Biomedical subjects
K Clarke
Publications and source records attributed to K Clarke.
31P NMR spectroscopy of hypertrophied rat heart: effect of graded global ischemia.
To investigate the cause for the greater susceptibility of hypertrophied hearts to ischemic injury, we determined the interrelations of total work output, contractile function and energy metabolism in isolated, perfused normal and hypertrophied rat hearts subjected to graded global ischemia. Cardiac hypertrophy was induced by giving rats seven daily injections of either triiodothyronine (0.2 mg/kg) or isoproterenol (5 mg/kg). All hearts were perfused at an aortic pressure of 100 mmHg in the isovolumic mode in an NMR spectrometer (7.05 Tesla). Heart rate, developed pressure, and coronary flow were monitored simultaneously with changes in pH, creatine phosphate, ATP and inorganic phosphate. During pre-ischemic perfusion, the total work output (rate-pressure product) of hyperthyroid hearts was 28% higher than that of control hearts, whereas hearts from isoproterenol-treated animals showed no difference. However, when related to unit muscle mass, work was normal in hyperthyroid hearts and 26% lower after isoproterenol. Contractile function per unit myocardium (developed pressure/g wet weight) was lower in the hypertrophied hearts. ATP content was the same in all groups. Creatine phosphate decreased 41% after triiodothyronine and 25% after isoproterenol. Inorganic phosphate levels and intracellular pH were similar in control and isoproterenol-treated rat hearts, but were higher in the hyperthyroid rat hearts. The phosphorylation potential and the free energy change of ATP hydrolysis were lowered by hypertrophy, the levels correlating with the depressed contractile function. At each ischemic flow rate, both work and contractile function per unit myocardium were the same for all hearts, but the relations between flow and phosphorylation potential were different for each type of heart. Thus, at low flow rates, hypertrophied hearts perform the same amount of work and have the same contractile function as control hearts, but with abnormal changes in energy metabolism, indicating that the relations of energy status to coronary flow, total work output and contractile function are altered during the process of hypertrophy.
Adenosine production and energy metabolism in ischaemic and metabolically stimulated rat heart.
Adenosine may modulate blood flow and electrical activity in heart in response to changes in myocardial energy metabolism. In the present study, 31P NMR spectroscopy was used to examine the relation between cytosolic phosphate metabolite levels and release of adenosine into the venous effluent of isovolumic heart during graded low-flow ischaemia or metabolic stimulation with isoproterenol. When coronary flow rate was varied in steps between 1.6 and 12 ml/min/g, cytosolic ATP levels did not change significantly but the phosphorylation potential exhibited a linear correlation with flow rate below approximately 7 ml/min/g. Purine release (adenosine and inosine) correlated linearly with the cytosolic phosphorylation potential and free AMP concentration. Metabolic stimulation of hearts with isoproterenol (0.4, 3.0, and 60 nM), produced a significant fall in cytosolic ATP levels and decreased the cytosolic phosphorylation potential. Purine release in these hearts increased exponentially as the cytosolic phosphorylation potential dropped, and as cytosolic free AMP increased. These results support a link between the phosphorylation potential and the mechanism of adenosine production during ischaemia and metabolic stimulation. Presumably, this link is the activity of the enzyme 5'-nucleotidase, which is responsible for converting AMP to adenosine, together with the concentration of its substrate, AMP. In low-flow ischaemia, cytosolic AMP may control adenosine formation. With isoproterenol stimulation, a more complex relationship exists, indicating possible allosteric regulation of the enzyme(s) responsible for adenosine formation, in addition to changes in AMP concentration.
Immunoaffinity chromatographic purification of amyloid-related proteins from Alzheimer's disease brain tissue.
We describe the preparation and characterisation of an immunoaffinity column of immobilised monoclonal antibody 1G10/2/3 which was raised against a synthetic peptide representing residues 8-17 of the A4 amyloid protein (or beta-protein) of Alzheimer's disease (AD). In previous work we have shown that this antibody reacts in formalin-fixed, paraffin-embedded tissue sections with plaque cores, plaque periphery and cerebrovascular amyloid of AD. We have used the column in the immunoaffinity isolation from extracts prepared from AD brain tissue of a protein with an apparent molecular weight of 31,000; this protein is reactive with 1G10/2/3 in Western blots. The same protein is also present, but at lower level, in normal control brain tissue. Possible relationships of this protein to the predicted structures for full-length A4-precursors are discussed. However, in view of the preliminary nature of the observations and potential problems relating to proteolysis occurring post-mortem or during the extraction process, firm conclusions cannot be drawn about any role for this molecule in the normal functioning of A4-precursors or in the conversion of A4-precursor to the deposits of A4 seen in AD brain. Nevertheless, we conclude that we are seeing a stable but truncated form of A4-precursor and it will be of interest to see if further studies can clarify the possible relevance of the protein to normal or pathological processes in human brain tissue.
Implications of working for patients for hospital medicine.
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Energy metabolism and contractile function in rat heart during graded, isovolumic perfusion using 31P nuclear magnetic resonance spectroscopy.
The isolated, perfused heart is known to exhibit a linear relation between aortic pressure, coronary flow rate, oxygen consumption and contractile function (rate-pressure product) over a wide range of aortic pressures. Our study sought to determine whether the cytosolic phosphorylation potential [( ATP]/[ADP][Pi]) is the link between mitochondrial respiration and contractile function in this preparation. 31P NMR spectroscopy was used to measure phosphate metabolite levels in isovolumic rat hearts during graded perfusion from 1.6 to 12.8 ml/min/g. It was found that an increase in contractile function paralleled the increase in flow rate, but that marked changes in creatine phosphate, inorganic phosphate and hydrogen ion concentration occurred only at lower flow rates. The cytosolic phosphorylation potential showed a high, positive correlation with contractile function at flow rates below 7.2 ml/min/g, which suggested that mitochondrial respiration was oxygen-limited and that the heart was ischemic. Thus, when oxygen limits myocardial oxidative phosphorylation, cytosolic energy metabolite levels may limit contractile function. At the higher flow rates studied, other metabolic controls may operate to link mitochondrial respiration and workload.
Temporal relation between energy metabolism and myocardial function during ischemia and reperfusion.
The purpose of the present investigation was to study the relation between energy metabolism and contractile function in the isovolumic guinea pig heart. 31P nuclear magnetic resonance spectroscopy was used to measure changes in the intracellular levels of creatine phosphate, ATP, inorganic phosphate, and pH during 2.43 min total global ischemia and 2.43 min reperfusion, with a time resolution of 9.7 s. From these data, cytosolic changes in the phosphorylation potential, [ATP]-to-[ADP] ratio, free-energy change of ATP hydrolysis, and concentration of free ADP were estimated. The simultaneous monitoring of functional and biochemical parameters allowed them to be directly correlated with respect to time and with respect to each other. No significant changes in ATP were detected at any time, but changes in all other biochemical data were highly correlated with changes in contractile function. Kinetic analysis, using a nonlinear least-squares fit of the experimental points, revealed that the changes in most parameters fitted monoexponential functions. Each parameter was ranked according to its half time, which revealed that the phosphorylation potential was the only metabolic parameter to change at a rate faster than loss of contractile function during ischemia, and all metabolic changes, with the exception of pH, led the recovery of contractile function during reperfusion, the most rapid change occurring in the free ADP concentration. It is concluded that the cytosolic phosphorylation potential controls the contractile function of the heart and that cytosolic free ADP is important in the control of mitochondrial oxidative phosphorylation.
The 31P-nuclear magnetic resonance spectrum of heart: will it be of diagnostic use in clinical cardiology?
Significant progress in two areas will be required before the application of magnetic resonance spectroscopy in clinical cardiology is realized. On the technical side, methods must be developed to allow NMR spectra to be obtained non-invasively from the heart uncontaminated by surrounding tissue and with sufficient spatial resolution and signal to noise to be of practical use. On the application side, the potential value of the information derived from the NMR spectrum to diagnosis must be demonstrated. This review addresses the latter problem by evaluating the information content of the 31P-spectrum of heart within the framework of the practical constraints imposed by its possible clinical application as opposed to its acknowledged research application.
Relation between the phosphocreatine to ATP ratio determined by 31P nuclear magnetic resonance spectroscopy and left ventricular function in underperfused guinea-pig heart.
The relation between the PC/ATP ratio and left ventricular function was examined in the Langendorff-perfused guinea-pig heart over a range of perfusion flow rates. PC/ATP ratios were determined from the 31P-nuclear magnetic resonance spectra of hearts obtained at 80.98 MHz and ventricular function estimated by measuring pressure in the left ventricle. When flow rates were increased over the range 0.6 to 6.0 ml/min, the PC/ATP ratio increased from 0.64 +/- 0.05 at 0.6 ml/min to 1.82 +/- 0.12 at 3.8 ml/min with no further increase up to a flow rate of 6.0 ml/min. Developed pressure (DP) increased with the flow rate up to 6.0 ml/min but the end diastolic pressure (EDP) also increased. The DP/EDP ratio was found to correlate closely with the PC/ATP ratio over the range of flow rates examined. The PC/ATP ratio may be a practical index of myocardial function available to the clinician when the topical magnetic resonance technique is fully developed.
A study of the selection and control of exercise casualties for hospital collective training.
A project sponsored by HQ AMS TA and executed by an experienced TA Commanding Officer enhanced the effectiveness of Hospital Collective Training by improving the standard of selection and documentation of the input of exercise casualties, and set up the basis of a comprehensive library of casualty cards for future use.
Evaluation of the stoichiometry and strength of chloroquine-porphyrin interactions by difference spectroscopy.
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Choroidal melanoma: comparison of CT, fundoscopy, and US.
Computed tomography (CT) was compared with fundoscopy and ultrasound (US) in 62 patients with primary choroidal melanoma. All lesions were detected with CT and fundoscopy and all but one with US. Of five cases of extrascleral extension, four were identified with CT and fundoscopy and two with US. CT best depicted the extent of retrobulbar tumor. Tumor thickness was best evaluated with CT, with good correlation between CT and US. Tumor enhancement was noted in all 51 patients who had both noncontrast and contrast CT. Because of its higher density, tumor could be distinguished from retinal detachment on CT scans in most cases.
Caesarean section under extradural analgesia in a patient with Ebstein's anomaly.
Ebstein's anomaly is a rare congenital malformation of the tricuspid valve, often associated with an atrial septal defect. Death occurs usually from cardiac arrhythmias. The successful use of a two-catheter technique for elective Caesarean section with extradural analgesia is described and the hazards associated with Ebstein's anomaly in pregnancy and anaesthesia are discussed.
Protein synthesis in the early stages of cardiac hypertrophy.
Cardiac hypertrophy, induced in rats by either tri-iodothyronine or isoproterenol, administered daily for 7 days, was monitored using several parameters. Both treatments increased RNA concentrations 24 hr after the first injection, while heart weight increased following 2 injections to 46% above control after 7 days. Cardiac protein synthetic activity, as determined by the rate of peptidyl-puromycin formation, was increased by both tri-iodothyronine and isoproterenol 24 hr after a single injection, implying an increase in the number of functional ribosomes. RNA activity (the rate of peptidyl-puromycin formation per unit RNA) remained constant, suggesting that neither accelerated rates of initiation or translation nor increased activation of pre-existing, non-translating ribosomes was involved in the observed increase in protein synthetic activity. In contrast, constant infusion of [14C] tyrosine indicated no change in protein synthetic rate 24 hr after a single tri-iodothyronine injection and decreased protein synthetic rate after isoproterenol injection. It is concluded that the use of [3H]puromycin to estimate protein synthetic activity may be a more sensitive procedure for detecting early changes in protein synthesis in cardiac hypertrophy than constant isotope infusion, owing to the problems associated with determining the precise precursor pool for protein synthesis in this latter method.
Planning resources.
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Interview with Kenneth Clarke.
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Species composition of mosquitoes collected in the Murray Valley of South-eastern Australia during an epidemic of arboviral encephalitis.
Mosquito activity at the height of an epidemic of arboviral encephalitis in the Murray Valley during the summer of 1974 was almost entirely crepuscular and nocturnal, but anecdotal evidence, indicated that day-biting Aedes species were also unusually prevalent during the first 4-5 weeks of the epidemic. Ninety-eight percent of the 138,359 mosquitoes captured in miniature light traps and by aspiration between 4th and 13th February, 1974, were Culex annulirostris, and 10 other species of 5 genera comprised the remaining 2%. In the one 'man-biting' collection 96% of 1,364 mosquitoes were Cx annulirostris. The overall capture rate for 51 light trap nights at 7 widely dispersed collecting sites was 2,675. At Barmah Forest 10 light trap nights yielded an average of 9,103 mosquitoes, with a maximum of 26,293 in one trap night.
Infanticide, illegitimacy and the medical profession in nineteenth century England.
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