Effect of pharmacologically induced smooth muscle activation on permeability in murine colitis.

BACKGROUND: Both intestinal permeability and contractility are altered in inflammatory bowel disease. Little is known about their mutual relation. Therefore, an in vitro organ bath technique was developed to investigate the simultaneous effects of inflammation on permeability and smooth muscle contractility in different segments of the colon. METHODS AND MATERIALS: BALB/c mice were exposed to a 10% dextran sulphate sodium drinking water solution for 7 days to induce a mild colitis, while control mice received normal tap water. Intestinal segments were placed in an oxygenated organ bath containing Krebs buffer. Permeability was measured by the transport of the marker molecules 3H-mannitol and 14C-polyethyleneglycol 4000. Contractility was measured through a pressure sensor. Smooth muscle relaxation was obtained by salbutamol and l-phenylephrine, whereas contraction was achieved by carbachol and 1-(3-chlorophenyl)-biguanide. RESULTS: The intensity of mucosal inflammation increased throughout the colon. Also, regional differences were observed in intestinal permeability. In both normal and inflamed distal colon segments, permeability was diminished compared with proximal colon segments and the non-inflamed ileum. Permeability in inflamed distal colon segments was significantly decreased compared with normal distal segments. Pharmacologically induced relaxation of smooth muscles did not affect this diminished permeability, although an increased motility positively affected permeability in inflamed and non-inflamed distal colon. CONCLUSIONS: Inflammation and permeability is inversely related. The use of pro-kinetics could counteract this disturbed permeability and, in turn, could regulate the disturbed production of inflammatory mediators

Reliability of residents' assessments of their postgraduate medical education learning environment:an observational study

Background: Even in anonymous evaluations of a postgraduate medical education (PGME) program, residents may be reluctant to provide an honest evaluation of their PGME program, because they fear embarrassment or repercussions from their supervisors if their anonymity as a respondent is endangered. This study was set up to test the hypothesis that current residents in a PGME program provide more positive evaluations of their PGME program than residents having completed it. We therefore compared PGME learning environment evaluations of current residents in the program to leaving residents having completed it. Methods: This observational study used data gathered routinely in the quality cycle of PGME programs at two Dutch teaching hospitals to test our hypothesis. At both hospitals, all current PGME residents are requested to complete the Scan of Postgraduate Education Environment Domains (SPEED) annually. Residents leaving the hospital after completion of the PGME program are also asked to complete the SPEED after an exit interview with the hospital's independent residency coordinator. All SPEED evaluations are collected and analysed anonymously. We compared the residents' grades (on a continuous scale ranging from 0 (poor) to 10 (excellent)) on the three SPEED domains (content, atmosphere, and organization of the program) and their mean (overall department grade) between current and leaving residents. Results: Mean (SD) overall SPEED department grades were 8.00 (0.52) for 287 current residents in 39 PGME programs and 8.07 (0.48) for 170 leaving residents in 39 programs. Neither the overall SPEED department grades (t test, p = 0.53, 95% CI for difference -0.16 to 0.31) nor the department SPEED domain grades (MANOVA, F(3, 62) = 0.79, p = 0.51) were significantly different between current and leaving residents. Conclusions: Residents leaving the program did not provide more critical evaluations of their PGME learning environment than current residents in the program. This suggests that current residents' evaluations of their postgraduate learning environment were not affected by social desirability bias or fear of repercussions from faculty

Endoscopic Versus Surgical Step-Up Approach for Infected Necrotizing Pancreatitis (ExTENSION):Long-term Follow-up of a Randomized Trial

Background & Aims: Previous randomized trials, including the Transluminal Endoscopic Step-Up Approach Versus Minimally Invasive Surgical Step-Up Approach in Patients With Infected Pancreatic Necrosis (TENSION) trial, demonstrated that the endoscopic step-up approach might be preferred over the surgical step-up approach in patients with infected necrotizing pancreatitis based on favorable short-term outcomes. We compared long-term clinical outcomes of both step-up approaches after a period of at least 5 years. Methods: In this long-term follow-up study, we reevaluated all clinical data on 83 patients (of the originally 98 included patients) from the TENSION trial who were still alive after the initial 6-month follow-up. The primary end point, similar to the TENSION trial, was a composite of death and major complications. Secondary end points included individual major complications, pancreaticocutaneous fistula, reinterventions, pancreatic insufficiency, and quality of life. Results: After a mean follow-up period of 7 years, the primary end point occurred in 27 patients (53%) in the endoscopy group and in 27 patients (57%) in the surgery group (risk ratio [RR], 0.93; 95% confidence interval [CI], 0.65–1.32; P = .688). Fewer pancreaticocutaneous fistulas were identified in the endoscopy group (8% vs 34%; RR, 0.23; 95% CI, 0.08–0.83). After the initial 6-month follow-up, the endoscopy group needed fewer reinterventions than the surgery group (7% vs 24%; RR, 0.29; 95% CI, 0.09–0.99). Pancreatic insufficiency and quality of life did not differ between groups. Conclusions: At long-term follow-up, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing death or major complications in patients with infected necrotizing pancreatitis. However, patients assigned to the endoscopic approach developed overall fewer pancreaticocutaneous fistulas and needed fewer reinterventions after the initial 6-month follow-up. Netherlands Trial Register no: NL8571

Colon ischemia:Right-sided colon involvement has a different presentation, etiology and worse outcome. A large retrospective cohort study in histology proven patients

Background: Colon ischemia (CI), is generally considered a non-occlusive mesenteric ischemia disorder that usually runs a benign course, but right-sided involvement (RCI) has been associated with worse outcome. The poor outcome of RCI has been associated with comorbidity, but more recently also with occlusions of the mesenteric arteries. We performed a retrospective analysis of a large cohort of CI-patients to assess differences in presentation, etiology, and comorbidity between right-sided colon ischemia (RCI) and non-right-sided colon ischemia (NRCI), and their relation to outcome. Methods: We performed a retrospective cohort study in two centers from 2000 to 2011 for Cl and analyzed clinical presentation, etiology, treatment and outcome. Diagnosis was based on full colonoscopy and/or surgical findings and confirmed by histopathology. Results: 239 patients were included (mean age 69, 52% female). RCI was found in 48% and NRCI in 52%. Patients with NRCI presented more often with rectal bleeding (87% vs. 45%; p Conclusions: RCI ischemia has different etiology, presentation, and outcome. The series shows a high proportion of - treatable - vessel occlusion. It reinforces the advice to perform CT angiography in RCI as means to improve its poor outcome. (C) 2017 Published by Elsevier Ltd

In a Dutch real-life inflammatory bowel disease score cohort with 90% prior anti-tumour necrosis factor failure, vedolizumab showed a 25% remission rate: a retrospective multicentre study

Background Vedolizumab is a humanised monoclonal antibody against α4β7-integrin capable of blocking the migration of several immune cells across endothelium expressing MAdCAM-1. This new class of biological drugs has shown efficacy in treating inflammatory bowel disease (IBD) in randomised clinical trials. Vedolizumab is registered since October 2014 in the Netherlands. Here, we describe the clinical experience in 3 centres using vedolizumab for ulcerative colitis (UC) and Crohn’s disease (CD). Methods We retrospectively analysed clinical activity and clinical response determined by a composite score based on a VAS scale for pain and fatigue, number of liquid stools, choice of treatment, patient’s ability to work or study, and the conclusion of the attending physician. Further laboratory parameters and the use of vedolizumab was studied. Results From October 2014 until November 2015, 48 patients with moderate/severe IBD (mean age 43, 39.6% male, 27; CD and 21 UC patients) were included; 90% had failed at least 1 tumour necrosis factor (TNF) antagonist before treatment. The average duration of disease before treatment with vedolizumab was 9.4 years (range 1–38 years). The average duration of vedolizumab treatment was 25.7 weeks (average 5.6 infusions administered). Concomitant medication included mesalazine (20%), MTX or Thiopurines (20%), Steroids (33%), and 27% was treated with vedolizumab as monotherapy. Further, 27 patients, 56 % (17 CD patients and 10 UC patients) responded to vedolizumab (average 6.8 doses; follow-up 32 weeks) 44% of these responders (7 CD patients and 5 UC patients) reached remission after average 7.2 infusions (41 weeks follow-up). In addition, 15 patients, 31% (7 CD patients, 8 UC patients) were primary non-responders. Moreover, 5 patients, 10% (2 CD patients, 3 UC patients) showed loss of response; 1 of them underwent surgery. In 1 CD patient (2%), vedolizumab was stopped after 1 infusion because of side effects (nasopharyngitis). Conclusion In this Dutch real-life IBD cohort with 90% prior anti-TNF failure, vedolizumab showed a 56% response and 25% remission rate without showing major adverse events