Duchenne Muscular Dystrophy

The objective of the study was to determine if low intensity, high frequency vibration training impacted the musculoskeletal system in a mouse model of Duchenne muscular dystrophy, relative to healthy mice. Three-week old wildtype (n = 26) and mdx mice (n = 22) were randomized to non-vibrated or vibrated (45 Hz and 0.6 g, 15 min/d, 5 d/wk) groups. In vivo and ex vivo contractile function of the anterior crural and extensor digitorum longus muscles, respectively, were assessed following 8 wks of vibration. Mdx mice were injected 5 and 1 days prior to sacrifice with Calcein and Xylenol, respectively. Muscles were prepared for histological and triglyceride analyses and subcutaneous and visceral fat pads were excised and weighed. Tibial bones were dissected and analyzed by micro-computed tomography for trabecular morphometry at the metaphysis, and cortical geometry and density at the mid-diaphysis. Three-point bending tests were used to assess cortical bone mechanical properties and a subset of tibiae was processed for dynamic histomorphometry. Vibration training for 8 wks did not alter trabecular morphometry, dynamic histomorphometry, cortical geometry, or mechanical properties (P$ 0.34). Vibration did not alter any measure of muscle contractile function (P$0.12); however the preservation of muscle function and morphology in mdx mice indicates vibration is not deleterious to muscle lacking dystrophin. Vibrated mice had smaller subcutaneous fat pads (P = 0.03) and higher intramuscular triglyceride concentrations (P = 0.03). These data suggest that vibration training at 45 Hz and 0.6 g did not significantly impact the tibial bone and the surrounding musculature, but may influence fat distribution in mice.

We studied the results in 46 patients with neuromuscular and neurogenic scoliosis (average age 13.5 years, range 6-19 years) who had had posterior fusion with a modified Luque technique between May 1985 and June 1992. The main criteria to recommend surgery were curve progression, loss of balance when sitting, control of the head and difficulties in wearing an external orthotic support. The mean preoperative curve was 63 ~ , the postoperative value was 24 ~ representing a correction of about 62%. The average number of stabilized segments was 13. In 39 out of 46 patients, lumbosacral fixation was included in the construct. Failure of implants, pseudarthroses and major losses of correction in purely neuromuscular scolioses could be avoided by using rigid segmental fixation and a dorsolateral fusion with a mixture of autologous and allogenous bone. The scoliosis most difficult to influence was found to be Friedreich's ataxia. In Duchenne muscular dystrophy the best method of treatment was surgery performed as early as possible, i.e. at the time of loss of walking capacity in the case of a scoliosis exceeding 20 ~ and with two consecutive X-rays proving curve progression. Analysis of our series does not confirm the morbidity and complication rates of previous studies.

Early signs of gait deviation in Duchenne muscular dystrophy Results. Spatial and temporal parameters showed significant differences between the two groups: cadence was increased and step length was decreased significantly in the DMD group. We found a significant increase in the range of anterior-posterior pelvic tilt and in pelvic rotation. In the frontal plane there was a tendency for an increased pelvic obliquity. Dynamic range of motion in sagittal plane showed a significant difference at the ankle, with an increased plantarflexion in swing in the dystrophic patients. Maximum dorsiflexion was reduced in the DMD group. Kinetic analysis showed significant differences in power generation and absorption at the hip joint and at the ankle joint. At knee there was a reduced flexor moment in mid-stance. Ankle showed a reduced dorsiflexor moment in terminal stance and pre-swing with a consequent reduction in the peakto-peak excursion. Conclusion and clinical rehabilitation impact. It was shown that instrumented gait analysis, being more sensitive than other clinical and functional assessment methods, allowed to quantify the very early modifications characterizing locomotion worsening in the first stage of the DMD.

Duchenne muscular dystrophy is a devastating neuromuscular disease caused by lack of the protein, dystrophin, in skeletal muscle and heart, although the biochemical mechanism by which dystrophin loss causes muscle dysfunction is unknown. Here we show that the dystrophin-deficient mdx mouse and a mouse lacking both dystrophin and the dystrophin-related protein, utrophin (dko), have abnormal electrocardiograms (ECGs). In skeletal muscle, dystrophin is normally associated with neuronal nitric oxide synthase (nNOS) at the sarcolemma. Consequently, we have measured NOS isoform activities in hearts from control, mdx and dko mice. In control mouse hearts, eNOS and nNOS activities increased by 120% and 47%, respectively, between 2 and 6 months of age. In mdx mice, myocardial nNOS activity was decreased by 60%, 84% and 80% at 2, 6 and 12 months of age, respectively. Similarly, hearts from dko mice showed a 65% decrease in nNOS activity compared to controls at 2 months of age. Endothelial NOS (eNOS) activity was not affected by dystrophin loss, but inducible NOS (iNOS) activity was seven-fold higher than control in the mdx mouse heart by 12 months of age. We conclude that lack of dystrophin in the mdx mouse results in abnormal ECGs that are associated with decreased myocardial nNOS and increased iNOS activities.

Proper assessment of disabilities is essential for rehabilitation of patients with Duchenne muscular dystrophy. The aim of this study was to identify and quantify the disabilities in children with Duchenne muscular dystrophy and correlate them with impairment. Thirty-one patients with Duchenne muscular dystrophy of age four years and above were studied. The motor functions were evaluated using total motor score, upper and lower extremity function grades and timed function tests. Disability was quanti ed with Barthel index. The mean scores of motor scales were: total motor score ¡52 § 7.8, total functional grade ¡4.4 § 1.9 and timed function score ¡12.5 § 5.8. Barthel index scores ranged from 45-95 with a mean of 70.8 § 12.7. Motor scales correlated with each other and with Barthel index. Thirty children had disabilities in multiple spheres of life, which were signi cantly in uenced by the motor power. Barthel index was useful in identifying and quantifying speci c areas of disabilities in these children. Evaluation of disabilities using speci c measures may be crucial for planning comprehensive management.

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene (Hoffman et al. 1987), which controls the expression of dystrophin. This protein, normally localized beneath the sarcolemma in normal muscle, is absent in muscle from DMD patients (Bonilla et al. 1988). DMD is also characterized by an abnormally high concentration of intracellular ionized calcium (Bodensteiner & Engel, 1978), which is thought to contribute to the final muscle necrosis. This resting calcium accumulation in DMD cells was also observed in

Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD. The main recommendations: 1) genetic testing in diagnostic suspicious cases should be the first line for diagnostic confirmation; 2) patients diagnosed with DMD should have steroids prescribed; 3) lack of published results for phase 3 clinical trials hinders, for now, the recommendation to use exon skipping or read-through agents. RESUMO Avanços na compreensão e no manejo da distrofia muscular de Duchenne (DMD) ocorreram desde a publicação de diretrizes internacionais em 2010. Nosso objetivo foi elaborar um consenso nacional baseado em evidências de cuidado multidisciplinar dos pacientes com DMD no Brasil. Utilizamos a técnica de Delphi combinada com revisão sistemática da literatura de 2010 a 2016 classificando níveis de evidência e graus de recomendação. Nossas recomendações foram divididas em duas partes. Apresentamos aqui a parte 1, descrevendo a metodologia utilizada e conceitos gerais da doença, e fornecemos recomendações sobre diagnóstico, tratamento com corticosteroides e novas perspectivas de tratamentos medicamentosos. As principais recomendações: 1) testes genéticos deveriam ser a primeira linha para confirmação de casos suspeitos; 2) pacientes com diagnóstico de DMD devem receber corticosteroides; 3) por enquanto, a falta de publicações de resultados dos ensaios clínicos de fase 3, dificulta recomendações de uso medicamentos que "saltam exons" ou "passam" por código de parada prematura.

We present a family with dystrophinopathy in whom the proband is a female aged 4.5 years, who presented with exertional muscle pain without weakness. Familial analysis identified a maternal nephew of the proband who demonstrated a similar clinical picture, with asymptomatic cardiomyopathy. A DNA analysis revealed an in-frame deletion in the proximal part of domain II of the dystrophin gene. Extensive familial analysis indicated that the asymptomatic maternal grandfather transmitted the deletion. This is the first report of a young female patient with exertional muscle pain as the only early presenting symptom of dystrophinopathy.

Genetically engineered mice (Myf5 nLacZ/؉ , Myf5 GFP-P/؉ ) allowing direct muscle satellite cell (SC) visualization indicate that, in addition to being located beneath myofiber basal laminae, SCs are strikingly close to capillaries. After GFP ؉ bone marrow transplantation, blood-borne cells occupying SC niches previously depleted by irradiation were similarly detected near vessels, thereby corroborating the anatomical stability of juxtavascular SC niches. Bromodeoxyuridine pulse-chase experiments also localize quiescent and less quiescent SCs near vessels. SCs, and to a lesser extent myonuclei, were nonrandomly associated with capillaries in humans. Significantly, they were correlated with capillarization of myofibers, regardless to their type, in normal muscle. They also varied in paradigmatic physiological and pathological situations associated with variations of capillary density, including amyopathic dermatomyositis, a unique condition in which muscle capillary loss occurs without myofiber damage, and in athletes in whom capillaries increase in number. Endothelial cell (EC) cultures specifically enhanced SC growth, through IGF-1, HGF, bFGF, PDGF-BB, and VEGF, and, accordingly, cycling SCs remained mainly juxtavascular. Conversely, differentiating myogenic cells were both proangiogenic in vitro and spatiotemporally associated with neoangiogenesis in muscular dystrophy. Thus, SCs are largely juxtavascular and reciprocally interact with ECs during differentiation to support angio-myogenesis.

Duchenne muscular dystrophy (DMD) is the most frequent muscle disorder in childhood. There are no data on the epidemiology of muscular dystrophy in Estonia and the other Baltic States. The present study assessed the incidence and prevalence of DMD in Estonia. A descriptive epidemiological study of DMD was carried out in children born and diagnosed between 1977 and 1999 in Estonia. Patients were identified using four different approaches. DMD was considered present in children with features that corresponded to the criteria established by the European Neuromuscular Centre. 20 incidence cases and 25 prevalence cases of definite DMD were identified. We found a DMD incidence rate of 11.91 £ 10 25 (95% CI; 7.28 -18.4) live born males from 1977 to 1990. The point prevalence rate of DMD was 12.76 £ 10 25 (95% CI; 8.26-18.84) of the under-20 male population as of January 1, 1998. The incidence and prevalence estimates in this report were in the range of similar studies from other countries. A muscle biopsy database and a neuromuscular disorders database were launched with this study. Considering the course of the disease, the prevalence should be estimated on the basis of the total male population ,20 years of age.

Background Several treatments are on the horizon for Duchenne muscular dystrophy (DMD), a terminal orphan disease. In many jurisdictions, decisions regarding pricing and reimbursement of these health technologies comprise evidence of value for money. Objective The objective of this study was to develop a cost-effectiveness model based on the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT), a new rating scale created specifically to measure disease progression in clinical practice and trials and model DMD in economic evaluations, and compare it with two alternative model structures. Methods We constructed three Markov cohort state-transition models to evaluate the cost-effectiveness of a hypothetical intervention for DMD versus standard of care in a UK setting. Model I was based on the DMDSAT, model II on stages of disease as defined in the DMD clinical care guidelines and model III on patients' ventilation status. The conceptual model structures were formulated in collaboration with three DMD experts. Results All three models were judged to have good validity with regards to the appropriateness of the choice of modelling technique, conceptual representation of the disease, model input data and model outcomes. Across frameworks, lifetime direct medical costs with standard of care ranged between £217,510 and £284,640, total costs between £624,240 and £713,840, and total number of quality-adjusted life-years between 5.96 and 7.17. Conclusions We present a first version of a model for the economic evaluation of treatments for DMD based on the DMDSAT, as well as two alternative frameworks encompassing conventional staging of disease progression. Our findings should be helpful to inform health technology assessments and health economic programmes of future treatments for DMD. Key Points for Decision Makers Duchenne muscular dystrophy (DMD) is an orphan disease associated with a substantial burden on affected patients, family caregivers and society. The Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT) is a new patient-reported outcome scale designed to measure disease progression in DMD. We present a cost-effectiveness model framework based on the DMDSAT simulating patients across the entire lifetime of disease.

BACKGROUND: Duchenne muscular dystrophy (DMD) is severe X-linked recessive congenital muscular dystrophy and the most common type of muscular dystrophy. Long-term corticosteroid therapy (LTCT) (started from the age of 4 years) is the most accessible and used pharmacological therapy of DMD in Romania. Several studies showed that "ASEA® redox supplement" (ARS) (which was approved as a dietary supplement in UE) is a very potent selective NRF2 activator, thus a very potent (indirect) antioxidant, with no toxicity up to high doses (in contrast with LTCT). PURPOSE: This research aims at discovering dietary supplements which may show comparable or even stronger beneficial effects (with less or none adverse effects) than LTCT in children with DMD whose parents refuse LTCT. METHODS: Three boy-patients with DMD (of ~4, ~5 and ~3 years of age) (whose parents refused LTCT) were treated with relatively high doses of ARS 3-7 ml/kg/day (usually combined with medium doses of L-carnitine and omega-3 fatty acids for various intellectual disabilities of two patients): periodic consults and rhabdomyolysis, medular and liver toxicity markers assessment (blood count, GGT, ASAT, ALAT, LDH, CK, CK-MB and serum myoglobin) were accomplished. RESULTS: From the first months of ARS-based treatment, all the rhabdomyolysis markers (with very high initial serum levels) dropped significantly, with no found medular/hepatic toxicity in all these three tested DMD children. CONCLUSIONS: (1) ARS appears to have remarkable antioxidant and immunomodulatory effects (strong NRF2 selective activation and NF-kB inhibition) and should be studied on larger groups of children with DMD under the age of 4 years old (but also on other age groups of children and even young adults), as an alternative to early corticosteroids; (2) ARS may also deserve future cohort studies as an adjuvant in many types of acute/chronic infectious/ non-infectious pulmonary/cardiac/renal/hepatic/ articular/skin autoimmune (and even malignant diseases) that imply high levels of tissular oxidative stress.
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Chronic pain in children is drawing increasing attention from families, clinicians, and researchers. Its prevalence is conservatively estimated at 15% to 20% of the pediatric population [1]. There remains, however, a paucity of published research on chronic pain in children with neuromuscular disease (NMD) . Neuromuscular disorders constitute a diverse spectrum of conditions that anatomically span the nerve (motor, sensory, or autonomic) and its supporting structures, the neuromuscular junction, and muscledskeletal, smooth, and cardiac. Encompassed are a wide variety of clinical entities including anterior horn cell disorders, neuropathies, neuromuscular junction disorders, and myopathies and muscular dystrophies. Our understanding of chronic pain in this group of disorders is strikingly limited. Gaps in our knowledge include the nature and scope of the associated pain (its frequency, intensity, and quality); areas of the body most affected; the impact of pain on function and quality of life; and pain treatments and their effectiveness.

Background "Use it or lose it" is a well known saying which is applicable to boys with Duchenne Muscular Dystrophy (DMD). Besides the direct effects of the muscular dystrophy, the increasing effort to perform activities, the fear of falling and the use of personal aids indirectly impair leg and arm functions as a result of disuse. Physical training could oppose this secondary physical deterioration. The No Use is Disuse (NUD) study is the first study in human subjects with DMD that will examine whether a low-intensity physical training is beneficial in terms of preservation of muscle endurance and functional abilities. The study consists of two training intervention studies: study 1 "Dynamic leg and arm training for ambulant and recently wheelchair-dependent boys with DMD and, study 2 "Functional training with arm support for boys with DMD who have been confined to a wheelchair for several years". This paper describes the hypotheses and methods of the NUD study. Methods Study 1 is an explorative randomized controlled trial with multiple baseline measurements. Thirty boys with a DNA-established diagnosis of DMD will be included. The intervention consists of a six-months physical training during which boys train their legs and arms with active and/or assisted cycling training equipment. The primary study outcomes are muscle endurance and functional abilities, assessed with a Six-Minute Bicycle Test and the Motor Function Measure. Study 2 has a within-group repeated measurements design and will include ten boys with DMD who have already been confined to a wheelchair for several years. The six-months physical training program consists of 1) a computer-assisted training and 2) a functional training with an arm support. The primary study outcome is functional abilities of the upper extremity, assessed with the Action Research Arm Test. Discussion The NUD study will fill part of the gap in the current knowledge about the possible effects of training in boys with DMD and will increase insight into what type of exercise should be recommended to boys with DMD. The study will finish at the end of 2010 and results are expected in 2011. Trial registration The Netherlands National Trial Register1631

Corticosteroid treatment is considered the 'gold standard' for Duchenne muscular dystrophy (DMD); however, it is also known to induce osteoporosis and thus increase the risk of vertebral fragility fractures. Good practice in the care of those with DMD requires prevention of these adverse effects. Treatments to increase bone mineral density include bisphosphonates and vitamin D and calcium supplements, and in adolescents with pubertal delay, testosterone. Bone health management is an important part of lifelong care for patients with DMD. To assess the effects of interventions to prevent or treat osteoporosis in children and adults with DMD taking long-term corticosteroids; to assess the effects of these interventions on the frequency of vertebral fragility fractures and long-bone fractures, and on quality of life; and to assess adverse events. On 12 September 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL Plus to identi...

The progress of science is punctuated by the advent of revolutionary technologies that provide new ways and scales to formulate scientific questions and advance knowledge. Following on from electron microscopy, cell culture and PCR, nextgeneration sequencing is one of these methodologies that is now changing the way that we understand viruses, particularly in the areas of genome sequencing, evolution, ecology, discovery and transcriptomics. Possibilities for these methodologies are only limited by our scientific imagination and, to some extent, by their cost, which has restricted their use to relatively small numbers of samples. Challenges remain, including the storage and analysis of the large amounts of data generated. As the chemistries employed mature, costs will decrease. In addition, improved methods for analysis will become available, opening yet further applications in virology including routine diagnostic work on individuals, and new understanding of the interaction between viral and host transcriptomes. An exciting era of viral exploration has begun, and will set us new challenges to understand the role of newly discovered viral diversity in both disease and health.

Early mortality in Duchenne muscular dystrophy (DMD) is related to cardiac and respiratory complications. A phase IIa double-blind randomized placebo-controlled clinical trial was conducted to investigate the tolerability and efficacy of idebenone therapy in children with DMD. Twenty-one DMD patients (aged 8-16 years) were randomly assigned to daily treatment with 450 mg idebenone (Catena®) (n=13) or placebo (n=8) for 12 months. All subjects completed the study and idebenone was safe and well tolerated. Idebenone treatment resulted in a trend (p=0.067) to increase peak systolic radial strain in the left ventricular inferolateral wall, the region of the heart that is earliest and most severely affected in DMD. A significant respiratory treatment effect on peak expiratory flow was observed (p=0.039 for PEF and p=0.042 for PEF percent predicted). Limitations of this study were the small sample size, and a skewed age distribution between treatment groups. Data from this study provided t...

Duchenne muscular dystrophy (DMD) is a genetic condition affecting predominantly boys that is characterized by fatal muscle weakness. While there is no cure, recent therapeutic advances have extended the lifespan of those with DMD considerably. Although the physiological basis of muscle pathology is welldocumented, less is known regarding the cognitive, behavioral, and psychosocial functioning of those afflicted. Several lines of evidence point to central nervous system involvement as an organic feature of DMD, challenging our view of the disorder as strictly neuromuscular. This report provides a review of the literature on neuropsychological and neurobehavioral functioning in DMD. Recent research identifying associations with DMD and neuropsychiatric disorders is also discussed. Lastly, the review presents implications of findings related to nonmotor aspects of DMD for improving the quality of life in those affected. While the literature is often contradictory in nature, this review highlights some key findings for consideration by clinicians, educators and parents when developing therapeutic interventions for this population.

Introduction: For late-or non-ambulant children with a neuromuscular disorder no suitable endurance tests are currently available. We developed the assisted 6-minute cycling test (A6MCT) for the legs and arms and investigated its psychometric properties in healthy boys and boys with Duchenne muscular dystrophy (DMD). Methods: Ninety-nine healthy boys and 30 boys with DMD (12 wheelchair-dependent) performed the A6MCT. Seventy healthy boys also performed the 6-minute walk test (6MWT), and 23 boys performed the A6MCT twice within 2 weeks. Boys with DMD also performed the Motor Function Measure (MFM). Results: The A6MCT was feasible for >90% of all boys. Boys with DMD achieved fewer cycling revolutions than controls. The A6MCT was positively correlated with the 6MWT and was reproducible in healthy boys, and it correlated with disease severity in boys with DMD. Conclusions: The A6MCT is a promising outcome measure for the follow-up of non-ambulant children with a neuromuscular disorder.

Interest in muscle MRI has been largely stimulated in the last few years by the recognition of an increasing number of genetic defects in the field of inherited neuromuscular disorders. Muscle ultrasound (US) and computed tomography (CT) have been used to detect the presence of muscle involvement in patients affected by these disorders, but until recently the use of muscle MRI has been, with a few exceptions, limited to detecting inflammatory forms. The aim of this review is to illustrate how muscle MRI, in combination with clinical evaluation, can contribute to the selection of appropriate genetic tests and more generally in the differential diagnosis of genetically distinct forms of neuromuscular disorders. Possible future applications of muscle MRI are also discussed.

The aim of this study was to investigate the suitability of the North Star Ambulatory Assessment as a possible outcome measure in multicentric clinical trials. More specifically we wished to investigate the level of training needed for achieving a good interobserver reliability in a multicentric setting.

Muscular dystrophies (MD) are a heterogeneous group of inherited neuromuscular disorders characterized by muscle necrosis and progressive muscle weakness. It is important for oral healthcare providers to be familiar with MD as special considerations are necessary to provide appropriate and safe dental care for these medically complex patients. This article briefly reviews the more common types of MD, namely, Duchenne MD, Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, limb-girdle MD, oculopharyngeal MD, and myotonic dystrophy. Aspects of their epidemiology, pathophysiology, clinical presentation, diagnosis, and medical management as well as oral health considerations are discussed.

Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, involves severe muscle degeneration, inflammation, fibrosis, and early death in afflicted boys. Matrix metalloproteinases (MMPs) are extracellular proteases that cause tissue degradation in several disease states. In this study, we tested the hypothesis that the expression levels of various MMPs are abnormally increased and that their inhibition will ameliorate muscle pathogenesis in animal models of DMD. Our results show that the transcript levels of several MMPs are significantly upregulated, whereas tissue inhibitors of MMPs are down-regulated, in dystrophic muscle of mdx mice. Chronic administration of batimastat (BB-94), a broad spectrum peptide inhibitor of MMPs, reduced necrosis, infiltration of macrophages, centronucleated fibers, and the expression of embryonic myosin heavy chain in skeletal muscle of mdx mice. Batimastat also reduced the expression of several inflammatory molecules and augmented the levels of sarcolemmal protein ␤-dystroglycan and neuronal nitric oxide in mdx mice. In addition, muscle force production in isometric contraction was increased in batimastat-treated mdx mice compared with those treated with vehicle alone. Furthermore, inhibition of MMPs using batimastat reduced the activation of mitogen-activated protein kinases and activator protein-1 in myofibers of mdx mice. Our study provides the novel evidence that the expression of MMPs is atypically increased in DMD , that their inhibition ameliorates pathogenesis , and that batimastat could prove to be a significant candidate for DMD therapy.

The present study describes the use of simple video games for a 5-week regimen of respiratory muscle training in 15 patients with Duchenne muscular dystrophy (DMD) at various stages of the disease. The games were re-arranged to be operated and driven by the respiratory efforts of the patient and to incorporate accurate ventilation and time measurements. Improvement in respiratory performance was determined by maximum voluntary ventilation (MVV), maximal achieved ventilation (VEmax) during a progressive isocapnic hyperventilation manoeuvre (PIHV) and the PIHV duration. The actual training period was 23 +/- 4 days (mean +/- S.D.) at ventilatory effort of 46 +/- 6% MVV, for 10 +/- 3 min day-1. Patients with moderate impairment of lung function tests (LFT) showed an improvement in MVV, VEmax, and duration of PIHV of 12 +/- 7% (p < 0.02), 53 +/- 25% (p < 0.001) 57 +/- 21% (p < 0.01), respectively. Improvements correlated with actual training time and ventilation level, %MVV, but negatively correlated with years of immobilization and with the initial MVV. We conclude that computerized respiratory games may be applied for breathing exercises and may improve respiratory performance in recently immobilized children with DMD who have moderate impairment of LFT.

Measurements of muscle strength in clinical trials of Duchenne muscular dystrophy have relied heavily on manual muscle testing (MMT). The high level of intra- and interrater variability of MMT compromises clinical study results. We compared the reliability of 12 clinical evaluators in performing MMT and quantitative muscle testing (QMT) on 12 children with muscular dystrophy. QMT was reliable, with an interclass correlation coefficient (ICC) of >0.9 for biceps and grip strength, and >0.8 for quadriceps strength. Training of both subjects and evaluators was easily accomplished. MMT was not as reliable, and required repeated training of evaluators to bring all groups to an ICC >0.75 for shoulder abduction, elbow and hip flexion, knee extension, and ankle dorsiflexion. We conclude that QMT shows greater reliability and is easier to implement than MMT. Consequently, QMT will be a superior measure of strength for use in pediatric, neuromuscular, multicenter clinical trials. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 787–793, 2001.

Originally prenatal diagnosis was confined to the diagnosis of metabolic disorders and depended on assaying enzyme levels in amniotic fluid. With the development of recombinant DNA technology, molecular diagnosis became possible for some genetic conditions late in the 1970s. Here we briefly review the history of molecular prenatal diagnostic testing, using Duchenne muscular dystrophy as an example, and describe how over the last 30 years we have moved from offering testing to a few affected individuals using techniques, such as Southern blotting to identify deletions, to more rapid and accurate PCR-based testing which identifies the precise change in dystrophin for a greater number of families. We discuss the potential for safer, earlier prenatal genetic diagnosis using cell free fetal DNA in maternal blood before concluding by speculating on how more recent techniques, such as next generation sequencing, might further impact on the potential for molecular prenatal testing. Progress is not without its challenges, and as cytogenetics and molecular genetics begin to unite into one, we foresee the main challenge will not be in identifying the genetic change, but rather in interpreting its significance, particularly in the prenatal setting where we frequently have no phenotype on which to base interpretation.

The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45-47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-α increases microRNA levels in vitro whereas NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression.

Background: Progressive movement limitation in patients with Duchenne's muscular dystrophy (DMD) may mask the onset of cardiac involvement. We aimed to determine whether myocardial performance index (MPI), either by conventional Doppler (CD) or ...

Mutations of the dystrophin DMD gene, essentially deletions of one or several exons, are the cause of two devastating and to date incurable diseases, Duchenne (DMD) and Becker (BMD) muscular dystrophies. Depending upon the preservation or not of the reading frame, dystrophin is completely absent in DMD, or present in either a mutated or a truncated form in BMD. DMD is a severe disease which leads to a premature death of the patients. Therapy approaches are evolving with the aim to transform the severe DMD in the BMD form of the disease by restoring the expression of a mutated or truncated dystrophin. These therapies are based on the assumption that BMD is a mild disease. However, this is not completely true as BMD patients are more or less severely affected and no molecular basis of this heterogeneity of the BMD form of the disease is yet understood. The aim of this review is to report for the correlation between dystrophin structures in BMD deletions in view of this heterogeneity and to emphasize that examining BMD patients in details is highly relevant to anticipate for DMD therapy effects.

Introduction: Prophylactic implantation of a cardioverter/ defibrillator (ICD) has been shown to reduce mortality in patients with chronic myocardial infarction (CMI) and an increased risk for life threatening ventricular arrhythmia (VA). The use of ICDs in this large patient population is still limited by high costs and possible adverse events including inappropriate discharges and progression of heart failure. VA is related to infarct size and seems to be related to infarct morphology. Contrast enhanced cardiovascular magnetic resonance imaging (ceCMR) can detect and quantify myocardial fibrosis in the setting of CMI and might therefore be a valuable tool for a more accurate risk stratification in this setting. Hypothesis: ceCMR can identify the subgroup developing VA in patients with prophylactic ICD implantation following MADIT criteria. Methods: We prospectively enrolled 52 patients (49 males, age 69 ± 10 years) with CMI and clinical indication for ICD therapy following MADIT criteria. Prior to implantation (36 ± 78 days) patients were investigated on a 1.5 T clinical scanner (Siemens Avanto © , Germany) to assess left ventricular function (LVEF), LV end-diastolic volume (LVEDV) and LV mass (sequence parameters: GRE SSFP, matrix 256 × 192, short axis stack; full LV coverage, no gap; slice thickness 6 mm). For quantitative assessment of infarct morphology late gadolinium enhancement (LGE) was performed including measurement of total and relative infarct mass (related to LV mass) and the degree of transmurality (DT) as defined by the percentage of transmurality in each scar. (sequence parameters: inversion recovery gradient echo; matrix 256 × 148, imaging 10 min after 0.2 μg/kg gadolinium DTPA; slice orientation equal to SSFP). MRI images were analysed using dedicated software (MASS © , Medis,