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1
Lomer, Miranda Clare Elizabeth. "Dietary microparticles and Crohn's disease." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401033.
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Biasci, Daniele. "Predicting prognosis in Crohn's disease." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/270034.
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Broadhurst, J. F. "Mesenteric fat in Crohn's disease." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1467053/.
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Crohn’s Disease is a chronic inflammatory disorder of the bowel affecting approximately 1 in 800 people in the UK. The terminal ileum is most commonly affected and the mesentery becomes thickened, a phenomenon known as ‘fat wrapping’. The cause is not understood. Elemental feeding can induce remission in Crohn’s disease and polyunsaturated fatty acid (PUFA) content may be the cause of a reduction in inflammation. Particular attention has focused on n-‐3 and n-‐6 PUFA content of elemental feeds. The aim of this study was to further characterize mesenteric fat in Crohn’s disease and to examine the effects of different PUFA on mesenteric inflammation in vitro. Samples of adipose tissue were collected from patients undergoing intestinal resection for Crohn’s disease and from controls. These were cultured in media and elemental (E028 and Emsogen) feeds containing different concentrations of n-‐3 and n-‐6 PUFA. Significant findings were that mesenteric (MF) and omental (OM) adipose tissue released more inflammatory cytokines IL-‐6, leptin and MCP-‐1 when cultured in media rich in n-‐6 PUFA compared to media rich in n-‐3 PUFAs. OM mean IL-‐6 concentrations were 18.6(3.1-‐21.8)ng/mL in n-‐6 PUFA vs 3.07(0.62-‐19.10)ng/mL in n-‐3 PUFA (p=0.018), MF IL-‐6 concentrations were 3.77(0.76-‐9.52)ng/mL in n-‐6 PUFA vs 1.5(0.42-‐2.61)ng/mL in n-‐3 PUFA (p=0.03). OM Leptin concentrations were 0.42(0.08-‐0.90)ng/mL in n-‐6 PUFA vs 0.08(0.07-‐0.14)ng/mL in n-‐3 PUFA (p=0.006), MF Leptin concentrations were 0.27(0.13-‐2.62)ng/mL in n-‐6 PUFA vs 0.12(0.07-‐0.31)ng/mL in n-‐3 PUFA (p=0.033). OM MCP-‐1 concentrations were 18.80(4.39-‐31.5)ng/mL in n-‐6 PUFA vs 1.83(0.69-‐4.82)ng/mL in n-‐3 PUFA (p=0.002) and MF MCP-‐1 concentration were 4.59(2.20-‐13.72)ng/mL in n-‐6 PUFA vs 1.20(0.82-‐3.39)ng/mL in n-‐3 PUFA (p=0.006). These findings show that n-‐6 PUFAs stimulate a greater inflammatory response from omental and mesenteric fat in vitro and may assist in formulating a more effective elemental feed for inducing remission in patients with active flares of Crohn’s disease.
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Bernell, Olle. "Surgery and recurrence in Crohn's disease /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-628-5102-0/.
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Mohiuddin, Mohhamed Khalid. "Post-operative Crohn's disease : can non-invasive faecal markers predict post-operative course of Crohn's disease." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1147.
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Background: Identifying Crohn’s disease recurrence in symptomatic patients after ileocaecal resection is difficult as symptoms may reflect the effect of surgery rather than active disease. The aim of this study was to evaluate faecal concentrations of granulocyte degradation products (faecal calprotectin and faecal lactoferrin) in this post-operative setting. Methods: A post-operative cohort of 104 patients (median follow up of 24 months) provided a single stool sample. A second cohort of 13 patients was followed prospectively for 1 year with regular faecal calprotectin (FC) and faecal lactoferrin (FL) measurements. Faecal measurements were compared with symptom diaries, the Harvey Bradshaw Index (HBI), endoscopic examination, C-reactive protein (CRP) and platelet measurement. Results: Both faecal calprotectin and faecal lactoferrin correlated significantly with Harvey Bradshaw Index (r = 0.532, P< 0.001, r = 0.687, P< 0.001 respectively). Twenty eight patients with severely clinically active disease had high mean (s.e) levels of faecal calprotectin (661.1(119.1) μg/g) and faecal lactoferrin (116.6(32.2) μg/g); and forty three patients with clinically inactive disease had low levels of faecal calprotectin (70.2(27.1) μg/g) and faecal lactoferrin (5.9(2.4) μg/g). In patients with mild to moderately clinically active disease, faecal calprotectin and faecal lactoferrin identified individuals with and without recurrent inflammatory disease. In the uncomplicated course, both markers (faecal calprotectin and lactoferrin) normalized within 2 months. Faecal markers were more accurate at predicting clinical disease activity than C-reactive protein, platelet count or endoscopic appearance. Conclusion: Faecal calprotectin and faecal lactoferrin are non-invasive tests that can help to identify disease recurrence in symptomatic post-operative patients [1].
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Baker, John Summers. "The function of innate immune genes in Crohn's disease." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.560924.
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Crohn's Disease (CD) is a debilitating condition characterised by chronic intermittent intestinal inflammation. More than 90 genetic polymorphisms are associated with CD susceptibility, including several in genes of the innate immune system. Here I present a series of experiments designed to enhance our knowledge of the roles of CD-associated polymorphisms in pathogenesis. Many therapeutic regimens are employed in CD treatment, but patients' responses to treatment and disease progression vary widely. There is great interest in studying whether analysis of patients' genotype at CD-associated polymorphisms can be used to predict their disease course, and guide clinical decision-making. To answer these questions, it is essential to be able routinely and cost- effectively to genotype patients at the full range of known CD-associated polymorphisms. The first project presented here describes the design and initial successful testing of a CD-specific genotyping microarray for use in genotype-phenotype studies. The polymorphism most strongly associated with CD susceptibility is in the pattern recognition receptor NOD2; the remaining experiments presented here study the function of NOD2 in primary human monocyte-derived Dendritic Cells (DCs). First, a microarray study is presented which characterises global transcriptional responses to NOD2 stimulation in DCs. NOD2 stimulation is shown to enhance transcriptional changes induced by Toll-Like Receptor 2 stimulation, and NOD2-mediated transcriptional regulation is shown to be lost in DCs expressing CD-associated NOD2 variants. Second, experiments are presented which describe development of a new protocol for proteomic analysis of post-translational protein modifications, and which identify a number of novel candidate targets of NOD2 signalling in DCs. Finally, a project is presented which demonstrates for the first time that NOD2 stimulation induces autophagy in DCs, in an NF-kB and RIPK2-dependent pathway. CD-associated polymorphisms in NOD2 and ATG 16Ll abolish NOD2-mediated autophagy induction, resulting in impaired bacterial handling and antigen presentation.
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Fernandez-Hernandez, Heriberto. "The Role of LRRK2 in Crohn's Disease." Thesis, Icahn School of Medicine at Mount Sinai, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10793069.
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Crohn’s Disease (CD) is a type of Inflammatory Bowel Disease (IBD) with increasing incidence worldwide. In the US alone, prevalence of CD is shown to be 214 per 100,000. CD is not fatal, but deeply impacts the quality of life of an individual. While existing therapies alleviate the symptoms of the disease, there is no cure yet. Even with proper treatment, as many as two-thirds to three-quarters of people with CD will require surgery, which involves high risk of compromised bowel function and malnutrition. Therefore, there is a great need for the development of novel therapies for treatment and prevention of the disease. A better understanding of how CD-associated genetic mutations impact biological pathways involved in disease pathogenesis could offer insights into the development of new therapeutic strategies.
An autophagy gene associated with CD is Leucine-rich repeat kinase 2 (LRRK2). LRRK2 is a multidomain protein with numerous suggested biological functions including vesicular traffic, immune response regulation and autophagy. While LRRK2’s involvement in Parkinson’s disease (PD) development has been investigated for over a decade, only recently have studies detected associations between LRRK2 mutations and susceptibility to CD. Recently, our group identified novel association signals at LRRK2 conferring CD risk, N2081D; or protection, N551K, tagging the R1398H-associated haplotype. Interestingly, the LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD.
The main goal of my thesis was to elucidate the functional consequences of these novel CD-associated LRRK2 mutations, N2081D and N551K+R1398H, on the autophagy process. To study autophagy and its role in regulating inflammation, the major component of CD, we utilized macrophages, white blood cells, important in the process of phagocytosis that highly express LRRK2. Through our study of human-derived macrophages, we found that carriers of the LRRK2 N2081D mutation exhibited impaired autophagy when compared to N551K+R1398H carriers and non-carriers. We also found that impaired autophagy in N2081D carriers was associated with increased total LRRK2 protein levels and defective lysosomal pH and tubulin acetylation regulation. Additionally, we studied autophagy in macrophages from wildtype (WT) and Lrrk2 knockout (KO) mice and found that the regulation of lysosomal pH in KO macrophages was significantly affected, further suggesting that LRRK2 may play a role in autophagy through regulation of lysosomal pH. Another experimental goal was to determine if knocking out Lrrk2 would result in changes to the microbiota in a mouse model with induced colitis and without. Specifically, we explored Lrrk2’s role in association with the microbiota and found that Lrrk2 participates in regulating microbial taxa under inflammatory circumstances.
In summary, our findings suggest that CD–associated mutations in the LRRK2 gene conferring risk (N2081D) or protection (N551K+R1398H) affect gene expression, lysosomal acidity and tubulin acetylation in monocyte-derived macrophages (MDM) implicating them in the process of autophagy. We also propose Lrrk2 as a modulator of microbiota changes under inflammation. These results should warrant future studies to explore LRRK2 as a potential target for new therapies to treat CD.
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Soroosh, Artin. "The Role of KIAA1199 in Crohn's Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396386453.
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Simmons, Jonathan David. "Candidate genes in inflammatory bowel disease - defining susceptibility, disease phenotype and long term outcome." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249575.
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Lapidus, Annika. "Crohn's disease in Stockholm county : epidemiological panorama and associated gallstone disease /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-2908-4.
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Harbord, Marcus William Nixon. "Investigation of acute inflammation in Crohn's disease and chronic granulomatous disease." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399572.
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Nasir, Bushra Farah. "Identifying Envirogenomic Signatures for Predicting the Clinical Outcomes of Crohn's Disease." Thesis, Griffith University, 2013. http://hdl.handle.net/10072/366228.
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A complex interplay between genetic susceptibility, environmental factors and clinical indicators seem to cause the development of Crohn’s disease (CD). Few disorders in clinical medicine are associated with as much chronic morbidity as CD. Genetic factors are the predetermined cause, whereas non-genetic factors seem to further trigger the development of CD. From epidemiological data, based on concordance statistics in family studies, via linkage analysis to Genome Wide Association Studies (GWAS) and Whole Genome Analysis (WGA), robust evidence have been gathered, implicating distinct genomic loci involved in genetic susceptibility to CD. Most recently, a meta-analysis has been able to implicate 71 distinct genomic loci that seem to be associated with CD development. A study published in the American Journal of Human Genetics has also recently identified more than 200 genes associated with CD, which is more than what have been found for any other disease so far. Monozygotic twins show approximately 50-60% disease concordance, with much lower rates in dizygotic twins (~10%), highlighting the role of both environmental and genetic components in the development of CD.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Sciences
Griffith Health
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Phillips, Anne Mairead. "Investigation of the phenotypic and genotypic determinants of disease susceptibility and progression in Crohn's Disease." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/9473.
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The inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gastrointestinal tract. Their aetiology is not fully understood but is thought to be a combination of the effect of environmental factors in a genetically susceptible person. The work presented is an examination of the phenotypic characteristics of CD in the Scottish population, and an investigation into genetic factors that may influence susceptibility and progression. An IBD cohort from Dundee was recruited (CD=367, UC=265), and extensive phenotypic information collected from these patients together with genomic DNA. Together with the Edinburgh CD cohort already established, the total CD population (n=1155) was examined for time to disease progression (stricturing and/or penetrating disease, according to the Montreal classification) and first resection; a multivariate analysis was performed for factors influencing these outcomes. In this Scottish CD population, the median time to disease progression and first resection was 14.2 years and 8.9 years respectively. The major factor influencing risk of resection and disease progression was disease location, with patients having pure ileal (L1) disease or ileocolonic (L3) disease being more susceptible than those with pure colonic (L2) disease. Compared with L2 disease, the hazards ratios (HR) for disease progression were 4.7 and 2.8, and risk of resection 5.2 and 2.6 for L1 and L3 disease respectively. Disease progression and risk of resection are surrogate markers of disease severity. To try to better understand the determinants of severe disease, a novel score for disease severity was developed and applied to the Dundee CD cohort. This composite score encompassed the variables of medical and surgical management, disease behaviour and location, nutritional status as well as hospitalisations, with a total score that could range from 1 to 16. A score of 7 or more was found to define the 50% of patients with the most severe disease. This cut-off was used to divide patients into less severe and more severe categories; phenotypic and genetic factors were examined for correlation with more severe disease. Genetic factors examined were the 32 most significant CD susceptibility single nucleotide polymorphisms (SNPs) uncovered by recent genome-wide association scans (GWAS). Factors correlated with more severe disease included disease location (L1, odds ratio (OR) 2.20, p=0.0025), age group at diagnosis (p=0.0004) and two CD susceptibility SNPs (rs9286879 and rs17582416; p=0.0085 and p=0.045 respectively). NOD2 was the first IBD susceptibility gene identified. In order to further define pathways involving NOD2, a yeast two-hybrid screen in our laboratory using NOD2 cDNA as the bait had already identified an interaction between NOD2 and UDP-Nacetyl- alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase (GALNT2). This enzyme is involved in O-glycosylation, important in the post translational modification of mucins. A GALNT2 genotype/phenotype analysis on the Edinburgh IBD population was completed, with the Dundee IBD population used as a replication cohort. In the Edinburgh IBD population, the GALNT2 tagging SNP rs7536663 was associated with CD susceptibility (OR 1.38, p=0.0008 vs controls), but replication was not achieved in the Dundee cohort (p=0.469). There was no association of any of the GALNT2 SNPs with UC. The GALNT2/NOD2 interaction was further investigated by completing coimmunoprecipitation between the two genes to characterise the level and type of interaction. An interaction between GALNT2 and NOD2 was confirmed in mammalian cells, with the interaction being at the N-terminal end of the NOD2 protein. GALNT2 expression in a cell line and biopsies was investigated by quantitative polymerase chain reaction and immunohistochemistry respectively. There were no statistically significant changes in GALNT2 or NOD2 mRNA expression in the LS174T cell line after stimulation with specific ligands for NOD2 and GALNT2. GALNT2 protein expression was characterised in intestinal biopsy samples to be predominantly in the lamina propria, with some expression in the enterocytes. To further define the contribution of mucin genes to IBD susceptibility, tagging SNPs across the MUC2, MUC3A and MUC19 genes were genotyped in the Edinburgh IBD cohort and examined for a link with IBD, CD and UC susceptibility, but associations were not found. In view of the strong association with CD susceptibility of a SNP near the MUC19 locus in a recent GWAS, tagging SNPs across the leucine rich repeat kinase-2 (LRRK2) gene, near the MUC19 gene, were also genotyped and examined in the Dundee cohort for an association with IBD, CD and UC susceptibility, but was also negative when corrected for multiple testing. The studies presented allow an improved understanding of the influence of phenotypic characteristics on disease progression, need for surgery and severity in CD. The role of disease location has been determined to be particularly critical, in keeping with other published studies. A detailed examination of the influence of specific genes on disease susceptibility has failed to definitely demonstrate an association between germline variation in GALNT2, MUC2, MUC3A, MUC19 or LRRK2 and IBD, CD or UC susceptibility. An interaction in mammalian cells between NOD2 and GALNT2 has been shown, but further work is required to demonstrate that this is a biologically relevant interaction.
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Geoffroy, Pierre. "The pharmacoepidemiology of Crohn's disease therapy in Saskatchewan." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ29698.pdf.
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Hayee, B. "Neutrophil function and bacterial clearance in Crohn's disease." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/20457/.
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The aetiology of Crohn’s disease (CD), a chronic inflammatory disorder primarily affecting the gastro-intestinal tract, remains obscure. The prevailing hypothesis centres on an aberrant adaptive immune response to intestinal bacteria. Intestinal lesions in CD are associated with granuloma formation, suggesting the persistence of antigenic (infectious) material. Perianal involvement (PI) in CD, in particular, is characterised by overt infection and abscess formation. However, to date no single infectious aetiology has been demonstrated. Inherited disorders of neutrophil function are associated with non-infectious, granulomatous, intestinal inflammation that is indistinguishable from CD in up to 50% of cases. Of these, 75-100% have PI. In these conditions, impaired clearance of bacteria occurs as a consequence, and intestinal inflammation arises without aberrant adaptive immune responses. Neutrophil dysfunction (inherited or otherwise) may contribute to the pathogenesis of both intestinal and perianal involvement in CD. Impaired neutrophil influx to sites of acute inflammation (induced by traumatic stimuli) has been demonstrated in CD. An inferred defect in bacterial clearance would provide a trigger for the induction of a granulomatous chronic inflammatory response, as it does in the inherited disorders of neutrophil function. Although other aspects of neutrophil function have been studied with respect to the pathogenesis of CD, the literature provides conflicting conclusions and it is unclear whether a primary neutrophil dysfunction could contribute. The work in this thesis tests the hypothesis that bacterial clearance is abnormal in CD, as well as investigating key aspects of neutrophil function in large cohorts of patients with intestinal and perianal involvement. For the first time, neutrophil influx to – and subsequent clearance of – E. coli in CD is shown to be attenuated in vivo, while – very significantly – the clearance of S. aureus is normal. Study of the neutrophil respiratory burst, however, reveals a small number of patients with undiagnosed primary neutrophil disorders (investigated further). In patients with perianal involvement, neutrophil adhesion is found to be defective and may be related to the lipid composition of plasma membranes. This would contribute to impaired neutrophil influx and bacterial persistence – leading to overt infection. In conclusion, although neutrophil function is likely to be normal in the majority of patients with CD, it may explain the development of PI. Furthermore, a small but significant group of patients with presumed ‘idiopathic’ CD may have an underlying inherited neutrophil defect. It is important to identify these patients in order to alter their treatment from the usual anti-inflammatory or immunosuppressive therapies commonly employed for CD. Bacterial persistence is likely to be a primary pathogenic phenomenon in CD and offers targets for therapeutic intervention.
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Sharma, Nidhi. "Characterising the role of TLE1 in Crohn's disease." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/22970.
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The inflammatory bowel diseases (IBD) are chronic, relapsing and remitting diseases of the gastrointestinal tract. There are two main types of IBD: Crohn’s disease (CD) and ulcerative colitis (UC). The prevalence of IBD is highest in the western world, approximately 100-200 people per 100,000 are affected. In recent years there has been a marked increase in the incidence of CD and UC, in both adults and children (Henderson et al., 2012; Molodecky et al., 2012). This is particularly relevant in Scotland where recent research shows that there has been a 79% increase in the number of cases of paediatric IBD since the 1990’s (Henderson et al., 2012). A yeast 2 hybrid screen identified TLE1as an interacting partner of the known CD susceptibility gene; Nucleotide- binding oligomerisation protein 2 (Nod2). An initial genome wide association study (GWAS) also found an association between the rs6559629 SNP, located in Tle1 and ileal CD (p =3.1 x 10-5) and showed that carriage of the Tle1 risk allele increases the effects of Nod2 mutations in CD. TLE1 functions as a transcriptional co repressor in a variety of different cellular and developmental pathways The work presented in this thesis investigates the potential role of TLE1 in CD. This has been approached using four different strategies: sequencing TLE1 in CD patients and controls, analysing the effects of knocking down TLE1 on genome wide expression, investigating whether the known IBD susceptibility protein XBP1 binds to a predicted binding site in TLE1 and investigating TLE1 levels and localisation in human intestinal samples from CD patients and controls Sequencing TLE1 exons and introns 15/16 and 16/17 in a Scottish cohort of 24 CD patients and healthy controls identified a number of potentially pathogenic exonic and intronic SNPs. Two exonic SNPs and thirteen intronic SNPs were identified and these were further investigated in larger Scottish (203 CD cases, 190 HC) and European cohorts (6,333 CD cases and 15,056 HC) but were not present at statistically significantly different frequencies. Secondly, the effects of TLE1 knock down on genome wide expression were analysed using an Illumina HT12 expression chip. The results showed that TLE1 knock down significantly altered expression of 19 loci (Bonferroni) and 526 loci (FDR). Four of the 19 Bonferroni significant loci are potentially involved in CD: RIOK1 (p=4.3×10-3), SGPL1 (p=4.3×10-3), TUSC3 (p=1.8×10-2) and CCND1 (p=2.7×10-3). Furthermore, expression of SGPL1 and RIOK1 were shown to be differentially expressed at the mRNA level between inflamed patients and controls. The third approach investigates a predicted binding site for the known IBD susceptibility gene, XBP1 in TLE1 which was identified using the Haploreg program. This work shows, using chromatin immunoprecipitation, that exogenous XBP1 does not appear to bind to this predicted binding site. Finally, TLE1 expression was analysed in human intestinal resection samples from patients of known NOD2 status. This work shows that TLE1 and NOD2 are expressed in Paneth cells, however TLE1 expression is not altered in patients carrying CD associated NOD2 variants. In this work TLE1 sequence, expression and potential interacting proteins have been analysed. The results presented suggests multiple mechanisms by which TLE1 may be influencing susceptibility to CD including: the unfolded protein response (TUSC3), S1P signalling and ribosome biogenesis. They also implicate TLE1 in Paneth cell function alongside NOD2. The exact means by which TLE1 may play a role in IBD pathogenesis has yet to be fully elucidated.
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MAESTRONI, ANNA MARIA. "DYSREGULATION OF INTESTINAL STEM CELLS IN CROHN'S DISEASE." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/621110.
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Riassunto
Introduzione. Numerosi fattori, tra cui eventi immunitari, agenti ambientali tossici, predisposizione
genetica e microbiota anormale svolgono un ruolo chiave nella patogenesi della malattia di Crohn,
ma il principale meccanismo alla base è ancora oggetto di studio. L'omeostasi della mucosa
intestinale si basa su un delicato equilibrio tra auto-rinnovamento e differenziazione, che è garantita
dal ricambio delle cellule staminali intestinali all'interno delle cripte. Recenti studi suggeriscono che
una differenziazione alterata delle cellule staminali intestinali (ISC) può facilitare l'insorgenza della
malattia di Crohn attraverso la formazione di una barriera antimicrobica difettosa, che consente ai
batteri intestinali di provocare l'infiammazione. Lo scopo del nostro studio è quello di esplorare se le
ISC sono danneggiate e le loro proprietà rigenerative sono alterate nella malattia di Crohn,
rappresentando così un nuovo attore nell'insorgenza della malattia e un potenziale bersaglio
terapeutico per ripristinare le capacità di auto-rinnovamento della mucosa intestinale.
Metodi. Su campioni intestinali (sia area marginale che infiammata rispetto alla sede della malattia)
ottenuti da pazienti con e senza malattia di Crohn è stata condotta un’analisi del trascrittoma per
valutare l'espressione dei marcatori per ISC. Le proprietà rigenerative delle ISC sono state studiate
utilizzando il test del mini-guts, in cui le cripte purificate sono state coltivate come organoidi
tridimensionali e la loro morfologia / sviluppo sono stati valutati. Infine, mini-guts sono stati
coltivati a partire dalle cripte di soggetti sani con siero di pazienti affetti da malattia di Crohn per
dimostrare se i fattori circolanti / citochine potessero esercitare un effetto significativo
nell'abrogazione dello sviluppo di organoidi e influenzare l'espressione dei marcatori per ISC.
Risultati. I marcatori per ISC, in particolare LGR5 e EPHB2, sono scarsamente espressi in cripte
isolate da campioni intestinali di pazienti con malattia di Crohn. È interessante notare che i
marcatori per ISC sono più preservati nella zona sana, mentre la loro espressione è quasi assente
nell'area infiammata. Ancora più importante, la capacità delle ISC di auto-rinnovamento testata nel
saggio mini-guts, è stata trovata significativamente ridotta nei pazienti con malattia di Crohn, con
solo il 40% dei mini-guts che si sviluppano da cripte ottenute dall'area marginale e meno del 5% da
quelle isolate dalla parte infiammata del campione intestinale. Quando i mini-guts ottenuti dalle
cripte dei controlli sono stati coltivati in presenza di siero di pazienti affetti da malattia di Crohn non
riuscivano a generare organoidi normali e mostravano una ridotta espressione dei marcatori per ISC
EPHB2 e LGR5.
Conclusione. Abbiamo dimostrato che il pool delle ISC è ridotto nella malattia di Crohn e che
questo si associa a una perdita di proprietà rigenerative delle ISC all'interno delle cripte. La crescita
di mini-gut in vitro in presenza del siero di pazienti affetti da morbo di Crohn, è quasi
completamente annullata, suggerendo quindi che nel contesto della malattia di Crohn esiste un
difetto del pool e della funzione rigenerativa delle ISC.Abstract Introduction. Several potential key factors, such as immune events, toxic environmental agents, genetic predisposition and abnormal microbiota have been established to play a role in the development of Crohn’s disease, but the mechanism behind it is still under investigation. Intestinal mucosa homeostasis relies on a delicate balance between self-renewal and differentiation, which is guaranteed by intestinal stem cells turnover within the local crypts. Recent studies suggested that an impaired differentiation of intestinal stem cells (ISCs) may facilitate the onset of Crohn’s disease via formation of a defective antimicrobial barrier, which enables intestinal bacteria to cause inflammation. The aim of our study is to explore whether ISCs are disrupted and their regenerative properties are altered in Crohn’s disease, thus representing a novel player in the disease onset and a potential therapeutic target to restore intestinal mucosa self-renewal abilities. Methods. A transcriptome analysis has been conducted on intestinal samples (both marginal and inflamed area with respect of the disease location) obtained from patients with and without Crohn’s disease to assess the expression of ISC markers. ISC regenerative properties have been tested by taking advantage of the mini-guts assay, where purified crypts were cultured as tridimensional organoids and their morphology/development were evaluated. Finally, mini-guts were grown from healthy subjects in serum of patients with Crohn’s disease to prove whether circulating factors/cytokines may exert a significant effect in abrogating organoids development and affect the expression of ISC markers. Results. ISC markers, particularly LGR5 and EPHB2, are poorly expressed in crypts isolated from intestinal samples of patients with Crohn’s disease. Interestingly, ISC markers are more preserved in the healthy zone, while their expression is nearly absent in the inflamed area. More importantly, ISC capability of self-renew tested in the mini-guts assay, was significantly abrogated in patients with Crohn’s disease, with only 40% of mini-guts developing from crypts obtained from the marginal area and less than 5% from those isolated from the inflamed portion of the intestinal sample. When cultured in the presence of serum of Crohn’s disease patients, mini-guts obtained from crypts of controls failed to generate normal self-renewed organoids and showed a reduced expression of EPHB2 and LGR5 ISC markers. Conclusion. We have demonstrated that the ISCs pool is reduced in Crohn’s disease and this is associated with a loss of regenerative properties of ISCs within the local crypts. When cultured in vitro with serum of patients with Crohn’s disease, mini-guts growth is fully abrogated thus suggesting that a defect in ISCs pool and function exist in the context of Crohn’s disease.
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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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Lynch, Teresa. "A qualitative descriptive study of youth with Crohn's disease a dissertation submitted to the Auckland University of Technology in partial fulfilment of the degree of Master of Health Science, Auckland University of Technology, December 2005." Full Dissertation. Abstract, 2005.
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Hanson, Catherine Elisabeth. "Clinical and histological implications of genotyping in Crohn's disease." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1334.
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Crohn’s disease is a common inflammatory bowel disease affecting approximately 1 in 1000 of the population in the UK. Surgery for Crohn’s disease is common with the majority of patients requiring surgery at some point in the course of the disease. Both genetic and environmental factors influence Crohn’s disease. Smoking significantly influences the disease course in Crohn’s disease with more frequent relapses and increased need for surgery. Recent research had concentrated on the genes predisposing to the development of Crohn’s disease. In 2001 the CARD15 (NOD2) gene was identified and since then ~30 genes have been found to be associated with Crohn’s disease. This thesis aimed to investigate the influence of CARD15 (NOD2) on the time to second operation in terminal ileal Crohn’s disease. Crohn’s disease affects all parts of the gastrointestinal tract but particularly the terminal ileum. A particular cell type, the Paneth cell, has been implicated in the pathogenesis of Crohn’s disease. Paneth cells are located at the base of Crypts of Liberkühn throughout the small intestine but are found in greatest numbers in the terminal ileum. Paneth cells contain and secrete antimicrobial peptides in response to bacterial products. They have been found to express CARD15 (NOD2). The expression of antimicrobial peptides and the CARD15 (NOD2) genotype were investigated using the technique of in situ hibridization. There are well characterized histological features of Crohn’s disease. The are no known histological features of Crohn’s disease associated with the CARD15 (NOD2) genotype. These features were investigated. Osteoporosis is an important complication of Crohn’s disease and it’s treatment. Predictors of those at risk for the development of Crohn’s disease would be clinically useful in targeting therapy. Genetic influences on bone mineral density and Crohn’s disease were investigated. Recent publications have furthered our knowledge of the genetic factors influencing the development of Crohn’s disease. The Newcastle cohort of patients contributed to this knowledge. The aim of this study was to investigate survival to second operation in terminal ileal Crohn’s disease. The effect of environmental factors including smoking and exposure to thiopurines was investigated. In particular the effect of CARD15(NOD2) genotype and carriage of the 5q31 haplotype was studied.
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Hancock, Laura. "Clinical and molecular characteristics of isolated colonic Crohn's disease." Thesis, Queen Mary, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520807.
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Cummings, James Rowland Fraser. "Linkage Disequilibrium Mapping of Chromosome 19 on Crohn's Disease." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531666.
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Marks, Daniel Joseph Benjamin. "Investigation of the acute inflammatory response in Crohn's disease." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1444862/.
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Most theories concerning the primary cause of Crohn's disease focus on over-activation of the immune response. Paradoxically, the defect may instead relate to diminished acute inflammation. Neutrophil accumulation to sites of dermal trauma has been shown to be reduced. Were the same phenomenon to occur in the gut, it might impair bacterial clearance thus provoking granuloma formation. In this thesis, a novel technique demonstrated attenuated neutrophil accumulation following trauma to the bowel. A modified skin window technique linked this failure of migration to defective IL-8 production. Polymorphisms in CARD15, associated with susceptibility to Crohn's disease, compounded the problem by abrogating the normal pro-inflammatory action of the protein but did not underlie the basic phenotype. Consequently, the response of macrophages to other inflammatory agonists was examined. IL-8 production was also impaired in Crohn's disease after stimulation with wound fluid, C5a or TNF-a. The response of Crohn's patients to gut bacteria was assessed directly in vivo by subcutaneous injection of killed Escherichia coli. This elicited substantial local inflammation in controls, manifested by an NO-mediated increase in blood flow. The response was considerably lower in Crohn's patients, particular those with colonic disease. In contrast, acute phase reactants were highest in the latter, supporting the hypothesis that an impaired local response can drive a systemic pro inflammatory state. The demonstration of attenuated acute inflammation in Crohn's disease may have important implications for understanding its pathogenesis and targeting novel therapies.
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Flanagan, Paul Kevin. "Bacteria-macrophage interactions in the pathogenesis of Crohn's disease." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3008673/.
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Crohn's disease (CD) is associated with defective innate immunity, including impaired neutrophil chemotaxis, and mucosal invasion by bacteria, particularly E. coli that replicate inside macrophage phagolysosomes. In this thesis several hypotheses were tested: (i) that CD macrophages might be defective at killing and or responding to Gram-negative bacteria, particularly E. coli; (ii) that killing of phagocytosed bacteria within macrophages might be enhanced by drugs such as hydroxychloroquine (HCQ) (previously shown to raise intravacuolar pH), and vitamin D (previously shown to enhance macrophage function). I assessed CD peripheral blood monocyte-derived macrophages (MDM) for their abilities to kill E. coli, with and without HCQ and vitamin D, and to generate neutrophil chemoattractants. MDM from patients with CD were similar to those from healthy controls (HC) in allowing replication of phagocytosed CD-derived E. coli: HM605 [CD N=10, mean fold replication in 3h: 1.08, (95% confidence interval (CI) 0.39-1.78); HC N=9, 1.50, (95%CI 1.02-1.97); P=0.15] and also in generation of neutrophil chemoattractants in response to E. coli (mean fold chemotaxis relative to control: CD 2.55, 95%CI 2.31-2.80; HC 2.65, 95%CI 2.46-2.85, P=0.42). The only possible exception was reduced bacterial killing in macrophages from the relatively rare patients homozygous for ATG16L1 polymorphisms, reported previously and confirmed in the single example in this series. HCQ and 1,25 OH2-vitamin D3 both caused dose-dependent inhibition of intra-macrophage E .coli replication 3h post-infection, HCQ: 73.9% inhibition (P < 0.001) at 1μg/mL, accompanied by raised intra-phagosomal pH, and 1,25OH2-Vitamin D3: 80.7% inhibition (P < 0.05) at 80nM. HCQ had synergistic effects with doxycycline and ciprofloxacin on killing of phagocytosed E. coli. Thus: CD and HC macrophages generally perform similarly in allowing replication of phagocytosed E. coli and generating neutrophil chemoattractants. Replication of phagocytosed E. coli was substantially decreased by HCQ and vitamin D. These warrant further therapeutic trials in CD in combination with relevant antibiotics.
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Daulatzai, Najibullah. "The aeitiopathogenesis of cutaneous wound failure in Crohn's disease." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/48044.
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Crohn’s disease (CD) is a multi-system condition with multiple cutaneous manifestations. Perineal wound failure is a common complication following surgery in CD. Despite advancements of our understanding of the underlying disease process in intestinal CD, our knowledge in the aetiopathogenesis of skin involvement is still lacking. Risk factors, which contribute to the development of an unhealed perineum following surgery was assessed. The rate for an unhealed perineum at 12 months following surgery was 23%. Poorer healing took place in patients with pre-existing perineal sepsis, but no significant difference was found between patients with IBD or cancer. Subsequent studies assessed immune cell function as a potential contributor to wound failure in CD. Dendritic cells (DC) are specialised antigen-presenting cells that play a central role in intestinal CD pathogenesis. DC dictate type of T-cell immunity and T-cell homing profiles, however wound DC have yet to be characterised. DC were successfully identified from all wound tissue. Expression of skin- homing molecule (CLA) was reduced on wound DC in CD compared with controls. Wound DC were found to stimulate dose-dependent allogeneic T-cell proliferation; both wound and blood DC from CD patients were significantly less stimulatory than their control DC counterparts. Furthermore, DC from CD patients generated T-cells with enhanced expression of CLA compared to T-cells stimulated by control DC in wound tissue and blood. Aberrant expression of skin-homing marker CLA on DC and T-cells that they stimulate may contribute to alterations in immune cell migration in CD. Taken with the restricted stimulatory capacity of DC in CD wounds, it is likely that a loss of DC function occurs contributing to wound failure. Histological assessment suggested an increase in plasma cells in CD wound tissue compared to non-CD wound tissue, further highlighting an immunological aetiology for the aberrant healing in CD. Finally, a randomised control study to assess quality of life benefits and effects on wound dimensions of regular wound digitation against current standard practice of community nurse-led dressings in the management of open perineal wounds was investigated. Wound digitation had a significant reduction in pain, restriction of daily activities and degree of induration, whilst having a comparable healing rate to regular dressings.
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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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Higgins, Lisa Mary. "Regulation of intestinal inflammation." Thesis, Queen Mary, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322813.
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Millar, Douglas Spencer. "Mycobacterium paratuberculosis, mycobacteria and chronic enteritis in humans and animals." Thesis, St George's, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308932.
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Thompson, Nicholas Paul. "An epidemiological assessment of early risk factors for Crohn's disease." Thesis, Queen Mary, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309308.
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Robson, K. F. "The employment experiences of ulcerative colitis and Crohn's disease sufferers." Thesis, Cardiff University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.541996.
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This study examines how inflammatory bowel disease sufferers manage the comparatively routine and regimented task of working given the intermittent and unpredictable nature of the condition. It addresses a lack of qualitative research on social aspects of IBD, and is also an empirical study on the body that explores the experience of a specific chronic illness, relating these issues to embodied social regulations that apply more generally. A postal questionnaire was administered to 400 members of a local patient support network, and from these, 21 interviews were conducted. In addition an email-based `virtual focus group' was developed and administered to reflect and harness active computer mediated support networks for IBD sufferers. Most do disclose information about their condition at work, and profess to prefer this over non-disclosure. Reasons for decisions about disclosure relate to the organisation and running of the workplace, how well the condition could be explained, how apparent the condition was, possible impacts on others' perceptions of them, and motivations to `be honest'. Disclosure strategies are identified which are associated with two styles of talking about the condition. `Event' accounts are based on events (e. g. medical treatment) marking out the course of the condition, while `physical' accounts draw primarily on felt experiences of symptoms. Three elements define capacity to work: condition severity, work environment factors and role status factors. Translating this capacity into full and competent worker status depends largely on whether work tasks can be performed without the breaking of social rules relating to the natural functions. The study demonstrates the importance of work in the lives of sufferers, and examines conditions that allow or prevent successful functioning at work. These factors rest primarily with neither medical aspects of the condition, nor social aspects arising from them, but from a complex and fluid dynamic constituted by both. iv
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Eddama, Mohammad. "The angiogenic characterisation of mesenteric adipose tissue in Crohn's disease." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10042169/.
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Introduction: Crohn’s disease (CD) has a distinct feature of mesenteric adipose tissue (AT) expansion, the role of which is unclear. This study hypothesises that the angiogenic mechanisms in CD mesenteric AT are dysregulated. Methods: Mesenteric, subcutaneous and omental AT were harvested from 30 patients who underwent ileocolic resection, including 19 CD and 11 controls. Angiogenic mechanisms were examined by: histology and immunohistochemistry; real time polymerase chain reaction (RT PCR) gene array; and enzyme linked immunosorbent assay (ELISA). ELISA was also used to assess the level of interleukin-6 (IL6) and vascular endothelial growth factor (VEGF) secretion by tissue over an incubation period of 36 hours. Angiogenic capacity was measured by matrigel angiogenic assay. Results: Microvascular density (MVD) was significantly (p < 0.01) higher in CD mesenteric AT (mean=29, SD=20) than control (mean=19, SD=12). Hypoxia inducible factor-1 (HIF1) staining was higher in CD mesenteric AT (n=22, 67%) than control (n=18, 22%) (Χ2(2)=11.2, p < 0.01). RT-PCR array confirmed that 47 (56%) of the angiogenic genes were >2-folds down-regulated in CD mesenteric AT. Correlation matrix showed significantly more negative correlations in CD mesenteric AT (n=711, 20%) than control (n=109, 3%) (X2(1)=501, p < 0.0001). The mean-z-score for negative correlation was significantly (p < 0.0001) stronger in CD mesenteric AT (mean=0.3, SD=0.2) than control (mean=0.1, SD=0.1). CD mesenteric AT protein expression of IL6 (mean=21 pg/mg, SD=18) and VEGF (mean=34 pg/mg, SD=19) were significantly (p < 0.05 and p < 0.01) lower than control (mean=39 pg/mg, SD=43) and (mean=57 pg/mg, SD=43) respectively. In-vitro secretion of IL6 and VEGF was similar in CD and control AT. Vascular sprouting was statistically significantly (p < 0.01) lower in CD mesenteric AT (mean=3.2, SD=3) than control (mean=5.2, SD=4.1). Conclusion: CD mesenteric AT demonstrated dysregulated angiogenesis and significantly lower capacity for vascular sprouting in comparison to control. The observed dysregulated angiogenesis may partly explain the role of mesentery in the perpetuation of CD inflammation.
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Ruffolo, Cesare. "Perineal and Pelvic Crohn's Disease: modern options for treatment strategies." Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3425616.
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Outline and summary of the thesis
The research project is divided in two parts: the first one describes the cytokine network in perineal and pelvic CD and its relation with the intestinal disease and the second one describes complex fistulas in perineal and pelvic Crohn’s disease.
In Chapter 1, the systemic cytokine network was analyzed in chronic perianal CD and in other control groups, confirming not only that TNF-alpha plays a major role in perianal CD but also the importance of IL-6 as a systemic mediator for chronic inflammation suggesting a possible role for its monoclonal antibody in this disease.
The next step was to evaluate the cytokine profile in the rectal mucosa of perianal CD patients and its relations with the local and systemic inflammatory status; particular attention was paid to its prognostic value in terms of need of surgery in perianal CD (Chapter 2).
In the third section of Part 1 (Chapter 3), the in vivo intimate correlation between systemic inflammation mediated either by the innate immune system or T cell-mediated immunity (expressed by cytokine levels) and intestinal inflammation (expressed by lactoferrin levels) in CD patients who had undergone ileo-colonic resection and were in clinical remission was taken into consideration.
The second part of the thesis was focused on complex fistulas (comunication to the bladder (or other urologic complications) or to the vagina) in perineal and pelvic CD.
First of all, the threshold to suspect urologic complications in CD was assessed in order to plan correct surgical management (Chapter 1). In Chapter 2 the outcome of surgical repair in a consecutive series of RV fistulas in patients with CD over a 13 year period, within a single referral institution was evaluated. Both early and late outcomes were assessed as was the influence of medical therapy, especially the use of anti-TNF agents, in the closure of these fistulas. At this point, in the third section of this part (Chapter 3), a systematic review on advancement flaps for RV fistulas in CD (transrectal vs transvaginal approach) was performed.La malattia perineale e pelvica di Crohn può essere, in alcuni casi, seria ed invalidante, ponendo problematiche sia di ordine diagnostico che terapeutico a gastroenterologi e chirurghi. Attualmente l’anticorpo monoclonale anti-TNF-alpha (??Infliximab) viene utilizzato per il trattamento del morbo di Crohn refrattaria alla terapia medica convenzionale. Tuttavia, nei pazienti affetti da tale patologia, la risposta all’Infliximab non è completa e recenti studi hanno ricordato l’importanza del trattamento chirurgico associato alla terapia medica nel controllo dell’infiammazione intestinale. Lo scopo della tesi è di analizzare il network citochinico coinvolto nelle complicanze perineali e pelviche della malattia di Crohn e di osservare, nell’era delle terapie biologiche, i risultati del trattamento chirurgico di queste complicanze. Il progetto di ricerca è suddiviso in due parti: la prima descrive il network citochinico nella localizzazione perineale e pelvica di Crohn ed i suoi rapporti con la malattia intestinale mentre la seconda si occupa del trattamento delle fistole complesse nel morbo di Crohn. Nel primo capitolo, è stato analizzato il network citochinico sistemico nella malattia perianale di Crohn ed in altri gruppi di controllo: si è confermato non solo il ruolo centrale che gioca il TNF-alpha nella malattia perianale di Crohn ma anche l’importanza dell’IL-6 come mediatore sistemico dell’infiammazione cronica, suggerendo un possibile utilizzo del suo anticorpo monoclonale in questa malattia. Tali risultati ci hanno spinto ad investigare il network citochinico nella mucosa rettale dei pazienti affetti da malattia perianale di Crohn (Capitolo 2). E’ stato dimostrato che i livelli tissutali di IL-6, IL-1beta? e TNF-alpha sono significativamente più elevati nei pazienti con malattia perianale di Crohn rispetto ai controlli, correlando significativamente con gli indici di attività di malattia; inoltre, i livelli tissutali di IL-1beta? e TNF-alpha correlano significativamente con il grado istologico di malattia. Infine, i livelli tissutali di IL-6 e IL-12 sono risultati essere predittivi di recidiva di malattia e della necessità di chirurgia a livello perianale. Nell’ultima sezione della prima parte (Capitolo 3), è stata evidenziata la correlazione significativa tra la lattoferrina fecale e l’asse IL-6-proteina C reattiva in pazienti con malattia di Crohn in fase di quiescenza in seguito ad intervento di resezione ileo-colica. Abbiamo ipotizzato che l’infiammazione intestinale subclinica, espressa dalla lattoferrina fecale, mantenga uno stato di lieve attività dell’infiammazione sistemica mediante la cascata IL-6-proteina C reattiva. Il ruolo di IL-1beta IL-12 TNF-alpha e TGF-beta1 sembra essere più complesso e legato in maniera meno diretta all’infiltrazione neutrofila mucosale. La seconda parte della tesi è focalizzata sul trattamento chirurgico delle fistole complesse (comunicazioni con la vescica e/o uretere o con la vagina) nella malattia perineale e pelvica di Crohn. Nel primo capitolo è stato rilevato che è necessaria una bassa soglia di sospetto di coinvolgimento ureterale e/o vescicale per affrontare tali problematiche in pazienti che saranno sottoposti ad intervento di resezione per la malattia intestinale. In presenza di una massa addominale palpabile in un paziente affetto da malattia di Crohn si consiglia di eseguire sempre un’ecografia o una TC dell’addome per escludere una complicanza urologica che può essere trattata pre-operatoriamente in modo da migliorare sia lo stato generale del paziente che il quadro intra-operatorio. Viene proposto un algoritmo esemplificativo dell’approccio diagnostico e terapeutico di queste complicanze. Nel capitolo 2, sono stati valutati i risultati del trattamento chirurgico in un gruppo di pazienti con fistole retto-vaginali e malattia di Crohn in un lasso di tempo di 13 anni; le pazienti appartengono al centro di riferimento per le malattie infiammatori croniche intestinali dell’ Università di Lovanio, in Belgio. E’ stato osservato che la chiusura della fistola a lungo termine è ottenuta, nella maggior parte delle pazienti, in seguito alla chirurgia; tuttavia, sono spesso necessari ripetuti interventi chirurgici. Pertanto, le pazienti con fistole retto-vaginali nella malattia di Crohn dovrebbero essere sottoposte ad intervento chirurgico in seguito a guarigione tissutale ottenuta con terapie biologiche. Nell’ultimo capitolo di tale parte, è stata eseguita una revisione sistematica della letteratura internazionale sui lembi d’avanzamento per le fistole retto-vaginali nella malattia di Crohn: approccio trans-rettale vs trans-vaginale. Anche se basato su un limitato numero di articoli con basso livello di evidenza clinica, tale studio suggerisce che non ci sono differenze in termini di risultati tra gli approcci tran-srettale e trans-vaginale. Il tasso di recidiva sembra essere minore in seguito all’approccio trans-rettale. Suggeriamo, pertanto, l’utilizzo dell’approccio trans-rettale come primo intervento, in assenza di stenosi anorettale, mentre l’approccio trans-vaginale potrebbe essere vantaggioso in caso di stenosi anorettale o, in seguito a fallimenti dell’approccio trans rettale.
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Xanthopoulos, Melissa Shepanski Nezu Arthur M. "The relationships among psychological distress, stress, disease symptom activity, and coping in adolescents diagnosed with Crohn's disease /." Philadelphia, Pa. : Drexel University, 2006. http://hdl.handle.net/1860/903.
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Larsson, Kjerstin. "Quality of Life and Coping with Ulcerative colitis and Crohn's disease." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8277.
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Dryland, Philippa A. "Crohn's disease: a biomarker approach in assessing disease state and the efficacy of dietary intervention." Thesis, University of Auckland, 2011. http://hdl.handle.net/2292/8495.
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Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disease resulting from an excessive immune response to intestinal microflora in genetically predisposed individuals. There is mounting evidence to suggest that the personalisation of diets to specific genotypes may be able to modulate the incidence and severity of disease in the IBD population. The move towards human dietary intervention studies is inevitable. It is therefore imperative that accurate and non-invasive methods for the evaluation and monitoring of an individual's disease state are identified and optimised. The aim of this study was to optimise the monitoring of disease development during mouse experiments, and develop biomarker investigation methods for assessing disease state and the efficacy of dietary interventions, with respect to IBD inflammation, for future human studies. This study investigated metabonomic and transcriptomic approaches to biomarker analysis for disease state identification in IBD mouse models. The aims of the study were twofold. The first aim concerned the analysis of nuclear magnetic resonance spectroscopy (NMR) as a suitable tool for the identification of biomarkers in biofluids, examining both individual biomarker methodology and pattern recognition analysis. The second aim addressed the use of pattern recognition analysis of gene expression profiles of spleen tissue to identify biomarkers associated with intestinal inflammatory events. This study has identified two individual biomarkers of intestinal inflammation from NMR analysis of urine for further validation: allantoin and sucrose. Multiple regression analysis (MRA) of binned NMR spectra was identified as an effective method of NMR pattern recognition analysis. The transcriptomic biomarker approach used correlation analysis to compare gene expression profiles with intestinal inflammation. Eight probes were identified as significantly correlated with a histological injury score (HIS). This study has developed and validated several biomarker analysis strategies that could be applied to human studies. Overall, MRA was found to be a valuable tool for biomarker pattern recognition identification and analysis. Both metabonomics and transcriptomics proved to be useful screening tools to identify biomarker profiles in IBD mouse models. The research has provided a critical foundation for identifying relevant biomarker profiles of accessible human tissues to support human dietary intervention studies related to the amelioration of symptoms associated with IBD.
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Barahona, Megan. "Nutrition and Inflammatory Bowel Disease| A curriculum for patients with Crohn's disease and ulcerative colitis." Thesis, California State University, Long Beach, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10142988.
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Targeted nutrition therapy aimed at reducing inflammation through diet is highly underutilized in the standard treatment of Inflammatory Bowel Disease (IBD). Therefore, the purpose of this directed project was to develop a nutrition curriculum for patients diagnosed with IBD. Specifically, the curriculum consists of five 30-minute PowerPoint presentations with corresponding lesson plans and topic-specific activities and provides specific nutrition recommendations for reducing inflammation and maintaining remission of IBD.
An expert panel comprised of two registered dietitians and a patient with IBD reviewed the curriculum using the Formative Evaluation Survey. Overall, average scores from the survey were positive, indicating that the curriculum is appropriate and provides valuable information for the intended audience. For future evaluation of this curriculum’s efficacy, a research project may be conducted that analyzes the effect of the curriculum nutrition recommendations on class participants’ disease status following implementation.
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Forder, Michael David. "Crohn's Disease : diagnostic and prognostic indicators with special reference to granulomas." Master's thesis, University of Cape Town, 1992. http://hdl.handle.net/11427/25570.
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The fact therefore remains that, at the present time, Crohn's disease is still an enigma. The aetiology and pathogenesis are obscure, the clinical findings and progression of the disease are unpredictable and the histological findings are often nonspecific. With this in mind, this dissertation attempts to define and document the incidence of certain histological features at presentation in a population of Crohn's disease patients from Groote Schuur Hospital. The main aim is to determine the incidence of granulomas in the study group as a whole, as well as to establish the distribution of granulomas within the bowel. A correlation between the presence of granulomas and the clinical activity of the disease (as assessed by the Crohn's Disease Activity Index) is also sought.
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Trebble, Timothy Mark. "The clinical and immunological response to fish oil in Crohn's disease." Thesis, Queen Mary, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438965.
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Mpofu, Chiedzo M. "Microbial Mannan As A Cause Of Phagocyte Dysfunction In Crohn's Disease." Thesis, University of Liverpool, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485903.
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Crohn's disease (CD) is a granulomatous condition that is mimicked by rare inherited disorders of phagocyte function and has clinical features compatible with an underlying impaired' defence against the gut microbiota. Crohn's'disease patients commonly have circulating antibodies (ASCA) against a mannan present in baker's yeast (Saccharomyces cerevisiae). I have investigated the possibility that S.cerevisiae mam?-ans may induce defects in phagocyte function. Saccharomyces cerevisiae mannan is shown to inhibit several of the functions of normal human peripheral blood neutrophils, monocytes and monocyte-derived macrophages including chemiluminescence and killing of phagocytosed bacteria. CD mucosa-associated E. coli isolates, that are less readily killed following internalization within adherent monocytes than a control ATCC259222 E. coli strain, undergo net replication inside adherent monocytes in the presence of S.cerevisiae mannan. S.cerevisiae mannan similarly enhanced survival of S. aureus within adherent monocytes. The epitope for ASCA is a mannose al-3 mannose disaccharide that binds snowdrop (Galanthus nivalis) lectin (GNA). A range of putative Crohn's diseaseassociated organisms was screened by GNA lectin blotting. The ASCA epitope was expressed by Mycobacterium avium paratuberculosis but not by M tuberculosis or E. coli. Crohn's disease may arise in part as a consequence of the suppression of mucosal phagocyte function by shed microbial mannans.
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Skelly, R. T. "The contribution of fibroblast phenotype to stricture formation in Crohn's disease." Thesis, Queen's University Belfast, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398093.
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Zamora, Samuel A. "Crohn's disease, investigation of intestinal permeability across families of affected children." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/mq24714.pdf.
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Minard, Janice P. "Staying close, spouse's experience with a partner's surgery for Crohn's disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ59392.pdf.
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Rao, Arati. "Therapeutic strategies for restoring linear growth in children with Crohn's disease." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/9005.
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Linear growth retardation affects up to 40% of children with Crohn’s disease (CD). It is caused by a combination of under\nutrition, and by a direct effect of cytokines on the axis linking human growth hormone (GH), insulin like growth factor\1 (IGF\1) and the growth plate of growing bones. In particular,the inflammation causes a functional insensitivity to GH, resulting in low circulating IGF\1. Current management is synonymous with the optimal management of childhood CD:to eliminate inflammation,and maintain remission. However, there is currently no consensus as to how to treat growth failure in patients whose inflammation remains intractable to treatment. This thesis examined the hypothesis that successful treatment of inflammation would improve linear growth in children with CD. We performed a series of retrospective studies examining a cohort of children aged ≤17 years with CD treated at Bart’s and The London Children Hospital. We determined the height standard deviation scores (SDS) of patients at diagnosis and investigated growth outcomes following treatments used to induce and maintain remission. These were:exclusive enteral nutrition (EEN), thiopurines and infliximab. Finally, as a potential new therapy, we considered the use of exogenously administered recombinant human IGF\1 (rhIGF\1) to restore plasma IGF\1 levels. We performed an open\labelled pharmacokinetic (PK) study of rhIGF\1 in 8 children with CD and growth failure. 9% of our patients had height SDS of \2 SDS at diagnosis; a four\fold increase compared to the normal age matched population. In addition, symptom duration negatively correlated with height SDS at diagnosis (r=\0.06; p=0.02). From 89 5 patients receiving EEN for primary induction of remission, 62.9% (56/89) of patients achieved complete remission. Over the course of 5 years, responders to EEN grew significantly better than non\responders (change in height SDS +0.18 [0.12] vs to \ 0.37 [0.13] respectively; p=0.005). This occurred despite no differences in duration of remission or treatment escalation between groups. 51% (26/51) patients treated with thiopurines were in remission at 12 months. These patients had improved growth (median change height SDS [IQR] 0.08 [\0.06 – 0.19] vs \0.24 [\0.61 \ \0.07] in non\responders; p=0.001). 39.2% (20/51) of these patients started anti\TNF therapy. However, over 12 months, we found that this conferred no improvement in growth (median [IQR] at 0 months\0.38 [\1.73 to \0.10] as compared to \0.61 [\ 1.72 to \0.09] at 12 months; p=0.43), irrespective of response to treatment. Subcutaneous treatment with 120 μg/kg twice daily rhIGF\1 restored plasma levels of IGF\1 in our patients, albeit it in some to high levels (median [range] concentration +2.09 [\1.27 to +5.21]). We were able to develop a PK mathematical model from these results to determine a more appropriate dosage. We found that in addition to patient’s age and weight, PCDAI also needs to be taken into consideration when determining dose. In summary, growth retardation is very common finding in paediatric CD. Response to EEN and thiopurines seems to result in beneficial effects upon growth. However, a number of children continued to have poor growth despite treatment. Our results show it is possible to increase circulating IGF\1 concentrations with exogenous injections, and develop a mathematical model to devise a dose to use in further trials.
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Quaranta, Maria. "A molecular genetic analysis of Crohn's disease susceptibility loci in psoriasis." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/a-molecular-genetic-analysis-of-crohns-disease-susceptibility-loci-in-psoriasis(bd43230e-4836-4a73-84e7-0da4212eb834).html.
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Psoriasis is an immune-mediated skin disorder that is inherited as a complex trait. Genome-wide linkage and association studies have identified a major disease susceptibility locus (PSORS1) and several genetic determinants of smaller effect. At least two of these (the IL12B and IL23R genes) have independently been associated with Crohn’’s disease (CD). Thus, the aim of this project was to investigate the genetic overlap between psoriasis and CD, with a view to identifying shared pathogenic pathways. In the first phase of the study, 26 CD variants were genotyped in 1,256 psoriatic patients and 2,938 unaffected individuals. Significant associations (FDR < 0.01) were observed for three markers, mapping to chromosomes 6p22, 21q21 and 21q22. The analysis of an independently ascertained dataset (1,348 cases vs. 1,368 controls) validated the chromosome 6p22 association, with the critical SNP (rs6908425) yielding a combined P value of 4 x 10-6. This marker lies within the CDKAL1 gene, which also harbours type 2 diabetes (T2D) associated alleles. Since the mechanisms mediating the pathogenic effect of CDKAL1 are poorly understood, an investigation into gene function was undertaken in the second part of the study. Real-time PCR analyses of multiple cDNA panels showed that CDKAL1 is abundantly expressed in immune cells, especially in CD4+ and CD19+ lymphocytes. Stable CDKAL1 knock-down cell lines generated by sh-RNA lentiviral transduction were also analysed. This showed that CDKAL1 silencing results in reduced cell proliferation and altered cell cycle progression. Transcription profiling of the knock- down cells identified a number of differentially expressed genes, mostly involved in housekeeping functions and inflammatory responses. Taken together, these findings indicate that CDKAL1 is a pleiotropic gene conferring susceptibility to psoriasis, CD and T2D. The results of functional studies suggest that this pathogenic role may be mediated by an effect on inflammatory responses and cell cycle progression.
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Sprakes, Michael Bramwell. "Clinical and molecular aspects of anti-TNF therapy in Crohn's disease." Thesis, University of Leeds, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659181.
Full textAbstract:
INTRODUCTION: Crohn's disease (CD) is a, relapsing and remitting inflammatory disorder of the gastrointestinal tract. The pathogenesis of CD is not entirely understood, but may represent a combination of immune, genetic, and environmental stressors. Recently, a number of genes have been discovered that confer susceptibility to CD, many of these functioning in the innate immune system and novel therapies that act on molecules associated with the innate immune system are being developed. The anti-tumour necrosis factor (TNF) therapies, infliximab and adalimumab, are two such treatments, however data relating to the longer-term efficacy and safety of these therapies in CD, along with their cost implications, are limited. NLRP3 is a pathogen recognition receptor which, amongst other ligands, recognises muramyl dipeptide (MDP), the major ligand sensed by NOD2, the first susceptibility gene identified in CD. The NLRP3 inflammasome has recently been associated with inflammation in rheumatoid arthritis (RA) and has been shown to be modulated following infliximab therapy in this condition. AIMS: Firstly, to determine the long-term efficacy, safety and cost implications of anti-TNF therapies in CD, and also to assess the efficacy of switching to a second anti-TNF upon failure or non-response to the initial anti-TNF treatment. Secondly, to investigate the NLRP3 inflammasome and other associated inflammatory molecules in patients with CD at both gene and protein level to analyse if the NLRP3 inflammasome is modulated in CD patients compared to healthy controls, and to determine if the inflammasome is modified following treatment with the anti-TNF therapy, infliximab.
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Nutting, Ruth. "Crohn's Disease and the Young Adult Couple: An Interpretative Phenomenological Study." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/73444.
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There are over 700,000 individuals living with Crohn's disease in the United States. Crohn's disease is a chronic inflammatory bowel illness that can have debilitating effects on individuals and their partners. There is ample literature on the various medical effects of Crohn's disease on the diagnosed individual but a dearth of literature on how Crohn's disease affects young adult individuals and their partners. This dissertation endeavors to fill this gap in the literature. Through Interpretative Phenomenological Analysis, this study explores how an individual's diagnosis of Crohn's disease is perceived to affect the couple relationship and young adult life-cycle transitions. From this study, healthcare providers can better understand how the numerous physical symptoms of Crohn's disease cause psychological and social implications for the diagnosed individual and partner. This understanding will allow healthcare providers to complete couple level clinical assessment and increase systemic interventions, promoting greater resilience among young adult couples.Ph. D.
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Watermeyer, Gillian. "Predicting poor outcome Crohn's disease at the time of first diagnosis." Master's thesis, University of Cape Town, 2013. http://hdl.handle.net/11427/9420.
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Over time, the majority of patients with Crohn's disease (CD) will develop irreversible gastrointestinal (GIT) damage, notably strictures or fistulas, impacting negatively on quality of life and resulting in hospitilisation and surgery. Early and aggressive drug therapy with immunomodulators (IMMs) and biologics may alter the likelihood of these complications and improve long-term outcomes. However, this approach is extremely expensive and carries its own battery of side-effects such as infections and malignancy. In addition there are a sizable number of patients with CD who will have a benign disease course and never require potent medical therapies or surgical intervention. As a result, there has recently been a surge of interest in early identification of those people who are at risk of developing complicated disease. The aim of our study was thus to indentify predictive factors for poor outcome CD in a South African setting, in order to select those who would most benefit from early and aggressive medical therapies.
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Ruttenberg, David. "Intestinal permeability to polyethylene glycol 400 in patients with Crohn's disease." Master's thesis, University of Cape Town, 1993. http://hdl.handle.net/11427/25587.
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An altered small intestinal permeability has been proposed as an important aetiological factor in the pathogenesis of inflammatory bowel disease. The relevant literature was reviewed. Intestinal permeability to Polyethylene glycol 400 in patients with Crohn' s disease, their relatives and healthy controls was examined and the data compared with studies of small bowel permeability to other similar sized probes. A new technique of analysis of urinary Polythylene Glycol 400 by High Performance Liquid Chromatography was described and compared with a previously established HPLC method. No evidence of an altered bowel permeability could be found using Polyethylene glycol 400, but the possibility that this may have been related to probe size and characteristics can not be excluded .
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Goodarzi, Mohammad T. "Glycosilation of two acute-phase proteins in cancer and inflammation." Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309405.
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McKaig, Brian Christopher. "The role of human intestinal myofibroblasts in intestinal wound repair and remodelling." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342024.
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