Le syndrome d’apnées obstructives du sommeil (SAOS) est associé à de nombreuses co-morbidités métaboliques et cardiovasculaires. L’hypoxie intermittente chronique, une des composantes du SAOS, induit des mécanismes intermédiaires délétères tels que stress oxydatif, inflammation, insulino-résistance ou encore dyslipidémie, à l’origine de ces comorbidités. Ces mécanismes intermédiaires sont également communs à d’autres pathologies respiratoires chroniques telles que la bronchopneumopathie chronique obstructive (BPCO) et le syndrome d’obésité hypoventilation (SOH).L’hypoxie intermittente et les mécanismes intermédiaires associés sont aussi à l’origine de l’existence et de la progression de la stéatopathie métabolique (« non alcoholic fatty liver disease »). Ce lien entre pathologies respiratoires chroniques et atteinte hépatique est un mécanisme essentiel mais plus récemment étudié des co-morbidités dans le SAOS et la BPCO. Différents biomarqueurs cardiométaboliques ont donc été étudiés dans ces pathologies respiratoires chroniques à la fois pour caractériser les co-morbidités et l’atteinte systémique et pour apprécier l’impact de différentes thérapeutiques. La première partie de cette thèse sera consacrée à une revue systématique des différents biomarqueurs cardio-métaboliques liés à chacune de ces 3 pathologies respiratoires chroniques : SAOS, BPCO et SOH.Le traitement du SAOS par pression positive continue (PPC) a un effet bénéfique sur les symptômes fonctionnels liés à cette pathologie. Cependant, l’impact de la PPC sur d’autres conséquences cardio-métaboliques délétères du SAOS reste encore à démontrer par des essais randomisés contrôlés, notamment sur l’atteinte hépatique.Dans la seconde partie de cette thèse, nous détaillerons l’impact de la PPC sur les différents marqueurs cardiométaboliques du SAOS à l’aide d’une revue systématique puis d’une étude randomisée contrôlée sur l’impact de la PPC sur les marqueurs d’atteinte hépatique.Par ailleurs, les patients atteints de SAOS, BPCO ou SOH reçoivent du fait de leur polypathologie (multimorbidité) des traitements médicamenteux multiples qui visent à contrôler au mieux les co-morbidités. Il est donc primordial de considérer la prise en charge globale de ces patients du point de vue de leurs traitements instrumentaux (PPC et ventilation non invasive) mais aussi en considérant l’impact des traitements médicamenteux associés. En effet, les traitements médicamenteux peuvent interférer avec la sévérité de la pathologie elle-même et impacter les biomarqueurs liés aux comorbidités associées. La troisième partie de cette thèse sera consacrée à l’étude d’un antihypertenseur chez le patient SAOS et envisagera l’influence des médicaments sur la pertinence de l’usage des bicarbonates comme marqueurs diagnostiques du SOH.En conclusion, nous insisterons sur la nécessité d’une prise en charge intégrée multi systémique et d’une prise en charge personnalisée de ces patients. / Obstructive sleep apnea (OSA) is associated with related metabolic and cardiovascular comorbidities. Chronic intermittent hypoxia the hallmark of OSA induces deleterious intermediary mechanisms such as oxidative stress, systemic inflammation, insulin resistance and dyslipidemia. Cardiovascular and metabolic comorbidities are also key features of other chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome (OHS). Chronic hypoxia and deleterious intermediary mechanisms also trigger occurrence and progression of non alcoholic fatty liver disease. This link between chronic respiratory diseases and liver injury is observed through modifications of specific liver biomarkers in OSA and COPD. A variety of cardiometabolic biomarkers have been studied for stratification of cardio-metabolic risk and assessing treatment impact in chronic respiratory diseases. The first part of this PhD thesis is a systematic review of cardio-metabolic biomarkers in 3 respiratory diseases: OSA, COPD and OHS.Continuous positive airway pressure (CPAP) the first line therapy for OSA improves symptoms and quality of life. However, CPAP effects on cardio-metabolic consequences remains still debated. In the second part of the PhD thesis, we will address CPAP impact on different cardiometabolic biomarkers and more specifically in markers of liver injury by reporting original results of a randomized controlled trial (RCT).Polypharmacy is usual in patients with OSA, COPD or OHS. Beyond CPAP or non invasive ventilation treatment, it is essential address the contribution of associated medications. Indeed, pharmacological treatments can interfere with the severity of the disease and control of associated comorbidities. The third part of the thesis will present a RCT evaluating Bosentan in hypertensive OSA patients and will present how medications for comorbidities decrease bicarbonate diagnosis value for OHS.We will conclude by underlining the crucial importance of personalized medicine and integrated care in chronic respiratory diseases.

Made available in DSpace on 2016-06-02T20:19:24Z (GMT). No. of bitstreams: 1 5861.pdf: 1042753 bytes, checksum: 0871887426e0f5b61aac05569b42b728 (MD5) Previous issue date: 2014-02-28 / Background: Work-Related Musculoskeletal Disorders (WMSDs) are associated with biomechanical and psychosocial risk factors. Accurate assessment of exposure at work by means of direct measurement equipment allows risk factors identification. Selfreported questionnaires and inflammatory biomarkers can also be applied in this context. Therefore, two studies were conducted aiming to understand these aspects. Objectives: Study 1 aimed to describe the biomechanical exposure of the lumbar spine and shoulders in industrial workers and to correlate biomechanical and psychosocial aspects with functional and clinical indicators. Study 2 aimed to determine whether inflammatory biomarkers are altered in individuals with WMSD performing occupational activities or simulated tasks in the laboratory by means of a systematic literature review. Methods: In study 1 twenty eight male workers were evaluated by questionnaires related to musculoskeletal symptoms, disability and workplace stress. Inclinometers (Logger Tecknologi, Åkarp, Sweden) were used to assess the postures at work. In Study 2, a survey was conducted in the electronic databases including Medline, Science Direct, Web of Science, Scopus and CINAHL. The last survey was conducted in May 2013. Studies that investigated the relationship between inflammatory markers and WMSD in individuals who performed work activities or simulated tasks were selected. There were no restrictions regarding the language and date of publication. Results: Study 1 showed that workers showed slight flexion of the lumbar spine. The elevation of the shoulders reached values above 90° in less than 4% of the work time. The lunch break showed lower lumbar spine and shoulders angular velocity. Significant correlations were found between time in flexion greater than 15 and symptoms in the lumbar spine in the last 12 months, lumbar inclination and social support, velocity and shoulder symptoms in the last 12 months and control and shoulder symptoms. Active workers had higher proportion of shoulder symptoms in the past 12 months and workers with low strain sought health care for symptoms in the shoulders more often. In Study 2 the electronic search yielded 410 studies, of which nine met the inclusion criteria, five quasi-experimental and four observational. No experimental study was found. Four studies were considered high and five low methodological quality. Interleukin 6 was evaluated in eight studies, TNFα in six studies, interleukin1β in four studies, C-reactive protein in three studies and interleukins 8 and 10 in two studies. Thirteen other inflammatory markers were found in only one study each. Conclusion: Exposure of workers to postural risk factors were described. The angular velocity differentiate exposure of work and rest. Correlation between biomechanical, psychosocial and clinical factors were found. Psychosocial factors may interfere with the biomechanical exposure. In relation to inflammatory biomarkers, the level of evidence obtained was inconclusive because the results were inconsistent between studies. Standardization of measures and methodological improvements are strongly recommended. / Contextualização: As Lesões por Esforços Repetitivos/Distúrbios Osteomusculares Relacionados ao Trabalho (LER/DORT) são associados a fatores de risco biomecânicos e psicossociais. A avaliação precisa da exposição no trabalho por meio de equipamentos de medida direta permite identificar os fatores de risco. Questionários auto-aplicáveis e biomarcadores inflamatórios também podem ser aplicados neste contexto. Diante disso, foram realizados dois estudos visando compreender estes aspectos. Objetivos: O Estudo 1 teve por objetivo descrever a exposição biomecânica da coluna lombar e ombros em trabalhadores de uma indústria de alumínio e correlacionar aspectos biomecânicos e psicossociais com indicadores clínicos e funcionais. O Estudo 2 teve por objetivo verificar se os biomarcadores inflamatórios estão alterados em indivíduos com LER/DORT que realizam atividades ocupacionais ou tarefas simuladas em laboratório por meio de uma revisão sistemática da literatura. Métodos: No estudo 1 foram avaliados 28 trabalhadores do sexo masculino por questionários referentes a sintomas musculoesqueléticos, incapacidade e estresse no trabalho. Inclinômetros (Logger Tecknologi, Åkarp, Sweden) foram utilizados para avaliar as posturas durante o trabalho. No Estudo 2 foi realizada uma pesquisa nas bases de dados eletrônicas Medline, Science Direct, Web of Science, Scopus e Cinahl. A última pesquisa foi realizada em maio de 2013. Foram selecionados estudos que investigaram a relação entre marcadores inflamatórios e LER/DORT em indivíduos que realizassem atividades ocupacionais ou tarefas simuladas. Não houve restrição em relação ao idioma e data de publicação. Resultados: O Estudo 1 mostrou que os trabalhadores apresentaram pequena flexão da coluna lombar. A elevação dos ombros atingiu valores superiores a 90º em menos que 4% do tempo. O intervalo de almoço apresentou menor velocidade angular para coluna lombar e ombros. Correlações significantes foram encontradas entre tempo em flexão maior que 15o e sintomas na coluna lombar nos últimos 12 meses, inclinação do tronco e apoio social, velocidade do ombro e sintomas nos últimos 12 meses e controle e sintomas do ombro. Trabalhadores ativos apresentaram maior proporção de sintomas no ombro nos últimos 12 meses e trabalhadores com baixo desgaste procuraram assistência à saúde por sintomas nos ombros com maior frequência. No Estudo 2 a busca eletrônica resultou em 410 estudos, dos quais nove atenderam aos critérios de inclusão, sendo cinco quase experimentais e quatro observacionais. Nenhum estudo experimental foi encontrado. Quatro estudos foram considerados de alta e cinco de baixa qualidade metodológica. A interleucina 6 foi avaliada em oito estudos, TNFα em seis estudos, interleucina1β em quatro estudos, proteína C reativa em três estudos e interleucinas 8 e 10 em dois estudos. Treze outros marcadores inflamatórios foram encontrados em apenas um estudo cada. Conclusão: A exposição dos trabalhadores aos fatores de risco posturais foi descrita. A velocidade angular permitiu diferenciar a exposição do trabalho e descanso. Houve correlação entre fatores biomecânicos, psicossociais e clínicos. Fatores psicossociais podem interferir na exposição biomecânica. Em relação aos biomarcadores inflamatórios, o nível de evidência obtido foi inconclusivo uma vez que os resultados foram inconsistentes entre os estudos. Padronização das medidas e cuidados metodológicos são fortemente recomendados.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / There is a great concern of consumers with health, food safety and nutritional value of foods that come with even more interest in sau-hum- ming, nutritious and great use food products. Aimed to evaluate the effect of seasonality and industrial heat treatment on fatty acids of milk and the biological response of rats on diets of different lipid sources submitted or not to physical activity profile. In assessing the effect of climate station and heat treatment on fatty acid profile of milk samples were collected (in natura, pasteurized and sterilized) for 11 consecutive months in the Rio Grande do Sul Dairy Industry. Samples were subjected to extraction lipids and after the determination of fatty acid profiles in gas chromatography, using patterns of fatty acids. The bioassay was conducted for a period of 52 days, we used 36 adult male Wistar rats, divided into 6 treatments of six animals each and were fed diet AIN- 93M, varying the source of lipids and regular physical activity: DCSA normolipídica control, with soybean oil and no physical activity; DCCA normolipídica control with soy oil and physical activity; DMSA fat with butter and no physical activity; DMCA fat with butter and physical activity; DGSA fat with hydrogenated vegetable fat and no physical activity; DGCA fat diet with hydrogenated vegetable fat and physical activity. We investigated the effect of treatments on feed intake, weight gain, feed conversion, feed efficiency ratio, weight, liver, kidneys, heart, epididymal fat digestibility of diets, blood parameters (total COL, HDL, TG, GLI , ALB, ALT, AST, urea, creatinine, IL-1, IL-6, IL-10, TNF-α, IFN-γ and PCRus) and the histology of the aortic arch. The sterilization of milk caused reduction of docosanoic fatty acids, conjugated linoleic acid (cis-9, trans-11) and eicosapentaenoic ratio PUFA: SFA. The seasonal variation caused in octadecatrienoic fatty acids, conjugated linoleic acid (cis- 9, trans-11), docosadienoic acid, and eicosapentaenoic ratio PUFA: SFA. The experimental diets interfere with the feed intake, weight gain, feed conversion ratio, feed efficiency coefficient, epididymal fat weight and total cholesterol blood parameters, alanine transaminase, aspartate transaminase, IL-1, IL-6 and IL-10. Physical activity influence on blood triglyceride, creatinine, IL-1, IL-6 and IL-10. The interaction between diet and physical activity was significant for TNF-α and INF-γ. From the results it can be concluded that the heat-treated milk (pasteurization and sterilization) produced in four seasons show variations in the fatty acid profile. The concomitant fat diet with regular physical activity promotes normal development and maintenance of experimental animals. / Existe uma grande preocupação dos consumidores com a saúde, segurança alimentar e valor nutricional dos alimentos com isso surgem interesse por produtos alimentícios ainda mais saudáveis, nutritivos e de grande aproveitamento. Objetivou-se avaliar o efeito da sazonalidade e do tratamento térmico industrial no perfil de ácidos graxos do leite e a resposta biológica de ratos com dietas de diferentes fontes lipídicas submetidos ou não à atividade física. Na avaliação do efeito da estação climática e do tratamento térmico no perfil de ácidos graxos, foram coletadas amostras de leite (in natura, pasteurizado e esterilizado) durante 11 meses consecutivos em Indústria de Laticínios do Rio Grande do Sul. As amostras foram submetidas a extração de lipídios e após a determinação do perfil de ácidos graxos em cromatografia gasosa, empregando-se padrões de ácidos graxos. O ensaio biológico foi conduzido por um período de 52 dias, utilizou-se 36 ratos Wistar machos adultos, distribuídos em 6 tratamentos de 6 animais cada, que receberam ração AIN-93M, variando a fonte de lipídeos e a prática regular de atividade física: DCSA controle normolipídica, com óleo de soja e sem atividade física; DCCA controle normolipídica, com de óleo de soja e com atividade física; DMSA hiperlipídica, com manteiga e sem atividade física; DMCA hiperlipídica, com manteiga e com atividade física; DGSA hiperlipídica, com gordura vegetal hidrogenada e sem atividade física; DGCA dieta hiperlipídica, com gordura vegetal hidrogenada e com atividade física. Investigou-se o efeito dos tratamentos sobre o consumo de ração, ganho de peso, conversão alimentar, coeficiente de eficiência alimentar, peso fígado, rins, coração, gordura epididimal, digestibilidade das dietas, parâmetros sanguíneos (COL total, HDL, TG, GLI, ALB, ALT, AST, uréia, creatinina, IL-1, IL-6, IL-10, TNF-α, IFN-γ e PCRus), bem como a histologia do arco aórtico. A esterilização do leite ocasionou diminuição dos ácidos graxos docosanóico, linoléico conjugado (cis-9, trans-11), eicosapentanóico e na relação PUFA:SFA. A sazonalidade causou variação nos ácidos graxos octadecatrienóico, linoléico conjugado (cis-9, trans-11), docosadienóico, eicosapentaenóico e relação PUFA:SFA. As dietas experimentais interferiram no consumo alimentar, ganho de peso, conversão alimentar, coeficiente de eficiência alimentar, peso da gordura epididimal e nos parâmetros sanguíneos de colesterol total, alanina transaminase, aspartato transaminase, IL-1, IL-6 e IL-10. A atividade física influenciou nas concentrações sanguíneas de triglicerídeos, creatinina, IL-1, IL-6 e IL-10. A interação entre dieta e atividade física foi significativa para TNF-α e INF-γ. Através dos resultados pode-se concluir que os leites submetidos a tratamentos térmicos (pasteurização e esterilização) produzidos nas quatro estações do ano apresentam variações no perfil de ácidos graxos. As dietas hiperlípidica concomitante com a prática regular de atividade física promovem a manutenção e desenvolvimento normal dos animais experimentais.

Monocytes exhibiting a pro-inflammatory phenotype play a key role in adhesion and development of atherosclerotic plaques. As an alternative to smoking, next-generation tobacco and nicotine products (NGP) are now widely used. However, little is known about their pro-inflammatory effects on monocytes. We investigated cell viability, anti-oxidant and pro-inflammatory gene and protein expression in THP-1 monocytes after exposure to aqueous smoke extracts (AqE) of a heated tobacco product (HTP), an electronic cigarette (e-cig), a conventional cigarette (3R4F) and pure nicotine (nic). Treatment with 3R4F reduced cell viability in a dose-dependent manner, whereas exposure to alternative smoking products showed no difference to control. At the highest non-lethal dose of 3R4F (20%), the following notable mRNA expression changes were observed for 3R4F, HTP, and e-cig respectively, relative to control; HMOX1 (6-fold, < 2-fold, < 2-fold), NQO1 (3.5-fold, < 2-fold, < 2-fold), CCL2 (4-fold, 3.5-fold, 2.5-fold), IL1B (4-fold, 3-fold, < 2-fold), IL8 (5-fold, 2-fold, 2-fold), TNF (2-fold, 2-fold, < 2-fold) and ICAM1 was below the 2-fold threshold for all products. With respect to protein expression, IL1B (3-fold, < 2-fold, < 2-fold) and IL8 (3.5-fold, 2-fold, 2-fold) were elevated over the 2-fold threshold, whereas CCL2, TNF, and ICAM1 were below 2-fold expression for all products. At higher doses, greater inductions were observed with all extracts; however, NGP responses were typically lower than 3R4F. In conclusion, anti-oxidative and pro-inflammatory processes were activated by all products. NGPs overall showed lower responses relative to controls than THP-1 cells exposed to 3R4F AqE.