Submitted by Renata Lopes (renatasil82@gmail.com) on 2018-06-26T10:52:38Z No. of bitstreams: 0 / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-06-27T15:27:12Z (GMT) No. of bitstreams: 0 / Made available in DSpace on 2018-06-27T15:27:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-05-25 / Introdução: A doença inflamatória intestinal (DII) é um grupo de doenças caracterizado por inflamação de natureza crônica e etiologia multifatorial, constituído principalmente pela doença de Crohn e pela retocolite ulcerativa. Tais doenças comprometem preferencialmente indivíduos jovens em fase produtiva, tem curso flutuante com fases de remissão e atividade, e frequentemente apresentam comportamento clínico agressivo, com impacto na qualidade de vida. O Clostridium difficile é um bastonete gram positivo, produtor de esporos, ubíquo na natureza e representa causa importante de diarreia associada ao uso de antimicrobianos, através da produção das toxinas A e B. A literatura tem relatado maior ocorrência da infecção por C. difficile (ICD) em pacientes com DII, o que aumenta o risco de recorrência da DII e pior evolução. Objetivo: Avaliar a prevalência, os aspectos epidemiológicos, os fatores associados e a evolução clínica da infecção por C. difficile em pacientes ambulatoriais com DII. Métodos: Neste estudo prospectivo longitudinal, realizado entre outubro de 2013 a julho de 2016, com 120 pacientes com DII (55% apresentando colite) e 40 controles não-DII foram avaliados para ICD, através de análise de amostras fecais para pesquisa de toxinas do C. difficile, através do teste de ELISA. Foi avaliado fatores de riscos associados a ICD. A regressão multivariada foi realizada para identificar preditores de ICD. Resultados: A proporção de pacientes com ICD foi significativamente maior em pacientes com DII em atividade que DII em remissão (28,8% vs. 5,6% vs. 0%, respectivamente, p = 0,001). Feminino (OR = 1,39, IC 95%, 1,13-17,18), idade mais jovem (OR = 0,77, IC 95%, 0,65-0,92), tratamento com esteróides (OR = 7,42, IC 95%, 5,17-40,20) e terapia com infliximabe (OR = 2,97, IC 95%, 1,99-24,63) foram independentemente associados com ICD. Houve aumento nas probabilidades de ter ICD em pacientes com prednisona. Conclusões: A ICD é uma condição altamente concorrente em pacientes com DII apresentando exacerbação de colite a nível ambulatorial. O sexo feminino, a idade mais jovem, a terapia com infliximabe e o uso de esteróides foram associados de forma independente à co-ocorrência de ICD. A maioria dos pacientes com ICD apresentaram doença leve a moderada e o tratamento com vancomicina foi muito efetivo, parecendo reduzir o risco de complicações graves relacionadas à ICD. / Introduction: Inflammatory bowel disease (IBD) comprises a group of diseases of multifactorial etiology, characterized by chronic and progressive inflammation of the gastrointestinal tract, consisting mainly of Crohn's disease and ulcerative colitis. Clostridium difficile is a gram-positive, spore-producing rod that is ubiquitous in nature and is an important cause of diarrhea associated with the use of antimicrobials and in immunocompromised patients. The literature has reported a higher occurrence of Clostridium difficile infection (CDI) in patients with IBD, leading to significant morbidity and mortality. Objective: To evaluate the prevalence, epidemiological aspects and clinical evolution of CDI in outpatients with recurrent IBD. Methods: In this prospective longitudinal study, conducted between October 2013 and July 2016, 120 patients with IBD (55% with colitis flare) and 40 non-IBD controls were evaluated for CDI by searching for toxins A and B in feces fresh by ELISA. All patients with CDI were treated with oral vancomycin and followed up for an additional six months. Multivariate regression was performed to identify predictors of CDI. Results: The proportion of patients with CDI was significantly higher in patients with active IBD than in those with IBD in remission or in non-IBD controls (28.8% vs. 5.6% vs. 0%, respectively, p = 0.001). Females (OR = 1.39, 95% CI, 1.13-17.18), younger age (OR = 0.77, 95% CI, 0.65-0.92), steroid treatment (OR = 7.42, 95% CI, 5.17-40.20) and infliximab therapy (OR = 2.97, 95% CI, 1.99-24.63) were independently associated with CDI. There was a dose-related increase in odds of having CDI in patients using prednisone. All patients treated with vancomycin responded to therapy, but 21% had recurrent CDI and 16% were hospitalized. Neither colectomy nor mortality was noticed.Conclusions: CDI is a highly concurrent condition in outpatients IBD with colitis flare. Females, younger age, infliximab therapy, and steroid use were independently associated with the cooccurrence of IBD. Most patients with CDI had mild to moderate disease and vancomycin treatment was very effective, seeming to reduce the risk of serious complications related to CDI.

Orientadores: Alba Regina Monteiro Souza Brito, Anderson Luiz Ferreira / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T14:15:42Z (GMT). No. of bitstreams: 1 Manzo_LuisPauloBognoni_M.pdf: 4711838 bytes, checksum: 0267d7f30b132c874529cd6a03786252 (MD5) Previous issue date: 2012 / Resumo: A retocolite Ulcerativa Inespecífica e a Doença de Chron são as principais doenças inflamatórias intestinais. Apesar dos crescentes esforços, não se sabe ainda suas causas. Os tratamentos ainda não são eficazes, as drogas atuais são eficazes na indução da remissão mas não determinam sua cura. Os efeitos colaterais são severos, o que acarreta em baixa adesão ao tratamento. Os produtos naturais tem sido fonte de compostos usados por todo o mundo em diferentes áreas da medicina e ciência. O tratamento oral com geléia real na dose de 100 mg/Kg mostrou-se capaz de aumentar os níveis de grupamentos sulfídrica (GSH) e também a atividade da enzima glutationa peroxidase (GSH-Px) em camundongos com colite induzida por TNBS. A expressão de COX-2 e NF-kB também foram diminuídos, tais resultados demonstram efeitos antioxidantes e antiinflamatórios da geléia real nesta dose neste modelo de colite experimental. O Tratamento intrarretal com a proteína MRJP3 (50 ?g/animal) foi capaz de diminuir os níveis de IL-1? no cólon dos camundongos Balb/c submetidos a colite induzida por DSS. Uma vez que os níveis de IL-6 e IL-10 não foram alterados pelo tratamento intrarretal com MRJP3 50 ?g/animal, podemos afirmar que a proteína não atua pela via da IL-10. Estes efeitos antioxidantes e anti-inflamatórios observados durante o desenvolvimento da colite induzida por TNBS e por DSS em camundongos, podem ser de significativa importância pois abrem portas e encorajam novas pesquisas com a geléia real e sua respectiva proteína MRJP3, motivando novos estudos acerca de outos agentes antioxidantes e outros mediadores anti-inflamatórios envolvidos nestes modelos de colite experimental / Abstract: Ulcerative Colitis and Chron's Disease are the two major forms of IBD. Despite all efforts, these complications of the GTI are still lacking an effective therapy for their cure. Side effects, high cost and low adhesion to treatment are among the negative aspects. Natural products have been a source of widely used compounds in distinct areas of medicine and research. Royal Jelly (RJ) 100 mg/Kg was capable of augmenting the levels of glutathione (GSH) and the activity of glutathione peroxidase (GSH-Px) in mice undergoing TNBS-induced colitis. Furthermore, COX-2 and NF-kB had their expression decreased by the oral administration of RJ 100 mg/Kg. Intra-rectal MRJP3 treatment (50 ?g/animal) was capable of decreasing the levels of IL-1? in mice undergoing DSS-induced colitis, whereas the levels of IL-10 and IL-6 were not altered by MRJP3 50 ?g instillation, what indicates that this decrease is not IL-10-induced. The antioxidant and anti-inflammatory effects observed during the development of DSS and TNBS-induced colitis in mice, may be of crucial importance, since they open and encourage new studies focused on this nourishing substance, especially in experimental models of colitis / Mestrado / Farmacologia / Mestre em Farmacologia

Orientadores: Claudio Saddy Rodrigues Coy, Raquel Franco Leal / Tese (Doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T16:55:09Z (GMT). No. of bitstreams: 1 Maldaun_Daisy_D.pdf: 1445844 bytes, checksum: ff748e47d7a55e600aa2c0b5596a7b15 (MD5) Previous issue date: 2012 / Resumo: Denominam-se doenças inflamatórias intestinais (DII) afecções crônicas consideradas auto-imunes, que acometem principalmente o aparelho digestório sendo que duas são mais representativas: retocolite ulcerativa inespecífica (RCUI) e doença de Crohn (DC). Apresentam incidência progressiva, não apenas em nosso meio mas também em âmbito mundial. A importância das DII na gastroenterologia e na saúde publica, em particular se deve a: serem afecções crônicas, que atingem principalmente os jovens; terem crescente incidência com impacto na qualidade de vida e consequentemente nas relações sociais; abordagem complexa; e resposta terapêutica variável. A forma como os pacientes vivenciam a doença está associada a fatores de organização e interação familiar. Na investigação clínica, pacientes acometidos por DII podem vivenciar de forma singular, o seu processo de adoecer em função da estrutura e da dinâmica da família a qual pertencem. Assim, a investigação dos fatores emocionais e da influência da dinâmica familiar na evolução das DII e a constatação da existência de poucas pesquisas realizadas sobre esse tema, nos levaram à realização desse estudo. Objetivo: compreender a influência da dinâmica familiar do paciente com DII, seja ela afetiva ou conflitante na percepção da enfermidade, sob a visão do paciente e de seus genitores. Método;: como escolha foi utilizado o Método Clinico Qualitativo. Foram avaliadas as seguintes categorias: :a) conhecimento da DII; b) o sentido que a DII representa; c) o inter-relacionamento familiar e as modificações advindas da doença; d) a forma como convivem com a sintomatologia da doença; e) o momento da hospitalização. Quinze pacientes com idade entre 18 e 39 anos e seus respectivos genitores, provenientes do Ambulatório de Doença Inflamatória Intestinal "Prof. Dr. Juvenal Ricardo Navarro Góes" do Centro de Diagnóstico de Doenças do Aparelho Digestivo (GASTROCENTRO) da FCM-UNICAMP) sem distinção de raça, naturalidade, condição social, escolaridade, nível sócio-econômico e crença. A coleta de dados envolveu a aplicação, para os pacientes e respectivos genitores, de: Entrevista Inicial e Roteiro de entrevista semi-estruturada, (elaborada pelos pesquisadores desse estudo), para obtenção de informações clinicas e de estrutura familiar. Resultados: a família, como uma unidade dinâmica, é o mais importante suporte social e pode ser considerada como uma importante fonte de estress, que exerce uma significativa influência sobre a saúde e doença de seus membros Os achados, nas categorias selecionadas, mostraram que os pacientes com DII e seus respectivos genitores vivenciam a enfermidade, tanto na exacerbação quanto na remissão de sua sintomatologia, de forma única e singular, com conseqüências psicológicas, sociais e profissionais, de acordo com o convívio e a influência da dinâmica familiar a qual pertencem. Conclusão: A influência da dinâmica familiar, seja afetiva ou conflitante, é relevante em relação à convivência com os sintomas da doença e suas conseqüências, em virtude da dificuldade de ambos, pacientes e genitores, em administrar as características de suas personalidades / Abstract: Inflammatory Bowel Diseases (IBD) are chronic conditions, considered autoimmune, which affects specially the digestive system with two of them being more representative: ulcerative colitis (UC) and Crohn disease (CD). These are diseases with progressive incidence, not only in our local environment but also worldwide. The IBD importance in gastroenterology and public health care, is due to: being chronic conditions that affects mainly young people; they have growing incidence with impact on quality of life and consequently on social relations; complex approach and therapeutic response variable. The way patients experience the disease is associated to organizational factors and family interaction. In clinic investigation, patients affected by IBD experience, in a unique way, the process of becoming ill in function of the family structure and dynamics that they belong. Thus, the investigation of emotional factors, family dynamics influence in the IBD evolution and confirmation of a few available research made over this topic, have leaded us to accomplish this study. Objective; to understand the influence of family dynamics with IBD patients, either arising from affective or conflicting with the perception of the illness from the patient's and his/her parent's perspective/point of view. Method; Qualitative Clinic method was employed and the following categories were evaluated: (a) IBD knowledge, (b) the meaning of what IBD stands for, (c) family interrelationship and modifications originating from the illness (d) how they live with the disease's symptomatology and (e) hospitalization.: Fifteen patients, age varying between 18 and 39 and their respective parents, from the IBD outpatients unit "Prof. Dr. Juvenal Ricardo Navarro Góes" (GASTROCENTRO) of FCM-UNICAMP) without distinction of race, origin, education or social-economic level, education, were evaluated. The data were collected by the application of semi-structural interview (elaborated by the researches of this study) with the patients and their respective parents in order to obtain clinical and family structure information. Results; The family, as a dynamic unit, is the most important core of social support and can be considered as an important source of stress, exercising significant influence on the health and illness of its members. The findings of the selected categories have shown that patients with IBD and their respective genitors experienced the illness, both in grave condition or remission, in a unique manner with psychological, social and professional consequences, according to the relationship and family dynamics. Conclusion;: The influence of family dynamics, whether emotional or conflicting, it is relevant in relation to living with the symptoms of the disease and its consequences, due to the difficulty of both, patients and parents, to manage the characteristics of their personalities / Doutorado / Fisiopatologia Cirúrgica / Doutora em Ciências

Orientador: Alba Regina Monteiro Souza Brito / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T00:33:18Z (GMT). No. of bitstreams: 1 Faria_FelipeMeirade_D.pdf: 5634635 bytes, checksum: 78374f3fbaac985834cc384c5652485c (MD5) Previous issue date: 2013 / Resumo: As doenças inflamatórias intestinais (DII) compreendem doença de Crohn e reto-colite ulcerativa inespecífica, ambas caracterizadas por processo inflamatório crônico e descontrolado no intestino mediado por células do sistema imune. DII tem sido objeto de extensas pesquisas nos últimos anos; indefinição sobre etiologia e ausência de tratamento eficaz os justificam. Nesse cenário, produtos naturais surgem como alternativas terapêuticas, uma vez que moléculas com atividade farmacológica pronunciada, especialmente compostos fenólicos, têm merecido destaque. Neste trabalho foram avaliadas três frações orgânicas (aquosa - Aq, butanólica - BuOH, e acetato de EtOAc) obtidas a partir das cascas de Rhizophora mangle em modelos experimentais de colite induzida por dextrana sal sódico (DSS) em camundongos e ácido 2,4,6-tri-nitro-benzeno-sulfônico (TNBS) em ratos. BuOH (0.5 e 1.5 mg.Kg-1) e EtOAc (1.5 mg.Kg-1) foram efetivas no modelo de colite por DSS, enquanto BuOH 0.5 mg.K-1 e EtOAc 1.5 mg.Kg-1 mostraram-se eficazes na colite aguda por TNBS. No modelo sub-crônico de colite os tratamentos BuOH e EtOAc reduziram novamente os danos causados pelo TNBS, embora BuOH tenha se mostrado mais eficiente. A avaliação de mediadores envolvidos nesses modelos experimentais mostrou que tanto BuOH quanto EtOAc exercem ação sobre a atividade da glutationa peroxidase (GSH-Px) e mieloperoxidase (MPO) bem como sobre os níveis das citocinas pró-inflamatórias fator de necrose tumoral-? (TNF-?), interferon-? (IFN-?), interleucinas 1?, 6 e 12 (IL-1?, IL-6 e IL-12), além de reduzirem a expressão de ciclo-oxigenase-2 (COX-2) no modelo de DSS. No modelo sub-crônico de colite induzida por TNBS, às duas frações atuaram sobre a atividade da GSH-Px e catalase (CAT) e sobre os níveis de glutationa (GSH), TNF-? e IL-12; EtOH também reduziu os níveis de IL-6 e levou ao aumento de citocina anti-inflamatória interleucina-10 (IL-10), BuOH por sua vez mostrou-se eficaz em reduzir o índice de peroxidação lipídica (TBARS) e atividade da MPO, atuando também sobre a expressão de ciclo-oxigenase-1 (COX-1). A análise fitoquímica revelou presença de procianidinas oligoméricas nas duas frações ativas, BuOH e EtOAc, sugerindo que estas substâncias sejam responsáveis pelos efeitos produzidos pelos tratamentos experimentais. As frações BuOH e EtOAc apresentaram efeitos importantes sobre os componentes imune, inflamatório e oxidante em modelos experimentais de colite induzida por TNBS e DSS em doses consideradas baixas para uma mistura de substâncias. As procianidinas de R. mangle surgem então como alternativa terapêutica interessante sobre as DII / Abstract: Inflammatory bowel diseases (IBD) comprises Crohn's disease and ulcerative colitis, both are characterized by an immune-mediated chronic inflammatory process in the gut. IBD have been studied over the past few years; undefined etiology and the absence of effective treatments justify these studies. In this scenario, natural products arises as therapeutic alternative, once various studies in animal models have shown efficient treatments. Nowadays, molecules with pronounced pharmacological activities, especially phenolic compounds, have been highlighted. In this work three organic fractions (aqueous - Aq, butanolic - BuOH and ethyl acetate - EtOAc) obtained from Rhizophora mangle barks were evaluated in experimental models of dextran sodium sulphate (DSS)-induced colitis in mice and 2,4,6-tri-nitro-benzene sulphonic acid (TNBS)-induced colitis in rats. BuOH (0.5 and 1.5 mg.Kg-1) and EtOAc (1.5 mg.Kg-1) were effective in the DSS-induced model, while BuOH (0.5 mg.Kg-1) and EtOAc (1.5 mg.Kg-1) were also effective in acute TNBS-induced model of colitis, which lead to the evaluation of these last ones in sub-chronic TNBS-induced models of colitis. In this model, both treatments reduced the injury provoked by the instillation of TNBS, although BuOH has shown more efficiency. The evaluation of the mediators involved in these experimental models showed that either BuOH as EtOAc act on the glutathione peroxidase (GSH-Px) and myeloperoxidase activities as well as on pro-inflammatory cytokines tumor necrosis factor- (TNF-?), interferon- (IFN-?) and interleukins -1?, 6 and 12 (IL-1, IL-6 and IL-12) levels, and down-regulation of ciclo-oxygenase-2 (COX-2) expression in the DSS-induced model of colitis. Whereas in the sub-chronic TNBS-induced model of colitis, both fractions showed effects on the GSH-Px and catalase (CAT) activities, and glutathione (GSH), TNF-? and IL-12 levels; EtOAc also reduced IL-6 levels and lead to the enhancement of the levels of an anti-inflammatory cytokine, interlukin-10 (IL-10), on the other hand BuOH showed to be efficient in reducing lipid peroxidation index (TBARS) and MPO activity, acting on the upregulation of cyclo-oxygenase-1 (COX-1). Phytochemistry analysis reveals the presence of oligomeric procyanidins in both fractions, BuOH and EtOAc, suggesting that these substances are responsible for the effects produced by the experimental treatments. BuOH and EtOAc fractions presented important effects on the immune, inflammatory and oxidant components in the experimental models of TNBS and DSS-induced colitis using doses, considered, lower for a mixture of substances. The procyanidins of R. mangle became an interesting alternative therapeutic for IBD / Doutorado / Farmacologia / Doutor em Farmacologia

No description available.

Irritable bowel syndrome (IBS), även kallat colon irritabile, tjocktarmsbesvär, känsligtarm, funktionella tarmbesvär och irritabel tarm, är ett samlingsnamn för åkommorsom drabbar mag-tarmkanalen, främst tjocktarmen. Mekanismen bakom IBS ärkomplex och det finns i dagens läge ingen botande medicinsk behandling. Vidbehandling av IBS fokuseras på att lindra symtomen. Ett av de mest framträdandesymtomen är buksmärta som med största sannolikhet härstammar från visceralöverkänslighet i kombination med en förändring av motiliteten i tarmarna. Syftet med denna litteraturstudie var att studera linaklotid och eluxadolins effekt vidsmärta orsakad av IBS jämfört med placebo. Linaklotid och eluxadolin är två av denyare läkemedelsalternativen på marknaden och viktiga tillskott sombehandlingsalternativ vid IBS på grund av fåtaligheten av tillfredställandemedicineringar vid abdominal smärta. De frågeställningar som behandlas i denna litteraturstudie är:- Vilken effekt på buksmärtan visar linaklotid och eluxadolin jämfört med placebo ikliniska studier?- Vilka biverkningar kan linaklotid och eluxadolin medföra? Litteraturstudien har baserats på artikelsökningar i den medicinska databasenPubMed. De sökord som använts är “linaclotide irritable bowel syndrome” och“eluxadoline irritable bowel syndrome”. Totalt presenteras tre kliniska prövningar, en fas II samt två fas III prövningar förlinaklotid respektive eluxadolin i denna litteraturstudie. Bäst effekt och samtidigt säkradoseringar uppnåddes vid linaklotid 290 μg dagligen och eluxadolin 100 mg 2 ggrdagligen. Linaklotid (290 μg/dag) visade sig under den senaste och mest omfattandefas III studien lindra buksmärta hos 36.9% jämfört med placebo 17.4%. Patienternamedräknade i denna procentsats upplevde en förbättring av smärtan med minst 30%jämfört från basperioden under minst 20 av de 26 veckorna som effekten undersöktes.Eluxadolin (100 mg 2 ggr/dag) visade i en sammanställning av de båda fas IIIprövningarna ge en lindring av buksmärta hos ca 31% av patienterna jämfört medplacebo 19.6%. Det var endast de patienter som rapporterade en minskning med minst30% av den abdominala smärtintensiteten under minst 50% av studiens längd somräknades med i denna jämförelse. Sammanfattningsvis visar resultaten i de senast utförda fas III studierna av bådelinaklotid och eluxadolin en signifikant skillnad i lindring av buksmärta i jämförelsemed placebo. Överlag svarade dock relativt få patienter på behandlingarna. Det återstår fortfarande mycket forskning inom ämnet IBS för att fullständigt kunnaklargöra för vad som förändras i kroppen då personen insjuknar i IBS och varför. Pågrund av att preparaten är nya på marknaden saknas även mer långvariga studier vilketvore önskvärt eftersom långtidsbehandling är väldigt vanligt vid IBS. Idag finns mångasmärtlindrande läkemedel med bevisad effekt för buksmärta, både äldre och nyareversioner som exempelvis linaklotid och eluxadolin. I studier söks efter så effektivaalternativ som möjligt men som även tolereras väl, ger få biverkningar då en långbehandlingstid är vanligt samt med målet att preparaten inte ska försämra den redanförekommande abdominala problematiken.

The detailed visualization of the small bowel at the radiographic series is restricted by factors as loops overlap and content absence that doesn't allow the contrast with the other structures, disabling many times, an accurate radiographic diagnosis. Despite the usefulness of the conventional contrast series in several diagnoses, significant alterations are needed to instigate modification in the positive contrast medium coat to make it evident. The objective of this study was to adjust an exam technique with intestinal double-contrast, based on techniques used in the human medicine, which resulted satisfactorily in the demonstration of the mucosal surface in the 30 dogs submitted to the exam. The double-contrast in the lumen was achieved by a combination of a positive contrast medium, recovering the mucosal surface, and a negative filling the lumen. Ambiental air and carboximethylcelullose were the negative contrast medium tested and both were radiographicly similar / A visualização detalhada do intestino delgado no exame radiográfico é limitada por fatores como a sobreposição das alças e a ausência de conteúdo, o que não permite o devido contraste com as demais estruturas, impossibilitando muitas vezes, um diagnóstico radiológico preciso. Apesar da utilidade da técnica convencional de exame contrastado em diversos diagnósticos, este necessita de alterações significativas para promover modificação no preenchimento feito pelo meio de contraste radiopaco e evidenciá-las radiograficamente. O objetivo deste trabalho foi adaptar uma técnica de exame com duplo-contraste intestinal, baseada em técnicas radiográficas usadas na medicina humana, a qual resultou satisfatoriamente na demonstração da superfície mucosa nos 30 cães submetidos ao exame. O duplo-contraste no interior das alças intestinais foi obtido pela combinação de um meio de contraste positivo, recobrindo a superfície mucosa, e um meio de contraste negativo, preenchendo o lúmen. Dois meios de contraste negativos foram testados: o ar ambiente e a carboximetilcelulose, os quais, radiologicamente, mostraram-se semelhantes

Les maladies inflammatoires chroniques de l’intestin font partie des pathologies immunitaires. Leur pathogenèse est directement liée à une réponse immune exagérée dirigée contre des bactéries commensales normalement présentes dans l’intestin, chez des individus génétiquement prédisposés. Parmi les facteurs favorisants, on trouve l’amélioration du niveau d’hygiène ainsi qu’une diminution des infections parasitaires. Des études épidémiologiques ont suggéré une relation entre la prévalence des infections par les helminthes et l’incidence des maladies inflammatoires chroniques de l’intestin dans les pays en développement. Ces infections parasitaires induisant une réponse immune de type Th2, il est donc proposé qu’elles participent la régulation des maladies inflammatoires médiées par une réponse immune de type Th1, comme la maladie de Crohn.Notre équipe s’est intéressée à l’effet immuno-modulateur d’une protéine du Schistosome, la P28GST (Glutathion S-transferase) dont les propriétés immunogénétiques pro-Th2 ont été démontrées précédemment dans des modèles expérimentaux et chez l’homme. Au cours de notre travail, nous avons montré que l’immunisation avec la P28GST était capable de diminuer de manière façon significative la colite expérimentale dans deux modèles animaux. L’immunisation avec cette enzyme parasitaire, produite sous forme recombinante, a réduit les scores cliniques et histologiques obtenus après induction de colite expérimentale par injection de l’haptène TNBS chez des rats Sprague Dawley rats ainsi que chez des souris C57Bl/6. Cet effet est associé à une diminution des marqueurs de l’inflammation (Myéloperoxidase) et de lexpression de l’ARN messager codant pour des cytokines pro-inflammatoires (IL-1β, IL-17 et TNF) dans le colon des animaux. Nous détectons une modulation de la réponse immune caractérisée par une diminution du profil Th1 mesuré par la présence d’ARN messager codant pour l’IFNγ vers un profil de type Th2, associé à une augmentation de l’ARN messager codant pour l’IL-4, l’IL-5 et l’IL-13. L’augmentation du rapport ARN messager Arg1/iNOS2 ainsi que la détection de cellules Arginase positives par immuno-histo chimie dans le colon des animaux immunisés suggèrent la présence de macrophages alternatifs (AAM), dont on connait le rôle anti-inflammatoire et l’association à une réponse de type Th2. Des résultats similaires ont été obtenus dans un autre modèle expérimental, chez la souris.Nous avons comparé l’effet de cette protéine du Schistosome avec l’effet de l’infection par des larves du parasite grâce à deux modèles d’infection : soit une infection au long cours (associé avec une réponse immune de type Th2), soit une infection récente (avec une réponse immune de type Th1). Nos résultats montrent que l’immunisation par une seule protéine de schistosome, la P28GST, réduit l’inflammation intestinale aussi bien que l’infection au long cours, tandis que les animaux récemment infectés n’étaient pas protégés de la colite. En conclusion, notre étude présente les premières évidences que l’immunisation avec une protéine recombinante de Schistosome pourrait réduire de manière préventive la colite expérimentale induite par l’injection d’une haptène dans deux modèles de rongeurs. Si les mécanismes d’action précis doivent encore être élucidés, nos travaux suggèrent que l’effet anti-inflammatoire de la P28 GST puisse avoir des applications dans la prévention de l’inflammation intestinale permettant d’envisager une utilisation chez l’homme, notamment dans la prévention des rechutes de la maladie de Crohn. / Inflammatory bowel diseases are considered part of immune-mediated inflammatory disorders. Their pathogenesis was linked to an inappropriate exaggerated immune response to commensal bacteria normally present in the bowel, in genetically predisposed individuals. Increase of the level of hygiene and decrease exposure to helminthic infections was suggested as predisposing factors to IBD. Epidemiologic data have given a clue on the relation of prevalence of helminthic infections and the incidence of inflammatory bowel diseases in developing countries. The Th2 polarized T cell response driven by helminthic infection has been linked to the attenuation of Th1 driven inflammatory responses, preventing some Th1 mediated autoimmune diseases in their host, including Crohn’s disease.Our work focused on the immuno-modulatory effect of a Schistosome protein – P28GST (a Glutathion S-transferase). Its immuno-genetique, pro-Th2, characters have been previously demonstrated in experimental models as well as clinical trials. We showed that immunization with P28GST was able to significantly reduce experimentally induced colitis in two animal models.Immunisation with this recombinant parasitic enzyme reduced clinical and histological scores of the TNBS induced colitis in both Sprague Dawley rats as well as in C57Bl/6 mice. This effect was associated with a decrease in the expression of inflammatory markers (Myeloperoxidase) as well as mRNA expression of pro-inflammatory cytokines (IL-1β, IL-17 and TNF) in the colon of sacrificed animals. We detected a shift of the immune response characterized with decrease of Th1 immune response assessed by the mRNA expression of IFNγ towards a less pathological Th2 immune response assessed by the mRNA expression of IL-4, IL-5 and IL-13. An increase in the ratio of mRNA expression of Arg1/iNOS2, as well as the immuno-histochemical detection of Arginase positive cells in the colon of the sacrificed animals suggested the presence of alternatively activated macrophages (AAMs) characterized by their anti-inflammatory effect and their association with the Th2 immune response. Similar results have been obtained in another animal model, the C57Bl/6 mice.We have also compared the effect of a single recombinant Schistosome protein to two models of infection with living schistosome parasites, either with long standing infection (associated with a Th2-type response) or with a recent onset exposure (a Th1-type response). Our results showed that immunisation with a single Schistosome protein, the P28GST; give similar results to established infection in term of reduction of intestinal inflammation, whereas recently infected rats were not protected against colitis.In conclusion, this study provides the first evidence that immunization with a recombinant protein from the Schistosome helminth parasite prevents hapten-induced colitis in two models of rodents. Although further studies are needed to illustrate the exact mechanisms of action implicated in the immuno-modulatory effect, P28GST is a promising molecule exerting a potent anti-inflammatory role in the prevention of colitis. The potential effect of this helminthic enzyme is actually taken in consideration in the prevention of Crohn’s disease relapses in humans.

The last half-century has seen a dramatic and alarming rise in the incidence of autoimmune disease in industrialized nations too rapid to be accounted for by genetics alone. Among those, Inflammatory Bowel Disease (IBD) has risen from a western disease affecting industrialized populations to an emerging global threat affecting diverse populations around the world. IBD is a complex disease that combines genetic susceptibility and environmental exposure, but one aspect appears to be clear: the involvement of the gut microbiome. Current thought holds that IBD is an autoimmune attack on commensal microbiota, causing extensive collateral damage to the host intestinal tissues in the process. However, it has remained unclear in the field whether the changes observed in the IBD microbiome are causative in nature or whether the microbiome is responding to already-underway inflammatory processes within the host. This dissertation investigates one host factor in particular with regard to the microbiome and the development of inflammation: sodium-hydrogen exchange at the brush border, mediated by sodium hydrogen exchanger 3 (NHE3). NHE3 is inhibited during active IBD, but its loss in knockout animals is also enough to promote spontaneous colitis in a microbiome-dependent fashion. This dissertation investigates the specific contribution of the microbiome in NHE3 knockout animals to determine whether loss of NHE3 may be mediating the onset of colitis through pro-inflammatory changes in the microbiome. Our results suggest that the microbiome fostered in an NHE3-deficient environment may accelerate the onset and severity of experimental colitis, though likely in concert with additional host factors.

M.Tech. / Irritable bowel syndrome (IBS) is a multifactoral disorder of the gastrointestinal tract causing disturbances in gastric motility, resulting in abdominal pain, bloating and abnormal bowel movements. It is defined as a 'disorder of gut function in the absence of structural pathology' (Palmer et a!, 2002). It is the most commonly encountered functional gastrointestinal disorder in the primary and secondary health care system with a prevalence in the general population of five to twenty percent (Bellini et a!, 2005). No definite aetiological factor has been isolated, but factors such as psychological stress, anxiety and depression, certain dietary intolerances, increase in abnormal sensitivity to visceral distension, and hormonal changes in women have been implicated in compounding the symptoms of IBS (Ohman & Simren, 2007). Current treatment regimes include dietary changes and symptomatic relief using allopathic medications, which come with the risk of side-effects and may lead to dependency (University of Maryland Medical Center, 2007). Homoeopathic studies which have addressed the physical symptoms as well as the psychological contributing factors associated with IBS, have recorded favourable results when treating this syndrome (Mathie & Robinson, 2006).The aim of this research was to determine the efficacy of Homoeopathic Similimum treatment in IBS. In order to recruit volunteers, this study was advertised in local newspapers, pharmacies and at the University of Johannesburg's Doornfontein Campus. Volunteers completed the Rome III Criteria evaluation to determine their suitability for this study, with the likelihood of any other bowel pathology having been excluded. Ten suitable female volunteers, ranging in age from twenty to thirty five, were selected having met the inclusion criteria. Over a period of three months, each participant partook in four homoeopathic consultations. The initial consultation involved the completion of the information and consent form, an explanation of the research procedures, general well-being and general symptom rating questionnaires were completed, a full homoeopathic case history was taken, and a physical examination was performed. A baseline of four weeks without treatment followed. Participants were requested to complete daily symptom rating scales and keep a daily food diary in the four weeks between consultations. This was continued throughout the study period. The subsequent follow-ups, of which there were three, consisted of a follow-up on the initial consultation, completion of general well-being and symptom rating questionnaire, and a physical examination. A homoeopathic similimum remedy was chosen based on each participant's unique symptoms. Using physical, mental, and emotional symptoms in accordance with classical homoeopathic principles, a single remedy that most suited the individual was chosen and prescribed. It was predicted that the study would provide an alternative and safe treatment option to relieve the symptoms ofiBS. The results of the study showed that the homoeopathic similimum remedy does not provide a statistically significant improvement in the symptoms of IBS. Clinically, however, most participants experienced a general trend of improvement in physical symptoms and general well-being .