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Biomedical subjects

M Hawkins

Publications and source records attributed to M Hawkins.

At least 19 recordsLinked to original sources
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↗
PubMed1991

Effect of drug and diet treatment of mild hypertension on diastolic blood pressure. The TAIM Research Group.

The Trial of Antihypertensive Interventions and Management is a multicenter randomized trial designed to examine the diastolic blood pressure response of various combinations of pharmacological and dietary interventions in the treatment of mild hypertension (diastolic blood pressure 90-100 mm Hg). Eight hundred and seventy-eight participants at 110-160% of ideal weight were randomly allocated to nine drug/diet treatment groups receiving either a placebo, chlorthalidone (25 mg), or atenolol (50 mg), combined with a usual, a weight loss, or a low sodium/high potassium diet. The primary outcome was diastolic blood pressure change from baseline to 6 months. Seven hundred and eighty-seven participants had follow-up data. The mean baseline diastolic blood pressure was 93.8 mm Hg; 55.9% of the participants were male, and the weight loss diet group lost an average of 4.7 kg. Multiple comparisons were accounted for in the analysis. A significantly greater lowering of diastolic blood pressure (12.4 mm Hg) was achieved in the atenolol group compared with either the low sodium/high potassium diet group (7.9 mm Hg, p = 0.001) or weight loss group (8.8 mm Hg, p = 0.006). Adding weight loss to chlorthalidone significantly enhanced blood pressure lowering (15.1 mm Hg) when compared with the diuretic alone (10.8 mm Hg, p = 0.002), but adding a low sodium/high potassium diet (12.2 mm Hg, p = 0.029) did not. In the short-term treatment of mild hypertension where diastolic blood pressure is the sole consideration, drugs outperform diet, and weight loss is beneficial, especially with diuretics.

Adrenergic beta-Antagonists↗
PubMed1990

Prevalence and prediction of osteopenia in chronic liver disease.

To obtain information on the prevalence and clinical and laboratory correlates of osteopenia in patients with chronic liver disease, we measured bone densities and 30 selected laboratory variables in 133 subjects (70 men, 63 women) with liver disease. Thirty-two had alcoholic liver disease, 18 had primary biliary cirrhosis, 16 had primary sclerosing cholangitis, 48 had other forms of cirrhosis (cryptogenic, posthepatic) and 19 had chronic hepatitis or fibrosis without cirrhosis. Bone densities of the lumbar spine and three sites of the proximal femur (neck, Ward's triangle, greater trochanter) were estimated by dual-photon absorptiometry. Bone densities at all sites were significantly correlated to one another (r = 0.4 to 0.9; 95% confidence intervals = 0.24-0.54 to 0.81-0.90; p less than 0.0001 for all). Compared with an age- and gender-matched reference group, patients with liver disease had highly significant decreases in bone densities (greater than 2 standard deviations below control values; p less than 0.0008 at all sites). Decreases were particularly marked (24% to 42%) at Ward's triangle, the site of the femoral neck particularly prone to fracture. The prevalence of decreased bone densities ranged from 10% to 56%, depending on the site studied and the nature of the liver disease. Among 30 laboratory variables studied, there were significant (p less than 0.05) correlations with bone densities at more than one site for urinary creatinine (r = 0.21, 0.25), urinary calcium (r = -0.18, -0.23), serum total alkaline phosphatase (r = -0.18, -0.27) and the liver-1 isozyme of serum alkaline phosphatase (r = -0.19, -0.26).(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Density↗
PubMed1990

Identification of a region in segment 1 of gelsolin critical for actin binding.

The actin severing and capping protein gelsolin contains three distinct actin binding sites. The smallest actin binding domain of approximately 15,000 Mr was originally obtained by limited proteolysis and it corresponds to the first of six repeating segments contained in the gelsolin sequence. We have expressed this domain (here termed segment 1 or N150 to define its amino acid length) in Escherichia coli, together with a series of smaller mutants truncated at either N- or C-terminal ends, in an attempt to localize residues critical of actin binding. Limited truncation of segment 1 by 11 residues at its N-terminal end has no observable effect on actin binding, but on removal of a further eight residues, actin binding is totally eliminated. Although this loss of actin binding may reflect ablation of critical residues, we cannot rule out the possibility that removal of these residues adversely affects the folding of the polypeptide chain during renaturation. Truncation at the C-terminus of segment 1 has a progressive effect on actin binding. Unlike intact segment 1, which shows no calcium sensitivity of actin binding within the resolution of our assays, a mutant with 19 residues deleted from its C-terminus shows unchanged affinity for actin in the presence of calcium, but approximately 100-fold weaker binding in its absence. Removal of an additional five residues from the C-terminus produces a mutant that binds actin only in calcium. Further limited truncation results in progressively weaker calcium dependent binding and all binding is eliminated when a total of 29 residues has been removed. Although none of the expressed proteins on their own binds calcium, 45Ca is trapped in the complexes, including the complex between actin and segment 1 itself. These results highlight a region close to the C-terminus of segment 1 that is essential for actin binding and demonstrate that calcium plays an important role in the high affinity actin binding by this domain of gelsolin.

Actins↗
PubMed1990

Dideoxycytidine alone and in an alternating schedule with zidovudine in children with symptomatic human immunodeficiency virus infection.

OBJECTIVE: To determine whether a short course of 2',3'-dideoxycytidine (ddC) could provide safe antiretroviral activity in children with symptomatic human immunodeficiency virus infection and whether it could be used with azidothymidine (AZT, zidovudine). The goal was to maintain uninterrupted antiretroviral therapy while sparing AZT-related myelosuppression and ddC-related neuropathy. METHODS: In a pilot study, we evaluated four dosage levels of ddC--0.015, 0.02, 0.03, and 0.04 mg/kg, given orally every 6 hours--in 15 children between 6 months and 13 years of age with Centers for Disease Control P2 (i.e., symptomatic) human immunodeficiency virus infection. Thirteen patients had not had any prior antiretroviral therapy; two patients had received and benefited from AZT, but dose-limiting neutropenia had developed. At each dosage level, ddC was given for 8 consecutive weeks and then stopped. After a 30-day rest, a schedule of ddC for 1 week was followed by 3 weeks of AZT therapy (180 mg/m2 every 6 hours); this alternating schedule was repeated for as long as tolerated. Age-appropriate psychometric testing was performed before the start of ddC therapy and after 8 weeks. RESULTS: During the 8 weeks of therapy with ddC alone, no neutropenia or anemia was observed; 6 of 9 patients had decreases in p24 antigen levels, and 8 of 15 had an increased CD4 cell count. At the 0.04 mg/kg level, a rash developed in three patients; mild mouth sores developed in 9 of 15 patients. On the alternating ddC/AZT schedule, no neuropathy was observed. CONCLUSIONS: 2',3'-Dideoxycytidine has antiretroviral activity in some children and appears to be safe for short intervals. Longer courses of ddC at lower dosage levels, and schedules integrating ddC into combination regimens, deserve to be explored.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Effects of prolonged administration of triazolam on adenosine A1 and A2 receptors in the brain of rats.

Continuous subcutaneous administration of triazolam, a benzodiazepine with short plasma half-life, for 10 days either decreased (31%, 2 mg/day) or increased (15%, 0.5 mg/day) radioligand binding to adenosine A2 receptors in the rat striatum. In a similar manner, we have shown previously that diazepam (5-10 mg/day), a benzodiazepine with a long plasma half-life attenuated radioligand binding to adenosine A2 receptors in the rat striatum by 45-25%.

Animals↗
PubMed1989

Pentobarbital attenuates the antinociceptive effect of intranigral morphine.

This study was conducted to characterize the temporal relationship between intranigral injection of morphine and the onset of antinociception. The principal findings are: 1) morphine produces antinociception on the hot plate test within three minutes after intranigral injection, 2) the tail flick reflex cannot be measured within the first 30 minutes following intranigral morphine due to motor effects, and 3) pentobarbital suppresses the antinociceptive effect of intranigral morphine on the tail flick test. These findings support the conclusion that the antinociceptive effects of intranigral morphine are mediate by the substantia nigra.

Animals↗
PubMed1989

The influence of fibronectin administration on the incidence of sepsis and septic mortality in severely injured patients. The Medical College of Georgia Fibronectin Research Group.

Eighty-five trauma patients between the ages of 18 and 55, with American College of Surgeon's (ACOS) trauma scores greater than or equal to 7 were entered into a double-blind, randomized, placebo-controlled study to assess the efficacy of prophylactic fibronectin (Fn) administration on clinical course, sepsis development, and septic mortality. Patients were randomized on admission to receive purified human virus-inactivated Fn or placebo control (human serum albumin, HSA). Fn or HSA was administered on a daily basis if and when the patient was Fn deficient (less than 75% normal). When a Fn deficiency was not evident, the patient received saline. Seventy one patients developed Fn deficiencies during their initial clinical course: 36 received Fn, 35 received HSA. Fourteen patients did not develop a Fn deficiency after trauma and thus received only saline. Analysis of admission data demonstrated no significant differences between the three groups with respect to extent of injury (injury severity score, ACOS trauma score) or physiologic assessments of organ function (serum creatinine, bilirubin, lactic acid). On day 1 after trauma, Fn levels were shown to correlate with other plasma proteins and cellular components (range of r values, 0.24 to 0.75; all p less than 0.05), but not with organ function parameters. Eighteen of 85 patients became septic as judged by clinical criteria. Ten of these patients had received Fn (10 of 36), five had received HSA (5 of 35), and three had received only saline (3 of 14) before the development of sepsis (differences not significant). When septic, nine of 17 patients developed Fn deficiencies. Six patients received Fn while septic, three received albumin, and eight received saline. Seven patients died: 5 of 6 Fn patients, 1 saline, and 1 HSA recipient. Our data suggest that exogenous Fn repletion in states of deficiency does not alter clinical course, the development of sepsis, or septic mortality.

Adolescent↗
PubMed1988

The vanadium nitrogenase of Azotobacter chroococcum. Purification and properties of the Fe protein.

1. Nitrogenase activity of a strain of Azotobacter chroococcum lacking the structural genes of Monitrogenase (nifHDK) was associated with a V + Fe-containing protein and an Fe-containing protein [Robson, Eady, Richardson, Miller, Hawkins & Postgate (1986) Nature (London) 322, 388-390; Eady, Robson, Richardson, Miller & Hawkins (1987) Biochem. J. 244, 197-207]. 2. The Fe protein was purified to homogeneity by the criterion of Coomassie Blue staining after electrophoresis in 10% or 17% (w/v) polyacrylamide gels in the presence of SDS. One type of subunit, of Mr 32,000 +/- 2000, was found. 3. The native protein had an Mr of 62,500 +/- 2500 and contained approximately 4 Fe atoms and 4 acid-labile sulphide groups per molecule. The amino acid composition was similar to those of other purified Fe proteins, and, characteristically, tryptophan was absent. The specific activities (nmol of protein/min per mg of protein) when assayed under optimum conditions with the VFe protein from this strain were 1211 for H2 evolution under Ar, 337 for NH3 from N2 formation and 349 for C2H2 reduction. Activity of the Fe protein was O2-labile with a t1/2 of 36 s in air. At low temperatures the dithionite-reduced protein exhibited e.p.r. signals consistent with the presence of both S = 1/2 and S = 3/2 spin states. These signals were similar to those given by other nitrogenase Fe proteins, as were the changes in their line shape that occurred in the presence of MgATP or MgADP. The absorbance spectra showed that an increase in absorption occurred in the visible range on reversible oxidation of the dithionite-reduced protein. The oxidized-minus-reduced epsilon 420 was 6000 M-1.cm-1.

Amino Acids↗