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Cotterill, Lynn. « Inflammatory bowel disease genetics ». Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/inflammatory-bowel-disease-genetics(daae1a60-2790-4280-b7d5-ac5ec7533c7c).html.
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Inflammatory bowel disease (IBD), which includes the subtypes Crohn's disease (CD) and ulcerative colitis (UC), is a common disease particularly in the Western world. IBD is characterised by inflammation of the small intestine and/or colon. The two subtypes affect different gut locations but both show an increased intestinal permeability or the 'leaky gut syndrome'. This led to the hypothesis that tight junction (TJ) proteins expressed in the epithelium may affect the intestinal permeability as a cause or effect of IBD.Initially, variants in the CARD15, IL23R and ATG16L1 genes, previously associated with an increased risk of IBD, were genotyped in a cohort of 500 IBD (295 CD and 205 UC) patients and 877 matched controls. These variants were significantly associated in our cohort. A random effects meta-analysis was undertaken on all previously reported CD associations with the variant rs2241880 from ATG16L1 (n=25, p=0.0017, OR: 1.36 95% CI 1.12-1.66) and with rs11209026 from IL23R (n=26, p=0.0006, OR: 0.37 95% CI 0.21-0.67), showing pooled odds ratios consistent with those reported in our cohort. Individuals carrying >1 CARD15 mutant variant were found to have a 2.5 fold increased risk of CD (p=0.0001). Candidate TJ proteins were chosen on the basis of previous reported associations and through the investigation of the claudin proteins which are abundant at TJs. Twenty one candidate genes were selected and 79 variants successfully genotyped in up to 1063 IBD (502 CD and 478 UC) and 870 control patients. Significant associations were detected with variants in the CLDN1, CLDN5 and CDH1 genes with CD; CLDN5, CLDN8 and CDH1 variants were associated to IBD; and the rs7791132 variant (between CLDN4 and ELN) and a CDH1 variant were associated to UC. The CLDN1 rs6809685 variant trended towards association in a Toronto ascertained IBD replication cohort (genotypic p=0.04, allelic p=0.06) suggesting this may be a novel IBD susceptibility variant. Small intestinal biopsies from CD patients with known rs6809685 genotypes showed a dose dependent reduced immunohistochemical staining of claudin 1 with carriage of the mutant G allele. Claudin 1 helps seal TJs and reduced levels may increase risk of CD.Peroxisome proliferator activator receptors (PPARs) can directly affect TJ proteins and could therefore affect intestinal permeability. Twelve PPARγ variants were genotyped in up to 1050 IBD (502 CD and 467 UC) and 725 control patients. Significant genotypic associations were found with the rs2067819 variant in CD (p=0.05) and IBD (p=0.02), and also the rs13099634 variant in UC (P=0.02). There was a strong gender difference particularly for rs2067819 and rs4135247, where allelic associations were highly significant and increased risk of IBD in men (p=0.01 and p=0.007 respectively). However no significant associations were found in the female cohort. Troglitazone a PPARα agonist increased Caco2 cell transepithelial electrical resistance (TEER), a marker of TJ integrity, and increased expression of claudins -3 and -4. In contrast, the PPARα antagonist GW6471 reduced the TEER without causing cell death and PPARγ ligands did not affect TEER measurements. In summary, using a robust cohort of cases and controls the data indicates that variants in genes encoding TJ proteins may affect susceptibility to IBD and that PPARs can regulate these proteins altering intestinal permeability.
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Pozuelo, del Río Marta. « Metagenomics in inflammatory bowel disease ». Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/669437.
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La microbiota intestinal desempeña un papel crucial en el manteniendo la homeostasis intesitnal. Alteraciones en la composición microbiana, también conocidas como disbisosis, pueden poner en peligro el estado de salud e incrementar el riesgo a padecer una enfermedad. Aunque muchas enfermedades se han asociado a cambios en la microbiota intestinal, todavía se desconoce si dichas alteraciones son la causa o la consecuencia de las patologías.
La enfermedad inflamatoria intestinal (EII) es una enfermedad inflamatoria crónica que se caracteriza por periodos de inflamación y constituye un problema de salud dado. La EII presenta dos subtipos: enfermedad de Crohn y colitis ulcerosa, con síntomas similares pero diferentes manifestaciones clínicas. La EII se ha relacionado ampliamente con cambios en la microbiota intestinal. A pesar de los múltiples estudios que existen, no hay un claro consenso en el perfil microbiano asociado a la enfermedad. Las principales discordancias se dan entre las diferencias asociadas a enfermedad de Crohn y la colitis ulcerosa. Algunos investigadores han demostrado que la composición microbiana en colitis ulcerosa es muy similar a la de individuos sanos y ambas difieren de la composición de enfermos de Crohn. En cambio, otros investigadores han visto que las diferencias de colitis ulcerosa y Crohn respecto a sanos son muy similares por lo que consideran ambos subtipos como una única enfermedad (EII).
El principal objetivo de esta tesis es determinar la disbiosis en una cohorte de EII española para evaluar hasta qué punto las funciones y composición microbiana difieren entre Crohn y colitis y si los datos de microbioma podrían emplearse como herramientas de diagnóstico. Para ello, analizamos muestras fecales de sanos, enfermos de Crohn y enfermos de colitis usando dos metodologías: secuenciación del gen 16SARNr (o 16S ADNr) y secuenciación por fragmentación del genoma.
Como se preveía, observamos la presencia de disbiosis en EII. Además, vimos que las alteraciones en composición microbiana y funciones eran diferentes para Crohn que para colitis, mostrando una mayor disbiosis en Crohn que en enfermos de colitis ulcerosa y con colitis mostrando un patrón muy similar a la microbiota de individuos sanos. Los resultados funcionales encontrados en esta tesis confirman la mayor disbiosis descrita en pacientes de Crohn en comparación con pacientes de colitis ulcerosa en composición microbiana. Estos individuos presentan una mayor cantidad de genes principalmente asociados a metabolismo y enfermedades inmunes que los enfermos de colitis ulcerosa y sanos.
A pesar de que los datos de 16S ADNr y secuenciación por fragmentación no detectaron las mismas diferencias entre Crohn y colitis, ambas metodologías permitieron la clasificación de los distintos subtipos de EII con una proporción similar. Más estudios son necesarios para validar los resultados de esta tesis en otras cohortes de pacientes que incluyan Crohn localizado en colon o pacientes recién diagnosticados que no hayan sido sometidos a tratamiento antes de la aplicación de estas metodologías como herramientas diagnósticas en clínica.The gut commensal microbiota is known to play a crucial role in maintaining intestinal homeostasis. Alterations in the microbial community composition, also known as dysbiosis, may put health status in risk and increase susceptibility to diseases. Although several diseases have been related to shifts in the gut microbiome composition, it is still uncertain whether those alterations are the cause or consequence of the disease. Inflammatory bowel disease (IBD) is a chronic inflammatory disease with periods of active and inactive inflammation that constitutes to an important health problem. It is divided in two subtypes: Crohn’s disease (CD) and ulcerative colitis (UC) that present similar symptoms but different clinical manifestations. IBD has been widely associated with an alteration of the gut microbiome composition. Nevertheless, there is no clear consensus on the microbial pattern characteristic of the disorders. Main discordances between studies are related to differences between UC and CD. Some previous publications indicate that UC microbial composition is very similar to healthy and differs from CD whereas others consider both subtypes as a unique entity and find high alterations in UC and CD microbial composition in comparison with the microbiome of healthy individuals. The aim of this thesis was to characterize the dysbiosis in a Spanish IBD cohort to evaluate to which extend the gut microbiome composition and function could be differentiated between CD and UC and whether microbiome data could be used as diagnostic and prognostic tools. For this purpose, we analyzed fecal samples of healthy individuals, CD (affected in the ileum) and UC patients using two different methodologies: 16S rRNA gene (or 16S rDNA) and shotgun (short genomic fragments) sequencing. As expected, we observed the presence of dysbiosis in IBD. Furthermore, we showed that microbial composition and function alterations were different for CD and UC, with greater dysbiosis in CD than in UC and with UC resembling more to a healthy state. Functional findings also confirmed this higher dysbiosis in CD than in UC and revealed genes implicated in metabolism pathways and in immune diseases in higher abundance in CD compared with healthy individuals and UC. Although 16S rDNA and shotgun data did not detect differences in the dysbiosis in CD and UC in a consistent manner, both methodologies allowed the classification of IBD subtypes in a similar proportion. Future studies should validate these results using other patient cohorts such as colonic CD or recently diagnosed patients before the application of these techniques as diagnostic tools in clinical practice.
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Geerling, B. J. « Inflammatory bowel disease and nutrition ». Maastricht : Maastricht : Universiteit Maastricht ; University Library, Maastricht University [Host], 1999. http://arno.unimaas.nl/show.cgi?fid=7216.
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Smith, Graeme Drummond. « Counselling in inflammatory bowel disease ». Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/12244.
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Introduction; The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), affect well over 100,000 people in the United Kingdom Health related quality of life (HRQOL) is influenced by many factors in IBD including; the nature and severity of the disease, socio-economic factors, age, psychological well-being as well as· the efficacy and complications of treatment. Pilot Studies; Quality of life was assessed in 140 IBD patients (70 CD/70 UC). Diarrhoea was, not surprisingly, the most commonly reported physical symptom in both CD and UC and impaired faecal continence caused great social disability, with 72% CD patients and 68% UC patients reporting urgency or incontinence. Over a third of all patients reported occupational problems associated with their disease. Anxiety, but not depression, was common in the CD group and a major source of anxiety in many cases was lack of information. Three-quarters of patients felt additional information would have enabled them to cope with their chronic illness. It is a common perception that the provision of psychological support, such as the use of counselling skills, may alleviate many of the psychosocial problems associated with IBD, but this has not yet been proven. Hypothesis: That a nurse led counselling service improves HRQOL in IB D patients. Study Group/Design: Fifty patients with CD (aged 16-64, 33 females), 50 UC patients (aged 17-60, 26 females), 50 healthy volunteers (HV, aged 17- 61, 27 females) and a disease control group comprising 28 psoriatic arthritis (PS) patients (aged 22-66, 16 females) undeiwent structured interviews and completed a range of questionnaires measuring several facets of quality of life and psychological well-being (Hospital Anxiety and Depression Score (HAD), Attitudes and Preferences (AP), Styles and Strategies (SS) and Short-form 36 (SF36)). Patients with IBD were then randomised to receive either a counselling package or routine clinical follow-up. The counselling package consisted of disease specific information and teaching of stress management techniques, based on the "Challenge to change" programme devised by Dr. Derek Roger at the University of York. HRQOL scores were compared on entry at 6 and 12 months. Results; At baseline the scores for all questionnaires were within the nonnal range in the UC, PS, and HV groups. However CD patients recorded significantly higher anxiety scores (p
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Gustavsson, Anders. « Therapy in inflammatory bowel disease ». Doctoral thesis, Örebro universitet, Institutionen för hälsovetenskap och medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-25599.
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The aim of this thesis is to study treatment of inflammatory bowel disease with respect to an acute severe attack of ulcerative colitis and endoscopic balloon dilation in stricturing Crohn’s disease. A retrospective follow-up was made in 158 patients who were given intensive intravenous corticosteroid treatment due a severe, moderate, or mild attack of ulcerative colitis between 1975 and 1982. After 10 years, the colectomy frequency in the severe disease group was 64%, and 49% and28% in the moderate and mild groups, respectively. Severity of the original attack did not influence the subsequent clinical course with respect to colectomy. In 2005, a controlled Swedish–Danish trial of infliximab as rescue therapy in an acute severe attack of steroid refractory ulcerative colitis showed that colectomy frequencies after 3 months were lower in infliximab-treated patients (29%) compared to placebo-treated patients (67%). After 3 years, a statistically significantly lower colectomy frequency remained in patients treated with infliximab (50%) compared to placebo (76%). Between 1989 and 2009, 178 patients underwent endoscopic balloon dilation due to intestinal strictures in Crohn’s disease. Seventy-five patients,with a follow-up of 5 years or longer, underwent dilations due to symptomatic strictures only. After 5 years of follow-up, 39/75 (52%) of the patients had undergone no further intervention or one additional dilation only, and 36% had had surgery. The complication frequency was 5.3%, of which 10 patients (1.3%) required surgery. In 83 patients, we studied whether smoking at diagnosis affected the outcome after index dilation. In the group of active smokers, 31/32 (97%) underwent another intervention compared to 18/33 (55%) in never smokers (HR 2.18, 95% CI: 1.22-3.93,p = 0.01). Clinical parameters such as sex, age at diagnosis, age at first dilation, balloon size, localisation of stricture, treatment with azathioprine and treatment period did not influence outcome.
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Matini, Lawrence. « Adaptation to Inflammatory Bowel Disease ». Thesis, University of Surrey, 2017. http://epubs.surrey.ac.uk/841456/.
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Inflammatory bowel disease (IBD) is a term used to describe two chronic diseases of the gastrointestinal tract: Ulcerative Colitis (UC) and Crohn's Disease (CD). Although the efficacy of treatment is continuously improving, Quality of Life (QoL) in this illness population remains low with many patients suffering from psychological and psychiatric comorbidities. Psychological interventions aimed at improving outcomes in these patients have largely demonstrated little improvement. This thesis argues that this may be the result of poor understanding of the experience of living with this condition with too little focus on the adaptation of the patient to their illness. This thesis aimed to address this gap in the literature through four empirical studies. Firstly, Study 1 used a qualitative design to (n = 22) to explore the lived experiences of patients with IBD and to conceptualise adaptation to IBD. The results highlighted the importance of making sense of the illness and the impact and feelings associated with the illness. This was transcended by a notion of uncertainty which was resolved by employing coping mechanisms to restore equilibrium between their identity before and after diagnosis, resulting in a 'new normal'. Study 2 then employed a cross-sectional design (n = 307) to develop a new measure of adaptation to IBD (the A-IBD) which after psychometric analysis revealed four subscales including person identity, patient identity, acceptance and expectations. This study also explored the degree of association of the A-IBD with existing measures of sense making (BIPQ) and QoL (IBDQ), to assess the ability of the A-IBD in predicting QoL and ascertain whether it could predict QoL over and above sense making. The results suggested the A-IBD was not synonymous with these constructs and had utility as a predictor of QoL even when accounting for the predictive ability of the BIPQ. Finally, Study 3 used a combination of qualitative and quantitative design (n = 16). Patients scoring in the top and bottom 25% of the A-IBD from Study 2 completed the measure again to assess the dynamic nature of adaptation and were interviewed about the factors that either encouraged or inhibited their degree of adaptation. This analysis revealed that adaptation is indeed dynamic, and that antecedents of adaptation include 'engagement', 'resilience' and certain 'contingencies' including disease and social factors. Overall, the findings from this thesis indicate that the treatment of IBD must be approached in a biopsychosocial manner, that adaptation can be measured effectively with the new tool and that adaptation, with an emphasis on the notion of person, not patient, predicts quality of life.
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Gerasimidis, Konstantinos. « Nutritional aspects and gut microbiota in paediatric inflammatory bowel disease ». Thesis, Thesis restricted. Connect to e-thesis to view abstract, 2009. http://theses.gla.ac.uk/826/.
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Thesis (Ph.D.) - University of Glasgow, 2009.Ph.D. thesis submitted to the Division of Developmental Medicine, Faculty of Medicine, University of Glasgow, 2009. Includes bibliographical references. Print version also available.
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Campbell, Simon Scott. « Azathioprine use in inflammatory bowel disease ». Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/24109.
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Ljung, Tryggve. « Nitric oxide in inflammatory bowel disease / ». Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-602-2/.
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Parkes, Miles. « The genetics of inflammatory bowel disease ». Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326030.
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Dalton, Harry Richard. « Suppressive phenomena in inflammatory bowel disease ». Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305970.
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Satsangi, Jack. « The genetics of inflammatory bowel disease ». Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337627.
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Eadala, Praveen. « Lactose sensitivity and inflammatory bowel disease ». Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/53992/.
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Controversy still exists as to the incidence, role and impact of lactose sensitivity in inflammatory bowel disease. The thesis shows that there is a higher than previously reported incidence of lactose sensitivity determined by a combination of genotype, breath test and symptoms after a lactose challenge. Lactose sensitivity in patients with inflammatory bowel disease who are in remission is 70%. There was no difference compared to healthy volunteers in terms of lactase genotyping; however there was a significantly greater prevalence of positive breath test and symptoms after lactose challenge. This suggests that lactose sensitivity in inflammatory bowel disease is related to the disease itself or a consequence of it and not due to a genetic predisposition. A significant proportion of inflammatory bowel disease patients [16%] are methane producers which warrants further investigation. A pilot study of reduced lactose intake in patients with Crohn’s disease and lactose sensitivity, who were in remission, showed a promising improvement in symptoms reported and quality of life scores. The Real-Time Polymerase Chain Reaction is simple and quick compared to Restrictive Fragment Length Polymorphism for assessing the lactase genotype. The Quintron MicroLyzer to assess breath samples after lactose challenge is preferred to the hand held Micro H2 meter. This detects methane in addition to hydrogen and without this a number of cases of lactose sensitivity would be II missed. It may be possible to predict a negative breath test with the absence of any GI symptoms after a breath test and vice-versa a positive breath test is very likely if multiple GI symptoms are reported. The ‘hidden’ lactose in drugs used to treat inflammatory bowel disease and co-existing conditions should be considered as it is present in many drugs and can make a significant contribution to the amount of lactose ingested; lactose free alternatives are widely available.
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Arsenescu, Razvan I. « NOVEL MECHANISMS IN INFLAMMATORY BOWEL DISEASE ». UKnowledge, 2011. http://uknowledge.uky.edu/gradschool_diss/211.
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Inflammatory Bowel Diseases, Crohn's Disease and Ulcerative colitis, are idiopathic chronic conditions with multifactorial determinants. In general, terms, intestinal inflammation results from abnormal host-microbe interactions. Alterations in homeostasis involve host genetic factors, environmental cues and unique luminal microbial niches. We have examined the coordinated expressions of several molecular targets relevant to the mucosal immune system and identified signature biomarkers of IBD. Qualitative and quantitative changes in the composition of microbiota can be related to unique immuno-phenotypes. This in turn can have more systemic effects that involve energy metabolism. Adiponectin, an adipose tissue derived adipokine, can restore cellular ATP levels and fulfills innate immune functions. We have concluded that IBD might represent a state of adiponectin resistance relating to chronic inflammation and obesity status.
Lastly we hypothesized that activation of xenobiotic pathway (AHR-aryl hydrocarbon receptor) can further modulate host immune and metabolic responses, and thus contribute to IBD phenotypes. We found that IBD is associated with robust mucosal, aryl hydrocarbon receptor pathway and related to proinflammatory cytokine secretion. We conclude that IBD heterogeneity is reflected through distinct immunophenotypes. Furthermore, environmental cues that involve the AhR receptor and adipose tissue derived adiponectin are important regulators of the inflammatory process in IBD.
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Rankin, B. J. « Colonic mucus in inflammatory bowel disease ». Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320821.
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Hamlin, Peter John. « Genetic studies in inflammatory bowel disease ». Thesis, University of Leeds, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400166.
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Collins, Carole Elizabeth. « Platelet dysfunction in inflammatory bowel disease ». Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362539.
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Kamperidis, Nikolaos. « Nutrient effects in inflammatory bowel disease ». Thesis, Queen Mary, University of London, 2016. http://qmro.qmul.ac.uk/xmlui/handle/123456789/23488.
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Background: Not only does IBD lead to nutritional deficiencies, but also nutrients influence its pathophysiology: exclusive enteral nutrition (EEN) is an effective primary treatment in Crohn's disease; and vitamin D (VitD) is involved in its pathogenesis and course. Aims: We hypothesised that nutrients impact on the course of IBD. We therefore studied the effect of EEN i) on long term clinical course in children; ii) on CD58, a costimulatory molecule at the intestinal epithelial cell (IEC) lines, iii) adults with Crohn's disease. We examined the possible effect of serum vitamin D levels on the course of IBD and also the possible role of ethnicity in our paediatric and adult populations that were treated with EEN but also in our general adult population. Results Chapter II: 56 paediatric patients with Crohn's disesase were followed up for 5 years. 57% of patients achieved remission after 6 weeks of EEN. Achievement of clinical remission within 6 weeks of EEN was significantly associated with a longer time to relapse and to treatment escalation. VitD deficiency was common; and those patients who were deficient were significantly more likely to require corticosteroids and also needed thiopurines sooner. Chapter III: CD58 was expressed in the IEC isolated from IBD patients and healthy controls. EN down-regulated the expression of CD58 on IEC lines. Chapter IV: 22 adult patients with Crohn's disease with a mean age of 30.8 years were given EEN and followed up for a mean time of 1.9 years. 22.7% of patients went into clinical remission and 77.3% experienced a clinical response. By the end of follow up 63.6% (14/22) of patients had clinically relapsed and 36.4% required surgery during their follow up. There was no difference between South Asian and Caucasian patients in the disease outcomes after administration of EEN. Chapter V: Bangladeshis were more often vitamin D deficient than white Caucasian patients; however vitamin D status was not associated with the course of IBD. Bangladeshis developed perianal disease and required thiopurines earlier in their disease course. Bangladeshi patients with UC had more extensive disease. Conclusions: EEN, when successful, improves the long term outcome of Crohn's disease in children, possibly in part, by down-regulating CD58 on the IEC. VitD deficiency may influence the clinical course of IBD; however our results were contradictory between children and adults and significantly limited by the assessment of the vitamin D level at a single time point.
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Khodiyar, Varsha Kumari. « Microarray profiling of inflammatory bowel disease ». Thesis, University of Leicester, 2002. http://hdl.handle.net/2381/29415.
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In this study of inflammatory bowel diseases (IBD, i.e. Crohn's disease and ulcerative colitis), the gene transcription profile of colonic IBD resection specimens were analysed by oligonucleotide microarray analysis. A total of 33,625 genes were profiled across 23 colonic mucosa samples; 5 involved Crohn's disease, 4 uninvolved Crohn's disease, 5 involved ulcerative colitis, 3 uninvolved ulcerative colitis and 6 samples from macroscopically normal areas of colorectal cancer resections (controls). A number of data-mining tools, encompassing clustering (e.g. hierarchical & K-means) and matrix-based methods were evaluated for the analysis of this microarray data. Mining strategies were formulated, tested and then applied to the data set to identify genes showing interesting and novel expression patterns across the samples. The application of these tools to the data set resulted in the generation of gene expression profiles for Crohn's disease and ulcerative colitis. Genes of interest were annotated using publicly accessible sequence and literature databases. Potential links by previous research in the inflammatory bowel disease field were analysed for selected genes. Common pathways emerging from the annotation effort and potentially linking together several of the genes of interest were investigated. Specifically, the energy deficiency hypothesis proposed by Roediger in 1980 and the relevance of potential cancer and apoptosis related genes were reviewed with regard to the findings.
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Johnston, Colette. « Metabolomic profiling in inflammatory bowel disease ». Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/metabolomic-profiling-in-inflammatory-bowel-disease(1eb7a48f-af12-4bd2-8497-ebad4eae0e4e).html.
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Introduction: Inflammatory bowel disease is a common, complex relapsing disorder characterised by immune dysregulation, altered intestinal permeability and microbial insult. Limited knowledge is available regarding the metabolic changes observed during progression of the disease, and limited biomarkers of disease available that have been validated and shown to be of sound clinical value. Aim of Study: A two stage metabolomics approach was adopted to determine if metabolic signature profiles, could distinguish inflammatory bowel disease Crohn’s disease (CD) patients from ulcerative colitis (UC) patients and from healthy controls. Methods: A serum metabolomics approach was undertaken to define metabolic changes associated with UC and CD. Serum samples from a discovery study of 30 UC, 30 CD and 29 ethnically, age and gender matched controls were analysed by ultra-performance liquid chromatography mass spectrometry. A subsequent validation study was preformed using 28UC, 31CD, and 29 gender matched controls were also analysed using UPLC-MS.ResultsClasses of metabolites, identified as biologically interesting and at significantly different levels (p<0.05) in comparisons of control and CD and UC cohorts included: steroids and steroid derivatives, phosphocholine, Vitamin D metabolites, fatty acids and conjugates, glycerolipids, isoprenoids, amino acids, and phosphosphingolipids. There were fewer discriminatory metabolites differentiating the CD and UC cohorts. Conclusion: Serum Metabolomic profiling may represent a novel technology which could be used to distinguish individuals with CD from those with UC and healthy controls.
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Hildebrand, Diane Rosemary. « Metabolomic profiling in inflammatory bowel disease ». Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28850.
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Introduction Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder that encompasses two major subtypes; Crohn’s Disease (CD) and Ulcerative Colitis (UC). Our knowledge regarding disease pathogesis is rapidly increasing. However, these disease entities provide challenges in diagnosis, monitoring of disease activity and assessing individual response to treatment, because there is a lack of validated clinical biomarkers. Metabolomics involves the study of numerous analytes that have very diverse physical and chemical properties and occur in a wide concentration range. Early evidence suggests there is potential for metabolomic profiling to be used in the differentiation of CD and UC. However, knowledge is limited regarding the metabolic changes seen in relation to disease activity or to medical or surgical treatments. Aims A metabolomics approach was taken to determine whether metabolomic profiles could distinguish between patients with CD or UC and healthy controls. We also aimed to define the relationship between metabolomic profile and disease activity, and to determine the effect of medical (anti-TNFa agents) and surgical treatment on the metabolome. Methods A metabolomics approach was undertaken. Serum and urine sample sets were collected from a total of 41 patients with ulcerative colitis, 43 patients with Crohn’s disease, and 62 healthy controls (HC). In order to allow a comparison of metablomic profile and disease activity, 4 sample sets were taken from the same patient at 3 monthly intervals over the period of one year. Those patients undergoing either surgical or biological treatment had sample sets taken pre and post intervention. Metabolomic analysis using gas chromatography time of flight mass spectrometry (GC-ToF-MS) and ultra-high performance liquid chromatography Fourier Transform mass spectrometry (UHPLC-FTMS) was carried out on both serum and urine. Results Serum and urine GC-ToF-MS and UHPLC-FTMS metabolomic analyses show differentiation between UC, CD and healthy controls, most significantly in urine analyses. No significant differentiation was seen in pre- and post-surgical patients, or pre- and post-biological therapy patients. It was possible to differentiate surgical patients from healthy controls, especially in the urine analyses. Metabolite identification revealed consistently more dietary variation in the healthy controls than in the IBD patients. Significant differences (p < 0.05) were seen between healthy controls and IBD patients in classes of metabolites relating to the citric acid cycle and the uronic acid pathway, as well as amino acids, fatty acids and cholesterols. The behaviour or location of disease, or the disease activity score did not appear to influence the metabolome in either serum or urine analyses using GC-ToF-MS and UHPLC-FTMS. Conclusion Metabolomic profiling of urine and serum in IBD may provide a novel methodology aiding both clinical diagnosis through biomarker development, and advancing knowledge of disease pathogenesis.
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Tsaprouni, Loukia G. « Histone acetylation and inflammatory mediators in inflammatory bowel disease ». Thesis, University of Bedfordshire, 2003. http://hdl.handle.net/10547/620761.
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During cell activation the tightly compacted DNA is made available to DNA-binding proteins allowing the induction of gene transcription. In the resting cell, DNA is packaged into chromatin whose fundamental subunit is the nucleosome, composed of an octamer of four core histones (H) 3, 4, 2A and 2B. During the induction of gene transcription, modification of histones, by acetylation, methylation etc., results in unwinding of the DNA, permitting access of large DNAbinding proteins, such as RNA polymerase II, and subsequent induction of gene transcription. This investigation initially examined the effects of pro-inflammatory stimuli LPS and TNF-a on the production of IL-8 in a macrophage cell line (U937 cells) and in two T-cell lines (Jurkat and HUT-78 cells) as a marker of NF-KB-directed inflammatory gene expression. The ability of dexamethasone (Dex) and triamcinolone acetonide (TA) (synthetic glucocorticoid agonists) to suppress expression of the inflammatory cytokine IL-8 and to regulate histone acetylation was also investigated in these cells. LPS and TNF-a caused an increase in IL-8 expression, which was further enhanced by the histone deacetylases inhibitor trichostatin A (TSA), suggesting a role for histone acetylation in IL-8 production in these cells. Dex and TA, repressed LPS- and TNF-a -induced IL-8 expression in all three cell lines. This effect of both Dex and TA was attenuated by TSA in all cell lines studied, where the effect of TSA was greater in TA stimulated cells. Stimulation of all cell lines with LPS and TNF-a induced acetylation of H4 lysine residues (K5, 8, 12 and 16), the highest elevation of which was for K8 and K12. Also demonstrate is a K5 and K16 specificity of acetylation by glucocorticoids, apparent in all cell lines studied. Dex and, to a greater extent, TA suppressed LPS- and TNFa-induced K8 and K12 acetylation. TSA attenuated the inhibitory effect of the glucocorticoids for all three cell lines. An inCrease in HDAC activity with GCs was observed and ChiP assay showed these events occur on the native IL-8 promoter via histone acetylation. Further studies investigated whether there were any links between histone acetylation and the regulation of apoptosis. It was showed that TSA induced apoptosis in cells previously stimulated with the inducer of oxidative stress hydrogen peroxide (H20 2). Studies into the activation of caspase 3 in LPS- and TNF-a stimulated cells revealed that the combinatory effect of Dex or TA with TSA Significantly enhanced expression of the marker in all three cell lines. In resting cells, Dex, and TA, in the presence of TSA downregulated caspase 3 expression. These findings support the notion that glucocorticoid actions on apoptosis is mediated, at least in part, through an action on histone acetylation. Finally, histone acetylation was investigated in vivo in two rat models of inflammation and in human subjects with inflammatory bowel disease (IBD). The results showed an increase in histone H4 acetylation lysine specificity of acetylation on K8 and K12 in inflamed tissue and Peyer's patches in animal models and in IBD patients. Whereas H3 acetylation was not elevated to the same extent in tissue and was restricted to the mantle zone of Peyer's patches. In general, the present studies on histone acetylation and inflammation (in animal models and IBD patients) underlined the possibility of a general mechanism linking activation of the transcription factor NFKB with histone acetylation. The ultimate objective of this work is to aid in the understanding of the mechanisms of how deregulation of chromosome structure leads to progression of the disease state. This knowledge may aid in the development of new therapeutic approaches or improved glucocorticoids.
23
Bresso, Francesca. « Genetic and molecular determinants in inflammatory bowel disease / ». Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-982-3/.
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24
Bhatti, Mansoor Ahmad. « A study of pro inflammatory mechanisms in inflammatory bowel disease ». Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249258.
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25
Salim, Sa'ad Yislam. « Mucosal dendritic cells in inflammatory bowel disease ». Doctoral thesis, Linköpings universitet, Kirurgi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-52234.
Texte intégralRésumé :
Crohn's disease, a chronic inflammation of the bowel, is a multi-factorial condition where uncontrolled immune responses to luminal bacteria occur in genetically predisposed individuals. The first observable clinical signs are small ulcers that form at a specialised form of epithelium, follicle-associated epithelium (FAB). The FAB covers immune inductive sites, Peyer's patches, which function primarily as sensory areas that sample the externaI gut environment. Dendritic cells are one of the key cells that are involved in sensing luminal contents and orchestrating the gut immune system. The main aim of this thesis was to determine whether the barrier of the FAB is breached in Crohn's disease and if dysfunctional immune regulators, namely dendritic cells, playaroIe in initiating and/or maintaining the chronic intestinal inflammation. Using biopsies and surgical specimens, we were able to show that in Crohn's disease, there was an increased transmucosaI transport of Escherichia coli compared to specimens from ulcerative colitis and non-inflammatory bowel disease (IBD) controIs. Dendritic cells internalised a higher percentage of bacteria that had translocated across the FAB in the Crohn's samples. Furthermore, significantly higher concentrations of TNF-u was released upon bacterial stimulation by tissues from patients with Crohn's disease than in controIs. We went on to characterise the dendritic cells present in the Peyer's patches of patients with Crohn's disease. We found an accumulation of both immature and mature dendritic cells beneath the FAB, in the sub-epithelial dome (SED). Normally, mature dendritic cells migrate towards T cell-rich areas. However, we observed mature dendritic cells accumulating in the SED because they lacked the CCR7 migratory receptor. Furthermore, they were more prone to take-up bacteria, and produced TNF-α. To study the function of mucosal dendritic cells, we performed isolation experiments and mixed Iymphocyte reactions. Dendritic cells from both the ileum and blood of patients with active Crohn's had reduced capacity for inducing T cell proliferation than non-IBD controIs. Blood dendritic cells of patients in remission had normalised function that was similar to dendritic cells from healthy controls. The SAMPl/YitFc mice, considered an appropriate murine model for Crohn's disease, had an inherent permeability defect that increased with the chronicity of intestinaI inflammation. However unlike in human Crohn's disease, dendritic cells did not seem to playaroIe in murine ileitis. This thesis highlights the accumulation of the actively surveying dendritic cells that are prone to bacterial internalisation, and points to their possible different functional roles in active versus in-active disease; thereby confirming dendritic cells as one ofthe key components in the pathogenesis ofCrohn's disease.
26
Ingram, John Robert. « Topical nicotine therapy for inflammatory bowel disease ». Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491900.
Texte intégralRésumé :
This thesis covers several areas which are related to the potential therapeutic effect of topical nicotine in ulcerative colitis (UC) and Crohn's colitis. It also examines a possible mechanism which may be pertinent to its mode of action. Transdermal nicotine is of benefit for active UC but adverse events (AEs) are frequent and limit its use. This prompted development of topical delivery systems which made direct application of nicotine to the colonic mucosa possible. Nicotine liquid enemas and delayed-release oral preparations produce lower systemic blood levels of nicotine and initial work with the enema in active DC gave encouraging results. My work commenced with a dose-ranging pharmacokinetic study of nicotine enemas to establish the maximum tolerated dose, which was subsequently used in a randomised, placebo-controlled trial which involved patients with active DC. Results for the primary endpoint - induction of clinical remission, were negative, although the enemas were welltolerated with only one withdrawal due to an AE. Plasma fibrinogen was measured in a subgroup ofpatients to assess the effects of nicotine and disease activity - there appeared to be no effect of topical nicotine on fibrinogen levels and plasma fibrinogen was not suf1iciently sensitive to be of clinic~l use as a biochemical marker of disease severity. Patients previously treated with nicotine in this depaltment had commented that urge~cy to defaecate settled quickly. To examine this, a comparative study of enema retention and preference was perfOlmed but there was no difference between nicotine and other enemas. 2 Supplied by The British Library - 'The world's knowledge' Smoking has a detrimental effect in Crohn's disease (CD) but this could be due to factors other than nicotine and related to smoking. Given the considerable overlap in the . . treatment ofUC and CD, a small pilot study of nicotine enemas for active Crohn's colitis was conducted; there was no clinical deterioration and some patients improved. A delayed-release oral formulation was given to patients with more extensiv~ colitis. There was a wide vmiation in the dose of nicotine tolerated; assessment of efficacy was limited because of the 'open' nature of the observations - but some patients appeared to benefit. The laboratory work was an extension of evidence that 0.7 nicotinic acetylcholine receptors (nAChRs) on monocytes have an impOltant anti-inflanunatory role. It is conceivable that nicotine exerts an anti-inflammatory effect through these receptors but there was no data relating to the colon. LabeIledo.-bungarotoxin was used to detect 0.7 nAChRs in human colonic mucosa. They were present on a few cells of the lamina proplia which are possibly dendritic cells (DCs) based on their morphological and phenotypic features. Future investigations might include the roles in colitis of delayed-release oral nicotine e and formulations which reproduce the phannacokinetic profile ofplasma nicotine seen in smokers. The possibility that nicotine may help us understand the pathogenesis ofcolitis and lead to therapeutic alternatives is attractive and requires further exploration.
27
Irving, Peter Miles. « Platelet-leucocyte aggregates in inflammatory bowel disease ». Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441946.
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Rahman, Arman. « Defensins and cytokines in inflammatory bowel disease ». Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1377.
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29
Simmonds, Nicola Jane. « Reactive oxygen metabolites and inflammatory bowel disease ». Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317911.
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30
Radford-Smith, Graham Lindsay. « Cytokine gene expression in inflammatory bowel disease ». Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296991.
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31
van, Heel David Alexander. « Identification of inflammatory bowel disease susceptibility genes ». Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249199.
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32
Williams, Horace Richard Timothy. « Urinary metabolic profiling in inflammatory bowel disease ». Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.508479.
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Cornish, Julie Ann. « Inflammatory bowel disease & ; female reproductive health ». Thesis, Imperial College London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539280.
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34
Andreoletti, Gaia. « Genomic analyses of paediatric inflammatory bowel disease ». Thesis, University of Southampton, 2016. https://eprints.soton.ac.uk/403112/.
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35
Elding, H. « Dissecting the genetics of Inflammatory Bowel Disease ». Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1464062/.
Texte intégralRésumé :
Inflammatory Bowel Disease (IBD) can be classified into two main subtypes: Crohn’s Disease (CD) and Ulcerative Colitis (UC). The aim of this study is to identify the genetic contribution to the susceptibility to IBD. In the first part of the study, I focused on Crohn’s Disease, the subtype that shows the greatest heritability. Using both pooled and sub-phenotype data, followed by replication, the results reveal substantial genetic heterogeneity and the total number of confirmed CD susceptibility loci was increased from 71 published by others to 200. This was achieved by analyzing the data using a multimarker approach and high-resolution genetic maps in Linkage Disequilibrium Units. In the second part of the study, I focused on Ulcerative Colitis. The results show that although UC has a lower reported heritability, many loci were also found for Ulcerative Colitis. Some of these overlap with those found for Crohn’s Disease.
36
Armentrout, Paige L. « Exploring Dietary Patterns in Inflammatory Bowel Disease ». The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555379444416158.
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37
Wong, L. H. J. « Optimising thiopurine therapy in inflammatory bowel disease ». Thesis, Exeter and Plymouth Peninsula Medical School, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701322.
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Lee, Cheng Hiang. « Paediatric Inflammatory Bowel Disease : Epidemiology and Immunopathogenesis ». Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/24013.
Texte intégralRésumé :
IBD is a chronic inflammatory disorder of the gut where the exact pathogenesis is not fully understood. The thesis makes important contributions to knowledge in this area. It presents previously unavailable information on the incidence of PIBD in NSW from 1968 to 2013. It also presents findings from an investigation of the immunopathogenesis of IBD based on 2 studies of monogenic IBD and lymphocyte immunophenotyping. The incidence of PIBD in NSW in 2013 was estimated to be 5.32 per 100,000 children, which represents a nearly 30-fold increase over the past 5 decades. This finding is consistent with the reported increase in incidence across the world. Novel mutations in the IL-10 receptor gene (c.583T>C and c.1368G>T) that lead to infantile onset IBD were identified. One of the mutations was de novo, prompting the need to consider an IL-10 pathway defect in patients with VEOIBD, even if the parents are non-consanguineous. TRIM22 variant (R442C) was discovered to cause a severe form of VEOIBD associated with granulomatous colitis and fistulising perianal disease. Subsequently, it was shown that TRIM22 regulates NOD2 mediated activation of downstream signalling pathways pertinent to viral and bacterial handling. Through lymphocyte immunophenotyping, it was established that a lack of Treg in numerical terms is unlikely to be the cause of uncontrolled inflammation in IBD. However, failure to induce Treg in inflamed tissue may play a role in the immunopathogenesis of IBD. Age-dependent changes in gut-homing CD4 T-cells were observed and may have clinical implications for the use of vedolizumab in children. Classifications of IBD based on genomics and immunopathogenesis pathways may be more helpful in the future to guide individualised therapy and risk management.
39
MURGIA, ANTONIO. « INFLAMMATORY BOWEL DISEASE STUDY : A METABOLOMICS APPROACH ». Doctoral thesis, Università degli Studi di Cagliari, 2018. http://hdl.handle.net/11584/255960.
Texte intégralRésumé :
Inflammatory bowel disease represents a group of chronic disorders that affect one or more parts of the intestine. Although recently the incidence of inflammatory bowel disease has noticeably increased, its aetiology is still unclear. No specific pathogen has been defined as a causative agent. Serological biomarkers have been recently proposed for diagnosis, but they remain untested in clinical applications. Moreover, current diagnostic and monitoring practices for inflammatory bowel disease are very invasive. Therefore, accurate tools for the early diagnosis, and in particular non-invasive strategies are needed. One area of recent interest is the relationship between the metabolome and microbiota in terms of inflammatory bowel disease pathogenesis and intervention strategies. Direct analysis of metabolites and their interaction with the gut microbial species is a rapidly growing field of research. In this context, metabolomics could represent a useful approach to understand possible pathological mechanisms or metabolite modification in different pathways. Metabolomics is based on the quantitative measurement of dynamic metabolic changes in living systems in response to physiological stimuli or genetic modifications, nutrients and drugs. Thanks to the comprehensive study of low molecular weight metabolites (<1500 Da) in biofluids and in tissues, metabolomics ensures the characterization of the metabolic phenotype of a living organism. In this work, the polar and the lipid metabolite profile of faecal and plasma samples of patients affected by inflammatory bowel disease and healthy patients has been studied by high resolution liquid chromatography coupled with several technological platforms such as a triple quadrupole, a quadrupole time of flight mass spectrometry and an ion mobility prior to multivariate statistical data analysis. By these means, differences between Crohn’s disease, ulcerative colitis and control samples were investigated. Results of discriminant analysis were considered with the aim to find the relevant metabolites unique for each class. The results highlight differences in the metabolite profile between the pathological and the control samples. In faecal samples, the most discriminant metabolites for both IBD classes were diacylglycerols, phosphatidylcholines triacylglycerols and tetra pyrrole compounds. Furthermore, plasma samples results showed modification of the lysophosphatidylcholine and phosphatidylcholine pathways strictly related to the arachidonic acid response. These results highlight similarity in the metabolic alteration occurring in both ulcerative colitis and Crohn’s disease when compared to healthy controls. Modification to the endocannabinoid system were also found regarding the ulcerative colitis plasma and faecal samples. All the lipid results were correlated with the targeted analysis of the polar metabolites profile. In conclusion, the application of metabolomics to faecal and plasma samples of IBD patients allows for the identification of metabolites that can be used as possible indicators of metabolic pathways implicated in the onset of these pathologies.
40
Berrill, James. « Symptoms of irritable bowel syndrome in patients with inflammatory bowel disease ». Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/61734/.
Texte intégralRésumé :
Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are both chronic relapsing intestinal disorders. Their symptom profiles overlap in terms of abdominal discomfort and altered bowel habit. Meta-‐analysis of patients with IBD demonstrates that 25-‐46% of those in clinical remission have symptoms compatible with IBS. These patients report lower quality of life scores compared to their asymptomatic counterparts. There is uncertainty as to the cause of these symptoms, and concern for the influence they may exert on clinical management. The work described in this thesis investigated the nature of IBS-‐type symptoms occurring in patients with IBD, examined potential diagnostic tools to distinguish between the respective conditions, and conducted a therapeutic trial for the management of functional symptoms in this setting. IBS-‐type symptoms were observed to occur more commonly in female IBD patients, were associated with high anxiety levels, and occurred in patients with no active inflammation as confirmed by a normal faecal calprotectin level. These findings are characteristic of irritable bowel syndrome, and suggest that this disorder may cause persistent symptoms during IBD remission. Two potential biomarkers of IBS were investigated. The first explored a hypothesis that IBS may be a systemic condition caused by the absorption of toxic metabolites produced by the bacterial fermentation of dietary carbohydrates. This mechanism would potentially explain both the gastrointestinal and the systemic symptoms that are observed in patients with IBS. It was proposed that toxic metabolites may covalently modify albumin in patients with IBS, however on investigation of this theory there was no significant difference observed between the plasma samples of IBS patients, IBD patients and healthy controls. The presence of systemic symptoms in patients with IBS and IBD was associated with higher anxiety levels. Cognitive function was also assessed as a potential biomarker of IBS following anecdotal reports that IBS patients experience impaired concentration. However no significant difference between IBS patients, IBD patients, and healthy controls was identified. Concurrent mood disorders, in particular depression, were associated with impaired performance of specific tasks in patients with IBD. A randomised-‐controlled trial of a mindfulness-‐based psychological intervention was performed in IBD patients with IBS-‐type symptoms or high perceived stress levels. Sub-‐group analysis demonstrated a significant improvement in quality of life in the intervention group in those patients who were experiencing IBS-‐type symptoms. Overall, these findings support the theory that IBS can cause persistent symptoms in IBD patients who are in remission. However, until the molecular mechanisms underlying IBS are identified and reliable biomarkers are developed, a systematic diagnostic approach is required to evaluate these patients. IBS-‐type symptoms in IBD patients represent a therapeutic target to improve quality of life and further trials of psychological intervention, medication and dietary modification are required.
41
Weersma, Rinse Karel. « Genetic susceptibility for inflammatory bowel diseases ». [S.l. : Groningen : s.n. ; University Library Groningen] [Host], 2007. http://irs.ub.rug.nl/ppn/304870935.
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42
Kalla, Rahul. « Biomarker discovery in inflammatory bowel diseases ». Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31040.
Texte intégralRésumé :
There is an unmet need for novel biomarker discovery in Inflammatory Bowel Diseases (IBD) to aid clinical management in several clinical settings including diagnosis and prognosis. With an ever-advancing repertoire of biological therapies on the horizon, it is important to personalise treatments at an early stage. The aim of this thesis is to explore the clinical utility of novel blood-based biomarkers in diagnosis, disease classification and prognosis in 2 cohorts: newly diagnosed IBD and acute severe colitis. Investigating the circulating methylome, 290 probes exhibited Holm significant IBD-associated methylation differences, including VMP1/MIR21 (p=7.5×10-14) and RPS6KA2 (1.1×10-19) and were consistent within the European cohort. 11 Differentially methylated positions (DMPs) predicted treatment escalation after Holm adjustment (top probe p=0.003). A panel of 6 probes identified 2 patient subgroups that have significantly different disease courses (Hazard Ratio (HR) 10.5, 95%CI: 4.3-25.6; logrank p=1.5×10-24). The 6 probe marker outperformed conventional biomarkers in predicting treatment escalation (hsCRP > 4mg/L, HR 3.2(1.7-5.8), logrank p=0.0004 and Alb < 36g/L, HR 2.9(1.5-5.6), p=0.0001). Within the same cohort, a novel proximity extension assay (PEA) was then utilised to identify novel diagnostic and prognostic protein markers. 61 proteins were significantly associated with IBD including MMP12 (Holm-adjusted p=4.1×10-26). A total of 9 proteins predicted disease course in this cohort. Using a panel of 7 randomly selected top prognostic probes, 2 patient groups were identified that had significantly different disease courses: logrank p=2.2×10-10, HR 5.6(2.0-15.6), outperforming conventional biomarkers in predicting treatment escalation (hsCRP > 4mg/L, HR 3.2(1.7- 5.8), logrank p=0.0003 and Alb < 36g/L, HR 2.7(1.4-5.2), p=0.0004). In a subcohort, serum calprotectin (SC) and conventional blood markers were investigated for their utility in diagnosis and prognosis in IBD. SC performed at par with CRP at differentiating IBD from controls with an area under the curve (AUC) of 0.87 (CI 0.81-0.92). For prognostication, both albumin and SC remained significant predictors of treatment escalation in IBD (logrank test p=5.1×10-5). MicroRNAs (miRNA) are small non-coding nucleic acids that have the capacity to modulate gene expression. Using small RNA sequencing in acute severe colitis (ASUC) and healthy controls (HC), 10 serum-based miRNA markers were significantly associated with acute severe colitis, including miR-30a-5p. Validating the findings using qPCR, miR-30a-5p was downregulated in ASUC (p=0.003). Furthermore, miR30a-5p remained a significant predictor of eventual colectomy in acute colitis (logrank test p=0.0014). These data highlight the translational potential for methylation, miRNA and proteomic biomarkers in diagnosing and prognosticating in IBD.
43
Neilly, Paul John David. « Inflammatory mediators and amino acid therapy in experimental inflammatory bowel disease ». Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361291.
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44
Halfvarson, Jonas. « Inflammatory bowel disease in twins : studies of genetics and environmental factors / ». Linköping : Univ, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med909s.pdf.
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45
Schreiber, Olof. « Microcirculation, Mucus and Microbiota in Inflammatory Bowel Disease ». Doctoral thesis, Uppsala universitet, Integrativ Fysiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-112718.
Texte intégralRésumé :
Inflammatory bowel diseases, (IBD), are a group of chronic disorders of the gastro-intestinal tract, and include Crohn’s disease (CD) and Ulcerative Colitis (UC). The pathogenesis is not known, but involves at least in part a loss of tolerance towards the commensal colonic microbiota. In this thesis, we show in animal models of CD and UC that the colonic mucosal blood flow increased compared to healthy animals. This blood flow increase is due to an up regulation of endothelial nitric oxide synthase (NOS). Further, we show in the UC model that the thickness of the firmly adherent colonic mucus layer increased compared to healthy animals. This increase is due to an up regulation of inducible NOS in the epithelium. Both the blood flow and mucus thickness increase appear to be protective mechanisms. We demonstrate that the firmly adherent colonic mucus layer acts as a partial barrier towards luminal bacteria. In the UC model, this barrier is destroyed, causing increased bacterial translocation. The adhesion molecule P-selectin was up regulated in the UC model, leading to increased interactions between leukocytes and the endothelium, but also increased interactions between platelets and the endothelium. This indicates that not only leukocytes, but also platelets are involved in colonic inflammation. The addition of the probiotic bacterial strain Lactobacillus reuteri prevented disease by normalizing P-selectin levels and endothelial interactions with leukocytes and platelets. Lactobacillus reuteri also decreased bacterial translocation over the epithelium. In summary, this thesis highlights the importance of colonic barrier functions, and investigates the role of the microbiota in experimental IBD.
46
Heikius, B. (Bengt). « Pancreatic and hepatobiliary disorders in inflammatory bowel disease ». Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514257561.
Texte intégralRésumé :
Abstract
Extraintestinal manifestations in inflammatory bowel disease (IBD) have been described with varying frequencies. The aim of this study was to estimate the prevalence of pancreatic duct abnormalities, exocrine and endocrine dysfunction, elevated pancreatic enzymes, hepato-biliary disease, coexisting cholangiographic and pancreatographic duct changes, and elevated serum levels of fibrosis markers in IBD, and to correlate the findings with clinical, endoscopic and histologic variables.
From a local patient register, 237 patients were randomly selected and studied. Of these, 170 had ulcerative colitis (UC), 46 had Crohn's disease (CD), and 21 had indeterminate colitis (IC). A detailed history was obtained from medical records and in a face-to-face interview. The patients were screened with a para-aminobenzoic acid (PABA) test and, for pancreatic enzymes, liver function tests, serum aminoterminal propeptide of type III procollagen (PIIINP), and laminin. Further pancreatic evaluation included endoscopic retrograde cholangiopancreato-graphy (ERCP), ultrasound (US), secretin test, and glucagon C-peptide test. Further hepatobiliary evaluation consisted of ERCP, US, and liver biopsy.
In IBD, the prevalence rates of pancreatic duct abnormalities and exocrine dysfunction were 8% and 4%, respectively. Parallel impairment of exocrine and endocrine functions was shown. Acute idiopathic pancreatitis may complicate IBD. About 7-17% presented with elevated pancreatic enzymes. Enzyme elevation was associated with extensive and histologically active disease and, in some cases, with primary sclerosing cholangitis (PSC). Abnormal liver test results were commoner in patients with CD than in patients with UC (30% versus 11%). The prevalence of PSC in IBD was 11%, which is higher than previously reported (3.7-7.5%). PSC was commoner in patients with CD than in patients with UC (17.4% versus 7.6%). About half of the PSC patients had concomitant pancreatic duct changes, and the prevalence of concurrent cholangiographic and pancreatographic duct changes in IBD was 4.6%. Both serum PIIINP and laminin were increased in IBD patients. This was not only seen in patients with hepatobiliary disease and PSC, but also in patients with pancreatic disease.
In conclusion, pancreatic and hepatobiliary complications in IBD occur with high and similar frequencies in all IBD categories and are associated with each other. They are not clearly associated with the clinical course of IBD.
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Hann, Bradley M. « Colonic epithelial cell apoptosis in inflammatory bowel disease ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ37955.pdf.
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Bernard, Nicole Kristine. « Glucagon-like peptide 2 and inflammatory bowel disease ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0016/MQ49596.pdf.
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Onnie, Clive Morris. « Genetic determinants of susceptibility to inflammatory bowel disease ». Thesis, King's College London (University of London), 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485696.
Texte intégralRésumé :
The aim of this thesis was to advance the current knowledge of the genetic determinants ofsusceptibility to inflammatory bowel disease (IBD), and examine their effect on disease phenotype. A DNA source from 1071 well clinically characterized patients with IBD disease (644 Crohn's Disease (CD), 427 ulcerative colitis (UC» was established. This was used both alone and in combination with an existing IBD collection to investigate candidate susceptibility genes as well as the relationship between genotype and phenotype. . The previously reported association ofthe IBD5 locus with CD was investigated to try and identify the true disease susceptibility alleles. The coding regions of 10 genes in and around the IBD5 locus was resequenced in 24 CD cases and a linkage disequilibrium (LD) map was derived of the 27 single nucleotide polymorphisms (SNPs) detected. Ten SNPs representative oftheobserved LD groups, were tested. for CD association. L503F in SLC22A4 was the only nonsynonymous SNP significantly associated with CD (p=0.003J,· but was not associated with disease in the absence ofother markers ofthe 250 kb risk haplotype. Two other SNPs, rsl1242115 inIRFJ and rsl7166050 in RAD50, lying outside the 250kb risk haplotype, also showed CD association (p=O.O19 and p=0.0080, respectively). The contribution ofthe IBD5 locus as well as the 3 CARDJ5 variants that increase susceptibility to CD, on the clinical phenotype ofCD was investigated. A novel association of CARDJ5 variants was found with the presence of granulomas. The strong association of CARDJ5 variants with ileal disease was confirmed. Although CARDJ5 mutations were significantly associated with stenotic disease behaviour, this was not independent of an ileal disease location, and reflects the strong association between ileal location and stenotic behaviour. An association of the IBD5 locus with perianal disease location was observed. The association oftheABCBJ variants, C3435T and G2677T/A with IBD was examined in a large case-control cohort.The effect ofthese variants was further examined with respect to phenotypic and epidemiological characteristics. The 2677T allele was significantly increased in British UC cases compared with controls (45.2% vs. 39.6%; P = 0.034). In particular, the TT genotype was significantly associated with severe UC (odds ratio [OR] 1.90; 95% CI 1.01-3.55) and the use of steroids in UC (OR 1.77; 95% CI 1.08-2.88).
50
Cook, W. B. « Iron absorption in health and inflammatory bowel disease ». Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597923.
Texte intégralRésumé :
Chapter 1 provides a general introduction while Chapter 2 investigates the relationships between dietary iron intake, disease activity and quality of life (QOL) in patients with IBD. Results indicated that non-haem iron intake was significantly associated with iron requirements for IBD patients but not healthy controls. Interestingly, for iron replete IBD patients, a significant positive correlation between iron intake and disease activity was noted. Correlation between QOL and iron intake was also observed. Chapter 3 investigated the acute effects of a single oral dose of ferrous sulphate on (i) iron absorption into serum and (ii) systemic nontransferrin bound iron (NTBI) generation. It also investigated whether baseline haematinics are an appropriate indicator of iron requirements in IBD subjects. Overall, iron absorption did not differ between IBD patients and healthy controls and both groups showed a similarly significant rise in NTBI following supplementation. However, in healthy controls baseline haematinics predicted iron absorption (i.e. iron requirements) but not in patients with IBD. Chapter 4 reports a laboratory-based investigation on the ability of different organic acids (OA) to alter the precipitation and redissolution properties of insoluble ferric hydroxide. The aim being to identify potential OA’s for use in a novel ferric iron supplement. Results showed that malic acid had significant effects on the precipitation and redissolution of ferric iron and may be efficacious as an iron supplement. Finally, in Chapter 5, in vivo testing of selected iron-organic acid mixtures was undertaken in human volunteers comparing the absorption to ferrous sulphate. Results showed that these were reasonably absorbed, albeit to a lesser extent than ferrous sulphate. Further work could trial these in IBD as side effects should be minimised while at least some iron would be absorbed.