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Vitamin-K antagonists (VKAs) have remained the mainstay of oral anticoagulant therapy for the treatment and prevention of thromboembolism. The management of treatment with VKAs is challenging due to their narrow therapeutic index and the wide interindividual variation in response to therapy. Variants of the CYP2C9and the VKORC1gene account for 30–50 of the variability in dosing requirements, and it has been proposed that genotyping of these loci could facilitate management of VKA therapy and minimize risk of overanticoagulation, even in very low doses. We present the first reported case of a patient with the compounded genotype CYP2C933and VKORC1-1639A/Aunder treatment with acenocoumarol, and review of other reported cases with analogous genotypic profiles but under treatment with warfarin.

Objective:We sought to investigate the short- and long- term effects of bosentan therapy on endothelial, inflammatory and fibrotic markers in patients with pulmonary arterial hypertension (PAH) and the relation to clinical and hemodynamic responses.Methods:We studied 16 patients with moderate-severe idiopathic PAH, in WHO functional class II-IV, despite conventional treatment. Patients received additional treatment with bosentan, 62.5 mg twice daily for 1 month, followed by 125 mg twice daily for 11 months. Study endpoints included 6-min walking distance (6MWD), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and plasma levels of intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), IL-6 and brain natriuretic peptide (BNP). Patients were assessed at baseline, 2 months and 12 months after initiation of bosentan.Results:At 2 months there was an improvement in 6MWD (p < 0.001) and functional class (p < 0.001) and a marked fall in PVR (p < 0.001), ICAM-1 (p < 0.001), IL-6 (p < 0.001)and BNP (p 0.001). At 12 months, 6MWD was further improved (p < 0.001), PVR remained significantly improved (p < 0.001), mPAP was significantly decreased (p < 0.001) and ICAM-1, IL-6 and BNP remained significantly lower (p < 0.001). Significant correlations were found between changes in ICAM-1 and cardiac index (r 0.59, p 0.01), IL-6 and PVR (r 0.51, p 0.04), BNP and 6MWD (r −0.53, p 0.03) and BNP and PAP (r 0.51, p 0.04) between 2- and 12-months treatment.Conclusions:In patients with moderate-severe PAH, the addition of bosentan to therapy, exerts favorable anti-inflammatory effects, which are associated with clinical and hemodynamic improvement.

Background:Heart-type fatty acid-binding protein (H-FABP) is considered a marker of myocardial necrosis but whether or not it is modified by myocardial ischemia is not clear. We sought to investigate if H-FABP serum levels increase following non-urgent coronary angioplasty.Methods:We studied 31 patients undergoing coronary angioplasty. Peripheral venous samples were drawn immediately before angioplasty, 1 h after the first balloon inflation and 24 h after the procedure and assayed for H-FABP.Results:Serum levels of H-FABP increased significantly at 1 h vs baseline from 2554 ± 1268 to 3322 ± 245 pg ml−1(p  0.024). However, no differences were observed between 1 h and 24 h after angioplasty (3268 ± 1861 vs 3322 ± 2459 pg ml−1, p  0.87). Moreover, no significant difference was observed when we compared 24 h after angioplasty with the baseline (3268 ± 1861vs 2554 ± 1268 pg ml−1, p  0.112).Conclusions:We conclude that H-FABP significantly increases after elective coronary angioplasty at 1 h compared with baseline values; whether or not this has any prognostic significance for future events, as it occurs with troponins, needs to be studied further.

To assess the effects of inspiratory muscle training (IMT) on autonomic activity, endothelial function, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with chronic heart failure.

Abundant evidence suggests that cytokines involve in the pathogenesis of latent autoimmune diabetes of adults (LADA). This is a slowly progressive form of type 1 diabetes, which is initially diagnosed as type 2 diabetes. In this study, healthy individuals LADA and type 2 diabetic patients were genotyped for IL-6-174G/C, TNF-α-308A/G, TGF-β1-codon10T/C, TGF-β1-codon25G/C, IL-10-1082A/G, IL-10-819T/C, IL-10-592A/C gene polymorphisms, by sequence-specific-primer polymerase chain reaction methodology. A significant difference in the frequencies of −1082A/G IL-10 alleles was observed, with the −1082*A allele (known to be associated with low IL-10 production), predominating in LADA diabetics than type 2 diabetics (p=0.036). No significant differences of genotypes, phenotypes, or haplotype frequencies in the remaining cytokine polymorphisms were observed. Analysis of allele combinations revealed a significant involvement of the low and high in vitroproduction IL-10 alleles in the development of LADA and type 2 diabetes, respectively. These results suggest that the G/A mutation at position −1082 of IL-10 promoter gene region might be one of the factors participating to the pathogenesis of LADA diabetes and that identification of cytokine gene polymorphisms might contribute to the characterization of the different types of diabetes mellitus.

The correlation between sequence homology and catalytic importance of a specific amino acid in the E. coliand Liver/Kidney/Bone (L/K/B) human alkaline phosphatase was investigated. For this reason Ala-l6l in the E. colienzyme was substituted with a threonine residue via site-specific mutagenesis. The homologous amino acid in the L/K/B alkaline phosphatase sequence has been shown to cause inactivation of the enzyme. In E. colialkaline phosphatase the Ala-l61→Thr substitution results in a mutant enzyme with virtually unchanged catalytic properties when compared to the wild-type enzyme. Our results show that Ala-161 in the E. colialkaline phosphatase does not have an important catalytic role. The results suggest that the three-dimensional topology of the L/K/B alkaline phosphatase may be different from that observed for the enzyme from E. coli.

Abstract: The aim of the present study was to investigate the influence of three different retinoids, isotretinoin, etretinate and acitretin, on the mitogenic response of peripheral blood mononuclear cells (PBMCs) to PHA and PMA in vitro. All three retinoids at high concentrations (10 –4 M ) significantly inhibited the mitogenic response of PBMCs to these mitogens. At lower concentrations (10 –5 M and 10 –6 M ) none of the three retinoids had any effect on PBMC proliferation in response to PHA. Interestingly, isotretinoin and etretinate significantly enhanced the PMA-induced stimulation of proliferation, whereas acitretin at 10 –5 M failed to influence the mitogenic response to PMA but enhanced it at 10 –6 M . The enhancing effects of retinoids on the proliferative response of PMA-stimulated PBMCs were reversed by rapamycin (10 ng/ml), an immunosuppressant known to inhibit the phorbol ester-induced protein kinase C pathway of lymphocyte activation. In conclusion, our study indicates that retinoids directly trigger the PMA-induced protein kinase C pathway of lymphocyte activation in a concentration-dependent manner. This observation could explain the findings of previous studies showing an in vivo immunopotentiating effect of retinoids on certain immune functions.