No abstract

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD. Autism Res 2016, 9: 621-631. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

No 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 methylationsensitive 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 þ promoted enzyme activity and methylation, while Cu þ , Pb 2 þ , Hg 2 þ and Al 3 þ 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.

Prevalence of autistic spectrum disorders (ASD) in Oman is unknown. We conducted a cross-sectional study to estimate the prevalence of ASD among 0-14 year old children. Diagnoses were made as per DSM-IV-TR criteria and supplemented with information collected with the standard Childhood Autism Rating Scale (CARS) questionnaire. A total 113 cases of ASD were enumerated nationwide, indicating an overall prevalence of 1.4 (95% CI 1.2, 1.7) cases per 10,000 children aged 0-14 years. More prevalent cases were among boys (75%) and among low-income families. Ritualistic interests were more common among girls as an onset-symptom compared to boys (p = 0.03). The reported low prevalence of ASD in Oman is likely due to under-diagnosis and under-reporting.

No abstract

There is diurnal fluctuation in endothelial function, which is associated with variation in the frequency of ischemic episodes.

No abstract