Reduction of exercise-induced ischemic regional myocardial dysfunction by verapamil in conscious dogs.
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Biomedical subjects
Publications and source records attributed to J Ross.
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We determined creatine kinase (CK) curve areas in 112 patients with acute myocardial infarction. Two-hour sampling was performed for the first 24 hours or until peak CK was reached, and a gamma density function was used to calculate curve areas from all available samples. Attempts to predict CK curve area by means of the portion of the curve prior to peak CK proved to be inaccurate; not until values 2 hours or more beyond peak CK were utilized did predicted and actual CK areas agree well. A good correlation (r = 0.93) was found between CK area and peak CK. To establish an approach for detecting peak CK in the clinical setting, a range of sampling intervals (4 to 24 hours) was assessed; 4- and 6-hour sampling intervals for 48 hours produced maximum CK values at or above 85% of true peak CK in 90% and 89% of patients, respectively, and average maximum CK at both sampling intervals exceeded 94% of that obtained with 2-hour samplings. We conclude that this simplified approach can provide a basis for estimating infarct severity in the individual patient.
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The molecular defect in four Kurdish Jews with homozygous, mRNA-deficient beta zero thalassemia was investigated. Electrophoretic profiles of pulse-labeled alpha- and beta-globin RNAs are similar to those of non-thalassemics; therefore, at least one of the thalassemic beta-globin alleles is transcribed. During a 30 min actinomycin D chase, most of the alpha- and beta-globin mRNA precursors and processing intermediates are converted to mRNA-sized RNA. Thalassemic and non-thalassemic beta-globin RNAs are indistinguishable, as determined by S1 nuclease mapping and RNA blotting. Non-thalassemic beta-globin mRNA is stable during a 30 min actinomycin chase, but 30%-75% of the thalassemic mRNA-sized molecules is degraded during that period. We conclude that the absence of beta-globin mRNA in this disease results from rapid turnover of beta-globin mRNA-sized molecules.
A rapid, sensitive, and specific solution-hybridization method is described that utilizes cloned, double-stranded DNA. The DNA is treated with restriction enzyme(s), and fragments are 32P-labeled at their 5' termini with polynucleotide kinase. A single fragment is partially purified by gel electrophoresis, denatured, and annealed with unlabeled RNA or DNA. The reaction mix is treated with S1 nuclease, precipitated with TCA, and the [32P]DNA counted. Hybridization is recognized only when the 32P label is associated with duplexes that are TCA-precipitable. The specificity of the method was analyzed by annealing experiments with cloned, human globin DNAs. Restriction fragments labeled in the 3' untranslated region of human beta globin clones formed S1-resistant, TCA-precipitable duplexes with beta globin DNA, but not with delta or gamma globin DNA. Thus, a major advantage of the method is that it can distinguish among homologous nucleic acids whose uniformly labeled cDNAs cross hybridize under moderately stringent conditions. This assay is as sensitive as the [3H]cDNA hybridization method, and it circumvents the requirement for purified mRNA as a template for [3H]cDNA synthesis. It also avoids a gel electrophoresis step, it is rapid and quantitative, and many samples can be simultaneously analyzed.
A variety of normal human ovarian tissues as well as benign and malignant human ovarian neoplasms have been examined in vitro for the presence of gonadotropin binding sites and gonadotropin-stimulable cAMP production, in order to determine whether gonadotropic hormones have an effect on ovarian tumors. Binding of either FSH or hCG, or both, was demonstrated in several tumors from each of the histologic subgroups of primary ovarian tumors, including epithelial, sex cord-stromal, and germ cell types. Cyclic AMP stimulation was found in one tumor of sex cord-stromal origin, in two of epithelial origin, in two of germ cell origin, and in one tumor-like condition, pregnancy luteoma. Additional biochemical studies are needed to characterize receptor sites and to relate them to histologic features, growth behavior in vivo, and serum gonadotropin levels.
We present an analysis of glycolysis based on experimental findings and an interpretation based on concepts of efficiency, resonance response, and control features available in highly nonlinear reaction kinetics. We begin with a model for the glycolytic mechanism that is comprehensive, includes a large number of known activations and inhibitions of enzymes by metabolites, and couples the phosphofructokinase (PFKase) and the pyruvate kinase (PKase) reactions. The PFKase and PKase reactions and the coupling between them are modeled according to experimental information, but we do not attempt to model the glyceraldehyde-3-phosphate dehydrogenase-3-phosphoglycerate kinase reaction. We use experimental data to obtain the best estimates for the kinetic parameters and test the model by calculating the concentration variations of the intermediate metabolites. We confirm oscillatory behavior and calculate the ATP/ADP ratio and the free-energy dissipation for an extended range of the kinetic parameters as a function of the driving force for the glycolytic pathway, a measure of which is the total adenine nucleotide concentration. We find agreement of the calculated results with experimental findings except for the insufficiently represented reactions. Our model shows that the average ATP/ADP ratio is increased and the average free-energy dissipation is decreased in an oscillatory compared with a steady state mode of operation. The average values of the ATP/ADP ratio and of the free energy dissipation change abruptly past the onset of sustained oscillations.
We have presented [Termonia, Y. & Ross, J. (1981) Proc. Natl. Acad. Sci. USA 78, 2952-2956] an analysis of glycolysis based on experimental findings. Here, we give an interpretation based on the concepts of efficiency, resonance response, and control features available to highly nonlinear reaction kinetics. The comprehensive model of glycolysis, for which we presented numerical evaluation of concentration oscillations, entropy production, and average ATP/ADP ratios is separated into two subsystems: one for the phosphofructokinase (PFKase) reaction, the other for the pyruvate kinase (PKase) reaction. We analyze each subsystem separately and find that, for a range of parameter values around the best estimates obtained from experimental data, the PFKase reaction exhibits sustained oscillations. The PKase reaction, on the other hand, is in a stable stationary state and shows an oscillatory relaxation. The period of the PFKase reaction is within 25% of that obtained by computer simulation of the full model. Moreover, if, for a given set of kinetic parameters, the period of the oscillations in the PFKase reaction is of the same order of magnitude as the period of the oscillatory relaxation of the PKase reaction, then the onset of oscillatory behavior past marginal stability forces a tuning of the PFKase reaction period to that of the PKase reaction. Thus, the PKase reaction tunes the frequency of the primary oscillophor, the PFKase reaction, so that a resonance response results in the PKase reaction. We find this result for a substantial range of parameters. The sharp increase in the ATP/ADP ratio and the decrease in the dissipation (entropy production) are seen to be a result of the forced tuning to resonance. The origin of the remarkable control feature of the tuning of one part of the pathway by another that follows in the reaction mechanism is the coupling of the two parts and, in the case of glycolysis, this is realized by the intermediate fructose 1,6-diphosphate, which participates crucially in the PFKase and PKase reactions.
Swabs were taken from the posterior fornix, perineum, and anorectum of 135 patients on three occasions during their pregnancy. Multiple isolates of beta-haemolytic streptococci of group B were obtained from 24 women, in 21 of whom the strains were examined by a highly discriminative serotyping and phage typing method. In 18 of these patients their own isolates were indistinguishable but different from those of other women with multiple isolates. Women yielding group B streptococci from the posterior fornix usually carried an indistinguishable strain in the anorectum.
Regional wall thickness and endocardial segment lengths in normal and ischemic zones of the left ventricle were measured simultaneously with ultrasonic-dimension gauges before and after chronic circumflex artery occlusion in conscious dogs. After 3 wk, end-diastolic segment lengths (EDL) in normal zones increase 10% (P less than 0.01), shortening increased 22% (P less than 0.05), and end-diastolic wall thickness (EDWT) was reduced by 12.8% (P less than 0.01). In ischemic zones at 3 wk, EDL was reduced by 15.4% (P less than 0.01), and subendocardial shortening recovered slightly to 15% of control; EDWT increased 11% at 3 days postocclusion and thereafter remained near control values (change not significant), but systolic wall thickening improved substantially, reaching 38% of control at 3 wk. Thus, tissue loss and slight return of function occurred in the ischemic subendocardium, whereas overall wall function (as reflected by regional wall thickening) improved considerably over time. These findings suggest that recovery of function in the outer layers of the wall after myocardial infarction modifies the close correlation between regional subendocardial segment and wall thickening dynamics observed acutely.
Ca2+ sensitivity of natural actomyosin (NAM) isolated from both the intact left ventricular free wall and an area of myocardial infarction (MI) was analyzed by use of superprecipitation response from 2 to 48 h after left anterior descending coronary artery ligation in the dog. NAM from the intact tissue showed normal superprecipitation and normal Ca2+ sensitivity. Four hours after coronary ligation, Ca2+ sensitivity was lowered only in the endocardial half of MI region; it was markedly decreased both in the epicardial and endocardial halves at 6 h and completely lost at 24 and 48 h. A superprecipitation response was, however, demonstrated in all samples, indicating that both myosin and actin preserved their functions in the course of MI. With polyacrylamide gel electrophoresis in sodium dodecyl sulfate, NAM from the MI region revealed moderate decrease of the tropomyosin-binding subunit of troponin(TN-T) and the Ca2+-binding subunit of troponin(TN-C) and drastic decrease of the inhibitory subunit of troponin(TN-I). This resulted in the formation of extra bands of low molecular weights. These results suggest that degradation of troponin subunits occurs relatively early (4 h after coronary artery occlusion) and from the endocardial half of MI region. This degradation may be caused by one or several proteases that preferentially degrade the regulatory proteins among myofibrillar proteins.
Gradual coronary constriction was elicited in conscious dogs by means of an implanted ameroid coronary constrictor. The functional state of the coronary collateral circulation was serially evaluated by means of regional contractile responses, using brief occlusions of the left circumflex coronary artery and strenuous running in the field. Although resting regional myocardial function was unchanged throughout the study, regional myocardial shortening during coronary occlusion decreased to 9% of control at 3-4 days after the operation; it then recovered progressively to 24% at 7-9 days, 45% at 15-18 days, and 94% at 20-24 days. Concomitantly, reactive hyperemia measured with a flowmeter declined from 300% at 3-4 days to 228, 88, and 0% at 7-9, 15-18, and 20-24 days, respectively. A bout of running held 21 days after the ameroid implant when resting regional function was well maintained induced severe regional and global dysfunction. These findings indicate the usefulness of regional myocardial contractile responses in assessing coronary collateral reserve.
Cardiac reflex responses to a series of partial inferior vena caval occlusions were studied in conscious previously instrumented dogs. Heart rate responses during the fall of systemic arterial pressure were mediated both by increased sympathetic tone and withdrawal of parasympathetic tone. Responses of the left-ventricular inotropic state, estimated from changes in left ventricular pressure rise (LV dP/dt), were studied early after release of a series of partial vena caval occlusions, and a positive linear relation between the prior fall in the systemic arterial pressure and the increase in LV dP/dt was demonstrated. Serial studies showed this effect of persist for at least 12 s beyond the reflex slowing of heart rate early after release of vena caval occlusion. The positive inotropic response was markedly attenuated by beta-adrenergic blockade and also occurred at a constant heart rate. It was present after adrenalectomy. These studies suggest that the integrated baroreceptor responses that are activated by a simultaneous decrease in the venous return and systemic arterial pressure play an important role in the regulation of left-ventricular inotropic state in the conscious dog.
The problem of when to recommend surgical treatment for valvular heart disease to avoid irreversible left ventricular damage has not been fully resolved. In aortic stenosis, left ventricular function tends to improve after aortic valve replacement even if it is markedly depressed, and operation solely to prevent irreversible left ventricular dysfunction does not seem indicated. In aortic regurgitation, left ventricular function also usually improves postoperatively if moderately depressed, but in an adult with relatively few symptoms operation should be considered when there is progressive or marked cardiomegaly with reduced systolic function. In chronic mitral regurgitation, limited studies indicate that if left ventricular size is markedly increased and the ejection fraction is even mildly reduced, left ventricular function deteriorates postoperatively; in such patients consideration of operation may be warranted even if symptoms are few. It is concluded that operative mortality and morbidity are now sufficiently low that valve replacement or repair can be considered primarily to preserve left ventricular function under certain circumstances.
Clinical studies were performed with groups of patients with ischaemic heart disease, patients with hyperthyroidism, and normal subjects, to investigate the possibility of a beta blocker withdrawal syndrome, by measurments of heart rate under conditions of increased sympathetic drive provided by standing with vasodilatation or by Valsalva's manoeuvre. A rebound increase in heart rate to levels significantly higher than the control heart rate off treatment was observed 2-5 days after stopping one or more weeks' treatment with dl-propranolol (160 mg/day), atenolol (200 mg/day), acebutolol (400 mg/day) or oxprenolol (160 mg/day).
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