Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice.

Hydrocephalus is a common and potentially devastating birth defect affecting the CNS, and its relationship with G protein-coupled receptors (GPCRs) is unknown. We have expressed 2, 4, or 6 copies of a GPCR--the human PAC1 receptor with a 130-kb transgene in the mouse nervous system in a pattern closely resembling that of the endogenous gene. Consistent with PAC1 actions, PKA and PKC activity were elevated in the brains of Tg mice. Remarkably, Tg mice developed dose-dependent hydrocephalus-like characteristics, including enlarged third and lateral ventricles and reduced cerebral cortex, corpus callosum, and subcommissural organ (SCO). Neuronal proliferation and apoptosis were implicated in hydrocephalus, and we observed significantly reduced neuronal proliferation and massively increased neuronal apoptosis in the developing cortex and SCO of Tg embryos, while neurite outgrowth and neuronal migration in vitro remain uncompromised. Ventricular ependymal cilia are crucial for directing cerebrospinal fluid flow, and ependyma of Tg mice exhibited disrupted cilia with increased phospho-CREB immunoreactivity. These data demonstrate that altered neuronal proliferation/apoptosis and disrupted ependymal cilia are the main factors contributing to hydrocephalus in PAC1-overexpressing mice. This is the first report to our knowledge demonstrating that misregulation of GPCRs can be involved in hydrocephalus-related neurodevelopmental disorders.

Does reducing your salt intake make you live longer?

A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether restricting dietary salt intake would provide protection from adverse cardiovascular events or mortality. Using the reported search, 462 papers were identified of which 14 papers represented the best evidence on the subject. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and weaknesses were tabulated. We conclude that restricting sodium intake to levels below 6 g per day as most international guidelines such as those of the AHA, the US Dietary Guideline Committee and the Scientific Advisory Committee on Nutrition recommend, clearly reduces blood pressure and in turn may reduce the need for antihypertensives by as much as 30%. However, the ability of dietary sodium restriction to reduce the incidence of cardiovascular events is more controversial due to the lack of adequately powered randomised trials or observational studies conducted with sufficient rigour. Some of the largest studies such as NHANES and TOHP, which do demonstrate a significant benefit, report a 20-30% relative reduction in adverse events which, due to the low rate of these events in the studies equates to an absolute risk reduction over 10-20 years in the region of 2-3% for protection from adverse cardiovascular events from sodium dietary restriction.