Biomedical subjects
Publications and source records attributed to R G Murray.
A 43-year-old woman with a 12-year history of palpitation was found to have recurrent monomorphic ventricular tachycardia resistant to beta-blockade but abolished by sleep.
The mechanism by which early intervention with beta-blockers reduces mortality in acute myocardial infarction is unclear. Therefore the effects of intravenous, followed by oral, metoprolol on indices of infarct size were studied in a double-blind fashion with a median delay of 6.75 hours from onset of symptoms. In 129 patients peak enzyme release and QRS score on the electrocardiogram were assessed, while myocardial perfusion score on thallium-201 scintigraphy was studied in 45 patients. There was a close correlation between all the indices of infarct size. While the correlation coefficients did not appear to be influenced by metoprolol treatment, the slope of the regression was affected. Peak aspartate aminotransferase and lactic dehydrogenase were lower by 11 and 7%, respectively, in the metoprolol-treated group, but no reduction was noted in QRS score or in thallium-201 perfusion defect size in the actively treated group. Thus, it seems likely that early intervention with metoprolol in acute myocardial infarction reduces mortality, not by limiting infarct size, but by some other mechanism.
The prognostic value of parameters noted on pre-discharge exercise testing was assessed in 300 survivors of acute myocardial infarction. Exercise testing was performed at a mean of 9 days post-infarction. Each patient's data were studied for the presence of ST-segment depression or elevation greater than or equal to 0.1 mV in any of the 12 leads recorded, angina pectoris, exertional hypotension and duration of exercise. The patients were followed for a mean of 12 months and the incidence of death, reinfarction, angina pectoris, heart failure and coronary revascularization procedures was noted. All variables studied, other than the presence of exercise-induced ST-segment elevation, were significantly associated with the occurrence of subsequent cardiac events (P less than 0.001). Exercise-induced ST-segment depression identified 80% of patients who developed complications and was significantly more sensitive than any of the other variables as a prognostic marker (P less than 0.05). The finding of angina pectoris, an abnormal blood pressure response or a limited exercise tolerance in association with exercise-induced ST-segment depression heightened the prognostic implications of this variable.
1. The relationship of reciprocal change on the electrocardiogram, at the time of acute myocardial infarction, to exercise-induced ST segment depression and coronary anatomy was studied in 125 post-infarct patients. 2. Eighty-three patients had reciprocal changes, 90 had exercise-induced ST depression and 72 had both of these findings. 3. Patients with reciprocal changes had larger myocardial infarctions, as assessed by peak enzyme release and ejection fraction, than patients without this finding. 4. Multi-vessel disease was significantly more common among patients with reciprocal changes and those with exercise-induced ST depression compared with patients without these findings. 5. The exercise test was more sensitive and had a higher predictive accuracy than reciprocal change when electrocardiographic changes were compared with findings at coronary angiography. 6. With both tests the antero-lateral leads were significantly more sensitive, but less specific, than the inferior leads in classifying patients. 7. Thus while both tests yielded information with regard to coronary anatomy in post-infarct patients, the exercise test was a better predictor of coronary anatomy than reciprocal change. 8. Therefore, reliance should not be placed on the presence or absence of reciprocal change alone when assessing patients for further investigation after myocardial infarction.
Pre-discharge exercise tests were performed in 359 survivors of an acute myocardial infarction to determine the frequency, characteristics and prognostic implications of silent ischaemia. Tests were negative in 152 patients (42%), silent ischaemia was observed in 103 (29%) and painful ischaemia in 82 (23%). Heart rates at the development of ischaemia and the final double products were similar in both ischaemic groups but patients with silent ischaemia were able to exercise for longer (13.1 +/- 0.5 min) than those with painful ischaemia (9.3 +/- 0.5 min; P less than 0.0001). The 12 month mortality rose from 2% in patients with a negative test, to 4% in those with silent ischaemia and to 8% in those with painful ischaemia. Re-infarction rates increased similarly across the groups (3%, 8% and 18% respectively). Patients with silent ischaemia subsequently developed angina more frequently (47%) than those with negative tests (16%; P less than 0.001). These results suggest that exercise-induced silent ischaemia following myocardial infarction was common, occurring in 29% of patients. Although the final myocardial oxygen consumption was similar in both ischaemic groups those with silent ischaemia were able to exercise for longer. Finally silent ischaemia conferred an intermediate risk of death or re-infarction and was a strong predictor of subsequent angina pectoris.
Negative staining revealed a tetragonal surface array (S layer) on all the members of a serogroup of Aeromonas hydrophila which possess high virulence for fish. The S layers were similar on all the strains examined, with unit cell dimensions of approximately 12 nm. A single representative strain, strain TF7, was selected for further analysis. Freeze-cleaved and etched preparations and sections for electron microscopy showed that the S layer was the outermost component of the cell envelope. This was confirmed by observation of thin sections. Computer-generated enhancements of the negatively stained micrographs showed the subunit organization to a resolution of less than 4 nm. Two structural units of identical lattice constants alternated in the array in both axes, and one of them was apparently dominant as the center of mass. The lesser unit was rotated 20 degrees from the dominant axes of symmetry and was formed by the junction of linker projections from a corner of the four components of the dominant unit. This interpretation was supported by finding that the array consists of a single polypeptide (molecular weight, 52,000). The unit cell as defined showed p4 symmetry, and a = b = 12.2 nm.
The influence of beta blockade on the ability of ST depression, during pre-discharge exercise testing, to predict coronary anatomy and subsequent complications was studied in 300 consecutive post-infarct patients, 125 of whom underwent cardiac catheterisation. At the time of exercise 62 patients were taking a beta blocker. The exercise test had a higher sensitivity in predicting multivessel disease in patients who were not taking beta blockers than in patients who were (95% v 76%). beta Blockade did not, however, influence the ability of the test to identify patients at risk of subsequent cardiac events (sensitivity 84% and 85% respectively). These results suggest that it is not necessary to stop treatment with beta blockers before predischarge exercise testing of patients who have had an acute myocardial infarction.
Proteus mirabilis PM23, unlike other motile strains of the species, differentiates in rich fluid media to form nonseptate filaments resembling the swarmer cells formed on solid media. The swarming activity of PM23 is greater than that of the other strains on solid media and it grows faster than another strain, IM47, in differentiation-supporting broth. This faster growth is not exhibited in broth that does not support differentiation. The differentiation of PM23 in brain-heart infusion broth occurs over a wide range of pH and temperature. Inhibitors of swarming on agar plates (p-nitrophenylglycerol and boric acid) and three chelating agents (EDTA, sodium cyanide, and sodium diethyldithiocarbamate) stop differentiation both on plates and in brain-heart infusion broth; however, EGTA is not effective even at 10 mM (10 times the minimum inhibitory concentration of EDTA). The inhibitory mechanisms of p-nitrophenylglycerol and boric acid are different from that of the chelating agents. The timing of EDTA inhibition suggests generation of a "signal" to differentiate after about 2 h growth. Prevention of differentiation by addition of Fe2+ and Zn2+ up to near the time that differentiation should appear suggests that these cations have a crucial involvement in the process of initiation. However, they are not effective as additives in allowing differentiation to occur in defined media or even nutrient broth; the further addition of nucleotides or cAMP was equally ineffective.
Polar membrane in Campylobacter jejuni has been visualized on membrane vesicles. It was composed of doughnut-shaped particles 5-6 nm in diameter, with stalks, arranged in a hexagonal array. This structure was stabilized on the membrane by a high ionic strength buffer in the presence of 2-mercaptoethanol. Histochemical staining indicated localized ATPase activity at the poles of the cells. An ATPase with distinctive properties has been isolated and purified from this organism; it gives a specific activity of approximately 0.3 units/mg of protein. Electron microscopy showed doughnut-shaped particles 5-6 nm in diameter. Nondissociating and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified enzyme revealed, respectively, a single band with ATPase activity and a molecular weight of ca. 75,000 Da. The enzyme was cold labile and activity was abolished by trypsin. Dicyclohexylcarbodiimide inhibited the membrane-bound form of the enzyme, but did not inhibit the soluble form. Oligomycin had no inhibitory activity on either form of the enzyme. The enzyme specifically hydrolysed ATP, but other nucleotide substrates were not degraded. The enzyme was activated by Mg2+ and inhibited by Ca2+, whereas other ions had no effect on activity. Antibodies prepared to this enzyme bound to the polar regions of whole cells as shown by protein A - colloidal gold immunoelectron microscopy. The antibodies to this ATPase cross reacted (shown by Western blotting) with four proteins from a whole-cell extract of this organism, two proteins in Aquaspirillum serpens MW5, and three proteins from Escherichia coli K12. They did not cross-react with any proteins from Spirillum volutans, Methanococcus voltae, Vibrio cholerae, or rat liver mitochondria. Antibodies raised against the F1-ATPase of E. coli K12 cross reacted with six proteins in a whole-cell extract of this organism, and one protein species in each of the whole-cell extracts of V. cholera, A. serpens MW5, S. volutans, and rat liver mitochondria. These antibodies did not recognize any whole cell proteins from either C. jejuni or M. voltae. These results along with the ATPase activity localized by histochemical staining suggest that polar membrane is an assembly of ATPase molecules at the poles of the cell and that the ATPase isolated from C. jejuni is serologically and structurally unusual.
In a district general hospital's coronary care unit (CCU) 197 patients with chest pain were admitted over a 6-month period and in 131 an acute myocardial infarction (AMI) was confirmed. 67 (51%) were eligible for thrombolytic therapy, on criteria laid down for a trial of streptokinase. Criteria for thrombolysis were not fulfilled in 41 (31%) and 12 patients (9%) had contraindications. These results suggest that around half of all patients with AMI and about one-third of patients presenting with chest pain and admitted to a CCU would be suitable for thrombolytic therapy. These data do not support the view that such therapy may be applicable to only a small minority of patients with AMI.
The efficacy of 12 lead exercise testing and rest/exercise 201Tl scintigraphy as indicators of coronary anatomy and prognosis was compared in 46 low risk survivors of acute myocardial infarction. The non invasive procedures were performed at discharge, and cardiac catheterization was performed six weeks post discharge. On exercise testing, ST depression in leads remote from the site of infarction was considered to indicate multivessel disease and reversible ischaemia. On 201Tl scintigraphy, a perfusion defect remote from the site of infarction indicated multivessel disease, while a defect which reperfused at rest indicated reversible ischaemia. During the mean follow-up of 13 +/- 3 months, 14(30%) patients experienced cardiac events. Thallium scintigraphy was a more sensitive, but less specific, indicator of multivessel disease than exercise testing. Both exercise testing and 201Tl scintigraphy had a similar sensitivity (79% vs 79%), specificity (78% vs 88%) and predictive accuracy (78% vs 85%) for predicting subsequent cardiac events. Thus, in our patient population, 201Tl scintigraphy could not be demonstrated to be superior to routine exercise testing in low risk patients post myocardial infarction.
A recently proposed analytical technique to determine whether an inotropic agent improves cardiac pumping performance via its vasodilatory or its positive inotropic effects was adopted to evaluate the pharmacological properties of a positive inotropic agent, dobutamine, and a vasodilatory calcium antagonist, felodipine, in patients with severe heart failure. This technique used a new principle of pump-load interaction, which states that for a given change in vascular input impedance unaccompanied by any direct alteration in the pumping characteristics all possible values of pump power output due to the change in impedance per se are confined within two calculated limits. When dobutamine was infused at 10 micrograms.kg-1.min-1 seven out of 10 patients had power output values above the defined limits, implying that the technique can identify correctly in vivo the direct positive inotropic effects of dobutamine in the presence of its vasodilating activity. In contrast, when 5-10 mg of felodipine was given to 10 patients the consequent power outputs were all within the defined limits, implying that the effects can be explained by vasodilatation alone. In conclusion, this study showed that the analytical technique can be applied clinically to detect the presence of drug induced positive inotropic effects in the midst of vasodilatation and therefore may be useful in determining whether inotropic agents actually improve cardiac function via their positive inotropic effects.
While long term beta-adrenergic blockade, introduced in the convalescent stage of myocardial infarction, may reduce subsequent mortality, the value of early beta-blockade in the acute phase is less certain. Therefore, the influence of beta-blockade on left ventricular performance and eventual infarct size was assessed in 61 consecutive patients with acute myocardial infarction. Metoprolol (15 mg i.v. followed by 200 mg day-1 orally) or placebo was administered in a double-blind, randomised fashion with a median delay of 5.9 hours from onset of symptoms. After 15 days of double blind therapy all patients were started on open treatment with metoprolol. All patients underwent haemodynamic monitoring for 24 hours and serial radionuclide ventriculography and thallium 201 scintigraphy. In the first hour metoprolol produced a decrease in cardiac output (1.3 l min-1; P less than 0.001) due to a reduction in heart rate (15 min-1; P less than 0.001) and a decrease in left ventricular stroke work index (10.7 g m m-2; P less than 0.001) due to a reduction in mean arterial pressure (10 mmHg; P less than 0.001). There was then a gradual attenuation in these changes. While metoprolol produced an increase in pulmonary capillary wedge pressure and in both end-diastolic and end-systolic volumes (P less than 0.05), these changes were confined to patients with a baseline pulmonary capillary wedge pressure below the median of 13 mmHg mercury. There was no significant change in stroke volume or in ejection fraction in response to metoprolol. There was no significant difference between the groups in left ventricular performance, as assessed by radionuclide ventriculography, or in scintigraphic infarct size, either at the end of the 15 days double-blind treatment or after 3 months open treatment with metoprolol. Thus, early intervention with metoprolol in acute myocardial infarction appeared to reduce myocardial oxygen consumption with no adverse haemodynamic effect. However, metoprolol failed to preserve left ventricular function, or to reduce apparent infarct size. These data suggest that the modest reduction in mortality reported in the acute phase studies of beta-blockade in myocardial infarction, is unlikely to be due to infarct reduction. It is more likely to be due to a secondary prevention or to an antiarrhythmic effect.
Dopexamine is a novel compound that has DA1-dopaminergic and beta 2-adrenergic agonist properties capable of producing beneficial systemic and renal vasodilation. The acute haemodynamic effects in 10 patients with low-output-state ischaemic cardiac failure (NYHA IV) were recorded before (control) and during graded incremental doses of dopexamine infusion from 0.5 to 6.0 micrograms/kg/min. Dopexamine produced a marked increase in cardiac index from 1.6 +/- 0.2 (control) to a maximum of 2.8 +/- 0.4 L/min/m2 (p less than 0.001) primarily by inducing vasodilation, with reduction in systemic vascular resistance from 1,720 +/- 136 (control) to 1,116 +/- 136 dynes.s.cm-5 (p less than 0.05). Using a more sophisticated analytical technique which enables us to separate direct inotropic from vasodilatory effects, we were able to identify, in eight of the patients, a direct dopexamine-induced positive inotropism. These beneficial central haemodynamic effects of dopexamine, when coupled with its known DA1-dopaminergic agonist property, indicate that dopexamine may have a place in the management of patients in severe heart failure.
The protein surface layers on the cell walls of mosquito-pathogenic and nonpathogenic Bacillus sphaericus strains were studied by structural, biochemical, and serological methods. The surface structure of two representative insect-pathogenic strains had the form of a delicate linear array with a repeat interval of 5 nm. This was distinctly different from the tetragonal array of the P-1 strain in spacing and arrangement. The surface layers were composed of acidic glycoproteins with molecular weights ranging from approximately 133,000 to 155,000. Peptide mapping and serological analysis of the surface proteins revealed eight distinct groups among the pathogens. These groups were very similar to the groupings determined by flagellar-antigen serotyping and bacteriophage typing.
Electron microscopy of the Azotobacter vinelandii tetragonal surface array, negatively stained with ammonium molybdate in the presence of 1 mM calcium chloride, showed an apparent repeat frequency of 12 to 13 nm. Image processing showed dominant tetrad units alternating with low-contrast cruciform structures formed at the junction of slender linkers extending from corner macromolecules of four adjoining dominant units. The actual unit cell showed p4 symmetry, and a = b = 18.4 nm. Distilled water extraction of the surface array released a multimeric form of the single 60,000 molecular-weight protein (S protein) which constitutes the surface layer. The molecular weight of the multimer was estimated at 255,000 by gel filtration, indicating a tetrameric structure of four identical subunits and suggesting that this multimer was the morphological subunit of the S layer. Tetrameric S protein exhibited low intrinsic stability once released from the outer membrane, dissociating into monomers when incubated in a variety of buffers including those which served as the base for defined media used to cultivate A. vinelandii. The tetramer could not be stabilized in these buffers at any temperature between 4 and 30 degrees C, but the addition of 2 to 5 mM Ca2+ or Mg2+ completely prevented its dissociation into monomers. Circular dichroism measurements indicated that the secondary structure of the tetramer was dominated by aperiodic and beta-sheet conformations, and the addition of Ca2+ did not produce any gross changes in this structure. Only the tetrameric form of S protein was able to reassemble in vitro in the presence of divalent cations onto the surface of cells stripped of their native S layer.
An attempt was made to stratify risk of subsequent cardiac events in post-infarct patients according to a combination of the results of clinical assessment, routine diagnostic investigations, and pre-discharge exercise testing in 350 consecutive patients who were followed up for one year. Patients were classified prospectively on the basis of the extent of myocardial damage as assessed by peak enzyme release, reciprocal change on the electrocardiogram at the time of myocardial infarction, Norris prognostic index, ability to perform a pre-discharge exercise test (and test result), and ability to tolerate beta adrenergic blockade on discharge. Of the 50 patients with contraindications to pre-discharge exercise testing, 26% died or had reinfarctions compared with 9% of the 300 exercised patients; the 24 non-exercised patients with evidence of extensive myocardial damage or reciprocal changes on the electrocardiogram were particularly at risk. Similarly, among the 300 exercised patients, extensive myocardial damage, reciprocal change on the electrocardiogram, and ST depression on exercise testing were the major risk markers in that each identified at least 75% of the patients who had subsequent cardiac events. The 63 exercised patients who had all three of these major risk markers constituted a high risk group: 18 (29%) died or had reinfarction. Of the remaining 237 patients, only 9 (4%) had cardiac events. The 35 high risk patients with exercise induced angina pectoris or clinical contraindications to beta blockade were particularly at risk; 15 (43%) died or had reinfarction. This approach to risk stratification identified a small cohort of high risk patients in a large population of myocardial infarction survivors; it also identified a large group with a very low risk of subsequent cardiac events.