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Biomedical subjects

M Hawkins

Publications and source records attributed to M Hawkins.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1988

Effects of RO 15-1788 on a running response rewarded on continuous or partial reinforcement schedules.

Two experiments were run in which rats were rewarded with food for running in a straight alley at one trial a day, followed by extinction of the running response. During acquisition of the response, reward was delivered either on a continuous reinforcement (CRF) or on a quasirandom 50% partial reinforcement (PRF) schedule. The groups given PRF were more resistant to extinction than those given CRF, the well-known partial reinforcement extinction effect. In Experiment 1 different groups of rats were injected during acquisition only with 1, 5 or 10 mg/kg of the benzodiazepine antagonist, RO 15-1788, or with placebo. In Experiment 2, 5 mg/kg RO 15-1788 or placebo were administered in a full cross-over design during acquisition, extinction or both. At the end of Experiment 2 only [3H]-flunitrazepam binding was measured in either the presence or absence of added gamma-aminobutyrate (GABA) in homogenates of hippocampi dissected from the animals that had received behavioural training. The drug affected running speeds during both acquisition and extinction in different ways depending upon the schedule of reinforcement (CRF or PRF) and also gave rise to enhanced GABA stimulation of [3H]-flunitrazepam binding. The results are discussed in relation to the hypothesis that the neurochemical pathways by which reinforcement schedules modify behaviour include a step influenced by benzodiazepine receptors.

Animals↗
PubMed1988

Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat.

The effects of the dopamine (DA) receptor agonists apomorphine, bromocriptine and pergolide were compared with those produced by a DA receptor antagonist, haloperidol, in rats implanted with electrodes for chronic sleep recordings. Apomorphine (0.025-2.0 mg/kg) and bromocriptine (0.25-6.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness (W) and increased slow wave sleep (SWS) and REM sleep (REMS), while large doses induced opposite effects. The effects of pergolide (0.05-0.5 mg/kg) on W and SWS were also biphasic, while REMS was suppressed over the range of dosages given. At 0.040 mg/kg, haloperidol increased W, while at 0.160 mg/kg it produced the opposite effect. Pretreatment with haloperidol (0.020 mg/kg) in a dose which preferentially acts at presynaptic sites reversed the effects of low doses of apomorphine, bromocriptine or pergolide on sleep and W. However, the compound differed substantially in its ability to block agonist effects. The increase in sleep after low doses of apomorphine, bromocriptine or pergolide could be related to activation of presynaptic D-2 receptors located on DA axons of mesolimbic and mesocortical systems. In addition, inhibition of norepinephrine and acetylcholine neurons having inhibitory D-2 receptors could contribute to the increase of sleep after small doses of the DA agonists.

Animals↗
PubMed1988

Desensitization of adenosine A2 receptors in the striatum of the rat following chronic treatment with diazepam.

Following prolonged treatment (7 days) with diazepam (10 mg/kg/day, using ALZET mini-osmotic pumps) in rats, the function of adenosine receptors was assessed in specific structures of the brain, using both agonist ligand binding and adenylate cyclase assays. Binding to A1 receptors was quantified using [3H]N6-[(R)-1-methyl-2-phenylethyl] adenosine, a selective ligand at A1 receptors. Differences in the binding of this ligand and that of [3H]5'-N-ethylcarboxamide adenosine, which binds to both A1 and A2 subtypes of receptors with similar affinities, were used to quantify A2 receptors. Treatment with diazepam failed to alter the binding of [3H]N6-[(R)-1-methyl-2-phenylethyl] adenosine in all areas of the brain studied. However, the binding of A2 receptors and A2 receptor-mediated stimulation of adenylate-cyclase were significantly attenuated in striatal membranes from diazepam-treated rats. Thus, the present study indicated that functional adenosine A2 receptors were desensitized after prolonged treatment with diazepam, since decreased agonist binding to A2 receptors paralleled an attenuation in the stimulation by adenosine of the activity of adenylate cyclase, an effect mediated by the A2 receptor. These results further indicate that the changes in adenosine A2 receptors correlated with significant short-lasting alterations in the sleep-wake cycle during the withdrawal of diazepam. The alterations in sleep-wakefulness did not correlate with the effect of diazepam on benzodiazepine receptors since no changes were observed in the binding of benzodiazepine receptors.

Adenylyl Cyclases↗
PubMed1988

Chronic administration of diazepam downregulates adenosine receptors in the rat brain.

Following chronic administration (10 or 20 days) of diazepam (5 mg/kg/day, subcutaneous pellets) or RO 15-1788 (5 mg/kg/day, intraperitoneally), adenosine and benzodiazepine receptors in different rat brain areas were assessed by radioligand binding studies using [3H]R-PIA for A1 receptors, [3H]NECA and [3H]R-PIA for A2 receptors and [3H]FNZ for benzodiazepine receptors. Chronic administration of diazepam for 10, but not for 20 days, decreased A2 receptors in the striatum by 46% (p less than 0.05) and A1 receptors in the hippocampus by 13% (p less than 0.05). Administration of diazepam for 10 days and 20 days failed to alter [3H]FNZ binding in all brain areas studied. However, 20 days of diazepam administration decreased the magnitude of GABA enhancement of [3H]FNZ binding in the cortex by 25% (p less than 0.05). In contrast, chronic administration of RO 15-1788 failed to alter [3H]R-PIA, [3H]NECA and [3H]FNZ binding in all brain areas. These results suggest that adenosine receptors may play a role in the CNS actions of benzodiazepines.

Animals↗
PubMed1988

Effects of chronic administration of caffeine on adenosine A1 and A2 receptors in rat brain.

Chronic administration of caffeine (75 mg/kg/day) to rats for 12 days increased [3H]R-PIA binding in the cerebral cortex and cerebellum and [3H]NECA binding to high affinity receptor sites in the striatum. The results indicate that both adenosine A1 and A2 receptor subtypes possess mechanisms of adaptation to chronic caffeine treatment. In addition, adenosine A1 receptor binding shows heterogenous neuroanatomical pattern indicating that the A1 response to caffeine treatment presents regional variation in the rat brain.

Adenosine↗
PubMed1987

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

1. Nitrogenase activity of a strain of Azotobacter chroococcum lacking the structural genes for conventional nitrogenase (nifHDK) was separated into two components: an Fe-containing protein and a vanadoprotein. 2. The larger protein was purified to homogeneity by the criterion of electrophoresis of 10% (w/v) acrylamide gels in the presence of SDS. Two types of subunit, of Mr 50,000 and 55,000, were present in equal amounts. 3. The protein had an Mr of 210,000 and contained 2 V atoms, 23 Fe atoms and 20 acid-labile sulphide groups per molecule. The Mo content was less than 0.06 g-atom/mol. All the common amino acids were present, with a predominance of acidic residues. Ultracentrifugal analysis gave a maximum sedimentation coefficient of 9.7 S and a symmetrical boundary at 5 mg of protein X ml-1; dissociation occurred at lower concentrations. The specific activities (nmol of product/min per mg of protein), when assayed under optimum conditions with the complementary Fe protein from this strain, were 1348 for H2 evolution, 350 for NH3 formation and 608 for acetylene reduction. Activity was O2-labile, with a t1/2 of 40 s in air. At low temperatures the dithionite-reduced protein showed e.p.r. signals at g = 5.6, 4.35, 3.77 and 1.93, consistent with an S = 3/2 ground state with an additional S = 1/2 centre giving rise to the feature at g = 1.93. The u.v. spectra of dithionite-reduced and thionine-oxidized protein were very similar. Oxidation resulted in a general increase in absorbance in the visible region. The shoulder at 380 nm in the spectrum of reduced protein was replaced with shoulders near 330 nm and 420 nm on oxidation.

Amino Acids↗