Munc18-1 promotes larger dense-core vesicle docking.

AbstractSecretory vesicles dock at the plasma membrane before Ca2+ triggers their exocytosis. Exocytosis requires the assembly of SNARE complexes formed by the vesicle protein Synaptobrevin and the membrane proteins Syntaxin-1 and SNAP-25. We analyzed the role of Munc18-1, a cytosolic binding partner of Syntaxin-1, in large dense-core vesicle (LDCV) secretion. Calcium-dependent LDCV exocytosis was reduced 10-fold in mouse chromaffin cells lacking Munc18-1, but the kinetic properties of the remaining release, including single fusion events, were not different from controls. Concomitantly, mutant cells displayed a 10-fold reduction in morphologically docked LDCVs. Moreover, acute overexpression of Munc18-1 in bovine chromaffin cells increased the amount of releasable vesicles and accelerated vesicle supply. We conclude that Munc18-1 functions upstream of SNARE complex formation and promotes LDCV docking

Functional outcome is tied to dynamic brain states after mild to moderate traumatic brain injury

The current study set out to investigate the dynamic functional connectome in relation to long-term recovery after mild to moderate traumatic brain injury (TBI). Longitudinal resting-state functional MRI data were collected (at 1 and 3 months postinjury) from a prospectively enrolled cohort consisting of 68 patients with TBI (92% mild TBI) and 20 healthy subjects. Patients underwent a neuropsychological assessment at 3 months postinjury. Outcome was measured using the Glasgow Outcome Scale Extended (GOS-E) at 6 months postinjury. The 57 patients who completed the GOS-E were classified as recovered completely (GOS-E = 8; n = 37) or incompletely (GOS-E < 8; n = 20). Neuropsychological test scores were similar for all groups. Patients with incomplete recovery spent less time in a segregated brain state compared to recovered patients during the second visit. Also, these patients moved less frequently from one meta-state to another as compared to healthy controls and recovered patients. Furthermore, incomplete recovery was associated with disruptions in cyclic state transition patterns, called attractors, during both visits. This study demonstrates that poor long-term functional recovery is associated with alterations in dynamics between brain networks, which becomes more marked as a function of time. These results could be related to psychological processes rather than injury-effects, which is an interesting area for further work. Another natural progression of the current study is to examine whether these dynamic measures can be used to monitor treatment effects

Outcomes of surgical treatment of non-metastatic gastric cancer in patients aged 70 and older:A systematic review and meta-analysis

The optimal surgical treatment strategy for gastric cancer in older patients needs to be carefully evaluated due to increased vulnerability of older patients. We performed a database search for randomized controlled trials (RCTs) and cohort studies that included patients ≥70 years with potentially resectable stage I-III gastric cancer. Postoperative and survival outcomes were compared between groups undergoing 1) gastrectomy vs conservative treatment (best supportive care or non-operative treatment), 2) minimally invasive (MIG) vs open gastrectomy (OG), or 3) extended vs limited lymphadenectomy. When possible, results were pooled using risk ratios (RR). Thirty-one studies were included. Six retrospective studies compared overall survival (OS) between gastrectomy (N = 2332) and conservative treatment (N = 246). Longer OS was reported in the gastrectomy group in all studies, but study quality was low and meta-analysis was not feasible. Eighteen cohort studies compared MIG (N = 3626) and OG (N = 5193). MIG was associated with fewer complications (pooled RR 0.68, 95% confidence interval 0.54–0.84). OS was not different between the groups. Two RCTs and five cohort studies compared outcomes between extended (N = 709) and limited lymphadenectomy (N = 1323). Complication rates were comparable between the groups. Two cohort studies found longer OS or cancer-specific survival after extended lymphadenectomy. No quality of life (QoL) or functional outcomes were reported. In older patients with gastric cancer, there is low-quality evidence for better OS after gastrectomy vs conservative treatment. Compared to OG, MIG was associated with less postoperative morbidity. The evidence to support extended lymphadenectomy is limited. QoL and functional outcomes should be addressed in future studies

The Collaboration on Attachment Transmission Synthesis (CATS): A Move to the Level of Individual-Participant-Data Meta-Analysis

Generations of researchers have tested and used attachment theory to understand children’s development. To bring coherence to the expansive set of findings from small-sample studies, the field early on adopted meta-analysis. Nevertheless, gaps in understanding intergenerational transmission of individual differences in attachment continue to exist. We discuss how attachment research has been addressing these challenges by collaborating in formulating questions and pooling data and resources for individual-participant-data meta-analyses. The collaborative model means that sharing hard-won and valuable data goes hand in hand with directly and intensively interacting with a large community of researchers in the initiation phase of research, deliberating on and critically reviewing new hypotheses, and providing access to a large, carefully curated pool of data for testing these hypotheses. Challenges in pooling data are also discussed

The feasibility and results of a population-based approach to evaluating prostate-specific antigen screening for prostate cancer in men with a raised familial risk

The feasibility of a population-based evaluation of screening for prostate cancer in men with a raised familial risk was investigated by studying reasons for non-participation and uptake rates according to postal recruitment and clinic contact. The levels of prostate-specific antigen (PSA) and the positive predictive values (PPV) for cancer in men referred with a raised PSA and in those biopsied were analysed. First-degree male relatives (FDRs) were identified through index cases (ICs): patients living in two regions of England and diagnosed with prostate cancer at age ⩽65 years from 1998 to 2004. First-degree relatives were eligible if they were aged 45–69 years, living in the UK and had no prior diagnosis of prostate cancer. Postal recruitment was low (45 of 1687 ICs agreed to their FDR being contacted: 2.7%) but this was partly due to ICs not having eligible FDRs. A third of ICs in clinic had eligible FDRs and 49% (192 out of 389) agreed to their FDR(s) being contacted. Of 220 eligible FDRs who initially consented, 170 (77.3%) had a new PSA test taken and 32 (14.5%) provided a previous PSA result. Among the 170 PSA tests, 10% (17) were ⩾4 ng ml−1 and 13.5% (23) tests above the age-related cutoffs. In 21 men referred, five were diagnosed with prostate cancer (PPV 24%; 95% CI 8, 47). To study further the effects of screening, patients with a raised familial risk should be counselled in clinic about screening of relatives and data routinely recorded so that the effects of screening on high-risk groups can be studied