM, 5 min) recruited  more ATP responders, shortened the ATP-mediated Ca2+ transient (≥ 1.4-fold),  and produced a delayed rise (≥ 3-fold) in the Ca2+ baseline, mimicking Ry. THI  and Ry, in combination, produced additive effects leading to uncoupling of IP3R  and RyR1 signals. THI altered ATP-mediated interleukin-6 secretion, initially  enhancing the rate of cytokine secretion but suppressing cytokine secretion  overall in Dcs. Dendritic cells are exquisitely sensitive to Thimerosal, with  one mechanism involving the uncoupling of positive and negative  regulation of Ca2+ signals contributed by RyR1.  

Excerpt: "Our findings that DCs primarily express the RyR1 channel complex and

that this complex is uncoupled by very low levels of THI with dysregulated IL-6  secretion raise intriguing questions about a molecular basis for immune  dyregulation and the possible role of the RyR1 complex in genetic susceptibility  of the immune system to mercury." 

48. Myeloid dendritic cells frequencies are increased in children with autism  spectrum disorder and associated with amygdala volume and repetitive  behaviors 

Brain, Behavior, and Immunity, Volume 31, July 2013, Pages 69–75,  Inflammation and Mental Health 

Elizabeth Breecea, b, Brian Paciottib, Christine Wu Nordahlb, c, Sally Ozonoffb,  c, Judy A. Van de Waterb, d, Sally J. Rogersb, c, David Amaralb, c, Paul  Ashwood 

a Department of Medical Microbiology and Immunology, University of California,  Davis, USA 

b The M.I.N.D. Institute, University of California, Davis, USA 

c Department of Psychiatry and Behavioral Sciences, University of California,  Davis, USA 

d Division of Rheumatology, Allergy and Clinical Immunology, University of  California, Davis, USA 

Abstract 

The pathophysiology of autism spectrum disorder (ASD) is not yet known;  however, studies suggest that dysfunction of the immune system affects many  children with ASD. Increasing evidence points to dysfunction of the innate  immune system including activation of microglia and perivascular macrophages,  increases in inflammatory cytokines/chemokines in brain tissue and CSF, and  abnormal peripheral monocyte cell function. Dendritic cells are major players in  innate immunity and have important functions in the phagocytosis of pathogens  or debris, antigen presentation, activation of naïve T cells, induction of tolerance  and cytokine/chemokine production. In this study, we assessed circulating  frequencies of myeloid dendritic cells (defined as Lin-1−BDCA1+CD11c+ and  Lin-1−BDCA3+CD123−) and plasmacytoid dendritic cells (Lin 

1−BDCA2+CD123+ or Lin-1−BDCA4+ CD11c−) in 57 children with ASD, and 29  typically developing controls of the same age, all of who were enrolled as part of  the Autism Phenome Project (APP). The frequencies of dendritic cells and  associations with behavioral assessment and MRI measurements of amygdala  volume were compared in the same participants. The frequencies of myeloid  dendritic cells were significantly increased in children with ASD compared to  typically developing controls (p < 0.03). Elevated frequencies of myeloid dendritic cells were positively associated with abnormal right and left amygdala  enlargement, severity of gastrointestinal symptoms and increased repetitive  behaviors. The frequencies of plasmacytoid dendritic cells were also associated  with amygdala volumes as well as developmental regression in children with  ASD. Dendritic cells play key roles in modulating immune responses and 

differences in frequencies or functions of these cells may result in immune  dysfunction in children with ASD. These data further implicate innate  immune cells in the complex pathophysiology of ASD. 

49. Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to  Methylmercury or Vaccines Containing Thimerosal 

Environmental Health Perspectives, Aug 2005. 

Thomas Burbacher, PhD [University of Washington]. 

This study demonstrates clearly and unequivocally that ethyl mercury, the kind of  mercury found in vaccines, not only ends up in the brain, but leaves double the  amount of inorganic mercury as methyl mercury, the kind of mercury found in  fish. Methyl mercury (organic mercury) has a half-life in the brain measured in  days (Rice), while thimerosal (organic mercury) once in the brain converts to  inorganic mercury at much higher rates, and inorganic mercury has a half-life in  the brain measured in years and decades (Rooney). This work is groundbreaking because little is known about ethyl mercury, and many health authorities have  asserted that the mercury found in vaccines is the "safe kind." This study also  delivers a strong rebuke of the Institute of Medicine's recommendation in 2004 to  no longer pursue the mercury-autism connection. 

Excerpt: "A recently published IOM review (IOM 2004) appears to have  abandoned the earlier recommendation [of studying mercury and autism] as well  as back away from the American Academy of Pediatrics goal [of removing  mercury from vaccines]. This approach is difficult to understand, given our  current limited knowledge of the toxicokinetics and developmental neurotoxicity  of thimerosal, a compound that has been (and will continue to be) injected in  millions of newborns and infants." 

Excerpt: “ The average brain-to-blood partitioning ratio of total Hg in the  thimerosal group was slightly higher than that in the MeHg group (3.5 ± 0.5 vs.  2.5 ± 0.3, t-test, p = 0.11). Thus, the brain to-blood Hg concentration ratio  established for MeHg will underestimate the amount of Hg in the brain after exposure to thimerosal. “ 

Abstract 

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 brain-to-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. Key  words: brain and blood distribution, elimination half-life, ethylmercury, infant  nonhuman primates, methylmercury, thimerosal. 

50. The retention time of inorganic mercury in the brain--a systematic review of the  evidence. 

Toxicol Appl Pharmacol. 2014 Feb 1;274(3):425-35. doi:  

10.1016/j.taap.2013.12.011. Epub 2013 Dec 22. 

Rooney JP. 

Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, 152-160 Pearse Street, Dublin 2, Ireland. Electronic address: 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. 

51. Alkyl Mercury-Induced Toxicity: Multiple Mechanisms of Action. Rev Environ Contam Toxicol. 2017;240:105-149. 

Risher JF, Tucker P. 

Division of Toxicology and Human Health Sciences, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road (MS F-58), Atlanta, GA, 30333, USA. 

Abstract 

There are a number of mechanisms by which alkylmercury compounds cause  toxic action in the body. Collectively, published studies reveal that there are some similarities between the mechanisms of the toxic action of the mono-alkyl  mercury compounds methylmercury (MeHg) and ethylmercury (EtHg). This paper represents a summary of some of the studies regarding these mechanisms of  action in order to facilitate the understanding of the many varied effects of  alkylmercurials in the human body. The similarities in mechanisms of toxicity for  MeHg and EtHg are presented and compared. The difference in manifested  toxicity of MeHg and EtHg are likely the result of the differences in  exposure, metabolism, and elimination from the body, rather than  differences in mechanisms of action between the two. 

Exerpts: 

Summary and Conclusions  

There are many commonalities/similarities in the mechanisms of toxic  action of methylmercury and ethylmercury (from thimerosal)... Evidence for the similarity of the various mechanisms of toxicity include the following:  

• Both MeHg and EtHg bind to the amino acid cysteine (Clarkson 1995; Wu  et al. 2008)...  

• Both decrease glutathione activity, thus providing less protection from  the oxidative stress caused by MeHg and EtHg (Carocci et al. 2014;  Ndountse and Chan (2008); Choi et al. 1996; Franco et al. 2006; Mori et al.  2007; Muller et al. 2001; Ndountse and Chan 2008; Wu et al. 2008)... 

• Both disrupt glutamate homeostasis (Farina et al. 2003a, b; Manfroi et al.  2004; Mutkus et al. 2005; Yin et al. 2007). 

• Both cause oxidative stress/creation of ROS (Dreiem and Seegal 2007;  Garg and Chang 2006; Myhre et al. 2003; Sharpe et al. 2012; Yin et al.  2007)...  

• Both cause effects on receptor binding/neurotransmitter release involving one or more transmitters (Basu et al. 2008; Coccini et al. 2000; Cooper et al. 2003; Fonfria et al. 2001; Ida-Eto et al. 2011; Ndountse and Chan 2008; Yuan and Atchison 2003).  

• Both cause DNA damage or impair DNA synthesis (Burke et al. 2006;  Sharpe et al. 2012; Wu et al. 2008).  

52. Metabolic endophenotype and related genotypes are associated with oxidative  stress in children with autism. 

Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56. 

James SJ1, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, Cutler P,  Bock K, Boris M, Bradstreet JJ, Baker SM, Gaylor DW. 

Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas  Children's Hospital Research Institute, Little Rock, Arkansas 

Abstract 

Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed  in early childhood that is characterized by impairment in reciprocal  communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have  been reproducibly identified. The metabolic phenotype of an individual reflects  the influence of endogenous and exogenous factors on genotype. As such, it  provides a window through which the interactive impact of genes and  environment may be viewed and relevant susceptibility factors identified.  Although abnormal methionine metabolism has been associated with other  neurologic disorders, these pathways and related polymorphisms have not been  evaluated in autistic children. Plasma levels of metabolites in methionine  transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205  controls. The metabolic results indicated that plasma methionine and the  ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the  autistic children relative to age-matched controls. In addition, plasma  levels of cysteine, glutathione, and the ratio of reduced to oxidized  glutathione, an indication of antioxidant capacity and redox homeostasis,  were significantly decreased. Differences in allele frequency and/or  significant gene-gene interactions were found for relevant genes encoding  the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G >  C), catechol-O-methyltransferase (COMT 472G > A),  

methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and

glutathione-S-transferase (GST M1). We propose that an increased  vulnerability to oxidative stress (endogenous or environmental) may  contribute to the development and clinical manifestations of autism. 

53. Brain and tissue levels of mercury after chronic methylmercury exposure in the  monkey. 

J Toxicol Environ Health. 1989;27(2):189-98. 

Rice DC 

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) days. 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. 

54. Interplay of glia activation and oxidative stress formation in fluoride and  aluminium exposure. 

Pathophysiology. 2015 Mar;22(1):39-48. doi: 10.1016/j.pathophys.2014.12.001.  Epub 2014 Dec 13. 

Akinrinade ID1, Memudu AE2, Ogundele OM3, Ajetunmobi OI4. 

BACKGROUND:

Oxidative stress formation is pivotal in the action of environmental agents which  trigger the activation of glial cells and neuroinflammation to stimulate  compensatory mechanisms aimed at restoring homeostasis. 

AIM: 

This study sets to demonstrate the interplay of fluoride (F) and aluminium (Al) in  brain metabolism. Specifically, it reveals how oxidative stress impacts the  activation of astrocytes (GFAP), mediates proinflammatory responses (microglia  and B-cells: CD68 and CD 20 respectively) and shows the pattern of lipid  peroxidation in the brain following fluoride and (or) aluminium treatment in vivo. METHOD: 

Male adult Wistar rats were treated with low and high doses of fluoride,  aluminium or combination of fluoride-aluminium for 30 days. The control group  received distilled water for the duration of the treatment. Blood and brain tissue  homogenates were prepared for colorimetric assay of stress biomarkers  [malonialdehyde (MDA) and superoxide dismutase (SOD)]. Subsequent analysis  involved immunodetection of astrocytes (anti-GFAP), microglial (anti-CD68) and  B-cells (anti-CD20) in coronal sections of the prefrontal cortex using antigen  retrieval immunohistochemistry. 

RESULT AND CONCLUSION: 

Aluminium, fluoride and a combination of aluminium-fluoride treatments caused  an increase in brain lipid peroxidation products and reactive oxygen species  (ROS) formation. Similarly, an increase in glial activation and inflammatory  response were seen in these groups versus the control. Oxidative stress induced glial activation (GFAP) and increased the expression of B cells (CD20). This also  corresponded to the extent of tissue damage and lipid peroxidation observed.  Taken together, the results suggest a close link between oxidative stress  neuroinflamation and degeneration in aluminium-fluoride toxicity. 

55. Increases in the Number of Reactive Glia in the Visual Cortex of Macaca  fascicularis Following Subclinical Long-Term Methyl Mercury Exposure 

Toxicology and Applied Pharmacology, 1994 

Charleston JS, Bolender RP, Mottet NK, Body RL, Vahter ME, Burbacher TM.,  Department of Pathology, School of Medicine, University of Washington 

Abstract 

The number of neurons, astrocytes, reactive glia, oligodendrocytes, endothelia,  and pericytes in the cortex of the calcarine sulcus of adult female Macaca  fascicularis following long-term subclinical exposure to methyl mercury (MeHg)  and mercuric chloride (inorganic mercury; IHg) has been estimated by use of the  optical volume fractionator stereology technique. Four groups of monkeys were  exposed to MeHg (50 micrograms Hg/kg body wt/day) by mouth for 6, 12, 18,  and 12 months followed by 6 months without exposure (clearance group). A fifth  group of monkeys was administered IHg (as HgCl2; 200 micrograms Hg/kg body  wt/day) by constant rate intravenous infusion via an indwelling catheter for 3  months. Reactive glia showed a significant increase in number for every  treatment group, increasing 72% in the 6-month, 152% in the 12-month, and 

120% in the 18-month MeHg exposed groups, and the number of reactive glia in  the clearance group remained elevated (89%). The IHg exposed group showed a 165% increase in the number of reactive glia. The IHg exposed group and the  clearance group had low levels of MeHg present within the tissue; however, the  level of IHg was elevated in both groups. These results suggest that the IHg  may be responsible for the increase in reactive glia. All other cell types,  including the neurons, showed no significant change in number at the prescribed  exposure level and durations. The identities of the reactive glial cells and the  implications for the long-term function and survivability of the neurons due to  changes in the glial population following subclinical long-term exposure to  mercury are discussed. 

56. Modeling the interplay between neurons and astrocytes in autism using human  induced pluripotent stem cells 

Biological Psychiatry, Available online 3 October 2017 

Fabiele Baldino Russo, Beatriz Camille Freitas, Graciela Conceição Pignatari,  Isabella Rodrigues Fernandes, Jonathan Sebat, Alysson Renato Muotri, Patricia  Cristina Baleeiro Beltrão-Braga 

Department of Microbiology, Institute of Biomedical Sciences, University of São  Paulo, São Paulo, SP, Brazil 

Department of Surgery, School of Veterinary Medicine, University of São Paulo,  São Paulo, SP, Brazil 

Department of Pediatrics/Rady Children's Hospital San Diego, Department of  Cellular & Molecular Medicine, Stem Cell Program, University of California San  Diego School of Medicine, Sanford Consortium for Regenerative Medicine, La  Jolla, CA, USA 

Department of Psychiatry, Cellular and Molecular Medicine, University of  California, San Diego, La Jolla, CA 92093, USA 

Department of Obstetrics, School of Arts, Sciences and Humanities, University of São Paulo, São Paulo, SP, Brazil 

Received 12 September 2016, Revised 14 August 2017, Accepted 17 September 2017,  

Abstract 

Background 

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders with  unclear etiology and imprecise genetic causes. The main goal of this work was to investigate neuronal connectivity and the interplay between neurons and 

astrocytes from non-syndromic ASD individuals using induced Pluripotent Stem  Cells (iPSCs). 

Methods 

Our iPSCs were derived from a clinically well-characterized cohort of three non syndromic ASD individuals, sharing common behaviors, and three controls, two  clones each. We generated mixed neural cultures analyzing synaptogenesis and  neuronal activity using a multi-electrode array (MEA) platform. Furthermore,  using an enriched astrocytes population we investigated their role in neuronal  maintenance. 

Results 

Our results revealed that ASD-derived neurons had a significant decrease in  synaptic gene expression and protein levels, glutamate neurotransmitter release  and, consequently, reduced spontaneous firing rate. Based on co-culture  experiments, we observed that ASD-derived astrocytes interfered with proper  neuronal development. In contrast, control-derived astrocytes rescued the  morphological neuronal phenotype and synaptogenesis defects from ASD  neuronal co-cultures. Furthermore, after identifying IL-6 secretion from astrocytes in our ASD individuals as a possible culprit for neural defects, we were able to  increase synaptogenesis by blocking IL-6 levels. 

Conclusions 

Our findings reveal astrocytes contribution to neuronal phenotype and  confirm previous studies linking IL-6 and autism, suggesting potential  novel therapeutic pathways for a subtype of ASD individuals. This is the first report demonstrating that glial dysfunctions could contribute to non-syndromic  autism pathophysiology using iPSCs modeling disease technology. 

57. Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism Annals of Neurology, Feb 2005. 

Diana L. Vargas, MD, Johns Hopkins University. 

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. 

Excerpt: "Because this neuroinflammatory process appears to be  associated with an ongoing and chronic mechanism of CNS dysfunction,  potential therapeutic interventions should focus on the control of its  detrimental effects and thereby eventually modify the clinical course of  autism." 

58. Aluminium in brain tissue in autism 

Journal of Trace Elements in Medicine and Biology 

Matthew Mold, Dorcas Umar, Andrew King, Christopher Exley,  

The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, ST5 5BG, United Kingdom 

Life Sciences, Keele University, Staffordshire, ST5 5BG, United Kingdom Department of Clinical Neuropathology, Kings College Hospital, London, SE5  9RS, United Kingdom 

26 November 2017 

Abstract 

Autism spectrum disorder is a neurodevelopmental disorder of unknown  aetiology. It is suggested to involve both genetic susceptibility and environmental  factors including in the latter environmental toxins. Human exposure to the  environmental toxin aluminium has been linked, if tentatively, to autism spectrum  disorder. Herein we have used transversely heated graphite furnace atomic  absorption spectrometry to measure, for the first time, the aluminium content of  brain tissue from donors with a diagnosis of autism. We have also used an  aluminium-selective fluor to identify aluminium in brain tissue using fluorescence  microscopy. The aluminium content of brain tissue in autism was consistently  high. The mean (standard deviation) aluminium content across all 5 individuals  for each lobe were 3.82(5.42), 2.30(2.00), 2.79(4.05) and 3.82(5.17) μg/g dry wt.  for the occipital, frontal, temporal and parietal lobes respectively. These are  some of the highest values for aluminium in human brain tissue yet  recorded and one has to question why, for example, the aluminium content  of the occipital lobe of a 15 year old boy would be 8.74 (11.59) μg/g dry wt.?

Aluminium-selective fluorescence microscopy was used to identify aluminium in  brain tissue in 10 donors. While aluminium was imaged associated with  neurones it appeared to be present intracellularly in microglia-like cells and other inflammatory non-neuronal cells in the meninges, vasculature, grey  and white matter. The pre-eminence of intracellular aluminium associated  with non-neuronal cells was a standout observation in autism brain tissue  and may offer clues as to both the origin of the brain aluminium as well as  a putative role in autism spectrum disorder. 

59. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. 

Biol Psychiatry. 2010 Aug 15;68(4):368-76. doi: 10.1016/j.biopsych.2010.05.024. 

Morgan JT1, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J,  Courchesne E, Everall IP. 

Department of Neuroscience, School of Medicine, University of California, San  Diego 

BACKGROUND: 

In the neurodevelopmental disorder autism, several neuroimmune abnormalities  have been reported. However, it is unknown whether microglial somal volume or  density are altered in the cortex and whether any alteration is associated with  age