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PubMed1996

Hypoosmotic shocks induce elevation of resting calcium level in Duchenne muscular dystrophy myotubes contracting in vitro.

In Duchenne muscular dystrophy (DMD) muscle cells which lack dystrophin, contraction seems to be a dominant factor contributing to the abnormal elevated intracellular calcium level. Human normal and DMD contracting myotubes cocultured with nervous cells were exposed to a hypotonic medium to mimic contraction-induced mechanical stress on the membrane, and the cytoplasmic calcium activity was simultaneously monitored (Indo-1). Hypotonic shocks induced a reversible [Ca2+]i increase in 81% of the DMD cells vs. 54% of control. In addition, responses were qualitatively different: most of DMD myotubes displayed a fast increase of Ca2+ flowing from the edge of the myotube while the response in normal cells was slow and diffuse. The fact that these responses were not affected by ryanodine, was in favour of an external source of Ca2+ involved in the hypoosmotic shocks. The localized increase of Ca2+ in DMD myotubes, inhibited by Gd3+, could result from sites of high mechanosensitive channel activity or density which could constitute a pathway for Ca2+ entry provided these cells contract.

Calcium↗

PubMed2005

Use of step activity monitoring for continuous physical activity assessment in boys with Duchenne muscular dystrophy.

OBJECTIVES: To evaluate the StepWatch Activity Monitor (SAM) as a quantitative measure of community ambulation, to investigate activity patterns and heart rate of ambulatory boys with Duchenne muscular dystrophy (DMD), and to correlate the step activity with measures of body composition and strength. DESIGN: Case-control study. SETTING: General community and laboratory. PARTICIPANTS: Sixteen ambulatory boys with DMD and 20 male controls (age range, 5-13 y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Laboratory determinations of body composition, knee extension strength, and minute-by-minute step rate and heart rate during 3 days of community activity. RESULTS: During the 3 days of activity, DMD subjects, when compared with controls, (1) had significantly more inactive minutes (1096+/-90 min/d vs 1028+/-85 min/d), (2) took significantly fewer steps and spent fewer minutes at moderate (66+/-31 min/d vs 94+/-30 min/d) and high step rates (43+/-30 min/d vs 72+/-38 min/d), (3) had higher resting heart rate (110+/-12 beats/min vs 94+/-7 beats/min) and lower increase in heart rate with increased step rate, and (4) had lower maximum heart rates (164+/-24 beats/min vs 208+/-16 beats/min). Percentage of body fat and knee extension strength correlated with total step activity in the DMD group but not in the control group. CONCLUSIONS: Step-rate monitoring with the SAM provides useful outcome measures with which to evaluate the activity of ambulatory boys with DMD. Their heart rate did not increase with activity to the same degree as observed in the control group.

Adolescent↗

PubMed2006

Nitric oxide synthase is up-regulated in muscle fibers in muscular dystrophy.

Nitric oxide (NO) mediates fundamental physiological actions on skeletal muscle. The neuronal NO synthase isoform (NOS1) was reported to be located exclusively in the sarcolemma. Its loss from the sarcolemma was associated with development of Duchenne muscular dystrophy (DMD). However, new studies evidence that all three NOS isoforms-NOS1, NOS2, and NOS3-are co-expressed in the sarcoplasm both in normal and in DMD skeletal muscles. To address this controversy, we assayed NOS expression in DMD myofibers in situ cytophotometrically and found NOS expression in DMD myofibers up-regulated. These results support the hypothesis that NO deficiency with consequent muscle degeneration in DMD results from NO scavenging by superoxides rather than from reduced NOS expression.

Biopsy↗

PubMed2004

A novel approach to identify Duchenne muscular dystrophy patients for aminoglycoside antibiotics therapy.

Aminoglycoside antibiotics have been found to suppress nonsense mutations located in the defective dystophin gene in mdx mice, suggesting a possible treatment for Duchenne muscular dystrophy (DMD). However, it is very difficult to find patients that are applicable for this therapy, because: (1) only 5-13% of DMD patients have nonsense mutations in the dystrophin gene, (2) it is challenging to find nonsense mutations in the gene because dystrophin cDNA is very long (14 kb), and (3) the efficiency of aminoglycoside-induced read-through is dependent on the kind of nonsense mutation. In order to develop a system for identifying candidates that qualify for aminoglycoside therapy, fibroblasts from nine DMD patients with nonsense mutation of dystrophin gene were isolated, induced to differentiate to myogenic lineage by AdMyoD, and exposed with gentamicin. The dystrophin expression in gentamicin-exposed myotubes was monitored by in vitro dystrophin staining and western blotting analysis. The results showed that gentamicin was able to induce dystrophin expression in the differentiated myotubes by the read-through of the nonsense mutation TGA in the gene; a read-through of the nonsense mutations TAA and TAG did not occur and consequently did not lead to dystrophin expression. Therefore, it is speculated that the aminoglycoside treatment is far more effective for DMD patients that have nonsense mutation TGA than for patients that have nonsense mutation TAA and TAG. In this study, we introduce an easy system to identify patients for this therapy and report for the first time, that dystrophin expression was detected in myotubes of DMD patients using gentamicin.

Anti-Bacterial Agents↗

PubMed2004

Peak negative myocardial velocity gradient and wall-thickening velocity during early diastole are noninvasive parameters of left ventricular diastolic function in patients with Duchenne's progressive muscular dystrophy.

Myocardial velocity gradient and wall-thickening velocity were measured in the interventricular septum and left ventricular posterior wall (LVPW) by color-coded M-mode Doppler tissue echocardiography in patients with Duchenne's progressive muscular dystrophy (DMD) with a normal shortening fraction (n = 14) and age-matched control subjects (n = 40). In the LVPW, peak myocardial velocity gradients during systole and early diastole were significantly lower for patients with DMD than in control subjects (P <.0005, and P <.0001, respectively). Peak myocardial wall-thickening velocities of the LVPW during systole and early diastole were also lower for patients with DMD (P <.0005 and P <.0001, respectively). Mitral peak atrial to early filling velocity ratio was not significantly different between the 2 groups. The cut-off values of peak myocardial velocity gradients and wall-thickening velocities of the LVPW during early diastole for differentiation between patients with DMD and control subjects were -5.8/s and -6.0 cm/s, respectively (sensitivity/specificity: 93%/93% and 93%/85%, respectively). In conclusion, wall thinning during early diastole is frequently abnormal in patients with DMD, even when conventional echocardiographic findings are normal.

Adolescent↗

PubMed2006

Anticipatory postural adjustments in a bimanual load-lifting task in children with Duchenne muscular dystrophy.

We investigated the consequences of a progressive damage to the muscular system on the organization of anticipatory postural adjustments (APA) in children with Duchenne muscular dystrophy (DMD). We used a bimanual load-lifting task requiring the stabilization of the forearm position despite its voluntary or imposed unloading. Eight children with DMD from 4 to 11 years of age were compared to eight typically developing (TD) children. Elbow angle and multiple surface EMGs were recorded and assessed the use of APA. The muscle weakness did not impair (1) the proprioceptive afference and the motor efference constituting the unloading reflex; and (2) the use of an anticipatory function in children with DMD. However, APA used for the forearm stabilization were less efficient in the group of children with DMD. We conclude that in DMD the muscular weakness could be a restraint to the efficiency of APA with respect to TD children.

Child↗

PubMed2004

Nanotribological characterization of digital micromirror devices using an atomic force microscope.

Texas Instruments' digital micromirror device (DMD) comprises an array of fast digital micromirrors, monolithically integrated onto and controlled by an underlying silicon memory chip. The DMD is one of the few success stories in the emerging field of MEMS. In this study, an atomic force microscope (AFM) has been used to characterize the nanotribological properties of the elements of the DMD. An AFM methodology was developed to identify and remove micromirrors of interest. The surface roughness, adhesion, friction, and stiffness properties of the DMD elements were studied. The influence of relative humidity and temperature on the behavior of the DMD element surfaces was also investigated. Potential mechanisms for wear and stiction are discussed in light of the findings.

Journal Article↗

PubMed2006

Transduction of myogenic cells by retargeted dual high-capacity hybrid viral vectors: robust dystrophin synthesis in duchenne muscular dystrophy muscle cells.

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), making it amenable to gene- or cell-based therapies. Another possible treatment entails the combination of both principles by transplantation of autologous myogenic cells after their genetic complementation. This approach requires efficient and stable transduction of these cells with recombinant DMD. Recently, we generated a dual high-capacity (hc) adenovirus (Ad)-adeno-associated virus (AAV) hybrid vector (HV) that can deliver two full-length dystrophin-encoding modules into target cells. We showed that HV transduction of human cells containing AAV Rep proteins leads to the insertion of foreign DNA into the AAVS1 locus. Here, we improved HV entry into muscle cells from DMD patients. After having verified that these cells barely express the coxsackie B virus and Ad receptor (CAR), which constitutes the attachment molecule for Ad serotype 5 (Ad5) fibers, we equipped dual hcAd/AAV HV particles with Ad serotype 50 fiber domains to achieve CAR-independent uptake. These retargeted vectors complemented much more efficiently the genetic defect of dystrophin-defective myoblasts and myotubes than their isogenic counterparts with conventional Ad5 fibers. Importantly, the accumulation of beta-dystroglycan along the membranes of vector-treated DMD myotubes indicated proper assembly of dystrophin-associated glycoprotein complexes.

Adenoviridae↗

PubMed1999

QT dispersion in patients with Duchenne-type progressive muscular dystrophy.

BACKGROUND: A high degree of QT dispersion is a risk factor for arrhythmic sudden death in patients with myocardial infarction and cardiomyopathy. Duchenne-type progressive muscular dystrophy (DMD) is also associated with the development of ventricular arrhythmias. The purpose of this study was to determine the relationship between QT interval dispersion and ventricular arrhythmias in patients with DMD. METHODS: Sixty-seven patients with DMD were studied. Standard 12-lead electrocardiograms and 24-hour Holter electrocardiograms were recorded, and the QT interval was determined in every lead of the standard electrocardiogram to determine the QT dispersion. QT dispersion was compared with the frequency of ventricular arrhythmias and the severity of skeletal muscle damage on the basis of the Swinyard and Deaver 8-stage scale. RESULTS: QT dispersion in all 67 patients averaged 54 +/- 18 ms. The QT dispersion was 49 +/- 16 ms in stage 5 patients, 61 +/- 22 ms in stage 6 patients, 52 +/- 17 ms in stage 7 patients, and 56 +/- 17 ms in stage 8 patients. Ventricular arrhythmias of Lown grade III or higher were observed in 3 of 35 patients with QT dispersion <60 ms and in 14 of 32 patients with QT dispersion >/=60 ms. Logistic regression analysis demonstrated that QT dispersion is an independent risk factor for ventricular arrhythmias of grade III or higher in patients with DMD. CONCLUSIONS: The incidence of ventricular arrhythmias of Lown grade III or higher was greater in patients with QT dispersion >/=60 ms than in patients with QT dispersion >60 ms. QT dispersion therefore is a risk factor for serious ventricular arrhythmias in patients with DMD.

Adolescent↗

PubMed1999

Cardioprotection for Duchenne's muscular dystrophy.

PURPOSE: To explore the use of neuroendocrine monitoring for more timely diagnosis of dilated cardiomyopathy (DCM) in Duchenne's muscular dystrophy (DMD) and to determine the effects of angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers on neuroendocrine levels, left ventricular diastolic diameter (LVDd), ejection fraction, and mortality rate on DMD. METHODS: Eighty-five patients with DMD underwent yearly cardiac monitoring including neuroendocrine screening. Eleven patients had symptoms of DCM develop once plasma neuroendocrine levels increased. At this point the patients received ACEI for 9 to 62 months (35.8 +/- 18.4 months) and beta-blockers for 7 to 60 months (31.6 +/- 20.1 months). RESULTS: The combination of ACEI and beta-blockers relieved symptoms and signs of heart failure in all 11 patients and significantly reduced atrial natriuretic protein (ANP) levels from 197.5 +/- 152.1 pg/mL to 25.5 +/- 16.2 pg/mL ( P <.002) at 15.5 +/- 8.2 months, brain natriuretic protein from 523.8 +/- 434.8 pg/mL to 59.3 +/- 24. 2 pg/mL ( P <.05) at 12.2 +/- 3.1 months (data complete for 5 patients), norepinephrine levels from 1114 +/- 689 pg/mL to 360 +/- 257 pg/mL at 20.5 +/- 9.6 months for 11 patients (P =.001), and LVDd from 65.9 +/- 9.2 mm to 63.3 +/- 6.3 mm (P =.15) at 15.0 +/- 7.4 months for 10 patients, including 3 for whom the LVDd increased by 2 to 6 mm. The combination increased left ventricular ejection fraction (LVEF) from 25.1% +/- 9.2% to 36.5% +/- 5.8% (P <.001) at 17.1 +/- 11.0 months for 10 patients. For 9 of the patients ANP levels remained lower throughout the 36.8 +/- 20.1 month course of the follow-up. Two patients had sudden severe re-elevations of ANP levels just before death from congestive heart failure after 44 and 23 months of therapy, respectively. CONCLUSION: Neuroendocrine level monitoring can assist in the diagnosis of DCM in patients with DMD. Combination therapy with ACEI and beta-blockers can significantly decrease neuroendocrine activation and LVDd and reverse symptoms and signs of congestive heart failure for patients with DMD.

Adolescent↗

PubMed2003

A preliminary randomized study of growth hormone administration in Becker and Duchenne muscular dystrophies.

AIM: Since growth hormone (GH) has proven beneficial in experimental heart failure, and the natural history of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is frequently complicated by the development of dilated cardiomyopathy, we administered GH to six patients with DMD and 10 with BMD, with the evidence of cardiac involvement. METHODS AND RESULTS: Patients were randomized to receive for 3 months either placebo or recombinant human GH, in a double-blind fashion. In GH-treated patients, left ventricular (LV) mass increased by 16% in BMD and by 29% in DMD (both p<0.01), with a significant increase of relative wall thickness (+19%). Systemic blood pressure remained unchanged, while LV end-systolic stress fell significantly by 13% in BMD and by 33% in DMD, with a slight increase of systolic function indexes. No changes were observed related to cardiac arrhythmias and skeletal muscle function in the patient groups during the treatment period, nor any side effects were observed. Brain natriuretic peptide, interleukin-6, and tumor necrosis factor-alpha circulating levels were elevated at baseline. While brain natriuretic peptide decreased by 40%, cytokine levels did not exhibit significant variations during the treatment period. CONCLUSIONS: The 3-month GH therapy in patients with DMD and BMD induces a hypertrophic response associated with a significant reduction of brain natriuretic peptide plasma levels and a slight improvement of systolic function, no changes in skeletal muscle function, and no side effects.

Adolescent↗

PubMed1997

Chemoprevention by lycopene of mouse lung neoplasia after combined initiation treatment with DEN, MNU and DMH.

An investigation was conducted to assess the chemopreventive potential of lycopene (LP), a naturally occurring hydrocarbon carotenoid found in tomatoes and their products, administered during the post-initiation stage in a multiorgan carcinogenesis model. One hundred eighteen B6C3F1 mice of both sexes were subjected to combined treatment with diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU) and 1,2-dimethylhydrazine (DMH) from day 11 after birth to week 9 (DMD treatment) (groups 1 and 2) or their vehicles (group 3). Then group 1 received LP (25 or 50 ppm in drinking water) for 21 weeks from weeks 11 to 32. Group 2 served as a carcinogen alone control and group 3 was given only LP (25 or 50 ppm). All surviving animals were sacrificed at week 32 and the major organs, including the liver, lung, kidney and colon, were histologically examined. The incidences and multiplicities of lung adenomas plus carcinomas combined in male mice in group 1 receiving 50 ppm LP were significantly decreased as compared to the DMD alone or DMD and 25 ppm LP groups (75.0 versus 18.8%, P < 0.02; 0.94 +/- 0.17 versus 0.25 +/- 0.14, P < 0.001). No such effect was observed for females. Although hepatocellular carcinomas were lacking in the DMD and LP groups while two cases were found in the DMD alone group, this difference was not statistically significant. The values for aberrant crypt foci (ACF) and tumors in the colon and kidney did not show any significant variation among the carcinogen-treated subgroups. The results suggest that LP exerts a chemopreventive effect limited to male lung carcinogenesis when given in the post-initiation stage to B6C3F1 mice.

1,2-Dimethylhydrazine↗

PubMed1998

Electroretinogram in Duchenne/Becker muscular dystrophy.

The authors studied all cases with dystrophinopathy consecutively reviewed between May 1995 and December 1996 by means of electroretinography (ERG), which was recorded using skin eyelid electrodes and with standard flash stimulation. This methodology can detect the functional abnormalities associated with dystrophinopathies. The most valuable parameter is the ratio of B-wave amplitude to A-wave amplitude (B/A amplitude ratio), which was greater than 2 in all normal control patients (n = 10) and nondystrophinopathic muscular dystrophy (MD) patients (n = 2). It was less than 2 in 100% (n = 16) of Duchenne muscular dystrophy (DMD) patients (mean ratio 0.73; range 0.4-1.26). It was less than 2 in 71% (n = 7) of Becker muscular dystrophy (BMD) patients (mean ratio 1.12; range 0.88-1.37), and less than 2 in 50% (n = 4) of definitive DMD carriers. Twenty-nine percent of BMD, 50% of DMD carriers, and the only case with asymptomatic dystrophinopathy had normal ratios (greater than 2). The differences between the mean ratios of control, DMD, and BMD groups were statistically significant, all of them with P < 0.001. ERG abnormalities of dystrophinopathies were associated with the more severe muscular phenotype but not with the presence or location of gene deletion. ERG is an easy and simple technique that is useful in cases of suspected dystrophinopathy with a nonconclusive molecular study. It is less useful in patients who are DMD carriers.

Adolescent↗

PubMed2001

A standardized method for the evaluation of respiratory muscle endurance in patients with Duchenne muscular dystrophy.

The aim of the study was to develop a standardized method using controlled breathing to quantify respiratory muscle endurance in children with Duchenne muscular dystrophy (DMD) and to test its reproducibility. In 10 DMD patients, all between 10 and 14 years (mean age, 11.5 +/- 1.5 years), except for two patients of 20 and 22 years, and 10 healthy children (mean age, 12 +/- 1 years), we measured the maximal time (Tlim) that a threshold load fixed at 35% of the individual maximal inspiratory pressure (Pimax) could be tolerated. We asked the children to maintain their rest breathing pattern until exhaustion using visual feedback and an auditory signal. The mean Tlim in the DMD children was 4.45 +/- 1.45 min and values were reproducible. All healthy children were able to obtain Tlim values greater than 30 min. The respiratory muscles of DMD children are more susceptible to fatigue than those of healthy subjects. This method should be satisfactory for estimating the effect of treatment and for the specific training of respiratory muscles in DMD patients without significant learning disability.

Adolescent↗

PubMed2002

Physical capacity in non-ambulatory people with Duchenne muscular dystrophy or spinal muscular atrophy: a longitudinal study.

The purpose of this study was to describe functional ability, muscle strength, forced vital capacity, and clinical events in participants with Duchenne muscular dystrophy (DMD) or spinal muscular atrophy (SMA) in the non-ambulatory stages of the diseases. Nineteen non-ambulatory participants with DMD (all males; 13 to 24 years) and 13 with SMA (six males, seven females; 11 to 57 years) were assessed once a year over 5 years. The assessments comprised functional ability measured with the EK scale and upper extremity grade, muscle strength measured with the manual muscle test, and forced vital capacity defined as a percentage of normal values (FVC%). In the DMD group all variables measured deteriorated and there was a direct correlation between them. In the SMA group only muscle strength and FVC% deteriorated and there was no close relation between the variables measured. In the DMD group, 16 participants had cardiorespiratory clinical events leading to death in five cases. In the SMA group only four participants had respiratory clinical events, none leading to death. Although the participants with SMA had been extremely weak and non-ambulatory since early childhood they were older and less exposed to life-threatening events than the participants with DMD.

Activities of Daily Living↗

PubMed2005

Diagnosis and management of Duchenne muscular dystrophy in a developing country over a 10-year period.

Clinical data on Duchenne muscular dystrophy (DMD) are lacking in developing countries. The objective of this study was to delineate the demographic characteristics, investigations, and outcome of 21 Malaysian males diagnosed with DMD over a period of 10 years. Mean age presentation was 3 years 8 months (SD 23mo; range 10 to 84mo), mean duration from first presentation to diagnosis was 3y 7mo (SD 26mo; range 5 to 84) and the mean age for loss of ambulation was 11 years (SD 25mo; range 102 to 168). There was family history of DMD in five of the 21 patients. Muscle biopsy showed confirmatory findings of DMD in the 16 patients tested. Molecular genetic analysis showed dystrophin gene deletions in 11 of these 16 patients. Four and seven of the students stopped schooling and had learning difficulties, respectively; only nine had satisfactory school performances. Eight out of 14 patients evaluated were classified as having severe to total dependency levels on the modified Barthel Index for activities of daily living assessment. DMD is associated with significant medical and social needs for a developing country such as Malaysia. Earlier referral, genetic counselling, and provision of support and rehabilitative services are the main priorities.

Adolescent↗

PubMed1982

Analysis of fibroblast proteins from patients with Duchenne muscular dystrophy by two-dimensional gel electrophoresis.

Duchenne muscular dystrophy (DMD), the most common and severe form of the muscular dystrophies, is an X-linked inborn error of metabolism with multiple tissue involvement. Although the major pathological changes are observed in skeletal muscle, abnormalities have also been detected in the heart, nervous system, red blood cells, lymphocytes and cultured skin fibroblasts. For many reasons, such as readily available tissue material, fewer secondary changes and the potential for prenatal diagnosis, cultured skin fibroblasts should be the tissue of choice to search for the primary defect. Several abnormalities have been reported in DMD fibroblasts, suggesting that the genetic abnormality is expressed in these cells. To search for potentially mutant protein(s) we have compared the protein composition of normal and DMD fibroblasts by two-dimensional gel electrophoresis and have now found one protein spot consistently missing in DMD cells. The nature of this protein and its relation to the DMD gene are unknown.

Autoradiography↗

PubMedDate not supplied

56K fibroblast protein not specific for Duchenne muscular dystrophy but for skin biopsy site.

Recently, we reported the detection by two-dimensional gel electrophoresis of a 56,000 (56K)-molecular weight polypeptide that was present in cultured skin fibroblasts from normal males but was not detectable in fibroblasts from Duchenne muscular dystrophy (DMD) patients. Since then we have established that the 56K polypeptide is not present in skin fibroblasts from normal females, DMD carrier females, or in normal male fibroblasts obtained from sources other than the Repository for Mutant Human Cell Strains, Montreal. Further inquiry has led to the discovery that all the normal male fibroblast cultures obtained from the Montreal repository had been established from preputial skin. Fibroblast cultures from DMD patients, DMD carriers, as well as other normal individuals, had been derived from non-genital skin biopsies. Thus, the absence of the 56K polypeptide is not specific for DMD, but rather is related to the site of skin biopsy.

Biopsy↗