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Biomedical subjects

I Mackie

Publications and source records attributed to I Mackie.

At least 37 records · Page 2Linked to original sources
PubMed1998

Binding of anticardiolipin antibodies to protein C via beta2-glycoprotein I (beta2-GPI): a possible mechanism in the inhibitory effect of antiphospholipid antibodies on the protein C system.

It is known that antiphospholipid antibodies (aPL) hamper the anticoagulant activity of the protein C system, but the mechanism is still obscure. In this study, we demonstrate that anticardiolipin antibodies (not anti-protein C autoantibodies) can bind protein C via beta2-GPI, which bears their binding epitope, in a fashion dependent on negatively charged phospholipids. We studied the binding of IgG from aPL to protein C in the presence of beta2-GPI by ELISA (anti-'protein C' antibody ELISA), and compared their binding with those obtained in the absence of beta2-GPI. In the anti-'protein C' antibody ELISA system, 47% of 78 aPL+ patients had a positive titre in the presence of cardiolipin (CL) and beta2-GPI, but binding was not found in the absence of beta2-GPI. Highly significant correlations were found between the titre of anti-'protein C' antibody in the presence of beta2-GPI and that of anti-beta2-GPI antibody (r = 0.802, P = 0.0001). We further analysed the interaction between protein C, phospholipids, beta2-GPI and human aCL MoAbs established from patients with antiphospholipid syndrome. In a first set of experiments, the binding of beta2-GPI to protein C and its phospholipid dependency were investigated. Beta2-GPI bound to protein C in the presence of CL or phosphatidylserine, but not in the presence of phosphatidylcholine or phosphatidylethanolamine. In a second group of experiments, the binding of three human monoclonal aCL recognizing the cryptic epitope of beta2-GPI (virtually anti-beta2-GPI antibodies) was evaluated in the presence of cardiolipin and beta2-GPI. All three human monoclonal aCL bound to protein C in the presence of CL and beta2-GPI, whereas they did not in the absence of either beta2-GPI or CL. These data suggest that protein C could be a target of aCL by making a complex with CL and beta2-GPI, leading to protein C dysfunction.

Adolescent↗
PubMed1998

Complications of radiologically placed central venous ports and Hickman catheters in patients with AIDS.

OBJECTIVE: To determine any differences in the complications following radiologic placement of 2 devices--Hickman catheters and central venous ports--to permit long-term central venous access in patients with AIDS. PATIENTS AND METHODS: Thirty-eight patients with AIDS received 52 long-term central venous access catheters. Seventeen received 23 Hickman catheters and 27 received 29 central venous ports (hence, 6 patients received both). Complications rates were determined retrospectively from clinical records and radiologic studies. RESULTS: The only acute complications were pneumothoraces--3 in the patients receiving Hickman catheters and 2 in the patients receiving central venous ports. Infections developed in 12 of the patients receiving Hickman catheters a median of 53 and a mean of 96 days after placement. Infection developed in 8 of the patients receiving central venous ports a median of 125 days and a mean of 184 days after placement. This difference was statistically significant (p < 0.001). The most common organism in these infections was Staphylococcus aureus. The only other nonacute complication was 1 nonocclusive thrombosis of the superior vena cava, which occurred in a patient with a Hickman catheter 240 days after placement and resolved once the catheter was removed. CONCLUSION: Central venous ports are preferred over Hickman catheters for long-term central venous access in patients with AIDS.

AIDS-Related Opportunistic Infections↗
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

The rationale, organisation and evaluation of a campaign to increase the use of sugar-free paediatric medicines.

OBJECTIVE: To conduct and evaluate a dental health education campaign to encourage the use of sugar-free rather than sugar-containing medicines. DESIGN: Meetings were organised for general medical practitioners, pharmacists and health visitors where the campaign was explained and discussed. Leaflets were given to parents by the health professionals. The campaign targeted the use of children's medicines from several aspects, namely when recommended, prescribed, sold and used. SETTING: The campaign was conducted in the North West Region. SUBJECTS: The campaign was directed at parents of young children, and health professionals, namely, general medical practitioners, pharmacists and health visitors. OUTCOME MEASURES: Evaluation was by means of questionnaires, sales figures and prescriptions of medicines. RESULTS: There was an increase in the proportion of sugar-free paracetamol prescribed in five out of six districts. The frequency of sugar intakes as an important cause of dental caries was not understood by many health professionals. CONCLUSIONS: Continued education for health professionals is needed in order to show the importance of the frequency of sugar intakes and to dispel some prevalent dental health misconceptions.

Acetaminophen↗
PubMed1996

Oral soft tissue trauma: gingival degloving.

Ideally gingival degloving following a traumatic episode should be treated as soon as possible by repositioning the displaced gingivae and mucosa. The cases reported are of degloving in the primary and permanent dentition. In both cases immediate assistance was sought from health professionals but no treatment was offered. The delay before attendance at the Dental Hospital meant that it was too late to offer active treatment. Instead supportive measures were instigated which resulted in eventual successful healing.

Accidents, Traffic↗
PubMed1996

Measurement of tooth mobility in children using the periotest.

This study investigated the use of the periotest for measuring tooth mobility of upper permanent incisor teeth in children. A total of 160 children, with equal numbers of boys and girls aged between 9 and 16 years had two periotest readings made on their four upper incisor teeth. In all 1,280 measurements were collected and analysed. The results showed that the second periotest readings were statistically significantly higher than the first. Periotest readings were lower for girls than boys of the same ages. The periotest may have a place as a diagnostic tool in paediatric dentistry and dental traumatology, however, further research is necessary before the periotest can be used to assist in the diagnosis and assessment of healing of traumatised teeth.

Adolescent↗
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↗
PubMed1995

Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach.

Five hundred consecutive women (median age 33 years; range 19-45) with a history of recurrent miscarriage (median 4; range 3-16) were screened for the presence of antiphospholipid antibodies (APA)-lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACA). The prevalence of persistently positive tests for LA was 9.6% and for immunoglobulin G (IgG) and immunoglobulin M (IgM) ACA was 3.3 and 2.2% respectively. Only seven women (1.4%) were LA and ACA positive. Repeat testing, after an interval of at least 8 weeks, demonstrated that only 65.7% of LA positive, 36.6% IgG ACA positive and 36.0% IgM ACA positive women on initial testing had a second positive test result. The dilute Russell's viper venom time detected the LA significantly more often than either the activated partial thromboplastin time or the kaolin clotting time (P < 0.001). There was no difference in the gestation of previous miscarriages between APA positive and APA negative women. There was no difference in the plasma beta 2-glycoprotein-I concentrations between APA positive and APA negative women with miscarriages and normal women. All women with a history of recurrent miscarriage should be tested for the presence of both LA and ACA. A second confirmatory test should be performed in those with an initial positive test result.

Abortion, Habitual↗
PubMed1995

Management of traumatically displaced permanent incisors: the gentle touch.

This paper reports three cases where permanent incisor teeth had been displaced following trauma. Owing to the circumstances at presentation the cases were not treated according to the usual recommendations. However, the final outcome in each case was excellent. These observations indicate that a prospective clinical trial is needed.

Child↗
PubMed1994

A helping hand?

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Child↗
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

Conjunctival involvement in malignancy-associated acanthosis nigricans.

Acanthosis nigricans classically presents with pigmented skin lesions over the neck, groin and axillae. It may involve the mucosal surfaces, particularly the oral mucosa. Conjunctival involvement is very rare, especially in the variety associated with malignancy. We report a case of acanthosis nigricans associated with squamous cell carcinoma of the bronchus where bilateral papillary conjunctivitis, progressing to hypertrophic papillary conjunctival and lid margin lesions, was the presenting feature. Topical treatment with corticosteroid and artificial tear drops resulted in the partial improvement of the ocular symptoms.

Acanthosis Nigricans↗
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↗