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Biomedical subjects

J R Mendell

Publications and source records attributed to J R Mendell.

At least 145 records · Page 8Linked to original sources
PubMed1987

Clinical investigation of Duchenne muscular dystrophy. Interesting results in a trial of prednisone.

We investigated the effect of high-dose prednisone therapy in 33 boys with Duchenne muscular dystrophy. The drug was given daily in doses of 1.5 mg/kg of body weight (to a maximum of 80 mg) for six months. Muscle strength, joint contractures, timed functional tests, functional ability, and pulmonary function were measured at the beginning and end of the treatment period. The trial was designed using natural history controls, and the power of the study was 0.80 to detect a slowing of 50% in the rate of progression. During the period of the trial, muscle strength, functional grades, timed functional tests, and pulmonary function improved. Contractures followed the expected natural history of the illness.

Adolescent↗
PubMed1987

Genetic heterogeneity in Duchenne dystrophy.

We evaluated 173 patients in the Clinical Investigation of Duchenne Dystrophy study to determine if patients from the same kindred were more alike clinically than patients within the study population as a whole. A high intrafamilial correlation was noted for age-adjusted muscle strength scores. While noninherited factors could, in part, explain the results, it seems likely that genetic heterogeneity may contribute to the observed similarity within Duchenne dystrophy kindreds.

Adolescent↗
PubMed1987

Clinical investigation in Duchenne dystrophy. VI. Double-blind controlled trial of nifedipine.

Excessive accumulation of intracellular calcium in Duchenne muscular dystrophy (DMD) may be a necessary step in the process that causes muscle damage in this disease. Because of this possibility, a controlled trial of the calcium channel blocking agent nifedipine was undertaken. One hundred and five patients were randomized and treated in a double-blind manner for 18 months. Muscle strength, contractures, functional ability, cardiopulmonary changes, and laboratory data were monitored. The dose of nifedipine was 0.75-1 mg/kg/day in the first 6 months and 1.5-2 mg/kg/day for the next 12 months. Satisfactory blood levels of nifedipine were attained. The study had a power greater than 0.99 to detect a slowing of the illness to 25% of its original rate of progression. No significant improvement was demonstrated in the treated group. One or more of the frequent mild side effects of flushing, dizziness, and leg edema, often associated with the use of nifedipine in adults, occurred transiently in approximately one-half of the patients in the nifedipine group and in 21% of the placebo group. Four patients died, two on nifedipine and two on placebo. This study demonstrates that nifedipine is safe to administer in children, but that it is without beneficial effect on the course of DMD.

Adolescent↗
PubMed1987

Studies on the pathogenesis of vincristine-induced neuropathy.

The pathogenesis of the peripheral neuropathy induced by vincristine is poorly understood, but interference of vinca alkaloids with microtubule assembly suggests that microtubule changes could be important. This possibility was studied by directly exposing the rat sciatic nerve to graded concentrations of vincristine sulfate. Microtubule length histograms prepared from randomly selected axons showed a unimodal distribution in vincristine and control axons. In vincristine-exposed axons, however, there was a shift to shorter length microtubules, and the mean measured length of microtubules (0.42 +/- 0.37 micron) was significantly (P less than 0.001) shorter than controls (0.67 +/- 0.55 micron). On cross-sections, the vincristine-exposed axons showed a decrease in the number of microtubules per square micrometer of axonal area compared to controls. These findings fit best with a loss of portion(s) of each microtubule and support the possibility that microtubules changes were associated with malorientation of microtubules and neurofilaments, accompanied by free vesicle accumulation and fragmentation of the smooth endoplasmic reticulum. These structural alterations would account for the previously observed abnormalities in axoplasmic transport and would also provide insight into the commonly observed peripheral neuropathy induced by vincristine treatment.

Animals↗
PubMed1987

Three cases of amyotrophic lateral sclerosis in a common occupational environment.

Three unrelated school teachers taught in the same school classroom for 2-5 years and subsequently developed amyotrophic lateral sclerosis (ALS) over an 18-year period. This clustering was not accompanied by an increased death rate for ALS in the county where the teachers lived and worked. Statistical analysis revealed that ALS as the cause of death for three teachers from the same school would be highly improbable as a random event. These findings suggest that the patient's shared school environment may have been a source of exposure to an agent pathogenetically significant in the development of their disease.

Amyotrophic Lateral Sclerosis↗
PubMed1987

Comparison of the effects of continuous subcutaneous infusion and split-mixed injection of insulin on nerve function in type I diabetes mellitus.

Comparable groups of type I diabetic patients (n = 19) were matched for age, duration of diabetes, mean HbA1 values, insulin requirements, degree of neuropathy, and the mean of nerve conduction velocities (CV) in median, ulnar, and peroneal motor and median, ulnar, and sural sensory nerves. One group (n = 9) was managed with continuous subcutaneous infusion of (regular) insulin (CSII); the other (n = 10) with split-mixed injections of (intermediate and regular) insulin (SMII). After 12 months, glucose regulation was equally and significantly improved in both groups (P less than 0.005), although it was not sufficiently intense to normalize mean total glycosylated hemoglobin values in either group. Furthermore treatment produced no difference between groups in the values for mean amplitude of glycemic excursions, 12 month average of consecutive M-values or in clinical evaluation. However, in the CSII group, mean CV had increased 6.4% (2.75 + 0.56 m/s; mean +/- SEM) versus 1.3% (0.57 +/- 0.54 m/s) in the SMII group (P less than 0.005). Multivariate analysis on a nerve-by-nerve basis found significantly improved conduction in 2/6 nerves (median motor; ulnar sensory) in the CSII group compared to the SMII group. These results suggest that CSII may provide a more favorable microenvironment for nerve repair.

Adult↗
PubMed1987

Chronic nephrotoxicity complicating cyclosporine treatment of chronic inflammatory demyelinating polyradiculoneuropathy.

We elected to use cyclosporin A (CsA) in a woman debilitated by refractory chronic inflammatory demyelinating polyradiculoneuropathy. Although strength improved coincident with CsA therapy, after 21 months she developed congestive heart failure and had a precipitous loss of renal function with chronic renal failure requiring hemodialysis. While most CsA-induced nephrotoxicity is dose related and reversible, the kidney biopsy in our patient showed chronic nephropathy, a complication previously unreported in the native kidney of a nontransplant patient. A slow rise in blood pressure preceded serum creatinine changes and was an early indicator of impending irreversible nephrotoxicity.

Adult↗
PubMed1987

Use of serum creatine kinase, pyruvate kinase, and genetic linkage for carrier detection in Duchenne and Becker dystrophy.

Carrier detection in Duchenne dystrophy (DD) and Becker dystrophy (BD) can be achieved with DNA probes that recognize restriction fragment length polymorphisms (RFLPs). In 22 families, we found that 16 of 23 females at risk for being DD or BD carriers could be provided with more definitive indications of carrier status beyond the use of creatine kinase/pyruvate kinase and pedigree analysis. RFLP analysis was not possible for six individuals despite potentially informative probes, because family members critical to the analysis were unavailable. In only one instance were all eight probes uninformative.

Creatine Kinase↗
PubMed1987

Evidence for central nervous system demyelination in chronic inflammatory demyelinating polyradiculoneuropathy.

It is unclear whether sporadic reports of concurrent multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represent coincidence or whether these two demyelinating disorders are pathogenically related. We utilized the sensitivity of magnetic resonance imaging (MRI) in detecting central nervous system (CNS) lesions to investigate 16 patients with CIDP. Six of the 16 had periventricular, subcortical, and brainstem white matter lesions indistinguishable from those seen in MS. Three of these patients had definite clinical and laboratory evidence of MS; three others with abnormal MRIs had no findings indicative of CNS disease. Previous reports have indicated that a significant number of MS patients have peripheral nerve demyelination. Our study suggests that many CIDP patients have concurrent CNS demyelination. Taken together, these observations support the existence of a central-peripheral inflammatory demyelinating syndrome. Whether this combined demyelinating syndrome lies on a spectrum between MS and CIDP or is a separate pathogenic entity will require further investigation.

Adult↗
PubMed1987

Carrier assessment for mothers and sisters of isolated Duchenne dystrophy cases: the importance of serum enzyme determinations.

DNA studies (restriction fragment length polymorphism linkage analysis and deletion analysis with pERT87) and serum creatine kinase/pyruvate kinase (CK/PK) measurements were done to determine the carrier status of 59 mothers and sisters of isolated Duchenne dystrophy (DD) cases. The results of DNA studies modified the carrier risks for 34 of the 59 (58%), but the derived risks often did not differ importantly from risks calculated by conventional methods. Elevated CK/PK provided strong evidence of the carrier state for 24 of the 59 (41%), and CK/PK frequently provided data unavailable through DNA studies. Serum enzyme determinations remain an important means of evaluating DD carrier suspects and are especially valuable in isolated-case families. Enzyme testing should be combined with DNA studies to achieve the best estimate of carrier risk.

Creatine Kinase↗
PubMed1986

Microvascular deposition of complement membrane attack complex in dermatomyositis.

We examined the role of the complement system in the pathogenesis of dermatomyositis. Using an antibody against the neoantigens of the terminal C5b-9 membrane attack complex, we performed immunocytochemical studies that localized this complex to the intramuscular microvasculature (arterioles and capillaries) of muscle biopsy specimens from 10 of 12 patients (83 percent) with childhood dermatomyositis and 5 of 19 patients (26 percent) with adult dermatomyositis. Fifty-two control specimens, including 14 from patients with polymyositis and 12 from patients with denervation atrophy (a condition known to be associated with necrotic capillaries), showed no deposition of membrane attack complex in the microvasculature. These findings indicate that the complement system is deposited, bound, and activated to completion within the intramuscular microvasculature of patients with dermatomyositis. In addition to providing further evidence for the presence of vasculopathy in dermatomyositis, these findings suggest a primary role for complement in mediating vessel injury in the disease, particularly in its childhood form.

Adult↗
PubMed1986

Phenytoin neuropathy: structural changes in the sural nerve.

Phenytoin has been implicated as a causative agent in peripheral neuropathy, although structural changes in nerve have not been characterized. A 47-year-old man was seen with clinical and electrophysiological signs of peripheral neuropathy after 30 years of phenytoin administration. Despite a modest dose of phenytoin (300 mg/day) blood levels were 31 to 38 micrograms/ml. A sural nerve biopsy showed a loss of large myelinated nerve fibers and a nonrandom clustered distribution of segmental demyelination and remyelination. The latter findings were accompanied by axonal shrinkage. Sixteen months after phenytoin was stopped, the patient's clinical and electrophysiological findings reflected improvement. These data indicate that long-term phenytoin administration can cause a reversible neuropathy characterized by axonal shrinkage and secondary demyelination.

Atrophy↗
PubMed1986

Specificity of human IgM monoclonal antibodies from patients with peripheral neuropathy.

Some patients with peripheral neuropathy and gammopathy have IgM monoclonal antibodies that react with the myelin-associated glycoprotein (MAG), some 20-26 kDa glycoproteins present only in the peripheral nervous system (PNS), and some acidic glycolipids that are also PNS-specific. This communication describes an investigation of 18 patients with IgM paraproteinemia and neuropathy to test for the presence of antibodies that react with each of these components. Eleven patients had IgM that reacted with MAG, and in all cases the IgM also reacted with the lower Mr glycoproteins and the acidic glycolipids that are specific for the PNS. With respect to the other 7 patients that did not react with MAG, in no instance did immune-staining of electroblots reveal the presence of reactivity with the 20-26 kDa glycoproteins of the PNS or with any other protein antigen in the PNS or central nervous system (CNS). However, these 7 patients fell into 3 categories with regard to reactivity with acidic glycolipids: three reacted with the acidic glycolipid fraction of both PNS and CNS tissue; two reacted with the acidic glycolipid fraction of the PNS but not the CNS; and two showed no reactivity with the acidic glycolipids from either PNS or CNS.

Animals↗
PubMed1986

Azathioprine toxicity in neuromuscular disease.

Azathioprine toxicity was examined in 64 consecutively treated patients with various neuromuscular diseases. Reversible leukopenia was seen in 14 patients (22%). Hepatotoxicity developed in six patients (9%), and a systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia occurred in eight patients (12%). Toxic effects limited the dose of azathioprine in 27 patients (42%) and led to discontinuation of therapy in 13 (20%). Macrocytosis developed in 20% of patients, but did not require an adjustment in the dose. Two patients received allopurinol and azathioprine; both developed reversible leukopenia and macrocytosis. Patients with hematologic and hepatic toxicity, but not those with systemic toxicity, successfully tolerated retreatment with azathioprine. Toxicity was delayed as long as 56 weeks after starting azathioprine in some patients.

Allopurinol↗
PubMed1985

Polyneuropathy and IgM monoclonal gammopathy: studies on the pathogenetic role of anti-myelin-associated glycoprotein antibody.

Attention has recently been directed toward patients having a polyneuropathy and a monoclonal IgM anti-myelin-associated glycoprotein (anti-MAG) antibody. The possibility of a pathogenetic role for the anti-MAG antibody in the evolution of the polyneuropathy and in the development of central nervous system signs, including tremor and ataxia, remains unresolved. In 5 patients with this syndrome whose clinical courses were followed closely, in 1 of whom a complete postmortem examination of the nervous system was performed, we made the following observations: the anti-MAG antibody did not localize to the compact layer of the myelin sheath in affected nerves, but did localize to areas of myelin splitting; anti-MAG antibody present in the sural nerve of an affected individual for 7 years was not associated with progressive pathology; anti-MAG antibody was not deposited in the central nervous system of an affected individual, although the antibody did bind to these same tissues in vitro; deposition of anti-MAG antibody observed at postmortem examination did not correlate with the degree of pathological change; and study of the peripheral nervous system favored a primary axonal neuropathy with secondary demyelination.

Adult↗
PubMed1985

The clinical spectrum of necrotizing angiopathy of the peripheral nervous system.

The peripheral neuropathy seen with necrotizing angiopathy is said to begin classically as a mononeuritis multiplex, usually associated with polyarteritis nodosa, rheumatoid arthritis, or systemic lupus erythematosus. Our experience, however, suggests that a large number of these patients do not have a well-defined collagen vascular disease or the typical clinical pattern. In 350 consecutive nerve biopsies (sural or superficial radial), 16 patients showed a necrotizing angiopathy in the epineurial blood vessels. Six of these 16 patients had a distal symmetrical sensorimotor polyneuropathy. The remaining 10 had a mononeuritis multiplex, although in 8 overlapping nerve involvement somewhat obscured the picture of mononeuritis. In 12 patients, no specific underlying collagen vascular disease could be diagnosed by accepted criteria despite extensive clinical, radiological, and serological evaluations. The peripheral neuropathy was the only objective evidence of vasculitis in 7 of these 12 patients. Our findings suggest that patients with a peripheral neuropathy secondary to necrotizing angiopathy often do not have a definable collagen vascular disease. In fact, peripheral neuropathy may be the sole manifestation of vasculitis. Furthermore, the neuropathy was found to be a distal symmetrical sensorimotor neuropathy in a higher proportion of cases than has been documented previously.

Adult↗
PubMed1985

Plasma exchange and prednisone in acute inflammatory polyradiculoneuropathy: a controlled randomized trial.

A controlled-randomized trial of plasma exchange combined with prednisone was compared to supportive care alone in patients with acute inflammatory polyradiculoneuropathy (AIP). The design of this study differs from other reported trials of plasma exchange in AIP because prednisone was used in the treatment group to prevent the possibility of antibody rebound. Furthermore, in this study, detailed muscle strength testing formed the principal basis for assessment of therapeutic efficacy while in the British, North American, and French studies, a functional assessment scale was used. Analysis of our data revealed no significant improvement in the treated group over the controls. The sample size, albeit small (12 treated and 13 controls), had the power (95% chance) to detect a change of two British Medical Research Council grades of strength between the groups. The difference in our results versus others (North American and French studies) probably reflects the adverse effects of prednisone on recovery in AIP. An additional consideration is that plasma exchange may have an overall modest effect on the course of AIP, less appreciated when individual muscles are tested compared to assessment by large functional categories.

Acute Disease↗