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Summary: Neuromuscular disorders are characterised by progressive muscle weakness, which in time causes functional impairment. To quantify the extent of disease progression, muscle force and functional ability can be measured. Which of these parameters changes most depends on the disease stage. In a previous study, we reported normal values for muscle force obtained by hand-held dynamometry in healthy children aged 4–16 years. In the present study, we report normal values for timed functional tests in healthy children aged 4–11 years. These normal values were compared with values obtained in 16 ambulant patients with Duchenne muscular dystrophy (DMD) aged 5–8 years to study the extent of functional impairment. In ambulant patients with DMD, we found that muscle function assessed by timed functional tests (running 9m and rising up from the floor) and muscle force assessed by hand-held dynamometry were severely impaired. However, a small reduction of muscle force was accompanied by a large reduction in functional ability. Therefore, in our group of ambulant patients with DMD, timed functional testing was the most sensitive parameter to determine the extent of disease progression. Timed functional testing may therefore be considered as an additional outcome measure in drug trials to evaluate the effects of therapy in ambulant patients with DMD and possibly in other neuromuscular disorders. [Copyright &y& Elsevier]

Abstract: We show that the drosophila gene encoding the dystrophin-like protein (DLP) is as complex as the mammalian dystrophin gene. Three 5′ promoters and three internal promoters regulate the expression of three full-length and three truncated products, respectively. The existence of this complex gene structure in such evolutionary remote organisms suggests that both types of products have diverse important functions. The promoters of both the DLP gene and the mammalian dystrophin gene are located in very large introns. These introns contribute significantly to the large size of the genes. The possible relevance of the conservation of the large size of introns containing promoters to the regulation of promoter activity is discussed. [Copyright &y& Elsevier]

Abstract: Non-viral gene transfer into skeletal muscle is enhanced by electroporation and myotoxin preconditioning of muscle following plasmid injection. We investigated in vivo delivery of naked DNA to mdx mouse muscle, utilising enhanced green fluorescent protein reporter vector (pEGFP) and a corrective nucleic acid to promote targeted corrective gene conversion at the mutant mdx mouse dystrophin (DMD mdx ) locus. Electroporation, myoablation with bupivacaine and a combined protocol, were applied to mdx muscle. We report up to 90% EGFP expression in electroporated mdx tibialis anterior muscle. Muscles preconditioned with bupivacaine showed low transgene expression with or without EP. Single EGFP+ve muscle fibre explants showed EGFP expression in mature fibres in preference to satellite cells. We observed a two-fold increase (P<0.005; t) in dystrophin protein, accompanied by wild-type (wt) DMD transcript in muscles injected with corrective nucleic acid over contralateral saline-injected TAs. By targeting the muscle fibres in preference to the satellite cells, plasmid-bourne transgenes delivered to dystrophic muscle will not penetrate the regenerative component of muscle. Whether in the context of targeted corrective gene conversion or therapeutic non-viral transgenes, under these conditions periodic re-administration will be required to promote phenotypic benefits in dystrophic muscle. [Copyright &y& Elsevier]

The manipulation of pre-mRNA to alter gene transcript splicing patterns offers considerable potential for many genetic disorders. In particular, the targeted removal of one or more exons from a gene transcript can skip over, or compensate for, disease-causing mutations. Duchenne muscular dystrophy (DMD), the most common and severe form of muscular dystrophy, is one such disorder that could benefit from this strategy. Splicing modulation can convert a DMD phenotype into the less severe allelic Becker-like phenotype. Recent studies using antisense oligonucleotide-targeted exon skipping to induce near normal dystrophin in vivo in animal models, and in vitro in DMD cell lines, highlight the promise of this approach. On the basis of these successes, human clinical trials could be realized in the near future. [Copyright &y& Elsevier]

We hypothesize that Duchenne muscular dystrophy and autism spectrum disorder/pervasive developmental disorder co-occur with a greater than random frequency. In this study, we set out to reject the hypothesis that Duchenne muscular dystrophy and autism spectrum disorder/pervasive developmental disorder co-occur no more often than expected by chance. Two index cases and six additional boys with concomitant Duchenne muscular dystrophy and autism spectrum disorder were identified in a muscular dystrophy clinic that approximates the total number of Duchenne muscular dystrophy boys (158) in the state of Massachusetts. The rate of prevalence (6 of 158) was compared with the prevalence rate of autism spectrum disorder in boys in the general population (1.6 in 1000). We rejected the hypothesis that Duchenne muscular dystrophy and autism spectrum disorder co-occurrence was likely to be explained by chance (P = .006). We identify a previously unrecognized association of Duchenne muscular dystrophy with autism spectrum disorder. Further work might elucidate the level of association between these two conditions, either at the genetic or at the protein level, and might clarify, at least partially, the neurobiologic mechanisms associated with autism spectrum disorder. [ABSTRACT FROM AUTHOR]

Abstract: Antisense oligodeoxynucleotide against the splicing enhancer sequence (SES) in exon 19 of the dystrophin gene have been shown to induce exon 19 skipping and promote the expression of internally deleted dystrophin by correcting the translational reading frame in the cultured Duchenne muscular dystrophy (DMD) myocytes with the deletion of exon 20. Transfection of the antisense oligodeoxynucleotide, therefore, has been proposed as a promising means for therapeutic modification of dystrophin mRNA of DMD, a fatal disorder caused by defects in the dystrophin gene. A systemic delivery method targeting the large number of diseased muscles remains to be established for clinical application of antisense oligodeoxynucleotide. In this study, we investigated capability of oligodeoxynucleotide transfer into the skeletal muscles of mdx mouse, a mouse model of DMD. Thirty-one mer phosphorothioate oligodeoxynucleotide complementary to the SES of dystrophin exon 19 was intraperitoneally administered to mdx mice without any carrier. Histochemical study disclosed that fluorescence-labeled oligodeoxynucleotide appeared in the nuclei of femoral skeletal muscle cell at the second day after injection of 20mg/kg BW oligodeoxynucleotide, and still visible at 14th day. Reverse transcription (RT)-PCR analysis of dystrophin transcript in these cells disclosed that a proportion of it showed skipping of exon 19 from second to seventh day after injection. These results showed that the intraperitoneally administered oligodeoxynucleotide could be transfected to nucleus of mdx skeletal muscle without any carrier and was able to induce exon skipping in vivo. [Copyright &y& Elsevier]

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease with death usually occurring because of respiratory failure. Signs of early respiratory insufficiency are usually first detectable in sleep. Objective: To study the presentation of sleep-related breathing disorder (SRBD) in patients with DMD. Method: A retrospective review of patients with DMD attending a tertiary paediatric sleep disorder clinic over a 5-year period. Symptoms, lung function and polysomnographic indices were reviewed. Results: A total of 34 patients with DMD were referred for respiratory assessment (1–15 years). Twenty-two (64%) reported sleep-related symptomatology. Forced vital capacity (FVC) was between 12 and 107% predicted ( n = 29). Thirty-two progressed to have polysomnography of which 15 were normal studies (median age: 10 years) and 10 (31%) were diagnostic of obstructive sleep apnoea (OSA) (median age: 8 years). A total of 11 patients (32%) showed hypoventilation (median age: 13 years) during the 5-year period and non-invasive ventilation (NIV) was offered to them. The median FVC of this group was 27% predicted. There was a significant improvement in the apnoea/hypopnoea index (AHI) (mean difference = 11.31, 95% CI = 5.91–16.70, P = 0.001) following the institution of NIV. Conclusions: The prevalence of SRBD in DMD is significant. There is a bimodal presentation of SRBD, with OSA found in the first decade and hypoventilation more commonly seen at the beginning of the second decade. Polysomnography is recommended in children with symptoms of OSA, or at the stage of becoming wheelchair-bound. In patients with the early stages of respiratory failure, assessment with polysomnography-identified sleep hypoventilation and assisted in initiating NIV. [ABSTRACT FROM AUTHOR]

Abstract: We investigated basic abnormalities of coagulation and fibrinolysis in Duchenne muscular dystrophy (DMD) patients with cardiac dysfunction. Forty seven patients with DMD, aged 13–37 years old, were enrolled. Based on left ventricular ejection fraction (LVEF) results determined by echocardiography, patients were divided into 3 groups: LVEF less than 30% (markedly depressed group), LVEF between 30 and 50% (slightly depressed), and LVEF greater than 50% (normal). We measured serum levels of total fibrin and fibrinogen degradation products (FDP), as well as plasma fibrinogen, thrombin–antithrombin complex (TAT), prothrombin fragment (F1+2), and D-dimer. The levels of TAT and F1+2 in the markedly depressed group were significantly elevated compared with the other groups, whereas FDP, fibrinogen, and D-dimer levels did not differ among the groups. We concluded that activated coagulation is associated with cardiac dysfunction in patients with DMD. [Copyright &y& Elsevier]

Abstract: The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to sarcolemmal instability and enhances the susceptibility of muscle fibers to contraction-induced injury. Various viral vectors have been used to deliver mini- and microdystrophin expression cassettes to muscles of dystrophin-deficient mdx mice, significantly increasing both the morphological and the functional properties of the muscles. However, dystrophin delivery to adult mdx mice has not yielded a complete rescue of the dystrophic phenotype. Here we investigated a novel strategy involving dual gene transfer of recombinant adeno-associated viral vectors expressing either microdystrophin (rAAV-μDys) or a muscle-specific isoform of Igf-1 (rAAV-mIgf-1). Injection of mdx muscles with rAAV-μDys reduced myofiber degeneration and turnover and increased their resistance to mechanical injury, but did not increase muscle mass or force generation. Injection of mdx muscles with rAAV-mIgf-1 led to increased muscle mass, but did not provide protection against mechanical injury or halt myofiber degeneration, leading to loss of the vector over time. In contrast, co-injection of the rAAV-μDys and rAAV-mIgf-1 vectors resulted in increased muscle mass and strength, reduced myofiber degeneration, and increased protection against contraction-induced injury. These results suggest that a dual-gene, combinatorial strategy could enhance the efficacy of gene therapy of DMD. [Copyright &y& Elsevier]

The author, who has a grown son with Duchenne Muscular Dystrophy (DMD), has personally experienced a lack of available information for parents about coping with DMD. Therefore, as a longtime personal goal, she developed this study to address that lack of information. Fifteen semi-structured interviews were conducted with 23 parents ( n = 7 with both parents; n = 1 with two sisters; n = 6 with mothers only; n = 1 with father only). The purpose of the interviews was to examine the strategies parents use to cope when their sons have DMD. The interviews were conducted in 12 states, taped and transcribed. Grounded theory analysis of the interview data indicated the willingness of these parents to share information to empower others like themselves. Parents want to be heard and valued as experts on DMD by medical and other professionals who interact with their sons. In addition, they want to proactively participate in their sons’ lives and to encourage other parents to do the same. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Upregulation of utrophin in muscle is currently being examined as a potential therapy for Duchenne muscular dystrophy patients. In this context, we generated transgenic mice harboring a 1.3kb human utrophin A promoter fragment driving expression of the lacZ gene. Characterization of reporter expression during postnatal muscle development revealed that the levels and localization of β-galactosidase parallel expression of utrophin A transcripts. Moreover, we noted that the utrophin A promoter is more active in slow soleus muscles. Additionally, expression of the reporter gene was regulated during muscle regeneration in a manner similar to utrophin A transcripts. Together, these results show that the utrophin A promoter-lacZ construct mirrors expression of utrophin A mRNAs indicating that this utrophin A promoter fragment confers temporal and spatial patterns of expression in skeletal muscle. This transgenic mouse will be valuable as an in vivo model for developing and testing molecules aimed at increasing utrophin A expression. [Copyright &y& Elsevier]

Abstract: This article reports on a clinical study concerning twenty-six children, siblings of children with muscular dystrophy aiming at assessing their identity and affective room to manoeuvre. Interviews, drawings and games of the children allow understanding their identity feeling, emotional environment and expressions of affects. The study shows how much the children have to force themselves to adapt to a family space that is invaded by the handicapped child. Some children try to avoid these constraints by running away, others circumvent them by idealizing the disabled child, and others adopt a caring attitude towards the disabled child, and through him, towards parental wounds. [Copyright &y& Elsevier]

Abstract: α-Dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), while β-dystroglycan is a type I integral membrane protein which anchors α-dystroglycan to the cell membrane via the N-terminal extracellular domain. The complex composed of α-and β-dystroglycan is called the dystroglycan complex. We reported previously a matrix metalloproteinase (MMP) activity that disrupts the dystroglycan complex by cleaving the extracellular domain of β-dystroglycan. This MMP creates a characteristic 30kDa fragment of β-dystroglycan that is detected by the monoclonal antibody 43DAG/8D5 directed against the C-terminus of β-dystroglycan. We also reported that the 30kDa fragment of β-dystroglycan was increased in the skeletal and cardiac muscles of cardiomyopathic hamsters, the model animals of sarcoglycanopathy, and that this resulted in the disruption of the link between the ECM and cell membrane via the dystroglycan complex. In this study, we investigated the proteolysis of β-dystroglycan in the biopsied skeletal muscles of various human muscular diseases, including sarcoglycanopathy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy, Miyoshi myopathy, LGMD2A, facioscapulohumeral muscular dystrophy, myotonic dystrophy and dermatomyositis/polymyositis. We show that the 30kDa fragment of β-dystroglycan is increased significantly in sarcoglycanopathy and DMD, but not in the other diseases. We propose that the proteolysis of β-dystroglycan may contribute to skeletal muscle degeneration by disrupting the link between the ECM and cell membrane in sarcoglycanopathy and DMD. [Copyright &y& Elsevier]

Mutations in myostatin (GDF8) cause marked increases in muscle mass, suggesting that this transforming growth factor-β (TGF-β) superfamily member negatively regulates muscle growth. Myostatin blockade therefore offers a strategy for reversing muscle wasting in Duchenne's muscular dystrophy (DMD) without resorting to genetic manipulation. Here, we demonstrate that pharmacological blockade using a myostatin propeptide stabilized by fusion to IgG-Fc improved pathophysiology of the mdx mouse model of DMD. Functional benefits evidenced by specific force improvement, exceeded those reported previously using myostatin antibody-mediated blockade. More importantly, use of a propeptide blockade strategy obviates possibilities of anti-idiotypic responses that could potentially limit the effectiveness of antibody-mediated myostatin blockade strategies over time. This study provides a novel pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD and since it uses an endogenous inhibitor of myostatin should help circumvent technical hurdles and toxicity associated with conventional gene or cell based therapies. [ABSTRACT FROM AUTHOR]

This study assessed the implications of changing the protocol for newborn screening for Duchenne muscular dystrophy (DMD) to make choice more explicit. In the intervention group, if screening was requested, a separate card was used. Mothers from both intervention and control groups completed a questionnaire providing data on satisfaction, awareness the test was optional, choice and worry. Overall the Intervention did improve satisfaction and awareness that the test was optional with no increase in levels of worry. However, some mothers felt they had been given a choice about screening, but were not aware that the test was optional. There is evidence that even with a rigorous service delivery protocol situations do arise where a decision to screen may not be 'consented'. This raises important questions about the feasibility of obtaining consent for other newborn screening tests and subsequent storage of DNA. [ABSTRACT FROM AUTHOR]

Abstract: Aquaporin-4 (AQP4) is the major water channel expressed in brain perivascular astrocyte processes. Although the role of AQP4 in brain edema has been extensively investigated, little information exists regarding its functional role at the blood–brain barrier (BBB). The purpose of this work is to integrate previous and recent data regarding AQP4 expression during BBB formation and depending on BBB integrity, using several experimental models. Results from studies on the chick optic tectum, a well-established model of BBB development, and the effect of lipopolysaccharide on the BBB integrity and on perivascular AQP4 expression have been analyzed and discussed. Moreover, data on the BBB structure and AQP4 expression in murine models of Duchenne muscular dystrophy are reviewed. In particular, published results obtained from mdx3cv mice have been analyzed together with new data obtained from mdx mice in which all the dystrophin isoforms including DP71 are strongly reduced. Finally, the role of the endothelial component on AQP4 cellular expression and distribution has been investigated using rat primary astrocytes and brain capillary endothelial cell co-cultures as an in vitro model of BBB. [Copyright &y& Elsevier]

Abstract: Remodeling of adherens junction, gap junction, and desmosomal proteins at the intercalated discs of cardiomyocytes in heart characterizes several animal models of cardiomyopathy, especially dilated cardiac myopathy (DCM). In this study, we show that the tight junction protein, claudin-5, is present in cardiac muscle and localizes to the lateral membranes of cardiomyocytes in normal mice. We further examined claudin-5 in utrophin/dystrophin-deficient (double knockout, dko) mice, a mouse model of muscular dystrophy with cardiomyopathy, and found that claudin-5 mRNA and protein levels are decreased in dko hearts as compared with normal. Intercalated disc cell junction proteins, and another tight junction protein, zonula occludens-1 (ZO-1), are not altered in the dko mouse. Ultrastructural data from dko hearts also shows that the lateral membranes of cardiomyocytes exhibit an abnormal wavy appearance. These data demonstrate that claudin-5 is specifically altered in dko hearts, suggesting that alterations of the lateral membranes of cardiomyocytes, rather than intercalated discs, are associated with cardiomyopathy in the dko mouse. [Copyright &y& Elsevier]

The knowledge of adult life with Duchenne muscular dystrophy (DMD) is sparse. The purpose of this study was to review existing information and describe body functional, social participatory and quality of life profiles of the ordinary adult Danish DMD patient. Sixty-five study subjects aged 18-42 years were included in a cross-sectional survey based on data from a semi-structured questionnaire comprising 197 items. The ordinary adult DMD patient states his quality of life as excellent; he is worried neither about his disease nor about the future. His assessment of income, hours of personal assistance, housing, years spent in school and ability to participate in desired activities are positive. Despite heavy immobilization, he is still capable of functioning in a variety of activities that are associated with normal life. He lacks qualifying education and he is in painful need of a love life. The frequency of pains is surprisingly high; nearly 40% has pains daily. The nature, magnitude, consequence and possible cure of these reported pains must be scrutinized. Parents and professionals, paediatricians not the least, must anticipate in all measures taken that the DMD boy grows up to manhood and will need competences for adult social life in all respects. [ABSTRACT FROM AUTHOR]

Corticosteroids are a diverse class of drugs that are used in a wide variety of clinical disorders. Anesthetists are most familiar with corticosteroids in the context of their use in conditions such as cerebral edema, asthma, acute respiratory distress syndrome, and in the prevention of postoperative nausea and vomiting. In recent years, the use of these drugs has gained prominence in the management of patients with Duchenne muscular dystrophy (DMD). Although reviews of DMD have been published in the anesthesia literature, none has discussed the effects of corticosteroids on the course of this debilitating disease. This review will focus on the role of corticosteroids and their implications for anesthetic management in DMD. [ABSTRACT FROM AUTHOR]

We assessed the cardiac findings in Duchenne muscular dystrophy (DMD) and Becker-Kiener muscular dystrophy (BMD) patients in the large outpatient group of our single-center institution. The analysis included the revision of patient records (retrospectively) and current echocardiography, electrocardiogram (ECG), and Holter ECG data (prospectively). Reduced left ventricular fraction shortening (FS)<25% was found in 24% of all patients (50 DMD, 12.1 ± 4.7 years: 20 BMD, 17.1 ± 8.5 years). Median age of onset of FS<25% was 16.8 ± 1.0 in DMD and 30.4 ± 3.4 in BMD; (p<0.05). Holter ECG in DMD demonstrated sinus tachycardia in 26% deprivation of circadian rhythm in 31%, and reduced heart rate variability in 51%. For these reasons, we recommend carrying out echocardiography annually in DMD and BMD>10 years. Because the rate of disturbances in the cardiac autonomic nervous system is high in DMD, we also recommend Holter ECG annually. Further investigation should be conducted to determine if treatment with ß-blockers and ACE inhibitors in combination reduces cardiac autonomic nervous imbalance, thus improving patient outcome in DMD. [ABSTRACT FROM AUTHOR]

Background Prednisone treatment is used to prolong ambulation in patients with Duchenne muscular dystrophy (DMD). However, since severe adverse effects often accompany prednisone treatment, it is debatable whether the benefits of prednisone treatment outweigh its adverse effects. Objectives To study the effects of prednisone on muscle function and to determine the extent of steroid-related adverse effects and their influence on the quality of life of ambulant patients with DMD. Design A randomized, placebo-controlled, crossover trial with 6 months of treatment: prednisone or placebo (0.75 mg/kg daily) during the first 10 days of each month. After a washout period of 2 months, patients received the other regimen for an additional 6 months. Setting University hospital and rehabilitation center in the Netherlands. Patients Seventeen ambulant patients with DMD aged 5 to 8 years. Main Outcome Measure Change in muscle function assessed by timed functional testing: running 9 m, climbing 4 standard-sized stairs, and rising from the floor to a standing position. Results The increase in time needed to run 9 m (P = .005) and to climb 4 standard-sized stairs (P = .02) was significantly lower during the prednisone period. Conclusions Prednisone slowed deterioration of muscle function and muscle force in ambulant patients with DMD. Although adverse effects were present, patient quality of life was not affected. Therefore, short-term prednisone treatment can be recommended to preserve motor functions in ambulant patients with DMD. [ABSTRACT FROM AUTHOR]

Provides information on the case of an Amish school-aged boy diagnosed with Duchene muscular dystrophy (DMD). Information on the disruptive behavior of the boy during his classes; Background of DMD, a muscular paralysis associated with muscle hypertrophy and accumulation of large amounts of fat in muscle; Percentage of DMD patients with some degree of mental retardation and cognitive deficiency.

Utrophin can function in muscle as a substitute for dystrophin and its over-expression has been used successfully to ameliorate mdx muscle pathology. Despite of this fact, there are no detailed studies on the expression of endogenous skeletal muscle utrophin- and dystrophin-associated glycoproteins throughout the life span of mdx mice. We have monitored, sequentially, the expression of matrix metalloproteinase-9 (MMP-9), myosin heavy chain, utrophin and ß-dystroglycan, as well as the mRNA expression of utrophin and of structurally related proteins, in mdx and control mice. We found an inverse relationship between concentration of muscle utrophin and abundance of groups of degenerative-regenerative fibers and of MMP-9 expression. There was also temporal correlation between the decline of utrophin at 15 days of age and the onset of muscle necrosis. Conversely, reappearance of utrophin, with a peak around 2 months of age, was followed by a progressive decline of necrosis. A lineal correlation between utrophin and ß-dystroglycan levels, not seen in controls, indicates that improvement of mdx is due to utrophin binding to dystrophin-associated glycoproteins. Utrophin and other structurally related protein transcripts were not up-regulated, suggesting a post-transcriptional regulation for utrophin in skeletal muscle. [ABSTRACT FROM AUTHOR]

Adenoviral vector (Ad)-mediated gene delivery of normal, full-length dystrophin to skeletal muscle provides a promising strategy for the treatment of Duchenne muscular dystrophy (DMD). However, cellular and humoral immune responses induced by vector gene transfer limit the application of this approach. Blockade of the costimulatory interaction between naïve T cells and antigen-presenting cells has proven to be a successful means to diminish immunity induced by gene transfer. In this study we explore the potential of supplementing dystrophin gene delivery to dystrophin-deficient Dmd mouse skeletal muscle with systemic gene delivery of CTLA4Ig and CD40Ig molecules to effect costimulatory blockade. We found that systemic administration of a high-capacity Ad (HC-Ad) vector carrying murine CTLA4Ig (AdmCTLA4Ig) either alone or codelivered with an HC-Ad vector carrying murine CD40Ig (AdmCD40Ig) provided sustained expression of recombinant full-length murine dystrophin from an HC-Ad vector carrying the dystrophin cDNA (AdmDys). The level of AdmDys vector genomes remained stable in animals cotreated with systemic delivery of vectors carrying molecules to block costimulation. In addition, muscle CD4+ and CD8+ T cell infiltrates and Th1 cytokine production by splenocytes were reduced. The production of neutralizing antibody against Ad vector was significantly inhibited in mice receiving systemic codelivery of both AdmCTLA4Ig and AdmCD40Ig, but not in the mice treated with AdmCTLA4Ig alone. The results suggested that coblockade of both CD28/B7 and CD40L/CD40 costimulatory pathways is required for effective inhibition of the Ad vector-induced humoral immune response in Dmd mice, whereas blockade of CD28/B7 alone by murine CTLA4Ig would be sufficient for prolonged dystrophin expression in treated muscle. [Copyright &y& Elsevier]

We compare the long-term benefits and side effects of deflazacort using two treatment protocols from Naples (N) and Toronto (T). Boys with Duchenne muscular dystrophy between the ages of 8 and 15 years and who had four or more years of deflazacort treatment were reviewed. Diagnostic criteria included males with proximal muscle weakness evident before 5 years, increased serum creatine kinase and genetic testing and/or a muscle biopsy consistent with Duchenne muscular dystrophy. Thirty-seven boys were treated with protocol-N using deflazacort at a dose of 0.6 mg/kg per day for the first 20 days of the month and no deflazacort for the remainder of the month. Boys with osteoporosis received daily vitamin D and calcium. Deflazacort treatment started between 4 and 8 years of age. Thirty-two were treated with protocol-T using deflazacort at a dose of 0.9 mg/kg per day, plus daily vitamin D and calcium. Treatment started between 6 and 8 years of age. All boys were monitored every 4–6 months. The results were compared with age-matched controls in the two groups (19 for protocol-N and 30 for protocol-T). For the boys treated with protocol-N, 97% were ambulatory at 9 years (control, 22%), 35% at 12 years (control, 0%), 25% at 15 years (control, 0%). For the 32 boys treated with protocol-T, 100% were ambulatory at 9 years (control, 48%), 83% at 12 years (control, 0%) and 77% at 15 years (control, 0%). No aids or leg braces were used for ambulation. In boys 13 years and older, a scoliosis of >20° developed in 30% of the boys on protocol-N, 16% on protocol-T and 90% of controls. For protocol-N, no cataracts were observed while in protocol-T, 30% of boys had asymptomatic cataracts that required no treatment. Fractures occurred in 19% (control 16%) of boys on protocol-N and 16% (control, 20%) of boys on protocol-T. This report illustrates: (a) the importance of collaborative studies in developing treatment protocols in Duchenne muscular dystrophy and (b) the long-term beneficial effects of deflazacort treatment in both protocols. However, the protocol-T seems to be more effective and frequently is associated with asymptomatic cataracts. [Copyright &y& Elsevier]

Plasma nitric oxide (NO) levels in Duchenne muscular dystrophy (DMD) patients were significantly lower than those observed in both healthy controls and in patients with other neuromuscular disorders. The correlation between NO level and ejection fraction was significant (r = –0.384, p = 0.0391) in the DMD group. Disruption of NO systems may contribute to the development of muscular dystrophy and have implications for therapeutic strategies. Copyright © 2004 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The mdx mouse, a model of the human disease Duchenne muscular dystrophy, has skeletal muscle fibres which display incompletely understood impaired contractile function. We explored the possibility that action potential-evoked Ca2+ release is altered in mdx fibres. Action potential-evoked Ca2+-dependent fluorescence transients were recorded, using both low and high affinity Ca2+ indicators, from enzymatically isolated fibres obtained from extensor digitorum longus (EDL) and flexor digitorum brevis (FDB) muscles of normal and mdx mice. Fibres were immobilized using either intracellular EGTA or N-benzyl-p-toluene sulphonamide, an inhibitor of the myosin II ATPase. We found that the amplitude of the action potential-evoked Ca2+ transients was significantly decreased in mdx mice with no measured difference in that of the surface action potential. In addition, Ca2+ transients recorded from mdx fibres in the absence of EGTA also displayed a marked prolongation of the slow decay phase. Model simulations of the action potential-evoked transients in the presence of high EGTA concentrations suggest that the reduction in the evoked sarcoplasmic reticulum Ca2+ release flux is responsible for the decrease in the peak of the Ca2+ transient in mdx fibres. Since the myoplasmic Ca2+ concentration is a critical regulator of muscle contraction, these results may help to explain the weakness observed in skeletal muscle fibres from mdx mice and, possibly, Duchenne muscular dystrophy patients. [ABSTRACT FROM AUTHOR]

Synapses on the motor neurons of patients with Duchenne muscular dystrophy (DMD) and myotonic dystrophy (MD) were studied immunohistochemically using antibodies against synaptobrevin and synaptophysin. Some motor neurons showed hyperproliferation of synapses on the soma and the proximal dendrites. Hyperproliferated synapses were non-cholinergic, because they were not identified with antibodies against vesicular acetylcholine transporter. Regeneration of motor nerve terminals in patients with muscular diseases may affect reorganization of the subsets of central synapses. [ABSTRACT FROM AUTHOR]

Mechanical ventilation of patients with Duchenne muscular dystrophy continues to be a subject of study. The purpose was to estimate prevalence, incidence, mortality and use of mechanical ventilation in the total Duchenne muscular dystrophy population in Denmark between 1977 and 2001 and further, to reconstruct the introduction of mechanical ventilation to assess the role of the patient organization. Study objects were collected from five sources and verifiable cases identified. Negotiations between health authorities and the patient organization constituted main empirical data for the reconstruction. While overall incidence remained stable at 2.0 per 105, prevalence rose from 3.1 to 5.5 per 105, mortality fell from 4.7 to 2.6 per 100 years at risk and prevalence of Duchenne muscular dystrophy ventilator users rose from 0.9 to 43.4 per 100. We conclude that survival of Duchenne muscular dystrophy patients has increased and ventilator use is probably a main reason. The patient organization exercised a key role but acted upon preconditions created by other players. [Copyright &y& Elsevier]

Primary deficiency of merosin causes a severe congenital muscular dystrophy (CMD) and a mouse dystrophy (dy/dy mouse). Also, its secondary deficiency is seen in some CMD with abnormal glycosylation of Α-dystroglycan, an extracellular membrane protein, which is the receptor of merosin and binds to dystrophin underlying the sarcolenma via Β-dystroglycan, a transmembrane protein. In immunogold and freeze-etch electron microscopic studies, merosin in basal lamina of normal skeletal muscles has a zonation in the distribution and is localized at the lamina lucida of muscle basal lamina, and dystrophin molecules are often closed to merosin molecules at the inside and outside surface of muscle plasma membrane. Moreover, merosin molecules exist as the short fine cross-bridge fibrils connecting the basal lamina to the neighboring outer leaflet of the muscle plasma membrane. In freeze-fracture studies, the changes in muscle plasma membranes of dy/dy mice reveal a markedly decreased density of orthogonal arrays (OAs) but normal density of intramembranous particles (IMPs), whereas depletions of IMPs with decreased OAs have been found in Fukyama-type congenital muscular dystrophy, Duchenne muscular dystrophy, and mdx mice. Thus, further studies including the functional role of OAs would be required to understand the pathomechanism of merosin-deficient CMD. [ABSTRACT FROM AUTHOR]

Purpose : The aim of this study is to determine the architectural barriers of children with Muscular Dystrophy at home according to their diminished functional capacity and its effect on their mother's back problem. Method : Twenty children with Muscular Dystrophy (11.1 ± 4.14 years) were evaluated with Brooke Scale and WeeFIM. Quebec and Oswestry Disability Scales were used for determining physical disability of their mothers (38.65 ± 5.91 years). The architectural barriers have been detected with attention to standard criterias of International Organizations for all countries around the world. Results : The heights of thresholds, switches of wall plugs, shelves, cupboards, mirrors, hangers, arm of windows and siphons were found to be higher than standard values. The relation between back disability questionnaire results of mothers and dependency level of children on Activity of Daily Living has showed negative correlation (p < 0.05). Conclusions : The protective back health programmes and home arrangements that are suitable for disabled children must be added to the neuromuscular rehabilitation programmes. [ABSTRACT FROM AUTHOR]

We report two cases of Duchenne muscular dystrophy that presented with laboratory evidence of acute transient myocardial cell damage. The mechanism for development of cardiomyopathy associated with Duchenne muscular dystrophy is not well understood, and this report raises the possibility that the progressive deterioration of cardiac function is punctuated by acute episodes of cell damage. [ABSTRACT FROM AUTHOR]

Introduction: Forward bending, rotation, lifting, carrying, pulling and pushing during bathroom activities, dressing, transferring, feeding, etc. increase stress on structures in the back and neck of mothers caring for disabled children. The aim of this study was to determine the effect of independence level of children with muscular dystrophies on their mother's low back pain. Methods: Thirty mothers who had children with muscular dystrophies were included in this study. They were divided two groups as mothers of nonambulatory (group 1) and ambulatory (group 2) disabled children. To investigate the activities of daily living the WeeFIM scale was used; to investigate the functional status the Broke Scale was used. Quebec Back Pain Disability Scale (QBPDS) was used to measure disability and a visual analogue scale (VAS) was used to measure pain in mothers. Results: The QBPDS scores of mothers were higher in group 1 (36.13 ± 17.9) than in group 2 (20.8 ± 14.87). There was positive correlation between QBPDS, pain duration, and VAS, in group 1. In group 2, QBPDS score was correlated only with the age of the mother. [ABSTRACT FROM AUTHOR]

From July 1980 to July 2001 64 patients with progressive muscular dystrophy were subjected to spinal instrumentation at the Shriners Hospital for Crippled Children, Mexico City Unit. It consisted of two groups with the main criteria of inclusion: non ambulatory patients, spinal deformity, minimum vital capacity up to 30%. The first group had C2 to different instrumentation levels, with a mean follow up of 5 years (range 1 month-13 years). The second group included instrumentations from C2-S1 with a mean follow up of 2.47 years (range 1-7 years). Both groups were non ambulatory at 10 years. The age at surgery was 11.14 (5-17) in the first group and 10.73 in the second one. When the instrumentation were C2-S1, the spinal stability, kypholordotic equilibrium, minimum vital capacity obtained and respiratory tract infections decreased and the life conditions of the most of the patients were better and the capability for using wheel chair improved. [ABSTRACT FROM AUTHOR]

Estimates the incidence of congenital brachial palsy in the United Kingdom. Causes and outcome of congenital brachial palsy; Factors associated with the occurrence of congenital brachial palsy.

Objective: To collect benchmark data on the MOS 36-Item Short-Form Health Status Survey (SF-36) in patients receiving noninvasive positive pressure ventilation and to examine whether health-related quality of life is influenced by the underlying disease or by physical parameters.Design and Setting: Multicentric clinical cross-sectional trial in four general wards specialized in noninvasive positive pressure ventilation.Patients and Participants: 226 patients (78 chronic obstructive pulmonary disease, 57 kyphoscoliosis, 20 posttuberculosis sequelae, 17 Duchenne muscular dystrophy, 13 polyneuropathy, 13 myopathy, 6 amyotrophic lateral sclerosis, 12 obesity-hypoventilation syndrome, 4 poliomyelitis sequelae, 3 phrenic nerve lesion, 3 central hypoventilation syndrome) who used noninvasive positive pressure ventilation for home mechanical ventilation.Measurements and Results: Health-related quality of life as assessed by the SF-36 was lower than in the general population. Overall the Physical Component Summary (PCS) was significantly lower than the general population norm; the Mental Component Summary (MCS) was also reduced but less markedly. Patients with chronic obstructive pulmonary disease were more impaired in MCS than those with kyphoscoliosis. PCS was significantly associated with age. Gender, lung function, and arterial blood gas values were not significant predictors of health-related quality of life.Conclusions: Benchmark SF-36 data in patients receiving noninvasive positive pressure ventilation are given. Although physical health is significantly impaired in these patients, this does not necessarily lead to mental limitation, and mental health is influenced by the underlying disease, but not by physical parameters. [ABSTRACT FROM AUTHOR]

Our objective was to study the prevalence of neuromuscular diseases in Chinese children. A prospective study of neuromuscular diseases in Chinese children was conducted from 1985 to 2001 in Hong Kong, which is a city in southern China. The population census of June 30, 2001, was used to calculate the prevalence of neuromuscular diseases in Chinese children. Altogether, 332 children aged < 19 years at first assessment with neuromuscular diseases confirmed by using electromyography, muscle biopsy, and/or molecular genetic study were included in the study. Of these, 228 (68%) had inherited and 104 (32%) had noninherited neuromuscular diseases. Of the inherited neuromuscular diseases, the most common were the dystrophinopathies, including Duchenne muscular dystrophy (n = 66) and Becker muscular dystrophy (n = 8). Spinal muscular atrophy was the second most common (n = 61). Of the noninherited neuromuscular disorders, myasthenia gravis was the most common (n = 62, 60%). Nearly 88% of the cases of myasthenia gravis were ocular type. The prevalence rate of neuromuscular diseases in June 2001 (n = 291 surviving) is estimated to be 214 × 10[sup−6]. The estimated prevalence rate of neuromuscular diseases in our Chinese children is 1 in 4669. (J Child Neurol 2003;18:217–219). [ABSTRACT FROM AUTHOR]

Most cases of Duchenne muscular dystrophy are caused by dystrophin gene mutations that disrupt the mRNA reading frame. Artificial exclusion (skipping) of a single exon would often restore the reading frame, giving rise to a shorter, but still functional dystrophin protein. Here, we analyzed the ability of antisense U7 small nuclear (sn)RNA derivatives to alter dystrophin pre-mRNA splicing. As a proof of principle, we first targeted the splice sites flanking exon 23 of dystrophin pre-mRNA in the wild-type muscle cell line C2C12 and showed precise exon 23 skipping. The same strategy was then successfully adapted to dystrophic immortalized mdx muscle cells where exon-23-skipped dystrophin mRNA rescued dystrophin protein synthesis. Moreover, we observed a stimulation of antisense U7 snRNA expression by the murine muscle creatine kinase enhancer. These results demonstrate that alteration of dystrophin pre-mRNA splicing could correct dystrophin gene mutations by expression of specific U7 snRNA constructs. [ABSTRACT FROM AUTHOR]

A lack of effective treatments for Duchenne muscular dystrophy, a fatal X-linked myopathy, has focused attention on the possibility of gene therapy. The aim of the gene therapy approach is the restoration of the dystrophin associated complex of proteins, one member of which is neuronal nitric oxide synthase, an important enzyme in signal transduction. Transgenic mdx mice and plasmid gene transfer of both human and murine recombinant dystrophins was used to assess whether nNOS could be restored to the sarcolemma following dystrophin gene transfer at a variety of levels of expression. Murine revertant fibres and human patients with different dystrophin deletions were used to assess the relationship between exon deletion and loss of neuronal nitric oxide synthase localization to the sarcolemma. We demonstrate that the domain encoded by exons 45–48 is required for localization of neuronal nitric oxide synthase to the sarcolemma. On the basis of these observations we suggest that neuronal nitric oxide synthase is a useful marker for complete restoration of the dystrophin associated complex and should be used as one of the criteria for selecting the recombinant molecule to be used for gene therapy in Duchenne muscular dystrophy. [Copyright &y& Elsevier]

The human dystrophin gene has seven generally recognised promoters and one, the so-called lymphocyte promoter, whose status remains uncertain. We re-evaluated this promoter in the light of recently available human and mouse genome sequences, and attempted to compare its activity in lymphocytes with that of the muscle promoter. We find that the lymphocyte promoter lies immediately adjacent to the chronic granulomatous disease gene, CYBB, approximately 4.5 megabases upstream of dystrophin exon 2. This makes the supposed lymphocyte dystrophin primary transcript 7 megabases in size, with an expected transcription time in excess of 2 days. We also find that lymphocyte promoter use in peripheral blood lymphocytes is negligible compared to that of the muscle promoter in the same tissue. Together with the presence in the intron of a sense-strand multi-exon gene, and lack of conserved linkage in the mouse, we propose that the lymphocyte promoter is not a biologically significant part of the dystrophin gene. [Copyright &y& Elsevier]

Daily prednisone improves strength in boys with Duchenne muscular dystrophy, but side effects are almost universal. We used a different dosing regimen of prednisone to determine if benefit to boys with Duchenne muscular dystrophy might be maintained with fewer side effects. Twice weekly oral prednisone was given each Friday and Saturday (5 mg/kg/dose). This total dose is twice as high as the daily low dosage prednisone regimen (0.75 mg/kg/day). Twenty boys (8.0±1.2 years) were treated. Historical control groups included 18 untreated boys (6.1±1.6 years) and four boys (7.3±0.6 years) treated with daily prednisone. Strength (using a hand-held manometer and grip meter) and timed functional testing were measured. There was an improvement in upper extremity strength for 95% of boys (n=20) at 6 months using quantitative strength testing. Improvement in lower extremity strength occurred in all boys with antigravity quadriceps strength (17/17). The improvement (P=0.001 for proximal upper extremities; P=0.002 for grip; and P<0.0001 for proximal lower extremities) was significant compared to untreated boys. Sixteen boys were treated continuously for more than 12 months (22±1.5 months). Of these, 15 remained significantly stronger than prior to treatment and 8/16 showed additional gains in strength after six months of treatment. Six boys were on the weekly prednisolone 2 years or longer without interruption. All six had upper and lower extremity strength at follow-up that was as good or better than at baseline. Functional testing improved in boys less than 8 years without contractures. Three boys without antigravity quadriceps strength at the start of treatment lost the ability to walk unassisted within 6 months. Eight other boys lost the ability to ambulate unassisted between 12 and 24 months of treatment. In each, progressive contractures developed. Linear growth was maintained in all boys on weekly treatment. Obesity rates did not differ from untreated boys. Twice weekly prednisone improved strength over 6–12 months in the majority of boys, but did not slow contracture development. Sustained benefit beyond 12 months is possible with fewer side effects compared to daily prednisone. [Copyright &y& Elsevier]

We reviewed the notes of 197 patients with Duchenne muscular dystrophy whose treatment was managed at the Newcastle muscle centre from 1967 to 2002, to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation altered the pattern of survival. Patients were grouped according to the decade of death and whether or not they were ventilated. Kaplan Meier survival analyses showed significant decade on decade improvement in survival. Mean age of death in the 1960s was 14.4 years, whereas for those ventilated since 1990 it was 25.3 years. Cardiomyopathy significantly shortened life expectancy from 19 years to a mean age of 16.9 years.Better coordinated care probably improved the chances of survival to 25 years from 0% in the 1960s to 4% in the 1970s and 12% in the 1980s, but the impact of nocturnal ventilation has further improved this chance to 53% for those ventilated since 1990. [Copyright &y& Elsevier]

Discusses a study that evaluated the parental perceptions of the importance of services, health issues and aspects of quality of life in boys with Duchenne muscular dystrophy (DMD). Disruption caused by DMD to the lives of boys and their families; Methodology; Results and discussion.

Dystrophin deficiency causes Duchenne muscular dystrophy (DMD). Hypertrophic feline muscular dystrophy (HFMD) is a homologous animal model of DMD. Our objective was to investigate the early changes caused by dystrophin deficiency in skeletal muscle of cats of 3–4 and 6–9 months. Obvious histological lesions were already present in the younger cats, and they increased in magnitude over time. They consisted of multifocal areas of degeneration and regeneration with mononuclear infiltration, and a wide variation in myofiber diameter, as evidenced by significantly increased variability coefficients in muscle fiber size, myofiber splitting, central nuclei, and hypercontracted myofibers. Widespread multifocal mineralizations were frequently observed. Endomysial and perimysial fibrosis was not a feature observed in axial or appendicular muscles, but was present in the diaphragm of two cats at necropsy. There was a significant decrease in the number of type 2A myofibers in dystrophin-deficient cats at both ages. Sarcolemmal dystrophin was mostly absent in all dystrophin-deficient cats; however, a small percentage of fibers stained positive, accounting for a faint residual band in the immunoblot. Carrier females had a mosaic staining pattern with irregular staining in most fibers, or even absent staining in rare fibers. However, no histological lesions were seen. Taken together, these data provide significant baseline information for further studies on the early changes associated with dystrophin deficiency in cats, or use of young dystrophin-deficient cats in therapeutic trials. [ABSTRACT FROM AUTHOR]

Purpose: To describe a child with Muscle-Eye-Brain disease (MEB), one of three types of congenital muscular dystrophy associated with ocular abnormalities. Methods: Case report. Results: The child showed severe visual impairment due to progressive myopia and retinal degeneration, a pachygyria-type of migration disorder of the brain with a nodular cortical surface, i.e. cobblestone cortex, as well as muscular weakness and severe mental retardation. Conclusion: Ophthalmological assessments are important to help to diagnose and follow children with congenital muscular dystrophy. [ABSTRACT FROM AUTHOR]

Examines arrhythmia in children with muscular dystrophy. Use of electrocardiography, signal-averaged electrocardiography, and Holter monitoring; Frequency of premature atrial and ventricular contractions; Efficacy of the equipment used to monitor arrhythmia.

Duchenne muscular dystrophy (DMD) is a fatal and crippling disease of skeletal muscle which displays increased fibre turnover and elevated levels of programmed cell death (PCD) in muscle stem cells. Previously we showed that this cell death is inhibited by the growth factor IGF-II. To determine the functional significance of PCD to the dystrophic phenotype, we used a transgene to over-express IGF-II in the mdx mouse. We found that ectopic expression of IGF-II inhibited the elevated PCD observed in skeletal muscles in the absence of functional dystrophin and significantly ameliorates the early gross histopathological changes in skeletal muscles characteristic of the dystrophic phenotype. Replacement of the dystrophin gene abolished abnormal skeletal muscle cell PCD levels in vivo in a dose-dependent manner and in dystrophic SMS cell lines cultured in vitro. Thus elevation of stem cell PCD in dystrophic skeletal muscle is a direct consequence of the loss of functional dystrophin. Together these data demonstrate that elevated skeletal muscle cell PCD is a critical component of dystrophic pathology and is inversely correlated with both dystrophin gene dosage and with muscle fibre pathology. Targeting PCD in dystrophic muscles reduces both PCD and the classical features of dystrophic pathology in the mdx mouse suggesting that IGF-II is a strong candidate for therapeutic intervention in the dystrophinopathies. Cell Death and Differentiation (2000) 7, 1109–1118. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy is associated with variable degrees of selective cognitive defect with lower scores for verbal intelligence and reading abilities. A number of findings have shown that rearrangements located in the second part of the gene seem to be preferentially associated with cognitive impairment. Several dystrophin transcripts are expressed in the brain. The more distal of them, Dp71, is predominant. We have carried out a mutational analysis of Dp71 transcript in 12DMD patients severely, mildly or not retarded, all without detectable deletion or duplication. We have detected five point mutations causing Dp71 premature translation termination. All were found among the more severely mentally retarded patients of this group (VIQ < 50 and/or no reading acquisition). [ABSTRACT FROM AUTHOR]

Aciculin is a novel adherens junction antigen extracted from human uterine smooth muscle that is reported to associate biochemically with dystrophin. We attempted to determine (i) the immunostainability of anti-aciculin antibody for the 6 histochemically normal human muscles and seven muscles from boys with Duchenne muscular dystrophy(DMD) and 11 disease control muscles, (ii) the ultrastructural localization of aciculin in normal skeletal myofibers, (iii) aciculin’s spacial relationship with dystrophin and β-spectrin, and (iv) if the aciculin is ultrastructurally colocalized with dystrophin, the distance from the aciculin epitope to the epitope of the dystrophin N- or C-terminal domain. For this, rabbit anti-aciculin antibody was generated against the synthetic peptide of aciculin fragment D [4]. Immunohistochemical staining showed that the immunostainability of DMD muscles for anti-aciculin antibody was markedly decreased as compared with normal and disease control muscles. Single and double immunogold labeling electron microscopy of 6 histochemically normal human quadriceps femoris muscles revealed that aciculin was present along the inner surface of muscle plasma membrane and that aciculin formed doublets more frequently with dystrophin (23.5 ± 1.8%; group mean ± SE) than with β-spectrin (12.8 ± 1.1%; P < 0.01 two tailed t test). Rabbit anti-aciculin antibody frequently formed doublets with monoclonal antibodies against the N- or C-terminal domain of dystrophin at the muscle cell surface. These results suggest that aciculin is associated with dystrophin and may interact with both the N- and C-terminal domains of dystrophin. [ABSTRACT FROM AUTHOR]