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Biomedical subjects

J R Mendell

Publications and source records attributed to J R Mendell.

At least 109 records · Page 6Linked to original sources
PubMed1992

Alterations in slow transport kinetics induced by estramustine phosphate, an agent binding to microtubule-associated proteins.

Estramustine phosphate (EP) disassembles microtubules by binding to microtubule-associated proteins (MAPs) rather than tubulin. In this study, EP-induced alterations of MAP integrity caused a unique form of axonal atrophy in rats. Initially, EP-induced axonal atrophy occurred in both proximal and distal axons of the sciatic nerve, characterized by an increase in neurofilament packing density, associated with a decrease in axonal area. In chronic exposure, distal axonal atrophy was associated with decreased numbers of microtubules, while the neurofilament number remained unaltered for the myelin spiral length. Continued exposure caused enlargement of proximal axons associated with an increase in neurofilament content. Correlative slow transport studies done at two different times, 7 and 14 days after [35S] methionine injection showed that EP retards the transport of cytoskeletal proteins migrating with both components of slow transport (SCa and SCb). However, there was a differential effect on SCb which showed progressive slowing along the nerve while the rate of SCa stayed relatively constant. In this model, the early occurring distal axonal atrophy can best be explained by reduced cytoskeletal components, particularly those traveling in SCb. Later in the course of intoxication, a relatively constant rate of SCa permitted continuous transport of neurofilament triplets, accounting for unaltered numbers of neurofilaments in distal axons with increased packing density. This model of axonal atrophy is unique because spacing of neurofilaments, not numbers determined axon size. Furthermore, EP-induced dissociation of the SCa and SCb kinetics suggests that MAPs play a role in the orderly, cohesive migration of slow transport components, essential for the normal organization of cytoskeleton.

Animals↗
PubMed1992

Case of the month: germline mosaicism in carriers of Duchenne muscular dystrophy.

Carrier testing in a Duchenne muscular dystrophy (DMD) family resulted in the identification of a case of germline mosaicism. Using dystrophin cDNA probes, this phenomenon was ascertained by the demonstration of a deletion junction fragment present in the DNA of the affected patient and one sister but absent in the mother's DNA. As a result of this finding carrier risk estimations, based on restriction fragment length polymorphism (RFLP) studies, were significantly altered. The case demonstrates the importance of cDNA deletion carrier testing and the counseling implications of germline mosaicism.

DNA Probes↗
PubMed1992

Framework multipoint map of the long arm of human chromosome 4 and telomeric localization of the gene for FSHD.

Mapping the long arm of Chromosome (Chr) 4 has assumed medical relevance with the establishment of linkage of facioscapulohumeral muscular dystrophy (FSHD) to distal 4q markers. We have constructed a multipoint linkage map using DNA markers that map to the long arm of Chr 4. Segregation data were collected for 17 DNA markers on the multigenerational CEPH mapping families, and data for one marker were taken from the published CEPH database. Genotypic information for six of these markers was also collected from a set of 24 families that exhibited inheritance of FSHD. Multipoint analyses allowed us to construct a map of 12 loci, connecting two previously separate linkage groups. Significant sex-specific differences in recombination were found for some genetic intervals. Four loci from the distal region of this map showed linkage with FSHD. A map using these terminal markers gave the strongest support for FSHD in the most distal position over all other possible positions.

Chromosome Mapping↗
PubMed1992

Expression of Schwann cell and peripheral T-cell activation epitopes in hereditary motor and sensory neuropathy.

To evaluate possible immune-mediated mechanisms in hereditary motor and sensory neuropathy (HMSN-I, Charcot-Marie-Tooth syndrome), we examined class II major histocompatibility complex antigen expression (MHC-II, HLA-DR) in Schwann cells and peripheral lymphocyte T-cell (Ta1, CD26) activation in five unrelated adults with HMSN-I. Evidence of increased activation expression was found in both compartments but the pattern did not suggest a general state of hyperimmunity or appear related to clinical characteristics of HMSN. Significantly increased CD26+ T-cell activation and greater than normal fluctuation of values occurred intermittently in sequential tests of eight HMSN patients and at single time points in 24 others. The combined data, consistent with repeated stimulations of an immune reaction under normal feedback control, suggest that HMSN-I expresses some characteristics also found in autoimmune polyneuropathies.

Adult↗
PubMed1992

Vasculitic neuropathy.

Peripheral neuropathy is common in many vasculitic syndromes and may be the only manifestation of the underlying vasculitic disease. Although traditional teaching has been that a true multiple mononeuropathy is the classic clinical presentation of vasculitic neuropathy, an overlapping (or extensive) multiple mononeuropathy or a distal symmetric polyneuropathy is commonly encountered. Similarly, the leukocytoclastic reaction has traditionally been considered the primary mechanism of vessel injury in these diseases, although more recent evidence suggests that cellular-mediated mechanisms may be more important in peripheral nerve. In this review, new concepts concerning the clinical presentation, pathogenesis, diagnosis, and treatment of vasculitic neuropathy are discussed, particularly in relation to the syndrome of isolated peripheral nerve vasculitis.

Biopsy↗
PubMed1992

Somatic reversion/suppression in Duchenne muscular dystrophy (DMD): evidence supporting a frame-restoring mechanism in rare dystrophin-positive fibers.

Many Duchenne muscular dystrophy (DMD) patients are known to have rare staining dystrophin-positive fibers, termed "revertants." The precise etiology of these rare fibers is unknown. The most likely explanation, however, is somatic mosaicism or somatic reversion/suppression. Immunocytochemistry was performed on serial sections from deleted and nondeleted patients, with a panel of antibodies--9219, 1377, 9218, and Dys-2--that span dystrophin. Both familial and nonfamilial patients possessed revertants. Either the same clusters or individual revertant fibers stained with amino- and carboxyl-terminal antibodies in all 14 DMD patients. In patients with deletions, revertants did not stain with antibodies raised to polypeptide sequences within the deletion. These results indicate that positively staining fibers are not the result of somatic mosaicism in deleted patients. Five of 10 patients without deletions had revertant fibers. In two of these patients, the revertant fibers did not stain with antibody 9218, which was generated against amino acids 2305-2554 and which corresponds to exons 48-52. The remaining antibodies from the panel stained the same fibers on separate serial sections in these two patients. The most likely mechanism giving rise to these positively staining fibers is a second site in-frame deletion. Antibodies generated to polypeptide sequences within deletions can be used to control for the natural occurrence of revertant fibers in myoblast transfer studies and may be useful in the detection of point mutations.

Antibodies↗
PubMed1991

The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis.

Accumulating evidence indicates that a complement-mediated microvasculopathy may play a pathogenic role in dermatomyositis. In a previous study, we demonstrated neoantigens of the C5b-9 complement membrane attack complex in the muscle microvasculature of childhood and adult cases of dermatomyositis. To further characterize the relationship between the vascular complement deposits and histologic changes, quantitative histopathologic analyses were performed on 39 dermatomyositis biopsy specimens (26 adult, 13 children). There was a significant correlation between the percentage of fascicles with fibers having focal myofibrillar loss, a change seen early in the evolution of ischemic muscle fiber damage, and the percentage of fascicles having capillary deposits of membrane attack complex. Conversely, in biopsy specimens with a higher percentage of fascicles with perifascicular atrophy, membrane attack complex deposits were significantly less common. A fascicle-by-fascicle analysis supported these observations. Patients whose biopsy specimens were negative for microvascular membrane attack complex had clinical weakness for a significantly longer time than those patients with vascular complement deposits. These data support the hypothesis that the complement-mediated vasculopathy is a primary immunopathogenic event in the evolution of muscle lesions in dermatomyositis.

Adult↗
PubMed1991

Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group.

A randomized, controlled trial of daily prednisone was conducted in 99 boys (aged 5 to 15 years) with Duchenne dystrophy to define the time course of improvement and the dose response to treatment. Prednisone at 0.3 mg/kg (n = 33), prednisone at 0.75 mg/kg (n = 34), and placebo (n = 32) were administered for 6 months. Patients were examined using manual muscle and myometry testing, timed functional testing, pulmonary function testing, and laboratory measurements at 10 days, 1 month, 2 months, 3 months, and 6 months of treatment. Boys treated with prednisone had stronger average muscle strength scores, than did boys treated with placebo as early as 10 days after starting therapy. At the 3-month visit, the boys in the group given 0.75 mg/kg of prednisone were significantly stronger than those in the group given 0.3 mg/kg of prednisone, indicating a dose response. At 6 months, significant side effects occurred in the group treated with 0.75 mg/kg of prednisone, including weight gain, cushingoid appearance, and excessive hari growth. Only weight gain was observed in the group taking prednisone at a dose of 0.3 mg/kg. Importantly, no side effects were evident at 10 days or 1 month of treatment, despite improvement in muscle strength and function. We conclude that prednisone produces a rapid increase in muscle strength in patients with Duchenne dystrophy and that this improvement is maximal at a prednisone dosage of 0.75 mg/kg or less.

Adolescent↗
PubMed1991

A comparison of daily and alternate-day prednisone therapy in the treatment of Duchenne muscular dystrophy.

We previously reported the results of a randomized, double-blind 6-month trial of prednisone therapy in which 102 boys aged 5 to 15 years with Duchenne muscular dystrophy received daily doses of 1.5 and 0.75 mg/kg per day and were compared with those receiving placebo. The strength and function in both prednisone-treated groups improved equally and were significantly better than in the placebo group. To compare alternate-day and daily dosing of prednisone with respect to benefits and adverse side effects, the placebo group was started on alternate-day prednisone therapy, and the treatment group regimens were changed to equivalent doses of alternate-day prednisone without breaking the double-blind nature. At the end of 6 months, the group that was changed from daily to alternate-day therapy had declined in strength back to levels observed 12 months previously, at the start of daily therapy. The group in which alternate-day therapy was started showed a significant improvement in strength at 3 months, similar in magnitude to the response of boys treated with daily therapy. However, their strength declined significantly in the subsequent 3 months compared with boys who received daily therapy. The frequency of side effects was not significantly different for alternate-day therapy compared with daily therapy. We conclude that alternate-day prednisone therapy effectively increases strength but does not sustain the improvement to the same extent as daily therapy or mitigate side effects.

Adolescent↗
PubMed1991

The Bruns-Garland syndrome (diabetic amyotrophy). Revisited 100 years later.

A group of 17 patients had proximal diabetic neuropathy characterized by abrupt onset of asymmetric pain and weakness. Fourteen patients had unilateral onset that later involved the other extremity in 3 days to 8 months. All patients reported stepwise or steady progression during 2 to 18 months that was documented during serial examinations. In 16 patients, both proximal and distal muscles were involved. Sural nerve biopsy specimens demonstrated multifocal variability in nerve fiber density manifesting as nonrandom fiber loss between and within fascicles compared with age-matched controls. These findings demonstrate that patients may have a rapidly evolving course of proximal diabetic neuropathy followed by continued progression for many months and emphasize the overlap between proximal diabetic neuropathies of presumed different types. Our cases and others cast doubt on notions supporting two distinct types of proximal diabetic neuropathies represented by the rapid evolution of asymmetric weakness on an ischemic basis, in contrast to a more slowly progressive condition of metabolic pathogenesis.

Action Potentials↗
PubMed1991

Amyloid filaments in inclusion body myositis. Novel findings provide insight into nature of filaments.

Inclusion body myositis (IBM) represents a serious debilitating disease of muscle without identifiable cause or treatment. Muscle biopsy specimens have characteristic rimmed vacuoles, varying degrees of inflammation, and, most importantly, cytoplasmic and intranuclear filamentous inclusions of unknown composition. Fresh-frozen sections of muscle biopsy specimens from 24 IBM cases were stained with Congo red dye (pH, 10.5 to 11.0). Control biopsy specimens included polymyositis, dermatomyositis, hereditary vacuolar myopathies of unknown cause, acid maltase deficiency, distal myopathy, oculopharyngeal dystrophy, and chloroquine myopathy. Sections were also immunostained with antibody to transthyretin, human P component, and immunoglobulin light chains. In the vacuolated fibers in IBM, amyloidogenic green-birefringent deposits were seen. Some deposits were delicate and wispy appearing, and others were plaque-like. The size of deposits varied, measuring 1 x 2 to 8 microns, and rarely up to 20 microns in length. The number of amyloid-positive fibers correlated with the number of vacuolated fibers. Similar deposits were seen in one case of distal myopathy and one hereditary vacuolar myopathy. Other control cases were negative for amyloid deposits. Antibody staining for known amyloidogenic proteins was negative. This study demonstrates that the filaments in IBM share properties with amyloid proteins. The location implies that this amyloid material is formed intracellularly, rather than having a systemic derivation. The association of amyloid deposits with autophagic vacuoles in IBM raises the likely possibility that the filaments represent a modification of a normal protein within an acidic degradative vacuolar compartment. An alternative possibility, considering the shared properties of IBM filaments and prions (which include size and amyloidogenic properties), is that IBM represents a human prion disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Long-term benefit from prednisone therapy in Duchenne muscular dystrophy.

Two successive, 6-month, randomized, double-blind, controlled trials of prednisone showed that 0.75 mg/kg/d was the optimal dose to improve strength in boys with Duchenne muscular dystrophy (DMD). We attempted to maintain 93 boys on that dose for an additional 2 years. During the 3 years of observation, the decline in average muscle strength scores of all boys taking prednisone was 0.072 units/yr, as compared with an expected decline of 0.341 units/yr from natural history controls. The occurrence of side effects in some boys prevented maintenance of the full dose, which may have lessened the response. At the time of last visit, dosages ranged from 0.15 mg/kg to 0.75 mg/kg. In addition to maintaining their strength, several of the boys actually improved their performance in lifting kilogram weights and in some timed function tests. Treatment of DMD with prednisone significantly slows the progression of weakness and loss of function for at least 3 years.

Adolescent↗
PubMed1991

Dystrophin expression and somatic reversion in prednisone-treated and untreated Duchenne dystrophy. CIDD Study Group.

The mechanism by which prednisone improves muscle strength and function in Duchenne muscular dystrophy (DMD) is unknown. We addressed the possibility that clinical improvement was related to prednisone-induced alterations in skeletal muscle dystrophin. We performed muscle biopsies on patients at the conclusion of a randomized, double-blind, 6-month trial of prednisone and analyzed dystrophin content using Western blots and antibody staining of tissue sections. These studies demonstrated no significant differences in dystrophin content between treatment (prednisone 1.5 mg/kg/d, n = 12; prednisone 0.75 mg/kg/d, n = 9) and placebo (n = 12) groups. Of interest, however, was the presence of varying numbers of dystrophin-positive fibers (revertants) occurring individually or in clusters in antibody-stained tissue sections of more than one-half of the Duchenne patients. Mutation analysis revealed that revertants occurred in DMD patients with identifiable deletions half of the Duchenne patients. Mutation analysis revealed that revertants occurred in DMD patients with identifiable deletions or duplications, and in nondeletion patients. Prednisone treatment did not influence the prevalence of revertants. Revertants are most likely due to a second-site mutation occurring in a somatic cell allowing for restoration of the translational reading frame of the dystrophin transcript.

Adolescent↗
PubMed1991

Mononuclear cell analysis of muscle biopsies in prednisone-treated and untreated Duchenne muscular dystrophy. CIDD Study Group.

A recent double-blind, placebo-controlled trial has shown that prednisone improves strength in patients with Duchenne muscular dystrophy. To determine whether immunosuppressant effects were important in mediating this improvement, we performed immunohistochemical analyses on muscle biopsies obtained at the conclusion of the trial. We studied 33 patients: 12 from the placebo group, nine from the low-dose prednisone group (0.75 mg/kg/d), and 12 from the high-dose group (1.5 mg/kg/d). There was a significant difference in total T cells (CD2+) between the placebo group and both treatment groups. Similarly, the number of CD8+ cytotoxic/suppressor T cells was significantly decreased in both treated groups compared with placebo. The number of muscle fibers focally invaded by lymphocytes was also significantly decreased in the two treated groups compared with controls. There were no differences between the low- and high-dose groups. The numbers of B cells, natural killer cells, CD4+ cells, macrophages, and necrotic muscle fibers were not significantly different in the treated and control groups. This study suggests that prednisone may improve strength in Duchenne muscular dystrophy through primarily immunologic mechanisms involving T lymphocytes.

Adolescent↗
PubMed1990

Immunocytochemical evidence for the retrograde transport of intraaxonal cathepsin D: possible relevance to the dying-back process.

Immunocytochemical localization of cathepsin D was studied in rat nerves using an antibody to cathepsin D (CD). In normal or control nerves, immunoreactive CD was present in the cytoplasm of Schwann cells but not in axons. In ligated or transected nerves, intraaxonal CD appeared as granular or elongated particles increasing with time at the cut end of the distal stump. In the proximal stump of transected nerves, CD was detected in the nascent axon tips, as well as in a length of axon extending up to the first node of Ranvier. In swollen axons induced by 2,5-hexanedione (HD), CD was associated with granular particles in areas where bidirectional organelle movement was impaired. This study represents the first documentation of intraaxonal CD and provides evidence that immunoreactive CD originates at the nerve terminal in conjunction with the anterograde-to-retrograde (A-R) conversion process of axoplasmic transport. When the A-R conversion process is induced at more proximal sites in the nerve by transection, CD can be observed. In circumstances where axoplasmic transport is impaired, such as nerves exposed to 2,5-HD or ligated and transected nerves, CD-positive granular particles were seen in association with retrogradely moving organelles and their accumulation was related to sites of preferential axonal degeneration.

Animals↗
PubMed1990

Centronuclear myopathy and type-1 hypotrophy without central nuclei. Distinct nosologic entities?

Four infants presented with severe hypotonia, weakness, and hypoventilation or apnea at birth. Their clinical presentations and courses resembled those of the x-linked recessive form of centronuclear myopathy. Histologic examination of their muscle biopsy specimens showed patterns ranging between centronuclear myopathy and type-1 hypotrophy without central nuclei. Regardless of their gender or the appearance of their biopsy specimens, the children all had a poor outcome. The clinical and biopsy findings in these infants suggest that centronuclear myopathy and type-1 hypotrophy without central nuclei do not represent distinct nosologic entities. It seems more likely that the histologic changes represent abnormalities in fiber size distribution and development, which are nonspecific and which reflect a primary defect at one or more sites in the neuraxis.

Biopsy↗