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1.  Narcissism predicts impulsive buying: phenotypic and genetic evidence 
Impulsive buying makes billions of dollars for retail businesses every year, particularly in an era of thriving e-commerce. Narcissism, characterized by impulsivity and materialism, may serve as a potential antecedent to impulsive buying. To test this hypothesis, two studies examined the relationship between narcissism and impulsive buying. In Study 1, we surveyed an online sample and found that while adaptive narcissism was not correlated with impulsive buying, maladaptive narcissism was significantly predictive of the impulsive buying tendency. By investigating 304 twin pairs, Study 2 showed that global narcissism and its two components, adaptive and maladaptive narcissism, as well as the impulsive buying tendency were heritable. The study found, moreover, that the connections between global narcissism and impulsive buying, and between maladaptive narcissism and impulsive buying were genetically based. These findings not only establish a link between narcissism and impulsive buying but also help to identify the origins of the link. The present studies deepen our understanding of narcissism, impulsive buying, and their interrelationship.
doi:10.3389/fpsyg.2015.00881
PMCID: PMC4493767  PMID: 26217251
impulsive buying; narcissism; maladaptive narcissism; adaptive narcissism; behavior genetics; twin study
2.  Responses in gut microbiota and fat metabolism to a halogenated methane analogue in Sprague Dawley rats 
Microbial Biotechnology  2015;8(3):519-526.
Recent studies on germ-free mice show that intestinal methanogens may be closely associated with host's adipose metabolism. The present study aimed to investigate effects of inhibition of intestinal methanogen populations on host fat metabolism by establishing a healthy Sprague Dawley (SD) rat model through the intragastric administration of bromochlordomethane (BCM). Forty-five 8-week old healthy male SD rats were randomly divided into five groups including one control and four BCM treatments. The experiment lasted 60 days with two separate 30-day experimental periods. At the end of first period, three BCM treatment groups were further used: one group continued with BCM treatment, one group stopped with BCM treatment, and the other one inoculated with faecal mixture of methanogens from rats. Results showed that the methanogen population in feces was reduced sixfold with no effect on the bacterial community by daily dosing with BCM. Daily gain, epididymal fat pad weight, levels of plasma low-density lipoprotein and cholesterol were significantly higher in the BCM-treated animals, while the high-density lipoprotein was lower than that of the control. The expression of PPARγ, LPL, PP2A, SREBP-1c, ChREBP, FASN and adiponectin genes in BCM treatment group was universally upregulated, while the expression of Fiaf gene was downregulated. After termination of BCM treatment and followed either with or without re-inocubation with faecal methanogen mixture, the rats had their faecal methanogen populations, blood parameters and gene expression returned to the original level. Results suggest that regulation of gut methanogens might be a possible approach to control host body weight.
doi:10.1111/1751-7915.12256
PMCID: PMC4408184  PMID: 25752448
3.  The Shh Signaling Pathway Is Upregulated in Multiple Cell Types in Cortical Ischemia and Influences the Outcome of Stroke in an Animal Model 
PLoS ONE  2015;10(4):e0124657.
Recently the sonic hedgehog (shh) signaling pathway has been shown to play an important role in regulating repair and regenerative responses after brain injury, including ischemia. However, the precise cellular components that express and upregulate the shh gene and the cellular components that respond to shh signaling remain to be identified. In this study, using a distal MCA occlusion model, our data show that the shh signal is upregulated both at the cortical area near the injury site and in the adjacent striatum. Multiple cell types upregulate shh signaling in ischemic brain, including neurons, reactive astrocytes and nestin-expressing cells. The shh signaling pathway genes are also expressed in the neural stem cells (NSCs) niche in the subventricular zone (SVZ). Conditional deletion of the shh gene in nestin-expressing cells both at the SVZ niche and at the ischemic site lead to significantly more severe behavioral deficits in these shh iKO mice after cortical stroke, measured using an automated open field locomotion apparatus (Student’s t-test, p<0.05). In contrast, animals given post-stroke treatment with the shh signaling agonist (SAG) demonstrated less deficits in behavioral function, compared to vehicle-treated mice. At 7 days after stroke, SAG-treated mice showed higher values in multiple horizontal movement parameters compared to vehicle treated mice (Student’s t-test, p<0.05) whereas there were no differences in pre-stroke measurements, (Student’s t-test, p>0.05). In summary, our data demonstrate that shh signaling plays critical and ongoing roles in response to ischemic injury and modulation of shh signaling in vivo alters the functional outcome after cortical ischemic injury.
doi:10.1371/journal.pone.0124657
PMCID: PMC4415811  PMID: 25927436
4.  High-order localized spoof surface plasmon resonances and experimental verifications 
Scientific Reports  2015;5:9590.
We theoretically demonstrated and experimentally verified high-order radial spoof localized surface plasmon resonances supported by textured metal particles. Through an effective medium theory and exact numerical simulations, we show the emergence of these geometrically-originated electromagnetic modes at microwave frequencies. The occurrence of high-order radial spoof plasmon resonances is experimentally verified in ultrathin disks. Their spectral and near-field properties are characterized experimentally, showing an excellent agreement with theoretical predictions. Our findings shed light into the nature of spoof localized surface plasmons, and open the way to the design of broadband plasmonic devices able to operate at very different frequency regimes.
doi:10.1038/srep09590
PMCID: PMC4397533  PMID: 25873523
5.  Addition to inhaled corticosteroids of leukotriene receptor antagonists versus theophylline for symptomatic asthma: a meta-analysis 
Journal of Thoracic Disease  2015;7(4):644-652.
Background
Inhaled corticosteroids (ICSs) are widely used in combination with second controller medications in the management of asthma in adults and children. There lacks a systematic comparison between addition of leukotriene receptor antagonists (LTRAs) and theophylline to ICS. The purpose of this meta-analysis was to evaluate the difference of the efficacy and safety profile of adding either LTRAs or theophylline to ICS in adults and children with symptomatic asthma.
Methods
Randomised controlled trials (RCTs) published prior to November 2014 were acquired through systematically searching and selected based on the established inclusion criteria for publications. The data extracted from the included studies were further analyzed by a meta-analysis.
Results
We included eight RCTs, of which six recruited adults and two recruited children aged 5 to 14 years. The primary outcomes were changes in lung function from baseline, including forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF). Overall, addition of LTRAs led to significantly better morning PEF {mean difference (MD) 16.94 [95% confidence interval (CI): 11.49-22.39] L/min, P<0.01} and FEV1 [MD 0.09 (95% CI: 0.03-0.15) L, P=0.005] as compared to addition of theophylline. There were no differences between the two treatments in terms of evening PEF, adverse events, rescue medication use and asthma exacerbation.
Conclusions
The combination of LTRA and ICS leads to modestly greater improvement in lung function than the combination of theophylline and ICS in the treatment of symptomatic asthma. Long-term trials are required to assess the efficacy and safety of these two therapies.
doi:10.3978/j.issn.2072-1439.2015.04.12
PMCID: PMC4419319  PMID: 25973230
Inhaled corticosteroids (ICSs); leukotriene receptor antagonists (LTRAs); theophylline; meta-analysis
6.  Structure of a filament of stacked octamers of human DMC1 recombinase 
Acta Crystallographica Section F  2013;69(Pt 4):382-386.
Octameric rings of DMC1 stacked into filaments in the crystal. Similar DMC1–DNA filaments have been observed previously using electron microscopy.
Eukaryal DMC1 proteins play a central role in homologous recombination in meiosis by assembling at the sites of programmed DNA double-strand breaks and carrying out a search for allelic DNA sequences located on homologous chromatids. They are close homologs of eukaryal Rad51 and archaeal RadA proteins and are remote homologs of bacterial RecA proteins. These recombinases (also called DNA strand-exchange proteins) promote a pivotal strand-exchange reaction between homologous single-stranded and double-stranded DNA substrates. An octameric form of a truncated human DMC1 devoid of its small N-terminal domain (residues 1–83) has been crystallized. The structure of the truncated DMC1 octamer is similar to that of the previously reported full-length DMC1 octamer, which has disordered N-terminal domains. In each protomer, only the ATP cap regions (Asp317–Glu323) show a noticeable conformational difference. The truncated DMC1 octamers further stack with alternate polarity into a filament. Similar filamentous assemblies of DMC1 have been observed to form on DNA by electron microscopy.
doi:10.1107/S1744309113005678
PMCID: PMC3614161  PMID: 23545642
DMC1 proteins; DNA strand-exchange proteins; recombinases
7.  Effects of dexamethasone on aquaporin-4 expression in brain tissue of rat with bacterial meningitis 
Aquaporin-4 (AQP4) is the most popular water channel protein expressed in brain tissue and plays a very important role in regulating the water balance in and outside of brain parenchyma. To investigate the expression of aquaporin-4 in the rat brain tissue after dexamethasone therapy of meningitis induced by Streptococcus pneumonia, total 40 of 3-week old Sprague-Dawley rats were divided into infection group (n=30) and normal control group (n=10). The meningitis groups were infected with 1×107 cfu/ml of Streptococcus pneumoniae and then randomized into no treatment (untreated group, n=10), treatment with ceftriaxone (CTRX group, n=10) and treatment with dexamethasone combined ceftriaxone (CTRX + DEXA group, n=10). The normal control group was established by using saline. The rats were euthanized when they reached terminal illness or five days after infection, followed by detection of AQP4 through using immunohistochemistry and Western blot methods. Data has showed that expression of AQP4 in model group remained higher than the control and treatment group (P<0.05). AQP4 expression in CTRX + DEXA group was lower than that in CTRX group (P<0.05). There was no statistical difference between CTRX + DEXA group and the control group (P>0.05). These data suggested that Dexamethasone could down-regulate the expression of AQP4 in the brain tissue of rats with meningitis and provides evidence for the mechanism of protective effect of Dexamethasone on central neurosystem.
PMCID: PMC4440131  PMID: 26045822
Dexamethasone; bacterial meningitis; aquaporin-4
8.  Epigenetic modulation of insulin-like growth factor-II overexpression by hepatitis B virus X protein in hepatocellular carcinoma 
Hepatitis B virus X protein (HBx) is involved in the pathogenesis of hepatocellular carcinoma (HCC). Overexpression of the transcripts from the P3 and P4 promoters of the insulin-like growth factor-II (IGF-II) gene is observed in HCC. The present study investigated the involvement of HBx in IGF-II overexpression and its epigenetic regulation. Firstly, the effects of HBx on P3 and P4 mRNA expression, the methylation status of the P3 and P4 promoters, and MBD2 expression were analyzed in human HCC cells and HCC samples. Next, interaction between HBx and MBD2 or CBP/p300 was assessed by co-immunoprecipitation, and HBx-mediated binding of MBD2 and CBP/p300 to the P3 and P4 promoters and the acetylation of the corresponding histones H3 and H4 were evaluated by quantitative chromatin immunoprecipitation. Finally, using siRNA knockdown, we investigated the roles of MBD2 and CBP/p300 in IGF-II overexpression and its epigenetic regulation. Our results showed that HBx promotes IGF-II expression via inducing the hypomethylation of the P3 and P4 promoters, and that HBx increases MBD2 expression, directly interacts with MBD2 and CBP/p300, and elevates their recruitment to the hypomethylated P3 and P4 promoters with increased acetylation levels of the corresponding histones H3 and H4. Further results showed that endogenous MBD2 and CBP/p300 are necessary for HBx-induced IGF-II overexpression and that CBP/p300 presence and CBP/p300-mediated acetylation of histones H3 and H4 are partially required for MBD2 binding and its demethylase activity. These data suggest that HBx induces MBD2-HBx-CBP/p300 complex formation via interaction with MBD2 and CBP/p300, which contributes to the hypomethylation and transcriptional activation of the IGF-II-P3 and P4 promoters and that CBP/p300-mediated acetylation of histones H3 and H4 may be a rate-limiting step for the hypomethylation and activation of these two promoters. This study provides an alternative mechanism for understanding the pathogenesis of HBx-mediated HCC.
PMCID: PMC4449429  PMID: 26045980
Hepatitis B virus X protein; hepatocellular carcinoma; insulin-like growth factor II; hypomethylation; MBD2-HBx-CBP/p300 complex
9.  Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design 
ACS Medicinal Chemistry Letters  2013;5(2):138-142.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα–PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα–9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors.
doi:10.1021/ml400378e
PMCID: PMC4027628  PMID: 24900786
PI3K; PI103; crystal structure; drug design; cancer therapy
10.  A tracer liquid image velocimetry for multi-layer radial flow in bioreactors 
Background
This paper presents a Tracer Liquid Image Velocimetry (TLIV) for multi-layer radial flow in bioreactors used for cells cultivation of tissue engineering. The goal of this approach is to use simple devices to get good measuring precision, specialized for the case in which the uniform level of fluid shear stress was required while fluid velocity varied smoothly.
Methods
Compared to the widely used Particles Image Velocimetry (PIV), this method adopted a bit of liquid as tracer, without the need of laser source. Sub-pixel positioning algorithm was used to overcome the adverse effects of the tracer liquid deformation. In addition, a neighborhood smoothing algorithm was used to restrict the measurement perturbation caused by diffusion. Experiments were carried out in a parallel plates flow chamber. And mathematical models of the flow chamber and Computational Fluid Dynamics (CFD) simulation were separately employed to validate the measurement precision of TLIV.
Results
The mean relative error between the simulated and measured data can be less than 2%, while in similar validations using PIV, the error was around 8.8%.
Conclusions
TLIV avoided the contradiction between the particles’ visibility and following performance with tested fluid, which is difficult to overcome in PIV. And TLIV is easier to popularize for its simple experimental condition and low cost.
doi:10.1186/s12938-015-0002-z
PMCID: PMC4339657  PMID: 25888748
Bioreactor; Fluid shear stress; Image velocimetry; Computational Fluid Dynamics; Parallel plates flow chamber
11.  Immune Function Abnormalities in Peripheral Blood Mononuclear Cell Cytokine Expression Differentiates Stages of Cutaneous T-Cell Lymphoma/Mycosis Fungoides 
Purpose
Mycosis fungoides (MF) is a cutaneous T-cell lymphoma (CTCL) characterized by neoplastic skin-homing T cells. To better understand the immunopathogenesis of MF, we analyzed the functional ability of peripheral blood mononuclear cells (PBMC) from early and late MF/CTCL patients to express cytokine genes. In late stage MF/CTCL, patients were separated into those with blood involvement (+B) and without blood involvement (−B).
Experimental Design
We analyzed TH1 (interleukin 2 (IL-2), IFN-γ), TH2 (IL-4, IL-5, IL-10, IL-13), and TH17 (IL-17) cytokine gene expression from activated PBMCs from normal (n = 12), psoriasis (n = 6), early MF/CTCL (n = 11), and late MF/CTCL+B (n = 4) and MF/CTCL-B (n = 3) by quantitative real-time PCR.
Results
PBMCs from early MF/CTCL and psoriasis showed higher induction of IL-2, IL-4, and IFN-γ genes than those from normal and late MF/CTCL-B and MF/CTCL+B (P < 0.05) in descending order. PBMCs from late MF/CTCL-B exhibited generally the highest level of IL-5, IL-10, IL-13, and IL-17 expression compared with the other groups. PBMCs from early MF/CTCL and late MF/CTCL−B had similarly elevated IL-13 and IL-17. Of all groups, PBMCs from late MF/CTCL+B had the lowest levels of IL-2 (P < 0.05), IL-4, IFN-γ, IL-13, and IL-17.
Conclusions
The different pattern of cytokine gene expression suggests a change in immune function in MF/CTCL from early MF/CTCL to late MF/CTCL−B to late MF/CTCL+B. These stages are consistent with localized disease associated with an anti-tumor immune response and late MF/CTCL associated with a loss of immune function mediated by malignant T cells that share regulatory T cell – like properties.
doi:10.1158/1078-0432.CCR-07-0610
PMCID: PMC4309376  PMID: 18245523
12.  Suppression of Mic60 compromises mitochondrial transcription and oxidative phosphorylation 
Scientific Reports  2015;5:7990.
Precise regulation of mtDNA transcription and oxidative phosphorylation (OXPHOS) is crucial for human health. As a component of mitochondrial contact site and cristae organizing system (MICOS), Mic60 plays a central role in mitochondrial morphology. However, it remains unclear whether Mic60 affects mitochondrial transcription. Here, we report that Mic60 interacts with mitochondrial transcription factors TFAM and TFB2M. Furthermore, we found that Mic60 knockdown compromises mitochondrial transcription and OXPHOS activities. Importantly, Mic60 deficiency decreased TFAM binding and mitochondrial RNA polymerase (POLRMT) recruitment to the mtDNA promoters. In addition, through mtDNA immunoprecipitation (mIP)-chromatin conformation capture (3C) assays, we found that Mic60 interacted with mtDNA and was involved in the architecture of mtDNA D-loop region. Taken together, our findings reveal a previously unrecognized important role of Mic60 in mtDNA transcription.
doi:10.1038/srep07990
PMCID: PMC4303897  PMID: 25612828
13.  Circulating MicroRNAs as a Novel Class of Diagnostic Biomarkers in Gastrointestinal Tumors Detection: A Meta-Analysis Based on 42 Articles 
PLoS ONE  2014;9(11):e113401.
Objective
MicroRNAs (miRNAs) have become the focus of most recent efforts in cancer research. However, there have been inconsistencies in the literature regarding the suitability of circulating miRNAs for early detection of gastrointestinal cancers. This study aims to assess the diagnostic performance of circulating miRNAs in detection of gastrointestinal cancer through a meta-analysis.
Methods
Eligible studies were selected by conducting a systematic literature search of public databases. The sensitivity and specificity were used to plot the summary receiver operator characteristic (SROC) curve and calculate the area under the SROC curve (AUC). The between-study heterogeneity was evaluated by Q test and I2 statistics. Subgroup analyses and meta-regression were further performed to explore the potential sources of heterogeneity. All analyses were performed using the STATA 12.0 software.
Results
A total of 107 studies from 42 articles were included for the meta-analysis according to the inclusion criteria. The overall analysis of all gastrointestinal cancers showed that circulating miRNAs have a relatively good diagnostic performance in gastrointestinal cancers, with a sensitivity of 0.75, a specificity of 0.81 and an AUC of 0.85. In addition, subgroup analyses based on different type of miRNA assay suggested that single-miRNA assay displayed a relatively low diagnostic performance with the AUC values of 0.84 for gastric cancer (GC) and 0.79 for colorectal cancer (CRC), while multiple-miRNAs assay significantly improved the diagnosing accuracy with AUC rising to 0.92 for GC and 0.89 for CRC. Another interesting finding was that plasma-based miRNA assay reach a higher accuracy compared with serum-based one for GC, while opposite conclusion was drawn for CRC.
Conclusions
In conclusion, circulating miRNAs, particularly the combination of multiple miRNAs, may present as promising biomarkers for the diagnosis of gastrointestinal cancers. Further large-scale prospective studies are necessary to validate their potential applicability in human cancer diagnosis.
doi:10.1371/journal.pone.0113401
PMCID: PMC4236157  PMID: 25406082
14.  The Neural Response to Maternal Stimuli: An ERP Study 
PLoS ONE  2014;9(11):e111391.
Mothers are important to all humans. Research has established that maternal information affects individuals' cognition, emotion, and behavior. We measured event-related potentials (ERPs) to examine attentional and evaluative processing of maternal stimuli while participants completed a Go/No-go Association Task that paired mother or others words with good or bad evaluative words. Behavioral data showed that participants responded faster to mother words paired with good than the mother words paired with bad but showed no difference in response to these others across conditions, reflecting a positive evaluation of mother. ERPs showed larger P200 and N200 in response to mother than in response to others, suggesting that mother attracted more attention than others. In the subsequent time window, mother in the mother + bad condition elicited a later and larger late positive potential (LPP) than it did in the mother + good condition, but this was not true for others, also suggesting a positive evaluation of mother. These results suggest that people differentiate mother from others during initial attentional stage, and evaluative mother positively during later stage.
doi:10.1371/journal.pone.0111391
PMCID: PMC4222870  PMID: 25375157
15.  Safety of rilpivirine plus nucleoside reverse-transcriptase inhibitors in HIV-infected Taiwanese with a higher prevalence of hepatitis virus infection 
Journal of the International AIDS Society  2014;17(4Suppl 3):19580.
Introduction
Combination antiretroviral therapy (cART) containing rilpivirine plus 2 NRTIs are effective antiretroviral (ARV) regimens for ARV-naive HIV-infected patients who had baseline plasma HIV RNA load (PVL) <5 log10 copies/mL and as switch therapy for those with viral suppression. In this study, we aimed to assess the short-term safety of rilpivirine-containing regimens among HIV-infected patients who initiated or switched to rilpivirine plus two NRTIs in Taiwan.
Materials and Methods
Between January and June 2014, medical records of all HIV-infected patients who initiated or switched to rilpivirine plus two NRTIs, during the follow-up were reviewed to assess the tolerance and adverse effects. Using a standardized data collection form, we recorded data of PVL and CD4 count, serologies for hepatitis B and C virus (HBV and HCV, respectively), haemogram, aminotransferases, bilirubin and serum creatinine before starting rilpivirine-containing regimens at four weeks and every 12 weeks thereafter.
Results
During the study period, medical records of 246 patients initiated their first ARV therapy with rilpivirine-containing regimens (n=90) or switched to rilpivirine-containing regimen from other regimens (156). Of the 246 patients, 73.4% were men who have sex with men and 9.1% and 25.6% tested positive for HBsAg and anti-HCV antibody, respectively. Baseline CD4 was 395 cells/mm3 (range, 2-1581) and PVL, 2.76 log10 copies/mL (range, <1.3>7.0 log10 copies/mL). As of 10 July, 23 patients (9.3%) stopped rilpivirine-containing regimens due to gastrointestinal upset (n=4), skin rash (2), depression (2), poor sleep (3), anaemia (4, all being with zidovudine/lamivudine), nail hyperpigmentation (1), presence of transmitted drug resistance (4), and elevated aminotransferase levels (1). The proportion of the patients with aminotransferases of fivefold or higher than the upper limit of normal (ULN) was 1.7% and 1.5% for AST and ALT, respectively, before starting rilpivirine-containing regimens; the respective value was 1.4% and 2.4% after 12 weeks of cART.
Conclusions
Rilpivirine-containing regimens were generally well tolerated and less than 10% of the patients had to stop rilpivirine due to various reasons. Despite a higher prevalence of chronic HBV or HCV infection, rilpivirine-containing regimens did not cause significant changes of aminotransferases from baseline.
doi:10.7448/IAS.17.4.19580
PMCID: PMC4224849  PMID: 25394087
16.  Incidence of recent HCV infection among persons seeking voluntary counselling and testing for HIV and sexually transmitted infections in Taiwan 
Journal of the International AIDS Society  2014;17(4Suppl 3):19640.
Introduction
The incidence of recent hepatitis C virus infection (HCV) infection has been noted to be increasing among men who have sex with men (MSM), especially those with HIV infection, in several resource-rich settings. In Taiwan, the incidence of recent HCV infection increased from 0 in 1994–2000, 2.29 in 2001–2005 to 10.13 per 1000 person-years of follow-up (PYFU) in 2006–2010. In this study, we aimed to estimate the incidence rate of recent HCV infection among those individuals who sought voluntary counselling and testing (VCT) service at a University Hospital.
Methods
Between May 2006 and December 2013, 18,246 tests for HIV antibody were performed among 12,143 individuals at the VCT services. A total of 2157 clients without HIV or HCV infection at baseline were included for estimation of incidence rate of recent HCV infection. Antibodies to HCV were determined with a third-generation enzyme immunoassay. A nested case-control study with four matched controls without HCV seroconversion for one HCV seroconverter was conducted to investigate the factors associated with recent HCV infection. Phylogenetic analysis was performed among the HCV strains obtained from VCT clients and patients coinfected with HIV and HCV between 2006 and 2013.
Results
During the study period, 2157 clients received a total of 8260 tests. The HCV seroprevalence at baseline was 0.3%. Of the 2150 HCV-negative clients who contributed 5074.99 PYFU, 17 developed HCV seroconversion (incidence rate, 3.35 per 1000 PYFU; 95% CI, 1.76–4.94); the rate increased from 2.28 per 1000 PYFU (95% CI, 0.05–4.51) in 2006–2009, to 3.33 per 1000 PYFU (95% CI, 0.86–5.80) in 2010–2011, to 4.94 per 1000 PYFU (95% CI, 0.99–8.99) in 2012–2013. In case-control study, HCV seroconverters were more likely to have HIV-infected partners, recent syphilis and a Rapid Plasma Reagin (RPR) titre of 4 or greater. In multivariate analysis, having HIV-infected partners remained as the only independent associated factors with HCV seroconversion (AOR, 6.931; 95% CI, 1.064–45.163). Phylogenetic analysis revealed transmission pairs and clusters, with most clustered sequences derived from MSM.
Conclusions
Similar to the observation among HIV-infected patients who are not IDUs, increasing trends of recent HCV infection also occur among the individuals who sought VCT services in Taiwan. Having HIV-infected partners is independently associated with recent HCV seroconversion.
doi:10.7448/IAS.17.4.19640
PMCID: PMC4224870  PMID: 25394144
17.  Effectiveness of a reduced dose of efavirenz plus 2 NRTIs as maintenance antiretroviral therapy with the guidance of therapeutic drug monitoring 
Journal of the International AIDS Society  2014;17(4Suppl 3):19524.
Introduction
Wide inter-patient variation of plasma efavirenz (EFV) concentrations has been observed, and a substantial proportion of HIV-positive patients may have unnecessarily higher plasma EFV concentrations than recommended while receiving EFV-containing combination antiretroviral therapy (cART) at the currently recommended daily dose of 600 mg. A lower daily dose (400 mg) of EFV has recently been demonstrated to be as efficacious as the recommended 600 mg when combined with tenofovir/mtricitabine in a multinational clinical trial, with a lower incidence of adverse effects. We aimed to use a therapeutic drug monitoring (TDM)-guided strategy to optimize the EFV dose in HIV-positive Taiwanese patients.
Materials and Methods
The plasma EFV concentrations at 12 hours (C12) after taking the previous dose were determined among HIV-positive adults who had received EFV-containing cART with viral suppression (plasma HIV RNA load (PVL) <200 copies/mL). For those with EFV C12 >2.0 mg/L, EFV (Stocrit, MSD) was reduced to half a tablet daily. Determinations of EFV C12 were repeated 4–12 weeks after switch using high-performance liquid chromatography. CYP2B6 G516T polymorphisms were determined using polymerase-chain-reaction restriction fragment-length polymorphism.
Results
Between April 2013 and June 2014, 111 patients (95.5% male; mean age, 39 years; 96.4% with PVL <40 copies/ml; 26.4% HBsAg-positive and 7.5% anti-HCV-positive) with plasma C12 efavirenz >2.0 mg/L were switched to a reduced dose (1/2# hs) of EFV; 45.5% of them had CYP2B6 G516T or TT genotypes; and 32.4% weighed 60 kg or less. The mean baseline EFV C12 before switch was 3.65 mg/L (interquartile range (IQR), 2.62–4.17) for 111 patients, which decreased to 1.96 mg/L (IQR, 1.53–2.33) for 64 patients who had completed follow-up of C12 EFV 4 weeks after switch, with a reduction of 49.4% (IQR, 38.9–57.0%). As of 10 July, 2014, all of the 38 patients (100%) who had completed at least one follow-up of PVL achieved undetectable PVL (<40 copies/ml) following switch to a reduced dose of EFV after a mean observation of 13 weeks (IQR, 7–15 weeks).
Conclusions
Switch to cART containing a half tablet of EFV (1/2#) in HIV-positive Taiwanese patients with higher plasma EFV concentrations who had achieved viral suppression could maintain successful viral suppression with the guidance of TDM.
doi:10.7448/IAS.17.4.19524
PMCID: PMC4224938  PMID: 25394033
18.  Seroincidence of HIV and prevalence of transmitted drug resistance of HIV-1 strains among persons seeking voluntary counselling and testing in Taiwan 
Journal of the International AIDS Society  2014;17(4Suppl 3):19758.
Introduction
The total case number of persons who are newly diagnosed with HIV continues to increase in Taiwan and men who have sex with men (MSM) have re-emerged as the leading risk group for HIV transmission. In this study, we aimed to estimate the incidence rate of HIV infection among those individuals who sought voluntary counselling and testing (VCT) service at a university hospital.
Methods
Between 1 April, 2006 and 31 December, 2013, 18,246 tests for HIV antibody were performed among 12143 individuals at the VCT service. A total of 2157 individuals who tested negative for anti-HIV antibody had subsequent follow-up tests at the same VCT service, which composed the study population for estimation of incidence rate of recent HIV infection. The BED assays were used to identify recent HIV infections that occurred within the previous six months before seeking VCT service.
Results
During the 6.5-year study period, 647 individuals were diagnosed as being HIV-positive, with an overall HIV seroprevalence of 3.55% (95% CI 3.27–3.82). The overall incidence rate of HIV infection was estimated 4.13 per 100 person-years of follow-up (95% CI 3.67–4.69 per 100 person-years of follow-up). MSM had an estimated 10-fold higher seroprevalence and seroincidence of HIV than heterosexuals. Of 647 clients testing positive for HIV, 603 clients were MSM (93.2%) and 477 patients (70.8%) subsequently sought HIV care at the hospital; 226 (47.4%) were diagnosed as having recent HIV infections by the BED assay, while 244 (51.2%) long-term infection and 7 without data by the BED assay. Of those patients, 173 (75.6%) and 178 patients (73.0%) with recent HIV infection and long-term infection had data of transmitted drug resistance mutations, respectively. The prevalence of transmitted drug resistance mutations to any class of antiretroviral therapy was 9.0% and 10.6% (p=0.68), respectively, of the HIV-1 strains from the patients with recent HIV infection and long-term infection, respectively.
Conclusions
The seroincidence rate of HIV among persons seeking VCT was estimated 4.13 per 100 person-years of follow-up. The prevalence of transmitted drug resistance to any class of antiretroviral agents was similar between those who were recently infected with HIV and those who had long-term infection in Taiwan.
doi:10.7448/IAS.17.4.19758
PMCID: PMC4225397  PMID: 25397503
19.  Antiretroviral therapy (ART) management of Low-Level Viremia in Taiwan (ALLEVIATE) 
Journal of the International AIDS Society  2014;17(4Suppl 3):19785.
Introduction
This retrospective study aimed to investigate that if switch of combination antiretroviral therapy (cART) would result in viral suppression (<40 copies/mL) at 48 weeks for patients with persistent low-level viremia after having received cART for six months or more at two hospitals designated for HIV care in Taiwan.
Materials and Methods
Between January 2001 and January 2013, patients were enrolled if plasma HIV RNA load (PVL) were >20 to <1000 copies/mL detected for six months or more [1, 2]. Using a standardized data collection form, we recorded data of PVL and CD4 count before cART and at the detection of low-level viremia, serologies for hepatitis B and C virus, risk factors, duration of cART exposure, years of HIV diagnosed and ever experiencing treatment failure. The strategy of switch is based on the clinical guidelines of BHIVA, which suggest change of cART from non-nucleoside reverse-transcriptase inhibitors (nNRTIs) or unboosted protease inhibitor (PI) to boosted PI, newer boosted PI or ARV of different mechanism [3].
Results
In this study, 165 patients were enrolled, 119 patients (72.1%) did not switch (Group 1), and 46 patients (27.9%) switched previous regimens to ARV of different mechanism (Group 2). The two groups differed significantly in the proportion of injecting drug users (IDU) (Group 1 vs Group 2, 10.9 vs 26.1%) and median PVL (67 vs 159 copies/mL), and the proportion of PVL<200 copies/mL (84.0% vs 58.7%) when low-level viremia was first detected. In Group 1, 39 (32.8%) continued two nucleoside reverse-transcriptase inhibitors (NRTIs) plus nNRTI; 29 (24.4%) 2 NRTIs plus PI, 47 (39.5%) 2 NRTIs plus boosted PI, and 4 (3.3%) 2 NRTIs plus integrase inhibitor (II). In Group 2, two (4.3%) switched to 2 NRTIs plus PI, 38 (82.6%) 2 NRTIs plus boosted PI, three (6.5%) 2 NRTIs plus II and three (6.5%) boosted PI plus II. In multivariate analysis, IDUs (adjusted odds ratio [AOR], 6.757; 95% CI 2.427–18.868) and PVL of 200–999 copies/mL at enrollment (AOR, 4.902; 95% CI 1.992–12.048) were more likely to be switched. At 48 weeks, patients in Group 2 were more likely to achieve PVL<40 copies/mL than Group 1 (82.6% vs 63.0%, p=0.016), while no difference was observed in achieving PVL <200 copies/mL between the two groups (95.7% vs 92.4%, p=0.729).
Conclusions
According to the clinical guidelines of BHIVA, patients with low-level viremia who switched to cART consisting of 2 NRTIs plus boosted PI or newer mechanisms were more likely to re-establish viral suppression to <40 copies/mL at week 48.
doi:10.7448/IAS.17.4.19785
PMCID: PMC4225405  PMID: 25397529
20.  A Novel Bradykinin-Related Dodecapeptide (RVALPPGFTPLR) from the Skin Secretion of the Fujian Large-Headed Frog (Limnonectes fujianensis) Exhibiting Unusual Structural and Functional Features 
Toxins  2014;6(10):2886-2898.
Bradykinin-related peptides (BRPs) are significant components of the defensive skin secretions of many anuran amphibians, and these secretions represent the source of the most diverse spectrum of such peptides so far encountered in nature. Of the many families of bioactive peptides that have been identified from this source, the BRPs uniquely appear to represent homologues of counterparts that have specific distributions and receptor targets within discrete vertebrate taxa, ranging from fishes through mammals. Their broad spectra of actions, including pain and inflammation induction and smooth muscle effects, make these peptides ideal weapons in predator deterrence. Here, we describe a novel 12-mer BRP (RVALPPGFTPLR-RVAL-(L1, T6, L8)-bradykinin) from the skin secretion of the Fujian large-headed frog (Limnonectes fujianensis). The C-terminal 9 residues of this BRP (-LPPGFTPLR) exhibit three amino acid substitutions (L/R at Position 1, T/S at Position 6 and L/F at Position 8) when compared to canonical mammalian bradykinin (BK), but are identical to the kinin sequence present within the cloned kininogen-2 from the Chinese soft-shelled turtle (Pelodiscus sinensis) and differ from that encoded by kininogen-2 of the Tibetan ground tit (Pseudopodoces humilis) at just a single site (F/L at Position 8). These data would imply that the novel BRP is an amphibian defensive agent against predation by sympatric turtles and also that the primary structure of the avian BK, ornithokinin (RPPGFTPLR), is not invariant within this taxon. Synthetic RVAL-(L1, T6, L8)-bradykinin was found to be an antagonist of BK-induced rat tail artery smooth muscle relaxation acting via the B2-receptor.
doi:10.3390/toxins6102886
PMCID: PMC4210874  PMID: 25268979
amphibian; skin secretion; molecular cloning; bradykinin; smooth muscle
21.  Serum vitamin D is associated with non-alcoholic fatty liver disease in Chinese males with normal weight and liver enzymes 
Acta Pharmacologica Sinica  2014;35(9):1150-1156.
Aim:
Considering the characterization of vitamin D deficiency as a risk factor of ectopic fat deposition, the association of serum 25-hydroxy vitamin D3 [25(OH)D3] levels with non-alcoholic fatty liver disease (NAFLD) was evaluated in Chinese men with normal body mass index (BMI) and enzyme markers of liver function.
Methods:
A total of 514 participants (22 to 79 years old) with normal BMI and liver enzymes were identified for analysis. Abdominal ultrasound was performed to diagnose NAFLD, and the fatty liver index (FLI) was calculated to quantify liver steatosis. Serum 25(OH)D3 levels were determined by an electrochemiluminescence immunoassay.
Results:
Among the entire study population, the mean levels of serum 25(OH)D3 were 15.32±5.77 ng/mL. However, when serum 25(OH)D3 levels were compared between non-NAFLD subjects (n=438) and NAFLD subjects (n=76), the latter showed significantly lower levels (15.65±5.89 ng/mL vs 13.46±4.65 ng/mL, P=0.002). In addition, serum 25(OH)D3 levels were found to be significantly correlated with FLI after adjustment for age and BMI (r=−0.108, P=0.014). Logistic regression showed that serum 25(OH)D3 levels were independently correlated with NAFLD (OR: 0.937, 95% CI: 0.884–0.993, P=0.028). Furthermore, stepwise regression analysis revealed that serum 25(OH)D3 levels were inversely associated with FLI (β=−0.055, P=0.040).
Conclusion:
The present study demonstrated that serum 25(OH)D3 levels were inversely associated with NAFLD, even in subjects with normal total body fat, suggesting a potential role of lower levels of vitamin D in the occurrence and development of NAFLD.
doi:10.1038/aps.2014.48
PMCID: PMC4155526  PMID: 25087999
25-hydroxy vitamin D3; non-alcoholic fatty liver disease; fatty liver index
22.  Comorbidities among the HIV-Infected Patients Aged 40 Years or Older in Taiwan 
PLoS ONE  2014;9(8):e104945.
Background
With the widespread use of combination antiretroviral therapy (cART), life expectancy of HIV-infected patients has significantly prolonged. An increasing number of HIV-infected patients are aging and concurrent use of medications are not uncommon for management of metabolic complications and cardiovascular diseases related to aging and prolonged exposure to cART.
Methods
We reviewed medical records of all HIV-infected patients aged 40 years or older who had been followed at a university hospital for HIV care in Taiwan between January and December 2013. A standardized case record form was used to collect information on demographics and clinical characteristics, comorbidity, cART, and concurrent medications.
Results
During the study period, 610 patients aged 40 to 49 years (mean, 44.1) and 310 aged 50 years or older (mean, 58.8) sought HIV care at this hospital. Compared with patients aged 40 to 49 years, those aged 50 years or older were significantly more likely to be female (15.9% vs 3.8%); to have received cART (97.7% vs 94.8%) and a lower plasma HIV RNA load (1.6 vs 1.7 log10 copies/ml); and to have diabetes mellitus (18.4% vs 4.6%), hypertension (31.0% vs 10.8%), hyperlipidemia (29.4% vs 11.6%), coronary artery disease (6.8% vs 0.5%), and an estimated glomerular filtration rate <60 ml/min/1.73 m2 (11.5% vs 2.7%); and were significantly less likely to have syphilis. Other than HIV infection, patients aged 50 years or older were more likely to have been receiving two or more concurrent medications than those aged 40 to 49 years (22.9% vs 6.4%).
Conclusions
Our findings show a significant proportion of the HIV-infected patients aged 50 years or older have multiple comorbidities that may increase the risk for cardiovascular and renal complications. Issues of poly-pharmacy among the HIV-infected patients who are aging should be addressed to ensure adherence and minimize drug-drug interactions.
doi:10.1371/journal.pone.0104945
PMCID: PMC4132082  PMID: 25119532
23.  Neural Manifestations of Implicit Self-Esteem: An ERP Study 
PLoS ONE  2014;9(7):e101837.
Behavioral research has established that humans implicitly tend to hold a positive view toward themselves. In this study, we employed the event-related potential (ERP) technique to explore neural manifestations of positive implicit self-esteem using the Go/Nogo association task (GNAT). Participants generated a response (Go) or withheld a response (Nogo) to self or others words and good or bad attributes. Behavioral data showed that participants responded faster to the self paired with good than the self paired with bad, whereas the opposite proved true for others, reflecting the positive nature of implicit self-esteem. ERP results showed an augmented N200 over the frontal areas in Nogo responses relative to Go responses. Moreover, the positive implicit self-positivity bias delayed the onset time of the N200 wave difference between Nogo and Go trials, suggesting that positive implicit self-esteem is manifested on neural activity about 270 ms after the presentation of self-relevant stimuli. These findings provide neural evidence for the positivity and automaticity of implicit self-esteem.
doi:10.1371/journal.pone.0101837
PMCID: PMC4090159  PMID: 25006966
24.  Decreased LINE-1 methylation levels in aldosterone-producing adenoma 
Purpose: Abnormal global DNA methylation levels are associated with many diseases. In this study, we examined long interspersed nuclear elements-1 (LINE-1) methylation as a biomarker for abnormal global DNA methylation and aldosterone-producing adenoma (APA). Methods: Tissues from 25 APA and 6 normal adrenal glands (NAs) were analyzed for LINE-1 methylation by real-time methylation-specific polymerase chain reaction. The estimated LINE-1 methylation level was then tested for correlation with the clinicopathologic parameters of APA patients. Results: The methylation index (MI) level for LINE-1 was 0.91 in NA samples and 0.77 in APA samples (P < 0.001). For the APA samples, there were no statistical correlations between the MI level and various clinicopathologic parameters such as gender (P = 0.07). Conclusion : LINE-1 methylation is significantly lower in APA samples than in NA samples. LINE-1 methylation is not correlated with the clinical characteristics of APA.
PMCID: PMC4129024  PMID: 25120789
Long interspersed nuclear elements-1; global DNA methylation; aldosterone-producing adenoma
25.  Feleucins: Novel Bombinin Precursor-Encoded Nonapeptide Amides from the Skin Secretion of Bombina variegata 
BioMed Research International  2014;2014:671362.
The first amphibian skin antimicrobial peptide (AMP) to be identified was named bombinin, reflecting its origin from the skin of the European yellow-bellied toad (Bombina variegata). Bombinins and their related peptides, the bombinin Hs, were subsequently reported from other bombinid toads. Molecular cloning of bombinin-encoding cDNAs from skin found that bombinins and bombinin Hs were coencoded on the same precursor proteins. Here, we report the molecular cloning of two novel cDNAs from a skin secretion-derived cDNA library of B. variegata whose open-reading frames each encode a novel bombinin (GIGGALLNVGKVALKGLAKGLAEHFANamide) and a C-terminally located single copy of a novel nonapeptide (FLGLLGGLLamide or FLGLIGSLLamide). These novel nonapeptides were named feleucin-BV1 and feleucin-BV2, respectively. The novel bombinin exhibited 89% identity to homologues from the toads, B. microdeladigitora and B. maxima. The feleucins exhibited no identity with any amphibian AMP archived in databases. Synthetic feleucins exhibited a weak activity against Staphylococcus aureus (128–256 mg/L) but feleucin-BV1 exhibited a synergistic action with the novel bombinin. The present report clearly demonstrates that the skin secretions of bombinid toads continue to represent a source of peptides of novel structure that could provide templates for the design of therapeutics.
doi:10.1155/2014/671362
PMCID: PMC4070539  PMID: 25003126

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