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Biomedical subjects

J Dawes

Publications and source records attributed to J Dawes.

At least 19 recordsLinked to original sources
PubMed1992

Effects of heparin and endothelial cell growth supplement on haemostatic functions of vascular endothelium.

Heparin in combination with endothelial cell growth factor (ECGF) affects physiological responses and growth of human umbilical vein endothelial cells (HUVEC). We have examined the effect of heparin, crude ECGF (endothelial cell growth supplement [ECGS]), or both on the basal and thrombin challenged output of metabolites by HUVEC. The supernatant and/or cell lysate was assayed for released prostacyclin, von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor and thrombospondin. Heparin modified release of all these metabolites when in combination with ECGS, and in general these responses were the opposite of those generated by inflammatory mediators such as interleukin-1. It has been postulated that heparin acts by potentiating the effect of ECGF, but heparin inhibited thrombospondin release and enhanced that of von Willebrand factor in the absence of ECGS, while ECGS alone inhibited release of plasminogen activator inhibitor. Thus, under our experimental conditions it would appear that heparin and crude ECGF can affect HUVEC independently of one another.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Human vascular endothelial cells catabolise exogenous glycosaminoglycans by a novel route.

Heparin and other anticoagulant glycosaminoglycans were radiolabelled with 125I and their catabolism by human vascular endothelial cells in culture was studied. Heparin, heparan sulphate and pentosan polysulphate were associated with the cellular fraction and incorporated into the subendothelial matrix, but dermatan sulphate was not found in either fraction. High molecular weight, fully desulphated carbohydrate chains were major catabolic products of all those glycosaminoglycans which were taken up by the cells. Pentosan polysulphate was not degraded further, but the catabolism of heparan sulphate, and to a lesser extent that of heparin, also yielded small oligosaccharides. Thus the first step in catabolism of exogenous glycosaminoglycans by human vascular endothelial cells appears to be complete desulphation, which destroys their biological activity, followed by depolymerisation of the carbohydrate chain. This alternative to the sequential action of lysosomal exoenzymes is dependent upon binding to the cell; thus dermatan sulphate, which is not associated with the cellular fraction, is not catabolised.

Binding Sites↗
PubMed1992

Antithrombin III Budapest: a single amino acid substitution (429Pro to Leu) in a region highly conserved in the serpin family.

Antithrombin III (AT) is a major plasma serine protease inhibitor and a member of the serpin family of proteins. We have characterized the molecular and genetic basis of AT Budapest, an inherited variant of AT that is associated with thrombotic disease in affected family members. A single amino acid substitution, 429Pro to Leu, was identified, occurring in a region of the molecule that is highly conserved in members of the serpin family. Two forms of variant protein were present in approximately equal amounts in the plasma of the propositus, who is homozygous for the mutation. One form, which had apparently normal Mr, bound heparin strongly and retained some residual thrombin inhibitory activity. The other form had only weak heparin affinity and no antiproteinase activity, and had slightly decreased mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreducing conditions; this normalized in the presence of a reducing agent, suggesting it was caused by a change in conformation. Additional support for a difference in conformation of the two forms of variant was provided by the finding that the fraction that bound heparin-Sepharose was recognized by a monoclonal antibody raised against normal AT, whereas the weak-affinity fraction was not.

Amino Acid Sequence↗
PubMed1992

Plasma concentrations of endogenous heparinoids in portal hypertension.

Bleeding as a complication of liver disease can occur in the absence of recognised haemostatic defects. It is now possible to measure the concentration of endogenous heparinoid substances in the blood using a competitive binding assay. One such substance, heparan sulphate (normal range < 600 ng/ml) was assayed in the plasma of 49 patients admitted because of oesophageal varices. In 27 patients with recent upper gastrointestinal bleeding the median plasma heparan sulphate value was 1700 ng/ml (interquartile (IQ) range 900-3900) compared with 390 ng/ml (IQ range 256-800) in 22 patients with no recent bleed (p < 0.01). As heparan sulphate is metabolised by the same route as exogenous heparin, an attempt to establish a cause for the raised heparan concentrations was made by measuring the clearance of exogenous heparin in 10 portal hypertensive patients and 10 controls. The median half life of heparin in plasma in the portal hypertensive patients (25.5 minutes; IQ range 22-34) was significantly longer (p < 0.007) than the median half life in the controls (18.7 minutes; IQ range 17-21.5). Thus, there is evidence of raised concentrations of endogenous heparin like substances in portal hypertensive patients after gastrointestinal bleeding. These high concentrations may result from reduced hepatic clearance.

Esophageal and Gastric Varices↗
PubMed1992

Neutrophil count and activation in vascular disease.

An elevated peripheral leucocyte count is associated with an increased risk of myocardial infarction and progression of coronary artery disease. The aim of this study was to determine neutrophil count and activation, measured as an increase in plasma neutrophil elastase, in patients with stable ischaemic heart disease, insulin-dependent diabetes mellitus and essential hypertension compared with a comparable group of control subjects. Neutrophil count and neutrophil elastase were raised significantly for patients with ischaemic heart disease (p less than 0.005; p less than 0.002), diabetes mellitus (p less than 0.001; p less than 0.01) and hypertension (p less than 0.05; p less than 0.0001) respectively compared to the control subjects. Neutrophil elastase did not correlate with subject age or leucocyte count. This study confirms the association between leucocyte count and vascular disease, and is consistent with neutrophil activation contributing to the progression of vascular disease.

Adult↗
PubMed1991

The pharmacokinetics of dermatan sulphate MF701 in healthy human volunteers.

1. The pharmacokinetics of dermatan sulphate MF701 were studied in 12 healthy males after administration of single intravenous bolus (200 mg), intramuscular (100 and 300 mg) and oral (1 g) doses. The study was conducted according to a within-subject crossover design in two paired blocks. 2. Plasma drug concentrations were measured using a competitive binding assay and a range of biological activity assays, including a sensitive catalysed thrombin inhibition test. 3. Following intravenous administration, plasma concentrations of dermatan sulphate determined by competitive binding assay were described by a two-compartment open model with an initial t1/2, in of 0.6 h and a t1/2,z of 7.5 h. Biological activity assays were insufficiently sensitive to detect the second phase, and therefore yielded apparent monoexponential kinetics. 4. After intramuscular injection the apparent bioavailability of dermatan sulphate was 16-20%. Plasma drug concentrations increased in proportion to dose when measured by competitive binding assay. Low concentrations persisted for more than 24 h at the higher dose, and these may prove therapeutically relevant on chronic administration. 5. We confirm that dermatan sulphate is the only glycosaminoglycan known to generate significant plasma concentrations following oral administration. Oral bioavailability was estimated to be 7%.

Adolescent↗
PubMed1978

beta-thromboglobulin and deep vein thrombosis.

The measurement of plasma beta-thromboglobulin as a potential diagnostic test for venous thrombosis has been investigated in 16 normal volunteers, 24 patients presenting with deep vein thrombosis (DVT) or pulmonary embolism and 46 patients screened by 125I fibrinogen test (IFT) for post-operative DVT. The normal mean was 33 ng/ml (range 15-117 ng/ml). Of the 24 patients with clinical thrombotic disease 22 presented with DVT confirmed by phlebogram or IFT and 2 presented with embolism confirmed by lung scan. At the time of first presentation 12 out of 24 had betaTG values greater than 70 ng/ml. All except 3 of this group of 24 patients had values of greater than 70 ng/ml at some stage during a subsequent week of daily sampling. DVT was detected in 13 out of 46 screened post-operative patients. There was a rise om betaTG observed within 24 hr of the IFT becoming positive but the mean rise did not reach significance at the 5% level. An association between DVT and high betaTG values has been confirmed. However, its clinical value cannot yet be fully elucidated until factors, probably related to blood sampling and clearance, are further investigated.

Beta-Globulins↗
PubMed1977

Plasma beta-thromboglobulin in diabetes mellitus.

The plasma beta-thromboglobulin (betaTG) content was measured in 56 diabetic patients with known complications of this disease, including neuropathy, retinopathy, and ischemic skin lesions. Although two patients were found to have elevated levels beyond the normal range, there was no significant difference between the diabetic group as a whole and the group of 35 controls. The significance of these findings with regard to the proposed contribution of small-vessel platelet sequestration in the pathogenesis of late complications of diabetes mellitus is discussed.

Beta-Globulins↗
PubMed1976

Antitumor activity of Corynebacterium parvum extracts.

Extracts of Corynebacterium parvum produced by mild hydrolysis of the whole organisms had antitumor activity if given iv 1 day before iv administration of fibrosarcoma cells or if given ip or sc in admixture with these cells. A lipid component seemed responsible for these effects. Unlike whole bacteria, they had little immunotherapeutic activity if given 3 days after sc tumor implantation unless absorbed onto latex. However, organisms treated with acid did not have any immunotherapeutic effect in this system either. The extracts, therefore, did have some antitumor activity, but full activity may depend on the integrity of the whole bacterium.

Animals↗