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D C Harrison

Publications and source records attributed to D C Harrison.

At least 37 records · Page 2Linked to original sources
PubMed2000

TR3 death receptor expression in the normal and ischaemic brain.

Members of the death receptor family may play a prominent role in developmental and pathological neuronal cell death. We report the expression of the TR3 and TR7 death receptors in the adult human and rat central nervous system. Whereas expression of TR3 appears to be high in the human cerebellum, with lower levels in other brain regions, robust expression is observed in many regions of the rat brain. We also analyzed modulation of death receptor expression in an in vivo rat model of acute stroke. In contrast to tumor necrosis factor receptor 1, Fas and p75(NGFR), which all show up-regulation specifically in lesioned cortex of the permanent middle cerebral artery occlusion model of stroke. TR3 shows a rapid global increase in both lesioned and unlesioned brain. In comparison, the recently described death receptor TR7 shows no change in this model. These data indicate that the death receptors show clear differences in patterns of expression in response to ischemic injury. ¿ 2000 IBRO. Published by Elsevier Science Ltd.

Amino Acid Sequence↗
PubMed1995

Failure of isradipine to reduce infarct size in mouse, gerbil, and rat models of cerebral ischemia.

BACKGROUND AND PURPOSE: The dihydropyridine L-type calcium channel blocker isradipine has been reported to exhibit neuroprotective properties in some, but not all, studies performed in the rat middle cerebral artery occlusion (MCAO) model. In the present study, we examined isradipine in several other models of focal and global ischemia: rat rose bengal, mouse MCAO, and gerbil bilateral carotid artery occlusion (BCAO). For comparison, a novel calcium channel blocker, SB201823A, that we have previously shown to be neuroprotective in rat and gerbil models was also examined in the mouse. METHODS: In the gerbil BCAO model, isradipine was administered at 2.5 mg/kg i.p. as a single dose 60 minutes after ischemia (n = 10). Corresponding controls received vehicle (n = 10), and sham-operated animals received no treatment (n = 6). Locomotor activity and histological assessments were made at 4 days after ischemia. In the rat photothrombotic occlusion model, isradipine was administered at 2.5 mg/kg i.p. as a single dose 60 minutes after ischemia (n = 10), and corresponding controls (n = 10) received vehicle. Histological assessment was made at 7 days after ischemia. In the mouse MCAO model, isradipine was also administered at 2.5 mg/kg i.p. as a single dose 60 minutes after ischemia. Histological assessments were made at 1 (n = 13), 2 (n = 9), and 4 (n = 9) days after ischemia. Vehicle numbers were n = 10, n = 6, and n = 8, respectively. Isradipine and SB201823A were also examined using a combined preischemia and postischemia regimen. Isradipine was administered at 2.5 mg/kg i.p. before occlusion, 1.25 mg/kg i.p. 1 hour after occlusion, 1.25 mg/kg i.p. 2 hours after occlusion, and 2.5 mg/kg twice a day for 3 days after occlusion (n = 16). Corresponding controls received vehicle at the same time points (n = 14). SB201823A was administered 30 minutes before occlusion, 30 minutes after occlusion, and twice daily for 3 days (n = 12). Corresponding controls received vehicle (n = 9). Histological assessment was performed at 4 days after ischemia. RESULTS: When given after ischemia, isradipine failed to affect lesion volume in both the rat and mouse models. In the gerbil, locomotor hyperactivity and hippocampal cell loss were unaffected. Given before and after ischemia in the mouse, isradipine was also ineffective, whereas SB201823A produced a significant reduction in lesion volume. CONCLUSIONS: The L-type calcium channel blocker isradipine was devoid of neuroprotective activity in focal and global models of cerebral ischemia in three species of normotensive animals. These results were compared with data for the novel calcium channel blocker SB201823A, which exhibited a significant effect after pre- and postocclusion administration in the mouse model of permanent focal ischemia.

Animals↗
PubMed1995

SB 201823-A antagonizes calcium currents in central neurons and reduces the effects of focal ischemia in rats and mice.

BACKGROUND AND PURPOSE: Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. We evaluated the ability of a novel neuronal calcium channel blocker, SB 201823-A, to block central neuronal calcium influx in vitro and to reduce ischemic injury in two rodent models of focal stroke. METHODS: Patch-clamp electrophysiology and intracellular Ca2+ imaging in rat hippocampal and cerebellar neurons were used to determine effects on neuronal calcium channel activity. Middle cerebral artery occlusion was performed in Fisher 344 rats and CD-1 mice to determine the effects on rodent focal ischemic injury and neurological deficits. Cardiovascular monitoring in conscious rats was conducted to determine cardiovascular liabilities of the compound. RESULTS: In cultured rat hippocampal cells, calcium current measured at plateau was reduced by 36 +/- 8% and 89 +/- 4% after 5 and 20 mumol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5 mumol/L SB 201823-A totally prevented initial calcium influx and reduced later calcium influx by 50 +/- 2.5% after N-methyl-D-aspartate/glycine stimulation (P < .01). KCl depolarization-induced calcium influx also was reduced by more than 95%. In rats, a single treatment with 10 mg/kg IV SB 201823-A beginning 30 minutes after focal ischemia decreased (P < .05) hemispheric infarct by 30.4% and infarct volume by 29.3% and reduced (P < .05) forelimb deficits by 47.8% and hindlimb deficits by 36.3%. In mice, treatments with 10 mg/kg IP SB 201823-A beginning 30 minutes after focal ischemia significantly reduced infarct volume by 41.5% (P < .01). No blood pressure effects were observed with the therapeutic dose of the compound. CONCLUSIONS: These results indicate that the new neuronal calcium channel blocker SB 201823-A can block stimulated calcium influx into central neurons and can provide neuroprotection in two models of focal cerebral ischemia without affecting blood pressure. Data from several different studies now indicate that the neuronal calcium channel antagonists are a promising therapy for the postischemic treatment of stroke.

Animals↗
PubMed1994

Managed care involvement by cardiovascular specialists: prevalence, attitudes and influence on practice.

OBJECTIVES: The purpose of this study was to determine the involvement in and attitudes toward managed care by cardiovascular specialists and the influence of such programs on their practices. BACKGROUND: No in-depth study has measured the impact of managed care on cardiovascular specialists. Therefore, we conducted a mail survey to determine the prevalence of managed care arrangements among cardiovascular specialists and variations among pediatric and adult cardiologists and cardiovascular surgeons; the types of managed care arrangements in which cardiovascular specialists are engaged; the reasons why those not participating in managed care have chosen not to do so; and the general attitudes among cardiovascular specialists with regard to various aspects of managed care. In addition, we evaluated the impact of managed care among several aspects of cardiovascular practice. METHODS: A questionnaire was mailed in the spring of 1993 to 4,577 practicing, domestic, American College of Cardiology (ACC) members selected at random from within each primary cardiovascular specialty group (adult cardiologists, pediatric cardiologists and cardiovascular surgeons). Additional data concerning practice characteristics were cross tabulated using results from the 1992 ACC membership profile survey. RESULTS: In total, 1,961 of the 4,577 members responded to the survey, representing a 43% response rate. Of all survey respondents, 76% reported entering into at least one relationship with a health maintenance organization (HMO) or preferred provider organization (PPO). Of those not participating in managed care arrangements, the most frequently mentioned reason was "concern over the quality of care." This reason was cited by 51% of those not entering into HMO relationships and 41% of those not participating in PPOs. The majority of respondents indicated that they do not strongly object to the gatekeeper approach to managing nonemergent patients, although more than half indicated concern that gatekeepers may not be appropriate in the management of cardiac emergencies. In addition, cardiovascular specialists report that under managed care, referrals have not increased, income has decreased, and managed care formularies have not substantially affected their ability to prescribe appropriate medication to their patients. CONCLUSIONS: Despite concerns over the quality of care and contract requirements and general philosophical opposition of cardiovascular specialists, most are becoming integrated into managed care environments.

Adult↗
PubMed1992

Plaque-associated immune reactivity as a tool for the diagnosis and treatment of atherosclerosis.

In summary, we have confirmed that a specific humoral immune reactivity involves human atherosclerotic plaque. By isolating some of the autoantigens and employing them in prototype immunoassays, we have been able to measure for the presence of plaque-specific antibodies. Extracted plaque antigens have also served as immunogens in monoclonal antibody generation. These have shown early promise as plaque-directed in vivo targeting agents. Further scientific evaluation and reagent development remains before the practical utility of employing such reagents or methods in the care of patients with atherosclerosis-related diseases can be ascertained.

Animals↗
PubMed1991

A pH-dependent phospholipase A2 contributes to loss of plasma membrane integrity during chemical hypoxia in rat hepatocytes.

Previous studies have suggested that alterations in phospholipid composition of plasma membranes may underlie lethal cell injury due to hypoxic and ischemic injury. The present study was designed to determine if such alterations are due to the activation of a pH-dependent phospholipase A2. Loss of cell viability and phospholipase A2 activity measured by arachidonic acid release increased in parallel during metabolic inhibition with KCN and iodoacetate (chemical hypoxia). Acidosis (pH 6.5) and the phospholipase inhibitors, dibucaine and mepacrine, delayed loss of cell viability and release of arachidonic acid to a similar extent. These findings suggest that a pH-dependent phospholipase A2 causes alterations in plasma membrane phospholipid composition after ATP-depletion which contribute to lethal cell injury.

Animals↗
PubMed1990

Histamine mediates myocardial damage by an H1 mechanism independent of coronary blood flow.

Administration of histamine to rabbits may result in myocardial damage similar to that produced by catecholamines and the anthracycline antibiotics. To explore the mechanisms involved in histamine-mediated myocardial damage, conscious New Zealand white rabbits were pretreated with H1 and H2 receptor blocking agents, alone and in combination, and then administered histamine. Coronary artery blood flow was measured with radiolabeled microspheres in rabbits that received histamine alone, and in those that received an H1 blocking agent and histamine. Rabbits that received an H1 blocking agent had a significant reduction in morphological injury which was scored as follows: grade 1, minimal or no injury; grade 2, moderate; and grade 3, severe injury (mean pathology score = 1.1 +/- 0.28 for histamine alone vs. 0.06 +/- 0.06 with H1 receptor blockade, p less than 0.05). Animals pretreated with H2 receptor blockade (mean pathology score = 1.2 +/- 0.49) were not protected against morphological injury. Coronary blood flow decreased in animals that received histamine alone: control = 2.61 +/- 0.38 vs. 1.80 +/- 0.30 ml/min/g (p less than 0.05), and in animals pretreated with H1 blockade; control = 3.29 +/- 0.34 vs. 1.91 +/- 0.28 ml/min/g (p less than 0.01). We conclude that histamine-mediated myocardial damage appears to be mediated by the H1 receptor system and that this appears to be independent of initial changes in global coronary blood flow.

Animals↗
PubMed1989

Arrhythmia prophylaxis after acute myocardial infarction: a decade of controversy.

Primary ventricular fibrillation continues to be a major complication of acute myocardial infarction occurring in 5-9% of patients in the coronary care unit and in a higher percentage of pre-hospital admissions. Prophylactic anti-arrhythmic drugs can prevent primary ventricular fibrillation. Lidocaine has been used for this purpose and can be administered safely and effectively in most patients by following well-established programs based on pharmacokinetic and pharmacodynamic data. The in-hospital mortality for patients with primary ventricular fibrillation exceeds that of matched controls not having the arrhythmia, and many studies show a higher 1-, 3-, and 5-year mortality. Other studies have failed to confirm these long-term results and have produced controversy among cardiologists. I continue to recommend prophylactic antiarrhythmic drugs for all patients with acute infarction, especially in those undergoing early interventional therapy.

Acute Disease↗
PubMed1988

The hard choices that we must make.

The cost of caring for patients with cardiovascular disease has increased more than 50% in the past five years. Much of this increase is due to the dissemination of new technologies that have proved effective for specific patient populations. Molecular biology, immunology, magnetic resonance imaging, and second generation cardiovascular drugs all promise more effective, noninvasive diagnostic and treatment methods--and continued higher costs. To avoid extreme solutions to cost-increase problems, results of clinical research must be better utilized to determine indications for high-cost procedures. Also important are improved methods of evaluating new technologies before dissemination; regionalization of high-cost services; and increased use of clinical data bases and sophisticated computer data handling, which furnish cost-effectiveness studies and tools for clinical decision-making.

Cardiac Surgical Procedures↗
PubMed1988

The hemodynamic effects of repeated bed rest exposure.

Hemodynamic changes were measured during stepwise exposure to lower-body negative pressure (LBNP) (5 min, -20, -30, and -40 mm Hg) in a group of seven physically active subjects before and after consecutive exposure to three 2-week bed rest periods. Bed rest exposures were separated by 3-week periods of ambulatory recovery. Dynamic exercise (68% max O2, 30 min each day) and isometric exercise (21% max leg extension, 30 min each day) performed during bed rest and reambulation failed to prevent deconditioning or accelerate the recovery process between bed rest exposures. Heart rate (HR) and end-diastolic volume index (EDVI) proved to be parameters showing greatest changes during LBNP. Heart rate increases at -40 mm Hg LBNP (compared to respective pre-LBNP levels) were 13.3%, 35.1%, and 51.0% for each of the pre-bed rest exposures, while respective changes after bed rest were 57.8%, 57.2%, and 75.5%. The significantly elevated HR responses during subsequent pre-bed rest (control) periods indicated incomplete recovery despite mild exercise and ambulation. Comparison of EDVI and HR revealed a similar linear regression relationship during LBNP before and after bed rest so that EDVI = 112.5-0.85 x HR, r = -0.97. We conclude from these findings that cardiovascular deconditioning for physically active individuals involves factors other than simple loss of plasma volume, requires at least 3 weeks or longer to return to the pre-bed rest state, and is not counteracted by the levels of aerobic and/or isometric exercise used in the present study.

Adult↗
PubMed1987

Pharmacokinetic and pharmacodynamic properties of beta-blocking drugs influencing choice in treatment of systemic hypertension.

Diuretics and beta blockers are the mainstay in treating mild and moderate systemic hypertension, but there is controversy as to which should be used first. Recent evidence of an increase in sudden death and a greater number of intolerable side effects in the diuretic-treated groups in the Multiple Risk Factor Intervention Trial in the U.S. and the Medical Research Council Trial in Great Britain has prompted some to suggest beta blockers as first-line therapy. However, beta blockers also have side effects, such as decreased ventricular function in patients with mild heart failure, increased airways resistance in those with chronic obstructive lung disease, increased plasma lipids, in particular low density lipoprotein cholesterol, and increased problems in patients with peripheral vascular disease and those with diabetes requiring insulin treatment. Many new beta-blocking drugs with different pharmacokinetic and pharmacodynamic properties allow the physician to choose the best one for each patient. beta-blocking drugs with long durations of action, high levels of bioavailability, beta 1 selectivity and intrinsic sympathomimetic activity appear most suitable for therapy. Cardioselectivity is suggested for patients with obstructive lung disease and peripheral vascular disease, and diabetic patients who take insulin. Long durations of action permit infrequent administration and recently agents with intrinsic sympathomimetic activity have been shown to have less effects on plasma lipid levels. Acebutolol also reduces ventricular arrhythmias, and may therefore be used to reduce sudden death in patients with coronary artery disease. The pharmacokinetic and pharmacodynamic properties of beta-blocking drugs can indicate the most appropriate choice for hypertensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗