A lesão medular gera uma condição crônica de saúde ao indivíduo que sofre a injúria e pode acarretar complicações, como o intestino neurogênico. A depender do nível neurológico da lesão, há expectativas de resultados para o funcionamento intestinal e medidas educativas devem ser implementadas ainda na fase aguda da lesão, visando a reabilitação. Estudo de delineamento metodológico que objetivou produzir vídeo educativo com as manobras de esvaziamento intestinal a ser utilizado no preparo de indivíduos com intestino neurogênico. A pesquisa, aprovada pelo Comitê de Ética, foi realizada em quatro etapas: etapa 1: Produção do roteiro e storyboard elaborados a partir das diretrizes do Guia traduzido: \"Intestino Neurogênico: Guia para Pessoas com Lesão Medular\"; etapa 2: Produção dos instrumentos; etapa 3: Coleta de dados; e por fim etapa 4: Produção do vídeo educativo. Foram utilizados dois instrumentos para a validação do roteiro e storyboard. O instrumento para validação de conteúdo continha 15 questões, divididas em quatro sessões e o de validação técnica possuía 11 questões, divididas em três sessões. Em cada sessão dos instrumentos tinha um campo para sugestões. A validade de conteúdo do roteiro e storyboard foi realizada por um comitê de dez juízes de conteúdo e três juízes técnicos. Os resultados demonstraram que todos os juízes de conteúdo eram do sexo feminino, com idade entre 30 a 58 anos. Quanto à atuação profissional atual e maior titulação acadêmica, a maioria trabalhava na área de reabilitação e tinha mestrado. As alternativas \"discordo fortemente\" e \"não sei\", não foram sinalizadas e a porcentagem de respostas total à opção \"concordo fortemente\" foi de 57,3% e \"concordo\" foi de 36,7%. A maioria das sugestões foi relacionada à mudança na linguagem, visando adequação ao público- alvo e para incrementar o uso de fotografias, figuras e animações. Quanto aos juízes técnicos, a maioria era do sexo masculino, com idade entre 37 a 45 anos. Atuavam como analista em mídias digitais e tecnologias educacionais, produção multimídia e em sistemas de informação, com predomínio do título de especialização. A porcentagem total de respostas \"concordo fortemente\" foi de 78,8% e \"concordo\" de 21,2%. Ressaltaram nas sugestões, o cuidado na edição e escolha dos recursos audiovisuais, de maneira a favorecer o interesse e a atenção do usuário. Cada item do instrumento de validação do roteiro e storyboard do vídeo obteve mais de 70% do conceito \"concordo fortemente\" e/ou \"concordo\" pelos juízes. Posteriormente o roteiro e storyboard foram adequados e as sugestões analisadas e acatadas conforme pertinência. A gravação do vídeo ocorreu no Centro de Simulação e no Centro de Informática de Ribeirão Preto da Universidade de São Paulo. A produção do vídeo favoreceu a utilização da prática baseada em evidência e contribuirá para o aprimoramento da assistência de enfermagem, com enfoque na educação de indivíduos com intestino neurogênico e seus cuidadores, além de se constituir em ferramenta tecnológica que poderá ser utilizada em ambiente de aprendizagem virtual e presencial / Spinal cord injury generates a chronic health condition to the individual suffering the injury and can lead to complications such as neurogenic bowel. Depending on the neurological level of injury, there are expectations of results for bowel function and educational measures should be implemented, even in the injury acute phase for the rehabilitation. Methodological design study aimed to produce an educational video with intestinal emptying maneuvers to be used in the preparation of patients with neurogenic bowel. The research, which was approved by the Ethics Committee, was performed in four steps: Step 1: Production and script storyboard drawn from the Guide guidelines translated: \"Neurogenic Bowel: A Guide for People with Spinal Cord Injury\"; Step 2: Production of instruments; Step 3: Data collection; and Step 4: Production of educational video. Two instruments for the validation script and storyboard were used. The instrument for content validation contained 15 questions divided into four sessions and the technical validation possessed 11 questions, divided into these three sessions. In each session of the instruments had a field for suggestions. The validity of the script and storyboard content was performed by an expert panel of 10 content and 3 technical judges. The results showed that all the contents of judges were female, aged 30-58 years. As for the current and highest academic degree professional practice, most working in rehabilitation and has mastered. Alternative \"strongly disagree\" and \"do not know\", were not marked and the percentage of total responses \"strongly agree\" was 57.3% and \"agree\" was 36.7%. Most of the suggestions was related to the change in language, aimed at adaptation to the target audience and to increase the use of photographs, pictures and animations. As for the technical judges, most were male, aged 37-45 years. Worked as an analyst in digital media and educational technologies, multimedia production and information systems, predominantly they had the title of master as expertise. The total percentage of responses \"strongly agree\" was 78.8% and \"agree\" 21.2%. They stressed the suggestions, care in editing and choice of audiovisual resources, in order to favor the interest and the user\'s attention. Each item script validation tool and Video storyboard obtained more than 70% of concept \"strongly agree\" and/or \"agree\" by the judges. Later the script and storyboard were adequate and suggestions analyzed and obeyed as relevance. Video recording took place in the Simulation Center and Ribeirao Preto Computer Centre at the University of São Paulo. The production of the video encouraged the use of evidence-based practice and contribute to the improvement of nursing care, focusing on education of individuals with neurogenic bowel and their caregivers, in addition to being in technological tool that can be used in educational settings virtual and face

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-04-18T19:23:38Z No. of bitstreams: 1 Micheli Stéfani Zarzecki.pdf: 2027524 bytes, checksum: 535aae8d63b5c3ca4ac4debb8ecb1f6f (MD5) / Made available in DSpace on 2016-04-18T19:23:38Z (GMT). No. of bitstreams: 1 Micheli Stéfani Zarzecki.pdf: 2027524 bytes, checksum: 535aae8d63b5c3ca4ac4debb8ecb1f6f (MD5) Previous issue date: 2016-02-19 / A Doença Inflamatória Intestinal (DII) é uma doença crônica, recidiva e de etiologia desconhecida. Fatores ambientais, estresse oxidativo e fatores imunológicos podem estar relacionados as causas dessa doença, e a colite ulcerativa e a doença de Crohn são exemplos dessa patologia. O mecanismo patogênico da DII é assumido como sendo um desequilíbrio da resposta imunológica a antígenos no ambiente intestinal. Os principais tratamentos das DII não são geralmente bem tolerados já que demonstram causar efeitos colaterais e, além disso, apresentam alta taxa de reincidências. A DII induzida por ácido 2,4,6-trinitrobenzeno sulfônico (TNBS) em modelos de roedores é caracterizada por aumento dos níveis de marcadores inflamatórios como TNF-α e interleucinas (IL-1β, IL-12, IL-17, IL-18 e IL-6). Tendo em vista a busca por alternativas eficazes nos tratamentos destas DII, os compostos orgânicos de selênio vêm se destacando como substâncias com potencial terapêutico, devido às suas atividades farmacológicas, como anti-inflamatória e antinociceptiva. Aliado a isso, o estudo de compostos de selênio combinados à oxiesteróis tem evidenciado resultados promissores. Demonstrou-se recentemente que o composto p-cloro-fenil-selenoesterol possui efeito antioxidante e anti-inflamatório em um modelo de dor e inflamação em camundongos. O objetivo desse trabalho foi investigar o efeito anti-inflamatório do composto p-cloro-fenil-viii selenoesterol (PCS), no modelo de DII induzida pelo TNBS em camundongos Swiss fêmeas. Os camundongos receberam o composto PCS) (10mg/kg; p.o.) durante todo o experimento (9 dias) por via oral. No quinto dia induziu-se a colite utilizando 2 mg de TNBS dissolvido em 0,1mL de uma solução de etanol a 50%, o qual foi administrado pela via intrarretal. No décimo dia, os camundongos foram eutanasiados e as amostras de sangue e cólon foram coletadas para as respectivas dosagens dos marcadores inflamatórios, de estresse oxidativo, analise histopatológica e sinais clínicos da doença. Os resultados obtidos demonstram que os animais tratados com TNBS apresentaram redução do comprimento colônico e aumento nos níveis da citocina pró inflamatória interleucina 6 (IL-6) e fator de necrose tumoral (TNF-α), e aumento dos níveis da enzima mieloperoxidase (MPO), tratamento com PCS foi capaz de reduzir os níveis das citocinas pró inflamatórias IL-6 e do TNF-α aos níveis do controle, além de evitar a redução do comprimento colônico que é um dos sinais da colite experimental induzida por TNBS. Nesse estudo também se observou uma melhora nos danos histológicos nos animais tratados com PCS em comparação com o grupo induzido por TNBS. Além disso, o tratamento com o PCS foi capaz de diminuir o estresse oxidativo e prevenir a diminuição das defesas antioxidantes no cólon de animais com DII induzida por TNBS. Portanto, nossos resultados sugerem que o tratamento com PCS apresentou uma melhora no quadro clínico da DII experimental em camundongos e que pode, futuramente e após mais estudos sobre este composto, tornar-se um potencial agente terapêutico para o tratamento de doenças inflamatórias, bem como as intestinais, colite ulcerativa e doença de Crohn. / The Inflammatory Bowel Disease (IBD) is a chronic, recurrent disease and of unknown etiology. Factors that may relate the causes of this disease are environmental factors, oxidative stress and immune factors. Example of this disease is the Ulcerative Colitis and Crohn's Disease. The main treatments of IBD are not generally well tolerated, they have side effects and have a high rate of relapse. The pathogenesis of IBD is assumed to be an imbalance of the immune response to antigens in the intestinal environment. IBD induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in rodent models is characterized by increased levels of inflammatory markers such as TNF-α and interleukins (IL-1β, IL-12, IL-17, IL- 18 and IL-6). The organic selenium compounds have been highlighted as substances with therapeutic potential because of their pharmacological activities such as anti-inflammatory and antinociceptive. Allied to this, the study combined with the selenium compounds oxiesteróis has shown promising results, it was demonstrated recently that PCS compound has antioxidant and anti-inflammatory effect in a model of pain and inflammation in mice. The aim of this study was to investigate the anti-inflammatory effect of p-chloro-phenyl-selenoesterol compound in IBD model induced by TNBS in Swiss female mice. The mice received the p-chlorophenyl-selenoesterol compound (PCS) (10mg / kg; po) throughout the experiment (9 days) orally. On the fifth day colitis was induced using 2 mg of TNBS dissolved in 0.1 mL of a 50% ethanol x solution, which was administered via intrarectal. On the tenth day, mice were euthanized and samples of blood and colon were collected for the respective levels of inflammatory markers of oxidative stress, histopathological and clinical signs of disease. The results show that animals treated with TNBS showed a reduction in colonic length, and increased levels of interleukin pro-inflammatory cytokine-6 (IL-6) and tumor necrosis factor (TNF-α) and increased levels of Myeloperoxidase enzyme (MPO), treatment with PCS was able to reduce the levels of pro inflammatory cytokines IL-6 and TNF-α levels to control and avoids the reduction in colonic length which is one of signs of experimental colitis induced by TNBS. In this study there was also an improvement in the histological analysis the animals treated with PCS compared with the group induced by TNBS. Furthermore, combined with improvements in inflammatory and histological parameters, treatment with PCS was able to decrease oxidative stress and prevent the decrease of antioxidant defenses in the colon of animals with TNBS-induced IBD. This finding suggests that treatment with PCS showed an improvement of the clinical picture in IBD in experimental mice and which could be a potential therapeutic agent for the treatment of inflammatory diseases, and intestinal, Ulcerative Colitis and Crohn's Disease.

Background The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) are chronic relapsing inflammatory disorders which have a rising incidence and cause significant morbidity. There are currently several treatment options with many more in the drug pipeline, but there are a lack of accurate biomarkers for decisions on treatment choice, assessment of disease activity and prognostication. There is a growing interest and desire for personalised or 'precision' medicine in IBD where novel biomarkers may help individualise IBD care in terms of diagnosis, choice of therapy, monitoring of response and detection of relapse. One class of functionally active biomarkers which have yet to be thoroughly investigated in IBD is damage-associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA). It has been recently shown that gut mitochondrial dysfunction can result in loss of epithelial barrier function and the development of colitis. Mitochondrial DAMPs have recently been described as elevated in several inflammatory diseases. Hypothesis The primary hypothesis of this thesis is that circulating levels of mtDNA is elevated in IBD. Secondary hypotheses are: (a) levels of other mitochondrial DAMPs are elevated in IBD, (b) circulating mtDNA can be used as a novel biomarker in IBD and (c) mtDNA is released locally at sites of inflammation in IBD. Methods Plasma and serum were collected prospectively from recruited IBD patients and non-IBD controls. Faeces and colonic tissue were collected from a subset of these patients. mtDNA in serum, plasma and faeces was measured using qPCR (amplifying COXIII/ND2 genes). Mass spectrometry was used to detect mitochondrial formylated peptides in the plasma of a subset of patients. IBD tissue was assessed for (a) mitochondrial damage using transmission electron microscopy (TEM) and (b) TLR9 expression, the target for mtDNA. Results 97 patients with IBD (67 UC and 30 CD), and 40 non-IBD controls were recruited. Plasma mtDNA levels were increased in UC and CD (both p < 0.0001) compared to non-IBD controls; with significant correlations with blood (CRP, albumin, white cell count), clinical and endoscopic markers of severity; and disease activity. In active UC, we detected significantly higher circulating mitochondrial formylated peptides and faecal mtDNA levels (vs. non-IBD controls [p < 0.01 and < 0.0001 respectively]) with demonstrable TEM evidence of intestinal mucosal mitochondrial damage. In active IBD, TLR9+ lamina propria inflammatory cells were significantly higher in UC/CD compared to controls (both p < 0.05). Conclusions Taken together, the findings suggest mtDNA is released during active inflammation in inflammatory bowel disease and is a potential novel mechanistic biomarker.

Pathogenesis of autoimmune and auto-inflammatory diseases is induced by auto-aggressive helper T (Th) cells (i.e. Th1 and Th17 cells), and can be controlled by regulatory T cells (Tregs) characterized by expression of the transcription factor Foxp3. Thus, development of autoimmunity is regulated by the balance of Tregs and Th1/Th17 cells. Prostaglandin E₂ (PGE₂) is a bioactive lipid mediator with immune-modulatory potential that acts through 4 receptors (EP1-4). It has been shown that PGE₂ facilitates Th1 and Th17 cell development and expansion, therefore promoting autoimmune inflammation. However, the role of PGE₂ in Treg development and function is largely unclear. The aim of this PhD was to test the hypothesis that PGE₂ regulates Treg development, function and subsequent immune response. I observed that in vivo inhibition of endogenous PGE₂ biosynthesis using a COX inhibitor resulted in increased Foxp3+ Tregs in various lymphoid organs. This response was prevented by addition of an EP4 agonist. PGE₂-EP4 signalling particularly inhibits RORγt+ Tregs in the intestine. This was not observed in either antibiotic-treated mice or MyD88/TRIF double-knockout mice, suggesting gut commensal microbiota involvement. In addition, PGE₂ has a role in microbiota-dependent regulation of intestinal CD11c+MHCII+CD11b+CD103- mononuclear phagocytes (MNPs) which drive intestinal Treg expansion through production of type 1 interferons. Consistent with these in vivo observations, gut microbial metabolites from indomethacin treated mice enhanced in vitro RORγt+ Treg differentiation in the dendritic cell- T cell co-culture system. Adoptive transfer of caecal microbiota from COX inhibitor- treated mice into naïve mice also provided protective benefits in a chemical (DSS)-induced colitis disease model. In summary, this work has demonstrated that PGE₂ affects intestinal Tregs, indicating a novel mechanism for interaction of PGE₂, the adaptive immune system and the gut microbiota in homeostasis within this environment. These findings increase our understanding of the role of PGE₂ in development of inflammatory bowel disease and offer potential therapeutic strategies for treating this disease.

A lesão medular gera uma condição crônica de saúde ao indivíduo que sofre a injúria e pode acarretar complicações, como o intestino neurogênico. A depender do nível neurológico da lesão, há expectativas de resultados para o funcionamento intestinal e medidas educativas devem ser implementadas ainda na fase aguda da lesão, visando a reabilitação. Estudo de delineamento metodológico que objetivou produzir vídeo educativo com as manobras de esvaziamento intestinal a ser utilizado no preparo de indivíduos com intestino neurogênico. A pesquisa, aprovada pelo Comitê de Ética, foi realizada em quatro etapas: etapa 1: Produção do roteiro e storyboard elaborados a partir das diretrizes do Guia traduzido: \"Intestino Neurogênico: Guia para Pessoas com Lesão Medular\"; etapa 2: Produção dos instrumentos; etapa 3: Coleta de dados; e por fim etapa 4: Produção do vídeo educativo. Foram utilizados dois instrumentos para a validação do roteiro e storyboard. O instrumento para validação de conteúdo continha 15 questões, divididas em quatro sessões e o de validação técnica possuía 11 questões, divididas em três sessões. Em cada sessão dos instrumentos tinha um campo para sugestões. A validade de conteúdo do roteiro e storyboard foi realizada por um comitê de dez juízes de conteúdo e três juízes técnicos. Os resultados demonstraram que todos os juízes de conteúdo eram do sexo feminino, com idade entre 30 a 58 anos. Quanto à atuação profissional atual e maior titulação acadêmica, a maioria trabalhava na área de reabilitação e tinha mestrado. As alternativas \"discordo fortemente\" e \"não sei\", não foram sinalizadas e a porcentagem de respostas total à opção \"concordo fortemente\" foi de 57,3% e \"concordo\" foi de 36,7%. A maioria das sugestões foi relacionada à mudança na linguagem, visando adequação ao público- alvo e para incrementar o uso de fotografias, figuras e animações. Quanto aos juízes técnicos, a maioria era do sexo masculino, com idade entre 37 a 45 anos. Atuavam como analista em mídias digitais e tecnologias educacionais, produção multimídia e em sistemas de informação, com predomínio do título de especialização. A porcentagem total de respostas \"concordo fortemente\" foi de 78,8% e \"concordo\" de 21,2%. Ressaltaram nas sugestões, o cuidado na edição e escolha dos recursos audiovisuais, de maneira a favorecer o interesse e a atenção do usuário. Cada item do instrumento de validação do roteiro e storyboard do vídeo obteve mais de 70% do conceito \"concordo fortemente\" e/ou \"concordo\" pelos juízes. Posteriormente o roteiro e storyboard foram adequados e as sugestões analisadas e acatadas conforme pertinência. A gravação do vídeo ocorreu no Centro de Simulação e no Centro de Informática de Ribeirão Preto da Universidade de São Paulo. A produção do vídeo favoreceu a utilização da prática baseada em evidência e contribuirá para o aprimoramento da assistência de enfermagem, com enfoque na educação de indivíduos com intestino neurogênico e seus cuidadores, além de se constituir em ferramenta tecnológica que poderá ser utilizada em ambiente de aprendizagem virtual e presencial / Spinal cord injury generates a chronic health condition to the individual suffering the injury and can lead to complications such as neurogenic bowel. Depending on the neurological level of injury, there are expectations of results for bowel function and educational measures should be implemented, even in the injury acute phase for the rehabilitation. Methodological design study aimed to produce an educational video with intestinal emptying maneuvers to be used in the preparation of patients with neurogenic bowel. The research, which was approved by the Ethics Committee, was performed in four steps: Step 1: Production and script storyboard drawn from the Guide guidelines translated: \"Neurogenic Bowel: A Guide for People with Spinal Cord Injury\"; Step 2: Production of instruments; Step 3: Data collection; and Step 4: Production of educational video. Two instruments for the validation script and storyboard were used. The instrument for content validation contained 15 questions divided into four sessions and the technical validation possessed 11 questions, divided into these three sessions. In each session of the instruments had a field for suggestions. The validity of the script and storyboard content was performed by an expert panel of 10 content and 3 technical judges. The results showed that all the contents of judges were female, aged 30-58 years. As for the current and highest academic degree professional practice, most working in rehabilitation and has mastered. Alternative \"strongly disagree\" and \"do not know\", were not marked and the percentage of total responses \"strongly agree\" was 57.3% and \"agree\" was 36.7%. Most of the suggestions was related to the change in language, aimed at adaptation to the target audience and to increase the use of photographs, pictures and animations. As for the technical judges, most were male, aged 37-45 years. Worked as an analyst in digital media and educational technologies, multimedia production and information systems, predominantly they had the title of master as expertise. The total percentage of responses \"strongly agree\" was 78.8% and \"agree\" 21.2%. They stressed the suggestions, care in editing and choice of audiovisual resources, in order to favor the interest and the user\'s attention. Each item script validation tool and Video storyboard obtained more than 70% of concept \"strongly agree\" and/or \"agree\" by the judges. Later the script and storyboard were adequate and suggestions analyzed and obeyed as relevance. Video recording took place in the Simulation Center and Ribeirao Preto Computer Centre at the University of São Paulo. The production of the video encouraged the use of evidence-based practice and contribute to the improvement of nursing care, focusing on education of individuals with neurogenic bowel and their caregivers, in addition to being in technological tool that can be used in educational settings virtual and face

As Doenças inflamatórias intestinais (DII) são multifatoriais e sua etiologia envolve susceptibilidade genética, fatores ambientais, disbiose e ativação exacerbada do sistema imunológico no intestino. Essas doenças também tem sido relacionadas a baixos níveis de dehidroepiandrosterona (DHEA), um hormônio precursor de diversos esteroides e relacionado à modulação das respostas imunes. Porém, os mecanismos precisos que relacionam as ações deste hormônio com a proteção ou susceptibilidade à doença de Crohn ou colite ulcerativa ainda não são totalmente conhecidos. Sendo assim, este projeto buscou entender o papel imunomodulador do DHEA exógeno in vitro e in vivo durante a inflamação intestinal experimental induzida por dextran sulfato de sódio (DSS) em camundongos C57BL/6. Inicialmente, in vitro, DHEA inibiu a proliferação de células do baço de forma dose dependente nas concentrações de 5?M, 50?M ou 100?M, com diminuição da produção de IFN-?. Este hormônio não foi tóxico para células de linhagem mieloide, embora tenha causado necrose em leucócitos nas doses mais elevada (50 ?M e 100?M), o que pode ter influenciado a diminuição das citocinas in vitro. Nos ensaios in vivo, os camundongos tratados com DHEA (40 mg/Kg) foram avaliados na fase de indução da doença (dia 6) e durante o reparo tecidual, quando os animais expostos ao DSS e ao DHEA por 9 dias foram mantidos na ausência destas drogas até o dia 15. Houve diminuição do escore pós-morte, melhora no peso e nos sinais clínicos da inflamação intestinal, com redução de monócitos no sangue periférico com 6 dias e aumento de neutrófilos circulantes na fase de reparo tecidual (15 dias). Ainda, a suplementação com DHEA levou à redução da celularidade da lâmina própria (LP) e ao restabelecimento do comprimento normal do intestino. O uso deste hormônio também diminuiu a expressão do RNAm de IL-6 e TGF-?, enquanto aumentou a expressão de IL-13 no colón dos animais durante a fase de indução da doença, o que provavelmente ajudou na atenuação da inflamação intestinal. Além disso, houve acúmulo de linfócitos CD4+ e CD8+ no baço e diminuição apenas de linfócitos CD4+ nos linfonodos mesentéricos (LNM), indicando retenção das células CD4+ no baço após uso do DHEA. O tratamento foi também capaz de aumentar a frequência de células CD4 produtoras de IL-4 e diminuir CD4+IFN-?+ no baço, além de reduzir a frequência de CD4+IL-17+ nos LNM, sugerindo efeito do DHEA no balanço das respostas Th1/Th2/Th17 relacionadas à colite. Em adição, as células de baço dos animais tratados com DHEA e expostos ao DSS se tornaram hiporresponsivas, como visto pela diminuição da proliferação após re-estímulos in vitro. Finalmente, DHEA foi capaz de atuar no metabolismo dos camundongos tratados, levando à diminuição de colesterol total e da fração LDL no soro durante a fase de indução da doença, sem gerar quaisquer disfunções hepáticas. Com isso, podemos concluir que o DHEA atua por meio do balanço das respostas imunes exacerbadas, minimizando os danos locais e sistêmicos causados pela inflamação intestinal induzida por DSS. / Inflammatory bowel diseases (IBD) are multifactorial diseases whose etiology involves genetic susceptibility, environmental factors, dysbiosis and exacerbated activation of the immune system in the gut. These diseases have also been associated to lower levels of dehydroepiandrosterone (DHEA), a precursor of various steroid hormones, related to modulation of immune responses. However, the precise mechanisms that link the actions of this hormone with protection or susceptibility to Crohn\'s disease or ulcerative colitis are still not fully understood. Thus, this project aimed to understand the immunomodulatory role of exogenous DHEA in vitro and in vivo in experimental intestinal inflammation induced by dextran sodium sulfate (DSS) in C57BL/6 mice. Initially, in vitro, DHEA inhibited the proliferation of spleen cells in a dose dependent way on the concentrations of 5?M, 50?M and 100?M, with decreased production of IFN-?. This hormone was not toxic to myeloid lineage cells, although it caused necrosis of leukocytes at the highest doses (50?M and 100?M), which may have influenced the decrease of the cytokines in vitro. Mice treated with DHEA (40 mg / kg) were evaluated at the induction phase of the disease (day 6) and during tissue repair, when animals exposed to DSS and DHEA for 9 days were maintained in the absence these drugs until the day 15. There was decrease of postmortem score, improved weight and clinical signs of intestinal inflammation, besides reduced peripheral blood monocytes on day 6, together with an increase in circulating neutrophils in tissue repair phase (15 days). Supplementation with DHEA also led to a reduction in cellularity of the lamina propria (LP) and to the restoration of normal length of the gut. The use of this hormone also decreased the expression of of IL-6 and TGF-? mRNA, while IL-13 was augmented in the colon of mice during the induction phase of the disease, a fact probably related to attenuation of intestinal inflammation. Furthermore, there was accumulation of CD4+ and CD8+ cells in the spleen along with decreased CD4+ leukocytes in mesenteric lymph nodes (MLN), indicating retention of CD4+ cells in the spleen after use of DHEA. The treatment was also able to increase the frequency of CD4+ cells producing IL-4 and decrease CD4+IFN-?+ in spleen, with reduced frequency of CD4+IL-17+ in the MLN, suggesting a role for DHEA on the balance of Th1/Th2/Th17 responses related colitis. In addition, splenocytes of mice treated with DHEA and exposed to DSS became hiporresponsives as seen by decreased proliferation after re-stimulation in vitro. Finally, DHEA was able to act on the metabolism of treated mice, leading to decreased total cholesterol and LDL cholesterol in serum during the induction phase of the disease, without generating any liver dysfunction. Thus, we concluded that DHEA acts by balancing the exacerbated immune responses, minimizing local and systemic damages caused by intestinal inflammation induced by DSS.

Objectives: Despite the toll of inflammatory bowel disease (IBD) on adjustment, many patients are resilient to the challenges associated with living with IBD, and successfully cope with their illness and thrive. Yet there is little research on why some individuals with IBD enter a trajectory of growth, while others may struggle to adapt. The aim of this study was to investigate the adjustment‐related factors that distinguished thriving, resilience, and loss in people with IBD across personal growth, life satisfaction, and relationship quality domains. Design: Prospective cohort design with two data collection points, 6 months apart. Methods: From a sample of 420 people with active IBD who completed an online survey, 152 participants completed the follow‐up survey and were included in the analyses. Participants completed measures of thriving, and cognitive, affective, social, and disease‐related variables known to predict adjustment. Results: Time 1 ANCOVAs and pairwise comparisons controlling for demographics distinguished loss from resilience and thriving on the four outcomes – coping efficacy, illness acceptance, depressive symptoms, and perceived social support – for all three domains. Time 2 ANCOVAs and pairwise comparisons controlling for baseline outcomes revealed that the Time thriving categories predicted differences in Time 2 adjustment, mainly for the life satisfaction domain, with those experiencing loss reporting poorer adjustment than those experiencing resilience and thriving. Conclusions: Findings highlight the distinctions among profiles of thriving, resilience, and loss in adjustment to IBD, and suggest that strategies that enhance coping and address depressive symptoms may optimize thriving in the context of IBD.

Background: The 5-hydroxytrptamine receptor 4 (5-HT4 receptor) is heavily expressed on colonic epithelial cells and has been targeted as a therapeutic for functional bowel symptoms and pain; however, adverse cardiac events related to 5-HT4 agonist treatment limited their therapeutic use. Previous studies in the Mawe laboratory have demonstrated that intraluminal application of a 5-HT4 agonist exerts protective epithelial actions in animal models of colitis, and accelerates recovery from colitis. The aim of this study was to test the effects of a luminally restricted 5-HT4 agonist in a mouse model of experimental colitis. Methods: The luminally restricted 5-HT4 agonist (Takeda Pharmaceuticals; 10 mg/kg) was administered to mice during active dextran sodium sulfate (DSS) induced colitis. Colitis activity was evaluated using disease activity index, a fecal lipocalin-2 assay, and histological damage scoring. Epithelial proliferation and colonic motility were also measured as readouts of the potential protective actions and colonic function, respectively. Results: Oral gavage and intracolonic delivery of this luminally restricted 5-HT4 agonist had no detectable effect on recovery from colitis or colonic motility as compared to vehicle. Additionally, in positive control experiments, we failed to see an effect of the 5-HT4 agonist, tegaserod, on colitis severity or colonic motility in any of the measures tested. Conclusions: In conclusion, it is unclear if the luminally restricted 5-HT4 agonist has any effect on recovery from DSS colitis. Given inconsistencies with the model and lack of an effect of tegaserod, additional studies will be required, possibly involving different doses and time points, to fully assess the actions of this luminally restricted compound in colitis recovery.

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Abstract Nutritional status affects every aspect of a child?s health. Thorough nutritional assessment is hampered by the lack of a single comprehensive tool, which can cover all aspects of nutritional assessment. In three distinct studies, this thesis investigated the nutritional status of hospitalised children, children with coeliac disease and children with inflammatory bowel disease. Study 1 The objectives of this study were to assess prevalence of malnutrition and nutritional risk, and define demographic and anthropometric factors associated with nutritional risk among hospitalized children. In this cross sectional study, 157 hospitalised children were assessed for nutritional status using nutritional risk score (NRS) and anthropometric measurements. We found that 4.5%, 8.9%, 15.1% and 10.4% children were wasted, stunted, overweight and obese respectively. However, with the NRS, 47.8% of the children were at high nutritional risk. These children at high risk had lower weight for age (p=0.02), lower BMI percentiles for age (p=0.001) and longer hospitalization (p=0.001) than children at no risk. Study 2 The objectives of this study were to determine nutritional parameters in children with coeliac disease. Twenty-five children with coeliac disease and an equal number of age and gender matched controls were enrolled and anthropometric measurements, BIA and leptin levels were analysed in all. No significant differences were found between the children with coeliac disease and controls in these parameters. BMI percentile correlated with leptin levels in children with coeliac disease. Study 3 The objectives of this study were to determine anthropometric parameters and leptin levels in children with IBD and ascertain if BMI correlates with leptin levels in these children. Thirty children with IBD and 60 age and gender matched controls were enrolled. Anthropometric measurements and leptin levels were analysed and compared with controls. IBD children had significantly low weight for age (p=0.002), BMI percentiles (p=0.001) and leptin levels (p=0.009) compared to controls. There was a correlation between BMI and leptin levels in IBD children. In conclusion, this thesis has shown that one quarter of hospitalized children were overweight or obese, and further, that half of the hospitalised children were at high risk of nutritional deterioration and these children had longer hospital stay than children at no risk. Children with coeliac disease had similar anthropometric measurements, body compartments and leptin levels to controls. However, children with IBD had lower anthropometric measurements and leptin levels, indicating under-nutrition. Nutritional assessment should be a mandatory part of clinical management with nutritional status assessed by various tools including NRS, anthropometry, BIA and leptin levels.