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Biomedical subjects

L J Hirsch

Publications and source records attributed to L J Hirsch.

12 recordsLinked to original sources
PubMed1992

The Monitored Atherosclerosis Regression Study (MARS). Design, methods and baseline results.

OBJECTIVE: The Monitored Atherosclerosis Regression Study (MARS) was designed to evaluate the effect of cholesterol lowering by monotherapy with an HMG-CoA reductase inhibitor on progression/regression of atherosclerosis in subjects with angiographically documented coronary artery disease. The purpose of this paper is to present the design, methods, and baseline results of MARS. DESIGN: MARS is a prospective, randomized, double-blind, placebo-controlled trial with baseline, 2-year, and 4-year coronary angiography as well as carotid, brachial, and popliteal ultrasonography. SETTING: Outpatient clinics at the University of Southern California School of Medicine and the University of Wisconsin School of Medicine. SUBJECTS: Two hundred seventy participants of both sexes were recruited directly from the cardiac catheterization laboratory or by chart review of patients having undergone cardiac catheterization in the past. Subjects were considered eligible if they had angiographically demonstrable atherosclerosis in 2 or more coronary artery segments, unaltered by angioplasty, with at least 1 lesion > or = 50% but < 100% diameter stenosis (%S). The inclusion range for total cholesterol (TC) was between 190 and 295 mg/dL. Exclusion factors were: triglycerides > or = 500 mg/dL; premenopausal females; uncontrolled hypertension; diabetes mellitus; untreated thyroid disease; liver dysfunction; renal insufficiency; congestive heart failure; major arrhythmia; left ventricular conduction defects; or any life-threatening disease. INTERVENTION: Subjects were placed on a low-fat, low-cholesterol diet and either 40 mg b.i.d. lovastatin (Mevacor) or placebo. Randomization was stratified by sex, smoking status, and TC. MAIN OUTCOME MEASURES: Per-subject average change in %S as determined by quantitative coronary angiography (QCA) is the primary angiographic endpoint. Secondary endpoints are: categorical analyses of the proportion of subjects with progression; human panel reading of coronary angiograms; and change in minimum lumen diameter (MLD) in mm by QCA. Carotid, brachial, and popliteal ultrasonography is also being performed. RESULTS: The subjects randomized into MARS are 91.5% male with an age range of 37 to 67 years (mean age 57.9 years). For the cohort, baseline lipids are (mean +/- SD): TC, 231 +/- 24 mg/dL; low-density lipoprotein cholesterol (LDL-C) by ultracentrifugation, 153 +/- 24 mg/dL; LDL-C, by calculation, 157 +/- 23 mg/dL; high-density lipoprotein cholesterol (HDL-C), 43 +/- 10 mg/dL; and triglycerides, 160 +/- 73 mg/dL. There were no significant differences between treatment groups in baseline lipid levels or baseline angiographic characteristics. CONCLUSIONS: MARS baseline data show adequacy of randomization with comparability of lovastatin and placebo groups in demographic, lipid, and angiographic characteristics.

Adult↗
PubMed1992

Background and methods for the lovastatin restenosis trial after percutaneous transluminal coronary angioplasty. The Lovastatin Restenosis Trial Study Group.

Restenosis remains a critical limitation of percutaneous transluminal coronary angioplasty (PTCA). Recent experimental and clinical data have suggested that lovastatin, an hydroxymethylglutaryl coenzyme A reductase inhibitor, may reduce the rate of restenosis through reduction of low density-lipoprotein (LDL) cholesterol or possibly by direct effects. Lovastatin may therefore produce favorable alterations in endothelial healing, resulting in a decreased smooth muscle cell proliferative response to injury after angioplasty. Emory University, in conjunction with Merck Research Laboratories, has initiated a 10-center double-blinded, placebo-controlled, randomized trial to assess the effect of both pretreatment and aggressive lipid lowering with lovastatin in reducing the rate of restenosis. Lovastatin achieves approximately 75% of its effect on LDL cholesterol by 1 week. Thus, patients scheduled for PTCA are randomly assigned pretreatment with lovastatin, 40 mg twice daily, or placebo 7 to 10 days before PTCA. Therapy is continued for 6 months, at which time repeat coronary arteriography is performed. A detailed safety algorithm was designed, with patients receiving lovastatin and matching placebo back-titrated on a 1:1 basis for LDL cholesterol less than 50 mg/dl. The power is a 90%, alpha = 0.05, 2-tailed test to reduce restenosis from 30 to 15%. The sample size is 360 patients in the 2 arms; allowing for a 10% dropout rate, approximately 400 patients will be randomized. Patients with successful PTCA, less than 50% residual diameter stenosis and greater than or equal to 20% diameter stenosis reduction are analyzed for restenosis at 4 to 6 months by quantitative coronary arteriography.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1992

Lack of increased cardiac output during hemoglobin hemodilution can be reversed with sodium nitroprusside.

To investigate a possible connection between EDRF or nitric oxide (NO) and the unchanged cardiac output (CO) during hemoglobin-hemodilution we infused nitroprusside (NP) in eight Hb-diluted dogs (Hct approximately 20%). Normal hypotensive doses of NP were not effective and supranormal doses (133.0 micrograms/kg/min) were needed to induce even a modest decrease in mean AoP (approximately 25 mmHg). With these NP doses, cardiac output increased 177%, diastolic AoP (afterload) decreased 30%, while systolic AoP and LVEDP (preload) were unchanged. Heart rate, LV contractility (pressure-volume function) and blood volume were not changed throughout the study. Normally, NP alone decreases both preload and afterload resulting in unchanged CO. In the Hb + NP dogs, CO increased because only afterload decreased suggesting a selective effect of Hb on venous and arterial smooth muscle relaxation. In hemodilution with nonhemoglobin colloids, CO increases primarily because the diluted blood offers less viscous resistance to ventricular ejection. It appears that in order for cardiac output to increases in the presence of Hb, some decrease in arteriolar resistance is needed, presumably to unmask the effects of reduced viscosity. These results suggest the unchanged CO during Hb-dilution is related to a selective effect of Hb on venous and arteriolar nitric oxide (EDRF) function.

Animals↗
PubMed1991

Comparison of bitemporal and unitemporal epilepsy defined by depth electroencephalography.

Of 166 consecutive patients studied with depth electroencephalography (EEG), 87 had seizures arising from one temporal lobe and 23 had seizures arising independently from each temporal lobe. We retrospectively reviewed and compared those patients with unitemporal and those with bitemporal seizures. There was no statistically significant differences between the two groups in terms of age at onset of seizures, duration of epilepsy, localization of scalp EEG abnormalities, surgical results, or pathological findings. The bitemporal group, however, had significantly fewer patients with a history of febrile seizures (p less than 0.025). Two patients with bitemporal seizures were later found to have extratemporal lesions, and one an extrahippocampal temporal lesion, on magnetic resonance scans; one patient's extratemporal lesion was resected and all habitual seizures stopped. These findings suggest that a single pathophysiological process accounts for unitemporal and some bitemporal epilepsy, but that independent onset of seizures from each temporal lobe detected by depth EEG may also indicate extratemporal foci.

Adolescent↗
PubMed1991

Temporal lobectomy in patients with bitemporal epilepsy defined by depth electroencephalography.

Patient selection for temporal lobectomy was reviewed for 23 patients with seizures that arose independently from each temporal lobe as detected by depth electroencephalography (EEG). Although neuropsychological testing, interictal EEG findings, imaging studies, and subclinical seizures were also considered, all patients offered temporal lobectomy had (1) at least 50% of the clinical seizures originating from the lobe to be resected, (2) adequate contralateral memory on testing with amobarbital, and (3) no clear evidence of an extratemporal focus. Eleven patients underwent temporal lobectomy. Pathological findings were considered positive in all nine specimens reviewed. Nine patients had no seizures, one had greater than 75% reduction in seizure frequency, and 1 had 50 to 75% reduction. Pathological features and clinical outcome were similar in the 6 patients with fewer than 80% and the 5 patients with at least 80% of seizures originating from the resected lobe. Thus, having fewer than 80% of seizures originate from one temporal lobe should not be an absolute contraindication for temporal lobectomy.

Adolescent↗
PubMed1991

Studies of central nervous system disorders with single photon emission computed tomography and positron emission tomography: evolution over the past 2 decades.

Single photon emission computed tomography (SPECT) was introduced in the 1960s to detect breakdowns in the blood-brain barrier and was replaced by x-ray computed tomography in the mid-1970s. The development of the deoxyglucose (DG) technique to measure regional cerebral glucose metabolism by employing either autoradiography, using 14CDG, or positron emission tomography (PET), using 18FDG, added a major dimension to the investigation of brain function. In the late 1970s and early 1980s, the FDG-PET technique was widely used to examine a variety of neuropsychiatric disorders. It soon became apparent that functional imaging was more sensitive than anatomic imaging in detecting abnormalities of the brain related to aging, dementia, tumors, seizures, cerebral vascular accidents, and psychiatric problems. Because of its complexity and the cost involved, PET was used in a limited number of centers in the United States. However, the success of PET resulted in the resurgence of interest in SPECT as an alternative technology after almost a decade. This became possible because of the synthesis of iodine 123- and technetium 99m-labeled radiopharmaceuticals to determine regional cerebral blood flow. Since blood flow and metabolism are coupled in most pathological states, patterns of abnormality noted on SPECT were similar to those seen on PET in many disorders. Since the introduction of high resolution SPECT imaging instruments, the role of SPECT has been further enhanced. The successful synthesis of both positron and single emitting radioligands to image dopamine and other receptors has started a new era in neurosciences and will have a far-reaching impact on the day-to-day practice of neuropsychiatry.

Adult↗
PubMed1991

Skeletal muscle blood flow and O2 uptake during intravenous nicotine with and without hypertension.

The mechanism by which nicotine causes peripheral vasoconstriction and its relationship to the increased risk of peripheral vascular disease in smokers are unknown. To study the peripheral vascular effects of nicotine, we measured hemodynamic responses and oxygen consumption of the in situ gracilis muscle during intravenous (i.v.) nicotine infusions in anesthetized dogs. Nicotine 36.0 micrograms/kg/min increased gracilis artery pressure (Pga) 91 +/- 17% and muscle vascular resistance (MVR) 96 +/- 18% whereas muscle blood flow (MBF) and oxygen consumption (MVO2) were unchanged from baseline. In dogs with extracorporeal-controlled normotension during nicotine infusion, however, Pga was held at baseline levels but similar increases in MVR were observed (95 +/- 11%) as flows decreased 52 +/- 9%. Oxygen consumption decreased in direct proportion (53 +/- 5%) to MBF, indicating complete impairment of oxygen extraction (A-VO2). Thus impaired oxygen extraction was masked in dogs in which Pga was allowed to increase because of sustained pressure-dependent flows. Phenoxybenzamine block of muscle alpha-adrenoceptors increased MBF and MVO2 in both normotensive and hypertensive dogs. Combined alpha- and beta-blockade effectively neutralized all sympathoadrenal responses in the muscle. All the above results occurred regardless of innervation. Plasma levels of norepinephrine (NE) and epinephrine (EPI) increased greater than 1,000% during nicotine infusion. Apparently, these levels were high enough to (a) override dilator effects of plasma EPI and (b) cause vasoconstriction in muscle independent of nerve supply. Infusion of nicotine in the gracilis artery had no effect on muscle hemodynamics. Nicotine-induced increase in plasma catecholamines resulted in a powerful constriction of both resistance and oxygen-exchange vessels of skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism.

In a canine model of pulmonary embolism (PE) produced by infusion of autologous blood clots, mean arterial blood pressure (MAP) decreased to 73 +/- 4 mm Hg while cardiac output (CO) decreased to less than 50 percent of baseline. Intravenous infusion of phenylephrine (PHEN) and norepinephrine (NE) restored MAP to somewhat above baseline values. However, only NE restored CO to control levels. The right ventricular myocardial blood flow increased 15 percent in the PE group with PHEN and 229 percent with NE at equipressor concentrations. The right ventricular myocardial oxygen consumption (RVMVo2) was not significantly different between PE and PE + PHEN while PE + NE increased RVMVO2 by 144 percent to 20.2 +/- 1.8 ml/min/100 g. The RV output was not adequately restored with PE, but when RV contractility was augmented with NE, RV output was restored to baseline. Right ventricular minute work increased 100 percent with NE and was maintained with a 100 percent increase in oxygen consumption. Calculated pulmonary vascular resistance (PVR) was decreased during PE by 36 percent with PE + PHEN while PVR in NE-treated dogs decreased by 59 percent. In NE-treated animals, systemic vascular resistance (SVR) was restored to control levels while in PHEN-treated animals SVR increased about 75 percent from baseline. We conclude that the salutary effects of NE on RV output are due to both alpha and beta receptor stimulation, which increased contractility, RVMBF, and RVMVo2, and decreased both PVR and SVR. In the PHEN-treated dogs, our indices of minute-work, RVMBF, and RVMVo2 suggest that coronary autoregulation was intact; however, there was no apparent benefit to RV output. This study suggests that in the clinical setting of acute PE, the judicious use of NE, rather than PHEN, may be more beneficial in restoring RV function and systemic hemodynamics.

Animals↗
PubMed1988

Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus.

To determine whether non-insulin-dependent diabetes is associated with specific alterations in the pattern of insulin secretion, we studied 16 patients with untreated diabetes and 14 matched controls. The rates of insulin secretion were calculated from measurements of peripheral C-peptide in blood samples taken at 15- to 20-minute intervals during a 24-hour period in which the subjects ate three mixed meals. Incremental responses of insulin secretion to meals were significantly lower in the diabetic patients (P less than 0.005), and the increases and decreases in insulin secretion after meals were more sluggish. These disruptions in secretory response were more marked after dinner than after breakfast, and a clear secretory response to dinner often could not be identified. Both the control and diabetic subjects secreted insulin in a series of discrete pulses. In the controls, a total of seven to eight pulses were identified in the period from 9 a.m. to 11 p.m., including the three post-meal periods (an average frequency of one pulse per 105 to 120 minutes), and two to four pulses were identified in the remaining 10 hours. The number of pulses in the patients and controls did not differ significantly. However, in the patients, the pulses after meals had a smaller amplitude (P less than 0.03) and were less frequently concomitant with a glucose pulse (54.7 +/- 4.9 vs. 82.2 +/- 5.0, P less than 0.001). Pulses also appeared less regularly in the patients. During glucose clamping to produce hyperglycemia (glucose level, 16.7 mmol per liter [300 mg per deciliter]), the diabetic subjects secreted, on the average, 70 percent less insulin than matched controls (P less than 0.001). These data suggest that profound alterations in the amount and temporal organization of stimulated insulin secretion may be important in the pathophysiology of beta-cell dysfunction in diabetes.

Blood Glucose↗
PubMed1976

Direct effects of various catecholamines on liver circulation in dogs.

As measured by electromagnetic blood flow transducers, direct infusion of epinephrine, norepinephrine, and dopamine into the portal vein (PV) produced a 40-50% decrease in hepatic arterial (HA) blood flow; isoproterenol increased HA flow by about 69%. No changes in PV flow or pressure were observed. Direct HA infusion of the vasoconstrictors decreased HA flow by amounts comparable to those occurring after PV infusion. However, HA infusion of isoproterenol increased HA flow only 15% suggesting a difference in beta-receptor population in the two vessels. When infused directly into the superior mesenteric artery (SMA), epinephrine and norepinephrine reduced SMA flow by about 45% and PV flow by 20-25%; HA flow increased 6-8%. Infusion of isoproterenol and dopamine into SMA increased SMA flow by 115% and 206% and PV flow by 60% and 70%, respectively, whereas HA flow decreased by 25% and 50%. Portal vein pressure increased less than 3 mmHg. Alpha- and beta-receptor blockade of the liver did not change significantly the alterations in hepatic arterial blood flow that were secondary to changes in portal venous blood flow. It is likely that regulation of hepatic arterial flow resides in mechanisms located within the liver sinusoids.

Adrenergic beta-Antagonists↗
PubMed1975

Contrasting splenic mechanisms in the blood clearance of red blood cells and colloidal particles.

We have studied the blood clearance and organ uptake of colloidal particles and of antibody-coated and chemically treated Na2 51Cr O4-labeled erythrocytes (RBC) in mice. Hepatic and splenic uptake of both colloidal particles and autologous RBC coated with rabbit antibody were reduced significantly following pretreatment of animals with cortisone acetate. Hepatic removal of RBC previously treated in vitro with N-ethyl-maleimide (NEM) or phenylhydrazine-HCl (PHZ) was similarly depressed by pretreatment with cortisone. In contrast, the splenic uptake of NEM- and PHZ-altered erythrocytes was unaffected by cortisone. Scanning and transmission electron microscopic examination of perfused spleens from PHZ-injected animals demonstrated extensive mechanical trapping of Heinz body-containing RBC in sinus wall apertures, whereas little erythrophagocytosis was observed. These studies suggested that, while clearance of inert particulate matter and of antibody-coated RBC from the blood occurred primarily by a cortisone-suppressible, presumably phagocytic process in the spleen, chemically altered RBC were removed primarily by a cortisone-insensitive filtration process in the splenic microvasculature.

Animals↗