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Biomedical subjects

M J Stuart

Publications and source records attributed to M J Stuart.

At least 19 recordsLinked to original sources
PubMed1992

15-Hydroxyeicosatetraenoic acid-mediated potentiation of thrombin-induced platelet functions occurs via enhanced production of phosphoinositide-derived second messengers--sn-1,2-diacylglycerol and inositol-1,4,5-trisphosphate.

We investigated whether biologically relevant concentrations of the mono-hydroxyeicosatetraenoic acids (mono-HETEs) modulate platelet functions. We report that 15-HETE, an eicosanoid produced by endothelial cells, granulocytes, and lymphocytes, potentiated platelet aggregation, nucleotide release, and elevation in intracellular calcium levels induced by a threshold concentration of thrombin (0.025 U/mL). Significant potentiation effects on these responses were observed at concentrations between 1 and 100 nmol/L. 15-HETE at these concentrations enhanced thrombin-induced platelet aggregation by 32% to 57%, nucleotide release by 40% to 65%, and elevation of intracellular calcium by 31% to 52% (P < .05 to .01). Both 12-HETE and 5-HETE, the structural isomers of 15-HETE, also potentiated thrombin-induced platelet aggregation and nucleotide release. While 12-HETE showed a small but significant effect at 100 pmol/L, 5-HETE had effects similar to those of 15-HETE at micromolar concentrations. To understand the mechanism of the HETE modulation of platelet functions, we studied the effect of 10 and 100 nmol/L 15-HETE on the production of sn-1,2-diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (1,4,5-IP3). 15-HETE enhanced thrombin-induced production of DAG and 1,4,5-IP3 in a time- and concentration-dependent manner. 15-HETE also potentiated agonist-induced phosphorylation of the 47-Kd platelet protein. These studies demonstrate an important modulatory role for 15-HETE on platelet functions. Since this eicosanoid is elevated in pathologic states associated with platelet hyperfunction, including diabetes mellitus and atherosclerosis, an elucidation of its mechanism(s) of action appears relevant to our understanding of the genesis of atherothrombotic vascular disease.

Adenosine Triphosphate↗
PubMed1992

1-Deamino-8 D-arginine vasopressin decreases the production of 13-hydroxyoctadecadienoic acid by endothelial cells.

1-Deamino-8 D-arginine vasopressin (DDAVP) has been used effectively to normalize the bleeding time in various hemostatic disorders. In von Willebrand disease the reduction in bleeding time is due to the preferential release of large multimers of von Willebrand factor from endothelial cells. However, since the bleeding time correction in patients with uremia and liver disease is independent of the release of von Willebrand antigen and activity, other mechanisms of action of DDAVP need to be considered. Endothelial cells generate several thromborepellant factors including 13-hydroxyoctadecadienoic acid (13-HODE), an inhibitor of platelet adhesion to subendothelium. Using cultured fetal bovine aortic endothelial cells (FBAECs), we have investigated whether DDAVP modulates the production of 13-HODE. We have demonstrated that 14C-linoleic acid labeled FBAECs release several oxygenated derivatives of linoleic acid following a 120 min incubation in the presence of serum. One of these products was identified by chromatographic procedures as 13-HODE. The production of 13-HODE was decreased significantly by DDAVP (1-100 ng/ml) with maximal reduction (approx. 25%) seen at 1 ng/ml of DDAVP. While vehicle treated control FBAECs generated 6780 +/- 690 cpm of 13-HODE per 10(6) cells (mean +/- SE, n = 8), DDAVP treated FBAECs produced 4950 +/- 310 (P < 0.01), 5390 +/- 390 (P < 0.01), and 5720 +/- 410 cpm (P < 0.05) of 13-HODE at 1, 10, and 100 ng/ml DDAVP respectively. Our findings of a decrease in 13-HODE would explain the previously observed morphologic changes of increased platelet adhesion to subendothelium following DDAVP infusion and contributes to our understanding of the mode of action of this therapeutic agent in hemostatic disorders.

Animals↗
PubMed1992

Traumatic disruption of the anterior tibial tendon while cross-country skiing. A case report.

Closed spontaneous rupture of the anterior tibial tendon is an uncommon injury that occurs after relatively minor trauma in middle-aged and elderly men. A 72-year-old retired physician sustained a complete anterior tibial tendon rupture while he was skiing cross-country. Direct primary repair of the tendon resulted in satisfactory restoration of muscle strength and return to an active life-style.

Aged↗
PubMed1979

Platelet function in the neonate.

Impairment of platelet function is well recognized in the neonate. The abnormalities include a reduction in platelet factor 3 activity and availability, a reduction in the release of nonmetabolic storage pool ADP and ATP, and platelet factor 4 following stimulation, decreased adhesiveness, and impaired aggregation with ADP, epinephrine, collagen, and thrombin. Whether the cause of the platelet abnormality and the impairment in platelet secretion is due to a "storage pool deficiency" or an "aspirin-like defect" has been unclear. However, recent data suggests that the neonatal platelet possesses neither a significant deficiency in prostaglandin synthesis nor a significant decrease in storage pool adenine nucleotides. The abnormalities noted appear most likely to be due to a membrane-related phenomenon.

Adenosine Diphosphate↗
PubMed1979

The post-aspirin bleeding time: a screening test for evaluating haemostatic disorders.

To evaluate the usefulness of the template bleeding time post-aspiring ingestion, this test was performed with other tests of haemostasis in 28 controls and 71 patients. The mean bleeding time (B.T.) in 24/28 true controls was 3.5 +/- 1 min (1 SD). Following the ingestion of 600 mg aspirin the B.T. was 6.3 +/- 1.4 min. Four out of 28 false 'controls' with negative bleeding histories were documented to have asymptomatic von Willebrand's disease and abnormal post-aspirin B.T. Of the 71 patients studied, 22 had initial B.T. that were abnormal (16 with classical von Willebrand's disease and six with platelet dysfunction). Of the remaining 49 patients with initially normal B.T., 30 had abnormal post-aspirin B.T. Of these 30 patients 13 had von Willebrand's disease. In eight, initially the abnormal B.T. post-aspirin was the only abnormality demonstrable but later they were shown to have von Willebrand's disease. In four the abnormal post-aspirin B.T. was combined with abnormal Ristocetin aggregations and a positive family history. These patients were presumed to have a variant of von Willebrand's disease. The remaining five had platelet dysfunctional states. Of the 19 patients with normal initial post-aspirin B.T., 16 demonstrated no haemostatic abnormality, and three were proven to have von Willebrand's disease. The aspirin tolerance test raised the sensitivity of the B.T. as a screening test for haemostasis from 40% to 94% in the abnormal patient population.

Adolescent↗
PubMed1979

Platelet dysfunction in homozygous beta-thalassemia.

This report details the results of studies performed in nine patients with homozygous beta-thalassemia evaluating platelet function and prostaglandin formation. Platelet malonyldialdehyde (MDA) formation in the presence of N-ethyl maleimide (NEM 1 mM) or thrombin (0.5 u/ml) was used as an indicator of platelet prostaglandin synthesis. The data on the nine patients revealed two distinct subgroups of patients. Six of nine thalassemics, demonstrated platelet abnormalities. Their mean bleeding time was 7.5 +/- 2.5 min (1 SD), significantly prolonged (P less than 0.005) when compared to a value of 3.5 +/- 1.0 min in normal controls. MDA formation in the presence of NEM was significantly decreased (P less than 0.005) to 2.41 +/- 0.49 (1 SD) when compared to a control value of 3.24 +/- 0.33 nmoles MDA/10(9) platelets. Similarly, the mean value for thrombin induced MDA was 0.98 +/- 0.18 nmoles which was decreased (P less than 0.02) when compared to a value of 1.26 +/- 0.2 in the controls. Platelet aggregations with adenosine diphosphate (ADP), epinephrine, and collagen were abnormal in all six patients. However, when platelets from these patients were mixed with platelets from donors who had ingested aspirin 2-8 hr before donation mutual correction and secondary irreversible aggregation of the mixture resulted. No mutual correction was observed when the thalassemic platelets were preincubated with aspirin in vitro before mixing with platelets from donors who had recently ingested aspirin. Although the total amount of platelet malonyldialdehyde formed by the thalassemic platelets in response to NEM and thrombin was decreased when compared to normal controls, this reduction was not the cause of the platelet aggregation abnormalities. This appears to be so because the amount of MDA, and, thus, prostaglandin endoperoxides synthesized by these platelets in response to external stimuli was sufficient to cause irreversible aggregation of platelets from donors who had recently ingested aspirin, and were, therefore, unable to synthesize their own endogenous platelet endoperoxides. In the remaining three patients, bleeding times, platelet aggregation, and MDA formation was normal. No correlation was observed between the platelet abnormalities noted and the magnitude of iron overload, presence of fibrin degradation products, liver function abnormalities, or the use of iron chelators in the individual patient. Family studies were normal. Although the platelet dysfunction does not appear to be of major significance in the usual patient with thalassemia major under normal circumstances, antiplatelet aggregating agents should be used with caution. Aspirin inhibits platelet endoperoxide and prostaglandin formation and this effect may potentiate the platelet dysfunction present in some patients with thalassemia major.

Adolescent↗
PubMed1979

Ethanol-inhibited platelet prostaglandin synthesis in vitro.

Inhibition of human platelet malonyldialdehyde (an indicator of platelet prostaglandin synthesis) in platelet-rich plasma, not found after 100 mg of ethanol per 100 ml in vitro, was dose-related at 200, 400 and 750 mg per 100 ml.

Adenosine Diphosphate↗
PubMed1979

Vitamin E and platelet function.

In both animals and humans, vitamin E deficiency is associated with platelet hyperaggregability. In six E-deficient children, thrombocytosis was associated with marked hyperaggregability of their platelets to ADP, epinephrine, and collagen. Platelet malonyldialdehyde (MDA) formation was used as an indicator of prostaglandin formation, and was found to be increased during the E deficiency state. Following E repletion, both platelet aggregation and platelet MDA formation returned to normal. The addition of vitamin E to platelets in vitro has been associated with inhibition of platelet release, aggregation, and MDA formation. Extending these in vitro observations further, six normal controls were given 1600 units of vitamin E orally daily for 2 weeks to elevate their plasma E levels and the E content of their platelets in vivo. Concomitant with the elevation in their plasma E levels, there was an inhibitory effect of 12--20% on platelet MDA formation following E ingestion. These studies suggest that E deficiency increases the in vivo synthesis of platelet endoperoxides and prostaglandins, and that E excess has the opposite effect, i.e., inhibition of the endoperoxide intermediates of prostaglandin synthesis.

Animals↗
PubMed1978

Spinal-fluid procoagulant activity: a sensitive indicator of central-nervous-system damage.

Testing the procoagulant activity (P.C.A.) of cerebrospinal fluid (C.S.F.) by measuring its effect on plasma-recalcification time is a useful indicator of central-nervous-system damage. C.S.F. from 22 normal children and adolescents aged 6 months to 17 years had a mean +/- S.D. P.C.A. of 14 +/- 6%. P.C.A. in 13 children with C.N.S. infection was significantly increased to 59 +/- 13%. In 8/13 of these children activity remained high (42 +/- 11%) after therapy. In patients with acute lymphatic leukemia (A.L.L.) 12 aged greater than 2 1/2 years and diagnosis had a normal activity (17 +/- 8%) and 4 patients aged less than 2 1/2 years at diagnosis had an activity of 21 +/- 8%; during C.N.S. prophylaxis with intrathecal methotrexate and/or cranial irradiation, mean activity in these 16 patients rose significantly to 41 +/- 11%. More than 2 years after treatment P.C.A. decreased towards normal in the older children but remained high in the younger group. 5 children with neurological sequelae (including 3 with A.L.L. and the post-irradiation syndrome) had the highest activities. Ether extraction showed that the active material had lipid properties. P.C.A. did not correlate with protein, lactic dehydrogenase, or cell count in C.S.F.

Adolescent↗
PubMed1978

Chronic idiopathic thrombocytopenic purpura. A familial immunodeficiency syndrome?

We studied three children with chronic idiopathic thrombocytopenic purpura (ITP) and their immediate families. All three patients and 10/13 family members manifested at least one immunologic defect, eg, decreased numbers of T lymphocytes (1/3, 5/13), diminished in vitro response to phytohemagglutinin (2/3, 6/13), dysgammaglobulinemia (2/3, 4/13), altered autoantibodies (1/3, 5/13), and decreased serum properdin levels (3/3, 2/13). In addition, one parent and two asymptomatic siblings of two of the propositi had shortened platelet life spans with normal platelet counts. The HLA antigens A3 and B7 were identified in all three families. There also appeared to be an association between a familial haplotype and the immunologic defects. Chronic ITP appears to occur in families with underlying immunologic defects, which are genetically related.

Adolescent↗
PubMed1978

Hemostatic alterations in inflammatory bowel disease: response to therapy.

Twelve patients with acute, untreated inflammatory bowel disease (IBD) were followed prospectively for coagulation and platelet function. With no symptomatic coagulopathy, abnormalities were found in all patients. With acute diseases, elevations of fibrinogen (9/12), factor V (8/12), and factor VIII (6/12) were common. Depressions of antithrombin III levels were also observed acutely (8/12). Abnormalities of platelets were both quantitative and qualitative. Thrombocytosis was present (11/12), and abnormalities in the rate and percent platelet aggregation were seen (9/10). During therapy, factors V and VIII, antithrombin III levels, and the quantitative and qualitative platelet abnormalities returned towards normal in direct correlation with sedimentation rate and clinical disease activity.

Adolescent↗
PubMed1978

Erythroid hypoplasia. An unusual presentation of childhood acute lymphocytic leukemia.

A 3-year-old girl had pancytopenia and bone marrow erythroid hypoplasia. The pancytopenia resolved without therapy, but the erythroid hypoplasia persisted for four months in spite of a five-week course of corticosteroid therapy. She responded briefly when androgens were added to the corticosteroid regimen, but within three weeks of stopping therapy she developed acute lymphocytic leukemia. The differential diagnosis of RBC aplasia in childhood is discussed. To our knowledge, this is the first case reported with erythroid hypoplasia as a prodrome of acute lymphocytic leukemia of childhood.

Anemia, Aplastic↗
PubMed1978

Consumptive coagulopathy. A complication of therapy of solid tumors in childhood.

The association of consumptive coagulopathy and malignancy is thought to be rare in pediatrics. In one patient with Ewing's sarcoma and in two with rhabdomyosarcoma consumptive coagulopathy developed in the presence of either diffuse metastatic disease or an extensive primary tumor. The coagulopathy was a major clinical problem, developing within five days of the onset of chemotherapy. Resolution coincided with the clinical response of the tumor.

Adolescent↗