Laboratory Evaluation of a Point-of-Care Downward-Flow Assay for Simultaneous Detection of Antibodies to Treponema pallidum and Human Immunodeficiency Virus.

Combining the detection of syphilis and HIV antibodies into one point-of-care test integrates syphilis screening into already existing HIV screening programs, which may be particularly beneficial in settings such as antenatal care. Using the INSTI Multiplex downward-flow immunoassay, we tested 200 stored serum samples from high-risk patients enrolled in a longitudinal study on HIV infection and syphilis in Peruvian men who have sex with men and transgender women. This rapid assay detected HIV and Treponema pallidum serum antibodies with sensitivities of 100% (95% confidence interval [CI], 95.9% to 100%) and 87.4% (95% CI, 81.4% to 92.0%), respectively, and specificities of 95.5% (95% CI, 89.9% to 98.5%) and 97.0% (95% CI, 84.2% to 99.9%), respectively (n = 200). The sensitivity for syphilis antibody detection was higher in patients with a rapid plasma reagin titer of ≥1:8 (97.3%) than in those with a titer of ≤1:4 (90%) or a nonreactive titer (66.7%).

Environmental factors modulate the effect of the APOE genetic polymorphism on plasma lipid concentrations: ecogenetic studies in a Mediterranean Spanish population.

To investigate APOE gene--environment interaction effects on plasma lipid concentrations, we conducted a cross-sectional study in a Mediterranean Spanish population consisting of 396 men and 513 women aged 18 to 66 years. The frequency of the epsilon 4 variant was 0.071 (95% confidence interval 0.059, 0.082), confirming the lower frequency of this allele in Southern Europe. In general, the carriers of the epsilon 2 variant had lower concentrations (P <.05) of total and low-density lipoprotein cholesterol (LDL-C), carriers of the epsilon 3 variant had intermediate concentrations, and carriers of the epsilon 4 variant had higher concentrations (P <.05) in both sexes, even after multivariate adjustment for age, body mass index, alcohol consumption, tobacco smoking, physical activity, marital status, and education. However, when the homogeneity of allelic effects according to environmental factors was tested, significant interaction terms were found. In women, an important interaction between alcohol consumption and the APOE polymorphism in determining LDL-C concentrations was found (P <.003). LDL-C concentrations in female drinkers with the epsilon 2 variant were significantly lower (P <.014) than in nondrinkers with the epsilon 2 variant. Likewise, in female drinkers with the epsilon 4 variant, LDL-C concentrations were also significantly (P <.010) lower than in nondrinkers with the epsilon 4 variant. Moreover, in female drinkers, LDL-C concentrations did not differ between carriers of the epsilon 4 and the epsilon 3 variants, and in nondrinkers, LDL-C concentrations did not differ between carriers of the epsilon 2 and the epsilon 3 variants. We also found a statistically significant interaction effect (P <.001) between the APOE polymorphism and physical activity in determining high-density lipoprotein cholesterol concentrations in men. Our results indicate that environmental factors are important modulators of the effect of the APOE polymorphism on plasma lipid concentrations.

[Apolipoprotein E gene polymorphism and risk of hypercholesterolemia: a case control study in a working population of Valencia]. / Polimorfismos en el gen de la apolipoproteína E y riesgo de hipercolesterolemia: un estudio de casos y controles en una población laboral de Valencia.

BACKGROUND: The apolipoprotein E (apoE) gene is polymorphic with three common alleles (epsilon 2, epsilon 3, epsilon 4) whose allelic frequency and association with lipid levels varies from population to population. The aim of this study was to estimate the association between these genetic variants and the risk of hypercholesterolemia in a Mediterranean Spanish population. PATIENTS AND METHODS: A case-control study in a working population from Valencia was carried out. A total of 330 cases (148 men and 182 women) with moderate hypercholesterolemia (total cholesterol > 200 mg/dl or with lipid lowering treatment) and age range 20 to 60 years, were identified. 330 normocholesterolemic controls matched by age and sex were selected. From all of them data of apoE genotype, body mass index, lipid and lipoprotein levels, socioeconomic and life-style variables were obtained. RESULTS: The epsilon 2 allele frequency was statistically lower in cases (0.033) than in controls (0.086). The epsilon 4 allele frequency was higher in cases (0.115) than in controls (0.039). In the crude logistic regression analysis, the apoE polymorphism was related (p < 0.001) to the risk of hypercholesterolemia. After adjustment by age, body mass index, educational level, tobacco smoking, alcohol consumption and physical activity the epsilon 2 allele was associated with a lower risk of hypercholesterolemia (odds ratio [OR] = 0.36; 95% confidence interval (CI): 0.20-0.64), and the epsilon 4 allele was associated with a higher risk (OR = 3.04; 95% CI: 1.82-5.06). CONCLUSIONS: The apoE genotype was significantly related to the risk of moderate hypercholesterolemia in the Mediterranean Spanish population.

The preclinical pharmacological profile of the potent and selective leukotriene B4 antagonist CP-195543.

CP-195543 [(+)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid] is a structurally novel, selective and potent leukotriene B4 (LTB4) receptor antagonist. In vitro CP-195543 inhibited [3H]LTB4 binding to high-affinity LTB4 receptors on human neutrophils (HN) and murine spleen membranes with IC50 values of 6.8 nM (Ki = 4.9 nM) and 37.0 nM (Ki = 26.9 nM), respectively. CP-195543 inhibited human and mouse neutrophil chemotaxis mediated by LTB4 with IC50 values of 2.4 nM and 7.5 nM, respectively. Evidence of noncompetitive antagonist effects on the HN high-affinity LTB4 receptor was obtained by Scatchard analysis of [3H]LTB4 binding to and chemotaxis of HN to LTB4. Scatchard analyses of [3H]LTB4 binding to low-affinity receptors on HN indicated that CP-195543 acted as a competitive antagonist at this receptor, and inhibition of LTB4-mediated CD11b up-regulation on HN was inhibited competitively by CP-195543 (pA2 = 7.66). In whole blood, CP-195543 also blocked CD11b up-regulation on HN (pA2 = 7.12) and murine neutrophils (pA2 = 7.06) with a similar potency. LTB4-mediated CD11b up-regulation on human monocytes and eosinophils in whole blood were inhibited by CP-195543 with IC50 values of 270 nM and 420 nM, respectively. CP-195543 at 10 microM failed to inhibit HN chemotaxis and CD11b up-regulation mediated through alternative (i.e., complement fragment 5a, interleukin-8, platelet-activating factor) G-protein-coupled chemotactic factor receptors. In vivo, after oral administration, CP-195543 blocked LTB4-mediated neutrophil infiltration in guinea pig and murine skin with ED50 values of 0.1 mg/kg and 2.8 mg/kg p.o., respectively. When administered in osmotic pumps, CP-195543 reduced the clinical symptoms and attendant weight loss in an IL-1-exacerbated murine model of collagen-induced arthritis with half-maximal effects associated with plasma drug levels of 0.4 to 0.5 microg/ml. Collectively these data provide evidence of the in vitro potency and in vivo efficacy of a novel LTB4 antagonist and support its clinical evaluation in a variety of inflammatory diseases in man.

trans-3-Benzyl-4-hydroxy-7-chromanylbenzoic acid derivatives as antagonists of the leukotriene B4 (LTB4) receptor.

The SAR of a series of 2-(7-chromanyl)benzoic acids has been investigated with the aim of identifying potent and selective LTB4 receptor antagonists that maintain potency in complex biological fluids. We found optimal activity in derivatives with electron-withdrawing groups in the benzoic acid ring and with an unsubstituted C-3 benzyl group on the chromanol nucleus. While compounds containing a 3-(4-phenyl)benzyl chromanol substituent were potent LTB4 receptor antagonists, the increased lipophilicity imparted by the additional phenyl substituent led to decreased potency in the presence of plasma proteins. From among the potent compounds identified, CP-195543, the 5'-trifluoromethyl 3-benzyl chromanol, was selected for development.