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Biomedical subjects

C H Thompson

Publications and source records attributed to C H Thompson.

At least 73 records · Page 4Linked to original sources
PubMed1994

pH control in rat skeletal muscle during exercise, recovery from exercise, and acute respiratory acidosis.

We used 31P magnetic resonance spectroscopy to compare the response of rat skeletal muscle to three kinds of proton load. During exercise (tetanic sciatic nerve stimulation), protons from lactic acid were buffered passively and consumed by net hydrolysis of phosphocreatine (PCr). During recovery from exercise, the pH-dependent efflux of protons produced by PCr resynthesis could be partially inhibited by amiloride or 4,4'-diisothiocyanostilbene-2,2'-disulphonate (DIDS), implicating both sodium/proton and bicarbonate/chloride exchange, but was not inhibited by simultaneous respiratory acidosis. In early recovery, up to 30% of proton efflux was mediated by lactate/proton cotransport. During acute respiratory acidosis at rest, the eventual change in muscle pH was consistent with passive buffering and was unaffected by amiloride or DIDS, implying no significant contribution of proton fluxes.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1994

Comparisons of ATP turnover in human muscle during ischemic and aerobic exercise using 31P magnetic resonance spectroscopy.

To investigate human muscle bioenergetics quantitatively in vivo, we used 31P magnetic resonance spectroscopy to study the flexor digitorum superficialis of four adult males during dynamic ischemic and aerobic exercise at 0.50-1.00 W and during recovery from aerobic exercise. During exercise, changes in pH and [PCr] were larger at higher power, but in aerobic exercise neither end-exercise [ADP] nor the initial postexercise PCr resynthesis rate altered with power. In ischemic exercise we estimated total ATP synthesis from the rates of PCr depletion and glycogenolysis (inferred using an analysis of proton buffering); this was linear with power output. In aerobic exercise, again we estimated ATP synthesis rates due to phosphocreatine hydrolysis and glycogenolysis (incorporating a correction for proton efflux) and also estimated oxidative ATP synthesis by difference, using the total ATP turnover rate established during ischemic exercise. We conclude that in early exercise oxidative ATP synthesis was small, increasing by the end of exercise to a value close (as predicted) to the initial postexercise rate of PCr resynthesis. Furthermore, a plausible estimate of proton efflux during aerobic exercise can be inferred from the pH-dependence of proton efflux in recovery.

Adenosine Triphosphate↗
PubMed1994

Detection of human papillomavirus type 16 E6/E7 transcripts in histologically cancer-free pelvic lymph nodes of patients with cervical carcinoma.

Human papillomavirus (HPV) 16 E6/E7 mRNAs have been detected in paraffin-embedded sections of histologically cancer-free pelvic lymph nodes from four of six patients with HPV 16-associated cervical cancer. The cDNA obtained from the viral mRNA by reverse transcription was amplified by the polymerase chain reaction (PCR). Transcripts were present in a small but significant proportion (6/42, 14%) of the histologically negative/HPV 16 DNA-positive lymph node blocks; but neither HPV 16 DNA nor transcripts were found in 12 lymph node blocks from two patients whose cervical cancers were not HPV-related. Both of the HPV 16 mRNAs detectable by the PCR primers used in the assay (the E6*I and the full-length E6 transcript) were found in the primary tumors, but the transcription patterns in the lymph nodes were variable. The presence of HPV E6/E7 mRNAs in lymph nodes of patients with HPV-related cancer may be a more sensitive indicator of metastasis than conventional histology. In addition, their detections is likely to be more significant than that of HPV DNA sequences alone. The practical significance of the findings, however, awaits correlation with the ultimate clinical outcome.

Adult↗
PubMed1994

Cytomegalovirus and cervical cancer: failure to detect a direct association or an interaction with human papillomaviruses.

To investigate the possibility of human cytomegalovirus (HCMV) involvement in the aetiology of cervical carcinoma or in the development of a more clinically aggressive cancer cell phenotype, biopsies of cervical cancer from 103 women undergoing primary therapy for invasive (Stage Ia to IV) cervical cancer were investigated using a polymerase chain reaction (PCR) designed to detect sequences from the IE mtrII region of HCMV. PCR assays were also used on the same specimens to identify the presence of common human papillomavirus (HPV) types associated with cervical cancer (HPV 16, 18, 31, 33, 52, and 58). Of the 103 cancers examined, only 4 contained detectable HCMV DNAs, a proportion lower than that found by another Australian group investigating the cervical carriage of HCMV in women with normal cervices. In contrast, 89 of these cancers were positive for HPV DNA sequences, with HPV 16 (65/103) and HPV 18 (17/103) being most commonly detected. Three of the 4 HCMV-positive tumors were also positive for HPV 16 DNA. An examination of the relevant histopathological and clinical data revealed no evidence to support a contention that cancers positive for HCMV are associated with any unusual histologic cell types or with aggressive clinical behavior.

Adenocarcinoma↗
PubMed1994

Metabolic abnormalities in skeletal muscle after myocardial infarction in the rat.

1. The effect of experimental myocardial infarction on exercise and recovery of rat skeletal muscle was studied using 31P n.m.r. 4 weeks post-operatively. 2. Myocardial infarction (12 +/- 3% of left ventricular volume), insufficient to produce haemodynamic manifestations of heart failure, was without significant effect on exercise bioenergetics of skeletal muscle. 3. Citrate synthase activity was reduced by 17% in the infarcted animals and there was a marked slowing of the rate of phosphocreatine recovery after infarction (half-time 0.7 +/- 0.1 min to 1.6 +/- 0.2 min) in the absence of evidence of left ventricular failure or hypertrophy. 4. The study of recovery bioenergetics could provide a more sensitive measure of mitochondrial function than exercise, where no bioenergetic abnormality was detected. 5. Myocardial infarction can produce evidence of mitochondrial abnormality in skeletal muscle in the absence of haemodynamic compromise.

Adenosine Diphosphate↗
PubMed1994

Uraemic muscle metabolism at rest and during exercise.

The effect of chronic renal failure and the accompanying hyperphosphataemia on muscle metabolism at rest and during exercise was examined in a group of undialysed patients suffering from chronic renal failure. 31P magnetic resonance spectroscopy was used to measure intracellular high-energy phosphates in resting muscle as well as changes in the concentrations of these metabolites during exercise and recovery from exercise. In resting muscle, cell [Pi] rose with plasma [Pi], and free [ADP] changed such that the phosphorylation potential ([ATP]/([ADP] x [Pi])), which probably controls mitochondrial oxidation in resting muscle, was preserved despite a wide variation in cell [Pi]. The maximal oxidative capacity of the muscle was calculated from the kinetics of phosphocreatine recovery after exercise. There was no reduction in uraemic muscle oxidative capacity compared to control muscle. This contrasts with our finding of a reduction in the mitochondrial oxidative capacity in the muscle of patients established on dialysis, suggesting that a substance crucial for mitochondrial function or substrate supply to mitochondria is removed by dialysis.

Adenosine Diphosphate↗
PubMed1993

A phase I study of the left-shifting agent BW12C79 plus mitomycin C and the effect on the skeletal muscle metabolism using 31P magnetic resonance spectroscopy.

BW12C79 stabilizes the oxyhemoglobin molecule resulting in a reversible left-shift of the oxygen saturation curve. The activity of a number of bioreductive anticancer drugs, such as mitomycin C, may be enhanced under hypoxic conditions. Twenty-four patients with various malignancies received BW12C79 and mitomycin C. BW12C79 was administered i.v. with a loading dose (20-50 mg/kg) over 1 h followed by a maintenance infusion of 4 mg/kg/h for 5 h. Percentage modification of the oxyhemoglobin (degree of left-shift) was dose related with maximum modification of 56% and was maintained for the duration of maintenance infusion of BW12C79. Hemoglobin electrophoresis showed a fast moving band consistent with the BW12C79-oxyhemoglobin complex. Side effects at the top dose level comprised headache, nausea/vomiting, vein irritation, and myocardial ischemia. One other patient suffered from an acute encephalopathy of unknown etiology a few days following BW12C79. 31P magnetic resonance spectroscopy of exercising calf muscles showed increased breakdown of high energy phosphate stores and a greater reduction in pH. Recovery of the high energy phosphate stores after exercise was slow. These results were consistent with reduced oxygen supply due to either a left shift of the oxygen saturation curve and/or reduced muscle blood flow. BW12C79 did not interfere with the pharmacokinetics of mitomycin C. In conclusion, this phase I study demonstrates the feasibility of achieving a significant left shift in the oxygen saturation curve in cancer patients which is maintained for at least 5 h with acceptable toxicity. The maximum tolerated dose of BW12C79 was 50 mg/kg loading infusion followed by a maintenance infusion of 4 mg/kg/h. Magnetic resonance spectroscopy results were consistent with reduced supply of oxygen to exercising skeletal muscle. BW12C79 may be of potential benefit as an adjunct to bioreductive drugs in the treatment of solid tumors.

Adult↗
PubMed1993

Physical training improves skeletal muscle metabolism in patients with chronic heart failure.

OBJECTIVES: This study investigated the effects of physical training on skeletal muscle metabolism in patients with chronic heart failure. BACKGROUND: Skeletal muscle metabolic abnormalities in patients with chronic heart failure have been associated with exercise intolerance. Muscle deconditioning is a possible mechanism for the intrinsic skeletal muscle metabolic changes seen in chronic heart failure. METHODS: We used phosphorus-31 nuclear magnetic resonance spectroscopy to study muscle metabolism during exercise in 12 patients with stable ischemic chronic heart failure undergoing 8 weeks of home-based bicycle exercise training in a randomized crossover controlled trial. Changes in muscle pH and concentrations of phosphocreatine and adenosine diphosphate (ADP) were measured in phosphorus-31 spectra of calf muscle obtained at rest, throughout incremental work load plantar flexion until exhaustion and during recovery from exercise. Results were compared with those in 15 age-matched control subjects who performed a single study only. RESULTS: Before training, phosphocreatine depletion, muscle acidification and the increase in ADP during the 1st 4 min of plantar flexion exercise were all increased (p < 0.04) compared with values in control subjects. Training produced an increase (p < 0.002) in incremental plantar flexion exercise tolerance. After training, phosphocreatine depletion and the increase in ADP during exercise were reduced significantly (p < 0.003) at all matched submaximal work loads and at peak exercise, although there was no significant change in the response of muscle pH to exercise. After training, changes in ADP were not significantly different from those in control subjects, although phosphocreatine depletion was still greater (p < 0.05) in trained patients than in control subjects. The phosphocreatine recovery half-time was significantly (p < 0.05) shorter after training, although there was no significant change in the half-time of adenosine diphosphate recovery. In untrained subjects, the initial rate of phosphocreatine resynthesis after exercise (a measure of the rate of oxidative adenosine triphosphate [ATP] synthesis) and the inferred maximal rate of mitochondrial ATP synthesis were reduced compared with rates in control subjects (p < 0.003) and both were significantly increased (p < 0.05) by training, so that they were not significantly different from values in control subjects. CONCLUSIONS: The reduction in phosphocreatine depletion and in the increase in ADP during exercise, and the enhanced rate of phosphocreatine resynthesis in recovery (which is independent of muscle mass) indicate that a substantial correction of the impaired oxidative capacity of skeletal muscle in chronic heart failure can be achieved by exercise training.

Adenosine Diphosphate↗
PubMed1993

Effect of tri-iodothyronine administration on skeletal muscle intracellular pH in the rat.

1. Male Wistar rats were injected with tri-iodothyronine intraperitoneally for either 3 or 5 days. 2. Using 31P nuclear magnetic resonance spectroscopy, skeletal muscle intracellular bioenergetics of the leg were studied at rest and during sciatic nerve stimulation. 3. Tri-iodothyronine caused intracellular alkalinization of the cell, implying that administration of tri-iodothyronine induces an alteration in the set point for the sodium/proton antiport, the chief controller of intracellular pH. 4. During stimulation, there was less acidification of the skeletal muscle cell in the tri-iodothyronine-injected rats, implying either increased intrinsic buffering capacity of the muscle or increased proton efflux possibly due to increased activity of the sodium/proton antiport. 5. Effective proton efflux from the skeletal muscle cell may be sensitive to circulating levels of tri-iodothyronine.

Animals↗
PubMed1993

No evidence of mitochondrial abnormality in skeletal muscle of patients with iron-deficient anaemia.

OBJECTIVES: Patients with iron deficiency anaemia complain of decreased exercise capacity. We asked whether this is due to defective oxidative ATP synthesis in skeletal muscle as a consequence of reduced blood oxygen content and/or intrinsic mitochondrial abnormalities. DESIGN: We used 31P magnetic resonance spectroscopy to examine skeletal muscle bioenergetics in iron-deficient patients and in age- and sex-matched controls. SETTING: The patients were recruited from the primary care population. SUBJECTS: We studied seven symptomatic female iron-deficient patients (aged 32-70 years) with haemoglobin (Hb) concentration, [Hb], 8.0 g dl-1. Six had menorrhagia, the cause in the seventh patient remained undiagnosed. Results were compared with those of 8 healthy female controls (aged 25-48 years) with mean [Hb] 13.7 g dl-1. RESULTS: The right calf muscle was by studied 31P magnetic resonance spectroscopy in a 1.9 T super-conducting magnet. We measured the intracellular concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), adenosine triphosphate (ATP) and the intracellular pH at rest, during plantar flexion exercise and during recovery from exercise. Exercise duration was reduced in the patients, yet end-exercise PCr/(PCr+Pi) was higher and adenosine diphosphate (ADP) lower than in controls. After exercise, initial PCr recovery was slowed but this was probably because of the lower cytosolic ADP concentration. CONCLUSIONS: Mitochondrial ATP synthesis was not limited by oxygen supply or an intrinsic mitochondrial defect. Therefore, the reduced exercise capacity seen in iron deficiency could be due to central causes and not to skeletal muscle metabolic abnormalities.

Adenosine Triphosphate↗
PubMed1993

The effect of iron deficiency on skeletal muscle metabolism of the rat.

Using 31P magnetic resonance spectroscopy we compared skeletal muscle bioenergetics in Wistar rats made chronically anaemic by being fed a diet deficient in iron for 6 weeks with chronically iron deficient animals given a normal diet as well as 5 mg iron dextran at 2 or 7 days before experimentation. Spectra of the gastrocnemius muscle were taken at rest and during stimulation of the sciatic nerve at 2 Hz for 10 min. Relative concentrations of intracellular phosphate (Pi), phosphocreatine (PCr) and ATP were determined. Iron deficiency increased PCr breakdown and production of acid in stimulated skeletal muscle. Recovery of PCr and Pi concentrations after exercise was slow. These metabolic changes are consistent with either a reduction in supply of oxygen to the muscle cell or altered oxidative phosphorylation by the mitochondria. The latter may be mediated by defective function of iron-containing proteins crucial in oxidative phosphorylation and this is suggested both by the observation that treatment with iron, sufficient to correct the anaemia, does not completely reverse the metabolic changes and that there is a different time course for such metabolic improvements and the observed increase in haemoglobin concentration.

Adenosine Diphosphate↗
PubMed1993

Skeletal muscle metabolism during exercise and recovery in patients with respiratory failure.

BACKGROUND: Patients with respiratory failure have early fatiguability which may be due to limitation of oxygen supply for oxidative (mitochondrial) ATP synthesis. Skeletal muscle in exercise and recovery was studied to examine the effect of chronic hypoxia on mitochondrial activity in vivo. METHODS: The skeletal muscle of five patients with respiratory failure (PaO2 < 9 kPa) was studied by phosphorus-31 magnetic resonance spectroscopy and compared with 10 age and sex matched controls. Patients lay in a 1.9 Tesla superconducting magnet with the gastrocnemius muscle overlying a six cm surface coil. Spectra were acquired at rest, during plantar flexion exercise, and during recovery from exercise. Relative concentrations of inorganic phosphate (Pi), phosphocreatine (PCr) and ATP were measured from peak areas, and pH and free ADP concentration were calculated. For the start of exercise, the rates of PCr depletion and estimated lactic acid production were calculated. For the post exercise recovery period, the initial rate of PCr recovery (a quantitative measure of mitochondrial ATP synthesis), the apparent Vmax for mitochondrial ATP synthesis (calculated from initial PCr resynthesis and the end exercise ADP concentration which drives this process), and the recovery half times of PCr, Pi, and ADP (also measures of mitochondrial function) were determined. RESULTS: Considerably greater and faster PCr depletion and intracellular acidosis were found during exercise. This is consistent with limitation of oxygen supply to the muscle and might explain the early fatiguability of these patients. There was no abnormality in recovery from exercise, however, suggesting that mitochondria function normally after exercise. CONCLUSIONS: These results are consistent with one or more of the following: (a) decreased level of activity of these patients; (b) changes in the fibre type of the muscle; (c) decreased oxygen supply to the muscle during exercise but not during recovery. They are not consistent with an intrinsic defect of mitochondrial ATP synthesis in skeletal muscle in respiratory failure.

Adenosine Triphosphate↗
PubMed1993

Skeletal muscle metabolism in uremic rats: a 31P-magnetic resonance study.

The effect of uremia on skeletal muscle metabolism of the rat was examined using 31P-magnetic resonance spectroscopy. Three weeks following either a 5/6 nephrectomy or a sham operation, Wistar rats were placed in a 7T magnet, and the sciatic nerve was stimulated for 10 min. Analysis of spectra allowed calculation of intracellular pH and the relative concentrations of phosphocreatine (PCr), inorganic phosphate (Pi) and ATP. [ADP] was calculated from the creatine kinase equilibrium. There was a significant reduction in the resting intracellular [Pi] despite an elevation in extracellular [Pi], probably due to a reduction in the activity of the membrane Na/Pi cotransporter on account of a reduced sodium gradient. Despite anemia and uremia, there were no significant metabolic abnormalities during exercise and recovery accompanying this substantial reduction in glomerular filtration rate implying that at this level of renal impairment, there is no mitochondrial dysfunction.

Adenosine Triphosphate↗
PubMed1993

Effect of chronic uraemia on skeletal muscle metabolism in man.

Fatigue and lethargy, common symptoms in uraemia, have been attributed to many factors. To assess possible bioenergetic contributions to this, we examined the forearm muscle of five patients in end-stage renal failure using 31P-magnetic resonance spectroscopy. There was a small increase in the ratio of intracellular inorganic phosphate to ATP in resting muscle, suggesting an increased cytosolic phosphate concentration. During exercise, increased phosphocreatine breakdown was accompanied by rapid intracellular acidification and an increase in calculated lactic acid accumulation in the muscle of the uraemic subjects, suggesting glycolysis dominating over oxidative phosphorylation as a source of ATP. After exercise, the half-time of phosphocreatine (PCr) recovery was longer in the uraemic subjects, suggesting diminished mitochondrial function. The initial rate of PCr resynthesis was not significantly decreased, but when account was taken of the high cytosolic ADP concentration (which drives mitochondrial oxidative ATP synthesis) the calculated maximum oxidative capacity was significantly reduced in the uraemic subjects. Thus there was evidence of mitochondrial dysfunction in uraemia due either to limitation of oxygen supply, reduced mitochondrial content, or an intrinsic mitochondrial defect. This resulted in increased phosphocreatine depletion and increased glycolytic ATP production during exercise and there was partial compensation of the mitochondrial abnormality by increased ADP concentration. In three of these patients studied after elevation of haemoglobin with erythropoeitin (from 8 to 12 g/dl), initial phosphocreatine breakdown and lactic acid accumulation during exercise were normalized, while exercise duration and calculated maximum oxidative capacity remained significantly abnormal. This suggests that anaemia contributes to these metabolic abnormalities but does not fully explain them.

Adenosine Triphosphate↗
PubMed1992

Prevalence and distribution of human papillomavirus type-16 DNA in pelvic lymph nodes of patients with cervical cancer and in women with no history of cervical abnormality.

The polymerase chain reaction (PCR) was used to investigate the prevalence and distribution of human papillomavirus (HPV)-16 DNA in paraffin sections of all pelvic lymph nodes removed from 14 patients with Stage Ib-cervical cancer at the time of resection of their primary tumours. The results were compared with those obtained from 8 women with no known history of cervical abnormality. In all, 22 cervical biopsies and 40 I lymph nodes (296 paraffin blocks) were examined. Nine of the 14 cervical cancer patients had primary tumours that were positive for HPV-16 DNA: only 3 of these had lymph nodes with histological evidence of metastasis, and HPV 16 DNA was detected in each of the corresponding paraffin blocks. HPV 16 DNA was also detected in varying proportions (8%-92%) of the histologically-negative lymph nodes from these women. There was no correlation between the HPV DNA-positive lymph nodes and their proximity to the primary tumour. HPV-16 DNA was not identified in any of the lymph nodes from the 5 women whose cancers were not HPV-16-related, or in those of women with no evidence of cervical abnormality. This preliminary survey suggests that HPV DNA is frequently transported from HPV-16-related cervical tumours to regional lymph nodes. However, its practical significance will not be clear until sufficient time has elapsed for correlation of the results with the clinical outcome.

Adult↗
PubMed1992

Detection of HPV DNA in archival specimens of cervical cancer using in situ hybridisation and the polymerase chain reaction.

An archival survey of 98 cervical cancer specimens dating from the 1920s to the 1980s was undertaken to determine whether changes had occurred in the prevalence of human papilloma-virus (HPV) DNA. HPV DNA was detected in paraffin sections of cancers fixed in 10% formalin by in situ hybridisation (ISH) using HPV 6, 11, 16, and 18 32P-labelled DNA probes under conditions of high stringency; and by the polymerase chain reaction (PCR) using 20-mer oligonucleotide primers to amplify 109 bases of the E6 region of HPV 16. In 30 instances results obtained from Southern blot hybridisations which had been carried out on specimens of fresh tissue from the same cancers collected during the 1980s were available for comparison. The rates of HPV DNA detection in cervical cancers ranged from 83% (by Southern or PCR) and 70% (by ISH) on specimens from the 1980s, to 50% and 63% (by ISH and PCR, respectively) on specimens from the 1920s. HPV 16 was by far the most common type, being identified by Southern or ISH in approximately 92% of HPV DNA-positive specimens. No significant change in the prevalence of HPV DNA, or of HPV types, in cervical cancers was found over the 65 year period examined.

Archives↗