Nicotinic acid adenine dinucleotide phosphate (NAADP) is a widespread and potent calcium-mobilizing messenger that is highly unusual in activating calcium channels located on acidic stores. However, the molecular identity of the target protein is unclear. In this study, we show that the previously uncharacterized human two-pore channels (TPC1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpression of TPC1 and attenuated after knockdown of TPC1, and that mutation of a single highly conserved residue within a putative pore region abrogated calcium release by NAADP. Thus, TPC1 is critical for NAADP action and is likely the long sought after target channel for NAADP.

We found that the selective stimulation of the intracellular, transmembrane G protein-coupled estrogen receptor (GPER), also known as GPR30, acutely lowers blood pressure after infusion in normotensive rats and dilates both rodent and human arterial blood vessels. Stimulation of GPER blocks vasoconstrictor-induced changes in intracellular calcium concentrations and vascular tone, as well as serum-stimulated cell proliferation of human vascular smooth muscle cells. Deletion of the GPER gene in mice abrogates vascular effects of GPER activation and is associated with visceral obesity. These findings suggest novel roles for GPER in protecting from cardiovascular disease and obesity.

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ObjectiveTo evaluate the clinical and economic burden associated with anastomotic leaks following colorectal surgery.MethodsRetrospective data (January 2008 to December 2010) were analyzed from patients who had colorectal surgery with and without postoperative leaks, using the Premier Perspective™ database. Data on in-hospital mortality, length of stay (LOS), re-admissions, postoperative infection, and costs were analyzed using univariate and multivariate analyses, and the propensity score matching (PSM) and generalized linear models (GLM).ResultsOf the patients, 6,174 (6.18 %) had anastomotic leaks within 30 days after colorectal surgery. Patients with leaks had 1.3 times higher 30-day re-admission rates and 0.8–1.9 times higher postoperative infection rates as compared with patients without leaks (P < 0.001 for both). Anastomotic leaks incurred additional LOS and hospital costs of 7.3 days and $24,129, respectively, only within the first hospitalization. Per 1,000 patients undergoing colorectal surgery, the economic burden associated with anastomotic leaks—including hospitalization and re-admission—was established as 9,500 days in prolonged LOS and $28.6 million in additional costs. Similar results were obtained from both the PSM and GLM for assessing total costs for hospitalization and re-admission.ConclusionsAnastomotic leaks in colorectal surgery increase the total clinical and economic burden by a factor of 0.6–1.9 for a 30-day re-admission, postoperative infection, LOS, and hospital costs.