Made available in DSpace on 2011-05-04T12:36:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2009 / A saúde auto-referida tem sido considerada um indicador útil de condições e desfechos de saúde entre indivíduos idosos, especialmente a mortalidade. Essa medida baseia-se na interpretação de aspectos físicos objetivos, de status mental, de expectativas e referenciais de comparação, representando uma percepção individual, própria de cada sujeito. Apesar da importância dos problemas masculinos de saúde no perfil de morbimortalidade da população brasileira idosa, os homens idosos têm sido pouco contemplados em estudos que analisem suas particularidades. Esta dissertação, composta por dois artigos, objetivou estudar as condições associadas à saúde auto-referida em homens idosos do município de Juiz de Fora, MG. O primeiro artigo é um estudo transversal, que busca contribuir para o entendimento de questões relacionadas às características de saúde dos homens idosos e a forma como estes avaliam sua saúde. Realizou-se a análise descritiva das variáveis do estudo e as relações entre saúde auto-referida e as co-variáveis foram exploradas através de razões de prevalência (RP), sendo a análise multivariada efetuada através da regressão de Poisson. A população de estudo foi constituída por 2876 homens, com idade média de 70,01 anos (DP= 7,21). Saúde razoável/ruim foi referida por quase 40 por cento dos idosos. Na análise bivariada, os homens de 70 anos ou mais (RP= 1,14 IC 95 por cento 1,04-1,25), sem companheira (RP= 1,15 IC 95 por cento 1,03-1,27), com baixa escolaridade (RP= 1,61 IC 95 por cento 1,41-1,83), que não trabalhavam (RP= 1,64 IC 95 por cento 1,43-1,88), eram sedentários (RP= 1,22 IC 95 por cento 1,11-1,34), usuários do SUS (RP= 1,53 IC 95 por cento 1,36-1,71), utilizavam medicação regular (RP=2,44 IC 95 por cento 2,13-2,79), relatavam internação recente (RP= 1,69 IC 95 por cento 1,54-1,86) e uma ou mais condições crônicas de saúde (RP=1,98 IC 95 por cento 1,68-2,33), apresentaram maior probabilidade de referir saúde razoável/ruim. No modelo multivariado, mantiveram-se associadas à saúde auto-referida razoável/ruim as variáveis: número de condições crônicas, uso de medicação regular (RP= 2,22 IC 95 por cento 1,93-2,54), internação recente (RP=1,54 IC 95 por cento 1,38-1,71), não trabalhar (RP= 1,37 IC 95 por cento 1,20-1,56), ter baixa escolaridade (RP= 1,27 IC 95 por cento 1,11-1,45) e ser usuário do sistema público de saúde (RP= 1,40 IC 95 por cento 1,24-1,58). Os resultados desse estudo reforçam a hipótese de que múltiplas questões estão relacionadas à auto-avaliação da saúde em populações idosas. Considerando que este é um bom indicador das condições de saúde nesse grupo etário, é necessário que os serviços de saúde desenvolvam estratégias para captação dos homens idosos com perfil de risco para saúde auto-referida ruim. O segundo artigo, um estudo de seguimento, teve o objetivo de analisar o possível papel da saúde auto-referida como variável preditora de mortalidade nesse grupo populacional. O método de Kaplan-Meier foi utilizado para a análise exploratória dos dados, comparando-se os indivíduos que relataram condição de saúde excelente/boa com aqueles que informaram condição de saúde razoável/ruim, em diferentes estratos de variáveis sóciodemográficas,de estilo de vida e de saúde, através do teste de log-rank, admitindo nível de significância estatística de 5 por cento. A análise multivariada foi efetuada através de modelos de regressão de Cox, com o método Enter, incluindo as variáveis que apresentaram associações estatisticamente significativas naanálise bivariada. A população deste estudo foi constituída por 2875 homens idosos, seguidos até a data do óbito ou do término do período de seguimento de dois anos, sendo então censurados os indivíduos vivos. Durante o seguimento, ocorreram 120 óbitos, sendo as doenças do aparelho circulatório (40 por cento), as neoplasias (22,5 por cento) e as doenças do aparelho respiratório (10 por cento) as principais causas de morte. Em praticamente todos os estratos de variáveis analisadas, os idosos com saúde auto-referida razoável/ruim apresentaram maior risco de morrer do que aqueles com saúde auto-referida excelente/boa. No modelo multivariado final, as variáveis saúde auto-referida razoável/ruim (HR=1,88 IC 95 por cento 1,29-2,72), idade (HR=1,05 IC 95 por cento 1,03-1,08), uso de serviço público de saúde (HR=1,69 IC 95 por cento 1,10-2,60), tabagismo atual (HR=1,94 IC 95 por cento 1,24-3,04) e doença cardiovascular aguda (HR=1,62 IC 95 por cento 1,06-2,47) se mostraram associadas à mortalidade. A saúde auto-referida mostrou-se uma importante variável preditora da mortalidade em homens idosos, em um período de seguimento de dois anos. Diante da importância da saúde auto-referida ruim na predição da mortalidade em homens idosos brasileiros, recomenda-se que os serviços de saúde incorporem esse indicador nas avaliações de saúde do usuário idoso. / Self-reported health has been considered a helpful indicator of health conditions and certain outcomes, especially mortality, in elderly people. This measure is based on the interpretation of objective physical aspects, mental status, expectations and referential systems of comparison, representing an individual perception. Studies have pointed to differences between genders not only in relation to determinants of self-reported health, but also in relation to its capacity to be a predictor of mortality and the magnitude of the associations. Despite the importance of male health problems in the morbimortality profile of the Brazilian elderly population, men have been little contemplated in studies that analyze their particularities. Two studies were carried out to analyze conditions associated to self-reported health in elderly men of Juiz de Fora city, MG. The first was a cross-sectional study, seeking to contribute to the understanding of questions related to the health characteristics of elderly men and the way they evaluate their health. A descriptive analysis of the study variables was performed and relations among self-reported health and covariates were explored through the estimation of prevalence ratios (PR). Multivariate analysis was performed through Poisson regression. The study population was formed by 2876 men, with average age of 70.01 years (SD= 7.21). Poor health was referred by almost 40% of the participants. Bivariate analysis showed that, men of 70 years or more (PR= 1.14 95% CI 1.04-1.25), without a companion (PR= 1.15 95% CI 1.03-1.27), with few years of schooling (PR= 1.61 CI 95% 1.41-1.83), who did not work (PR= 1.64 95% CI 1.43-1.88), were sedentary (PR= 1.22 95% CI 1.11-1.34), were users of public health services (PR= 1.53 95% CI 1.36-1.71), used medication regularly (PR=2.44 95% CI 2.13- 2.79), related recent admission to a hospital (PR= 1.69 95% CI 1.54-1.86) and presented at least one chronic health condition (PR=1.98 CI 95% 1.68-2.33), had greater probability to relate poor health. In the multivariate model, the variables: regular use of medications (PR= 2.22 95% CI 1.93-2.54), recent admission to a hospital (PR= 1.54 95% CI 1.38-1.71), not be working (PR= 1.37 95% CI 1.20-1.56), few years of schooling (PR= 1.27 95% CI 1.11-1.45) and to be a user of public health services (PR= 1.40 95% CI 1.24-1.58) remained associated to poor self-reported health. The results of this study strengthen the hypothesis that multiple questions are related to the evaluation of self-reported health in aged populations. Considering that this variable is a strong indicator of health conditions in this age group, it is important that health services develop strategies to attract aged men with a risk profile for poor self-reported health. The second was a follow-up study performed to analyze the possible role of self-reported health as a predictor of mortality in this population group and the study population consisted of 2875 elderly men, followed for two years or until their death, whichever came first. During the follow-up, 120 deaths occurred and cardiovascular diseases (40%), neoplasias (22.5%) and respiratory diseases (10%) were the major causes. Elders with self-reported poor health presented a greater risk of death, compared to those with self-reported good/excellent health in almost all stratus of the analyzed variables. In the final model, the variable poor self-reported health (HR=1.88 95% CI 1.29-2.72), age (HR=1.05 95% CI 1.03-1.08), use of the public health services system (HR=1.69 95% CI 1.10-2.60), current use of cigarette smoking (HR=1.94 95% CI 1.24-3.04) and self-reported ardiovascular disease (HR=1.62 95% CI 1.06-2.47) were independently associated to mortality. As poor self-reported health seems to be a good predictor of mortality for elderly men, it is important that health care services incorporate this indicator in the health evaluation of this population group.

As citocinas têm papel importante como mediadores através das respostas imunológicas. A Interleucina-21, importante regulador dos linfócitos T e B, é produzida por linfócitos CD4 ativados, e está implicada na patogênese do diabetes autoimune em modelo animal, o NOD. A região promotora da IL-21, que contempla sítios de controle da expressão gênica em camundongos, o NFATc2, T-bet e c-MAF, foi estudada pela primeira vez em humanos portadores de diabetes tipo 1A, neste trabalho. Foi analisado também a freqüência do polimorfismo C1858T do gene PTPN22, que tem sido associado em estudos recentes como fator de risco importante para diabetes tipo1A e outras doenças autoimunes. Associou-se ainda, autoanticorpos pancreáticos e não-pancreáticos em diabéticos e grupo controle normal, e estes resultados foram analisados com ambos os genes. Foram estudados 612 DM1A e 792 indivíduos do grupo controle. Após extração de DNA genômico, a região 5proximal da região promotora do gene da Il-21, -448+83pb, foi seqüenciada em 309 brasileiros diabéticos tipo 1A e 189 indivíduos do grupo controle. A genotipagem do polimorfismo C1858T do gene PTPN22, por RFLP, foi realizada em 434 diabéticos e 689 controles, bem como os alelos HLA-DRB1. Foi encontrada uma variação alélica, em heterozigoze, na posição g.-241 T>A, em apenas uma paciente, que apresentou idade de diagnóstico aos 30 anos de idade. Esta variante alélica não foi encontrada nos 497 indivíduos (308 DM1A e 189 grupo controle). A freqüência dos alelos polimórficos (CT/TT) foi maior nos diabéticos (18.7%) que no grupo controle (10.6%), OR 1,94 e p<0,001. O polimorfismo C1858T do gene PTPN22 associou-se à maior freqüência dos autoanticorpos pancreático anti-GAD65 (p=0,002) e não-pancreático anti-TG (p=0,001), quando avaliados os dois grupos juntos, DM1A e grupo controle. Os diabéticos apresentaram maior freüência dos autoanticorpos como segue: autoanticorpos pancreáticos: anti-GAD65: 225 /482 (46.7%) vs 13/786 (1.7%), p<0.001; anti-IA2 : 204/469 (43.5%) vs 15/786 (1.9%), p<0.001. Autoanticorpos não-pancreáticos: FAN: 60/234 (25.6%) vs 13/239 (5.4%), p<0.001; anti-TPO: 64/279 (22.9%) vs 34/495 (6.9%), p<0.001; anti-TG : 65/278 (23.4%) vs 44/489 (9%), p<0.001; TRAb: 14/187 (7.5%) vs 1/327 (0.3%), p<0.001; anti-21-OH : 8/154 (5,2%) vs 1/160 (0,6%), p< 0,001. Os autoanticorpos a seguir foram realizados apenas nos pacientes diabéticos: anti-tTG 5/73% (6.8%), anti-Endom 10/176 (5.7%). Com exceção do anti-GAD65 e anti-TG, nenhum outro autoanticorpo associou-se ao polimorfismo do gene PTPN22. Os alelos HLA-DR3/DR$ predominaram nos diabéticos (p<0,001). Concluimos então que o polimorfismo C1858T do gene PTPN22 e os alelos HLA-DR3/DR4 estão associados ao risco de DM1A. Variantes alélicas na região 5 proximal do gene da IL-21 parece não ser predisponente à suscetibilidade ao DM1A e outras doenças autoimunes. Autoanticorpos órgão-específicos são mais freqüentes em diabéticos, principalmente nas glândulas adrenal e tireóide. O polimorfismo C1858T do gene PTPN22 está associado à maior freqüência dos autoanticorpos anti-GAD65 e antitireoglobulina / Objective: Cytokines are central mediators of inflammation through innate and adaptive immune responses. IL-21, a critical regulator of T and B cell function, is produced by various subsets of CD4+ T cells, and it has been implicated in the pathogenesis of non obese diabetes mouse. The proximal promoter of IL-21, which controls its Th-cell-subset-specific expression through the action of NFATc2, T-bet and c-MAF in animal models, was evaluated in type 1A diabetes (T1AD) patients for the first time. This study also analyzed the 1858T PTPN22 polymorphism, which has recently emerged as an important risk factor for T1AD and other autoimmune diseases. Moreover, islet and other organ-specific autoantibodies were quantified in T1AD patients and healthy controls and the results were correlated with both genes. Research design and methods: The case series comprised 612 T1AD patients and 792 healthy control (HC) individuals. Genomic DNA extraction was performed by salting-out in purified blood leukocytes. The region encompassing -448+83 bp of IL-21 gene was amplified and sequenced using genomic DNA from 309 Brazilian T1AD patients and 189 control individuals. RFLP genotyping of C1858T PTPN22 was performed in 689 controls and 434 T1D patients. HLA DR3/DR4 alleles were also evaluated. Results: A heterozygous allelic variant (g.-241 T>A) was found in only one patient, who was 30 years old at the onset of disease. This allelic variant was not found in 497 individuals (308 T1AD patients and 189 healthy controls). The PTPN22 1858T allele frequency was greater in patients (18.7%) than in controls (10.6%): odds ratio of 1.94; p<0.001. An association was found between C1858T polymorphism and higher frequency of GAD65 Ab (p=0.002) and TG Ab (p=0.011), among both T1AD and HC. Type 1 diabetes patients presented higher frequency of the following autoantibodies, compared with HC (p<0.001): GAD65 Ab (46.7% vs 1.7%); IA2 Ab (43.5% vs 1.9%); ANA (25.6% vs 5.4%); TPO Ab (22.9% vs 6.9%); TG Ab (23.4% vs 9.0%); TRAb (7.5% vs 0.3%); 21-OH Ab (5,2% vs 0,6%). The following antibodies were evaluated only in T1AD: tTG Ab (6.8%) anti-Endom (5.7%). Except by GAD65 Ab and TG Ab, no association was found between C1858T polymorphism and these autoantibodies.HLA-DR3/DR4 alleles predominated in T1D patients (p<0.001) Conclusions: C1858T PTPN22 polymorphism and the HLA-DR3 and/or DR4 alleles were associated with proneness to T1AD. Allelic variants at the 5\' proximal region of the IL-21 gene do not seem to predispose to susceptibility to T1AD and other autoimmune endocrine diseases. Autoantibodies specific to other organs and tissues are frequent in T1AD carriers, mainly to the thyroid glands. The 1858T PTPN22 polymorphism was associated with higher frequency of GAD65A and TGA.

INTRODUÇÃO: A sofisticação dos métodos de diagnóstico por imagem, em especial o ultra-som, contribuiu para que nódulos cada vez menores fossem diagnosticados com maior freqüência. Nódulos tireóideos são encontrados ao exame ultra-sonográfico, em até 17% das mulheres adultas. A lobectomia total é considerada procedimento adequado para o tratamento dos nódulos benignos laterais da tireóide. O hipotireoidismo pode ocorrer em 5% a 35% dos doentes, após esse procedimento e está relacionado tanto com a quantidade de tecido glandular remanescente, quanto com a sua qualidade funcional. Neste estudo avaliou-se a ocorrência do hipotireoidismo após lobectomia total, visando identificar os indivíduos com maior risco de desenvolver essa doença. MÉTODOS: No período de março de 1996 a julho de 2005, foram selecionados 228 indivíduos eutireóideos submetidos à lobectomia total da tireóide por bócio não tóxico, do Departamento de Cirurgia de Cabeça e Pescoço do Instituto Brasileiro de Controle do Câncer e da clínica privada do autor. Realizou-se estudo retrospectivo com 186 indivíduos passíveis de análise, considerando os níveis séricos de tireotrofina (TSH) pré e pós-operatórios e a dosagem de anticorpos antitireóideos. O volume do coto tireóideo remanescente foi determinado por exame ultrasonográfico. Os exames anatomopatológicos foram revistos e quantificaram, por meio da análise semiquantitativa, os agregados linfocitários e os folículos linfóides: graduados de 0 a IV e de 0 a III, respectivamente. O hipotireoidismo foi diagnosticado quando TSH = 5,5 mU/L em até oito semanas após a operação. RESULTADOS: Houve predomínio do sexo feminino neste estudo (88%), com a idade variando de 16 a 72 anos e com média de 45 anos. O tempo médio de seguimento foi de 29 meses, variando de seis meses a nove anos. Foi identificado TSH = 5,5 mU/L em 61 casos (32,8%). Bócio foi o diagnóstico de 82% dos hipotireóideos e 80,7% dos eutireóideos. A idade, o sexo e a quantidade de infiltrados linfocitários não apresentaram diferença estatística entre os indivíduos eutireóideos e hipotireóideos após o procedimento. Os fatores relacionados ao hipotireoidismo pósoperatório foram: valor médio de TSH pré-operatório, que registrou 2,1mU/L, entre os hipotireóideos, e 1,2 mU/L, entre os eutireóideos (p<0.001); volume médio do coto remanescente da tireóide, que indicou 3,9 cm3 no grupo com hipotireoidismo e 6,0 cm3 no grupo sem doença (p=0,003); lobectomia direita (p=0,006); positividade do anticorpo antiperoxidase (AcTPO) (p=0,009). O TSH pré-operatório > 2,0 mU/L aumentou em 7,1 vezes a possibilidade de ocorrer hipotireoidismo após lobectomia total e, quando foi considerada a lobectomia direita e o volume do coto remanescente = 4,0 cm3, a possibilidade de apresentar hipotireoidismo pós-operatório foi 7,4 vezes maior. CONCLUSÕES: O hipotireoidismo pós-operatório ocorreu em 32,8% dos indivíduos submetidos à lobectomia total por bócio não tóxico. Pequeno volume do remanescente tireóideo ao ultra-som, inferior a 4,0cm3, e a remoção do lobo direito estiveram relacionados com maior risco para o hipotireoidismo. Fatores determinantes do estado funcional da glândula, como os níveis elevados, porém ainda normais, do TSH no préoperatório e a presença AcTPO positivos também se mostraram relacionados com o risco elevado para o hipotireoidismo pós-operatório. / INTRODUCTION: Thyroid nodules, recently, have their diagnosis increased because of the improvement of imaging methods, especially ultrasound. Around 17% of these nodules may be identified in adult women by ultrasound. Total lobectomy is considered an appropriate procedure for benign thyroid nodules. Hypothyroidism may occur in 5% to 35% patients after total lobectomy and it is related to the volume of the remnant thyroid tissue and its functional quality. This study was designed to evaluate the incidence of postoperative hypothyroidism and to determine patients with high risk for this disease. METHODS: From March 1996 to July 2005, 228 euthyroid patients, from the Department of Head and Neck Surgery of the Brazilian Institute for Cancer Control (IBCC) and from the author?s private office, had a total lobectomy due to non-toxic goiter. Out of these patients, 186 were selected for this retrospectively study. Thyrotrophin (TSH) levels, antithyroid antibodies, volume of the remnant thyroid by ultrasound and a semiquantitatively review of the histological specimens considering lymphocytic infiltration were studied. Hypothyroidism was defined for TSH = 5,5 mU/L up to eight weeks postoperative. RESULTS: Women were predominant (88%) with ages varying from 16 to 72 years old and the median age of 45 years old. The average time of follow-up was 29 months, ranging from six months to nine years. TSH ³ 5,5 mU/L occurred in 61 patients (32,8%). Adenomatous goiter was the principal diagnosis in 82% of the hypothyroids patients and 80,7% of the euthyroids. Age, sex and lymphocytic infiltrate did not show any difference between the two groups. Postoperative hypothyroidism was related to: higher preoperative TSH level than the euthyroids postoperative patients (2,1 mU/L versus 1,2 mU/L, respectively) (p<0,001), smaller thyroid remnant volume, 3,9 cm3 in hypothyroid group against 6,0 cm3 in the euthyroid group (p=0,003), right lobectomy while the euthyroid patients had more left lobectomy (p=0,006) and, finally, higher positive titles of the antiperoxidase antibodies (AcTPO) (p=0,009). The risk for postoperative hypothyroidism was 7.1 times higher for those with preoperative TSH > 2,0 mU/L. When right lobectomy was analyzed with the remnant volume = 4,0 cm3, the risk for postoperative hypothyroidism was 7,4. CONCLUSIONS: Postoperative hypothyroidism occurs in 32,8% of patients who have undergone a total lobectomy for non-toxic goiter. Possible indicators for development of postoperative hypothyroidism are: preoperative TSH > 2,0 mU/L and postoperative positive AcTPO, small thyroid volume at ultrasound, and right lobectomy.

Side-channel attacks have become a realistic threat to the implementations of cryptographic algorithms. By analyzing the unintentional, side-channel leakage, the attacker is able to recover the secret of the target. Recently, a new type of side-channel leakage has been discovered, called far field EM emissions. Unlike attacks based on near field EM emissions or power consumption, the attack based on far field EM emissions is able to extract the secret key from the victim device of several meters distance. However, existing deep-learning attacks based far field EM commonly use a random or grid search method to optimize neural networks’ hyperparameters. Recently, an automated way for deep learning hyperparameter tuning based on Auto- Keras library, called AutoSCA framework, was applied to near-field EM attacks. In this work, we investigate if AutoSCA could help far field EM side-channel attacks. In our experiments, the target is a Bluetooth-5 supported Nordic Semiconductor nRF52832 development kit implementation of Advanced Encryption Standard (AES). Our experiments show that, by using a deep-learning model generated by the AutoSCA framework, we need 485 traces on average to recover a subkey from traces captured at 15 meters distance from the victim device without repeating each encryption. For the same conditions, the state-of-the-art method uses 510 traces. Furthermore, our model contains only 667,433 trainable parameters in total, implying that it requires roughly 9 times less training resources compared to the larger models in the previous work. / Angrepp på sidokanaler har blivit ett realistiskt hot mot implementeringen av kryptografiska algoritmer.Genom att analysera det oavsiktliga läckaget kan angriparen hitta hemligheten bakom målet.Nyligen har en ny typ av sidokanalläckage upptäckts, kallad fjärrfälts EM-utsläpp.Till skillnad från attacker baserade på nära fält EM- utsläpp eller energiförbrukning, kan attacken baserad på yttre fält EM-utsläpp extrahera den hemliga nyckeln från den skadade anordningen på flera meter avstånd.Men befintliga djupinlärningsattacker baserade på långt fält EM använder ofta en slumpmässig sökmetod för att optimera nervnätens hyperparametrar. Nyligen tillämpades ett automatiserat sätt för djupinlärning av hyperparametern baserad på Auto-Keras- bibliotek, AutoSCA- ramverket, vid EM-angrepp nära fältet.I det här arbetet undersöker vi om AutoSCA kan hjälpa till med EM-angrepp.I våra experiment är målet en Bluetooth-5-stödd nordisk semidirigent nR52832- utvecklingsutrustning för avancerad krypteringsstandard (AES).Våra experiment visar att genom att använda en djupinlärningsmodell skapad av AutoSCA-ramverket, behöver vi 485-spår i genomsnitt för att hämta en subnyckel från spår tagna på 15- meters avstånd från offrets apparat utan att upprepa varje kryptering.Under samma förhållanden använder den senaste metoden 510-spår.Dessutom innehåller vår modell bara 667,433-parametrar som totalt kan användas för utbildning, vilket innebär att det krävs ungefär nio gånger mindre utbildningsresurser jämfört med de större modellerna i det tidigare arbetet.

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The topic of this dissertation is " The work of J. Brodsky: methods and forms of self-identification". The work is devoted to the philological reconstruction and analysis of the forms and techniques of the poet's self-identification, implemented in his poetry and prose. The study analyzed the specifics of the figurative series of the poet's lyrics in the aspect of his self-reflection, considered the poetic message as a specific genre form of Brodsky's self-identification, analyzed the poems dedicated to "M. B." in the aspect of the realization of the poet's self-identification through a love drama. Attention was also paid to the study of the nature of autobiography in Brodsky's memoir essays, the study of the poet's public speeches as a way of expressing self-identification, and the analysis of the genre of open writing as a form of public behavior. The essay "Letter to Horace" is considered as the final stage in the development of Brodsky's poetic self-awareness. The main features of Brodsky's self-identification were identified and analyzed, such as a tendency to alienation, the construction of an automyph and the linguistic utopia of the poet. / Тема данной диссертации – «Творчество И. Бродского: приёмы и формы самоидентификации». Работа посвящена филологической реконструкции и анализу форм и приемов самоидентификации поэта, реализованных в его поэзии и прозе. В рамках исследования был проведен анализ специфики образного ряда лирики поэта в аспекте его авторефлексии, рассмотрено поэтическое письмо-послание как специфической жанровой формы самоидентификации Бродского, проанализированы стихотворения, посвященные «М. Б.», в аспекте реализации самоидентификации поэта через любовную драму. Также было уделено внимание изучению характера автобиографизма в мемуарных эссе Бродского, исследованию публичных выступлений поэта как способа выражения самоидентификации, анализу жанра открытого письма как формы публичного поведения. Как завершающий этап развития поэтического самосознания Бродского рассмотрено эссе «Письмо Горацию». Были выявлены и проанализированы основные черты самоидентификации Бродского, такие как склонность к отчуждению, конструирование автомифа и лингвистическая утопия поэта.

L’implication des cellules B dans le développement de l’auto-immunité ne cesse d’être illustrée par de récentes publications. Les cellules présentent des peptides du soi aux cellules T auto-réactives ce qui mène à la production de cytokines pro-inflammatoires et d’anticorps auto-réactifs. Dans le présent document, nous explorons la présentation antigénique et la modification post-traductionnelle du complexe majeur d’histocompatibilité II (CMH-II). MARCH1 est une E3 ubiquitine ligase qui cible le CMH-II et le relocalise le complexe vers les endosomes de recyclage. Ainsi, MARCH1 est un inhibiteur de la présentation d’antigènes exogènes. Ici, nous démontrons que MARCH1 est exprimé seulement dans la sous-population des cellules B folliculaires et que cette expression est perdue lors de l’entrée dans les centres germinatifs. Nous proposons que MARCH1 établie une barrière de formation de centres germinatifs. Nous démontrons le lien entre MARCH1 et la hausse de CMH-II à la surface des cellules B à la suite d’un traitement à l’IL-10. De plus, nous avons testé plusieurs stimuli activateurs des cellules B et démontrons que MARCH1 est régulé à la baisse dans tous les cas. De plus, nous mettons en valeurs le rôle de la voie canonique d’activation de NF-κB dans cette régulation de MARCH1. Finalement, nous avons développé un système de lentivirus exprimant MARCH1 qui nous permet de forcer l’expression de MARCH1 dans des cellules réfractaires à la transfection. Nous discutons de l’implication de cette régulation du CMH-II par MARCH1 dans le développement de maladies auto-immunes. / Increasing evidence suggests a major role for B cells in the onset of auto-immune diseases. B cells present self-antigens to auto-reactive T cells which leads to the production of pro-inflammatory cytokines and auto-immune antibodies. Here we look at the process of antigen presentation and at post-transcriptional modifications of the MHC-II molecule. MARCH1 is an E3 ubiquitin ligase which targets MHC-II and re-localises the complex into recycling endosomes. Thus, MARCH1 is a direct inhibitor of exogenous antigen presentation. Here we show that only follicular B cells express MARCH1 and that upon germinal center entry, these cells lose all traces of MARCH1. We propose that MARCH1 may establish a threshold for germinal center creation. Moreover we demonstrate that the well-established increase in surface MHC-II induced by IL-10 on murine B cells is a result of a decrease in MARCH1 expression. We tested different B cell activation stimuli and showed that upon activation, MARCH1 mRNA is decreased in a time-dependent manner. In addition, we demonstrate the implication of the canonical NF-κB pathway in this regulation. Finally, we developed a lentiviral vector system expressing MARCH1 which enables us to force the expression of our target protein in non-transfectable cell types. We discuss the implication of MARCH1 in the presentation of self-antigens to auto-reactive T cells and the generation of auto-immunity.

Les autotransporteurs monomériques représentent le système de sécrétion le plus simple et le plus utilisé chez les bactéries à Gram négatif. Les autotransporteurs monomériques sont des protéines modulaires qui contiennent toute l’information pour leur sécrétion dans leur séquence. Les phénotypes associés à l’expression d’un autotransporteur peuvent être très variés et, souvent, les autotransporteurs sont des protéines multifonctionnelles. C’est le cas notamment des autotransporteurs AIDA-I, TibA et Ag43 d’Escherichia coli qui promouvoient l’adhésion et l’invasion de cellules épithéliales, l’auto-agrégation des bactéries et la formation de biofilm. Ces trois autotransporteurs ont d’ailleurs été regroupés dans une même famille, appelée les autotransporteurs auto-associatifs (SAATs). À cause de leur fonctionnalité, les SAATs sont considérés comme étant d’importants facteurs de virulence d’Escherichia coli. Toutefois, il existe plusieurs différences entre les SAATs qui ne sont pas bien comprises, si bien que leur rôle pour les bactéries n’est toujours pas bien compris. Nous avons donc d’abord caractérisé TibA, le membre des SAATs le moins bien étudié à l’aide d’une étude structure-fonction. Nous avons observé que TibA était une protéine modulaire et que son domaine fonctionnel était composé de deux modules : un module d’auto-agrégation en N-terminal et un module d’adhésion en C-terminal. En comparant nos résultats avec ceux obtenus pour les autres SAATs, nous avons réalisé que l’organisation des trois SAATs était très variée, c’est-à-dire que les trois SAATs sont composés de modules différents. Nous avons par ailleurs observé cet arrangement en modules lorsque nous avons analysé plusieurs séquences d’aidA, suggérant qu’un mécanisme d’échange et d’acquisition de modules était à la base de l’évolution des SAATs. Sans surprise, nous avons aussi observé que la famille des SAATs ne se limitait pas à AIDA-I, TibA et Ag43 et ne se limitait pas à Escherichia coli. La comparaison a aussi révélé l’importance du phénotype d’auto-agrégation dans la fonctionnalité des SAATs. Nous avons donc entrepris une étude du mécanisme d’auto-agrégation. Nos résultats on montré que l’auto-agrégation était le résultat d’une interaction directe SAAT/SAAT et ont mis en évidence un mécanisme similaire à celui utilisé par les cadhérines eucaryotes. De plus, nous avons observé que, comme les cadhérines, les SAATs étaient impliqués dans des interactions homophiliques; un SAAT interagit donc spécifiquement avec lui-même et non avec un différent SAAT. Finalement, les SAATs font parties des quelques protéines qui sont glycosylées chez Escherichia coli. Nous avons déterminé que le rôle de la glycosylation de TibA était de stabiliser la protéine et de lui donner la flexibilité nécessaire pour moduler sa conformation et, ainsi, être pleinement fonctionnelle. Globalement, nos résultats suggèrent que les SAATs sont des molécules « cadhérines-like » qui permettent la reconnaissance de soi chez les bactéries. Une telle habilité à discriminer entre le soi et le non-soi pourrait donc être utilisée par les bactéries pour organiser les communautés bactériennes. / Autotransporters are versatile virulence factors of Gram-negative bacteria and use one of the simplest and most widespread secretion system in bacteria. The name autotransporter originate from the observation that all the information needed for the secretion of the protein is encoded in its own sequence, meaning that autotransporters do not need a specialized secretion apparatus. Many autotransporters are multifunctional proteins and can perform a large variety of functions. The self-associating autotransporters (SAATs), represented by AIDA-I, TibA and Ag43, are such multifunctional proteins and can mediate the adhesion and invasion of epithelial cells, the auto-aggregation of bacteria and the formation of biofilm. Because of these functionalities, SAATs are considered important virulence factors of Escherichia coli. However, there are many differences between the SAATs and we still do not know their exact role for the bacteria. Therefore, we have realized a structure-function study of TibA, the least studied SAAT. Our study showed that TibA is a modular protein and that the functional domain of TibA is composed of two modules: an N-terminal module responsible for auto-aggregation and a C-terminal module responsible for adhesion. Our results showed that the organization of AIDA-I, TibA and Ag43 is different and that the SAATs represent different assemblies of modules. We also observed the modular organization when we analyzed various sequence of aidA, suggesting that the SAATs have evolved by a mechanism of domain shuffling. Not surprisingly, we have found new SAATs in Escherichia coli and in other proteobacteria. Our results also highlighted the importance of auto-aggregation in the functionality of the SAATs. We therefore assessed the mechanism of SAAT-mediated auto-aggregation of bacteria. Our results showed that SAATs mediate auto-aggregation of bacteria through direct SAAT/SAAT interactions and that these interactions were reminiscent of the interactions made by cadherin molecules in eukaryotes. We further observed that the SAATs were involved in homophilic interactions, as it is the case with cadherin molecules. SAATs are part of the few proteins that are glycosylated in Escherichia coli. We therefore characterized the glycosylation of TibA and found that glycosylation of TibA stabilized the protein and allowed the protein to modulate its conformation, resulting in a fully functional protein. Taken together, our results suggest that the SAATs may be cadherin-like molecules by bacteria in order to discriminate between self and non-self. Such an ability to discriminate self from non-self is rarely evoked in bacteria, but could play a role in the organization of multicellular communities.

La stagnation est un phénomène fréquent dans le domaine de la natation, bien qu’inexpliqué et incompris, pour lequel peu de solutions sont proposées. Malgré quelques recherches sur ce phénomène, notamment au baseball, la littérature sur le sujet demeure incomplète et ne permet pas de bien cerner le problème de la stagnation. Ainsi, cette étude a pour but premier d’identifier et de comprendre les causes possibles de la stagnation, les changements émotionnels, physiques et sociaux engendrés par un tel phénomène et les stratégies utilisées par les athlètes pour gérer la stagnation. Le deuxième objectif de cette étude est de jeter un regard sur l’impact de l’optimisme sur la résolution de la stagnation. Pour ce faire, des entrevues semi-structurées ont été menées auprès de onze nageurs ayant compétitionné au niveau national canadien. Les nageurs étaient divisés en trois groupes: les nageurs ayant résolu leur stagnation et qui continuent de nager, les nageurs ayant cessé la compétition de natation suite à une stagnation non résolue et ceux qui nagent encore malgré une stagnation non résolue. Les candidats sélectionnés ont complété deux questionnaires sur l’optimisme, le LOT-R et l’ASQ. L’analyse des résultats, réalisée grâce à la théorisation ancrée, a permis de déterminer un ensemble d’émotions vécues par les athlètes et d’identifier des stratégies afin de résoudre la stagnation. Les résultats de cette étude indiquent qu’une balance entre l’optimisme et le pessimisme, une motivation intrinsèque ainsi qu’une auto-détermination chez l'athlète sont des éléments importants afin de surmonter une stagnation. / Even if unexplained and misunderstood, a slump is a frequent phenomenon among high level swimmers for which few solutions are proposed. Despite some previous research especially in the sport of baseball, the literature on this topic is fairly incomplete and does not provide a complete understanding of the problem. Therefore, the primary goal of this study is to get a better understanding of the possible causes of a slump and the emotional, mental, physical and social changes generated by this phenomenon and the strategies used by swimmers in order to break through their slumps. The second goal of this study is to examine the impact of optimism on the resolution of a slump. To reach these goals, semi-structured interviews were held with eleven swimmers who competed at the national level in Canada. Swimmers were divided into three groups: swimmers who resolved their slumps and are still swimming, swimmers who stopped competitive swimming because of an unresolved slump and swimmers who are still swimming even though they are still enduring a slump. Subjects selected were also asked to complete two optimism questionnaires (LOT-R and ASQ). Data analysis, using the grounded theory, identified an emotional patterns experienced by swimmers and certain strategies used by swimmers to resolve their slump. Finally, the results of this study suggest that a balance between optimism and pessimism, an intrinsic motivation and a perception of auto-determination are important elements when trying to overcome a slump.

La polyarthrite rhumatoïde (PR) est le rhumatisme inflammatoire chronique le plus fréquent. La PR est une maladie génétique où il existe plusieurs allèles de susceptibilité HLA-DRB1. Les auto-anticorps anti-protéines citrullinées sont les plus spécifiques de la PR. Ils sont détectés par les tests anti-peptides cycliques citrullinés (anti-CCP). 1/L’objectif de notre premier travail était de montrer l’influence des allèles susceptibilité HLA-DR sur la présence d’anti-CCP dans notre population marseillaise de PR. Nous avons montré que les allèles de susceptibilité HLA-DR ne sont pas nécessaires à la présence des anticorps anti-CCP. Nous avons mis en évidence une association entre l’allèle HLA-DRB1*04:04 et la présence des anti-CCP.2/Environ un tiers des patients présentant une PR n’ont pas d’anticorps anti-CCP. Nous avons donc recherché des nouveaux auto-anticorps pour le diagnostic de la maladie.Les auto-anticorps dirigés contre le domaine catalytique de la protéine B-Raf (v raf murine sarcoma viral oncogen homologue B1) ont été identifiés par la technique des puces à protéines chez les patients PR. B-Raf est une sérine-thréonine kinase qui est impliquée dans la voie des MAP-kinases. Nous avons montré que les auto-anticorps anti-B-Raf activent B-Raf. Nous avons montré que le peptide p25 de B-Raf est spécifiquement reconnu par les auto-anticorps des PR. Les auto-anticorps anti-p25 identifient 21% des patients PR sans anticorps anti-CCP.3/En utilisant des puces à protéines, nous avons identifié 24 nouveaux auto-antigènes associés aux PR débutantes. Quatre de ces auto-antigènes ont été validés par ELISA : GABA(A) receptor associated protein like, zinc finger protein 706, tropomyosin 2 et WIBG (within BGCN homolog (Drosophila)). Les auto-anticorps anti-WIBG identifient exclusivement les PR.Ces nouveaux auto-antigènes pourront être utilisés dans le diagnostic des PR débutantes et des PR sans anticorps anti-CCP. / Rheumatoid arthritis (RA) is a chronic inflammatory disease with a prevalence of 0.5% wordwilde. HLA-DR genes are the strongest genetic prevalence in RA. The sera of RA patients contain many auto-antibodies. The most characteristic are directed at citrullinated proteins (ACPA). ACPA can be detected by commercially available enzyme-linked immune-absorbent assays using synthetic cyclic citrullinated peptides (CCP).1/In the first work we tested whether the presence of RA associated HLA-DRB1 alleles individually influences anti-CCP production in a population of RA from Marseille. We showed RA associated HLA-DR alleles are not mandatory for the production of anti-CCP. HLA-DRB1*04:04 was the most strongly associated with the presence of anti-CCP in RA sera. 2/ Anti-CCP antibodies are detected in 65% of RA patients. We wanted to detect new auto-antibodies for the diagnosis of RA.By screening protein arrays we found that B-Raf (v raf murine sarcoma viral oncogen homologue B1) is a major non-citrullinated auto-antigen recognized by 35% of RA patients’sera. B-Raf encodes a serine threonine-kinase involved in the MAPK signaling pathway. We showed that anti-B-Raf auto-antibodies activate the in vitro phosphorylation of MEK1 mediated by B-Raf.We found that one peptide of B-Raf, p25, is specifically recognized by auto-antibodies from RA patients. Of interest, anti-p25 auto-antibodies are detected in 21% of anti-CCP negative RA patients.3/We identified 24 new auto-antigens associated with RA patients with disease duration less than one year using 8000 human protein arrays. We identified four auto-antigens recognized almost uniquely by sera of early RA patients: GABA(A) receptor associated protein like, zinc finger protein 706, tropomyosin 2 and WIBG (within BGCN homolog (Drosophila)). These reactivities were confirmed by ELISA on purified proteins. Auto-antibodies to anti-WIBG identify exclusively RA patients’sera. These new auto-antigens could be used for the diagnosis of anti-CCP negative RA patients and in early RA.