Although Munc18-1 was originally identified as a syntaxin1-interacting protein, the physiological significance of this interaction remains unclear. In fact, recent studies of Munc18-1 mutants have suggested that Munc18-1 plays a critical role for docking of secretory vesicles, independent of syntaxin1 regulation. Here we investigated the role of Munc18-1 in syntaxin1 localization by generating stable neuroendocrine cell lines in which Munc18-1 was strongly down-regulated. In these cells, the secretion capability, as well as the docking of dense-core vesicles, was significantly reduced. More importantly, not only was the expression level of syntaxin1 reduced, but the localization of syntaxin1 at the plasma membrane was also severely perturbed. The mislocalized syntaxin1 resided primarily in the perinuclear region of the cells, in which it was highly colocalized with Secretogranin II, a marker protein for dense-core vesicles. In contrast, the expression level and the plasma membrane localization of SNAP-25 were not affected. Furthermore, the syntaxin1 localization and the secretion capability were restored upon transfection-mediated reintroduction of Munc18-1. Our results indicate that endogenous Munc18-1 plays a critical role for the plasma membrane localization of syntaxin1 in neuroendocrine cells and therefore necessitates the interpretation of Munc18-1 mutant phenotypes to be in terms of mislocalized syntaxin1.

Background and objectives To investigate the feasibility of delivering a functional exercise-based prehabilitation intervention and its effects on postoperative length of hospital stay, preoperative physical functioning and health-related quality of life in elective colorectal surgery. Materials and methods In this randomised controlled feasibility trial, 22 elective colorectal surgery patients were randomly assigned to exercise prehabilitation (n = 11) or standard care (n = 11). Feasibility of delivering the intervention was assessed based on recruitment and compliance to the intervention. Impact on postoperative length of hospital stay and complications, preoperative physical functioning (timed up and go test, five times sit to stand, stair climb test, handgrip dynamometry and 6-min walk test) and health-related quality of life were also assessed. Results Over 42% of patients (84/198) screened were deemed ineligible for prehabilitation due to insufficient time existing prior to scheduled surgery. Of those who were eligible, approximately 18% consented to the trial. Median length of hospital stay was 8 [range 6-27] and 10 [range 5-12] days respectively for the standard care and prehabilitation groups. Patterns towards preoperative improvements for the timed up and go test, stair climb test and 6-min walk test were observed for all participants receiving prehabilitation but not standard care. Conclusions Despite prehabilitation appearing to convey positive benefits on physical functioning, short surgical wait times and patient engagement represent major obstacles to implementing exercise prehabilitation programmes in colorectal cancer patients.

Although CAPS1 was originally identified as a soluble factor that reconstitutes Ca 2؉ -dependent secretion from permeabilized neuroendocrine cells, its exact function in intact mammalian cells remains controversial. Here we investigate the role for CAPS1 by generating stable cell lines in which CAPS1 is strongly down-regulated. In these cells, Ca 2؉ -dependent secretion was strongly reduced not only of catecholamine but also of a transfected neuropeptide. These secretion defects were rescued by infusion of CAPS1-containing brain cytosol or by transfectionmediated expression of CAPS1. Whole cell patch clamp recording revealed significant reductions in slow burst and sustained release components of exocytosis in the knockdown cells. Unexpectedly, they also accumulated higher amounts of endogenous and exogenous transmitters, which were attributable to reductions in constitutive secretion. Electron microscopy did not reveal abnormalities in the number or docking of dense core vesicles. Our results indicate that CAPS1 plays critical roles not only in Ca 2؉ -dependent, regulated exocytosis but also in constitutive exocytosis downstream of vesicle docking. However, they do not support the role for CAPS1 in loading transmitters into dense core vesicles.Catecholamines such as dopamine and noradrenaline are released from secretory vesicles through regulated and constitutive secretory processes. Distinct types of secretory vesicles account for the storage and secretion of different neurotransmitters and peptides/neuromodulators. Synaptic vesicles are responsible for the storage and secretion of classic neurotransmitters such as glutamate, glycine, and ␥-aminobutyric acid, whereas dense core vesicles are responsible for the storage and secretion of peptides and catecholamines. Ca

In RCTs with statistically nonsignificant primary outcomes published in surgical journals, the reporting and interpretation of findings was frequently inconsistent with the results.