An investigation of CYP2D6 genotype and response to metoprolol CR/XL during dose titration in patients with heart failure: a MERIT-HF substudy.

To explore the pharmacogenetic effects of the cytochrome P450 (CYP)2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional *4 allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6*4 allele (EM: *1*1, 60.4%; IM: *1*4, 35.8%; and PM: *4*4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6*4 allele dose-response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT-HF-defined titration schedule remains recommended for all patients, regardless of genotype.

Evaluation of a catalase-based urine test for the detection of urinary tract infection in dogs and cats.

BACKGROUND: Bacterial infection of the urinary tract is a common disorder in dogs and cats. Although microscopic examination of urine sediment is routinely used to screen for infection, this test can lack sensitivity or require expertise. A reliable in-clinic screening test would be a useful adjunct for the identification of dogs and cats with bacterial urinary tract infection (UTI). HYPOTHESIS: That a catalase-based urine test (Accutest Uriscreen™) is a more sensitive screening test for UTI in dogs and cats than urine microscopic sediment examination. ANIMALS: One hundred and sixty client-owned dogs and cats. METHODS: Surplus urine from animals presented to a veterinary teaching hospital was used in this prospective observational study. A routine urinalysis, aerobic bacterial culture, and the Uriscreen test were performed on cystocentesis samples. Sensitivity and specificity with 95% confidence intervals and positive and negative likelihood ratios were calculated for Uriscreen and microscopic sediment examination using culture results as the gold standard. RESULTS: Bacterial culture was positive in 27/165 (16.4%) samples. The sensitivity, specificity, and positive and negative likelihood ratios for the Uriscreen were 89%, 71%, 3.0, and 0.15, respectively. Sensitivity, specificity, and positive and negative likelihood ratios for urine sediment microscopic examination were 78%, 90%, 7.8, and 0.24, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: The Uriscreen is a more sensitive screening test for UTI in dogs and cats than sediment examination; however, the urine sediment examination was more specific. A negative Uriscreen result helps exclude UTI; however, urine bacterial culture is still necessary to exclude or confirm UTI in all cases.

Serum protein electrophoresis: any role in monitoring for antiretroviral therapy?

BACKGROUND: Developing world are always looking for monitoring tools during reagent shortage and equipments troubles which are very frequent. The aim of this study was to evaluate Serum Protein Electrophoresis (SPE) as a marker for assessing HIV treatment response. METHODS: A cross-sectional study was conducted with 220 participants in four distinct groups: Symptomatic HIV positive patients [specifically those on antiretroviral treatment (ART) versus those not on ART] asymptomatic HIV positive patients, and healthy blood donors. Five serum protein fractions (Albumin, Alpha-1, Alpha-2, Beta, and Gamma) were compared between these groups after measuring the density of the fractions. RESULTS: Concentration of gamma globulin was lowest among healthy blood donors, intermediate and comparable among asymptomatic HIV positive and symptomatic HIV positive on ART and highest among untreated symptomatic HIV positive. Concentration of gamma globulin was inversely correlated with the disease stage (p < 0.001). CONCLUSION: In this study, conducted in a setting where the burden of infectious diseases is high, the density of gamma globulin and albumin fractions were significantly associated with HIV status, and among HIV positive patients, with stage of HIV disease and ART. These results suggest that the feasibility of using SPE for monitoring the response of ART in low resource settings should be further explored.

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.

An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals at risk of coronary events. A WOSCOPS substudy.

AIMS: The Glycine389 variant of the beta-1 adrenergic receptor generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant and may confer protection against coronary events similar to that observed with beta-blockers. The aim of this study was to ascertain whether this Glycine389 variant protects against coronary events. METHODS AND RESULTS: We identified the genotype at position 389 of the beta1AR in 1554 individuals taken from men enrolled in the West of Scotland Coronary Prevention Study. Men with a coronary event (event group) were each matched for age and smoking status with two control subjects from the same cohort who had not had a coronary event (control group). We compared the distribution of genotypes in the event and control groups. Conditional logistic regression was used to calculate odds ratios for each of the genotypes. The prevalence of the three genotypes in the entire cohort was ArgArg 53.5%, ArgGly 39.6%, GlyGly 6.9%. The Arg389Gly beta-1 adrenergic receptor polymorphism was not associated with coronary events. Using the ArgArg genotype as the reference, the odds ratio for the ArgGly genotype was 1.1 (95% CI, 0.88-1.38) and for the GlyGly genotype it was 1.05 (95% CI, 0.68-1.62). CONCLUSION: Our longitudinal case-control study demonstrates that the Glycine389 variant of the beta-1 adrenergic receptor does not protect against coronary events.

Utilisation of transluminal extraction atherectomy in the treatment of saphenous vein graft disease: two case reports.

Saphenous vein graft disease is an increasing problem as more patients undergo bypass grafting and to date the most effective management strategy remains undefined. The major limitations of angioplasty for saphenous vein graft lesions are the risk of distal embolization and restenosis. Primary stenting in this situation results in superior lumen enlargement and higher procedural success but is still associated with significant restenosis. We describe two cases in which transluminal extraction (TEC) atherectomy is utilised for the treatment of vein graft disease with good immediate and long term angiographic results. The first case reports the use of TEC atherectomy for the primary treatment of a discrete eccentric filling defect, and the second case describes the use of this technique in the management of in-stent restenosis.

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. 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).

Naturally occurring xanthine urolithiasis in a domestic shorthair cat.

A five-year-old neutered male domestic shorthair cat was presented after three episodes of urethral obstruction and anuria requiring relief urethral catheterisation. A double contrast cystogram revealed the presence of multiple small cystoliths which were radiolucent on plain radiographs. A perineal urethrostomy and a cystotomy were performed to relieve the urethral obstruction and to remove the cystoliths. Quantitative analysis revealed the cystoliths to be composed of 100 per cent xanthine. Clinical history suggested the xanthinuria to be naturally occurring. Unfortunately, the cat was killed in a road traffic accident two months after the surgical procedure, preventing further long-term assessment.

Neoplastic angina: a case report.

A 54-year-old Caucasian woman, with a 1-year history of exertional angina was investigated by means of coronary angiography. On injection of contrast into both coronary arteries an unusual area of capillary blushing was seen around the point of a left main stem stenosis. At surgery a mass was seen arising from the area of the aortic root extending around the left main stem. Histology confirmed this to be an aortic paraganglioma. Three-vessel coronary artery bypass grafting was performed and at 6-month follow-up the patient remained symptom free.

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.

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").

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.

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.

The cloning and characterization of phage promoters, directing high expression of luciferase in Pseudomonas syringae pv. phaseolicola, allowing single cell and microcolony detection.

Regions of DNA containing promoter sequences from a Pseudomonas syringae pv. phaseolicola-specific phage (phi 11P) were identified by shotgun cloning into a broad-host-range promoter-probe vector (pQF70). When used in conjunction with the luciferase reporter genes, one of these DNA fragments, 19H, directed gene expression at a level which enabled the subsequent light output (bioluminescence) of single cells of P. syringae pv. phaseolicola to be detected and visualized using a charge-coupled device (CCD). The P. syringae pv. phaseolicola phi 11P, 19H and P. aeruginosa phi PLS27, HcM promoters gave a 50-fold increase in bioluminescence (maximum relative light output) compared to similar constructs containing other well-characterized promoters, for example, tetracycline. Similar bioluminescent characteristics of the transformed bacterium, were observed during growth with and without antibiotic-selection. When lux+ bacteria were inoculated onto French bean leaf (Phaseolus vulgaris L.), the resultant secondary halo blight lesions were bioluminescent and during phylloplane colonization by the lux+ bacterium, bioluminescence on leaf surfaces was detected and imaged by the CCD. Use of these newly identified promoters, combined with the greatly increased sensitivity of bioluminescence detection by the CCD, thus provided a new dimension for the study of natural ecological populations during the bacterial colonization of plants.

Preclinical and early clinical studies with BW 1370U87, a reversible competitive monoamine oxidase-A inhibitor.

BW 1370U87 is unique among potent inhibitors of monoamine oxidase-A (MAO-A) in that it contains no nitrogen. Like other MAO-A inhibitors, BW 1370U87 elevates neurotransmitter amines in the brain over the same dose range at which it exhibits positive activities in animal models of depressive illness. However, BW 1370U87 differs from most other MAO inhibitors in that its mechanism of action follows simple competitive kinetics, so that an unusually high concentration of tyramine in peripheral tissues may displace the inhibitor from MAO-A sites in the intestine and liver. In addition, BW 1370U87 concentrations in brains of rats appear much higher than in plasma, whereas extensive metabolism of the parent compound in the liver produces weaker MAO-A inhibitors with the same type of competitive mechanism. Early phase-I safety trials at acute doses up to 2,000 mg of BW 1370U87 showed no adverse reactions, whereas MHPG in urine was decreased, indicating that in vivo inhibition of MAO-A was achieved in humans. Thus BW 1370U87 represents a new agent with potential therapeutic application in depression and other CNS illnesses.

Sulfasalazine inhibits lyso-PAF: acetyl-COA acetyltransferase.

Sulfasalazine produced a dose-dependent inhibition of the enzymatic synthesis of platelet-activating factor (PAF) in lysates of rat pleural neutrophils, with an IC50 of 50 microM. Major metabolites of sulfasalazine, 5-aminosalicylic acid and sulfapyridine, inhibited this enzymatic synthesis at much higher concentrations. Inhibition of arachidonate 5-lipoxygenase by sulfasalazine and its major metabolites was also observed at higher concentrations (2-3 mM). Because PAF is a potent mediator of inflammatory responses, an inhibition of PAF synthesis by sulfasalazine may contribute to its therapeutic actions in conditions such as ulcerative colitis and rheumatic illnesses.