Introdução: Pacientes com Doença de Crohn (DC) apresentam alto risco de eventos tromboembólicos (TE), muitas vezes, associados a alta morbimortalidade. É conhecido o papel da inflamação na fisiopatologia da trombose na doença Inflamatória Intestinal (DII), entretanto, o significado da inflamação subclínica ainda se mantém obscuro na literatura. Este estudo avaliou o efeito da atividade endoscópica no perfil de coagulação dos pacientes com DC em remissão clínica. Métodos: entre os dias 22 de maio de 2015 e 26 de abril de 2017, foram triados 261 pacientes com DC em possível remissão clínica, sendo realizadas ao todo 229 colonoscopias. Das 229 colonoscopias realizadas, 164 pacientes estavam realmente em remissão clínica (confirmados com CDAI <= 150) e foram alocados em dois grupos: 75 no grupo de atividade endoscópica (AE) (SES-CD >= 7), 89 no grupo de remissão endoscópica (RE) (SES-CD <= 2). Cinquenta controles saudáveis pareados por sexo e idade foram eleitos. Medimos, nos 3 grupos, além da geração de trombina - pelo método Calibrated Automated Thrombogram (CAT), com e sem trombomodulina, - a atividade do fator tecidual (FT), fibrinogênio, D-dímero, Fator VIII, ADAMTS-13, Fator de von Willebrand - antígeno e cofator de ristocetina (cWF). Coletamos dados sobre a duração da doença, extensão, comportamento, localização, tratamento farmacológico, história prévia de cirurgias, calprotectina fecal, qualidade de vida (por meio do IBDQ), além dos fatores de risco para TE, como hospitalização recente, uso de corticoide atual, status do tabagismo, assim como marcadores de trombofilia hereditária ou adquirida. Seguimos os pacientes por 1 ano de observação, avaliando a variação no CDAI e IBDQ no período. Resultados: A maioria dos pacientes apresentou comprometimento ileocolônico (43%), com comportamento inflamatório (40%), seguido de estenosante (30%) e fistulizante (30%). 67% estavam em uso de imunossupressores e 52% em uso de biológicos. Os fatores de risco para TE e todos os outros marcadores de trombofilia, incluindo deficiência de proteína C e S, anticardiolipina, resistência à proteína C, antitrombina, mutações da protrombina e do Fator V, foram semelhantes em ambos os grupos, exceto pelo anticoagulante lúpico, maior no grupo de AE (8,1% vs. 1,3%, p=0,047). Como esperado, o grupo de AE apresentou níveis significativamente maiores de PCR, calprotectina fecal e plaquetas. Além disso, este grupo apresentou uma maior atividade do fator tecidual vs. o grupo de RE vs. controles (127 vs. 103 vs. 84, p = 0,001). Embora o grupo DC tivesse maiores níveis de FVW:Ag e FVW:RCo, FVW/ADAMTS-13, Fator VIII e trombomodulina vs. controles, não houve diferença estatística entre os grupos de AE e RE. Os níveis de geração de trombina foram semelhantes entre os 3 grupos, com ou sem trombomodulina. Conclusão: Esses dados evidenciam que existe uma disfunção endotelial inerente à DC, e, que, em pacientes com AE, essa disfunção pode ser ainda maior pela maior exposição do FT. Embora, a presença de inflamação e dano endotelial contribuam para esse estado procoagulante, em pacientes com doença subclínica, há um estado de compensação permanente, uma vez que a quantidade de trombina gerada foi a mesma entre os grupos. Este equilíbrio pode estar comprometido diante de outros fatores tromboembólicos, aumentando, assim, o risco de trombose / Background: Crohn\'s disease patients (CD) have a high risk of thromboembolic events (TE), often associated with high morbidity and mortality. Involvement of inflammation in TE is well known, but significance of the sub-clinical inflammation in this process is not the rule. Thus, the aim of this study is to evaluate the effect of the endoscopic activity in the coagulation profile in CD in clinical remission. Methods: Between May/2015 and April/2017, 261 CD patients in supposed clinical remission, were screened, and 229 had a colonoscopy done, resulting in the inclusion of 164 CD patients in clinical remission confirmed by a CDAI <= 150. They were allocated in two groups: 75 in the endoscopic activity (EA) group (SES-CD >= 7), and 89 in the endoscopic remission (ER) group (SES-CD <= 2). 50 healthy controls matched for sex and age were chosen. We measured in the 3 groups, in addition to the generation of thrombin - through the Calibrated Automated Thrombogram (CAT), with and without thrombomodulin, - the activity of tissue factor (TF), fibrinogen, D-dimer, Factor VIII, ADAMTS-13 and von Willebrand Factor - antigen (VWF) and ristocetin cofactor (VWF:RCo). We collected data regarding the duration of the disease, extension, behavior, location, pharmacological treatment, previous history of surgeries, fecal calprotectin, quality of life (through IBDQ), as well as risk factors for TE such as recent hospitalization, current corticoid use, smoking status, as well as markers of hereditary or acquired thrombophilia. We followed the patients for 1 year of observation, evaluating the variation in CDAI and IBDQ. Results: Most of the patients had ileocolonic involvement (43%), with inflammatory behavior (40%), followed by stenosing (30%) and fistulizing (30%). 67% were in use of immunosuppressors and 52% in use of biological drugs. Risk factors for TE besides other markers of thrombophilia, including protein C and S deficiency, anticardiolipin, protein C resistance, antithrombin, prothrombin and Factor V mutations, were similar in both groups except for the lupus anticoagulant, higher in the EA group (8.1% vs. 1.3%, p = 0.047). As expected, the EA group had significantly higher levels of CRP, fecal calprotectin and platelets. In addition, this group had a higher activity of TF vs. ER group vs. controls (127 vs. 103 vs. 84, p = 0.001). Although the DC group had had higher levels of VWF and VWF:RCo, VWF/ADAMTS-13, Factor VIII and thrombomodulin vs. controls, there was no statistical difference between the EA and ER groups. Thrombin generation levels were similar between the 3 groups, with or without thrombomodulin. Conclusion: These data show that there is an inherent endothelial dysfunction in CD, moreover in patients with EA, this dysfunction may be even greater, due to the exposure of TF. Although the presence of inflammation and endothelial damage contribute to this procoagulant condition, in patients with subclinical disease, there is a permanent compensatory state, since the amount of thrombin generated was the same between the groups. This balance may be compromised by other thromboembolic factors, thus increasing the risk of thrombosis

Orientador: José Murilo Robilotta Zeitune / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T02:57:17Z (GMT). No. of bitstreams: 1 Parente_JoseMiguelLuz_D.pdf: 3595737 bytes, checksum: a5229b134d3c146b3029f45e146e580e (MD5) Previous issue date: 2014 / Resumo: Introdução: Doença de Crohn (DC) e Retocolite Ulcerativa Idiopática (RCUI) são as duas principais doenças inflamatórias intestinais (DII), cuja prevalência é mais expressiva no norte da Europa, Estados Unidos da América e Canadá. Mais recentemente, elas passaram a ser detectadas em frequência crescente em todos os continentes. O objetivo desta pesquisa foi analisar as características demográficas e fenótipos clínicos dos pacientes com DII no Nordeste brasileiro, referentes à época da confirmação do diagnóstico. Casuística e Método: Este é um estudo descritivo e transversal, o qual foi aprovado pelo Comitê de Ética e Pesquisa da UFPI. Foram incluídos censitariamente os pacientes com DII que faziam seguimento clínico em serviços especializados de hospitais universitários em todas as capitais do Nordeste do Brasil. As variáveis analisadas foram: as características demográficas e socioeconômicas, e os dados clínicos de DC e RCUI de acordo com a classificação de Montreal. As análises estatísticas incluíram: média, mediana e desvio padrão para variáveis quantitativas; teste do qui-quadrado (c2) de Pearson para análise das variáveis qualitativas. O nível de significância adotado foi de 5%. Resultados: Foram incluídos 913 indivíduos com DII, sendo 486 (52,1%) com RCUI, 412 (44,2%) com DC e 35 (3,7%) com colite não classificada (CNC). A idade dos pacientes variou de 8 anos a 83 anos, média de 37,9 (DP = 14,4) anos, sendo 469 (50,3%) mulheres. Em todo o período estudado (1975 ¿ 2013), o atraso na confirmação diagnóstica foi de 31,0 meses. As características preponderantes dos pacientes com DC, segundo a classificação de Montreal foram: idade entre 17 e 40 anos (A2), localização com envolvimento de cólons (L2) e comportamento inflamatório (B1). Para os pacientes com RCUI, houve predomínio de pacientes com idade entre 17 e 40 anos e extensão da doença até ângulo esplênico (E2). Conclusão: Este estudo demonstrou que houve expressivo aumento na frequência de DC e RCUI na região Nordeste do Brasil nos últimos trinta anos / Abstract: Introduction: Usually, inflammatory bowel diseases (IBD), as Crohn's disease (CD) and ulcerative colitis (UC), have been described in northern Europe, United States of America and Canada. In the last decades, IBD frequency has been also increased in all continents. The aim of the study was to analyze the demographic characteristics and clinical phenotypes of IBD in the northeastern of Brazil, according to the time of the diagnosis. Casuistic and methods: This is a cross-sectional study, which was approved by the Institutional Ethics and Research Committee. We included patients who were undergoing medical treatment for IBD in specialized centers in the Federal University Hospitals from all Northeasthern areas in Brazil. Demographic and socioeconomic characteristics were analyzed, as well as clinical data of CD and UC according to the Montreal classification. Statistical analyses included mean, median and standard deviations for quantitative variables, and the Pearson chi-square (c2) test for qualitative variables. The level of significance adopted was 5%. Results: A total of 913 patients with IBD were included, 486 (52,1%) with UC, 412 (44,2%) with CD and 35 (3,7%) with unclassified colitis (UnC). The ages ranged from 8 years to 83 years, mean 37.9 (SD = 14.4) years. Of the total, 469 (50.3%) were women. Throughout the study period (1975 ¿ 2013), the delay in diagnosis confirmation was 31.0 months. The predominant characteristics of CD patients, according to the Montreal classification were: age between 17 and 40 years (A1); colon location (L2); and inflammatory behavior (B1). For patients with UC, there was a predominant age between 17 and 40 years, and left colitis (E2). Conclusion: This study showed that there was significant increase in the frequency of IBD (CD and UC) in northeastern of Brazil over the past thirty years / Doutorado / Medicina Interna / Doutor em Ciências Médicas

La maladie de Crohn (MC) et la rectocolite hémorragique (RCH) sont les deux principales formes cliniques des maladies inflammatoires chroniques de l’intestin (MICI) responsables d’une atteinte inflammatoire de la paroi du tube digestif avec des ulcérations extensives. Ce sont des maladies fréquentes en Europe et en Amérique du Nord avec plus de 2.5 millions de malades. Du fait de l’augmentation importante de leur prévalence, de leur morbidité, du retentissement sur la qualité de vie des malades et du coût de leur prise en charge médicale, les MICI sont devenues un problème majeur de santé publique. Au cours de ces maladies, l’inflammation intestinale peut être contrôlée par les traitements médicamenteux ou la chirurgie sans pour autant obtenir de guérison complète et définitive. Bien que leur origine reste mal connue, l’hypothèse actuelle présente les MICI comme des maladies multifactorielles, secondaires à une réponse immunitaire muqueuse anormale dirigée contre la flore intestinale, survenant chez des individus génétiquement prédisposés et entrainant une inflammation intestinale. Le but du travail était d’explorer les mécanismes à l’origine de cette inflammation intestinale associée au développement des MICI en étudiant plus particulièrement certains facteurs environnementaux, moléculaires et microbiens. Nous avons étudiés tout d’abord l’aluminium comme facteur environnemental en démontrant qu’il pouvait participer au développement et à l’aggravation de l’inflammation intestinale sur des modèles de colite chez la souris. Nous avons ensuite étudié un facteur moléculaire important pour l’apoptose des cellules, la caspase-8. Nous avons montré que cette caspase-8 maintenait l’homéostasie intestinale des cellules épithéliales intestinales et que sont absence entraînait une inflammation intestinale ressemblant à la maladie de Crohn. Finalement nous nous sommes intéressés à un facteur microbien, Saccharomyces cerevisiae CNCM I-3856 qui est une levure. Nous avons démontré que cette levure était capable d’induire un effet anti-inflammatoire et analgésique chez l’animal en activant PPAR&#947; dans le colon. Chez l’homme nous avons montré dans une étude randomisée que Saccharomyces cerevisiae CNCM I-3856 réduisait les douleurs abdominales chez les patients atteints du syndrome de l’intestin irritable. En conclusion, l’exploration de ces trois facteurs environnementaux, moléculaires et microbiens permet de mieux comprendre le développement de l’inflammation intestinale. La perspective de ce travail est le développement dans un futur proche des nouvelles thérapeutiques ciblées permettant de lutter contre l’inflammation intestinale. / Crohn's disease (CD) and ulcerative colitis (UC) are the two main clinical forms of chronic inflammatory bowel disease (IBD) responsible for intestinal inflammation with extensive ulceration of the mucosa. These are common diseases in Europe and North America with over 2.5 million patients. Due to the significant increase in their prevalence, their morbidity, the impact on quality of life of patients and the cost of their medical care, IBD has become a major public health problem. In these diseases, intestinal inflammation may be controlled by drug treatment or surgery without obtaining a complete and final cure. Although their origin remains unclear, the current hypothesis presents IBD as multifactorial diseases secondary to an abnormal mucosal immune response directed against the intestinal flora, occurring in genetically predisposed individuals and causing intestinal inflammation. The aim of this work was to explore the mechanisms behind this intestinal inflammation associated with the development of IBD studying some particular environmental, molecular and microbial factors. We studied first the aluminum as an environmental factor and demonstrated that he could participate in the development and exacerbation of intestinal inflammation in models of colitis in mice. We then studied an important factor in molecular cell apoptosis, caspase-8. We have shown that caspase-8 was maintaining intestinal homeostasis in intestinal epithelial cells and that absence of caspase-8 leads to intestinal inflammation mimicking Crohn's disease. Finally we studied a microbial factor, Saccharomyces cerevisiae CNCM I-3856 which is yeast. We demonstrated that this yeast was capable of inducing an anti-inflammatory and analgesic effect in animals by activating PPARgamma in the colon. In humans we have shown in a randomized study that Saccharomyces cerevisiae CNCM I-3856 reduced abdominal pain in patients with irritable bowel syndrome. In conclusion, the exploration of these three environmental molecular and microbial factors helps to better understand the development of intestinal inflammation. The perspective of this work is the development in the near future of new targeted therapies directed against intestinal inflammation.

The objectives of this thesis were to synthesize existing RCT evidence and post-market observational evidence of TNF-α inhibitors in IBD. Two separate systematic reviews were performed: an overview of systematic reviews of RCTs, and a systematic review of post-market observational studies of TNF-α inhibitors in Crohn’s disease and ulcerative colitis. The overview of systematic reviews included 37 studies. RCT evidence demonstrated superiority of all agents to placebo in Crohn’s disease and ulcerative colitis, with no increased risk of malignancy or serious adverse events. Network meta-analyses have not shown superiority of any agent compared to another. The second systematic review included 255 studies. Included studies were deemed to be unamenable to pooling with substantial methodological and clinical diversity. Available evidence is insufficient to determine whether real-world effectiveness and safety is consistent with RCTs, but suggests no increased risk of malignancy and no difference in efficacy between adalimumab and infliximab.

Inflammatory bowel disease (IBD), which includes the subtypes Crohn's disease (CD) and ulcerative colitis (UC), is a common disease particularly in the Western world. IBD is characterised by inflammation of the small intestine and/or colon. The two subtypes affect different gut locations but both show an increased intestinal permeability or the 'leaky gut syndrome'. This led to the hypothesis that tight junction (TJ) proteins expressed in the epithelium may affect the intestinal permeability as a cause or effect of IBD.Initially, variants in the CARD15, IL23R and ATG16L1 genes, previously associated with an increased risk of IBD, were genotyped in a cohort of 500 IBD (295 CD and 205 UC) patients and 877 matched controls. These variants were significantly associated in our cohort. A random effects meta-analysis was undertaken on all previously reported CD associations with the variant rs2241880 from ATG16L1 (n=25, p=0.0017, OR: 1.36 95% CI 1.12-1.66) and with rs11209026 from IL23R (n=26, p=0.0006, OR: 0.37 95% CI 0.21-0.67), showing pooled odds ratios consistent with those reported in our cohort. Individuals carrying >1 CARD15 mutant variant were found to have a 2.5 fold increased risk of CD (p=0.0001). Candidate TJ proteins were chosen on the basis of previous reported associations and through the investigation of the claudin proteins which are abundant at TJs. Twenty one candidate genes were selected and 79 variants successfully genotyped in up to 1063 IBD (502 CD and 478 UC) and 870 control patients. Significant associations were detected with variants in the CLDN1, CLDN5 and CDH1 genes with CD; CLDN5, CLDN8 and CDH1 variants were associated to IBD; and the rs7791132 variant (between CLDN4 and ELN) and a CDH1 variant were associated to UC. The CLDN1 rs6809685 variant trended towards association in a Toronto ascertained IBD replication cohort (genotypic p=0.04, allelic p=0.06) suggesting this may be a novel IBD susceptibility variant. Small intestinal biopsies from CD patients with known rs6809685 genotypes showed a dose dependent reduced immunohistochemical staining of claudin 1 with carriage of the mutant G allele. Claudin 1 helps seal TJs and reduced levels may increase risk of CD.Peroxisome proliferator activator receptors (PPARs) can directly affect TJ proteins and could therefore affect intestinal permeability. Twelve PPARγ variants were genotyped in up to 1050 IBD (502 CD and 467 UC) and 725 control patients. Significant genotypic associations were found with the rs2067819 variant in CD (p=0.05) and IBD (p=0.02), and also the rs13099634 variant in UC (P=0.02). There was a strong gender difference particularly for rs2067819 and rs4135247, where allelic associations were highly significant and increased risk of IBD in men (p=0.01 and p=0.007 respectively). However no significant associations were found in the female cohort. Troglitazone a PPARα agonist increased Caco2 cell transepithelial electrical resistance (TEER), a marker of TJ integrity, and increased expression of claudins -3 and -4. In contrast, the PPARα antagonist GW6471 reduced the TEER without causing cell death and PPARγ ligands did not affect TEER measurements. In summary, using a robust cohort of cases and controls the data indicates that variants in genes encoding TJ proteins may affect susceptibility to IBD and that PPARs can regulate these proteins altering intestinal permeability.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-21T16:51:59Z No. of bitstreams: 1 carlavaleriadealvarengaantunes.pdf: 1487917 bytes, checksum: c0d630797135f7fb32b18c3ae9000d7c (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T18:46:52Z (GMT) No. of bitstreams: 1 carlavaleriadealvarengaantunes.pdf: 1487917 bytes, checksum: c0d630797135f7fb32b18c3ae9000d7c (MD5) / Made available in DSpace on 2016-01-25T18:46:52Z (GMT). No. of bitstreams: 1 carlavaleriadealvarengaantunes.pdf: 1487917 bytes, checksum: c0d630797135f7fb32b18c3ae9000d7c (MD5) Previous issue date: 2014-07-10 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / Anemia de difícil tratamento é uma manifestação clínica comumente observada nos pacientes portadores de doenças inflamatórias intestinais, sendo responsável por prejuízo significativo na qualidade de vida destes pacientes. O objetivo deste estudo foi avaliar, nos pacientes com doença inflamatória intestinal, a prevalência e os fatores de risco da anemia suas possíveis etiologias. Neste estudo de corte prospectivo observacional foram recrutados: 100 pacientes portadores de Doença de Crohn e 100 pacientes portadores de Retocolite ulcerativa, diagnosticados e acompanhados regularmente no Centro de Doenças Inflamatórias Intestinais do Hospital Universitário da Universidade Federal de Juiz de Fora, para avaliação hematológica, bioquímica e imunológica. Foram obtidas amostras de sangue (20 ml) e realizados os seguintes exames em todos os pacientes: hemograma completo, VGM, HGM, CHGM, plaquetas, ácido fólico, vitamina B12, reticulócitos, índice de saturação da transferrina, ferritina, ferro sérico, PCR e VHS. Foram adotados para o diagnóstico de anemia os mesmos critérios da WHO (World Health Organization). Foi considerado Anemia por Deficiência de Ferro quando houve diminuição dos níveis séricos de ferro (< 37 μg/dl para mulheres e < de 59 μg/dl para homens), da ferritina (<30μg/l- na ausência de dados clínicos, laboratoriais ou endoscópicos de inflamação intestinal e < 100 μg/l - na presença de quaisquer destes dados), do índice de saturação da transferrina (<16%). Foi considerado Anemia da Doença Crônica quando houve diminuição dos níveis séricos de ferro (< 37 μg/dl para mulheres e < de 59 μg/dl para homens), aumento da ferritina (>100μg/l) e diminuição do índice de saturação da transferrina (<16%). - na presença de dados clínicos, laboratoriais ou endoscópicos de inflamação intestinal e Anemia Mista quando houve diminuição dos níveis séricos de ferro (< 37 μg/dl para mulheres e < de 59 μg/dl para homens) e ferritina entre 30 e 100μg/l. As anemias foram classificadas em hiporregenerativas quando a contagem absoluta de reticulócitos estava abaixo de 50000 e normoproliferativas ou normorregenerativas quando a contagem absoluta de reticulócitos estava acima de 100000/mm³. / Anemia difficult to treat is a clinical manifestation commonly seen in patients with inflammatory bowel disease , being responsible for significant impairment in quality of life of these patients. The aim of this study was to evaluate, in patients with inflammatory bowel disease, the prevalence and factors risk of anemia and possible etiologies of anemia in their possible occurrence. In this cross-sectional study of adult patients with inflammatory bowel disease (IBD) were recruited, of which: 100 patients with Crohn's disease and 100 patients with ulcerative colitis, diagnosed and regularly followed at the Center for Inflammatory Bowel Diseases , University Hospital, Federal University of Juiz de Fora , for haematological, biochemical and immunological evaluation. Blood samples ( 20 ml ) were obtained and the following examinations were performed in all patients: CBC, MCV, MCH , CHCM , platelets , folic acid, vitamin B12 , reticulocytes , transferrin saturation index , ferritin , serum iron, CRP and ESR . For the diagnosis of anemia the same criteria of WHO (World Health Organization) were adopted . Was considered Iron Deficiency Anemia when there was a decrease in serum iron levels ( < 37 mg / dl for women and < 59 g / dl for men ) , ferritin (< 30μg/l - in the absence of clinical, laboratory data or endoscopic intestinal inflammation and <100 mg / l - in the presence of any of these data) , the ratio of transferrin saturation (<16 %). Anemia was considered the Crohnic Disease Anemia when there was a decrease in serum iron levels (< 37 mg / dl for women and < 59 g / dl for men), elevated ferritin ( > 100μg / l ) and decreased transferrin saturation index (<16 %). - in the presence of clinical, laboratory and endoscopic data of intestinal inflammation and Mix Anemia when there was a decrease in serum iron levels ( < 37 mg / dl for women and < 59 g / dl for men) and ferritin between 30 and 100μg / l . Anemia were classified into hiporregenerative when absolute reticulocyte count was below 50,000 and normoproliferative or normorregenerative when the absolute reticulocyte count was above 100,000.

Gut microbiota is considered an important factor in the development of various diseases including inflammatory bowel disease (IBD, n = 127), Ulcerative colitis, Crohn's disease, and colorectal cancer (CRC, n = 64). A part of this thtesis is to prepare clinical material of different sorts (stool, biopsy) for sequencing on Illumina Miseq platform. This is achieved trough DNA isolation, amplification of 16S and internal transcribed spacer (ITS), normalization and ligation of sequencing adaptors. The aim of this project is to describe the differences between microbiota in healthy and diseased subjects in case of IBD or unimpaired and tumorous tissue for CRC patients. This research is also being based on cultivation, where a fresh stool samples (n = 3) are cultivated in a broad range of conditions, which enables us to obtain ecophysiological and species diversity of these samples by traditional and molecular methods. The cultivable fungi are also assigned reliable taxonomy by amplification of relevant genes (ITS1, β tubulin, second largest subunit of RNA polymerase II, RPB2) followed by both-sided Sanger sequencing. Selected species of fungi are processed into lysates, which are used for stimulation of mice macrofage cell line (RAW). Therefore the impact on immunity response is studied in vitro and...

Background: Inflammatory Bowel Disease (IBD) is a chronic, relapsing, autoimmune disease, affecting one in every 150 Canadians. Failure to induce remission of IBD with pharmacotherapy can necessitate surgical interventions, such as the creation of an ostomy. Ostomy surgery can help manage severe IBD and thus improve quality of life; however, individuals living with IBD report the possibility of ostomy surgery as a top concern, which can lead them to refuse or delay this decision until the disease becomes life threatening. Research Objective: The aim of this study is to understand what factors influence the decision to have ostomy surgery in young women with IBD, how the perception of the surgery compares to the reality of living with an ostomy, and the role healthcare professionals play in this decision. Methods: Nine participants who (1) identify as female, (2) are between the ages of 19 and 30, and (3) are currently living with an ostomy to treat IBD were recruited for this study. Additionally, seven healthcare professionals who work with IBD patients were recruited. Participants were invited for an individual, semi-structured interview. Findings: Young adult women living with an ostomy to treat their IBD reflected on their initial fears and concerns about undergoing surgery. Due to the severity of their illness, the majority of participants had requested surgery after having some time to adjust to the idea. This request, however, was often met with resistance or obstacles in the healthcare system. Healthcare professionals share mixed perceptions of ostomy surgery, with some viewing it as a last resort and others perceiving it as a treatment option. Once surgery had been performed, young adult women describe some challenges adjusting to life with an ostomy; but the majority report experiencing an overall improvement in quality of life. Conclusion: Understanding the perceptions that influence how young women perceive ostomies prior to versus after surgery will help identify the factors that influence the decision-making process for ostomy surgery, such as gender, age and stigma. Challenging current beliefs and assumptions may allow more supportive conversations between healthcare professionals and patients and provide insight on the actual lived experience of young women living with an ostomy. / Graduate / 2023-01-13

This thesis focuses on the importance of intermediate products of biosynthetic and catabolic pathway of cholesterol. The aim of the first part of the thesis is mainly to investigate, whether statins (HMG- CoA reductase inhibitors) possess antitumor properties and to compare the differences in antitumor potential of individual statins. The other part of the thesis aims at the utilization of 7α-hydroxycholest-4-en-3-one (C4), a promising marker of cholesterol 7α-monooxygenase (CYP7A1) activity and bile acid malabsorption. We demonstrated antitumor effect of statins on an experimental model of pancreatic cancer. Individual statins, however, differed significantly in their efficacy, depending on their physico-chemical properties. Our data suggests, that the most likely (but not the only) mechanism of antitumor effect of statins is decreased prenylation of signaling proteins, especially Ras protooncogene. We set up a reliable method for measurement of C4, which facilitated our research in CYP7A1 regulation. We demonstrated, that promoter polymorphism -203A>C might affect CYP7A1 activity, that diurnal variability of CYP7A1 activity might be triggered by insulin, and that insulin resistance in patients with non-alcoholic fatty liver disease impedes the feedback regulation of CYP7A1, which may lead to disease...

The intestinal microbiota is composed of up to 100 trillion microorganisms of which bacteria are overwhelming majority. The microbiota affects the development of the immune system, defence against pathogens, host nutrition, vitamin synthesis or fat storage and its composition is changing throughout life. Some studies point to an association between microbiota composition and the development of inflammatory bowel disease. One of the treatment options is anti-TNFα antibodies therapy, which uptake or antagonize the TNFα cytokine that otherwise mediates inflammation in the intestinal mucosa. The aim of the thesis was to examine how this treatment affects the composition of the intestinal bacteriome in paediatric patients with Crohn's disease, and to find specific bacterial taxa, whose abundance changes during the treatment. By inclusion of patients with juvenile idiopathic arthritis, also treated with anti-TNFα, the study aims to discern specific effects of therapeutically induced intestinal restitution (observable in patients with Crohn's disease) from general effects of anti-TNFα therapy. Stool samples from healthy children were used to determine "healthy" bacteriome. The composition of the bacteriome was studied by profiling the variable region of the V4 gene of 16S rDNA from patients stool samples...