Warfarin, a commonly prescribed anticoagulant, exhibited large inter-individual and inter-ethnic differences in the dose required for its anticoagulation effect. Asian populations, including Chinese, require a much lower maintenance dose than Caucasians, for which the mechanisms still remain unknown. We determined DNA sequence variants in CYP2C9 and VKORC1 in 16 Chinese patients having warfarin sensitivity (< or = 1.5 mg/day, n = 11) or resistance (> or = 6.0 mg/day, n = 5), 104 randomly selected Chinese patients receiving warfarin, 95 normal Chinese controls and 92 normal Caucasians. We identified three CYP2C9 variants, CYP2C9*3, T299A and P382L, in four warfarin-sensitive patients. A novel VKORC1 promoter polymorphism (-1639 G > A) presented in the homozygous form (genotype AA) was found in all warfarin-sensitive patients. The resistant patients were either AG or GG. Among the 104 randomly selected Chinese patients receiving warfarin, AA genotype also had lower dose than the AG/GG genotype (P < 0.0001). Frequencies of AA, AG and GG genotypes were comparable in Chinese patients receiving warfarin (79.7, 17.6 and 2.7%) and normal Chinese controls (82, 18 and 0%), but differed significantly from Caucasians (14, 47 and 39%) (P < 0.0001). The promoter polymorphism abolished the E-box consensus sequences and dual luciferase assay revealed that VOKRC1 promoter with the G allele had a 44% increase of activity when compared with the A allele. The differences in allele frequencies of A/G allele and its levels of VKORC1 promoter activity may underscore the inter-individual differences in warfarin dosage as well as inter-ethnic differences between Chinese and Caucasians.

Background: Modified Nutrition Risk in the Critically Ill (m-NUTRIC) score is used to evaluate the nutritional risk of patients in intensive care units (ICUs). This study aimed to investigate whether m-NUTRIC can be used as a predictive factor related to the outcome of patients in surgical ICU (SICU) and to identify which patients will benefit from aggressive nutritional intervention according to the results of m-NUTRIC score. Methods: A total of 205 patients who were admitted to surgical ICU (SICU) with ventilator use for more than 24 hours were enrolled. The m-NUTRIC score data were calculated the day when the patients were admitted to SICU. Patients were divided into two groups according to their m-NUTRIC score: the low-risk group (<5 points, 116 patients) and the high risk group (≥5 points, 89 patients). Results: In this study, a total of 205 patients were enrolled for analysis, including patients in the low-risk group (n = 116) and those in the high risk group (n = 89). The mean duration of ventilator use was 3.6 ± 6.5 days, and average SICU stays for all patients was 5.1 ± 7.4 days. The SICU mortality was significantly higher in the high-risk group (10.3% vs 1.7%). Comparison between survivals and nonsurvivals was carried out, and the data showed that the AKI, Vasopressors, SOFA, APACHE-II, m-NUTRIC score, and shock patient were all significantly associated with higher mortality. The multivariate analysis revealed that acute kidney injury (OR = 13.16; 95% confidence intervals = 3.69–46.92; p < 0.0001) and m-NUTRIC score were independent factors of ICU mortality in these patients. A receiver operating characteristic curve was used to calculate the area under the curve, which was 0.801. The data indicated that high m-NUTRIC score were significantly associated with SICU mortality with the cutoff score > 4 (sensitivity = 90.5%, specificity = 62.3%, p < 0.001). Conclusion: We found in this study that the high m-NUTRIC score is an independent factor of ICU mortality, and m-NUTRIC score can be used as an initial screening tool for nutritional assessment in patients admitted to surgical ICU. Further investigations to evaluate whether the aggressive nutritional intervention would be beneficial in the SICU patients with higher m-NUTRIC score is mandatory.

Background/Purpose: TRB3 (tribbles 3), an apoptosis-regulated gene, increases during endoplasmic reticulum stress. Hypoxia can induce inflammatory mediators and apoptosis in cardiomyocytes. However, the expression of TRB3 in cardiomyocyte apoptosis under hypoxia is not thoroughly known. We investigated the regulation mechanism of TRB3 expression and apoptosis induced by hypoxia in cardiomyocytes. Methods: An in vivo model of acute myocardial infarction (AMI) was applied in adult Wistar rats to induce myocardial hypoxia. Rat neonatal cardiomyocytes were subjected to 2.5% O 2 to induce hypoxia. Results: The expression of TRB3 was evaluated in cultured rat neonatal cardiomyocytes subjected to hypoxia. Hypoxia significantly enhanced TRB3 protein and mRNA expression. Adding c-jun N-terminal kinase (JNK) inhibitor SP600125, JNK small interfering RNA (siRNA), tumor necrosis factor-a (TNF-a) antibody, and atorvastatin 30 minutes before hypoxia reversed the induction of TRB3 protein. A gel-shift assay showed the DNA-binding activity of growth arrest and DNA damage-inducible gene 153 (GADD153), which increased after hypoxia. Hypoxia increased, whereas the TRB3-mut plasmid, SP600125, and TNF-a antibody abolished the hypoxia-induced TRB3 promoter activity. Hypoxia increased the secretion of TNF-a from cardiomyocytes. Exogenous administration of TNF-a recombinant protein to the cardiomyocytes without hypoxia increased TRB3 protein expression, similar to that observed after hypoxia. Hypoxia-induced cardiomyocyte apoptosis is inhibited by TRB3 siRNA, the TNF-a antibody, and atorvastatin. Atorvastatin reduced the TRB3 expression and cardiomyocyte apoptosis induced by AMI. Hypoxia induces TRB3 through TNF-a, JNK, and the GADD153 pathway. Conclusion: Treatment of atorvastatin inhibits the expression of TRB3 and cardiomyocyte apoptosis induced by AMI and hypoxia.

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