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Biomedical subjects

M Andrew

Publications and source records attributed to M Andrew.

At least 73 records · Page 4Linked to original sources
PubMed1998

Morphological and biochemical features affecting the antithrombotic properties of the aorta in adult rabbits and rabbit pups.

We hypothesised that there are important physiologic differences in arterial wall structure and function with respect to antithrombotic activity in the very young (pre-puberty) compared to adults. Electron microscopy, gel electrophoresis, and activity assays were used to examine differences in aorta structure and function comparing prepubertal rabbits (pups) to adult rabbits. Differences in endothelial function, extracellular matrix structure, proteoglycan (PG) distribution and glycosaminoglycan (GAG) content and function were shown. In both intima and media, total PG, chondroitin sulfate (CS) PG and heparan sulfate (HS) PG content were significantly increased in pups compared to adult rabbits. These findings corresponded to increased concentrations by mass analyses of CS GAG and DS GAG in aortas from pups. There was also a significant increase in antithrombin activity in pups due to HS GAG. In conclusion, differences in both structure and antithrombin activity of aortas from pups compared to adult rabbits suggest that young arteries may have greater antithrombotic potential that is, at least in part, related to increased HS GAG.

Aging↗
PubMed1998

Enhanced thrombin regulation during warfarin therapy in children compared to adults.

The intensity of warfarin therapy for prevention of primary and secondary thromboembolic complications in paediatric patients, is extrapolated from guidelines for adults, which may not be optimal. Therefore, we assessed thrombin regulation ex vivo and in vitro in plasmas from 40 children (1 to 18 years old with a median age of 13 years) and 27 adults receiving warfarin with an international normalized ratio of 2 to 3 (child: 2.5 +/- 0.15; adult: 2.4 +/- 0.14). Ex vivo concentrations of prothrombin fragment 1.2 were significantly lower in children (0.30 +/- 0.03 nM) compared to adults (0.45 +/- 0.04 nM; p <0.01). Thrombin generation in defibrinated plasmas (Arvin) was decreased and delayed for children compared to adults when activated by either activated partial thromboplastin time (child = 32 +/- 1.7, adult = 45 +/- 1.9 microM x s) or prothrombin time (child = 35 +/- 0.7, adult = 46 +/- 1.0 microM x s) reagents (p <0.01 for both). Although plasma concentrations of factors (F) II, FVII, FIX, F X, protein C and protein S were similar, more of the thrombin generated was complexed to alpha2 macroglobulin (alpha2M) at times close to peak thrombin activity (60 s) in plasma from children (general linear analysis of variance; p <0.03). Thus, increased alpha2M levels may enhance thrombin regulation in paediatric compared to adult patients receiving warfarin, suggesting that clinical trials in children, using less intense warfarin treatment, may be required to determine optimum therapy.

Adolescent↗
PubMed1998

A novel antithrombin-heparin covalent complex: antithrombotic and bleeding studies in rabbits.

Heparin has been used extensively for prophylaxis and treatment of deep vein thrombosis. However, heparin has several limitations including a short intravenous half-life, inability to inhibit clot-bound thrombin, and bleeding. We have developed a covalent antithrombin-heparin complex (ATH) that has a longer intravenous half-life and greater anticoagulant activity than heparin. The antithrombotic activity of ATH was tested in a rabbit jugular vein thrombosis treatment model. Administration of ATH caused a 17% reduction in clot weight compared with an increase of 24, 60, 172 and 135% for administration of antithrombin plus heparin, heparin, antithrombin and saline, respectively. Clot weight and fibrin accretion were both significantly lower in the ATH group than in the antithrombin plus heparin group (P < 0.05). The peak anti-factor-Xa activity was fourfold higher in the ATH group than in the antithrombin plus heparin group. Using a rabbit bleeding ear model, there was no significant difference in cumulative blood loss between ATH and antithrombin plus heparin groups, at similar plasma anti-factor-Xa levels. In conclusion, ATH has superior antithrombotic activity and similar bleeding effect compared with heparin on a mass basis. The enhanced antithrombotic activity of ATH may be a result of its increased anticoagulant activity or its longer half life, or both.

Animals↗
PubMed1997

Covalent antithrombin-heparin complexes with high anticoagulant activity. Intravenous, subcutaneous, and intratracheal administration.

Although heparin has been used clinically for prophylaxis and treatment of thrombosis, it has suffered from problems such as short duration within compartments in vivo that require long term anticoagulation. A covalent antithrombin-heparin complex has been produced with high anticoagulant activity and a long half-life relative to heparin. The product had high anti-factor Xa and antithrombin activities compared with noncovalent mixtures of antithrombin and heparin (861 and 753 units/mg versus 209 and 198 units/mg, respectively). Reaction with thrombin was rapid with bimolecular and second order rate constants of 1.3 x 10(9) M-1 s-1 and 3.1 x 10(9) M-1 s-1, respectively. The intravenous half-life of the complex in rabbits was 2.6 h as compared with 0.32 h for similar loads of heparin. Subcutaneous injection of antithrombin-heparin resulted in plasma levels (peaking at 24-30 h) that were still detectable 96 h post-injection. Given the increased lifetime in these vascular and intravascular spaces, use of the covalent complex in the lung was investigated. Activity of antithrombin-heparin instilled into rabbit lungs remained for 48 h with no detection of any complex systemically. Thus, this highly active agent has features required for pulmonary sequestration as a possible treatment for thrombotic diseases such as respiratory distress syndrome.

Animals↗
PubMed1997

The use of D-dimer testing and impedance plethysmographic examination in patients with clinical indications of deep vein thrombosis.

OBJECTIVE: To prospectively test the hypothesis that a diagnosis of deep vein thrombosis can be excluded in outpatients who present with clinical indications of deep vein thrombosis and whose results of D-dimer testing and impedance plethysmographic examination on the day of presentation are normal. DESIGN: Prospective cohort study. SETTING: Four university-affiliated hospitals. METHODS: Three hundred ninety-eight consecutive patients with clinical indications of deep vein thrombosis were included in the final analysis. All patients underwent an assessment of pretest probability, bedside D-dimer testing, and impedance plethysmographic examination. In most patients, if the results of D-dimer testing and impedance plethysmographic examination were negative for deep vein thrombosis, anticoagulants were withheld and patients were followed up for 3 months. If the results of one or both tests were abnormal, an examination using venous compression ultrasonography or phlebography was performed. RESULTS: In the majority of patients (69%), the results of D-dimer testing and impedance plethysmographic examination were normal. This combination had a negative predictive value of 98.5% (95% confidence interval, 96.3-99.6) for deep vein thrombosis. CONCLUSION: The results of the D-dimer assay and impedance plethysmographic examination on the day of presentation can be used to treat the majority of outpatients who present with clinical indications of deep vein thrombosis without further testing.

Adult↗
PubMed1997

A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats.

Long-term heparin treatment causes osteoporosis through, an as yet, undefined mechanism. To investigate this phenomenon and to determine the relative benefits of low-molecular-weight heparin (LMWH) use, we treated rats with once daily subcutaneous injections of either unfractionated heparin (1.0 U/g or 0.5 U/g), the LMWH, Tinzaparin (1.0 U/g or 0.5 U/g), or placebo (saline) for a period of 32 days. The effects on bone were then compared both histomorphometrically and biochemically by measuring urinary type I collagen cross-linked pyridinoline (PYD) and serum alkaline phosphatase, markers of bone resorption and formation, respectively. Histomorphometric analysis of the distal third of the right femur, in the region proximal to the epiphyseal growth plate, demonstrated that both heparin and LMWH decrease cancellous bone volume in a dose-dependent fashion, but that heparin causes significantly more cancellous bone loss than does LMWH. Although both heparin and LMWH decrease osteoblast and osteoid surface to a similar extent, only heparin increases osteoclast surface. In support of these histomorphometric findings, biochemical markers of bone turnover demonstrated that both heparin and LMWH treatment produce a dose-dependent decrease in serum alkaline phosphatase, consistent with reduced bone formation, whereas only heparin causes a transient increase in urinary PYD, consistent with an increase in bone resorption. Based on these observations, we conclude that heparin decreases cancellous bone volume both by decreasing the rate of bone formation and increasing the rate of bone resorption. In contrast, LMWH, causes less osteopenia than heparin because it only decreases the rate of bone formation.

Alkaline Phosphatase↗
PubMed1997

The relevance of developmental hemostasis to hemorrhagic disorders of newborns.

The hemostatic system is a dynamic evolving process that is age-dependent. Components of the hemostatic system are synthesized in early fetal life and do not cross the placenta from mother to fetus. However, plasma concentrations of proteins involved in hemostasis significantly differ from adults. Physiological reference ranges are available for premature infants, full-term infants and children from ages 1 to 16 years. In the coagulation system, plasma concentrations of the vitamin K-dependent and contact factors are decreased at birth, whereas other factors such as fibrinogen, FV, FVIII, and FXIII are similar or increased compared with adults at birth. In the fibrinolytic system, plasma concentrations of plasminogen are decreased at birth, whereas tissue plasminogen activator and plasminogen activator inhibitor are increased. Clinically, the hemostatic system of the young is effective and healthy infants do not suffer from spontaneous hemorrhagic complications. However, infants are more vulnerable, compared with older patients, for bleeding in the presence of either congenital or acquired haemostatic defects. Severe congenital bleeding disorders, although rare, frequently present in the newborn period. The most common acquired causes of bleeding newborns include disseminated intravascular coagulation, vitamin K deficiency, and liver disease. A description of these disorders and treatment guidelines are provided.

Blood Coagulation↗
PubMed1997

Heparin therapy in pediatric patients.

Advances in tertiary care pediatrics have resulted in heparin being one of the most frequently prescribed drugs in children's hospitals. Heparin is essential for cardiopulmonary bypass, extracorporeal membrane oxygenation, renal dialyses, maintenance of patency of venous and arterial catheters, and treatment of thromboembolic events. Currently, protocols validated in adults are used for children. However, optimal use of heparin in pediatric patients will likely differ from adults because of age-dependent physiologic and pathologic differences in hemostasis that influence the activities of heparin. The following review summarizes the influence of age on heparin anticoagulant activities, and pharmacokinetics. The indications, monitoring, therapeutic range, factors influencing dose-response relationships, and side effects of heparin therapy in pediatric patients are discussed. Finally the current and future indications for low-molecular-weight heparins in pediatric patients are summarized. Multi-centered, international clinical trials are urgently needed to assess and optimize the use of heparin in pediatric patients in a variety of clinical settings. Until these studies are completed, recommendations for adults provide guidelines for children.

Adult↗
PubMed1997

Hyperekplexia: abnormal startle response due to glycine receptor mutations.

BACKGROUND: Hyperekplexia is a rare but well-delineated clinical syndrome of pathological startle response and neonatal hypertonia. Many cases result from mutations in the alpha 1 subunit of the glycine receptor (GLRA 1). METHOD: The clinical features, management and recent genetic studies of hyperekplexia are reviewed. RESULTS: Diagnosis of the disorder should not be difficult, if one is aware of the syndrome. The treatment of first choice is with the benzodiazepine drug clonazepam, which often causes a dramatic although incomplete diminution of startle. Both recessive and dominant mutations in GLRA 1 have been found in affected individuals. The study of mouse mutants with startle phenotypes suggests that the remainder of cases may well be due to mutations in the beta subunit of the glycine receptor. CONCLUSIONS: Hyperekplexia is the first human disease shown to result from mutations within a neurotransmitter gene. The demonstration of both dominant and recessive inheritance resulting from different mutations in the same gene is of considerable interest, as other neuropsychiatric disorders may result from mutations in ligand-gated ion channels. Mutation analysis of GLRA 1 is also likely to be useful as an aid to genetic counselling and in diagnostic evaluation of neonatal hypertonia.

Diagnosis, Differential↗
PubMed1997

Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass.

The haemostatic system and the use of heparin during cardiopulmonary bypass (CPB) have been studied extensively in adults but not in children. Results from adult trials cannot be extrapolated to children because of age-dependent physiologic differences in haemostasis. We studied 22 consecutive paediatric patients who underwent CPB at The Hospital for Sick Children, Toronto. Fibrinogen, factors II, V, VII, VIII, IX, XII, prekallikrein, protein C, protein S, antithrombin (AT), heparin cofactor II, alpha 2-macroglobulin, plasminogen, alpha 2-antiplasmin, tissue plasminogen activator (tPA), plasminogen activator inhibitor, thrombin-AT complexes (TAT), D-dimer, heparin (by both anti-factor Xa assay and protamine titration) and activated clotting time (ACT) were assayed perioperatively. The timing of the sampling was: pre heparin, post heparin, after initiation of CPB, during hypothermia, post hypothermia, post protamine reversal and 24 h post CPB. Plasma concentrations of all haemostatic proteins decreased by an average of 56% immediately following the initiation of CPB due to haemodilution. During CPB, the majority of procoagulants, inhibitors and some components of the fibrinolytic system (plasminogen, alpha 2 AP) remained stable. However, plasma concentrations of TAT and D-dimers increased during CPB showing that significant activation of the coagulation and fibrinolytic systems occurred. Mechanisms responsible for the activation of haemostasis are likely complex. However, low plasma concentrations of heparin (< 2.0 units/ml in 45% of patients) during CPB were likely a major contributing etiology. ACT values showed a poor correlation (r = 0.38) with heparin concentrations likely due to concurrent haemodilution of haemostatic factors, activation of haemostatic system, hypothermia and activation of platelets. In conclusion, CPB in paediatric patients causes global decreases of components of the coagulation and fibrinolytic systems, primarily by haemodilution and secondarily by consumption.

Adolescent↗
PubMed1996

Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo.

Long-term heparin treatment causes osteoporosis through an as yet undefined mechanism. To investigate this phenomenon, we treated rats with once daily subcutaneous injections of heparin (in doses ranging from 0.25 to 1.0 U/g) or saline for 8 to 32 days and monitored the effects on bone both histomorphometrically and by serial measurements of urinary type 1 collagen cross linked-pyridinoline (PYD) and serum alkaline phosphatase, markers of bone resorption and formation, respectively. Histomorphometric analysis of the distal third of the right femur in the region proximal to the epiphyseal growth plate showed that heparin induces both a time- and dose-dependent decreased in trabecular bone volume, with the majority of trabecular bone loss occurring within the first 8 days of treatment. Thus, heparin doses of 1.0 U/g/d resulted in a 32% loss of trabecular bone. Heparin-treated rats also showed a 37% decrease in osteoblast surface as well as a 75% decrease in osteoid surface. In contrast, heparin treatment had the opposite effect on osteoclast surface, which was 43% higher in heparin-treated rats, as compared with that in control rats. Biochemical markers of bone turnover showed that heparin treatment produced a dose-dependent decrease in serum alkaline phosphatase and a transient increase in urinary PYD, thus confirming the histomorphometric data. Based on these observations, we conclude that heparin decreases trabecular bone volume both by decreasing the rate of bone formation and increasing the rate of bone resorption.

Alkaline Phosphatase↗
PubMed1996

Hemostatic complications in renal disorders of the young.

This review focuses on the hemorrhagic and thrombotic complications sometimes associated with the most common renal disorders in children. A Medline search of the literature was conducted from 1966 to January 1995, using combinations of key words appropriate for each disorder. Additional references were located through the bibliographies of the publications and recent journals were searched independently. The most common renal disorders with hemostatic complications in children were: renal vein thrombosis (268 children in 80 publications), hemolytic uremic syndrome (473 children in 29 publications), nephrotic syndrome (4,158 children in 51 publications), renal transplantation (3,976 children in 14 publications), glomerulonephritis (20 publications), end-stage renal disease, and dialysis (22 publications). The age distribution, clinical presentation, etiology, diagnosis, treatment, and outcome of the affected children were analyzed for each disorder. Children with inherited pre-thrombotic disorders usually do not present during childhood unless there is a secondary risk factor. Similarly, most children with renal disease do not develop thromboembolic complications. Therefore, when a child with a renal disorder develops a thromboembolic event, evaluation for an inherited pre-thrombotic disorder should be seriously considered. Guidelines for the use of heparin and warfarin in these children (both therapeutically and prophylactically) are given. At this time, the risk/benefit of thrombolytic therapy in children is not known and a general recommendation for thrombolytic therapy cannot be made.

Adolescent↗
PubMed1996

Topography and immunogenicity of bluetongue virus VP7 epitopes.

The core of bluetongue virus (BTV) consists of ten dsRNA viral genome segments and five proteins, including two major (VP7 and VP3) and three minor (VP1, VP4 and VP6) components. The major core protein VP7 is believed to be an important structural constituent because it interacts, not only with the underlying core protein VP3, but also with two outer capsid proteins (VP2 and VP5). In this communication we summarise data on the mapping of at least six different epitopes of VP7 distributed along the molecule. Two of the six epitopes have not been mapped previously. The accessibility of these epitopes in intact virions and core particles was analysed using immunoelectron microscopy. The epitope located near the N-terminus of VP7 was accessible at the surface of intact virions and core particles. Epitopes in other parts of the VP7 molecule were detected weakly in core particles but not in intact virions. These results support the proposal that VP7 molecules are orientated with their N-terminus accessible on the surface of either the particle or at least one of the three different channels observed by cryoelectron microscopy in the outer capsid layer. Analysis of the immune response to BTV-infected or -immunised sheep and rabbits to three selected epitopes, which are located in different regions of the VP7 molecule, demonstrated that all of them were recognised by the animals tested. These results provided further molecular evidence suggesting that VP7 is indeed a major immunogenic antigen ideal for BTV antibody detection.

Animals↗
PubMed1996

Indications and drugs for anticoagulation therapy in children.

The indications for using anticoagulants in children are reviewed. These include venous thromboembolic disease, thrombosis associated with central venous lines, inherited conditions, arterial thromboembolic disease and umbilical catheterization. The anticoagulants presently available for paediatric use consist of heparin and oral agents including low molecular weight heparin (LMWH). The problems associated with their use in children are examined and potential advantages described. Increasing numbers of children are now requiring anticoagulant therapy and the potential advantages of LMWHs makes it imperative that randomized, controlled trials be carried out in children in prophylactic as well as therapeutic situations.

Animals↗
PubMed1996

Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.

OBJECTIVE: To compare low-molecular-weight preparations of heparin (LMWH) with standard heparin in children requiring anticoagulant treatment for thromboembolic disease. METHODS: We treated 25 children who required heparin, but were at significant risk of bleeding, with LMWH (enoxaparin, Rhone-Poulenc Rorer). The median age was 4 years (range, newborn to 17 years), with nine infants less than 2 months of age. Fourteen children had a deep vein thrombosis or pulmonary embolism, nine had thrombotic complications in the central nervous system, and two had complex congenital heart disease, for which they received prophylaxis at a lower dosage (0.5 mg/kg given subcutaneously twice a day). The remaining 23 children received an initial dose of 1 mg/kg, every 12 hours subcutaneously, with subsequent doses adjusted to achieve a 4-hour anti-factor Xa level between 0.5 and 1.0 unit/ml. RESULTS: Newborn infants had increased dose requirements; an average of 1.60 units/kg was required to achieve therapeutic heparin levels. For the remaining children, the initial dose of 1.0 mg/kg was sufficient. After the initial dose adjustment, LMWH was administered with twice-weekly monitoring. The median duration of therapy with LMWH was 14 days. Two children with previously documented gastrointestinal ulcers bled and required transfusion therapy. Therapy with LMWH was continued without further events. There were no new thrombotic events during the treatment with LMWH. The cost of administering LMWH compared with heparin was reduced by 30% because of decreased laboratory monitoring, blood sampling times, intravenous starts, and nursing time. Needle punctures were reduced with LMWH therapy by the placement of a subcutaneous catheter. CONCLUSION: These results provide the basis for a randomized, controlled trial comparing LMWH with standard heparin in pediatric patients.

Adolescent↗
PubMed1996

Coping with the absurd: a first-time educational researcher's reflection.

Learning research through doing it often left me feeling confused, but I also experienced a well defined sense of 'well that's exactly what I thought all along', as I sought to clarify my uncertainties by turning to the literature. This feeling is, according to Schön & Bamberger, a type of historical revisionism where the student attributes insight to the moment when it occurs. They suggest that when the insight occurs, the 'moves on the way, tend to disappear' (1991, p207). This paper attempts to set down these moves and concludes with an exhortation to keep educational research rooted in the experience and interest of the student.

Adaptation, Psychological↗
PubMed1996

Age-related changes in factor VII proteolysis in vivo.

Previous studies have reported that pre-operative plasmas of patients over the age of 40 years who developed post-operative deep vein thrombosis (DVT) had approximately twice the amount of proteolysed factor VII found in plasmas of patients in whom prophylaxis with heparin or low M(r) heparin was successful. These and other studies also reported higher concentrations of thrombin-antithrombin III in pre- and post-operative plasmas of patients who developed post-operative thrombosis than in plasmas of patients in whom prophylaxis was successful. Whether the extent of factor VII proteolysis seen in the patients who developed post-operative DVT is related to the severity of their disease or age is not known. This report investigated age-related changes in the concentrations of total factor VII protein, factor VII zymogen, factor VIIa, tissue factor pathway inhibitor, thrombin-antithrombin III, and prothrombin fragment 1 + 2 in normal plasmas and the relationships between these parameters. With the exception of thrombin-antithrombin III, statistically significant increases in the concentrations of these parameters with age were found. Additionally, the differences between the concentrations of total factor VII protein and factor VII zymogen, an index factor VII proteolysis in vivo, were statistically significant only for individuals over age 40. Using linear regression analysis, a significant correlation was found to exist between the concentrations of plasma factor VIIa and prothrombin fragment 1 + 2. Since factor VIIa-tissue factor probably initiates coagulation in vivo, we hypothesize that the elevated plasma factor VIIa (reflecting a less tightly regulated tissue factor activity and therefore increased thrombin production in vivo) accounts for the high risk for post-operative thrombosis seen in individuals over the age of 40.

Adolescent↗