Submitted by Setor de Tratamento da Informa??o - BC/PUCRS (tede2@pucrs.br) on 2016-06-20T19:58:33Z No. of bitstreams: 1 DIS_ELAINE_DE_FATIMA_ADORNE_COMPLETO.pdf: 1701974 bytes, checksum: 69c11202314750b7607fd6400a9bc315 (MD5) / Made available in DSpace on 2016-06-20T19:58:34Z (GMT). No. of bitstreams: 1 DIS_ELAINE_DE_FATIMA_ADORNE_COMPLETO.pdf: 1701974 bytes, checksum: 69c11202314750b7607fd6400a9bc315 (MD5) Previous issue date: 2016-03-03 / Introduction: The association betweenchangesin lipid metabolismand chronicinflammatory bowel diseasesis not well established. It is observed thatinflammatory markers which arepresent inCrohn's disease (CD) and inulcerative colitis(UC) are also presentin metabolicsituationsthat are characterized byatherogenicdyslipidemia. It ispossible to assumethat changes inlipid profilemay be associated withchronic inflammation,potentiallyaggravating theclinical situationand increasing the riskof cardiovascular diseases. Aim: This research aims to investigate the associationbetween patients? lipidprofile who areunderinflammatory bowel disease andtheactivity levelsof chronicinflammatory disease. Method: Cross-sectional studyof patients who are followedin the Inflammatory Bowel Disease(IBD)clinic ofS?o LucasHospital atPontif?ciaUniversidadeCat?licado Rio Grande do Sul. We have evaluateddemographic and anthropometric data,andbiochemicaltests (C-reactive protein, erythrocyte sedimentation rate, blood count andlipid profile). Patientswere classified accordingto the severity ofCrohn's diseaseregarding Harvey-Bradshaw index forinflammatory activity; in relation toulcerative colitis, the classification followedthe severity ofacuteoutbreakaccording toTrueloveandWitts. Results:The study involved 122 patients of both genders who are under chronic inflammatory bowel disease. The patients were divided into two groups: Crohn's disease (n = 64; 52.5%) and ulcerative colitis (n = 58; 47.5%). Their average age is 41.6 around 12.6 years and their body mass index(BMI) is 25 around 4.4 kg/m2. Concerning the laboratory markers which were evaluated, we have found that LDL-c was higher in UC when compared to LDL-c CD (110.0 +35.8 x 91.3?33.1 mg/dL; p= 0.006). Regarding Harvey-Bradshaw indexforinflammatory activity, 63.8% of CD patients have had mild disease activity and CRP was the only marker in correlation to the disease severity (p = 0. 027). In UC, the distribution of patients according to Truelove and Witts index showed that 63.2% of patients have had mild disease; while for markers lipid, HDL-c levels (p = 0.036) and total cholesterol (p = 0.028) were correlated to the disease severity. HDL-c was the only lipoproteins that have presented, in 67.6% of the sample,valuesbelow those recommended by the Brazilian Society of Cardiology. Conclusion:We have concludedthat in IBDpatients, it is clear that theLDL-cissignificantly higherinUC. TheHDL-c,in both diseases,has presentedlevels below recommended. Among CDpatients, those who werein moresevere inflammatorysituationhave presented significantlyhigher levelsof CRP whencomparedto UCpatients. In relation totheseverity of the disease, which is determinedbyHarvey-Bradshaw indexorCDandTrueloveandWittsforUC, patients from both groups havebehavedsimilarly. / Introdu??o: A associa??o entre altera??es no metabolismo lip?dico e doen?as inflamat?rias intestinais cr?nicas n?o est? bem estabelecida. Observa-se que marcadores inflamat?rios presentes na Doen?a de Crohn (DC) e na Retocolite Ulcerativa Inespec?fica (RCUI) tamb?m est?o presentes em situa??es metab?licas que se caracterizam por dislipidemias aterog?nicas. ? poss?vel supor que as altera??es no perfil lip?dico podem estar associadas a processos inflamat?rios cr?nicos, potencialmente, agravar a situa??o cl?nica e aumentar o risco de doen?as cardiovasculares. Objetivo: Verificar a associa??o entre o perfil lip?dico de pacientes com doen?a inflamat?ria intestinal e os n?veis de atividade da doen?a inflamat?ria cr?nica. M?todo: Estudo transversal de pacientes acompanhados no ambulat?rio de Doen?a Inflamat?ria Intestinal do Hospital S?o Lucas da Pontif?cia Universidade Cat?lica do Rio Grande do Sul. Foram avaliados dados demogr?ficos, antropom?tricos e exames bioqu?micos (prote?na C reativa, velocidade de hemossedimenta??o, hemograma e perfil lip?dico). Os pacientes foram classificados quanto ? gravidade da Doen?a de Crohn de acordo com o ?ndice de atividade inflamat?ria de Harvey-Bradshaw e, na Retocolite Ulcerativa Inespec?fica, quanto ? gravidade do surto agudo segundo Truelove e Witts. Resultados: Participaram do estudo 122 pacientes de ambos os sexos com doen?a inflamat?ria intestinal cr?nica, divididos em dois grupos: doen?a de Crohn (n= 64; 52,5%) e retocolite ulcerativa inespec?fica (n= 58; 47,5%). M?dia de idade de 41,6 ?12,6 anos e m?dia de IMC de 25 ? 4,4kg/m2. Quanto aos marcadores laboratoriais avaliados, verificamos que o LDL-c mostrou-se mais elevado na RCUI quando comparado ao LDL-c da DC (110,0 +35,8 x 91,3?33,1 mg/dL; p= 0, 006). Em rela??o ao ?ndice de atividade inflamat?ria de Harvey-Bradshaw, 63,8% dos pacientes com DC apresentaram atividade leve da doen?a e a PCR foi o ?nico marcador que apresentou correla??o com a gravidade da doen?a (p= 0, 027). Na RCUI, a distribui??o dos pacientes conforme o ?ndice de Truelove e Witts demonstrou que 63,2% dos pacientes estavam com doen?a leve. Quanto aos marcadores lip?dicos, o HDL-c (p=0,036) e o colesterol total (p=0,028) apresentaram correla??o com a gravidade da doen?a. O HDL-c foi a ?nica das lipoprote?nas que apresentou valores abaixo dos recomendados pela Sociedade Brasileira de Cardiologia em 67,6% da amostra. Conclus?o: Podemos concluir que, em pacientes com DII, verifica-se que o LDL-c est? significativamente mais elevado na RCUI. O HDL-c em ambas as doen?as apresentou n?veis abaixo dos recomendados. Entre os pacientes com DC, os que se apresentam em situa??o inflamat?ria mais grave apresentaram valores significativamente mais elevados da PCR, quando comparados aos pacientes com RCUI. Em rela??o ? gravidade da doen?a determinada pelos ?ndices de Harvey-Bradshaw para DC e de Truelove e Witts para RCUI, os pacientes dos dois grupos comportaram-se de maneira semelhante.

Submitted by CARINA DE FÁTIMA DE SIBIA null (carinasibia@gmail.com) on 2017-02-21T19:28:25Z No. of bitstreams: 1 tese final 21.2.pdf: 1461578 bytes, checksum: aaee8aaa84b0ad8485b183d6dc28a095 (MD5) / Rejected by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br), reason: O arquivo submetido está na orientação paisagem, o arquivo deve estar na orientação retrato on 2017-02-24T19:02:56Z (GMT) / Submitted by CARINA DE FÁTIMA DE SIBIA null (carinasibia@gmail.com) on 2017-02-24T22:08:47Z No. of bitstreams: 1 tese .pdf: 1294801 bytes, checksum: dd9a234277b605736e3567a3692c2d48 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-03-06T16:57:54Z (GMT) No. of bitstreams: 1 sibia_cf_me_bot.pdf: 1294801 bytes, checksum: dd9a234277b605736e3567a3692c2d48 (MD5) / Made available in DSpace on 2017-03-06T16:57:54Z (GMT). No. of bitstreams: 1 sibia_cf_me_bot.pdf: 1294801 bytes, checksum: dd9a234277b605736e3567a3692c2d48 (MD5) Previous issue date: 2017-01-31 / Introdução: A doença de Crohn (DC) e a retocolite ulcerativa (RCU) são as duas principais doenças que compõem a doença inflamatória intestinal (DII). Estudos indicam que vários genes estão diferencialmente expressos em DC. vs. RCU. Entretanto, os mecanismos moleculares de desenvolvimento e progressão das diferentes formas da DII ainda não foram elucidados. Considerando que os microRNAs (miRNAs) são potentes reguladores da expressão gênica e têm papel importante em várias doenças humanas, estes podem constituir biomarcadores com potencial diagnóstico, prognóstico e terapêutico em DII. Objetivos: Identificar miRNAs desregulados em DII, distinguindo DC e RCU; identificar genes-alvo dos miRNAs alterados e redes de interação entre miRNAs e genes-alvo em DII. Materiais e Métodos: Foi utilizada estratégia de meta-análise para identificação de dados de expressão de miRNAs em DII. Após aplicação dos critérios de inclusão e exclusão, foram selecionados 10 estudos para extração dos dados. Desses estudos, foram identificados miRNAs significativamente desregulados (nível de alteração ou FC>=2 e p<0,05) e coletadas informações sobre o tipo e o número de amostras analisadas (soro, plasma ou tecido) de pacientes com DC ou RCU, plataformas utilizadas para análise de expressão de miRNAs e validação dos dados, entre outras. A seguir, foram aplicadas as ferramentas de bioinformática mirwalk 2.0 para predição de genes-alvo regulados pelos miRNAs e STRING e BiNGO para identificação de redes de interação entre miRNAs e genes-alvo e funções biológicas, respectivamente. Resultados: Entre os miRNAs com expressão aumentada, foram identificados 17 em DC e 62 em RCU. Entre os miRNAs com expressão diminuída, foram identificados 18 em DC e 31 em RCU. Os miRNAs que mostraram o maior número de interações com genes-alvo na DC foram: let-7a-5p, let-7b-5p, miR-199a-5p, miR-150-5p, miR-362-3p e miR-224-5p. Em RCU, os miRNAs desregulados e com maior número de interações foram miR-155-5p, miR-24-5p, miR-335-5p e miR-16-5p. Conclusões e Perspectivas Futuras: Foram identificadas redes de interação entre miRNAs e genes-alvo associados a processos biológicos de inflamação e resposta imune. Os miRNAs identificados modulam vias moleculares potencialmente envolvidas na patogênese da DII. Estudos como esse podem contribuir para a melhoria do diagnóstico e no desenvolvimento de tratamentos direcionados e mais precisos para pacientes com DC e RCU.

La maladie de Crohn (MC) est une maladie inflammatoire chronique de l’intestin (MICI), dont la physiopathologie résulterait d’une interaction anormale entre le microbiote intestinal et le système immunitaire de l’hôte sous l’influence de facteurs génétiques et environnementaux. Au sein de ce microbiote, les E. coli adhérents et invasifs (AIEC) colonisent la muqueuse iléale des patients atteints de la MC et sont capables de survivre et se multiplier à l’intérieur des macrophages. Par ailleurs, les objectifs thérapeutiques de la MC et notamment la cicatrisation muqueuse endoscopique nécessitent des endoscopies répétées, peu acceptables du point de vue des patients. Parmi les moyens alternatifs, la calprotectine fécale est le marqueur fécal de référence même si ses performances semblent diminuées dans certaines situations comme la maladie iléale pure. Le premier objectif de ces travaux étaient de comparer la capacité des macrophages dérivés de monocytes (MDM) issus de patients atteints de MC, de rectocolite hémorragique (RCH) ou de sujets sains à contrôler l’infection par les AIEC et d’identifier les facteurs associés à cette multiplication des AIEC et notamment le rôle des polymorphismes génétiques associés à la MC en lien avec l’autophagie. Les AIEC se multipliaient de manière plus importante que la souche non pathogène K12 dans les macrophages quel que soit leur origine. L’entrée des AIEC (1h post- infection) ne variait pas en fonction de la provenance des macrophages. La survie des AIEC était augmentée dans les MDM issus de patients MC comparés à ceux issus de RCH ou de sujets contrôles. En analyse multivariée, cette survie était positivement corrélée à la sécrétion d’IL1β mais était diminuée en présence des variants à risque pour ULK1 (p=0,046) et XBP1 (p=0,014). Les MDM issus de patients MC étaient incapable de contrôler la multiplication des AIEC contrairement à ceux issus de RCH ou de sujets contrôles d’autant plus en présence du variant à risque pour IRGM (p=0,045). L’infection des MDM de patients MC par les bactéries AIEC induit un profil de sécrétion cytokinique pro-inflammatoire. La deuxième partie de ces travaux avait pour but de comparer les performances de la chitinase 3-like 1 fécale (CHI3L1), une protéine de l’hôte interagissant avec un facteur de virulence des AIEC, et la métalloprotéase matricielle 9 (MMP-9) pour détecter l’activité inflammatoire endoscopique de la MC en comparaison du marqueur fécal de référence, la calprotectine. Les taux de CHI3L1, de MMP-9 et de calprotectine fécales étaient corrélés au ‘Crohn’s Disease Endoscopic Index of Severity’ (CDEIS) et étaient significativement augmentés en présence d’ulcérations endoscopiques. En cas d’atteinte iléale pure, la CHI3L1 fécale semblait mieux corrélée au CDEIS que la calprotectine fécale. Le seuil de CHI3L1 fécale de 15 ng/g présentait de meilleures performances que la calprotectine fécale pour détecter la présence d’ulcérations endoscopiques. La MMP-9 étaient un marqueur performant pour détecter la présence de lésions endoscopiques dans les MICI. En conclusion, nous avons montré qu’il existe un défaut des macrophages à contrôler l’infection par les bactéries AIEC chez les patients atteints de MC en rapport avec les variants à risque impliqués dans l’autophagie conduisant à un phénotype de macrophages pro-inflammatoires. La CHI3L1 fécale, connue comme une protéine de l’hôte interagissant avec un facteur de virulence des AIEC, tout comme la MMP-9 semblent être de bons marqueurs d’activité endoscopique dans les MICI. / Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) whose pathophysiology results from an abnormal interaction between the gut microbiota and the host's immune system under the influence of genetic and environmental factors. . Within this microbiota, adherent and invasive E. coli (AIEC) colonize the ileal mucosa of patients with CD and are able to survive and multiply within macrophages. Moreover, the therapeutic objectives of CD, and especially endoscopic mucosal healing, require repeated endoscopies, which are not acceptable from the patients' point of view. Among alternative means, fecal calprotectin is the fecal marker of reference even if its performance seems to be diminished in certain situations like pure ileal disease. The primary objective of this work was to compare the ability of monocyte-derived macrophages (MDM) from patients with CD, ulcerative colitis (UC) or healthy subjects to control AIEC infection and to identify associated with this multiplication of AIEC and in particular the role of genetic polymorphisms associated with CD in connection with autophagy. AIEC multiplied more than non-pathogenic strain K12 in macrophages irrespective of their origin. The entry of the AIEC (1h post-infection) did not vary according to the origin of the macrophages. The survival of AIEC was increased in MDM from MC patients compared to those from HCR or control subjects. In multivariate analysis, this survival was positively correlated with the secretion of IL1β but was decreased in the presence of the variants at risk for ULK1 (p = 0.046) and XBP1 (p = 0.014). MDM from MC patients were unable to control the multiplication of AIEC, unlike those from HCR or control subjects, especially in the presence of the variant at risk for IRGM (p = 0.045). Infection of MDM from MC patients by AIEC bacteria induces a pro-inflammatory cytokine secretion pattern. The second part of this work aimed to compare the performance of faecal chitinase 3-like 1 (CHI3L1), a host protein interacting with AIEC virulence factor, and matrix metalloprotease 9 (MMP-9). to detect the endoscopic inflammatory activity of MC in comparison with the standard fecal marker, calprotectin. Fecal CHI3L1, MMP-9 and calprotectin levels were correlated with Crohn's Disease Endoscopic Index of Severity (CDEIS) and were significantly increased in the presence of endoscopic ulcerations. In case of pure ileal involvement, fecal CHI3L1 seemed better correlated with CDEIS than fecal calprotectin. The fecal CHI3L1 threshold of 15 ng / g showed better performance than faecal calprotectin in detecting the presence of endoscopic ulcerations. MMP-9 was a powerful marker for detecting the presence of endoscopic lesions in IBD. In conclusion, we have shown that there is a macrophage defect to control infection by AIEC bacteria in patients with CD related to atopic risk variants involved in autophagy leading to a pro-inflammatory macrophage phenotype . Fecal CHI3L1, known as a host protein interacting with AIEC virulence factor, as well as MMP-9 appear to be good markers of endoscopic activity in IBD.

Background The conventional ileostomy can be avoided. Many attempts have been performed. The first successful solution was the continent ileostomy- Kock pouch. The high rate of complications and revisions some experienced forced surgeon to try to restore the continence by the mechanism of the anus involving an ileal pouch. Both procedures afterwards documented excellent functional outcome, but the complication rates were not negligible and the long-term failure rate were increasing. Different surgical refinements were done and the risk factors for complications and failures were investigated as experience and materials increased. Restoring of the integrity of anal function and the succsess of the ileal pouch-anal anastomosis shadowed the practise of the forerunner: the continent ileostomy reservoir. This latter procedure was more demanding and seemed in the first year of ileal pouchanal anastomosis era to have significant more complications and revisional surgery. The worldwide adoption of the pelvic pouch decreased the need for the continent ileostomy and a vicious circle evolved. Today only few centres perform the procedure. Patients who are not suitable for ileal anal-pouch anastomosis are seldom offered the possibility of having a continent ileostomy. Aims The aims of the study was to investigate surgical load, complications and long-term functional outcome and to define factors which affect these subjects in patients operated with ileal pouch-anal anastomosis, continent ileostomy or both in one single surgical department during the same period and without any institutional learning curve, and furthermore, to compare and contrast the two options. Material and methods From 1984 to 2005(7) 304 (315) patients were operated with IPAA at St. Olavs Hospital (earlier: Regional Hospital of Trondheim). From 1983 to 2002(7) 50 (65) patients had a continent ileostomy constructed. This was an observational study in the scope of surveillance and quality assurance. All patients were offered a planed regularly annual outpatient clinic follow up programme including a prospective standardised interview on clinical outcome. This was a supplement to clinical investigation with endoscopy and consecutive documentation of complications and other factors affecting the patients’ health. Data were recorded in the medical chart. In this system, all patients had recorded dataset. However, the intervals between data recordings differ and the intervals increased by time. All inpatients data were included. Standard descriptive statistical analysis and simple associations were undertaken. Handling longitudinal data with limited cases, varying time intervals was done in a Times Series Cross Sectional data model, analysed, and adjusted for several factors affecting functional outcome. Multivariable analysis was done. Results The estimated failure rate at 20 years was 11.4% for ileal pouch-anal anastomosis and 11.6% for continent ileostomy. Salvage procedures rates were 31% vs. 38%, respectively (p=0.06). The salvage procedures in IPAA included local procedures and redoes with laparotomy. Salvage procedures in CI were related to the function of the nipple valve, mainly nipple valve sliding and less frequent stenosis or fistulas. Complications rates were high. In pelvic pouch surgery, half of the patients would need re-operations in 20 years. Ten percentages had early anastomotic separation without septic complications. Four percentages had early pelvic septic complications. Fistulas and sepsis at the anastomotic site were the main severe complications, often leading to pouch failure. Closing of the loop ileostomy was accompanied with complications in six percentages. In the patients (48) who did not have a covering stoma the overall complications rate did not differ from those with a loop ileostomy, although nine needed a secondary stoma. Covering stoma seems to postpone anastomotic complications. Handsewn anastomosis had more strictures, but otherwise the complications rates were similar to stapled anastomosis. Patients having the diagnosis changed to Crohn`s diseases had more complications and higher failure rate. Early anastomotic complications were associated with long-term complications. In patients with continent ileostomy the nipple valve sliding is the main cause of revision. One third needed revision once or several times. At 20 years follow-up, half of the patients would need surgery due to complications. Although many patients with CI need several revisions, all patients were continent at the last follow up with a stable intubation frequency of 3 – 5 per 24 hour. The failure of the pelvic pouch is the end of severe complications. Two third of the failures had the pouch excision or permanent ileostomy with the pouch in situ. One third underwent a conversion to CI, with equal surgical and functional outcome as other patients with CI. In IPAA, bowel movements at day were between 5-6 at day and 0-1 at night. The rates of more or less frequent incontinence were about 10%, and 41% and 55% had reported soling at day and night respectively. The long-term functional outcome did not deteriorate with time: ie. observational time, as an independent factor did not influence outcome. Factors influencing the outcome were found but the impact of gender, age, protective stoma, hand-sewn anastomosis and early complications were negligible. Pouchitis did significantly influence functional outcome negatively, but did not create deterioration over time. Estimated pouchitis rate in IPAA was 43% for more than 20 years. The onset of the first pouchitis appears mostly in the 5-6 first years after surgery. The crude rate was 35% and 6% of the patients had chronic pouchitis. Severe/chronic pouchitis was associated with primary sclerosing cholangitis, but not with pyoderma gangrenousum or diagnosed joint affections. Idiopathic pouchitis were absent among patients with familial adenomatous polyposis. In continent ileostomy the rate of pouchitis was 26%. Conclusion The complications in both the pelvic pouch surgery and the surgery of continent ileostomy are considerable. Although not similar the surgical load are in the same order of magnitude. For the continent ileostomy revisional surgery are to be expected. The failure rate of both procedures are high and in long-term similar. The long-term functional outcome are however stabile and excellent. The failed pelvic pouch can be converted to a continent ileostomy in selected and motivated patients. The entity of pouchitis is conflicting and has to be divided into several different entities both on clinical, constitutional and other differentiating features. Patients with PSC should be informed of a possible higher risk of severe and chronic pouchitis after IPAA.

En person som drabbats av den inflammatoriska tarmsjukdomen Mb Crohn är under ett svårt skov ofta i behov av sjukvårdskontakt. Skovet kan innebära blodiga diarréer flera gånger per dygn, buksmärta och feber. För att minska patientens lidande är det viktigt att sjukvårdskontakten blir positiv för patienten.   Syftet med studien var att undersöka hur patienter med Mb Crohn upplevde kontakten med vårdpersonal samt vilka faktorer som påverkade kontakten. Den metod som användes var en kvalitativ innehållsanalys som gjordes av text från sex bloggar skrivna av personer med Mb Crohn. En blogg kan beskrivas som en dagbok, publicerad via internet.   Resultatet visade att kontakten med vårdpersonal gav både positiva och negativa upplevelser. Faktorer som gjorde upplevelsen positiv var när personalen fanns tillgänglig samt gav möjlighet till delaktighet. Då personalen visade sig kompetent, engagerad och empatisk upplevdes trygghet och bekräftelse. Faktorer som gjorde upplevelsen negativ var när personalen gav fel eller bristfällig information och behandling, inte gav utlovade besked i rätt tid eller inte visade intresse för patienternas åsikter. Känslor som då upplevdes var otrygghet, maktlöshet, frustration och förlorad autonomi. De negativa faktorerna övervägde.   Slutsatsen av denna studie är att vårdpersonal kan utveckla sin förmåga i kontakten med patienter med Mb Crohn. Att vårdpersonal vid utbildningstillfällen reflekterar över informanternas erfarenheter i vårdsituationer, är förslag som kan leda till en bättre vård

Thèse de doctorat : Biologie Cellulaire et Nutrition : Nancy 1 : 2009. / Titre provenant de l'écran-titre.

Thèse de doctorat : Biologie Moléculaire : Nancy 1 : 2008. / Titre provenant de l'écran-titre.

Thèse de doctorat : Sciences de la Vie et de la Santé : Strasbourg 1 : 2007. / Thèse soutenue sur un ensemble de travaux. Titre provenant de l'écran-titre. Bibliogr. 12 p.

The gastro-intestinal (GI) tract represents the largest surface of the body and is continuously exposed to the microbial environment. In such anatomy, the survival of the host requires that the intestinal microbial flora be contained without excessive immune-reactivity to commensal bacteria while retaining the ability to respond to episodic pathogens. The discriminative recognition between beneficial commensal bacteria and potentially harmful pathogens demands an accurate interpretation by the GI mucosal immune system. Any defects in the processes of innate immune recognition and killing may lead to the development and perpetuation of chronic intestinal inflammation, namely inflammatory bowel disease (i.e. Crohn's disease (CD) and ulcerative colitis (UC)) and post-infectious irritable bowel syndrome (PI-IBS). The aim of ours studies was to evaluate the contribution of candidate genes, involved in the homeostasis and regulation of the intestinal innate immune response, to the susceptibility to CD, DC, and PI-IBS. In the first phase, we describe functional and genetic association results supporting NLRP3, encoding NALP3/cryopyrin, as a novel CD susceptibility gene. We subsequently report that the MEFV gene, encoding pyrin, known to interact with and be involved in the same pathway as NALP3/cryopyrin, does not contribute to CD and DC susceptibility. No CD or DC additional associations were observed upon NLRP3-MEFV gene-gene interaction analyses. In the third phase, we report the first association study evaluating genetic determinants for PI-IBS, using the well-characterized Walkerton population cohort. We uncovered variants in the TLR9, CDH1, and IL6 regions associated with PI-IBS susceptibility. These results are in keeping with the pathophysiologic changes observed in patients with PI-IBS, which include increased intestinal permeability and intestinal immune activation. / Overall, these results contribute to a better understanding of the genetic susceptibility to CD, DC and PI-IBS and shed light on new pathogenic signaling pathways in the development of these diseases.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.