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Biomedical subjects

P Collins

Publications and source records attributed to P Collins.

At least 199 records · Page 11Linked to original sources
PubMed1994

Aggressive management of doxorubicin-induced cardiomyopathy associated with 'low' doses of doxorubicin.

There is a dose-effect relationship between doxorubicin and the incidence of symptomatic cardiac failure. It is generally thought that doses below 500-550 mg/m2 are safe but, when objective measures of cardiac function are used, it becomes apparent that degrees of cardiac failure occur at doses below this. We present here the case histories of two patients who developed very severe cardiac failure at cumulative doses well below 500 mg/m2 but who survived their initial cardiac illness due to aggressive intervention. In one case, the patient was successfully treated by orthotopic cardiac transplantation.

Adolescent↗
PubMed1994

Nitric oxide accounts for dose-dependent estrogen-mediated coronary relaxation after acute estrogen withdrawal.

BACKGROUND: Estrogen replacement therapy reduces the risk of coronary heart disease in postmenopausal women, and estrogen treatment modulates endothelium-dependent vasodilation in ovariectomized, atherosclerotic monkeys. Estradiol-17 beta also induces relaxation in isolated rabbit coronary arteries as well as cerebral basilar arteries. The estrogen concentrations required to induce such relaxation are in the pharmacological range (10(-6) to 10(-5) mol/L). METHODS AND RESULTS: The present study was designed to test whether the sensitivity and specificity of the relaxing response of coronary vascular smooth muscle to exogenous estradiol-17 beta is dependent on the sex hormone status of the animal. In coronary artery rings contracted with PGF2 alpha (3 x 10(-5) mol/L), estradiol-17 beta caused significant relaxation at a physiological estrogen concentration (10(-9) mol/L), in coronary artery rings from oophorectomized, estrogen-treated and acutely estrogen-withdrawn rabbits only. Relaxation induced by estradiol-17 beta at lower concentrations (10(-9) to 10(-6) mol/L) in these rings was 20 +/- 6%, 42 +/- 8%, 54 +/- 9%, and 75 +/- 8%, respectively, compared with 4 +/- 2%, 12 +/- 5%, 16 +/- 7%, and 25 +/- 12% and 5 +/- 2%, 12 +/- 5%, 18 +/- 8%, and 23 +/- 10% in rings from estrogen-maintained and oophorectomized rabbits, respectively (P < .01). The relaxation in coronary artery rings from estrogen-treated and acutely estrogen-withdrawn rabbits was endothelium and nitric oxide dependent since it was abolished by endothelium removal and the nitric oxide synthase inhibitor N omega-nitro-L-arginine. CONCLUSIONS: This study demonstrates that estrogen-induced, endothelium-dependent relaxation of coronary arteries may, in some species, depend on the sex hormone status of the animal. These findings may help to better understand the effects of ovarian steroids in the coronary circulation of females.

Animals↗
PubMed1994

Hormone replacement therapy and the cardiovascular system. Nonlipid effects.

Coronary heart disease (CHD) is the leading cause of death in women, and the risk of this disease rises markedly after loss of ovarian function. Hormone replacement therapy (HRT) can reduce the incidence of CHD in postmenopausal women by 50%. HRT causes changes in lipids and lipoproteins, but it is now clear that many other effects of gonadal steroid hormones have important influences on the cardiovascular system. These nonlipid effects include a variety of changes in other metabolic risk factors for CHD, as well as direct arterial effects. Insulin resistance and hyperinsulinaemia may be pivotal disturbances in the pathogenesis of CHD. Estradiol reverses the effects of menopause on glucose and insulin metabolism, resulting in an increase in pancreatic insulin secretion and a decrease in insulin resistance, although other types of estrogen may not do this. Androgenic progestogens may oppose this potentially beneficial effect on insulin resistance. Central obesity is linked with many CHD risk factors, and HRT reverses the increased fat distribution that results from loss of ovarian function at the menopause. HRT may also improve the balance between coagulation and fibrinolysis, resulting in a reduction in arterial thrombosis. Finally, estradiol acts directly on the arterial wall, modifying both endothelium-dependent and calcium-dependent processes. These actions result in improved blood flow and reduced blood pressure and, importantly, have the potential to reduce myocardial ischaemia.

Adipose Tissue↗
PubMed1994

Factor VIIa and other haemostatic variables following bone marrow transplantation.

Hepatic venocclusive disease causes considerable morbidity and mortality following bone marrow transplantation. There are two hypotheses regarding the aetiology of this syndrome; firstly that changes in plasma coagulation factors and natural anticoagulants lead to a prothrombotic state and secondly that endothelial cell activation stimulates intravascular deposition of fibrin. We have investigated these mechanisms by measuring the changes in proteins C and S and factors VII and X in the post transplant period and by using the plasma concentration of factor VIIa as an in vivo marker of potential endothelial cell tissue factor expression. Protein C fell in both allograft and autograft patients but more so in the allografts. Similar results were found for factors VII and X. These changes were predominantly due to hepatic dysfunction induced by the chemo-radiotherapy. Factor VIIa levels were unchanged in both the allograft and autograft patients. We conclude that there is no convincing evidence for a procoagulant state following BMT as there are both anticoagulant and procoagulant changes. The absence of any changes in factor VIIa levels suggests that tissue factor was not exposed to the general circulation following BMT but does not exclude focal expression at the sites of thrombosis.

Bone Marrow Transplantation↗
PubMed1994

6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine.

The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinson's disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.

Animals↗
PubMed1993

Beneficial effect of oestrogen on exercise-induced myocardial ischaemia in women with coronary artery disease.

Oestradiol-17 beta causes relaxation of isolated coronary arteries and increases blood flow in several vascular beds in human beings and animals. Oestrogen replacement therapy is associated with a lower incidence of cardiovascular disease, but the acute effects of oestradiol-17 beta on myocardial ischaemia are unknown. We have studied the acute effect of sublingual oestradiol-17 beta on exercise-induced myocardial ischaemia in eleven women (mean age 58 [SD 8] years) with coronary artery disease. The women did two treadmill exercise tests on separate days; 40 min before the test they took sublingual oestradiol-17 beta (1 mg) or placebo, in random order. Plasma oestradiol-17 beta concentrations were confirmed to be higher after sublingual oestradiol-17 beta than after placebo (2531 [1192] vs 155 [168] pmol/L, p < 0.001). Oestradiol-17 beta increased both time to 1 mm ST depression (456 [214] vs 579 [191] s, p < 0.004; difference of medians 92 [95% CI 46-254]) and total exercise time (569 [249] vs 658 [193] s, p < 0.01; difference 54 [10-212]). Acute administration of oestradiol-17 beta therefore has a beneficial effect on myocardial ischaemia in women with coronary artery disease. This effect may be due to a direct coronary-relaxing effect, to peripheral vasodilation, or to a combination of these mechanisms. Oestradiol-17 beta may prove to be a useful adjunct to the treatment of angina in postmenopausal women with coronary heart disease.

Administration, Sublingual↗
PubMed1993

Cardiovascular protection by oestrogen--a calcium antagonist effect?

During their premenopausal years, women have a lower risk than men of getting cardiovascular disease. This protection continues after the menopause if women receive oestrogen replacement. Based on new experimental evidence we propose that some of the cardiovascular benefits of oestrogen replacement therapy may be due to a long-term calcium antagonist effect of oestrogen.

Animals↗
PubMed1993

Sensitivity monitoring of clinical isolates of herpes simplex virus to acyclovir.

Zovirax (acyclovir, ACV) is now widely accepted as a safe and effective treatment for the management of herpes simplex virus (HSV) infections in normal and immunocompromised patients. However, a common concern with regard to the widespread use of any antimicrobial agent is resistance. The virus specific mechanism of action of ACV involves two virus encoded enzymes, thymidine kinase (TK) and DNA polymerase. Any alteration in the genes coding for these two enzymes would therefore be expected to confer resistance. The findings from two extensive resistance monitoring programs have shown that in immunocompetent patients receiving ACV for the management of acute HSV disease, the incidence of resistance is extremely rare. The situation in the immunocompromised is different. In this patient group HSV disease is severe and protracted often requiring prolonged therapy thus increasing the exposure of the virus to drug. As a result HSV isolates resistant to ACV have occasionally been recovered. Biochemical and genetic analysis of the resistant clinical isolates has shown that resistance in the most part is due to an inability of the virus to produce TK which mirrors the findings with cell culture derived resistant virus. Laboratory studies would indicate that TK-deficient virus would have little clinical impact. Significantly, resistance has rarely been attributed to alterations in the substrate specificity of TK or DNA polymerase. The biological significance of these mutants is unclear but to date there has been no evidence of transmission of resistant virus.

Acyclovir↗
PubMed1993

The effect of low density lipoprotein composition on the regulation of cellular cholesterol synthesis: a comparison in diabetic and non-diabetic subjects.

This study investigates compositional differences in low density lipoprotein (LDL) subfractions and their relationship to cellular cholesterol synthesis. We examined ten normocholesterolaemic (serum cholesterol < 6.5 mM) non-diabetic subjects (group 1) and compared them with ten normocholesterolaemic (group 2) and ten hypercholesterolaemic (group 3) (serum cholesterol > 6.5 mM) type 2 (non-insulin-dependent) diabetic patients. Serum cholesterol levels for groups 1, 2 and 3 were 5.19 +/- 0.27, 5.20 +/- 0.27 and 7.51 +/- 0.31 mM. LDL (density 1.006-1.028 g/l) and LDL2 (1.028-1.063 g/l) were isolated by density gradient ultracentrifugation. A significantly greater proportion of cholesterol was carried in LDL2 than LDL1 in all groups. There was a significantly lower cholesterol/protein ratio in LDL1 from the hypercholesterolaemic diabetic patients compared with controls. The LDL esterified/free cholesterol ratio was significantly greater in both LDL1 and LDL2 in the hypercholesterolaemic diabetic patients compared with the other two groups. There was a negative correlation between inhibition of cholesterol synthesis and the esterified/free cholesterol ratio of both LDL1 (r = 0.56, P < 0.002) and LDL2 (r = 0.63, P < 0.001). Cellular cholesterol of 41.0 +/- 0.3 microgram/mg cell protein in the hypercholesterolaemic diabetic patients was also significantly higher compared with values of 30.32 +/- 2.0 and 34.1 +/- 4.2 micrograms/mg cell protein for the normocholesterolaemic non-diabetic and diabetic groups. In vitro LDL esterification led to a decrease in LDL receptor-mediated binding and resulted in a 40% reduction in the ability of the LDL to suppress cholesterol synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1993

Electromyographical differentiation of the components of perioral movements induced by SKF 38393 and physostigmine in the rat.

Facial electromyography (EMG) coupled with visual observation was used to investigate spontaneous and drug induced perioral movements in freely moving rats. Four separate perioral behaviours were identified; facial tremor, purposeless chewing, gaping and yawning. Facial tremor, yawning and gaping but not purposeless chewing produced characteristic EMG signals. Normal rats displayed a low level of purposeless chewing, occasional bursts of facial tremor but not gaping or yawning. Each burst of facial tremor was accompanied by a transient increase in purposeless chewing. Administration of the D1 agonist SKF 38393 induced a dose related increase in bursts of facial tremors and consequently an increase in the total number of purposeless chews. Gaping and yawning were not induced by SKF 38393 administration. Administration of the cholinesterase inhibitor physostigmine (0.1-0.4 mg/kg) induced a dose related increase in the total number of purposeless chews, but primarily these were not associated with facial tremor. Administration of physostigmine also increased gaping and yawning. Administration of the D1 antagonist SCH 23390 almost abolished facial tremor in normal treated rats but only partially reduced that induced by SKF 38393 and physostigmine. SCH 23390 reduced purposeless chewing in SKF 38393 treated rats but not in normal or physostigmine treated animals. Administration of the cholinergic antagonist atropine almost abolished facial tremor in normal and physostigmine treated rats, but only reduced by 46% that induced by SKF 38393. Atropine reduced purposeless chewing in normal, physostigmine and SKF 38393 treated animals. Physostigmine induced gaping and yawning were abolished by atropine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Effect of chronic trifluoperazine administration and subsequent withdrawal on the production and persistence of perioral behaviours in two rat strains.

The effect of chronic administration of trifluoperazine on the perioral movement profile of Wistar and Sprague-Dawley rats was examined. Perioral movements were characterised by visual observations, coupled with electromyographic recording from the masseter muscle. In drug-naive animals from both strains the spectrum of perioral behaviours was essentially identical, primarily consisting of purposeless chewing, accompanied by occasional bursts of facial tremor and teeth chattering, with occasional yawning. Each burst of facial tremor was accompanied by a transient increase in the rate of purposeless chewing. Wistar rats exhibited a higher level of spontaneous purposeless chewing compared to Sprague-Dawley rats. In both strains, chronic administration of trifluoperazine (5 mg/kg per day, PO) for 5 months induced an increase in perioral behaviour, which primarily consisted of enhanced purposeless chewing. In Wistar rats the drug-induced increase in purposeless chewing was accompanied by an increase in the incidence of yawning, with no change in the incidence of either facial tremor or teeth chattering. In contrast, Sprague-Dawley rats displayed a drug-induced increase in purposeless chewing, accompanied by an increase in the incidence of facial tremor and teeth chattering, but not yawning. In Wistar rats withdrawal of trifluoperazine diminished but did not reverse the drug-induced increase in purposeless chewing. Drug withdrawal also precipitated a transient increase in the incidence of facial tremor and teeth chattering, but had no effect on yawning. In Wistar rats, the level of purposeless chewing and the incidence of yawning remained elevated above control levels for at least 13 weeks after drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Glycosylated low density lipoprotein is more sensitive to oxidation: implications for the diabetic patient?

Oxidised low density lipoprotein (LDL) is considered to be atherogenic. This study examined the relationship between glycosylation and oxidation of LDL from 10 normocholesterolaemic Type 2 diabetic patients, 10 hypercholesterolaemic Type 2 diabetic patients, and 10 normocholesterolaemic non-diabetic subjects. LDL was isolated by sequential ultracentrifugation and susceptibility to oxidation assessed by measuring thiobarbituric reactive substances (TBARS) during a 4-h oxidation period. LDL glycosylation was measured by aminophenylborate gel chromatography. Results demonstrated an increased susceptibility to oxidation in LDL from both diabetic groups, the mean 3-h TBARS values being 35.2 +/- 2.1 and 36.4 +/- 2.6 nmol MDA/mg LDL protein for normocholesterolaemic and hypercholesterolaemic diabetic patients compared with 24.5 +/- 2.5 nmol MDA/mg LDL protein for control subjects. LDL glycosylation of 2.20% +/- 0.11% and 2.89% +/- 0.46% for normocholesterolaemic and hypercholesterolaemic diabetic LDL was significantly higher than that for the non-diabetic control subjects of 1.60% +/- 0.12% (P < 0.02). There was a significant positive correlation (P < 0.005) between LDL glycosylation and LDL oxidation. The esterified/free cholesterol ratio which correlated positively with oxidation (P < 0.01) was significantly higher in LDL from both diabetic groups compared with LDL from control subjects (P < 0.01). Thus the increased incidence of atherosclerosis in diabetes may be related to glycosylation of LDL through its increased susceptibility to oxidation.

Cholesterol↗
PubMed1993

Migration pathways, differentiation and survival of macroglial cells from a xenograft implanted into the thalamus of newborn mice.

Embryonic rabbit corpus callosum transplants were grafted into thalamus of newborn shiverer mice in order to compare the fates of oligodendroglial and astroglial cells derived from the transplants. Our model allowed the identification of the two populations of macroglial cells. The thalamus was chosen as site of implantation because of its situation at a crossroad of numerous neuronal fascicles. Previous studies, where the dorsal striatum was used as site of implantation, had shown that corpus callosum was one of the favorite routes of migration for both populations of macroglial cells. In the present study special attention was given to the comparison of the migration pathways and areas of settlement of implanted astroglia and oligodendroglia. The internal capsule, the medial lemniscus, the crus cerebri and the thalamic radiations were used by both populations of transplant derived macroglial cells for their migrations through the host parenchyma. They integrated into the host tissue on these routes or further away in areas such as the putamen, the mesencephalon or the colliculi. Signs of degeneration of the implanted astroglia were often observed after 1 month post-implantation.

Animals↗
PubMed1993

Superior mesenteric artery blood flow in man measured with intra-arterial Doppler catheters: effect of octreotide.

Changes in splanchnic blood flow are important in the pathogenesis of portal hypertension, but research in this area is hampered by the difficulty in measuring splanchnic arterial blood flow in man. We therefore investigated the use of intra-arterial Doppler catheters in measuring superior mesenteric artery blood flow in man and assessed the effect of intravenous octreotide on superior mesenteric artery blood flow in a placebo-controlled double-blind study. Nine experiments were performed in a flow model using vessels with internal diameters of 6.5, 4.5 and 3.0 mm, with flow rates ranging from 50 to 700 ml/min. In this model the catheters gave instantaneous, reproducible measurements of blood flow in vessels of 6.5 mm internal diameter with a mean error ranging from +5.3% to +36.4%, compared to electromagnetic flowmetry, but were less accurate in smaller vessels. When used in patients, the catheters provided stable, reproducible measurements of superior mesenteric blood flow, in 16 out of 20 patients studied. In a double-blind placebo-controlled study, including 12 subjects, superior mesenteric artery blood flow was significantly reduced in patients receiving octreotide. We suggest that measurement of splanchnic arterial blood flow using intra-arterial Doppler catheters may be a useful additional investigation in the assessment of splanchnic vascular pathophysiology and pharmacology in man.

Adenoma↗
PubMed1993

Change or business as usual? A challenge for health care leaders contemplating total quality management.

The authors describe Total Quality Management (TQM) as an organizational change strategy. Health care leaders who implement TQM only as a "program" may achieve limited success. Leaders who respond to incentives that motivate personal change, understand the dynamics of socioeconomic transformation and put people (especially employees) first can positively influence organizational culture leading to successful change. A leader self-examination is recommended to evaluate personal readiness for the change that TQM represents.

Canada↗
PubMed1993

Cyclosporine and cremaphor modulate von Willebrand factor release from cultured human endothelial cells.

Cyclosporine has been associated with microangiopathic hemolysis (MAHA) and other thrombotic complications of bone marrow and renal transplantation. MAHA is characterized by intravascular platelet aggregation, which, in some situations, is thought to be mediated by hyperactive high molecular weight von Willebrand factor (vWF). We have hypothesized that transplant-related MAHA may be caused by CsA-mediated release of von Willebrand factor from endothelial cells. This hypothesis was tested by studying vWF release from human umbilical vein endothelial cells primed with either CsA or cremophor EL. CsA and cremophor alone did not increase vWF release until toxic concentrations were reached (50-100 micrograms/ml). However, at therapeutic concentrations (0.1-5 micrograms/ml) vWF release by cells stimulated with thrombin, histamine, PMA, and the calcium ionophore A23187 was enhanced by both CsA and cremophor in a concentration-dependent manner. In single isolated endothelial cells, the thrombin-induced increase in cytosolic free calcium was enhanced by both CsA and cremophor. Preincubation for 24 hr with CsA but not cremophor suppressed vWF release after thrombin stimulation. These observations were mirrored by a concentration-dependent suppression of [3H]thymidine uptake by CsA. We conclude that CsA vehicle, cremophor, enhances stimulated vWF release in vitro, probably by processes dependent upon increased cytosolic free calcium. This suggests a possible mechanism for thrombotic transplant complications.

Calcium↗