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Biomedical subjects

S Machin

Publications and source records attributed to S Machin.

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↗
PubMed2005

The expression of prion protein (PrP(C)) in the megakaryocyte lineage.

BACKGROUND: Cellular prion protein (PrP(C)) is a naturally occurring protein in normal individuals which adopts an abnormal conformation, termed scrapie prion protein (PrP(Sc)) that is associated with disease. There is great concern that clinically asymptomatic variant Creutzfeldt-Jacob disease (vCJD) may transmit PrP(Sc) in blood transfusion products. PrP(C) is widely expressed and has been found in human blood. The majority of cellular borne PrP(C) is associated with platelets (84%). Although PrP(C) mRNA has been demonstrated in platelets, the quantity is unknown and may not reflect the total PrP(C) present. OBJECTIVE: To investigate the expression of PrP(C) in the megakaryocyte lineage. METHODS: The expression of PrP(C) was studied in CD34+ cells, cultured megakaryocytes and platelets using electron microscopy, flow cytometry, semi-quantitative RT-PCR and immunofluorescence confocal microscopy. RESULTS AND CONCLUSIONS: The expression of PrP(C) appeared to increase with differentiation and polyploidization in the megakaryocyte lineage. PrP(C) was located within platelet alpha-granules and its source is likely to be from megakaryocyte precursors. If PrP(Sc) has a similar distribution, these results have implications for the selection of blood donors and preparation of cell-depleted blood products.

Antigens, CD34↗
PubMed2004

Clinical epidemiology of childhood cancer in Central America and Caribbean countries.

BACKGROUND: Countries with scarce resources have the right to appropriate essential health care but very few reports discuss how this can be achieved. We assessed the survival of a large cohort of pediatric oncological patients to provide hard data on which to base realistic evaluation and planning schemes. PATIENTS AND METHODS: This multicenter retrospective survey covered consecutively diagnosed and treated patients admitted to eight national level hospitals in seven countries in Central America and the Caribbean. The research protocol was discussed extensively, so the data to be collected and the criteria for their evaluation were clearly pre-defined. We analysed 2214 patients diagnosed between 1996 and 1999 with various cancers, classified as hemato-oncological disorders (70%) and solid tumors (30%). RESULTS: Three-year overall survival was 48.4% [standard error (SE) 1.3]. Detailed analysis of acute lymphoblastic leukemia highlighted the wide intercountry variability: 3-year survival was 62.2% (SE 5.3) in Cuba, 74.2% (SE 3.3) in Costa Rica, 61.7% (SE 4.9) in Nicaragua, and lower in the other four countries. CONCLUSIONS: The yield of diagnostic-therapeutic protocols depends largely on the context of care in which they are applied. This paper documents the importance of including epidemiological research in interventions for cooperation in complex health areas such as pediatric oncology.

Caribbean Region↗
PubMed2002

The PFA-100: a potential rapid screening tool for the assessment of platelet dysfunction.

The PFA-100 is a device that simulates high shear dependent platelet function in vitro and thus is particularly useful for screening for von Willebrand's disease (VWD). The aim of this study was to assess the overall potential of the PFA-100 as a primary clinical screening tool using the wide spectrum of clinical samples assessed for platelet function within our institution. The PFA-100 test was performed using both collagen/ADP (CADP) and collagen/epinephrine (CEPI) cartridges on samples from 337 patients with a wide variety of haemostatic defects. One hundred and eighty-two patients were defined as having normal platelet function based on classical laboratory tests and von Willebrand factor levels. The overall clinical sensitivity of the PFA-100 for platelet abnormalities (including VWD) was 81% for CADP and 86% for CEPI. The overall specificity was found to be 82% for CADP and 80% for CEPI. When utilizing both cartridges in combination (with both results either higher or lower than the upper cutoff of the normal ranges), the overall false positive and false negative rates were 12% and 6%, respectively. The PFA-100 proved to be sensitive in detecting classical defects by giving prolonged closure times in samples from patients with major platelet function defects (e.g. von Willebrand's disease, Glanzmann's thrombasthenia and Bernard Soulier syndrome). However, there were a small number of false negative results (6%) obtained with various milder platelet defects (e.g. Hermansky Pudlak syndrome, storage pool and release defects, type I VWD and macrothrombocytopenia). The PFA-100 test provides a useful rapid screening tool and should increase the efficiency and reduce the cost of the routine diagnosis of platelet dysfunction.

Adenosine Diphosphate↗
PubMed2002

Fluctuations in levels of antiphospholipid antibodies and increased coagulation activation markers in normal and heparin-treated antiphospholipid syndrome pregnancies.

Antiphospholipid antibodies (aPL) are associated with an increased risk of thrombosis and recurrent miscarriage. We assessed levels of coagulation activation markers and aPL during normal pregnancy and in women with the antiphospholipid syndrome (aPS). Fluctuations in aPL levels were observed in all patients with aPS. No particular pattern of antibody positivity, or fluctuation in aPL level, was associated with poor pregnancy outcome. A significant increase was observed in levels of factor Xlla (FXIIa; P < 0.001), factor VIIa (FVIIa, P < 0.001), thrombin antithrombin complexes (TAT; P < 0.001), prothrombin fragment F1.2 (F1.2; P < 0.001) and D-dimer (DD; P < 0.05) during normal pregnancy. Factor VIIa, TAT, F1.2 and DD increased significantly before 20 weeks gestation, while a statistically significant increase in FXIIa levels was first detected between weeks 20 and 30 of gestation. In pregnant women with aPS, increases in FXIIa were similar to those in normal pregnancy, but increased FVIIa levels were not observed until after 30 weeks gestation. Similar to normal pregnancy, increased levels of TAT and F1.2 were detected in aPS pregnancies before 20 weeks gestation, but increased DD were not observed until after week 20. Surprisingly, women with aPS receiving low molecular weight heparin prophylaxis had significantly higher (P = 0.02) levels of TAT (median 8.6; interquartile range (IQR) 6.5-20.8) between weeks 20 and 30 of gestation compared to the normal pregnant population (median 5.9; IQR 4.7-7.9), thus indicating increased thrombin generation in women with aPS in mid-pregnancy.

Antibodies, Antiphospholipid↗
PubMed2001

Comparison of glycocalicin, thrombopoietin and reticulated platelet measurement as markers of platelet turnover in HIV+ samples.

It is important to distinguish between decreased platelet/megakaryocyte production or increased peripheral platelet destruction as causes of thrombocytopenia. The measurement of reticulated platelets, plasma glycocalicin and thrombopoietin (TPO) levels are potentially of use as discriminators. Thrombocytopenia occurs in many HIV+ patients, and plasma glycocalicin has previously been shown to be elevated in this patient group. Reticulated platelets, glycocalicin and TPO were measured in samples from 56 HIV+ subjects and 20 healthy normal controls. The glycocalicin index (GCI--the glycocalicin levels adjusted for the platelet count) measured in HIV+ subjects was found to be significantly elevated when compared to normal controls (mean GCI 1.5 and 1.27, p = 0.04), while the percentage of reticulated platelets and TPO levels were not. Thrombocytopenic HIV+ subjects had significantly elevated mean GCI (2.8 and 1.4, p < 0.0001), TPO (85.2 and 27.2 pg/ml, p = 0.002), percentage of reticulated platelets (15.3 and 10.8%, p = 0.01), and significantly reduced absolute numbers of reticulated platelets (16.2 and 24.5 x 10(9)/l, p = 0.0004) when compared to non-thrombocytopenic HIV+ subjects. GCI and percentage of reticulated platelets exhibited a significant positive correlation (r = 0.4, p = 0.002) in HIV+ subjects. The reticulated platelet, TPO and GCI data suggests that thrombocytopenic HIV+ subjects have normal platelet production, and increased peripheral platelet destruction.

Adult↗
PubMed2001

An interlaboratory study of a candidate reference method for platelet counting.

A multinational interlaboratory task force explored the important variables of platelet reference counting and developed a candidate flow cytometric reference method based on the RBC/platelet ratio. A multicenter comparison was performed to determine whether the method met the necessary criteria and was precise enough to be recommended as a new reference method. Each laboratory analyzed serial dilutions of normal specimens, stabilized material, and at least 60 patient specimens with a range of platelet counts from 1 to 400 x 10(3)/microL (1-400 x 10(9)/L). Pooled analysis of the serial dilutions showed that RBC-platelet and RBC-RBC coincidence events became negligible at sufficiently high dilutions (i.e., > 1:1,000). All laboratories demonstrated excellent intra-assay and acceptable interlaboratory precision. Two antibodies (CD61 and CD41) were used for identifying platelets and individually gave acceptable results, but in a minority of samples, staining differences were observed. The optimum method thus uses a double-labeling procedure with a final dilution factor of 1:1,000. The study demonstrated that this method meets the criteria for a reference platelet count.

Anticoagulants↗
PubMed1998

Endothelial dysfunction in critically ill patients: the effect of haemofiltration.

OBJECTIVES: To examine the effect of a single episode of continuous venovenous haemofiltration (CVVH) on indicators of endothelial injury and the protein C/S system in critically ill patients. DESIGN: Observational study. SETTING: University teaching hospital intensive care unit. PATIENTS: 12 critically ill patients with acute renal failure receiving their first episode of CVVH. INTERVENTIONS: Blood samples were collected prior to starting CVVH and at 15 min and 1, 3-4, 8-12, and 24 h, and at 24-h intervals thereafter until the filter clotted. MEASUREMENTS AND RESULTS: Soluble tissue factor, soluble thrombomodulin, E-selectin and endothelin-1 were measured as indicators of endothelial injury. Changes in the protein C/S system were assessed by measurement of protein C (PC) and both free and total protein S (PS). Levels of PC and both free and total PS were subnormal in 6 and 11 patients, respectively, prior to CVVH, but there were no further changes during CVVH. Levels of tissue factor, thrombomodulin, E-selectin, and endothelin-1 were raised prior to haemofiltration in 9, 10, 9 and 9 patients, respectively. There were further increases during CVVH in at least one, but not all, of the markers of endothelial injury in most patients. There was no consistency between the changes in different markers of endothelial injury during haemofiltration in individual patients. CONCLUSIONS: The PC/PS system and endothelial integrity is compromised in critically ill patients prior to haemofiltration, but a single episode of CVVH has little effect on the PC/PS system. The increase in markers of endothelial dysfunction seen during CVVH is more likely to be related to the underlying condition of the patient rather than any specific consequence arising from the technique itself.

Acute Kidney Injury↗
PubMed1998

Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion.

Vascular occlusion has a central role in the pathophysiology of sickle cell disease (SCD) and, although there is little evidence that thrombosis alone is responsible, patients with sickle cell disease are known to have an ill-defined but increased thrombotic risk. The most serious complication of this in childhood is stroke which occurs in 7-10% of children and a further 14% have asymptomatic cerebrovascular disease (CVD) on imaging. We have performed a comprehensive profile of coagulation inhibitors and markers of thrombin generation in 96 children (83 nontransfused [NTx] and 13 transfused [Tx]) with steady-state SCD and 18 healthy sibling controls. The levels of protein S (free and total) and heparin cofactor II were reduced in both the NTx and Tx groups compared to controls and protein C and APC resistance ratios were reduced in the NTx group only. Antithrombin levels were not different from controls. Thrombin-antithrombin complexes and prothrombin fragment F1+2 were increased in both patient groups. In the NTx subgroups with or without CVD there were no differences for any of the parameters measured except for lower haemoglobin levels and higher white cell counts in those with asymptomatic CVD. We conclude that children with SCD have a reduction in levels of the majority of the coagulation inhibitors and increased thrombin generation in the steady-state and these are only partially reversed by transfusion. However, these abnormalities do not appear to play a primary role in the development of cerebrovascular disease.

Activated Protein C Resistance↗
PubMed1998

Anti-beta2-glycoprotein I, anti-prothrombin and anticardiolipin antibodies in a longitudinal study of patients with systemic lupus erythematosus and the antiphospholipid syndrome.

OBJECTIVE: To determine anti-beta2 glycoprotein-I (anti-beta2GPI) and anti-prothrombin (anti-ProT) antibody levels, and the IgG subclass distribution of anti-beta2GPI antibodies, in serial samples from patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) having initial or recurrent thrombotic/neurological (T/N) events during the study period. To investigate the correlations between these antibodies and beta2GPI antigen, anticardiolipin antibody (aCL), anti-double-stranded (ds) DNA, C3 levels and disease activity. METHODS: Fifty serum samples were identified from seven patients with SLE who had had T/N events during the follow-up from a cohort under long-term follow-up. IgG anti-beta2GPI, anti-ProT, aCL, IgG subclasses of anti-beta2GPI and beta2GPI antigen levels were determined by ELISA. Corresponding disease activity [British Isles Lupus Assessment Group (BILAG)], anti-dsDNA and C3 levels were compared. RESULTS: IgG anti-beta2GPI antibody levels were elevated in six of the patients before and after the T/N events with less marked fluctuations than aCL antibody levels. The predominant subclass of anti-beta2GPI antibodies was IgG2 before and after the T/N events. IgG anti-ProT antibodies were negative in all cases. There was a significant but weak correlation between anti-beta2GPI and aCL antibodies. No correlation was found between disease activity and IgG anti-beta2GPI antibody and beta2GPI antigen levels. There were fluctuations in beta2GPI antigen levels and a trend to increase after T/N events was observed in some patients. CONCLUSION: Most of the patients with a T/N event during the study period had IgG anti-beta2GPI, but not IgG anti-ProT antibodies. Many IgG aCL-negative samples were found to have IgG anti-beta2GPI activity during the follow-up period. The predominant subclass of IgG anti-beta2GPI was IgG2, which may have importance in the pathogenesis of APS. beta2GPI antigen levels were found to be increased in some patients with SLE after T/N events. IgG anti-beta2GPI antibodies may be used as an adjunctive marker of future T/N events in patients with SLE and APS with aCL antibodies and lupus anticoagulant.

Adult↗
PubMed1997

Continuous venovenous haemofiltration using polyacrylonitrile filters does not activate contact system and intrinsic coagulation pathways.

OBJECTIVES: To investigate whether continuous venovenous haemofiltration using polyacrylonitrile filters causes activation of the contact system and intrinsic coagulation pathways and if this, and/or low plasma levels of endogenous anticoagulants, influences filter lifespan. DESIGN: Observational study. SETTING: University Teaching Hospital Intensive Care Unit. PATIENTS: Twelve critically ill patients with acute renal failure receiving continuous venovenous haemofiltration. INTERVENTIONS: Blood samples were taken before starting haemofiltration, at 15 min, 1 h, 3-4 h, 8-12 h, 24 h and at 24-h intervals thereafter until filter blockage occurred. Measurement was made of the contact and intrinsic coagulation system proteins factor XII, activated factor XII and prekallikrein and the protease inhibitors antithrombin III, heparin co-factor II, alpha 2-macroglobulin and C1-esterase inhibitor. Thrombin-antithrombin complex levels were measured to provide evidence of thrombin generation. RESULTS: (i) Factor XII, prekallikrein and contact system inhibitors were subnormal in 10/12 and activated factor XII raised in 11/12 patients at baseline, implying pre-existing contact pathway activation. (ii) No change occurred during haemofiltration in the intrinsic coagulation pathway factor or inhibitor levels. (iii) Clotting of the filter circuit within the first 24 h occurred in 5/12 and was associated with low baseline levels of antithrombin III and heparin co-factor II. Only in these patients did thrombin-antithrombin complex levels rise significantly. CONCLUSIONS: The contact system was not activated further by continuous venovenous haemofiltration using polyacrylonitrile filters in critically ill patients. Premature clotting of the haemofilter circuit was more common in patients with very low levels of antithrombin III and heparin co-factor II; although this was related to thrombin generation, the intrinsic coagulation pathway does not appear to be implicated.

Acrylic Resins↗
PubMed1997

Evaluating the pin money hypothesis: the relationship between women's labour market activity, family income and poverty in Britain.

"In this paper we evaluate the hypothesis that the over-representation of women amongst the low paid is of little importance because women's earnings account for only a small proportion of total family income. Data from the [United Kingdom] General Household Survey (GHS), together with attitudinal evidence from three cross-sectional data sources, indicate that women's earnings are in fact an important and growing component of family income. The majority of the growth in the share of women's earnings occurs as a result of changing family labour structures; women's earnings are playing an increasingly important role in keeping their families out of poverty."

Developed Countries↗
PubMed1996

Evaluation of a low molecular weight modulator of human plasminogen activator inhibitor-1 activity.

A critical component in the regulation of thrombus formation and clearance is the balance between tissue plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1). An increase in the plasma concentration of PAI-1 has been proposed as a risk factor in thrombotic disease. Inhibition of PAI-1 activity may have utility in the treatment of thromboembolic disease. We report here the evaluation of three diketopiperazine-based low molecular weight inhibitors of PAI-1 activity (XR334, XR1853 and XR5082). In vitro these compounds reversed the inhibitory effects of PAI-1 against both tPA and urokinase (UK) (IC50: 5 to 80 muM). In contrast, other serpin-serine protease interactions, including alpha 1-antitrypsin-trypsin, alpha 2-antiplasmin- plasmin and antithrombin-thrombin, were not affected, neither did these inhibitors affect global tests of haemostasis. In the light of this promising in vitro profile these compounds were evaluated in a standard radioisotopic assay of clot lysis in whole rat blood following intravenous administration. In this assay these compounds dose-dependently enhanced fibrinolysis ex vivo. After intravenous bolus administration XR334, XR1853 and XR5082 at 5 mg/kg increased clot lysis by 32.0 +/- 5.1% SEM (n = 25, p < 0.01), 36.7 +/- 3.5% SEM (n = 36, p < 0.01) and 60.0 +/- 2.8% SEM (n = 17, p < 0.01) respectively compared to vehicle. Intravenous infusion of these compounds (1 mg/kg/min for 20 min) significantly prolonged (approximately twofold) the time to blood vessel occlusion in the rat electrically-stimulated carotid artery thrombosis model. Thus, these low molecular weight inhibitors of PAI-1 activity enhanced fibrinolysis ex vivo and protected against thrombus formation in the rat.

Animals↗
PubMed1995

Blockade of the human platelet GPIIb/IIIa receptor by a murine monoclonal antibody Fab fragment (7E3): potent dose-dependent inhibition of platelet function.

The platelet glycoprotein (GP) IIb/IIIa receptor can bind fibrinogen, von Willebrand factor, and other adhesive ligands; this binding is the final common pathway mediating platelet aggregation. The purpose of this study was to evaluate the safety and platelet inhibitory characteristics of the Fab fragment of the murine monoclonal anti-GPII/IIIa 7E3 antibody (m7E3 Fab) when administered intravenously as a single bolus dose, as a single and repeat bolus dose, and as a single bolus dose followed by continuous infusions of varying duration. Various dosage regimens of m7E3 Fab were studied in 74 patients with stable angina. Dosage regimens included single doses of m7E3 Fab from 0.1 to 0.3 mg/kg, a single dose of 0.20-0.30 mg/kg, and a repeat dose of 0.05 mg/kg, or a loading dose followed by a continuous infusion of m7E3 Fab for up to 36 hours. To assess the effect of m7E3 Fab on platelet function, quantitative blockade of GPIIb/IIIa receptors, inhibition of ex vivo platelet aggregation, and template bleeding time were measured in all patients. Dose-dependent inhibition of platelet function was evident in response to escalating bolus doses of m7E3 Fab, with maximum inhibition observed at 0.25-0.30 mg/kg body weight; at the 0.30 mg/kg dose, mean (+/- SE) GPIIb/IIIa receptor blockade was 81 +/- 3%, ex vivo platelet aggregation in response to 20 microM ADP was 14 +/- 6% of baseline, and the median bleeding time was > 20 minutes. Although platelet function gradually recovered following a single bolus injection, platelet inhibition could be sustained by continuous, low-dose infusion of the antibody. Platelet inhibition occurred within minutes, but m7E3 Fab that did not bind to platelets cleared rapidly from circulation. Sixteen percent of the m7E3 Fab-injected subjects exhibited low titer, human anti-murine antibody responses. No significant bleeding or allergic reactions were observed in any patients. One of the 74 patients developed transient thrombocytopenia soon after receiving m7E3 Fab. These studies establish that m7E3 Fab can be administered safely at doses that cause profound inhibition of platelet function.

Adult↗
PubMed1994

Heparin clearance during continuous veno-venous haemofiltration.

OBJECTIVE: To determine whether premature clotting of haemofiltration circuits could be related to heparin removal across the filter membrane into the ultrafiltrate. DESIGN: Randomised study using either unfractionated (n = 8) or low molecular weight (n = 7) heparin for anticoagulation of the haemofiltration circuit at 1000 and 600 U/h respectively. Samples were drawn at 1 and 2 h from arterial and venous limbs of the haemofilter circuit for measurement of plasma heparin (as anti-Factor Xa activity), antithrombin III and haematocrit. Ultrafiltrate samples were collected at the same time for measurement of anti-Xa activity. SETTING: Intensive care unit. PATIENTS: Patients in acute renal failure requiring haemofiltration. RESULTS: Both unfractionated and low molecular weight heparin plasma levels were within the range required for therapeutic anticoagulation in all but one patient at 2 h. Ultrafiltrate anti-Xa levels were insignificant. Antithrombin III levels in these critically ill patients were subnormal in 11 of the 15 studies. CONCLUSIONS: Despite their small sizes, neither unfractionated nor low molecular weight heparins cross the haemofilter membrane into the ultrafiltrate in any measurable quantity. Both heparins were present in plasma at a level suitable for therapeutic anticoagulation. Subnormal levels of antithrombin III may be an important factor in determining filter longevity.

Acute Kidney Injury↗
PubMed1993

Flow cytometric observations on the in vivo use of Fab fragments of a chimaeric monoclonal antibody to platelet glycoprotein IIb-IIIa.

Fluorescence flow cytometry (FC) was employed to monitor the platelet surface in humans receiving intravenous infusions of Fab fragments of a chimaeric (murine/human) construct of monoclonal antibody 7E3, which binds to the fibrinogen receptor (glycoprotein IIb-IIIa) and inhibits platelet aggregation. Platelet surface-bound chimaeric 7E3-Fab (c7E3-Fab) was measured using a fluorescein-conjugated polyclonal anti-7E3 antibody and residual c7E3-Fab binding capacity was measured using fluorescein-conjugated c7E3-Fab. Turbidometrically measured platelet aggregation response to ADP was shown to be a linear function (r = 0.9) of the logarithm of residual free binding sites for c7E3-Fab. The distribution of c7E3-Fab in the platelet population was unimodal at all time points following the infusion, demonstrating in vivo transfer of antibody to newly released circulating platelets. Clearance of platelet surface-bound antibody followed an exponential model but all circulating platelets were bearing c7E3-Fab at time points well beyond the lifespan of the platelets exposed to c7E3-Fab during the infusion. Ex vivo and in vitro mixing experiments showed that c7E3-Fab transfer between platelets was possible and suggested that differences in the in vivo kinetics between monovalent and bivalent forms of monoclonal antibodies might be relevant in their therapeutic application.

Adenosine Diphosphate↗