PubMed Health⌕ Search

Biomedical subjects

J Stuart

Publications and source records attributed to J Stuart.

At least 73 records · Page 4Linked to original sources
PubMed1993

Serotonin and genetic differences in sensitivity and tolerance to ethanol hypothermia.

Mice have been selectively bred for genetic sensitivity (COLD) or insensitivity (HOT) to acute ethanol-induced hypothermia. COLD mice readily develop tolerance to the hypothermic effects of ethanol (EtOH) when it is chronically administered, while HOT mice do not. A number of studies have implicated serotonergic systems in both sensitivity and the development of tolerance to the hypothermic and ataxic effects of EtOH. In the experiments reported here, we administered the serotonin (5HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) to HOT and COLD mice before the acute and chronic administration of equipotent doses of EtOH. 5,7-DHT lesions significantly reduced (by about 65%) whole brain levels of 5HT in both selected lines. This treatment reduced sensitivity to acute EtOH hypothermia in COLD, but not in HOT mice, and blocked the development of tolerance only in COLD mice. Metabolites of 5HT, norepinephrine, and dopamine were generally increased in hypothalamic and brain stem tissue after acute EtOH injection, but HOT and COLD mice were not differentially susceptible to these effects. These results suggest that genes affecting 5HT systems may mediate some of the differences in response to the hypothermic effects of EtOH characterizing HOT and COLD mice.

5,7-Dihydroxytryptamine↗
PubMed1993

Effect of transdermal oestradiol on the haemostatic balance of menopausal women.

OBJECTIVE: To determine the effect of transdermal oestrogen replacement therapy on the haemostatic balance of menopausal women. DESIGN: Open, parallel group, prospective study. SETTING: Three hospital-based menopause clinics. SUBJECTS: Fifty-two postmenopausal women receiving transdermal hormone replacement therapy (Estrapak 50) for 6 months. Comparison group of 48 untreated postmenopausal women studied in parallel. MAIN OUTCOME MEASURES: Changes in platelet number, plasma concentrations of coagulation factors and their natural inhibitors, fibrinolytic activity, and rheological parameters. RESULTS: Estrapak 50 had no significant thrombophilic effect on any of the outcome measures. CONCLUSION: The haemostatic balance and thus the risk of thrombosis would not appear to be upset by this dose of transdermal oestrogen.

Administration, Cutaneous↗
PubMed1993

Effect of patient age on tests of the acute-phase response.

Tests of the acute-phase response are used to screen for occult disease in the elderly, but there is little consensus as to their diagnostic value because of uncertainty as to the effect of age on reference ranges. We have therefore measured, as a function of age, the blood concentration of acute-phase proteins (C-reactive protein, alpha 1-acid glycoprotein, fibrinogen, albumin, and globulin) in parallel with three screening tests of the acute-phase response (erythrocyte sedimentation rate, plasma viscosity, and zeta sedimentation ratio). The study included 164 healthy individuals (age range, 25 to 84 years) plus 91 elderly ill but ambulant patients (age range, 65 to 84 years) from a family practitioner screening clinic. Reference ranges for the erythrocyte sedimentation rate, plasma viscosity, and zeta sedimentation ratio rose with age, with the erythrocyte sedimentation rate showing a particularly wide reference range. Healthy individuals aged 75 to 84 years, compared with those aged 65 to 74 years, showed a trend to a lower reference range for all three screening tests that may have reflected survival of the fittest individuals to the higher decade. Precise reference ranges are therefore required in the elderly; when these were used, the three screening tests showed a significant difference between elderly well and ill individuals.

Acute-Phase Proteins↗
PubMed1993

Comparative study of the adhesion of sickle cells and malarial-parasitized red cells to cultured endothelium.

Increased adhesion of red cells to vascular endothelium has been implicated in the pathogenesis of falciparum malaria and sickle cell disease. We have carried out a comparative study of the adhesiveness of normal (AA), sickle trait (AS), and homozygous sickle (SS) red cells, with and without parasitization by Plasmodium falciparum, with an in vitro flow system. Adhesion of nonparasitized red cells to cultured human umbilical vein endothelial cells (either glutaraldehyde fixed or untreated) was strongly dependent on the wall shear stress. Many AA and SS cells adhered at low stress (0.02 Pa), but far fewer did so when the stress was increased to a physiologic level (0.1 Pa). Compared with AA cells, SS adhered in greater number (about threefold) and required greater stress (about two-fold) for their subsequent removal. In contrast, the efficiency of adhesion of AA cells parasitized by Plasmodium falciparum was essentially constant up to 0.1 Pa, where it was about 1000 times greater than the efficiency for nonparasitized cells. The stress required to remove parasitized cells was about 6 times that for controls. When parasites were grown in SS cells, fewer cells adhered than when parasites were grown in AA cells. However, the adhesion of malarial-parasitised AS cells was only slightly less than that of parasitized AA cells, so that modulation of adhesion is unlikely to underlie the protective effect of sickle gene in malaria. Adhesion of red cells to endothelium may promote blockage of microvessels, and the interaction of parasitized cells appears strong enough to directly cause ischemic complications in falciparum malaria.

Anemia, Sickle Cell↗
PubMed1992

Early treatment with parenteral penicillin in meningococcal disease.

OBJECTIVE: To measure the effect of parenteral antibiotics given before admission to hospital on mortality and on bacteriological investigations in meningococcal disease. DESIGN: Retrospective review of hospital notes and laboratory and public health medicine department records. SETTING: Three health districts in south west England. SUBJECTS: Patients with meningococcal disease in Gloucester district presenting between 1 January 1982 and 31 December 1991 (n = 190); patients with meningococcal disease in Plymouth (n = 118) and Bath (n = 73) districts presenting between 1 January 1988 and 31 December 1991 (total = 381). MAIN OUTCOME MEASURE: Number of deaths from meningococcal disease. RESULTS: Parenteral antibiotic given by general practitioners was associated with a substantial reduction in mortality (from 9% to 5%; relative risk 0.6, 95% confidence interval 0.2 to 1.5); patients with a rash were more likely to be given parenteral antibiotics, and mortality was further reduced (from 12% to 5%; 0.5, 0.2 to 1.4). In a district where such treatment was regularly encouraged its use increased from 5% to 40% of cases over 10 years (p = 0.00001). Treatment with parenteral antibiotics before admission made isolation of meningococci from blood and cerebrospinal fluid less likely but did not affect nasopharyngeal cultures. CONCLUSIONS: General practitioners should carry benzylpenicillin in their emergency bags at all times and should administer it promptly, preferably intravenously, whenever meningococcal disease is suspected, unless the patient has had an anaphylactic reaction to penicillin. Specimens for culture should include a nasopharyngeal swab.

Humans↗
PubMed1992

Photooxidation of skeletal muscle sarcoplasmic reticulum induces rapid calcium release.

The photooxidizing xanthene dye rose bengal is shown to induce rapid Ca2+ release from skeletal muscle sarcoplasmic reticulum (SR) vesicles. In the presence of light, nanomolar concentrations of rose bengal increase the Ca2+ permeability of the SR and stimulate the production of singlet oxygen (1O2). In the absence of light, no 1O2 production is measured. Under these conditions, higher concentrations of rose bengal (micromolar) are required to stimulate Ca2+ release. Furthermore, removal of oxygen from the release medium results in marked inhibition of the light-dependent reaction rate. Rose bengal-induced Ca2+ release is relatively insensitive to Mg2+. At nanomolar concentrations, rose bengal inhibits [3H]ryanodine binding to its receptor. beta,gamma-Methyleneadenosine 5'-triphosphate, a nonhydrolyzable analog of ATP, inhibits rose bengal-induced Ca2+ release and prevents rose bengal inhibition of [3H]ryanodine binding. Ethoxyformic anhydride, a histidine modifying reagent, at millimolar concentrations induces Ca2+ release from SR vesicles in a manner similar to that of rose bengal. The molecular mechanism underlying rose bengal modification of the Ca2+ release system of the SR appears to involve a modification of a histidyl residue associated with the Ca2+ release protein from SR. The light-dependent reaction appears to be mediated by singlet oxygen.

Adenosine Triphosphatases↗
PubMed1992

Rose bengal activates the Ca2+ release channel from skeletal muscle sarcoplasmic reticulum.

The photooxidizing xanthene dye rose bengal (10 nM to 1 microM) stimulates rapid Ca2+ release from skeletal muscle sarcoplasmic reticulum vesicles. Following fusion of sarcoplasmic reticulum (SR) vesicles to an artificial bilayer, reconstituted Ca2+ channel activity is stimulated by nanomolar concentrations of rose bengal in the presence of a broad-spectrum light source. Rose bengal does not appear to affect K+ channels present in the SR. Following reconstitution of the sulfhydryl-activated 106-kDa Ca2+ channel protein into a bilayer, rose bengal activates the isolated protein in a light-dependent manner. Ryanodine at a concentration of 10 nM is shown to lock the 106-kDa channel protein in a subconductance state which can be reversed by subsequent addition of 500 nM rose bengal. This apparent displacement of bound ryanodine by nanomolar concentrations of rose bengal is also directly observed upon measurement of [3H]ryanodine binding to JSR vesicles. These observations indicate that photooxidation of rose bengal causes a stimulation of the Ca2+ release protein from skeletal muscle sarcoplasmic reticulum by interacting with the ryanodine binding site. Furthermore, similar effects of rose bengal on isolated SR vesicles, on single channel measurements following fusion of SR vesicles, and following incorporation of the isolated 106-kDa protein strongly implicates the 106-kDa sulfhydryl-activated Ca2+ channel protein in the Ca2+ release process.

Animals↗
PubMed1992

Rheological analysis of the adhesive interactions of red blood cells parasitized by Plasmodium falciparum.

Adhesion of parasitized red blood cells (RBCs) to vascular endothelium is thought to be a key factor in the pathology of falciparum malaria. However, quantitative analyses of the intercellular forces and of the effects of flow on adhesion have been lacking. We have characterized cytoadhesion of RBCs parasitized by the strains ITO4 (which can bind to receptors ICAM-1 or CD36) and FCR3A2 (which can bind to CD36 only) using micropipette manipulation and flow chamber techniques. Target cells were unfixed or glutaraldehyde-fixed human umbilical vein endothelial cells (HUVEC, bearing ICAM-1 only) or human amelanotic melanoma cells (C32, bearing CD36 and ICAM-1). In the static, micropipette assay, 60% to 70% of parasitized cells would adhere when tested at up to three successive sites. The percentage of cells adhering and the force required for their detachment (approximately 10(-10) N) were similar for each combination of parasite strain and adhesion target (ITO4/HUVEC, ITO4/C32, FCR3A2/C32). In the flow chamber, efficiency of initial adhesion of parasitized cells was essentially constant (at about 1%) up to a stress of 0.1 Pa, and then decreased rapidly with increasing stress. Either receptor (ICAM-1 or CD36) could immobilize flowing cells at a physiologic flow stress (0.1 Pa), but the numbers of cells adhering varied for the different combinations (ITO4/C32 greater than ITO4/HUVEC greater than FCR3A2/C32). When flow was increased in steps, adhered cells were gradually washed off but many could withstand stresses at which they would not initially adhere. The force for detachment estimated in this way was similar to the pipette value, and again, was similar for the different combinations of strains and targets. Adhesion from flow depends on the affinity between surfaces being above a critical level, and once adhesion is established, the fracture energy determines resistance to disruption of adhesion. The results show that the fracture energy is greater than the affinity (ie, that adhesion becomes stabilized after it is initially established) and that the ratio of affinity to fracture energy is different for different receptor/ligand pairs, with ICAM-1 appearing to be the more efficient immobilizing receptor. Also, static and flow-based assays of adhesion clearly differ; the affinity is less critical in the static situation, so that most parasitized cells were capable of adhering in a static assay, but fewer did so under flow. Adhesiveness varied markedly from cell to cell, both for targets and parasitized cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Nitrendipine is a potent inhibitor of the Ca(2+)-activated K+ channel of human erythrocytes.

Nitrendipine, a classical blocker of L-type Ca2+ channels, is shown to be a potent inhibitor of the Ca(2+)-activated K+ channel of human erythrocytes. In erythrocytes suspended in a solution with physiological Na+ and K+ concentrations and in which the channel was activated using the Ca2+ ionophore ionomycin, nitrendipine inhibited K+(86Rb+) influx with an I50 of around 130 nM. Similar results were obtained for K+(86Rb+) efflux, and for K+(86Rb+) influx into cells suspended in a high-K+ medium.

Calcium↗
PubMed1992

Rheological changes in the prodromal and established phases of sickle cell vaso-occlusive crisis.

A rheological study has been made in 20 patients with sickle cell anaemia in the steady state and in the prodromal and established phases of 12 vaso-occlusive crises. Rheology of sickle cells was studied by discontinuous density gradient fractionation and by filtration through pores of 5 microns diameter. The prodromal phase of crisis (day 1), when compared with mean steady state values, was associated with the development of a sub-population of poorly deformable dense cells. This sub-population appeared 1 or more days before the acute-phase rise in C-reactive protein, orosomucoid, fibrinogen, plasma viscosity and leucocytes, and before the rise in serum lactate dehydrogenase. As crisis evolved, the sub-population decreased to steady-state values, or below, by days 6-7. Identification of the prodromal phase of sickle cell crisis has allowed the detection of rheological changes of potential aetiological significance.

Acute-Phase Reaction↗
PubMed1992

Substituted benzaldehydes (12C79 and 589C80) that stabilize oxyhaemoglobin also protect sickle cells against calcium-mediated dehydration.

Reversibly sickled cells from patients with homozygous sickle-cell disease were prepared by Percoll-Isopaque density gradient separation and subjected to 15 h of cyclical deoxygenation-reoxygenation in the presence of Ca. After 15 h the sickle cells became dehydrated, losing volume secondary to K efflux via the Ca-activated (Gardos) channel, and showed impaired filterability through 5 microns diameter pores. The substituted benzaldehydes 12C79 and 589C80, which stabilize the oxy-conformation of sickle haemoglobin, showed an additional protective effect at pharmacological concentration by maintaining the K concentration, mean cell volume, and deformability of sickle cells. Drugs that increase the oxygen affinity of sickle haemoglobin may be more effective than specific inhibitors of Ca entry or K efflux in preserving the cation homeostasis and deformability of sickle cells during sickling in vivo.

Anemia, Sickle Cell↗
PubMed1992

Mode of action and comparative efficacy of pharmacological agents that inhibit calcium-dependent dehydration of sickle cells.

1. Selected Ca-channel antagonists were tested at 20 microM as inhibitors of Ca(2+)-uptake in human sickle red cells. Nitrendipine, fendiline, and bepridil (and its stereoisomers), were found to be as effective as methoxyverapamil (D-600) in inhibiting a fraction (25%) of Ca(2+)-uptake. In contrast cetiedil and Org 30701 were ineffective. 2. The drugs were subsequently tested as inhibitors of Ca(2+)-induced K+ efflux (Gardos) from sickle cells. They all showed inhibitory activity, with the order of efficacy nitrendipine greater than fendiline greater than bepridil greater than cetiedil greater than Org 30701. 3. With a 15 h programme of deoxygenation/reoxygenation cycles in a gas exchanger, it was shown that the inhibitors protected against cellular dehydration and loss of filterability in the order nitrendipine greater than fendiline greater than bepridil greater than cetiedil greater than Org 30701. However, significant stomatocytosis occurred at high concentrations of cetiedil, and bepridil (including its stereoisomers and analogues) impairing cell deformability. 4. It is concluded that Ca-antagonists may partially block both Ca(2+)-uptake and Ca(2+)-induced K+ efflux. The latter pathway is significant in contributing to sickle cell dehydration and nitrendipine is the most effective inhibitor of this route.

Anemia, Sickle Cell↗
PubMed1992

Subclinical ischaemic episodes during the steady state of sickle cell anaemia.

AIMS: To determine the clinical, haematological, biochemical and rheological changes that occur in the asymptomatic steady state of sickle cell anaemia. METHODS: Patient self-assessment visual analogue scores (for wellbeing and tiredness), the blood concentration of acute phase proteins (C-reactive protein, orosomucoid, and fibrinogen), and blood rheology (percentage of dense cells and the number of sickled cells that occluded pores 5 microns in diameter) were studied longitudinally on 10 occasions in each of 20 outpatients with sickle cell anaemia. RESULTS: Patients in the steady state showed fluctuation in visual analogue scores, in concentration of acute phase proteins, and in rheological parameters consistent with minor episodes of tissue injury. Significantly more variation in acute phase proteins occurred in the steady state of 14 of the 20 patients who developed one or more vaso-occlusive crises during the 16 month study period. Rheological fluctuation in the steady state simulated rheological change during crisis, namely a transient rise and then fall in the number of dense and poorly filterable cells. CONCLUSIONS: The term "steady state" is a misnomer, being characterised by biochemical and rheological fluctuation consistent with minor episodes of microvascular occlusion that are insufficient to cause the overt tissue infarction of painful crisis.

Acute-Phase Proteins↗
PubMed1991

KCl cotransport in HbAA and HbSS red cells: activation by intracellular acidity and disappearance during maturation.

Low intracellular pH was shown to be a potent activator of the KCl cotransport system in HbSS red cells, and in reticulocyte-rich fractions of HbAA red cells. Rheological experiments indicated that cell dehydration via the KCl cotransporter in response to low pH decreased the filterability of HbSS red cells. In vitro maturation experiments showed that the KCl cotransport system was rendered cryptic rapidly, in contrast to choline transport, and serine transport via system ASC, which disappeared much more slowly.

Anemia, Sickle Cell↗
PubMed1991

Assessment of Diesse Ves-matic automated system for measuring erythrocyte sedimentation rate.

Measurement of the erythrocyte sedimentation rate (ESR) using a closed tube system reduces the biohazard risk to laboratory staff. The Diesse Ves-matic system offers manual or vacuum collection of blood into plastic tubes, automated mixing of the sample, and automated reading of the end point after 20 minutes of sedimentation. This system was compared with the 1977 Westergren ESR method of the International Council for Standardization in Haematology (ICSH) and with the 1988 ICSH undiluted ESR method. Manually collected Ves-matic samples showed good agreement with ICSH values, although there was a tendency to false low results at low ESR values which may represent dilution of plasma protein with excess citrate. Vacuum collected Ves-matic samples also showed good agreement with ICSH values, although there was a tendency to false high results which may reflect a change in the blood: citrate ratio caused by loss of anticoagulant diluent or vacuum from plastic tubes during storage. The Diesse Ves-matic system incorporates several improvements over previous technology and offers a safer, quicker, and more standardised ESR.

Acute-Phase Reaction↗
PubMed1991

Evaluation of a 200 mm long vacuum aspiration tube for measurement of erythrocyte sedimentation rate.

The ESrT-system 200 comprises a 215 mm long vacuum aspiration venepuncture tube which contains anticoagulant diluent for the measurement of the erythrocyte sedimentation rate (ESR) without direct handling of the blood sample. This combines the advantage of a tube of "Westergren" length with a reduction in biohazard risk. Blood from 160 patients (ESR range 2-135 mm/first hour) was tested in parallel with the selected Westergren ESR method of the International Committee for Standardization in Haematology (ICSH) and a close correlation (r = 0.967) between the two methods was obtained. A second Westergren ESR, using anticoagulated but undiluted blood, was measured on 58 specimens to give an ICSH "expected" ESR. The ESrT-system 200 result was within 12 mm/first hour of the "expected" result for 91% of the specimens. This new ESR system is simple to use, does not require mathematical correction of the ESR reading for tube length, and gives results that are comparable with those obtained with the ICSH Westergren method.

Blood Sedimentation↗