Monthly Research Review July 2017

This month I have included some research into melatonin, intestinal permeability and vitamin D, as well as the usual ASD research review.


Melatonin Supplementation, a Strategy to Prevent Neurological Diseases through Maintaining Integrity of Blood Brain Barrier in Old People. Full pdf. “Decreased melatonin levels may account for the BBB [Blood brain Barrier] damage in old people who often face the common stress of sepsis and neuroinflammation. Melatonin supplementation treatment significantly inhibits such events. Therefore, continuous daily melatonin supplementation may help prevent sepsis and neuroinflammation-related neurological diseases through maintaining the integrity of BBB in old people. Since melatonin has low toxicity profile and high efficacy in many pathophysiological states, it should be more commonly tested/used in the medical and veterinary arenas.”

Intestinal Permeability

Gut: An underestimated target organ for Aluminum.Aluminum is particularly present in food, beverages, some drugs and airbone dust. In our food, aluminum is superimposed via additives and cooking utensils. Therefore, the tolerable intake of aluminum is exceeded for a significant part of the world population, especially in children who are more vulnerable to toxic effects of pollutants than adults. Faced with this oral aluminum influx, intestinal tract is an essential barrier, especially as 38% of ingested aluminum accumulates at the intestinal mucosa. Although still poorly documented to date, the impact of oral exposure to aluminum in conditions relevant to real human exposure appears to be deleterious for gut homeostasis. Aluminum ingestion affects the regulation of the permeability, the microflora and the immune function of intestine. Nowadays, several arguments are consistent with an involvement of aluminum as an environmental risk factor for inflammatory bowel diseases.”

Leaky Gut As a Danger Signal for Autoimmune Diseases. Full pdf. “The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of toxins, antigens, and bacteria in the lumen to enter the blood stream creating a ‘leaky gut’. In individuals with a genetic predisposition, a leaky gut may allow environmental factors to enter the body and trigger the initiation and development of autoimmune disease.”

‘Leaky gut’ or intestinal permeability can be tested via an Intestinal Permeability Test, and more recently blood Zonulin test has become available in Australia.

Vitamin D

Vitamin D status is inversely associated with markers of risk for type 2 diabetes: A population based study in Victoria, Australia. Full pdf. “Higher 25OHD status was associated with lower prevalent FPG [fasting plasma glucose]as well as lower HbA1c concentrations after accounting for socio-demographic, lifestyle variables and MetS components. Such outcomes could suggest a direct role for the vitamin in the prevention of T2DM.”


Level of inflammatory cytokines in rheumatoid arthritis patients: Correlation with 25-hydroxy vitamin D and reactive oxygen Species. Full pdf. “Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder. Reactive oxygen species (ROS) and pro-inflammatory cytokines have been believed to be involved in the etiopathogenesis of the disease. The aim of the study was to determine the correlation of inflammatory cytokines with 25-hydroxy vitamin D and ROS. This study for the first time shows the association of inflammatory cytokines with 25-hydroxy vitamin D and ROS in RA patients. The results suggest that 25-hydroxy vitamin D being an immune modulator is decreased in the serum of RA patients. Further ROS and cytokines play an important role in the pathogenesis of RA and are responsible for increasing the severity of disease.”


Autism Spectrum Disorder

Status of essential elements in autism spectrum disorder: systematic review and meta-analysis.Meta-analyses showed that the hair concentrations of chromium, cobalt, iodine, iron, and magnesium in ASD patients were significantly lower than those of control subjects, while there were higher magnesium levels in the hair of ASD patients compared to that of controls. Patients with ASD had higher blood levels of copper and lower levels of zinc compared to controls. Further urinary iodine levels in patients with ASD were decreased in comparison with controls.”

Dietary DHA, Bioaccessibility, and Neurobehavioural Development in Children.As main conclusions, it can be mentioned that high DHA intake may prevent autism disorder. However, more studies are required to strengthen the connection between autism and dietary DHA.”

Study on the Association among Mycotoxins and other Variables in Children with Autism. Full text. “Mycotoxins are agricultural contaminants of fungal origin that represent real risk factors for human health and especially for children. Thus, the main hypothesis of this work is that the deterioration of the clinical manifestation of autism in children may result from the exposure to mycotoxins through the consumption of contaminated food. These results suggest the need for a deeper examination of the role that mycotoxins may have on the etiology of ASD.”

Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms. Full pdf. “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. 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.”

Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT.Data suggest a potential role for vitamin D in autism spectrum disorder (ASD). 38 children completed the trial. Baseline 25(OH)D was 54.2±19.7 nmol/L. Following vitamin D3 supplementation, there was a significant increase in 25(OH)D to 83.8 nmol/L but no effect on the primary endpoint. However, there was an improvement in self-care on DD-CGAS. In contrast, there was also a trend toward decreased inappropriate speech in the placebo group. Vitamin D supplementation had no effect on the primary outcome with limited and inconsistent effects in children with ASD.”

Aripiprazole-Related Diurnal Enuresis in Children: 2 Cases (Aripiprazole-Related Enuresis).Aripiprazole is an atypical antipsychotic with dopaminergic and serotonergic effects. Enuresis as an adverse effect has been reported with aripiprazole use in children with autism spectrum disorders. Here, we report 2 cases without autism spectrum disorders who developed diurnal enuresis after starting aripiprazole and ceased after discontinuation of the medication.”

The Co-Occurrence of Autism Spectrum Disorder in Children With ADHD.Approximately one in eight children currently diagnosed with ADHD was also diagnosed with ASD. Children diagnosed with both disorders had greater treatment needs, more co-occurring conditions, and were more likely to have a combined hyperactive/impulsive and inattentive ADHD subtype.”

Gluten- and casein-free diet and autism spectrum disorders in children: a systematic review.Six RCTs (214 participants) were included. One trial found that compared with the control group, in the GFCF diet group there were significant improvements in the scores for the ‘communication’ subdomain of the Autism Diagnostic Observation Schedule and for the ‘social interaction’ subdomain of the Gilliam Autism Rating Scale. Another trial found significant differences between groups in the post-intervention scores for the ‘autistic traits’, ‘communication’, and ‘social contact’ subdomains of a standardized Danish scheme. The remaining differences, if present, referred to parent-based assessment tools or other developmental/ASD-related features. No adverse events associated with a GFCF diet were reported. Overall, there is little evidence that a GFCF diet is beneficial for the symptoms of ASD in children.” Again those children for which a GFCF diet is beneficial get lost in the statistics. Unfortunately the review is not open-access, therefore we do not know which studies were selected.

Tryptophan status in autism spectrum disorder and the influence of supplementation on its level. Full text. “Some dietary-derived essential compounds, such as the amino acid tryptophan, appear to be impaired in patients with ASD. Tryptophan (Trp) plays a significant role in the human organism and serves as a precursor for a wide range of bioactive compounds, including major neurotransmitters. Research indicates that tryptophan might be deficient in subjects with ASD. Statistical evaluations in the concentration of tryptophan in ASD patients with different severity of symptoms were reported. A significant difference in tryptophan levels in all groups was observed. Supplementation with B vitamins and magnesium has an influence on the Trp concentration. These results assess that the Trp level in ASD subjects is critical and that intake of B vitamins and magnesium with diet might influence its metabolic homeostasis.”

Prenatal fever and autism risk. Full text. “Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Maternal exposure to second-trimester fever was associated with increased ASD risk. Risk increased markedly with exposure to three or more fever episodes after 12 weeks’ gestation. ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks’ gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD.”

Risk of Second Seizure in Pediatric Patients With Idiopathic Autism.Epilepsy is a comorbidity of idiopathic autism spectrum disorder. Patients with idiopathic autism spectrum disorder, ≥1 seizure, and age 2 to 23 years were included. 153 patients were included; 141 (92%) had a second seizure. The average age at first seizure was 7.14 years (median: 5.08 years) and 8.12 years (median: 7.3 years) at second seizure. Average time between first and second seizure was 7.68 months. A high risk of seizure recurrence was found in this population. There was a short time to second seizure, with most having a recurrence within 1 year.”

Homocysteine as a Diagnostic and Etiopathogenic Factor in Children with Autism Spectrum Disorder. “The aim of our study was assessment of hair magnesium and serum homocysteine concentrations in children with autism. Our research showed normal magnesium blood levels and significantly high homocysteine levels and very low hair magnesium levels, low concentration of hair magnesium progresses with age. Our hypothesis is that magnesium deficiency, as a relevant epigenetic factor, might be decreasing methylation of homocysteine, therefore decreasing genome transcription and lowering the synaptic plasticity. We suggest that analysis of hair magnesium and serum homocysteine levels might be useful in identification of children with autism spectrum disorder, as well as control of its treatment. Obtained results and performed analysis might therefore justify supplementation of magnesium among children with autism.”

Neurodevelopmental Delay Diagnosis Rates Are Increased in a Region with Aerial Pesticide Application. Full text. “A number of studies have implicated pesticides in childhood developmental delay (DD) and autism spectrum disorder (ASD). To study this factor, we examined ASD/DD diagnoses rates in an area near our regional medical center that employs yearly aerial pyrethroid pesticide applications to combat mosquito-borne encephalitis. The aim of this study was to determine if areas with aerial pesticide exposure had higher rates of ASD/DD diagnoses. This regional study identified higher rates of ASD/DD diagnoses in an area with aerial pesticides application. codes with aerial pyrethroid exposure were 37% more likely to have higher rates of ASD/DD.”

Increased risk for an atypical autism diagnosis following Thimerosal-containing vaccine exposure in the United States: A prospective longitudinal case-control study in the Vaccine Safety Datalink.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 and still added to some vaccines today. Concerns about the toxic effects from Thimerosal-containing childhood vaccines and the risk of an atypical autism diagnosis were evaluated in this study. Cases diagnosed with atypical autism were statistically significantly more likely to have received greater overall and dose-dependent exposures to Hg from TM-HepB vaccines administered within the first month of life, first two months of life, and first six months of life than the controls. Similar phenomena were observed when cases and controls were separated by gender. The present study provides important epidemiological evidence significantly associating increasing Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of atypical autism diagnosis, and suggests that Thimerosal should be eliminated from vaccines.”

Herbal Medicine Treatment for Children with Autism Spectrum Disorder: A Systematic Review. Full text. “The results of this systematic review indicated that herbal medicines combined with conventional treatment seem to have a positive effect on the treatment of ASD in children. Herbal medicines plus integrative therapy as an adjuvant to conventional therapy also have an encouraging effect in the treatment of autistic children. However, owing to the low methodological quality of the included studies, small sample size, and diversity of herbal medicines, firm conclusions could not be drawn.”

Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Full text. “Suramin was first synthesized in 1916, making it one of the oldest manmade drugs still in medical use. It is used to treat African sleeping sickness. Here, we report the findings of the Suramin Autism Treatment-1 (SAT-1) trial, the first direct test of suramin, the cell danger hypothesis, and the relevance of abnormal purinergic signaling in children with ASD. A single intravenous dose of suramin was associated with improved scores for language, social interaction, and decreased restricted or repetitive behaviors. None of these improvements occurred in the five children who received placebo. The generalizability of these findings is unknown. These studies showed that low-dose suramin was effective in treating ASD-like symptoms and did not produce toxicity even when used for at least 4 months. These data help form the foundation for future studies that will test the safety and efficacy of suramin, provide fresh directions for the development of new antipurinergic drugs, and add support to the hypothesis that a potentially treatable metabolic syndrome may contribute to the pathogenesis of autism.”

Human Embryonic Stem Cells in the Treatment of Autism: A Case Series. Full text. “Human embryonic stem cell therapy has been shown to improve blood perfusion in the brain; thus, this therapy may be effective in improving motor skills, social skills, and cognition in patients with autism spectrum disorder. The patients showed improvements in eye coordination, writing, balancing, cognition, and speech and showed reduced hypersensitivity to noises and smells.”

The amino acid profile in blood plasma of young boys with autism. Full text. “The mean plasma concentration values of citrulline, g-aminobutyric acid, isoleucine, leucine, phenylalanine, tryptophan and ornithine were significantly lower in boys with autism as compared to the control group. None of the amino acids measured differentiate autistic children from healthy children. The sum of exogenous amino acids was lower in the study group than in the control group but this difference was not statistically significant. Lower levels of exogenous amino acids confirm the possible role of these amino acids in autism. Determination of exogenous amino acids in plasma, however, cannot be used as a diagnostic test but it can still support autistic patients care.”

Serum thyroid-stimulating hormone and interleukin-8 levels in boys with autism spectrum disorder. Full pdf. “Eleven proteins were found that together could confirm ASD with modest accuracy using multiple training and test sets. Two of the 11 proteins identified here were further tested using a different detection platform and with a larger sample of ASD and TD boys. The two proteins, thyroid-stimulating hormone (TSH) and interleukin-8 (IL-8), have been previously identified as putative biomarkers for ASD. TSH levels were significantly lower in ASD boys, whereas IL-8 levels were significantly elevated. The diagnostic accuracy for ASD based upon TSH or IL-8 levels alone varied from 74 to 76%, but using both proteins together, the diagnostic accuracy increased to 82%. In addition, TSH levels were negatively correlated with the Autism Diagnostic Observation Schedule subdomain scores.”

Fetal and postnatal metal dysregulation in autism.Significant divergences are apparent in metal uptake between ASD cases and their control siblings, but only during discrete developmental periods. Cases have reduced uptake of essential elements manganese and zinc, and higher uptake of the neurotoxin lead. Manganese and lead are also correlated with ASD severity and autistic traits. Our study suggests that metal toxicant uptake and essential element deficiency during specific developmental windows increases ASD risk and severity, supporting the hypothesis of systemic elemental dysregulation in ASD.”

For more research into ASD that your medical professional is not reading. Just follow the link to my Autism page, and scroll down to Current Research –  Selected research articles of interest.

Be informed, NOT misinformed!