Neurobeachin Regulates Glutamate- and GABA-Receptor Targeting to Synapses via Distinct Pathways.

Neurotransmission and synaptic strength depend on expression of post-synaptic receptors on the cell surface. Post-translational modification of receptors, trafficking to the synapse through the secretory pathway, and subsequent insertion into the synapse involves interaction of the receptor with A-kinase anchor proteins (AKAPs) and scaffolding proteins. Neurobeachin (Nbea), a brain specific AKAP, is required for synaptic surface expression of both glutamate and GABA receptors. Here, we investigated the role of Nbea-dependent targeting of postsynaptic receptors by studying Nbea interaction with synapse-associated protein 102 (SAP102/Dlg3) and protein kinase A subunit II (PKA II). A Nbea mutant lacking the PKA binding domain showed a similar distribution as wild-type Nbea in Nbea null neurons and partially restored GABA receptor surface expression. To understand the relevance of Nbea interaction with SAP102, we analysed SAP102 null mutant mice. Nbea levels were reduced by ~80% in SAP102 null mice, but glutamatergic receptor expression was normal. A single-point mutation in the pleckstrin homology domain of Nbea (E2218R) resulted in loss of binding with SAP102. When expressed in Nbea null neurons, this mutant fully restored GABA receptor surface expression, but not glutamate receptor expression. Our results suggest that the PKA-binding domain is not essential for Nbea's role in receptor targeting and that Nbea targets glutamate and GABA receptors to the synapse via distinct molecular pathways by interacting with specific effector proteins.

Determinants of percent expenditure of household income due to childhood diarrhoea in rural Bangladesh.

There is limited information on percent expenditure of household income due to childhood diarrhoea especially in rural Bangladesh. A total of 4205 children aged <5 years with acute diarrhoea were studied. Percent expenditure was calculated as total expenditure for the diarrhoeal episode divided by monthly family income, multiplied by 100. Overall median percent expenditure was 3·04 (range 0·01-94·35). For Vibrio cholerae it was 6·42 (range 0·52-82·85), for enterotoxigenic Escherichia coli 3·10 (range 0·22-91·87), for Shigella 3·17 (range 0·06-77·80), and for rotavirus 3·08 (range 0·06-48·00). In a multinomial logistic regression model, for the upper tertile of percent expenditure, significant higher odds were found for male sex, travelling a longer distance to reach hospital (⩾median of 4 miles), seeking care elsewhere before attending hospital, vomiting, higher frequency of purging (⩾10 times/day), some or severe dehydration and stunting. V. cholerae was the highest and rotavirus was the least responsible pathogen for percent expenditure of household income due to childhood diarrhoea.

Aetiologies of diarrhoea in adults from urban and rural treatment facilities in Bangladesh.

The objective of our analysis was to describe the aetiology, clinical features, and socio-demographic background of adults with diarrhoea attending different urban and rural diarrhoeal disease hospitals in Bangladesh. Between January 2010 and December 2011, a total of 5054 adult diarrhoeal patients aged ⩾20 years were enrolled into the Diarrhoeal Disease Surveillance Systems at four different hospitals (two rural and two urban) of Bangladesh. Middle-aged [adjusted odds ratio (aOR) 0·28, 95% confidence interval (CI) 0·23-0·35, P < 0·001] and elderly (aOR 0·15, 95% CI 0·11-0·20, P < 0·001) patients were more likely to present to rural diarrhoeal disease facilities than urban ones. Vibrio cholerae was the most commonly isolated pathogen (16%) of the four pathogens tested followed by rotavirus (5%), enterotoxigenic Escherichia coli (ETEC) (4%), and Shigella (4%). Of these pathogens, V. cholerae (19% vs. 11%, P < 0·001), ETEC (9% vs. 4%, P < 0·001), and rotavirus (5% vs. 3%, P = 0·013) were more commonly detected from patients presenting to urban hospitals than rural hospitals, but Shigella was more frequently isolated from patients presenting to rural hospitals than urban hospitals (7% vs. 2%, P < 0·001). The isolation rate of Shigella was higher in the elderly than in younger adults (8% vs. 3%, P < 0·001). Some or severe dehydration was higher in urban adults than rural adults (P < 0·001). Our findings indicate that despite economic and other progress made, conditions facilitating transmission of V. cholerae and Shigella prevail in adults with diarrhoea in Bangladesh and further efforts are needed to control these infections.

Geographical diversity in seasonality of major diarrhoeal pathogens in Bangladesh observed between 2010 and 2012.

The study aimed to determine the geographical diversity in seasonality of major diarrhoeal pathogens among 21 138 patients enrolled between 2010 and 2012 in two urban and two rural sites in Bangladesh under the surveillance system of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b). Distinct patterns in seasonality were found for rotavirus diarrhoea which peaked in winter across the sites (December and January) and dipped during the rainy season (May) in urban Dhaka, August in Mirpur and July in Matlab, equated by time-series analysis using quasi-Poisson regression model. Significant seasonality for shigellosis was observed in Dhaka and rural Mirzapur. Cholera had robust seasonality in Dhaka and Matlab in the hot and rainy seasons. For enterotoxogenic Escherichia coli (ETEC) diarrhoea, clearly defined seasonality was observed in Dhaka (summer). Understanding the seasonality of such pathogens can improve case management with appropriate therapy, allowing policy-makers to identify periods of high disease burden.

Aetiology and clinical features of dysentery in children aged <5 years in rural Bangladesh.

The study identified the common aetiological agents and prominent clinical features of dysentery cases in children aged <5 years and compared this to non-dysentery diarrhoeal cases from the same population. From January 2010 to December 2011, 2324 children aged <5 years received treatment at Kumudini Hospital, of which 682 (29%) presented with dysentery. Of the dysenteric children, aetiology could not be determined for over half (61%). Shigella spp. accounted for 32% of dysentery cases. Significant associations were found between presence of blood in stool and: child age (24-59 months) [odds ratio (OR) 2.21, 95% confidence interval (CI) 1.49-3.27], no treatment of drinking water at home (OR 2.00, 95% CI 1.09-3.67), vomiting (OR 0.19, 95% CI 0.14-0.25), abdominal pain (OR 4.68, 95% CI 3.24-6.77), straining (OR 16.45, 95% CI 11.92-22.69), wasting (OR 1.66, 95% CI 1.15-2.41), and presence of Shigella in stool (OR 6.25, 95% CI 4.20-9.29) after controlling for confounders. This study makes it clear that appropriate public health strategies are needed to reduce the burden of dysentery in Bangladesh.

Efficacy and safety of carvedilol in infants with dilated cardiomyopathy: a preliminary report.

BACKGROUND: Carvedilol has proven to be beneficial in a majority of adult patients with congestive heart failure. Although the experience from adult patients may be extrapolated to older children, symptomatic infants remain a subset for whom dosage, safety and efficacy need to be established. The purpose of this study was to assess whether treatment with carvedilol is efficacious and safe for infants with dilated cardiomyopathy who do not show satisfactory clinical improvement despite treatment with conventional medications. METHODS AND RESULTS: Eight infants with dilated cardiomyopathy (ejection fraction <30%) who were symptomatic despite tailored treatment with decongestive medications, were enrolled in the study. Echocardiographic findings and heart failure symptom scores were analyzed before and after starting carvedilol. Patients were hospitalized and monitored for side-effects during up-titration of carvedilol. At a follow-up of 4.5+/-2.2 months, patients receiving carvedilol showed a significant improvement in the left ventricular ejection fraction (38.5+/-11% v. 24.4+/-5%), and heart failure symptom score (p<0.05). No adverse events related to carvedilol administration occurred. There were no deaths. CONCLUSIONS: Carvedilol is well tolerated in infants with dilated cardiomyopathy and there is significant improvement in their functional status. Optimal timing of starting therapy, dosage and long-term effects need to be investigated with multi-institutional trials.