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Biomedical subjects

J R Mendell

Publications and source records attributed to J R Mendell.

At least 127 records · Page 7Linked to original sources
PubMed1990

Diagnosis of Maryland/German familial amyloidotic polyneuropathy using allele-specific, enzymatically amplified, genomic DNA.

Diagnoses of familial amyloidotic polyneuropathies have been traditionally based on attempts to distinguish clinical features and ancestry or geographic origin of cases. Most are associated with extracellular deposition of a variant prealbumin (also known as transthyretin). Recent molecular studies demonstrated eight distinct amyloid-associated point mutations in the prealbumin gene on the long arm of chromosome 18 that are associated with hereditary amyloidosis. These findings provide for means of diagnosis using recombinant DNA methods. In a family with the Maryland/German type of familial amyloidotic polyneuropathy, the proband and 2 of 5 at-risk offspring were diagnosed using the polymerase chain reaction. Allele-specific enzymatic amplification of genomic DNA demonstrated the histidine-58 variant prealbumin gene. This study confirms the point mutation of the prealbumin gene as a cause for this type of familial amyloidotic polyneuropathy. Preclinical diagnosis illustrates the potential for development of treatment strategies prior to disease onset.

Adult↗
PubMed1990

Randomized, double-blind trial of mazindol in Duchenne dystrophy.

There is evidence that growth hormone may be related to the progression of weakness in Duchenne dystrophy. We conducted a 12-month controlled trial of mazindol, a putative growth hormone secretion inhibitor, in 83 boys with Duchenne dystrophy. Muscle strength, contractures, functional ability and pulmonary function were tested at baseline, and 6 and 12 months after treatment with mazindol (3 mg/d) or placebo. The study was designed to have a power of greater than 0.90 to detect a slowing to 25% of the expected rate of progression of weakness at P less than 0.05. Mazindol did not benefit strength at any point in the study. Side effects attributable to mazindol included decreased appetite (36%), dry mouth (10%), behavioral change (22%), and gastrointestinal symptoms (18%); mazindol dosage was reduced in 43% of patients. The effect of mazindol on GH secretion was estimated indirectly by comparing the postabsorptive IGF-I levels obtained following 3, 6, 9, and 12 months in the mazindol treated to those in the placebo groups. Although mazindol-treated patients gained less weight and height than placebo-treated patients, no significant effect on IGF-I levels was observed. Mazindol doses not slow the progression of weakness in Duchenne dystrophy.

Behavior↗
PubMed1990

Recurrent respiratory insufficiency and depressed ventilatory drive complicating mitochondrial myopathies.

Three patients with mitochondrial myopathies and progressive external ophthalmoplegia had repeated episodes of respiratory failure requiring assisted ventilation. Studies in these patients and asymptomatic family members, as well as a sporadic case of Kearns-Sayre syndrome, demonstrated markedly depressed ventilatory drive responses to hypoxia. In 2 patients, there was also decreased drive to hypercapnia. The reduced ventilatory drive appears to be due to an altered neural control system that may cause episodic life-threatening hypoventilation occurring especially in relation to surgery, sedation, or intercurrent infection.

Adult↗
PubMed1990

Determination of carrier status in Duchenne and Becker muscular dystrophies by quantitative polymerase chain reaction and allele-specific oligonucleotides.

Detection of carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), in the deletion cases, involves calculating gene dosage from Southern blots. We show that the analysis of dosage can also be made from the polymerase chain reaction (PCR) with use of allele-specific oligonucleotides (ASOs). The deletion-prone exons are amplified, transferred to a membrane, and hybridized with ASOs complementary to the exons; the autoradiographic bands are then quantified with a densitometer. After determining the quantitative conditions of the amplification reaction, we were able to identify deletions in a DMD/BMD carrier female. The determination of carrier status via PCR removes several of the technical limitations of Southern analysis and is also cost- and labor-effective.

Alleles↗
PubMed1989

Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy.

We performed a randomized, double-blind, controlled six-month trial of prednisone in 103 boys with Duchenne's muscular dystrophy (age, 5 to 15 years). The patients were assigned to one of three regimens: prednisone, 0.75 mg per kilogram of body weight per day (n = 33); prednisone, 1.5 mg per kilogram per day (n = 34); or placebo (n = 36). The groups were initially comparable in all measures of muscle function. Both prednisone groups had significant improvement of similar degree in the summary scores of muscle strength and function. Improvement began as early as one month and peaked by three months. At six months the high-dose prednisone group, as compared with the placebo group, had improvement in the time needed to rise from a supine to a standing position (3.4 vs. 6.2 seconds), to walk 9 m (7.0 vs. 9.7 seconds), and to climb four stairs (4.0 vs. 7.1 seconds), in lifting a weight (2.1 vs. 1.2 kg), and in forced vital capacity (1.7 vs. 1.5 liters) (P less than 0.001 for all comparisons). There was an increase in urinary creatinine excretion (261 vs. 190 mg per 24 hours), which suggested an increase in total muscle mass. However, the prednisone-treated patients who had required long-leg braces (n = 5) or wheelchairs (n = 11) continued to require them. The most frequent side effects were weight gain, cushingoid appearance, and excessive hair growth. We conclude from this six-month study that prednisone improves the strength and function of patients with Duchenne's muscular dystrophy. However, further research is required to identify the mechanisms responsible for these improvements and to determine whether prolonged treatment with corticosteroids may be warranted despite their side effects.

Adolescent↗
PubMed1989

Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria.

Over a 10-year period, we followed up 60 patients (35 men and 25 women) with chronic inflammatory demyelinating polyradiculoneuropathy. Diagnosis was based on previously outlined criteria. Patients were treated in a uniform manner and the overwhelming majority, 56 (94.9%) of 59 treated patients, initially responded to immunosuppressive therapy. The time for initial improvement was 1.9 +/- 3.6 months while the time to reach a clinical plateau was 6.6 +/- 5.4 months. The course was monophasic in 32 patients (53.3%) and relapsing in 28 (46.6%). Despite the initial responsiveness, only 24 (40%) of 60 patients are in partial or complete remission, receiving no medication. Two patients died. We were unable to identify specific clinical or laboratory features at the time of diagnosis that predicted outcome. Our data analysis, along with previous reports, suggests that chronic inflammatory demyelinating polyradiculoneuropathy may be more heterogeneous than previously emphasized. In this light, we have proposed diagnostic criteria that allow for the heterogeneity but at the same time provide for a more consistent approach to better establish the natural history of this condition.

Biopsy↗
PubMed1989

Peripheral nerve vasculitis: immune characterization of the vascular lesions.

Quantitative immunohistochemical analyses were performed on 22 nerve biopsy specimens from patients with systemic vasculitis (n = 14) or isolated vasculitis of peripheral nerve (n = 8). In the vascular lesions the cellular infiltrates were composed primarily of T cells (71 +/- 18%; mean +/- SD) and macrophages (27 +/- 17%), and the majority of the T cells (65 +/- 20%) were cytotoxic/suppressor CD8 cells. B cells were seen in only 4 cases and constituted less than 2% of all cells. Natural killer cells and polymorphonuclear leukocytes were rare, and a leukocytoclastic response was not observed. Fourteen biopsy specimens had vascular deposits of immunoglobulins G and M and complement components C3 and C5b-9 membrane attack complex, while 4 had only the latter. The fact that the immunoglobulin and complement deposits were seen only in vessels that had corresponding intense cellular infiltrates suggests an important, but perhaps not primary, role for immune complexes in causing the vascular lesions. Statistical analysis revealed striking similarities in the lesions of patients with isolated nerve vasculitis and those with systemic vasculitides, suggesting a common pathogenic mechanism. Collectively, our observations suggest an important role for a T-cell-dependent cell-mediated process as a primary mechanism of vessel injury in peripheral nerve vasculitis.

Biopsy↗
PubMed1989

Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics.

A 36-year-old man with myoclonic epilepsy and ragged-red fibers (MERRF) died after more than 18 years of follow-up study. He was 1 of 3 affected siblings and the offspring of an affected mother, suggesting maternal transmission. At autopsy, there was neuronal loss and gliosis in the dentate nucleus of the cerebellum and in the inferior olivary nucleus. Skeletal muscle showed ragged-red fibers, and paracrystalline inclusions in mitochondria by electron microscopy. Biochemical analysis showed a generalized partial defect of cytochrome c oxidase (COX) in mitochondria isolated from all tissues, including brain, heart, skeletal muscle, kidney, and liver. The Michaelis constant (Km) for cytochrome c was abnormally low, suggesting a defect of the mitochondrially encoded subunit II of COX. Immunological studies (enzyme-linked immunosorbent assay, dot-blot, Western blot, and immunohistochemistry) showed that the holoenzyme was decreased but subunit II was decreased more than the holocomplex or the nuclearly encoded subunit IV. However, Northern and Southern blots showed that the gene for subunit II, as well as the genes for subunits I, III, IV, and VIII, were of normal size and were normally transcribed. A point mutation or a small deletion of mitochondrial DNA, probably affecting the COX-II gene, may be responsible for the COX deficiency in this case of MERRF.

Adolescent↗
PubMed1989

Duchenne muscular dystrophy: patterns of clinical progression and effects of supportive therapy.

Two-hundred eighty-three boys with Duchenne dystrophy and 10 with Becker dystrophy have been followed for up to 10 years in a protocol that accurately measured their function, strength, contractures, and back curvature. Clinical heterogeneity is noted. Patients whose muscles were stronger were more likely to die from a cardiomyopathy. Weaker patients died from respiratory failure. A series of milestones is defined, which is of use in following the illness in an individual patient. This approach permits a scoring system that allows the severity of the disease to be defined in an individual boy. Evaluation of physical therapy and surgical intervention shows that night splints and scoliosis surgery are effective forms of treatment.

Cardiomyopathies↗
PubMed1988

Gastric hypomotility in Duchenne's muscular dystrophy.

In Duchenne's muscular dystrophy, functional impairment of smooth muscle in the gastrointestinal tract can cause acute gastric dilatation and intestinal pseudo-obstruction that may be fatal. We describe a patient with this syndrome who at autopsy had smooth-muscle degeneration of the stomach. To provide objective evidence of functional smooth-muscle impairment in Duchenne's dystrophy, we performed gastric-emptying studies in 11 patients and 11 normal controls, using technetium-99m radionuclide scintigraphy in a test meal of oatmeal. The patients with Duchenne's dystrophy had delayed gastric-emptying times (118.18 +/- 32.21 minutes [mean +/- SEM]) as compared with controls (42.5 +/- 3.4 minutes, P less than 0.01). The cause of the pathological and functional abnormalities we describe in smooth muscle is unknown but may be a deficiency of dystrophin, the recently identified gene product of the Duchenne's muscular dystrophy locus.

Adolescent↗
PubMed1988

Evoked potentials in chronic inflammatory demyelinating polyneuropathy.

Eighteen patients with chronic inflammatory demyelinating polyneuropathy were studied with evoked potentials to assess for evidence of central nervous system demyelination. Both visual and brain-stem auditory evoked responses were obtained, and the results were compared with magnetic resonance imaging (MRI). An evoked potential was abnormal in nine of 18 patients, five of whom had central nervous system evidence of demyelination by MRI. Evoked potentials identified four patients with probable anterior optic pathway involvement that was not demonstrable by MRI. These findings continue to support that chronic inflammatory demyelinating polyneuropathy is associated with a central demyelinating disorder and more importantly emphasize the possibility of a common pathogenic mechanism in central and peripheral nerve demyelination.

Brain Stem↗
PubMed1988

Clinical investigation in Duchenne muscular dystrophy: penicillamine and vitamin E.

A double-blind controlled trial of penicillamine and vitamin E against placebo was conducted in 106 boys with Duchenne muscular dystrophy. Nine dropped out of the study after being randomized. Patients were evaluated using an established protocol that measures muscle strength, joint contractures, functional grade, and pulmonary function. The trial lasted for 18 months. The power of the study to detect a 75% slowing of the disease was 0.95 at a P less than 0.05. No therapeutic effect was observed in the patients taking penicillamine and vitamin E as compared with those taking placebo.

Child↗
PubMed1988

Scapuloperoneal neuropathy: a distinct clinicopathologic entity.

Peripheral neuropathy as a cause for the scapuloperoneal syndrome continues to be controversial. This report provides further evidence in support of a scapuloperoneal neuropathy as a separate nosologic entity. Three men had a slowly progressive disorder of 5-17 years duration with prominent weakness and atrophy of scapular stabilizer, shoulder girdle and distal lower extremity muscles accompanied by a distal pan-modality sensory loss. Electrodiagnostic studies and sural nerve biopsies indicated a primary axonal neuropathy with secondary demyelination and remyelination.

Aged↗
PubMed1988

Recent advances in Duchenne and Becker muscular dystrophy.

The recent identification of the gene and gene product altered in Duchenne and Becker dystrophy has opened up new and exciting avenues to an understanding of these diseases. This article presents the clinical features, pathology, genetics, and management of Duchenne and Becker muscular dystrophy. These issues are discussed in light of the rapidly accumulating knowledge concerning the molecular basis for the two disorders.

Humans↗
PubMed1988

Characterization of a murine model for human bismuth encephalopathy.

An epidemic of bismuth (Bi)-related neurotoxicity in France remains poorly understood, partly because no satisfactory animal model exists. We have now characterized such a model. Single or multiple intraperitoneal injections of Bi subnitrate into female mice produced neurologic signs (myoclonus, ataxia, tremors, convulsions) and blood (1.2 micrograms/g) and brain (8.4 micrograms/g) Bi levels like those in human cases. Hydrocephalus and axonal swellings in spinal cord were the major neuropathologic lesions.

Animals↗
PubMed1987

Clinical investigation of Duchenne muscular dystrophy. A methodology for therapeutic trials based on natural history controls.

Between 1979 and 1987 we documented the natural history of Duchenne muscular dystrophy in 170 patients, aged from 3 to 23 years, by making serial measurements in over 5000 individual evaluations. This database makes it possible to design and conduct therapeutic trials using natural history controls. Such trials do not replace the need for randomized placebo-controlled trials of promising agents but they do require fewer patients, are cost-effective, and permit the use of high-risk therapy where toxicity monitoring may be important. Natural history-controlled trials, therefore, may serve as a screening method for new therapeutic agents. Drugs showing a significant benefit can then be evaluated in a randomized controlled trial.

Adolescent↗