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Biomedical subjects

R H Edwards

Publications and source records attributed to R H Edwards.

At least 199 records · Page 11Linked to original sources
PubMed1990

Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle's disease.

Patients with McArdle's disease (myophosphorylase deficiency) cannot use muscle glycogen as an energy source during exercise. They therefore are an ideal model to learn about the metabolic adaptations which develop during endurance exercise leading to glycogen depletion. This review summarizes the current knowledge of ammonia and amino acid metabolism in these patients and also adds several new data. During incremental exercise tests in patients with McArdle's disease, forearm venous plasma ammonia concentration rises to a value between 200 and 500 microM. Femoral arteriovenous difference studies show that muscle produces the ammonia. The leg release of both ammonia and glutamine (in mumol/min) has been estimated to be five- to tenfold larger in one of these patients than in healthy individuals exercising at comparable relative work load. Patients with McArdle's disease have a larger uptake of branched-chain amino acids (BCAA) by exercising leg muscles and show a more rapid activation of the muscle branched-chain 2-oxo acid dehydrogenase complex, a key enzyme in the degradation of the BCAA. In general, supplements of BCAA taken before the exercise test lead to a deterioration of exercise performance and a higher increase in heart rate and plasma ammonia during exercise, whereas supplements of branched-chain 2-oxo acids improve exercise performance and lead to a smaller increase in heart rate and plasma ammonia. At constant power output, patients with McArdle's disease show a rapid increase in heart rate and exertion perceived in the exercising muscles, which peak within 10 min after the start of exercise and then fall again ("second wind"). Peak heart rate and peak exertion coincide with a peak in plasma ammonia. Ammonia production during exercise in these patients is estimated to exceed the reported breakdown of ATP to IMP and therefore most likely originates from the metabolism of amino acids. Deamination of amino acids via the reactions of the purine nucleotide cycle and glutamate dehydrogenase are possible pathways. Deamination of glutamine, released by muscle, by glutaminase present in the endothelial cells of the vascular system may also contribute to the ammonia production. The observations made in these patients have led to the hypothesis that excessive acceleration of the metabolism of BCAA drains 2-oxoglutarate in the primary aminotransferase reaction and thus reduces flux in the citric acid cycle and impedes aerobic oxidation of glucose and fatty acids. This draining effect is normally counteracted by the anaplerotic conversion of muscle glycogen to citric acid cycle intermediates, a reaction which is severely hampered in these patients due to the glycogen breakdown defect.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids, Branched-Chain↗
PubMed1990

Effects of calcium ionophore on vitamin E-deficient rat muscle.

Damage to skeletal muscles may be mediated via free radicals or intracellular calcium overload. To look for inter-relationships between these pathways we have examined the effect of intracellular Ca overload on muscles from rats fed on either a vitamin E-deficient or vitamin E-sufficient diet and assessed the non-enzymic lipid peroxidation in these muscles by examining the production of thiobarbituric acid reactive substances by homogenates. Vitamin E-deficient muscles were more susceptible to Ca-induced intracellular enzyme efflux and this was acutely corrected by supplementation of the external medium with 230 mumol alpha-tocopherol/l. Vitamin E-deficient muscles showed increased levels of basal lipid peroxides and were more susceptible to iron-catalysed lipid peroxidation. Addition of the Ca ionophore A23187 increased lipid peroxidation in vitamin E-deficient muscle homogenates, but had the opposite effect in vitamin E-sufficient muscles. These results demonstrate that vitamin E-deficient muscle has an increased susceptibility to intracellular Ca overload, but that this effect cannot be explained by a direct stimulatory effect of the ionophore on non-enzymic lipid peroxidation.

Animals↗
PubMed1990

Wilms' tumor presenting as sudden death due to tumor embolism.

The clinical and pathologic features of two unusual cases of Wilms' tumor are described. Both cases presented as sudden death due to tumor embolus. One patient, a 7-year-old girl, had a massive tumor embolus filling the right main pulmonary artery. The second patient, a 6-year-old boy, had pulmonary artery tumor embolus, widespread metastases to lungs, lymph nodes, mesentery, bowel, brain, and nerves, and tumor emboli in the myocardial and epicardial vessels and carotid artery. The renal vein was invaded in both patients. The histologic characteristics of the two tumors was strikingly similar, both showing a blastemal predominant pattern with minimal epithelial differentiation in the form of tubules. Anaplasia was not a feature. To our knowledge, the initial presentation of Wilms' tumor as sudden and unexpected death has not been previously described.

Child↗
PubMed1989

Effects of clenbuterol and propranolol on muscle mass. Evidence that clenbuterol stimulates muscle beta-adrenoceptors to induce hypertrophy.

1. A single subcutaneous injection of clenbuterol hydrochloride (0.125 mg/kg body wt.) to female Wistar rats produced a rapid increase in muscle cyclic AMP and lactate concentrations and a decrease in muscle glycogen concentrations. These changes are characteristic of muscle beta-adrenoceptor stimulation and were abolished by intraperitoneal injection of propranolol (12.5 mg/kg) 15 min before clenbuterol administration. 2. When this dose of clenbuterol was injected twice daily, the changes in muscle metabolite concentrations which followed its acute administration persisted until day 7 of treatment, and were accompanied by increases in muscle mass, body weight and muscle protein synthesis rate (ks). When the clenbuterol injections were preceded by propranolol injections (12.5 mg/kg administered according to the protocol described above), or if animals were treated with propranolol only, the values of these variables were not significantly different from those of sham-injected controls. 3. In rats fed on a semi-synthetic diet (PW3) supplemented with 2 mg of clenbuterol/kg of diet for 7 days, the muscle mass was greater than that of rats fed on unsupplemented PW3. The increased muscle mass was accompanied by increased muscle lactate and decreased muscle glycogen concentrations. When PW3 was supplemented with 2 mg of clenbuterol/kg and 200 mg of propranolol/kg, the increase in muscle mass remained, but decreased muscle glycogen concentrations and increased muscle lactate concentrations were also observed. 4. These data are consistent with the hypothesis that clenbuterol influences muscle growth via beta-adrenoceptor stimulation.

Animals↗
PubMed1989

Directed expression of NGF to pancreatic beta cells in transgenic mice leads to selective hyperinnervation of the islets.

Nerve growth factor (NGF) is implicated in the differentiation of neurons in both the central and peripheral nervous systems. As a new approach to its role in neuronal development, we have used transgenic mice to selectively overexpress NGF in an innervated peripheral tissue, the islets of the pancreas. In two lines of mice, directed expression of NGF in the beta cells elicits a dramatic increase in the innervation of the islets, but not the surrounding exocrine tissue, by one class of sympathetic neurons. In contrast, the innervation by sensory and parasympathetic neurons appears unchanged. The results indicate that expression of NGF by a target tissue during neuronal development selectively influences the characteristics of its innervation.

Animals↗
PubMed1989

Nerve growth factor induces the proto-oncogene c-jun in PC12 cells.

Nerve growth factor (NGF) induces the rapid but transient expression of two transcripts with homology to the proto-oncogene c-jun (AP-1) in PC12 cells. The c-jun transcripts increase within 15 min after NGF addition, peak at 1 h, and decline to basal level by 4 h. Actinomycin D inhibits the increase, and cycloheximide prevents the decrease of c-jun mRNA. Cyclic AMP induces a similar transient rise in c-jun transcripts in PC12 cells. The human melanoma cell line A875 that also expresses the NGF receptor expresses c-jun RNA constitutively, and the level of c-jun RNA is not affected significantly by NGF. NGF does not alter the RNA level of transcription factor SP-1 in PC12 cells. The results suggest that activation of the putative transcription factor c-jun is one of the early cellular responses of PC12 cells to NGF and that c-jun mRNA expression is dependent on cellular transcription and regulated by stabilization of c-jun mRNA.

Adrenal Gland Neoplasms↗
PubMed1989

Inhibition of Ca2+-induced cytosolic enzyme efflux from skeletal muscle by vitamin E and related compounds.

1. Efflux of an intracellular enzyme (creatine kinase) from normal rat skeletal muscles was induced by treatment with the Ca2+ ionophore A23187. Addition of alpha-tocopherol (230 microM) to the incubation medium was found to significantly diminish this efflux, and this effect was mimicked by alpha-tocopherol acetate, phytol and isophytol, but not by Trolox C (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). 2. Analysis of muscle cation content has shown that these protective effects of alpha-tocopherol etc. are not due to an inhibition of the Ca2+ accumulating effects of the ionophore. 3. Non-enzymic lipid peroxidation of skeletal-muscle homogenates was found to be inhibited by alpha-tocopherol and Trolox C, partially inhibited by phytol and isophytol, but unaffected by alpha-tocopherol acetate. 4. The activity of lipoxygenase enzymes was partially inhibited by alpha-tocopherol, phytol and isophytol, but not by alpha-tocopherol acetate or Trolox C. 5. Prostaglandin E2 efflux from isolated skeletal muscles was stimulated by treatment with the Ca2+ ionophore, but this was unaffected by alpha-tocopherol treatment.

Animals↗
PubMed1989

Image localized 31P magnetic resonance spectroscopy of the human liver.

Image localized 31P magnetic resonance (MR) spectroscopy of the liver was performed in twelve normal volunteers and seven patients with hepatic tumours. The tumours which were clearly imaged by proton MR could also be distinguished from normal tissue because of spectral differences. The malignant tumours had significantly elevated phosphomonoester/inorganic phosphate and phosphomonoester/beta-adenosine triphosphate ratios, probably due to elevated tumour concentrations of phosphocholine and phosphoethanolamine, which are intermediates in the synthesis of membrane phospholipids. The pH values of the malignant tumours were elevated compared to normal hepatic parenchyma. Liver spectra in two patients with the commonest benign hepatic neoplasm, cavernous haemangioma, differed from both normal tissue and the malignant tumours in having a very low signal/noise ratio but apparently normal relative levels of phosphomonoester.

Adult↗
PubMed1989

Characterization of the spleen by in vivo image guided 31P magnetic resonance spectroscopy.

Image localized 31P magnetic resonance spectroscopy of the spleen was performed in six normal volunteers, 13 patients with splenomegaly due to haematological malignancies, and two patients with benign causes of splenomegaly. The malignant disorders had elevated phosphomonoesters (PME) compared to controls, probably due to increased turnover of membrane phospholipids, with variable alterations in high energy phosphates. There appeared to be no relationship between grade of malignancy and relative PME peak area. An overlap in spectral characteristics between the benign and malignant cases of splenomegaly existed. Serial studies in a patient with high grade lymphoma receiving combination chemotherapy showed changes in phosphorus spectra, with an increase in the phosphodiester/beta adenosine triphosphate ratio.

Adult↗
PubMed1989

Lectin binding and desmin expression during necrosis, regeneration, and neurogenic atrophy of human skeletal muscle.

Changes in the cytoplasm of skeletal muscle fibres during necrosis, regeneration, and neurogenic atrophy have been studied in a wide range of human neuromuscular diseases with a panel of eleven biotinylated lectins and by immunohistochemical staining for the cytoskeletal protein desmin. Increased binding of several lectins was observed in both necrotic and regenerating fibres, with Concanavalin A the most consistently positive lectin. Staining for desmin was strong in the cytoplasm of regenerating and partially damaged fibres and was lost in necrotic fibres, although there were differences in the staining reactions of the two antidesmin antibodies used. In fibres which had undergone neurogenic atrophy, cytoplasmic lectin binding was seen only with Griffonia simplicifolia 1 lectin, and desmin was expressed more strongly than in normal fibres. Lectin binding and immunohistochemical staining from desmin can supplement the information obtained from muscle biopsies by conventional histochemical methods and lead to a better understanding of the mechanisms of muscle damage.

Adolescent↗
PubMed1989

Exercise-induced activation of the branched-chain 2-oxo acid dehydrogenase in human muscle.

The present study was conducted to investigate the metabolic regulation of the oxidation of branched-chain amino acids (BCAA) by exercise in human skeletal muscle. Five trained male volunteers were exercised on a cycle ergometer at 70% +/- 10% (mean +/- SD) of their maximal oxygen consumption (VO2max). Percutaneous quadriceps muscle biopsies were obtained under local anaesthesia at rest and after 30 and 120 min of exercise. In the muscle samples the active and total amount of the branched-chain 2-oxo acid dehydrogenase complex (BC-complex), the regulatory enzyme in the oxidative pathway of the BCAA, were measured. Glycogen content and activity of mitochondrial marker enzymes were also measured. Blood samples were obtained every 20 min for the measurement of metabolites. Heart rate and rated perceived exertion on the Borg scale were recorded every 10 min. At rest 4.0% +/- 2.5% of the BC complex was active, after 30 min of exercise 9.9% +/- 9.0% and after 120 min 17.5% +/- 8.5% (mean +/- SD). Exercise did not change the total activity. The largest activation was seen in two of the subjects who developed higher blood lactates early on during exercise and decreased their muscle glycogen more (indications of anaerobic metabolism). These data demonstrate that in trained individuals significant increases in the activity of the BC-complex occur only after prolonged intense exercise. In spite of the 4-fold activation, the data support the classical view that amino acids and protein do not contribute substantially as an energy source during exercise, since VO2 increased more than 20-fold.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1989

Effect of low frequency fatigue on human muscle strength and fatigability during subsequent stimulated activity.

Fatiguing contractions of the adductor pollicis muscle were produced by intermittent supramaximal stimulation of the ulnar nerve in a set frequency pattern, in six normal subjects. At the end of an initial fatiguing contraction series, low frequency fatigue (LFF) had been induced and persisted at 15 min of recovery. Stimulated fatiguing activity was then repeated in an identical fashion to the initial series. At high frequencies, declines in force were similar for both series. At low frequencies, declines in force were greater during the second series despite similar changes in compound muscle action potential amplitude. This confirmation that LFF persists during subsequent stimulated activity, and reduces low but not high frequency fatigue resistance, suggests that the impaired endurance of fatigued muscle during voluntary activity primarily results from peripheral changes at low frequency. These findings also have implications for therapeutic electrical stimulation of muscle.

Action Potentials↗
PubMed1989

Implantation metastasis as a cause of local recurrence of colorectal carcinoma.

Local recurrence of colorectal carcinoma postoperatively is due to locally unresected tumor, lymphatic permeation by tumor, or intraoperative implantation of viable shed cancer cells. One hundred eighty-five patients with colorectal carcinoma underwent resection for cure. Of these patients, 40 received diluted formalin intraluminally for prevention of local recurrence, and the remainder received no cancericidal agent. Distribution by tumor size and stage was similar in both groups. Local recurrence occurred in 2.6 percent of formalin-treated patients and 14.3 percent of untreated patients. The difference in recurrence rates was significant (p less than 0.05). No significant difference between the two groups was present in the actuarial survival curves. The 5-year survival rate was 66.6 percent in the formalin-treated group and 50.5 percent in the control group. No suture line recurrences were observed in the treated group. Our results indicate that intraluminal fixation of cancer cells before opening the bowel is an effective method of reducing local recurrence after resection of colorectal cancer.

Aged↗
PubMed1989

Myofibrillar activation failure in McArdle's disease.

Contractile properties of the adductor pollicis muscle were examined in 9 normal volunteers and 7 patients with histochemically proven myophosphorylase deficiency (McArdle's disease). Fatiguing contractions were produced by supramaximal stimulation of the ulnar nerve, delivered over a range of frequencies, to allow further examination of the mechanisms responsible for the premature fatigue in patients. The excessive reductions in force, demonstrated in patients at all frequencies, were not associated at high frequencies (50 and 100 Hz) with excessive declines in excitation (measured as compound muscle action potential). These results demonstrate that, in patients, myofibrillar activation failure occurs over and above that due to excitation failure. Abnormal slowing of relaxation mechanisms was also confirmed. These findings appear consistent with the hypothesis of inhibition of various ATPases by metabolic products. The observed, clear differences between normal subjects and myophosphorylase-deficient patients constitute the basis of an objective screening procedure for this and other glycolytic disorders.

Adolescent↗
PubMed1989

Effect of mazindol on dystrophic mice and on growth in young rats.

1. Mazindol, which has been proposed as a therapy for muscular dystrophy because of a suppression of growth hormone release was administered orally (0.1 mg/kg body wt/day) for approximately six weeks to healthy young rats and dystrophic mice. 2. Mazindol had no effect on the dystrophic mice. 3. Mazindol treated rats had reduced wt gain, but this effect was due to appetite suppression not growth hormone inhibition. 4. No effect of mazindol was seen on rat muscle, but there were significant increases in liver, heart and kidney wts compared to controls.

Animals↗
PubMed1989

Developmental regulation of nerve growth factor and its receptor in the rat caudate-putamen.

In prior studies, nerve growth factor (NGF) administration induced a robust, selective increase in the neurochemical differentiation of caudate-putamen cholinergic neurons. In this study, expression of NGF and its receptor was examined to determine whether endogenous NGF might serve as a neurotrophic factor for these neurons. The temporal pattern of NGF gene expression and the levels of NGF mRNA and protein were distinct from those found in other brain regions. NGF and high-affinity NGF binding were present during cholinergic neurochemical differentiation and persisted into adult-hood. An increase in NGF binding during the third postnatal week was correlated with increasing choline acetyltransferase activity. The data are consistent with a role for endogenous NGF in the development and, possibly, the maintenance of caudate-putamen cholinergic neurons.

Animals↗