Biomedical subjects
H I Miller
Publications and source records attributed to H I Miller.
A novel mechanism for Ca(2+)-dependent regulation of hepatic gluconeogenesis: stimulation of mitochondrial phosphoenolpyruvate synthesis by Ca2+.
1. Isolated guinea pig liver mitochondria were used to assess a possible effect of Ca2+ on the rate of phosphoenolpyruvate (PEP) synthesis. 2. PEP synthesis from 2-oxoglutarate (2-OG), but not from malate, was stimulated by [Ca2+] between 200 and 1200 nM. The effect was more pronounced at low [2-OG] (i.e. 0.1 and 0.3 mM) and it reached 58 and 22%, respectively, at 1200 nM as compared to 200 nM [Ca2+]. 3. Ruthenium red (1.8 microM) totally suppressed the stimulatory effect of Ca2+. 4. Malonate (5 mM) abolished PEP formation with 2-OG alone but inhibited only slightly the process with 2-OG + malate. 5. The results suggest that the stimulation by Ca2+ of 2-OG dehydrogenase and, therefore, of GTP synthesis, provides a mechanism for an enhanced PEP synthesis and for regulation of hepatic gluconeogenesis by Ca(2+)-mobilizing hormones.
Regulation of biotechnology.
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Risk-based oversight of experiments in the environment.
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Randomized controlled trial of late in-hospital angiography and angioplasty versus conservative management after treatment with recombinant tissue-type plasminogen activator in acute myocardial infarction.
Although both the European Cooperative Study Group and the Thrombolysis in Myocardial Infarction IIB trial indicated that angiography and angioplasty as routine measures after thrombolytic treatment do not improve clinical outcome in patients with acute myocardial infarction, the potential benefit of angioplasty may have been negated by the fact that the procedure was performed too soon (less than 32 hours) after admission. A similar study was designed in which delayed invasive treatment was compared with conservative treatment in 201 patients with acute myocardial infarction given recombinant tissue-type plasminogen activator. The 97 patients randomized to the invasive group underwent routine coronary angiography and angioplasty 5 +/- 2 days after thrombolytic therapy, whereas the 104 patients randomized to the conservative group underwent angiography only for recurrent postinfarction angina or exercise-induced ischemia. Baseline characteristics of both groups were similar. In the invasive group, 92 patients underwent angiography, 49 angioplasty and 11 coronary artery bypass surgery. In the conservative group, 40 patients experienced early ischemia, 39 underwent angiography, 20 angioplasty and 4 coronary artery bypass surgery. Reinfarction rate and preservation of left ventricular function at discharge or 8 weeks after discharge did not differ in the 2 groups. Total mortality after a mean follow-up of 10 months was 8 of 97 in the invasive and 4 of 104 in the conservative groups (p = 0.15). However, if only patients who died after the timing of the scheduled protocol catheterization in the invasive arm were included, mortality was 5 of 94 and 0 of 100 in the invasive and conservative treatment groups, respectively (p = 0.02). (ABSTRACT TRUNCATED AT 250 WORDS)
Improved survival but not left ventricular function with early and prehospital treatment with tissue plasminogen activator in acute myocardial infarction.
One hundred ninety patients with acute myocardial infarction (AMI) were treated with recombinant tissue-type plasminogen activator (rt-PA) 2.0 +/- 0.8 hours after the onset of symptoms. Eighty-seven patients were enrolled via mobile intensive care units and 103 through the emergency ward. Patients who were enrolled via the mobile intensive care units were randomized to immediate, prehospital treatment initiation, or to delayed, in-hospital treatment initiation. All 190 patients except 2 underwent delayed coronary angiography and, when indicated, angioplasty at 72 hours after enrollment. Patients treated within 2 hours and those treated 2 to 4 hours after symptom onset had similar preservation of left ventricular function, and similar prevalence of congestive heart failure at discharge. Patients treated within 2 hours of symptom onset had significantly lower short- (0.0 vs 6.3%, p = 0.01) and long-term (1.0 vs 9.5%, p = 0.03) mortality. Prehospital initiation of rt-PA appeared to be safe and feasible and resulted in a 40-minute decrease in the time from symptom onset to treatment initiation.
When is a drug 'safe'?
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Pulmonary venous flow determined by Doppler echocardiography in mitral stenosis.
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Effects of caffeine intake during gestation and lactation on bones of young growing rats.
The objective of this study was to evaluate the extended effect of caffeine intake received during gestation and lactation on the mandible and femur of rats. Timed-pregnant dams were divided into two groups. Dams of group 1 were fed a 20% protein diet throughout the experimental period from day 9 of gestation. Dams of group 2 were also fed a 20% protein diet, supplemented with caffeine (1 mg/100 g of body weight). Upon delivery, 8 pups were assigned to each dam, and the dams were continued on their respective diets. At weaning (day 22 postnatally), only male rats were selected. Pups of both groups were fed a 20% protein diet without caffeine. At day 56 postnatally the rats were killed. Mandibles and femurs were removed and the following parameters analyzed: weight, physical dimension, volume, and Knoop microhardness. Caffeine intake during gestation and lactation resulted in an impairment of femur growth and development and to a lesser extent mandibular growth and development. The early effects of caffeine in the maternal diet were lasting, as noted by the lack of recovery of the offspring even after changing to a caffeine-free diet for an extended time after weaning.
Should thrombolytic therapy be administered in the mobile intensive care unit in patients with evolving myocardial infarction? A pilot study.
The growing recognition of the importance of early thrombolysis in evolving myocardial infarction was the basis for the present study, which evaluated the effectiveness, feasibility and safety of prehospital thrombolytic therapy. In a relatively small study, 118 patients were allocated to receive either prehospital treatment with recombinant tissue-type plasminogen activator (rt-PA) in the mobile intensive care unit (group A, 74 patients) or hospital treatment (group B, 44 patients). A total of 120 mg of rt-PA was infused over a period of 6 h. All patients were fully heparinized and underwent radionuclide left ventriculography and coronary angiography during hospitalization. Although group A was treated significantly earlier than group B after onset of symptoms (94 +/- 36 versus 137 +/- 45 min, respectively; p less than 0.001), no significant differences were observed between the groups in 1) extent of myocardial necrosis, 2) global left ventricular ejection fraction at discharge, 3) patency of infarct-related artery, 4) length of hospital stay, and 5) mortality at 60 days. However, a trend to a lower incidence of congestive heart failure at hospital discharge was observed in the prehospital-treated compared with the hospital-treated group (7% versus 16%, respectively; p = NS). No major complications occurred during transportation. It is concluded that myocardial infarction can be accurately diagnosed and thrombolytic therapy initiated relatively safely during the prehospital phase by the mobile intensive care team, thus instituting a beneficial clinical trend in favor of prehospital thrombolysis.
Repeat infusion of recombinant tissue-type plasminogen activator in patients with acute myocardial infarction and early recurrent myocardial ischemia.
When conventional treatment of patients with early clinical reinfarction after thrombolytic therapy fails, mechanical revascularization may be attempted. An alternative strategy, repeat thrombolytic infusions, is reported. Fifty-two patients with acute myocardial infarction were treated with one or two additional thrombolytic infusions of recombinant tissue-type plasminogen activator (rt-PA) because of nonsustained ischemia after initial treatment with rt-PA or streptokinase. Thirty-five patients received the second infusion within 1 h of the first; 13 patients received the second infusion 1 to 72 h after the first and 4 patients received it later during their hospitalization. Bleeding complications occurred in 10 patients (19%); however, most of these were minor (no intracranial bleeding) and only 2 patients required blood transfusion. In 14 patients in whom the decrease in fibrinogen and plasminogen levels was measured after the first and second infusions, this decrease was only 25% and 63%, respectively--only slightly higher than the 22% and 53% decreases measured in 63 patients who had only one rt-PA infusion. In 44 patients (85%), the acute ischemia resolved completely within 1 h after initiation of the second infusion. In 23 patients (44%), pain and ST segment elevation did not recur and invasive coronary intervention was avoided. Thus, repeat rt-PA infusions can stabilize a substantial number of patients with acute reinfarction and, even when relief is temporary, repeat rt-PA infusions can minimize myocardial damage while patients await mechanical revascularization.
Human gene therapy: part of a therapeutic continuum.
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Rapid resolution of ST elevation and prediction of clinical outcome in patients undergoing thrombolysis with alteplase (recombinant tissue-type plasminogen activator): results of the Israeli Study of Early Intervention in Myocardial Infarction.
Alteplase (recombinant tissue-type plasminogen activator (rt-PA)) was infused within four hours of onset of symptoms in 286 patients with acute myocardial infarction. Delayed coronary angiography was performed 72 hours after admission with coronary angioplasty if indicated. Electrocardiographic monitoring was continuous during the first hour of treatment. The sum of the ST segment elevations (sigma ST) was calculated on electrocardiograms recorded at entry and an hour later. ST elevations resolved rapidly within one hour of treatment in 189 patients and persisted in 97 patients. Rapid resolution of ST elevation correlated with angiographic coronary patency as determined by coronary angiography 72 hours after admission. The patients with rapid resolution of sigma ST had significantly smaller infarcts and a better clinical outcome than the patients with persistent ST elevation. sigma ST values at entry and one hour after treatment had no additional independent predictive value. Rapid resolution of ST elevations in patients undergoing thrombolysis with alteplase was associated with a significantly smaller release of creatine kinase, better preservation of left ventricular function, lower morbidity, and less short and long term mortality. Rapid resolution of sigma ST elevation is an efficient indicator of clinical outcome in groups of patients with acute myocardial infarction undergoing thrombolysis with alteplase.
Early thrombolytic therapy does not enhance the recovery of the right ventricle in patients with acute inferior myocardial infarction and predominant right ventricular involvement.
In this study we report the effects of early thrombolytic therapy on the recovery of the right ventricle after an acute myocardial infarction. Sixty-five patients presenting with their first inferior myocardial infarction and predominant right ventricular involvement were consecutively treated as follows: group A (20 patients) conservatively (without thrombolytic therapy), group B (19 patients) with streptokinase and group C (26 patients) with recombinant tissue type plasminogen activator. Coronary angiography was performed within 72 h after admission in 52 patients (10 of group A, 18 of group B and in 24 patients of group C) followed by transluminal coronary angioplasty in 26. All groups had similar characteristics except for a higher mean age in group A. Within 3 months, a remarkable improvement in right ventricular function and a major increase in ejection fraction was observed for all three patient groups. Improvement of right ventricular function was more prominent in patients with residual flow through the infarct-related artery. The beneficial course was comparable in all the groups, unaffected by the type of medical treatment applied, or by the performance of coronary angioplasty. No further significant change occurred beyond this period. Thus, early thrombolytic therapy does not augment the generally favorable course of recovery of the right ventricle from acute infarction.
Purification of a ubiquitin protein peptidase from yeast with efficient in vitro assays.
In eukaryotic cells ubiquitin is synthesized as a polyubiquitin protein or as a protein fused at the carboxyl terminus to other polypeptides. An enzyme activity, ubiquitin protein peptidase, has been proposed to process these precursors by cleaving the peptide bond between adjoining ubiquitin molecules or between ubiquitin and the fused peptides. Using the cleavage of a 35S-labeled yeast ubiquitin protein fused to a synthetic 38-residue peptide obtained by in vivo metabolic labeling in Escherichia coli in an expression system based on the interaction of bacteriophage T7 RNA polymerase and its promoter, it is possible to detect a processing activity in soluble yeast extract. The specificity of the cleavage suggests this activity could be the in vivo processing activity for various ubiquitin precursor proteins in yeast cells. A similarly labeled ubiquitin protein fused to one cysteine residue was also utilized to detect an activity capable of removing a single cysteine residue from ubiquitin in a soluble extract. Employing assays based on the cleavage of labeled ubiquitin protein fusions, a ubiquitin protein peptidase activity from Saccharomyces cerevisiae was purified about 15,000-fold to yield a protein mixture consisting of only a few protein species. The major protein band which comigrated with the activities in in vitro assays has an apparent molecular weight of 29,000 when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two other protein species, about 20,000 and 10,000 in molecular weight, also comigrated with the in vitro activities throughout the purification procedure. Though our most purified protein fraction was shown to cleave various artificial ubiquitin protein fusions under our experimental conditions, it cannot cleave a ubiquitin dimer protein, suggesting the existence of functionally distinct ubiquitin protein peptidases. Our experimental protocol for preparing various labeled ubiquitin protein precursors provides a means to explore various processing enzymes existing in cells. The same protocol may also be adapted to prepare substrates for the study of other specific protein processing enzymes.
Correlation of baseline plasminogen activator inhibitor activity with patency of the infarct artery after thrombolytic therapy in acute myocardial infarction.
Increased levels of plasminogen activator inhibitor (PAI) have recently been described in patients with acute myocardial infarction (AMI). To correlate PAI levels to patency of infarct arteries after thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA), 125 consecutive patients with AMI were examined. Blood levels of fibrinogen, plasminogen, tissue plasminogen activator (t-PA) and PAI were measured before treatment initiation, 10 minutes after completion of rt-PA infusion and 24 and 48 hours after treatment. Coronary angiography, performed in all patients 72 hours after beginning rt-PA infusion, revealed patent infarct arteries in 97 patients and occluded infarct arteries in 28 patients. Pretreatment levels of PAI were significantly higher in patients with occluded infarct arteries (18.0 +/- 11.5 vs 10.5 +/- 9.3 IU/ml, p less than 0.01). Conceivably, higher levels of PAI may interfere with the natural thrombolytic process and make pharmacologic thrombolytic intervention less effective.