Submitted by Nadir Basilio (nadirsb@uninove.br) on 2018-07-23T18:59:32Z No. of bitstreams: 1 Ezequiel Fernandes de Oliveira.pdf: 4647261 bytes, checksum: 39fab29afa3f1852d5a83294cc11eb4b (MD5) / Made available in DSpace on 2018-07-23T18:59:32Z (GMT). No. of bitstreams: 1 Ezequiel Fernandes de Oliveira.pdf: 4647261 bytes, checksum: 39fab29afa3f1852d5a83294cc11eb4b (MD5) Previous issue date: 2017-11-13 / Introduction: Our hypothesis is that patients with MG present a poor sleep due to the presence of respiratory disorders, compromised by the weakness of the ventilatory muscles, causing worsening of the clinical condition and quality of life. Objectives: To investigate the physiological pattern of sleep through polysomnography, to verify pulmonary function and ventilatory muscle strength through spirometry and manovacuometry, and to perform the translation, cultural adaptation and validation of two specific scales to evaluate the clinical evolution of patients with MG, denominated "Quantitative Test for Myasthenia Gravis" and "Composite Scale for Myasthenia Gravis". Material and methods: This is a cross-sectional study involving patients with MG. Clinical evaluations were performed at the UNINOVE Sleep Laboratory, at the Neuromuscular Diseases Research Unit at UNIFESP, at the Santa Casa de São Paulo Department of Neurology and at the Department of Neurology at the Hospital do Servidor Público Estadual of São Paulo. Results: The results of this thesis are separated into three studies. Study I: article entitled "Sleep, lung function and quality of life in patients with Myasthenia gravis: A cross-sectional study" published in the journal Neuromuscular Disorders. Study II: entitled "Brazilian- Portuguese translation, cross-cultural adaptation and validation of the Myasthenia Gravis Composite scale. A multicentric study." published in the journal Arquivos de Neuropsiquiatria. Study III: entitled "Quantitative Myasthenia gravis Score: a Brazilian multicenter study for translation, cultural adaptation and validation", published in the journal Arquivos de Neuropsiquiatria. Conclusion: Patients with MG presented a considerable presence of DRS with worsening quality of life. They presented reduced values in the maximum ventilatory pressures associated with normal values of pulmonary function. The translation and validation of the scales were performed successfully and we believe that the use of our Portuguese version from Brazil will assist in the care of patients with MG, including a more accurate monitoring of the clinical rehabilitation process. / Introdução: Nossa hipótese é que os pacientes com MG apresentam um sono de má qualidade devido a presença de distúrbios respiratórios, comprometido pela fraqueza dos músculos ventilatórios acarretando em piora da condição clinica e qualidade de vida. Objetivos: Investigar o padrão fisiológico do sono através da polissonografia, verificar a função pulmonar e a força muscular ventilatória através de espirometria e manovacuometria e realizar a tradução, adaptação cultural e validação de duas escalas específicas para avaliar a evolução clínica de pacientes com MG, denominados “Teste Quantitativo para Miastenia gravis" e "Escala composta para Miastenia gravis". Material e métodos: Trata-se de um estudo transversal envolvendo pacientes com MG. As avaliações clínicas foram realizadas no Laboratório do sono da UNINOVE, no Setor de Investigação de Doenças Neuromusculares da UNIFESP, no Departamento de Neurologia da Santa Casa de São Paulo e no Departamento de Neurologia do Hospital do Servidor Público Estadual de São Paulo. Resultados: Os resultados desta tese são separados em três estudos. Estudo I: artigo intitulado "Sono, função pulmonar e qualidade de vida em pacientes com Miastenia gravis: Um estudo transversal" publicado no periódico Neuromuscular Disorders. Estudo II: intitulado "Tradução, adaptação cultural e validação da escala Composta de Miastenia gravis para a língua portuguesa do Brasil: estudo multicêntrico" publicado no periódico Arquivos de Neuropsiquiatria. Estudo III: intitulado "Teste Quantitativo para Miastenia gravis: estudo multicêntrico brasileiro para tradução, adaptação cultural e validação. " publicado no periódico Arquivos de Neuropsiquiatria. Conclusão: Os pacientes com MG apresentaram uma presença considerável de DRS com piora na qualidade de vida. Apresentaram valores reduzidos nas pressões máximas ventilatória associados com valores normais de função pulmonar. A tradução e validação das escalas foram realizadas com sucesso e acreditamos que o uso da nossa versão em português do Brasil irá auxiliar no atendimento de pacientes com MG, incluindo um monitoramento mais preciso do processo de reabilitação clinica.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24528号 / 医博第4970号 / 新制||医||1065(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊藤 能永, 教授 羽賀 博典, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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L'inactivité physique est considérée comme le 4ème facteur de risque de décès dans le monde. Aujourd’hui un défi de santé publique est d’augmenter l’activité physique (AP) des citoyens. Cependant, l'augmentation du volume et de l'intensité de l'AP peut être impossible ou déconseillée dans certaines populations. La myasthénie auto-immune (MG) est une maladie rare dans laquelle un dysfonctionnement de la jonction neuromusculaire provoque une faiblesse et une fatigue. Les symptômes peuvent entraîner une déficience fonctionnelle et une activité réduite, menant à un déconditionnement secondaire. Le présent travail a étudié les symptômes cliniques, la qualité de vie et l'activité physique dans une cohorte de sujets atteints de MG. Les données présentées ici montrent que certaines personnes mènent un mode de vie sédentaire mais d'autres participent à des activités physiques régulières et de haute intensité. La qualité de vie ne semble pas être liée aux comportements d'activité physique et n'est pas améliorée par l'ajout d'un programme d'exercice structuré. Notamment, il a été démontré que l’exercice est sans danger dans les cas de MG stabilisée. De plus, l'exercice procure d'autres avantages tels qu’une meilleure capacité de marche et une éventuelle augmentation sensible de la force. Enfin, nous révélons que même si la fatigue est un symptôme caractéristique de la MG, nous n’avons pas trouvé de fatigue musculaire supérieure à celle de témoins sains, ce qui suggère que la fatigue perçue pourrait davantage être liée à la faiblesse musculaire. En conclusion, nous recommandons qu'un programme d’exercice physique adapté et sur-mesure soit proposé aux personnes atteintes de MG afin de prévenir le déconditionnement et les comorbidités secondaires. Des recherches supplémentaires sont nécessaires pour définir le type et le dosage optimal de l'exercice.Myasthénie auto-immune, qualité de vie, activité physique, exercice physique, fatigue / Physical Activity and Quality of Life in Auto-Immune Myasthenia GravisPhysical inactivity is considered the 4th leading risk factor for death worldwide, linked to increased chronic disease and social isolation. Public health campaigns to encourage increased activity are rife. However, increasing physical activity levels and intensities may not be possible or advised in certain patient populations. Myasthenia gravis (MG) is a rare, auto-immune disease in which dysfunction at the neuromuscular junction causes weakness and fatigue. Symptoms can cause functional impairment and reduced activity, creating the increased burden of deconditioning in addition to primary disease symptoms. The present work investigated clinical symptoms, MG-specific health-related quality of life and activity levels in individuals with MG. Data presented here show that whilst some individuals lead a sedentary lifestyle, others participate in regular, high-intensity exercise. QoL does not seem to be related to physical activity patterns and is not improved with the addition of a structured exercise program. Exercise provides other benefits such as increased walking capacity and a possible increase in strength. Importantly, exercise has been shown to be safe in stabilized myasthenia. Finally, we reveal that whilst fatigue is a hallmark symptom in MG, formal testing demonstrated that muscle fatigue was not greater than healthy controls suggesting that perceived fatigue may be related to weakness. In light of these results we would recommend that subjects with MG are encouraged to reduce their daily sedentary behaviour and to undertake a regular exercise program to prevent deconditioning and potentially improve functional capacities. The optimal type and dosage of exercise remains to be elucidated.

Autoimmune myasthenia gravis (MG) is a muscular disease mediated by autoantibodies, mainly directed against the acetylcholine receptor (AChR). The pathogenic antibodies are especially produced in the thymus, which is often characterized by a hyperplasia with germinal centers. Recent studies demonstrated the overexpression of chemokines and the abnormal development of high endothelial venules (HEV) in the MG thymus. The aim of my thesis was to better understand the mechanisms that lead to thymic hyperplasia in MG by analyzing the role of chemokines in peripheral cell recruitment. We demonstrated that the number of HEVs correlated with the degree of hyperplasia suggesting a direct link between HEVs and peripheral cell recruitment. To define its mechanism of action, we examined which chemokines were expressed on thymic HEVs. We uniquely detected SDF-1 and observed that B cells, myeloid dendritic cells (mDCs), plasmacytoid DCs and monocytes/macrophages that expressed the SDF-1 receptor CXCR4 localized inside and around thymic HEV. In parallel we observed a decreased CXCR4 expression and a decreased number of mDCs and also monocytes in the periphery suggesting their recruitment to the MG thymus. As the MG thymus was recently characterized by the overexpression of CXCL13 in thymic epithelial cells (TECs), we investigated its contribution to thymic hyperplasia. We therefore generated a transgenic mouse model overexpressing in medullary TECs CXCL13 under the control of keratin 5. We demonstrated that transgenic K5-CXCL13 mice specifically overexpressed CXCL13 in the thymus, while no other tested chemokines were upregulated. Preliminary results showed that elevated levels of CXCL13 resulted in an increased number of B cells in the thymus of transgenic mice, which localized preferentially in loose aggregates in medullary areas. We are presently investigating if immunization with purified AChR induces experimental MG with thymic hyperplasia in these mice. Myasthenic mice with a hyperplastic thymus could present a new animal model for MG with a phenotype that is closer to the human disease than the current MG model. As the hyperplastic MG thymus displays the hallmarks of a viral signature, we investigated the effect of pathogen-associated molecules on thymic changes associated with MG. We demonstrated that dsRNA signaling induced by Poly(I:C) specifically triggers the overexpression of α-AChR in human TECs through the release of IFN-I. We also observed that IFN-I was able to upregulate CXCL13 and CCL21, similarly to what is observed in the MG thymus. In addition, Poly(I:C) injections in wildtype mice, but not in IFN-I receptor KO mice, specifically increase thymic expression of α-AChR and, in parallel, CXCL13 and CCL21 expression. In periphery, Poly(I:C) even induced an anti-AChR autoimmune response characterized by a significant production of serum anti-AChR antibodies and a specific proliferation of B cells. Overall the results obtained in the course of my PhD showed that the abnormal development of SDF-1-expressing HEVs and the CXCL13 overexpression play a central role in the recruitment of peripheral cells to the MG thymus. Once these cells have arrived in the inflammatory environment, which is characteristic for MG, they could develop an autoimmune reaction against AChR. New therapeutic molecules that control chemokine expression and angiogenic processes could diminish the development of thymic hyperplasia and avoid thymectomy or the use of corticoids.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2016-05-24T20:16:20Z No. of bitstreams: 1 Ezequiel Fernandes de Oliveira.pdf: 6004865 bytes, checksum: 1533cb1828601a79b30eb9ae6ce24420 (MD5) / Made available in DSpace on 2016-05-24T20:16:20Z (GMT). No. of bitstreams: 1 Ezequiel Fernandes de Oliveira.pdf: 6004865 bytes, checksum: 1533cb1828601a79b30eb9ae6ce24420 (MD5) Previous issue date: 2014-12-01 / Introduction: Autoimmune myasthenia gravis is an chronic disease inflammatory characterized by progressive weakness of the skeletal muscles due to a change in the synapses between the nerves and muscle fibers. The manifestations of the respiratory system are generally attributed to the weakness of the diaphragm and other accessory muscles of ventilation leading to breathlessness. Among these manifestations, we highlight the onset of sleep-disordered breathing (SDB) due to weakening of the muscles of the oropharynx. Objectives: To verify the lung function, respiratory muscle strength, and physiological variables during sleep in patients with myasthenia gravis clinically stable. Methods: This is a prospective cross-sectional descriptive study, following a study protocol previously published. Patients were recruited consecutively from the Setor de Investigação de Doenças Neuromusculares of the Universidade Federal de São Paulo in accordance with the eligibility criteria, and referred to the Sleep Laboratory of Universidade Nove de Julho, São Paulo (Brazil). Results: The study included 18 patients The mean age of 42,66±10,91 (15 women). Regarding lung function only two patients had a restrictive ventilatory pattern. The maximum ventilatory pressures observed were considerably reduced in most patients when compared to reference values. Regarding sleep, highlight observe a significant decrease in oxyhemoglobin saturation, reduced REM sleep time, increased stage NREM3, considerable increase of apnea and hypopnea per hour and a high risk for obstructive sleep apnea. Discussion: Data on sleep-related disorders in patients with Autoimmune myasthenia gravis in the literature are scarce and inconclusive, with few studies using basal nocturnal polysomnography. Conclusion: Clinically stable patients with autoimmune myasthenia gravis have a high prevalence of sleep respiratory disorders and a significant reduction in maximal inspiratory and expiratory pressures with reduced quality of life. / Introdução: A Miastenia gravis auto imune adquirida é uma doença crônica, inflamatória, caracterizada pela fraqueza progressiva dos músculos esqueléticos, devido a uma alteração na junção sináptica entre os nervos e as fibras musculares. As manifestações no sistema respiratório geralmente são atribuídas à fraqueza do músculo diafragma e demais músculos acessórios da ventilação levando à dispneia. Dentre estas manifestações, destacamos o surgimento dos transtornos respiratórios do sono (DRS) devido ao enfraquecimento da musculatura da região orofaríngea. Objetivos Verificar a função pulmonar, a força muscular ventilatória e as variáveis fisiológicas do sono em pacientes com Miastenia gravis. Métodos: Trata-se de um estudo transversal descritivo prospectivo. Os pacientes foram recrutados de forma consecutiva do Setor de Investigação de Doenças Neuromusculares da Universidade Federal de São Paulo de acordo com os critérios de elegibilidade, seguindo um protocolo padronizado e encaminhados ao Laboratório do Sono da Universidade Nove de Julho, São Paulo (Brasil). Resultados: Participaram deste estudo 18 pacientes com média de idade de 42,66±10,91 (15 mulheres). Em relação a função pulmonar apenas dois pacientes apresentaram um padrão ventilatório restritivo. As pressões ventilatórias máximas observadas foram consideravelmente reduzidas na maioria dos pacientes quando comparados a normalidade. Em relação ao sono, observamos uma queda significativa da saturação da oxihemoglobina, reduzido tempo de sono REM, aumento do estágio NREM3, considerável aumento do índice de apneia e hipopneia. Discussão Os dados sobre transtornos relacionados ao sono e qualidade do sono em Miastenia gravis na literatura são escassos e baseados nos resultados inconclusivos, com poucos estudos realizados por meio de polissonografia basal noturna. Conclusão: Pacientes com MG auto imune adquirida apresentam uma alta prevalência de distúrbios respiratórios sono e uma significativa redução das pressões máximas inspiratórias e expiratórias com consequente comprometimento da qualidade de vida.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2016-05-25T18:25:43Z No. of bitstreams: 1 Sergio Roberto Nacif.pdf: 1795162 bytes, checksum: 7b6d72682614593467c7e6265c34a637 (MD5) / Made available in DSpace on 2016-05-25T18:25:43Z (GMT). No. of bitstreams: 1 Sergio Roberto Nacif.pdf: 1795162 bytes, checksum: 7b6d72682614593467c7e6265c34a637 (MD5) Previous issue date: 2014-12-16 / Introduction: Obstructive sleep apnea (OSA) is a breathing disorder characterized by the collapse of the upper airway and has significant prevalence in the general population and specifically in neuromuscular diseases. Objective: To determine the effectiveness of the negative expiratory pressure (NEP) test as a screening to the OSA in myasthenia gravis patients. Method: The study included 15 patients (12 women) from the Setor de Investigação de Doenças Neuromusculares and Associação Brasileira de Miastenia Grave (ABRAMI), which underwent overnight standard polysomnography (PSG), spirometry, manovacuometer and NEP test. Results: The mean age was 41.46 ± 11.32 years, mean weight of 78.4 ± 15.28 kg and the mean body mass index was 29.34 ± 5,3kg / m2. The physiological variables of sleep observed in PSG draw attention to the oxygen saturation nadir, for the sleep latency and total sleep rapid eyes movement (REM) time, apnea-hypopnea index (AHI) and snoring time. The mean AHI was 17.5 ± 21.7, being most obstructive origin events. Regarding the Berlin Questionnaire, only one of the fifteen patients evaluated presented low risk for OSA. Regarding the Epworth Sleepiness Scale, we observed that six patients (40%) did not presented excessive daytime sleepiness, three (20%) had mild drowsiness, five individuos presented moderate (33.4%) and only one patient (6.6%) was classified with severe excessive daytime sleepiness with a score of 22 to a maximum of 24 points. The statistics analyses verify the existence of correlation between anthropometric variables, physiological PSG variables, Epworth Sleepiness Scale and Berlin questionnaire show higher values for body mass index (BMI), waist circumference and AHI. Conclusion: We can conclude that patients with MG have lower values of ventilatory maximum pressures associated with normal lung function. They also feature a considerable number of sleep disordered breathing associated with fall oxyhemoglobin saturation and reduced REM sleep, with consequent presence of excessive daytime sleepiness and high risk for OSA. Although we did not observe a correlation between the PNE test with AHI, our data show that patients with moderate-severe OSA have greatly reduced V0,2% (<20%). / Introdução: A apneia obstrutiva do sono (AOS) é um distúrbio respiratório caracterizado pelo colapso da via aérea superior com importante prevalência na população em geral e especificamente nas doenças neuromusculares. Objetivo: Verificar a eficácia do teste da pressão negativa expiratória (PNE) como proposta de screening para AOS em pacientes com Miastenia gravis. Método: Participaram deste estudo 15 pacientes (12 mulheres) provenientes do Setor de Investigação de Doenças Neuromusculares e Associação Brasileira de Miastenia Grave, os quais foram submetidos à polissonografia basal noturna (PSG), espirometria, manovacuometria e teste da PNE. Resultados: A média de idade foi de 41,46 ± 11,32 anos, peso médio de 78,4 ± 15,28 kg e o índice de massa corpórea médio foi de 29,34 ± 5,3kg/m2. As variáveis fisiológicas do sono observadas na PSG chamam a atenção para a saturação periférica mínima de oxigênio, para a latência e tempo total de sono REM, IAH e tempo de ronco. O IAH médio foi de 17,5 ± 21,7 sendo a maioria eventos obstrutivos. A análise estatística para verificação da existência de correlação entre as variáveis PNE e IAH mostrou um R de -0,5 com um valor de p= 0,06 e, para PNE/IDO/h um R -0,45 com um valor de p= 0,08. Quando correlacionamos os valores obtidos no teste de PNE com pressões de -6 e -10cm/H2O observamos uma excelente correlação de R = 0,825 com um p = 0,0000. Em relação ao questionário clínico de Berlim, dos quinze pacientes avaliados apenas um apresentou baixo risco para AOS. As análises estatísticas para verificação da existência de correlação entre as variáveis antropométricas, fisiológicas da PSG, escala de Epworth e questionário de Berlim mostram valores significativos apenas para o IMC, circunferência abdominal e IAH. Conclusão: Pacientes com MG apresentam redução das pressões máximas ventilatórias associado a função pulmonar normal. Também apresentam um considerável IAH associado a queda da saturação da oxihemoglobina e redução do sono REM, com consequente presença de sonolência excessiva diurna e alto risco para AOS. Embora não tenha sido observado uma correlação entre o teste do PNE com o IAH, nossos dados mostram que pacientes com Myasthenia gravis com AOS moderada-grave apresentam grande redução do V0,2%.

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