Xanthones are natural products present in plants and microorganisms. In plants, their biosynthesis starts with regioselective cyclization of 2,3′,4,6-tetrahydroxybenzophenone to either 1,3,5- or 1,3,7-trihydroxyxanthones, catalysed by cytochrome P450 (CYP) enzymes. Here we isolate and express CYP81AA-coding sequences from Hypericum calycinum and H. perforatum in yeast. Microsomes catalyse two consecutive reactions, that is, 3′-hydroxylation of 2,4,6-trihydroxybenzophenone and C–O phenol coupling of the resulting 2,3′,4,6-tetrahydroxybenzophenone. Relative to the inserted 3′-hydroxyl, the orthologues Hc/HpCYP81AA1 cyclize via the para position to form 1,3,7-trihydroxyxanthone, whereas the paralogue HpCYP81AA2 directs cyclization to the ortho position, yielding the isomeric 1,3,5-trihydroxyxanthone. Homology modelling and reciprocal mutagenesis reveal the impact of S375, L378 and A483 on controlling the regioselectivity of HpCYP81AA2, which is converted into HpCYP81AA1 by sextuple mutation. However, the reciprocal mutations in HpCYP81AA1 barely affect its regiospecificity. Product docking rationalizes the alternative C–O phenol coupling reactions. Our results help understand the machinery of bifunctional CYPs.

NULL

NULL

NULL

NULL

The objective of this study was to investigate the influence of simultaneous factors that potentially keep patients far from achieving target INR range at discharge in hospitalized patients. Prospective cross-sectional observational study conducted at the Cardiology Department and Intensive Care Unit (ICU) of the Assiut University Hospitals. One-hundred and twenty patients were enrolled in the study from July 2013 to January 2014. Outcome measures were discharge INRs, bleeding and thromboembolic episodes. Bivariate analysis and multinomial logistic regression were conducted to determine independent risk factors that can keep patients outside target INR range. Patients who were newly initiated warfarin on hospital admission were given low initiation dose (2.8 mg ± 0.9). They were more likely to have INR values below 1.5 during hospital stay, 13 (27.7%) patients compared with 9 (12.3%) previously treated patients, respectively (p= .034). We found that the best predictors of achieving below target INR range relative to within target INR range were; shorter hospital stay periods (OR, 0.82 for every day increase [95% CI, 0.72–0.94]), being a male patient (OR, 2.86 [95% CI, 1.05–7.69]), concurrent infection (OR, 0.21 [95% CI, 0.07–0.59]) and new initiation of warfarin therapy on hospital admission (OR, 3.73 [95% CI,1.28–10.9]). Gender, new initiation of warfarin therapy on hospital admission, shorter hospital stay periods and concurrent infection can have a significant effect on discharge INRs. Initiation of warfarin without giving loading doses increases the risk of having INRs below 1.5 during hospital stay and increases the likelihood of a patient to be discharged with INR below target range. Following warfarin dosing nomograms and careful monitoring of the effect of various factors on warfarin response should be greatly considered

The objective of this study was to investigate the influence of simultaneous factors that potentially keep patients far from achieving target INR range at discharge in hospitalized patients. Prospective cross-sectional observational study conducted at the Cardiology Department and Intensive Care Unit (ICU) of the Assiut University Hospitals. One-hundred and twenty patients were enrolled in the study from July 2013 to January 2014. Outcome measures were discharge INRs, bleeding and thromboembolic episodes. Bivariate analysis and multinomial logistic regression were conducted to determine independent risk factors that can keep patients outside target INR range. Patients who were newly initiated warfarin on hospital admission were given low initiation dose (2.8 mg ± 0.9). They were more likely to have INR values below 1.5 during hospital stay, 13 (27.7%) patients compared with 9 (12.3%) previously treated patients, respectively (p= .034). We found that the best predictors of achieving below target INR range relative to within target INR range were; shorter hospital stay periods (OR, 0.82 for every day increase [95% CI, 0.72–0.94]), being a male patient (OR, 2.86 [95% CI, 1.05–7.69]), concurrent infection (OR, 0.21 [95% CI, 0.07–0.59]) and new initiation of warfarin therapy on hospital admission (OR, 3.73 [95% CI,1.28–10.9]). Gender, new initiation of warfarin therapy on hospital admission, shorter hospital stay periods and concurrent infection can have a significant effect on discharge INRs. Initiation of warfarin without giving loading doses increases the risk of having INRs below 1.5 during hospital stay and increases the likelihood of a patient to be discharged with INR below target range. Following warfarin dosing nomograms and careful monitoring of the effect of various factors on warfarin response should be greatly considered

The objective of this study was to investigate the influence of simultaneous factors that potentially keep patients far from achieving target INR range at discharge in hospitalized patients. Prospective cross-sectional observational study conducted at the Cardiology Department and Intensive Care Unit (ICU) of the Assiut University Hospitals. One-hundred and twenty patients were enrolled in the study from July 2013 to January 2014. Outcome measures were discharge INRs, bleeding and thromboembolic episodes. Bivariate analysis and multinomial logistic regression were conducted to determine independent risk factors that can keep patients outside target INR range. Patients who were newly initiated warfarin on hospital admission were given low initiation dose (2.8 mg ± 0.9). They were more likely to have INR values below 1.5 during hospital stay, 13 (27.7%) patients compared with 9 (12.3%) previously treated patients, respectively (p= .034). We found that the best predictors of achieving below target INR range relative to within target INR range were; shorter hospital stay periods (OR, 0.82 for every day increase [95% CI, 0.72–0.94]), being a male patient (OR, 2.86 [95% CI, 1.05–7.69]), concurrent infection (OR, 0.21 [95% CI, 0.07–0.59]) and new initiation of warfarin therapy on hospital admission (OR, 3.73 [95% CI,1.28–10.9]). Gender, new initiation of warfarin therapy on hospital admission, shorter hospital stay periods and concurrent infection can have a significant effect on discharge INRs. Initiation of warfarin without giving loading doses increases the risk of having INRs below 1.5 during hospital stay and increases the likelihood of a patient to be discharged with INR below target range. Following warfarin dosing nomograms and careful monitoring of the effect of various factors on warfarin response should be greatly considered

The objective of this study was to investigate the influence of simultaneous factors that potentially keep patients far from achieving target INR range at discharge in hospitalized patients. Prospective cross-sectional observational study conducted at the Cardiology Department and Intensive Care Unit (ICU) of the Assiut University Hospitals. One-hundred and twenty patients were enrolled in the study from July 2013 to January 2014. Outcome measures were discharge INRs, bleeding and thromboembolic episodes. Bivariate analysis and multinomial logistic regression were conducted to determine independent risk factors that can keep patients outside target INR range. Patients who were newly initiated warfarin on hospital admission were given low initiation dose (2.8 mg ± 0.9). They were more likely to have INR values below 1.5 during hospital stay, 13 (27.7%) patients compared with 9 (12.3%) previously treated patients, respectively (p= .034). We found that the best predictors of achieving below target INR range relative to within target INR range were; shorter hospital stay periods (OR, 0.82 for every day increase [95% CI, 0.72–0.94]), being a male patient (OR, 2.86 [95% CI, 1.05–7.69]), concurrent infection (OR, 0.21 [95% CI, 0.07–0.59]) and new initiation of warfarin therapy on hospital admission (OR, 3.73 [95% CI,1.28–10.9]). Gender, new initiation of warfarin therapy on hospital admission, shorter hospital stay periods and concurrent infection can have a significant effect on discharge INRs. Initiation of warfarin without giving loading doses increases the risk of having INRs below 1.5 during hospital stay and increases the likelihood of a patient to be discharged with INR below target range. Following warfarin dosing nomograms and careful monitoring of the effect of various factors on warfarin response should be greatly considered

As a continuation of the work on EtOAc fraction of the Indonesian sponge Acanthostrongylophora ingens, 2 new alkaloids: one pyrimidine-β-carboline alkaloid named ingenine A (2) and one pyrimidine-γ-carboline alkaloid named ingenine B (3), along with annomontine (1) were isolated. Their structures were unambiguously established on the basis of NMR spectroscopy (1 H, 13C, 1 H-1 H COSY, HMQC, and HMBC) and mass spectral data. This is the first report of isolation pyrimidine-γ-carboline alkaloid from natural source. Compounds 1 and 3 showed pronounced cytotoxicity against the murine lymphoma L5178Y cancer cell line with ED50 7.8 and 9.1 μg/mL respectively, while compound 2 showed weak activity.