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Biomedical subjects

M J Stuart

Publications and source records attributed to M J Stuart.

At least 109 records · Page 6Linked to original sources
PubMed1982

Arachidonic acid metabolism in the neonatal platelet.

An assessment of arachidonic acid metabolism in the platelet of the neonate was performed. The uptake of [14C]arachidonic acid into platelets of both the neonate and the adult were similar. Neonatal platelets, however, released a significantly greater amount (P less than .001) of prelabeled arachidonic acid (24.7% +/- 2.8%) in response to the physiologic agent thrombin when compared with platelets from adult control subjects (14.6% +/- 0.8%). When the activities of the lipoxygenase (12-L-hydroxy-5,8,10,14-eicosatetraenoic acid) and cyclooxygenase pathways (12-L-hydroxy-5,8,10-heptadecatrienoic acid and thromboxane B2) were evaluated following incubation of platelets with [14C]arachidonic acid, significant differences were observed between adult and neonatal platelets. Platelets from the neonate produced less (P less than .01) thromboxane B2 (11.1% +/- 1.7%) when compared with platelets from adult control subjects (19% +/- 1.7%). In contrast, the lipoxygenase product 12-L-hydroxy-5,8,10,14-eicostatetraenoic acid was increased (P less than .005) in the platelet from the neonate (41.5% +/- 2%), when compared with the adult (31.2% +/- 2.1%). The observation that the availability of substrate arachidonic acid is increased in the platelet of the neonate may have general implications in neonatal pathophysiologic processes.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1981

Irradiation decreases vascular prostacyclin formation with no concomitant effect on platelet thromboxane production.

Effects of irradiation on vascular tissue include endothelial cell degeneration, vasoconstriction, and thrombus formation. The effect of irradiation on the in-vitro production of prostacyclin (PGI2) was evaluated, since it is a potent antithrombotic metabolite and vasodilator. After a single dose of 200 rad, umbilical artery PGI2 levels were much decreased when estimated both be bioassay and by evaluation of the stable end-product of PGI2, 6-keto-prostaglandin in Fl alpha. The mean PGI2 production in control tissue was 0.94 +/- 0.14 (1SEM) ng/mg vascular tissue compared with 0.18 +/- 0.07 ng/mg in paired irradiated vessels (p less than 0.001). However, irradiation had no effect on platelet thromboxane formation in a dose rage of 200-2000 rad. Since radiotherapy is routinely administered for the whole period of therapy in daily dose fractions similar to the in-vitro experimental dose used in this study, recovery of vascular PGI2 production may be inhibited for the total period of radiotherapy.

Blood Platelets↗
PubMed1981

Decrease prostacyclin production: a characteristic of chronic placental insufficiency syndromes.

Prostacyclin production in neonates born at various gestational ages (28 weeks to term) was compared with that in neonates born of pregnancies complicated by various acute and chronic placental insufficiency states. Prostacyclin levels were reflected by the amount of conversion of 14C arachidonic acid to 6-keto-PGF1 alpha (the stable end-product of prostacyclin) by umbilical arteries. The uptake of 14C arachidonic acid by the umbilical arteries was also determined, and since this was similar for all groups it was not the cause of the differences noted in prostacyclin production. Neonates born of normal pregnancies had similar levels of prostacyclin production regardless of gestational age. Prostacyclin production was very low in neonates born of pregnancies complicated by chronic placental insufficiency (intrauterine growth retardation, essential hypertension, and pre-eclampsia), but normal with acute placental insufficiency (abruptio placentae). Hence the decrease in fetal prostacyclin production in pre-eclampsia is not related to gestational age; furthermore, it is also seen in other chronic placental insufficiency states.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Predicting acute vs chronic childhood idiopathic thrombocytopenic purpura.

We studied 12 children with idiopathic thrombocytopenic purpura (ITP) to determine if selected immune measurements could prospectively distinguish chronic ITP from acute ITP. Immunologic assessment included immunoglobulin levels, T- and B-cell enumeration, in vitro lymphocyte stimulation by phytohemagglutinin, and a screen for autoantibodies. The most consistent difference observed was that unstimulated lymphocytes in chronic ITP had an increased basal rate of thymidine incorporation. The same assays were performed on eight other children in whom the diagnosis of chronic ITP already had been established. A similar abnormality was found in this group. Study of lymphocyte proliferation in patients with ITP appears useful in predicting the course of the disease.

Acute Disease↗
PubMed1981

Effect of endotoxin on arachidonic acid release and thromboxane B2 production by human platelets.

Plasma thromboxane A2, which is elevated during endotoxemia, has previously been shown to be a major factor contributing to the mortality and morbidity that occurs in endotoxin shock in the experimental animal. Using a minimal dose of Escherichia coli endotoxin (1 microgram/ml), we have demonstrated that the preincubation of human platelets with endotoxin induces changes in platelet arachidonic acid release and the subsequent conversion of the released arachidonic acid to thromboxane B2, and stable end product of thromboxane A2. In paired experiments, in the presence of endotoxin, the addition of the aggregating agent thrombin (0.5 U/ml) caused human platelets to release 29.1 +/- 3.4% of 14C-arachidonic acid from prelabeled platelet phospholipids. This value was significantly elevated (p less than 0.02) when compared with the release of 14C-arachidonic acid from platelets in the absence of endotoxin (21.9 +/- 3.6%). Similarly, comparison of the results of the conversion of the released arachidonic acid to platelet thromboxane B2 (TxB2) revealed that TxB2 production was significantly increased (P less than 0.01) when human platelets were preincubated with endotoxin prior to the addition of thrombin (6.1 +/- 0.6%) when compared with TxB2 formation observed in the absence of endotoxin (3.4 +/- 0.5%). The absolute amount of released arachidonic acid that was converted to TxB2 in the presence of endotoxin (1.8 +/- 0.3%) was also significantly higher (P less than 0.01) than the value observed in its absence (0.8 +/- 0.2%) was also significantly higher (P less than 0.01) than the value observed in its absence (0.8 +/- 0.2%). This study suggests that one of the tissue sources of the proaggregatory vasoconstrictor thromboxane A2 during endotoxemia is the platelet.

Arachidonic Acids↗
PubMed1981

Deficiency of plasma prostacyclin or PGI2 regenerating ability in sickle cell anaemia.

We have demonstrated that patients with sickle cell disease greater than 2 years of age have a marked decrease in their plasma PGI2 or prostacyclin regenerating ability (0.05 +/- 0.08 ng/mg of vascular tissue) when compared to normal controls (0.44 +/- 0.12). This abnormality was not present in other chronic haemolytic states, and was not related to concomitant hyposplenism. Normal activity was observed in patients with sickle cell disease following a period of prophylactic red cell transfusions (0.32 +/- 0.13). Since vascular prostacyclin is antiaggregatory and antithrombotic, the deficiency in the prostacyclin regenerating ability of patients with sickle cell disease may play a pathogenic role in the development of the microvascular and thrombotic complications seen in this disorder.

Adolescent↗
PubMed1981

Deficiency of plasma PGI2-like regenerating activity in neonatal plasma. Reversal by vitamin E in vitro.

Blood from full-term newborns was compared to adult blood for its ability to regenerate prostaglandin I2 (PGI2)-like activity from vascular tissue. The neonate possesses a markedly decreased ability to regenerate PGI2 (0.10 4/- 0.07 ng/mg vascular tissue) when compared to the adult (0.42 +/- 0.12). This decreased activity was not due to the presence of an inhibitor in neonatal blood. The impaired ability of neonatal blood to regenerate PGI2-like activity was related to its markedly decreased antioxidant potential and was corrected (0.34 +/- 0.08 ng/mg vascular tissue) by the addition of Vitamin E in vitro. Plasma PGI2-like regenerating activity had normalized by 3 to 5 months of age (0.41 +/- 0.11 ng/mg).

Adult↗
PubMed1981

Abnormal platelet function and arachidonate metabolism in chronic idiopathic thrombocytopenic purpura.

We observed several patients with chronic idiopathic thrombocytopenic purpura (ITP) whose bleeding times were more prolonged than would have been expected from their platelet counts. To investigate this further, we performed in vivo and in vitro platelet function studies, assessed arachidonate metabolism, and measured platelet-associated IgG (PAIGG) in seven patients with chronic ITP. The bleeding times of three of the patients were prolonged for greater than 7 min, and all of these patients had impaired platelet aggregation and abnormal platelet arachidonic acid metabolism as reflected by increased production of the lipoxygenase product HETE and a concomitant decrease in cyclooxygenase products, TXB2 and HHT (p less than 0.001). The abnormalities noted were not due to concomitant drug ingestion, since they were present on repeated evaluation. There was no relationship between the platelet count and the bleeding time; however, there was a significant inverse correlation between the bleeding time and TXB2 production in all patients evaluated (r = 0.81; p less than 0.05). There was no relationship between the level of platelet-associated IgG and any parameter of platelet aggregation or arachidonate metabolism. The abnormalities noted should be looked for in the individual patient with chronic ITP, since the bleeding tendency is exacerbated by the superimposed impairment of platelet function even at platelet counts of greater than 50,000/cu mm, levels generally regarded as "safe."

Adolescent↗
PubMed1981

Decreased prostacyclin production in the infant of the diabetic mother.

Maternal diabetes mellitus is recognized to be a predisposing factor to thrombosis in the neonate. In the adult with diabetes, abnormalities in the metabolism of AA by the platelet and vessel wall occur, which result in an increase in proaggregatory platelet thromboxane A2. A decrease in antiaggregatory vascular PGI2 has been demonstrated in the diabetic rat, although conclusive proof of a similar abnormality is lacking in humans. We evaluated vascular AA metabolism in 10 IDM (groups II and III comparison to 20 control neonates of gestational ages 32 to 40 weeks (group I). Mean uptakes of labeled AA into vascular tissue of both controls and IDM were similar. The conversion of [14C] AA to 6-keto-PGF1 alpha was not dependent on gestational age (r = 0.223) in the control neonates, with a mean value of 5.2% +/- 1.3 (1 S.D.). A marked decrease (p less than 0.001) in 6-keto-PGF1 alpha formation to 1.7% +/- 0.3 was found in the group II IDM of mothers with poor diabetic control (HbA1c = 9.3% +/- 0.5). In the group III neonates whose mothers had normal HBA1c levels (6.1% +/- 0.9), 6-keto-PGF1 alpha production was normal at 4.9% +/- 0.8. Although no correlation between maternal fasting blood glucose and neonatal 6-keto-PGF1 alpha was demonstrable, a significant inverse correlation (r = 0.872; p less than 0.02) was observed between maternal HbA1c levels and the conversion of AA to 6-keto-PGF1 alpha in the vascular tissues of the IDM. It appear possible that abnormalities in platelet-vascular AA metabolism may play an etiologic role in the vascular complications present in some IDM.

Adolescent↗
PubMed1980

Effect of cholesterol on production of thromboxane b2 by platelets in vitro.

We altered platelet cholesterol by incubating the cells with either "cholesterol-rich" or "cholesterol-poor" liposomes. These platelets were then used to study the influence of cholesterol content on the metabolism of arachidonic acid, a fatty acid that serves as the critical precursor in the platelet for formation of the potent aggregating agent thromboxane A2. After addition of the aggregating agent thrombin, cholesterol-enriched platelets released 18.1 +/- 0.6 per cent (mean +/- 1 S.E.M.) [14C]arachidonic acid from prelabeled platelet phospholipids. This value was higher (P less than 0.001) than that for cholesterol-depleted platelets (14.6 +/- 1.0 per cent). Conversion of released arachidonic acid to platelet thromboxane B2 (the stable end product of thromboxane A2) was also higher in cholesterol-rich platelets (22.6 +/- 3.9 per cent) than in cholesterol-depleted platelets (13.8 +/- 2.7 per cent). These studies show that changes in the cholesterol content of human platelets in vitro have a significant effect on platelt metabolism of arachidonic acid. N Engl J Med 302:6-10, 1980).

Arachidonic Acids↗
PubMed1980

Alteration in the balance of prostaglandin and thromboxane synthesis in diabetic rats.

An evaluation of platelet and vascular (aortic) arachidonic acid metabolism was performed in Lewis male rats rendered diabetic by injection of streptozotocin, and the results were compared to those in matched controls. Parameters evaluated included the release of this fatty acid from prelabeled platelets and aortas and conversion of labeled fatty acid to thromboxane B2 and 6-keto-PGF1 alpha in platelets and aortas, respectively. Diabetic rat platelets showed markedly increased release of arachidonic acid with thrombin used as the aggregating stimulus. Conversion of arachidonic acid to thromboxane B2 was slightly, but not significantly, higher in the diabetic rats. In the vessel, thrombin-stimulated release of arachidonic acid was slightly, but not significantly, increased in the diabetic animals when compared to controls. This finding was associated with a decrease in vascular production of 6-keto-PGF1 alpha both in vascular tissues incubated with arachidonic acid alone and in vascular tissues incubated with thrombin. The changes observed both in platelet and vascular metabolism of arachidonic acid were corrected by islet issue transplantation, suggesting a disease-specific effect. The changes observed in arachidonic acid metabolism suggest a significant imbalance in thromboxane A2 and PGI2 production in diabetic rats. Such changes might promote the development of the microvascular changes seen in diabetes mellitus.

Animals↗
PubMed1980

The influence of albumin and calcium on human platelet arachidonic acid metabolism.

The effects of in vitro changes in calcium and albumin on human platelet arachidonic acid metabolism were evaluated. Hypoalbuminemia enhanced the conversion of released 14C-arachidonic acid from prelabeled platelet phospholipids to the metabolites of the platelet cyclooxygenase and lipoxygenase pathways. This effect was, however, associated with a decreased release of arachidonic acid in the presence of hypoalbuminemia, such that the overall conversion of released 14C-arachidonic acid to platelet thromboxane B2 was similar in the presence of physiologic albumin concentration (3.5 g/dl) or at decreased albumin concentrations of 0.7 and 0.0 g/dl. External calcium was shown to be important for optimal platelet arachidonic acid release, with maximal release occurring at 1 mM calcium.

5,8,11,14-Eicosatetraynoic Acid↗
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↗