Biomedical subjects

R T Moxley

Publications and source records attributed to R T Moxley.

At least 19 recordsLinked to original sources

PubMed1992

Early predictors of poor outcome in congenital fiber-type disproportion myopathy.

We report the cases of eight children with histologic findings in the muscle of congenital fiber-type disproportion myopathy. Five had severe muscle weakness at birth; three of them died at 6 months, 18 months, and 6.5 years of age, respectively, and the other two are ventilator dependent and need total care at 2.5 and 4 years of age. The five children with severe weakness at birth had profound respiratory muscle weakness and needed assisted ventilation since early infancy. They also had severe facial and bulbar muscle weakness that required tube feeding, and four had gastrostomy. Ptosis and marked external ophthalmoparesis were also noted. Our study shows that the presence of the above constellation of signs at birth or in early infancy is a predictor of a high rate of mortality in infancy and poor developmental outcome in the survivors.

Child↗

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

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↗

PubMed1990

Myotonia fluctuans.

Autosomal-dominantly inherited nondystrophic myotonic disorders are an interesting group of muscle diseases that provide considerable opportunity for future molecular genetic studies to identify the genes responsible for specific membrane functions. A family with such a myotonic disorder is described with features that are distinctly different from myotonia congenita and paramyotonia congenita. Five members were affected in three generations. The myotonia fluctuated to an unusual degree. It did not worsen with cold but increased markedly with potassium loading. Muscle weakness never occurred. Analysis of the contraction force of the flexor digitorum muscle showed a unique type of myotonia, namely, exercise-induced delayed-onset myotonia. Microelectrode studies done on one muscle biopsy specimen revealed a normal chloride conductance of the muscle fiber membrane.

Adult↗

PubMed1990

Seizures following carotid endarterectomy.

Cerebral infarction, headache, and hypertension are well-known complications of carotid endarectomy (CEA). Seizures are a less frequent, but important complication. We describe eight patients with focal and generalized seizures following CEA. Seizures occurred 6 to 13 days after CEA. All began as focal motor seizures contralateral to the side of the CEA, and six patients developed generalized tonoclonic seizures. Lorazepam and phenytoin sodium controlled the seizures. Five patients without evidence of stroke on computed tomographic scan were normal in follow-up and had no further seizures. The other three patients had mild deficits. One developed a chronic seizure disorder. The pathogenesis of this syndrome following CEA remains unclear, but may involve cerebral hyperperfusion, cerebral embolization, or both.

Aged↗

PubMed1990

Autosomal dominant cramping disease.

A family was studied in which four generations (16 of 41 members) suffered from painful recurrent muscle cramping. A clear pattern of autosomal dominant inheritance was noted. The cramping first developed during adolescence or early adulthood. Electromyographic analysis indicated a neurogenic origin. The cramps seemed to be due to dysfunction of the motor neurons. The mechanisms underlying this alteration are unclear and require further investigation.

Adolescent↗

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

Functional testing.

Functional testing is useful to monitor the natural history of several neuromuscular disorders, and to measure the efficacy of therapeutic agents in clinical trials. A major limitation of functional testing is that a single test is often not appropriate throughout all stages of disease. The same limitation holds true for other measurements of disease progression. MMT and quantitative myometry become technically difficult to perform and lack sensitivity to disease progression at some stages in the course of DMD, ALS, and spinal muscular atrophy. Other limitations of functional testing are its lack of sensitivity to detect a subtle improvement or decline in muscle strength, and the difficulty of applying standard statistical methods to analyze disease progression or therapeutic efficacy. The advantages of functional testing outweigh the limitations. Function testing uses daily activities to monitor disease progression. Patient's appreciate improvements in function more readily than improvements in muscle strength. Functional testing is easily standardized and is reliable. It can be performed, with little or no expense, in almost any clinical setting. The primary challenge for investigators who wish to incorporate functional tests is to identify functional tests that best measure the natural history of the specific disease under investigation. Further, functional testing allows the clinician to provide an educated guess on the likely future course of disease.

Activities of Daily Living↗

PubMed1990

Hypothyroid neuropathy and myopathy: clinical and electrodiagnostic longitudinal findings.

The clinical and electrodiagnostic findings before and during 6 years of therapy are reported in a 59-year-old man with severe hypothyroidism. He had severe sensory neuropathy, carpal and tarsal tunnel syndromes, mild motor neuropathy and moderately severe myopathy. The sensory signs and symptoms disappeared in the 3rd and 4th years of treatment, respectively. Muscle cramps and pain subsided within 2 years, but mild proximal muscle weakness and atrophy persisted. The sensory distal latencies remained slightly prolonged and the electromyographic changes improved. This case shows that thyroid hormone replacement eliminates the neuropathic manifestations of severe hypothyroidism. In contrast, the myopathic features, such as weakness and muscle wasting, may persist despite maintenance of the euthyroid state.

Electrodiagnosis↗

PubMed1990

Location of phosphotyrosine-containing proteins by immunocytochemistry in the rat forebrain corresponds to the distribution of the insulin receptor.

Cellular regulation by certain growth factor receptors and protooncogene products involves tyrosine kinase activity with the resultant tyrosine phosphorylation of protein substrates. In the present report we describe the distribution of phosphotyrosine-containing material detected by immunocytochemistry (ICC) in the rat forebrain. Specificity of the affinity-purified antibody against phosphotyrosine used in the ICC technique was demonstrated by the ability of phosphotyrosine and p-nitrophenyl phosphate but not phosphoserine, phosphothreonine, or L-tyrosine to inhibit the immunostaining reaction. With ICC, relatively high amounts of phosphotyrosine-positive material were observed in neurons in specific structures that included the supraoptic, paraventricular, and arcuate nuclei; the median eminence; medial habenula; subfornical organ; and piriform cortex. Moderate to high amounts were present in the cerebral cortical layers II-IV and in the pyramidal cell layer of the hippocampus. Small to moderate amounts were detected in a few other locations. Glial elements showed minimal staining. Other areas of the rat forebrain failed to react with this antibody. Importantly, the distribution of the areas positive for phosphotyrosine agreed to a remarkable extent with the distribution of the brain insulin receptor, which itself has tyrosine kinase activity. These findings suggest a relationship between the insulin receptor and the increased phosphotyrosine content of these neurons and support the concept that the brain insulin receptor is active in vivo.

Animals↗

PubMed1990

Acute effects of insulin-like growth factor I and insulin on glucose metabolism in vivo.

We have compared the actions of insulin-like growth factor (IGF-I) and insulin on glucose metabolism in vivo, using the glucose clamp technique in rats. Both hormones caused dose-dependent inhibition of hepatic glucose production, stimulation of whole body glucose disposal, and an increase in the glucose metabolic rate of specific muscles. Infusion of IGF-I also decreased the plasma concentration of insulin. An an infusion rate of 0.57 nmol.kg-1.min-1, IGF-I led to stimulation of whole body glucose uptake that was similar to the glucose uptake produced by infusion of 0.01 nmol.kg-1.min-1 insulin. The glucose metabolic rate, as measured by 2-deoxy-D-glucose uptake, was comparable in quadriceps femoris, soleus, and diaphragm muscles during the infusion of 0.57 nmol.kg-1.min-1 IGF-I and 0.01 nmol.kg-1.min-1 insulin. However, at these rates of infusion, IGF-I caused only a 38 +/- 6% inhibition of hepatic glucose output compared with 66 +/- 12% inhibition by insulin (P less than 0.05). Thus, under these conditions, muscle is more responsive than liver to IGF-I, which agrees with the complement of IGF-I receptors in the two tissues.

Animals↗

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

Rippling muscle disease.

Six patients from two families with an autosomal dominantly inherited disease, apparently a myopathy, are described. Their major complaint was muscle stiffness, primarily in the legs. The muscles displayed an unusual sensitivity to stretch, manifested by rippling waves of muscle contraction. These rippling contractions were not accompanied by muscle fiber action potentials. Nonspecific, mild abnormalities were seen on muscle biopsy. These findings raise the possibility that there is an intracellular derangement in the muscle fiber responsible for the muscle rippling; further studies are necessary to establish the underlying pathophysiologic condition.

Adult↗

PubMed1989

Phenytoin-induced improvement in muscle cramping and insulin action in three patients with the syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy.

Phenytoin sodium has been used to treat muscle cramps of diverse causes, and is known to increase insulin sensitivity during long-term use. We have previously described a syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy with continual muscle cramping. The effect of 300 mg/d of phenytoin (Dilantin) on muscle cramping and carbohydrate economy was studied in three affected patients and four control subjects. Oral glucose tolerance tests, euglycemic insulin infusion studies, and monocyte insulin binding tests were conducted before and after phenytoin administration. All three patients had notable improvement in muscle cramps. In response to phenytoin, metabolic improvements were variable, with improvement characteristically better in patients with less severe baseline metabolic abnormalities. Patient 1, with the mildest degree of glucose intolerance, had decreased fasting insulin and blood glucose levels, improved glucose tolerance, and insulin-mediated glucose disposal, associated with an increase in monocyte insulin receptors. Patient 2 had reduced fasting plasma glucose and insulin levels and improved oral glucose tolerance, suggesting a beneficial effect on carbohydrate metabolism. Patient 3, with the most severely impaired carbohydrate economy, showed no metabolic improvement despite marked lessening of muscle pain. These clinical characteristics were unaffected in control subjects. We conclude that phenytoin is of value in the therapy of muscle cramps and glucose intolerance in patients with this syndrome.

Acanthosis Nigricans↗

PubMed1989

Treatment of muscular dystrophies.

1. Specific therapies to cure the muscular dystrophies are not yet available. Therapeutic trials designed on the basis of our understanding of the pathophysiology of these disorders have had only limited success. 2. However, recent investigations in Duchenne muscular dystrophy have identified the abnormal gene and the missing or defective gene product, dystrophin. 3. These discoveries provide information which will lead to more rational and specific therapeutic approaches. 4. The advances in genetic research have led to more effective preventive therapy. Gene mapping has been applied successfully in carrier detection and antenatal diagnosis, and specific gene probes will soon become available for carrier testing for the two most common forms of muscular dystrophy, Duchenne muscular dystrophy and myotonic dystrophy. 5. Supportive therapies for muscular dystrophy patients now include respiratory support for selected patients with chronic respiratory insufficiency. 6. This review will focus on the two most common muscular dystrophies, Duchenne muscular dystrophy and myotonic dystrophy.

Animals↗

PubMed1989

Distribution of insulin receptor-like immunoreactivity in the rat forebrain.

Previous studies have suggested that insulin may play a role in the hormonal regulation of neurotransmitter metabolisms within the central nervous system. In order to provide additional information to support this hypothesis, we examined the distribution of insulin receptors within the forebrain of adult male rats. Insulin receptors were localized by immunocytochemistry, using an antibody directed against the carboxy-terminus of the beta-subunit of the insulin receptor. The antibody specificity was tested by immunoprecipitation of brain insulin receptors with antiserum and the purity of the receptor-antibody preparation was determined using hormone binding-assays with radiolabeled insulin and insulin-like growth factor-l. Insulin receptor-like immunoreactivity was found in a widespread, but selective, distribution on neurons throughout the rat forebrain. Double-labeling with glial fibrillary acidic protein did not demonstrate any detectable insulin receptor-like immunoreactivity on glial cells. Areas with the highest density of insulin receptor-like immunoreactivity were found in the olfactory bulbs, hypothalamus and median eminence, medial habenula, subthalamic nucleus, subfornical organ, CA 1/2 pyramidal cell layer of the hippocampus and piriform cortex. Double-staining of hypothalamic sections with somatostatin and vasopressin antisera revealed insulin receptor-like immunoreactivity on a subpopulation of somatostatin neurons in the periventricular region and on vasopressin neurons in the supraoptic nucleus. A moderately dense insulin receptor-like immunoreactivity was observed in layers II-IV of cerebral cortex, medial amygdala, reticular thalamic nucleus, zona incerta, and preoptic and septal regions, whereas a low density of insulin receptor-like immunoreactive neurons was found in basolateral amygdala and most thalamic regions. The basal ganglia and most parts of the thalamus were almost devoid of insulin receptor-like immunoreactivity. Our findings provide morphological support for a direct action of insulin on selected regions of the rat forebrain and suggest that the insulin receptor may modulate synaptic transmission or the release of neurotransmitters and peptide hormones in the CNS.

Animals↗

PubMed1989

Randomized controlled trial of testosterone in myotonic dystrophy.

Because testosterone has an anabolic effect in myotonic dystrophy, we conducted a 12-month, randomized, double-blind therapeutic trial of testosterone enanthate (3 mg/kg/wk) in 40 men with myotonic dystrophy. We evaluated strength by manual muscle tests, quantitative myometry, pulmonary function, and quantitative functional assessment. A sustained, significant elevation of testosterone levels was produced but there was no effect on any measurement of muscle strength. Muscle mass as estimated by creatinine excretion and lean body mass (40K method) increased significantly. We conclude that testosterone does not improve strength in myotonic dystrophy despite increasing muscle mass.

Acne Vulgaris↗