Aujourd’hui, face à l’épidémie d’obésité, de plus en plus de personnes ont recours à la chirurgie bariatrique, qui permet une perte de poids importante et une amélioration des conditions métaboliques associées à l’obésité. L’adaptation gastro-intestinale après la chirurgie et ses conséquences métaboliques sont cependant peu connues. Nous avons développé des modèles murins de bypass gastriques et de gastrectomie longitudinale (sleeve) et nous avons caractérisé l’adaptation morphologique et fonctionnelle de l’épithélium gastro-intestinal après ces chirurgies afin de comprendre l’origine des améliorations métaboliques. Nous avons montré que l’estomac était remodelé après les deux chirurgies, suggérant une augmentation de la production acide par les cellules pariétales et une altération de la production de gastrine et de ghréline. Après le bypass, l’anse alimentaire était hyperplasique et la consommation intestinale de glucose était augmentée chez le rat et l’homme; après la sleeve, l’absorption de glucose lors du repas était diminuée. De plus, l’augmentation du nombre de cellules entéroendocrines observée après le bypass, et l’augmentation de leur densité après la sleeve pourraient participer à l’hypersécrétion des hormones incrétines. L’ensemble de ces mécanismes pourrait contribuer à améliorer le contrôle de la glycémie. Enfin, le mini-bypass chez le rat a induit une malabsorption protéique et des fuites énergétiques majeures qui n’étaient pas compensées par l’hyperplasie intestinale ou l’augmentation de l’expression des transporteurs de peptides. Cette thèse montre l’importance du tractus gastro-intestinal dans les conséquences métaboliques de la chirurgie bariatrique / In today’s global epidemic of obesity, more and more people are undergoing bariatric surgery, which is the best known treatment available to lose weight and treat obesity-associated diseases. Yet, little is known about gastrointestinal (GI) adaptation and its metabolic consequences after surgery. We developed original models of Roux-en-Y gastric bypass (RYGB), mini-bypass (MGB) and vertical sleeve gastrectomy (VSG) in rats, and we characterized the morphological and functional adaptations of the GI epithelium after these surgeries in order to understand the origin of the observed metabolic improvements. We reported profound changes in the remaining gastric mucosa of rats having undergone RYGB and VSG, suggesting an increase in acid production by parietal cells and an impaired production of gastrin and ghrelin. In RYGB rats and patients, the alimentary limb was hyperplasic and intestinal glucose consumption was increased. After VSG, the absorption of glucose during meals appeared diminished. These adaptations could participate in the lowering of blood glucose after surgery. In addition, the increased number of enteroendocrine cells observed in RYGB rats and patients, and their increased density in VSG rats, could contribute to the higher secretion of incretin hormone and improved glycemic control in operated individuals. Finally, we demonstrated in rats that the MGB was more malabsorptive than the RYGB. Indeed, we observed an increased fecal loss of nitrogen and energy despite intestinal overgrowth and higher expression of peptide transporters. This thesis brings new insight to the role of the GI tract in the metabolic outcomes of bariatric surgeries

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21148号 / 農博第2274号 / 新制||農||1058(附属図書館) / 学位論文||H30||N5122(農学部図書室) / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 金本 龍平, 教授 保川 清, 教授 谷 史人 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

No description available.

The field of guideline development has made considerable progress in the past twenty years, particularly after the introduction of GRADE in 2004. However, there are many shortcomings in current guideline development including failure to use GRADE, low quality systematic reviews, and excessive delays from the publication of practice changing evidence to new recommendations. The objective of this thesis is to describe the development of evidence-based recommendations, to document methodological issues that arose and describe how the research team addressed the questions, and to document how the ultimate guidelines contributed to optimization of treatment in clinical practice. The relevant guidelines address the issues of gastrointestinal bleeding prophylaxis and coronavirus disease 2019 (COVID-19). The thesis begins by presenting three methodological issues that arose during the planning and implementation of the guideline process and the initial process of how the research team addressed the challenges. The thesis subsequently presents a published paper that documents recommendations regarding gastrointestinal bleeding prophylaxis in critically ill patients. Then, this thesis presents a published systematic review and meta-analysis addressing efficacy and safety of corticosteroids in COVID-19 based on direct evidence from patients with COVID-19, and indirect evidence from acute respiratory distress syndrome, community-acquired pneumonia, severe acute respiratory syndrome, middle east respiratory syndrome and influenza. Further, the thesis includes a published paper describing recommendations regarding corticosteroids, convalescent plasma and antiviral drugs in COVID-19 on the basis of evidence available very early during the pandemic. This thesis ends by presenting how the methodological issues were ultimately addressed in the relevant guidelines, the importance of the guidelines themselves, and presents perspectives on future research and opportunities in guideline development. / Thesis / Candidate in Philosophy

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a widely used class of drugs, due in part to the effective anti-inflammatory and analgesic properties they exhibit. Unfortunately, NSAIDs also exhibit substantial gastrointestinal (GI) toxicity. The mechanisms underlying the ability of NSAIDs to cause ulceration in the stomach and proximal duodenum are well understood, and this injury can largely be prevented through the suppression of gastric acid secretion by proton pump inhibitors (PPIs) or histamine H2 receptor antagonists (H2RAs). In contrast, the pathogenesis of small intestinal injury induced by NSAIDs (i.e., NSAID-enteropathy) is poorly understood, and there are no proven-effective therapies. This is a major clinical concern as NSAID-induced enteropathy and bleeding occur more frequently than NSAID-induced gastropathy, and is associated with significantly higher rates of morbidity and mortality. There is clear evidence that indicates important contributions to NSAID-enteropathy by bile, enteric bacteria, and the enterohepatic circulation of NSAIDs. However, it is not clear which of these mechanisms is/are the primary driver(s) of intestinal damage and injury. There is also evidence that hydrogen sulfide (H2S) can protect the GI mucosa from ulceration and reduce the severity of NSAID-induced GI damage, although the mechanisms of H2S-induced intestinal protection remain to be determined. Therefore, the central aim of this thesis was to evaluate the roles of bile, enteric bacteria, and the enterohepatic circulation of NSAIDs in the pathogenesis of NSAID-enteropathy, and to investigate the ability of H2S to protect the small intestine from NSAID-induced damage. Chapter 1 is an introduction to the relevant literature and Chapter 2 is an outline of the thesis scope and objectives. In Chapter 3, I demonstrated that the co-administration of an H2S-releasing agent protected rats from NSAID-induced enteropathy, in part by preventing NSAID-induced dysbiosis and bile cytotoxicity. In Chapter 4 and 5, I established that the co-administration of PPIs and H2RAs exacerbated NSAID-enteropathy in part by causing intestinal dysbiosis and enhanced bile cytotoxicity. Lastly, I demonstrated that the small intestine-sparing effects of an H2S-releasing NSAID, ATB-346, are partly attributable to the reduced enterohepatic circulation of ATB-346 or the naproxen liberated from this drug (Chapter 5). In summary, the work presented in this thesis provided novel understanding of the complicated pathogenesis of NSAID-enteropathy by confirming that the nature of the bile, the enterohepatic circulation of NSAIDs, and the nature of the intestinal microbiota are of paramount importance. In addition, the results also demonstrated that hydrogen sulfide represents an effective preventative therapy for NSAID-enteropathy and that H2S-releasing NSAIDs, such as ATB-346, have remarkable preclinical safety. / Thesis / Doctor of Philosophy (PhD)

京都大学 / 新制・課程博士 / 博士(理学) / 甲第24458号 / 理博第4957号 / 新制||理||1708(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 高橋 淑子, 准教授 佐藤 ゆたか, 教授 中務 真人 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Introduction: Routine drain placement is still widely used in both sleeve gastrectomy (SG) and Roux en Y gastric bypass (REYGB). There is mounting evidence that drains may increase complication risk without preventing reoperation or other complications. Methods: Data from 2017 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) Participant Use File was evaluated for drain use during laparoscopic REYGB and SG. Primary outcomes were superficial and deep surgical site infections (SSI), reintervention/reoperation, and readmission. Preoperative patient risk factors were also compared to evaluate for association with drain placement. Results: A total of 148 260 patients fit the inclusion criteria. Drains were used in 23 190 (15.6%) cases and not used in 125 070 (84.4%). Drain placement during surgery was associated with increased odds of superficial SSI, deep incisional SSI, and organ space SSI. Patients with drains were found to have increased odds of requiring at least 1 reoperation or intervention within 30 days of surgery. Preoperative risk factors associated with drain placement included diabetes mellitus, a history of chronic obstructive pulmonary disease, and oxygen dependence. Smokers were slightly less likely to have a drain placed. There was no significant association with chronic steroid and immunosuppressant usage. Conclusion: There is mounting data against drain placement during bariatric surgery. Prior studies using MBSAQIP data have shown an increased complication rate with drains, and our data set supports the idea that drains may increase complications after surgery. While no randomized prospective trials have been performed looking at drain usage in bariatric surgery, the growing retrospective data certainly inform against the regular use of drains.

Background: Dual antiplatelet therapy (DAPT) remains the cornerstone management for the prevention of acute stent thrombosis after percutaneous intervention (PCI). Situations mandating early interruption of DAPT carry a high risk of ischemic complications. Perioperative bridge therapy using Cangrelor, an intravenous P2Y2 inhibitor, may offer a potential solution. Unfortunately, evidence for its use in non-cardiac procedures is limited. Methods: Our protocol demonstrates successful off-label use of IV Cangrelor bridge therapy in a non-cardiac surgery patient. We describe a case of a 77-year old male; triple therapy with Aspirin, Apixaban, and Ticagrelor for recent drug-eluting stent placement required immediate surgical resection of stage I colonic adenocarcinoma. Results: Cangrelor bridge therapy was utilized both preoperatively and postoperatively without ischemic or bleeding complications. The patient tolerated exploratory laparoscopic colectomy with minimal bleeding and good post-op recovery. Conclusion: Minimizing the interruption of DAPT therapy in high-risk patients is achievable. However, careful planning with a team-based approach involving surgeons, cardiologists and pharmacists, along with close clinical follow-up and vigilant management of anti-platelet therapy is recommended.

This study investigated the effects of chronic stress on mucin expression in the GIT of mice. Sixteen ICR male mice were randomly divided into treated and control animals. Restraint stress was applied to the treated group for 21 days. Body weight (BW) changes and feed consumed (FC) were regularly recorded. After 21 days mice were euthanized and blood, GIT mucosa, and GIT sections were collected. Serum corticosterone levels were determined. The GIT sections were fixed, paraffin embedded, sectioned, and stained with AB-PAS to visualize goblet cells. Mucin expression was determined using qPCR. As expected stressed mice showed higher corticosterone than the control animals. BW decreased in the stressed group. Histology showed a decrease in goblet cells in stressed mice. Muc1 and Muc4 in the colon and Muc3 in the duodenum were upregulated in stressed animals. These findings suggest that chronic stress may affect mucin expression in the GIT.

This thesis is concerned with the use of some of the newer techniques in a study of some of the effects of cigarette smoking on gastric secretion and gastric motility in normal subjects and in patients with active duodenal ulcers.