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Biomedical subjects

V Dubowitz

Publications and source records attributed to V Dubowitz.

368 records · Page 21Linked to original sources
PubMedDate not supplied

Steroids in Duchenne muscular dystrophy; pilot study of a new low-dosage schedule.

Prednisolone has been shown to improve strength in Duchenne dystrophy, the improvement starting within 10 days of treatment and reaching a maximum by 3 months, and then plateauing. Unfortunately this has been associated with an unacceptably high level of side effects. In an attempt to obtain the benefit of steroids without the side effects we devised an intermittent low dosage schedule, with 0.75 mg kg-1 day-1 for 10 days at the beginning of each calendar month. To date 32 boys with Duchenne dystrophy have been enrolled into an open randomized trial. Preliminary data show an influence on strength at 6 months but a slow decline at 12 and 18 months. The weight gain and other side effects have been much less than with continuous therapy.

Child↗
PubMedDate not supplied

Expression of dystrophin-associated glycoproteins and utrophin in carriers of Duchenne muscular dystrophy.

The expression of dystrophin, the dystrophin-associated proteins and utrophin has been studied immunocytochemically in three young, manifesting carriers of Duchenne muscular dystrophy, aged 3, 5 and 12 yrs, one adult manifesting carrier, aged 60 yrs, and one presumptive carrier with a raised serum creatine kinase, aged 24 yrs, the mother of the 5-yr-old manifesting carrier. The manifesting carriers had variable degrees of weakness; the presumptive carrier had no weakness. Morphological abnormalities were also variable and were most marked in the young manifesting carriers. The three young manifesting carriers and the presumptive carrier had a mosaic pattern of dystrophin-positive and dystrophin-negative fibres. All the dystrophin-associated proteins were reduced in the dystrophin-deficient fibres, giving a similar mosaic pattern to dystrophin. Expression of dystrophin and the dystrophin-associated proteins was normal in the adult manifesting carrier. Utrophin was detected on the sarcolemma of fibres both with and without dystrophin and the dystrophin-associated proteins. Thus, dystrophin and utrophin are co-expressed in several fibres in carriers. The results emphasize the close association between dystrophin and the glycoprotein complex and their role in the pathogenesis of muscle damage. In addition, the presence of utrophin in fibres with greatly reduced glycoproteins suggests that very little of the glycoprotein complex may be required to anchor the amount of utrophin expressed at the sarcolemma in these particular cases.

Child↗
PubMedDate not supplied

The natural history of type I (severe) spinal muscular atrophy.

The clinical features of 36 patients who satisfied the diagnostic criteria for type I (severe) spinal muscular atrophy (Werdnig-Hoffmann disease) are reported. Survival data for both the whole cohort and for groups within the cohort subdivided on the age of onset are presented. These data suggest that the patients with onset at birth or within the first 2 months of life have a more uniformly poor prognosis with earlier death. This is of potential importance in any therapeutic trials in the future whose outcome may be based on length of survival.

Adolescent↗
PubMedDate not supplied

Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder for which the biochemical defect is as yet unknown. Recently, two cloned segments of human X-chromosome DNA have been described which detect structural alterations within or near the genetic locus responsible for the disorder. Both of these cloned segments were described as tightly linked to the locus and were capable of detecting deletions in the DNA of boys affected with DMD. In an attempt to determine more precisely the occurrence of these deletions within a large population of DMD patients and the accuracy of one of the segments, DXS164 (pERT87), in determining the inheritance of the DMD X chromosome, the subclones 1, 8 and 15 were made available to many investigators throughout the world. Here we describe the combined results of more than 20 research laboratories with respect to the occurrence of deletions at the DXS164 locus in DNA samples isolated from patients with DMD and Becker muscular dystrophy (BMD). The results indicate that the DXS164 locus apparently recombines with DMD 5% of the time, but is probably located between independent sites of mutation which yield DMD. The breakpoints of some deletions are delineated within the DXS164 locus, and it is evident that the deletions at the DMD locus are frequent and extremely large.

Chromosome Deletion↗
PubMedDate not supplied

What is muscular dystrophy? Forty years of progressive ignorance.

This lecture traces recent advances in knowledge of the muscular dystrophies, as well as their increasing complexity. They are described through the eyes of the author from his first exposure to and complete ignorance of the disease in the late 1950s, through the advent of modern techniques, to the molecular genetic revolution, with the recognition of individual genes and proteins for disorders within the muscular dystrophy umbrella. There initially seemed to be a logical sequence of linked membrane proteins from dystrophin in Duchenne and Becker dystrophy, through the dystrophin-associated glycoproteins (sarcoglycans) in some of the limb girdle muscular dystrophies (LGMD), to the extracellular matrix protein merosin (alpha-2 laminin) in congenital muscular dystrophy (CMD). The first spoke in the wheel came with the discovery of a calcium activated protease enzyme, calpain 3, in one form of LGMD, and subsequently another novel non-membrane protein, dysferlin, in another. There are currently at least eight distinct genetic forms of LGMD alone, and another eight separate genetic entities in the CMD group. This has highlighted our ignorance of the pathogenesis of the muscular dystrophies in relation to a diverse array of protein deficiencies. To compound things further, the X-linked and dominant forms of Emery-Dreifuss muscular dystrophy have recently been linked to emerin and lamin A/C, respectively, two proteins of the nuclear membrane, opening up yet another new ballpark of discovery.

Diagnosis, Differential↗
PubMedDate not supplied

A comparative study of in vitro proliferative responses to mitogens and immunoglobulin production in patients with inflammatory muscle disease.

The classification of inflammatory muscle disorders is at best confusing owing to the wide spectrum of clinical, histological and serological findings within this group of patients. Although it is generally agreed that most cases reflect an autoimmune disorder with skeletal muscle as the primary target tissue, additional features of the more common form of the disease in juvenile patients, dermatomyositis, have suggested that it may differ in aetiology and pathogenesis from other forms of inflammatory muscle disease. Some adults may also be included within this category. In this study, we have divided patients with inflammatory muscle disease into two groups, 8 adult patients with 'pure' polymyositis and 13 children with dermatomyositis, and compared their in vitro lymphocyte function. Abnormal proliferative responses to T-cell mitogens were shown by peripheral blood mononuclear cells (PBM) from adult patients. PBM from the children gave values similar to normal control children. In vitro immunoglobulin production by cells from adult patients was comparable with appropriate controls both in the presence and absence of pokeweed mitogen. Childhood controls responded similarly to normal adults. PBM from the juvenile patients with dermatomyositis, however, produced significantly elevated levels of immunoglobulin spontaneously, with little or no increase for most patients following mitogen stimulation. This defective response was shown to be a consequence of activated T- and B-cells present in their peripheral blood and was not related to clinical parameters or drug therapy.

Adolescent↗
PubMedDate not supplied

Juvenile dermatomyositis: serial studies of circulating autoantibodies to a 56kD nuclear protein.

In this study we report that circulating antibodies recognising a 56kD protein, which is a component of large nuclear ribonuclear particles, are commonly found in children with juvenile onset dermatomyositis (JDM). These autoantibodies, as detected by Western blotting, were present in over 90% (24/26) of sera from JDM patients, which exceeds the number of patients with adult onset myositis who express this antibody (up to 85%). In addition, they were not found in healthy controls. Serial bleeds taken during the course of the disease in eleven children with JDM enabled us to follow the titre of anti-56kD autoantibodies. Sera were also tested by indirect immunofluorescence for anti-nuclear antibodies (ANA) using Hep2 cells as substrate. These studies revealed two distinct patient groups: Group 1 with anti-56kD antibody positive and ANA positive; and Group 2 with anti-56kD antibody positive and ANA negative. In Group 1 there was some correlation between disease activity and anti-56kD levels which was absent among patients in Group 2.

Antibodies, Antinuclear↗