Cross-genetic determination of maternal and neonatal immune mediators during pregnancy.

BACKGROUND:The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control. METHODS:This is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h2g) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome. RESULTS:We show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype. CONCLUSIONS:Our results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders

Unlocking the condoms: The effect on sales and theft

Community pharmacies may place condoms in locked displays or behind glass, thereby reducing access and consequent use. Objective: Quantify sales and theft of condoms when condoms were unlocked and removed from behind glass in grocery pharmacies Methods: Design. In this pilot study, condom displays were unlocked in selected pharmacies for three months. Participants. Eight grocery pharmacies in central Iowa agreed to participate. Intervention. Stores provided inventory at baseline, sales/theft thereafter in three monthly reports and sales for the same period one-year earlier. Outcome measures. Descriptive statistics quantified condom theft and sales. Number of pharmacies leaving condoms unlocked after the intervention was determined. Results: Theft varied by pharmacy and ranged from an average of 1.33 boxes (units) per month to 27.33 per month. All stores experienced some increase in sales during the intervention. Two locations decided to re-lock their displays, only one indicated theft as the reason. Conclusion: After removing condoms from locked displays, more condoms were purchased and stolen from the study pharmacies. Sales outweighed theft in all pharmacies.Las farmacias comunitarias pueden situar los condones en estanterías cerradas o detrás de un cristal, reduciendo así el acceso y consiguientemente el uso. Objetivo: Cuantificar las ventas y el robo de condones cuando están libres y retirados de detrás de un cristal en las farmacias. Métodos: Diseño. En este estudio piloto, se abrieron las estanterías de los condones en unas farmacias seleccionadas durante tres meses. Participantes. Ocho farmacias en el centro de Iowa aceptaron participar. Intervención. Las farmacias proporcionaron el inventario al principio, informes de las ventas/robos en los tres meses posteriores y las ventas para ese mismo periodo de un año antes. Medidas de resultados. La estadística descriptiva cuantificó las ventas y robos de condones. Se determinó el número de farmacias que dejaron los condones abiertos después de la intervención. Resultados: Los robos variaron por farmacia y oscilaron entre una media de 1,33 cajas (unidades) por mes a 27,33 por mes. Todas las farmacias experimentaron algún aumento en las ventas durante la intervención. Dos establecimientos decidieron volver a cerrar los expositores de condones, y sólo uno indicó el robo como causa. Conclusión: Después de retirar los condones de los expositores cerrados, se vendieron y robaron más condones en las farmacias estudiadas. Las ventas sobrepasaron los robos en todas las farmacias

Identification of the antigenic epitopes of maternal autoantibodies in autism spectrum disorders.

Several groups have described the presence of fetal brain-reactive maternal autoantibodies in the plasma of some mothers whose children have autism spectrum disorder (ASD). We previously identified seven autoantigens targeted by these maternal autoantibodies, each of which is expressed at significant levels in the developing brain and has demonstrated roles in typical neurodevelopment. To further understand the binding repertoire of the maternal autoantibodies, as well as the presence of any meaningful differences with respect to the recognition and binding of these ASD-specific autoantibodies to each of these neuronal autoantigens, we utilized overlapping peptide microarrays incubated with maternal plasma samples obtained from the Childhood Autism Risk from Genetics and Environment (CHARGE) Study. In an effort to identify the most commonly recognized (immunodominant) epitope sequences targeted by maternal autoantibodies for each of the seven ASD-specific autoantigens, arrays were screened with plasma from mothers with children across diagnostic groups (ASD and typically developing (TD)) that were positive for at least one antigen by western blot (N = 67) or negative control mothers unreactive to any of the autoantigens (N = 18). Of the 63 peptides identified with the discovery microarrays, at least one immunodominant peptide was successfully identified for each of the seven antigenic proteins using subsequent selective screening microarrays. Furthermore, while limited by our relatively small sample size, there were peptides that were distinctly recognized by autoantibodies relative to diagnosis For example, reactivity was observed exclusively in mothers of children of ASD towards several peptides, including the LDH-B peptides DCIIIVVSNPVDILT (9.1% ASD vs. 0% TD; odds ratio (95% CI) = 6.644 (0.355-124.384)) and PVAEEEATVPNNKIT (5.5% ASD vs. 0% TD; odds ratio (95% CI) = 4.067 (0.203-81.403)).These results suggest that there are differences in the binding repertoire between the antigen positive ASD and TD maternal samples. Further, the autoantibodies in plasma from mothers of children with ASD bound to a more diverse set of peptides, and there were specific peptide binding combinations observed only in this group. Future studies are underway to determine the critical amino acids necessary for autoantibody binding, which will be essential in developing a potential therapeutic strategy for maternal autoantibody related (MAR) ASD

Alpha oscillatory activity during attentional control in children with Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), and ASD+ADHD

BACKGROUND: Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) share impairments in top-down and bottom-up modulation of attention. However, it is not yet well understood if co-occurrence of ASD and ADHD reflects a distinct or additive profile of attention deficits. We aimed to characterise alpha oscillatory activity (stimulus-locked alpha desynchronisation and prestimulus alpha) as an index of integration of top-down and bottom-up attentional processes in ASD and ADHD. METHODS: Children with ASD, ADHD, comorbid ASD+ADHD, and typically-developing children completed a fixed-choice reaction-time task (‘Fast task’) while neurophysiological activity was recorded. Outcome measures were derived from source-decomposed neurophysiological data. Main measures of interest were prestimulus alpha power and alpha desynchronisation (difference between poststimulus and prestimulus alpha). Poststimulus activity linked to attention allocation (P1, P3), attentional control (N2), and cognitive control (theta synchronisation, 100–600 ms) was also examined. ANOVA was used to test differences across diagnostics groups on these measures. Spearman’s correlations were used to investigate the relationship between attentional control processes (alpha oscillations), central executive functions (theta synchronisation), early visual processing (P1), and behavioural performance. RESULTS: Children with ADHD (ADHD and ASD+ADHD) showed attenuated alpha desynchronisation, indicating poor integration of top-down and bottom-up attentional processes. Children with ADHD showed reduced N2 and P3 amplitudes, while children with ASD (ASD and ASD+ADHD) showed greater N2 amplitude, indicating atypical attentional control and attention allocation across ASD and ADHD. In the ASD group, prestimulus alpha and theta synchronisation were negatively correlated, and alpha desynchronisation and theta synchronisation were positively correlated, suggesting an atypical association between attentional control processes and executive functions. CONCLUSIONS: ASD and ADHD are associated with disorder-specific impairments, while children with ASD+ADHD overall presented an additive profile with attentional deficits of both disorders. Importantly, these findings may inform the improvement of transdiagnostic procedures and optimisation of personalised intervention approaches

An Exploratory Examination of Neonatal Cytokines and Chemokines as Predictors of Autism Risk: The Early Markers for Autism Study.

BackgroundThe identification of an early biomarker for autism spectrum disorder (ASD) would improve the determination of risk, leading to earlier diagnosis and, potentially, earlier intervention and improved outcomes.MethodsData were generated from the Early Markers for Autism study, a population-based case-control study of prenatal and neonatal biomarkers of ASD. Newborn bloodspots of children with ASD (n = 370), children with developmental delay (n = 140), and general population (GP) controls (n = 378) were analyzed for 42 different immune markers using a Luminex multiplex platform. Comparisons of immune marker concentrations between groups were examined using logistic regression and partial least squares discriminant analysis.ResultsChildren with ASD had significantly increased neonatal levels of interleukin-6 (IL-6) and IL-8 compared with GP controls. An increase in IL-8 was especially significant in the ASD group with early onset compared with the GP group, with an adjusted odds ratio of 1.97 (95% confidence interval, 1.39-2.83; p = .00014). In addition, children with ASD had significantly elevated levels of eotaxin-1, interferon-γ, and IL-12p70 relative to children with developmental delay. We observed no significant differences in levels of immune markers between the developmental delay and GP groups.ConclusionsElevated levels of some inflammatory markers in newborn bloodspots indicated a higher degree of immune activation at birth in children who were subsequently diagnosed with ASD. The data from this exploratory study suggest that with further expansion, the development of neonatal bloodspot testing for cytokine/chemokine levels might lead to the identification of biomarkers that provide an accurate assessment of ASD risk at birth