Transforming growth factor beta 1 (TGF-beta1) ist ein multifunktionales Zytokin, welches eine Rolle in der Sepsis und in der Sepsis-induzierten Myopathie spielen könnte. Weiterhin könnten erhöhte TGF-beta1-Level zur Muskelschwäche, die mit der Intensivpflege assoziiert ist (engl. intensiv care unit-acquired weakness, ICUAW), beitragen. Der TGF-beta1- Signalweg wurde in Skelettmuskelbiopsien von ICUAW-Patienten heraufreguliert. Secreted frizzled related protein 2 (SFRP2) wurde in einer Gen-Set-Anreicherungsanalyse als das am höchsten regulierte Gen identifiziert. Im Mausmodell führten Sepsis und Hunger zu einer verringerten Sfrp2-Expression, während dies in der Denervation-induzierten Skelettmuskelatrophie nicht festzustellen war. In differenzierten C2C12-Myotuben führte TGF-beta1 zu einer verringerten Sfrp2-mRNA- und Proteinexpression. Luciferase-Assays deuteten auf eine TGF-beta1-abhängige Herunterregulation von Sfrp2 hin, welche auf Promoterebene durch mögliche negative regulatorische Elemente im Sfrp2-Promoter vermittelt wurde. Weiterhin wurde eine TGF-beta1 induzierte Muskelatrophie durch transkriptionelle Repression der myosin heavy chain Gene beobachtet. Im Gegensatz dazu veränderte TGF-beta1 nicht den proteasomalen Abbau muskulärer Proteine. Die Genexpression von Tripartite motif containing 63 und F-box only protein 32 war hingegen leicht herunterreguliert. TGF-beta1-induzierte Atrophie in differenzierten C2C12-Myotuben wurde teilweise durch rekombinantes Sfrp2 aufgehoben. Weiterhin wurde eine direkte physikalische Interaktion zwischen Sfrp2 und TGF-beta1 gefunden, welche diesen Effekt verursacht haben könnte. Zusammengefasst lässt sich feststellen, dass der TGF-beta1- Signalweg eine wichtige Rolle in der ICUAW durch Inhibition der myosin heavy chain Expression spielt. TGF-beta1-abhängige Herunterregulation von Sfrp2 könnte zu einer Feedback-Antwort, die das Ausmaß der Atrophie durch TGF-beta1 verstärkt, führen. / Transforming growth factor beta 1 (TGF-beta1) is a multifunctional cytokine that may play a role in sepsis and in sepsis-induced myopathy. Our group speculated that increased TGF-beta1 could contribute to intensive care (ICU)-acquired weakness (ICUAW), a catastrophic muscle disease in critically ill patients. We found that TGF-beta1 signaling in skeletal muscle biopsies of ICUAW patients was upregulated. Secreted frizzled related protein 2 (SFRP2) was the most regulated gene identified by gene set enrichment analysis (GSEA). I then studied the regulation and function of SFRP2 in different skeletal muscle atrophy models. In three mouse models, downregulated Sfrp2 expression was observed in sepsis and starvation, but not in denervation-induced skeletal muscle atrophy. In differentiated C2C12 myotubes, TGF-beta1 downregulated Sfrp2 expression on both mRNA and protein levels. Luciferase assays suggested that TGF-beta1-dependent downregulation of Sfrp2 was mediated at the promoter level through possible negative regulatory elements in the Sfrp2 promoter. I also observed that TGF-beta1-induced muscle atrophy was accompanied by transcriptional repression of myosin heavy chain genes. In contrast, TGF-beta1 did not increase proteasomal degradation of muscular proteins since gene expression of Tripartite motif containing 63 (Trim63) and F-box only protein (Fbxo32) was not upregulated; instead, they were slightly downregulated. TGF- beta1-induced differentiated C2C12 myotube atrophy was partially reversed by recombinant Sfrp2. This inhibitory effect could have resulted from direct interaction between Sfrp2 and TGF-beta1, since I found a physical interaction between these two proteins. Taken together, TGF-beta1 signaling pathway could play an important role in ICUAW via inhibition of myosin heavy chain expression. TGF-beta1-dependent downregulation of Sfrp2 may establish a feedback loop augmenting the atrophic effect of TGF-beta1.

Submitted by Maicon Juliano Schmidt (maicons) on 2015-05-08T19:40:28Z No. of bitstreams: 1 Mirela Rosa.pdf: 33214432 bytes, checksum: 6b8afee33b9a338a882f4914815741d2 (MD5) / Made available in DSpace on 2015-05-08T19:40:28Z (GMT). No. of bitstreams: 1 Mirela Rosa.pdf: 33214432 bytes, checksum: 6b8afee33b9a338a882f4914815741d2 (MD5) Previous issue date: 2013-01-31 / Nenhuma / O Design de Serviços é constituído de uma metodologia que utiliza um conjunto de ferramentas que permitem projetar soluções para melhorar a percepção dos usuários sobre os serviços, que podem ser aplicadas em diversas áreas e contextos. Conforme a complexidade de cada setor, se torna necessário considerar abordagens de projeto que tornariam os resultados desta metodologia mais eficazes e mensuráveis, como é o caso da Saúde. Alguns autores que vêm pesquisando a aplicação neste setor, sugerem uma possível integração do Design baseado em evidências (DBE) e do Design baseado em experiências (DBEx) para viabilizar que um projeto orientado pelo usuário seja implementado em larga escala. Em busca da investigação sobre a lógica de evidências, foi estudada uma ferramenta utilizada no setor de serviços chamada Mecanismo da Função Produção (MFP), que prevê a quantificação das perdas dos processos. O presente estudo teve como contexto o Intensivismo Adulto (CTI) de um hospital privado em Porto Alegre e aplicou um caso em Design de Serviços com a lógica das evidências através da ferramenta MFP, para o desenvolvimento de uma abordagem integrada. Foi utilizado o método de pesquisa-ação com a descrição de todo o processo de projeto e dos resultados obtidos. A partir das análises pode-se constatar que (i) o olhar das evidências contribui para replicações dos resultados do projeto em casos futuros, (ii) o MFP pode ser um argumento para justificar a realização de um projeto em Design e (iii) para a integração das experiências com as evidências no setor hospitalar, pode-se gerenciar o projeto de modo a destinar um tempo maior para o diagnóstico e para a implementação. / Service Design consists of a methodology that uses a set of tools to create solutions to improve users perception on services, which can be applied in many fields and contexts. As the complexity of each field, it is necessary to consider approaches that would make results of this methodology more effective and measurable, such as health sector. Some authors have been research application of Service Design in this sector, and suggest a possible integration of evidence-based design (EBD) and experience-based design (ExBD) to enable a user-oriented design on a large scale implementation. In search on the logic of evidence, we studied a tool used in service sector called Mechanism of the Production Function, that provides quantification of loss processes. The present study was context in Intensive Care Unit (ICU) of a private hospital in Porto Alegre and applied a case of Service Design with the logic of the evidence through MFP tool for the development of an integrated approach. We used the method of action research with the description of the whole design process and results. From the analysis it was found that (i) the look of the evidence contributes to replication of project outcomes in future cases, (ii) MFP is an argument supporting the realization of a Design project and (iii) to integrate experiences with evidence in the hospital sector, we can manage the project in order to devote more time to the diagnosis and implementation.

Made available in DSpace on 2014-07-29T15:30:40Z (GMT). No. of bitstreams: 1 Dissertacao part1 Denise Milioli Ferreira.pdf: 425784 bytes, checksum: 2fa9fb3f87bb9afd8a2ef9c5ee09a0a8 (MD5) Previous issue date: 2001-12-14 / Accidental tetanus is a millenary disease of high lethal indices, even when proven and effective, low cost prophylactics are available. Several studies have tried to identify the physiopathological process which releases the succession of clinical manifestations of the disease. The objective of these studies is to recognize and make available a new strategy for the treatment of tetanus after exposition to the toxin. The diagnosis of tetanus is eminently clinical. Several factors may occur during the evolution of the disease which complicate its prognosis. The most frequent complications are infections and autonomic dysfunction. Several therapeutic options exist. However, they have a supportive and symptomatic role. This study has as its objective to show the complexity which involves the physiopathological process and treatment of accidental tetanus as well as to emphasize that the only effective way of reducing tetanic mortality is, doubtless, a better vaccine coverage of susceptible individuals. NOTE: Essay with review articles. This is the sum of the first. / O Tétano acidental é uma doença milenar, que mesmo com a disponibilidade de profilaxia de comprovada eficácia e baixo custo, mantém alta taxa demorbiletalidade. Vários estudos vêm tentando identificar em nível biomolecular, o processo fisiopatológico que desencadeia as manifestações clínicas da doença, com o objetivo de conhecer e disponibilizar uma nova estratégia para o tratamento do tétano, após a exposição à toxina e sua fixação nos neurotransmissores. O diagnostico do tétano é eminentemente clínico. Podem ocorrer várias complicações durante a evolução da doença que comprometem o seu prognóstico. As complicações mais freqüentes e de maior gravidade são as infecciosas e a disautonomia simpática. Existem várias opções para o tratamento do tétano, todas porém de caráter suportivo e sintomático. Este estudo tem como objetivos: ressaltar a complexidade do processo fisiopatológico e do tratamento do tétano acidental e enfatizar como única forma efetiva de se reduzir a morbiletalidade do tétano, a cobertura vacinal das populações susceptíveis, constituída basicamente por adultos e idosos. OBS: Dissertação com artigos de revisão. Este é o resumo do primeiro.

Introduction: Epidemiological studies have indicated that 5-38% of influenza like illnesses (ILI) develop into severe disease due to, among others, factors such as; underlying chronic diseases, age, pregnancy, and viral mutations. There are suggestions that dual or multiple virus infections may affect disease severity. This study investigated the association between co-infection between influenza A viruses and other respiratory viruses and disease severity. Methodology: Datum for samples from North West England tested between January 2007 and June 2012 was analysed for patterns of co-infection between influenza A viruses and ten respiratory viruses. Risk of hospitalization to a general ward ICU or death in single versus mixed infections was assessed using multiple logistic regression models. Results: One or more viruses were identified in 37.8% (11,715/30,975) of samples, of which 10.4% (1,214) were mixed infections and 89.6% (10,501) were single infections. Among patients with influenza A(H1N1)pdm09, co-infections occurred in 4.7% (137⁄2,879) vs. 6.5% (59⁄902) in those with seasonal influenza A virus infection. In general, patients with mixed respiratory virus infections had a higher risk of admission to a general ward (OR: 1.43, 95% CI: 1.2 – 1.7, p = <0.0001) than those with a single infection. Co-infection between seasonal influenza A viruses and influenza B virus was associated with a significant increase in the risk of admission to ICU/ death (OR: 22.0, 95% CI: 2.21 – 219.8 p = 0.008). RSV/seasonal influenza A viruses co-infection also associated with increased risk but this was not statistically significant. For the pandemic influenza A(H1N1)pdm09 virus, RSV and AdV co-infection increased risk of hospitalization to a general ward, whereas Flu B increased risk of admission to ICU/ death, but none of these were statistically significant. Considering only single infections, RSV and hPIV1-3 increased risk of admission to a general ward (OR: 1.49, 95% CI: 1.28 – 1.73, p = <0.0001 and OR: 1.34, 95% CI: 1.003 – 1.8, p = 0.05) and admission to ICU/ death (OR: 1.5, 95% CI: 1.20 – 2.0, p = <0.0001 and OR: 1.60, 95% CI: 1.02 – 2.40, p = 0.04). Conclusion: Co-infection is a significant predictor of disease outcome; there is insufficient public health data on this subject as not all samples sent for investigation of respiratory virus infection are tested for all respiratory viruses. Integration of testing for respiratory viruses’ co-infections into routine clinical practice and R&D on integrated drugs and vaccines for influenza A&B, RSV, and AdV, and development of multi-target diagnostic tests is encouraged.