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Biomedical subjects

I MacGregor

Publications and source records attributed to I MacGregor.

At least 19 recordsLinked to original sources
PubMed2006

Prion protein in patients with renal failure.

We previously found elevated levels of prion protein (PrP(C)) in the blood plasma of 16 patients with renal failure. We studied a further 20 patients with renal failure, and all had a significantly higher PrP(C) concentration than healthy normal subjects (P < 0.0001). Renal dialysis did not remove plasma PrP(C) in these patients. Because dialysis patients receive heparin during dialysis, which could potentially bind to PrP(C), the concentration of PrP(C) was measured in patients receiving heparin for cardiopulmonary bypass and was found to be similar to normal controls. We also studied several other groups with chronic illnesses and found that patients with thrombotic thrombocytopenic purpura and sickle cell anaemia had normal plasma PrP(C) levels, but that those with beta-thalassaemia had slightly elevated levels of plasma PrP(C). This suggests that the observations in renal failure were not just part of a generalized response to chronic illness or acute phase reaction. The mechanism of elevated plasma PrP(C) levels in renal disease is unknown, but this shows that plasma PrP(C) is not a specific marker of neurological disease or Creutzfeldt-Jakob disease.

Adult↗
PubMed2001

Prion protein and developments in its detection.

The theoretical risk of transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusions has led to replacement of UK-derived plasma for fractionation by plasma sourced outwith the UK and the introduction of leucodepletion of donated blood and its components. Prion protein in an abnormal conformation (PrPsc) has been identified as inextricably linked with the infectivity of transmissible spongiform encephalopathies such as vCJD and in this review some of its properties relevant to its detection are considered. In particular its insolubility in nonionic detergents and its partial resistance to proteinase K digestion have provided methods for separating it from the normal abundant isoform PrPc prior to subsequent detection, usually by means of antibody probes. As yet no antibodies which discriminate between the abnormal and normal isoforms have been identified with the sole exception of one which is not suitable for generally used immunodetection systems. Most detection systems, such as immunohistochemistry or Western blotting, have been optimized for brain or lympho-reticular tissues. Much less information is available for assays applied to blood or plasma, although some recent publications provide indications of their feasibility. However, a number of obstacles remain to be overcome. These include the issues of assay validation, detection of extremely low levels of PrPsc in the presence of large excesses of PrPc, lack of available standardized reagents, assay specificity and practicality for large-scale screening use. Progress towards these goals is reviewed.

Animals↗
PubMed2001

The release of prion protein from platelets during storage of apheresis platelets.

BACKGROUND: Recent studies using a time-resolved fluoroimmunoassay method (dissociation-enhanced lanthanide fluoroimmunoassay) showed that platelets and plasma are the main reservoir of the normal isoform of cell-associated prion protein (PrPc) in human blood. The aims of the present study were to monitor PrPc levels in various fractions of apheresis platelets during storage by using the DELFIA method and to assess the association of this release with alpha-granule protein ss-thrombo-globulin and cytoplasmic LDH. STUDY DESIGN AND METHODS: Units of apheresis platelets (n = 6) were obtained from volunteer donors by the use of a cell separator and stored up to 10 days. Samples (7-9 mL) were aseptically collected from each unit on storage Days 1, 2, 3, 4, 5, 8, and 10. Platelet-poor plasma and apheresis platelets were prepared and the former split into two fractions, one centrifuged at 40,000 x g for 2 hours at 4 degrees C to remove microparticles. The spun microparticles, apheresis platelets and platelet samples, platelet-poor plasma, and high-spun plasma fractions were stored in a frozen state until they were tested. RESULTS: The results showed that the mean overall levels of PrPc throughout storage remained within 15 percent of Day 1 levels. In contrast, the mean cellular levels in platelets significantly decreased to 46 percent of Day 1 levels by Day 10 of storage (p<0.01), while the corresponding levels in plasma significantly rose as much as 329 percent (p<0.01). Moreover, although microparticle-bound PrPc was released during storage, it was increasingly superseded by soluble protein. PrPc and ss-thrombo-globulin release exhibited very similar patterns (p<0.01). In contrast, LDH showed a significant increase in high-spun plasma only toward the end of the storage period (p<0.01). CONCLUSION: These results indicate that PrPc is released from platelets during the storage of apheresis platelets and that this release is probably due mainly to platelet activation and alpha-granule release in the first few days of storage. Moreover, the released PrPc is increasingly composed of soluble proteins, as the storage period exceeds 5 days.

Blood Platelets↗
PubMed1999

Application of a time-resolved fluoroimmunoassay for the analysis of normal prion protein in human blood and its components.

BACKGROUND AND OBJECTIVES: To quantify the cellular isoform of prion protein (PrP(c)) in human blood using a new time-resolved dissociation-enhanced fluoroimmunoassay (DELFIA). MATERIALS AND METHODS: The DELFIA was optimised for human blood samples and applied to isolated cell and plasma fractions from blood donations. The physicochemical properties of PrP(c) were analysed. RESULTS: 26. 5% of blood PrP(c) was associated with the platelet fraction, 0.8% with polymorphonuclear leucocytes, 2.4% with mononuclear leucocytes, 1.8% with red cells and 68.5% with plasma (mean values from 4 processed donations). CONCLUSION: The majority of blood PrP(c) is found in the platelet and plasma compartments.

Antigens↗
PubMed1996

Neutrophil elastase: a determinant of endothelial damage and reperfusion injury after liver transplantation?

Reperfusion injury has been implicated in the development of primary graft dysfunction (PGD) after liver transplantation. Neutrophil migration and activation may be involved in the pathogenesis of this injury. We studied neutrophil activation and its role in the etiology of PGD by measuring neutrophil elastase by radioimmunoassay, in serial blood samples of 19 patients before, during, and for 24 hr after transplantation. In a subgroup of patients, we also measured soluble thrombomodulin at the same time points as a marker of endothelial damage. The pretransplant elastase level was significantly raised (40.13+/-4.84 ng/ml, mean+/-SEM) compared with levels of healthy controls (18.7+/-5.6 ng/ml, P<0.05). A marked increase in elastase activity followed reperfusion, with a peak at 2 hr (370+/-50.5 ng/ml, P<0.01). Thereafter, there was a decline, but elastase remained elevated at 24 hr (186+/-60.94 ng/ml). The mean increase in neutrophil elastase after reperfusion correlated significantly with markers of graft function (P<0.05) and with the mean rise in soluble thrombomodulin (P=0.042), which increased from a pretransplant level of 81.2+/-11.32 to 186+/-50.4 ng/ml, 6 hr after reperfusion (P<0.05). The results of this study indicate that marked neutrophil activation and endothelial cell damage occurs after graft reperfusion during orthotopic liver transplantation, and the degree of activation correlates with markers of graft function, which may suggest a role in the etiology of PGD.

Biomarkers↗
PubMed1995

In vivo models of thrombogenic potential: usefulness and limitations.

The thrombogenicity of prothrombin complex concentrates (PCCs) has been known as a risk factor since their first clinical use about 30 years ago. The development of in vivo models to define the thrombogenic components in PCCs was instrumental in providing a logical basis for selecting in vitro assays to screen for the distribution of such components during the manufacture of PCCs, and to minimize their appearance in the final product. Even so, these thrombogenic components are not completely removed, as shown in our canine nonstasis model of thrombogenicity: PCCs were still found to elicit a thrombogenic response, shown by increased fibrinopeptide A, fibrin(ogen) degradation products, activated partial thromboplastin time, and decreased fibrinogen and platelet counts when clinically relevant doses were used. The new generation of high-purity factor IX (HP-FIX) concentrates differs from PCCs because these products contain only negligible amounts of clotting factors other than factor IX, lower amounts of activated clotting factors, and, in products we have assayed, no coagulant-active phospholipids. When we infused a number of HP-FIX products in the canine nonstasis model, no thrombogenic response was observed at doses considerably greater than PCC doses that did elicit a response. Likewise, HP-FIX products were much less thrombogenic than PCCs when tested in small-animal stasis and nonstasis thrombogenicity models. Small-animal models are also useful for evaluating the role of factor IXa as a potential thrombogenic contaminant of concentrates and ensuring minimal amounts in the final product. The limitations associated with extrapolating in vivo model data will be shown to be minimal if ongoing clinical studies continue to demonstrate the low thrombogenic potential of HP-FIX concentrates in humans.

Animals↗
PubMed1995

Plasma elastase levels and the development of the adult respiratory distress syndrome.

Inflammatory cells, particularly neutrophil granulocytes, have been implicated in the pathogenesis of the adult respiratory distress syndrome (ARDS). In this study, we investigated whether a relationship exists between neutrophil elastase in the plasma of multiple-trauma patients on initial hospital presentation and the subsequent development of lung injury and ARDS. Sixty-one multiple-trauma patients were enrolled prospectively. Neutrophil elastase was measured by a specific radioimmunoassay, and analysis was performed by nonparametric statistical methods. A highly significantly elevated plasma elastase level was found in patients who progressed to ARDS (median 217 ng/ml, range 127 to 480) (n = 8) compared with those who did not (median 117 ng/ml, range 21.4 to 685) (n = 53) (p = 0.009). Significant correlation was found between initial elastase values and subsequent requirement for mechanical ventilation (p = 0.01), lowest arterial oxygen saturation/oxygen supplementation recorded (p = 0.003), and organ failure score (p = 0.006). This study shows that within minutes of the initiating trauma event, there is evidence of enhanced neutrophil degranulation as manifested by elevated levels of immunoreactive neutrophil elastase in the peripheral blood. The level of this enzyme correlates with the degree of subsequent lung injury and ARDS. These findings reinforce the importance of neutrophils and their secretory products in early ARDS disease pathogenesis.

Adolescent↗
PubMed1983

Heparin receptors on mouse macrophages.

This study deals with the nature of the attachment between the macrophage cell membrane and heparin molecules. Treatments intended to remove or internalise macrophage receptors (trypsinisation and stimulation of phagocytosis respectively) were shown to considerably modulate the attachment of heparin. An excess of heparin fractions ranging in mean molecular weight from 8100 to 25700 all inhibited attachment of 35S heparin as did a mixed isomer chondroitin sulphate preparation. Our study provides evidence for the presence of receptors for sulphated glycosamino-glycans on the mouse macrophage cell membrane.

Animals↗
PubMed1982

Inhibition of human factor Xa by various plasma protease inhibitors.

The inhibitory effects of the plasma protease inhibitors antithrombin III, alpha 2-macroglobulin and alpha 1-antitrypsin on the activity of human factor Xa have been studied using purified proteins. The rate of inhibition was determined by measuring the residual factor Xa activity at timed intervals utilizing the synthetic peptide susbtrate Bz-Ile-Glu(piperidyl)-Gly-Arg-pNA. Kinetic analysis with varying molar concentrations of inhibitors demonstrated that the inhibition of factor Xa by antithromin III, alpha 2-macroglobulin and alpha 1-antitrypsin followed second-order kinetics. Calculated values of the rate constants for the inhibition of factor Xa by antithrombin III, alpha 2-macroglobulin and alpha 1-antitrypsin were 5.8 . 10(4), 4.00 . 10(4) and 1.36 . 10(4) M -1 . min -1, respectively. The plasma concentrations of the inhibitors can be used to assess their potential relative effectiveness against factor Xa. In plasma this was found as alpha 1-antitrypsin greater than antithrombin III greater than alpha 2-macroglobulin in the ratio 4.64: 2.08: 1.0. Cephalin was shown to inhibit the rate of reaction between factor Xa and antithrombin III.

Antithrombin III↗
PubMed1977

Gastric emptying of liquid meals and pancreatic and biliary secretion after subtotal gastrectomy or truncal vagotomy and pyloroplasty in man.

Pancreatic and biliary secretion and gastric emptying rates of a liquid test meal (LTM) were determined in normal persons, in patients with subtotal gastrectomy with gastroduodenostomy (STG-BI) or with gastrojejunostomy (STG-BII), and in patients with truncal vagotomy and pyloroplasty (V&P). In all operated persons, rapid gastric emptying diluted intraluminal contents, with consequent abnormally low concentrations of trypsin and bile salts initially, a pattern that was not corrected by addition of intravenous hormones to the meal stimulus. Trypsin output in V&P's after the LTM was significantly depressed to 40% of normal, but was normal in the STG groups. The delay in reaching normal values for trypsin and bile salt concentrations, was more marked in STG-BII owing to sequestration of secretions in the afferent loop. The low luminal concentrations of digestive secretions for the first 60 to 80 min after a LTM are therefore attributable to rapid gastric emptying in all operated groups, and in V&P to a depressed pancreatic enzyme response also. In STG-BII, afferent loop sequestration exaggerates the delay in attainment of normal intraluminal concentrations. The combined disturbance in STG-BII produces greater abnormalities than seen in STG-BI.

Adult↗