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Bayesian methods are becoming increasingly used in applied psychological research. Previous researchers have thoroughly written about much of the details already, including the philosophy underlying Bayesian methods, computational issues associated with Bayesian model estimation, Bayesian model development and summary, and the role of Bayesian methods in the so-called replication crisis. In this paper, we seek to provide case studies comparing the use of frequentist methods to the use of Bayesian methods in applied psychological research. These case studies are intended to 'illustrate by example' the ways that Bayesian modelling differs from frequentist modelling and the differing conclusions that one may arrive at using the two methods. The intended audience is applied psychological researchers who have been trained in the traditional frequentist framework, who are familiar with mixed-effects models and who are curious about how statistical results might look in a Bayesian context. Along with our case studies, we provide general opinions and guidance on the use of Bayesian methods in applied psychological research.

To investigate the ability of a T2-weighted (W) magnetic resonance imaging (MRI)-based radiomics signature to differentiate solid non-small-cell lung carcinoma (NSCLC) from small-cell lung carcinoma (SCLC).The present retrospective study enrolled 152 eligible patients (NSCLC = 125, SCLC = 27). All patients underwent MRI using a 3 T scanner and radiomics features were extracted from T2W MRI. The least absolute shrinkage and selection operator (LASSO) logistic regression model was used to identify the optimal radiomics features for the construction of a radiomics model to differentiate solid NSCLC from SCLC. Threefold cross validation repeated 10 times was used for model training and evaluation. The conventional MRI morphology features of the lesions were also evaluated. The performance of the conventional MRI morphological features, and the radiomics signature model and nomogram model (combining radiomics signature with conventional MRI morphological features) was evaluated using receiver operating characteristic (ROC) curve analysis.Five optimal features were chosen to build a radiomics signature. There was no significant difference in age, gender, and the largest diameter. The radiomics signature and conventional MRI morphological features (only pleural indentation and lymph node enlargement) were independent predictive factors for differentiating solid NSCLC from SCLC. The area under the ROC curves (AUCs) for MRI morphological features, and the radiomics model, and nomogram model was 0.69, 0.85, and 0.90 (ROC), respectively.The T2W MRI-based radiomics signature is a potential non-invasive approach for distinguishing solid NSCLC from SCLC.

Aims For a given passively-distributed lipophilic drug, the extent of in vivo distribution (pharmacokinetic volume of distribution, Vd ) in obese individuals increases in relation to the degree of obesity. The present study had the objective of evaluating drug distribution in relation to in vitro lipophilicity, and the relative increase in Vd associated with obesity across a series of drugs. Methods Cohorts of normal-weight control and obese subjects received single doses of drugs ranging from hydrophilic (acetaminophen, salicylate) to lipophilic (imipramine, verapamil). Lipid solubility was measured by the log-transformed values of the high-pressure liquid chromatographic (HPLC) retention index (Log10 (HPLC)), and the octanol-water partition coefficient (LogP). Results Among normal-weight controls, Vd normalized for protein binding was highly correlated with Log10 (HPLC) (R2 = .65) and with LogP (R2 = .78). Vd of all drugs was increased in the obese cohort, but the relative increase (compared to controls) for individual drugs was disproportionately greater as lipid solubility increased. Since clearance was unrelated to lipophilicity, the increased Vd produced a parallel disproportionate increase in elimination half-life in the obese cohort that was associated with Log10 (HPLC) (R2 = .62). Conclusion Lipophilicity is a principal correlate of in vivo Vd , as well as the increased Vd of drugs in obese patients. The consequent prolongation of half-life in obesity has clinical safety implications in terms of delayed drug accumulation and washout during and after chronic dosage. The magnitude and importance of this effect for a given drug depends on the degree of obesity, as well as the lipid-solubility of the specific drug.

Wa Na Qi(), is a traditional-curing male impotence medicinal. We have made several conclusions through a field investigation to Antarctica, material medica literature research, and current market investigation. Throughout history, Wa Na Qi (also known ashaigou shen) was a word of vague connotation which was not the meaning of a specific product. However, the most common meaning of Wa Na Qi was the penises of several different species of seals. The name Wa Na Qi was adapted from a foreign word, and it is believed to sound like walrus, which has also been credited as a source for Wa Na Qi. In Chinese, Wa Na was a reference to the roundness of the walrus but eventually became a general description of heaviness. Later, it became a name for fur seals. The Song Dynasty Materia Medica腽肭脐为一味传统的补肾壮阳药，通过本草考证、香港及内地市场及生产厂家的调查，南极半岛及南设得兰群岛海域的实地考察，提出以下结论：腽肭脐(海狗肾)在历史上其实是一个比较笼统的概念，主要指源自海狗、海豹类几种海洋动物的外肾。腽肭脐一词，属于古代的外来语，其读音贴近海狗肾来源之一的海象Walrus一词。因为海象的肥耎，汉语中出现了一个音译词"腽肭"。最初宋代的《本草图经》与明代的《本草品汇精要》描述的原动物为海豹类。《本草纲目》(金陵版)所绘者与有鬃毛的海狗(毛皮海狮)的特征比较符合。《补遗雷公炮制便览》及此后本草书中，加入了主观臆想成分，进而以讹传讹。通过在南极周边海域的实地考察，了解到历史上腽肭脐可能源自海狗(毛皮海狮)及海豹类，这与现今药材市场海狗与海豹两大种群基本吻合。经对现今中国内地与香港市场品种实地考察，以海狗肾之名售卖者，包括海狗、海象、海豹类外生殖器。.

The oral direct-acting antiviral drug (DAA) offers tremendous opportunities to eliminate hepatitis C. We analyzed the market trends, price trends and global treatment progress of DAA drugs by reviewing the guidelines recommended by the World Health Organization for the treatment of hepatitis C, and discusses the current accessibility of DAA treatment and its influencing factors. The results show that WHO recommends the use of DAA for treatment of hepatitis C, but the price of DAA is expensive. Although some countries have taken measures to lower prices and improve accessibility, the advancement of DAA treatment has been unsatisfactory and coverage is still not high. In addition to price, factors such as strategy, health system, accessibility and service provision need to be considered, and public health methods should be adopted to promote DAA treatment to achieve the elimination of hepatitis C.全口服直接抗病毒药物（DAA）的上市为消除丙肝带来巨大机遇。本文通过梳理世界卫生组织近年更新的关于丙肝治疗的指南建议，并分析DAA药品的市场动态、价格趋势以及全球治疗进展，探讨目前DAA药物价格情况，治疗的可及性及其影响因素。结果显示WHO推荐使用DAA进行治疗，但DAA的价格昂贵，虽然各国采取措施降低价格，提高可及性，但DAA治疗的推进却不尽如人意，覆盖面依然不高。除了价格以外，还需考虑策略、卫生系统、可及性和服务提供等因素，采用公共卫生方法，推进DAA治疗，以实现丙肝的消除。.

This meta-analysis aimed to clarify the actual association between the phosphodiesterase type 5 inhibitors (PDE5-Is) use and the risk of melanoma in erectile dysfunction (ED) patients. A systematic literature search was conducted in online databases in October, 2016 to identify studies focusing on the association between PDE5-Is use and the risk of melanoma. Summarized multivariate adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to assess the strength of associations. A total of six clinical trials containing more than one million participants were included. ED patients using PDE5-Is shared a significant high risk of melanoma (RR=1.12, 95% CI=1.03-1.21, p=0.006). Positive associations were observed in all kinds of prescriptions: single prescription (RR=1.20, 95% CI=1.06-1.35, p=0.003), medium number of prescription (RR=1.15, 95% CI=1.01-1.30, p=0.03), and high number of prescription (RR=1.18, 95% CI=1.05-1.34, P=0.006). Additionally, PDE5-Is were also found to be significantly associated with increased risk of basal cell carcinoma (RR=1.14, 95% CI=1.09-1.19, p

Although Flotillin 1 (FLOT1) is highly expressed in various human cancers, its relationship with ovarian cancer (OC) remains unknown. This study determines FLOT1 expression in human ovarian tumors and examines its effect on OC cell proliferation. FLOT1 protein expression was assessed in a tissue microarray by immunohistochemical staining. We found that 81.48% malignant and 50% borderline tumors were FLOT1 protein-positive, whereas benign tumors and normal ovarian tissues were negative. The staining was strongest in serous malignant tumor and transitional cell carcinoma and weakest in mucinous tumor. Differentially expressed FLOT1 in freshly isolated serous tumors was confirmed by Western blot and we then evaluated FLOT1 expression association with OC patients' clinical characteristics. Histological typing established that FLOT1 protein expression was significantly associated with serous tumor (P Keywords: cell proliferation, epithelial ovarian cancer, FLOT1, miRNA, therapeutic target, tumorigenesis.

Summary Epstein–Barr virus (EBV) is a well-documented aetiological factor for multiple sclerosis (MS). EBV encodes at least 44 microRNAs (miRNAs) that are readily detectable in the circulation of human. Previous studies have demonstrated that EBV-encoded miRNAs regulate host immune response and may serve as biomarkers for EBV-associated diseases. However, the roles of EBV miRNAs in MS are still unknown. To fill the gap, we conducted a comprehensive profiling of 44 mature EBV miRNAs in 30 relapsing–remitting MS (RRMS) patients at relapse and 30 matched healthy controls. Expression levels of ebv-miR-BHRF1-2-5p and ebv-miR-BHRF1-3 were elevated significantly in the circulation and correlated positively with the expanded disability status scale (EDSS) scores of MS patients. Receiver operating characteristic (ROC) analyses confirmed that the expression of these two miRNAs distinguished MS patients clearly from healthy controls. Luciferase assays revealed that ebv-miR-BHRF1-2-5p may directly target MALT1 (mucosa-associated lymphoid tissue lymphoma transport protein 1), a key regulator of immune homeostasis. In conclusion, we described the expression of EBV miRNAs in MS and preliminarily validated the potential target genes of significantly altered EBV miRNAs. The findings may pave the way for prospective study about the pathogenesis of MS.

Amelogenesis imperfecta (AI) is a group of genetic disorders of defective dental enamel. Mutation of

Summary Background Various risk factors for surgical site infection (SSI) have been identified such as age, overweight, duration of surgery, blood loss, etc. Intraperitoneal chemotherapy during surgery is a common procedure in patients with gastric cancer, yet its impact on SSI has not been evaluated. Aim To evaluate whether intra-operative intraperitoneal chemotherapy is a key risk factor for organ/space SSI in patients with gastric cancer. Methods All patients with gastric cancer who underwent surgery at the Department of Gastrointestinal Surgery between January 2008 and December 2013 were studied. The organ/space SSI rates were compared between patients who received intra-operative intraperitoneal chemotherapy and patients who did not receive intra-operative intraperitoneal chemotherapy, and the risk factors for organ/space SSI were analysed by univariate and multi-variate regression analyses. The microbial causes of organ/space SSI were also identified. Findings Of the eligible 845 patients, 356 received intra-operative intraperitoneal chemotherapy, and the organ/space SSI rate was higher in these patients compared with patients who did not receive intra-operative intraperitoneal chemotherapy (9.01% vs 3.88%; P = 0.002). Univariate analysis confirmed the significance of this finding (odds ratio 2.443; P = 0.003). As a result, hospital stay was increased in patients who received intra-operative intraperitoneal chemotherapy {mean 20.91 days [95% confidence interval (CI) 19.76–22.06] vs 29.72 days (95% CI 25.46–33.99); P = 0.000}. The results also suggested that intra-operative intraperitoneal chemotherapy may be associated with more Gram-negative bacterial infections. Conclusion Intra-operative intraperitoneal chemotherapy is a significant risk factor for organ/space SSI in patients with gastric cancer.

Background Chinese women tend to have small and dense breasts and ultrasound is a common method for breast cancer screening in China. However, its efficacy and cost comparing with mammography has not been evaluated in randomised trials. Methods At 14 breast centres across China during 2008-2010, 13 339 high-risk women aged 30-65 years were randomised to be screened by mammography alone, ultrasound alone, or by both methods at enrollment and 1-year follow-up. Results A total of 12 519 and 8692 women underwent the initial and second screenings, respectively. Among the 30 cancers (of which 15 were stage 0/I) detected, 5 (0.72/1000) were in the mammography group, 11 (1.51/1000) in the ultrasound group, and 14 (2.02/1000) in the combined group (P=0.12). In the combined group, ultrasound detected all the 14 cancers, whereas mammography detected 8, making ultrasound more sensitive (100 vs 57.1%, P=0.04) with a better diagnostic accuracy (0.999 vs 0.766, P=0.01). There was no difference between mammography and ultrasound in specificity (100 vs 99.9%, P=0.51) and positive predictive value (72.7 vs 70.0%; P=0.87). To detect one cancer, the costs of ultrasound, mammography, and combined modality were $7876, $45 253, and $21 599, respectively. Conclusions Ultrasound is superior to mammography for breast cancer screening in high-risk Chinese women.

The influence of dexmedetomidine on postoperative delirium (POD) in adult surgical patients remains controversial. We aimed to analyse whether dexmedetomidine use could decrease POD incidence in this population and its relation to timing of dexmedetomidine administration and patient age.We used random-effects modelled meta-analysis, trial sequential analysis, and followed Cochrane methodology with Grading of Recommendations Assessment, Development, and Evaluation (GRADE). PubMed and Cochrane library were searched up to July 2017 for randomised controlled trials that analysed POD incidence of adult surgical patients (age ≥18 yr) after dexmedetomidine administration.Eighteen studies (comprising 3309 patients) were included. There was decreased risk of POD with dexmedetomidine use for the entire adult surgical population [odds ratio (OR) 0.35; 95% confidence interval (CI) 0.24-0.51)], with firm evidence from trial sequential analysis. Pre-specified subgroup analyses confirmed this result with firm evidence for cardiac and non-cardiac surgical patients, (OR 0.41; 95% CI 0.26-0.63) and (OR 0.33; 95% CI 0.18-0.59), respectively. We also found firm evidence for reduction of POD if dexmedetomidine is administered during the postoperative period (OR 0.30; 95% CI 0.21-0.44), in patients aged65 yr (OR 0.19; 95% CI 0.10-0.36) or ≥65 yr (OR 0.44; 95% CI 0.30-0.65). Evidence for dexmedetomidine's influence on secondary outcomes (in-hospital mortality, intensive care unit and hospital length of stay, bradycardia, and hypotension) is thus far insufficient to draw conclusions.Dexmedetomidine can reduce POD incidence for adult cardiac and non-cardiac surgical patients. The optimal dose and timing of dexmedetomidine and influence on other outcomes or particular patient populations with risk factors warrants further studies.PROSPERO: CRD42017072380.

Over 30 years ago, black Africans from Kenya and Ghana were shown to metabolize acetaminophen faster by glucuronidation and slower by oxidation compared with white Scottish Europeans. The objectives of this study were to determine whether similar differences exist between African-Americans and European-Americans, and to identify genetic polymorphisms that could explain these potential differences. Acetaminophen plasma pharmacokinetics and partial urinary metabolite clearances via glucuronidation, sulfation, and oxidation were determined in healthy African-Americans (18 men, 23 women) and European-Americans (34 men, 20 women) following a 1-g oral dose. There were no differences in acetaminophen total plasma, glucuronidation, or sulfation clearance values between African-Americans and European-Americans. However, median oxidation clearance was 37% lower in African-Americans versus European-Americans (0.57 versus 0.90 ml/min per kilogram; P = 0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11-14%; P < 0.01) were observed for acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate in women versus men. The UGT2B15*2 polymorphism was associated with variant-allele-number proportional reductions in acetaminophen total clearance (by 15-27%; P < 0.001) and glucuronidation partial clearance (by 23-48%; P < 0.001). UGT2B15 *2/*2 genotype subjects also showed higher acetaminophen protein-adduct concentrations than *1/*2 (by 42%; P = 0.003) and *1/*1 (by 41%; P = 0.003) individuals. Finally, CYP2E1 *1D/*1D genotype African-Americans had lower oxidation clearance than *1C/*1D (by 42%; P = 0.041) and *1C/*1C (by 44%; P = 0.048) African-Americans. Consequently, African-Americans oxidize acetaminophen more slowly than European-Americans, which may be partially explained by the CYP2E1*1D polymorphism. UGT2B15*2 influences acetaminophen pharmacokinetics in both African-Americans and European-Americans.

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis and hepatocellular carcinoma. Currently pegylated interferon (IFN) combined with ribavirin remains the best therapeutic approach, although patients infected with HCV genotype I may benefit from adding protease inhibitors as 'triple therapy'. MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate gene expression and have recently been shown to play an important role in human innate immune response and as an antiviral in chimpanzees. We studied the effect of miR-130a on the HCV replication. We found that miR-130a significantly inhibits HCV replication in both HCV replicon and J6-/JFH1-infected cells. Over expression of miR-130a upregulated the expression of type I IFN (IFN-α/IFN -β), ISG15, USP18 and MxA, which are involved in innate immune response and decreased expression of miR-122, a well-defined miRNA promoting HCV production. In conclusion, miR-130a inhibits HCV replication/production by restoring host innate immune responses and/or downregulating pro-HCV miR-122. miR-130a might be a potential drug target by modulating host innate immune responses to combat HCV infection.

Breast cancer is a leading cause of cancer death among women, and the failure of normal apoptosis has been proved in the development of breast cancer. The phytoestrogen, calycosin, is extracted from Chinese medical herb Radix astragali. We recently reported that calycosin successfully stimulated proliferation of ER-positive MCF-7 human breast cancer cells at low concentration. In the present study, we assessed the proapoptotic function of calycosin in MCF-7 cells at high concentration in vitro, as well as the possible mechanism of its effect. MCF-7 cells were treated with different concentrations of calycosin, and then detected by MTT assay for cellular viability, Hoechst assay, and flow cytometry for apoptosis. RASD1 is identified as a Ras-family member and a regulator in MAPK-mediated cascade leading to cell proliferation or apoptosis. To provide insight into the functions of RASD1 signaling pathway in calycosin-induced apoptosis, the expression of Bcl-2, Bax, and RASD1 in calycosin-treated cells were determined by Western blot assay. The results showed that high concentrations of calycosin significantly suppressed the proliferation of MCF-7 cells and promoted cell apoptosis. Moreover, compared with control group, the expression of Bcl-2 decreased with calycosin in MCF-7 cells, while Bax increased, which was significantly correlated with elevated expression of RASD1. Together, we present evidence that at relatively high concentration calycosin triggered cell apoptosis through the mitochondrial apoptotic pathway by upregulating RASD1. And for the first time, this study revealed that calycosin may have potential as a therapeutic agent for the treatment of breast cancer.

Summary Introduction Detection of leukemogenic fusion transcripts in acute myeloid leukemia (AML) is critical for AML diagnosis. NanoString nCounter system is a novel probe-based gene expression platform capable of measuring up to 800 targets with advantages of reproducibility, accuracy, and sample type flexibility. To study the potential application of NanoString in leukemia at clinic, we used this technology to detect AML leukemogenic fusion transcripts and compared the performances with clinical molecular assays. Methods We developed a NanoString assay to detect seven leukemogenic fusion transcripts, namely RUNX1-RUNX1T1 (e5e12), PML-RARA (bcr1, bcr2, and bcr3), and CBFB-MYH11 (e5e12, e5e8, and e5e7). We set up the cut-off value for each fusion transcript and tested 42 de novo AML samples. We compared the results with reverse transcriptase-polymerase chain reaction (RT-PCR) and TaqMan reverse quantitative-polymerase chain reaction (RQ-PCR), the molecular methods standardly used at clinic. Results We demonstrated that the NanoString and RT-PCR results correlate well (P < 0.0001) and are highly concordant (95.2%). Using TaqMan RQ-PCR as a validation method and gold standard, we demonstrated superior accuracy and sensitivity of NanoString compared to RT-PCR and comparable specificity. Furthermore, we showed that NanoString is not as sensitive as TaqMan RQ-PCR in detecting very low level of fusion transcripts. Conclusions NanoString can serve as a reliable and alternative molecular method to multiplexed RT-PCR for diagnosis of de novo AML with the perspective of screening/quantitation of a large number of leukemogenic fusion transcripts and prognostic genes. However, NanoString may not be an alternative method for monitoring minimal residual disease in AML.

To study the HIV-1 genotypes and transmitted drug resistance (TDR) in Dehong prefecture of Yunnan province in 2014.A total of 70 plasma samples of recently reported HIV-infected individuals between 16 and 25 years old were collected in Dehong prefecture from January to August 2014. Among them, 58 samples which met the criterion of HIV drug resistance threshold survey (HIVDR-TS) were subjected to genetic drug resistance detection.50 plasma samples were successfully sequenced and analyzed. Among them, 34.0% were Chinese and 66.0% were Burmese. Based on pol sequences, all the identified HIV genotypes would include CRF01_AE (28.0%), subtype C(20.0%), URF(20.0% ), CRF62_BC(10.0% ), CRF08_BC(8.0% ), CRF07_BC (4.0%), CRF64_BC(4.0%), subtype B(4.0%) and CRF55_01B(2.0%). One drug, which resistant mutation to proteinase inhibitors had been detected in one sequence. Based on the statistical method of HIVDR-TS, the prevalence of transmitted HIV-1 drug resistance was adjusted as5%.The proportion of Burmese was relatively higher among those newly reported HIV-infected individuals aged 16 to 25 in Dehong. We noticed that the novel circulating recombinant forms began to function. However, the level of transmission through HIV-1 drug resistant strains still kept low in Dehong.

Summary Objectives MicroRNAs (miRNAs) play an important role in the regulation of chondrogenesis of mesenchymal stem cells, but their expression still remains unknown in human adipose-derived stem cells (hADSCs). In this study the miRNA expression profile during chondrogenic differentiation of hADSC and the potential mechanism whereby miRNAs may affect the process of chondrogenesis are considered. Methods hADSCs were isolated and cultured. The expression of chondrogenic proteins was detected using enzyme-linked immunosorbent assay (ELISA). miRNA expression profiles before and after chondrogenic induction were obtained using miRNA microarray essay and differently expressed miRNAs were primarily verified using quantitative real-time polymerase chain reaction (qRT-PCR). Putative targets of the miRNAs were predicted using online software programs MiRanda, TargetScan and miRBase. Results Twelve miRNAs were found to be differentially expressed pre- and post-chondrogenic induction by over a two-fold change, including eight up-regulated miRNAs (miR-193b, miR-199a-3p/hsa-miR-199b-3p, miR-455-3p, miR-210, miR-381, miR-92a, miR-320c, and miR-136), and four down-regulated miRNAs (miR-490-5p, miR-4287, miR-BART8*, and miR-US25-1*). qRT-PCR analysis further confirmed these results. Predicted target genes of the differentially expressed miRNAs were based on the overlap of at least two online prediction algorithms, with the known functions of regulating chondrogenic differentiation, self-renewal, signal transduction and cell cycle control. Conclusions In this study we have identified a group of miRNAs and their target genes, which may play important roles in regulating chondrogenic differentiation of hADSCs. Our results provide the basis for further investigation into the molecular mechanism of chondrogenesis in hADSCs and their differentiation for cartilage engineering.

The objective of this study was to examine the effects of cell-adhesion peptides incorporated into collagen scaffolds on corneal epithelial cell stratification. Peptides (YIGSR, YIGSRIKVAV, IKVAVYIGSR and negative control YISGR) were first chemically attached to dendrimers. The peptide-modified dendrimers were then used as collagen cross-linkers. This permitted the incorporation of the peptides into the bulk structure of the collagen gels. The amount of peptide incorporated into the collagen gels was determined by 125I radiolabelling to be between 0.064 and 6.4 microg/mg collagen for YIGSR, and between 0.1187 to 11.87 microg/mg collagen for YIGSRIKVAV and IKVAVYIGSR. Corneal epithelial cell monolayers were grown on the surface of the collagen scaffolds and then exposed to conditions that promoted stratification as a stratified epithelial layer is desired in a tissue-engineered cornea. It was found that all of the incorporated peptides promoted stratification of the cells with the exception of the negative control YISGR. A synergistic effect of the combined sequences from laminin was observed, with the orientation of the peptide sequences having a great impact on the ability of the materials to promote cell stratification.

Background Tolerance to remifentanil during sevoflurane anesthesia may increase postoperative analgesic requirements. Low-dose naloxone not only has been shown to block the development of acute opioid tolerance but also to ameliorate undesired opioid-induced side effects. We hypothesized that naloxone prevents the acute opioid tolerance produced by a large dose of remifentanil, and reduces the incidence of opioid-induced side effects. Methods Seventy-two patients undergoing open colorectal surgery were randomly assigned to receive intraoperative remifentanil (1) small dose at 0.1 μg/kg/min; (2) large dose at 0.30 μg/kg/min; or (3) large dose at 0.30 μg/kg/min combined with low-dose naloxone at 0.25 μg/kg/h just after the induction. Cumulative morphine consumption, postoperative pain scores, incidence of opioid-related side effects, time to recovery of bowel function, and length of hospital stay were recorded. Results Cumulative morphine consumption at 24 h after surgery was higher in the large-dose remifentanil group (28 ± 12 mg) compared with the small-dose remifentanil group (17 ± 12 mg), and large-dose remifentanil–naloxone group (18 ± 9 mg), (P

UDP-glucuronosyltransferase 2B7 (UGT2B7) is involved in the glucuronidation of a wide array of clinically important drugs and endogenous compounds in humans. The aim of this study was to identify an isoform-selective probe substrate that could be used to investigate genetic and environmental influences on glucuronidation mediated by UGT2B7. Three potential probe substrates [3'-azido-3'-deoxythymidine (AZT), morphine, and codeine], were evaluated using recombinant UGTs and human liver microsomes (HLMs; n = 54). Of 11 different UGTs screened, UGT2B7 was the principal isoform mediating AZT glucuronidation, morphine-3-glucuronidation, and morphine-6-glucuronidation. Codeine was glucuronidated equally well by UGT2B4 and UGT2B7. Enzyme kinetic analysis of these activities typically showed higher apparent Km values for HLMs (pooled and individual) compared with UGT2B7. This difference was least (less than 2-fold higher Km) for AZT glucuronidation and greatest (3- to 6-fold higher Km) for codeine glucuronidation. Microsomal UGT2B7 protein content correlated well with AZT glucuronidation (rs = 0.77), to a lesser extent with morphine-3-glucuronidation (rs = 0.50) and morphine-6-glucuronidation (rs = 0.51), but very weakly with codeine glucuronidation (rs = 0.33). Livers were also genotyped for the UGT2B7*2 (H268Y) polymorphism. No effect of genotype on microsomal glucuronidation or UGT2B7 protein content was observed. In conclusion, although both AZT and morphine can serve as in vitro probe substrates for UGT2B7, AZT appears to be more selective than morphine. Codeine is not a useful UGT2B7 probe substrate because of significant glucuronidation by UGT2B4. The UGT2B7*2 polymorphism is not a determinant of glucuronidation of AZT, morphine, or codeine in HLMs.

(R,S)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that is metabolized primarily by hepatic glucuronidation. In previous studies, S-oxazepam (but not R-oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study was to identify UDP-glucuronosyltransferase (UGT) isoforms mediating R- and S-oxazepam glucuronidation in human liver, with the long term objective of elucidating the molecular genetic basis for this drug metabolism polymorphism. All available recombinant UGT isoforms were screened for R- and S-oxazepam glucuronidation activities. Enzyme kinetic parameters were then determined in representative human liver microsomes (HLMs) and in UGTs that showed significant activity. Of 12 different UGTs evaluated, only UGT2B15 showed significant S-oxazepam glucuronidation. Furthermore, the apparent K(m) for UGT2B15 (29-35 microM) was similar to values determined for HLMs (43-60 microM). In contrast, R-oxazepam was glucuronidated by UGT1A9 and UGT2B7. Although apparent K(m) values for HLMs (256-303 microM) were most similar to UGT2B7 (333 microM) rather than UGT1A9 (12 microM), intrinsic clearance values for UGT1A9 were 10 times higher than for UGT2B7. A common genetic variation results in aspartate (UGT2B15*1) or tyrosine (UGT2B15*2) at position 85 of the UGT2B15 protein. Microsomes from human embryonic kidney (HEK)-293 cells overexpressing UGT2B15*1 showed 5 times higher S-oxazepam glucuronidation activity than did UGT2B15*2 microsomes. Similar results were obtained for other substrates, including eugenol, naringenin, 4-methylumbelliferone, and androstane-3alpha-diol. In conclusion, S-oxazepam is stereoselectively glucuronidated by UGT2B15, whereas R-oxazepam is glucuronidated by multiple UGT isoforms. Allelic variation associated with the UGT2B15 gene may explain polymorphic S-oxazepam glucuronidation in humans.

A series of segmented polyurethanes based on methylene diisocyanate/poly (tetramethylene oxide) and chain extended with either ethylene diamine or butane diol in combination with a generation 2 polypropylenimine octaamine dendrimer were synthesized. For polymer synthesis, the dendrimers were protected with either t-boc or Fmoc groups and were incorporated into the polyurethane microstructure to permit further functionalization with biologically active groups. Following deprotection, the dendrimers were reacted with succinimidyl propionate polyethylene oxide (SPA-PEO) to improve the protein resistance of the polymers and to examine the potential of this technique for polymer functionalization. Different synthesis techniques were examined to optimize the incorporation of the PEO into the polymer microstructure. Incorporation of the dendrimers and the PEO were confirmed by NMR and FTIR. Gel permeation chromatography was used to examine the molecular weights of the various polyurethanes. The dendrimer incorporated polymers had significantly lower molecular weights than the ED or BDO chain extended controls, likely due to lower reactivity of the dendrimers as a result of steric factors. Following PEO reaction, the molecular weights of the resultant polymers were consistent with the levels of PEO incorporation noted by comparison of peak intensities in the NMR spectra. Due to the highly hydrophilic nature of the PEO, some migration to the polymer surface was expected. Water contact angles and XPS, used to characterize the surfaces, suggest that there was some PEO enrichment at the surface of the polymers. Adsorption of radiolabeled fibrinogen to the polymer surfaces was decreased by a factor of approximately 40% in some of the PEO incorporated polymers. There were also differences in the patterns of plasma protein adsorption on the various surfaces as evaluated by SDS PAGE and immunoblotting. Therefore, the use of dendrimers in biomaterials for incorporation of a large number of functional groups seems to be promising.

To evaluate the association between late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) and major adverse events in dilated cardiomyopathy (DCM) patients.Databases, including PubMed, Ovid, and EMBASE, were searched for studies evaluating LGE at CMR in DCM patient prognostication. Clinical outcomes were analysed using fixed-effects models or, in cases of significant heterogeneity, random-effects models.In the meta-analysis of 13 studies on 1675 DCM patients with a mean follow-up of 3 years, LGE is associated with all-cause mortality (pooled odds ratio, 3.43 [95% confidence interval, 2.26-5.22], p0.00001), cardiac death/transplantation (3.65 [1.80-7.40], p=0.0003), hospitalisation for heart failure (2.87 [1.53-5.39], p=0.001), major arrhythmia events (sudden cardiac death, sustained ventricular tachycardia or fibrillation, appropriate implantable cardioverter-defibrillator (ICD) discharge/pacing, and syncope: 4.24 [2.95-6.08], p0.00001), and sudden cardiac death (3.33 [1.80-6.17], p=0.0001).LGE in DCM patients appears to be associated with mortality and major cardiac events, underscoring its potential as an independent index for risk stratification and treatment guidance.