BACKGROUND: Inflammatory bowel disease (IBD) is a group of conditions characterized by chronic inflammation of the gastrointestinal (GI) tract. A new diagnosis of IBD in children and adolescents can have significant psychosocial effects on both the patient and the family. Child and parental coping strategies play a crucial role in the adjustment to IBD, especially within the first year of the diagnosis. AIMS: The primary aim of the study was to assess the stability of coping measures over time in children and parents following a new pediatric IBD diagnosis. The study also aimed to assess the impact of parental coping on parental healthcare resource utilization for children with newly diagnosed IBD, as well as the impact of parental coping on anxiety, depression, and quality of life in children with newly diagnosed IBD. METHODS: This was a prospective, longitudinal cohort study at Boston Children’s Hospital (BCH) that focused on children and adolescents with newly diagnosed IBD, as well as their parents. Patients and their parents were approached at the time they enrolled in the study and then again about 12 months later as part of a one-year follow-up. At both time points, they were asked to fill out various questionnaires about psychological functioning and answer other questions about medical care. RESULTS: The study identified and encountered 465 IBD patients, of which 126 were eligible for recruitment. There were 70 patients and families who signed a consent form for enrollment, 55 who fully or partially completed the questionnaires at baseline, and only 5 who also completed the questionnaires at follow-up. Due to the limited number of participants who completed the questionnaires at follow-up, no definitive conclusions could be drawn about the stability of coping measures over time. Parental anxiety, parental depression, frequent parental stress, and difficult parental stress were all found to be positively correlated with healthcare utilization and negatively correlated with the child’s quality of life. Parental anxiety, frequent parental stress, and difficult parental stress were all found to be positively correlated with the child’s anxiety. Parental depression, frequent parental stress, and difficult parental stress were all found to be positively correlated with the child’s depression. CONCLUSION: Preliminary findings suggest that poor parental coping leads to decreased child quality of life and increased healthcare utilization, child anxiety, and child depression. A larger sample size is needed to accurately evaluate the stability of coping measures over time. The next steps for this study involve further examination of the impact of parental coping and enrollment of more patients and families.

Murine small intestinal CD103+ dendritic cells (DCs) produce retinoic acid (RA) through retinaldehyde dehydrogenase (RALDH) activity, thereby inducing ‘gut-homing’ α4β7 and CCR9 on T cells they activate, enhancing TGF-β-mediated induction of Foxp3+ regulatory T cells and suppressing induction of pro-inflammatory TH17 cells. RALDH activity of CD103+ DCs is reduced in mouse models of inflammatory bowel disease (IBD) but the role of RALDH activity in human intestinal DCs in the pathogenesis of IBD is undefined. This project aimed to determine the influence of inflammation on RALDH activity of antigen presenting cell (APC) subsets including CD103+ DCs within human distal intestinal mucosa. RALDH activity was identified by Aldefluor assay in intestinal DCs (CD103+ and CD103- subsets) alongside ALDH1A2 expression in healthy controls. In contrast with mouse models, RALDH activity was not reduced in CD103+ DCs from IBD patients. An increased frequency of CD14+ macrophages (MФ) of IBD patients displayed ALDH1A1-associated RALDH activity compared with healthy controls. Blood CD14+ monocytes, putative precursors of intestinal CD14+ MФ, of healthy controls and IBD patients displayed ALDH1A1-associated RALDH activity indicating RALDH is systemically acquired by monocytes and upregulated within the mucosa of IBD patients, or alternatively that RALDH+ monocytes are selectively recruited in IBD. In vitro, inhibition of RA receptor-α signalling blocked GM-CSF-mediated differentiation of TNFα-producing pro-inflammatory RALDH+ CD14+ MФ from monocytes, consistent with enhanced RALDH activity of intestinal CD14+ MФ in IBD supporting a pro-inflammatory phenotype. Soluble intestinal mediators including prostaglandin E2 suppressed RALDH activity of MoDCs in vitro, whilst mediators from inflamed IBD mucosa conditioned MoDCs to imprint enhanced levels of α4β7 expression on naive CD4+ T cells independent of RALDH activity. This study provides the first systematic analysis of RALDH activity in human intestinal APCs and indicates important distinctions between mouse models and human IBD.

The purpose of this study was to describe how adolescents aged 12-18 years with inflammatory bowel disease experience their illness and what coping strategies they use to manage their illness and improve their wellbeing. The method used was a descriptive literature study, and the result of the study included 15 scientific articles. Our results showed that IBD affected the adolescent’s everyday life and social life with friends, family and activities. The adolescents also reported that they experienced a feeling of vulnerability, altered body image and that they saw themselves as different from healthy subjects. Adolescents with IBD have been shown to use the same coping strategies that healthy adolescents are using, that is, confrontational, evasive, independent and optimistic coping. The avoidance coping is more prevalent in adolescents with IBD, as the use of such strategies is specific for IBD because of illness symptoms. There is a need for more research directed at young people with IBD, since previous research is based mostly on adults' experiences of illness.

No description available.

This thesis explores aspects pertinent to the phenotypic classification of paediatric patients with inflammatory bowel disease (IBD). In the current era it has never been more important to have rigourous phenotypic classification to facilitate genotype-phenotype correlation studies as well as to optimize design of clinical trials of emerging therapies, where frequently response may differ according to phenotype of disease. The first study examined the reliability of the Montreal Classification for classifying paediatric IBD patients. This is the first study exploring the reliability of phenotypic classification in a paediatric population. The reliability of assigning an overall diagnosis of type of IBD was good, but not excellent. Amongst Crohn’s disease patients, reliability of assigning disease behaviour was excellent, while the reliability of assigning disease location categories varied from fair to good. The percentage agreement when describing disease extent for ulcerative colitis was high. The second study described the evolution of disease phenotype in a cohort of paediatric IBD patients. Similar to observations in adult-onset IBD, disease location was found to be relatively stable, while Crohn’s disease behaviour evolves from an inflammatory to a stricturing and/or penetrating phenotype in 20% of patients by 5 years of follow-up. The final study explored the association between 2 polymorphisms in the NOD2 gene with the requirement for intestinal resection (a surrogate marker of complicated disease) in models that included and excluded disease duration. Although no difference was found, this may have been influenced by data quality, which was suboptimal. In conclusion, this thesis has demonstrated that imprecision exists in the phenotyping of paediatric IBD patients, in whom phenotypic characteristics evolve over time. It is pertinent that disease duration be considered in any study attempting to make phenotypic correlations.

This thesis explores aspects pertinent to the phenotypic classification of paediatric patients with inflammatory bowel disease (IBD). In the current era it has never been more important to have rigourous phenotypic classification to facilitate genotype-phenotype correlation studies as well as to optimize design of clinical trials of emerging therapies, where frequently response may differ according to phenotype of disease. The first study examined the reliability of the Montreal Classification for classifying paediatric IBD patients. This is the first study exploring the reliability of phenotypic classification in a paediatric population. The reliability of assigning an overall diagnosis of type of IBD was good, but not excellent. Amongst Crohn’s disease patients, reliability of assigning disease behaviour was excellent, while the reliability of assigning disease location categories varied from fair to good. The percentage agreement when describing disease extent for ulcerative colitis was high. The second study described the evolution of disease phenotype in a cohort of paediatric IBD patients. Similar to observations in adult-onset IBD, disease location was found to be relatively stable, while Crohn’s disease behaviour evolves from an inflammatory to a stricturing and/or penetrating phenotype in 20% of patients by 5 years of follow-up. The final study explored the association between 2 polymorphisms in the NOD2 gene with the requirement for intestinal resection (a surrogate marker of complicated disease) in models that included and excluded disease duration. Although no difference was found, this may have been influenced by data quality, which was suboptimal. In conclusion, this thesis has demonstrated that imprecision exists in the phenotyping of paediatric IBD patients, in whom phenotypic characteristics evolve over time. It is pertinent that disease duration be considered in any study attempting to make phenotypic correlations.

The gastrointestinal (GI) tract is subject to regulation by several neuronal networks, one of which is the sympathetic nervous system (SNS). Inflammatory bowel diseases (IBD), most importantly Crohn’s disease and ulcerative colitis, are chronic diseases of the GI tract that result in such functional symptoms as abdominal pain and diarrhea. These symptoms suggest an important role for dysregulation of the SNS in IBD, since this branch of the autonomic nervous system aids in regulation of blood flow, secretion and motility. Inflammatory cytokines that are elevated in the serum and tissue of IBD patients can have wide-ranging effects on neuronal function in vitro, and may be responsible for the functional alterations observed in vivo. With these neuronal alterations in mind, we hypothesized that interleukin-17, a novel cytokine with a central role in the pathogenesis of IBD, modulates the properties of sympathetic neurons innervating the gastrointestinal tract. Using electrophysiological techniques and Ca2+ imaging, we examined the effect of IL-17 on currents passing through voltage-gated Ca2+ channels in neurons from the superior mesenteric ganglion, which innervates the gut, and found that IL-17 inhibited these currents. In parallel, we found that IL-17 enhances the growth of sympathetic neurites in vitro. These effects depend upon activation of the nuclear factor κB (NF-κB) pathway, and do not appear to require glial cells. Therefore, dysregulated neural function during IBD may be due to direct effects of IL-17 on sympathetic neurons. / Thesis (Master, Physiology) -- Queen's University, 2009-09-03 11:33:53.63

No description available.

Background: Reliable biomarkers are needed to evade the risk of injury, invasiveness and discomfort of endoscopies, which are required for inflammatory bowel disease (IBD) diagnosis and extent of disease assessment in ulcerative colitis (UC) patients. The need for biomarkers is accentuated in children, wherein the most frequently used IBD biomarker yields low specificity. Proteomics of clinical samples or their enriched components is a means to evaluate and identify alterations in proteins reflective of disease, with the potential for use as biomarkers and for providing insight on disease pathogenesis. Methods: Proteins were isolated from the intestinal mucosal-luminal interface (MLI), collected from the ascending and descending colon of pediatric treatment-naive patients. The intestinal MLI proteomes of 42 IBD and 18 control patients were analyzed by high resolution mass spectrometry (HRMS). Multivariate analysis and receiver operating characteristics curves were performed to develop protein biomarker panels to discriminate IBD from control, and for UC extent of disease. ELISAs were used to assess a subset of biomarker candidates in stool samples from an independent pediatric cohort (n=24). Extracellular vesicles (EVs) were isolated by ultracentrifugation from the intestinal MLI of 11 IBD and seven control patients, and analyzed by electron microscopy, nanoparticle tracking analysis and HRMS. Results: A biomarker panel of four proteins classified patients as either controls or active IBD with 97.5% accuracy. A second biomarker panel correctly classified 100% of UC patients as presenting with pancolitis or non-pancolitis. The differential protein expression of two biomarker candidates (catalase and leukotriene A-4 hydrolase) identified from the intestinal MLI was comparable in stool samples. Comparison of EV proteomes isolated from IBD patients and controls identified differential expression of processes related to host defense and immunity. Conclusions: Proteomic analysis of clinical samples identified differentially expressed proteins that can classify IBD patients from non-IBD controls and distinguish UC patients with pancolitis from those without pancolitis; proteins identified in intestinal aspirates displayed consistent differential expression in stool. Furthermore enrichment of EVs from the intestinal MLI indicates that these may contribute to the dysregulated host response against the intestinal microbiota which is observed in IBD.

L’homéostasie des muqueuses intestinale et cutanée dépend des interactions complexes entre le microbiote, l’épithélium et le système immunitaire de l’hôte. Des mécanismes régulateurs divers coopèrent afin de maintenir l’équilibre physiologique, et un défaut dans ces mécanismes entrainent des situations pathologiques. Le glucagon like peptide 2 (GLP-2) est un neuropeptide caractérisé par des propriétés prolifératives et anti-inflammatoires. Le potentiel thérapeutique des analogues de GLP-2 est actuellement évalué dans des essais cliniques pour des maladies digestives. Les effets du GLP-2 dans l’intestin sont médiés par son récepteur GLP-2 receptor (GLP-2R). Malgré la présence des nombreuses études évaluant l’expression cellulaire et la distribution tissulaire du GLP-2R, celles-ci restent controversées, que ca soit chez l’homme ou les rongeurs. Il est admis que l’expression du GLP-2R était confinée au tube digestif, principalement à l’intestin proximal, malgré des études évoquant une expression extra-intestinale. Une meilleure compréhension de l’expression et de la distribution de GLP-2R est nécessaire pour élucider les fonctions biologiques de GLP-2. Nous avons réalisé une cartographie de l’expression de GLP-2R dans différents organes murins ainsi que dans des lignées immortalisées humaines et murines. Nous avons également évalué l’expression intestinale du GLP-2R dans 2 modèles de colites induites chez la souris et dans des biopsies intestinales des patients atteints de maladies inflammatoires chroniques de l’intestin (MICI). Nous avons démontré que GLP-2R était exprimé en dehors du tube digestif notamment dans la vessie, le système nerveux central, le mésentère, les ganglions mésentériques, la rate et le foie. Nous avons également montré que la plus forte expression de GLP-2R dans le tube digestif était détectée dans le colon proximal et le rectum. Dans les modèles murins de colites et chez les patients atteints de MICI, l’expression du GLP-2R était diminuée, notamment dans les zones inflammatoires. Ceci pose la question le rôle physiopathologique des analogues de GLP-2 dans les maladies inflammatoires digestives. En conclusion, les hypothèses précédentes considérant une expression du GLP-2R majoritaire dans le tube proximal doivent être reconsidérées. Les fonctions physiologiques extra-intestinales du GLP-2 doivent être explorés afin d’anticiper des effets indésirables extra-digestifs des analogues de GLP2. / Intestinal and skin physiologies are quite similar as far as the homeostasis in both depends on complex interactions between the microbiota, the epithelium and the host immune system. Diverse regulatory mechanisms cooperate to maintain the equilibrium, and a breakdown in these pathways may precipitate pathological conditions. Glucagon like peptide 2 (GLP-2) represents one of the hot topics in research in intestinal physiology. Its dual function as an anti-inflammatory agent and growth factor has led to its consideration in therapeutic strategies and GLP-2 analogs are currently in clinical trials for several digestive diseases. The integrative responses to GLP-2 are mediated via the GLP-2 receptor (GLP-2R). Despite extensive research, precise tissue distribution of GLP-2R expression remains controversial both in rodents and humans. It is widely believed that GLP-2R expression is restricted to the gastrointestinal tract, mainly to the proximal bowel, despite the presence of few studies reporting extra-intestinal expression. Thus, to enhance our knowledge concerning the potential functions of GLP-2 analogs, a better understanding for GLP-2R expression is considered necessary. We therefore realized a panel of GLP-2R expression in mice tissues and in several human, murine and rat cells lines. Given the therapeutic beneficial effects of GLP-2 analogs in intestinal disorders, we investigated the intestinal expression of GLP-2R in mice models of chemically-induced colitis and in inflammatory bowel disease (IBD) patients. We demonstrated that GLP-2R is more widely expressed than expected with significant expression in several mice tissues including bladder, central nervous system, mesenteric adipose tissue, mesenteric lymph nodes, spleen, and liver. We also showed that the expression of GLP-2R in the gastrointestinal tract follows an increasing gradient toward the distal gut with highest expression in the colon and rectum. Interestingly, the intestinal expression of GLP-2R is significantly decreased in experimental mice models of colitis and in IBD patients which raised the point of the physiological role of GLP-2 analogs in digestive disease patients. Overall, previous hypotheses limiting GLP-2R expression and function to proximal bowel need to be revisited, and further studies should address the extra-intestinal biological function of GLP-2.