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Biomedical subjects

M J Jackson

Publications and source records attributed to M J Jackson.

At least 91 records · Page 5Linked to original sources
PubMed1996

Indicators of free radical activity in patients developing radiation pneumonitis.

PURPOSE: Radiation pneumonitis is thought to occur as the result of excess free radical generation following radiotherapy. Various in vitro studies have shown that large doses of irradiation can cause membrane lipid peroxidation and the oxidation of protein sulphuryl groups. We, therefore, studied two circulating markers of lipid peroxidation and an indicator of "catalytic iron" (potentially available iron to catalyze the generation of free radicals) in patients undergoing radiotherapy. METHODS AND MATERIALS: The 9,11 diene conjugate of 9,12 linoleic acid, expressed as their molar ratio (percentage molar ratio (MR)) and thiobarbituric acid reactive acid-substances (TBARS), as well as levels of circulating desferrioxamine-chelatable iron assay, were assayed. Serial blood samples were taken over a 3-month period in 25 patients with inoperable nonsmall cell lung cancer. RESULTS: Ten patients developed radiation pneumonitis. The patients who developed pneumonitis showed a tendency for the serum percentage molar ratio to increase after a week. The change in the percentage molar ratio between Time 0 and 1 week of radiotherapy was significantly higher in the group that subsequently developed pneumonitis compared to the group that did not (p = 0.002). The initial serum TBARS levels in patients were not significantly elevated compared to controls and there was no difference in the serum TBARS levels in the pneumonitis and nonpneumonitis groups throughout the study period. After 1 week of radiotherapy the group that subsequently developed pneumonitis had a significantly higher level of desferrioxamine-chelatable iron (DFx-iron) compared with the nonpneumonitis group (p = 0.05). CONCLUSION: These data suggest that both the percentage MR and DFx-iron appear to reflect an increased susceptibility to develop radiation pneumonitis and after 1 week of radiotherapy they indicate patients who are likely to subsequently develop pneumonitis. Hence, these indicators could indicate the group of patients that could benefit from intervention therapies with antioxidants.

Adult↗
PubMed1996

Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia.

Defects of the mitochondrial respiratory chain are increasingly being recognized as an important cause of neurological disease in humans. In many of these patients, the biochemical defect results from an abnormality of the mitochondrial genome. Respiratory chain defects involving complex II, which is entirely encoded by the nuclear genome, are comparatively rare. We report the clinical and biochemical findings in 2 elderly sisters who presented with late-onset neurodegenerative disease. In both patients, a partial deficiency of complex II (approximately 50% of control values) was shown to be present in mitochondria from muscle and platelets. The enzyme defect was not expressed in cultured skin fibroblasts or immortalized lymphocytes. There was an overexpression of the 70-kd flavoprotein subunit in muscle mitochondria from both patients, although we showed that this subunit is present in normal amounts in mitochondrial membranes. Our studies highlight the diversity of the clinical presentation of respiratory chain disease and that complex II deficiency should enter the differential diagnosis of certain patients with late-onset neurodegenerative disease.

Ataxia↗
PubMed1996

Induction of astrocyte argininosuccinate synthetase and argininosuccinate lyase by dibutyryl cyclic AMP and dexamethasone.

Arginine is an intermediate in the elimination of excess nitrogen and is the substrate for nitric oxide synthesis. Arginine synthesis has been reported in brain tissue. We have studied the activity of the arginine biosynthetic enzymes argininosuccinate synthetase and argininosuccinate lyase in dexamethasone and/or dibutyryl cyclic AMP treated rat astrocyte cultures. Argininosuccinate lyase activity was stimulated by treatment with either effector and an additive effect was obtained when both agents were added simultaneously. Argininosuccinate synthetase was also increased in dexamethasone treated astrocytes. The effect of dibutyryl cyclic AMP on argininosuccinate synthetase was variable, suggesting a role for additional factors in its regulation as compared to argininosuccinate lyase. Regulation of arginine synthesis in astrocytes may be important to insure that arginine is not limiting for nitric oxide synthesis in neural tissue.

Adenylyl Cyclases↗
PubMed1996

Investigation by polymerase chain reaction of enteroviral infection in patients with chronic fatigue syndrome.

1. Chronic fatigue syndrome is characterized by muscle fatigue and pain at rest, symptoms which are usually exacerbated with exercise. Although various studies have shown minor, non-specific morphological and biochemical changes in muscle of patients with chronic fatigue syndrome, no consistent defect has been identified. Some have suggested that an enteroviral infection in muscle may cause the chronic muscle fatigue seen in patients with chronic fatigue syndrome, with acute infection directly and irreversibly impairing mitochondrial function, and persistent infection depressing muscle protein synthesis and metabolism. 2. To clarify the involvement of enterovirus infection in chronic fatigue syndrome, muscle biopsies from a group of patients with chronic fatigue syndrome were examined for the presence of enteroviral RNA by reverse transcriptase-polymerase chain reaction techniques in relation to functional studies of muscle mitochondria and the muscle RNA/DNA ratio. 3. Fifty-eight percent of patients reported an uncharacterized 'viral infection' before the onset of their illness, but none of the muscle samples from 34 patients contained detectable amounts of enteroviral RNA. Muscle tissue had a general reduction in the RNA/DNA ratio and mitochondrial enzyme activities with no specific abnormality in the activity of enzymes encoded partially on the mitochondrial genome (cytochrome-c oxidase) or nuclear genome (citrate synthase, succinate reductase). 4. These data provide no evidence of an enteroviral infection in muscle of patients with chronic fatigue syndrome, although this does not exclude a role of enterovirus in initiating the disease process. The general reduction in RNA/DNA ratio and mitochondrial enzyme activities is consistent with a general reduction in habitual activity.

Adult↗
PubMed1996

Fasting increases the extent of muscle necrosis in the mdx mouse.

1. The effects of fasting for 48 h were investigated in C57BL/10 (wild type) and age-matched C57BL/10 dystrophin-deficient (mdx) mice. 2. Fasting resulted in an increased percentage of necrotic fibres in muscles from the hindlimb and lumbar regions of mdx mice. The percentage of necrotic fibres of forelimb and chest muscles of mdx mice was unaltered by fasting. In wild-type mice, very few necrotic fibres were observed after fasting. 3. The necrotic changes in fasted mdx muscle were not accompanied by altered energy status as evaluated by muscle ATP and phosphocreatine concentrations. 4. A significantly decreased rectal temperature was observed in mdx but not in wild-type mice after fasting. 5. Fasting would normally be expected to cause a reduction in muscle fibre size. The high prevalence of necrosis in fasted mdx mice is therefore an unusual response that may be related to disturbance of the mechanisms which, in the fed state, compensate for the dystrophin deficiency in these animals.

Animals↗
PubMed1996

Dietary supplementation with carotenoids: effects on alpha-tocopherol levels and susceptibility of tissues to oxidative stress.

The ability of dietary supplementation with carotenoids to protect chick tissues against oxidative stress in vitro was examined. Male Leghorn chicks were fed on diets supplemented (100 mg supplement/kg diet) with either beta-carotene, zeaxanthin (beta,beta-carotene-3,3'-diol), canthaxanthin (beta,beta-carotene-4,4'-dione) or alpha-tocopherol, or on a control diet, from 1 d old until 37 d of age. Tissues (liver, heart, skeletal muscle and plasma) were removed and assayed for total carotenoids and alpha-tocopherol content and portions subjected to oxidative stress by incubation of homogenates with cumene hydroperoxide and FeSo4. Animals receiving zeaxanthin and canthaxanthin had significantly greater carotenoid concentrations in liver, heart, muscle and plasma compared with untreated controls (P < 0.05); animals fed on diets supplemented with beta-carotene, or alpha-tocopherol did not have significantly different tissue carotenoid contents compared with untreated controls. alpha-Tocopherol supplementation elevated alpha-tocopherol levels in all tissues examined (P < 0.05). Supplementation with carotenoids did not affect tissue alpha-tocopherol levels, but beta-carotene lowered plasma alpha-tocopherol levels by 50% (P < 0.05). Incubation of plasma or tissue homogenates with oxidant stressors induced lipid peroxidation (production of thiobarbituric-acid reactive substances) in all tissues. Animals given alpha-tocopherol, beta-carotene or zeaxanthin had a reduced susceptibility to oxidant stress in liver compared with unsupplemented controls (P < 0.05), and alpha-tocopherol-supplemented animals had reduced susceptibility in skeletal muscle compared with tocopherol-supplemented animals had reduced susceptibility in skeletal muscle compared with unsupplemented controls (P < 0.05). Canthaxanthin supplementation did not influence the susceptibility to oxidant stress in any tissue examined. These results suggest that zeaxanthin, a carotenoid present in animal and human diets, may have significant activity as an antioxidant against oxidative stress in tissues.

Animals↗
PubMed1996

Serum indicators of free radical activity in idiopathic pulmonary fibrosis.

Serum levels of free radical activity were measured in 37 patients with idiopathic pulmonary fibrosis (IPF) and 16 control subjects. Three assays used were (1) simultaneously measured levels of the 9,11-diene conjugate of linoleic acid and 9,12-linoleic acid expressed as a percent molar ratio (%MR), a measure of free-radical-mediated lipid peroxidation; (2) thiobarbituric acid reactive substances (TBARS), one of which is malondialdehyde; (3) desferrioxamine-chelatable iron assay, a measure of the potential iron available to catalyze free radical generation. Mean %MR, TBARS and desferrioxamine-chelatable iron were all elevated initially in patients with IPF compared with control subjects (%MR, p < 0.0001; TBARS, p = 0.0013; desferrioxamine-chelatable iron, p = 0.0029). Furthermore, the serum %MR was higher in a subset of patients with clinically worsening IPF than in those patients with clinically stable disease (p = 0.002). Treatment did not appear to affect the three different serum indicators of free radical activity. Thus, lipid peroxidation appears to be increased in patients with IPF and is associated with an increase in desferrioxamine-chelatable iron levels. Serum % MR levels appeared to correlate with clinical disease activity, and they may have a role in monitoring disease activity.

Aged↗
PubMed1996

Ischemia-reperfusion-induced muscle damage. Protective effect of corticosteroids and antioxidants in rabbits.

We examined the potential protective effect of pretreatment with corticosteroids or antioxidants (ascorbic acid or allopurinol) in rabbits with reperfusion-induced damage to skeletal muscle after ischemia. 4 hours of limb ischemia induced by a pneumatic tourniquet, followed by reperfusion for 1 hour, caused a considerable amount of ultrastructural damage to the anterior tibialis muscles accompanied by a rise in circulating creatine kinase activity. Pretreatment of animals with depomedrone by a single 8 mg bolus injection led to a preservation of the anterior tibialis structure on both light and electron microscopy. High-dose continuous intravenous infusion with ascorbic acid (80 mg/hr) throughout the period of ischemia and reperfusion also preserved skeletal muscle structure, although allopurinol in various doses had no protective effect. These data are fully compatible with a mechanism of ischemia/reperfusion-induced injury to skeletal muscle, involving generation of oxygen radicals and neutrophil sequestration and activation. They also indicate that damage to human skeletal muscle caused by prolonged use of a tourniquet is likely to be reduced by simple pharmacological interventions.

Allopurinol↗
PubMed1995

Cortical blindness during left internal mammary angiography.

Two cases of transient cortical blindness during coronary and graft angiography are described. In both cases, the onset of blindness was immediately preceded by manipulation of a guidewire in the left subclavian artery during attempts to selectively engage the internal mammary artery. Vertebral angiography was performed in the first patient and the appearances were compatible with multiple emboli in the posterior circulation. This patient was anticoagulated with intravenous heparin. His vision recovered within 72 h, but a mild visual agnosia persisted and it was only after nearly 3 weeks that all neurological deficits had resolved. The second patient recovered fully within 15 min. We postulate that emboli occurring as a result of manipulation of the guidewire close to the origin of the left vertebral artery was the cause of the cortical blindness in both these patients, although vasospasm as a contributory factor cannot be excluded. With an increasing need for investigation of patients after coronary artery bypass grafting, angiographers should be aware that selective internal mammary graft angiography may carry a higher than normal risk of neurological complications. The use of a guidewire to manipulate the catheter in the subclavian artery may increase this risk.

Angiography↗
PubMed1995

Neonatal Fanconi syndrome due to deficiency of complex III of the respiratory chain.

Fanconi syndrome is an important presentation of respiratory chain disease. We report three patients who presented in the neonatal period with Fanconi syndrome, lactic acidosis and intrauterine growth retardation. In all three patients the major biochemical defect was in complex III of the mitochondrial respiratory chain, a relatively uncommon defect. The diagnosis could only be made by muscle biopsy as the defect was not expressed in cultured skin fibroblasts. Treatment with vitamins C and K3 and ubiquinone did not alter the course of the disease and all patients died before the age of 4 months.

Acidosis, Lactic↗
PubMed1995

Effect of dibutyryl cyclic AMP and dexamethasone on glutamine synthetase gene expression in rat astrocytes in culture.

Astrocytes are the primary site of glutamate conversion to glutamine in the brain. We examined the effects of treatment with either dibutyryl cyclic AMP and/or the synthetic glucocorticoid dexamethasone on glutamine synthetase enzyme activity and steady-state mRNA levels in cultured neonatal rat astrocytes. Treatment of cultures with dibutyryl cyclic AMP alone (0.25 mM-1.0 mM) increased glutamine synthetase activity and steady state mRNA levels in a dose-dependent manner. Similarly, treatment with dexamethasone alone (10(-7)-10(-5) M) increased glutamine synthetase mRNA levels and enzyme activity. When astrocytes were treated with both effectors, additive increases in glutamine synthetase activity and mRNA were obtained. However, the additive effects were observed only when the effect of dibutyryl cyclic AMP alone was not maximal. These findings suggest that the actions of these effectors are mediated at the level of mRNA accumulation. The induction of glutamine synthetase mRNA by dibutyryl cyclic AMP was dependent on protein synthesis while the dexamethasone effect was not. Glucocorticoids and cyclic AMP are known to exert their effects on gene expression by different molecular mechanisms. Possible crosstalk between these effector pathways may occur in regulation of astrocyte glutamine synthetase expression.

Analysis of Variance↗
PubMed1995

Effects of cocaine on leakage of creatine kinase from skeletal muscle: in vitro and in vivo studies in mice.

The mechanism of cocaine-induced rhabdomyolysis and/or muscle damage has not been elucidated. To determine if cocaine has a direct effect on muscle, isolated soleus and EDL muscles were incubated in the presence of 1 mM and 0.2 mM cocaine using a pulse and continuous exposure protocol. The release of creatine kinase from the isolated EDL muscle was statistically significant only when muscles were exposed to 1 mM cocaine for a period of 30 minutes. These findings suggest that cocaine-induced creatine kinase release could be mediated by a direct action on the fibers. It is also possible, however, that cocaine-induced muscle damage and creatine kinase release may be mediated via an indirect effect. It is possible that cocaine's vasoconstrictor effects could lead to muscle damage via an ischemia-reperfusion injury leading to free radical formation and lipid peroxidation. This study, therefore, also investigated the possibility that cocaine-induced cytosolic enzyme release may be mediated via the formation of free radicals leading to lipid peroxidation. To test this hypothesis, muscle total glutathione levels, a free radical scavenger, and muscle thiobarbituric acid reactive substances (TBARS), a measurement of lipid peroxidation, were examined following an acute IV cocaine dose in mice. Sedentary BalbC mice were injected with cocaine (40 mg/kg) or normal saline via the tail vein. Creatine kinase levels in serum and total glutathione and TBARS in liver and muscle were determined at 4, 8, and 24 hrs. Serum creatine kinase levels were significantly elevated 5-fold, while TBARS were elevated 100% in the gastrocnemius muscle of cocaine-treated animals at 4 hrs compared to normal saline controls. However, serum creatine kinase levels, total glutathione and TBARS in the gastrocnemius muscle were not statistically different at 8 or 12 hrs; or in the liver and anterior tibialis muscle at 4, 8, or 24 hrs. The present findings suggests that lipid peroxidation may be occurring in skeletal muscle after a single IV cocaine dose in mice.

Animals↗
PubMed1995

How does dystrophin deficiency lead to muscle degeneration?--evidence from the mdx mouse.

The mdx mouse has a defect in the same gene as boys with Duchenne muscular dystrophy, which results in the absence of the protein product, dystrophin. A large number of recent studies have used the mdx mouse model to examine the potential role of dystrophy in normal muscle and the mechanisms by which dystrophin-deficiency leads to myopathy. This review discusses critically the results of these studies and their relevance to understanding the mechanisms by which dystrophin-deficiency leads to muscle necrosis.

Animals↗