Biomedical subjects
Publications and source records attributed to H L White.
Platelet lysates obtained from blood of humans, dogs, and rats catalyzed the transamination of 4-aminobutyrate with 2-oxoglutarate as cosubstrate. Human platelet 4-aminobutyrate:2-oxoglutarate aminotransferase (36.5 +/- 3.2 picomoles per minute per milligram of platelet protein) resembled the brain enzyme in kinetic properties and in response to cofactors and inhibitors.
Homogenates of 5 neuroblastoma cell lines found to produce prostaglandin products from exogenous [14C]arachidonate, with specific enzyme activities ranging from 60 to 365 pmol per min per mg protein. Under identical conditions a glial cell line was much less active. PGF2 alpha and PGE2 were the major products from neuroblastoma cells, with PGF2 alpha predominating in all cases. The prostaglandin synthesizing activity of neuroblastoma extracts was at least an order of magnitude higher than activities reported for endogenous prostaglandin synthesis in brain tissues. The pattern of products was similar to that achieved after incubation of a rat brain microsomal extract with [14C]arachidonate, although the enzyme activity of neuroblastoma was about 200-fold higher. The presence of a relatively high prostaglandin cyclooxygenate activity in cultured neuroblastoma cells is of particular interest in that these cells may be useful model systems for studies of some aspects of neuronal prostaglandin synthesis.
A real time data processing system for a group of three clinical chemistry laboratories (one base and two satellite) has been developed as a successor to one used previously. This paper describes both the inadequacies of the previous worksheet-based system and the advantages of the new system, including flexibility, fast response and comprehensiveness, incorporating urgent routine and long delay (that is, endocrine) requests, and the use of a parallel flow work scheme.
In the preceding article the hardware and organisation of a new data processing system were described. This paper deals with the file structure and operation, the use of management information, the economical use of disc-file space and hardware, and the transferability of the system.
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Red blood cell catechol-O-methyltransferase (COMT) activity was compared across different depressive diagnoses. In a sample of 88 depressed inpatients, using defined criteria, no difference was found in respect of enzyme activity and the following categories: primary, secondary, delusional, nondelusional, endogenous, nonendogenous (neurotic), characterological depressions. COMT did not vary with age or sex. A significant increase in COMT activity was noted in agitated, depressed males, as compared to other groups.
Lysed aortic smooth muscle cells, when incubated with [14C] arachidonate, synthesized only one radioactive product, which was identified as 6-keto-PGF1alpha. Formation of this product from smooth muscle cell lysates was stimulated when human platelet extracts were added to the system, and further stimulation was observed when imidazole, a selective inhibitor of thromboxane synthesis, was added to this coupled system. These observations indicate that the cyclooxygenase of the smooth muscle cells was rate-limiting, that the prostacyclin synthetase of these cells can utilize endoperoxides produced by platelets, and that blocking of thromboxane synthesis might, under certain conditions, shunt arachidonate metabolism toward prostacyclin formation.
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The authors treated 19 depressive inpatients double-blind with a mean dose of 78 mg/day of phenelzine for 3 weeks to determine the possible relationship between monoamine oxidase (MAO) inhibition and the effectiveness of phenelzine. Clinical ratings made on the Hamilton Depression Rating Scale, the Beck Depression Inventory, and the SCL-90 indicated a minimum of 60% MAO inhibition had to be achieved for the drug to be consistently beneficial.
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Infusion of arachidonic acid through the guinea pig lung or the cat spleen causes a release of thromboxane A2 and prostaglandins, as measured by bioassay. After incubation of human platelets with arachidonate similar metabolites are formed, as demonstrated chromatographically. Infusion of imidazole (50-75 microgram/ml) through the lung or spleen specifically inhibits thromboxane A2 production and diverts the pathway to the prostaglandins, mainly prostaglandin F2alpha. In human platelets imidazole causes a dose-dependent inhibition of thromboxane A2 formation (ID50 5.5 X 10(-4) M). This inhibition is accompanied by a dose-dependent increase in prostaglandin F2alpha. Since thromboxane A2 induces platelet aggregation and is a potent vasoconstrictor, diversion of pathways to prostaglandins with opposite or less potent action might be of relevance in the treatment of cardiovascular diseases.
Twenty-eight derivatives of histidine were tested as inhibitors of histidine decarboxylase from rat stomach. Potent inhibition was observed with the methyl ester of L-histidine (1) which had a Ki = 1.8 X 10(-6) M. Substitution on 1 at various positions resulted in a decrease or complete loss of inhibition. Substituent requirements for inhibition of histidine decarboxylase are discussed. A simple disposable apparatus for the radiometric assay of histidine decarboxylase is described.
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Imipramine and phenelzine were ineffective in the treatment of five primary unipolar depressives with delusions, even when plasma levels of imipramine and desmethylimipramine or activity of platelet monoamine oxidase suggested that an adequate dose of drug had been given. Four patients went on to receive ECT and all responded well. Five non-delusional patients responded satisfactorily to the antidepressant drug given. Nine out of ten subjects were women. Non-delusional patients showed some placebo response. ECT is considered to be the treatment of choice in the acute phase of delusional depression in women.
The enzyme system which synthesizes prostaglandins and thromboxanes in extracts of washed human platelets has been characterized with respect to kinetic parameters, pH and cofactor dependence, and inhibitor potencies. Arachidonate and dihomo-gamma-linolenate were shown to be mutually competitive substrates, thus providing biochemical support for the assumption that both substrates are metabolized by the same cyclooxygenase, although they are ultimately metabolized to different patterns of products. Products of the synthetase of human leucocytes qualitatively resemble those obtained with human platelets. The prostaglandin synthetase of bovine seminal vesicles was studied under similar conditions, and kinetic parameters and inhibitor potencies were compared with those of platelet extracts.
The activity of platelet monoamine oxidase in 12 chronic schizophrenic patients was not significantly different from that in a matched group of normal individuals. The authors emphasize the importance of simultaneous processing of control and patient blood samples and the use of carefully controlled techniques, since relatively minor changes in procedure can markedly influence platelet yield and leucocyte contamination.
When baseline red blood cell catechol O-methyltransferase (COMT) was measured in 15 unipolar depressive women, the authors found a linear correlation between COMT and response to imipramine (best outcome occurring at low COMT). The results of this study were not related to such variables as intensity of depression, family history, or psychiatric history. The authors suggest that this assay may be useful either as a predictor of response to the drug or as a guide in choosing the optimum dose.
Catechol O-methyltransferase of lysed human red blood cells was assayed under optimal conditions, using saturating concentrations of the substrates, S-adenosyl-L-methionine and 3-4-dihydroxybenzoic acid. The mean enzyme activity found in 24 normal subjects was 29-2 nmol/hr/ml RBC. The mean activity in blood of 33 female unipolar depressives was not significantly different from normal. However, higher enzyme activities were observed in the blood of 11 schizophrenic patients (38-9 nmol/hr/ml RBC). Partially purified enzyme preparations from blood of normal and schizophrenic individuals were indistinguishable with respect to substrate specificities, isoelectric pH values, and ratios of the two O-methylated products. Therefore it is unlikely that any defect in O-methylation which may occur in schizophrenia can be attributed to a change in the intrinsic properties of erythrocyte catechol O-methyltransferase.