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Biomedical subjects

M Hawkins

Publications and source records attributed to M Hawkins.

At least 73 records · Page 4Linked to original sources
PubMed1995

Quantitation of hepatic glucose fluxes and pathways of hepatic glycogen synthesis in conscious mice.

Mice were studied with the euglycemic hyperinsulinemic and the hyperglycemic clamp techniques after a 6-h fast: 1) euglycemic (6.7 +/- 0.2 mM) hyperinsulinemia (approximately 800 microU/ml); 2) hyperglycemic (15.3 +/- 0.4 mM) hyperinsulinemia (approximately 800 microU/ml). All mice received an infusion of [3-3H]glucose and [U-14C]lactate. Basal hepatic glucose production (HGP) averaged approximately 170 mumol.kg-1.min-1 in both groups. During euglycemic and hyperglycemic hyperinsulinemia, HGP decreased by 53% (to 76.7 +/- 11.1 mumol.kg-1.min-1; P < 0.01) and 74% (to 43.3 +/- 7.2 mumol.kg-1.min-1; P < 0.01), respectively. Hyperglycemia increased glucose cycling (by 2.1-fold; P < 0.01) and the contribution of gluconeogenesis to HGP (88 vs. 43%; P < 0.01) while decreasing that of glycogenolysis (12 vs. 57%; P < 0.01). The percentage of neosynthetized hepatic glycogen formed via the direct pathway was markedly increased during hyperglycemia (53 +/- 2% vs. 23 +/- 3%; P < 0.01): These data indicate that the assessment of hepatic glucose fluxes can be accomplished in conscious unrestrained mice and that, in the presence of hyperinsulinemia, hyperglycemia causes 1) a further inhibition of HGP mainly via inhibition of glycogenolysis and increase in hepatic glucose cycling; and 2) about a fivefold stimulation in the direct pathway of hepatic glycogen formation.

Animals↗
PubMed1995

In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats.

To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (approximately 7 mM) insulin (approximately 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4 +/- 0.2 mM), diabetic (D; PG = 19.7 +/- 1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6 +/- 0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease Rd (360-420 min = 39.2 +/- 3.6 vs. 60-120 min = 42.2 +/- 3.7 mg/kg.min; P = NS). GlcN infusion raised plasma GlcN concentrations to approximately 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased Rd in CON (360-420 min = 30.4 +/- 1.3 vs. 60-120 min = 44.1 +/- 3.5 mg/kg.min; P < 0.01) and D + PHL (360-420 min = 29.4 +/- 2.5 vs. 60-120 min = 43.8 +/- 2.9 mg/kg.min; P < 0.01), but not in D (5-7 h = 21.5 +/- 0.8 vs. 0-2 h = 24.3 +/- 1.1 mg/kg.min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.

Animals↗
PubMed1995

Suicide in Oxford University students, 1976-1990.

BACKGROUND: The aim was to determine the extent, characteristics and timing of suicide in Oxford University students. METHOD: Students who died from suicide or undetermined cause between October 1976 and September 1990 were identified through University records and individual colleges. Information about each student was sought from coroners, college staff, general practitioners and hospital case notes. RESULTS: There were 21 suicides (16 men and 5 women) and one open verdict (female). The observed number of suicides (O) was greater than the number expected (E = 11.09) on the basis of mortality statistics for England and Wales (O/E = 1.89; 95% CI 1.17 to 2.90). When deaths due to undetermined cause were included, however, the difference between O and E (17.03) was much reduced (O/E = 1.29; 95% CI 0.81 to 1.95). There was no evidence of an association with the Finals examination but two-thirds of the students had been worried about academic achievement or their courses. Nearly half appeared to have had a psychiatric disorder (mostly depression). CONCLUSIONS: The much publicised apparent excess of Oxford University student suicides may be partly artefactual. Measures for preventing student suicides include careful induction upon arrival at university, means of alleviating academic stress and worries, and readily available and closely associated student counselling and psychiatric services.

Cause of Death↗
PubMed1994

Reduced customary activity in chronic heart failure: assessment with a new shoe-mounted pedometer.

Although many methods exist to assess the degree of incapacity of patients with chronic heart failure during normal daily activities, all have their limitations. In this study we describe a new shoe-mounted pedometer and compare it with body worn pedometers in normal volunteers and in patients with chronic heart failure. Ten young normal healthy volunteers participated in a comparison of the new shoe-mounted device with body born pedometers and counting a direct footfall. Seventeen patients with chronic heart failure and 10 aged-matched healthy elderly subjects participated in a comparison of both pedometers over 7 days. In the young volunteers the shoe-mounted pedometers were more accurate than the body-borne devices. With both pedometers the patients with chronic heart failure had a reduced level of activity compared with the normal volunteers over the 1 week period (P = 0.01). In both the patients and volunteers the shoe-mounted device recorded a higher score than the body borne pedometers (P < 0.01). The electronic shoe mounted pedometers are a more accurate way of assessing customary activity. In patients with chronic heart failure customary activity is substantially reduced compared with fit healthy elderly subjects.

Activities of Daily Living↗
PubMed1994

Patterns of neuroendocrine activation at rest and during exercise following acute myocardial infarction.

Previous studies of neurohumoral activation following myocardial infarction have concentrated on the within-hospital phase and have only made measurements at rest. The objectives of this study were to measure neuroendocrine activity in the early convalescent phase of myocardial infarction at rest and during symptom-limited maximal exercise and to study the effects of early drug therapy. We studied 75 patients, mean age 57 (range 37-74) without evidence of overt heart failure, following Q-wave myocardial infarction. Patients were studied a mean of 17 days following myocardial infarction and compared with 11 age-matched control subjects. Plasma noradrenaline, adrenaline, atrial natriuretic peptide and plasma renin activity were measured at rest, at submaximal and symptom-limited maximal treadmill exercise. At the time of study 40 patients were taking beta-blockers, 19 diuretics and 16 no treatment. Atrial natriuretic peptide levels were higher at rest (P = 0.0001) and at symptom-limited exercise (P = 0.002) in the patient group than in the control subjects. Although there were no significant resting differences between the patient subgroups, at symptom-limited exercise plasma atrial natriuretic peptide levels were significantly higher in the patients taking beta-blockers than in the other patient groups (P = 0.001). Plasma renin activity was no different between the patients and the control subjects at rest or during exercise. Those patients taking diuretics had higher values at rest (P = 0.001) and during exercise (P = 0.005) compared with the remaining patients. There were no significant differences in resting or maximal exercise levels of plasma noradrenaline and adrenaline between the patients and the control subjects (all P > 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1994

Exposure to biogenic silica fibers and respiratory health in Hawaii sugarcane workers.

We conducted a cross-sectional environmental and medical survey of 355 male sugarcane workers in Hawaii to determine whether exposure to biogenic silica fibers (BSF) affected their respiratory health. Exposures to BSF ranged from nondetectable to more than 0.700 BSF/mL and varied by job and department. Respiratory symptoms, chest radiograph findings, and pulmonary function were not associated with BSF exposures. Cigarette smoking was associated with respiratory symptoms and pulmonary obstruction. Fifteen workers had pleural thickening or pleural plaques and 3 of these workers were exposed to BSF for more than 10 years. BSF exposure does not appear to influence the respiratory health of sugarcane workers; however, further study is warranted.

Agriculture↗
PubMed1993

Human actin depolymerizing factor mediates a pH-sensitive destruction of actin filaments.

ADF (actin depolymerizing factor) is an M(r) 19,000 actin-binding protein present in many vertebrate tissues and particularly abundant in neuronal cells. We have cloned human ADF and here show it to be identical in sequence to porcine destrin. Human ADF expressed in Escherichia coli behaves like native ADF from porcine brain. It binds to G-actin at pH 8 with a 1:1 stoichiometry and Kd approximately 0.2 microM, thereby sequestering monomers and preventing polymerization. It does not cosediment with F-actin at this pH, but severs actin filaments in a calcium-insensitive manner. The severing activity is only about 0.1% efficient. By contrast, at pH values below 7, ADF binds to actin filaments in a highly cooperative manner and at a 1:1 ratio to filament subunits. When the pH is raised to 8.0, the decorated filaments are rapidly severed and depolymerized.

Actin Depolymerizing Factors↗
PubMed1993

Factors associated with suicide after parasuicide in young people.

OBJECTIVE: To determine factors associated with completed suicide in young parasuicide patients. DESIGN: Case-control study. SETTING: Regional poisoning treatment centre in a teaching general hospital. SUBJECTS: Patients who, between 1968 and 1985 when aged 15-24 years, were admitted to the regional poisoning treatment centre because of deliberate self poisoning or self injury. Cases (n = 62) consisted of those who by the end of 1985 had died locally from either suicide (n = 41) or possible suicide (n = 21). Controls (n = 124) were patients who were known not to have died locally during the study period. Two controls were selected for each case, matched by sex, age (within two years), and length of follow up. MAIN OUTCOME MEASURES: Possible predictors of completed suicide. RESULTS: Univariate analysis (conditional logistic regression) showed that risk of death due to suicide and possible suicide was associated with six factors: social class V (odds ratio 2.7, 95% confidence interval 1.1 to 6.7), unemployment (2.8, 1.4 to 5.8), previous inpatient psychiatric treatment (4.9, 2.2 to 10.9), substance misuse (3.3, 1.6 to 6.8), personality disorder (2.1, 1.03 to 4.4), and previous attempted suicide (2.3, 1.2 to 4.4). Multivariate analysis identified two factors as significantly contributing to the model that best discriminated between the cases and controls: substance misuse (alcohol or drugs, or both) (adjusted odds ratio 3.9) and previous inpatient psychiatric treatment (3.7). These factors seemed to be associated with suicide after attempted suicide in both the short term (less than 12 months) and the long term (one year or more) and were also identified when the analysis was restricted to subjects who definitely died by suicide and their controls. CONCLUSIONS: Suicide after parasuicide in young people is associated with substance misuse. This suggests that prevention of suicide in young people who attempt suicide might be improved by close liaison between general hospital services for patients who have attempted suicide and services for young substance misusers and by measures aimed at preventing substance misuse in young people.

Adolescent↗
PubMed1993

A prospective population-based study of microalbuminuria as a predictor of mortality in NIDDM.

OBJECTIVE: To assess prospectively the relationship between microalbuminuria and mortality in a geographically defined population of NIDDM patients and to determine the relative importance of microalbuminuria as a risk factor for mortality. RESEARCH DESIGN AND METHODS: A survey of known diabetes undertaken in 1982 identified a cohort of 249 NIDDM patients. Follow-up information was available for 246 patients who contributed 1498 person-yr exposure and were followed up for a mean period of 6.1 yr. The median age of the cohort at entry was 68 yr (range 28-89 yr), and the median duration of diabetes was 7 yr (range 1-41 yr). At baseline, a clinical examination was performed and a random daytime urine specimen was obtained for measurement of urinary albumin concentration. RESULTS: UAC results were available for 236 patients: 45 (19%) patients had a UAC > 15- < 40 mg/L; 36 (15%) had a UAC 40-200 mg/L; 10 (4%) had a UAC > 200 mg/L; and 145 (61%) had a normal UAC < or = 15 mg/L. During the follow-up period, 93 patients died. All-causes mortality, expressed as standardized mortality ratio (SMR = 149) and coronary heart disease mortality (CHD SMR = 166) were significantly increased. This excess mortality was significant in women (all-causes SMR = 194, CHD SMR = 234) but not in men (all-causes SMR = 118, CHD SMR = 128). On univariate analysis, systolic blood pressure was the only significant association with albumin concentration (P = 0.0002). An age-stratified log-rank test was conducted to determine the effect of potential explanatory variables on survival. Survival distributions were significantly different for known duration of diabetes (P = 0.045), intermittent claudication (P = 0.012), severity of retinopathy, lens opacity (P < 0.001) and UAC (P = 0.013) and diastolic blood pressure approached significance (P = 0.051). After adjusting for the effects of these potentially confounding variables identified by the log-rank analysis, significant predictors of early mortality on multivariate survival analysis were age, UAC of 40-200 mg/L (relative risk = 2.2, 95% confidence interval 1.3-3.7), more severe retinopathy (relative risk = 3.4, 95% confidence interval 1.9-6.0), and lens opacity (relative risk = 2.4, 95% confidence interval 1.6-3.8). CONCLUSIONS: The findings from this population-based cohort confirm the predictive power of microalbuminuria as a risk factor for mortality in NIDDM. In contrast to prospective studies of conventional cardiovascular risk factors in NIDDM, consistent evidence indicates that microalbuminuria is an independent predictor of excess mortality regardless of the collection procedure used.

Adolescent↗
PubMed1992

Food in chronic heart failure: improvement in central haemodynamics but deleterious effects on exercise tolerance.

Food has been known to have significant central haemodynamic effects for over half a century; it causes an increase in cardiac output and a fall in systemic vascular resistance. These changes are potentially desirable in patients with chronic heart failure but how they relate to exercise tolerance is unknown. This study was designed to examine the haemodynamic effects of food with changes in exercise capability in a group of patients with chronic heart failure. Fifteen patients with chronic heart failure and 10 normal control subjects were studied. They underwent treadmill exercise testing whilst fasting and after a standardized meal. Measurements were made of symptom-limited exercise tolerance, cardiac output, limb blood flow and respiratory gases. Superior mesenteric artery blood flow was measured fasting and postprandially only. Despite an increase in cardiac output, at rest and during exercise, which was not, however, as great as that in the control subjects, the symptom-limited exercise tolerance of the patients fell by 37 s postprandially (P < 0.05). Superior mesenteric artery blood flow increased postprandially by a mean of 133 ml.min-1 (P < 0.05) in the patients and 424 ml.min-1 (P < 0.01) in the control subjects. Calf blood flow increased in both groups during exercise, but there was no change in limb blood flow when comparisons were made between the fasting and postprandial states. The normal postprandial increase in oxygen consumption did not occur in the patients although their minute ventilation was higher than the control subjects (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Regional blood flow in chronic heart failure: the reason for the lack of correlation between patients' exercise tolerance and cardiac output?

BACKGROUND: In patients with chronic heart failure there is no relation between cardiac output and symptom limited exercise tolerance measured on a bicycle or treadmill. Furthermore, the increase in cardiac output in response to treatment may not be matched by a similar increase in exercise tolerance. More important in determining exercise capability is blood flow to skeletal muscle. This implies that the reduction in skeletal muscle blood flow is not directly proportional to the reduction in cardiac output and that there are regional differences in blood flow in patients with heart failure. METHODS: Cardiac output and regional blood flow measured in 30 patients with chronic heart failure were compared with values obtained from 10 healthy controls. Measurements were made at rest and in response to treadmill exercise and were all made non-invasively. RESULTS: Cardiac output was lower in the patients at rest and during exercise. Blood flow in the superior mesenteric and renal arteries was also lower in the patients and represented a different proportion of cardiac output than in the controls. In response to exercise the increase in blood flow to the calf and therefore to skeletal muscle, was reduced in the patients. In the patients there was no correlation between resting cardiac output and blood flow in the superior mesenteric artery, renal artery, or calf. CONCLUSIONS: Because blood flow to skeletal muscle and to the kidneys is likely to be important in determining patients' symptoms this factor may explain why central haemodynamic variables do not correlate with the exercise tolerance in patients with chronic heart failure.

Aged↗
PubMed1992

The integrated response of the cardiovascular system to food.

To obtain information about the integrated response of the cardiovascular system to food, cardiac output and regional blood flow (superior mesenteric artery, renal artery and calf blood flow) were measured in 14 normal young healthy subjects after an overnight fast and following a standard 800-kcal meal. Results were compared with 8 subjects who remained fasted throughout the study. Cardiac output increased from a mean (SEM) fasting value of 4.8 (0.3) l/min to a peak after 30 min of 6.1 (0.5) l/min (p < 0.001). Superior mesenteric blood flow increased from a fasting value of 463 (45) to a peak of 854 (110) ml/min also after 30 min (p < 0.001). These changes were accompanied by a significant fall in both systemic vascular resistance and superior mesenteric vascular resistance (p < 0.001). Only at the 15-min postprandial measurements was there a significant relationship between the increase in cardiac output and superior mesenteric artery blood flow (r = 0.62, p = 0.02). Calf blood flow increased and vascular resistance fell postprandially (p < 0.05), but there was little change in right renal artery blood flow. There was an insignificant fall in renal vascular resistance. Heart rate increased from a resting value of 65 (3) to a peak of 77 (4) beats/min after 15 and 30 min (p < 0.001), diastolic blood pressure fell postprandially with little change in systolic blood pressure. These results suggest that in healthy young subjects the increase in gut blood flow is met by an increase in cardiac output, with little evidence of redirection from other vascular beds. The early postprandial increase in superior mesenteric blood flow may account for the increase in cardiac output, although the magnitude of the change is much greater for cardiac output than superior mesenteric artery blood flow.

Adult↗
PubMed1991

Effects of continuous naloxone administration on ventral tegmental self-stimulation.

Continuous subcutaneous administration of naloxone (3 mg/kg/h), shifted ventral tegmental self-stimulation rate-frequency curves to the right, without suppressing behavioral performance. In addition this chronic blockade of opioid receptors altered mu binding parameters in the hippocampus and olfactory tubercle of naloxone-treated animals. These findings speak to the role opioid peptides paly in the mediation of brain stimulation reward.

Animals↗
PubMed1991

Dideoxyinosine in children with symptomatic human immunodeficiency virus infection.

BACKGROUND: 2',3'-Dideoxyinosine (ddl) is a dideoxynucleoside with potent activity in vitro against the human immunodeficiency virus (HIV). In initial clinical trials in adults, ddl showed evidence of antiretroviral activity with little hematologic toxicity. METHODS: We conducted a phase I-II study in 43 children with symptomatic (CDC class P-2) HIV infection. Of these children, 16 (median age, 10 years) had previously received zidovudine, and 27 (median age, 2.6 years) had not. ddl was administered orally in three divided doses totalling 60, 120, 180, 360, or 540 mg per square meter of body-surface area per day for 24 weeks. Eight of the 43 patients did not complete 24 weeks of ddl: 6 died, 1 was withdrawn because of progressive disease, and the other because of toxicity. RESULTS: After oral administration, ddl was rapidly absorbed, although its bioavailability varied greatly among patients. Pancreatitis developed in two children, one receiving ddl at each of the two highest doses. The median CD4 cell count in 38 patients with paired counts increased from 0.218 x 10(9) per liter (218 per cubic millimeter) at base line to 0.327 x 10(9) per liter (327 per cubic millimeter) after 20 to 24 weeks (P = 0.001). Those with CD4 cell counts above 0.1 x 10(9) per liter (100 per cubic millimeter) at base line were significantly more likely to improve in this respect. The median levels of p24 antigen (in 27 patients with detectable levels at entry) declined from 272 pg per milliliter at base line to 77 pg per milliliter at 20 to 24 weeks (P = 0.005). The plasma concentration of ddl correlated significantly with both the degree of decline in the p24 antigen and the degree of improvement in IQ score. Improvement in clinical and immunologic measures occurred in both the previously untreated patients and in those who had been treated with zidovudine. CONCLUSIONS: Dideoxyinosine was well tolerated and showed promising antiretroviral activity in HIV-infected children. The correlation between the clinical response and the plasma concentration of ddl indicates that bioavailability is an important consideration in the use of ddl to treat HIV infection and that individualized pharmacokinetic monitoring and dose adjustment may be important for optimal activity.

Administration, Oral↗
PubMed1991

The effect of soluflazine on adenosine receptors in the rat brain.

Soluflazine, a potent adenosine transport inhibitor, was intracerebroventricularly administered to rats via ALZET mini osmotic pumps (4nmole, 0.5 L/hr) for 14 days and the effect on adenosine receptors was determined in specific brain areas. Soluflazine decreased adenosine A1 radioligand binding in the hippocampus as measured by [3H]R-PIA, and lowered adenosine A2 binding sites in the striatum, as estimated by the "NECA minus R-PIA" assay. Previous work from our lab has shown the ability of diazepam and triazolam to decrease adenosine binding in the same brain areas. The data show that a specific adenosine transport inhibitor produces the same effect on adenosine receptors as benzodiazepines, and suggest a role for adenosine in the CNS effects of benzodiazepines.

Adenosine↗
PubMed1991

Radioligand binding to adenosine receptors and adenosine uptake sites in different brain regions of normal and narcoleptic dogs.

The present study compares the characteristics of radioligand binding to adenosine receptors and adenosine uptake sites in 100- and 50-day-old normal and narcoleptic dogs. Binding to A1 receptors was quantified using a selective A1 agonist ([3H]N6-[(R)-1-methyl-2-phenylethyl] adenosine, [3H]R-PIA) and an antagonist ([3H]dipropyl-8-cyclopentyl-xanthine, [3H]CPX). Differences in the binding of [3H]R-PIA and that of [3H]5'-ethylcarboxamide adenosine ([3H]NECA), which binds to both A1 and A2 receptors with similar affinities, were used to quantify A2 receptors. Nucleoside transport sites were labeled with [3H]nitrobenzylthioinosine ([3H]NBTI), a potent inhibitor of nucleoside transport systems. The present study offered no evidence that either adenosine A1 receptors and adenosine uptake sites in the frontal cortex or adenosine A2 receptors in the putamen were altered in narcoleptic dogs. However, we found that adenosine A1 receptors in the dog exist in different affinity states and that the affinity state in which the receptor is found depends on the brain region examined. A characterization of these low- and high-affinity sites was performed and results indicated that these sites cannot be explained by a single interaction of the A1 receptor with a single G-protein population.

Adenosine↗