Functional and immunological aspects of small bowel transplantation : an experimental study in dogs

Small bowel transplantation is thought to be the ultimate therapeutic treatment for patients with an irreversible short bowel syndrome and those with intolerance to long-term total parenteral nutrition. Although the small bowel was one of the first organs to be transplanted experimentally, it is the last to be engrafted successfully in humans. The extreme immunogenicity of the small bowel graft and its compromised function after the transplantation procedure still hamper clinical small bowel transplantation as an established therapy. This thesis tries to answer several questions concerning immunological and functional aspects of intestinal transplantation in a pre-clinical animal model. The experiments were performed at the Laboratory for Experimental Surgery, Erasmus University Rotterdam. In part A of this thesis an overview of the problems encountered with the short bowel syndrome is given. In addition, the past and present experiences of experimental and clinical small bowel transplantations are extensively described. Part A ends with the scope of this study, formulating questions and objectives of investigation. In part B the general materials and methods used in the experiments are described. Part C is a compilation of adapted versions of original articles, in which the general materials and methods are omitted. These articles are a reflection of the questions raised in chapter 3. The general discussion of our experimental results is given in part D. Finally, several avenues for future experimental and clinical small bowel transplantation are proposed

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

Thioguanine is Effective as Maintenance Therapy for Inflammatory Bowel Disease: A Prospective Multicentre Registry Study

Background and Aims: Thioguanine is a well-tolerated and effective therapy for inflammatory bowel disease [IBD] patients. Prospective effectiveness data are needed to substantiate the role of thioguanine as a maintenance therapy for IBD. Methods: IBD patients who previously failed azathioprine or mercaptopurine and initiated thioguanine were prospectively followed for 12 months starting when corticosteroid-free clinical remission was achieved (Harvey-Bradshaw Index [HBI] ≤ 4 or Simple Clinical Colitis Activity Index [SCCAI] ≤ 2). The primary endpoint was corticosteroid-free clinical remission throughout 12 months. Loss of clinical remission was defined as SCCAI > 2 or HBI > 4, need of surgery, escalation of therapy, initiation of corticosteroids or study discontinuation. Additional endpoints were adverse events, drug survival, physician global assessment [PGA] and quality of life [QoL]. Results: Sustained corticosteroid-free clinical remission at 3, 6 or 12 months was observed in 75 [69%], 66 [61%] and 49 [45%] of 108 patients, respectively. Thioguanine was continued in 86 patients [80%] for at least 12 months. Loss of response [55%] included escalation to biologicals in 15%, corticosteroids in 10% and surgery in 3%. According to PGA scores, 82% of patients were still in remission after 12 months and QoL scores remained stable. Adverse events leading to discontinuation were reported in 11%, infections in 10%, myelo- and hepatotoxicity each in 6%, and portal hypertension in 1% of patients. Conclusion: Sustained corticosteroid-free clinical remission over 12 months was achieved in 45% of IBD patients on monotherapy with thioguanine. A drug continuation rate of 80%, together with favourable PGA and QoL scores, underlines the tolerability and effectiveness of thioguanine for IBD

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

Long-term survival of DLA-matched segmental small-bowel allografts in dogs

The aim of this study was to investigate the combined effect of DLA matching and immunosuppressive therapy on the survival of segmental small-bowel allografts in dogs. Orthotopic segmental small-bowel transplantations (25 to 30% of total small bowel length) were performed in two stages: first a heterotopic segmental small bowel transplantation, followed after 5 to 8 weeks by a second-stage operation during which the heterotopic graft was placed in an orthotopic position and the native small bowel was resected. All dogs received cyclosporine immunosuppression. Control dogs (n=4), subjected to total enterectomy, survived 37.3±7.1 days (mean ± SEM). Recipients of DLA-mismatched small bowel grafts (n=6) survived 113.2±37.0 days, which was a significantly shorter time than dogs with a DLAmatched graft (n=6, 211.5±38.8 days, P&lt;0.05). None of the matched allografts was rejected during CsA treatment, whereas four of six mismatched grafts were (P&lt;0.05). The control dogs uniformly showed progressive weight loss, steatorrhea, and hypoalbuminemia. The dogs with DLA-mismatched grafts did not regain initial body weight, whereas animals with DLAmatched grafts recovered preoperative weight after 20 weeks. Both transplanted groups showed near-normal fecal fat excretions and constant serum albumin, cholesterol, and triglyceride levels, whereas serum total protein levels increased during follow-up. We conclude that segmental small bowel transplantation between DLAmatched donor-recipient pairs results in long-term survivors with an adequate nutritional status. This may have important implications for future living-related small-bowel transplantation.</p