La dystrophie musculaire de Duchenne (DMD) est une maladie liée à l'X caractérisée par la détérioration progressive des muscles en raison de l'absence de la protéine dystrophine. Les muscles atteints chez l'homme ou dans des modèles animaux (souris mdx) présentent une fibrose, accumulation excessive de protéines de la matrice extracellulaire. Parmi les facteurs induisant la fibrose se trouvent le Facteur de Croissance de Transformation de type β (TGF-β) et le Facteur de Croissance du Tissu Conjonctif (CTGF). Ce dernier est une cible de la voie de signalisation médiée par TGF-β/SMAD et est responsable des effets profibrotiques de TGF-β. La régulation de l'expression de CTGF médiée par TGF-β dans les cellules musculaires est peu connue. Nous décrivons ici un nouvel élément de liaison SMAD situé dans la région 5’UTR du gène de CTGF, important pour l'expression de CTGF médiée par le TGF-β dans des myoblastes. De plus, nos résultats suggèrent que d'autres sites de liaison du facteur de transcription présents dans le 5’UTR du gène de CTGF sont importants pour cette expression.Par ailleurs, le Facteur de Nécrose Tumorale (TNF) est une cytokine inflammatoire présente dans les muscles atteints de DMD et est responsable de la nécrose du muscle et de l'infiltration de cellules inflammatoires. Nous montrons que l’expression du récepteur soluble TNFRI par électrotransfert (ET) dans le muscle tibialis anterior de la souris atténue l'inflammation, les dommages et la fibrose dans le muscle squelettique des souris mdx, et provoque une augmentation de la force musculaire. Par conséquent, nous proposons l'ET comme thérapie efficace anti-TNF pour le traitement de dystrophies musculaires. / The Duchenne Muscular Dystrophy (DMD) is an X-linked disease characterized by progressive damage in the muscle due to the absence of the dystrophin protein. Fibrosis, the excessive accumulation of extracellular matrix (ECM) proteins, is also present in the muscle of DMD patients and several animal models (such as the mdx mice). Among the factors that induce fibrosis are Transforming Growth Factor type β (TGF-β) and Connective Tissue Growth Factor (CTGF), the latter being a target of the TGF-β/SMAD signaling pathway and is the responsible for the profibrotic effects of TGF-β and are augmented in fibrosis tissues. Little is known about the regulation of the expression of CTGF mediated by TGF-β in muscle cells. In here, we described a novel SMAD Binding Element (SBE) located in the 5’ UTR region of the CTGF gene important for the TGF-β mediated expression of CTGF in myoblasts. In addition, our results suggest that additional transcription factor binding sites present in the 5’ UTR of the CTGF gene are important for this expression. On the other hand, the Tumor Necrosis Factor (TNF) is an inflammatory cytokine that is present in DMD muscles and is responsible for muscle necrosis and inflammatory cell infiltration. In this study, we show that the increased expression of the soluble TNF Receptor I by electrotransfer (ET) in the tibialis anterior muscle attenuates inflammation, damage and fibrosis in the skeletal muscle of the mdx mice. In addition, we found increased muscle strength in the mdx mice. Therefore, we propose that ET could be used as an efficient anti-TNF therapy for treating muscle dystrophies.

Orientadores: Maria Júlia Marques, Elaine Minatel / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-27T05:58:01Z (GMT). No. of bitstreams: 1 Perim_VivianePanegassi_M.pdf: 2625016 bytes, checksum: bb4c51a87dbe0dfa88e64cad10dda694 (MD5) Previous issue date: 2015 / Resumo: A Distrofia Muscular de Duchenne (DMD) é uma doença causada pela ausência da proteína distrofina e se caracteriza por degeneração muscular progressiva. A deficiência da distrofina na DMD e nos camundongos mdx, modelo experimental da DMD, promove mionecrose. O processo inflamatório que se instala exacerba a mionecrose e aumenta o estresse oxidativo. O estresse oxidativo tem sido proposto como um fator importante para a progressão da doença. As espécies reativas de oxigênio promovem danos nas fibras distróficas, comprometendo proteínas e lipídios da membrana, gerando grandes quantidades de lipofuscina e 4-HNE, indicadores de estresse oxidativo. Este trabalho tem como objetivo verificar se o ômega-3 diminui o estresse oxidativo em diferentes músculos distróficos (bíceps, diafragma e quadríceps) do camundongo mdx jovem. Observamos que o ômega-3 diminuiu a lipofuscina e o 4-HNE nos músculos estudados. A atividade das enzimas antioxidantes SOD, GPx e GR estava aparentemente diminuída no diafragma distrófico, quando comparado ao diafragma normal. No diafragma, o ômega-3 promoveu aumento discreto da atividade da SOD e da GPx. O músculo quadríceps não apresentou alterações significativas destas enzimas, tanto no mdx controle, quanto no mdx tratado com ômega-3. O ômega-3 promoveu melhora da distrofinopatia (redução da CK, diminuição da inflamação e aumento da regeneração muscular). Concluímos que o ômega-3 diminui o estresse oxidativo (reduz a lipofuscina e o 4-HNE), principalmente no músculo diafragma, provavelmente por este ser mais afetado que o quadríceps. A atividade aparentemente reduzida das enzimas antioxidantes no diafragma do mdx controle pode sugerir menor capacidade de tamponamento das espécies reativas de oxigênio neste músculo. Isto pode contribuir, pelo menos em parte, para o maior estresse oxidativo e maior acometimento do diafragma em relação ao quadríceps. Estes dados sugerem que o ômega-3 possa ter uma ação positiva em melhorar o estresse oxidativo em diferentes músculos distróficos, tornando-o potencialmente útil para a terapia da DMD / Abstract: Duchenne muscle dystrophy (DMD) is a disease caused by the absence of dystrophin characterized by progressive muscle degeneration. In DMD and in the mdx mice model of DMD, the inflammatory process exacerbates myonecrosis and increases oxidative stress. Oxidative stress has been proposed as an important factor in disease progression. Reactive oxygen species promote damage in dystrophic fibers, affecting proteins and lipids of the membrane, generating large amounts of lipofuscin and 4-HNE, markers of oxidative stress. This study aims to determine whether ômega-3 therapy reduces oxidative stress in different dystrophic muscles (biceps, diaphragm and quadriceps) of mdx mouse, at earlier stages of the disease. Ômega-3 decreased lipofuscin and 4-HNE in all the muscles studied. The activity of the antioxidant enzymes SOD, GPx and GR was apparently reduced in mdx diaphragm control as compared to normal mice. In the diaphragm, ômega-3 promoted a slight increase in the activity of SOD and GPx. The quadriceps muscle showed no significant changes in the activity of these enzymes in mdx control, and ômega-3 did not change this profile. Ômega-3 also ammeliorated dystrophinopathy (reduced CK, decreased inflammation and increased muscle regeneration). We conclude that ômega-3 reduces oxidative stress (by decreasing lipofuscin and 4-HNE), mainly in the dystrophic diaphragm, possibly because this muscle is more affected than the quadriceps. The apparent decreased activity of antioxidant enzymes in the mdx diaphragm may suggest a poor capacity of this muscle to buffer the reactive oxygen species. This may contribute, at least in part, to the increased oxidative stress in the diaphragm and to the fact that this muscle will turn out to be the more affected muscle in the mdx. The present results suggest that ômega-3 may have a positive effect in improving oxidative stress in different dystrophic muscles, making it potentially useful for DMD therapy / Mestrado / Biologia Celular / Mestra em Biologia Celular e Estrutural

Contextualização: Devido ao aumento progressivo da fraqueza muscular na DMD, novos movimentos compensatórios e variação no tempo de execução de atividades funcionais são utilizados para prolongar a atividade funcional. Objetivos: Descrever a evolução dos movimentos compensatórios, observados nas atividades de sentar e de levantar da cadeira em crianças com DMD durante um ano. Comparar e correlacionar a evolução do tempo de execução dessas atividades com o número de movimentos compensatórios, e analisar a responsividade do tempo de execução dessa atividade em análise semestral, durante um ano. Método: Foram acompanhadas 23 crianças com DMD, deambulantes, com idade entre 5 e 12 anos, por um ano. Foram estudadas as atividades de sentar e de levantar da cadeira em 3 momentos (inicial, após seis e após doze meses) por meio da Escala de Avaliação Funcional para DMD (FES-DMD-D1). Utilizou-se ANOVAs para comparar a evolução do tempo de execução e do número movimentos compensatórios (escores das fases e subfases da FES-DMD-D1). O teste post hoc de Tukey foi utilizado quando identificado efeito principal significativo e o teste de Spearman, para correlacionar essas variáveis. A responsividade do tempo de execução foi analisada por meio do teste de tamanho do efeito (ES) e a média de resposta padronizada (MRP). Resultados: A evolução das atividades de sentar e de levantar da cadeira ao longo de 12 meses apresentou aumento significante do número dos movimentos compensatórios e do tempo de execução. Somente a atividade de levantar apresentou correlação de moderada a forte com o tempo de execução, e o tempo de execução desta atividade foi responsivo a partir de seis meses. Conclusão: Houve aumento progressivo do número dos movimentos compensatórios e do tempo de execução das atividades de sentar e levantar da cadeira, no período de um ano. Somente o levantar da cadeira apresentou correlação entre as variáveis estudadas. Para uma avaliação mais precisa da progressão da doença, sugerimos acompanhamento do tempo de execução da atividade de levantar da cadeira e, sempre que possível acompanhada da análise de presença de movimentos compensatórios / Background: With the progressive increase of muscle weakness in patients with DMD, new compensatory movements are employed to maintain the performance of functional activities. Objective: To describe the evolution of compensatory movements observed in sitting and rising from a chair in children with DMD. Compare and correlate the evolution of timed performance of these activities and the number of compensatory movements in one year. To analyze the responsiveness of timed performance in six-month and one year intervals. Method: Twenty-three ambulatory children with DMD, aged 5 to 12 years, were followed during one year. Sitting and rising from a chair were evaluated in three moments (initial assessment, after six and after twelve months) with the Functional Assessment Scale for DMD, domain 1 (FES-DMD-D1). Analyses of variance (ANOVA) compared the timed performances and numbers of compensatory movements (scores on the phases and subphases of FES-DMD-D1). Post hoc Tukey tests were used when a significant main effect was identified and the Spearman test was used to correlate these variables. Responsiveness of the timed performance was described by the effect size (ES) and the standardized response mean (SRM). Results: The progression of sitting and rising from a chair in one year resulted in a significant increase in FES-DMD-D1 scores and timed performance. Only rising from a chair showed moderate to strong correlation with timed performance. Timed performance was responsive in six months and one year reassessments. Conclusion: There was a progressive increase in the number of compensatory movements and timed performance of sitting and rising from a chair. Only rising from a chair showed correlation between compensatory movements and timed performance. For a more accurate assessment of DMD progression, we suggest monitoring the timed performance of rising from a chair and, whenever possible, scoring the compensatory movements

Introdução: A distrofia muscular de Duchenne (DMD) é uma doença genética e hereditária que leva ao enfraquecimento da musculatura esquelética, respiratória e cardíaca de maneira progressiva e irreversível. Para pessoas gravemente comprometidas, a realidade virtual vem surgindo como uma forma de intervenção que traz uma nova possibilidade de interação com a comunidade. Os smartphones estão se tornando a próxima modernidade funcional para pessoas deficientes, não apenas pela acessibilidade, mas também pela conveniência da comunicação. Objetivo: Verificar se pessoas com DMD melhoram o desempenho motor quando realizam uma tarefa visuo-motora de labirinto virtual em um telefone móvel (smartphone). Método: Participaram do estudo 50 pessoas com DMD e 50 pessoas controles com desenvolvimento típico (DT), com idade entre 10 e 35 anos. A caracterização da amostra foi feita por meio das escalas Vignos, Egen Klassifikation, e Medida da Função Motora. A tarefa consistiu em completar o percurso de um labirinto virtual no jogo para telefone móvel (smartphone) Marble Maze Classic®, por meio de movimentos de punho e mão para mover a bola virtual pelo labirinto. Para mensurar o desempenho motor, foi cronometrado o tempo (em segundos) utilizado para completar o labirinto. O desempenho foi avaliado considerando os resultados nas fases de aquisição, retenção e transferência, e interpretados sob o ponto de vista teórico da aprendizagem motora. Resultados: A prática do jogo de labirinto no celular promoveu uma melhora no desempenho durante a aquisição em ambos os grupos, que se manteve na fase de retenção. Nas transferências, o desempenho no grupo DMD foi similar ao grupo DT, com a exceção da transferência para a mão contralateral (não dominante). No entanto, o grupo com DMD apresentou um tempo de movimento maior em todas as fases de aprendizagem comparado ao grupo DT. Conclusão: A prática de uma tarefa visuo-motora em um jogo de telefone móvel promoveu uma melhora no desempenho com padrões de aprendizagem similares em ambos os grupos. O desempenho pode ser influenciado pela dificuldade da tarefa, e para as pessoas com DMD, os déficits motores são responsáveis pela menor velocidade de execução, mas não é um impeditivo para a utilização dos smartphones por esta população / Background: Duchenne Muscular Dystrophy (DMD) is a genetic and hereditary disease that leads to a progressive and irreversible weakening of the skeletal, respiratory, and cardiac muscles. For the severely compromised subjects, virtual reality (VR) has been appearing as an intervention form that brings a new possibility of interaction with the community. Smartphones are likely to become the next functional modernity for handicapped, not only for accessibility but also for the convenience of communication. Objective: To verify whether people with DMD improve performance when doing a visual-motor task using a smartphone game. Method: The study included 50 patients with DMD and 50 healthy control subjects with Typical Development (TD), aged between 10 and 35 years. The characterization of the sample was given through Vignos scales, Egen Klassifikation, and the Motor Function Measure. The task consisted in to complete the journey of a virtual maze in the Marble Maze Classic® game for mobile phone (smartphone), moving a virtual ball using both hand and wrist movements. For the motor performance assessment it was measured the time (in seconds) used to complete the maze. The motor performance was assessed considering the results in acquisition, short-term retention and transfer, and interpreted from the theoretical framework of motor learning. Results: The practice of the smartphone maze game promoted an improvement in performance during acquisition in both groups, which remained in the retention phase. At the transfer phases, the performance in DMD group was similar to the performance of TD group, with the exception for the transfer to the contralateral hand (non-dominant). However, the group with DMD showed longer movement time at all stages of learning compared with the TD group. Conclusion: We conclude that the practice of a visual-motor task in a mobile phone game promoted an improvement in performance with similar patterns of learning in both groups. The performance can be influenced by the task difficulty, and motor deficits are responsible for the lower speed execution in DMD people, however, this is not an impediment for smartphone use by this population

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

Contextualização: O tempo e, mais recentemente, a análise dos movimentos compensatórios, têm sido utilizados na avaliação funcional de crianças com distrofia muscular de Duchenne (DMD). Embora estejam relacionadas, essas duas variáveis podem progredir distintamente em crianças com DMD, no intervalo de um ano. Objetivo: Descrever e comparar a evolução do tempo e dos movimentos compensatórios durante atividades de locomoção em crianças com DMD no período de um ano. Método: Foram avaliados filmes de 32 meninos (média de idade 10 anos) durante a marcha em local plano, por 10 m, o subir e o descer quatro degraus. O tempo foi cronometrado e utilizou-se a escala de avaliação funcional para DMD (Functional Evaluation Scale for Duchenne Muscular Dystrophy, FES-DMD) para pontuar os movimentos compensatórios. Aplicou-se a análise multivariável de variância (MANOVA), com (alfa < 0.05) para comparar as variáveis em três momentos: avaliação inicial (AV0), após 6 meses (AV6) e após 12 meses (AV12). Resultados: Os movimentos compensatórios mais comuns observados durante a marcha foram flexão plantar de tornozelos, aumento da base de apoio, anteriorização de cabeça e tronco e aumento da dissociação de cinturas. Na atividade de subir degraus foram flexão plantar de tornozelos, aumento da base de apoio, hiperlordose lombar e aumento da inclinação lateral do tronco. Ao descer degraus, esses movimentos também foram observados, acrescidos de rotação de tronco, flexão do joelho de apoio, flexão plantar do tornozelo de balanço e descida parando em cada degrau. A MANOVA mostrou que as variáveis aumentaram significativamente no período de um ano (p < 0,05 para todas as comparações) durante a marcha, o subir e o descer degraus. Interações entre o tempo e a pontuação dos movimentos compensatórios evidenciaram progressões distintas durante o subir e descer degraus (p < 0,05 para ambos). Durante a marcha, o tempo aumentou 47% e a pontuação dos movimentos compensatórios aumentou 55%. Ao subir degraus, o tempo aumentou 144% e a pontuação dos movimentos compensatórios aumentou 44%. Durante o descer degraus, o tempo aumentou 186% e a pontuação dos movimentos compensatórios aumentou 58%. Conclusão: Na marcha, as crianças com DMD mostraram aumento discretamente maior dos movimentos compensatórios, quando comparado ao aumento do tempo. Durante o subir e descer degraus, o aumento do tempo foi mais expressivo do que o aumento dos movimentos compensatórios. Acompanhar a evolução do tempo e dos movimentos compensatórios em crianças com DMD permitiu uma avaliação mais precisa e o acompanhamento da progressão das tarefas de locomoção / Introduction: Timed performance and, more recently, compensatory movements, have been used to assess children with Duchenne muscular dystrophy (DMD). Although being strongly related, these variables may progress distinctly within one year. Objective: To describe and compare the progression of timed performance and compensatory movements on locomotion tasks in children with DMD, followed for one year. Method: Films of 32 boys (mean age 10 yrs) performing 10-m walking, climbing up and down four steps were analyzed. Time was digitally measured and compensatory movements were quantified with the Functional Evaluation Scale for DMD (FES-DMD). Multivariate analyses of variance (MANOVAs) (alfa < 0.05) compared the variables on three assessments: initial (A0), after 6 months (A6) and after 12 months (A12). Results: The most common compensatory movements on walking were ankles plantar flexion, increased base of support, head and trunk anteriorization and increased upper and lower body dissociation. On climbing up steps, ankles plantar flexion, increased base of support, lumbar hyperlordosis and excessive trunk lateral inclination. On climbing down steps, these movements were also observed, associated to trunk rotation, stance knee flexion, equinus swing foot and pauses after steps. MANOVAs showed that both variables increased significantly within one year (p < 0.05 for all comparisons) on walking, climbing up and climbing down steps. Interactions between timed performance and compensatory movements evidenced distinct progressions of timed performance and compensatory movements on climbing up and down steps (p < 0.05 for both). On walking, timed performance increased 47% and compensatory movements increased 55%. On climbing up steps, timed performance increased 144% and compensatory movements increased 44%. On climbing down steps, timed performance increased 186% and compensatory movements increased 58%. Conclusion: On walking, children with DMD showed a discrete higher increase of compensatory movements, compared to the increase of timed performance. However, when climbing up and down steps, the timed performance increased much more than the compensatory movements. Evaluating the progression of timed performance and compensatory movements in children with DMD allowed more precise assessment and follow up of locomotion tasks evolution

Introdução: A Distrofia Muscular de Duchenne (DMD) é caracterizada como uma fraqueza muscular progressiva que leva à incapacidade. Devido às dificuldades funcionais enfrentadas pelos indivíduos com DMD, o uso da tecnologia assistiva é essencial para proporcionar ou promover habilidades funcionais. Na DMD, além do comprometimento musculoesquelético, uma disfunção autonômica cardíaca também tem sido relatada. Assim, visamos investigar as respostas autonômicas agudas de indivíduos com DMD durante a realização de uma tarefa no computador. Método: A variabilidade da frequência cardíaca foi avaliada através de métodos lineares e não lineares, utilizando uma cinta torácica com equipamento de monitoramento de eletrocardiograma (ECG). Assim, 45 indivíduos foram incluídos no grupo com DMD e 45 no grupo de desenvolvimento típico (controle), avaliados for 20 minutos em repouso sentado e 5 minutos com a realização de uma tarefa no computador. Resultados: Os indivíduos com DMD apresentaram menor modulação cardíaca parassimpática durante o repouso, que diminuiu ainda mais durante a tarefa no computador. Conclusão: Indivíduos com DMD exibiram respostas autonômicas cardíacas mais intensas durante a tarefa no computador / Introduction: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness that leads to disability. Due to functional difficulties faced by individuals with DMD, the use of assistive technology is essential to provide or expand functional abilities. In DMD, as well as musculoskeletal impairment, cardiac autonomic dysfunction has also been reported. Thus, we aimed to investigate acute cardiac autonomic responses in a computer task of DMD subjects. Method: Heart rate variability was evaluated through linear and nonlinear methods, using a breast strap electrocardiogram (ECG) measuring device. Thus, 45 subjects were included in the group with DMD and 45 in the typical development (control) group, assessed for 20 minutes sitting at rest and five minutes with a task on the computer. Results: Individuals with DMD had lower parasympathetic cardiac modulation at rest, which decreased further during the task on the computer. Conclusion: Individuals with DMD exhibited more intense cardiac autonomic responses during computer tasks

La dystrophie musculaire de Duchenne (DMD) entraine une perte progressive de la force musculaire. L'objectif de ce présent travail est d'étudier la sensibilité d'une méthode acoustique échographique (50 MHz) et d'une méthode résonante (25 kHz) aux changements de propriétés des tissus musculaires de souris mdx modèles. Les paramètres mesurés sont l'atténuation ultrasonore pour la méthode échographique et le module complexe de cisaillement pour la méthode résonante. Dans ce manuscrit nous exposons le développement de ces deux méthodes adaptées à l'étude de deux tissus musculaires de souris : le diaphragme et la peau. La méthode échographique a permis de quantifier les changements de propriétés biologiques du diaphragme en fonction du pourcentage de zone non musculaire sur des souris âgées de 3 mois à 24 mois. La méthode résonante, génère un champ de pression dans le tissu induisant un cisaillement dans le tissu. Cette méthode a permis d'estimer des différences de propriétés mécaniques sur le diaphragme et sur la peau entre les tissus sains et tissu pathologiques. Les résultats obtenus autorisent à penser que le développement de la méthode résonante pour des applications in vivo chez l'Homme atteint de DMD est possible. / The muscular dystrophy of Duchenne (DMD) lead a progressive loss of the muscular strength. The objective of this present work is to study the sensibility of an ultrasound acoustic method (50 MHz) and a résonant method (25 kHz) to the changes of properties of muscle tissues of mdx mice models. The mesured parameters are the ultrasound attenuation for the echographic method and the complexe shear modulus for the résonant method.In this manuscript we explain the development of these two methods adapted to the study of two muscular tissues of mouse: the diaphragm and the skin. The ultrasound method allowed to quantify the changes of biological properties of the diaphragm according to the percentage of non muscular area on 3-month-old mice in 24 months. The résonant acoustic method, generates a field pressure in the tissue leading a shearing tissue. This method allowed to estimate différences of mechanical properties on the diaphragm and on the skin between healthy tissues and pathological tissues. We think the obtained results authorize the development of the resonant method for in vivo applications to human touched by DMD.

La régénération musculaire implique des interactions fonctionnelles entre différents types de cellules mononucléées. Parmi elles, citons les progéniteurs myogéniques (MPs), qui fusionnent pour générer de nouvelles myofibres en réponse à une blessure, et les cellules immunitaires qui envahissent les muscles endommagés. Des dépôts transitoires fibrotiques et d’adipocytes sont observés dans les muscles en régénération qui cependant persistent dans la dystrophie musculaire de Duchenne (DMD) et au cours du vieillissement. Nous avons démontré que les progéniteurs fibro-adipogéniques (FAPs) exprimant le marqueur de surface PDGFRα, contribueraient au développement des dépôts non myogéniques dans les muscles sains. En effet, ces progéniteurs se différencient en adipocytes blancs fonctionnels, bien qu’étant insensibles à l’insuline, et génèrent des myofibroblastes. Quant à la fibrose des muscles DMD, elle se formerait à partir de la différenciation à la fois des MPs et des FAPs. Dans les muscles sains, les FAPs stimulent la myogenèse des MPs au cours de la régénération, alors que les myotubes et les macrophages pro-inflammatoires inhibent l’adipogenèse et la fibrogenèse des FAPs. Pour les progéniteurs âgés ou dystrophiques, les interactions cellulaires entre les FAPs et les MPs sont perturbées. De manière intéressante, la régulation des FAPs DMD ou âgés peut être restaurée en remplaçant les MPs DMD ou âgés par des MPs jeunes et sains. Nos résultats montrent que les muscles humains contiennent des progéniteurs fibro-adipogéniques qui jouent un rôle central dans la régulation de l’homéostasie musculaire en interagissant avec les progéniteurs myogéniques et les macrophages / Muscle regeneration involves functional interactions between different types of mononuclear cells including myogenic progenitors (MPs) and macrophages. Following injury, damaged muscles are invaded by immune cells and MPs fuse to generate new myofibres. Transient fibrotic and adipocyte deposits are observed in regenerating muscles, which however persist in Duchenne muscular dystrophy (DMD) and during aging. We demonstrated that fibro-adipogenic progenitors (FAPs) expressing the PDGFRα surface marker would contribute to the development of non-myogenic deposits in healthy muscles. Indeed, these progenitors differentiate into functional white adipocytes that have the feature to be insulino-resistant, and give rise to myofibroblastes. Intramuscular fibrosis in DMD patients could be formed from both FAPs and MPs differentiation. In healthy muscles, FAPs stimulate myogenesis of MPs during regeneration, while myotubes and pro-inflammatory macrophages inhibit the adipogenesis and fibrogenesis of FAPs. Cellular interactions between FAPs and MPs are disrupted for DMD or aged progenitors. Interestingly, they are restored if aged or DMD FAPs are replaced by healthy and young MPs. Our results show that the human muscles contain fibro-adipogenic progenitors that play a crucial role in the control of muscle homeostasis by interacting with myogenic progenitors and macrophages

Hintergrund: Neue, individualisierte symptomatische und kausal orientierte Behandlungsmöglichkeiten haben in den vergangenen Jahren zu einer Veränderung der Krankheitsverläufe und der Langzeitprognose von seltenen neurologischen, zuvor im Kindes- oder Jugendalter lebenslimitierenden Erkrankungen geführt. Für diese Erkrankungen gibt es wenig standardisierte Behandlungsalgorithmen zur Rolle und Implementierung der spezialisierten Palliativversorgung. Die Muskeldystrophie Duchenne (DMD) gehört zu diesen seltenen, progredienten, lebenslimitierenden neuromuskulären Erkrankungen des Kindes-, Jugend- und zunehmend auch des jungen Erwachsenenalters, die in Deutschland ca. 1.500 Menschen betrifft. Palliativmedizinische Ansätze und Prinzipien sollen gemäß der Erklärung der ACT (Association for Children with Life-Threatening or Terminal Conditions and their Families) bei lebenslimitierenden Erkrankungen ab Diagnosestellung umgesetzt werden. Dies kann sowohl auf der allgemeinen als auch auf der spezialisierten (Palliativ)Versorgungsebene realisiert werden. Fragestellung: In der Studie wird die Palliativversorgung bei Patienten mit DMD und ihrer Familien in Deutschland hinsichtlich der Bedarfe und „unmet needs“, die gesundheitliche Situation und Symptome, die ambulante und stationäre Versorgung, die Einstellungen zu Sterben und Tod sowie die Wahrnehmung von Palliative Care analysiert. Ziel ist die Analyse der Ist-Situation und in Folge die Entwicklung eines kollaborativen integrierten Modells für die Palliativversorgung bei jungen Menschen mit einer lebenslimitierenden neurologischen Erkrankung. Material und Methoden: Ein trianguliertes Mixed-Methods-Design aus (1) qualitativen, (2) quantitativen und (3) versorgungsepidemiologischen Forschungsmethoden wurde umgesetzt. (ad 1) Semistrukturierte Interviews mit Patienten(-familien) wurden geführt und mit der qualitativen Inhaltsanalyse nach Mayring analysiert. (ad 2) Ein Online-Fragebogen an Patienten ab einem Alter von 10 Jahren und deren Familien wurde über das deutsche DMD-Patientenregister und die Universitätskliniken Dresden und Essen versandt. Die erhobenen Daten zur Soziodemografie, gesundheitlichen Situation und Symptomprävalenz, ambulanten und stationären Versorgung, Behandlungszufriedenheit, Kenntnis und Nutzung von Hospiz- und Palliativversorgungsstrukturen sowie die Einstellungen zu Sterben und Tod wurden deskriptiv und interferenzanalytisch untersucht. (ad 3) Die Krankenhausbehandlung der G71.0-Diagnosefälle (Muskeldystrophie) der Jahre 2005 bis 2015 wurde anhand von Mikrodaten der DRG-Statistik umfassend analysiert. Ergebnisse: Die qualitative Analyse der Interviews mit neun Patienten(-familien) (Mittelwert Patientenalter 20,8 Jahre) ergab Bedarfe hinsichtlich multiprofessioneller Beratung, der Antizipation des Krankheitsverlaufs, passender und verfügbarer Versorgungsstrukturen, der Transition in die Erwachsenenversorgung und des Anliegens, das Lebensende innerhalb der Familie oder mit Ärzten zu thematisieren. Die Stichprobe der quantitativen Analyse (Online-Fragebogen) umfasste 150 Patienten (Rücklaufquote 28 %; entspricht ca. 15 % der deutschen DMD-Patienten ab einem Alter von 10 Jahren; Mittelwert Patientenalter 19,8 Jahre; 13 % gehfähig, 23 % nicht mehr gehfähig bei erhaltener Arm- und Handfunktion, 64 % ohne Gehfähigkeit und Armfunktion; 79 % bei den Eltern lebend; 78 % ausschließlich durch die Familie versorgt). Die Patienten gaben folgende Symptome an: Schmerz (bei 57 % aller Patienten), Fatigue (43 %), Depression (30 %), Obstipation (25 %) und Dyspnoe (7 %). Zur Symptombehandlung machten die Patienten folgende Angaben: Schmerz 71 % ohne bzw. ohne zufriedenstellende Behandlung, Fatigue 84 %, Depression 73 %, Obstipation 56 %, Dyspnoe 40 %. Die medizinischen Primärversorger waren vorrangig Pädiater (45 %) und Allgemeinmediziner (37 %). Bis zum 18. Lebensjahr erfolgte in 92 % der Fälle eine multiprofessionelle Versorgung, ab dem 18. Lebensjahr nur zu 45 %. Die multiprofessionelle Versorgung hatte keinen signifikanten Einfluss auf die Symptomprävalenz oder Frequenz der Krankenhausaufnahmen. Probleme im Transitionsprozess wurden in den Interviews der qualitativen Phase der Studie formuliert und waren auch in der quantitativen Studienphase sowohl für den ambulanten Bereich (Online-Befragung: Weiterversorgung von 26 % der Erwachsenen durch Pädiater) als auch die stationäre Versorgung (DRG-Statistik: Behandlung von 22 % der 20-24-jährigen Patienten in pädiatrischen Fachabteilungen) nachweisbar. In der stationären Versorgung erfolgte laut Online-Befragung (55 % der Patienten mit elektiven und 32 % mit akuten Krankenhausaufenthalten in den zwei Jahren vor dem Befragungszeitpunkt) und der Analyse der DRG-Statistik (2005-2015: pro Jahr ca. 2.100 Krankenhausaufenthalte von Patienten mit Muskeldystrophie [MD] als Haupt- oder Nebendiagnose im Alter von 0-34 Jahren) ein wesentlicher Teil der (Palliativ-)Versorgung. Laut DRG-Statistik gab es die meisten Krankenhausaufenthalte in der Gruppe der 10-19-jährigen; jedoch ist bei den jungen Erwachsenen (20-34 Jahre) ein besonders starker Zuwachs der Zahl der Krankenhausaufnahmen (74 %) zu verzeichnen. Geplante Krankenhauseinweisungen (70 % der Aufnahmen) erfolgten v. a. in den Fachabteilungen Pädiatrie (40 %), Pneumologie (17 %) und Innere Medizin ohne Pneumologie (13 %). Notfälle (30 % der Aufnahmen, Anstieg zwischen 2006 und 2015 über alle Altersgruppen hinweg um 44 %) wurden vorrangig in der Pädiatrie (49 %), Inneren Medizin (20 %) und Chirurgie/Orthopädie (13 %) behandelt. Lediglich 30 % der Krankenhausaufenthalte resultierten aus der Diagnose „Muskeldystrophie“ an sich, bei 70 % lagen andere Hauptdiagnosen (Komplikationen der Muskeldystrophie, Begleiterkrankungen) zugrunde. Die Verweildauer der Patienten lag im Mittel bei 5,5 Tagen; 55 % waren Kurzlieger mit einer Verweildauer von maximal drei Tagen. Pro Jahr verstarben ca. 35 MD-Patienten im Krankenhaus, häufig nach Notfalleinweisungen und v. a. in den Fachabteilungen Innere Medizin (36 %) und Pädiatrie (28 %). Ein Viertel der stationär verstorbenen Patienten war zwischen 15 und 19 Jahre alt, die Hälfte 20 -24 Jahre und ein Drittel 25 - 34 Jahre. Strukturen der Hospiz- und Palliativversorgung waren 70 % aller Online-Befragten bekannt und wurden von 18 % genutzt. Laut DRG-Statistik fanden 6 % aller Krankenhausaufenthalte der MD-Patienten auf Palliativstationen statt, fast ausschließlich bei Patienten mit onkologischen Begleiterkrankungen. Patienten als auch Eltern fühlten sich sehr gut zum Krankheitsverlauf informiert, bei anstehenden Entscheidungsprozessen eingebunden und empfanden die zur Verfügung gestellte Zeit der Behandelnden als ausreichend. Kritischer wurde die erhaltene emotionale Unterstützung bewertet. Die Themen Sterben und Tod wurden in der Arzt-Patienten-Kommunikation selten besprochen. Der Wunsch, Behandlungsentscheidungen im Voraus zu treffen, hatte eine hohe Bedeutung und nahm mit steigendem Lebensalter zu. Internet und soziale Medien wurden zur Krankheitsverarbeitung und -bewältigung zurückhaltend genutzt. Schlussfolgerungen: Die triangulierte Datenanalyse ergibt „unmet needs“ im Symptommanagement, den Notfalleinweisungen in Krankenhäuser, der überwiegenden Pflege durch die Eltern ohne externe Unterstützung, der Transition sowie der ärztlichen Kommunikation über Sterben und Tod. Kompetenzen von Palliativversorgern liegen in den Themenfeldern multiprofessionelle Symptomkontrolle und -behandlung, aufsuchende Koordination, Beratung, Krisenintervention, Unterstützung im stationären Bereich, Kommunikation zur vorausschauenden Planung (Advance Care Planning) und zu Sterben und Tod sowie Versorgung am Lebensende. Komplexe, schwer behandelbare, belastende Symptome trotz optimaler Therapie durch Haus- und Fachärzte, komplexe Versorgungssituationen mit (drohender) Überlastung der Angehörigen oder mit erforderlichem hohen koordinativen Aufwand, Häufung von Krankenhausaufenthalten sowie komplexe stationäre Behandlungssituationen, der Wunsch nach Therapiezielgesprächen oder das Lebensende bieten Schnittstellen für den Einbezug spezialisierter Palliativversorger. Aus der Datenanalyse wurde ein kollaboratives integriertes Modell für die Palliativversorgung bei jungen Menschen mit einer lebenslimitierenden neurologischen Erkrankung entwickelt. Es wurden Schnittstellen und Grenzen der jeweiligen Versorgungsebenen definiert. Demnach können Primärversorger durch spezialisierte Palliativversorger ergänzt werden, um die bestmögliche Lebensqualität von Menschen mit einer DMD umfassend und orientiert an deren Wünschen und Bedürfnissen zu sichern.:1. EINLEITUNG 12 1.1. Die Muskeldystrophie Duchenne 12 1.1.1. Prävalenz 12 1.1.2. Der klinische Verlauf der Muskeldystrophe Duchenne 13 1.1.3. Versorgungssituation von Patienten mit Muskeldystrophie Duchenne in Deutschland 16 1.2. Palliativversorgung bei der Muskeldystrophie Duchenne 19 1.2.1. Definition 19 1.2.2. Grundlagen 20 1.2.3. Strukturen 21 1.2.4. Empfehlungen 26 1.2.5. Forschungsstand 28 1.3. Versorgungsforschung 33 1.3.1. Teilgebiet der Gesundheitssystemforschung 33 1.3.2. Versorgungsforschung bei Patienten mit einer Muskeldystrophie Duchenne 35 2. ZIELSTELLUNG 37 3. METHODIK 39 3.1. Ethikvotum 40 3.2. Qualitative Forschung 40 3.2.1. Interviews 40 3.2.2. Kohorte 41 3.3. Quantitative Forschung 42 3.3.1. Online-Befragung 42 3.3.2. Kohorte 43 3.4. Versorgungsepidemiologische Forschung 43 3.4.1. Analyse der DRG-Statistik 43 3.4.2. Kohorte 44 4. ERGEBNISSE 47 4.1. Ergebnisse der qualitativen Forschung 47 4.1.1. Soziodemografische Daten und Versorgungssituation 47 4.1.2. Themen und Problemfelder aus Patienten- und Elternsicht 48 4.1.2.1. Bedürfnis nach multiprofessioneller Behandlung 48 4.1.2.2. Antizipation des Krankheitsverlaufs 48 4.1.2.3. Bedürfnis nach passenden und verfügbaren Versorgungsstrukturen 49 4.1.2.4. Umsetzung der Transition 49 4.1.2.5. Wahrnehmung von Palliativ- und Hospizversorgung 50 4.2. Ergebnisse der quantitativen Forschung 56 4.2.1. Kohorte 56 4.2.2. Soziodemografische Daten 57 4.2.2.1. Altersverteilung 57 4.2.2.2. Regionale Verteilung der Wohnorte 57 4.2.2.3. Lebensort 59 4.2.2.4. Pflegerische Versorgung 60 4.2.2.5. Bildungs- und Beschäftigungssituation 61 4.2.2.6. Zusammenfassung 63 4.2.3. Krankheitsstadien und Atemhilfen 64 4.2.4. Symptomprävalenz und -behandlung 65 4.2.4.1. Schmerz 67 4.2.4.2. Fatigue 68 4.2.4.3. Depression 69 4.2.4.4. Obstipation 70 4.2.4.5. Dyspnoe 70 4.2.4.6. Symptombehandlung aus Patientenperspektive 71 4.2.4.7. Zusammenfassung 72 4.2.5. Die ambulante Versorgung 73 4.2.5.1. Die hausärztliche Versorgung 73 4.2.5.2. Die interdisziplinäre und multiprofessionelle Versorgung 74 4.2.5.3. Zusammenfassung 76 4.2.6. Die stationäre Versorgung 77 4.2.6.1. Elektive Krankenhausaufenthalte 77 4.2.6.2. Akute Krankenhausaufenthalte 79 4.2.6.3. Zusammenfassung 82 4.2.7. Einflussfaktoren und Auswirkungen multiprofessioneller Versorgung 83 4.2.7.1. Alter 83 4.2.7.2. Allgemeine ärztliche Versorgung 84 4.2.7.3. Bundesländerspezifische Unterschiede 84 4.2.7.4. Lebensort 85 4.2.7.5. Symptomprävalenz und -behandlung 86 4.2.7.6. Elektive und akute Krankenhausaufenthalte 87 4.2.7.7. Zusammenfassung 90 4.2.8. Palliativversorgung 92 4.2.8.1. Kenntnis und Inanspruchnahme von Strukturen der Palliativversorgung 92 4.2.8.2. Ansprechpartner in gesundheitlichen Krisen 93 4.2.8.3. Haltung zu palliativen Themenfeldern 94 4.2.8.4. Zusammenfassung 96 4.3. Versorgungsepidemiologische Analyse der G71.0-Diagnosefälle der DRG-Statistik der Jahre 2005-2015 97 4.3.1. Kohorte 97 4.3.1.1. Gesamtzahlen 97 4.3.1.2. Altersgruppen 98 4.3.2. Patientenwohnorte und Krankenhausstandorte 100 4.3.2.1. Wohnorte der Patienten 101 4.3.2.2. Krankenhausstandorte 102 4.3.3. Aufnahmeanlässe und Aufnahmegründe 104 4.3.3.1. Aufnahmeanlässe 104 4.3.3.2. Aufnahmegrund 105 4.3.4. Notfalleinweisungen 106 4.3.4.1. Altersgruppen bei Notfalleinweisungen 106 4.3.4.2. Fachabteilungen bei Notfalleinweisungen 108 4.3.5. Komorbiditäten 110 4.3.5.1. Aufnahmebegründende Diagnosen 110 4.3.5.2. Altersverteilung bei den Hauptdiagnosen Muskeldystrophie und respiratorische Insuffizienz 114 4.3.6. Fachabteilungen 115 4.3.6.1. Fachabteilungen mit längster Verweildauer 115 4.3.6.2. Erwachsene Patienten in pädiatrischen Fachabteilungen 117 4.3.7. Verweildauer 118 4.3.7.1. Verweildauer nach Altersgruppen 118 4.3.7.2. Verweildauern bei elektiven Aufnahmen und Notfalleinweisungen 120 4.3.7.3. Verweildauer bei den Hauptdiagnosen Muskeldystrophie und respiratorische Insuffizienz 121 4.3.8. Entlassungsgründe 123 4.3.9. Stationäre Behandlung auf Palliativstationen 123 4.3.10. Versterben im Krankenhaus 125 4.3.11. Zusammenfassung 126 5. DISKUSSION 128 5.1. Die Versorgungssituation junger Menschen mit Muskeldystrophie Duchenne in Deutschland – eine Populationsperspektive 128 5.1.1. Soziodemografie: Alter, Wohn- und Lebensort, Pflege und Beschäftigungssituation 128 5.1.2. Stadien der Erkrankung 132 5.2. Die Versorgungssituation von jungen Menschen mit Muskeldystrophie Duchenne in Deutschland aus medizinischer Perspektive 134 5.2.1. Symptomprävalenz und -behandlung 134 5.2.2. Ambulante multiprofessionelle Versorgung 138 5.2.3. Stationäre Versorgung 140 5.3. Die Versorgungssituation von Menschen mit Muskeldystrophie Duchenne in Deutschland aus der Perspektive der Palliativversorgung 143 5.3.1. Inanspruchnahme von Strukturen der Palliativversorgung 144 5.3.2. Problemstellungen und Unzulänglichkeiten in der Versorgung 146 5.3.2.1. Symptommanagement 147 5.3.2.2. Familiäre Belastung 148 5.3.2.3. Transition 149 5.3.2.4. Emotionale Unterstützung und Kommunikation zu Sterben und Tod 151 5.4. Entwicklung des Modells einer kollaborativen integrierten Palliativversorgung für junge Menschen mit einer lebenslimitierenden neurologischen Erkrankung am Beispiel der Muskeldystrophie Duchenne 153 5.4.1. Themenfeld 1: Symptommanagement 155 5.4.2. Themenfeld 2: Krisenintervention 156 5.4.3. Themenfeld 3: Familiäre Entlastung 157 5.4.4. Themenfeld 4: Koordination 158 5.4.5. Themenfeld 5: Unterstützung bei Krankenhausaufenthalten 159 5.4.6. Themenfeld 6: Advance Care Planning 160 5.4.7. Themenfeld 7: Versorgung am Lebensende 161 5.5. Diskussion des Mixed-Methods-Ansatzes im Kontext der Versorgungsforschung 163 5.5.1. Diskussion des qualitativen Forschungsdesigns 163 5.5.2. Diskussion des quantitativen Forschungsdesigns 164 5.5.3. Diskussion des versorgungsepidemiologischen Analysedesigns 166 5.6. Limitationen der Studie 168 5.6.1. Stichprobenumfang und Repräsentativität 168 5.6.2. Methodik 168 5.7. Ausblick und weitere Forschungsfragen 169 6. ZUSAMMENFASSUNG 171 7. SUMMARY 174 8. LITERATURVERZEICHNIS 177 9. ANHANG 193 / Background: In recent years, new, individualized symptomatic and causally oriented treatment options have led to a change in the course and long-term prognosis of rare neurological diseases that were previously life-limiting in childhood or adolescence. To date, there are few standardized treatment algorithms for the role and implementation of specialized palliative care. (DMD) is one of these rare, progressive, life-limiting neuromuscular diseases of childhood, adolescence, and increasingly young adulthood, affecting approximately 1,500 people in Germany. According to the statement of the ACT (Association for Children with Life-Threatening or Terminal Conditions and their Families), palliative care approaches and principles in life-limiting diseases should be implemented beginning with the moment of diagnosis. This can be put into practice on the general as well as on the specialized (palliative) care level. Research question: The study analyzes palliative care in DMD patients and their families in Germany with regard to needs and unmet needs, health situation and symptoms, outpatient and inpatient care, attitudes toward dying and death, and perceptions of palliative care. The aim is to analyze the current situation and subsequently develop a collaborative integrated model for palliative care in young people with a life-limiting neurological disease. Materials and methods: A mixed-methods design of (1) qualitative, (2) quantitative, and (3) care epidemiological research methods was used. (ad 1) Semi-structured interviews with patients (and their families) were conducted and analyzed using Mayring's qualitative content analysis. (ad 2) An online questionnaire for patients aged 10 years and older and their families was distributed via the German DMD patient registry and the university hospitals of Dresden and Essen. Data collected on socio-demographics, health situation and symptom prevalence, outpatient and inpatient care, treatment satisfaction, knowledge and use of hospice and palliative care structures, and attitudes toward dying and death were analyzed descriptively and by interference analysis. (ad 3) Hospital treatment of G71.0 diagnosis cases (muscular dystrophy) from 2005 to 2015 was comprehensively analyzed using microdata from DRG statistics. Results: The qualitative analysis of the interviews with nine patients (and their families) (mean patient age 20.8 years) revealed needs regarding multi-professional counseling, anticipation of the course of the disease, appropriate and available care structures, transition to adult care, and the desire to talk about the end of life with the family or with physicians. The sample of the quantitative analysis (online questionnaire) included 150 patients (response rate 28%; corresponding to approximately 15% of German DMD patients aged 10 years and older; mean patient age 19.8 years; 13% ambulatory, 23% no longer ambulatory with preserved arm and hand function, 64% without ambulation and arm function; 79% living with parents; 78% cared for exclusively by family). Patients reported the following symptoms: Pain (in 57% of all patients), fatigue (43%), depression (30%), constipation (25%), and dyspnea (7%). Regarding symptom management, patients provided the following information: pain 71% with no or no satisfactory treatment, fatigue 84%, depression 73%, constipation 56%, dyspnea 40%. Primary medical care providers were primarily pediatricians (45%) and general practitioners (37%). Multi-professional care was provided in 92% of cases up to the age of 18, and in only 45% of cases after the age of 18. Multi-professional care had no significant effect on symptom prevalence or frequency of hospital admissions. Problems in the transition process were voiced in the interviews of the qualitative phase of the study and were detectable in the quantitative study phase both in the outpatient setting (online survey: continuing care of 26% of adults by pediatricians) and in inpatient care (DRG statistics: treatment of 22% of 20-24-year-old patients in pediatric departments). Inpatient care provided a substantial amount of (palliative) care according to the online survey (55% of patients with elective and 32% with acute hospitalizations in the 2 years prior to the survey date) and analysis of DRG statistics (2005-2015: approximately 2,100 hospitalizations per year of patients with muscular dystrophy [MD] as a principal or secondary diagnosis aged 0-34 years). According to DRG statistics, most hospitalizations occurred in the 10-19 year old group; however, young adults (20-34 years) experienced a particularly large increase in the number of hospitalizations (74%). Planned hospitalizations (70% of admissions) occurred primarily in the departments of pediatrics (40%), pulmonology (17%), and internal medicine excluding pulmonology (13%). Emergency cases (30 % of admissions, increase of 44 % between 2006 and 2015 across all age groups) were primarily treated in pediatrics (49 %), internal medicine (20 %), and surgery/orthopedics (13 %). Only 30% of hospitalizations resulted from the diagnosis of muscular dystrophy per se; 70% were due to other main diagnoses (complications of muscular dystrophy, concomitant diseases). The average length of stay of the patients was 5.5 days; 55 % were short-stay patients with a maximum length of stay of three days. Approximately 35 MD patients died in the hospital each year, often after emergency admissions and primarily in the departments of internal medicine (36%) and pediatrics (28%). One quarter of the inpatients who died were between 15 and 19 years of age, half of them 20-24 years, and one 25-34 years. Hospice and palliative care structures were known to 70% of all online respondents and used by 18%. According to DRG statistics, 6% of all hospitalizations of MD patients took place in palliative care units, almost exclusively for patients with oncological comorbidities. Patients as well as parents felt very well informed about the course of the disease, involved in upcoming decision-making processes, and felt that the time provided by the treating staff was sufficient. The emotional support received was evaluated more critically. The topics of dying and death were rarely discussed in doctor-patient communication. The desire to make treatment decisions in advance had high importance and increased with advancing age. Internet and social media were used with restraint for illness management and coping. Conclusions: Triangulated data analysis shows unmet needs in symptom management, emergency hospitalizations, predominant care by parents without external support, transition and physician communication about dying and death. Competencies of palliative care providers are in the fields of multi-professional symptom control and treatment, outreach coordination, counseling, crisis intervention, inpatient support, advance care planning communication, and dying and death and end-of-life care. Complex, difficult-to-treat, distressing symptoms despite optimal therapy by primary care physicians and specialists, complex care situations with (threatening) overload of relatives or with required high coordinative effort, accumulation of hospitalizations as well as complex inpatient treatment situations, the desire for therapy goal discussions or the end of life offer interfaces for the involvement of specialized palliative care providers. Based on the data analysis, a collaborative integrated model for palliative care of young people with life-limiting neurological disease was developed. Interfaces and limits of the respective care levels were defined. According to this model, primary care providers can be complemented by specialized palliative care providers to comprehensively ensure the best possible quality of life for people with a DMD based on their wishes and needs.:1. EINLEITUNG 12 1.1. Die Muskeldystrophie Duchenne 12 1.1.1. Prävalenz 12 1.1.2. Der klinische Verlauf der Muskeldystrophe Duchenne 13 1.1.3. Versorgungssituation von Patienten mit Muskeldystrophie Duchenne in Deutschland 16 1.2. Palliativversorgung bei der Muskeldystrophie Duchenne 19 1.2.1. Definition 19 1.2.2. Grundlagen 20 1.2.3. Strukturen 21 1.2.4. Empfehlungen 26 1.2.5. Forschungsstand 28 1.3. Versorgungsforschung 33 1.3.1. Teilgebiet der Gesundheitssystemforschung 33 1.3.2. Versorgungsforschung bei Patienten mit einer Muskeldystrophie Duchenne 35 2. ZIELSTELLUNG 37 3. METHODIK 39 3.1. Ethikvotum 40 3.2. Qualitative Forschung 40 3.2.1. Interviews 40 3.2.2. Kohorte 41 3.3. Quantitative Forschung 42 3.3.1. Online-Befragung 42 3.3.2. Kohorte 43 3.4. Versorgungsepidemiologische Forschung 43 3.4.1. Analyse der DRG-Statistik 43 3.4.2. Kohorte 44 4. ERGEBNISSE 47 4.1. Ergebnisse der qualitativen Forschung 47 4.1.1. Soziodemografische Daten und Versorgungssituation 47 4.1.2. Themen und Problemfelder aus Patienten- und Elternsicht 48 4.1.2.1. Bedürfnis nach multiprofessioneller Behandlung 48 4.1.2.2. Antizipation des Krankheitsverlaufs 48 4.1.2.3. Bedürfnis nach passenden und verfügbaren Versorgungsstrukturen 49 4.1.2.4. Umsetzung der Transition 49 4.1.2.5. Wahrnehmung von Palliativ- und Hospizversorgung 50 4.2. Ergebnisse der quantitativen Forschung 56 4.2.1. Kohorte 56 4.2.2. Soziodemografische Daten 57 4.2.2.1. Altersverteilung 57 4.2.2.2. Regionale Verteilung der Wohnorte 57 4.2.2.3. Lebensort 59 4.2.2.4. Pflegerische Versorgung 60 4.2.2.5. Bildungs- und Beschäftigungssituation 61 4.2.2.6. Zusammenfassung 63 4.2.3. Krankheitsstadien und Atemhilfen 64 4.2.4. Symptomprävalenz und -behandlung 65 4.2.4.1. Schmerz 67 4.2.4.2. Fatigue 68 4.2.4.3. Depression 69 4.2.4.4. Obstipation 70 4.2.4.5. Dyspnoe 70 4.2.4.6. Symptombehandlung aus Patientenperspektive 71 4.2.4.7. Zusammenfassung 72 4.2.5. Die ambulante Versorgung 73 4.2.5.1. Die hausärztliche Versorgung 73 4.2.5.2. Die interdisziplinäre und multiprofessionelle Versorgung 74 4.2.5.3. Zusammenfassung 76 4.2.6. Die stationäre Versorgung 77 4.2.6.1. Elektive Krankenhausaufenthalte 77 4.2.6.2. Akute Krankenhausaufenthalte 79 4.2.6.3. Zusammenfassung 82 4.2.7. Einflussfaktoren und Auswirkungen multiprofessioneller Versorgung 83 4.2.7.1. Alter 83 4.2.7.2. Allgemeine ärztliche Versorgung 84 4.2.7.3. Bundesländerspezifische Unterschiede 84 4.2.7.4. Lebensort 85 4.2.7.5. Symptomprävalenz und -behandlung 86 4.2.7.6. Elektive und akute Krankenhausaufenthalte 87 4.2.7.7. Zusammenfassung 90 4.2.8. Palliativversorgung 92 4.2.8.1. Kenntnis und Inanspruchnahme von Strukturen der Palliativversorgung 92 4.2.8.2. Ansprechpartner in gesundheitlichen Krisen 93 4.2.8.3. Haltung zu palliativen Themenfeldern 94 4.2.8.4. Zusammenfassung 96 4.3. Versorgungsepidemiologische Analyse der G71.0-Diagnosefälle der DRG-Statistik der Jahre 2005-2015 97 4.3.1. Kohorte 97 4.3.1.1. Gesamtzahlen 97 4.3.1.2. Altersgruppen 98 4.3.2. Patientenwohnorte und Krankenhausstandorte 100 4.3.2.1. Wohnorte der Patienten 101 4.3.2.2. Krankenhausstandorte 102 4.3.3. Aufnahmeanlässe und Aufnahmegründe 104 4.3.3.1. Aufnahmeanlässe 104 4.3.3.2. Aufnahmegrund 105 4.3.4. Notfalleinweisungen 106 4.3.4.1. Altersgruppen bei Notfalleinweisungen 106 4.3.4.2. Fachabteilungen bei Notfalleinweisungen 108 4.3.5. Komorbiditäten 110 4.3.5.1. Aufnahmebegründende Diagnosen 110 4.3.5.2. Altersverteilung bei den Hauptdiagnosen Muskeldystrophie und respiratorische Insuffizienz 114 4.3.6. Fachabteilungen 115 4.3.6.1. Fachabteilungen mit längster Verweildauer 115 4.3.6.2. Erwachsene Patienten in pädiatrischen Fachabteilungen 117 4.3.7. Verweildauer 118 4.3.7.1. Verweildauer nach Altersgruppen 118 4.3.7.2. Verweildauern bei elektiven Aufnahmen und Notfalleinweisungen 120 4.3.7.3. Verweildauer bei den Hauptdiagnosen Muskeldystrophie und respiratorische Insuffizienz 121 4.3.8. Entlassungsgründe 123 4.3.9. Stationäre Behandlung auf Palliativstationen 123 4.3.10. Versterben im Krankenhaus 125 4.3.11. Zusammenfassung 126 5. DISKUSSION 128 5.1. Die Versorgungssituation junger Menschen mit Muskeldystrophie Duchenne in Deutschland – eine Populationsperspektive 128 5.1.1. Soziodemografie: Alter, Wohn- und Lebensort, Pflege und Beschäftigungssituation 128 5.1.2. Stadien der Erkrankung 132 5.2. Die Versorgungssituation von jungen Menschen mit Muskeldystrophie Duchenne in Deutschland aus medizinischer Perspektive 134 5.2.1. Symptomprävalenz und -behandlung 134 5.2.2. Ambulante multiprofessionelle Versorgung 138 5.2.3. Stationäre Versorgung 140 5.3. Die Versorgungssituation von Menschen mit Muskeldystrophie Duchenne in Deutschland aus der Perspektive der Palliativversorgung 143 5.3.1. Inanspruchnahme von Strukturen der Palliativversorgung 144 5.3.2. Problemstellungen und Unzulänglichkeiten in der Versorgung 146 5.3.2.1. Symptommanagement 147 5.3.2.2. Familiäre Belastung 148 5.3.2.3. Transition 149 5.3.2.4. Emotionale Unterstützung und Kommunikation zu Sterben und Tod 151 5.4. Entwicklung des Modells einer kollaborativen integrierten Palliativversorgung für junge Menschen mit einer lebenslimitierenden neurologischen Erkrankung am Beispiel der Muskeldystrophie Duchenne 153 5.4.1. Themenfeld 1: Symptommanagement 155 5.4.2. Themenfeld 2: Krisenintervention 156 5.4.3. Themenfeld 3: Familiäre Entlastung 157 5.4.4. Themenfeld 4: Koordination 158 5.4.5. Themenfeld 5: Unterstützung bei Krankenhausaufenthalten 159 5.4.6. Themenfeld 6: Advance Care Planning 160 5.4.7. Themenfeld 7: Versorgung am Lebensende 161 5.5. Diskussion des Mixed-Methods-Ansatzes im Kontext der Versorgungsforschung 163 5.5.1. Diskussion des qualitativen Forschungsdesigns 163 5.5.2. Diskussion des quantitativen Forschungsdesigns 164 5.5.3. Diskussion des versorgungsepidemiologischen Analysedesigns 166 5.6. Limitationen der Studie 168 5.6.1. Stichprobenumfang und Repräsentativität 168 5.6.2. Methodik 168 5.7. Ausblick und weitere Forschungsfragen 169 6. ZUSAMMENFASSUNG 171 7. SUMMARY 174 8. LITERATURVERZEICHNIS 177 9. ANHANG 193