Objetivo: Avaliar a responsividade da escala de avaliação funcional para pacientes com distrofia muscular de Duchenne (DMD), domínio 1 - sentar e levantar da cadeira (FES-DMD-D1). Método: Estudo observacional, retrospectivo e longitudinal (seguimento por um ano). Foi estudada, utilizando o software FES-DMD-DATA, uma amostra de 150 avaliações da atividade de sentar e levantar da cadeira, a partir de um banco de imagens com filmes de 30 crianças com DMD, executando atividades funcionais, avaliadas a cada três meses, em um período de um ano. A avaliação da FES-DMD-D1 foi aplicada por fisioterapeuta treinado, considerando os escores das fases de flexão, de contato e de extensão da atividade de sentar na cadeira e, das fases de flexão, de transferência e de extensão da atividade de levantar da cadeira. Para avaliar a responsividade da FES-DMD-D1 foram analisadas as avaliações dos períodos de seguimento de três, seis, nove e doze meses, por meio do tamanho do efeito (TE) e da média de resposta padronizada (MRP). Resultados: A responsividade da atividade de sentar na cadeira foi considerada de pequena a moderada nas avaliações a cada três meses (TE de 0,22 a 0,49 e MRP de 0,32 a 0,54), de pequena a moderada a cada seis meses (TE de 0,50 a 0,61 e MRP de 0,41 a 0,61), de pequena a grande a cada nove meses (TE de 0,69 a 1,11 e MRP de 0,49 a 0,79) e grande no período de um ano (TE de 1,07 e MRP de 0,80). Na atividade de levantar da cadeira, a responsividade foi pequena a cada três meses (TE de 0,21 a 0,35 e MRP de 0,28 a 0,45), de pequena a grande a cada seis meses (TE de 0,45 a 0,62 e MRP de 0,50 a 0,96), de moderada a grande a cada nove meses (TE de 0,76 a 0,89 e MRP de 0,74 a 1,47) e grande em um ano (TE de 1,28 e MRP de 1,24). Conclusão: A FES-DMD-D1 mostrou responsividade de moderada a grande, aumentando gradativamente nos intervalos de seis, nove e doze meses. Dessa forma, é indicado o uso da FES-DMD-D1 a partir de seis meses / Objective: To evaluate the responsiveness of the functional evaluation scale for patients with Duchenne muscular dystrophy (DMD) - domain 1: sitting and standing from the chair (FES-DMD-D1). Method: Observational, retrospective and longitudinal study with one year follow-up. A sample of 150 evaluations of sitting and rising from the chair was studied, using the FES-DMD-DATA software, from a bank of images of 30 children with DMD performing functional activities, evaluated every three months in a period of one year. FES-DMD-D1, which explores the scores of the phases of flexion, contact, extension of the activity of sitting on the chair, and of the phases of flexion, transference, extension of the activity of rising from the chair was applied by a trained physiotherapist. To evaluate the responsiveness of FES-DMD-D1 we considered the follow-up evaluations after three, six, nine and twelve months. The analysis used the effect size (ES) and standardized response mean (SRM). Results: The responsiveness of sitting on the chair was considered low to moderate in evaluations with three months intervals (ES from 0.22 to 0.49 and SRM from 0.32 to 0.54), low to moderate with six months intervals (ES from 0.50 to 0.61 and SRM from 0.41 to 0.61), low to high in nine months intervals (ES from 0.69 to 1.11 and SRM from 0.49 to 0.79) and high in the reassessment after one year (ES from 1.07 and SRM from 0.80). The responsiveness of the rising from the chair was low in three months (ES from 0.21 to 0.35 and SRM from 0.28 to 0.45), from low to high in six months (ES from 0.45 to 0.62 and SRM from 0.50 to 0.96), moderate to high in nine months (ES from 0.76 to 0.89 and SRM from 0.74 to 1.47) and high in a year (ES from 1.28 and SRM from 1.24). Conclusion: FES-DMD-D1 showed moderate to high responsiveness, gradually increasing for intervals of six, nine and twelve months. Thus, the use of FES-DMD-D1 is indicated from six months

A musculatura estriada de cães Golden Retriever, jovens e adultos, provenientes do Canil GRMD-Brasil, foram analisadas sob microscopia de luz. Para tanto, foram coletadas amostras do músculo bíceps femoral de um cão adulto não-acometido e um acometido por distrofia muscular, e dos músculos bíceps femoral, semitendinoso, diafragma e miocárdio ventricular esquerdo de dois cães jovens acometidos, as quais foram coradas pelas técnicas de hematoxilina-eosina, tricrômico de Masson e sirius red F3BA. Todos os músculos examinados do cão adulto e dos jovens portadores de distrofia apresentaram lesões musculares. As lesões observadas na musculatura esquelética de todos os cães acometidos incluíram: perda de organização das fibras musculares, variação no diâmetro das fibras, aumento do tecido conjuntivo perimisial e endomisial, este no animal adulto. As lesões eram mais evidentes no animal adulto. O diafragma apresentou fibras hipercidófilas, com contorno mais definido; necrose envolvendo grupos de fibras musculares; espessamento do conjuntivo perimisial e edema endomisial. A musculatura da língua mostrou variação do diâmetro das fibras; fibrose perimisial e infiltração de tecido adiposo no epimísio. No miocárdio identificou-se leve a moderada fibrose e aumento do espaço endomisial. Nossos achados demonstram as lesões produzidas por essa patologia na musculatura esquelética, comparativamente com a musculatura de animais não-acometidos e corroboram o descrito para cães acometidos por distrofia muscular, GRMD, de outros criatórios / The striated muscle of young and adults Golden Retriever dogs, from the GRMD-Brazil Kennel, had been analyzed under light microscopy. Samples of biceps femoral muscle of a healthy control adult dog and of an adult Golden Retriever muscular dystrophy (GRMD), and of the femoral, semitendinosus, biceps femoral, diaphragm, and left ventricular myocardium muscles of two young GRMD had been collected to be stained with HE, Masson trichrome and sirius red F3BA stain. All the examined muscles of the adult and young GRMD had presented muscular injuries. The injuries observed in the skeletal musculature included: dearrangement of muscular fibers, variation in the fiber diameter, increase of the perimisial and endomisial connective tissue, the latter in the adult dog. The lesions were more evident in the adult GRMD. The diaphragm presented hyperacidophyly fibers, with more defined contour; necrosis involving groups of muscular fibers; increase of perimisial connective tissue and endomisial edema. The tongue musculature showed variation of the fibers diameter; perimisial fibrosis and fat infiltration in the epimysial space. In the myocardium it was identified moderate fibrosis and increase of the endomysial space. Our findings demonstrate the injuries produced for this pathology in the skeletal musculature, comparatively with the healthy control dog, and corroborate that described for GRMD of other GRMD-kennels

OBJETIVO: Investigar a relação entre força muscular e função motora, em pacientes com DMD, em um período de 4 anos consecutivos, a partir de avaliações semestrais. MÉTODO: A força muscular foi medida por meio de testes manuais e o cálculo por grupo muscular seguiu o proposto pelo Medical Research Council (MRC) e a função motora pelo método de Medida da Função Motora (MFM), em 43 pacientes (8-30 anos). Foi realizada uma análise descritiva e o teste de correlação de Spearman. Foram investigadas as relações entre pontuações totais e parciais da MRC e da MFM. RESULTADOS: O estudo evidenciou correlações classificadas de moderada a forte relação entre a força muscular e função motora, principalmente com o escore total da MFM e a dimensão D2 (musculatura axial e função motora proximal). Foi encontrada relação negativa moderada entre idade e essas variáveis. CONCLUSÃO: A perda progressiva da função motora tem relação direta e proporcional com a diminuição da força muscular. Quanto maior a idade do paciente, pior sua função motora e força muscular, fornecendo com essa informação, indicadores adicionais da progressão da doença / OBJECTIVE: This study investigated this relationship and examined whether muscle strength and/or motor function would be related to age in DMD. METHODS: Muscle strength was measured by the Medical Research Council scale (MRC) and motor function by the Motor Function Measure (MFM) in 43 patients (8-30 yrs). Spearman tests, descriptive analysis, investigated the relationships between total/ partial scores of MRC and MFM. RESULTS: Total MRC and MFM scores were strongly related to each other and moderately related to age. Many strong relationships between partial MRC and MFM scores were found, mostly between partial MRC scores and MFM dimension 2 (axial and proximal motor function). CONCLUSION: It is possible to predict that the progressive loss of motor function has direct relationship to decreased muscle strength. That the older the patient, the worse their motor function and muscle strength, providing with this information, additional indicators of disease progression

Neste trabalho a determinação de elementos químicos em tecidos biológicos (sangue total, ossos e orgãos) de camundongos distróficos, usados como modelo animal da Distrofia Mucular de Duchenne (DMD), foi realizada utilizando técnica analítica nuclear. O objetivo do presente trabalho foi a determinação dos valores de referência para elementos de relevância em bioquímica clínica (Ca, Cl, K, Mg e Na) e nutricional (Br e S) em sangue total, tíbia, quadríceps anterior e coração de camundongos da linhagem distrófica Dmdmdx/J (10 machos e 10 fêmeas) e grupo controle C57BL/6J (10 machos), utilizando a técnica de Análise por Ativação com Nêutrons AAN. Para obter mais detalhes das alterações que esta disfunção pode causar nesses tecidos biológicos, foram calculadas matrizes de correlação entre as espécies Dmdmdx/J e comparadas ao grupo controle C57BL/6J. Para a realização deste estudo 119 amostras de tecidos biológicos foram irradiadas no reator nuclear IEA-R1 no IPEN (São Paulo, Brasil). Os resultados de análise, por AAN, constituem as primeiras estimativas para os valores de referência nesses tecidos biológicos dos camundongos Dmdmdx/J e C57BL/6J. Além disso, as alterações em alguns dos coeficientes de correlações entre os animais saudáveis e com disfunção indicam uma conexão entre esses elementos no sangue, tíbia, quadríceps e coração. Esses dados poderão auxiliar pesquisadores avaliar e comparar as vantagens e desvantagens dos diferentes tratamentos, realizados na distrofia muscular, quando estes modelos animais forem empregados, auxiliando os pesquisadores a avaliar a eficácia de novos procedimentos terapêuticos antes de serem empregados em paciente com DMD. / In this work the determination of chemistry elements in biological tissues (whole blood, bones and organs) of dystrophic mice, used as animal model of Duchenne Muscular Dystrophy (DMD), was performed using analytical nuclear technique. The aim of this work was to determine reference values of elements of clinical (Ca, Cl, K, Mg, Na) and nutritional (Br and S) relevance in whole blood, tibia, quadriceps and hearts from Dmdmdx/J (10 males and 10 females) dystrophic mice and C57BL/6J (10 males) control group mice, using Neutron Activation Analysis technique (NAA). To show in more details the alterations that this disease may cause in these biological tissues, correlations matrixes of the DMDmdx/J mouse strain were generated and compared with C57BL/6J control group. For this study 119 samples of biological tissue were irradiated in the IEA-R1 nuclear reactor at IPEN (São Paulo, Brazil). The concentrations of these elements in biological tissues of Dmdmdx/J and C57B/6J mice are the first indicative interval for reference values. Moreover, the alteration in some correlation coefficients data among the elements in the health status and in the diseased status indicates a connection between these elements in whole blood, tibia, quadriceps and heart. These results may help the researchers to evaluate the efficiency of new treatments and to compare the advantages of different treatment approaches before performing tests in patients with muscular dystrophy.

A progressão da distrofia muscular de Duchenne (DMD) resulta no surgimento de múltiplas e variadas sinergias para compensar a fraqueza muscular e para lidar com as demandas de tarefas funcionais, como por exemplo, a marcha. Alguns instrumentos de avaliação funcional para pessoas com DMD permite a análise subjetiva (descrição) e objetiva (escore) sem levar em consideração os movimentos compensatórios. Por esta razão, os médicos e os fisioterapeutas enfrentam dificuldades na avaliação clínica e tomada de decisão. Este estudo teve como objetivo elaborar o domínio marcha da Escala de Avaliação Funcional para DMD / Functional Evaluation Scale (FES-DMD-D4), testar sua confiabilidade intraexaminador e interexaminadores e sua relação com a idade, escala Vignos e tempo de desempenho da marcha. Uma amostra de 120 vídeos da marcha de 30 crianças com DMD foi analisada. Os movimentos detectados foram classificados considerando suas características cinesiológicos e padrões de compensações. FES-DMD-D4 foi criada e submetida à avaliação de 10 especialistas. Após a incorporação das sugestões propostas, a escala foi utilizada no total da amostra para avaliação por três examinadores. Foi calculada a confiabilidade intraexaminador e interexaminadores utilizando ICC. As relações entre o FES-DMD-D4 e a idade, a escala Vignos e o tempo de desempenho foram testadas com teste de correlação de Spearman (p < 0,05). A FES-DMD-D4 foi composta por três fases, e 14 itens. Coeficientes de correlação intraclasse variaram de aceitável (0,79) a excelente (0,98). A pontuação total da FES-DMD-D4 correlacionou-se com a idade e o tempo de desempenho, mas não com a escala Vignos / The progression of Duchenne Muscular Dystrophy (DMD) results in the emergence of multiple and varied synergies to compensate muscle weakness and to deal with the demands of functional tasks, such as gait. Few functional evaluation instruments for people with DMD allows for subjective analysis (description) and objective (score) without taking into account the compensatory movements. For this reason, clinicians and physiotherapists face difficulties in clinical assessment and decision-making. This study aimed to elaborate the gait domain of the Functional Evaluation Scale for DMD, gait domain (FES-DMD-D4) and to test its reliability intraexaminer and interexaminers and its relationship with age, Vignos score and timed motor performance. A sample of 120 gait videos of 30 children with DMD was analyzed. The detected movements were classified, considering the kinesiological characteristics of the compensation movements. FES-DMD-D4 was created and submitted to the review of 10 experts. After the incorporation of the suggestions proposed by the experts, the scale was used to analyse a total sample by 3 examiners. The reliability intraexaminer and interexaminers was calculated using ICC. The relationships between FES-DMD-D4 and age, Vignos score and timed motor performance was tested with Spearman correlation test (p < 0.05). The FES-DMD-D4 was composed of 3 phases, and 14 items. Intraclass correlation coefficients ranged from acceptable (0.79) to excellent (0.98). The scores on FES-DMD-D4 correlated to age and timed motor performance, but not to Vignos score

L’objectif central de cette thèse de Doctorat était d’investiguer les dysfonctions mitochondriales qui surviennent précocement au cours de la phase compensée du remodelage ventriculaire pathologique et qui pourraient jouer un rôle causal dans la progression vers l’insuffisance cardiaque. Nos travaux antérieurs, réalisés à l’aide d’un modèle de surcharge volumique chronique induite par une fistule aorto-cavale (ACF) chez le Rat WKHA, ont montré qu’au cours du remodelage ventriculaire, les mitochondries développaient une vulnérabilité à l’ouverture du pore de perméabilité transitionnelle (PTP : un élément clé de la signalisation de la mort cellulaire) [1]. Ceci était observable au stade compensé du remodelage en absence des dysfonctions mitochondriales majeures typiquement observées dans le cœur insuffisant. Ces résultats nous ont amenés à suggérer que la vulnérabilité à l’ouverture du PTP pourrait constituer un mécanisme précoce favorisant la progression de la cardiopathie. Dans l’étude 1 de cette thèse, nous avons tenté de tester cette hypothèse en induisant une ACF chez deux souches de rats affichant de très nettes différences au niveau de la propension à développer l’insuffisance cardiaque : les souches WKHA et Sprague Dawley (SD). Nos études in vitro sur organelles isolées et in situ sur l’organe entier ont permis de confirmer que, dans le cœur ACF, les mitochondries développent une vulnérabilité à l’ouverture du PTP et à l’activation de la voie mitochondriale de la mort cellulaire lorsqu’exposées à des stress pertinents à la pathologie (surcharge calcique, ischémie-reperfusion [I-R]). Cependant, bien que comparativement aux animaux WKHA, les animaux SD démontraient un remodelage ventriculaire plus rapide et prononcé et une progression précoce vers l’insuffisance cardiaque, aucune différence n’était observable entre les deux groupes au niveau des dysfonctions mitochondriales, suggérant quelles ne sont pas à l’origine de la progression plus rapide de la pathologie chez la souche SD, à tout le moins en réponse à la surcharge volumique. Nous avons par la suite déterminé, à l’aide des mêmes approches expérimentales, si cette vulnérabilité mitochondriale était observable dans une cardiopathie d’étiologie différente, plus spécifiquement celle qui est associée à la dystrophie musculaire de Duchenne (DMD), une maladie génétique causée par une mutation de la protéine dystrophine. Nos études menées (études 2-4) sur de jeunes souris mdx (le modèle murin de la DMD) exemptes de tout signe clinique de cardiopathie n’ont révélé aucune différence au niveau des fonctions mitochondriales de base. Cependant, tout comme dans le modèle d’ACF, les mitochondries dans le cœur de souris mdx étaient significativement plus vulnérables à l’ouverture du PTP lorsque soumises à une I-R (étude 2). Par ailleurs, nous avons démontré que l’administration aiguë de sildénafil aux souris mdx induisait une abolition de l’ouverture du PTP et de ses conséquences signalétiques, une diminution marquée du dommage tissulaire et une meilleure récupération fonctionnelle à la suite de l’I-R (étude 3). Nous avons ensuite testé chez la souris mdx l’administration aiguë de SS31, un peptide anti-oxydant ciblé aux mitochondries, cependant aucun effet protecteur n’a été observé, suggérant que le tamponnement des radicaux libres est d’une utilité limitée si les perturbations de l’homéostasie calcique typiques à cette pathologie ne sont pas traitées simultanément (étude 4). Globalement, les travaux effectués au cours de cette thèse démontrent que la vulnérabilité à l’ouverture du PTP constitue une dysfonction précoce et commune qui survient au cours de remodelages ventriculaires pathologiques d’étiologies différentes. Par ailleurs, ces travaux suggèrent des stratégies d’intervention pharmacologiques ciblant ce processus, dont l’efficacité pour la prévention de l’insuffisance cardiaque demande à être établie. / The central objective of this doctoral thesis was to investigate the mitochondrial dysfunction that occurs early during the compensated phase of pathological ventricular remodeling and which may play a causal role in the progression to heart failure. Our previous work using a model of chronic volume overload induced by aorto-caval fistula (ACF) in rats WKHA showed that during the ventricular remodeling, mitochondria developed a vulnerability to permeability transition pore opening (PTP: a key component of cell death signaling) [1]. This was observed at the stage of compensated remodeling in the absence of major mitochondrial dysfunction typically observed in the failing heart. These results led us to suggest that the vulnerability to PTP opening could be a mechanism facilitating the progression of the cardiomyopathy. In our first study of this thesis we have attempted to test this hypothesis by inducing ACF in two strains of rats displaying sharp differences in the propensity to develop heart failure: WKHA strains and Sprague Dawley (SD). Our studies in vitro on isolated organelles and in situ on the whole organ have confirmed that, in the ACF heart, mitochondria develop a vulnerability to PTP opening and activation of mitochondrial cell death when exposed to stresses relevant to the pathology (calcium overload, ischemia-reperfusion [I-R]). However, SD animals compared to WKHA showed a more rapid and pronounced ventricular remodeling and early progression to heart failure, no difference was found between the two groups in terms of mitochondrial dysfunction, suggesting that this is not behind the more rapid progression of the disease in the SD strain, at least in response to volume overload. We subsequently determined, using the same experimental approaches, if this vulnerability was observed in mitochondria of heart disease from other etiology more specifically that associated with Duchenne muscular dystrophy (DMD), a genetic disease caused by a mutation of the protein dystrophin. Our studies (studies 2-4) on young mdx mice (the mouse model of DMD) free of clinical signs of heart disease showed no difference in basal mitochondrial functions. However, as in the model of ACF, the mitochondria of mdx mice heart were significantly more vulnerable to PTP opening when subjected to I-R (study 2). Furthermore, we demonstrated that acute administration of sildenafil to mdx mice abolished the PTP opening and its signaling consequences, markedly reduced of tissue damage and improved functional recovery following I-R (Study 3). We then tested in mdx mice acute administration of SS31, an antioxidant peptide that targets and accumulates in mitochondria. However, no protective effect was observed, suggesting that the buffering of free radicals have a limited utility if the typical perturbations of the calcium homeostasis in this disease are not treated simultaneously (Study 4). Overall, the work done during this thesis show that the vulnerability to PTP opening is a common and early dysfunction that occurs during pathological ventricular remodeling of different etiologies. Moreover, these studies suggest pharmacological intervention strategies targeting this process, whose effectiveness in preventing heart failure needs to be established.

[Truncated abstract] The pro-inflammatory cytokine tumour necrosis factor (TNF) has a critical role in skeletal muscle atrophy. The catabolic effect of TNF is partially due to abrogation of the anabolic insulin-like growth factor 1 (IGF-1) signalling pathway. However, the precise signalling events that lead to the loss of myofibrillar protein following activation of TNF receptor are unknown. The over arching aim of the study is to determine the mechanisms of by which TNF induces atrophy in differentiated muscles cells. To achieve this aim a series of experiments were performed to: 1) investigate the molecular events that lead to TNF mediated myofibre atrophy, 2) determine to what extent c-Jun N-terminal Kinase (JNK) signalling plays a part in TNF induced myotube atrophy, and in TNF-mediated inhibition of IGF-1 induced hypertrophy, and 3) use inhibitors of JNK to block the catabolic effects of TNF. 1) To investigate the molecular events that lead to TNF mediated myofibre atrophy, the experiments were conducted using C2C12 mouse myotube cultures and primary myotube cultures derived from FVB mice, and transgenic mice which over-express Class 2 IGF-1 Ea in skeletal muscles (IGF:C2). The treatment of mature C2C12 and FVB primary myotubes (respectively at 7 and 4 days after fusion medium) with 10 ng/mL of TNF for 3 days resulted in statistically significant myotube atrophy (decreased mean width). The observed TNF-mediated atrophy has not previously been demonstrated in tissue cultured myotubes. In contrast, addition of IGF-1 (20 ng/ml) to 7 day C2C12 myotubes for 3 days resulted in significant hypertrophy. ... The most suitable inhibitor was TAT-TIJIP and was thus used in subsequent studies. Inhibition of JNK activity by TAT-TIJIP was confirmed indirectly by detecting nuclear translocation of c- Jun, which is a downstream target of phosphorylated JNK. Immunohistochemical analyses showed nuclear localisation and phosphorylation of c-Jun in TNF treated myotubes. Nuclear localisation and phosphorylation of c-Jun was not observed in cultures pre-treated with TAT-TIJIP before TNF treatment, nor in the untreated control myotubes. 3) The use of JNK inhibitors to block the catabolic effects of TNF was tested using C2C12 and primary myotube cultures. Pre-treatment of C2C12 and primary FVB myotubes with the JNK inhibitor TAT-TIJIP, 30 min before TNF administration (for 3 days) prevented myotube atrophy. The mean width of myotubes pre-treated with TATTIJIP prior to TNF treatment closely resembled that of the control myotubes. Administration of TNF in combination with TAT-TIJIP for 3 days to C2C12 myotubes prevented myotube atrophy and unexpectedly resulted in hypertrophy when compared to the mean widths of untreated and TAT-TIJIP treated myotubes. This trend was also demonstrated in the FVB primary cultures. These combined results strongly support the role of JNK in TNF-mediated atrophy. Preliminary studies were carried out in vivo using the mdx mouse model of muscular dystrophy, TAT-TIJIP was administered via intraperitoneal injection to the mice for 3 days at a dose of 10 mg/ml, however the results form this study are inconclusive. These novel observations are of considerable interest to the field of muscle wasting because they demonstrate for the first time TNF-mediated myotube atrophy, the role of JNK in situations of TNF induced muscle atrophy, and explore the use of JNK inhibitors to prevent muscle atrophy.

A progressão da distrofia muscular de Duchenne (DMD) resulta no surgimento de múltiplas e variadas sinergias para compensar a fraqueza muscular e para lidar com as demandas de tarefas funcionais, como por exemplo, a marcha. Alguns instrumentos de avaliação funcional para pessoas com DMD permite a análise subjetiva (descrição) e objetiva (escore) sem levar em consideração os movimentos compensatórios. Por esta razão, os médicos e os fisioterapeutas enfrentam dificuldades na avaliação clínica e tomada de decisão. Este estudo teve como objetivo elaborar o domínio marcha da Escala de Avaliação Funcional para DMD / Functional Evaluation Scale (FES-DMD-D4), testar sua confiabilidade intraexaminador e interexaminadores e sua relação com a idade, escala Vignos e tempo de desempenho da marcha. Uma amostra de 120 vídeos da marcha de 30 crianças com DMD foi analisada. Os movimentos detectados foram classificados considerando suas características cinesiológicos e padrões de compensações. FES-DMD-D4 foi criada e submetida à avaliação de 10 especialistas. Após a incorporação das sugestões propostas, a escala foi utilizada no total da amostra para avaliação por três examinadores. Foi calculada a confiabilidade intraexaminador e interexaminadores utilizando ICC. As relações entre o FES-DMD-D4 e a idade, a escala Vignos e o tempo de desempenho foram testadas com teste de correlação de Spearman (p < 0,05). A FES-DMD-D4 foi composta por três fases, e 14 itens. Coeficientes de correlação intraclasse variaram de aceitável (0,79) a excelente (0,98). A pontuação total da FES-DMD-D4 correlacionou-se com a idade e o tempo de desempenho, mas não com a escala Vignos / The progression of Duchenne Muscular Dystrophy (DMD) results in the emergence of multiple and varied synergies to compensate muscle weakness and to deal with the demands of functional tasks, such as gait. Few functional evaluation instruments for people with DMD allows for subjective analysis (description) and objective (score) without taking into account the compensatory movements. For this reason, clinicians and physiotherapists face difficulties in clinical assessment and decision-making. This study aimed to elaborate the gait domain of the Functional Evaluation Scale for DMD, gait domain (FES-DMD-D4) and to test its reliability intraexaminer and interexaminers and its relationship with age, Vignos score and timed motor performance. A sample of 120 gait videos of 30 children with DMD was analyzed. The detected movements were classified, considering the kinesiological characteristics of the compensation movements. FES-DMD-D4 was created and submitted to the review of 10 experts. After the incorporation of the suggestions proposed by the experts, the scale was used to analyse a total sample by 3 examiners. The reliability intraexaminer and interexaminers was calculated using ICC. The relationships between FES-DMD-D4 and age, Vignos score and timed motor performance was tested with Spearman correlation test (p < 0.05). The FES-DMD-D4 was composed of 3 phases, and 14 items. Intraclass correlation coefficients ranged from acceptable (0.79) to excellent (0.98). The scores on FES-DMD-D4 correlated to age and timed motor performance, but not to Vignos score

Orientadores: Maria Julia Marques, Humberto Santo Neto / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-10T12:44:34Z (GMT). No. of bitstreams: 1 Pertille_Adriana_D.pdf: 3109380 bytes, checksum: b99b5c31b8c138b7d403dd2de4f6629c (MD5) Previous issue date: 2008 / Resumo: A distrofia muscular de Duchenne (DMD) é caracterizada pela falta de distrofina, proteína estrutural do sarcolema que promove a sua estabilização. Em ausência de distrofina, ocorre aumento da permeabilidade ao cálcio e conseqüente mionecrose. Músculos como tibial anterior, sóleo, diafragma e esternomastóide sofrem ciclos de mionecrose e regeneração muscular. Por outro lado, os músculos extra-oculares (EO) não apresentam degeneração, sendo protegidos da falta da distrofina. A atividade das proteínas ligadas ao Ca++ pode ser um dos mecanismos envolvidos para explicar tal proteção. Nossos resultados revelaram aumento significativo do conteúdo da calmodulina (CaM) e quinase da cadeia leve de miosina (MLCK) no músculos EO mdx quando comparado ao controle. A quantidade da calpaína 1 dos músculos EO distróficos foi igual ao controle, confirmando a ausência do processo de degeneração muscular. Também verificamos se alterações no padrão de distribuição dos receptores de acetilcolina (ACh) e dos terminais nervosos, observadas em junções neuromusculares distróficas, são decorrentes da falta da distrofina ou da regeneração da fibra muscular. O padrão de distribuição dos receptores ACh nos músculos retos e oblíquos distróficos, não mostraram alteração quando comparados ao controle. No músculo retrator do bulbo mdx (parcialmente afetado pela distrofia) 56% dos receptores apresentaram padrão de distribuição alterado. Nossos resultados sugerem que a distrofina ou o complexo distrofina-glicoproteínas (CDG), não estão diretamente envolvidos na organização dos receptores nos músculos EO / Abstract: Duchenne muscular dystrophy (DMD) is characterized by the lack of dystrophin, structural protein that provides stability to the sarcolemma. In the absence of dystrophin, causes increased calcium permeability, leading to myonecrosis. Tibialis anterior, soleus, diaphragm and stermomastoid muscles undergoes myonecrosis and regeneration cycles. However, extraocular muscles (EO) do not show degeneration and are spared of the lack of dystrophin. We investigated whether this protection is related to an activated of calcium-binding proteins. Ours results showed significantly increased of calmodulin (CaM) and of the myosin light chain kinase (MLCK) in the mdx EO compared to control muscles. Calpain quantity in the dystrophic EO was equal of the control, confirmed the lack of the degeneration muscular processed. We also investigated whether changes in acetylcholine (Ach) receptor distribution at the neuromuscular junction and the nerve terminal, showed in the dystrophic neuromuscular junction, which could be correlated to the lack of dystrophy or the muscle fiber regeneration. Distribution ACh receptor in the dystrophic rectus and oblique exhibited no changes compared to control. In mdx retractor bulbi (partial affected by the dystrophy) 56% of the receptor exhibited distribution altered. Taken together, the results suggest the dystrophin or the dystrophin-glycoprotein complex does not influence the distribution of acetylcholine receptors at the neuromuscular junction of spared EO / Doutorado / Anatomia / Doutor em Biologia Celular e Estrutural

A musculatura estriada de cães Golden Retriever, jovens e adultos, provenientes do Canil GRMD-Brasil, foram analisadas sob microscopia de luz. Para tanto, foram coletadas amostras do músculo bíceps femoral de um cão adulto não-acometido e um acometido por distrofia muscular, e dos músculos bíceps femoral, semitendinoso, diafragma e miocárdio ventricular esquerdo de dois cães jovens acometidos, as quais foram coradas pelas técnicas de hematoxilina-eosina, tricrômico de Masson e sirius red F3BA. Todos os músculos examinados do cão adulto e dos jovens portadores de distrofia apresentaram lesões musculares. As lesões observadas na musculatura esquelética de todos os cães acometidos incluíram: perda de organização das fibras musculares, variação no diâmetro das fibras, aumento do tecido conjuntivo perimisial e endomisial, este no animal adulto. As lesões eram mais evidentes no animal adulto. O diafragma apresentou fibras hipercidófilas, com contorno mais definido; necrose envolvendo grupos de fibras musculares; espessamento do conjuntivo perimisial e edema endomisial. A musculatura da língua mostrou variação do diâmetro das fibras; fibrose perimisial e infiltração de tecido adiposo no epimísio. No miocárdio identificou-se leve a moderada fibrose e aumento do espaço endomisial. Nossos achados demonstram as lesões produzidas por essa patologia na musculatura esquelética, comparativamente com a musculatura de animais não-acometidos e corroboram o descrito para cães acometidos por distrofia muscular, GRMD, de outros criatórios / The striated muscle of young and adults Golden Retriever dogs, from the GRMD-Brazil Kennel, had been analyzed under light microscopy. Samples of biceps femoral muscle of a healthy control adult dog and of an adult Golden Retriever muscular dystrophy (GRMD), and of the femoral, semitendinosus, biceps femoral, diaphragm, and left ventricular myocardium muscles of two young GRMD had been collected to be stained with HE, Masson trichrome and sirius red F3BA stain. All the examined muscles of the adult and young GRMD had presented muscular injuries. The injuries observed in the skeletal musculature included: dearrangement of muscular fibers, variation in the fiber diameter, increase of the perimisial and endomisial connective tissue, the latter in the adult dog. The lesions were more evident in the adult GRMD. The diaphragm presented hyperacidophyly fibers, with more defined contour; necrosis involving groups of muscular fibers; increase of perimisial connective tissue and endomisial edema. The tongue musculature showed variation of the fibers diameter; perimisial fibrosis and fat infiltration in the epimysial space. In the myocardium it was identified moderate fibrosis and increase of the endomysial space. Our findings demonstrate the injuries produced for this pathology in the skeletal musculature, comparatively with the healthy control dog, and corroborate that described for GRMD of other GRMD-kennels