Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

Deflazacort for the treatment of Duchenne Dystrophy: A systematic review

BACKGROUND: To complete a systematic review and meta-analysis based on the clinical question: Is Deflazacort (DFZ), a prednisolone derivative, an effective therapy for improving strength, with acceptable side effects, in children with Duchenne Dystrophy (DD)? METHODS: MEDLINE, EMBASE, Current Contents, Dissertation Abstracts, Health Star, PsychINFO and Cochrane, were searched using the following inclusion criteria: 1) A randomized controlled trial comparing DFZ with placebo or another therapy; 2) Male participants age 2–18 years with DD; 3) Outcomes of (a) any form of strength or functional testing, or (b) any form of side effect. RESULTS: Fifteen studies of potential relevance were identified, with five meeting the inclusion criteria. These five studies included 291 children and were published in English language journals between 1994 and 2000. Two studies compared DFZ versus placebo, two studies compared DFZ with prednisone and one study had both placebo and prednisone comparisions. Two large trials were identified that have not been published in article format. Due to the heterogeneity in outcome measures and the inconsistent reporting of summary statistics a meta-analytic approach could not be taken. CONCLUSIONS: Examining individual studies it appears that DFZ improves strength and functional outcomes compared to placebo, but it remains unclear if it has a benefit over prednisone on similar outcomes. Two trials found that DFZ causes less weight gain than prednisone

Clinical Heterogeneity of Duchenne Muscular Dystrophy (DMD): Definition of Sub-Phenotypes and Predictive Criteria by Long-Term Follow-Up

International audienceBACKGROUND: To explore clinical heterogeneity of Duchenne muscular dystrophy (DMD), viewed as a major obstacle to the interpretation of therapeutic trials METHODOLOGY/PRINCIPAL FINDINGS: A retrospective single institution long-term follow-up study was carried out in DMD patients with both complete lack of muscle dystrophin and genotyping. An exploratory series (series 1) was used to assess phenotypic heterogeneity and to identify early criteria predicting future outcome; it included 75 consecutive steroid-free patients, longitudinally evaluated for motor, respiratory, cardiac and cognitive functions (median follow-up: 10.5 yrs). A validation series (series 2) was used to test robustness of the selected predictive criteria; it included 34 more routinely evaluated patients (age>12 yrs). Multivariate analysis of series 1 classified 70/75 patients into 4 clusters with distinctive intellectual and motor outcomes: A (early infantile DMD, 20%): severe intellectual and motor outcomes; B (classical DMD, 28%): intermediate intellectual and poor motor outcome; C (moderate pure motor DMD, 22%): normal intelligence and delayed motor impairment; and D (severe pure motor DMD, 30%): normal intelligence and poor motor outcome. Group A patients had the most severe respiratory and cardiac involvement. Frequency of mutations upstream to exon 30 increased from group A to D, but genotype/phenotype correlations were restricted to cognition (IQ>71: OR 7.7, 95%CI 1.6-20.4, p6 at 8 yrs" with "normal or borderline mental status" reliably assigned patients to group C (sensitivity: 1, specificity: 0.94). These criteria were also predictive of "early infantile DMD" and "moderate pure motor DMD" in series 2. CONCLUSIONS/SIGNIFICANCE: DMD can be divided into 4 sub-phenotypes differing by severity of muscle and brain dysfunction. Simple early criteria can be used to include patients with similar outcomes in future therapeutic trials

Aconitase B Is Required for Optimal Growth of Xanthomonas campestris pv. vesicatoria in Pepper Plants

The aerobic plant pathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv) colonizes the intercellular spaces of pepper and tomato. One enzyme that might contribute to the successful proliferation of Xcv in the host is the iron-sulfur protein aconitase, which catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle and might also sense reactive oxygen species (ROS) and changes in cellular iron levels. Xcv contains three putative aconitases, two of which, acnA and acnB, are encoded by a single chromosomal locus. The focus of this study is aconitase B (AcnB). acnB is co-transcribed with two genes, XCV1925 and XCV1926, encoding putative nucleic acid-binding proteins. In vitro growth of acnB mutants was like wild type, whereas in planta growth and symptom formation in pepper plants were impaired. While acnA, XCV1925 or XCV1926 mutants showed a wild-type phenotype with respect to bacterial growth and in planta symptom formation, proliferation of the acnB mutant in susceptible pepper plants was significantly impaired. Furthermore, the deletion of acnB led to reduced HR induction in resistant pepper plants and an increased susceptibility to the superoxide-generating compound menadione. As AcnB complemented the growth deficiency of an Escherichia coli aconitase mutant, it is likely to be an active aconitase. We therefore propose that optimal growth and survival of Xcv in pepper plants depends on AcnB, which might be required for the utilization of citrate as carbon source and could also help protect the bacterium against oxidative stress

Individuals with chronic low back pain have greater difficulty in engaging in positive lifestyle behaviours than those without back pain: An assessment of health literacy

Background: Despite the large volume of research dedicated to understanding chronic low back pain (CLBP), patient outcomes remain modest while healthcare costs continue to rise, creating a major public health burden. Health literacy - the ability to seek, understand and utilise health information - has been identified as an important factor in the course of other chronic conditions and may be important in the aetiology of CLBP. Many of the currently available health literacy measurement tools are limited since they measure narrow aspects of health literacy. The Health Literacy Measurement Scale (HeLMS) was developed recently to measure broader elements of health literacy. The aim of this study was to measure broad elements of health literacy among individuals with CLBP and without LBP using the HeLMS.Methods: Thirty-six community-dwelling adults with CLBP and 44 with no history of LBP responded to the HeLMS. Individuals were recruited as part of a larger community-based spinal health study in Western Australia. Scores for the eight domains of the HeLMS as well as individual item responses were compared between the groups.Results: HeLMS scores were similar between individuals with and without CLBP for seven of the eight health literacy domains (p &gt; 0.05). However, compared to individuals with no history of LBP, those with CLBP had a significantly lower score in the domain &lsquo;Patient attitudes towards their health&rsquo; (mean difference [95% CI]: 0.46 [0.11- 0.82]) and significantly lower scores for each of the individual items within this domain (p &lt; 0.05). Moderate effect sizes ranged from d = 0.47-0.65.Conclusions: Although no differences were identified in HeLMS scores between the groups for seven of the health literacy domains, adults with CLBP reported greater difficulty in engaging in general positive health behaviours. This aspect of health literacy suggests that self-management support initiatives may benefit individuals with CLBP.<br /

Physical training in boys with Duchenne Muscular Dystrophy: the protocol of the No Use is Disuse study

Contains fulltext : 89740.pdf (publisher's version ) (Open Access)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

Relationship between muscle strength and motor function in Duchenne muscular dystrophy

ABSTRACT Measuring muscle strength and motor function is part of Duchenne muscular dystrophy (DMD) assessment. However, the relationship between these variables is controversial. Objective To investigate the relationship between muscle strength and motor function and between these variables and age. Method Muscle strength was measured by Medical Research Council (MRC) scale and motor function, by Motor Function Measure (MFM), in 40 non-ambulatory patients. Spearman tests investigated the relationships between muscle strength, motor function and age. Results Total MRC and MFM scores were strongly related to each other (r = 0.94; p 0.05). Strong and moderate relationships between partial muscle strength and motor function scores were found. Higher correlation coefficients were found between total scores and Dimensions 2 (axial/ proximal control) and 3 (distal control) of MFM. Conclusion Muscle strength and motor function are strongly correlated and seem to decrease proportionally in DMD

Collaborative translational research leading to multicenter clinical trials in Duchenne muscular dystrophy: the Cooperative International Neuromuscular Research Group (CINRG)

Progress in the development of rationally based therapies for Duchenne muscular dystrophy has been accelerated by encouraging multidisciplinary, multi-institutional collaboration between basic science and clinical investigators in the Cooperative International Research Group. We combined existing research efforts in pathophysiology by a gene expression profiling laboratory with the efforts of animal facilities capable of conducting high-throughput drug screening and toxicity testing to identify safe and effective drug compounds that target different parts of the pathophysiologic cascade in a genome-wide drug discovery approach. Simultaneously, we developed a clinical trial coordinating center and an international network of collaborating physicians and clinics where those drugs could be tested in large-scale clinical trials. We hope that by bringing together investigators at these facilities and providing the infrastructure to support their research, we can rapidly move new bench discoveries through animal model screening and into therapeutic testing in humans in a safe, timely and cost-effective setting