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Biomedical subjects

C H Thompson

Publications and source records attributed to C H Thompson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Skeletal muscle metabolism before and after gemfibrozil treatment in dialysed patients with chronic renal failure.

Patients with chronic renal failure appear at greater risk for skeletal muscle side effects from the fibric acid group of lipid lowering agents. In order to determine whether sub-clinical defects of skeletal muscle metabolism can be detected in dyslipidaemic dialysis-dependent patients receiving fibrates. we studied nine patients before and after three months of gemfibrozil therapy (300-600 mg daily). Aerobic and anaerobic metabolism of the right calf muscle was examined at rest and during exercise using 31P magnetic resonance spectroscopy. Near infra-red spectroscopy was used to assess skeletal muscle re-oxygenation following ischaemic exercise of the arm. Following gemfibrozil treatment plasma triglycerides fell significantly 3.0 +/- 0.5 mM (SEM) to 1.5 +/- 0.2 mM. Gemfibrozil did not affect the established metabolic defects that exist in the skeletal muscle of the dialysed patient. Skeletal muscle re-oxygenation was not significantly lower in renal failure and was not altered by gemfibrozil. Gemfibrozil (600 mg daily) significantly improved the lipid profile of chronic renal failure and was not associated with clinical or bioenergetic impairment of skeletal muscle metabolism.

Adult↗
PubMed1995

Brain abnormalities in Duchenne muscular dystrophy: phosphorus-31 magnetic resonance spectroscopy and neuropsychological study.

Duchenne muscular dystrophy (DMD) is one of a range of muscular dystrophies caused by abnormalities of the short arm of the X chromosome (Xp21), which often cause mental retardation in addition to progressive muscular weakness. Normal dystrophin expression is lacking in both skeletal muscle and brain of affected subjects. Phosphorus-31 magnetic resonance spectroscopy has shown several abnormalities in skeletal muscle in DMD. We looked for similar abnormalities in brain in patients with DMD and related the findings to neuropsychological test results. We studied by magnetic resonance spectroscopy 19 boys (aged 76-167 months) diagnosed as having DMD and 19 control boys of similar age (87-135 months). Intelligence quotient (IQ) was assessed with the Wechsler Intelligence Scale for children. The DMD patients had significantly higher values than the controls in the brain ratios of inorganic phosphate to adenosine triphosphate (mean 0.53 [SD 0.21] vs 0.36 [0.09], p = 0.003), to phosphomonoesters (0.40 [0.07] vs 0.29 [0.07], p = 0.0001), and to phosphocreatine (0.44 [0.10] vs 0.37 [0.08], p = 0.02). There were significant differences between the DMD patients and the controls in full-scale IQ (76 [16] vs 101 [16], p = 0.0001), performance IQ (78 [17] vs 94 [14], p = 0.003), and verbal IQ (78 [17] vs 106 [17], p = 0.0001). These altered metabolite ratios parallel the findings in dystrophic muscle and suggest bioenergetic similarities in tissues that lack dystrophin.

Adenosine Triphosphate↗
PubMed1995

ATP production and mechanical work in exercising skeletal muscle: a theoretical analysis applied to 31P magnetic resonance spectroscopic studies of dialyzed uremic patients.

31P magnetic resonance spectroscopy (31P MRS) can yield much information about bioenergetics in skeletal muscle. During mixed aerobic/glycolytic exercise, changes in phosphocreatine (PCr) concentration and pH may be abnormal because of reduced muscle mass or reduced efficiency (which the authors combine here as "effective muscle mass") or because of reduced oxidative capacity. The authors show how these can be distinguished by calculating the nonoxidative and oxidative costs of mechanical work, and also of work per unit of effective muscle mass (measured using the initial rate of ATP turnover). These quantities are substantially time-independent during incremental exercise, and so can be used to compare exercise studies of differing duration. The authors illustrate this analysis by showing that in dialyzed patients with chronic renal failure, the substantial exercise abnormalities seen by 31P MRS are due mainly to a decrease in effective muscle mass, which outweighs the oxidative defect implied by the abnormal PCr recovery kinetics.

Adenosine Triphosphate↗
PubMed1995

Identification of E6/E7 transcription patterns in HPV 16-positive cervical cancers using the reverse transcription/polymerase chain reaction.

Studies indicate the presence of four different forms of human papillomavirus (HPV) E6/E7 mRNA resulting from differences in transcription patterns and post-transcriptional nuclear splicing. Through a retrospective analysis of 28 cervical cancer patients, correlations were sought between E6/E7 transcription patterns and histologic type, FIGO stage, and tumor aggression. A combined reverse transcription/polymerase chain reaction was used to study E6/E7 transcription patterns in fresh and/or fixed paraffin-embedded tissues of HPV 16-positive cervical cancers. Random cervical biopsies from nine women with no history of cervical disease were included as controls. Two sets of primers used in the investigations detected the full-length (FL) E6, E6*I, and E6*II mRNAs and the FL E6 and E6*I mRNAs, respectively; eight of the tumors were also analyzed using a third primer combination designed to identify the E6*III mRNA. At least two of the transcripts were detected in all of the tumors, whereas E6/E7 mRNAs were not identified in any of the control cervical biopsies. Overall, the transcription patterns were consistent, but the major E6*I mRNA was not detected in two of the tumors. No relationship was found between the E6/E7 transcription patterns and the histological type and differentiation of the tumors, nor with the FIGO stage and the clinical behavior of the disease. The study confirms that E6/E7 transcription is a constant feature of HPV 16-related carcinoma, but the findings indicate that there may be no clinical advantage in adding E6/E7 mRNA detection to the routine assessment of cervical tumors.

Adult↗
PubMed1995

Associations between oncogenic human papillomaviruses and local invasive patterns in cervical cancer.

The polymerase chain reaction (PCR) was used to detect human papillomavirus (HPV) DNA in Formalin-acetic acid alcohol (FAA)-fixed paraffin-embedded tissue from 40 patients whose primary cervical cancers showed a tentacular pattern of invasion at their advancing edges, and 40 patients (matched by age, International Federation of Obstetrics and Gynecology (FIGO) stage and histology type) whose tumors showed broad front invasion. The rate of HPV DNA positivity was the same in both the tentacular and the broad front tumors (83%), but the ratios of HPV 16 to HPV 18 in the two groups were markedly different (20:10 versus 27:4, respectively). HPV type 18 was detected more frequently in tentacular than broad front tumors (P = 0.03). The overall rates of recurrence and mortality were 15 and 9%, respectively (18 and 10% in the tentacular group compared with 13 and 8% in the broad front group). Univariate analysis showed statistically significant associations between HPV 18 and tumor recurrence (P = 0.04), but not between a tentacular pattern of invasion and tumor recurrence (P < 0.05). The findings to emerge from this survey indicate that the presence of particular HPV types may, in part, mediate the histological and clinical behavior of cervical cancers.

Adult↗
PubMed1995

A relationship between impaired fetal growth and reduced muscle glycolysis revealed by 31P magnetic resonance spectroscopy.

Thinness at birth is associated with insulin resistance and an increased prevalence of non-insulin-dependent diabetes mellitus in adult life. As muscle is an important site of insulin resistance, and because thin babies have reduced muscle mass, thinness at birth may affect muscle structure and function and impair carbohydrate metabolism. We have therefore used 31P magnetic resonance spectroscopy to investigate the bioenergetics of gastrocnemius and flexor digitorum superficialis muscles in 16 normoglycaemic women who had a low ( < or = 23 kg/m3) and 9 women who had a high (> 23 kg/m3) ponderal index at birth. In the flexor digitorum superficialis study anaerobic metabolism was stressed with a constant heavy workload. Low ponderal index subjects fatigued more rapidly (3.3 vs 5.8 min); as phosphocreatine decreased, the accompanying drop in muscle pH was less than in the high ponderal index group. In the first minute of exercise phosphocreatine fell and adenosine diphosphate rose more rapidly (p=0.04 and 0.03, respectively). Gastrocnemius showed a similar trend late in exercise (this exercise was more oxidative, becoming more anaerobic with increasing workload). These changes were not explained by differences in body composition, muscle mass or blood flow. The findings are consistent with a decreased lactic acid and glycolytic adenosine triphosphate production in the low ponderal index group and suggest the possibility that the mechanisms which control substrate utilisation and metabolism in adult life be programmed during prenatal life.

Adenosine Diphosphate↗
PubMed1995

Human papillomavirus deoxyribonucleic acid as a prognostic indicator in early-stage cervical cancer: a possible role for type 18.

OBJECTIVE: Our purpose was to determine the prognostic significance of human papillomavirus deoxyribonucleic acid in cervical cancers. STUDY DESIGN: The polymerase chain reaction was used to detect human papillomavirus deoxyribonucleic acid types 6, 11, 16, 18, 31, 33, 52, or 58 in tumors from 148 patients (equal numbers of whom were disease free or had relapses) surgically treated for stage IB or IIA cancers in a major Australian hospital. Cox regression modeling was used to assess the effect of human papillomavirus status on tumor recurrence, taking into account patient age, clinical stage, histologic node status, and type of tumor. RESULTS: Seventy of 74 (95%) of the recurring tumors and 62 of 74 (84%) of the nonrecurring tumors were human papillomavirus deoxyribonucleic acid positive. The rates of positivity of types 16 and 18 were 64% versus 31% in the recurrers and 65% versus 14% in the nonrecurrers. Human papillomavirus type 18 positivity was associated with a greater risk of recurrence than was type 16 positivity (hazard ratio 1.8; p = 0.03). Clinical stage, nodal metastasis, and young age (< or = 35 years) also had adverse effects on relapse (hazard ratio for each approximately 2). CONCLUSION: Human papillomavirus type 18 positivity is a risk factor for tumor recurrence in surgically treated cervical cancer.

Adult↗
PubMed1995

Bryostatin 1, a novel antineoplastic agent and protein kinase C activator, induces human myalgia and muscle metabolic defects: a 31P magnetic resonance spectroscopic study.

Bryostatin 1, a novel antineoplastic agent and protein kinase C (PKC) activator, has been found to induce myalgia (muscle pain) 48 h after administration in clinical trials. This is the dose-limiting toxicity and has restricted the duration of therapy in phase I trials. To investigate the mechanisms and try to increase toleration of the drug, we studied calf muscle metabolism of 14 patients at rest and during exercise and subsequent recovery using 31P magnetic resonance spectroscopy (MRS) before and 4 h, 48-72 h and 1-2 weeks following bryostatin therapy. In resting muscle there was a significant (P < 0.001) increase in the phosphodiester/adenosine 5'-triphosphate (PDE/ATP) ratio 48 h post bryostatin and in patients with myalgia compared with pre-bryostatin control studies. Following exercise, patients with myalgia showed significantly slower phosphocreatine (PCr) and ADP recovery half-time (P < or = 0.05) suggesting impaired mitochondrial (oxidative) energy production, possibly due to a direct effect on the mitochondria or secondary to reduced blood flow. The apparent proton efflux rate following exercise was significantly reduced 4 h after bryostatin (P < or = 0.05), suggesting reduced blood flow. The rate of post-exercise reoxygenation was studied in four patients by near-infrared spectroscopy 4 h post bryostatin. In three of these the rate was reduced, consistent with reduced muscle blood flow. Bryostatin 1 appeared to cause a long-lasting impairment of oxidative metabolism and proton washout from muscle, consistent with a vasoconstrictive action. Thus these studies provide evidence for two mechanisms of the dose-limiting toxicity for bryostatin. Prospective studies on the use of vasodilators to improve the tolerance of the drug should be carried out.

Adenosine Triphosphate↗
PubMed1995

Rat skeletal muscle metabolism in experimental heart failure: effects of physical training.

Skeletal muscle metabolic abnormalities exist in chronic heart failure. The influence of physical training on muscle metabolism after myocardial infarction was studied in a rat model. 31P magnetic resonance spectroscopy and enzyme assays were performed in Wistar rats 12 weeks after coronary artery ligation. Infarcted rats were allocated randomly to either 6 weeks of training or non-training. Spectra were collected from the calf muscles during sciatic nerve stimulation at 2 Hz. Fibre typing and enzymatic assays were performed on the muscles of the contralateral non stimulated leg. Post-mortem rats were also divided into severe and moderate heart failure according to the lung weight per body weight. At 200 g twitch tension, phosphocreatine and pH were found to be significantly lower in the non-trained severe heart failure group compared with the other groups. Phosphocreatine recovery half-time was significantly longer in the non-trained group with severe heart failure and correlated with the citrate synthase activity in the muscle. The training did not induce a change in the enzyme activities in the infarcted animals with moderate heart failure but did correct the lower citrate synthase activity in the non-trained severe heart failure animals. This normalization of muscle metabolism was achieved by training without any change in calf muscle mass, making atrophy unlikely to be the sole cause of the metabolic changes in heart failure. Training in rats with severe heart failure can reverse the abnormalities of skeletal muscle metabolism, implicating decreased physical activity in the aetiology of these changes.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1995

Skeletal muscle mitochondrial function studied by kinetic analysis of postexercise phosphocreatine resynthesis.

To investigate mitochondrial regulation and its response to a defect in oxidative metabolism, we used 31P-magnetic resonance spectroscopy to study phosphocreatine (PCr) recovery in rat leg muscle after sciatic nerve stimulation at 1-4 Hz. We studied normal animals and animals with defective skeletal muscle mitochondrial function after experimental cardiac infarction. To analyze these data, we used three current theoretical approaches to the control of mitochondrial ATP synthesis, based on its hyperbolic relationship to cytosolic ADP concentration and on its linear relationships to PCr concentration and the free energy of ATP hydrolysis. The mitochondrial ADP concentration for one-half maximum rate of ATP synthesis appeared at least twice as high as the 30 microM expected from in vitro studies. According to all three approaches, the apparent maximum rate of ATP synthesis was independent of stimulation frequency and end-exercise pH and PCr and ADP concentrations and was reduced by approximately 50% after experimental cardiac infarction. Analysis of PCr recovery kinetics is a robust and practical way to study mitochondrial regulation and to quantify effective mitochondrial defects in vivo.

Adenosine Diphosphate↗
PubMed1995

Triiodothyronine-induced changes in proton efflux from rat skeletal muscle in vivo.

Hyperthyroidism is associated with muscle weakness, abnormal aerobic metabolism and increased lactate production. Muscle cell acidification during exercise is reduced, suggesting abnormally increased proton efflux. Using 31P magnetic resonance spectroscopy to measure cell pH and phosphocreatine concentration, we quantified effective proton efflux from rat leg muscle in vivo following 10-Hz sciatic nerve stimulation in seven rats injected with triiodothyronine (T3) for 5 days and in 11 controls. Proton efflux during recovery was sigmoidally pH-dependent in both groups but the initial proton efflux rate did not differ (16 +/- 3 mmol.kg-1.min-1 in treated animals vs 15 +/- mmol.kg-1.min.-1 in controls), despite significantly smaller pH change from basal in treated animals (0.60 +/- 0.04 vs 0.78 +/- 0.03 in controls, p = 0.002). The pH dependence of proton efflux can be characterized by an apparent Km, defined as the pH below basal at which proton efflux rate falls to half its start-of-recovery value. This Km was smaller in the T3-treated group (0.44 +/- 0.04 vs 0.59 +/- 0.03 in controls, p = 0.02). This suggests an increased affinity for protons by cell membrane proton transport processes such as the sodium-proton antiporter and may explain some of the metabolic changes seen clinically in hyperthyroid skeletal muscle.

Animals↗
PubMed1995

Abnormal ATP turnover in rat leg muscle during exercise and recovery following myocardial infarction.

OBJECTIVE: Clinical and animal studies show increased acidification of skeletal muscle during exercise in heart failure, implying increased anaerobic metabolism, and impaired recovery from exercise, implying defective oxidative function. This study aimed to define the quantitative relationship between these changes in exercise and recovery and relate skeletal muscle bioenergetics to cardiovascular function. METHODS: Wistar rats were studied four weeks after myocardial infarction or a sham operation. 31P magnetic resonance spectroscopy of the hind leg muscle was used to estimate rates of oxidative and non-oxidative ATP synthesis from changes in pH and phosphocreatine concentration during sciatic nerve stimulation and to estimate the maximum rate of mitochondrial ATP synthesis from the kinetics of phosphocreatine recovery after stimulation. RESULTS: Following myocardial infarction, cardiac function was abnormal, with evidence of left ventricular hypertrophy, failure, and diminished arterial pressure. There was impaired phosphocreatine recovery, suggesting an approximate halving of the maximum rate of mitochondrial ATP synthesis. CONCLUSIONS: The response to exercise of the infarct group was abnormal and was quantitatively consistent with the reduced maximum rate of mitochondrial ATP synthesis inferred from recovery, the oxidative deficit during exercise being made up by increased glycogenolysis, causing sufficient acidification to prevent an appropriate increase in [ADP].

Adenosine Triphosphate↗