Magister en ciencias médicas mención nutrición / En Chile, así como en otros países del mundo, ha ido aumentando la importancia del cáncer. Actualmente es la segunda causa de muerte en nuestro país, constituyendo en la actualidad un problema de salud pública. La desnutrición frecuentemente se asocia a cáncer, constituyendo un índice pronóstico, pues se asocia a resultados adversos en pacientes portadores de patologías neoplásicas. Resulta importante contar con métodos fáciles , reproducibles, objetivos e idealmente de bajo costo, para la evaluación nutricional del paciente oncológico. La Evaluación Global Subjetiva Generada por el Paciente (EGS-GP) cumple las características antes señaladas, siendo considerada actualmente como el método gold estándar. Los parámetros bioquímicos clásicos ( como albúmina, linfocitos, prealbumina, etc) y la antropometría tiene limitaciones en su interpretación en este grupo de pacientes. El deterioro de la fuerza muscular es un fenómeno bien conocido que ocurre en la desnutrición asociada a enfermedad y los cambios en ella , preceden a los cambios en los parámetros nutricionales clásicos, por lo que la alteración en test funcionales , como la dinamometría de mano, podrían resultar útiles en el diagnóstico de desnutrición. Objetivo: determinar si la dinamometría de mano tiene mejor asociación con EGS-GP, que los parámetros antropométricos (pliegue tricipital y circunferencia muscular braquial) y albúmina, para el diagnóstico de desnutrición en el paciente oncológico hospitalizado, en un hospital público de Chile. Sujetos y método: estudio transversal, realizado en Hospital del Salvador que incluyó 167 pacientes portadores de cáncer( tumores sólidos y hematológicos), en los cuales se realizó evaluación nutricional con EGS-GP con y sin puntaje, medidas antropométricas (peso, talla, índice de masa corporal ( IMC), medición de pliegue tricipital y bicipital, determinación de circunferencia muscular del brazo), parámetros bioquímicos ( albúmina plasmática, linfocitos totales), medición de dinamometría de mano, determinación del índice de Karnosfky y obtención en registro médico de proteína C reactiva. Se utilizaron las pruebas de chi-cuadrado y Fisher exact para determinar asociación, coeficiente Kappa para evaluar concordancia entre variables, coeficiente de Speraman para definir correlación, test de Anova para evaluar diferencia entre grupos. Se consideró un valor de p < 0,05. Resultados: de los 167 sujetos incluidos en es estudio, 83 pacientes fueron hombres y 84 mujeres. La edad promedio de la muestra fue de 56 + 19,4 años. 1 pacientes portaban patología oncohematológica y 112 tumores sólidos, siendo los tumores del tubo digestivo los más frecuentes, alcanzando el 40 % de la muestra. De acuerdo al IMC, el 50, 3% de los pacientes se encontraban en rango de normopeso. El 58,7 % de los pacientes tuvieron albuminemia en rango normal. En relación a la EGS-GP, el 78,4 % de los pacientes de la muestra tenían algún grado de desnutrición, de los cuales el 49,1% fueron clasificados como severamente desnutridos. Se observó asociación entre EGS-GP con dinamometría ( X2 = 5,228; p= 0,02), con pliegue tricipital (X2 = 10,255 ; p= 0,01) y con CMB (X2 = 10,629 ; p= 0,01); pero no con albuminemia (X2 = 3,501 ; p= 0,61). No se observó asociación entre tipo de cáncer (X2 = 3,858 ; p= 0,05) y ejercicio con dinamometría (Estadístico de Fisher = 0,231 ; p= 0,122 ). Al evaluar la relación puntaje de EGS-GP versus dinamometría se encuentra una correlación inversa, pero débil ( Rho Spearman -0,161; p= 0,039). La misma situación ocurre al relacionar dinamometría con pliegue tricipital ( Rho Spearman – 0,88; p=0,257). No existe concordancia entre EGS- GP y dinamometría (kappa = -0,41; p =0,022) . Conclusión: La dinamometría de mano tiene mejor asociación con EGS-GP que la albuminemia, pero no mejor que pliegue tricipital y CMB. Por esta razón los parámetros antropométricos, para este tipo de pacientes sigue siendo la mejor opción de evaluación nutricional. / In Chile, as in other countries of the world, has been increasing the importance of cancer. Currently it is the second cause of death in our country, being a public health problem. Frequently, malnutrition is associated with cancer, constituting a prognostic index, since it is associated with adverse outcome in patients with neoplastic pathologies. It is important to have with easy, reproducible, objective and ideally inexpensive methods for the nutritional evaluation of cancer patients. The Patient Generated Subjective Global Assessment (EGS-GP by Spanish initials), fulfills the above-mentioned characteristics and currently it is considered as the standard gold method. The classical biochemical parameters (such as albumin, lymphocytes, prealbumin, etc) and the anthropometry have limitations in their interpretation in this group of patients. The deterioration of muscle strength is a well-known phenomenon that occurs in malnutrition associated with a disease. In fact, muscle deterioration precedes changes in the classic nutritional parameters, so that the alteration in functional tests, such as hand dynamometry, could be useful in the diagnosis of malnutrition. Objective: To determine if the hand dynamometry has a better association with EGS-GP that the anthropometric parameters (tricipital skinfold and brachial muscle circumference) and albumin, for the diagnosis of malnutrition in hospitalized cancer patient, in a public hospital in Chile. Subjects and method: a cross-sectional study conducted at Hospital del Salvador, which included 167 cancer patients (solid and haematological tumors). These patients underwent nutritional evaluation with EGS-GP, with and without score, anthropometric measurements (weight, height, body mass index (BMI), tricipital and bicipital skinfold measurement, determination of arm circumference, biochemical parameters (plasma albumin, total 9 lymphocytes), hand dynamometry measurement, determination of Karnosfky index and obtaining on medical record of C-reactive protein. Chi-square and Fisher exact tests were used to determine the association, Kappa coefficient was used to evaluate the concordance between variables, Sperman coefficient was used to define the correlation, and Anova test was used to evaluate the difference between groups. A value of p < 0.05 was considered. Results: Of the 167 subjects included in this study, 83 patients were men and 84 women. The mean age of the sample was 56 + 19.4 years. %1 patients had oncohematologic pathology and 112 patients had solid tumors, with tumors of the digestive tract being the most frequent, reaching 40% on the sample. According to the BMI, the 50.3% of patients were in normal weight range. 58.7% of patients had albuminemia in the normal range. Regarding the EGS-GP, the 78.4% of patients in the sample had some degree of malnutrition, of which, 49.1% were classified as severely malnourished. An association between EGS-GP with dynamometry (X2 = 5.228; p = 0.02), with tricipital skinfold (X2 = 10.255; p = 0.01) and with CMB (X2 = 10.629; p=0.01); but no with albuminemia (X2 = 3.501; p = 0.61), was observed. There was no association between type pf cancer (X2 = 3.858; p = 0.05) and exercise with dynamometry (Fisher’s statistic = 0.231; p = 0.122). When evaluating the relationship of EGS-GP score versus dynamometry, an inverse but weak correlation was found (Rho Spearman – 0.161; p = 0.039). The same situation occurs when dynamometry is associated with tricipital skinfold (Rho Spearman – 0.88; p = 0.257). There is no agreement between EGS-GP and dynamometry (kappa = 0.41; p = 0.022). Conclusion: Hand dynamometry has better association with EGS-GP than albuminemia, but no better than tricipital skinfold and CMB. For this reason, the anthropometric parameters remains the best option of nutritional evaluation for this type of patients.

Orientador: Alessandro Moura Zagatto / Banca: Cleber Ferraresi / Banca: Fernando Diefenthaeler / Resumo: O objetivo geral da presente dissertação foi investigar os efeitos de duas doses de TFBM sobre o tempo até a exaustão em esforço retangular no domínio severo em ciclo ergômetro, explorando durante o exercício as respostas fisiológicas decorrentes da atividade muscular (i.e., metabólicas, gasométricas, eletromiográficas e respiratórias), assim como, os aspectos centrais e periféricos da fadiga muscular após esforço. Para isso, dois estudos foram realizados, estudo 1 e 2. Participaram do projeto 27 voluntários (14 participantes no estudo 1 e 13 no estudo 2. O estudo 1 teve como objetivo investigar os efeitos de duas doses de TFBM sobre aspectos centrais e periféricos da fadiga muscular após esforço de ciclismo em carga constante no domínio severo (Δ60%) com duração equalizada, analisando também, as respostas neuromusculares durante o esforço. Os sujeitos realizaram 5 esforços em dias distintos, um na forma de familiarização e um na forma controle, ambos até à exaustão e três, com duração idêntica à atingida na condição controle, precedidos por uma das três intervenções utilizadas no presente estudo: TFBM na dose de 260 J, TFBM na dose de 130 J e placebo, TFBM com o aparelho desligado (estudo randomizado, cruzado com duplo-cegamento). Durante o esforço as repostas eletromiográficas de músculos do membro inferior dominante foram avaliadas e antes e após esforço, contrações voluntárias máximas associada à eletroestimulação periférica do nervo femoral foram efetuadas, objetivando i... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The general objective of this dissertation was to investigate the effects of two doses of photobiomodulation (PBM) on time to exhaustion in a constant load cycling effort at severe domain (Δ60%, [CLE60]), exploring during the exercise the physiological responses resulting from muscular activity (ie, metabolic, gasometric, electromyographic and respiratory), as well as the central and peripheral aspects of muscle fatigue after effort. For this, two studies were carried out, study 1 and 2. Twenty-seven volunteers (14 participants in study 1 and 13 in study 2) participated in the study. Study 1 aimed to investigate the effects of two doses of PBM on central and peripheral aspects after CLE60 with equalized duration (ie, isotime) as well as the neuromuscular responses during the exercise. The subjects performed 5 efforts on different days, one in the form of familiarization and one in the control form, both until exhaustion. The last three efforts were performed with the same duration as that reached in the control condition, preceded by one of the three interventions used in the present study: PBM at the dose of 260 J, PBM at 130 J and placebo (PBM with the device switched off, dose of 0 J). During the last 4 exercises, the electromyographic responses of muscles of the dominant lower limb were evaluated and before and after the last three efforts, neuromuscular evaluations associated with peripheral electrical stimulation of the femoral nerve were performed, aiming to investigat... (Complete abstract click electronic access below) / Mestre

Contextualização - A distrofia muscular de cinturas tipo 2A ou calpainopatia é uma desordem causada pelas mutações no gene CAPN3 (15q15.1) que codifica a calpaína. Entender como ocorre a perda de força muscular, da mobilidade articular e suas relações com a função nestes pacientes pode auxiliar na melhor compreensão da evolução da doença e indicar os biomarcadores pertinentes para o acompanhamento desta doença. Objetivo - Descrever e correlacionar a força muscular, a amplitude de movimentos articulares (ADM) e a função de um grupo de pacientes brasileiros com distrofia muscular de cinturas tipo 2A (calpainopatia). Método - Trata-se de um estudo transversal. A população estudada foi composta por 50 pacientes acompanhados no Centro de Pesquisa sobre o Genoma Humano e Células Tronco (CEGH-CEL) do Instituto de Biociências da Universidade de São Paulo, São Paulo, Brasil. Foram coletados os dados de força muscular (Medical Research Council - MRC), amplitude de movimento, escala de Vignos, escala de Medida de Independência Funcional (MIF), teste de caminhada de 10 metros (TC10m) e Escala Egen Klassifikation (EK). Para análise de correlação entre a força muscular e função foram utilizados os testes de correlação de Pearson e de Spearman. Resultados - Houve correlação positiva forte entre o índice de força muscular de cotovelo e o escore da Escala de Medida de independência funcional total (MIFT) (rho=0.70) e correlação negativa forte entre a Escala de Vignos e escore da MIFT (rho= -0.90). No teste de caminhada de 10 metros, a média do tempo utilizado pelos participantes foi de 17.82 segundos. Os resultados mostraram correlação negativa moderada entre o escore da escala EK e o índice de força muscular (MRC) dos segmentos corporais do cotovelo (rho= -0.51) e punho (r= -0.40) para o subgrupo cadeirantes. A amplitude de movimento não é um biomarcador pertinente para o acompanhamento da doença, pois não apresentou correlação com as demais variáveis deste estudo. A maioria dos pacientes apresentou limitações articulares na região de joelho e tornozelo, condizentes com outras pesquisas. A comparação da força muscular entre os músculos extensores dos joelhos direito e esquerdo mostrou diferença significativa (p < 0.02). Conclusão - Amostra brasileira apresentou incidência similar com os países do continente europeu (32%). Os escores de força muscular mostraram correlação com a função motora. Nossos achados permitem determinar, com melhor embasamento, os biomarcadores funcionais força muscular e função como os mais indicados na prática clínica e de pesquisa / Contextualization - Limb-girdle muscular dystrophy type 2A or calpainopathy is a disorder caused by mutation in the CAPN3 gene (15q15.1) that codes for calpain. Understanding how loss of muscular strength, joint mobility and their relationship with the function in these patients can help in better understanding the evolution of the disease and indicate the biomarkers pertinent to the follow-up of this disease. Objective - To describe and correlate muscle strength, range of joint movements (ROM) and function of a group of Brazilian patients with limb-girdle muscular dystrophy type 2A (calpainopathy). Method - This is a cross-sectional study. The studied population was composed for 50 patients at the Center for the Study of the Human Genome (CSHG) of the Institute of Biosciences of the University of São Paulo, São Paulo, Brazil. The data recorded were muscle strength (Medical Research Council - MRC), range of motion, Vignos scale, Functional Independence Measure (FIM), 10-meter walk test and Egen Klassifikation scale (EK). Para análise de correlação entre a força muscular e função foram utilizados os testes de correlação de Pearson e de Spearman. Results - There was a strong positive correlation between MRC and FIM (rho=0.70) and negative correlation between the Vignos Scale and FIM (rho= -0.90). The 10-meter walk test, the mean time used by participants was 17.82 seconds. The results showed a moderate negative correlation between the EK scale score and the MRC of the elbow (rho = -0.51) and wrist (r = -0.40) for the wheelchair subgroup. The range of motion is not a biomarker pertinent to the disease follow-up, since it did not present a correlation with the other variables of this study. The patients had contractures around the knee and ankle, is in keeping with what other studies. The comparison of muscle strength between the extensor muscles of the right and left knees showed a significant difference (p < 0.02). Conclusion - Brazilian sample had an incidence similar with the countries of the European continent (32%). The scores of muscle strength and motor function showed correlation. Our findings allow us to determine, with better foundation, functional biomarkers muscle strength and function as the most indicated in clinical practice and research

As distrofias musculares são doenças genéticas causadas por mutações em diferentes genes caracterizadas por degeneração muscular, prejuízos locomotores e, geralmente, morte precoce. Dentre elas, a de Duchenne, causada por mutações no gene que codifica para a proteína distrofina, é a mais comum e grave, tendo os camundongos MDX como modelo experimental mais utilizado. O objetivo do presente estudo foi testar quatro abordagens terapêuticas potencias neste modelo animal, divididas em dois experimentos: 1. treinamento físico voluntário em roda de atividade e/ou drogas agonistas das proteínas AMPK e PPAR em dias alternados (AICAR: 100 mg.Kg-1.dia-1, ip; GW 1516: 5 mg.Kg-1.dia-1, gavagem); 2. células-tronco estromais humanas provenientes de lipoaspiração (um milhão a cada injeção intravenosa; uma injeção a cada 10 dias nos dois primeiros meses de tratamento e injeções mensais nos quatro meses subsequentes) e/ou suplementação com os aminoácidos alanina e glutamina (10 mg.kg-1.dia-1, injeção diária intraperitoneal). Em relação ao primeiro experimento, o principal achado foi que os animais submetidos ao treinamento físico associado às drogas apresentaram índices de função muscular superiores aos outros grupos. Já em relação ao segundo grupo de análises, foi observado que os animais submetidos à terapia celular apresentaram tempo de vida significativamente maior quando comparados aos animais não tratados e aos tratados com ambas as terapias. Tais resultados, nunca demonstrados previamente pela literatura científica, podem contribuir para o entendimento da fisiopatologia das distrofias musculares e para o avanço de potenciais abordagens terapêuticas. / Muscular dystrophies are genetic diseases caused by mutations in different genes. They are characterized by muscle degeneration, motor prejudices and, generally, early death. Among them, Duchenne muscular dystrophy (DMD) is the most common and severe form and it is caused by mutations in the dystrophin gene. The most widely used animal model of DMD is the MDX mouse. The aim of this study was to test four potential therapeutic approaches assigned in two experiments: 1. voluntary exercise training in activity road and/or AMPK and PPAR agonists drugs every other day in MDX mice (AICAR: 100 mg.Kg-1.day-1, IP; GW 1516: 5 mg.Kg-1.day-1, gavage); 2. Intravenous injection of stromal stem cells from human adipose tissue (106 cells every 10 days in the first two months and monthly injections in the following four months) and/or alanine and glutamine amino acids supplementation (10 mg.Kg-1.day-1, daily IP injections). In the first experiment we demonstrated that mdx mice submitted to exercise training associated to drugs presented improved muscle function when compared to the other groups. In the second experiment, on the other hand, it was observed that the animals submitted to cell therapy presented increased survival when compared to non injected animals and animals treated with both approaches. These results, here demonstrated for the first time, can contribute to understand the physiopathology of muscular dystrophies and may give insights for future therapeutic approaches

Distrofia muscular de Duchenne é uma desordem neuromuscular causada pela mutação ou deleção do gene da distrofina, a qual é ligada ao cromossomo X. Estudos recentes têm demonstrado o importante papel da distrofina no SNC, sendo sua deficiência relacionada com uma variedade de anormalidades na função do SNC, como comportamento e disfunção cognitiva. Os modelos animais mais adequados para esses estudos são os que apresentam o quadro clinico mais semelhante ao da DMD encontrada em humanos, como cães Golden Retriever com distrofia muscular (GRMD). Por não haver ainda estudos a respeito do SNC de animais GRMD, o objetivo deste trabalho foi analisar a morfologia do encéfalo dos GRMD e o de animais não distróficos, através de análise macroscópica, utilizando métodos de medição e registro fotográfico, e análise microscópica, utilizando a técnica de coloração de violeta cresil modificada. Entretanto, usando a metodologia proposta, não foi possível verificar diferenças significativas no encéfalo quando comparados os animais distróficos e os não distróficos, o que está em concordância com a literatura para a DMD usando os mesmos parâmetros. Em tempo, existe uma variação individual na morfologia do encéfalo do cão, independente de serem animais do grupo de distróficos ou controles. Outras técnicas devem ser aplicadas a fim de elucidar as consequências da ausência total ou parcial da distrofina no SNC / Duchenne muscular dystrophy is a neuromuscular disorder caused by the mutation or deletion of the dystrophin gene, which is linked to chromosome X. Recent studies have shown the important role of dystrophin in the CNS, and its related defect with a variety of abnormalities in the function of CNS, such as behavior and cognitive dysfunction. The most suitable animals models for these studies are those with the most similar clinical picture to DMD found in humans, as Golden Retriever dogs with muscular dystrophy (GRMD). There are no further studies on the GRMD animal CNS, and the aim of this study was to analyze the morphology of the brain of GRMD and not dystrophic animals through macroscopic analysis using measurement and photographic registration methods, and microscopic analysis using the modified cresyl violet staining technique. However, using the proposed methodology, we could not find significant differences in the brain when comparing the dystrophic animals and non-dystrophic, which is in agreement with the literature for DMD using the same parameters. In time, there is individual variation in dog brain morphology, whether they are animals of the dystrophic group or controls. Other techniques should be applied in order to elucidate the consequences of the total or partial absence of dystrophin in the CNS

by Wu Kwok Hang. / Thesis (M.Ph.)--Chinese University of Hong Kong, 1988. / Bibliography: leaves 213-229.

Wearable robotics for assistance and rehabilitation are not yet considered commercially mainstream products, and as a result have not yet seen advanced controls systems and interfaces. Consequently, the available technology is mostly adapted from systems used in parallel technologies, rather than custom applications intended for human use. This study concerns itself with the design and development of a custom control system for a 2-degree of freedom powered upper extremity orthosis capable of driving elbow flexion/extension 135º and humeral rotation 95º . The orthosis has been evaluated for use as both a long-term assistive technology device for persons with disabilities, and as a short-term rehabilitative tool for persons recovering injury. The target demographics for such a device vary in age, cognitive ability and physical function, thus requiring several input parameters requiring consideration. This study includes a full evaluation of the potential users of the device, as well as parameter considerations that are required during the design phase. The final control system is capable of driving each DOF independently or simultaneously, for a more realistic and natural coupled-motion, with proportional control by pulse-width modulation. The dual-axis joystick interface wirelessly transmits to the 1.21 pound control pack which houses a custom microcontroller-driven PCB and 1800 milliamp-hour lithium-ion rechargeable battery capable of delivering 4 hours of running time. Upon integration with the 2 DOF orthosis device, a user may complete full range of motion with up to 5 pounds in their hand in less than 7 seconds, providing full functionality to complete acts of daily living, thus improving quality of life.

Made available in DSpace on 2019-03-29T23:21:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-12-15 / Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease that can express itself as four distinct clinical manifestations: type I - progressive spinal muscular atrophy (Werdnig-Hoffmann disease); type II -intermediate spinal muscular atrophy; type III - juvenile spinal muscular atrophy (Kugelberg-Welander disease); type IV - adult spinal muscular atrophy. The children affected by types I and II present with motor and respiratory impairment, resulting in low quality of life (QOL). The aim of this study was to investigate the QOL of children with SMA type I and II from their own perspective and from that of their main caregivers. In total, 12 main caregiver/children pairs with SMA type I and II, registered by the Brazilian Association of Spinal Amyotrophy (ABRAME), and with the pathology diagnosed through DNA analysis, took part in the research. This multimethodological study, conducted between february and august 2008, used the following data collection instruments: a health-related quality of life (HRQol) instrument validated in Brazil for use in children, PedsQLTM 4.0; a sociodemographic chart and a series of interviews. These instruments contained the domains and indicators of childhood QOL proposed by Sabeh, Verdugo and Prieto (2006). The mean age of the children was 5.7 years and the main caregiver in each case was the child's mother. The use of instruments that explored the subjectivity of the participants enabled a closer approximation to what the children and their mothers believed to be a good life. The qualitative data were analyzed according to Bardin's content analysis and a descriptive analysis of the quantitative data to support the qualitative analysis was also performed. The results showed good QOL, from the perspective of both the children and their mothers. The discourses of both the children and their mothers demonstrate that the emotional well-being of the latter is preserved, a finding confirmed by the result of the PedsQLTM, on which a mean score of 76.7 was obtained. Physical well-being domain showed the greatest contradictions in the mothers' discourses, obtaining the worst result on the PedsQLTM (mean score of 24.7). This can be explained by the serious motor and respiratory impairments that the children display; however, it did not have a negative impact on the other domains. In the personal development and activities domain the school activities indicator was explored; the discourses of the mothers and of the children indicate good development of this aspect. The results of PedsQLTM for this item were: for children between 2 and 4 years of age the mean score was 55.6 and for those over 5 years of age it was 94. The material well-being domain was determined by the sociodemographic chart and by the children's discourses, showing a positive result for this aspect. It is important to point out that there was agreement in all the domains between the discourses of the mothers and of the children. The findings of this study revealed the QOL perceptions of children with a chronic disease that causes significant motor and respiratory impairment, as well as the perceptions of their mothers. This may serve to assist in developing health strategies aimed at an improved quality of life for these children in accordance with the principle of equity proclaimed by the National Health System (SUS) in the National Health Policy of Persons with Deficiency and with the actual desires of the children themselves. / A atrofia muscular espinhal (AME) é uma doença neuromuscular autossômica recessiva que se apresenta sob quatro formas distintas de manifestação clínica: tipo I - atrofia muscular espinhal progressiva (doença de Werdnig Hoffmann); tipo II - atrofia muscular espinhal na forma intermediária; tipo III - atrofia muscular espinhal juvenil (doença de Kugelberg Welander); tipo IV - atrofia muscular espinhal forma adulta. As crianças acometidas pelos tipos I e II apresentam sérios comprometimentos motores e respiratórios; deste modo, é possível se imaginar uma baixa qualidade de vida (QV) destas crianças. Esta pesquisa teve por objetivo investigar a QV de crianças com AME tipo I e II na visão das mesmas e na de seus cuidadores principais. Participaram deste estudo 12 díades cuidador principal/crianças com AME tipo I e II cadastradas pela Associação Brasileira de Amiotrofia Espinhal (ABRAME) e com a patologia diagnosticada através de exame de DNA. Trata-se de uma pesquisa multimetodológica, desenvolvida no período de fevereiro a agosto de 2008 e que teve como instrumentos de coleta de dados: um instrumento de avaliação de qualidade de vida relacionada à saúde (QVRS) validado no Brasil para ser utilizado com crianças - PedsQLTM 4.0, uma ficha sociodemográfica e roteiros de entrevistas. Estes instrumentos tiveram como base teórica de fundamentação os domínios e indicadores de QV na infância propostos por Sabeh, Verdugo e Prieto (2006). A idade média das crianças foi de 5,7 anos e o cuidador principal foi, em todos os casos, as mães das mesmas. A utilização de instrumentos que explorassem a subjetividade dos participantes possibilitou uma maior aproximação da realidade do que a criança e suas mães consideram como sendo uma vida boa. Os dados qualitativos foram analisados segundo a Análise de Conteúdo de Bardin e foi realizada uma análise descritiva dos dados quantitativos, os quais apoiaram a análise qualitativa. Os resultados evidenciaram boa QV tanto na percepção das crianças como na de suas mães. As falas das mães e também as das crianças demonstram que estas têm bem-estar emocional preservado, achado este confirmado pelo resultado do PedsQLTM no qual obteve escore médio de 70,6. O domínio relações interpessoais apresentou bom resultado tanto na fala das mães quanto na das crianças, o escore médio obtido no PedsQLTM para este aspecto foi de 76,7. O domínio bem-estar físico foi o que apresentou maiores contradições nas falas das mães e o que obteve pior resultado no PedsQLTM (escore médio 24,7), isto é justificado pelos graves comprometimentos motores e respiratórios que as crianças apresentam, contudo não provocou reflexo negativo nos outros domínios. No domínio desenvolvimento pessoal e atividades foi explorado o indicador atividades escolares; as falas das mães e das crianças referem-se a um bom desenvolvimento neste aspecto. Os resultados do PedsQLTM para este aspecto foram: para crianças de 2 a 4 anos o escore médio foi de 55,6 e para os participantes acima de 5 anos foi de 94. O domínio bem-estar material foi verificado pela ficha sociodemográfica e pela fala das crianças, as quais demonstraram resultado positivo para este aspecto. É importante salientar que em todos os aspectos houve concordância entre as falas das mães e das crianças. Os achados desta pesquisa possibilitaram conhecer as percepções de QV de crianças com uma doença crônica que acarreta grandes perdas do ponto de vista motor e respiratório, assim como as percepções de suas mães a este respeito. Isto poderá servir de subsídio para a formulação de estratégias de saúde direcionadas para uma vida de qualidade para estas crianças em consonância com o princípio da eqüidade do Sistema Único de Saúde (SUS), com a Política Nacional de Saúde da Pessoa Portadora de Deficiência e a aproximação dos desejos das crianças em realidade.

En 1997, le caractère culard, un phénotype hypermusclé chez le bovin, est attribué à des mutations dans le gène de la myostatine (MSTN). Depuis, il a été confirmé qu’une baisse de l’activité de la MSTN conduisait à une augmentation de la masse musculaire chez d’autres espèces, y compris chez l’Homme. L’identification de ce facteur et des conséquences de son invalidation sur le développement musculaire ouvre de nombreuses perspectives en médecine humaine comme, par exemple, chez des personnes ayant eu une fonte musculaire importante suite à une immobilisation prolongée ou en conséquence du vieillissement ou d’une maladie chronique. L’objectif majeur de ce projet de recherche a consisté à évaluer de nouvelles stratégies permettant d’augmenter la masse musculaire chez la souris. Pour ce faire, nous nous sommes intéressés à une métalloprotéine de la matrice extracellulaire (MEC), la décorine (DCN), dont l’interaction avec la MSTN a été caractérisée comme étant zinc dépendante. Suite à l’injection de ce Small Leucine Rich Proteoglycan (SLRP) chez la souris dystrophique mdx et Gamma-sarcoglycan-/-, nous avons constaté une augmentation de la masse musculaire consécutive à un phénomène d’hypertrophie associé ou non à de l’hyperplasie. Des études de dose/cinétique ont montré que l’effet positif de la décorine sur la croissance musculaire était maximal 21 jours après administration. Nous avons également découvert qu’un fragment peptidique de 41 acides aminés du domaine N-terminal de la protéine DCN murine conservait une activité anti-myostatine et induisait une hypertrophie musculaire chez la souris dystrophique. Ce domaine, site de l’interaction directe entre la MSTN et la DCN, présente un motif CX3CXCX6C, caractéristique des SLRPs de classe I, dont le cluster de cystéines et son interaction avec le zinc ont été décrits comme indispensables à l’activité anti-MSTN de la DCN. Différentes études concernant les mécanismes induits lors de la séquestration de la MSTN par la DCN dans la MEC ont également été conduites afin d’expliquer les phénomènes observés chez la souris. Enfin, nous avons étudié le potentiel de la DCN pour favoriser la greffe de cellules myogéniques et développé différentes approches de thérapie génique. / In 1997, the double-muscling phenotype, a marked hypermuscularity in cattle, was related to mutations in the myostatin (MSTN) gene. Since, it was confirmed that a decrease of the myostatin’s activity drives an increase of the muscular mass in others species, including Human. The identification of this factor and the consequences of its invalidation on the muscular development open many perspectives in human medicine, as, for example, for people whom have an important muscular loss fallow up an extended immobilization or in consequence of old age or a chronic disease. The main purpose of this research project was to evaluate some new strategies permitting the increase of the muscular mass in mice. To achieve that, we investigated in detail the decorin (DCN), a metalloprotein of the extracellular matrix (ECM), interacting with MSTN in a zinc-dependent manner. After intramuscular injection of this Small Leucine Rich Proteoglycan (SLRP) in mdx and Gamma-Sarcoglycan-/- dystrophic mice, we observed a significant increase of the muscle mass conducted by hypertrophy associated or not with hyperplasia. Dose and cinetic studies showed that the positive effect of the decorin on muscular growth was maximal 21 days after administration. Furthermore, we showed that a peptide encompassing the 31-71 sequence retains full myostatin binding capacity and intramuscular injection of this peptide induces muscle hypertrophy in dystrophic mice. This direct interaction site between MSTN and DCN contains a conserved CX3CXCX6C pattern of class I SLRPs, whose cluster of cysteins and its interaction with zinc were shown to be crucial in the anti-MSTN activity of DCN. Various studies of the mechanism resulting of the sequestration of MSTN by DCN in ECM were conducted in order to explain the phenomenom observed in mice. Al last, we have studied the potential of DCN in the cellular transplantation and developped different anti-myostatin strategies of genetic therapy.

Phospholipids are the major components of cell membranes and have a wide variety of structures, shapes and properties. Different ratios of phospholipid species confer different properties to membranes and contribute to the normal function of organelles. We have previously shown that acute phosphatidylcholine (PC) biosynthesis inhibition leads to a severe form of lipid imbalance that disrupts ER morphology and structure. Furthermore, our previous studies also revealed a mechanism for ER proteostasis under conditions of lipid-imbalance-induced ER stress in yeast, whereby unfolded ER proteins are removed by lipid droplets (LDs) and targeted to the vacuole for degradation by microlipophagy. Here, we find that LDs also contribute to ER proteostasis during chemically induced ER stress. Furthermore, we find that ER stress results in an increase in ubiquitinated proteins in LDs as well as recruitment of cytosolic and ER heat shock proteins, as well as ER proteins to LDs. ER stress-induced microlipophagy does not require core ATG genes and can occur in the absence of lipid ordered microdomains (Lo) in the vacuolar membrane. Instead, we find that the ESCRT machinery is up-regulated and localizes to the vacuolar membrane in response to ER stress induced microlipophagy and that ESCRT I, II and III complexes are required for microlipophagy in response to each of these stressors. Similar to yeast, we find that lipid imbalance in skeletal muscle from CHKB CMD, new autosomal recessive CMD (Congenital Muscular Dystrophy) caused by a mutation of choline kinase beta (CHKB), results in abnormal SR/ER morphology. CHKB is the first enzyme in the de novo PC biosynthesis pathway and causes phospholipid imbalance in cell membranes similar to that observed in yeast. Besides the disruption of SR morphology, we also detect a dysfunction of the Ryanodine Receptor (RyR), the Ca2+ channels responsible for initiating muscle contraction. Specifically, we observe abnormal RyR morphology and increased association of RyRs with lipid droplets (LD) in muscle fibers from a CHKB CMD patient. Finally, we detect ER stress and pronounced UPR activation in rmd mice, a mouse model of CHKB CMD. Given these results, we propose that inhibition of PC biosynthesis leads to phospholipid imbalance in the SR, which in turn, causes RyR leakage and ER stress which lead to mitochondrial dysfunction and dystrophy in CHKB CMD.