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PubMed2005

Early onset of inflammation and later involvement of TGFbeta in Duchenne muscular dystrophy.

OBJECTIVE: To identify stage-specific induction of molecular pathology pathways in Duchenne muscular dystrophy (DMD). METHODS: We performed mRNA profiling using muscles from fetopsies, infants (aged 8 to 10 months), and symptomatic patients (aged 5 to 12 years) with DMD, and age- and sex-matched controls. We performed immunohistochemistry to determine changes at the protein level and protein localization. RESULTS: Activated tissue dendritic cells, expression of toll-like receptor 7, and strong induction of nuclear factor-kappaB pathways occurred soon after birth in DMD muscle. Two muscle wasting pathways, atrogin-1 and myostatin, were not induced at any stage of the disease. Normal muscle showed accumulation of glycolytic and oxidative metabolism capacity with increased age, but this accumulation failed in DMD. The transforming growth factor (TGF)-beta pathway was strongly induced in symptomatic patients, with expression of TGFbeta type II receptor and apoptosis signal-regulating kinase 1 proteins on subsets of mature DMD myofibers. CONCLUSIONS: Our data show stage-specific remodeling of human dystrophin-deficient muscle, with inflammatory pathways predominating in the presymptomatic stages and acute activation of TGFbeta and failure of metabolic pathways later in the disease.

Child↗
PubMed1979

Quantitative ultrastructural study of muscle satellite cells in Duchenne dystrophy.

Quantitative ultrastructural studies of satellite cell populations, and nuclear chromatin analysis of satellite cell nuclei and true subsarcolemmal nuclei were carried out in normal and Duchenne muscular dystrophy (DMD) muscles. There was a remarkable increase in the number of satellite cells in muscles of patients with mild to moderate stages of DMD, as compared to preclinical or very early and probably advanced stages of DMD, and a significant increase in euchromatin content was found in the satellite cell nuclei in DMD. Since it is generally accepted that satellite cells participate actively in muscle fiber regeneration, this study suggests that muscle fiber regeneration is ineffective in DMD.

Adolescent↗
PubMed2006

Accurate pixel-to-pixel correspondence adjustment in a digital micromirror device camera by using the phase-shifting moiré method.

A camera based on the digital micromirror device (DMD) technology has been previously developed. In this optical system, the correspondence of each mirror of the DMD to each pixel of the CCD cannot readily be done since the pixel sizes of the DMD and the CCD are very small. An accurate pixel-to-pixel correspondence adjustment in the DMD camera by means of the phase-shifting moiré method is proposed. To perform high accurate adjustment of the optical system, the phase distribution of a moiré fringe pattern is analyzed when the CCD pixels and the DMD mirrors have a mismatch and/or misalignment with each other. This technique does not need a complicated setting or complex image processing to generate the moiré fringe pattern, and it needs only one captured image. In the adjustment experiment, the proposed method provided very accurate adjustment whose error was less than 1/25 pixel. An experiment of phase analysis to demonstrate the usefulness was performed.

Journal Article↗
PubMed2006

A multiplex assay for the detection and mapping of complex glycerol kinase deficiency.

BACKGROUND: Glycerol kinase deficiency (GKD) is an X-linked recessive disorder that presents in both isolated and complex forms. The contiguous deletion that leads to GKD also commonly affects NR0B1 (DAX1), the gene associated with adrenal hypoplasia congenita, and DMD, the Duchenne muscular dystrophy gene. Molecular testing to delineate this deletion is expensive and has only limited availability. METHODS: We designed a multiplex PCR assay for the detection and mapping of a contiguous deletion potentially affecting the IL1RAPL1, NR0B1, GK, and DMD genes in a 29-month-old male patient with GKD. RESULTS: Multiplex PCR detected a contiguous deletion that involved the IL1RAPL1, NR0B1, GK, and DMD genes. Although the patient had a creatine kinase concentration within the reference interval, further mapping with PCR revealed that exon 74 was the last intact exon at the 3' end of the DMD gene. CONCLUSIONS: Multiplex PCR is an effective and inexpensive way to detect and map the contiguous deletion in cases of complex GKD. The extension of a deletion to include DMD exon 75 in a patient with a creatine kinase concentration within the reference interval suggests that this region of the gene may not be essential for protein function.

Child, Preschool↗
PubMed2005

Cardiac and sternocleidomastoid muscle involvement in Duchenne muscular dystrophy: an MRI study.

OBJECTIVE: To examine the extent of cardiac muscle and sternocleidomastoid muscle (SCM) involvement detected by MRI measurement of T2 relaxation time in patients with Duchenne muscular dystrophy (DMD) and no cardiorespiratory symptoms. DESIGN: Prospective controlled study. SETTING: Teaching referral hospital and university hospital. SUBJECTS: Seventeen patients with DMD (age range, 7 to 25 years) and 17 age-matched control subjects. All patients were free of cardiac or respiratory complaints and had normal ECG, echocardiograph, and Holter monitor examination findings. METHODS: We assessed respiratory function by means of standard pulmonary function testing. MRI measurements included the T2 relaxation time of the myocardium and the SCM in patients and control subjects. RESULTS: The FVC and FEV1 values were lower in patients with DMD than in age-matched control subjects, whereas the FEV1/FVC ratio was normal in all subjects. Patients with DMD had lower T2 relaxation time of the heart (37.8 +/- 6.1 ms vs 58.1 +/- 7.1 ms, p < 0.001) and lower T2 relaxation time of the right SCM (24.5 +/- 2.6 ms vs 42.2 +/- 1.3 ms, p < 0.001) and left SCM (23.2 +/- 3.2 ms vs 42.2 +/- 1.6 ms, p < 0.001), compared to control subjects (+/- SD). In children (< 12 years of age), the T2 of the SCM was lower than that of the control subjects, but T2 of the heart did not differ between the two groups. In the patient group, T2 relaxation time of the heart decreased with age (r = - 0.80, p < 0.001). In patients with FVC < 80% of predicted, the T2 values of the heart were lower than the T2 values of patients with FVC > or = 80% of predicted (35.6 +/- 5.8 ms vs 41.8 +/- 4.6 ms, p < 0.05). CONCLUSIONS: MRI measurements of the T2 relaxation time in the myocardium and SCM of patients with DMD and no cardiorespiratory symptoms are abnormal, indicating altered tissue composition. These measurements may prove a clinically useful test for monitoring cardiac and respiratory muscle involvement in these patients.

Adolescent↗
PubMed2006

Combined fluorescence in situ hybridization and PRINS for the analysis of the Dystrophin gene.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused in most cases by deletions of the DMD gene. These rearrangements are detectable in affected boys and men by a simple multiplex polymerase chain reaction approach. However, this technique is not able to disclose DMD deletions in heterozygous female carriers, and different approaches must be used in these cases. Here, we describe an approach based on the combined use of primed in situ labeling and fluorescence in situ hybridization techniques for the detection of single DMD exons in fixed metaphase chromosomes and interphase nuclei of both male and female subjects, suggesting the usefulness of this tool in the detection of small intragenic deletions of the DMD gene.

Chromosomes, Human↗
PubMed1990

Long-term observation of cardiac function in Duchenne's muscular dystrophy. Evaluation using systolic time intervals and echocardiography.

Cardiac involvement is common in patients with Duchenne type muscular dystrophy (DMD). However, published reports of long-term follow-up studies in the same patients are very rare. The purpose of this study was to clarify the natural course of cardiac dysfunction in DMD, and to analyze the relationship between the deterioration of cardiac function and skeletal muscular function. The cardiac function was serially evaluated for 2-12 years in 34 patients with DMD. The systolic time intervals and echocardiography were used for evaluating the cardiac function. The PEP/ET (pre-ejection period/ejection time) of systolic time intervals significantly deteriorated in 9-12 years (p less than 0.001). The maximal systolic and diastolic endocardial velocity (MSEV and MDEV) and the D/S ratio of echocardiography significantly deteriorated in 5 years (p less than 0.001). The D/S ratio is the ratio of the mean systolic velocity and the mean diastolic velocity of the left ventricular posterior wall. In almost half the patients, the deterioration of these parameters was correlated with that of Swinyard's stage. The Swinyard's functional ability stage demonstrates the grade of the skeletal muscular dysfunction. However, there was no correlation between the deterioration of cardiac function and Swinyard's stage in the other half of the patients. Correlation coefficient in the whole group was 0.32 (p = n.s.) between the PEP/ET and Swinyard's stage, and was -0.15 (p = n.s.) between the D/S ratio and Swinyard's stage. Although the mean left ventricular ejection fraction calculated using echocardiography was slightly decreased for 5 years, no significant change was detected in the whole group. One patient had progressive deterioration of left ventricular function despite mild skeletal muscular dysfunction, and died from congestive heart failure. The cardiac dysfunction was predominant. We named it 'cardiac type' DMD. Since deterioration of cardiac function was not always correlated with deterioration of skeletal muscular function (Swinyard's stage), cardiac function must be carefully monitored in patients with DMD.

Adolescent↗
PubMed1993

Evaluation of myocardial damage in Duchenne's muscular dystrophy with thallium-201 myocardial SPECT.

Myocardial damage and cardiopulmonary functions in patients with Duchenne's muscular dystrophy (DMD) were assessed using thallium-201 myocardial single-photon emission computed tomography (SPECT) and technetium-99m multigated radionuclide angiography. Twenty-five patients with DMD were divided into 4 groups according to percent of perfusion defect (%PD) calculated by the bull's-eye method and age. PD was detected in 24 (96.0%) of 25 patients with DMD, and it spread from the left ventricular lateral wall to the anterior wall and/or interventricular septum. PD was detected even in a 6-year-old DMD boy. Patients in Group I (%PD > or = 10 and age < 15 years old) were shown to have a higher risk of left-sided heart failure without respiratory failure. Patients in Group II (%PD > or = 10 and age > or = 15) showed decreased pulmonary function and worsened arterial blood gas values as compared with Group IV (%PD < 10 and age > or = 15). There was no significant difference in cardiac function among the 4 groups. It is postulated that myocardial damage in Group II patients is dependent primarily on a deficiency of dystrophin and on chronic respiratory failure, and that some of them are at risk of cardiopulmonary failure. It is concluded that myocardial SPECT is useful for the early diagnosis of myocardial damage and evaluation of cardiopulmonary function in DMD patients.

Child↗
PubMed1995

Notched T wave as evidence of autonomic nervous lability in Duchenne progressive muscular dystrophy.

We investigated the significance of notched T waves on the ECG in 30 patients with Duchenne progressive muscular dystrophy (DMD) and 50 age-matched controls using noninvasive cardiovascular examinations and measurement of urinary catecholamines. Notched T waves were more frequently observed in patients with DMD than in control subjects (46.7% vs. 20.0%, p < 0.05). Moreover, their frequency was age-independent in DMD, whereas they decreased with age in controls. Patients with notched T waves showed significantly increased heart rate, prolonged QTc and augmented excretion of urinary adrenaline compared with patients without them. There were no significant differences in casual BP or incidences of characteristic UCG abnormalities, such as mitral valve prolapse, and ECG abnormalities, such as tall R waves in the right precordial leads, between DMD patients with and without notched T waves. These findings suggest that notched T waves are associated with accelerated sympathetic nervous activity rather than progressive cardiac involvement in DMD.

Adolescent↗
PubMed2007

Cardiomyopathy of Duchenne muscular dystrophy: pathogenesis and prospect of membrane sealants as a new therapeutic approach.

Duchenne muscular dystrophy (DMD) is a devastating progressive disease of striated muscle deterioration. This fatal X-linked disorder results from the loss of the protein dystrophin, which in turn causes striated muscle membrane instability. Cardiac dysfunction is a growing problem in patients with DMD, but relatively little is known about the pathophysiology of the dystrophic heart. At present, there is no effective treatment for DMD and the current clinical approaches are primarily supportive in nature. This review will discuss the pathogenesis of DMD in the heart and discuss how these pathogenic processes have led to a new class of agents directed specifically at restoring membrane integrity to dystrophic myocardium. The tri-block poloxamers, specifically poloxamer 188 (P188), are able to stabilize the membranes of dystrophic myocardium in animal models and may offer a new therapeutic approach for cardiac disease in DMD.

Animals↗
PubMedDate not supplied

Progressive muscular dystrophy--Duchenne type. Controversies of the kinesitherapy treatment.

The authors carried out a study of children with progressive muscular dystrophy of Duchenne type (DMD), giving special attention to physiatrical follow-up, having in mind that the practice of exercises has been debated very much in the specialized literature. The goal of this study is to try to settle the limits for the utilization of kinesitherapy which should be applied only in specific situations, such as: after skeletal muscular trauma or when the respiratory system is at risk. In this situation the physiatrical procedure would be to restrict physical activity, with early use of wheelchairs and the exclusion of the use of orthoses for orthostatism. DMD, at present, has been considered a result of duplication (60%), deletion (5 to 6%) or point mutations at gen Xp21 (Zatz, 1994), that codifies a protein called Dystrophin (Hoffman et al., 1987). Dystrophin is a cytoskeletal sarcolemmic protein that constitutes about .002% of the total protein of the muscle, present in skeletal fibers concentrated in muscle tendinous joints, which supplies mechanical reinforcement to the surface of the membrane during stretching and shortening physical activity. This protein is absent in DMD cases, wherefore, the sarcolemma undergoes a segmentary necrosis losing its contractile property during eccentric and concentric physical activity. The importance of physiatrical follow-up for DMD patients is to avoid deformities and tendon shortening, to ameliorate the patient's quality of life, to provide respiratory assistance and general counseling to members of the patient's family. The objective of this study is to try to clarify the risks and possibilities of kinesitherapy applied to DMD cases.

Child↗
PubMed2002

Time dependent changes of variables associated with malocclusion in patients with Duchenne muscular dystrophy.

Time dependent changes of parameters associated with malocclusion in patients with Duchenne muscular dystrophy (DMD) were examined in four dental developmental stages in 34 patients. We adopted activities of daily living (ADL) score, dental arch, craniofacial morphology, and electromyograms of the masseter and temporalis muscle as parameters. A comparison was made with the results in DMD subjects to data from healthy subjects with normal occlusion reported in the literature. In DMD subjects, manifestations of open-bite were related to ADL score, sagittal shortening and transverse expansion of the dental arch and vertical overgrowth of the lower jaw. Posterior cross-bite malocclusion was associated with differences in the time dependent changes between the jaws in transverse expansion. The malocclusion in DMD subjects was also related to the time dependent disproportional changes in masticatory muscle function by EMG. Occlusal deviation in DMD subjects became apparent at the late mixed dentition and malocclusion became definitely manifest from early permanent dentition.

Activities of Daily Living↗
PubMed1994

Immunostaining of dystrophin and utrophin in skeletal muscle of dystrophinopathies.

Immunostaining of biopsied skeletal muscle of 4 Duchenne (DMD), 12 Becker muscular dystrophy (BMD) and 3 DMD carriers' was performed using monoclonal antibodies against dystrophin and utrophin. In DMD, dystrophin-negative staining was observed except for revertant fibers which showed different stain patterns for each antibody. In 7 BMDs, there was faint/patchy stain in cases of deletion between exons 45-52, while in one case there was deletion between exons 12-17 and no stain was noted relevant to the deletion site. Moreover, in 2 cases of undetectable deletion, antibodies which recognize a terminal portion of the C-terminal domain revealed the absent stain. In DMD, the utrophin-positive fibers corresponded to dystrophin-negative fibers. In BMD, this relationship did not necessarily occur in each fiber. In DMD carriers, a cluster of dystrophin-negative fibers which was positive for utrophin were prominent. In dystrophinopathy, the immunostaining of dystrophin and utrophin is useful, in combination with dystrophin gene analysis to make a definite diagnosis.

Adolescent↗
PubMedDate not supplied

Electrophoretic studies of muscle proteins in Duchenne muscular dystrophy and other neuromuscular disorders--with special reference to the change of dystrophin.

We studied total SDS-solubilized muscle proteins (TMP) of Duchenne muscular dystrophy (DMD) and other neuromuscular disorders, with special attention to the change of dystrophin suspected of being the product of DMD locus. SDS gel electrophoresis of DMD patients showed an absence of band 5 and an extreme faintness of band 2 with a decrease of band 4', 5', and 5''. Immunoblot analysis, using anti-dystrophin antibodies (anti-30 kd and anti-60 kd polyclonals), showed an absence of dystrophin in all 6 DMD cases. In other neuromuscular disorders, there was no change of TMP, and dystrophin was clearly detectable. To elucidate the degenerative mechanism of DMD muscle, further studies, including the problem of clarifying the physiological role of dystrophin, are necessary.

Adult↗
PubMed1998

The effect of in vitro fermentation on specific gravity and sedimentation measurements of forage particles.

Dry matter degradability (DMD), gas production (GP), functional specific gravity (FSG), volume of gas associated (GA), water-holding capacity (WHC), and sedimentation measurements of orchard-grass (OG) and alfalfa (AA) hays (ground through a 8-mm screen) were studied before and after in vitro incubation with ruminal fluid for 2, 4, 8, 24, 48, and 72 h. The DMD was higher for AA than for OG (P < .001), but GP did not differ. The FSG of unfermented OG and AA was .59 and .73, respectively (P < .01). During fermentation, the FSG of OG increased more than did that of AA (from .93 to 1.39 for OG and from .97 to 1.27 for AA after 2 and 72 h, respectively), and GA decreased more rapidly (from .94 to -.04 mL/g DM and from .74 to .15 mL/g DM, respectively). The DMD was positively correlated with FSG (r = .83; P < .001) and, therefore, negatively with GA (r = -.72; P < .01). The WHC increased similarly in the two forages with fermentation time. Unfermented and fermented samples were incubated in sedimentation columns filled with distilled water for 19, 37, 75, 150, and 300 s. After 300 s of sedimentation time, the unfermented AA and OG samples tended to float (91.1 and 72.7% of DM, respectively). In contrast, fermented samples tended to sediment (90.7 and 90.9% of DM, respectively). There were only small effects of forage species and fermentation time on sedimentation tendency. Correlations between sedimentation measurements and DMD and FSG were not significant, with the only exception of DM recovered in the lower section of sedimentation columns after 75 s, which was particularly correlated with DMD (P < .01) and FSG (P < .05). The results suggest that degradation rate of fibrous particles is related to changes in FSG and GA and, therefore, could influence ruminal transit. However, FSG was unable to predict accurately the sedimentation behavior of samples.

Animal Feed↗
PubMed2005

Cell surface and gene expression regulation molecules in dystrophinopathy: mdx vs. Duchenne.

Duchenne muscular dystrophy (DMD) is secondary to loss-of-function mutations in the dystrophin gene. The causes underlying the progression of DMD, differential muscle involvement, and the discrepancies in phenotypes among species with the same genetic defect are not understood. The mdx mouse, an animal model with dystrophin mutation, has a milder phenotype. This article reviews the available information on expression of signaling-related molecules in DMD and mdx. Extracellular matrix proteoglycans, growth factors, integrins, caveolin-3, and neuronal nitric oxide synthase expression do not show significant differences. Calcineurin is inconsistently activated in mdx. which is associated with lack of cardiomyopathy, compared to the permanent calcineurin activation in mdx/utrophin null mice that have a DMD-like cardiomyopathy. Levels of focal adhesion kinase (FAK) and extracellular regulated kinases (ERKs) differ among mdx and DMD. Further work is needed to identify the point of discrepancy in these signaling molecules' pathways in dystrophynopathies.

Animals↗
PubMed1999

Creatine kinase, cell membrane and Duchenne muscular dystrophy.

In 1958 Professor Setsuro Ebashi found that serum creatine kinase activity is increased in patients suffering from various muscular dystrophies, especially Duchenne muscular dystrophy (DMD). He and others proposed that creatine kinase passes through the cell membrane as it is released from DMD muscle fibers. Since then, it has been found that dystrophin and dystrophin-associated proteins are connected to several other components, including the basal lamina and subsarcolemmal cytoskeletal networks on the cell membrane, while dystrophin anchors these dystrophin-associated proteins to the actin filaments inside the muscle cell. In DMD muscle, dystrophin has been found to be absent and dystroglycans and sarcoglycans decreased. However, how creatine kinase molecules can pass through the DMD muscle cell membrane still remains unanswered. On the basis of recent findings on the structure of the protein layers which sandwich the lipid bilayer of muscle cell membranes, this essay stresses the importance of these lipid bilayers in protecting creatine kinase release from protoplasma in normal muscle. It further indicates the possibility that the absence of dystrophin in DMD muscle during muscle contraction may result in temporal damage to the lipid bilayer.

Binding Sites↗
PubMed1999

The role of tissue studies in facilitating early initiation of antimycobacterial treatment in AIDS patients with disseminated mycobacterial disease.

SETTING: The question of whether aggressive investigations are useful in diagnosis and initiation of treatment in AIDS patients with disseminated mycobacterial disease (DMD) is still under debate. OBJECTIVE: To define the role of tissue studies in facilitating early initiation of antimycobacterial treatment and in establishing diagnosis in AIDS patients with DMD. DESIGN: From July 1994 through June 1997, 167 AIDS cases with fever were evaluated by stepwise investigation using a standardized protocol. Data of DMD cases were analyzed to define the role of tissue studies. RESULTS: A total of 40 cases of culture-proven DMD were identified. Antimycobacterial treatment was initiated due to positive acid-fast bacilli smears of sputum in only five cases. In the remaining cases, positive pathologic findings from tissue biopsies (lymph node, bone marrow or liver) facilitated early initiation of treatment in 60% (21/35). In 50% of all cases (20/40), the diagnosis could not have been established if cultures of tissue biopsies had not been performed. Both the pathologic examinations and mycobacterial cultures from liver biopsies had positivity rates of more than 50% (53.8% and 69.2%, respectively). CONCLUSIONS: Tissue studies were useful in facilitating early initiation of treatment and establishing diagnosis at least in half of the AIDS cases with DMD. Liver biopsy is worthwhile if the cause of fever is not discovered using less invasive investigations.

AIDS-Related Opportunistic Infections↗