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1.  Pentoxifylline as a rescue treatment for DMD 
Neurology  2012;78(12):904-913.
To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD).
This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (∼20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test.
A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs.
The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period.
Classification of evidence:
This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.
PMCID: PMC3306159  PMID: 22402864
2.  Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy 
Neurology  2011;77(5):444-452.
To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD).
A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months.
Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone.
Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens.
Classification of evidence:
This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.
PMCID: PMC3146308  PMID: 21753160
3.  Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy 
Neurology  2012;79(2):159-162.
To test the effect of the single nucleotide polymorphism −66 T>G (rs28357094) in the osteopontin gene (SPP1) on functional measures over 12 months in Duchenne muscular dystrophy (DMD).
This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the North Star Ambulatory Assessment (NSAA) and the 6-Minute Walk Test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups.
Eighty patients were selected (age 4.1–19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA (p = 0.013) and 6MWT (p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values.
These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.
PMCID: PMC3390537  PMID: 22744661
4.  CINRG Pilot trial of Coenzyme Q10 in steroid treated Duchenne Muscular Dystrophy 
Muscle & nerve  2011;44(2):174-178.
Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin deficient muscle.
We performed an open label, “add-on” pilot study of CoQ10 in thirteen 5–10 year old DMD patients on steroids. The primary outcome measure was the total Quantitative Muscle Testing (QMT) score.
Twelve of 16 children (mean age 8.03±1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 μg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in 8.5 % increase in muscle strength (p=0.03).
This pilot study found the addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD.
PMCID: PMC3136634  PMID: 21698649
Duchenne muscular dystrophy; CoQ10; steroids; muscle strength testing; clinical trial
5.  24 Month Longitudinal Data in Ambulant Boys with Duchenne Muscular Dystrophy 
PLoS ONE  2013;8(1):e52512.
The aim of the study was i) to assess the spectrum of changes over 24 months in ambulant boys affected by Duchenne muscular dystrophy, ii) to establish the difference between the first and the second year results and iii) to identify possible early markers of loss of ambulation.
One hundred and thirteen patients (age range 4.1–17, mean 8.2) fulfilled the inclusion criteria, 67 of the 113 were on daily and 40 on intermittent steroids, while 6 were not on steroids. All were assessed using the 6 Minute Walk Test (6MWT), the North Star Ambulatory Assessment (NSAA) and timed test.
On the 6MWT there was an average overall decline of −22.7 (SD 81.0) in the first year and of −64.7 (SD 123.1) in the second year. On the NSAA the average overall decline was of −1.86 (SD 4.21) in the first year and of −2.98 (SD 5.19) in the second year. Fourteen children lost ambulation, one in the first year and the other 13 in the second year of the study. A distance of at least 330 meters on the 6MWT, or a NSAA score of 18 at baseline reduced significantly the risk of losing ambulation within 2 years.
These results can be of help at the time of using inclusion criteria for a study in ambulant patients in order to minimize the risk of patients who may lose ambulation within the time of the trial.
PMCID: PMC3543414  PMID: 23326337
6.  Percent-Predicted 6-Minute Walk Distance in Duchenne Muscular Dystrophy to Account for Maturational Influences 
PLoS Currents  2012;4:RRN1297.
We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter.
PMCID: PMC3269886  PMID: 22306689
7.  Percent-Predicted 6-Minute Walk Distance in Duchenne Muscular Dystrophy to Account for Maturational Influences 
PLoS Currents  2012;4:RRN1297.
We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter.
PMCID: PMC3269886  PMID: 22306689
8.  Being ambulatory does not secure respiratory functions of Duchenne patients 
The aim of this work was to assess the respiratory functions of ambulatory Duchenne patients and to propose an earlier time period for intervention.
Materials and Methods:
Lung functions and North Star Ambulatory Assessment (NSAA) scores of Duchenne patients were evaluated simultaneously.
Thirty ambulatory Duchenne patients were included in this study. NSAA scores of the patients were directly correlated with arm abduction, arm adduction, and shoulder flexion strengths. Forced expiratory volume in 1 second percent predicted and forced vital capacity (FVC) percent predicted correlated inversely to age and to the NSAA score. Twelve of 13 patients with FVC values lower than 80% of predicted had NSAA scores below 24 points. None of the patients who were younger than 7 years had FVC values lower than 80% of predicted.
Annual spirometry is necessary for Duchenne patients older than 6 years regardless of the ambulatory status.
PMCID: PMC3200040  PMID: 22028530
Duchenne muscular dystrophy; north star ambulatory assessment; respiratory functions
9.  A suspended act: increased reflectivity and gender-dependent electrophysiological change following Quadrato Motor Training 
Quadrato Motor Training (QMT) is a specifically-structured walking meditation, aimed at improving reflectivity and lowering habitual thought and movement. Here we set out to examine the possible effect of QMT on reflectivity, employing the Hidden Figures Test (HFT), which assesses both spatial performance (measured by correct answers) as well as reflectivity (interpolated from correct answers and reaction time). In the first study (n = 24, only females), we showed that QMT significantly improves HFT performance, compared to two groups, controlling for cognitive or motor aspects of the QMT: Verbal Training (identical cognitive training with verbal response) and Simple Motor Training (similar motor training with reduced choice requirements). These results show that QMT improves HFT performance above the pre-post expected learning. In the second study, building on previous literature showing gender-dependent effects on cognitive performance, we conducted a preliminary pilot examining gender-dependent effect of training on reflectivity and its electrophysiological counterparts. EEG analyses focused on theta, alpha and gamma coherence. HFT performance and resting-state EEG were measured in 37 participants (20 males), using a within-subject pre-post design. Following training, HFT performance improved in both genders. However, we found a gender-dependent difference in functional connectivity: while theta and alpha intra-hemispheric coherence was enhanced in females, the opposite pattern was found in males. These results are discussed in relation to neuronal efficiency theory. Together, the results demonstrate that QMT improves spatial performance, and may involve a gender-dependent electrophysiological effect. This study emphasizes both the importance of studying gender-related training effects within the contemplative neuroscience endeavor, as well as the need to widen its scope toward including “contemplation in action.”
PMCID: PMC3909823  PMID: 24550872
motor training; reflectivity; spatial cognition; EEG coherence; gender
10.  Relationships of thigh muscle contractile and non-contractile tissue with function, strength, and age in boys with Duchenne muscular dystrophy 
Neuromuscular Disorders  2011;22(1):16-25.
The purpose of this study was to assess the contractile and non-contractile content in thigh muscles of patients with Duchenne muscular dystrophy (DMD) and determine the relationship with functional abilities. Magnetic resonance images of the thigh were acquired in 28 boys with DMD and 10 unaffected boys. Muscle strength, timed functional tests, and the Brookes Lower Extremity scale were also assessed. Non-contractile content in the DMD group was significantly greater than in the control group for six muscles, including rectus femoris, biceps femoris-long head and adductor magnus. Non-contractile content in the total thigh musculature assessed by MRI correlated with the Brookes scale (rs=0.75) and supine-up test (rs=0.68), as well as other functional measures. An age-related specific torque increase was observed in the control group (rs=0.96), but not the DMD (rs=0.06). These findings demonstrate that MRI measures of contractile and non-contractile content can provide important information about disease progression in DMD.
PMCID: PMC3215817  PMID: 21807516
Duchenne muscular dystrophy; muscle strength; magnetic resonance imaging
11.  Optimized Inversion Recovery Sequences for Quantitative T1 and Magnetization Transfer Imaging 
Inversion recovery sequences that vary the inversion time (ti) have been employed to determine T1 and, more recently, quantitative magnetization transfer (qMT) parameters. Specifically, in previous work, the inversion recovery pulse sequences varied ti only, while maintaining a constant delay (td) between repetitions. T1 values were determined by fitting to an exponential function, and qMT parameters were then determined by fitting to a bi-exponential function with an approximate solution. In the current study, new protocols are employed, which vary both ti and td and fit the data with minimal approximations. Cramer-Rao lower bounds (CRLB) are calculated to search for acquisition schemes that will maximize the precision efficiencies of T1 and qMT parameters. This approach is supported by Monte Carlo simulations. Measurements on MnCl2 samples verified the optimal T1 schemes. The optimal qMT schemes are confirmed by measurements on a series of cross linked bovine serum albumin (BSA) phantoms of varying concentrations. The effects of varying the number of sampling data points are also explored, and a rapid acquisition scheme is demonstrated in vivo. These new optimized quantitative imaging methods provide an improved means for determining T1 and MT parameter values compared to previous inversion recovery based methods.
PMCID: PMC2943213  PMID: 20665793
Quantitative magnetization transfer; T1 measurement; Inversion recovery; Bi-exponential recovery; Optimal acquisition scheme; Precision efficiency
12.  6 Minute Walk Test in Duchenne MD Patients with Different Mutations: 12 Month Changes 
PLoS ONE  2014;9(1):e83400.
In the last few years some of the therapeutical approaches for Duchenne muscular dystrophy (DMD) are specifically targeting distinct groups of mutations, such as deletions eligible for skipping of individual exons. The aim of this observational study was to establish whether patients with distinct groups of mutations have different profiles of changes on the 6 minute walk test (6MWT) over a 12 month period.
The 6MWT was performed in 191 ambulant DMD boys at baseline and 12 months later. The results were analysed using a test for heterogeneity in order to establish possible differences among different types of mutations (deletions, duplications, point mutations) and among subgroups of deletions eligible to skip individual exons.
At baseline the 6MWD ranged between 180 and 560,80 metres (mean 378,06, SD 74,13). The 12 month changes ranged between −325 and 175 (mean −10.8 meters, SD 69.2). Although boys with duplications had better results than those with the other types of mutations, the difference was not significant.
Similarly, boys eligible for skipping of the exon 44 had better baseline results and less drastic changes than those eligible for skipping exon 45 or 53, but the difference was not significant.
even if there are some differences among subgroups, the mean 12 month changes in each subgroup were all within a narrow Range: from the mean of the whole DMD cohort. This information will be of help at the time of designing clinical trials with small numbers of eligible patients.
PMCID: PMC3885414  PMID: 24421885
13.  Utility of Cystatin C to monitor renal function in Duchenne muscular dystrophy 
Muscle & nerve  2009;40(3):438-442.
Creatinine as a marker of renal function has limited value in Duchenne muscular dystrophy (DMD) because of reduced muscle mass. Alternative methods of assessing renal function are sorely needed. Cystatin C, a nonglycosylated protein unaffected by muscle mass, is potentially an ideal biomarker of nephrotoxicity for this population but requires validation.
75 subjects were recruited: 35 DMD (mean age 10.8 ± 5.4 years, corticosteroids n = 19, ambulatory n = 26), 29 healthy controls, 10 with renal disease, and one DMD with renal failure.
Cystatin C levels in DMD were normal irrespective of age, ambulation or corticosteroid treatment. Serum cystatin C was 0.67 ± 0.11 mg/L compared to normal controls 0.69 ± 0.09. mg/L. In these same individuals serum creatinine was severely reduced (0.27 ± 0.12 mg/dL) versus normals (0.75 ± 0.15 mg/dL, p < 0.01). In one DMD subject in renal failure, cystatin C was elevated.
This study demonstrates the potential value of cystatin C as a biomarker for monitoring renal function in DMD. Its applicability extends to other neuromuscular diseases.
PMCID: PMC2740988  PMID: 19623638
Duchenne muscular dystrophy; Cystatin C; serum creatinine; biomarker; renal function
14.  Physical training in boys with Duchenne Muscular Dystrophy: the protocol of the No Use is Disuse study 
BMC Pediatrics  2010;10:55.
"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.
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.
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
PMCID: PMC2929216  PMID: 20691042
15.  Lack of Functional Benefit with Glutamine versus Placebo in Duchenne Muscular Dystrophy: A Randomized Crossover Trial 
PLoS ONE  2009;4(5):e5448.
Oral glutamine decreases whole body protein breakdown in Duchenne muscular dystrophy (DMD). We evaluated the functional benefit of 4 months oral glutamine in DMD.
Methodology/Principal Findings
30 ambulant DMD boys were included in this double-blind, randomized crossover trial with 2 intervention periods: glutamine (0.5 g/kg/d) and placebo, 4 months each, separated by a 1-month wash-out, at 3 outpatient clinical investigation centers in France. Functional benefit was tested by comparing glutamine versus placebo on change in walking speed at 4 months. Secondary outcome measures were: 2-minute walk test, work, power, muscle mass (urinary creatinine), markers of myofibrillar protein breakdown (urinary 3-methyl-histidine/creatinine), serum creatine phospho-kinase, body composition (fat free mass, fat mass percentage), safety and oral nutrient intake. There was no improvement in the primary end point (walking speed) or in secondary measures of muscle function (2-minute walk test, work, power) in the glutamine group compared with placebo. However, subjects receiving glutamine or placebo showed no deterioration in functional measures over the course of the 9-month trial. No differences in muscle mass, markers of protein breakdown or serum creatine phosho-kinase were observed, except for a blunted increase in fat free mass in the glutamine group which led to a greater increase in fat mass percentage. Glutamine was safe and well-tolerated.
This trial did not identify additional benefit of 4 months oral glutamine over placebo on muscle mass or function in ambulatory DMD boys. Although apparently safe, current data cannot support routine supplementation in this population as a whole, until further research proves otherwise.
Trial Registration NCT00296621
PMCID: PMC2673684  PMID: 19421321
16.  Participation and quality of life in children with Duchenne muscular dystrophy using the International Classification of Functioning, Disability, and Health 
Duchenne muscular dystrophy (DMD) is characterized by muscle damage and progressive loss of muscle function in male children. DMD is one of the most devastating genetically linked neuromuscular diseases for which there is currently no cure. Most clinical studies for DMD utilize a standard protocol for measurement exploring pathophysiology, muscle strength and timed tasks. However, we propose that examining broader components of health as emphasized by the International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY) may be of great value to children and their families, and important outcomes for future clinical trials.
Fifty boys with DMD and 25 unaffected age-matched boys completed two self-report measures: the Children’s Assessment of Participation and Enjoyment and the Pediatric Quality of Life InventoryTM 4.0. We investigated differences between the two groups with regard to participation in life activities and perceived quality of life (QoL). Additionally, we compared participation in activities and QoL in both cohorts of younger and older boys.
Participation in physical activities was significantly lower in boys with DMD than unaffected boys. Perceived QoL was markedly diminished in children with DMD relative to unaffected controls, except in the emotional domain. The amount of time boys engage in an activity, as well as participation in social activities, declined for our older boys with DMD but no changes were observed for our older unaffected boys. For both groups, QoL remained constant over time.
The ICF-CY provides a conceptual framework and specific terminology that facilitates investigation of the consequences of impairment in children and youth. Our study is one of the first to explore participation in a cohort of boys with DMD. It was not surprising that activities of choice for boys with DMD were less physical in nature than unaffected boys their age, but the consequences of less social engagement as the boys with DMD age is of great concern. Results from our study underscore the need to further evaluate activities that children elect to participate in, with special emphasis on facilitators and barriers to participation and how participation changes throughout the course of a disease.
PMCID: PMC3358238  PMID: 22545870
Duchenne muscular dystrophy; ICF; Participation; Quality of life
17.  Quantitative magnetization transfer imaging of human brain at 7 T☆ 
NeuroImage  2012;64:640-649.
Quantitative magnetization transfer (qMT) imaging yields indices describing the interactions between free water protons and immobile macromolecular protons. These indices include the macromolecular to free pool size ratio (PSR), which has been shown to be correlated with myelin content in white matter. Because of the long scan times required for whole-brain imaging (≈20–30 min), qMT studies of the human brain have not found widespread application. Herein, we investigated whether the increased signal-to-noise ratio available at 7.0 T could be used to reduce qMT scan times. More specifically, we developed a selective inversion recovery (SIR) qMT imaging protocol with a i) novel transmit radiofrequency (B1+) and static field (B0) insensitive inversion pulse, ii) turbo field-echo readout, and iii) reduced TR. In vivo qMT data were obtained in the brains of healthy volunteers at 7.0 T using the resulting protocol (scan time≈40 s/slice, resolution=2×2×3 mm3). Reliability was also assessed in repeated acquisitions. The results of this study demonstrate that SIR qMT imaging can be reliably performed within the radiofrequency power restrictions present at 7.0 T, even in the presence of large B1+ and B0 inhomogeneities. Consistent with qMT studies at lower field strengths, the observed PSR values were higher in white matter (mean±SD=17.6±1.3%) relative to gray matter (10.3±1.6%) at 7.0 T. In addition, regional variations in PSR were observed in white matter. Together, these results suggest that qMT measurements are feasible at 7.0 T and may eventually allow for the high-resolution assessment of changes in composition throughout the normal and diseased human brain in vivo.
PMCID: PMC3625658  PMID: 22940589
Magnetization transfer; 7 T; White matter; Myelin; Brain; Multiple sclerosis
18.  The 6-Minute Walk Test and Person-Reported Outcomes in Boys with Duchenne Muscular Dystrophy and Typically Developing Controls: Longitudinal Comparisons and Clinically-Meaningful Changes Over One Year 
PLoS Currents  2013;
Introduction: Data is currently lacking anchoring a 30-meter longitudinal change in walking ability by 6-minute walk test (6MWT) in Duchenne muscular dystrophy as a minimal clinically important difference and “clinically meaningful” person-reported outcomes (PROs) at differing levels of ambulatory ability. Methods: We describe correlation between measures, 1-year change in measures, and correlation of 1-year changes between measures for the six-minute walk test (6MWT), 10-meter run/walk velocity, PedsQL and POSNA Pediatric Outcomes Data Collection Instrument (PODCI) in 24 4-12 year old. ambulatory DMD and 36 typical controls, and determine if minimal clinically important differences (MCID) of PROs contribute to different estimates of 6-minute walk distance (6MWD) change at differing levels of ability. Results: PedsQL total and physical function and PODCI global, transfer/mobility and sports/physical function PROs demonstrated significant differences between DMD and controls (p<0.00001). In DMD, 6MWD and 10-meter run/walk velocity were correlated with PODCI domain scores, with the transfer/mobility scale showing the strongest relationship (r=0.79 and r=0.76). In DMD, 6MWD distance and 10-meter run/walk velocity weakly correlated with PedsQL domain scores. In DMD, 6MWD, 10-meter run/walk velocity, and PODCI global and transfer and basic mobility demonstrated significant one-year change and exceeded the amount of change representing MCID. In DMD, 6MWD change highly correlated with change in PODCI global and PODCI transfer/mobility scores (r=0.76 and r=0.93). PODCI global and PODCI transfer/mobility scales provided the best estimates of 6MWT performance. A “meaningful” 4.5 point change in a low PODCI transfer / basic mobility score of 30 to 34.5 was associated with a 5.6m 6MWD change from 150.3 to 155.9m. At PODCI levels closer to normative levels for healthy controls, the change in 6MWD distance associated with a “meaningful” change in PODCI scores was almost 46m. Discussion: At lower levels of function, smaller increases in 6MWD result in meaningful change in quality of life (QoL) instrument scores. At higher levels of function, larger increases may be necessary to achieve the same QoL change score.
PMCID: PMC3712467  PMID: 23867975
19.  Autologous bone marrow mononuclear cell transplantation in Duchenne muscular dystrophy – a case report 
Patient: Male, 9
Final Diagnosis: Duchenne muscular dystrophy
Symptoms: Hyporeflexia • hypotonia • weaknes of lower limbs
Medication: —
Clinical Procedure: —
Specialty: Neurology
Congenital defects/diseases
Duchenne muscular dystrophy (DMD) is a fatal, genetic, progressive, degenerating muscle disorder. Current treatment options are palliative. Newer options of cellular therapy promise to alter the disease process. Preclinical studies have successfully tested myogenic, neurogenic potential and dystrophin expression of bone marrow mononuclear cells.
Case Report:
We treated a 9-year-old boy suffering from DMD with serial autologous bone marrow mononuclear cell transplantations followed by multidisciplinary rehabilitation. Brooke-Vignos score was 10 and he was wheelchair-bound. Over 36 months, gradual progressive improvement was noticed in muscle strength, ambulation with assistive devices, fine motor movements, Brooke-Vignos score, and functional independence measure score. Nine months after the transplantation, electromyography findings showed development of new normal motor unit potentials of the vastus medialis muscle.
Magnetic resonance imaging scan of musculoskeletal systems showed no increase in fatty infiltration. This case report provides early investigative findings or the restorative effects of cellular therapy in DMD.
PMCID: PMC3976215
Stem Cell Transplantation; Autologous Bone Marrow Mono Nuclear Cells; Electromyography; Muscular Dystrophy; Duchenne – congenital
20.  Liquid formulation of pentoxifylline is a poorly tolerated treatment for Duchenne dystrophy 
Muscle & nerve  2011;44(2):170-173.
To perform an open label, pilot study of an orally administered liquid formulation of immediate release pentoxifylline (PTX) to patients with Duchenne muscular dystrophy (DMD). Treatment efficacy, safety and tolerability were assessed.
The tolerability and safety of PTX, measures of muscle strength and function were evaluated during 12 months of treatment with PTX.
Seventeen boys with DMD, between 4 and 8 years, were enrolled at one of 5 Cooperative International Neuromuscular Research Group (CINRG) centers. Only 9 were able to complete the 12 month PTX treatment phase; the primary reasons for discontinuation were adverse events. Intolerable gastrointestinal side effects were experienced by 65% of participants. Two participants experienced severe leukopenia that resolved with medication withdrawal.
Open-label treatment with liquid formulation of immediate release PTX resulted in a high level of adverse event in boys with DMD. Poor tolerability of this PTX formulation precluded adequate assessment of efficacy.
PMCID: PMC3136640  PMID: 21674534
Duchenne; Muscular Dystrophy; Leukopenia; Pentoxifylline; Clinical Trial
21.  In-vivo multi-exponential T2, magnetization transfer and quantitative histology in a rat model of intramyelinic edema☆☆☆ 
NeuroImage : Clinical  2013;2:810-817.
Two MRI methods, multi-exponential analysis of transverse relaxation (MET2) and quantitative magnetization transfer (qMT), were used along with quantitative evaluation of histology in a study of intra-myelinic edema in rat spinal white matter. The results showed a strong linear correlation between a distinct long-T2 signal from MET2 analysis and the edema water volume fraction as measured by histology, although this analysis overestimated the edema water content by ≈ 100% relative to quantitative histological measurements. This overestimation was reasoned to result from the effects of inter-compartmental water exchange on observed transverse relaxation. Commonly studied MRI markers for myelin, the myelin water fraction (from MET2 analysis) and the macromolecular pool size ratio (from qMT analysis) produced results that could not be explained purely by changes in myelin content. The results demonstrate the potential for MET2 analysis as well as the limits of putative myelin markers for characterizing white matter abnormalities involving intra-myelinic edema.
•We studied a rat model of intra-myelinic edema induced by hexachlorophene ingestion.•We used multi-exponential T2 (MET2) and quantitative magnetization transfer MRI.•Histology was quantitatively evaluated to measure edema volume and myelin content.•MET2 provides a measure that correlates but overestimates with edema volume fraction.•MET2 measure of edema is affected by microscopic water dynamics.
PMCID: PMC3777678  PMID: 24179832
MRI; T2; Magnetization transfer; Edema
22.  The effect of posterior spinal fusion on respiratory function in Duchenne muscular dystrophy 
European Spine Journal  2012;22(2):411-416.
Posterior instrumented spinal fusion is indicated for progressive scoliosis that develops in Duchenne muscular dystrophy (DMD) patients. Whilst spinal fusion is known to improve quality of life, there is inconsistency amongst the literature regarding its specific effect on respiratory function. Our objective was to determine the effect of scoliosis correction by posterior spinal fusion on respiratory function in a large cohort of patients with DMD. Patients with DMD undergoing posterior spinal fusion were compared to patients with DMD not undergoing surgical intervention.
An observational study of 65 patients with DMD associated scoliosis, born between 1961 and 2001: 28 of which underwent correction of scoliosis via posterior spinal fusion (Surgical Group) and 37 of which did not undergo surgical intervention (Non-Surgical Group). Pulmonary function was assessed using traditional spirometry. Comparisons were made between groups at set times, and by way of rates of change over time.
There was no correlation between the level of respiratory dysfunction and the severity of scoliosis (as measured by Cobb angle) for the whole cohort. The Surgical Group had significantly worse respiratory function at a comparable age pre-operatively compared to the Non-Surgical Group, as measured by per cent predicted forced vital capacity (p = 0.02) on spirometry. The rate of decline of forced vital capacity and per cent predicted forced vital capacity was not slowed following surgery compared to the non-operated cases. There was no significant difference in survival between the two groups.
Severity of scoliosis was not a key determinant of respiratory dysfunction. Posterior spinal fusion did not reduce the rate of respiratory function decline. These two points suggest that intrinsic respiratory muscle weakness is the main determinant of decline in respiratory function in DMD.
PMCID: PMC3555614  PMID: 23179984
Duchenne muscular dystrophy; Dystrophin; Respiratory function; Spirometry; Scoliosis; Surgical intervention
23.  Six-Minute Walk Test: Reference Values and Prediction Equation in Healthy Boys Aged 5 to12 Years 
PLoS ONE  2013;8(12):e84120.
This study aimed to (1) generate normative data in healthy boys aged 5–12 years for the six-minute walk test (6MWT), an outcome measure currently used in clinical trials in Duchenne muscular dystrophy (DMD), (2) to describe the relation with anthropometric variables and myometry, and (3) to compare our data with published equations.
The 6MWT was conducted in 442 boys according to a standardized protocol, as currently used in clinical trials in DMD. Maximal voluntary isometric contractions for knee flexion and extension were recorded with a hand-held myometer.
The 6MWD increased significantly with age, from 478.0±44.1 m at age 5, to 650.0±76.8 m at age 12, with the steepest increase between 5 and 8 years. Age- and height related percentile curves of the 6MWD were developed. Correlations with anthropometric variables were fair to good (age r = 0.60, height r = 0.57, weight r = 0.44). Myometric variables (knee flexors and extensors) showed correlations of 0.46 and 0.50 respectively. When dividing into two age categories (5–8 years, 9–12 years), these magnitudes of correlations only applied to the younger age group. Additionally, predicted values were calculated according to available reference equations (Geiger and Ben Saad), indicating an overestimation by those equations. Finally, the Geiger equation was refitted to our population.
The percentile curves according to age and height provide a useful tool in the assessment of ambulatory capacity in boys aged 5 to 12 years. Significant correlations with anthropometric variables and myometry were only found in the 5–8 years age group. The Geiger prediction equation, currently used to assess ambulatory capacity in DMD was refitted to obtain a more accurate prediction model based on a large sample with a homogenous distribution across the age categories 5 to 12 years and applying the methodology as currently used in clinical trials in DMD.
PMCID: PMC3877199  PMID: 24391899
24.  Community Structure Analysis of Gene Interaction Networks in Duchenne Muscular Dystrophy 
PLoS ONE  2013;8(6):e67237.
Duchenne Muscular Dystrophy (DMD) is an important pathology associated with the human skeletal muscle and has been studied extensively. Gene expression measurements on skeletal muscle of patients afflicted with DMD provides the opportunity to understand the underlying mechanisms that lead to the pathology. Community structure analysis is a useful computational technique for understanding and modeling genetic interaction networks. In this paper, we leverage this technique in combination with gene expression measurements from normal and DMD patient skeletal muscle tissue to study the structure of genetic interactions in the context of DMD. We define a novel framework for transforming a raw dataset of gene expression measurements into an interaction network, and subsequently apply algorithms for community structure analysis for the extraction of topological communities. The emergent communities are analyzed from a biological standpoint in terms of their constituent biological pathways, and an interpretation that draws correlations between functional and structural organization of the genetic interactions is presented. We also compare these communities and associated functions in pathology against those in normal human skeletal muscle. In particular, differential enhancements are observed in the following pathways between pathological and normal cases: Metabolic, Focal adhesion, Regulation of actin cytoskeleton and Cell adhesion, and implication of these mechanisms are supported by prior work. Furthermore, our study also includes a gene-level analysis to identify genes that are involved in the coupling between the pathways of interest. We believe that our results serve to highlight important distinguishing features in the structural/functional organization of constituent biological pathways, as it relates to normal and DMD cases, and provide the mechanistic basis for further biological investigations into specific pathways differently regulated between normal and DMD patients. These findings have the potential to serve as fertile ground for therapeutic applications involving targeted drug development for DMD.
PMCID: PMC3686745  PMID: 23840633
25.  Insights into bone health in Duchenne muscular dystrophy 
BoneKEy reports  2012;1:9.
Poor bone health is a significant problem for patients with Duchenne muscular dystrophy (DMD), a progressive, disabling disease. Although the primary focus of DMD disease pathogenesis is degeneration of striated muscle, impairment of bone health likely has a role in the disease that has only been superficially examined to date. Deficiency of bone mineral density and increased incidence of bone fractures are well-recognized clinical components of the DMD phenotype. Furthermore, therapy with corticosteroids, an approved treatment for DMD that prolongs ambulation, may have multiple effects on bone health in DMD patients. This review examines the evidence in preclinical models and in human DMD disease that provides insight into the role performed by bone in the disease pathogenesis and phenotype of DMD. The information reviewed here points toward the need for mechanistic and therapeutic studies to optimize bone health in DMD patients.
PMCID: PMC3727795  PMID: 23951421

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