A expressão de Smads e de membros da família AP1/ jun-fos podem refletir alterações da via de TGFb, uma via importante para o câncer epidermóide de cabeça e pescoço (HNSCC). Encontramos expressão aumentada dos mRNAs das Smads1-8 em HNSCC em comparação com tecido normal adjacente, por RPA. Além disso, as curvas de sobrevida de Kaplan Meier e a análise multivariada mostraram que a Smad6+ parece ser um fator determinante de bom prognóstico em HNSCC. Quanto a família AP-1, mensurado por Northern blot, somente Fra-1 mostrou-se aumentado no tumor e associado à presença de linfonodos comprometidos. Nossos dados sugerem que a positividade de Smad6 possa ser marcador de bom prognóstico em HNSCC / Smad and AP1 messenger RNA expression may underlie disruptions affecting TGFb signaling in head and neck squamous cell carcinoma (HNSCC). Analysis of Smads1-8 mRNA expression by RPA has shown Smad expression is globally increased in tumor as compared to adjacent normal tissue. Kaplan Meier survival curves and multivariate analysis revealed that Smad6 positivity in tumor was an independent good prognostic factor in HNSCC. In relation to AP-1, as measured by Northern blot, only Fra-1 was overexpressed in tumor and directly related to the presence of lymph node involvement. Our data suggest that Smad6 may be a marker of good prognosis in HNSCC

A perda da permeabilidade seletiva de membrana celular causada pela isquemia leva ao acúmulo de sódio e edema miocárdico. Este fenômeno tem implicações importantes na estrutura e função do ventrículo esquerdo, nas primeiras horas após infarto do miocárdio. Objetivou-se investigar a hipótese de que, durante as primeiras horas após oclusão coronária prolongada e restabelecimento de fluxo completo, a taxa de acúmulo de sódio miocárdico é determinado pela integridade da microvasculatura. Utilizou-se imagem de ressonância magnética do sódio-23 em 3 dimensões, para monitorizar as alterações do conteúdo de sódio miocárdico no tempo, em um modelo canino in vivo e com tórax fechado (n = 19) de infarto do miocárdio e reperfusão. Seis animais apresentaram fibrilação ventricular durante a oclusão ou imediatamente após reperfusão coronária, não completando o protocolo. Em quatro experimentos não se detectou nenhuma área de infarto, por nenhum dos métodos utilizados. Um animal foi submetido a oclusão coronária permanente. Os oito animais restantes constituíram o grupo de infartos reperfundidos. Destes, infartos com obstrução microvascular (n = 4), detectados por microesfera radioativa e por imagem por ressonância magnética do hidrogênio realçada com contraste, mostraram uma taxa menor de acúmulo de sódio, assim como um menor fluxo sangüíneo 20 minutos e 6 horas após reperfusão. A ausência de obstrução microvascular nos infartos (n = 4) esteve associada a taxas maiores de acúmulo do sódio e maior restabelecimento do fluxo sangüíneo miocárdico. Além disso, o tamanho do infarto por imagem por ressonância magnética do sódio-23 apresentou boa correlação com o tamanho do infarto pela anatomopatologia (cloreto de trifeniltetrazólio ou TTC) e pela imagem de ressonância do hidrogênio realçada por contraste (hiperintensificação ou realce tardio) 9 horas após reperfusão. Conclui-se que, em infartos do miocárdio reperfundidos, o acúmulo de sódio é dependente da integridade microvascular e está diminuído em regiões de obstrução microvascular, comparado com regiões miocárdicas com microvasculatura patente. A imagem por ressonância do sódio-23 pode ser um instrumento útil para a monitorização in vivo do conteúdo do sódio no infarto agudo do miocárdio. / Loss of membrane permeability caused by ischemia leads to cellular sodium accumulation and myocardial edema. This phenomenon has important implications to left ventricular structure and function in the first hours after myocardial infarction. We hypothesized that during this period of time, after prolonged coronary occlusion and complete reflow, the rate of myocardial sodium accumulation is governed by microvascular integrity. We used 3-dimensional 23 Na magnetic resonance imaging to monitor myocardial sodium content changes over time in an in vivo closed-chest canine model (n = 19) of myocardial infarction and reperfusion. Six animals had ventricular fibrillation during occlusion or immediately after coronary reperfusion, and did not finish the protocol. Myocardial infarction was not detected in four experiments, by any of utilized methods. In one experiment, we produced permanent coronary occlusion. The remaining eight animals constituted the reperfused myocardial infarction group. From those, infarcts with microvascular obstruction n = 4) defined by both radioactive microsphere and contrast-enhanced 1 H magnetic resonance imaging showed a slower rate of sodium accumulation as well as lower blood flow at 20 minutes and 6 hours after reperfusion. Conversely, the absence of microvascular obstruction (n = 4) was associated with faster rates of sodium accumulation and greater blood flow restoration. In addition, infarct size by 23 Na magnetic resonance imaging correlated best with infarct size by triphenyltetrazolium chloride and contrast-enhanced 1 H magnetic resonance imaging at 9 hours after reperfusion. We conclude that in reperfused myocardial infarction, sodium accumulation is dependent on microvascular integrity and is slower in regions of microvascular obstruction compared with those with patent microvasculature. Finally, 23 Na magnetic resonance imaging can be a useful tool for monitoring in vivo myocardial sodium content in acute myocardial infarction.

β2-glicoproteína I (β2GPI) é encontrada (200µg/mL) no plasma, 60% livre e 40% em lipoproteínas. Esta proteína de fase aguda, com afinidade por superfícies negativas pode ser clivada pela plasmina. Fragmentos são purificados como dímeros ou multímeros de β2GPI. Formas monomérica e dimérica de β2GPI foram purificadas de soro humano e identificadas por SDS-PAGE, imunoblot e ELISA Somente a forma monomérica foi detectada no teste ELISA Os efeitos de ambas as formas sobre o burst respiratório de polimorfonucleares humanos (PMN), estimulados in vitro com zymosan opsonizado, foram estudados por quimioluminescência amplificada por luminol ou lucigenina e citometria de fluxo, pela oxidação do OCFH. A forma monomérica inibiu a quimioluminescência amplificada por luminol (-43.6 x -7.33 AEU/s), mas não por lucigenina, e aumentou a oxidação de DCFH e a produção de Óxido Nítrico (•NO). É provável que o •No, via peroxinitrito, medeie os efeitos de β2GPI sobre o burst respiratório de PMN. / Circulating blood contains approximately 200µg/mL of β 2-glycoprotein I (β2GPI), either free (60%) or lipoprotein bound (40%). This acute phase protein, with affinity for negative surfaces, can be cleaved by plasmin. Fragments purify as dimeric or multimeric (β2GPI. Both (β2GPI forms were purified from human sera and identified by SDS-PAGE, immunoblotting and ELISA. ELISA reactivity was dependent on the monomeric status of (β2GPI. The effects of dimeric and monomeric (β2GPI upon respiratory burst of human polimorphonuclear neutrophils (PMN) stimulated in vitro with opsonized zymosan were studied. Respiratory burst was evaluated by luminol- or lucigenin-amplified chemiluminescence, or by DCFH oxidation (flow-cytometry assay). The monomeric, but not the dimeric form, inhibited the luminol chemiluminescence of zymosan-stimulated PMNs (-43.6 x -7.33 AEU/s). Lucigenin chemiluminescence was insensitive to (β2-GPI. Monomeric (β2GPI increases both DCFH oxidation and nitric oxide production. Nitric oxide, probably through peroxynitrite reactions, mediates (β2GPI effects upon PMNs respiratory burst.

O propósito da presente investigação foi avaliar o papel da atividade física no desenvolvimento de enfisema induzido por papaína em ratos. Para tanto, ratos Wistar foram randomicamente divididos em quatro grupos (n = 10 para cada grupo) que receberam, respectivamente, infusão intra-traqueal de papaína (6 mg em 1 mL de NaCl 0,9%) ou veículo e foram submetidos ou não ao protocolo de exercício em uma esteira ergométrica. Os ratos exercitaram-se a 13,3 m/min, 6 dias por semana, durante 9 semanas (o tempo de exercício foi aumentado gradualmente, de 10 a 35 min). Foram medidas a elastância e a resistência do sistema respiratório (Ers e Rrs, respectivamente), o peso e tamanho do coração, volume das câmaras cardíacas, diâmetro médio das fibras cardíacas e diâmetro alveolar médio. Após 9 semanas de atividade física não houve diferença para os valores de Ers e Rrs entre os quatro grupos experimentais. Houve um aumento estatisticamente significativo do peso do coração preenchido por solução de formaldeído nos grupos de animais submetidos à atividade física comparados aos grupos de animais sedentários (P = 0,007). Não houve diferenças significativas entre os dois grupos que fizeram exercício físico (tendo ou não recebido papaína) ou entre os dois grupos sedentários. O volume das câmaras cardíacas direita e esquerda não foram diferentes entre os diferentes grupos. O diâmetro médio das fibras do ventrículo esquerdo foi significativamente maior nos grupos submetidos à atividade física quando comparados aos grupos sedentários (P = 0,006). O diâmetro alveolar médio foi significativamente maior em ratos que receberam papaína quando comparados aos ratos que receberam salina intratraqueal (P = 0,025). Entretanto o diâmetro alveolar médio foi significativamente maior nos animais que receberam instilação intratraqueal de papaína e que foram submetidos à atividade física, quando comparados aos animais que foram instilados com papaína, mas não foram submetidos ao condicionamento físico. Concluímos que a atividade física pode aumentar à lesão alveolar induzida pela infusão de papaína / The purpose of the present study was to evaluate the role of exercise training on the development of papain-induced emphysema in rats. Wistar rats were randomly assigned to four groups (n = 10 for each group) that received, respectively, intratracheal infusion of papain (6 mg in 1 mL NaCl 0.9%) or vehicle and were submitted or not to a protocol of exercise on a treadmill. Rats exercised at 13.3 m/min, 6 days per week, for 9 weeks (increasing exercise time, from 10 to 35 min). We measured respiratory system elastance (Ers) and resistance (Rrs), the size and weight of the heart and mean alveolar diameter (Lm). After 9 weeks of exercise training, there were no differences in Rrs and Ers values among the four experimental groups. There was a significant increase in the heart weight filled with formaldehyde solute in animals submitted to exercise training compared to the sedentary groups (P = 0.007). There were no differences between the two groups submitted to exercise training (receiving or not papaine) or between the sedentary groups. There were no differences in cardiac chambers volume between all groups. The left ventricule fibers mean diameter was significantly greater in rats submitted to exercise training compared to sedentary rats (P = 0.006). Lm was significantly greater in rats that received papain compared to saline-infused rats (P = 0.025). However, Lm was significantly greater in papain + exercise rats compared to rats that received papain and were not submitted to exercise. We conclude that exercise training can increase alveolar damage induced by papain infusion

Este estudo mostra como o rolamento do pé de pacientes com polineuropatia diabética pode ser melhorado com exercícios para pés e tornozelos, visando a recuperação muscular e articular comprometidos pela doença. Um ensaio clínico randomizado, paralelo, com um braço de crossover, e avaliador cego, foi conduzido. Cinquenta e cinco pacientes com polineuropatia diabética foram randomizados e alocados para o grupo controle (n=29) e grupo intervenção (n=26). A intervenção foi aplicada por 12 semanas, 2 vezes por semana, por 40 a 60 minutos cada sessão. As variáveis primárias foram definidas como as que descrevem o rolamento do pé: pressão plantar em seis regiões plantares de interesse. As variáveis secundárias foram a cinética e cinemática de tornozelo no plano sagital, e as medidas clínicas da função de pés e tornozelo (teste de função muscular manual, testes funcionais), de sinais e sintomas da polineuropatia diabética, exame físico dos pés e teste de confiança e equilíbrio em atividades da marcha. Os efeitos de tempo (baseline e 12 semanas), de grupo (controle e intervenção) e de interação foram calculados por meio de ANOVAs casewise 2 fatores, e para as comparações intragrupo do grupo intervenção (baseline, 12 semanas e 24 semanas) foram usadas ANOVAs para medidas repetidas. As variáveis não paramétricas foram comparadas entre grupos por meio de testes de Mann-Whitney e entre os tempos de intervenção por meio do teste de Wilcoxon. Adotou-se um ? de 5% para diferenças estatísticas e o coeficiente d de Cohen para descrição do tamanho do efeito da intervenção. Após 12 semanas de exercícios, observou-se mudanças positivas no rolamento do pé. Houve uma suavização do contato do calcanhar no apoio inicial, refletido pelo aumento do tempo do pico de pressão e da integral do pico de pressão. O médio-pé aumentou sua participação no rolamento observado pela diminuição da velocidade média do deslocamento do centro de pressão e aumento da integral do pico de pressão. O antepé lateral passou a realizar o apoio no solo antecipadamente em relação ao antepé medial, que previamente à intervenção aconteciam concomitantemente, e esse resultado foi evidenciado pela antecipação do tempo do pico de pressão em antepé lateral após a intervenção. A ação de hálux e dedos também aumentou (aumento de integral do pico de pressão e picos de pressão), em uma patologia marcada pela diminuição do contato do hálux e desenvolvimento de dedos em garra, que diminui o contato dos dedos com o solo. O grupo controle apresentou algumas pioras com relação à função muscular e parâmetros cinéticos e cinemáticos de tornozelo, enquanto que o grupo intervenção mostrou melhora na função de muitos grupos musculares, em testes funcionais e no pico de momento extensor na fase de aplainamento do pé. Apesar do protocolo de intervenção ter sido construído de modo a permitir que o paciente incorpore os exercícios na sua rotina diária, a aderência a este tipo de intervenção deve ser estudada, já que grande parte das variáveis retornaram ao baseline após o período de follow up. Ações preventivas são fundamentais para diminuir as complicações devastadoras da neuropatia diabética / This study shows how the foot rollover process during gait of patients with diabetic polyneuropathy can be improved with exercises for foot and ankle, aiming at the recovery of the muscles and joints affected by the disease. A clinical trial randomized, parallel, one arm of crossover, with blind assessment was conducted. Fifty-five patients with diabetic polineuropathy were randomly allocated to the control group (n = 29) and intervention group (n = 26). The intervention was applied for 12 weeks, twice a week, for 40 to 60 minutes per session. The primary variables were defined as those that describe the foot rollover: plantar pressure in 6 plantar areas of interest. The secondary variables were kinetic and kinematics of the ankle in the sagittal plane were calculated, and the clinical measures of foot and ankle function (manual muscle function testing, functional testing), signs and symptoms of diabetic polyneuropathy, physical examination of the feet and balance and confidence test in gait activities. The time effects (baseline and 12 weeks), group effects (control and intervention groups) and interaction effects were calculated using casewise two factos ANOVAs, and for intragroup comparisons of intervention group (baseline, 12 weeks and 24 weeks) it was used ANOVAs for repeated measures. The nonparametric variables were compared between groups using Mann-Whitney tests and between periods of assessment using Wilcoxon test. We adopted an ? of 5% for statistical differences and the Cohen\'s d coefficient for description of the effect size. After 12 weeks ofexercises, there were positive changes in the foot rollover process. There was a softening of heel contact in initial contact, reflected by the increase in time to peak pressure and the pressure time integral. The midfoot increased its participation observed by the decrease in speed of displacement of the center of pressure and increased pressure time integral. The lateral forefoot contact was earlier relative to the medial forefoot, that occurred at the same time before intervention, observed by the early time to peak pressure of lateral forefoot after the intervention. The participation of the hallux and toes also increased (increase of pressure time integral and peak pressure), in a pathology that is marked by decreased contact of the hallux and development of claw toes, which reduces contact of the toes with the ground. CG showed some worsening in relation to muscle function and kinematic and kinetic parameters of the ankle, while the IG showed improvement in the function of many muscles groups, functional tests and peak extensor moment during the forefoot contact. The intervention protocol was constructed to allow the patient to incorporate exercise into their daily routine, but adherence to treatment should be studied and motivational strategies need to be applied, since most of the variables returned to baseline after the follow up period (12 weeks after the intervention). Preventive actions are critical to reducing the devastating complications of diabetic neuropathy

Introdução: Distrofia muscular progressiva nas formas de Duchenne (DMD) e Becker (DMB) são doenças caracterizadas por progressiva degeneração musculoesquelética e substituição por tecido fibrogorduroso. O envolvimento cardíaco está presente em 80% dos pacientes, apresenta curso clínico silencioso e é diagnosticado tardiamente pelos métodos tradicionais. Objetivos: 1. Investigar a progressão da fibrose miocárdica pela ressonância magnética cardíaca (RMC), em ensaio clínico randomizado para tratamento ou não com IECA, de pacientes com DMD e DMB e fração de ejeção ventricular esquerda (FEVE) preservada, por um período de 02 anos. 2. Investigar se há mutações genéticas específicas que sejam preditoras do acometimento miocárdico diagnosticado pela RMC. 3. Comparar os achados do ECG, radiografia de tórax e ecocardiograma com os da RMC. Métodos: Entre 1/6/2009 e 1/6/2012 foram incluídos 76 pacientes com diagnóstico de DMD e DMB. Todos os pacientes realizaram duas RMCs com intervalo médio de 2,05±0,11 anos, com técnicas de cine ressonância para avaliação da função ventricular e realce tardio miocárdico para avaliação da fibrose miocárdica. A fibrose miocárdica foi quantificada por software específico para obtenção do percentual da massa de fibrose do VE com análise semi automática, utilizando os desvios padrões da média dos valores de intensidade do sinal do miocárdio normal. Os valores acima de 5 desvios padrões da média do miocárdio normal foram considerados como fibrose miocárdica. Os 42 pacientes com fibrose miocárdica e FEVE normal foram randomizado em 2 grupos, com 21 deles recebendo tratamento com IECA e 21 sem qualquer tratamento para cardiomiopatia. Após 2 anos, novas RMCs foram realizadas para avaliar a evolução da fibrose e a FEVE. Resultados: Notou-se fibrose miocárdica em 72,3% dos pacientes, sendo que 55,6 % não apresentavam disfunção sistólica. Verificou-se uma correlação positiva significativa entre idade e percentual de fibrose na RMC basal (r=0,338, p=0,014) e seguimento (r=0,315, p=0,006). Os pacientes randomizados e tratados com IECA apresentaram menor evolução do percentual de fibrose do que os randomizados não tratados (3,1±7,4% versus 10,0±6,2% respectivamente, p=0,001). Na análise linear multivariada, verificamos que pertencer ao grupo tratado diminui a progressão do percentual de fibrose (y=-4,51x+29,63 ajustado por idade, CK e percentual de fibrose basal, p=0,039) e indica uma tendência de menor probabilidade de apresentar fração de ejeção do VE < 50% na RMC seguimento (OR= 3,18, p= 0,102, por regressão logística). Os pacientes com mutação nos exons menores que 45 do gene da distrofina apresentaram maior percentual de fibrose que os com mutação dos exons maiores ou iguais ao 45 na RMC basal (27,9±18,4% versus 12,1±13,4%, respectivamente, p=0,006) e seguimento (33,1±21,1% versus 18,8±16,9%, respectivamente, p=0,024). A avaliação conjunta por métodos tradicionais (radiografia de tórax, ECG e ecocardiografia) apresentou baixa sensibilidade de 47,3% e valor preditivo negativo de 34,1% para o diagnóstico do envolvimento cardíaco na DMD e DMB, em pacientes com FEVE normal e fibrose miocárdica na RMC. Conclusões: O ensaio clínico randomizado, por um período de 2 anos, em pacientes com DMD e DMB, com fibrose miocárdica diagnosticada pela RMC e FEVE preservada, demonstrou significativa maior progressão da fibrose miocárdica nos pacientes que não fizerem uso de IECA. Existe uma correlação significativa entre o local de mutação no gene da distrofina e o acometimento cardíaco. O ECG, o eco e radiografia de tórax apresentaram baixa sensibilidade e baixo valor preditivo negativo para detecção do envolvimento cardíaco precoce nos pacientes com DMD e DMB / Introduction: Duchenne and Becker muscular dystrophies (DMD and BMD) are diseases characterized by progressive skeletal muscle degeneration and replacement by fibro fatty tissue. Cardiac involvement is frequent, as high as 70 - 80% of patients, and often develops clinically silent, without any evident early clinical signs. Traditional diagnostic methods (ECG, chest x-ray and echocardiography) are only able to diagnose cardiac involvement at a later stage. Objectives: 1. To investigate the progression of myocardial fibrosis by cardiac magnetic resonance (CMR), in a randomized clinical trial for treatment with ACE inhibitors, in patients with DMD or BMD and preserved left ventricular ejection fraction (LVEF), for a period of 02 years. 2. To investigate whether there are specific genetic mutations that are predictive of myocardial involvement detected by CMR. 3. To compare the findings of ECG, chest radiography and echocardiography with those found by CMR. Methods: Between 01/06/2009 and 01/06/2012 76 patients with DMD and BMD were included. All patients underwent two CMRs with a mean interval of 2.05±0.11 years, using cine resonance for function evaluation and myocardial delayed enhancement technique for myocardial fibrosis detection. Myocardial fibrosis was quantified by specific software for obtaining fibrosis mass, as percentage of LV mass, using semi-automatic fibrosis analysis and standard deviations of the mean values of signal intensity of the normal myocardium. A value of five standard deviations above the mean of a normal myocardium were considered myocardial fibrosis. The 42 patients with myocardial fibrosis and normal LVEF were randomized into 2 groups, with 21 of them receiving ACE inhibitor treatment and 21 no treatment for cardiomyopathy. After 2 years, new CMRs were performed to evaluate fibrosis extent and LVEF. Results: Myocardial fibrosis was noted in 72.3% of the patients, 55.6% showed no systolic dysfunction. There was a significant positive correlation between age and myocardial fibrosis at the CMR baseline (r=0.338, p=0.014) and follow-up (r=0.315, p=0.006). Patients randomized and treated with ACE inhibitors had lower evolution of myocardial fibrosis than those who were randomized and untreated (3.1±7.4% vs.10.0±6.2%, respectively, p=0.001). Using multivariate regression analysis, we found that belonging to the treated group decreases the progression of myocardial fibrosis (y=-4.51x+29.63 adjusted for age, CK and baseline myocardial fibrosis, p=0.039) and indicated a trend for lower probability of presenting LVEF<50% at follow-up CMR (OR= 3.18, p= 0.102, by logistic regression). Patients with mutations in exons less than 45 had greater extent of myocardial fibrosis than patients with mutations in exons greater than or equal to 45 in CMR at baseline (27.9±18.4% vs. 12.1±13.4%, respectively, p=0.006) and at follow-up (33.1±21.1% vs. 18.8±16.9%, respectively, p=0.024). Conclusions: In this 2-year follow-up randomized clinical trial in patients with DMD and BMD with preserved LVEF, myocardial fibrosis diagnosed by CMR, showed significantly greater progression in patients not receiving ACE inhibitors therapy. There was a significant correlation between the site of mutation in the dystrophin gene and cardiac involvement. ECG, echocardiography and chest radiography showed low sensitivity and low negative predictive value for early detection of cardiac involvement (myocardial fibrosis by CMR) in patients with DMD and BMD

A fenomenologia da síndrome de Tourette (ST) é complexa. Apesar de tiques motores e vocais serem as características definidoras da síndrome, muitas pessoas relatam ter urgências premonitórias (fenômenos sensoriais) de difícil descrição. A história natural da ST também é variável, com alguns indivíduos que experimentam uma redução acentuada nos tiques até o final da segunda década de vida, enquanto outros permanecem com sintomas ao longo de toda a vida adulta. Os objetivos principais desta tese são três: (1) desenvolver um instrumento de avaliação clínica com boa validade e confiabilidade para ST; (2) investigar os fenômenos sensoriais (FS) associados a ST; e (3) documentar o curso da gravidade dos tiques durante as duas primeiras décadas de vida. Para atingir esses objetivos incluíram-se grupos de pacientes clinicamente bem caracterizados e de artigos científicos publicados em periódicos internacionais de alto impacto. A Escala de Gravidade Global de tiques de Yale (YGTSS) apresentou excelentes propriedades psicométricas, o que foi replicado em estudos independentes. Também emergiu como a escala de gravidade mais utilizada em ensaios clínicos randomizados para ST em todo o mundo. Os FS, particularmente urgências premonitórias, são comumente relatados entre os indivíduos com ST com a partir da idade de 10 anos. Há uma sobreposição considerável com os FS descritos por indivíduos com Transtorno Obsessivo- Compulsivo (TOC). Os tiques costumam ter seu início na primeira década de vida e, então, seguem um curso flutuante com mudança do seu repertório. Conforme documentado no terceiro estudo, para a maioria dos pacientes, o período de pior gravidade dos tiques ocorre geralmente entre 7 e 15 anos de idade, após o qual a gravidade declina gradualmente. Esta queda dos sintomas de tiques é consistente com os dados epidemiológicos disponíveis que indicam uma prevalência muito menor de ST entre adultos do que crianças. Em resumo, há um esforço para incremento da caracterização fenomenológica e da história natural da ST. Revisões da YGTSS devem ser consideradas. Avanços significativos foram feitos para caracterizar e mensurar os FS associados a ST. Estudos acerca das bases neurobiológicas, da fenomenologia e da história natural da ST estão em andamento no sentido de identificar os indicadores prognósticos / The phenomenology of Tourette syndrome is complex. Although overt motor and vocal tics are the defining features of Tourette syndrome, many individuals report experiencing sensory \"urges,\" which are often difficult to describe. The natural history of this condition is also variable, with some individuals experiencing a marked reduction in tics by the end of the second decade of life while others go on to have a lifelong condition. The aim of this thesis was three-fold: (1) to develop a valid and reliable clinical rating instrument; (2) to investigate the sensory phenomena associated with Tourette syndrome; and (3) to document the course of tic severity over the course of the first two decades of life. Each of these three studies involved groups of patients with Tourette syndrome or a chronic tic disorder and each of these studies has been published in a peer-reviewed journal. The Yale Global Tic Severity Scale (YGTSS) has excellent psychometric properties that have been independently replicated. It has also emerged as the most widely used clinician-rated tic severity scale in randomized clinical trials around the world. Sensory phenomena, particularly premonitory urges, are commonly reported among individuals with Tourette syndrome by the age of 10 years. There is considerable overlap with the sensory phenomena described by individuals with Obsessive-Compulsive Disorder. Tics usually have their onset in the first decade of life. They then follow a waxing and waning course and a changing repertoire of tics. As documented in the third study, for a majority of patients the period of worst tic severity usually falls between the ages of 7 and 15 years of age, after which tic severity gradually declines. This falloff in tic symptoms is consistent with available epidemiological data that indicate a much lower prevalence of Tourette syndrome among adults than children. This decline in tic severity has been confirmed in subsequent studies. In summary, incremental progress is being made in our efforts to characterize the phenomenology and natural history of Tourette syndrome. Revisions to the YGTSS should be considered. Significant advances have been made in measuring the premonitory urges associated with Tourette syndrome. The neurobiological underpinnings of the phenomenology and natural history of Tourette syndrome are currently underway in an effort to identify prognostic indicators

心肺功能是其中一項體能特質，而對於進行較長時間的中至高劇烈程度運動十分重要，也會影響日常活動和健康。但是，還沒有研究香港華裔長者心肺功能水平及其與體能活動參與程度和健康的關條。 / 招募對象是從現有的兩個追蹤研究來的[男女骨折研究(n=998 和884 )和頸動脈粥樣硬化研究( 191 名婦女)， 70 - 79 歲年長男士最大攝氧量的參考範圖為22.3-23.0 毫升/分鐘/公斤(95%信賴區間) , 80 歲以上為19.2-20.2 毫升/分鐘/公斤。80 歲以上女性的參考範園為17.0-18.3 毫升/公斤/分鐘， 70-79 歲為19.3-20.0毫升/公斤/分鐘， 60-69 歲為2 1. 7-23.0 毫升/公斤/分鐘和年齡55-59 歲為22 .1 -23.8毫升/公斤/分鐘。男性的心肺功能與腰圍有相關性。<.0001) ，而女性的相關性還要加上體重(p<.02) ，與年齡有關的最大攝氧量衰退在男性為0.368 毫升/公斤/分鐘/年，而女性為0 .238 毫升/公斤/分鐘/年。 / 70 - 79 歲年長男士6 分鐘步行距離的參考範圍為453.3-466 公尺， 80 歲以上為382.6-403.3 公尺。80 歲以上女性的參考範圍為333.9-357.2公尺和年齡70-79 歲為396.1-406.8 公尺。6 分鐘步行距離與腰圍、身高和學歷有相關性(p:S:.05) ，與年齡有關的6 分鐘步行距離衰退在男性為9.06 公尺/年，而女性為7.35 公尺/年。從長者活動評估量表得出的體能活動參與程度被認為是與最大攝氧量成正相關(男性:r=.241，'女性:r=.214 )和6 分鐘步行距離(男性: r=.257，女性:r=.1 84) 。長者日常步行時間越長最大攝氧量和6 分鐘步行距離較佳(p≤01) ，進行劇烈運動的女性有正常最大攝氧量的機會較高(p=.041) 。男性能符合美國運動醫學學院或香港衛生署指引的明顯比不能達到指引的有較好的心肺功能。能達到指引的男性有1. 68 倍的概率有正常的心肺功能。回溯性研究追查過去的PASE 分數與現在最大攝氧量的相關性，反應出過去的體能活動參與程度對現在的心肺功能影響隨時間減少(男性由目前回到7 年前: r=0.241、0.168、0.120; 女性: r= .214、0.106、0.069 )。 / 患有高血壓男性的最大攝氧量和6 分鐘步行距離較差(p=.014) ，曾患有心肌硬塞或心絞痛男性和糖尿病女性的6 分鐘步行距離較差(p<.04) 。最大攝氧量分別與由社區認知篩選工具評估的男性認知水平（r=.107)和男女長者憂鬱量表分數男性:r=-.112 ，女性: r=-.123) 有相關性。另一方面， 6 分鐘步行距離被發現分別與簡易智能狀態測驗p<.02) 、男性的社區認知篩選工具(p=.046)的認知級別和男女長者憂鬱量表的抑鬱狀態p<.04)有差別。 / 最大攝氧量和6分鐘步行距離的年齡調整相關性連中高程度(男性:R=.459、女性: R=.425) 。除了與最大攝氧量有滿意的相關性，6分鐘步行距離與精神健康有比較密切的相關性。6分鐘步行距離可作為香港華裔長者最大攝氧量的體能代表值。 / Cardiorespiratory fitness (CRF) is one of the main attributes which is important toper form moderate-to-high intensity exercise for prolonged periods which affects daily activities as well as health. However, there are no studies among HK Chinese Elders' CRF and the relationship between this important parameter of physical fitness, PA participation and health outcomes. / By recruiting subjects from two existing cohort studies, the Osteoporetic Fractures in Men & Women Study (n=998 & 884 respectively) and the Carotid Atherosclerosis Study (191 women), the reference ranges of VO₂ peak for men were 22.3-23.0ml/min/kg (95% C.I.) at age 70-79y, and 19.2-20.2 ml/min/kg at age ≥80y. Forwomen, the reference range at age ≥80y was 17.0-18.3 ml/kg/min, 70-79y was19.3-20.0 ml/kg/min, 60-69y was 21.7-23.0 ml/kg/min and for age 55-59y was22.1-23.8 ml/kg/min. Men's VO₂ peak was associated with waist circumference(WC, p<.000l) while women's VO₂ peak additionally associated with weight (p<.02).There was an age-related decline in VO₂ peak at 0.368 ml/kg/minly in men and 0.238ml/kg/minly in women. / The reference ranges of 6MWD for men were 453.3-466.6m (95% C.I.) at age 70-79y, and 382.6-403.3m at age ≥80y. For women, the reference range at age 80≥y was 333.9-357.2m and for age 70-79y was 396.1-406.8 ml/kg/min. 6MWD was associated with WC, height and education (p≤.05). There was an age-related decline in 6MWD at 9.06m/y in men and 7.35m/y in women. / Elders' participation in PA assessed by the Physical Activity Scale for Elderly (PASE), was positively correlated with VO₂ peak (r=.241 in men, r=.214 in women) and 6MWD (r=.257 in men, r=.184 in women). Elderly walked more everyday have better VO₂peak and longer 6MWD (p≤ .0l). Women did more strenuous sport had higher chance of having normal CRF (p=.041). Men who met the guidelines by American College of Sports Medicine (ACSM) & Department of Health (DH), HK had better VO₂ peak than those who failed to meet that guidelines (p<.005). By following the PA guidelines, men had a 1.68-fold probability having normal CRF. A novel approach to retrospectively explore the correlation between the past PASE score and the present VO₂ peak revealed that the effect of past PA participation diminished with time (correlations for men from present, 4y and 7y ago: r=.241, .168, .120; for women r=.214, .106, .069). / Men with hypertension had significantly lower V02 peak and shorter 6MWD (p<.03). Men with history of myocardial infarction and angina also walked shorter in 6MWT while women only with diabetes had shorter 6MWD (p<.04). CRF was found to be correlated with cognitive level in men estimated by CSI-D (p<.0001) and GDS-15 score in both genders (r=-.112 in men, r=-.123 in women). On the other hand, 6MWD was found to be different across cognitive status estimated by MMSE (p<.02) & CSI-D (p=.046 in men only), and depression status estimated by GDS-15 (p<.04) in both genders. / Age-adjusted correlation between VO₂ peak & 6MWD was moderately high (R=.459 in men; R=.425 in women). In addition to the satisfactory correlation with VO₂ peak, stronger associations were found 6MWD, cognitive and mental health. It was suggested 6MWD might be a feasible surrogate for VO₂ peak as a physical fitness measure among HK Chinese elderly. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Yau, Chung Fai Forrest. / "December 2011." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 215-237). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese; appendix in Chinese. / ABSTRACT (IN ENGLISH) --- p.I / ABSTRACT (IN CHINESE) --- p.IV / ACKNOWLEDGEMENT --- p.VI / LIST OF CONTENTS --- p.VII / LIST OF TABLES --- p.XII / SELECTED ABBREVIATIONS --- p.XV / Chapter 1 --- BACKGROUND & OBJECTIVES --- p.1 / Chapter 1.1 --- INTRODUCTION --- p.1 / Chapter 1.2 --- OBJECTIVES OF THE STUDY --- p.3 / Chapter 1.3 --- OUTLINES OF THE THESIS --- p.4 / Chapter 2 --- LITERATURE REVIEW --- p.6 / Chapter 2.1 --- ELDERLY POPULATIONS --- p.6 / Chapter 2.1.1 --- Health --- p.6 / Chapter 2.1.1.1 --- Hypertension, Coronary Heart Disease & Stoke --- p.8 / Chapter 2.1.1.2 --- Diabetes --- p.10 / Chapter 2.1.1.3 --- Chronic Obstructive Pulmonary Disease --- p.11 / Chapter 2.1.1.4 --- Cognitive Function --- p.12 / Chapter 2.1.1.5 --- Depression --- p.13 / Chapter 2.2 --- THE RELATIONSHIP BETWEEN PA & HEALTH --- p.15 / Chapter 2.2.1 --- Participation in PA --- p.22 / Chapter 2.2.1.1 --- PA Recommendation --- p.24 / Chapter 2.2.2 --- Indirect Estimation ofPA Participation --- p.25 / Chapter 2.2.2.1 --- Physical Activity Scale for Elderly. --- p.26 / Chapter 2.3. --- PHYSICAL FITNESS & HEALTH. --- p.28 / Chapter 2.3.1 --- Definition of Physical Fitness. --- p.28 / Chapter 2.3.1.1 --- Cardiorespiratory Fitness --- p.30 / Chapter 2.3.2 --- Direct Assessment of Physical Fitness --- p.33 / Chapter 2.3.2.1 --- Cardiopulmonary Exercise Test --- p.33 / Chapter 2.3.2.1.1 --- Affordable Device for CPET --- p.35 / Chapter 2.3.2.2 --- Six Minutes Walk Test --- p.36 / Chapter 3 --- MATERIALS & METHODS --- p.39 / Chapter 3.1 --- SUBJECTS --- p.39 / Chapter 3.1.1 --- Subjects Source --- p.39 / Chapter 3.1.1.1 --- The Osteoporetic Fractures in Men & Women Study --- p.39 / Chapter 3.1.1.2 --- Carotid Atherosclerosis Study --- p.40 / Chapter 3.1.2 --- Follow up Situation --- p.40 / Chapter 3.1.3 --- Ethical Consideration --- p.41 / Chapter 3.2 --- INSTRUMENTATION --- p.41 / Chapter 3.2.1 --- Questionnaire --- p.41 / Chapter 3.2.1.1 --- Medical History --- p.41 / Chapter 3.2.1.2 --- Smoking Habit --- p.41 / Chapter 3.2.1.3 --- Cognitive & Mental Health --- p.42 / Chapter 3.2.1.3.1 --- Cantonese Mini Mental State Examination & Community Screening Instrument for Dementia --- p.42 / Chapter 3.2.1.3.2 --- Geriatric Depression Scale-15 --- p.42 / Chapter 3.2.1.4 --- Physical Activity Scale for Elderly --- p.43 / Chapter 3.2.1.5 --- Veteran Specific Activity Questionnaire --- p.44 / Chapter 3.2.2 --- Physical Measurements --- p.45 / Chapter 3.2.2.1 --- Height, Weight & Fat Percentage --- p.45 / Chapter 3.2.2.2 --- Waist, Hip Circumferences & WHR --- p.45 / Chapter 3.2.2.3 --- Blood Pressure --- p.45 / Chapter 3.2.2.4 --- Electrocardiograph --- p.46 / Chapter 3.2.3. --- Fitness Tests --- p.46 / Chapter 3.2.3.1 --- Cardiopuhuonary Exercise Test --- p.46 / Chapter 3.2.3.1.1 --- Exclusion Criteria --- p.46 / Chapter 3.2.3.1.2 --- PreTest Consideration --- p.47 / Chapter 3.2.3.1.3 --- Test Sequence & Measures --- p.48 / Chapter 3.2.3.1.4 --- Test Tennination Criteria --- p.49 / Chapter 3.2.3.2 --- Six Minutes Walk Test --- p.50 / Chapter 3.2.3.2.1 --- Six Minute Walk Test Sequence --- p.50 / Chapter 3.3 --- STATISTICS --- p.52 / Chapter 3.3.1 --- Description of Variables --- p.52 / Chapter 3.3.2 --- General Statistical Method --- p.53 / Chapter 3.3.3 --- Comparison between VO₂ peak & 6MWD Relationship with other Variables --- p.54 / Chapter 4 --- RESULTS --- p.56 / Chapter 4.1 --- RESPONSE & PARTICIPATION OF SUBJECTS --- p.56 / Chapter 4.2 --- DEMOGRAPHIC PROPERTIES --- p.63 / Chapter 4.2.1 --- Men --- p.63 / Chapter 4.2.2 --- Women --- p.68 / Chapter 4.2.3 --- Sample Representativeness --- p.71 / Chapter 4.2.4 --- Physical Measurements --- p.75 / Chapter 4.2.4.1 --- Peak Oxygen Uptake --- p.75 / Chapter 4.2.4.2 --- Correlations with Demographic Properties --- p.82 / Chapter 4.2.4.2.1 --- Mean VO₂ peak in Different WC Status --- p.83 / Chapter 4.2.4.2.2 --- Reference Range across Age Groups 98 --- p.84 / Chapter 4.2.4.2.3 --- Mllltivariat Analysis of VO₂ peak --- p.86 / Chapter 4.2.4.3 --- Six Minutes Walk Test --- p.88 / Chapter 4.2.4.3.1 --- UnivariateAnalysis with Demographic Properties --- p.90 / Chapter 4.2.4.3.2 --- Mean 6MWD by WC Status --- p.92 / Chapter 4.2.4.3.3 --- Reference Range by Age Groups --- p.92 / Chapter 4.2.4.3.4 --- Multivariate analysis of 6MWD --- p.94 / Chapter 4.2.5 --- Physical Activity Scale for Elderly --- p.96 / Chapter 4.2.5.1 --- Univariate Analysis with Demographic Properties --- p.97 / Chapter 4.2.5.2 --- Reference Range across Age Groups --- p.98 / Chapter 4.2.5.3 --- Reference Range of PASE --- p.99 / Chapter 4.2.5.4 --- Multivariate Analysis of PASE --- p.100 / Chapter 4.2.6 --- Cognitive & Mental Scores --- p.101 / Chapter 4.2.6.1 --- Community Screening Instrument for Dementia --- p.101 / Chapter 4.2.6.2 --- Mini-Mental State Examination --- p.102 / Chapter 4.2.6.3 --- Geriatric Depression Scale-15 --- p.103 / Chapter 4.3 --- CORRELATIONS OF CRF TESTS --- p.104 / Chapter 4.3.1.1 --- Relationship between 6MWD & VO₂ peak --- p.104 / Chapter 4.3.1.1.1 --- Pearson Correlation between 6MWD & VO₂ peak --- p.104 / Chapter 4.4 --- CRF & LIFESTYLES --- p.106 / Chapter 4.4.1 --- How PA correlates with CRF --- p.107 / Chapter 4.4.1.1 --- Relationship between PASE& VO₂ Peak --- p.107 / Chapter 4.4.1.1.1 --- Pearson Correlation between PASE & V02 peak. --- p.107 / Chapter 4.4.1.1.2 --- Mean VO₂ peak by Quartiles of PASE --- p.109 / Chapter 4.4.1.1.3 --- Mean PASE scores by VO₂ peak status --- p.110 / Chapter 4.4.1.1.4 --- Relationship between PASE leisure activities & VO₂ peak --- p.111 / Chapter 4.4.1.1.5 --- Time spent daily on PASE leisure activities by VO₂ peak status --- p.113 / Chapter 4.4.1.2 --- Relationship between PASE & 6MWD --- p.116 / Chapter 4.4.1.2.1 --- Mean 6MWD by Quartiles of PASE --- p.118 / Chapter 4.4.2 --- Relationship between CRF & Recommended PA Guidelines --- p.119 / Chapter 4.4.2.1 --- ACSM Guidelines --- p.119 / Chapter 4.4.2.2 --- HKDH Guidelines --- p.121 / Chapter 4.4.3 --- Does PASE in the Past Predict Present Maximal Oxygen Uptake --- p.122 / Chapter 4.4.3.1 --- Pearson Correlation between PASE at 3y before & Present VO₂ peak --- p.122 / Chapter 4.4.3.2 --- Pearson Correlation between PASE at 7y before & Present VO₂ peak --- p.124 / Chapter 4.5 --- CRF & HEALTH --- p.126 / Chapter 4.5.1 --- CRF & Physical Health --- p.126 / Chapter 4.5.1.1 --- Relationship between VO₂ peak & Medical History --- p.126 / Chapter 4.5.1.2 --- Relationship between 6MWD and medical history --- p.129 / Chapter 4.5.1.2.1 --- Mean 6MWD of men by chronic diseases --- p.130 / Chapter 4.5.1.2.2 --- Mean 6MWD of women by diabetes --- p.134 / Chapter 4.5.1.3 --- Comparison between VO₂ peak & 6MWD relationship with medical history --- p.135 / Chapter 4.5.2 --- CRF & Cognitive Function --- p.137 / Chapter 4.5.2.1 --- Relationship between MMSE& VO₂ Peak --- p.137 / Chapter 4.5.2.1.1 --- Pearson Correlation betweenMMSE & VO₂ peak --- p.137 / Chapter 4.5.2.1.2 --- Mean VO₂ peak by MMSE Status --- p.139 / Chapter 4.5.2.2 --- Relationship between MMSE & 6MWD --- p.141 / Chapter 4.5.2.2.1. --- Pearson Correlation between MMSE & 6MWD --- p.141 / Chapter 4.5.2.2.2 --- Mean 6MWD by MMSE category --- p.143 / Chapter 4.5.2.3 --- Relationship between CSID & VO₂ peak --- p.144 / Chapter 4.5.2.3.1 --- Pearson Correlation between CSID & VO₂ peak --- p.144 / Chapter 4.5.2.3.2 --- Mean VO₂ peak by CSID Classification --- p.146 / Chapter 4.5.2.4 --- Relationship between CSID & 6MWD --- p.147 / Chapter 4.5.2.4.1 --- Pearson Correlation between CSID & 6MWD --- p.147 / Chapter 4.5.2.4.2 --- Mean 6MWD by CSID Classification --- p.149 / Chapter 4.5.2.5 --- Comparison between VO₂ peak & 6MWD relationship with Cognitive Function --- p.150 / Chapter 4.5.2.5.1 --- Pearson Correlation between MMSE & 6MWD --- p.151 / Chapter 4.5.2.5.2 --- Mean 6MWD by MMSE category --- p.151 / Chapter 4.5.2.5.3 --- Pearson Correlation between CSID & 6MWD --- p.152 / Chapter 4.5.2.5.4 --- Mean 6MWD by CSID Classification --- p.153 / Chapter 4.5.3 --- CRF & Depression --- p.154 / Chapter 4.5.3.1 --- Relationship between GDS & VO₂ peak --- p.154 / Chapter 4.5.3.1.1 --- Speannan Correlation between GDS & VO₂ peak --- p.154 / Chapter 4.5.3.1.2 --- Logistic Regression Analysis --- p.154 / Chapter 4.5.3.2. --- Relationship between GDS & 6MWD --- p.156 / Chapter 4.5.3.2.1. --- Spearman Correlation between GDS & 6MWD --- p.156 / Chapter 4.5.3.2.2. --- Mean 6MWD by depression status. --- p.156 / Chapter 4.5.3.3. --- Comparison between VO₂ peak & 6MWD relationship with GDS --- p.158 / Chapter 4.5.3.3.1. --- Pears on Correlation between GDS & 6MWD --- p.158 / Chapter 4.5.3.3.2. --- Mean 6MWD by depression status --- p.158 / Chapter 5 --- DISCUSSION --- p.160 / Chapter 5.1 --- INTERPRETATION OF RESULTS --- p.160 / Chapter 5.1.1 --- Physical Fitness --- p.160 / Chapter 5.1.1.1 --- Cardiorespiratory Fitness --- p.160 / Chapter 5.1.1.1.1 --- Mode for CPET --- p.160 / Chapter 5.1.1.1.2 --- Criteria for VO₂ peak --- p.161 / Chapter 5.1.1.1.3 --- Reference Range of VO₂ peak among HK elderly --- p.164 / Chapter 5.1.1.1.4 --- Age Related Decline in VO₂ peak --- p.169 / Chapter 5.1.1.1.5 --- Repeatability of Measurements using FitMate[superscript TM] Pro --- p.170 / Chapter 5.1.1.1.6 --- Smoking --- p.170 / Chapter 5.1.1.2 --- Six Minutes Walk Test --- p.171 / Chapter 5.1.1.2.1 --- Reference Range of 6MWD among HK Elderly --- p.172 / Chapter 5.1.2 --- How Estimated PA Level Correlated to CRF --- p.173 / Chapter 5.1.2.1 --- CRF &PA --- p.174 / Chapter 5.1.2.2 --- CRF & Leisure Activities --- p.176 / Chapter 5.1.3 --- Elderly CRF of those who met Recommended PA Guidelines --- p.177 / Chapter 5.1.4 --- Could Past PA Participation Predict Present CRF --- p.180 / Chapter 5.1.5 --- Health --- p.181 / Chapter 5.1.5.1 --- Physical Health --- p.181 / Chapter 5.1.5.2 --- Dementia --- p.185 / Chapter 5.1.5.2.1 --- Community Screening Instrument for Dementia --- p.186 / Chapter 5.1.5.2.2 --- Mini-Mental State Examination --- p.188 / Chapter 5.1.5.2.3 --- Possible Mechanisms of Cognitive Decline & Benefits ofPA --- p.191 / Chapter 5.1.5.3. --- Depression --- p.193 / Chapter 5.1.5.3.1 --- Possible Mechanism of Depression & Benefits of PA --- p.197 / Chapter 5.1.6 --- 6MWD, a Better Physical Fitness Surrogate than VO₂ peak --- p.200 / Chapter 5.2 --- LIMITATIONS AND STRENGTH --- p.205 / Chapter 5.3 --- FUTURE STUDIES --- p.210 / Chapter 6 --- CONCLUSION --- p.211 / Chapter 7 --- REFERENCES --- p.215 / APPENDIX --- p.238

Introdução: Distrofia muscular progressiva nas formas de Duchenne (DMD) e Becker (DMB) são doenças caracterizadas por progressiva degeneração musculoesquelética e substituição por tecido fibrogorduroso. O envolvimento cardíaco está presente em 80% dos pacientes, apresenta curso clínico silencioso e é diagnosticado tardiamente pelos métodos tradicionais. Objetivos: 1. Investigar a progressão da fibrose miocárdica pela ressonância magnética cardíaca (RMC), em ensaio clínico randomizado para tratamento ou não com IECA, de pacientes com DMD e DMB e fração de ejeção ventricular esquerda (FEVE) preservada, por um período de 02 anos. 2. Investigar se há mutações genéticas específicas que sejam preditoras do acometimento miocárdico diagnosticado pela RMC. 3. Comparar os achados do ECG, radiografia de tórax e ecocardiograma com os da RMC. Métodos: Entre 1/6/2009 e 1/6/2012 foram incluídos 76 pacientes com diagnóstico de DMD e DMB. Todos os pacientes realizaram duas RMCs com intervalo médio de 2,05±0,11 anos, com técnicas de cine ressonância para avaliação da função ventricular e realce tardio miocárdico para avaliação da fibrose miocárdica. A fibrose miocárdica foi quantificada por software específico para obtenção do percentual da massa de fibrose do VE com análise semi automática, utilizando os desvios padrões da média dos valores de intensidade do sinal do miocárdio normal. Os valores acima de 5 desvios padrões da média do miocárdio normal foram considerados como fibrose miocárdica. Os 42 pacientes com fibrose miocárdica e FEVE normal foram randomizado em 2 grupos, com 21 deles recebendo tratamento com IECA e 21 sem qualquer tratamento para cardiomiopatia. Após 2 anos, novas RMCs foram realizadas para avaliar a evolução da fibrose e a FEVE. Resultados: Notou-se fibrose miocárdica em 72,3% dos pacientes, sendo que 55,6 % não apresentavam disfunção sistólica. Verificou-se uma correlação positiva significativa entre idade e percentual de fibrose na RMC basal (r=0,338, p=0,014) e seguimento (r=0,315, p=0,006). Os pacientes randomizados e tratados com IECA apresentaram menor evolução do percentual de fibrose do que os randomizados não tratados (3,1±7,4% versus 10,0±6,2% respectivamente, p=0,001). Na análise linear multivariada, verificamos que pertencer ao grupo tratado diminui a progressão do percentual de fibrose (y=-4,51x+29,63 ajustado por idade, CK e percentual de fibrose basal, p=0,039) e indica uma tendência de menor probabilidade de apresentar fração de ejeção do VE < 50% na RMC seguimento (OR= 3,18, p= 0,102, por regressão logística). Os pacientes com mutação nos exons menores que 45 do gene da distrofina apresentaram maior percentual de fibrose que os com mutação dos exons maiores ou iguais ao 45 na RMC basal (27,9±18,4% versus 12,1±13,4%, respectivamente, p=0,006) e seguimento (33,1±21,1% versus 18,8±16,9%, respectivamente, p=0,024). A avaliação conjunta por métodos tradicionais (radiografia de tórax, ECG e ecocardiografia) apresentou baixa sensibilidade de 47,3% e valor preditivo negativo de 34,1% para o diagnóstico do envolvimento cardíaco na DMD e DMB, em pacientes com FEVE normal e fibrose miocárdica na RMC. Conclusões: O ensaio clínico randomizado, por um período de 2 anos, em pacientes com DMD e DMB, com fibrose miocárdica diagnosticada pela RMC e FEVE preservada, demonstrou significativa maior progressão da fibrose miocárdica nos pacientes que não fizerem uso de IECA. Existe uma correlação significativa entre o local de mutação no gene da distrofina e o acometimento cardíaco. O ECG, o eco e radiografia de tórax apresentaram baixa sensibilidade e baixo valor preditivo negativo para detecção do envolvimento cardíaco precoce nos pacientes com DMD e DMB / Introduction: Duchenne and Becker muscular dystrophies (DMD and BMD) are diseases characterized by progressive skeletal muscle degeneration and replacement by fibro fatty tissue. Cardiac involvement is frequent, as high as 70 - 80% of patients, and often develops clinically silent, without any evident early clinical signs. Traditional diagnostic methods (ECG, chest x-ray and echocardiography) are only able to diagnose cardiac involvement at a later stage. Objectives: 1. To investigate the progression of myocardial fibrosis by cardiac magnetic resonance (CMR), in a randomized clinical trial for treatment with ACE inhibitors, in patients with DMD or BMD and preserved left ventricular ejection fraction (LVEF), for a period of 02 years. 2. To investigate whether there are specific genetic mutations that are predictive of myocardial involvement detected by CMR. 3. To compare the findings of ECG, chest radiography and echocardiography with those found by CMR. Methods: Between 01/06/2009 and 01/06/2012 76 patients with DMD and BMD were included. All patients underwent two CMRs with a mean interval of 2.05±0.11 years, using cine resonance for function evaluation and myocardial delayed enhancement technique for myocardial fibrosis detection. Myocardial fibrosis was quantified by specific software for obtaining fibrosis mass, as percentage of LV mass, using semi-automatic fibrosis analysis and standard deviations of the mean values of signal intensity of the normal myocardium. A value of five standard deviations above the mean of a normal myocardium were considered myocardial fibrosis. The 42 patients with myocardial fibrosis and normal LVEF were randomized into 2 groups, with 21 of them receiving ACE inhibitor treatment and 21 no treatment for cardiomyopathy. After 2 years, new CMRs were performed to evaluate fibrosis extent and LVEF. Results: Myocardial fibrosis was noted in 72.3% of the patients, 55.6% showed no systolic dysfunction. There was a significant positive correlation between age and myocardial fibrosis at the CMR baseline (r=0.338, p=0.014) and follow-up (r=0.315, p=0.006). Patients randomized and treated with ACE inhibitors had lower evolution of myocardial fibrosis than those who were randomized and untreated (3.1±7.4% vs.10.0±6.2%, respectively, p=0.001). Using multivariate regression analysis, we found that belonging to the treated group decreases the progression of myocardial fibrosis (y=-4.51x+29.63 adjusted for age, CK and baseline myocardial fibrosis, p=0.039) and indicated a trend for lower probability of presenting LVEF<50% at follow-up CMR (OR= 3.18, p= 0.102, by logistic regression). Patients with mutations in exons less than 45 had greater extent of myocardial fibrosis than patients with mutations in exons greater than or equal to 45 in CMR at baseline (27.9±18.4% vs. 12.1±13.4%, respectively, p=0.006) and at follow-up (33.1±21.1% vs. 18.8±16.9%, respectively, p=0.024). Conclusions: In this 2-year follow-up randomized clinical trial in patients with DMD and BMD with preserved LVEF, myocardial fibrosis diagnosed by CMR, showed significantly greater progression in patients not receiving ACE inhibitors therapy. There was a significant correlation between the site of mutation in the dystrophin gene and cardiac involvement. ECG, echocardiography and chest radiography showed low sensitivity and low negative predictive value for early detection of cardiac involvement (myocardial fibrosis by CMR) in patients with DMD and BMD

A perda da permeabilidade seletiva de membrana celular causada pela isquemia leva ao acúmulo de sódio e edema miocárdico. Este fenômeno tem implicações importantes na estrutura e função do ventrículo esquerdo, nas primeiras horas após infarto do miocárdio. Objetivou-se investigar a hipótese de que, durante as primeiras horas após oclusão coronária prolongada e restabelecimento de fluxo completo, a taxa de acúmulo de sódio miocárdico é determinado pela integridade da microvasculatura. Utilizou-se imagem de ressonância magnética do sódio-23 em 3 dimensões, para monitorizar as alterações do conteúdo de sódio miocárdico no tempo, em um modelo canino in vivo e com tórax fechado (n = 19) de infarto do miocárdio e reperfusão. Seis animais apresentaram fibrilação ventricular durante a oclusão ou imediatamente após reperfusão coronária, não completando o protocolo. Em quatro experimentos não se detectou nenhuma área de infarto, por nenhum dos métodos utilizados. Um animal foi submetido a oclusão coronária permanente. Os oito animais restantes constituíram o grupo de infartos reperfundidos. Destes, infartos com obstrução microvascular (n = 4), detectados por microesfera radioativa e por imagem por ressonância magnética do hidrogênio realçada com contraste, mostraram uma taxa menor de acúmulo de sódio, assim como um menor fluxo sangüíneo 20 minutos e 6 horas após reperfusão. A ausência de obstrução microvascular nos infartos (n = 4) esteve associada a taxas maiores de acúmulo do sódio e maior restabelecimento do fluxo sangüíneo miocárdico. Além disso, o tamanho do infarto por imagem por ressonância magnética do sódio-23 apresentou boa correlação com o tamanho do infarto pela anatomopatologia (cloreto de trifeniltetrazólio ou TTC) e pela imagem de ressonância do hidrogênio realçada por contraste (hiperintensificação ou realce tardio) 9 horas após reperfusão. Conclui-se que, em infartos do miocárdio reperfundidos, o acúmulo de sódio é dependente da integridade microvascular e está diminuído em regiões de obstrução microvascular, comparado com regiões miocárdicas com microvasculatura patente. A imagem por ressonância do sódio-23 pode ser um instrumento útil para a monitorização in vivo do conteúdo do sódio no infarto agudo do miocárdio. / Loss of membrane permeability caused by ischemia leads to cellular sodium accumulation and myocardial edema. This phenomenon has important implications to left ventricular structure and function in the first hours after myocardial infarction. We hypothesized that during this period of time, after prolonged coronary occlusion and complete reflow, the rate of myocardial sodium accumulation is governed by microvascular integrity. We used 3-dimensional 23 Na magnetic resonance imaging to monitor myocardial sodium content changes over time in an in vivo closed-chest canine model (n = 19) of myocardial infarction and reperfusion. Six animals had ventricular fibrillation during occlusion or immediately after coronary reperfusion, and did not finish the protocol. Myocardial infarction was not detected in four experiments, by any of utilized methods. In one experiment, we produced permanent coronary occlusion. The remaining eight animals constituted the reperfused myocardial infarction group. From those, infarcts with microvascular obstruction n = 4) defined by both radioactive microsphere and contrast-enhanced 1 H magnetic resonance imaging showed a slower rate of sodium accumulation as well as lower blood flow at 20 minutes and 6 hours after reperfusion. Conversely, the absence of microvascular obstruction (n = 4) was associated with faster rates of sodium accumulation and greater blood flow restoration. In addition, infarct size by 23 Na magnetic resonance imaging correlated best with infarct size by triphenyltetrazolium chloride and contrast-enhanced 1 H magnetic resonance imaging at 9 hours after reperfusion. We conclude that in reperfused myocardial infarction, sodium accumulation is dependent on microvascular integrity and is slower in regions of microvascular obstruction compared with those with patent microvasculature. Finally, 23 Na magnetic resonance imaging can be a useful tool for monitoring in vivo myocardial sodium content in acute myocardial infarction.