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

By -

 

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 or other potential covariates. 

METHODS: 

Microglia in sections from the dorsolateral prefrontal cortex of  

nonmacrencephalic male cases with autism (n = 13) and control cases (n = 9)  were visualized via ionized calcium binding adapter molecule 1  

immunohistochemistry. In addition to a neuropathological assessment, microglial  cell density was stereologically estimated via optical fractionator and average  somal volume was quantified via isotropic nucleator. 

RESULTS: 

Microglia appeared markedly activated in 5 of 13 cases with autism, including 2  of 3 under age 6, and marginally activated in an additional 4 of 13 cases.  Morphological alterations included somal enlargement, process retraction and  thickening, and extension of filopodia from processes. Average microglial somal  volume was significantly increased in white matter (p = .013), with a trend in gray  matter (p = .098). Microglial cell density was increased in gray matter (p = .002).  Seizure history did not influence any activation measure. 

CONCLUSIONS: 

The activation profile described represents a neuropathological alteration in a  sizeable fraction of cases with autism. Given its early presence, microglial  activation may play a central role in the pathogenesis of autism in a substantial  proportion of patients. Alternatively, activation may represent a response of the  innate neuroimmune system to synaptic, neuronal, or neuronal network  disturbances, or reflect genetic and/or environmental abnormalities impacting  multiple cellular populations.

60. Transcriptome analysis reveals dysregulation of innate immune response genes  and neuronal activity-dependent genes in autism 

Nature Communications 5, Article number: 5748 doi:10.1038/ncomms6748 Received 28 September 2014 Accepted 03 November 2014 Published 10  December 2014 

Department of Medicine, McKusick-Nathans Institute of Genetic Medicine, Johns  Hopkins University School of Medicine, Baltimore, Maryland 21205, USA Simone Gupta, Shannon E. Ellis, Foram N. Ashar, Anna Moes, Joel S. Bader  Dan E. Arking 

Department of Biomedical Engineering, Johns Hopkins University School of  Medicine, Baltimore, Maryland 21205, USA 

Joel S. Bader & Jianan Zhan 

Department of Neurology, University of Alabama at Birmingham, Birmingham,  Alabama 35294, USA 

Andrew B. West 

Abstract 

Recent studies of genomic variation associated with autism have suggested the  existence of extreme heterogeneity. Large-scale transcriptomics should  complement these results to identify core molecular pathways underlying autism.  Here we report results from a large-scale RNA sequencing effort, utilizing region matched autism and control brains to identify neuronal and microglial genes  robustly dysregulated in autism cortical brain. Remarkably, we note that a gene  expression module corresponding to M2-activation states in microglia is  negatively correlated with a differentially expressed neuronal module,  implicating dysregulated microglial responses in concert with altered  neuronal activity-dependent genes in autism brains. These observations  provide pathways and candidate genes that highlight the interplay between  innate immunity and neuronal activity in the aetiology of autism. 

61. Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene  expression in human brain cells in primary culture. 

J Inorg Biochem. 2005 Sep;99(9):1895-8. 

Lukiw WJ1, Percy ME, Kruck TP. 

Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 8B8, New  Orleans, LA 70112-2272, USA. wlukiw@lsuhsc.edu 

Abstract 

Aluminum, the most abundant neurotoxic metal in our biosphere, has been  implicated in the etiology of several neurodegenerative disorders including 

Alzheimer's disease (AD). To further understand aluminum's influence on gene  expression, we examined total messenger RNA levels in untransformed human  neural cells exposed to 100 nanomolar aluminum sulfate using high density DNA  microarrays that interrogate the expression of every human gene. Preliminary  data indicate that of the most altered gene expression levels, 17/24 (70.8%) of  aluminum-affected genes, and 7/8 (87.5%) of aluminum-induced genes exhibit  expression patterns similar to those observed in AD. The seven genes found to  be significantly up-regulated by aluminum encode pro-inflammatory or pro apoptotic signaling elements, including NF-kappaB subunits, interleukin-1beta  precursor, cytosolic phospholipase A2, cyclooxygenase-2, beta-amyloid  precursor protein and DAXX, a regulatory protein known to induce apoptosis and  repress transcription. The promoters of genes up-regulated by aluminum are  enriched in binding sites for the stress-inducible transcription factors HIF-1 and NF-kappaB, suggesting a role for aluminum, HIF-1 and NF-kappaB in  driving atypical, pro-inflammatory and pro-apoptotic gene expression. The  effect of aluminum on specific stress-related gene expression patterns in human  brain cells clearly warrant further investigation. 

62. Aberrant NF-kappaB expression in autism spectrum condition: a mechanism for  neuroinflammation. 

Front Psychiatry. 2011 May 13;2:27. doi: 10.3389/fpsyt.2011.00027. eCollection  2011. 

Young AM1, Campbell E, Lynch S, Suckling J, Powis SJ. 

Bute Medical School, University of St. Andrews Fife, Scotland, UK. 

Abstract 

Autism spectrum condition (ASC) is recognized as having an inflammatory  component. Post-mortem brain samples from patients with ASC display  neuroglial activation and inflammatory markers in cerebrospinal fluid, although  little is known about the underlying molecular mechanisms. Nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB) is a protein found in almost all  cell types and mediates regulation of immune response by inducing the  expression of inflammatory cytokines and chemokines, establishing a feedback  mechanism that can produce chronic or excessive inflammation. This article  describes immunodetection and immunofluorescence measurements of NF-κB in human post-mortem samples of orbitofrontal cortex tissue donated to two  independent centers: London Brain Bank, Kings College London, UK (ASC: n = 3, controls: n = 4) and Autism Tissue Program, Harvard Brain Bank, USA (ASC: n = 6, controls: n = 5). The hypothesis was that concentrations of NF-κB would be  elevated, especially in activated microglia in ASC, and pH would be  concomitantly reduced (i.e., acidification). Neurons, astrocytes, and microglia all  demonstrated increased extranuclear and nuclear translocated NF-κB p65  expression in brain tissue from ASC donors relative to samples from matched  controls. These between-groups differences were increased in astrocytes and  microglia relative to neurons, but particularly pronounced for highly mature  microglia. Measurement of pH in homogenized samples demonstrated a 0.98-

unit difference in means and a strong (F = 98.3; p = 0.00018) linear relationship to the expression of nuclear translocated NF-κB in mature microglia. Acridine  orange staining localized pH reductions to lysosomal compartments. In  summary, NF-κB is aberrantly expressed in orbitofrontal cortex in patients  with ASC, as part of a putative molecular cascade leading to inflammation,  especially of resident immune cells in brain regions associated with the  behavioral and clinical symptoms of ASC. 

63. A Study of Nuclear Transcription Factor-Kappa B in Childhood Autism PLoS One. 2011; 6(5): e19488. 

Usha S. Naik,1 Charitha Gangadharan,2 Kanakalatha Abbagani,1 Balakrishna  Nagalla,3 Niranjan Dasari,1 and Sunil K. Manna2,* 

Monica Uddin, Editor 

Department of Psychiatry, Osmania Medical College, Hyderabad, India Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics,  Nampally, Hyderabad, India 

National Institute of Nutrition, Hyderabad, India 

University of Michigan, United States of America 

Abstract 

Background 

Several children with autism show regression in language and social  development while maintaining normal motor milestones. A clear period of normal development followed by regression and subsequent improvement with  treatment, suggests a multifactorial etiology. The role of inflammation in autism is  now a major area of study. Viral and bacterial infections, hypoxia, or medication  could affect both foetus and infant. These stressors could upregulate  transcription factors like nuclear factor kappa B (NF-κB), a master switch for  many genes including some implicated in autism like tumor necrosis factor  (TNF). On this hypothesis, it was proposed to determine NF-κB in children with  autism. 

Methods 

Peripheral blood samples of 67 children with autism and 29 control children were  evaluated for NF-κB using electrophoretic mobility shift assay (EMSA). A  phosphor imaging technique was used to quantify values. The fold increase over  the control sample was calculated and statistical analysis was carried out using  SPSS 15. 

Results 

We have noted significant increase in NF-κB DNA binding activity in peripheral  blood samples of children with autism. When the fold increase of NF-κB in cases  (n = 67) was compared with that of controls (n = 29), there was a significant  difference (3.14 vs. 1.40, respectively; p<0.02).

Conclusion 

This finding has immense value in understanding many of the known  biochemical changes reported in autism. As NF-κB is a response to  stressors of several kinds and a master switch for many genes, autism may then arise at least in part from an NF-κB pathway gone awry. 

64. Autism: A Brain Disorder, or A Disorder That Affects the Brain? Clinical Neuropsychiatry, 2005 

Martha R. Herbert M.D., Ph.D., Harvard University 

Autism is defined behaviorally, as a syndrome of abnormalities involving  language, social reciprocity and hyperfocus or reduced behavioral flexibility. It is  clearly heterogeneous, and it can be accompanied by unusual talents as well as  by impairments, but its underlying biological and genetic basis in unknown.  Autism has been modeled as a brain-based, strongly genetic disorder, but  emerging findings and hypotheses support a broader model of the condition as a  genetically influenced and systemic. These include imaging, neuropathology and  psychological evidence of pervasive (and not just specific) brain and phenotypic  features; postnatal evolution and chronic persistence of brain, behavior and  tissue changes (e.g. inflammation) and physical illness symptomatology (e.g.  gastrointestinal, immune, recurrent infection); overlap with other disorders; and  reports of rate increases and improvement or recovery that support a role for  modulation of the condition by environmental factors (e.g. exacerbation or  triggering by toxins, infectious agents, or others stressors, or improvement by  treatment). Modeling autism more broadly encompasses previous work, but also  encourages the expansion of research and treatment to include intermediary  domains of molecular and cellular mechanisms, as well as chronic tissue,  metabolic and somatic changes previously addressed only to a limited degree.  The heterogeneous biologies underlying autism may conceivably converge onto  the autism profile via multiple mechanisms on the one hand and processing and  connectivity abnormalities on the other may illuminate relevant final common  pathways and contribute to focusing on the search for treatment targets in this  biologically and etiologically heterogeneous behavioral syndrome. 

65. Multivariate techniques enable a biochemical classification of children with  autism spectrum disorder versus typically developing peers: A comparison and ‐ validation study 

Daniel P. Howsmon Troy Vargason Robert A. Rubin Leanna Delhey Marie  Tippett Shannon Rose Sirish C. Bennuri John C. Slattery Stepan Melnyk S. Jill James Richard E. Frye Juergen Hahn

Bioengineering & Translational Medicine, 14 May 2018  

https://doi.org/10.1002/btm2.10095 

Funding information National Institutes of Health, Grant/Award Number:  1R01AI110642 

Abstract 

Autism spectrum disorder (ASD) is a developmental disorder which is currently  only diagnosed through behavioral testing. Impaired folate dependent one ‐ carbon metabolism (FOCM) and transsulfuration (TS) pathways have been  implicated in ASD, and recently a study involving multivariate analysis based  upon Fisher Discriminant Analysis returned very promising results for predicting  an ASD diagnosis. This article takes another step toward the goal of developing a biochemical diagnostic for ASD by comparing five classification algorithms on  existing data of FOCM/TS metabolites, and also validating the classification  results with new data from an ASD cohort. The comparison results indicate a high sensitivity and specificity for the original data set and up to a 88% correct  classification of the ASD cohort at an expected 5% misclassification rate for  typically developing controls. These results form the foundation for the ‐ development of a biochemical test for ASD which promises to aid diagnosis of  ASD and provide biochemical understanding of the disease, applicable to at least a subset of the ASD population. 

66. Activation of Methionine Synthase by Insulin-like Growth Factor-1 and Dopamine: a Target for Neurodevelopmental Toxins and Thimerosal 

Mol Psychiatry. 2004 Apr;9(4):358-70. 

Waly M, Olteanu H, Banerjee R, Choi SW, Mason JB, Parker BS, Sukumar S,  Shim S, Sharma A, Benzecry JM, Power-Charnitsky VA, Deth RC. Department  of Pharmaceutical Sciences, Northeastern University, Boston, MA  

Abstract 

Methylation events play a critical role in the ability of growth factors to promote  normal development. Neurodevelopmental toxins, such as ethanol and heavy  metals, interrupt growth factor signaling, raising the possibility that they might  exert adverse effects on methylation. We found that insulin-like growth factor-1  (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate dependent methylation of phospholipids in SH-SY5Y human neuroblastoma  cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation  of this pathway increased DNA methylation, while its inhibition increased  methylation-sensitive gene expression. Ethanol potently interfered with IGF-1  activation of MS and blocked its effect on DNA methylation, whereas it did not  inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine stimulated MS activity, as well as folate-dependent phospholipid methylation:  Cu(2+) promoted enzyme activity and methylation, while Cu(+), Pb(2+), Hg(2+)  and Al(3+) were inhibitory. The ethylmercury-containing preservative thimerosal 

inhibited both IGF-1- and dopamine-stimulated methylation with an IC(50) of 1  nM and eliminated MS activity. Our findings outline a novel growth factor  signaling pathway that regulates MS activity and thereby modulates methylation  reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be  an important target of neurodevelopmental toxins. 

67. Validation of the Phenomenon of Autistic Regression Using Home Videotapes Archives of General Psychiatry, 2005 

Emily Werner, PhD; Geraldine Dawson, PhD, University of Washington 

Abstract 

Objective To validate parental report of autistic regression using behavioral data  coded from home videotapes of children with autism spectrum disorder (ASD) vs  typical development taken at 12 and 24 months of age. 

Design Home videotapes of 56 children’s first and second birthday parties were  collected from parents of young children with ASD with and without a reported  history of regression and typically developing children. Child behaviors were  coded by raters blind to child diagnosis and regression history. A parent interview that elicited information about parents’ recall of early symptoms from birth was  also administered. 

Setting Participants were recruited from a multidisciplinary study of autism  conducted at a major university. 

Participants Fifteen children with ASD with a history of regression, 21 children  with ASD with early-onset autism, and 20 typically developing children and their  parents participated. 

Main Outcome Measures Observations of children’s communicative, social,  affective, repetitive behaviors, and toy play coded from videotapes of the  toddlers’ first and second birthday parties. 

Results Analyses revealed that infants with ASD with regression show similar use of joint attention and more frequent use of words and babble compared with  typical infants at 12 months of age. In contrast, infants with ASD with early onset  of symptoms and no regression displayed fewer joint attention and  communicative behaviors at 12 months of age. By 24 months of age, both groups of toddlers with ASD displayed fewer instances of word use, vocalizations,  declarative pointing, social gaze, and orienting to name as compared with  typically developing 24-month-olds. 

Parent interview data suggested that some children with regression displayed  difficulties in regulatory behavior before the regression occurred. 

Conclusion This study validates the existence of early autistic regression.

68. Blood Levels of Mercury Are Related to Diagnosis of Autism: A Reanalysis of an  Important Data Set 

Journal of Child Neurology, Vol. 22, No. 11, 1308-1311 (2007) 

M. Catherine DeSoto, PhD, Robert T. Hitlan, PhD -Department of Psychology,  University of Northern Iowa, Cedar Falls, Iowa 

Abstract 

The question of what is leading to the apparent increase in autism is of great  importance. Like the link between aspirin and heart attack, even a small effect  can have major health implications. If there is any link between autism and  mercury, it is absolutely crucial that the first reports of the question are not falsely stating that no link occurs. We have reanalyzed the data set originally  reported by Ip et al. in 2004 and have found that the original p value was in  error and that a significant relation does exist between the blood levels of  mercury and diagnosis of an autism spectrum disorder. Moreover, the hair  sample analysis results offer some support for the idea that persons with  autism may be less efficient and more variable at eliminating mercury from  the blood. 

69. Empirical Data Confirm Autism Symptoms Related to Aluminum and  Acetaminophen Exposure 

Entropy, November 7, 2012 

Stephanie Seneff, Robert M. Davidson and Jingjing Liu 

Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute  of Technology, Cambridge, MA 02139, USA, Internal Medicine Group Practice,  PhyNet, Inc., Longview, TX 75604, USA 

Abstract 

Autism is a condition characterized by impaired cognitive and social skills,  associated with compromised immune function. The incidence is alarmingly on  the rise, and environmental factors are increasingly suspected to play a role. This paper investigates word frequency patterns in the U.S. CDC Vaccine Adverse  Events Reporting System (VAERS) database. Our results provide strong  evidence supporting a link between autism and the aluminum in vaccines. A  literature review showing toxicity of aluminum in human physiology offers further  support. Mentions of autism in VAERS increased steadily at the end of the last  century, during a period when mercury was being phased out, while aluminum  adjuvant burden was being increased. Using standard log-likelihood ratio  techniques, we identify several signs and symptoms that are significantly more 

prevalent in vaccine reports after 2000, including cellulitis, seizure, depression,  fatigue, pain and death, which are also significantly associated with aluminum containing vaccines. We propose that children with the autism diagnosis are  especially vulnerable to toxic metals such as aluminum and mercury due to insufficient serum sulfate and glutathione. A strong correlation between  autism and the MMR (Measles, Mumps, Rubella) vaccine is also observed,  which may be partially explained via an increased sensitivity to  acetaminophen administered to control fever. 

70. Glutathione-related factors and oxidative stress in autism, a review. Curr Med Chem. 2012;19(23):4000-5. 

Ghanizadeh A1, Akhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M,  Firoozabadi A. 

Research Center for Psychiatry and Behavioral Sciences, Shiraz University of  Medical Sciences, School of Medicine, Shiraz, Iran. ghanizad@sina.tums.ac.ir 

Abstract 

Autism spectrum disorders are complex neuro-developmental disorders whose  neurobiology is proposed to be associated with oxidative stress which is induced  by reactive oxygen species. The process of oxidative stress can be a target for  therapeutic interventions. In this study, we aimed to review the role of oxidative  stress, plasma glutathione (GSH), and related factors as the potential sources of  damage to the brain as well as the possible related factors which reduce the  oxidative stress. Methylation capacity, sulfates level, and the total glutathione  level are decreased in autism. On the other hand, both oxidized glutathione and  the ratio of oxidized to reduced glutathione are increased in autism. In addition,  the activity of glutathione peroxidase, superoxide dismutase, and catalase, as a  part of the antioxidative stress system are decreased. The current literature  suggests an imbalance of oxidative and anti-oxidative stress systems in  autism. Glutathione is involved in neuro-protection against oxidative stress and neuro-inflammation in autism by improving the anti-oxidative stress  system. Decreasing the oxidative stress might be a potential treatment for  autism. 

71. Developmental Regression and Mitochondrial Dysfunction in a Child With Autism J Child Neurol. 2006 Feb;21(2):170-2. 

Jon S. Poling, MD, PhD, Department of Neurology and Neurosurgery Johns Hopkins Hospital 

Jon S. Poling, Richard E. Frye, John Shoffner and Andrew W. Zimmerman

Abstract 

Autistic spectrum disorders can be associated with mitochondrial dysfunction. We present a singleton case of developmental regression and oxidative  phosphorylation disorder in a 19-month-old girl. Subtle abnormalities in the  serum creatine kinase level, aspartate aminotransferase, and serum bicarbonate  led us to perform a muscle biopsy, which showed type I myofiber atrophy,  increased lipid content, and reduced cytochrome c oxidase activity. There were  marked reductions in enzymatic activities for complex I and III. Complex IV  (cytochrome c oxidase) activity was near the 5% confidence level. To determine  the frequency of routine laboratory abnormalities in similar patients, we  performed a retrospective study including 159 patients with autism (Diagnostic  and Statistical Manual of Mental Disorders-IV and Childhood Autism Rating  Scale) not previously diagnosed with metabolic disorders and 94 age-matched  controls with other neurologic disorders. Aspartate aminotransferase was  elevated in 38% of patients with autism compared with 15% of controls (P  <.0001). The serum creatine kinase level also was abnormally elevated in 22  (47%) of 47 patients with autism. These data suggest that further metabolic  evaluation is indicated in autistic patients and that defects of oxidative  phosphorylation might be prevalent. 

Excerpt: "Children who have (mitochondrial-related) dysfunctional cellular  energy metabolism might be more prone to undergo autistic regression  between 18 and 30 months of age if they also have infections or  immunizations at the same time.” 

72. Oxidative Stress in Autism: Elevated Cerebellar 3-nitrotyrosine Levels American Journal of Biochemistry and Biotechnology 4 (2): 73-84, 2008 Elizabeth M. Sajdel-Sulkowska, - Dept of Psychiatry, Harvard Medical School 

Shows a potential link between mercury and the autopsied brains of young  people with autism. A marker for oxidative stress was 68.9% higher in autistic  brain issue than controls (a statistically significant result), while mercury levels  were 68.2% higher. 

Abstract  

It has been suggested that oxidative stress and/or mercury compounds play an  important role in the pathophysiology of autism. This study compared for the first  time the cerebellar levels of the oxidative stress marker 3-nitrotyrosine (3-NT),  mercury (Hg) and the antioxidant selenium (Se) levels between control and  autistic subjects. Tissue homogenates were prepared in the presence of protease inhibitors from the frozen cerebellar tissue of control (n=10; mean age, 15.5  years; mean PMI, 15.5 hours) and autistic (n=9; mean age 12.1 years; mean  PMI, 19.3 hours) subjects. The concentration of cerebellar 3-NT, determined by  ELISA, in controls ranged from 13.69 to 49.04 pmol g-1 of tissue; the  concentration of 3-NT in autistic cases ranged from 3.91 to 333.03 pmol g-1 of 

tissue. Mean cerebellar 3-NT was elevated in autism by 68.9% and the increase  was statistically significant (p=0.045). Cerebellar Hg, measured by atomic  absorption spectrometry ranged from 0.9 to 35 pmol g-1 tissue in controls (n=10)  and from 3.2 to 80.7 pmol g-1 tissue in autistic cases (n=9); the 68.2% increase in cerebellar Hg was not statistically significant. However, there was a positive  correlation between cerebellar 3-NT and Hg levels (r=0.7961, p=0.0001). A small  decrease in cerebellar Se levels in autism, measured by atomic absorption  spectroscopy, was not statistically significant but was accompanied by a 42.9%  reduction in the molar ratio of Se to Hg in the autistic cerebellum. While  preliminary, the results of the present study add elevated oxidative stress  markers in brain to the growing body of data reflecting greater oxidative stress in  autism. 

Excerpt: The preliminary data suggest a need for more extensive studies of  oxidative stress, its relationship to the environmental factors and its  possible attenuation by antioxidants in autism.” 

73. Large Brains in Autism: The Challenge of Pervasive Abnormality Neuroscientist. 2005 Oct;11(5):417-40. 

Herbert MR., Harvard University 

Pediatric Neurology, Center for Morphometric Analysis, Massachusetts General  Hospital, Charleston, MA  

Abstract 

The most replicated finding in autism neuroanatomy-a tendency to unusually  large brains-has seemed paradoxical in relation to the specificity of the  abnormalities in three behavioral domains that define autism. We now know a  range of things about this phenomenon, including that brains in autism have a  growth spurt shortly after birth and then slow in growth a few short years  afterward, that only younger but not older brains are larger in autism than in  controls, that white matter contributes disproportionately to this volume increase  and in a nonuniform pattern suggesting postnatal pathology, that functional  connectivity among regions of autistic brains is diminished, and that  neuroinflammation (including microgliosis and astrogliosis) appears to be present in autistic brain tissue from childhood through adulthood. Alongside these  pervasive brain tissue and functional abnormalities, there have arisen theories of  pervasive or widespread neural information processing or signal coordination  abnormalities (such as weak central coherence, impaired complex processing,  and underconnectivity), which are argued to underlie the specific observable  behavioral features of autism. This convergence of findings and models suggests that a systems- and chronic disease-based reformulation of function and  pathophysiology in autism needs to be considered, and it opens the possibility for new treatment targets.. 

Excerpt: "Oxidative stress, brain inflammation, and microgliosis have been  much documented in association with toxic exposures including various 

heavy metals...the awareness that the brain as well as medical conditions  of children with autism may be conditioned by chronic biomedical  abnormalities such as inflammation opens the possibility that meaningful  biomedical interventions may be possible well past the window of maximal  neuroplasticity in early childhood because the basis for assuming that all  deficits can be attributed to fixed early developmental alterations in neural  architecture has now been undermined." 

74. Evidence of Toxicity, Oxidative Stress, and Neuronal Insult in Autism J Toxicol Environ Health B Crit Rev. 2006 Nov-Dec;9(6):485-99. 

Kern JK, Jones AM. 

Department of Psychiatry, University of Texas Southwestern Medical Center at  Dallas, Dallas, Texas  

Abstract 

According to the Autism Society of America, autism is now considered to be an  epidemic. The increase in the rate of autism revealed by epidemiological studies  and government reports implicates the importance of external or environmental  factors that may be changing. This article discusses the evidence for the case  that some children with autism may become autistic from neuronal cell death or  brain damage sometime after birth as result of insult; and addresses the  hypotheses that toxicity and oxidative stress may be a cause of neuronal insult in autism. The article first describes the Purkinje cell loss found in autism, Purkinje  cell physiology and vulnerability, and the evidence for postnatal cell loss. Second, the article describes the increased brain volume in autism and how it may be  related to the Purkinje cell loss. Third, the evidence for toxicity and oxidative  stress is covered and the possible involvement of glutathione is discussed.  Finally, the article discusses what may be happening over the course of  development and the multiple factors that may interplay and make these children  more vulnerable to toxicity, oxidative stress, and neuronal insult. 

75. Oxidative Stress in Autism 

Pathophysiology. 2006 Aug;13(3):171-81. Epub 2006 Jun 12. 

Chauhan A, Chauhan V. 

NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill  Road, Staten Island, NY  

Abstract 

Autism is a severe developmental disorder with poorly understood etiology.  Oxidative stress in autism has been studied at the membrane level and also by 

measuring products of lipid peroxidation, detoxifying agents (such as  glutathione), and antioxidants involved in the defense system against reactive  oxygen species (ROS). Lipid peroxidation markers are elevated in autism,  indicating that oxidative stress is increased in this disease. Levels of major  antioxidant serum proteins, namely transferrin (iron-binding protein) and  ceruloplasmin (copper-binding protein), are decreased in children with autism.  There is a positive correlation between reduced levels of these proteins and loss  of previously acquired language skills in children with autism. The alterations in  ceruloplasmin and transferrin levels may lead to abnormal iron and copper  metabolism in autism. The membrane phospholipids, the prime target of ROS,  are also altered in autism. The levels of phosphatidylethanolamine (PE) are  decreased, and phosphatidylserine (PS) levels are increased in the erythrocyte  membrane of children with autism as compared to their unaffected siblings.  Several studies have suggested alterations in the activities of antioxidant  enzymes such as superoxide dismutase, glutathione peroxidase, and catalase in  autism. Additionally, altered glutathione levels and homocysteine/methionine  metabolism, increased inflammation, excitotoxicity, as well as mitochondrial and  immune dysfunction have been suggested in autism. Furthermore, environmental and genetic factors may increase vulnerability to oxidative stress in autism. Taken together, these studies suggest increased oxidative stress in autism that may  contribute to the development of this disease. A mechanism linking oxidative  stress with membrane lipid abnormalities, inflammation, aberrant immune  response, impaired energy metabolism and excitotoxicity, leading to clinical  symptoms and pathogenesis of autism is proposed. 

Excerpt: "Upon completion of this article, participants should be able to: 1.  Be aware of laboratory and clinical evidence of greater oxidative stress in  autism. 2. Understand how gut, brain, nutritional, and toxic status in autism are consistent with greater oxidative stress. 3. Describe how anti-oxidant  nutrients are used in the contemporary treatment of autism." 

76. Thimerosal Neurotoxicity is Associated with Glutathione Depletion: Protection  with Glutathione Precursors 

Neurotoxicology. 2005 Jan;26(1):1-8. 

James SJ, Slikker W 3rd, Melnyk S, New E, Pogribna M, Jernigan S. 

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

Abstract 

Thimerosol is an antiseptic containing 49.5% ethyl mercury that has been used  for years as a preservative in many infant vaccines and in flu vaccines.  Environmental methyl mercury has been shown to be highly neurotoxic,  especially to the developing brain. Because mercury has a high affinity for thiol  (sulfhydryl (-SH)) groups, the thiol-containing antioxidant, glutathione (GSH),  provides the major intracellular defense against mercury-induced neurotoxicity.  Cultured neuroblastoma cells were found to have lower levels of GSH and 

increased sensitivity to thimerosol toxicity compared to glioblastoma cells that  have higher basal levels of intracellular GSH. Thimerosal-induced cytotoxicity  was associated with depletion of intracellular GSH in both cell lines. Pretreatment with 100 microM glutathione ethyl ester or N-acetylcysteine (NAC),  but not methionine, resulted in a significant increase in intracellular GSH in both  cell types. Further, pretreatment of the cells with glutathione ethyl ester or NAC  prevented cytotoxicity with exposure to 15 microM Thimerosal. Although  Thimerosal has been recently removed from most children's vaccines, it is still  present in flu vaccines given to pregnant women, the elderly, and to children in  developing countries. The potential protective effect of GSH or NAC against  mercury toxicity warrants further research as possible adjunct therapy to  individuals still receiving Thimerosal-containing vaccinations. 

77. Toxic metals and oxidative stress part I: mechanisms involved in metal-induced  oxidative damage. 

Curr Top Med Chem. 2001 Dec;1(6):529-39. 

Ercal N1, Gurer-Orhan H, Aykin-Burns N. 

University of Missouri-Rolla, Department of Chemistry, 65409-0010, USA.  nercal@umr.edu 

Abstract 

Toxic metals (lead, cadmium, mercury and arsenic) are widely found in our  environment. Humans are exposed to these metals from numerous sources,  including contaminated air, water, soil and food. Recent studies indicate that  transition metals act as catalysts in the oxidative reactions of biological  macromolecules therefore the toxicities associated with these metals might be  due to oxidative tissue damage. Redox-active metals, such as iron, copper and  chromium, undergo redox cycling whereas redox-inactive metals, such as lead,  cadmium, mercury and others deplete cells' major antioxidants, particularly thiol containing antioxidants and enzymes. Either redox-active or redox-inactive  metals may cause an increase in production of reactive oxygen species (ROS)  such as hydroxyl radical (HO.), superoxide radical (O2.-) or hydrogen peroxide  (H2O2). Enhanced generation of ROS can overwhelm cells' intrinsic antioxidant  defenses, and result in a condition known as "oxidative stress". Cells under  oxidative stress display various dysfunctions due to lesions caused by ROS to  lipids, proteins and DNA. Consequently, it is suggested that metal-induced  oxidative stress in cells can be partially responsible for the toxic effects of  heavy metals. Several studies are underway to determine the effect of  antioxidant supplementation following heavy metal exposure. Data suggest that antioxidants may play an important role in abating some hazards of  heavy metals. In order to prove the importance of using antioxidants in heavy  metal poisoning, pertinent biochemical mechanisms for metal-induced oxidative  stress should be reviewed.

78. Aluminum adjuvant linked to gulf war illness induces motor neuron death in mice Neuromolecular Med. 2007;9(1):83-100. 

Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA. 

Department of Ophthalmology and Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada.  

Abstract 

Gulf War illness (GWI) affects a significant percentage of veterans of the 1991  conflict, but its origin remains unknown. Associated with some cases of GWI are  increased incidences of amyotrophic lateral sclerosis and other neurological  disorders. Whereas many environmental factors have been linked to GWI, the  role of the anthrax vaccine has come under increasing scrutiny. Among the  vaccine's potentially toxic components are the adjuvants aluminum hydroxide  and squalene. To examine whether these compounds might contribute to  neuronal deficits associated with GWI, an animal model for examining the  potential neurological impact of aluminum hydroxide, squalene, or aluminum  hydroxide combined with squalene was developed. Young, male colony CD-1  mice were injected with the adjuvants at doses equivalent to those given to US  military service personnel. All mice were subjected to a battery of motor and  cognitive-behavioral tests over a 6-mo period postinjections. Following sacrifice,  central nervous system tissues were examined using immunohistochemistry for  evidence of inflammation and cell death. Behavioral testing showed motor  deficits in the aluminum treatment group that expressed as a progressive  decrease in strength measured by the wire-mesh hang test (final deficit at 24 wk;  about 50%). Significant cognitive deficits in water-maze learning were observed  in the combined aluminum and squalene group (4.3 errors per trial) compared  with the controls (0.2 errors per trial) after 20 wk. Apoptotic neurons were  identified in aluminum-injected animals that showed significantly increased  activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor  cortex (192%) compared with the controls. Aluminum-treated groups also  showed significant motor neuron loss (35%) and increased numbers of  astrocytes (350%) in the lumbar spinal cord. The findings suggest a possible role for the aluminum adjuvant in some neurological features associated with GWI  and possibly an additional role for the combination of adjuvants. 

79. Enrichment of Elevated Plasma F2t-Isoprostane Levels in Individuals with Autism Who Are Stratified by Presence of Gastrointestinal Dysfunction 

PLoS ONE 8(7): e68444. 

Gorrindo P, Lane CJ, Lee EB, McLaughlin B, Levitt P (July 3, 2013)  Funding: This work was supported in part by National Institutes of Health awards 

National Institute of Child Health and Human Development R21HD065289 (PL),  National Institute of General Medical Sciences T32GM07347 for the Vanderbilt  Medical Scientist Training Program (PG), National Center for Research  Resources TL1RR024978 (PG), and National Center for Advancing Translational  Sciences UL1TR000445 for the Vanderbilt Institute for Clinical and Translational  Research. Additional support was provided by the Marino Autism Research  Institute, the Pediatric Clinical Research Center at Vanderbilt University, The  Scott Family Foundation, and the Vanderbilt Autism Treatment Network Site, a  program funded by Autism Speaks. 

AbstractEtiology is unknown in the majority of individuals with autism spectrum  disorder (ASD). One strategy to investigate pathogenesis is to stratify this  heterogeneous disorder based on a prominent phenotypic feature that enriches  for homogeneity within population strata. Co-occurring gastrointestinal  dysfunction (GID) characterizes a subset of children with ASD. Our current  objective was to investigate a potential pathophysiological measure to test the  hypothesis that children with both ASD and GID have a more severe metabolic  dysfunction than children with ASD-only, given that the highly metabolically active brain and gastrointestinal system may additively contribute measurable  impairment. Plasma levels of F2t-Isoprostanes (F2-IsoPs), a gold standard  biomarker of oxidative stress, were measured in 87 children in four groups: ASD GID, ASD-only, GID-only and Unaffected. F2-IsoP levels were elevated in all 3  clinical groups compared to the Unaffected group, with the ASD-GID group  significantly elevated above the ASD-only group (mean, SD in pg/mg: ASD-GID  53.6, 24.4; ASD-only 36.5, 13.3; p = 0.007). Adjusting for age, sex, and  triglyceride levels, F2-IsoP levels remained significantly different between study  groups, with a moderate effect size of ηp2 = 0.187 (p = 0.001). Elevation in  peripheral oxidative stress is consistent with, and may contribute to, the  more severe functional impairments in the ASD-GID group. With unique  medical, metabolic, and behavioral features in children with ASD-GID, the  present findings serve as a compelling rationale for both individualized  approaches to clinical care and integrated studies of biomarker enrichment in  ASD subgroups that may better address the complex etiology of ASD. 

80. Reduced levels of mercury in first baby haircuts of autistic children. Int J Toxicol. 2003 Jul-Aug;22(4):277-85. 

Holmes AS, Blaxill MF, Haley BE. 

Abstract 

Reported rates of autism have increased sharply in the United States and the  United Kingdom. One possible factor underlying these increases is increased  exposure to mercury through thimerosal-containing vaccines, but vaccine  exposures need to be evaluated in the context of cumulative exposures during  gestation and early infancy. Differential rates of postnatal mercury elimination  may explain why similar gestational and infant exposures produce variable  neurological effects. First baby haircut samples were obtained from 94 children 

diagnosed with autism using Diagnostic and Statistical Manual of Mental  Disorders, 4th edition (DSM IV) criteria and 45 age- and gender-matched  controls. Information on diet, dental amalgam fillings, vaccine history, Rho D  immunoglobulin administration, and autism symptom severity was collected  through a maternal survey questionnaire and clinical observation. Hair mercury  levels in the autistic group were 0.47 ppm versus 3.63 ppm in controls, a  significant difference. The mothers in the autistic group had significantly higher  levels of mercury exposure through Rho D immunoglobulin injections and  amalgam fillings than control mothers. Within the autistic group, hair mercury  levels varied significantly across mildly, moderately, and severely autistic  children, with mean group levels of 0.79, 0.46, and 0.21 ppm, respectively. Hair  mercury levels among controls were significantly correlated with the number of  the mothers' amalgam fillings and their fish consumption as well as exposure to  mercury through childhood vaccines, correlations that were absent in the autistic  group. Hair excretion patterns among autistic infants were significantly reduced  relative to control. These data cast doubt on the efficacy of traditional hair  analysis as a measure of total mercury exposure in a subset of the population. In  light of the biological plausibility of mercury's role in neurodevelopmental  disorders, the present study provides further insight into one possible mechanism by which early mercury exposures could increase the risk of autism. 

81. A Case Series of Children with Apparent Mercury Toxic Encephalopathies  Manifesting with Clinical Symptoms of Regressive Autistic Disorder 

J Toxicol Environ Health A. 2007 May 15;70(10):837-51. 

Geier DA, Geier MR. 

Institute of Chronic Illnesses, Inc., Silver Spring, Maryland, USA. Abstract 

Impairments in social relatedness and communication, repetitive behaviors, and  stereotypic abnormal movement patterns characterize autism spectrum disorders (ASDs). It is clear that while genetic factors are important to the pathogenesis of  ASDs, mercury exposure can induce immune, sensory, neurological, motor, and  

behavioral dysfunctions similar to traits defining or associated with ASDs. The  Institutional Review Board of the Institute for Chronic Illnesses (Office for Human  Research Protections, U.S. Department of Health and Human Services, IRB  number IRB00005375) approved the present study. A case series of nine patients who presented to the Genetic Centers of America for a genetic/developmental  evaluation are discussed. Eight of nine patients (one patient was found to have  an ASD due to Rett's syndrome) (a) had regressive ASDs; (b) had elevated levels of androgens; (c) excreted significant amounts of mercury post chelation  challenge; (d) had biochemical evidence of decreased function in their  glutathione pathways; (e) had no known significant mercury exposure except  from Thimerosal-containing vaccines/Rho(D)-immune globulin preparations; and  (f) had alternate causes for their regressive ASDs ruled out. There was a 

significant dose-response relationship between the severity of the regressive  ASDs observed and the total mercury dose children received from Thimerosal containing vaccines/Rho (D)-immune globulin preparations. Based upon  differential diagnoses, 8 of 9 patients examined were exposed to significant  mercury from Thimerosal-containing biologic/vaccine preparations during their  fetal/infant developmental periods, and subsequently, between 12 and 24 mo of  age, these previously normally developing children suffered mercury toxic  encephalopathies that manifested with clinical symptoms consistent with  regressive ASDs. Evidence for mercury intoxication should be considered  in the differential diagnosis as contributing to some regressive ASDs. 

82. The Changing Prevalence of Autism In California  

Journal of Autism and Developmental Disorders, April 2003 

Mark Blaxill, MBA 

This study helps to refute the supposition made by some researchers that  autism's epidemic may only be due to "diagnostic substitution". 

Excerpt: "They have suggested that 'diagnostic substitution' accounts for  an apparent increase in the incidence of autism in California that is not  real. This hypothesized substitution is not supported by proper and  detailed analyses of the California data." 

83. California Autism Prevalence Trends from 1931 to 2014 and Comparison to  National ASD Data from IDEA and ADDM. 

J Autism Dev Disord. 2018 Jul 5.  

Nevison C, Blaxill M, Zahorodny W. 

Abstract 

Time trends in U.S. autism prevalence from three ongoing datasets [Individuals  with Disabilities Education Act, Autism and Developmental Disabilities Monitoring  Network, and California Department of Developmental Services (CDDS)] are  calculated using two different methods: (1) constant-age tracking of 8 year-olds  and (2) age-resolved snapshots. The data are consistent across methods in  showing a strong upward trend over time. The prevalence of autism in the CDDS  dataset, the longest of the three data records, increased from 0.001% in the  cohort born in 1931 to 1.2% among 5 year-olds born in 2012. This increase  began around ~ 1940 at a rate that has gradually accelerated over time,  including notable change points around birth years 1980, 1990 and, most  recently, 2007.

84. Diagnostic Substitution for Intellectual Disability: A Flawed Explanation for the  Rise in Autism 

Journal of Autism and Developmental Disorders First Online: 06 June 2017, DOI: 10.1007/s10803-017-3187-0 

Cynthia D. Nevison, Mark Blaxill 

Abstract 

Time trends in autism spectrum disorder (ASD) and intellectual disability (ID)  prevalence from the United States Individuals with Disabilities Education Act data were computed from 2000 to 2011 for each state and each age from 6 to 17.  These trends did not support the hypothesis that diagnostic substitution  for ID can explain the ASD rise over recent decades, although the hypothesis  appeared more plausible when the data were aggregated across all states and  ages. Nationwide ID prevalence declined steeply over the last two decades, but  the decline was driven mainly by ~15 states accounting for only one-fourth of the  U.S. school population. More commonly, including in the most populous  states, ID prevalence stayed relatively constant while ASD prevalence rose  sharply. 

85. Mitochondrial Energy-Deficient Endophenotype in Autism 

American Journal of Biochemistry and Biotechnology 4 (2): 198-207, 2008 

J. Jay Gargus and Faiqa Imtiaz 

Department of Physiology and Biophysics and Department of Pediatrics, Section  of Human Genetics, School of Medicine, University of California, Irvine, Arabian  Diagnostics Laboratory, King Faisal Specialist Hospital and Research Centre 

Abstract: While evidence points to a multigenic etiology of most autism, the  pathophysiology of the disorder has yet to be defined and the underlying genes  and biochemical pathways they subserve remain unknown. Autism is considered  to be influenced by a combination of various genetic, environmental and  immunological factors; more recently, evidence has suggested that increased vulnerability to oxidative stress may be involved in the etiology of this  multifactorial disorder. 

Furthermore, recent studies have pointed to a subset of autism associated with  the biochemical endophenotype of mitochondrial energy deficiency, identified as  a subtle impairment in fat and carbohydrate oxidation. This phenotype is similar,  but more subtle than those seen in classic mitochondrial defects. In some cases  

the beginnings of the genetic underpinnings of these mitochondrial defects are  emerging, such as mild mitochondrial dysfunction and secondary carnitine  deficiency observed in the subset of autistic patients with an inverted duplication  of chromosome 15q11-q13. In addition, rare cases of familial autism associated  with sudden infant death syndrome (SIDS) or associated with abnormalities in  cellular calcium homeostasis, such as malignant hyperthermia or cardiac 

arrhythmia, are beginning to emerge. Such special cases suggest that the  pathophysiology of autism may comprise pathways that are directly or  indirectly involved in mitochondrial energy production and to further probe  this connection three new avenues seem worthy of exploration: 1) metabolomic  clinical studies provoking controlled aerobic exercise stress to expand the  biochemical phenotype, 2) high-throughput expression arrays to directly survey  activity of the genes underlying these biochemical pathways and 3) model  systems, either based upon neuronal stem cells or model genetic organisms, to  discover novel genetic and environmental inputs into these pathways. 

86. Pathways to Defective Brain Function and Plasticity 

American Journal of Biochemistry and Biotechnology 4 (2): 167-176, 2008 

Matthew P. Anderson, Brian S. Hooker and Martha R. Herbert 

Departments of Neurology and Pathology, Harvard Medical School/Beth Israel  Deaconess Medical Center, Harvard Institutes of Medicine, High Throughput  Biology Team, Fundamental Science Directorate, Pacific Northwest National  Laboratory, Pediatric Neurology/Center for Morphometric Analysis,  Massachusetts General Hospital/Harvard Medical School, and Center for Child  and Adolescent Development, Cambridge Health Alliance/Harvard Medical  School 

Abstract: We review evidence to support a model where the disease process  underlying autism may begin when an in utero or early postnatal environmental,  infectious, seizure, or autoimmune insult triggers an immune response that  increases reactive oxygen species (ROS) production in the brain that leads to  DNA damage (nuclear and mitochondrial) and metabolic enzyme blockade and  that these inflammatory and oxidative stressors persist beyond early  development (with potential further exacerbations), producing ongoing functional  consequences. In organs with a high metabolic demand such as the central  nervous system, the continued use of mitochondria with damaged DNA and  impaired metabolic enzyme function may generate additional ROS which will  cause persistent activation of the innate immune system leading to more ROS  production. Such a mechanism would self-sustain and possibly progressively  worsen. The mitochondrial dysfunction and altered redox signal transduction  pathways found in autism would conspire to activate both astroglia and microglia. These activated cells can then initiate a broad-spectrum proinflammatory gene  response. Beyond the direct effects of ROS on neuronal function, receptors on  neurons that bind the inflammatory mediators may serve to inhibit neuronal  signaling to protect them from excitotoxic damage during various pathologic  insults (e.g., infection). In autism, over-zealous neuroinflammatory responses could not only influence neural developmental processes, but may more  significantly impair neural signaling involved in cognition in an ongoing  fashion. This model makes specific predictions in patients and experimental  animal models and suggests a number of targets sites of intervention. Our model of potentially reversible pathophysiological mechanisms in autism motivates our 

hope that effective therapies may soon appear on the horizon. 

87. Heavy-Metal Toxicity—With Emphasis on Mercury 

John Neustadt, ND, and Steve Pieczenik, MD, PhD 

Research Review 

Conclusion: Metals are ubiquitous in our environment, and exposure to them is  inevitable. However, not all people accumulate toxic levels of metals or exhibit  symptoms of metal toxicity, suggesting that genetics play a role in their potential  to damage health. Metal toxicity creates multisystem dysfunction, which  appears to be mediated primarily through mitochondrial damage from  glutathione depletion. 

Accurate screening can increase the likelihood that patients with potential metal  toxicity are identified. The most accurate screening method for assessing  chronic-metals exposure and metals load in the body is a provoked urine test. 

88. Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment American Journal of Biochemistry and Biotechnology 4 (2): 208-217, 2008 

Daniel A. Rossignol, J. Jeffrey Bradstreet, International Child Development  Resource Center, 

Abstract 

Classical mitochondrial diseases occur in a subset of individuals with autism and  are usually caused by genetic anomalies or mitochondrial respiratory pathway  deficits. However, in many cases of autism, there is evidence of mitochondrial  dysfunction (MtD) without the classic features associated with mitochondrial  disease. MtD appears to be more common in autism and presents with less  severe signs and symptoms. It is not associated with discernable mitochondrial  pathology in muscle biopsy specimens despite objective evidence of lowered  mitochondrial functioning. Exposure to environmental toxins is the likely  etiology for MtD in autism. This dysfunction then contributes to a number  of diagnostic symptoms and comorbidities observed in autism including:  cognitive impairment, language deficits, abnormal energy metabolism,  chronic gastrointestinal problems, abnormalities in fatty acid oxidation,  and increased oxidative stress. MtD and oxidative stress may also explain  the high male to female ratio found in autism due to increased male  vulnerability to these dysfunctions. 

Biomarkers for mitochondrial dysfunction have been identified, but seem widely  under-utilized despite available therapeutic interventions. Nutritional  supplementation to decrease oxidative stress along with factors to improve 

reduced glutathione, as well as hyperbaric oxygen therapy (HBOT) represent  supported and rationale approaches. The underlying pathophysiology and  autistic symptoms of affected individuals would be expected to either improve or  cease worsening once effective treatment for MtD is implemented. 

89. Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic Based Associations, and Non-Energy-Related Mechanisms 

Oxid Med Cell Longev. 2017 May 29.  

Keren K. Griffiths and Richard J. Levy 

Department of Anesthesiology, Columbia University Medical Center, New York,  NY, USA 

Abstract 

Autism spectrum disorder (ASD), the fastest growing developmental disability in  the United States, represents a group of neurodevelopmental disorders  characterized by impaired social interaction and communication as well as  restricted and repetitive behavior. The underlying cause of autism is unknown  and therapy is currently limited to targeting behavioral abnormalities. Emerging  studies suggest a link between mitochondrial dysfunction and ASD. Here, we  review the evidence demonstrating this potential connection. We focus  specifically on biochemical links, genetic-based associations, non-energy related  mechanisms, and novel therapeutic strategies. 

Conclusion 

The literature reviewed here suggests a link between abnormalities in  mitochondrial homeostasis and ASD and provides biochemical and genetic evidence to support a role for mitochondrial dysfunction in the  pathogenesis of the autism phenotype. Mechanistically, the connection may  involve defects in bioenergetic capacity as well as non-energy related pathways.  However, it is not clear if mitochondrial impairments cause ASD or if they are  merely associated with the disease process. Positive patient behavioral  responses to conventional mitochondrial disease therapies are promising,  however, further investigation is necessary. Future work should focus on  determining how mitochondrial dysfunction causes the autistic phenotype as well  as how defects in mitochondrial homeostasis predispose individuals to ASD via  interaction with environmental toxins, dietary factors, and epigenetic  modifications during critical periods of development. Establishing a causative  relationship between mitochondrial dysfunction and ASD and elucidating the  exact mechanisms will permit the development of more precisely targeted  therapies in the future. Ultimately, with improved knowledge and innovation, we  may one day be able to prevent or cure autism.

90. Proximity to point sources of environmental mercury release as a predictor of  autism prevalence 

Health & Place, 2008 

Raymond F. Palmer, Stephen Blanchard, Robert Wood 

University of Texas Health Science Center, San Antonio Department of Family  and Community Medicine, Our Lady of the Lake University, San Antonio Texas,  Chair, Department of Sociology 

This study should be viewed as hypothesis-generating - a first step in examining  the potential role of environmental mercury and childhood developmental  disorders. Nothing is known about specific exposure routes, dosage, timing, and  individual susceptibility. We suspect that persistent low-dose exposures to  various environmental toxicants, including mercury, that occur during  critical windows of neural development among genetically susceptible  children (with a diminished capacity for metabolizing accumulated  toxicants) may increase the risk for developmental disorders such as  autism. Successfully identifying the specific combination of environmental  exposures and genetic susceptibilities can inform the development of targeted  prevention intervention strategies. 

91. Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical  characterization, and medical conditions 

Developmental Medicine & Child Neurology, 2007 

Guiomar Oliveira MD PhD, Centro de Desenvolvimento da Criança, Hospital  Pediátrico de Coimbra; Assunção Ataíde BSc, Direcção Regional de Educação  do Centro Coimbra; 

Carla Marques MSc, Centro de Desenvolvimento da Criança, Hospital Pediátrico de Coimbra; Teresa S Miguel BSc, Direcção Regional de Educação do Centro,  Coimbra; 

Ana Margarida Coutinho BSc, Instituto Gulbenkian de Ciência, Oeiras; Luísa  Mota-Vieira PhD, Unidade de Genética e Patologia moleculares, Hospital do  Divino Espírito Santo, Ponta Delgada, Açores; Esmeralda Gonçalves PhD;  Nazaré Mendes Lopes PhD, Faculdade de Ciências e Tecnologia, Universidade  de Coimbra; Vitor Rodrigues MD PhD; Henrique Carmona da Mota MD PhD,  Faculdade de Medicina, Universidade de Coimbra, Coimbra; Astrid Moura  Vicente PhD, Instituto Gulbenkian de Ciência, Oeiras, Portugal. 

*Correspondence to first author at Hospital Pediátrico de Coimbra, Av Bissaya  Barreto, 3000-076 Coimbra, Portugal. E-mail: guiomar@hpc.chc.min-saude.pt 

Abstract: The objective of this study was to estimate the prevalence of autistic  spectrum disorder (ASD) and identify its clinical characterization, and medical  conditions in a paediatric population in Portugal. A school survey was conducted  in elementary schools, targeting 332 808 school-aged children in the mainland 

and 10 910 in the Azores islands. Referred children were directly assessed using the Diagnostic and Statistical Manual of Mental Disorders (4th edn), the Autism  Diagnostic Interview–Revised, and the Childhood Autism Rating Scale. Clinical  history and a laboratory investigation was performed. In parallel, a systematic  multi-source search of children known to have autism was carried out in a  restricted region. The global prevalence of ASD per 10 000 was 9.2 in mainland,  and 15.6 in the Azores, with intriguing regional differences. A diversity of  associated medical conditions was documented in 20%, with an  unexpectedly high rate of mitochondrial respiratory chain disorders. 

92. Thimerosal induces neuronal cell apoptosis by causing cytochrome c and  apoptosis-inducing factor release from mitochondria. 

International Journal of Molecular Medicine, 2006 

Yel L, Brown LE, Su K, Gollapudi S, Gupta S.Department of Medicine, University  of California, Irvine, CA 92697, USA. lyel@uci.edu 

There is a worldwide increasing concern over the neurological risks of thimerosal (ethylmercury thiosalicylate) which is an organic mercury compound that is  commonly used as an antimicrobial preservative. In this study, we show that  thimerosal, at nanomolar concentrations, induces neuronal cell death through the mitochondrial pathway. Thimerosal, in a concentration- and time-dependent  manner, decreased cell viability as assessed by calcein-ethidium staining and  caused apoptosis detected by Hoechst 33258 dye. Thimerosal-induced  apoptosis was associated with depolarization of mitochondrial membrane,  generation of reactive oxygen species, and release of cytochrome c and  apoptosis-inducing factor (AIF) from mitochondria to cytosol. Although thimerosal did not affect cellular expression of Bax at the protein level, we observed  translocation of Bax from cytosol to mitochondria. Finally, caspase-9 and  caspase-3 were activated in the absence of caspase-8 activation. Our data  suggest that thimerosal causes apoptosis in neuroblastoma cells by changing the mitochondrial microenvironment. 

93. Mitochondrial mediated thimerosal-induced apoptosis in a human neuroblastoma cell line (SK-N-SH). 

Neurotoxicology. 2005 

Humphrey ML, Cole MP, Pendergrass JC, Kiningham KK. Department of  Pharmacology, Joan C. Edwards School of Medicine, Marshall University,  Huntington, WV 25704-9388, USA. 

Environmental exposure to mercurials continues to be a public health issue due 

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

94. Possible Immunological Disorders in Autism: Concomitant Autoimmunity and  Immune Tolerance 

The Egyptian Journal of Immunology, 2006 

Maha I. Sh. Kawashti, Omnia R. Amin Nadia G. Rowehy 

Microbiology Department, Faculty of Medicine (For Girls), Al Azhar University,  Cairo, Egypt, Psychiatry Department, Faculty of Medicine, Cairo University,  Cairo, Egypt and Serology Lab King Fahad General Hospital, Jeddah, K.S.A. 

Abstract: Autism is a pervasive developmental disorder that affect children early  in their life. Immunological disorders is one of several contributing factors that  have been suggested to cause autism. Thirty autistic children aged 3-6 years and thirty non-autistic psychologically-free siblings were studied. Circulating IgA and  IgG autoantibodies to casein and gluten dietary proteins were detected by  enzyme-immunoassays (EIA). Circulating IgG antibodies to measles, mumps and rubella vaccine (M.M.R) and cytomeglovirus were investigated by EIA. Results  revealed high seropositivity for autoantibodies to casein and gluten: 83.3% and  50% respectively in autistic children as compared to 10% and 6.7% positivity in  the control group. Surprisingly, circulating anti-measles, anti-mumps and anti rubella IgG were positive in only 50%, 73.3% and 53.3% respectively as 

compared to 100% positivity in the control group. Anti-CMV IgG was positive in  43.3% of the autistic children as compared to 7% in the control group. It is  concluded that, autoimmune response to dietary proteins and deficient  immune response to measles, mumps and rubella vaccine antigens might  be associated with autism, as a leading cause or a resulting event. Further  research is needed to confirm these findings. 

95. Pediatric Vaccines Influence Primate Behavior, and Amygdala Growth and Opioid Ligand Binding 

Friday, May 16, 2008: IMFAR 

L. Hewitson , Obstetrics, Gynecology and Reproductive Sciences, University of  Pittsburgh, Pittsburgh, PA B. Lopresti , Radiology, University of Pittsburgh,  Pittsburgh, PA C. Stott , Thoughtful House Center for Children, Austin, TX J.  Tomko , Pittsburgh Development Center, University of Pittsburgh, Pittsburgh, PA  L. Houser , Pittsburgh Development Center, University of Pittsburgh, Pittsburgh,  PA E. Klein , Division of Laboratory Animal Resources, University of Pittsburgh,  Pittsburgh, PA C. Castro , Obstetrics, Gynecology and Reproductive Sciences,  University of Pittsburgh, Pittsburgh, PA G. Sackett , Psychology, Washington  National Primate Research Center, Seattle, WA S. Gupta , Medicine, Pathology & Laboratory Medicine, University of California - Irvine, Irvine, CA D. Atwood ,  Chemistry, University of Kentucky, Lexington, KY L. Blue , Chemistry, University  of Kentucky, Lexington, KY E. R. White , Chemistry, University of Kentucky,  Lexington, KY A. Wakefield , Thoughtful House Center for Children, Austin, TX 

Abstract 

Background: Macaques are commonly used in pre-clinical vaccine safety testing, but the combined childhood vaccine regimen, rather than individual vaccines, has not been studied. Childhood vaccines are a possible causal factor in autism, and  abnormal behaviors and anomalous amygdala growth are potentially inter-related features of this condition. 

Objectives: The objective of this study was to compare early infant cognition and  behavior with amygdala size and opioid binding in rhesus macaques receiving  the recommended childhood vaccines (1994-1999), the majority of which  contained the bactericidal preservative ethylmercurithiosalicylic acid (thimerosal). 

Methods: Macaques were administered the recommended infant vaccines,  adjusted for age and thimerosal dose (exposed; N=13), or saline (unexposed;  N=3). Primate development, cognition and social behavior were assessed for  both vaccinated and unvaccinated infants using standardized tests developed at  the Washington National Primate Research Center. Amygdala growth and  binding were measured serially by MRI and by the binding of the non-selective  opioid antagonist [11C]diprenorphine, measured by PET, respectively, before (T1) and after (T2) the administration of the measles-mumps-rubella vaccine (MMR).

Results: Compared with unexposed animals, significant  

neurodevelopmental deficits were evident for exposed animals in survival  reflexes, tests of color discrimination and reversal, and learning sets.  Differences in behaviors were observed between exposed and unexposed  animals and within the exposed group before and after MMR vaccination.  Compared with unexposed animals, exposed animals showed attenuation  of amygdala growth and differences in the amygdala binding of  [11C]diprenorphine. Interaction models identified significant associations  between specific aberrant social and non-social behaviors, isotope  binding, and vaccine exposure. 

Conclusions: This animal model, which examines for the first time,  behavioral, functional, and neuromorphometric consequences of the  childhood vaccine regimen, mimics certain neurological abnormalities of  autism. The findings raise important safety issues while providing a potential  model for examining aspects of causation and disease pathogenesis in acquired  disorders of behavior and development. 

96. Thimerosal exposure in infants and neurodevelopmental disorders: An  assessment of computerized medical records in the Vaccine Safety Datalink. 

Young HA, Geier DA, Geier MR. 

The George Washington University School of Public Health and Health Services,  Department of Epidemiology and Biostatistics, United States. 

Abstract 

The study evaluated possible associations between neurodevelopmental  disorders (NDs) and exposure to mercury (Hg) from Thimerosal-containing  vaccines (TCVs) by examining the automated Vaccine Safety Datalink (VSD). A  total of 278,624 subjects were identified in birth cohorts from 1990-1996 that had  received their first oral polio vaccination by 3 months of age in the VSD. The birth cohort prevalence rate of medically diagnosed International Classification of  Disease, 9th revision (ICD-9) specific NDs and control outcomes were  calculated. Exposures to Hg from TCVs were calculated by birth cohort for  specific exposure windows from birth-7 months and birth-13 months of age.  Poisson regression analysis was used to model the association between the  prevalence of outcomes and Hg doses from TCVs. Consistent significantly  increased rate ratios were observed for autism, autism spectrum disorders, tics, attention deficit disorder, and emotional disturbances with Hg  exposure from TCVs. By contrast, none of the control outcomes had  significantly increased rate ratios with Hg exposure from TCVs. Routine  childhood vaccination should be continued to help reduce the morbidity and  mortality associated with infectious diseases, but efforts should be undertaken to  remove Hg from vaccines. Additional studies should be conducted to further  evaluate the relationship between Hg exposure and NDs.


97. Glutathione, oxidative stress and neurodegeneration 

Schulz JB, Lindenau J, Seyfried J, Dichgans J. 

Neurodegeneration Laboratory, Department of Neurology, University of Tübingen, Germany. 

Eur J Biochem. 2000 Aug;267(16):4904-11. 

Abstract 

There is significant evidence that the pathogenesis of several  neurodegenerative diseases, including Parkinson's disease, Alzheimer's  disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve  the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that  may either lead to or result from oxidative stress in neurodegenerative disorders.  Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed  for the pathogenesis of Parkinson's disease, because a decrease in total  glutathione concentrations in the substantia nigra has been observed in  preclinical stages, at a time at which other biochemical changes are not yet  detectable. Because glutathione does not cross the blood-brain barrier other  treatment options to increase brain concentrations of glutathione including  glutathione analogs, mimetics or precursors are discussed. 

98. Hepatitis B triple series vaccine and developmental disability in US children aged 1-9 years 

Carolyn Gallagher a; Melody Goodman, Graduate Program in Public Health,  Stony Brook University Medical Center, Health Sciences Center, New York, USA 

Journal Toxicological & Environmental Chemistry, Volume 90, Issue 5 September 2008 , pages 997 - 1008 

Abstract 

This study investigated the association between vaccination with the Hepatitis B  triple series vaccine prior to 2000 and developmental disability in children aged  1–9 years (n = 1824), proxied by parental report that their child receives early  intervention or special education services (EIS). National Health and Nutrition  Examination Survey 1999–2000 data were analyzed and adjusted for survey  design by Taylor Linearization using SAS version 9.1 software, with SAS callable  SUDAAN version 9.0.1. The odds of receiving EIS were approximately nine times as great for vaccinated boys (n = 46) as for unvaccinated boys (n = 7), after  adjustment for confounders. This study found statistically significant  evidence to suggest that boys in United States who were vaccinated with 

the triple series Hepatitis B vaccine, during the time period in which  vaccines were manufactured with thimerosal, were more susceptible to  developmental disability than were unvaccinated boys. 

99. IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination that involves the down-regulation of the IL4 receptor in the hippocampus 

Cytokine 

Xiao Wang, Junhua Yang, Zhiwei Xing, Hongyang Zhang, Yaru Wen, Fangfang  Qi, Zejie Zuo, Jie Xu, Zhibin Yao 

Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun  Yat-sen University, PR China 

Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan  School of Medicine, Sun Yat-sen University, PR China 

ABSTRACT 

We have previously verified that neonatal hepatitis B vaccination induced  hippocampal neuroinflammation and behavior impairments in mice. However, the exact mechanism of these effects remain unclear. In this study, we observed that  neonatal hepatitis B vaccination induced an anti-inflammatory cytokine response  lasting for 4–5 weeks in both the serum and the hippocampus, primarily indicated by elevated IL-4 levels. Three weeks after the vaccination schedule, however,  hepatitis B vaccine (HBV)-mice showed delayed hippocampal  

neuroinflammation. In periphery, IL-4 is the major cytokine induced by this  vaccine. Correlation analyses showed a positive relationship in the IL-4 levels  between serum and hippocampus in HBV-mice. Thus, we investigated whether  neonatal over-exposure to systemic IL-4 influences brain and behavior. We  observed that mice injected intraperitoneally with recombinant mouse IL-4 (mIL 4) during early life had similar neuroinflammation and cognition impairment  similar to those induced by neonatal hepatitis B vaccination. Next, the  mechanism underlying the effects of IL-4 on brain in mice was explored using a  series of experiments. In brief, these experiments showed that IL-4 mediates the  delayed neurobehavioral impairments induced by neonatal hepatitis B  vaccination, which involves the permeability of neonatal blood–brain barrier and  the down-regulation of IL-4 receptor. This finding suggests that clinical events concerning neonatal IL-4 over-exposure, including neonatal hepatitis B  vaccination and allergic asthma in human infants, may have adverse  implications for brain development and cognition.


100. The risk of neurodevelopmental disorders at age 10 years associated with blood concentrations of interleukins 4 and 10 during the first postnatal month of  children born extremely preterm. 

Cytokine. 2018 May 12;110:181-188. doi: 10.1016/j.cyto.2018.05.004.  

Leviton A, Joseph RM, Allred EN, Fichorova RN, O'Shea TM, Kuban KKC,  Dammann O7. 

Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.  Electronic address: alan.leviton@childrens.harvard.edu. 

Boston University School of Medicine, Boston, MA, USA. 

Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. 

University of North Carolina School of Medicine, Chapel Hill, NC, USA. Boston Medical Center and Boston University School of Medicine, Boston, MA,  USA. 

Tufts University School of Medicine, Boston, MA 02111, USA; Perinatal  Neuroepidemiology Unit, Department of Gynecology and Obstetrics, Hannover  Medical School, 30623 Hannover, Germany 

Abstract 

BACKGROUND: 

Interleukin (IL)-4 and IL-10 are viewed mainly as anti-inflammatory cytokines.  Yet, high concentrations have also been associated with inflammation-related  diseases in newborns. 

METHODS: 

We measured the concentrations of IL-4 and IL-10, as well as IL-8 and ICAM-1 in blood specimens collected on postnatal day 21 (N = 555), day 28 (N = 521), and  both days 21 and 28 (N = 449) from children born extremely preterm (EP)  (<28 weeks gestation) who at age 10 years had a DAS-II IQ Z-score > -2 (which  approximates a score of >70) and the following assessments, CCC-2, and CSI-4, DAS-II, NEPSY-II, OWLS-II, SCQ, and WIAT-III. Selected children also were  assessed with the ADI-R and the ADOS-2. We modeled the risk of low scores or  dysfunctions associated with top quartile concentrations of IL-4 and IL-10 on  each day and on both days. 

RESULTS: 

The risks of low scores on the Animal Sorting and Arrows components of the  NEPSY-II, both components of the OWLS-II, and the PseudoWord and Spelling  components of the WIAT-III were heightened among children who had top  quartile concentrations of IL-4 on postnatal days 21 and 28. Children who had  high concentrations of IL-10 on days 21 and 28, individually and collectively,  were at increased risk of low scores on the WIAT-III Spelling component. High  concentrations of IL-4 on day 28 were associated with autism spectrum disorder  (ASD). High concentrations of IL-10 on day 28 were also associated with a  doubling of ASD risk, but this did not achieve statistical significance. Top quartile 

concentrations of IL-4 and IL10 on both days were not associated with increased  risk of social, language, or behavioral dysfunctions. 

CONCLUSION: 

Among children born EP, those who had top quartile concentrations of IL-4  and/or IL-10 on postnatal days 21 and/or 28 were more likely than their  peers to have low scores on components of the NEPSY-II, OWLS-II, and  WIAT-III assessments, as well as identification as having an ASD. 

101. Induction of metallothionein in mouse cerebellum and cerebrum with low dose thimerosal injection. 

Minami T, Miyata E, Sakamoto Y, Yamazaki H, Ichida S., Department of Life  Sciences, School of Science & Engineering, Kinki University, 3-4-1 Kowakae,  Higashi-osaka, Osaka, 577-8502, Japan, minamita@life.kindai.ac.jp. 

Cell Biology and Toxicology. 2009 Apr 9. [Epub ahead of print] 

Abstract 

Thimerosal, an ethyl mercury compound, is used worldwide as a vaccine  preservative. We previously observed that the mercury concentration in mouse  brains did not increase with the clinical dose of thimerosal injection, but the  concentration increased in the brain after the injection of thimerosal with  lipopolysaccharide, even if a low dose of thimerosal was administered.  Thimerosal may penetrate the brain, but is undetectable when a clinical dose of  thimerosal is injected; therefore, the induction of metallothionein (MT) messenger RNA (mRNA) and protein was observed in the cerebellum and cerebrum of mice  after thimerosal injection, as MT is an inducible protein. MT-1 mRNA was  expressed at 6 and 9 h in both the cerebrum and cerebellum, but MT-1 mRNA  expression in the cerebellum was three times higher than that in the cerebrum  after the injection of 12 microg/kg thimerosal. MT-2 mRNA was not expressed  until 24 h in both organs. MT-3 mRNA was expressed in the cerebellum from 6 to 15 h after the injection, but not in the cerebrum until 24 h. MT-1 and MT-3  mRNAs were expressed in the cerebellum in a dose-dependent manner.  Furthermore, MT-1 protein was detected from 6 to 72 h in the cerebellum after 12 microg/kg of thimerosal was injected and peaked at 10 h. MT-2 was detected in  the cerebellum only at 10 h. In the cerebrum, little MT-1 protein was detected at  10 and 24 h, and there were no peaks of MT-2 protein in the cerebrum. In  conclusion, MT-1 and MT-3 mRNAs but not MT-2 mRNA are easily expressed in  the cerebellum rather than in the cerebrum by the injection of low-dose  thimerosal. It is thought that the cerebellum is a sensitive organ against  thimerosal. As a result of the present findings, in combination with the brain pathology observed in patients diagnosed with autism, the present study  helps to support the possible biological plausibility for how low-dose  exposure to mercury from thimerosal-containing vaccines may be  associated with autism.


102                 Mercury induces inflammatory mediator release from human mast cells

 

Duraisamy Kempuraj, Shahrzad Asadi, Bodi Zhang, Akrivi Manola, Jennifer Hogan, Erika Peterson, Theoharis C Theoharides

Journal of Neuroinflammation 2010, 7:20 doi:10.1186/1742-2094-7-20 Abstract

Background: Mercury is known to be neurotoxic, but its effects on the immune

system are less well known. Mast cells are involved in allergic reactions, but also in innate and acquired immunity, as well as in inflammation. Many patients with Autism Spectrum Disorders (ASD) have “allergic” symptoms; moreover, the prevalence of ASD in patients with mastocytosis, characterized by numerous hyperactive mast cells in most tissues, is 10-fold higher than the general population suggesting mast cell involvement. We, therefore, investigated the effect of mercuric chloride (HgCl2) on human mast cell activation.

 

Methods: Human leukemic cultured LAD2 mast cells and normal human umbilical cord bloodderived cultured mast cells (hCBMCs) were stimulated by HgCl2 (0.1- 10 μM) for either 10 min for beta-hexosaminidase release or 24 hr for measuring vascular endothelial growth factor (VEGF) and IL-6 release by ELISA.

 

Results: HgCl2 induced a 2-fold increase in β-hexosaminidase release, and also significant VEGF release at 0.1 and 1 μM (311±32 pg/106 cells and 443±143 pg/106 cells, respectively) from LAD2 mast cells compared to control cells (227±17 pg/106 cells, n=5, p<0.05). Addition of HgCl2 (0.1 μM) to the proinflammatory neuropeptide substance P (SP, 0.1 μM) had synergestic action in inducing VEGF from LAD2 mast cells. HgCl2 also stimulated significant VEGF release (360 ± 100 pg/106 cells at 1 μM, n=5, p<0.05) from hCBMCs compared to control cells (182 ±57 pg/106 cells), and IL-6 release (466±57 pg/106 cells at

0.1 μM) compared to untreated cells (13±25 pg/106 cells, n=5, p<0.05). Addition of HgCl2 (0.1 μM) to SP (5 μM) further increased IL-6 release. Conclusions: HgCl2 stimulates VEGF and IL-6 release from human mast cells. This phenomenon could disrupt the blood-brain-barrier and permit brain inflammation. As a result, the findings of the present study provide a biological mechanism for how low levels of mercury may contribute to ASD pathogenesis.

 

103   Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders

 

Neuroscience

Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute and Department of Psychiatry and Behavioral Sciences, UC Davis School of Medicine, University of California, Sacramento, CA 95817;

Departments of Psychiatry and Biostatistics, Harvard University Schools of Medicine and Public Health, McLean Hospital, Belmont, MA 02478; and Department of Radiology, UC Davis School of Medicine, University of California, Sacramento, CA 95817

 

Proc Natl Acad Sci U S A. 2011 Dec 13; 108(50): 20195–20200.

Published online 2011 Nov 28. doi: 10.1073/pnas.1107560108

 

 

Christine Wu Nordahl, Nicholas Lange, Deana D. Li, Lou Ann Barnett, Aaron Lee, Michael H. Buonocore, Tony J. Simon, Sally Rogers, Sally Ozonoff, and David G. Amarala,

 

ABSTRACT

Autism is a heterogeneous disorder with multiple behavioral and biological phenotypes. Accelerated brain growth during early childhood is a well- established biological feature of autism. Onset pattern, i.e., early onset or regressive, is an intensely studied behavioral phenotype of autism. There is currently little known, however, about whether, or how, onset status maps onto the abnormal brain growth. We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism.

Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4–6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism.

 

 

 

104   Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders

 

Molecular AutismBrain, Cognition and Behavior, Published: 29 November 2016

 

Maria Fiorentino, Anna Sapone, Stefania Senger, Stephanie S. Camhi, Sarah M. Kadzielski, Timothy M. Buie, Deanna L. Kelly, Nicola Cascella and Alessio Fasano

 

Abstract

 

Background

Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene–environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood–brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD.

 

Methods

Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated.

 

Results

Claudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls.

 

Conclusions

In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.

 

 

 

105   Influence of pediatric vaccines on amygdala growth and opioid ligand binding in rhesus macaque infants: A pilot study

 

Acta Neurobiol Exp 2010, 70: 147–164 Polish Neuroscience Society - PTBUN, Nencki Institute of Experimental Biology

 

Laura Hewitson1,2,*, Brian J. Lopresti3, Carol Stott4, N. Scott Mason3 and

Jaime Tomko1

 

Department of Obstetrics and Gynecology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Thoughtful House Center for Children, Austin, TX, USA; Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 4Independent Chartered Scientist, Cambridge, UK;

 

Abstract

This longitudinal, case-control pilot study examined amygdala growth in rhesus macaque infants receiving the complete US childhood vaccine schedule (1994- 1999). Longitudinal structural and functional neuroimaging was undertaken to examine central effects of the vaccine regimen on the developing brain. Vaccine- exposed and saline-injected control infants underwent MRI and PET imaging at approximately 4 and 6 months of age, representing two specific timeframes within the vaccination schedule. Volumetric analyses showed that exposed animals did not undergo the maturational changes over time in amygdala volume that was observed in unexposed animals. After controlling for left amygdala volume, the binding of the opioid antagonist [11C]diprenorphine (DPN) in exposed animals remained relatively constant over time, compared with unexposed animals, in which a significant decrease in [11C]DPN binding occurred. These results suggest that maturational changes in amygdala volume and the binding capacity of [11C]DPN in the amygdala was significantly altered in infant macaques receiving the vaccine schedule.

The macaque infant is a relevant animal model in which to investigate specific environmental exposures and structural/functional neuroimaging during neurodevelopment.

 

 

 

106  Cultured lymphocytes from autistic children and non-autistic siblings up- regulate heat shock protein RNA in response to thimerosal challenge.

 

Neurotoxicology. 2006 Sep;27(5):685-92. Epub 2006 Jun 16. Walker SJ, Segal J, Aschner M.

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27156, USA. swalker@wfubmc.edu

Abstract

 

Abstract

There are reports suggesting that some autistic children are unable to mount an adequate response following exposure to environmental toxins. This potential deficit, coupled with the similarity in clinical presentations of autism and some heavy metal toxicities, has led to the suggestion that heavy metal poisoning might play a role in the etiology of autism in uniquely susceptible individuals.

Thimerosal, an anti-microbial preservative previously added routinely to childhood multi-dose vaccines, is composed of 49.6% ethyl mercury. Based on the levels of this toxin that children receive through routine immunization

schedules in the first years of life, it has been postulated that thimerosal may be a potential triggering mechanism contributing to autism in susceptible individuals. One potential risk factor in these individuals may be an inability to adequately up- regulate metallothionein (MT) biosynthesis in response to presentation of a heavy metal challenge. To investigate this hypothesis, cultured lymphocytes (obtained from the Autism Genetic Resource Exchange, AGRE) from autistic children and non-autistic siblings were challenged with either 10 microM ethyl mercury, 150 microM zinc, or fresh media (control). Following the challenge, total RNA was extracted and used to query "whole genome" DNA microarrays.

Cultured lymphocytes challenged with zinc responded with an impressive up- regulation of MT transcripts (at least nine different MTs were over-expressed) while cells challenged with thimerosal responded by up-regulating numerous heat shock protein transcripts, but not MTs. Although there were no apparent differences between autistic and non-autistic sibling responses in this very small sampling group, the differences in expression profiles between those cells treated with zinc versus thimerosal were dramatic. Determining cellular response, at the level of gene expression, has important implications for the understanding and treatment of conditions that result from exposure to neurotoxic compounds.

 

 

 

107    Sorting out the spinning of autism: heavy metals and the question of incidence

 

Acta Neurobiol Exp 2010, 70: 165–176

 

Mary Catherine DeSoto* and Robert T. Hitlan, Department of Psychology, University of Northern Iowa, Cedar Falls, Iowa, USA

 

The reasons for the rise in autism prevalence are a subject of heated professional debate. Featuring a critical appraisal of some research used to question whether there is a rise in cases and if rising levels of autism are related to environmental

exposure to toxins (Soden et al. 2007, Thompson et al. 2007, Barbaresi et al. 2009) we aim to evaluate the actual state of scientific knowledge. In addition, we surveyed the empirical research on the topic of autism and heavy metal toxins. Overall, the various causes that have led to the increase in autism diagnosis are likely multi-faceted, and understanding the causes is one of the most important health topics today. We argue that scientific research does not support rejecting the link between the neurodevelopmental disorder of autism and toxic exposures.

 

 

 

108    Urinary Porphyrin Excretion in Neurotypical and Autistic Children Environ Health Perspect. 2010 Oct;118(10):1450-7. Epub 2010 Jun 24.

Woods JS, Armel SE, Fulton DI, Allen J, Wessels K, Simmonds PL, Granpeesheh D, Mumper E, Bradstreet JJ, Echeverria D, Heyer NJ, Rooney JP., Department of Environmental and Occupational Health Sciences, University of Washington

 

Abstract

BACKGROUND: Increased urinary concentrations of pentacarboxyl-, precopro- and copro-porphyrins have been associated with prolonged mercury (Hg) exposure in adults, and comparable increases have been attributed to Hg exposure in children with autism (AU).

 

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

 

METHODS: This exploratory study enrolled 278 children 2-12 years of age. We evaluated three groups: AU, pervasive developmental disorder-not otherwise specified (PDD-NOS), and NT. Mothers/caregivers provided information at enrollment regarding medical, dental, and dietary exposures. Urine samples from all children were acquired for analyses of porphyrin, creatinine, and Hg.

Differences between groups for mean porphyrin and Hg levels were evaluated. Logistic regression analysis was conducted to determine whether porphyrin levels were associated with increased risk of autism.

 

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

 

 

 

109  Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

 

Molecular Psychiatry advance online publication 25 January 2011;doi: 10.1038/mp.2010.136

D A Rossignol and R E Frye Abstract

A comprehensive literature search was performed to collate evidence of

mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary

objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (~0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B- vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD.

 

 

 

110   Sensitization effect of thimerosal is mediated in vitro via reactive oxygen species and calcium signaling.

 

Toxicology. 2010 July - August;274(1-3):1-9. Epub 2010 May 10. Migdal C, Foggia L, Tailhardat M, Courtellemont P, Haftek M, Serres M.

Thimerosal, a mercury derivative composed of ethyl mercury chloride (EtHgCl) and thiosalicylic acid (TSA), is widely used as a preservative in vaccines and cosmetic products and causes cutaneous reactions. Since dendritic cells (DCs) play an essential role in the immune response, the sensitization potency of chemicals was studied in vitro using U937, a human promyelomonocytic cell line that is used as a surrogate of monocytic differentiation and activation. Currently, this cell line is under ECVAM (European Center for the Validation of Alternative Methods) validation as an alternative method for discriminating chemicals.

Thimerosal and mercury derivatives induced in U937 an overexpression of CD86 and interleukin (IL)-8 secretion similarly to 1-chloro-2,4-dinitrobenzene (DNCB), a sensitizer used as a positive control for DC activation. Non-sensitizers, dichloronitrobenzene (DCNB), TSA and sodium dodecyl sulfate (SDS), an irritant, had no effect. U937 activation was prevented by cell pretreatment with N-acetyl-l- cysteine (NAC) but not with thiol-independent antioxidants except vitamin E which affected CD86 expression by preventing lipid peroxidation of cell membranes. Thimerosal, EtHgCl and DNCB induced glutathione (GSH) depletion and reactive oxygen species (ROS) within 15min; another peak was detected after 2h for mercury compounds only. MitoSOX, a specific mitochondrial fluorescent probe, confirmed that ROS were essentially produced by mitochondria in correlation with its membrane depolarization. Changes in mitochondrial membrane permeability induced by mercury were reversed by NAC but not by thiol-independent antioxidants. Thimerosal and EtHgCl also induced a calcium (Ca(2+)) influx with a peak at 3h, suggesting that Ca(2+) influx is a secondary event following ROS induction as Ca(2+) influx was suppressed after pretreatment with NAC but not with thiol-independent antioxidants. Ca(2+) influx was also suppressed when culture medium was deprived of Ca(2+) confirming the specificity of the measure. In conclusion, these data suggest that thimerosal induced U937 activation via oxidative stress from mitochondrial stores and mitochondrial membrane depolarization with a primordial effect of thiol groups. A cross-talk between ROS and Ca(2+) influx was demonstrated.

 

 

 

111              What's going on? The question of time trends in autism.

 

Public Health Rep. 2004 Nov-Dec;119(6):536-51. Blaxill MF.

Abstract

Increases in the reported prevalence of autism and autistic spectrum disorders in recent years have fueled concern over possible environmental causes. The author reviews the available survey literature and finds evidence of large increases in prevalence in both the United States and the United Kingdom that cannot be explained by changes in diagnostic criteria or improvements in case ascertainment. Incomplete ascertainment of autism cases in young child populations is the largest source of predictable bias in prevalence surveys; however, this bias has, if anything, worked against the detection of an upward trend in recent surveys. Comparison of autism rates by year of birth for specific geographies provides the strongest basis for trend assessment. Such comparisons show large recent increases in rates of autism and autistic spectrum disorders in both the U.S. and the U.K. Reported rates of autism in the United States increased from < 3 per 10,000 children in the 1970s to > 30 per 10,000 children in the 1990s, a 10-fold increase. In the United Kingdom, autism rates rose from < 10 per 10,000 in the 1980s to roughly 30 per 10,000 in the 1990s. Reported rates for the full spectrum of autistic disorders rose from the 5 to 10 per 10,000 range to the 50 to 80 per 10,000 range in the two countries. A

precautionary approach suggests that the rising incidence of autism should be a matter of urgent public concern.

 

 

112                     Vaccines and Autism

 

Laboratory medicine, September 2002, number 9, volume 33 Bernard Rimland, PhD, Woody McGinnis, MD

Autism Research Institute, San Diego, CA

 

Excerpt: "Vaccinations may be one of the triggers for autism. Substantial data demonstrate immune abnormality in many autistic children consistent with impaired resistance to infection, activation of inflammatory response, and autoimmunity. Impaired resistance may predispose to vaccine injury in autism."

 

 

 

113                    Theoretical aspects of autism: Causes—A review

 

Journal of Immunotoxicology, January-March 2011, Vol. 8, No. 1 , Pages 68-79 Helen V. Ratajczak, PhD

Autism, a member of the pervasive developmental disorders (PDDs), has been increasing dramatically since its description by Leo Kanner in 1943. First estimated to occur in 4 to 5 per 10,000 children, the incidence of autism is now 1 per 110 in the United States, and 1 per 64 in the United Kingdom, with similar incidences throughout the world. Searching information from 1943 to the present in PubMed and Ovid Medline databases, this review summarizes results that correlate the timing of changes in incidence with environmental changes. Autism could result from more than one cause, with different manifestations in different individuals that share common symptoms. Documented causes of autism include genetic mutations and/or deletions, viral infections, and encephalitis following vaccination. Therefore, autism is the result of genetic defects and/or inflammation of the brain. The inflammation could be caused by a defective placenta, immature blood-brain barrier, the immune response of the mother to infection while pregnant, a premature birth, encephalitis in the child after birth, or a toxic environment.

 

 

 

114  Preterm birth, vaccination and neurodevelopmental disorders: a cross- sectional study of 6- to 12-year-old vaccinated and unvaccinated children

 

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

 

J Transl Sci 3: DOI: 10.15761/JTS.1000187, April 24, 2017

 

Abstract

From about 8% to 27% of extremely preterm infants develop symptoms of autism spectrum disorder, but the causes are not well understood. Preterm infants receive the same doses of the recommended vaccines and on the same schedule as term infants. The possible role of vaccination in neurodevelopmental disorders (NDD) among premature infants is unknown, in part because pre- licensure clinical trials of pediatric vaccines have excluded ex-preterm infants.

This paper explores the association between preterm birth, vaccination and NDD, based on a secondary analysis of data from an anonymous survey of mothers, comparing the birth history and health outcomes of vaccinated and unvaccinated homeschool children 6 to 12 years of age. A convenience sample of 666 children was obtained, of which 261 (39%) were unvaccinated, 7.5% had an NDD (defined as a learning disability, Attention Deficit Hyperactivity Disorder and/or Autism Spectrum Disorder), and 7.7% were born preterm. No association was found between preterm birth and NDD in the absence of vaccination, but vaccination was significantly associated with NDD in children born at term (OR 2.7, 95% CI: 1.2, 6.0). However, vaccination coupled with preterm birth was associated with increasing odds of NDD, ranging from 5.4 (95% CI: 2.5, 11.9) compared to vaccinated but non-preterm children, to 14.5 (95% CI: 5.4, 38.7) compared to children who were neither preterm nor vaccinated.

The results of this pilot study suggest clues to the epidemiology and causation of NDD but question the safety of current vaccination practices for preterm infants. Further research is needed to validate and investigate these associations in order to optimize the impact of vaccines on children’s health.

 

 

 

115  Iatrogenic exposure to mercury after hepatitis B vaccination in preterm infants

 

The Journal of Pediatrics, Volume 136, Issue 5, May 2000, Pages 679–681

 

Gregory V. Stajich, PharmD, Gaylord P. Lopez, PharmD, ABAT, Sokei W. Harry, MBBS, MPH, William R. Sexson, MD

Mercer University, Southern School of Pharmacy, Atlanta, Georgia; Georgia Poison Center, Grady Health System, Atlanta; Georgia Poison Center, Georgia Health System, Atlanta and Emory University, School of Medicine, Atlanta, Georgia.

 

Thimerosal, a derivative of mercury, is used as a preservative in hepatitis B vaccines. We measured total mercury levels before and after the administration of this vaccine in 15 preterm and 5 term infants. Comparison of pre- and post-

vaccination mercury levels showed a significant increase in both preterm and term infants after vaccination. Additionally, post-vaccination mercury levels were significantly higher in preterm infants as compared with term infants. Because mercury is known to be a potential neurotoxin to infants, further study of its pharmacodynamics is warranted.

 

 

 

116 Infants born late/moderately preterm are at increased risk for a positive autism screen at 2 years of age.

 

J Pediatr. 2015 Feb;166(2):269-75.e3. doi: 10.1016/j.jpeds.2014.10.053. Epub 2014 Dec 2.

 

Guy A1, Seaton SE2, Boyle EM2, Draper ES2, Field DJ2, Manktelow BN2, Marlow N3, Smith LK2, Johnson S4.

 

1Department of Health Sciences, University of Leicester, Leicester, United Kingdom; School of Psychology, University of Warwick, Coventry, United Kingdom.

2Department of Health Sciences, University of Leicester, Leicester, United Kingdom.

3Department of Academic Neonatology, Institute for Women's Health, University College London, London, United Kingdom.

4Department of Health Sciences, University of Leicester, Leicester, United Kingdom. Electronic address: sjj19@le.ac.uk.

 

Abstract OBJECTIVES:

To assess the prevalence of positive screens using the Modified Checklist for Autism in Toddlers (M-CHAT) questionnaire and follow-up interview in late and moderately preterm (LMPT; 32-36 weeks) infants and term-born controls.

STUDY DESIGN:

Population-based prospective cohort study of 1130 LMPT and 1255 term-born infants. Parents completed the M-CHAT questionnaire at 2-years corrected age. Parents of infants with positive questionnaire screens were followed up with a telephone interview to clarify failed items. The M-CHAT questionnaire was re- scored, and infants were classified as true or false positives. Neurosensory, cognitive, and behavioral outcomes were assessed using parent report.

RESULTS:

Parents of 634 (57%) LMPT and 761 (62%) term-born infants completed the M- CHAT questionnaire. LMPT infants had significantly higher risk of a positive questionnaire screen compared with controls (14.5% vs 9.2%; relative risk [RR] 1.58; 95% CI 1.18, 2.11). After follow-up, significantly more LMPT infants than

controls had a true positive screen (2.4% vs 0.5%; RR 4.52; 1.51, 13.56). This remained significant after excluding infants with neurosensory impairments (2.0% vs 0.5%; RR 3.67; 1.19, 11.3).

CONCLUSIONS:

LMPT infants are at significantly increased risk for positive autistic screen. An M-CHAT follow-up interview is essential as screening for autism spectrum disorders is especially confounded in preterm populations. Infants with false positive screens are at risk for cognitive and behavioral problems.

 

 

 

117  Preterm birth and mortality and morbidity: a population-based quasi- experimental study.

 

JAMA Psychiatry. 2013 Nov;70(11):1231-40. doi: 10.1001/jamapsychiatry.2013.2107.

 

D'Onofrio BM1, Class QA, Rickert ME, Larsson H, Långström N, Lichtenstein P.

 

Department of Psychological and Brain Sciences, Indiana University- Bloomington.

 

Abstract IMPORTANCE:

Preterm birth is associated with increased mortality and morbidity. However, previous studies have been unable to rigorously examine whether confounding factors cause these associations rather than the harmful effects of being born preterm.

OBJECTIVE:

To estimate the extent to which the associations between early gestational age and offspring mortality and morbidity are the result of confounding factors by using a quasi-experimental design, the sibling-comparison approach, and by controlling for statistical covariates that varied within families.

DESIGN, SETTING, AND PARTICIPANTS:

A population-based cohort study, combining Swedish registries to identify all individuals born in Sweden from 1973 to 2008 (3,300,708 offspring of 1,736,735 mothers) and link them with multiple outcomes.

MAIN OUTCOMES AND MEASURES:

Offspring mortality (during infancy and throughout young adulthood) and psychiatric (psychotic or bipolar disorder, autism, attention-deficit/hyperactivity disorder, suicide attempts, substance use, and criminality), academic (failing grades and educational attainment), and social (partnering, parenthood, low income, and social welfare benefits) outcomes through 2009.

RESULTS:

In the population, there was a dose-response relationship between early gestation and the outcome measures. For example, extreme preterm birth (23- 27 weeks of gestation) was associated with infant mortality (odds ratio, 288.1; 95% CI, 271.7-305.5), autism (hazard ratio [HR], 3.2; 95% CI, 2.6-4.0),

low educational attainment (HR, 1.7; 1.5-2.0), and social welfare benefits (HR, 1.3; 1.2-1.5) compared with offspring born at term. The associations between early gestation and mortality and psychiatric morbidity generally were robust when comparing differentially exposed siblings and controlling for statistical covariates, whereas the associations with academic and some social problems were greatly or completely attenuated in the fixed-effects models.

CONCLUSIONS AND RELEVANCE:

The mechanisms responsible for the associations between preterm birth and mortality and morbidity are outcome-specific. Associations between preterm birth and mortality and psychiatric morbidity are largely independent of shared familial confounds and measured covariates, consistent with a causal inference.

However, some associations, particularly predicting suicide attempt, educational attainment, and social welfare benefits, are the result of confounding factors. The findings emphasize the importance of both reducing preterm birth and providing wraparound services to all siblings in families with an offspring born preterm.

 

 

 

118  Ancestry of pink disease (infantile acrodynia) identified as a risk factor for autism spectrum disorders.

goal

J Toxicol Environ Health A. 2011 Sep 15;74(18):1185-94. Shandley K, Austin DW.

 

Swinburne Autism Bio-Research Initiative (SABRI), Brain and Psychological Sciences Research Centre , Swinburne University of Technology , Hawthorn , Victoria , Australia.

 

Abstract

Pink disease (infantile acrodynia) was especially prevalent in the first half of the 20th century. Primarily attributed to exposure to mercury (Hg) commonly found in teething powders, the condition was developed by approximately 1 in 500 exposed children. The differential risk factor was identified as an idiosyncratic sensitivity to Hg. Autismspectrum disorders (ASD) have also been postulated to be produced by Hg. Analogous to the pink disease experience, Hg exposure is widespread yet only a fraction of exposed children develop an ASD, suggesting sensitivity to Hg may also be present in children with an ASD. The objective of this study was to test the hypothesis that individuals with a known hypersensitivity to Hg (pink disease survivors) may be more likely to have descendants with an ASD. Five hundred and twenty-two participants who had previously been diagnosed with pink disease completed a survey on the health outcomes of their descendants. The prevalence rates of ASD and a variety of other clinical conditions diagnosed in childhood (attention deficit hyperactivity disorder, epilepsy, Fragile X syndrome, and Down syndrome) were compared to well-established general population prevalence rates. The results showed the prevalence rate of ASD among the grandchildren of pink disease survivors (1 in 22) to be significantly higher than the comparable general population prevalence rate (1 in 160). The results support the hypothesis that Hg sensitivity may be a heritable/genetic risk factor for ASD.

 

 

 

119 Risk Factors for Autistic Regression: Results of an Ambispective Cohort Study.

J Child Neurol. 2012 Jan 30. [Epub ahead of print]

 

Zhang Y, Xu Q, Liu J, Li SC, Xu X., Department of Child Health Care, Children's Hospital of Fudan University,Shanghai, China.

 

Abstract

A subgroup of children diagnosed with autism experience developmental regression featured by a loss of previously acquired abilities. The pathogeny of autistic regression is unknown, although many risk factors likely exist. To better characterize autistic regression and investigate the association between autistic regression and potential influencing factors in Chinese autistic children, we conducted an ambispective study with a cohort of 170 autistic subjects.

Analyses by multiple logistic regression showed significant correlations between autistic regression and febrile seizures (OR = 3.53, 95% CI = 1.17- 10.65, P = .025), as well as with a family history of neuropsychiatric disorders (OR = 3.62, 95% CI = 1.35-9.71, P = .011). This study suggests that febrile seizures and family history of neuropsychiatric disorders are correlated with autistic regression.

 

 

 

120  Early Seizures Prematurely Unsilence Auditory Synapses to Disrupt Thalamocortical Critical Period Plasticity.

 

Cell Rep. 2018 May 29;23(9):2533-2540. doi: 10.1016/j.celrep.2018.04.108.

 

Sun H, Takesian AE, Wang TT, Lippman-Bell JJ, Hensch TK, Jensen FE.

 

Department of Neurology, Perelman School of Medicine, University of Pennsylvania

 

F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School

Department of Neuroscience, Carleton University Abstract

Heightened neural excitability in infancy and childhood results in increased

susceptibility to seizures. Such early-life seizures are associated with language deficits and autism that can result from aberrant development of the auditory cortex. Here, we show that early-life seizures disrupt a critical period (CP) for tonotopic map plasticity in primary auditory cortex (A1). We show that this CP is characterized by a prevalence of "silent," NMDA-receptor (NMDAR)-only, glutamate receptor synapses in auditory cortex that become "unsilenced" due to activity-dependent AMPA receptor (AMPAR) insertion.

Induction of seizures prior to this CP occludes tonotopic map plasticity by prematurely unsilencing NMDAR-only synapses. Further, brief treatment with the AMPAR antagonist NBQX following seizures, prior to the CP, prevents synapse unsilencing and permits subsequent A1 plasticity. These findings reveal that

early-life seizures modify CP regulators and suggest that therapeutic targets for early post-seizure treatment can rescue CP plasticity.

 

 

 121  MMR vaccination and febrile seizures: evaluation of susceptible subgroups and long-term prognosis.

 

Vestergaard M1, Hviid A, Madsen KM, Wohlfahrt J, Thorsen P, Schendel D, Melbye M, Olsen J.

 

JAMA. 2004 Jul 21;292(3):351-7.

 

Abstract CONTEXT:

The rate of febrile seizures increases following measles, mumps, and rubella (MMR) vaccination but it is unknown whether the rate varies according to personal or family history of seizures, perinatal factors, or socioeconomic status. Furthermore, little is known about the long-term outcome of febrile seizures following vaccination.

OBJECTIVES:

To estimate incidence rate ratios (RRs) and risk differences of febrile seizures following MMR vaccination within subgroups of children and to evaluate the clinical outcome of febrile seizures following vaccination.

DESIGN, SETTING, AND PARTICIPANTS:

A population-based cohort study of all children born in Denmark between January 1, 1991, and December 31, 1998, who were alive at 3 months; 537,171 children were followed up until December 31, 1999, by using data from the Danish Civil Registration System and 4 other national registries.

MAIN OUTCOME MEASURES:

Incidence of first febrile seizure, recurrent febrile seizures, and subsequent epilepsy.

RESULTS:

A total of 439,251 children (82%) received MMR vaccination and 17,986 children developed febrile seizures at least once; 973 of these febrile seizures occurred within 2 weeks of MMR vaccination. The RR of febrile seizures increased during the 2 weeks following MMR vaccination (2.75; 95% confidence interval [CI], 2.55- 2.97), and thereafter was close to the observed RR for nonvaccinated children.

The RR did not vary significantly in the subgroups of children that had been defined by their family history of seizures, perinatal factors, or socioeconomic status. At 15 to 17 months, the risk difference of febrile seizures within 2 weeks following MMR vaccination was 1.56 per 1000 children overall (95% CI, 1.44-

1.68), 3.97 per 1000 (95% CI, 2.90-5.40) for siblings of children with a history of

febrile seizures, and 19.47 per 1000 (95% CI, 16.05-23.55) for children with a personal history of febrile seizures. Children with febrile seizures following MMR vaccinations had a slightly increased rate of recurrent febrile seizures (RR, 1.19; 95% CI, 1.01-1.41) but no increased rate of epilepsy (RR, 0.70; 95% CI, 0.33- 1.50) compared with children who were nonvaccinated at the time of their first febrile seizure.

CONCLUSIONS:

MMR vaccination was associated with a transient increased rate of febrile seizures but the risk difference was small even in high-risk children. The long- term rate of epilepsy was not increased in children who had febrile seizures following vaccination compared with children who had febrile seizures of a different etiology.

 

 

 

122  Common variants associated with general and MMR vaccine–related febrile seizures

 

Bjarke Feenstra, Björn Pasternak, Frank Geller, Lisbeth Carstensen, Tongfei Wang, Fen Huang, Jennifer L Eitson, Mads V Hollegaard, Henrik Svanström, Mogens Vestergaard, David M Hougaard, John W Schoggins, Lily Yeh Jan, Mads Melbye & Anders Hviid

 

Nature Genetics (2014) doi:10.1038/ng.3129

 

Received 20 May 2014 Accepted 03 October 2014 Published online 26 October

2014

 

Abstract

Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination. We conducted a series of genome- wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259: P = 5.9 × 10−12 versus controls, P = 1.2 × 10−9 versus MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653: P = 9.6 × 10−11 versus controls, P = 1.6 × 10−9 versus MMR-unrelated febrile seizures). Furthermore, four loci were associated with febrile seizures in general, implicating the sodium channel genes SCN1A (rs6432860: P = 2.2 × 10−16) and SCN2A (rs3769955: P

= 3.1 × 10−10), a TMEM16 family gene (ANO3; rs114444506: P = 3.7 × 10−20)

and a region associated with magnesium levels (12q21.33; rs11105468: P = 3.4

× 10−11). Finally, we show the functional relevance of ANO3 (TMEM16C) with electrophysiological experiments in wild-type and knockout rats.

 

 

 

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

 

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

 

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

 

Abstract BACKGROUND:

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

 

METHODS:

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

 

RESULTS:

Four to 12 days post 12 month vaccination, children had a 1.33 (1.29-1.38) increased relative incidence of the combined endpoint compared to the control period, or at least one event during the risk interval for every 168 children vaccinated. Ten to 12 days post 18 month vaccination, the relative incidence was

1.25 (95%, 1.17-1.33) which represented at least one excess event for every 730 children vaccinated. The primary reason for increased events was statistically significant elevations in emergency room visits following all vaccinations. There were non-significant increases in hospital admissions. There were an additional 20 febrile seizures for every 100,000 vaccinated at 12 months.

 

CONCLUSIONS:

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

 

 

 

124         Reduced GABAergic Action in the Autistic Brain.

 

Curr Biol. 2015 Dec 16. pii: S0960-9822(15)01413-X. doi: 10.1016/j.cub.2015.11.019.

 

Robertson CE1, Ratai EM2, Kanwisher N3.

 

1Harvard Society of Fellows, Harvard University, Cambridge, MA 02138, USA; McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02138, USA. Electronic address: carolinerobertson@fas.harvard.edu.

2Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

3McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02138, USA.

Abstract

An imbalance between excitatory/inhibitory neurotransmission has been posited as a central characteristic of the neurobiology of autism [1], inspired in part by the striking prevalence of seizures among individuals with the disorder [2]. Evidence supporting this hypothesis has specifically implicated the signaling pathway of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), in this putative imbalance: GABA receptor genes have been associated with autism in linkage and copy number variation studies [3-7], fewer GABA receptor subunits have been observed in the post-mortem tissue of autistic individuals [8, 9], and GABAergic signaling is disrupted across heterogeneous mouse models of autism [10]. Yet, empirical evidence supporting this hypothesis in humans is lacking, leaving a gulf between animal and human studies of the condition. Here, we present a direct link between GABA signaling and autistic perceptual symptomatology. We first demonstrate a robust, replicated autistic deficit in binocular rivalry [11], a basic visual function that is thought to rely on the balance of excitation/inhibition in visual cortex [12-15]. Then, using magnetic resonance spectroscopy, we demonstrate a tight linkage between binocular rivalry dynamics in typical participants and both GABA and glutamate levels in the visual cortex. Finally, we show that the link between GABA and binocular rivalry dynamics is completely and specifically absent in autism. These results suggest a disruption in inhibitory signaling in the autistic brain and forge a translational path between animal and human models of the condition.

 

 

 

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

 

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

 

Duszczyk-Budhathoki M, Olczak M, Lehner M, Majewska MD. Marie Curie Chairs Program, Department of Pharmacology and Physiology of Nervous System, Institute of Psychiatry and Neurology, 02-957, Warsaw, Poland.

 

Abstract

Thimerosal, a mercury-containing vaccine preservative, is a suspected factor in the etiology of neurodevelopmental disorders. We previously showed that its administration to infant rats causes behavioral, neurochemical and neuropathological abnormalities similar to those present in autism. Here we examined, using microdialysis, the effect of thimerosal on extracellular levels of neuroactive amino acids in the rat prefrontal cortex (PFC). Thimerosal administration (4 injections, i.m., 240 μg Hg/kg on postnatal days 7, 9, 11, 15) induced lasting changes in amino acid overflow: an increase of glutamate and aspartate accompanied by a decrease of glycine and alanine; measured 10-14 weeks after the injections. Four injections of thimerosal at a dose of 12.5 μg Hg/kg did not alter glutamate and aspartate concentrations at microdialysis time (but based on thimerosal pharmacokinetics, could have been effective soon after its injection). Application of thimerosal to the PFC in perfusion fluid evoked a rapid increase of glutamate overflow. Coadministration of the neurosteroid,

dehydroepiandrosterone sulfate (DHEAS; 80 mg/kg; i.p.) prevented the thimerosal effect on glutamate and aspartate; the steroid alone had no influence on these amino acids. Coapplication of DHEAS with thimerosal in perfusion fluid also blocked the acute action of thimerosal on glutamate. In contrast, DHEAS alone reduced overflow of glycine and alanine, somewhat potentiating the thimerosal effect on these amino acids. Since excessive accumulation of extracellular glutamate is linked with excitotoxicity, our data imply that neonatal exposure to thimerosal-containing vaccines might induce excitotoxic brain injuries, leading to neurodevelopmental disorders. DHEAS may partially protect against mercurials-induced neurotoxicity.

 

 

 

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

 

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

 

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

 

Abstract

Thimerosal added to some pediatric vaccines is suspected in pathogenesis of several neurodevelopmental disorders. Our previous study showed that thimerosal administered to suckling rats causes persistent, endogenous opioid- mediated hypoalgesia. Here we examined, using immunohistochemical staining technique, the density of μ-opioid receptors (MORs) in the brains of rats, which in the second postnatal week received four i.m. injections of thimerosal at doses 12, 240, 1,440 or 3,000 μg Hg/kg. The periaqueductal gray, caudate putamen and hippocampus were examined. Thimerosal administration caused dose- dependent statistically significant increase in MOR densities in the periaqueductal gray and caudate putamen, but decrease in the dentate gyrus, where it was accompanied by the presence of degenerating neurons and loss of synaptic vesicle marker (synaptophysin). These data document that exposure to thimerosal during early postnatal life produces lasting alterations in the densities of brain opioid receptors along with other neuropathological changes, which may disturb brain development.

 

 

 

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

 

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

 

Mary Holland, Louis Conte, Robert Krakow and Lisa Colin

 

Executive Summary

In 1986, Congress created the Vaccine Injury Compensation Program (VICP) under the National Childhood Vaccine Injury Act (1986 Law). This Program has original jurisdiction for children’s claims of vaccine injury. Because almost all children receive multiple vaccinations for daycare and school, it is critically important that the Program provides fundamental fairness, due process and transparency.

 

This empirical investigation, published in a peer-reviewed law journal, examines claims that the VICP compensated for vaccine-induced encephalopathy and seizure disorder. The VICP has compensated approximately 2,500 claims of vaccine injury since the inception of the program. This study found 83 cases of acknowledged vaccine-induced brain damage that include autism, a disorder that affects speech, social communication and behavior. In 21 published cases of the Court of Federal Claims, which administers the VICP, the Court stated that the petitioners had autism or described autism unambiguously. In 62 remaining cases, the authors identified settlement agreements where Health and Human Services (HHS) compensated children with vaccine-induced brain damage, who also have autism or an autism spectrum disorder.

 

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

 

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

 

Using publicly available information, the investigation shows that the VICP has been compensating cases of vaccine-induced brain damage associated with autism for more than twenty years. This investigation suggests that officials at HHS, the Department of Justice and the Court of Federal Claims may have been aware of this association but failed to publicly disclose it.

 

The study calls on Congress to thoroughly investigate the VICP, including a medical investigation of compensated claims of vaccine injury. This investigation calls on Congress to get answers to these critically important unanswered questions.

 

 

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

 

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

 

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

 

Abstract

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

 

 

 

129  Hepatitis B vaccine induces apoptotic death in Hepa1-6 cells Apoptosis. 2012 Jan 17. Hamza H, Cao J, Li X, Li C, Zhu M, Zhao S.

Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China, Heyam68_hamza@yahoo.com.

 

Abstract

Vaccines can have adverse side-effects, and these are predominantly associated with the inclusion of chemical additives such as aluminum hydroxide adjuvant.

The objective of this study was to establish an in vitro model system amenable to

mechanistic investigations of cytotoxicity induced by hepatitis B vaccine, and to investigate the mechanisms of vaccine-induced cell death. The mouse liver hepatoma cell line Hepa1-6 was treated with two doses of adjuvanted (aluminium hydroxide) hepatitis B vaccine (0.5 and 1 μg protein per ml) and cell integrity was measured after 24, 48 and 72 h. Hepatitis B vaccine exposure increased cell apoptosis as detected by flow cytometry and TUNEL assay. Vaccine exposure was accompanied by significant increases in the levels of activated caspase 3, a key effector caspase in the apoptosis cascade. Early transcriptional events were detected by qRT-PCR. We report that hepatitis B vaccine exposure resulted in significant upregulation of the key genes encoding caspase 7, caspase 9, Inhibitor caspase-activated DNase (ICAD), Rho-associated coiled-coil containing protein kinase 1 (ROCK-1), and Apoptotic protease activating factor 1 (Apaf-1).

Upregulation of cleaved caspase 3,7 were detected by western blot in addition to Apaf-1 and caspase 9 expressions argues that cell death takes place via the intrinsic apoptotic pathway in which release of cytochrome c from the mitochondria triggers the assembly of a caspase activation complex. We conclude that exposure of Hepa1-6 cells to a low dose of adjuvanted hepatitis B vaccine leads to loss of mitochondrial integrity, apoptosis induction, and cell death, apoptosis effect was observed also in C2C12 mouse myoblast cell line after treated with low dose of vaccine (0.3, 0.1,

0.05 μg/ml). In addition In vivo apoptotic effect of hepatitis B vaccine was observed in mouse liver.

 

 

 

130Thimerosal Induces Apoptosis in a Neuroblastoma Model via the cJun N- Terminal Kinase Pathway.

 

Toxicological Sciences 92 (1). 246-253

 

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

 

 

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

 

EXCERPT: In recent years, controversy has surrounded the use of thimerosal in vaccines as mercury is a known neurotoxin and nephrotoxin. Since the controversy began in the late 1990's, much of the thimerosal has been removed from vaccines administered to children in the United States. However, it remains in some, such as the influenza vaccine, and is added to multidose vials used in countries around the world. Studies concentrating on thimerosal-induced neurotoxicity are limited, and exposure guidelines, such as those set by the Food and Drug Administration, are based on research with methylmercury.

Interestingly, some in vitro and in vivo studies suggest that ethylmercury may react differently than methylmercury (Aschner and Aschner, 1990; Harry et al., 2004; Magos et al., 1985). Few studies with thimerosal have focused on determining specific signaling pathways involved in neurotoxicity. Establishing these pathways may be an important step in discovering methods of alleviating

toxic outcomes in patients exposed to thimerosal….Our study is the first demonstration that thimerosal can induce the activation of JNK and AP-1 in the SK-N-SH neuroblastoma cell line. We showed that activation of cJun and AP-1 transcriptional activity following thimerosal treatment does not appear to be involved in the induction of apoptosis, as demonstrated with the studies using the cJun dominant negative. Furthermore, we were able to show that JNK is an essential upstream component of this pathway through the use of the JNK inhibitor SP600125. This compound was able to attenuate activation of downstream components of mitochondrial-mediated cell death and subsequently protect the cells from apoptosis. These results are significant because identifying specific signaling pathways activated in response to thimerosal exposure presents pharmacological targets for attenuating potential toxicity in patients exposed to thimerosal-containing products.

 

 

 

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

 

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

 

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

 

Abstract

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

 

 

 

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

 

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

 

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

 

Abstract

BACKGROUND:

Autism prevalence in California, based on individuals eligible for state-funded services, rose throughout the 1990s. The extent to which this trend is explained by changes in age at diagnosis or inclusion of milder cases has not been previously evaluated.

METHODS:

Autism cases were identified from 1990 through 2006 in databases of the California Department of Developmental Services, which coordinates services for individuals with specific developmental disorders. The main outcomes were population incident cases younger than age 10 years for each quarter, cumulative incidence by age and birth year, age-specific incidence rates stratified by birth year, and proportions of diagnoses by age across birth years.

RESULTS:

Autism incidence in children rose throughout the period. Cumulative incidence to 5 years of age per 10,000 births rose consistently from 6.2 for 1990 births to 42.5 for 2001 births. Age-specific incidence rates increased most steeply for 2- and 3- year olds. The proportion diagnosed by age 5 years increased only slightly, from 54% for 1990 births to 61% for 1996 births. Changing age at diagnosis can explain a 12% increase, and inclusion of milder cases, a 56% increase.

CONCLUSIONS:

Autism incidence in California shows no sign yet of plateauing. Younger ages at diagnosis, differential migration, changes in diagnostic criteria, and inclusion of milder cases do not fully explain the observed increases. Other artifacts have yet to be quantified, and as a result, the extent to which the continued rise represents a true increase in the occurrence of autism remains unclear.

 

 

 

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

 

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

 

Author Affiliations

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

 

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

 

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

 

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

 

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

 

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

 

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

Abstract Background

Long-term biodistribution of nanomaterials used in medicine is largely unknown. This is the case for alum, the most widely used vaccine adjuvant, which is a nanocrystalline compound spontaneously forming micron/submicron-sized agglomerates. Although generally well tolerated, alum is occasionally detected within monocyte-lineage cells long after immunization in presumably susceptible individuals with systemic/neurologic manifestations or autoimmune (inflammatory) syndrome induced by adjuvants (ASIA).

Methods:

On the grounds of preliminary investigations in 252 patients with alum-associated ASIA showing both a selective increase of circulating CCL2, the major monocyte

chemoattractant, and a variation in the CCL2 gene, we designed mouse experiments to assess biodistribution of vaccine-derived aluminum and of alum- particle fluorescent surrogates injected in muscle. Aluminum was detected in tissues by Morin stain and particle induced X-ray emission) (PIXE) Both 500 nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids (Al- Rho) were used.

Results:

Intramuscular injection of alum-containing vaccine was associated with the appearance of aluminum deposits in distant organs, such as spleen and brain where they were still detected one year after injection. Both fluorescent materials injected into muscle translocated to draining lymph nodes (DLNs) and thereafter were detected associated with phagocytes in blood and spleen.

Particles linearly accumulated in the brain up to the six-month endpoint; they were first found in perivascular CD11b+ cells and then in microglia and other neural cells. DLN ablation dramatically reduced the biodistribution. Cerebral translocation was not observed after direct intravenous injection, but significantly increased in mice with chronically altered blood-brain-barrier. Loss/gain-of- function experiments consistently implicated CCL2 in systemic diffusion of Al-Rho particles captured by monocyte-lineage cells and in their subsequent neurodelivery. Stereotactic particle injection pointed out brain retention as a factor of progressive particle accumulation.

Conclusion

Nanomaterials can be transported by monocyte-lineage cells to DLNs, blood and spleen, and, similarly to HIV, may use CCL2-dependent mechanisms to penetrate the brain. This occurs at a very low rate in normal conditions explaining good overall tolerance of alum despite its strong neurotoxic potential. However, continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in the case of overimmunization or immature/altered blood brain barrier or high constitutive CCL-2 production.

 

 

 

134  Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders

 

Maria Fiorentino, Anna Sapone, Stefania Senger, Stephanie S. Camhi, Sarah M. Kadzielski, Timothy M. Buie, Deanna L. Kelly, Nicola Cascella & Alessio Fasano

Molecular Autism volume 7, Article number: 49 (2016) Abstract

Background

Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene–environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood–brain barrier (BBB), can be part of the chain of events leading to these disorders. Our

goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD.

 

Methods

Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated.

 

Results

Claudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls.

 

Conclusions

In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.

 

 

 

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

Med Hypotheses. 2004;62(5):788-94. Blaxill MF, Redwood L, Bernard S. Abstract

The autism-mercury hypothesis first described by Bernard et al. has generated much interest and controversy. The Institute of Medicine (IOM) reviewed the connection between mercury-containing vaccines and neurodevelopmental disorders, including autism. They concluded that the hypothesis was biologically plausible but that there was insufficient evidence to accept or reject a causal connection and recommended a comprehensive research program. Without citing new experimental evidence, a number of observers have offered opinions on the subject, some of which reject the IOM's conclusions. In a recent review, Nelson and Bauman argue that a link between the preservative thimerosal, the source of the mercury in childhood vaccines, is improbable. In their defense of thimerosal, these authors take a narrow view of the original hypothesis, provide

no new evidence, and rely on selective citations and flawed reasoning. We provide evidence here to refute the Nelson and Bauman critique and to defend the autism-mercury hypothesis.

 

 

 

136Autism Spectrum Disorders in Relation to Distribution of Hazardous Air Pollutants in the SF Bay Area

 

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

 

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

 

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

 

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

 

 

 

137 Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas

 

Health Place. 2006 Jun;12(2):203-9.

 

Palmer RF, Blanchard S, Stein Z, Mandell D, Miller C.

 

University of Texas Health Science Center, San Antonio Department of Family and Community Medicine, 7703 Floyd Curl Drive, San Antonio, Texas

 

Abstract

The association between environmentally released mercury, special education and autism rates in Texas was investigated using data from the Texas Education Department and the United States Environmental Protection Agency. A Poisson regression analysis adjusted for school district population size, economic and demographic factors was used. There was a significant increase in the rates of special education students and autism rates associated with increases in environmentally released mercury. On average, for each 1,000 lb of environmentally released mercury, there was a 43% increase in the rate of special education services and a 61% increase in the rate of autism. The association between environmentally released mercury and special education rates were fully mediated by increased autism rates. This ecological study suggests the need for further research regarding the association between

environmentally released mercury and developmental disorders such as autism. These results have implications for policy planning and cost analysis.

 

 

 

138 Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury.

 

Sci Total Environ. 2015 Dec 1;536:245-51. doi: 10.1016/j.scitotenv.2015.07.024. Epub 2015 Jul 25.

 

Dickerson AS1, Rahbar MH2, Han I3, Bakian AV4, Bilder DA5, Harrington RA6, Pettygrove S7, Durkin M8, Kirby RS9, Wingate MS10, Tian LH11, Zahorodny WM12, Pearson DA13, Moyé LA 3rd14, Baio J15.

 

1Biostatistics/Epidemiology/Research Design (BERD) Core, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Aisha.S.Dickerson@uth.tmc.edu.

2Biostatistics/Epidemiology/Research Design (BERD) Core, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Division of Epidemiology, Human Genetics, and Environmental Sciences (EHGES), University of Texas School of Public Health at Houston, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Mohammad.H.Rahbar@uth.tmc.edu.

3Division of Epidemiology, Human Genetics, and Environmental Sciences (EHGES), University of Texas School of Public Health at Houston, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Inkyu.Han@uth.tmc.edu.

4Division of Child Psychiatry, Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT 84108, USA. Electronic address: Amanda.Bakian@hsc.utah.edu.

5Division of Child Psychiatry, Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT 84108, USA. Electronic address: Deborah.Bilder@hsc.utah.edu.

6Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Electronic address: rharrin5@jhu.edu. 7Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85721, USA. Electronic address: sydneyp@u.arizona.edu.

8Waisman Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA. Electronic address: mdurkin@wisc.edu.

9Department of Community and Family Health, College of Public Health, University of South Florida, Tampa, FL 33612, USA. Electronic address: rkirby@health.usf.edu.

10Department of Health Care Organization and Policy, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35205, USA.. Electronic address: mslay@uab.edu.

11National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. Electronic address: bsr4@cdc.gov.

12Department of Pediatrics, Rutgers New Jersey Medical School, Newark, NJ 07103, USA. Electronic address: zahorodn@njms.rutgers.edu.

13Department of Psychiatry and Behavioral Sciences, University of Texas Medical School, Houston, TX 77054, USA. Electronic address: Deborah.A.Pearson@uth.tmc.edu.

14Division of Biostatistics, University of Texas School of Public Health at Houston, Houston, TX 77030, USA. Electronic address: Lemuel.A.Moye@uth.tmc.edu.

15National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. Electronic address: xzb1@cdc.gov.

 

Abstract

Prenatal and perinatal exposures to air pollutants have been shown to adversely affect birth outcomes in offspring and may contribute to prevalence of autism spectrum disorder (ASD). For this ecologic study, we evaluated the association between ASD prevalence, at the census tract level, and proximity of tract centroids to the closest industrial facilities releasing arsenic, lead or mercury during the 1990s. We used 2000 to 2008 surveillance data from five sites of the Autism and Developmental Disabilities Monitoring (ADDM) network and 2000 census data to estimate prevalence. Multi-level negative binomial regression models were used to test associations between ASD prevalence and proximity to industrial facilities in existence from 1991 to 1999 according to the US Environmental Protection Agency Toxics Release Inventory (USEPA-TRI). Data for 2489 census tracts showed that after adjustment for demographic and socio-economic area-based characteristics, ASD prevalence was higher in census tracts located in the closest 10th percentile compared of distance to those in the furthest 50th percentile (adjusted RR=1.27, 95% CI: (1.00, 1.61), P=0.049). The findings observed in this study are suggestive of the association between urban residential proximity to industrial facilities emitting air pollutants and higher ASD prevalence.

 

 

 

139 Inflammatory Responses to Trivalent Influenza Virus Vaccine Among Pregnant Women

 

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

 

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

 

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

 

Abstract Objective

In the U.S., seasonal trivalent influenza vaccination (TIV) is currently universally recommended for all pregnant women. However, data on the maternal inflammatory response to vaccination is lacking and would better delineate the safety and clinical utility of immunization. In addition, for research purposes, vaccination has been used as a mild immune trigger to examine in vivo inflammatory responses in nonpregnant adults. The utility of such a model in pregnancy is unknown. Given the clinical and empirical justifications, the current study examined the magnitude, time course, and variance in inflammatory responses following seasonal influenza virus vaccination among pregnant women.

Methods

Women were assessed prior to and at one day (n=15), two days (n=10), or approximately one week (n=21) following TIV. Serum interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP), and macrophage migration inhibitory factor (MIF) were determined by high sensitivity immunoassay.

Results

Significant increases in CRP were seen at one and two days post-vaccination (ps

<.05). A similar effect was seen for TNF-α, for which an increase at two days post-vaccination approached statistical significance (p = .06). There was considerable variability in magnitude of response; coefficients of variation for change at two days post-vaccination ranged from 122% to 728%, with the greatest variability in IL-6 responses at this timepoint.

Conclusions

Trivalent influenza virus vaccination elicits a measurable inflammatory response among pregnant women. There is sufficient variability in response for testing associations with clinical outcomes. As adverse perinatal health outcomes including preeclampsia and preterm birth have an inflammatory component, a tendency toward greater inflammatory responding to immune triggers may predict risk of adverse outcomes, providing insight into biological mechanisms underlying risk. The inflammatory response elicited by vaccination is substantially milder and more transient than seen in infectious illness, arguing for the clinical value of vaccination. However, further research is needed to confirm that the mild inflammatory response elicited by vaccination is benign in pregnancy

 

 

 

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

 

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

 

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

 

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

 

Abstract

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

 

 

 

141 What is regressive autism and why does it occur? Is it the consequence of multi-systemic dysfunction affecting the elimination of heavy metals and the ability to regulate neural temperature?

 

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

 

Graham E. Ewing

Montague Healthcare, Nottingham United Kingdom Abstract

There is a compelling argument that the occurrence of regressive autism is attributable to genetic and chromosomal abnormalities, arising from the overuse of vaccines, which subsequently affects the stability and function of the autonomic nervous system and physiological systems. That sense perception is linked to the autonomic nervous system and the function of the physiological systems enables us to examine the significance of autistic symptoms from a systemic perspective. Failure of the excretory system influences elimination of heavy metals and facilitates their accumulation and subsequent manifestation as neurotoxins: the long-term consequences of which would lead to neurodegeneration, cognitive and developmental problems. It may also influence regulation of neural hyperthermia. This article explores the issues and concludes that sensory dysfunction and systemic failure, manifested as autism, is the inevitable consequence arising from subtle DNA alteration and consequently from the overuse of vaccines.

 

 

 

142                   Neurologic adverse events following vaccination

Prog Health Sci 2012, Vol 2 , No1

 

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

 

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

 

Abstract

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

 

Discussion by Sienkiewicz et. al.:

"Among the "major" neurological complications, usually manifesting more than 48 hours after vaccination and which might be the cause of permanent damage to the central nervous system (CNS), the following are listed: seizures - especially if there is no increase in body temperature, hypotonic- hyporesponsive episodes, postvaccinal encephalitis, postvaccinal encephalopathy [6, 8-11] and autism [10, 12-14]."

 

 

 

143 Immunological and autoimmune considerations of Autism Spectrum Disorders.

 

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

 

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

Jerusalem, Israel. Abstract

Autism Spectrum Disorders (ASD) are a group of heterogeneous

neurodevelopmental conditions presenting in early childhood with a prevalence ranging from 0.7% to 2.64%. Social interaction and communication skills are impaired and children often present with unusual repetitive behavior. The condition persists for life with major implications for the individual, the family and the entire health care system. While the etiology of ASD remains unknown, various clues suggest a possible association with altered immune responses and ASD. Inflammation in the brain and CNS has been reported by several groups with notable microglia activation and increased cytokine production in

postmortem brain specimens of young and old individuals with ASD. Moreover several laboratories have isolated distinctive brain and CNS reactive antibodies from individuals with ASD. Large population based epidemiological studies have established a correlation between ASD and a family history of autoimmune diseases, associations with MHC complex haplotypes, and abnormal levels of various inflammatory cytokines and immunological markers in the blood. In addition, there is evidence that antibodies that are only present in some mothers of children with ASD bind to fetal brain proteins and may be a marker or risk factor for ASD. Studies involving the injection of these ASD specific maternal serum antibodies into pregnant mice during gestation, or gestational exposure of Rhesus monkeys to IgG subclass of these antibodies, have consistently elicited behavioral changes in offspring that have relevance to ASD. We will summarize the various types of studies associating ASD with the immune system, critically evaluate the quality of these studies, and attempt to integrate them in a way that clarifies the areas of immune and autoimmune phenomena in ASD research that will be important indicators for future research.

 

 

 

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

 

PLoS ONE 8(3): e58058. doi:10.1371/journal.pone.0058058 Walker SJ, Fortunato J, Gonzalez LG, Krigsman A

Abstract

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

require further confirmation in a validation cohort.

 

 

 

145 Early Disruption of the Microbiome Leading to Decreased Antioxidant Capacity and Epigenetic Changes: Implications for the Rise in Autism

 

Front. Cell. Neurosci., 15 August 2018 | https://doi.org/10.3389/fncel.2018.00256

 

Rebecca S. Eshraghi, Richard C. Deth, Rahul Mittal, Mayank Aranke, Sae-In S. Kay4, Baharak Moshiree and Adrien A. Eshraghi

 

 

Currently, 1 out of every 59 children in the United States is diagnosed with autism. While initial research to find the possible causes for autism were mostly focused on the genome, more recent studies indicate a significant role for epigenetic regulation of gene expression and the microbiome. In this review article, we examine the connections between early disruption of the developing microbiome and gastrointestinal tract function, with particular regard to susceptibility to autism. The biological mechanisms that accompany individuals with autism are reviewed in this manuscript including immune system dysregulation, inflammation, oxidative stress, metabolic and methylation abnormalities as well as gastrointestinal distress. We propose that these autism-associated biological mechanisms may be caused and/or sustained by dysbiosis, an alteration to the composition of resident commensal communities relative to the community found in healthy individuals and its redox and epigenetic consequences, changes that in part can be due to early use and over-use of antibiotics across generations. Further studies are warranted to clarify the contribution of oxidative stress and gut microbiome in the pathophysiology of autism. A better understanding of the microbiome and gastrointestinal tract in relation to autism will provide promising new opportunities to develop novel treatment modalities.

 

 

 

146  Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits

 

Mol Psychiatry. 2014 Apr;19(4):495-503. doi: 10.1038/mp.2013.41. Epub 2013 Apr 23.

 

Wong CC1, Meaburn EL2, Ronald A2, Price TS3, Jeffries AR1, Schalkwyk LC1, Plomin R1, Mill J4.

 

1  King's College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, London, UK.

2  1] King's College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, London, UK [2] Department of Psychological Sciences, Birkbeck, University of London, London, UK.

3  1] King's College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, London, UK [2] Institute of Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, PA, USA.

4  1] King's College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, London, UK [2] University of Exeter Medical School, Exeter University, St Luke's Campus, Exeter, UK.

 

 

Abstract

Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort.

This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

 

"Exerpt

These findings concur with mounting data suggesting that environmentally mediated effects on the epigenome may be relatively common and important for disease."

 

 

 

 

147 Correlations between gene expression and mercury levels in blood of boys with and without autism.

 

Neurotox Res. 2011 Jan;19(1):31-48. doi: 10.1007/s12640-009-9137-7. Epub 2009 Nov 24.

 

Stamova B1, Green PG, Tian Y, Hertz-Picciotto I, Pessah IN, Hansen R, Yang X, Teng J, Gregg JP, Ashwood P, Van de Water J, Sharp FR.

 

Department of Neurology, University of California at Davis Medical Center, Sacramento, CA 95817, USA. boryana.stamova@ucdmc.ucdavis.edu

 

Abstract

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

 

 

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

 

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

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

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

 

 

 

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

 

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

 

Kawashima H, Mori T, Kashiwagi Y, Takekuma K, Hoshika A, Wakefield A. Department of Paediatrics, Tokyo Medical University, Japan.

Abstract

It has been reported that measles virus may be present in the intestine of patients with Crohn's disease. Additionally, a new syndrome has been reported in children with autism who exhibited developmental regression and gastrointestinal symptoms (autistic enterocolitis), in some cases soon after MMR vaccine. It is not known whether the virus, if confirmed to be present in these patients, derives from either wild strains or vaccine strains. In order to characterize the strains that may be present, we have carried out the detection of measles genomic RNA in peripheral mononuclear cells (PBMC) in eight patients with Crohn's disease, three patients with ulcerative colitis, and nine children with autistic enterocolitis. As controls, we examined healthy children and patients with SSPE, SLE, HIV-1 (a total of eight cases). RNA was purified from PBMC by Ficoll-paque, followed by reverse transcription using AMV; cDNAs were subjected to nested PCR for detection of specific regions of the hemagglutinin (H) and fusion (F) gene regions. Positive samples were sequenced directly, in nucleotides 8393-8676 (H region) or 5325-5465 (from noncoding F to coding F region). One of eight patients with Crohn disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn's disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains. The results were concordant with the exposure history of the patients. Persistence of measles virus was confirmed in PBMC in some patients with chronic intestinal inflammation.

 

 

 

150  Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations

 

 

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

 

L Tomljenovic, CA Shaw

 

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

 

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

 

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

 

Abstract

Immune challenges during early development, including those vaccine-induced, can lead to permanent detrimental alterations of the brain and immune function. Experimental evidence also shows that simultaneous administration of as little as two to three immune adjuvants can overcome genetic resistance to autoimmunity. In some developed countries, by the time children are 4 to 6 years old, they will have received a total of 126 antigenic compounds along with high amounts of aluminum (Al) adjuvants through routine vaccinations. According to the US Food and Drug Administration, safety assessments for vaccines have often not included appropriate toxicity studies because vaccines have not been viewed as inherently toxic. Taken together, these observations raise plausible concerns about the overall safety of current childhood vaccination programs.

When assessing adjuvant toxicity in children, several key points ought to be considered: (i) infants and children should not be viewed as “small adults” with regard to toxicological risk as their unique physiology makes them much more vulnerable to toxic insults; (ii) in adult humans Al vaccine adjuvants have been linked to a variety of serious autoimmune and inflammatory conditions (i.e., “ASIA”), yet children are regularly exposed to much higher amounts of Al from vaccines than adults; (iii) it is often assumed that peripheral immune responses do not affect brain function. However, it is now clearly established that there is a bidirectional neuro-immune cross-talk that plays crucial roles in immunoregulation as well as brain function. In turn, perturbations of the neuro-immune axis have been demonstrated in many autoimmune diseases encompassed in “ASIA” and are thought to be driven by a hyperactive immune response; and (iv) the same components of the neuro- immune axis that play key roles in brain development and immune function are heavily targeted by Al adjuvants. In summary, research evidence shows that increasing concerns about current vaccination practices may indeed be warranted. Because children may be most at risk of vaccine-induced complications, a rigorous evaluation of the vaccine-related adverse health impacts in the pediatric population is urgently needed.

 

 

 

151               Etiology of autism spectrum disorders: Genes, environment, or both?

 

OA Autism 2014 Jun 10;2(2):11

 

C Shaw, S Sheth, D Li, L Tomljenovic

University of British Columbia, Vancouver, British Columbia, Canada Introduction

Thus far, most of the research on both neurodevelopmental and neurodegenerative disorders has been focused on finding the presumed underlying genetic causes, while much less emphasis has been put on potential environmental factors. While some forms of autism are clearly genetic, the fact remains that heritability factors cannot adequately explain all reported cases nor their drastic increase over the last few decades. In particular, studies on twins

have now shown that common environmental factors account for 55% of their risk for developing autism while genetic susceptibility explains only 37% of cases. Because the prenatal environment and early postnatal environment are shared between twins and because overt symptoms of autism emerge around the end of the first year of life, it is likely that at least some of the environmental factors contributing to the risk of autism exert their deleterious neurodevelopmental effect during this early period of life. Indeed, evidence has now emerged showing that autism may in part result from early-life immune insults induced by environmental xenobiotics. One of the most common xenobiotic with immuno- stimulating as well as neurotoxic properties to which infants under two years of age are routinely exposed worldwide is the aluminum (Al) vaccine adjuvant. In this review we discuss the mechanisms by which Al can induce adverse neurological and immunological effects and how these may provide important clues of Al’s putative role in autism. Because of the tight connection between the development of the immune and the central nervous system, the possibility that immune-overstimulation in early infancy via vaccinations may play a role in neurobehavioural disorders needs to be carefully considered.

 

Conclusion

There is now sufficient evidence from both human and animal studies showing that cumulative exposure to aluminium adjuvants is not as benign as previously assumed. Given that vaccines are the only medical intervention that we attempt to deliver to every living human on earth and that by far the largest target population for vaccination are healthy children, a better appreciation and understanding of vaccine adjuvant risks appears warranted.

 

 

 

152Thiol-modulated mechanisms of the cytotoxicity of thimerosal and inhibition of DNA topoisomerase II alpha.

 

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

 

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

 

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

 

Abstract

Thimerosal is an organic mercury compound that is widely used as a preservative in vaccines and other solution formulations. The use of thimerosal has caused concern about its ability to cause neurological abnormalities due to mercury accumulation during a normal schedule of childhood vaccinations. While the chemistry and the biological effects of methylmercury have been well-studied, those of thimerosal have not. Thimerosal reacted rapidly with cysteine, GSH, human serum albumin, and single-stranded DNA to form ethylmercury adducts that were detectable by mass spectrometry. These results indicated that thimerosal would be quickly metabolized in vivo because of its reactions with protein and nonprotein thiols. Thimerosal also potently inhibited the

decatenation activity of DNA topoisomerase II alpha, likely through reaction with critical free cysteine thiol groups. Thimerosal, however, did not act as a topoisomerase II poison and the lack of cross-resistance with a K562 cell line with a decreased level of topoisomerase II alpha (K/VP.5 cells) suggested that inhibition of topoisomerase II alpha was not a significant mechanism for the inhibition of cell growth. Depletion of intracellular GSH with buthionine sulfoximine treatment greatly increased the K562 cell growth inhibitory effects of thimerosal, which showed that intracellular glutathione had a major role in protecting cells from thimerosal. Pretreatment of thimerosal with glutathione did not, however, change its K562 cell growth inhibitory effects, a result consistent with the rapid exchange of the ethylmercury adduct among various thiol-containing cellular reactants. Thimerosal-induced single and double strand breaks in K562 cells were consistent with a rapid induction of apoptosis. In conclusion, these studies have elucidated some of the chemistry and biological activities of the interaction of thimerosal with topoisomerase II alpha and protein and nonprotein thiols and with DNA.

 

 

 

153               Topoisomerases facilitate transcription of long genes linked to autism

 

Nature (2013) doi:10.1038/nature12504

Received 17 January 2013 Accepted 24 July 2013 Published online 28 August

2013

 

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

 

Abstract

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

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

 

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

Shaw CA, Tomljenovic L. Abstract

We have examined the neurotoxicity of aluminum in humans and animals under various conditions, following different routes of administration, and provide an overview of the various associated disease states. The literature demonstrates clearly negative impacts of aluminum on the nervous system across the age span. In adults, aluminum exposure can lead to apparently age-related neurological deficits resembling Alzheimer's and has been linked to this disease and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models. In addition, injection of aluminum adjuvants in an attempt to model Gulf War syndrome and associated neurological deficits leads to an ALS phenotype in young male mice. In young children, a highly significant correlation exists between the number of pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part, from autoimmune reactions, as part of the ASIA syndrome.

 

 

 

 

155  Transcriptomic Analyses of Neurotoxic Effects in Mouse Brain After Intermittent Neonatal Administration of Thimerosal.

 

Toxicol Sci. 2014 Apr 4.

 

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.

 

 

 

156                 Self-organized criticality theory of autoimmunity.

 

PLoS One. 2009 Dec 31;4(12):e8382. doi: 10.1371/journal.pone.0008382. Tsumiyama K1, Miyazaki Y, Shiozawa S.

Department of Biophysics, Kobe University Graduate School of Health Science, Kobe, Japan.

 

Abstract BACKGROUND:

The cause of autoimmunity, which is unknown, is investigated from a different angle, i.e., the defect in immune 'system', to explain the cause of autoimmunity.

 

METHODOLOGY/PRINCIPAL FINDINGS:

Repeated immunization with antigen causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4(+) T cells led to the development of autoantibody-inducing CD4(+) T (aiCD4(+) T) cell which had undergone T cell receptor (TCR) revision and was capable of inducing autoantibodies. The aiCD4(+) T cell was induced by de novo TCR revision but not by cross-reaction, and subsequently overstimulated CD8(+) T cells, driving them to become antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross-presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE).

 

CONCLUSIONS/SIGNIFICANCE:

Systemic autoimmunity appears to be the inevitable consequence of over- stimulating the host's immune 'system' by repeated immunization with antigen, to the levels that surpass system's self-organized criticality.

 

 

 

157 Can Awareness of Medical Pathophysiology in Autism Lead to Primary Care Autism Prevention Strategies?

 

Elizabeth Mumper, MD, FAAP

 

N A J Med Sci. 2013;6(3):134-144. DOI: 10.7156/najms.2013.0603134

 

Abstract

Emerging research suggests that the timing of environmental factors in the presence of genetic predispositions has influenced the increase in autism spectrum disorders over the past several decades. A review of the medical literature suggests that autism may be impacted by environmental toxicants, breastfeeding duration, gut flora composition, nutritional status, acetaminophen use, vaccine practices and use of antibiotics and/or frequency of infections. The author reports her retrospective clinical research in a general pediatric practice (Advocates for Children), which shows a modest trend toward lower prevalence of autism than her previous pediatric practice or recent CDC data. Out of 294 general pediatrics patients followed since 2005 there were zero new cases of autism (p value 0.014). Given the prevalence of autism for that cohort of 1 in 50 children in the United States, it is important to consider implementing strategies in primary care practice that could potentially modify environmental factors or affect the timing of environmental triggers contributing to autism.

 

 

 

158              Autism: a novel form of mercury poisoning

 

Medical Hypotheses (2001) 56(4), 462–471, 2001 Harcourt Publishers Ltd doi: 10.1054/mehy.2000.1281,

 

S. Bernard, A. Enayati, L. Redwood, H. Roger, T. Binstock ARC Research, Cranford, New Jersey, USA

Summary Autism is a syndrome characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recent epidemiological studies suggest that autism may affect 1 in 150 US children. Exposure to mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism, and the similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Thimerosal, a preservative added to many vaccines, has become a major source of mercury in children who, within their first two years, may have received a quantity of mercury that exceeds safety guidelines. A review of medical literature and US government data suggests that:

(i) many cases of idiopathic autism are induced by early mercury exposure from thimerosal; (ii) this type of autism represents an unrecognized mercurial syndrome; and (iii) genetic and non-genetic factors establish a predisposition whereby thimerosal’s adverse effects occur only in some children.

159 [Autistic syndrome (Kanner) and vaccination against smallpox (author's transl)].

 

Eggers C.

Klin Padiatr. 1976 Mar;188(2):172-80. [Article in German] Abstract

3-4 weeks following an otherwise uncomplicated first vaccination against smallpox a boy, then aged 15 months and last seen at the age of 5 1/2 years, gradually developed a complete Kanner syndrome. The question whether vaccination and early infantile autism might be connected is being discussed. A causal relationship is considered extremely unlikely. But vaccination is recognized as having a starter function for the onset of autism.

 

 

 

160               Autistic disturbances of affective contact.

Nervous Child 2, 217-250 (1943) Kanner L.

Johns Hopkins University

 

“Case 3. Richard M. was referred to the Johns Hopkins Hospital on February 5, 1941, at 3 years, 3 months of age, with the complaint of deafness because he did not talk and did not respond to questions.”

 

“Following smallpox vaccination at 12 months, he had an attack of diarrhea and fever, from which he recovered in somewhat less than a week.”

 

“In September, 1940, the mother, in commenting on Richard's failure to talk, remarked in her notes: I can't be sure just when he stopped the imitation of words sounds. It seems that he has gone backward mentally gradually for the last two years.”

 

Richard M:

 

November 1937 – Born

 

November 1938 – Vaccinated with Smallpox vaccine

 

September 1940 – Mother reports developmental regression beginning approximately two years previously

 

February 1941 – Referred to Hopkins for evaluation

 

1943 – Becomes the third child to be described as autistic by Leo Kanner in his disorder defining paper, the first paper published on autism.


Resolving & Reversing Vaccine Injury:

Please checkout my vaccine detoxification protocol that has helped many, including myself, to reverse debilitating vaccine injury symptoms: Zinglepathy Rx: Detoxification Protocol & Protecting Against Spike Protein Shedding



Email Address: rx@zinglepathy.com

Blog: www.Zinglepathy.com

Online Health Store: www.ZinglepathyRx.store

Etsy Page - Health Consultation & Astrology Readings: www.zinglepathyrx.net

Twitter: @cjzingle

Twitter: @ZinglepathyRx

Telegram Channel: https://t.me/XoanaRa

Telegram Message: https://t.me/ZinglepathyRx

Instagram: @cjzingle

Pinterest: @ZinglepathyRx

Facebook Page: https://www.facebook.com/XoanaRaStarseed

Comments

Post a Comment

Popular posts from this blog

Zeoboost(Zeolite Powder) 90 Day Detox Instructions: Detox Heavy Metals & Reverse "Incurable" Diseases & Illnesses

By -
Image
  Vaccine Health Damages: Heavy Metal Health Damages: Zeoboost Detox (Zeolite Powder) (Also helps cure cancer, autoimmune, autism, psoriasis, & more): To Detox The Heavy Metals In this article I will cover: About Zeoboost (Zeolite Powder) 90 Day Zeoboost Detox Instructions (Where To Purchase) Zeolite Cautions My Story & How Zeoboost Changed My Life About Zeoboost (Zeolite Powder): Zeolite is a silica-based volcanic ash (sand-like mineral) that forms over time.  Zeolite is an alkaline mineral that is very porous and has a negative charge. Since most toxins, such as heavy metals, radiation, and pesticides, are positively charged, zeolite is pulled to the toxins, like a magnet, and sucks them up into its structure.These dangerous substances become trapped in zeolite’s cage structure, and are then safely and gently carried out of the body.    Instead of offering one particle size, our zeolite is micronized into a range of particle sizes insuring a more complete full-body detox. Sma
Read more

Revival Of 100-Year-Old Healing Tesla Coil: High-Frequency Violet Ray Therapy

By -
Image
  This blog post outlines 100-year-old Tesla healing technology that has been suppressed from the public due to its success in healing many different illnesses and health problems. At the bottom of this post, I provide a URL link where you can purchase your own Violet Ray Healing Device. This device I have used on my own healing journey.  PURCHASE HERE:   Tesla Violet Ray High Frequency Healing Device with User Manual Handbook (zinglepathyrx.net) SCIENTIFICALLY ACCEPTED EFFECTS OF VIOLET RAYS: l---Cause cells to absorb more oxygen. 2---Speed up burning of oxygen. 3---Increase elimination of waste. 4---Restore cells to health. 5---Increase blood supply in given area. 6---Stimulate secretions of glands. 7---Raise body heat without temperature. 8---Destroy germs.  9---Soothe the nerves; build nerve tissue. 10---Remove dead tissue and adhesions. 11---Lower blood pressure.  12---Promote normal growth.   AILMENTS SUCCESSFULLY TREATED WITH VIOLET RAYS: ·      Asthm
Read more

PARASITES: The #1 Contributor To Illness, Disease, & Cancer

By -
Image
  Parasites QuickFacts: Making up approximately 70 percent of all invading organisms , protozoa are invisible to the naked eye. According to experts, an estimated 7 million people across the U.S. have some form of protozoa living inside of them . While it may be unpleasant to consider, it is true that the human host can coexist quite comfortably with a few worms, unless they reproduce in great numbers and create organ obstruction.  Experts claim that ' some type of worm is already in the intestines of over 75 percent of the world's population '. Approximately 1 billion people are infected with ascaris parasites.   The most common of all the worms in the United States, the pinworm parasite, is most prevalent in children.   Just about any symptom known to man can be caused by the various stages of trichinosis parasite infection, which can masquerade as at least fifty more familiar diseases ranging from flu to generalized and specific aches and pains.  Beef tapeworms have a li
Read more