High-throughput screen detects calcium signaling dysfunction in typical sporadic autism spectrum disorder.

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders without any defined uniting pathophysiology. Ca2+ signaling is emerging as a potential node in the genetic architecture of the disorder. We previously reported decreased inositol trisphosphate (IP3)-mediated Ca2+ release from the endoplasmic reticulum in several rare monogenic syndromes highly comorbid with autism - fragile X and tuberous sclerosis types 1 and 2 syndromes. We now extend those findings to a cohort of subjects with sporadic ASD without any known mutations. We developed and applied a high throughput Fluorometric Imaging Plate Reader (FLIPR) assay to monitor agonist-evoked Ca2+ signals in human primary skin fibroblasts. Our results indicate that IP3 -mediated Ca2+ release from the endoplasmic reticulum in response to activation of purinergic receptors is significantly depressed in subjects with sporadic as well as rare syndromic forms of ASD. We propose that deficits in IP3-mediated Ca2+ signaling represent a convergent hub function shared across the spectrum of autistic disorders - whether caused by rare highly penetrant mutations or sporadic forms - and holds promise as a biomarker for diagnosis and novel drug discovery.

Quantitative estimation of left atrial linear dimension on a transthoracic echocardiogram using an electrocardiographic formulaic assessment.

A proportionate and incremental association between left atrial (LA) dilatation on a transthoracic echocardiogram (TTE) and increasing severity in abnormal atrial depolarization can be described by the regression formula: LA dimension in parasternal long-axis view (in millimeters) = 2.47 + 0.29 [P-wave duration (in milliseconds)]. However, prospective testing of this formula for LA quantification with comparison to other TTE indexes is lacking. We prospectively obtained 12-lead electrocardiograms for 72 consecutive patients before individual, nonemergent TTE assessment. P waves were assessed independently to the nearest 10 ms for application of the formula with a Bland-Altman plot. P-wave durations were obtained specifically from lead II and also from any lead that yielded the widest measurement. There was a strong formulaic correlation with LA measurement by TTE (p <0.00000001; r = 0.662), irrespective of electrocardiographic lead used. However, as the measurement difference increased between that in any lead and lead II, correlation strength increased. Correlation was not significantly affected by commonly measured electrocardiographic and TTE indexes, such as, PR interval, QRS complex, and left ventricular end-diastolic as well as systolic dimensions, after adjustment for these variables. Moreover, when the P-wave axis remained within the normal range, the correlation strength increased. The Bland-Altman plot also showed good agreement of LA dimension assessment between formulaic estimation and TTE measurement. In conclusion, there is good agreement and correlation between formulaic estimation and that of TTE for measurement of LA linear dimension. The LA regression formula is an indirect asset that could perhaps supplement LA quantification on TTE in certain circumstances.