Developmental neurotoxicants and the vulnerable male brain: a systematic review of suspected neurotoxicants that disproportionally affect males.

The prevalence of neurodevelopmental disorders (NDs), including autism spectrum disorder, attention­deficit/hyperactivity disorder, tic disorder, obsessive­compulsive disorder, and emotional disturbances, has increased notably in the past few decades. To date, debate continues as to the origins of NDs. Increases in widespread exposure to and bioaccumulation of chemical neurotoxicants have paralleled the upsurge in NDs, and are suggested to be causal agents for NDs. One consistent aspect of NDs is the male preponderance. This review considers the issue of male preponderance by reviewing the gender­specific neurotoxic effects of recognized neurotoxicant chemicals to assess their possible etiology in NDs. This investigation consisted of a systematic literature review of original studies published from 1970-2016 on suspected neurotoxicants, to examine whether they have a disproportionate adverse effect based on gender. Based on that review, the neurotoxicants exhibiting consistent gender­specific effects, with exposed males being more affected (than similarly exposed females), were: lead, Thimerosal/ethylmercury, some organochlorine pesticides (e.g., dieldrin, endosulfan, and heptachlor), and air pollution. The next group identified were neurotoxicants exhibiting gender­specific neurotoxic effects, with males being somewhat (but not consistently) more affected than females: mercury vapor, polychlorinated biphenyls (PCBs), and organophosphate pesticides. Finally, there was a group of studies in which the neurotoxicants exhibited apparent gender­related neurotoxic effects but failed to show whether exposed males were consistently more affected than females: inorganic mercury salts, methylmercury species, and certain endocrine disruptors (e.g., phthalates and BPA). The overall conclusion from the studies reviewed was that the brain in males is more vulnerable to many toxic exposures than it is in females. Evidence suggests that the reasons for the male brain being more vulnerable include: (1) greater glutathione availability in females; (2) greater sulfate­based detoxification capacity in females; (3) potentiating effects of co­exposure to neurotoxicants and testosterone; (4) greater neuroinflammatory response in males; (5) reduced vulnerability to oxidative stress in females; and (6) neuroprotective effects of female hormones (estrogen and progesterone), especially in the reduction of inflammation and oxidative stress.

A longitudinal cohort study of the relationship between Thimerosal-containing hepatitis B vaccination and specific delays in development in the United States: Assessment of attributable risk and lifetime care costs.

Epidemiological evidence suggests a link between mercury (Hg) exposure from Thimerosal-containing vaccines and specific delays in development. A hypothesis-testing longitudinal cohort study (n=49,835) using medical records in the Vaccine Safety Datalink (VSD) was undertaken to evaluate the relationship between exposure to Hg from Thimerosal-containing hepatitis B vaccines (T-HBVs) administered at specific intervals in the first 6months of life and specific delays in development [International Classification of Disease, 9th revision (ICD-9): 315.xx] among children born between 1991 and 1994 and continuously enrolled from birth for at least 5.81years. Infants receiving increased Hg doses from T-HBVs administered within the first month, the first 2months, and the first 6months of life were significantly more likely to be diagnosed with specific delays in development than infants receiving no Hg doses from T-HBVs. During the decade in which T-HBVs were routinely recommended and administered to US infants (1991-2001), an estimated 0.5-1million additional US children were diagnosed with specific delays in development as a consequence of 25µg or 37.5µg organic Hg from T-HBVs administered within the first 6months of life. The resulting lifetime costs to the United States may exceed $1 trillion.

Thimerosal: clinical, epidemiologic and biochemical studies.

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

Shared Brain Connectivity Issues, Symptoms, and Comorbidities in Autism Spectrum Disorder, Attention Deficit/Hyperactivity Disorder, and Tourette Syndrome.

The prevalence of neurodevelopmental disorders, including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and Tourette syndrome (TS), has increased over the past two decades. Currently, about one in six children in the United States is diagnosed as having a neurodevelopmental disorder. Evidence suggests that ASD, ADHD, and TS have similar neuropathology, which includes long-range underconnectivity and short-range overconnectivity. They also share similar symptomatology with considerable overlap in their core and associated symptoms and a frequent overlap in their comorbid conditions. Consequently, it is apparent that ASD, ADHD, and TS diagnoses belong to a broader spectrum of neurodevelopmental illness. Biologically, long-range underconnectivity and short-range overconnectivity are plausibly related to neuronal insult (e.g., neurotoxicity, neuroinflammation, excitotoxicity, sustained microglial activation, proinflammatory cytokines, toxic exposure, and oxidative stress). Therefore, these disorders may a share a similar etiology. The main purpose of this review is to critically examine the evidence that ASD, ADHD, and TS belong to a broader spectrum of neurodevelopmental illness, an abnormal connectivity spectrum disorder, which results from neural long-range underconnectivity and short-range overconnectivity. The review also discusses the possible reasons for these neuropathological connectivity findings. In addition, this review examines the role and issue of axonal injury and regeneration in order to better understand the neuropathophysiological interplay between short- and long-range axons in connectivity issues.

Thimerosal exposure and increased risk for diagnosed tic disorder in the United States: a case-control study.

A hypothesis testing, case-control study evaluated automated medical records for exposure to organic-Hg from Thimerosal-containing hepatitis B vaccines (TM-HepB) administered at specific intervals in the first six-months-of-life among cases diagnosed with a tic disorder (TD) or cerebral degeneration (CD) (an outcome not biologically plausibly linked to TM exposure) in comparison to controls; both cases and controls were continuously enrolled from birth (born from 1991-2000) within the Vaccine Safety Datalink (VSD) database. TD cases were significantly more likely than controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (odds ratio (OR)=1.59, p<0.00001), first two-months-of-life (OR=1.59, p<0.00001), and first six-months-of-life (OR=2.97, p<0.00001). Male TD cases were significantly more likely than male controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (OR =1.65, p<0.0001), first two-months-of-life (OR=1.64, p<0.0001), and first six months-of-life (OR=2.47, p<0.05), where as female TD were significantly more likely than female controls to have received increased organic-Hg from TM-HepB administered within the first six-months-of-life (OR=4.97, p<0.05). By contrast, CD cases were no more likely than controls to have received increased organic-Hg exposure from TM-HepB administered at any period studied within the first six-months-of-life. Although routine childhood vaccination is considered an important public health tool to combat infectious diseases, the present study associates increasing organic-Hg exposure from TM-HepB and the subsequent risk of a TD diagnosis.

A case-control study evaluating the relationship between thimerosal-containing haemophilus influenzae type b vaccine administration and the risk for a pervasive developmental disorder diagnosis in the United States.

Thimerosal is an organic mercury (Hg)-containing compound (49.55 % Hg by weight) historically added to many multi-dose vials of vaccine as a preservative. A hypothesis testing case-control study evaluated automated medical records in the Vaccine Safety Datalink (VSD) for organic Hg exposure from Thimerosal in Haemophilus influenzae type b (Hib)-containing vaccines administered at specific times within the first 15 months of life among subjects diagnosed with pervasive developmental disorder (PDD) (n = 534) in comparison to controls. The generally accepted biologically non-plausible linkage between Thimerosal exposure and subsequent diagnosis of febrile seizure (n = 5886) was examined as a control outcome. Cases diagnosed with PDD received significantly more organic Hg within the first 6 months of life (odds ratio (OR) = 1.97, p < 0.001) and first 15 months of life (OR = 3.94, p < 0.0001) than controls, whereas cases diagnosed with febrile seizure were no more likely than controls to have received increased organic Hg. On a per microgram of organic Hg basis, cases diagnosed with a PDD in comparison to controls were at significantly greater odds (OR = 1.0197, p < 0.0001) of receiving increasing organic Hg exposure within the first 15 months of life, whereas cases diagnosed febrile seizure were no more likely than controls (OR = 0.999, p > 0.20) to have received increasing organic Hg exposure within the first 15 months of life. Routine childhood vaccination is an important public health tool to reduce the morbidity and mortality associated with infectious diseases, but the present study provides new epidemiological evidence of a significant relationship between increasing organic Hg exposure from Thimerosal-containing vaccines and the subsequent risk of PDD diagnosis in males and females.

Thimerosal-containing hepatitis B vaccination and the risk for diagnosed specific delays in development in the United States: a case-control study in the vaccine safety datalink.

BACKGROUND: Within the first 3 years of life, the brain develops rapidly. Its development is characterized by critical developmental periods for speech, vision, hearing, language, balance, etc.; and alteration in any of the processes occurring in those critical periods can lead to specific delays in development. AIMS: The present study evaluated the potential toxic effects of organic-mercury exposure from Thimerosal (49.55% mercury by weight) in childhood vaccines and its hypothesized possible relationship with specific delays in development. MATERIALS AND METHODS: A hypothesis testing case-control study was undertaken to evaluate the relationship between exposure to Thimerosal-containing hepatitis B vaccines administered at specific intervals in the first 6 months among cases diagnosed with specific delays in development and controls born between 1991-2000, utilizing data in the Vaccine Safety Datalink database. RESULTS: Cases were significantly more likely than controls to have received increased organic-mercury from Thimerosal-containing hepatitis B vaccine administered in the first, second, and sixth month of life. CONCLUSION: Though routine childhood vaccination may be an important public health tool to reduce the morbidity and mortality associated with infectious diseases, the present study supports an association between increasing organic-mercury exposure from Thimerosal-containing childhood vaccines and the subsequent risk of specific delays in development among males and females.

A dose-response relationship between organic mercury exposure from thimerosal-containing vaccines and neurodevelopmental disorders.

A hypothesis testing case-control study evaluated concerns about the toxic effects of organic-mercury (Hg) exposure from thimerosal-containing (49.55% Hg by weight) vaccines on the risk of neurodevelopmental disorders (NDs). Automated medical records were examined to identify cases and controls enrolled from their date-of-birth (1991-2000) in the Vaccine Safety Datalink (VSD) project. ND cases were diagnosed with pervasive developmental disorder (PDD), specific developmental delay, tic disorder or hyperkinetic syndrome of childhood. In addition, putative non-thimerosal-related outcomes of febrile seizure, failure to thrive and cerebral degenerations were examined. The cumulative total dose of Hg exposure from thimerosal-containing hepatitis B vaccine (T-HBV) administered within the first six months of life was calculated. On a per microgram of organic-Hg basis, PDD (odds ratio (OR) = 1.054), specific developmental delay (OR = 1.035), tic disorder (OR = 1.034) and hyperkinetic syndrome of childhood (OR = 1.05) cases were significantly more likely than controls to receive increased organic-Hg exposure. By contrast, none of the non-thimerosal related outcomes were significantly more likely than the controls to have received increased organic-Hg exposure. Routine childhood vaccination may be an important public health tool to reduce infectious disease-associated morbidity/mortality, but the present study significantly associates organic-Hg exposure from T-HBV with an increased risk of an ND diagnosis.

Thimerosal as discrimination: vaccine disparity in the UN Minamata Convention on mercury.

When addressing toxins, one unmistakable parallel exists between biology and politics: developing children and developing nations are those most vulnerable to toxic exposures. This disturbing parallel is the subject of this critical review, which examines the use and distribution of the mercury (Hg)-based compound, thimerosal, in vaccines. Developed in 1927, thimerosal is 49.55% Hg by weight and breaks down in the body into ethyl-Hg chloride, ethyl-Hg hydroxide and sodium thiosalicylate. Since the early 1930s, there has been evidence indicating that thimerosal poses a hazard to the health of human beings and is ineffective as an antimicrobial agent. While children in the developed and predominantly western nations receive doses of mostly no-thimerosal and reduced-thimerosal vaccines, children in the developing nations receive many doses of several unreduced thimerosal-containing vaccines (TCVs). Thus, thimerosal has continued to be a part of the global vaccine supply and its acceptability as a component of vaccine formulations remained unchallenged until 2010, when the United Nations (UN), through the UN Environment Programme, began negotiations to write the global, legally binding Minamata Convention on Hg. During the negotiations, TCVs were dropped from the list of Hg-containing products to be regulated. Consequently, a double standard in vaccine safety, which previously existed due to ignorance and economic reasons, has now been institutionalised as global policy. Ultimately, the Minamata Convention on Hg has sanctioned the inequitable distribution of thimerosal by specifically exempting TCVs from regulation, condoning a two-tier standard of vaccine safety: a predominantly no-thimerosal and reduced-thimerosal standard for developed nations and a predominantly thimerosal-containing one for developing nations. This disparity must now be evaluated urgently as a potential form of institutionalised discrimination.

New science challenges old notion that mercury dental amalgam is safe.

Mercury dental amalgam has a long history of ostensibly safe use despite its continuous release of mercury vapor. Two key studies known as the Children's Amalgam Trials are widely cited as evidence of safety. However, four recent reanalyses of one of these trials now suggest harm, particularly to boys with common genetic variants. These and other studies suggest that susceptibility to mercury toxicity differs among individuals based on multiple genes, not all of which have been identified. These studies further suggest that the levels of exposure to mercury vapor from dental amalgams may be unsafe for certain subpopulations. Moreover, a simple comparison of typical exposures versus regulatory safety standards suggests that many people receive unsafe exposures. Chronic mercury toxicity is especially insidious because symptoms are variable and nonspecific, diagnostic tests are often misunderstood, and treatments are speculative at best. Throughout the world, efforts are underway to phase down or eliminate the use of mercury dental amalgam.

Evidence supporting a link between dental amalgams and chronic illness, fatigue, depression, anxiety, and suicide.

The purpose of this review is to examine the evidence for a relationship between mercury (Hg) exposure from dental amalgams and certain idiopathic chronic illnesses--chronic fatigue syndrome (CFS), fibromyalgia (FM), depression, anxiety, and suicide. Dental amalgam is a commonly used dental restorative material that contains approximately 50% elemental mercury (Hg0) by weight and releases Hg0 vapor. Studies have shown that chronic Hg exposure from various sources including dental amalgams is associated with numerous health complaints, including fatigue, anxiety, and depression--and these are among the main symptoms that are associated with CFS and FM. In addition, several studies have shown that the removal of amalgams is associated with improvement in these symptoms. Although the issue of amalgam safety is still under debate, the preponderance of evidence suggests that Hg exposure from dental amalgams may cause or contribute to many chronic conditions. Thus, consideration of Hg toxicity may be central to the effective clinical investigation of many chronic illnesses, particularly those involving fatigue and depression.

A two-phase study evaluating the relationship between Thimerosal-containing vaccine administration and the risk for an autism spectrum disorder diagnosis in the United States.

BACKGROUND: Autism spectrum disorder (ASD) is defined by standardized criteria of qualitative impairments in social interaction, qualitative impairments in communication, and restricted and stereotyped patterns of behavior, interests, and activities. A significant number of children diagnosed with ASD suffer a loss of previously-acquired skills, which is suggestive of neurodegeneration or a type of progressive encephalopathy with an etiological pathogenic basis occurring after birth. To date, the etiology of ASD remains under debate, however, many studies suggest toxicity, especially from mercury (Hg), in individuals diagnosed with an ASD. The present study evaluated concerns about the toxic effects of organic-Hg exposure from Thimerosal (49.55% Hg by weight) in childhood vaccines by conducting a two-phased (hypothesis generating/hypothesis testing) study with documented exposure to varying levels of Thimerosal from vaccinations. METHODS: A hypothesis generating cohort study was undertaken to evaluate the relationship between exposure to organic-Hg from a Thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis (DTaP) vaccine in comparison to a Thimerosal-free DTaP vaccine administered, from 1998 through 2000, for the risk of ASD as reported in the Vaccine Adverse Event Reporting System (VAERS) database (phase I). A hypothesis testing case-control study was undertaken to evaluate the relationship between organic-Hg exposure from Thimerosal-containing hepatitis B vaccines administered at specific intervals in the first six months of life among cases diagnosed with an ASD and controls born between 1991 through 1999 in the Vaccine Safety Datalink (VSD) database (phase II). RESULTS: In phase I, it was observed that there was a significantly increased risk ratio for the incidence of ASD reported following the Thimerosal-containing DTaP vaccine in comparison to the Thimerosal-free DTaP vaccine. In phase II, it was observed that cases diagnosed with an ASD were significantly more likely than controls to receive increased organic-Hg from Thimerosal-containing hepatitis B vaccine administered within the first, second, and sixth month of life. CONCLUSIONS: Routine childhood vaccination is an important public health tool to reduce the morbidity and mortality associated with infectious diseases, but the present study provides new epidemiological evidence supporting an association between increasing organic-Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of an ASD diagnosis.

Thimerosal exposure and the role of sulfation chemistry and thiol availability in autism.

Autism spectrum disorder (ASD) is a neurological disorder in which a significant number of the children experience a developmental regression characterized by a loss of previously acquired skills and abilities. Typically reported are losses of verbal, nonverbal, and social abilities. Several recent studies suggest that children diagnosed with an ASD have abnormal sulfation chemistry, limited thiol availability, and decreased glutathione (GSH) reserve capacity, resulting in a compromised oxidation/reduction (redox) and detoxification capacity. Research indicates that the availability of thiols, particularly GSH, can influence the effects of thimerosal (TM) and other mercury (Hg) compounds. TM is an organomercurial compound (49.55% Hg by weight) that has been, and continues to be, used as a preservative in many childhood vaccines, particularly in developing countries. Thiol-modulating mechanisms affecting the cytotoxicity of TM have been identified. Importantly, the emergence of ASD symptoms post-6 months of age temporally follows the administration of many childhood vaccines. The purpose of the present critical review is provide mechanistic insight regarding how limited thiol availability, abnormal sulfation chemistry, and decreased GSH reserve capacity in children with an ASD could make them more susceptible to the toxic effects of TM routinely administered as part of mandated childhood immunization schedules.

Handgrip strength in autism spectrum disorder compared with controls.

The study examined handgrip strength in participants diagnosed with an autism spectrum disorder (ASD) as compared with neurotypical children. Thirty-three children, aged 2-17 years, with an ASD and 33 gender-, race-, and age-matched neurotypical controls were tested using a handgrip dynamometer. The handgrip strength in participants with an ASD was significantly (p < 0.0001) lower than the neurotypical controls. The mean handgrip strength was 39.4 ± 17.7 kPa in children with ASD and 65.1 ± 26.7 kPa in controls. The results support the hypothesis that children with an ASD have significantly poorer handgrip strength as compared with neurotypical children. Because the handheld dynamometer has been shown to be a valid tool for measuring overall muscle strength, the results suggest that children with ASD have muscle weakness. Future studies are needed to determine the extent of muscle weakness in ASD, its ramifications, and the possible benefits of muscle strengthening. The present study provides support for the use of handgrip strength as a tool for the assessment of targeted treatment in ASD.

Hair toxic metal concentrations and autism spectrum disorder severity in young children.

Previous studies have found a higher body-burden of toxic metals, particularly mercury (Hg), among subjects diagnosed with an autism spectrum disorder (ASD) in comparison to neurotypical controls. Moreover, Hg body-burden was associated with ASD severity. This cross-sectional study examined the potential correlation between hair toxic metal concentrations and ASD severity in a prospective cohort of participants diagnosed with moderate to severe ASD. The Institutional Review Board at the University of Texas Southwestern Medical Center at Dallas (Dallas, TX) approved the present study. Qualifying study participants (n = 18) were evaluated for ASD severity using the Childhood Autism Rating Scale (CARS) and quantitatively for arsenic, Hg, cadmium, lead, chromium, cobalt, nickel, aluminum, tin, uranium, and manganese using hair toxic element testing by Doctor's Data (a CLIA-approved laboratory). CARS scoring and hair toxic element testing were blinded to one another. Increasing hair Hg concentrations significantly correlated with increased ASD severity. In contrast, no significant correlations were observed between any other of the hair toxic metals examined and ASD severity. This study helps to provide additional mechanistic support for Hg in the etiology of ASD severity, and is supported by an increasing number of recent critical reviews that provide biological plausibility for the role of Hg exposure in the pathogenesis of ASDs.

Evidence of parallels between mercury intoxication and the brain pathology in autism.

The purpose of this review is to examine the parallels between the effects mercury intoxication on the brain and the brain pathology found in autism spectrum disorder (ASD). This review finds evidence of many parallels between the two, including: (1) microtubule degeneration, specifically large, long-range axon degeneration with subsequent abortive axonal sprouting (short, thin axons); (2) dentritic overgrowth; (3) neuroinflammation; (4) microglial/astrocytic activation; (5) brain immune response activation; (6) elevated glial fibrillary acidic protein; (7) oxidative stress and lipid peroxidation; (8) decreased reduced glutathione levels and elevated oxidized glutathione; (9) mitochondrial dysfunction; (10) disruption in calcium homeostasis and signaling; (11) inhibition of glutamic acid decarboxylase (GAD) activity; (12) disruption of GABAergic and glutamatergic homeostasis; (13) inhibition of IGF-1 and methionine synthase activity; (14) impairment in methylation; (15) vascular endothelial cell dysfunction and pathological changes of the blood vessels; (16) decreased cerebral/cerebellar blood flow; (17) increased amyloid precursor protein; (18) loss of granule and Purkinje neurons in the cerebellum; (19) increased pro-inflammatory cytokine levels in the brain (TNF-α, IFN-γ, IL-1ß, IL-8); and (20) aberrant nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). This review also discusses the ability of mercury to potentiate and work synergistically with other toxins and pathogens in a way that may contribute to the brain pathology in ASD. The evidence suggests that mercury may be either causal or contributory in the brain pathology in ASD, possibly working synergistically with other toxic compounds or pathogens to produce the brain pathology observed in those diagnosed with an ASD.

An evaluation of the role and treatment of elevated male hormones in autism spectrum disorders.

Autism, Asperger's syndrome (AS), and pervasive developmental disorder - not otherwise specified (PDD-NOS) compose the overall diagnostic category of autism spectrum disorder (ASD). Subjects diagnosed with an ASD have a male:female ratio of 4:1, and among subjects diagnosed with AS the male:female ratio is as high as 9:1. The purpose of this study was to examine evidence of the association between hyperandrogenism and autistic traits (ATs) among subjects diagnosed with an ASD, and to evaluate the effectiveness of anti-androgen therapy as a means to help treat ATs in subjects diagnosed with an ASD. Evidence of hyperandrogenism in subjects diagnosed with an ASD is supported by multiple studies in the areas of psychological framework, brain pathology, tissue culture, and pre- and postnatal androgen levels. Data from subjects diagnosed with other conditions associated with elevated androgens reveals many of these individuals have ATs. Finally, in a placebo-controlled trial of testosterone administration to neurotypical subjects, testosterone was found to increase ATs. In addition, a controlled trial of human transsexuals revealed a significant increase in ATs in female-to-male transsexuals and a decrease in ATs in male-to-female transsexuals. Data from multiple animals and human clinical trials suggest that antiandrogen medications have the ability to significantly reduce ATs in patients diagnosed with an ASD. In light of the robust association between hyperandrogenism and ASD, it is recommended subjects diagnosed with an ASD should undergo routine screening for elevated androgens, and appropriate treatment should be initiated for those with elevated androgens.

The temporal relationship between RotaTeq immunization and intussusception adverse events in the Vaccine Adverse Event Reporting System (VAERS).

BACKGROUND: In August of 2006, the Advisory Committee on Immunization Practices (ACIP) recommended RotaTeq for routine vaccination of US infants. The hypothesis tested in the present study is that rotavirus vaccines are associated with an increased risk of intussusception adverse events (AEs) characterized by an onset in a biologically plausible a priori identified temporal period post-vaccination (days 3 to 7). MATERIAL/METHODS: The Vaccine Adverse Event Reporting System (VAERS) updated as of December 28, 2010 was analyzed. RESULTS: Following RotaTeq vaccination, a significantly (p<0.001) higher percentage of AEs were classified as serious, permanently disabling, resulted in hospitalizations, or were life-threatening among intussusception AEs in comparison to the total AE reports (removing intussusception AE reports) submitted to VAERS. A significantly greater portion of intussusception AEs in comparison to the portion of total AE reports (removing intussusception AE reports) were reported to VAERS in the onset interval from 3 to 7 days post-RotaTeq vaccination than within the onset interval from 1 to 2 days post-RotaTeq vaccination (78.7% vs. 29.1%, risk ratio=2.7, 95% CI=2.4-3.0, p<0.0001). It was assumed in our onset time-trend analyses of the distribution of AEs following Rota-Teq vaccination that the AE's should be equally likely to be reported with an onset time for each day, from 1 to 9 days post-vaccination or, alternatively, should follow similar daily proportions as observed for total AEs reports (removing intussusception AE reports). Results of this onset time-trend analyses of the distribution of intussusception AEs reported to VAERS following Rota-Teq vaccination revealed significant differences (p<0.001) from our expectations. Consistent and similarly remarkable trends were observed for intussusception AE reports associated with RotaShield vaccine. CONCLUSIONS: The present study significantly associates RotaTeq vaccination with intussusception AEs.

A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders.

BACKGROUND: L-carnitine was proposed as a potential treatment for patients diagnosed with an autism spectrum disorder to improve mitochondrial dysfunction, but no prior randomized controlled trials have been conducted. MATERIAL/METHODS: Thirty subjects diagnosed with an ASD were randomly assigned to receive a standardized regimen (50 mg L-carnitine/kg bodyweight/day) of liquid L-carnitine (n=19) or placebo (n=11) for 3-months. Measures included changes in professionally completed Childhood Autism Rating Scale (CARS), hand muscle testing, and modified clinical global impression (CGI) forms; parent completed Autism Treatment Evaluation Checklist (ATEC), treatment adherence measurement (TAM), frequency and intensity of side effect rating (FISER)/global rating of side effect burden (GRSEB)/patient report of incidence of side effects (PRISE) forms; and lab testing. RESULTS: Significant improvements were observed in CARS (-2.03, 95% CI=-3.7 to -0.31), CGI (-0.69, 95% CI=-1.1 to -0.06), and ATEC scores. Significant correlations between changes in serum free-carnitine levels and positive clinical changes were observed for hand muscle strength (R2=0.23, P=0.046), cognitive scores (R2=0.27, P=0.019), and CARS scores (R2=0.20, P=0.047). Study subjects were protocol-compliant (average adherence was >85%) and generally well-tolerated the L-carnitine therapy given. CONCLUSIONS: L-carnitine therapy (50 mg/kilogram-bodyweight/day) administered for 3-months significantly improved several clinical measurements of ASD severity, but subsequent studies are recommended.

A significant relationship between mercury exposure from dental amalgams and urinary porphyrins: a further assessment of the Casa Pia children's dental amalgam trial.

Previous studies noted specific changes in urinary porphyrin excretion patterns associated with exposure to mercury (Hg) in animals and humans. In our study, urinary porphyrin concentrations were examined in normal children 8-18 years-old from a reanalysis of data provided from a randomized, prospective clinical trial that was designed to evaluate the potential health consequences of prolonged exposure to Hg from dental amalgam fillings (the parent study). Our analysis examined dose-dependent correlations between increasing Hg exposure from dental amalgams and urinary porphyrins utilizing statistical models with adjustments for the baseline level (i.e. study year 1) of the following variables: urinary Hg, each urinary porphyrin measure, gender, race, and the level of lead (Pb) in each subject's blood. Significant dose-dependent correlations between cumulative exposure to Hg from dental amalgams and urinary porphyrins associated with Hg body-burden (pentacarboxyporphyrin, precoproporphyrin, and coproporphyrin) were observed. Overall, 5-10% increases in Hg-associated porphyrins for subjects receiving an average number of dental amalgam fillings in comparison to subjects receiving only composite fillings were observed over the 8-year course of the study. In contrast, no significant correlations were observed between cumulative exposure to Hg from dental amalgams and urinary porphyrins not associated with Hg body-burden (uroporphyrin, heptacarboxyporphyrin, and hexacarboxyporphyrin). In conclusion, our study, in contrast to the no-effect results published from the parent study, further establishes the sensitivity and specificity of specific urinary porphyrins as a biomarker for low-level Hg body-burden, and also reveals that dental amalgams are a significant chronic contributor to Hg body-burden.