Biomedical subjects
Publications and source records attributed to D Stone.
The effect of nifedipine on exercise left ventricular function and coronary haemodynamics was studied in a group of patients with coronary artery disease. Nifedipine, unlike nitroglycerin, appears to act as a primary coronary vasodilator and was able to reverse exercise induced changes in ventricular function.
Steroid receptor assays play an important role in determining the efficiency of endocrine therapy for patients with breast cancer. Other tumors could also be hormonally dependent and patients with these tumours might also benefit from endocrine manipulation. Thus, patients with meningiomas were tested for the presence or absence of estrogen and progesterone receptors. The results showed that a majority of meningiomas lacked estrogen receptors but contained large amounts of progesterone receptor. Therefore, it should be possible to use antiprogestin therapy in cases where complete surgical resection of meningiomas is not possible.
1 Dexamethasone and hydrocortisone induced the release of anti-phospholipase proteins into the peritoneal cavities of rats. 2 Adrenocorticotrophic hormone (ACTH) also releases these proteins in normal but not in adrenalectomized rats. 3 Peritoneal lavage proteins were separated by ion-exchange and size exclusion chromatography. The anti-phospholipase activity occurred in four separate fractions with the major component having an apparent mol. wt. of 40 k. 4 Column fractions containing these anti-phospholipase proteins had anti-inflammatory effects in the rat carrageenin pleurisy model whereas other fractions were inactive. 5 The proteins appear to be identical to macrocortin and lipomodulin, the 'second messengers' of glucocorticoid hormone action on the arachidonate system.
To examine which factors affect the reproducibility of ejection fraction (EF), pulmonary transit time (PTT) and segmental wall motion assessed from first-pass radionuclide angiograms (FPRA), 32 patients who had FPRA were randomized for site of injection of isotope (right or left arm) and projection (right or left anterior oblique [RAO or LAO]). The quality of injected bolus was measured from the full width at half maximum (FWHM) of the bolus time-activity curve in the superior vena cava. All patients had two sequential studies on each of two consecutive days, and each study was analyzed independently by two observers. For EF, inter- and intraobserver correlations ranged from 0.94-0.98. EF was higher in the RAO than the LAO projection (mean 47.4% vs 40.3%, p less than 0.001), but neither injection site nor bolus FWHM affected the results. For PTT, interobserver correlations ranged from 0.75-0.93 and intraobserver correlations from 0.61-0.85. Variability in PTT was large, and inter- and intraobserver variabilities were directly related to bolus FWHM (mean 0.60 +/- 0.21 second for interobserver differences in PTT of less than 2.0 seconds, mean 1.55 +/- 0.86 seconds for interobserver differences in PTT of greater than 2 seconds [p less than 0.005]). Differences in FWHM between sequential studies were 0.28 +/- 0.29 second when intraobserver differences in PTT were less than 2 seconds and 1.04 +/- 0.67 seconds when differences in PTT were greater than 2.0 seconds (p less than 0.005). Variations in PTT were not related to differences in projection or injection site. Wall motion was highly reproducible for both projections. In the RAO projection, one of 116 anterior segments (0.9%), one of 116 apical segments (0.9%), and four of 116 inferior segments (3%) were judged normal from one observer's images and abnormal from another. In the LAO view, discrepancies occurred in one of 126 septal segments (0.8%), two of 126 apical segments (1.6%) and four of 126 posterolateral segments (3%). This study shows that EF and wall motion are highly reproducible in any projection, but the choice of projection significantly affects the values for EF from FPRA. PTT measurements are less reliable, highly bolus dependent, and their use in clinical practice depends on quality control of the bolus of injected radionuclide.
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The two isozymes of dihydrofolate reductase (Forms 1 and 2) from, a Trimethoprim-resistant strain of Escherichia coli (RT500) were separated and purified to homogeneity using a simple procedure based on differential elution from a Methotrexate affinity column. The complete amino acid sequence of the Form 2 isozyme was determined, and it differs from that of Form 1 in only one position. Residue 28 is arginine in Form 2 and leucine in Form 1. However, the isozymes differ greatly in their binding and kinetic properties. Equilibrium dialysis studies showed the Trimethoprim dissociation constants of Form 2 are about 50-fold greater than those of Form 1 in both the binary complex and the ternary complex with NADPH. Similarly, the Methotrexate dissociation constant of Form 2 is about 10-fold greater than that of Form 1. The two isozymes also differ in their turnover numbers at pH 7 (Form 1 is 10-fold more active) and inhibition by divalent cations. Form 1 is extremely sensitive to BaCl2 (50% inhibition at 0.5 mM), whereas Form 2 is much less sensitive (50% inhibition at 60 mM). In the presence of 10 mM BaCl2, Form 1 has the functional characteristics of Form 2. Its turnover number is decreased, its Trimethoprim Ki is increased, and the shape of its pH-activity profile is identical with that of Form 2. The x-ray structures and amino acid sequences of several bacterial dihydrofolate reductases indicate that Asp-27 is important in inhibitor binding and may be involved in catalysis. The present data provide kinetic evidence for this hypothesis, and it is proposed that almost all the unusual characteristics of Form 2 are the direct result of a charge interaction between Arg-28 and Asp-27. A similar interaction between Ba2+ and the Asp-27 of Form 1 can result in an enzyme complex that is kinetically similar to Form 2.
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A double-balloon catheter was used to evaluate the female urethra in 51 patients. Six different radiographic appearances were identified. Three of the categories are considered variants of normal. One of the categories consisted of eight patients with urethral diverticula. All showed large rounded or lobulated collections of contrast material which were adjacent to the urethra and which persisted on postvoid films. Other abnormalities should be closely correlated with the clinical findings to determine their significance. The diagnosis of urethral diverticulum may be missed, as physical examination and endoscopy can be negative. Therefore, the optimal method for identifying its presence and extent includes both a double-balloon catheter study and a voiding cystourethrogram.
The insulins of New World hystricomorph rodents exhibit many novel amino acid changes in primary structure when compared with other mammalian insulins. These changes give rise to unusual properties (low potency, failure to self-associate) not shared by other naturally-occurring insulins. We report here on the primary structure, zinc-binding properties and circular dichroism (CD) of porcupine-insulin (Hystrix cristata), the first Old World hystricomorph insulin to be investigated, and discuss the changes in primary structure of the hormone in relation to its properties. Residue B22 is strongly implicated as being responsible for the unusual properties of porcupine insulin.
Because exposure to compounds of arsenic has been implicated as a cause of cancer, an investigation of the mutagenicity of sodium aresenite in E coli and in Chinese hamster cells was performed. In the E coli system, Trp + revertants were not induced by arsenite in a variety of experimental protocols including spot tests, treat and plate protocols, and fluctuation tests. The mutator effect of a tif-1 strain was partially blocked by arsenite. Arsenite did not cause the induction of lambda prophage. In Chinese hamster cells, arsenite did not induce ouabain-resistant mutants or thioguanine-resistant mutants. We conclude that arsenite is not mutagenic to E coli or to Chinese hamster cells. When added to the plating medium, arsenite can act as an anti-mutagen by inhibition of induction of the error-prone SOS repair system in E coli.
Thirteen patients with left ventricular aneurysms complicating myocardial infarction were studied by contrast angiography and by first pass radionuclide ventriculography. The ejection fraction of the contractile segment (EFCS) was measured from both studies using a double hemishperoid model, and the values correlated closely. There was a monotonic relation between EFCS and stroke volume index measured from thermodilution cardiac outputs carried out simultaneously with the radionuclide study. When radionuclide ventriculography was performed at submaximal supine exercise, changes in EFCS paralleled changes in the total left ventricular ejection fraction in 10 of the 13 cases. In nine patients, changes in EFCS paralleled changes in stroke volume index and the relation between EFCS and stroke volume index was maintained at exercise. After administration of the vasodilator isosorbide dinitrate to 12 patients, repeat exercise radionuclide ventriculography showed an improvement in left ventricular ejection fraction and in eight patients EFCS improved. First pass radionuclide ventriculography can accurately estimate EFCS, which may be an important factor in predicting the likely response to aneurysmectomy. Changes in EFCS on exercise are reflected in changes in total left ventricular ejection fraction and stroke volume index. Isosorbide dinitrate may improve contractile segment function on exercise.
A 38-year-old women presented with an 11-year history of angina pectoris. Coronary arteriography disclosed a large right coronary artery which filled the entire left coronary tree retrogradely. The left main coronary artery ended blindly and was not connected to the aortic root. There were no atherosclerotic lesions in any vessel. Exercise thallium-20l scintigrams showed a perfusion defect in the anterior region of the left ventricle and exercise first pass radionuclide ventriculography showed anterior hypokinesis of the left ventricle with an ejection fraction of 54 per cent, compared with 60 per cent at rest. An aortocoronary saphenous vein graft was constructed to the left coronary artery. Four months after operation the patient is free from symptoms. Repeat thallium scintigrams were normal. Exercise radionuclide ventriculography after operation disclosed no wall motion abnormality, and ejection fraction on exercise was 70 per cent. The mechanism of angina in this patient is unclear but may have been related to the abnormal timing of delivery of blood to the left ventricular myocardium. Dual radionuclide stress testing showed abnormalities after operation. This non-invasive approach may be useful in the assessment of the physiological significance of coronary anomalies and of the value of corrective surgery.
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Explore the source record for details and available documents.
Porcine liver dihydrofolate reductase has been purified 18,000-fold to homogeneity. The properties of the purified enzyme were compared to those of dihydrofolate reductase from L1210 cells, the only mammalian reductase for which complete amino acid sequence data are available. The enzymes are very similar when compared on the basis of mechanism and kinetic constants, molecular weights, isoelectric points, and stimulation by salt. A comparison of the amino acid sequences of both enzymes shows an overall identity of 89%. Thus, the similarities seen in inhibitor-binding profiles of mammalian enzymes reflect the close relationship of these enzymes at the molecular level.
The amino acid sequence of a trimethoprim-resistant dihydrofolate reductase (EC 1.5.1.3) specified by the R-plasmid R67 is described. The sequence was deduced from automatic and manual sequence analysis of the intact protein, the fragments produced by cyanogen bromide cleavage, and peptides derived from the largest cyanogen bromide fragment by digestion with trypsin, Staphylococcus aureus V8 proteus, chymotrypsin, and Lysobacter enzymogenes alpha-lytic protease. The complete sequence comprises 78 residues in a single polypeptide chain of molecular weight 8444. No evidence of heterogeneity was obtained, indicating that all subunits of the native enzyme are identical. Comparison of the sequence with that of all known dihydrofolate reductases shows no significant sequence homology.
Dihydrofolate reductase, specified by the type II plasmid of a trimethoprim-resistant Escherichia coli, was purified 40-fold to homogeneity using a combination of gel filtration, DEAE-Sephacel chromatography, and hydrophobic chromatography. The final product shows a single protein band on polyacrylamide gel electrophoresis and has a specific activity of 1.0 unit/mg. The molecular weight of the purified enzyme is 36,000 as determined both by gel filtration and Ferguson analysis of polyacrylamide gel electrophoresis. In contrast, a single polypeptide with a molecular weight of 8,500 was observed on sodium dodecyl sulfate-gel electrophoresis. These experiments suggest that, unlike any bacteria or vertebrate dihydrofolate reductase previously examined, the type II R plasmid reductase is a tetramer composed of four identical subunits. A partial amino acid sequence determination shows no heterogeneity of the subunits and also no clear homology with any reductase sequence previously reported.