4-aminobutyrate:2-oxoglutarate aminotransferase in blood platelets.

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.

Prevalence and predictors of HIV infection amongst Malian students.

The objectives of this cross-sectional study were to assess the prevalence and identify predictors of HIV-1 and HIV-2 infection among students in three cities of Mali. Between January and June 2005, we assessed HIV knowledge, attitudes, associated sexual behaviors and tested HIV serostatus among 950 high school and university students in Sikasso, Bamako, and Koulikoro cities, using a combination of enzyme-linked immunosorbent assay (ELISA) and Western blot testing. Univariate and logistic regression analyses were used to determine predictors of infection among students. Mean HIV prevalence was 3.1%, ranging from 1.8% in Sikasso to 3.6% in Bamako. The results showed the presence of all three HIV subtypes in Bamako, though HIV-1 predominated in all cities. Infection rates were slightly higher among males (3.6%) than among females (2.8%), but the difference was not significant. The single significant predictor of HIV infection was knowledge of HIV routes of transmission (p=0.01). HIV prevalence rates observed in this population were higher than general adult prevalence rates previously reported for Mali. HIV/AIDS education and prevention campaigns should be targeted to students at both the secondary and university levels. Students may represent an informative HIV sentinel population for Mali.

Examining the sensitivity of an injury surveillance program using population-based estimates.

This study uses population-based estimates to assess the sensitivity and representativeness of an injury surveillance system using a 1-year population-based approach. Data from the Ottawa Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) site (Children's Hospital of Eastern Ontario) were compared with those from six expansion sites. The overall sensitivity of CHIRPP was 43% of all treated injuries and 57% of injuries treated at emergency departments. CHIRPP was less likely to be representative for older children and more likely to capture children with more severe injuries. The limitations related to using CHIRPP for representing population-based injury remain fairly stable over time. A one-time population-based sample can provide useful information to add to routinely collected injury surveillance.

Syndromic management training for non-formal care providers in Pakistan improves quality of care for sexually transmitted diseases STD care: a randomized clinical trial.

We conducted a randomized, controlled, three-armed trial to assess whether training in syndromic management, with provision of packets, could improve the quality of STD services provided among non-formal care providers. The quality of STD case management service, observed by "incognito patients" in both intervention groups, improved substantially compared to the control group (p < 0.05). The training-and-packets group performed better in service delivery, HIV-testing referral, and condom provision when compared to the training-only group (all p < 0.05). The training-and-packets group also retained more knowledge and practiced more skillfully at six months post-intervention when compared to the training-only group (p < 0.05). Exit interviews of clients suggested that 81% of providers in the intervention groups offered advice on condom use when compared to none of those in the control group (p < 0.001). Syndromic management training and free syndrome packets for non-formal providers had a positive impact on the quality of STD care among the trained providers.

Platelet monoamine oxidase activity and the classification of depression.

An attempt was made to compare platelet monoamine oxidase (MAO) activity in descriptively based types of nonbipolar depression. Platelet MAO activity was significantly higher in depression secondary to chronic anxiety, compared with primary unipolar depression and depression secondary to borderline personality, and in women compared with men. No significant differences were observed between endogenous-nonendogenous, delusional-nondelusional, psychomotor states, or different age groups.

Catechol-O-methyltransferase activity and classification of depression.

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.

Inhibition of platelet monoamine oxidase in depressed subjects treated with phenelzine.

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.

Red blood cell catechol O-methyl transferase and response to imipramine in unipolar depressive women.

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.

Platelet monoamine oxidase activity in schizophrenia.

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.

Selective inhibitors of monoamine oxidase. 2. Arylamide SAR.

Monoamine oxidase (MAO) exists in two forms distinguishable by substrate specificity. Inhibition of MAO A is believed to be responsible for the antidepressant activity of MAO inhibitors. A group of N-arylacetamides are highly specific inhibitors of MAO A, some with IC50 values in the 10-100 nM range. The requirements for high activity and specificity include a nearly linear tricyclic aromatic portion but a larger and a smaller central ring component. The amide group, which is best acetamido, is optimally placed para to the smaller central group. The size and shape of the aromatic moiety appear to be the major influence on activity and specificity for MAO A.

Inhibition of histidine decarboxylase. Derivatives of histidine.

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.

Selective inhibitors of monoamine oxidase (MAO). 5. 1-Substituted phenoxathiin inhibitors containing no nitrogen that inhibit MAO A by binding it to a hydrophobic site.

It is believed that a monoamine oxidase (MAO) inhibitor specific for MAO A, which is reversibly bound to this enzyme and displaceable by tyramine, will be an antidepressant which will not cause a rise in blood pressure when tyramine-containing foods are ingested. Some linear tricyclic compounds with a larger and a smaller group forming the central ring and with a lipophilic group ortho to the larger group (here mostly the SO2 function of phenoxathiin 10,10-dioxide) are reported to have the sought properties. Potency appears to require short length and relatively small cross section for the substituent. The 1-ethyl (13), 1-vinyl (22), 1-trifluoromethyl (27), and 1-iodo (76) phenoxathiin dioxides had the best profiles. Structure-activity relationships, syntheses, and a possible rationale for the selectivity of these compounds and related tricyclics are given. Compound 13 was selected for further development. A summary of pharmacological data for 13 is given.

Selective inhibitors of monoamine oxidase. 3. Structure-activity relationship of tricyclics bearing imidazoline, oxadiazole, or tetrazole groups.

Inhibition of monoamine oxidase A (MAO A) is believed to cause antidepressant and possibly antianxiety effects. The previous paper had developed structure-activity relationships (SAR) for in vitro MAO A inhibition by tricyclic N-arylamides. It is shown in this paper that the same in vitro SAR can be carried over to tricyclics whose potentially toxic amide function is replaced by an appropriately substituted imidazoline, a 1,2,4- or 1,3,4-oxadiazole, or an alkylated tetrazole moiety. Dialysis of the inhibitor from the enzyme was used as a measure of reversibility which correlates with a low ability to cause a blood pressure rise with ingested tyramine ("cheese effect").

Selective inhibitors of monoamine oxidase. 4. SAR of tricyclic N-methylcarboxamides and congeners binding at the tricyclics' hydrophilic binding site.

Linear [6.6.6] tricyclic moieties whose center ring is made of two atoms of differing size (here primarily thioxanth-9-ones and phenoxathiins) monosubstituted meta to the sulfur by C(O)NHMe include potent and selective inhibitors of monoamine oxidase A. Similarities with effects on SAR of acylamide and of diazapentacyclic substitution on such rings, including positional variables, the requirement for monomethylation (primary and dialkylated amides are inactive and higher monoalkylated amides show little or no potency), and that sulfur is optimally in sulfone form, suggest that binding to the enzyme occurs similarly in each series. No significantly greater rise in blood pressure was found in rats given sufficient 8 to inhibit most brain and liver MAO A and then followed by oral tyramine than was found on administration of tyramine to controls. This is in contrast to a large blood pressure rise in rats pretreated with phenelzine followed by tyramine, and in accord with the belief that an inhibitor selective for MAO A which is reversibly bound to the enzyme and therefore displaced by any ingested tyramine will not lead to the "cheese effect" (hypertension during treatment with MAO inhibitors usually caused by ingestion of foods containing tyramine).

Effects of GTP?S and other nucleotides on phosphoinositide metabolism in crude rat brain synaptosomal preparations.

Crude nerve-ending preparations from rat brain were labeled with either [(32)P]phosphate or myo[2-(3)H]inositol in order to observe effects of guanosine 5?-[?-thio]triphosphate (GTP?S) and other nucleotides on phosphoinositides, phosphatidate and inositol phosphates. This system exhibited typical responses to muscarinic agonists, including acetylcholine-a decrease in net labeling of [(32)P]polyphosphoinositides, an increase in labeling of [(32)P]phosphatidate, and a stimulation of [(3)H]inositol phosphate formation. GTP?S and other nucleotides may not readily penetrate intact synaptosomal membranes to cause activation of phospholipase C via an interaction with G proteins, and, as might be expected, there was no indication that G-protein interaction occurred in these preparations. However, other effects were observed. GTP?S decreased net [(32)P] incorporation in phosphatidylinositol (PI) and polyphosphoinositides in a dose-dependent manner. GTP?S also caused an initial marked stimulation of [(32)P] labeling of phosphatidate, suggesting a possible inhibition in the conversion of phosphatidic acid to PI. Other nucleotides [GTP, ATP, Gpp(NH)p, GMP] produced qualitatively similar effects on phosphoinositides. Thus GTP?S and other nucleotides, at physiologically relevant concentrations, may influence phosphoinositide turnover via extracellular or other mechanisms, in addition to the proposed interaction of GTP with G-proteins within membranes.

Diversion of prostaglandin endoperoxide metabolism by selective inhibition of thromboxane A2 biosynthesis in lung, spleen or platelets.

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.

Cholesterol management in general practice.

Ninety general practitioners from the Fylde coast of Lancashire responded to a questionnaire regarding lipid management, revealing that only 22% aim for a target total cholesterol of < or = 5.2 mmol/l in patients with established ischaemic heart disease. One third are reassessing the cholesterol in these patients at yearly intervals or less frequently, and 36% select 65 years or less as the upper age limit for screening. Approximately 50% of GPs screen for hypercholesterolaemia in patients with cerebral or peripheral vascular disease. Primary screening and treatment of hypercholesterolaemia within the 'at risk' asymptomatic population is well established with 72% of GPs screening hypertensives, 88% screening diabetics and almost all screening patients with an adverse family history, but the therapeutic cholesterol targets vary widely between individual practitioners.

An enzymatic method for detecting MAO-A and MAO-B inhibitors in plasma and its application in studies with reversible MAO-A selective inhibitors.

A general method was developed for the simultaneous enzymatic assay of MAO-A and MAO-B inhibitors in plasma of pretreated animals. After extraction of the inhibitor from plasma into an appropriate volatile organic solvent, dried aliquots of the organic layer are incubated with a buffered rat brain MAO preparation and substrates, [3H]serotonin and [14C]phenethylamine. Under conditions employed, the presence in plasma of MAO-A and/or B inhibitors can be detected.

Species differences in monoamine oxidase-A and -B as revealed by sensitivity to trypsin.

Monoamine oxidase-A and -B of brain and peripheral tissues of human, dog, rat, and rabbit have been characterized with respect to kinetic parameters and response to limited trypsin treatment. MAO-A in all extracts was inactivated by trypsin to an extent that was species dependent, but not related to the nature of the tissue, to MAO-A/B ratios, or to kinetic parameters. MAO-B activity of human, dog, and rat was unaffected by trypsin under the conditions employed, but rabbit MAO-B was sensitive. Inactivation patterns obtained with the trypsin treatment described in this study provide additional evidence that structures of both MAO-A and MAO-B show species-specific variations.

Extracts of Ginkgo biloba leaves inhibit monoamine oxidase.

Extracts of Ginkgo biloba leaves produce reversible inhibition of rat brain monoamine (MAO). Both MAO-A and -B types were inhibited to a similar extent. The MAO inhibitory compound(s) were present in dried or fresh Ginkgo biloba leaves as well as in commercially available capsules of Ginkgo biloba and appear to be heat stable with relatively low molecular weight. MAO inhibition by Ginkgo biloba may be a mechanism underlying reported anti-stress and anxiolytic activities of this natural product.