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The effects of amyloid b protein on voltage-gated K 1 channel currents were studied using the whole-cell patch-clamp technique. The 1±40 amino acid form of amyloid b protein was applied to primary cultures of rat cerebellar granule and cortical neurones for 24 h. Both the unaggregated and aggregated forms of the peptide, which have differing biological activities, were used. In cerebellar granule neurones, 24-h pre-incubation with 1 mM unaggregated amyloid b protein resulted in a 60% increase in the`A'-type component of K 1 current. Increased delayed recti®er activity was Cd 21 -sensitive and was presumed to be secondary to an increase in voltage-gated Ca 21 channel current activity. Unaggregated amyloid b protein had no effect on any component of the K 1 channel current in cortical neurones. One micromolar of aggregated amyloid b protein had no effect on K 1 channel current in either cell type but reduced cell survival within 24 h as measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assays. The unaggregated form of amyloid b protein had no neurotoxic effects when applied to either neurone type for up to 72 h. These data indicate that the unaggregated, nonpathological form of amyloid b protein causes changes in the ion channel function of neurones, possibly re¯ecting a physiological role for the peptide.

Alzheimer's disease (AD) is more prevalent following an ischemic or hypoxic episode, such as stroke. Indeed, brain levels of amyloid precursor protein (APP) and the cytotoxic amyloid b peptide (Ab) fragment are enhanced in these patients and in animal models following experimental ischaemia. We have investigated the effect of chronic hypoxia (CH; 2.5% O 2 , 24 h) on processing of APP in the human neuroblastoma, SH-SY5Y. We demonstrate that constitutive and muscarinic-receptor-enhanced secretion of the a-secretase cleaved fragment of APP, sAPPa, was reduced by 60% in CH cells. The caspase inhibitor BOC-D(Ome)FMK did not reverse this effect of CH, and CH cells were as viable as controls, based on MTT assays. Thus, loss of sAPPa is not related to cell death or caspase processing of APP. Preincubation with antioxidants did not reverse the effect of CH, and the effect could not be mimicked by H 2 O 2 , discounting the involvement of reactive oxygen species in hypoxic loss of sAPPa. CH did not affect muscarinic activation of extracellular-signal regulated kinase. However, expression of ADAM 10 (widely believed to be a-secretase) was decreased approximately 50% following CH. Thus, CH selectively decreases processing of APP by the a-secretase pathway, most likely by decreasing levels of ADAM 10.

Summary Obesity is a chronic disease in which the abnormal or excessive accumulation of body fat leads to impaired health and increased risk of mortality and chronic health complications. Prevalence of obesity is rising rapidly in South and Southeast Asia, with potentially serious consequences for local economies, healthcare systems, and quality of life. Our group of obesity specialists from Bangladesh, Brunei Darussalam, India, Indonesia, Malaysia, Philippines, Singapore, Sri Lanka, Thailand, and Viet Nam undertook to develop consensus recommendations for management and care of adults and children with obesity in South and Southeast Asia. To this end, we identified and researched 12 clinical questions related to obesity. These questions address the optimal approaches for identifying and staging obesity, treatment (lifestyle, behavioral, pharmacologic, and surgical options) and maintenance of reduced weight, as well as issues related to weight stigma and patient engagement in the clinical setting. We achieved consensus on 42 clinical recommendations that address these questions. An algorithm describing obesity care is presented, keyed to the various consensus recommendations.