Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-05-06T19:06:26Z No. of bitstreams: 1 glauciosilvadesouza.pdf: 303622 bytes, checksum: 139fcd6cbe1e2b7218e5e48cff0864ba (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-06-08T14:41:58Z (GMT) No. of bitstreams: 1 glauciosilvadesouza.pdf: 303622 bytes, checksum: 139fcd6cbe1e2b7218e5e48cff0864ba (MD5) / Made available in DSpace on 2016-06-08T14:41:58Z (GMT). No. of bitstreams: 1 glauciosilvadesouza.pdf: 303622 bytes, checksum: 139fcd6cbe1e2b7218e5e48cff0864ba (MD5) Previous issue date: 2013-03-27 / As taxas de hospitalização e de cirurgia são consideradas marcadores de agressividade da Doença de Crohn (DC). Os custos do tratamento da DC variam consideravelmente entre os pacientes, mas as hospitalizações, incluindo aquelas em que houve cirurgia, representam um maior impacto nos custos do tratamento da doença. Reduzir a taxa de hospitalização e cirurgia são pontos cruciais na redução dos custos do tratamento da doença. Foram avaliados os efeitos da azatioprina (AZA) comparado com os da mesalazina (MSZ) na incidência de hospitalização por todas as causas ou hospitalização relacionada a cirurgia. Foram analisados 72 pacientes com DC ileocecal sub-oclusiva que responderam ao tratamento clínico inicial. Os pacientes foram então randomizados em 2 grupos de tratamento AZA (2-3 mg/Kg dia) ou MSZ (3,2g/dia) por um período de 3 anos. As a taxa de hospitalização por todas as causas e de hospitalização relacionada a cirurgia foram observadas e comparadas entre os grupos. Também foi analisada a taxa de internação por paciente, o tempo de hospitalização e o intervalo até a primeira hospitalização. As variáveis demográficas foram similares nos grupos AZA e MSZ. A proporção de pacientes hospitalizados em 36 meses por todas as causas foi menor nos pacientes tratados com AZA, comparado àqueles que receberam MSZ (0,39 vs. 0,83, respectivamente; p=0,001). O grupo AZA também teve menor incidência de hospitalizações cirúrgicas (0,25 vs. 0,56, respectivamente; p = 0,011). O número de admissões por pacientes (0,7 vs.1,41, p=0,001) e o tempo de internação (3,8 vs.7,7 dias; p=0,002) também foram menores no grupo AZA. O intervalo até a primeira hospitalização no grupo AZA foi maior que aquele do grupo MSZ (27 vs. 17,9 meses, respectivamente; p=0,001). Pacientes com DC ileocecal sub-oclusiva tratados com AZA tiveram menor taxa de hospitalização por todas as causas e hospitalizações com cirurgia quando comparados a pacientes que receberam tratamento com MSZ num período de 3 anos. O uso prolongado de AZA na DC ileocecal em pacientes sub-ocluidos pode reduzir os custos do tratamento da doença. / Hospitalization and surgery are considered to be hallmarks of more aggressive behavior in Crohn’s disease (CD). Although the cost of CD treatment differs considerably, it is remarkable that hospitalization costs, including surgery, comprise the biggest amount of the total treatment cost. Decreasing hospitalization and surgery rates is of pivotal importance to reduce the health-care costs in this clinical setting. We evaluated the effect of azathioprine (AZA) when compared with mesalazine (MSZ) on incidence of hospitalizations due to all-causes and for CD-related surgical procedures. In this controlled, randomized study 72 subjects with sub-occlusive ileocecal CD were randomized for AZA (2-3 mg/kg per day) or MSZ (3.2 g per day) therapy during a 3-year period. The primary end point was the hospitalization rate due to all-causes as well as for surgical procedures during this period evaluated between the groups. The secondary outcomes were the total inpatient admission number, the length of hospitalization and the time interval until first hospitalization. Patients treated with AZA or MSZ were comparable according to demographics and disease characteristics. On an intention-to-treat basis, the proportion of patients hospitalized on 36 months due to all-causes was lower in patients treated with AZA when compared to those on MSZ (0.39 vs. 0.83, respectively; p=0.035). The AZA group had also significantly lower rates of hospitalization for surgical intervention (0.25 vs. 0.56, respectively; p=0.011). The number of admissions (0.70 vs. 1.41, p=0.001) and the length of hospitalization (3.8 vs. 7.7 days; p=0.002) were both lower in AZA-patients. The time interval until first hospitalization in AZA-group was significantly higher than in those on MSZ (27 vs. 17.9 months, respectively; p=0.001). Patients with sub-occlusive ileocecal CD treated with AZA had lower hospitalization rates due to all-causes and for surgical management of CD when compared to those treated with MSZ in a 3-years period. The long term use of AZA in ileocecal CD patients recovering from a sub-occlusion episode can save health-care cost.

Submitted by isabela.moljf@hotmail.com (isabela.moljf@hotmail.com) on 2017-05-19T13:37:35Z No. of bitstreams: 1 luizgustavodeoliveira.pdf: 3109049 bytes, checksum: 4df3b04529f2b0980313cfda47b84ab7 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-05-19T14:46:00Z (GMT) No. of bitstreams: 1 luizgustavodeoliveira.pdf: 3109049 bytes, checksum: 4df3b04529f2b0980313cfda47b84ab7 (MD5) / Made available in DSpace on 2017-05-19T14:46:00Z (GMT). No. of bitstreams: 1 luizgustavodeoliveira.pdf: 3109049 bytes, checksum: 4df3b04529f2b0980313cfda47b84ab7 (MD5) Previous issue date: 2013-03-22 / Doenças inflamatórias intestinais, entre elas colite ulcerativa e doença de Crohn, compreendem um amplo espectro de afecções que apresentam em comum inflamação crônica do trato gastrointestinal. Colite ulcerativa afeta exclusivamente o cólon e o reto, possui etiologia ainda pouco conhecida podendo estar relacionada com fatores ambientais, genéticos e de resposta imune. O tratamento se baseia em medicamentos como aminossalicilatos, glicocorticóides e imunossupressores, porém seus efeitos colaterais atrapalham a adesão do paciente ao tratamento por longos períodos. Condroitim sulfato (CS) e glucosamina (GlcN) são atualmente indicados para o tratamento de doenças inflamatórias, como a osteoartrite, principalmente por apresentarem efeito anti-inflamatório ao diminuírem a ação do fator de transcrição NF-kB diminuindo a expressão de metaloproteases (MMP), TNF-α, iNOS entre outros mediadores inflamatórios. O objetivo deste trabalho foi analisar os efeitos da associação de CS e GlcN na colite ulcerativa experimental induzida por dextran sulfato de sódio (DSS) em ratos Wistar. Para isso foram avaliados o índice de atividade da doença (IAD), parâmetros hematológicos e bioquímicos, morfológicos e a atividade de MMP-2 e -9 da matriz extracelular no intestino grosso, concentração de NO tecidual e concentração de glicosaminoglicanos. Os animais foram divididos em quatro grupos: (1) controle, (2) controle + CS/GlcN, (3) DSS , (4) DSS + CS/GlcN. Observamos que o tratamento com CS/GlcN melhorou a severidade da colite aguda em ratos, verificado pela redução do score histológico e melhora de parâmetros hematológicos. CS/GlcN também reduziu a destruição de células caliciformes observados pelo azul de alcian, bem como a produção de óxido nítrico, a atividade de mieloperoxidase e metaloproteases, principalmente de MMP-9. Além disso, foi observado uma redução na concentração de GAGs total no grupo DSS + CS/GlcN quando comparado ao grupo DSS. Portanto, a administração de CS/GlcN apresentou melhoras em alguns dos parâmetros avaliados principalmente na atividade de MMP-9, mostrando um potencial destes compostos para futura utilização no tratamento dessa patologia. / Inflammatory bowel disease, including ulcerative colitis and Crohn's disease comprising a broad spectrum of diseases those have in common chronic inflammation of the gastrointestinal tract. Ulcerative colitis affects only the colon and rectum, has still poorly understood etiology and this could may be related to environmental factors, genetic and immune response. Treatment is based on drugs as aminosalicylates, immunosuppressants and glucocorticoids, but its side effects hinder patient compliance with treatment for long periods. Chondroitin sulphate (CS) and glucosamine (GlcN) are currently indicated for treatment of inflammatory diseases such as osteoarthritis, mainly because of the anti-inflammatory effect by decreasing the activity of transcription factor NF-kB and decreasing the expression of metalloproteases (MMP), TNF-α, iNOS and other inflammatory mediators. The objective of this study was to analyze the effects of the combination of CS and GlcN in experimental ulcerative colitis model induced by dextran sulfate sodium (DSS) in rats. To do so we evaluated the disease activity index (DAI), haematological and biochemical parameters, morphological changes and activity of MMP-2 and -9, NO and glycosaminoglycans concentration in the large intestine. Animals were divided into four groups: (1) control, (2) control + CS / GlcN, (3) DSS-induced colitis, (4) DSS + CS / GlcN. We observed that treatment with CS/GlcN improved the severity of acute colitis in rats verified by histological score reduction and improvement in hematological parameters. CS/GlcN also reduced goblet cells destruction observed by alcian blue, as well as nitric oxide production, the activity of myeloperoxidase and metalloproteases, especially MMP-9. Moreover, we observed a reduction in the concentration of total GAG + DSS group CS / GlcN when compared to DSS. Therefore, administration of CS/GlcN showed improvements in some of the parameters evaluated mainly on the activity of MMP-9, showing a potential future use of these compounds for the treatment of this pathology.

La maladie de Crohn et la rectocolite hémorragique font partie des maladies inflammatoires chroniques de l'intestin (MICI). Le principal objectif des traitements anti-inflammatoires est de favoriser la délivrance du principe actif localement, spécifiquement sur les zones enflammées et de limiter les effets indésirables. Ainsi, plusieurs systèmes à libération colonique de molécules actives ont été développés. Parmi eux, les pellets présentent de nombreux avantages par rapport aux formes solides unitaires conventionnelles. Dans un premier temps, des pellets comptant une substance anti-inflammatoire naturelle et nutritive, la rutine, ont été développés. L'intérêt de cette molécule est de réduire considérablement les effets secondaires qui constituent un véritable problème dans les traitements actuels des MICI. Les pellets ont été enrobé avec les polysaccharides naturels se dégradant avec la flore colonique. Les études in vitro ont démontré une libération minimale du principe actif au niveau de l'estomac et du petit intestin. Par contre, une libération rapide et totale a été observée lors de l'exposition des pellets dans les conditions du milieu colonique. Les résultats des tests in vivo ont démontré que la rutine a atténué considérablement l'inflammation au niveau de colon et les pellets enrobés ont été aussi efficaces que les pellets d'acide 5-aminosalicylique (5-ASA) commercialisés. L'administration orale de rutine via les pellets enrobés et préparés avec le chitosan semble être une approche prometteuse, permettant la libération du principe actif au niveau des zones enflammées, pour le traitement des MICI tout en réduisant les effets secondaires. Le deuxième but de notre travail était d'élucider l'impact du chitosan, un polymère mucoadhésif, sur l'efficacité thérapeutique. Les pellets de 5-ASA ont été préparés à partir de cellulose microcristalline avec ou sans chitosan. Un enrobage constitué d'un polymère pH dépendant,1' Eudragit® FS, a ensuite été réalisé autour du noyau. Les tests de dissolution ont montré que le principe actif n'était pas libéré du pellet après 2 h en milieu acide. En revanche,la libération était rapide dans un milieu simulant l'environnement colonique. Les tests ex vivo avec les pellets contenant le chitosan ont montré des propriétés mucoadhésives importantes qui ont été confirmées par la concentration élevée du métabolite de 5-ASA dans les tissus coloniques des rats. De plus, nous avons a démontré que les pellets permettaient d'atténuer de façon significative l'inflammation du côlon. Ainsi, les pellets bioadhésifs enrobés possèdent des propriétés bénéfiques supplémentaires pour la libération du 5-ASA au niveau du côlon par rapport à des formes multidoses commercialisées pour le traitement des MICI. / Crohn's disease and ulcerative colitis are two related but distinct chronic inflammatory disorders of gastrointestinal tract (GIT), commonly denoted as inflammatory bowel disease(IBD). The main goal of the anti-inflammatory treatment of this disorder is to achieve maximal drug concentration in inflamed area and reduce systemic adverse effects. For this purpose several colon-spécifie drug delivery systems have been investigated. In addition, the design of pellets as oral drug delivery systems may provide many advantages over single unit preparations and thus improve patient compliance. It is well known that most existing treatments of IBD are associated with significant side effects and for this reason the formulation with a " food like " composition was designed. In the first part of our study, therapeutic efficiency of rutin/chitosan pellets with coatings based on natural polysaccharides degraded by colonie microbiota compared to commercialized 5-aminosalicylic acid (5-ASA) pellets was investigated. Release profiles ofcoated pellets showed a minimal drug release in simulated stomach and small intestine following by rapid drug release upon exposure to the colonie fluid. The results from in vivo testing showed that rutin attenuated efficiently inflammation in the colon and coated pellets were as effective as 5-ASA pellets in mitigating experimental colitis. The studies demonstrated that rutin administration via chitosan core coated pellets seems to be apromising approach for colon-specific delivery since they could interact easily with the mucin layer and deliver drug especially to the inflamed colonie area to relieve symptoms of IBD omitting side effects related to conventional treatment. The second objective of this thesis was to explore the impact of additional mucoadhesive polymer chitosan in the pellets core on the therapeutic efficiency. For this purpose, 5-ASA loaded pellets were produced by extrusion/spheronisation method and subsequently coated with pH-sensitive polymer Eudragit® FS. No drug release at pH 1.2within 2 h, and release as intended in the simulated distal ileum and colon was observed. Chitosan-core pellets showed efficient mucoadhesive properties in ex vivo bioadhesion testing which were also confirmed by increased concentration of 5-ASA metabolite in the colonie tissues in rats. The pellets were tested in preexisting colitis and the results revealed significant attenuation of the colonie inflammation. We can conclude, that bioadhesive chitosan-corepellets showed additional beneficial properties for colonie 5-ASA delivery in the treatment of IBD over marketed dosage formulation.

Bakgrund: Crohns sjukdom och ulcerös kolit är kroniska, inflammatoriska tarmsjukdomar som under de senaste decennierna har ökat påtagligt. De kan drabba människor i alla åldrar och ha en negativ påverkan på patienternas livskvalitet. Sjuksköterskan har en viktig roll i att se till att patienterna får tillräckligt med information och stöd för att klara av att sköta sin egenvård. Syfte: Syftet var att belysa hur patienter med Crohns sjukdom och ulcerös kolit upplevde symtomens påverkan i det dagliga livet och hur de anpassat sin tillvaro efter sjukdomen. Metod: En litteraturöversikt grundad på elva vårdvetenskapliga studier med kvalitativ design genomfördes. Studierna analyserades utifrån det valda syftet och nyckelfynd sammanställdes under två huvudteman. Resultat: Litteraturöversikten belyste hur deltagarna upplevde sjukdomarnas symtom och vilken påverkan de hade på det vardagliga livet. Här beskrevs påverkan på familjeliv, relationer, sociala sammanhang och arbetsliv. Sammanfattande utgjorde sjukdomarna ett hinder. Vidare beskrevs sjukdomarnas emotionella påverkan och hur deltagarna upplevde att de led av en osynlig sjukdom. Avslutningsvis visas vilka attityder deltagarna hade mot livet, vilka strategier som använts för att hantera sjukdomen och att acceptans av sjukdomen var viktig för att lära sig att leva med den. Diskussion: Resultatfynden har diskuterats utifrån Callista Roys adaptionsmodell och kopplats till andra vetenskapliga studier. Livet med en kronisk sjukdom innebär ständiga förändringar och sjuksköterskan kan genom att identifiera faktorer som påverkar adaptionen hjälpa patienten att uppnå balans. / Background: Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases that have increased significantly in recent decades. The diseases can debut at all ages, and they have a negative effect on the patients´ quality of life. A nurse has an important part of ensuring that patients receive sufficient information and support to manage their self-care. Aim: The purpose was to illuminate how patients with Crohn's disease and ulcerative colitis experienced the effects of the symptoms in their daily lives and how they adapted to the disease. Method: A literature review based on eleven nursing studies with qualitative design was conducted. The studies were analyzed based on the chosen purpose and key findings were compiled under two main themes. Results: The literature review illustrated how the participants experienced the symptoms of the disease and what impact they had on everyday life. The impact on family life, relationships, social contexts and working life were described. In summary, the disease was an obstacle. The emotional impact of the disease and how the participants perceived that they suffered from an invisible disease were described. Finally, what attitudes the participants had towards life, what strategies were used to manage the disease, and that acceptance of the disease was important for learning to handle it. Discussion: The findings have been discussed based on Callista Roys adaptation model and linked to other scientific studies. Life with a chronic disease involves constant changes, and the nurse can help the patient to achieve balance by identifying factors that affect the adaptation.

Dans de nombreuses pathologies digestives dont les maladies inflammatoires chroniques intestinales (MICI), l'intégrité de la barrière épithéliale est rompue. Cette perte d'intégrité est notamment due à la réduction ou la perte d'expression des jonctions adhérentes composées du complexe E-cadhérine/caténines. Il est donc important d'identifier de nouvelles molécules capables de réguler ce complexe dans les MICI. C'est dans ce contexte que nous nous sommes intéréssés à une levure non pathogène, Saccharomyces boulardii (Sb) utilisée dans la prévention et le traitement de désordres gastro-intestinaux et qui présente des bénéfices thérapeutiques chez les patients atteints de MICI, notamment en régulant l'intégrité de la barrière intestinale. L'étude que nous avons réalisée sur des explants tissulaires provenant de patients atteints de MICI nous a permis de mettre en évidence que le surnageant de Sb (Sbs) protège la morphologie tissulaire et maintient l'expression de la E-cadhérine à la membrane. In vitro nous avons également pu montrer que Sbs accélère la ré-expression de la E-cadhérine à la membrane en régulant son recyclage par les endosomes (Rab11A), entrainant ainsi la restauration et le renforcement de la barrière épithéliale intestinale. / Some intestinal pathologies including inflammatory bowel disease (IBD) are associated with an altered barrier function. The reduction or the lost of adherens junctions composed by E-cadherin/catenins complex are linked to changes in the barrier integrity. Characterization of molecules targeting the E-cadherin/catenins complex during IBD is crucial for the development of alternative therapies. From this perspective, we focus ours studies on a non pathogenic yeast, Saccharomyces boulardii, used to prevent and treat gastro-intestinal disorders and may have beneficial effects in IBD treatment, including the regulation of barrier integrity. Ours studies on colonic explants from IBD patients showed that Sb supernatant (Sbs) protects epithelial morphology and maintains E-cadherin expression at the cell surface. In vitro study pointed out that Sbs accelerated the recovery of E-cadherin at the cell membrane. This process involved the modulation of the recycling of E-cadherin by endosomes (Rab11A), leading to restoration and strengthening of intestinal barrier function.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-21T13:29:23Z No. of bitstreams: 1 fernandomendoncavidigal.pdf: 1080288 bytes, checksum: 1512d97ed552f3d14c85e421c3f6c0b9 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T18:45:58Z (GMT) No. of bitstreams: 1 fernandomendoncavidigal.pdf: 1080288 bytes, checksum: 1512d97ed552f3d14c85e421c3f6c0b9 (MD5) / Made available in DSpace on 2016-01-25T18:45:58Z (GMT). No. of bitstreams: 1 fernandomendoncavidigal.pdf: 1080288 bytes, checksum: 1512d97ed552f3d14c85e421c3f6c0b9 (MD5) Previous issue date: 2014-12-12 / Introdução: Pacientes com Doença de Crohn (DC) suboclusiva que receberam tratamento com azatioprina (AZA) tiveram menores taxas de re-hospitalização devido a todas as causas e para tratamento operatório da DC quando comparados àqueles tratados com mesalazina durante um período de três anos. Nós investigamos se a AZA também foi efetiva para a prevenção da obstrução intestinal recorrente. Material e Métodos: Taxas de obstrução intestinal recorrente foram comparadas entre pacientes tratados com AZA e aqueles tratados com mesalazina. Nós avaliamos o intervalo de tempo livre de obstrução intestinal assim como a sobrevida livre de oclusão para ambos os grupos. Resultados: Houve uma taxa cumulativa significativamente mais baixa de pacientes com suboclusão recorrente no grupo da AZA (43,8%) comparado ao grupo da mesalazina (79,4%; OR 3,34, 95% IC 1,67-8,6; p = 0,003) com o número necessário para prevenir um episódio de suboclusão de 3,7 a favor da AZA. O intervalo de tempo livre de oclusão foi maior no grupo da AZA comparado ao grupo da mesalazina (28,8 vs. 18,3 meses, p = 0,000). A sobrevida livre de oclusão aos 12, 24 e 36 meses foi significativamente maior no grupo da AZA (91%, 81%, e 72%, respectivamente) do que no grupo da mesalazina (64,7%, 35,3%, e 23,5%, respectivamente; p < 0.05 para todas as comparações). Conclusão: Em uma análise exploratória de pacientes com DC ileocecal suboclusiva, a terapia de manutenção com AZA é mais efetiva que a mesalazina para evitar ou postergar a obstrução intestinal recorrente durante um período de três anos de tratamento. / Background: Patients with subocclusive Crohn’s disease (CD) who received azathioprine (AZA) therapy had lower re-hospitalization rates due to all causes and for surgical management of CD compared to those treated with mesalazine during a 3-year period. We investigated whether AZA also was effective for prevention of recurrent bowel obstruction. Material and Methods: Rates of recurrent bowel occlusion were compared between patients treated with AZA and those treated with mesalazine. We assessed the time interval-off intestinal obstruction as well as the occlusion-free survival for both groups. Results: There was a significantly lower cumulative rate of patients with recurrent subocclusion in the AZA group (43.8%) compared with the mesalazine group (79.4%; OR 3.34, 95% CI 1.67-8.6; P= 0.003) with a number needed to treat in order to prevent one subocclusion episode of 3.7 favoring AZA. The occlusion-free time interval was longer in AZA compared with the mesalazine group (28.8 vs. 18.3 months; P=0.000).The occlusion-free survival at 12, 24, and 36 months was significantly higher in the AZA group (91%, 81%, and 72%, respectively) than in the mesalazine arm (64.7%, 35.3%, and 23.5%, respectively; P<0.05 for all comparisons). Conclusions: In an exploratory analysis of patients with subocclusive ileocecal CD maintenance therapy with AZA is more effective than mesalazine for eliminating or postponing recurrent intestinal obstruction through 3 years of therapy.

As doenças inflamatórias intestinais (DII) são causadas por desequilíbrio entre as respostas imunes efetoras e reguladoras na mucosa intestinal e podem ser moduladas pelo eixo hipotálamo-hipófise-adrenal (HPA) por meio de interações neuroimunoendócrinas e secreção de cortisol. Embora os glicocorticóides (GC) sejam utilizados para tratar a DII, o cortisol produzido pelas glândulas supra-renais também está envolvido na resposta ao estresse, que pode levar a doenças inflamatórias descontroladas. Portanto, o objetivo deste trabalho é avaliar a participação do eixo HPA na modulação da resposta imune de mucosa intestinal. Para tal, camundongos C57BL/6 foram submetidos à remoção das glândulas adrenais seguida por indução de colite pela administração de água contendo 3% de dextran sulfato de sódio (DSS). Os resultados demonstraram que a ausência das adrenais levou à maior suscetibilidade à doença e mortalidade precoce, fenômeno que não foi prevenido pela reposição de GC. Os animais adrenalectomizados com colite apresentaram níveis significativamente menores de LPS, concomitantemente ao aumento de IL-6 no soro quando comparados aos camundongos não adrenalectomizados. Além disso, os animais adrenalectomizados apresentaram menor celularidade na lâmina própria (LP), menos áreas de erosão e menor escore histopatológico associado ao aumento de IFN-? e FasL, no intestino, sem produção local compensatória de corticosterona. Houve aumento na atividade das enzimas mieloperoxidase (MPO), N- acetilglicosaminidase (NAG) e eosinófilo-peroxidase (EPO) no intestino dos animais expostos ao DSS quando comparados ao grupo de camundongos controles saudáveis, independentemente da presença do eixo HPA intacto e o tratamento com GC nos animais adrenalectomizados levou à redução significativa da atividade de MPO. Também foi observado na LP dos camundongos adrenalectomizados aumento significativo na frequência de células dendríticas tolerogênicas CD11b+CD11c+CD103+, T auxiliares (CD3+CD4+), T citolíticas (CD3+CD8+) e NKT (CD3+CD49b+), além de redução significativa da população de células dendríticas pró-inflamatórias CD11b+CD11c+CD103-, leucócitos CD11b+ e linfócitos intra-epiteliais, de maneira dependente de GC. A ausência do eixo HPA intacto levou à diminuição de leucócitos totais no baço quando comparados ao grupo com colite, relacionada principalmente à redução significativa na frequência de células NKT (CD3+CD49b+), as quais foram restauradas nos camundongos tratados com GC exógenos. Durante a exposição ao DSS houve aumento de células Th2 e Th1 no baço dos camundongos não adrenalectomizados, enquanto que a remoção das adrenais levou a notável redução na população de células T CD4 produtoras de IL-4, IL-10, IFN-? ou IL-17, com aumento de células Th17 e diminuição significativa de células Th1 no baço dos camundongos adrenalectomizados e tratados com GC. De forma interessante, houve menor acúmulo de células T reguladoras juntamente à redução na intensidade média de fluorescência (MFI) de FOXP3 em células T CD4+CD25+ do baço dos camundongos adrenalectomizados expostos ao DSS, de maneira geral dependente de GC. Por fim, esta diminuição de mecanismos reguladores foi acompanhada de menor índice de proliferação e aumento de IL-10 no sobrenadante de cultura de esplenócitos de camundongos com o eixo HPA não ii funcional, indicando que a ausência de GC endógenos pode alterar significativamente a homeostase do sistema imunológico. Juntos, nossos resultados demonstram que o eixo HPA é importante na modulação da resposta imunológica durante a colite induzida experimentalmente / Inflammatory bowel diseases (IBD) are caused by imbalance between regulatory and effector immune responses in the intestinal mucosa and can be modulated by the hypothalamic-pituitary-adrenal (HPA) axis via neuroimmune endocrine interactions and secretion of cortisol. Although glucocorticoids (GC) are used to treat IBD, cortisol produced by the adrenals glands is also involved in the stress response, which can lead to uncontrolled inflammatory diseases. Therefore, the aim of this study was to evaluate the HPA axis in the modulation of the immune response of intestinal mucosa. C57BL/6 mice were subjected to removal of the adrenal glands followed by induction of colitis by administration of water containing 3% dextran sulfate sodium (DSS). The results showed that the absence of adrenals led to increased susceptibility to disease and early mortality, a phenomenon that was not prevented by GC replacement. Adrenalectomized animals exposed to DSS had significantly lower levels of LPS, concomitantly to increased IL-6 in the serum when compared to non-adrenalectomized mice. In addition, adrenalectomized animals had lower cellularity in the lamina propria (LP), less erosion areas and less histopathologic score associated with increased IFN-? and FasL in the intestine, without compensatory local production of corticosterone. There was an increase in the activity of the myeloperoxidase (MPO) enzyme, N- acetilglicosaminidase (NAG) and eosinophil-peroxidase (EPO) in the intestines of DSS-exposed animals when compared to the healthy control group of mice, regardless of the presence of intact HPA axis, while treatment with GC led to significantly reduced MPO activity. It was also observed in the LP of adrenalectomized mice significant increase in the frequency of tolerogenic dendritic cells CD11b+CD11c+CD103+, helper T (CD3+ CD4+), cytolytic T (CD3+ CD8+) and NKT (CD3+ CD49b+) besides significant reduction in the population of pro-inflammatory dendritic cells CD11c+ CD11b+ CD103-, leukocyte CD11b+ and intraepithelial lymphocytes, GC-dependent manner. The absence HPA intact carried decrease in total leukocytes in spleen when compared to the group with colitis, related mainly to significant reduction in the frequency of NKT cells (CD3+CD49b+), which were restored in the GC treated mice. During exposure to DSS there was increased Th2 and Th1 cells in the spleen of non-adrenalectomized mice, while the removal of the adrenals was associated to a marked reduction in the population of CD4 T cells producing IL-4, IL-10, IFN-? or IL-17 with increased Th17 cells and significant decrease in Th1 cells in the spleen of adrenalectomized mice treated with GC. Interestingly there was less accumulation of regulatory T cells together to a reduction in mean fluorescence intensity (MFI) of FOXP3 in CD4+CD25+ T cells in the spleen of mice exposed to DSS after adrenalectomy, most dependent on GC. Finally, the decline of regulatory mechanisms was accompanied by lower rates of proliferation and increased IL-10 in the supernatant culture of splenocytes of mice with disrupted HPA axis, indicating that the absence of endogenous GC altered significantly the homeostasis of the immune system. Together, our results demonstrate that the HPA axis is important in modulating the immune response during experimentally induced colitis

Philosophiae Doctor - PhD / Background: A subtype of inflammatory bowel disease, Crohn' s disease is thought to represent a complex interaction between environmental factors, a defective immune system, the gastrointestinal microbiome and genetic' susceptibility; however; the-prevalence of different susceptibility mutations appears to vary between population groups, implying distinctions in disease pathogenesis or risk. Vitamin D, signaling through the vitamin D receptor, appears to have numerous effects on the immune system, and deficiency has been shown to playa role in both the pathogenesis and severity of experimental inflammatory bowel disease. However, the literature surrounding the association between vitamin D concentrations and disease severity in Crohn's disease is limited, and no such literature exists in South Africa. Furthermore, a paucity of data exists on the racial variability of Crohn' s disease phenotype in the Western Cape population of South Africa, as well as environmental factors in childhood associated with future Crohn's disease development. Aims: The three primary aims of the study were to investigate: 1) the racial variability of, Crohn's disease phenotype, defined by the Montreal classification scheme, as well as Crohn's disease behavior, using predefined definitions, stratified as 'complicated' or 'uncomplicated', based on a cross-sectional study design; 2) the association between childhood environmental exposures and the subsequent development of Crohn's disease, with specific emphasis on the timing of exposure, based on a case-control study design; and 3) the association between serum 25(OH)D concentration with Crohn's disease activity, measured by the Harvey Bradshaw Index, based on a cross-sectional study design; in this process, various vitamin D thresholds for predicting a high disease activity score were investigated, and the serum 25(OH)D concentrations were compared with those of the healthy controls to evaluate the prevalence of vitamin D deficiency. Design: This was a case control study, as well as two cross-sectional evaluations of the case control study data, of all consecutive Crohn's disease patients (ages 18-70 years) seen between September 2011 and January 2013 during their normally scheduled appointments at Schuur Hospital and Tygerberg Hospital. Control subjects for the study were identified from the same populations giving rise to the Crohn's disease cases. An investigator-administrated questionnaire was used to identify numerous demographic and lifestyle variables, as well as childhood environmental exposures during three age intervals; 0-5, 6-10 and 11-18 years. Clinical variables at diagnosis and time of study enrolment were determined via a review of medical and pharmacy records, as well as clinical examination by the consulting gastroenterologist. Serum 25(OH)D was measured using the SIEMENS ADIVA Centaur® XP Vitamin D Immunoassay [Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA]. Vitamin D status was classified as either 'deficient' or 'sufficient', and was analyzed in 2 ways: ~20 ng/mL versus ~21 ng/mL; and ~29 ng/mL versus ~30 ng/mL, respectively. One year after study completion, a total of 40 (10%) randomly selected participants from the cohort completed the interviewer-administered questionnaire for a second time. A kappa statistic was used in order to measure the agreement between repeated data for the questionnaire. Only data pertaining to the three age intervals (0-5, 6-10 and 11-18 years) was extracted in this process. Results: One hundred and ninety four Crohn's disease patients and 213 controls meeting our inclusion criteria were identified; 35 (18%) and 19 (9%) were White, 152 (78%) and 177 (83%) were Coloured, and 7(4%) and 17 (8%) were South African Black, respectively. No subjects reported being of Asian or Indian ethnicity. Overall, 125 (31%) of the cohort were male. On multiple logistic regression analysis, Coloured Crohn's disease patients were significantly more likely to develop 'complicated' Crohn's disease (60% versus 9%, P = 0.023) during the disease course when compared to White Crohn's disease patients. In addition, significantly more White subjects had successfully discontinued cigarette smoking at study enrolment (31% versus 7% reduction, P = 0.02). No additional interracial differences were found. A low proportion inflammatory bowel diseases family history was observed among the Coloured and Black subjects. When evaluating childhood environmental exposures, multiple logistic regression analysis showed that during the age interval 6-10 years, never having consumed unpasteurized milk [(OR = 6.43; 95% Cl, 3.02-14.81), (K =0.79; 95% Cl, 0.39-1.00)] and never having a donkey, horse, sheep or cow on the property [(OR = 3.10; 95% Cl, 1.42-7.21), (K = 0.84; 95% Cl, 0.12-1.00)], significantly increased the risk of developing future Crohn's disease. During the age interval 11-18 years, an independent risk-association was identified for; never having consumed unpasteurized milk (OR = 2.60; 95% Cl, 1.17-6.10) and second-hand cigarette smoke exposure (OR = 1.93; 95% Cl, 1.13-3.35). For the vitamin Danalysis, 186 Crohn's disease patients and 199 control subjects met the study inclusion criteria. Overall, 113 (29%) of the cohort were male. Forty four percent of the cohort had a deficient vitamin D concentration (::;20 ng/ml.), no participants had severely deficient vitamin D concentrations, and 26% of the cohort had sufficient vitamin D concentrations (:::30 ng/mL). Fifty-three percent of the controls and 34% of the cases had vitamin D concentrations ::;20 ng/mL (P < 0.001). On multiple logistic regression analysis, higher Harvey Bradshaw Index scores and not having taken vitamin D supplementation in the six months prior to enrolment were identified as independent predictors of vitamin D deficiency in Crohn's disease patients; defined either as ::;20 ng/mL, or as ::;29 ng/mL (P < 0.001). Compared to patients with Harvey Bradshaw Index <5, those with Harvey Bradshaw Index 2:8 were 2.5-times more likely to have vitamin D concentrations ::;21 ng/mL (PR = 2.5; 95% Cl, 1.30-6.30). The risk was similar, though not as high, if deficiency was defined as ::;29ng/ml. (PR = 2.0; 95% Cl, 1.20-3.50). Conclusions: Coloured Crohn's disease patients were significantly more likely to develop 'complicated' Crohn's disease over time when compared to White Crohn's disease patients. Limited microbial exposures and exposure to second-hand cigarette smoke during childhood is associated with future development Crohn's diseases. However the inconsistencies between each age interval with regards to the identified risk factors may imply that the effect of different viruses or bacteria on the development of immune structures varies according to the timing of exposure. The finding that lower serum 25(OH)D was associated with moderate to severe Crohn's disease activity suggests that this patient population may benefit from vitamin D supplementation in order to achieve, or maintain a serum 25(OH)D concentration of at least 30 ng/mL.

Bakgrund: Inflammatorisk tarmsjukdom (IBD) är samlingsnamn för kroniska mag-och tarmsjukdomar och innefattar Crohns sjukdom (CD) samt Ulcerös kolit (UK). Båda sjukdomar löper i skov med återkommande, långvariga diarréer med förbättrings-och försämringsperioder och kan relateras till fysiska, psykiska samt sociala faktorer. Då uppenbara orsaker eller symtom ej finns är det på många sätt en dold sjukdom och kan skapa otillräcklig förståelse för patientens specifika behov. För att patienten ska få rätt stöd i hanteringen av sjukdomen samt få en god omvårdnad, bör sjuksköterskan att ha gott bemötande, tillräcklig kunskap där vården ges på ett personcentrerat, evidensbaserat sätt. Syfte: Syftet var att beskriva patienters upplevelse av att leva med inflammatorisk tarmsjukdom, IBD. Metod: En litteraturöversikt valdes som metod och baserades på tio kvalitativa artiklar. Databassökningar gjordes från CINAHL Complete och Medline with full text. Artiklarna analyserades enligt Fribergs fem steg. Resultat: I resultatet framkom sex teman utifrån patienternas upplevelse; påverkan av IBD på självbilden, påverkan av IBD i relationer och sociala sammanhang, patienters upplevelse av hälso- och sjukvården, känslomässig påverkan, utveckling och acceptans samt påverkan av IBD i arbetslivet. Diskussion: Resultatdiskussionen diskuterades av författarna utifrån Katie Erikssons caritativa teori om att lindra lidande och utifrån centrala fynd utifrån temaområden i resultatet. / Background: Inflammatory bowel disease (IBD) is the collective name for chronic gastrointestinal disorders and includes Crohn's disease (CD) and Ulcerative colitis (UK). Both diseases relapses with recurring, long-term diarrhea with improvement and deterioration periods and can be related to physical, mental and social factors. In the absence of obvious causes or symptoms, it is in many ways a hidden disease and can create scarce understanding of the patient's specific needs. In order for the patient to receive the right support in the management of the disease and to receive good nursing care, the nurse have to give good care, have sufficient knowledge and care for the patient in a person-centered, evidence-based way. Aim: The purpose was to describe the patient’s experiences of living with inflammatory bowel disease, IBD. Method: A literature review was chosen as the method and was based on ten qualitative articles. Database searches were performed from CINAHL Complete and Medline with full text. The articles were analyzed according to Friberg's five steps. Results: In the result, six themes emerged from the patients' experience; the influence of IBD on the self-image, the influence of IBD in relationships and social contexts, patients' experience of health care, emotional impact, development and acceptance, and the influence of IBD in working life. Discussion: The results discussion was discussed by the authors on the basis of Katie Eriksson's charitable theory of alleviating suffering and on the basis of central findings based on thematic areas in the result.

The effect of serum 25-hydroxycholekalciferol levels on musculoskeletal system in children with inflammatory bowel disease Background: Low bone mineral density and osteoporosis represent severe secondary complications that can be a result of childhood chronic disease. According to Frost's mechanostat theory impaired muscle functions may contribute to the changes observed on the skeleton. Aims: The aim of this study was to: 1) evaluate parameters of bone mineral density, bone geometry and dynamic muscle functions in children and adolescent with chronic disease - inflammatory bowel disease (IBD) and type 1 diabetes (T1D); 2) evaluate a possible effect of vitamin D deficiency and vitamin D supplementation or duration of the disease on the musculoskeletal unit; 3) determine clinical or laboratory predictors of muscle and bone parameters. Methods: The study was divided into two substudies according to the diagnosis. Seventy patients with IBD (median age 13.8 years) were included in one study, fifty-five of which completed all of the planned procedures. During the study, IBD patients were supplemented with 2000 IU/d of vitamin D. In the second study 95 patients with T1D were included (median age 16.4 years). BMD and bone geometry of non-dominant tibia was evaluated using peripheral quantitative computed...