The TULA-family consists of two proteins implicated in cellular regulation. TULA-1 is expressed in T-cells and is involved in apoptosis. TULA-2 is a ubiquitously expressed phosphatase that suppresses receptor-mediated signaling. T cells from mice lacking TULA-1 and 2 (double knockout, or dKO) are hypersensitive to TCR stimulation. This may be due to these proteins having a similar function working synergistically or dissimilar functions having a convergent effect. To understand functional interaction of these proteins we have characterized TULA-family knockout mice without and during an immune challenge. We show that CD4+ T cells of dKO mice have a characteristic CD45RB distribution, and that within the CD45RBlow subset effector/memory T cells are expanded only in dKO, but not in single knockouts (sKO) of either TULA-1 or TULA-2. However, CD4+ T cells of sKO and wild-type (WT) mice respond differently to TCR stimulation as seen using signaling and responses in vitro. To evaluate consequences of TULA deficiency in vivo, we utilized two mouse models of inflammatory bowel disease: TNBS-induced colitis and colitis induced by the adoptive transfer of CD45RBhigh CD4+ T cells. Studies utilizing TNBS indicate that deficiency of any TULA-family protein exacerbates TNBS-induced colitis. Likewise, dKO CD45RBhigh CD4+ T cells were significantly more colitogenic than cells from WT mice in the transfer model. Taken together, our data indicate that TULA-family proteins are key to the physiological regulation of T-cell reactivity that drives intestinal inflammation. / Microbiology and Immunology

Introduction: Intestinal obstruction is a common cause of hospital admissions and carries a mortality rate around 5%. We hypothesized that surgical intervention reduces mortality among these patients. Methods: We conducted a retrospective cohort study using the 2006 Nationwide Inpatient Sample (NIS) to analyze patients with a diagnosis of intestinal obstruction without hernia. We used multiple variable logistic regression to calculate the odds ratio for surgery as a predictor of death after adjusting for illness severity. Results: Among 38,931 patients, 17,544 (45.1%) underwent operative intervention for intestinal obstructions. Surgical patients were slightly younger than non-surgical patients (65 vs. 68 years), and had more severe illness, as measured by the disease staging: mortality scale (115.45 vs. 97.95, p<0.001). After adjusting for illness severity, surgery was protective from mortality (adjusted odds ratio 0.617, 95% CI 0.535-0.710, p<0.001). This finding was validated with 2 other methods of severity adjustment. Among surgery patients, there were fewer days to surgery among survivors (1 day) than non-survivors (2 days), p<0.001. The risk of bowel necrosis increased as time from admission to surgery increased. A greater percentage of surgical patients (77.5%) were discharged home compared to non-surgical patients (76.3%), p=0.007. Conclusion: Surgery is associated with a reduced odds of in-hospital mortality among patients urgently or emergently admitted with intestinal obstruction without hernia. Delaying operative intervention is associated with an increased odds of bowel necrosis and death in these patients. / Clinical Research and Translational Medicine

Serotonin (5-hydroxytryptamine [5-HT]) is a key enteric signaling molecule that is implicated in many gastrointestinal (GI) disorders, including inflammatory bowel disease (IBD). Enterochromaffin (EC) cells are a key subgroup of enteric endocrine cells and produce the majority of 5-HT via tryptophan hydroxylase 1 (Tph1) in the gut. Recently, we have identified a pivotal role of 5-HT in the pathogenesis of experimental colitis, whereby 5-HT plays as a pro-inflammatory molecule. Gut function as well as pathology rely on interactions with gut microbiota. The intestinal epithelial cells produce antimicrobial peptides (AMPs), maintaining the mucosal barrier by shaping gut microbiota composition. Among the AMPs, β-defensins are the most well investigated subtype in the colon. Aberrant β-defensin expression has been reported in association with various GI disease pathogenesis including IBD. As EC cells are dispersed throughout the intestinal epithelium, it seems possible that 5-HT can modify β-defensin production which can regulate gut inflammation by influencing gut microbial composition. Colitis was induced with dextran sulfate sodium (DSS) in Tph1+/+ and Tph1-/- (which have lower amounts of 5-HT in gut). Tph1-/- mice exhibited higher levels of β-defensin in the colon, compared with wild-type littermates post-DSS. In addition, increased expression of β-defensin in Tph1-/- mice was suppressed by 5-hydroxytryptophan (5-HTP; precursor of 5-HT) treatment. 5-HT treatment resulted in decreased human β-defensin (hBD) 1 and hBD-2 expression in HT-29 cells. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is essential for maintaining β-defensin expression in the colon. GW-9662, PPAR-γ antagonist, reduced mouse β-defensin (mBD) 1 and mBD-3 (orthologue of hBD-2). Furthermore, disrupting 5-HT7 receptors, but not 5-HT3 or 5-HT4, led to enhanced expression of PPAR-γ via ERK1/2-dependent mechanism. These observations provide us with novel information on pivotal role of gut-derived 5-HT in innate immune response and highlight the potential benefits of targeting 5-HT signaling in various GI disorders such as IBD. / Thesis / Master of Science (MSc)

Yes / Our aim is to provide an understanding of the experience of women with IBD who have made the transition to motherhood. Twenty-two mothers with IBD were recruited from around the UK. Semi-structured interviews were conducted and analyzed using thematic analysis. The central concept – Blurred Lines – offers a novel frame for understanding the transition to motherhood with IBD through identifying parallels between having IBD and becoming, and being, a mother. Parallels clustered into three main themes: Need for Readiness, Lifestyle Changes, and Monitoring Personal and Physical Development. Hence, women with IBD are in some ways well prepared for the challenges of motherhood even though, as a group, they tend to restrict their reproductive choices. We recommend health professionals initiate conversations about reproduction early and provide a multidisciplinary approach to pregnancy and IBD in which women have confidence that their on-going treatment will be integrated successfully with their maternity care. / Crohn’s & Colitis UK [grant number SP2013/2].

Bakgrund: Kroniska inflammatoriska tarmsjukdomar (IBD) innefattar i första hand Ulcerös kolit (UC) och Crohns sjukdom (CD) vilka är de vanligast förekommande inflammatoriska tarmsjukdomarna. IBD karaktäriseras av symtom som smärta i mag-tarmkanalen, diarré, blod i avföringen och att symtomen går i skov. Syfte: Syftet med denna litteraturstudie var att belysa patienters upplevelser av att leva med en kronisk inflammatorisk tarmsjukdom. Metod: Metoden som användes i studien var allmän litteraturstudie. Vidare användes en induktiv ansats i denna litteraturstudie. Resultat: Resultatet visade att IBD påverkar patienter på flera nivåer. Nivåerna delades in i fyra kategorier: Psykisk hälsa vid IBD, Fysisk aktivitet och energinivåer vid IBD, Samverkan med sjukvårdspersonal vid IBD samt Kosthållning och nutrition vid IBD. Konklusion: Patienter som led av IBD upplevde att sjukdomen har en negativ påverkan på den psykiska hälsan. Dessutom påverkade IBD patienters energinivåer till att patienter hade svårt att utföra vardagliga aktiviteter, främst när de genomgick skov. De patienter som fick möjligheten att vara delaktiga i sin vård upplevde i högre grad minskad ångest relaterat till vald behandlingsmetod. Vidare upplevde patienter att sjukvården inte gav den hjälp gällande kostrådgivning som de själva kände sig behöva. / Background: Inflammatory bowel disease (IBD) primarily includes ulcerative colitis (UC) and crohn's disease (CD), which are the most common forms of inflammatory bowel diseases. IBD are characterized by symptoms such as bowel pain, diarrhea, blood in the stool, and that the symptoms often manifest in flares. Aim: The aim of the study was to illustrate patients experiences of living with inflammatory bowel disease. Method: The method used in this study was a general literature study. Furthermore an inductive approach was used in the study. Results: The result showed that IBD affects patients on different levels. The levels were divided into four categories: Mental health and IBD, Physical health and energy levels and IBD, Collaboration with healthcare personnel and IBD, and Diet and nutrition and IBD. Conclusion: Patients that suffered from IBD experienced a negative affect on their mental health. Additionally, the diagnosis affected the patients energy levels, which led to struggles in the day to day life, foremost when they went through a flare. The patients that participated in their own treatment, experienced lower anxiety in relation to their treatment. Moreover, the patients described that they did not get the help they required when it came to their diet changes.

No / This session considers the double contrast barium enema examination (DCBE) in investigation of bowel pathology and discusses its place alongside other imaging modalities and alternative investigations. Tips on equipment use, technique and reporting will be offered.

Yes / Video capsule endoscopy (VCE) is a revolutionary technology for the early diagnosis of gastric disorders. However, owing to the high redundancy and subtle manifestation of anomalies among thousands of frames, the manual construal of VCE videos requires considerable patience, focus, and time. The automatic analysis of these videos using computational methods is a challenge as the capsule is untamed in motion and captures frames inaptly. Several machine learning (ML) methods, including recent deep convolutional neural networks approaches, have been adopted after evaluating their potential of improving the VCE analysis. However, the clinical impact of these methods is yet to be investigated. This survey aimed to highlight the gaps between existing ML-based research methodologies and clinically significant rules recently established by gastroenterologists based on VCE. A framework for interpreting raw frames into contextually relevant frame-level findings and subsequently merging these findings with meta-data to obtain a disease-level diagnosis was formulated. Frame-level findings can be more intelligible for discriminative learning when organized in a taxonomical hierarchy. The proposed taxonomical hierarchy, which is formulated based on pathological and visual similarities, may yield better classification metrics by setting inference classes at a higher level than training classes. Mapping from the frame level to the disease level was structured in the form of a graph based on clinical relevance inspired by the recent international consensus developed by domain experts. Furthermore, existing methods for VCE summarization, classification, segmentation, detection, and localization were critically evaluated and compared based on aspects deemed significant by clinicians. Numerous studies pertain to single anomaly detection instead of a pragmatic approach in a clinical setting. The challenges and opportunities associated with VCE analysis were delineated. A focus on maximizing the discriminative power of features corresponding to various subtle lesions and anomalies may help cope with the diverse and mimicking nature of different VCE frames. Large multicenter datasets must be created to cope with data sparsity, bias, and class imbalance. Explainability, reliability, traceability, and transparency are important for an ML-based diagnostics system in a VCE. Existing ethical and legal bindings narrow the scope of possibilities where ML can potentially be leveraged in healthcare. Despite these limitations, ML based video capsule endoscopy will revolutionize clinical practice, aiding clinicians in rapid and accurate diagnosis.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13601号 / 論医博第2311号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊藤 能永, 教授 椛島 健治, 教授 松田 秀一 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25168号 / 医博第5054号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 上野 英樹, 教授 波多野 悦朗, 教授 伊藤 能永 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduktion: Irritable bowel syndrome, IBS, är den vanligaste funktionella tarmsjukdomen och påverkar ungefär 11 % av befolkningen. Forskningsresultat antyder att förändringar i mikroorganismernas sammansättning i tarmen, känd som dysbios, kan spela en roll i uppkomsten och patofysiologin vid IBS. Detta har ökat intresset för behandlingar som fokuserar på att återställa balansen av dessa mikroorganismer genom probiotika. Det finns dock begränsad forskning om effekten av probiotika på förstoppningsdominerad IBS (IBS-c), vilket indikerar ett behov av ytterligare studier på området.  Syfte: Att utforska litteraturen angående effekten av probiotika som behandling vid IBS-c hos vuxna.  Metod: Studien genomfördes som en litteraturstudie baserad på sökning av vetenskapliga originalartiklar i Pubmeds sökmotor Medline. Datainsamlingen startade i februari 2024 med inklusionskriterierna RCT-studier om effekten av probiotika vid IBS-c hos vuxna. Sökningen resulterade i 212 artiklar, vars titlar och nyckelord först granskades efter dess relevans för syftet, d.v.s. om de studerade probiotikas effekt på symtomen vid just IBS-c eller inte, och där föll många bort då de bara verkade studera generell IBS. 35 artiklar valdes då för vidare läsning av abstrakt, och slutligen ansågs fem RCT-studier möta inklusionskriterierna för denna litteraturstudie. Resultat: Studie 1, som undersökte två probiotikakombinationer, hade bäst utfall med signifikant förbättring av samtliga IBS-symtom och med trestjärnig signifikansnivå. I studie 2 visades signifikanta förbättringar av buksmärta, uppblåsthet, avföringskonsistens och den sammansatta IBS-poängen men med enstjärnig signifikansnivå. Studie 3 visade en signifikant förbättring av den sammansatta IBS-poängen samt buksmärta men också med en enstjärnig signifikansnivå. Studie 4 visade en signifikant förbättring av buksmärta och livskvalitet med en enstjärnig signifikansnivå, och i studie 5 förbättrades endast avföringsfrekvensen blygsamt i de två olika probiotikagrupperna som testades. Diskussion: En signifikant symtomförbättring av buksmärta jämfört med placebo sågs i alla studier utom en. Bäst utfall hade studie 1 som studerade probiotikakombinationerna L. acidophilus och L. reuteri, och L. plantarum, L. rhamnosus och B. lactis mot placebo, som visade signifikant förbättring av samtliga symtom (buksmärta, uppblåsthet, gasbildning, förstoppning och negativ livskvalitet). Svårigheten att dra säkra slutsatser från de granskade studierna beror på svagheter i studierna, olika deltagarantal, låga signifikansnivåer, hög placeboeffekt och variationer i undersökta probiotikastammar. De olika utfallen i studierna ger anledning att tro att effekten av probiotika är beroende av vilken typ av probiotika som testas.  Slutsats: Probiotika hade signifikant effekt på buksmärta och avföringskonsistens, men inte på uppblåsthet, gasbildning, livskvalitet eller den sammansatta upplevelsen av IBS-symtom. Variationen i studiernas probiotikaarter och doser, tillsammans med små studiepopulationer och metodologiska svagheter, gör det svårt att avgöra vilken probiotika som är mest effektiv mot IBS-c-symtom. För att kunna dra säkra slutsatser krävs fler och större studier med standardiserade metoder.