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Background: Recently, there have been conflicting results reporting an increased risk of AR or MR associated with oral fluoroquinolones (FQs).This study investigated whether the use of FQs increases the risk of mitral regurgitation (MR) or aortic regurgitation (AR). Methods: A retrospective cohort study was conducted by using the Taiwan National Health Insurance research database. A unidirectional case-crossover design without selecting controls from an external population was adopted in this study. A total of 26,650 adult patients with new onset of AR or MR between January 1, 2000, and December 31, 2012, were identified. The risk of outcomes was compared between the hazard period and one of the randomly selected referent periods of the same individuals. Results: Before exclusion of pneumonia diagnosed within 2 months before the index date, patients who took FQs had a significantly greater risk of AR or MR (adjusted odds ratio [aOR] 1.51, 95% confidence interval [CI] 1.30–1.77), any AR (combined AR and MR) (aOR 1.50, 95% CI 1.10–2.04), and any MR (combined AR and MR) (aOR 1.37, 95% CI 1.16–1.62). After exclusion of pneumonia, FQs exposure remained significantly associated with a greater risk of MR (aOR 1.38, 95% CI 1.17–1.62) and any MR (aOR 1.25, 95% CI 1.05–1.48). Conclusions: The findings suggested that patients treated with FQs could be warned about the potential risk for MR even after considering the possibility of protopathic bias. Reducing unnecessary FQs prescriptions may be considered to reduce the risk of valvular heart disease. [ABSTRACT FROM AUTHOR]

Background: In the realm of Gut-Brain axis research, existing evidence points to a complex bidirectional regulatory mechanism between gut microbiota and the brain. However, the question of whether a causal relationship exists between gut microbiota and specific types of brain tumors, such as gliomas, remains unresolved. To address this gap, we employed publicly available Genome-Wide Association Study (GWAS) and MIOBEN databases, conducting an in-depth analysis using Two-Sample Mendelian Randomization (MR). Method: We carried out two sets of MR analyses. The preliminary analysis included fewer instrumental variables due to a high genome-wide statistical significance threshold (5×10−8). To enable a more comprehensive and detailed analysis, we adjusted the significance threshold to 1×10−5. We performed linkage disequilibrium analysis (R2 <0.001, clumping distance = 10,000kb) and detailed screening of palindromic SNPs, followed by MR analysis and validation through sensitivity analysis. Results: Our findings reveal a causal relationship between gut microbiota and gliomas. Further confirmation via Inverse Variance Weighting (IVW) identified eight specific microbial communities related to gliomas. Notably, the Peptostreptococcaceae and Olsenella communities appear to have a protective effect, reducing glioma risk. Conclusion: This study not only confirms the causal link between gut microbiota and gliomas but also suggests a new avenue for future glioma treatment. [ABSTRACT FROM AUTHOR]

The enhancement of digital transformation is of paramount importance for business development. This study employs machine learning to establish a predictive model for digital transformation, investigates crucial factors that influence digital transformation, and proposes corresponding improvement strategies. Initially, four commonly used machine learning algorithms are compared, revealing that the Extreme tree classification (ETC) algorithm exhibits the most accurate prediction. Subsequently, through correlation analysis and recursive elimination, key features that impact digital transformation are selected resulting in the corresponding feature subset. Shapley Additive Explanation (SHAP) values are then employed to perform an interpretable analysis on the predictive model, elucidating the effects of each key feature on digital transformation and obtaining critical feature values. Lastly, informed by practical considerations, we propose a quantitative adjustment strategy to enhance the degree of digital transformation in enterprises, which provides guidance for digital development. [ABSTRACT FROM AUTHOR]

Background: Urolithiasis is a common urological disease with increasing incidence worldwide, and preventing its risk poses significant challenges. Here, we used Mendelian randomization (MR) framework to genetically assess the causal nature of multifaceted risk factors on urolithiasis. Methods: 17 potential risk factors associated with urolithiasis were collected from recently published observational studies, which can be categorized basically into lifestyle factors and circulating biomarkers. The instrumental variables of risk factors were selected from large-scale genome-wide association studies (N ≤ 607,291). Summary-level data on urolithiasis were obtained from UK Biobank (UKB) (3,625 cases and 459,308 noncases) and the FinnGen consortium (5,347 cases and 213,445 noncases). The univariable and multivariable MR analyses were applied to evaluate the causal, independent effect of these potential risk factors upon urolithiasis. Effects from the two consortia were combined by the meta-analysis methods. Results: Higher genetically predicted sex hormone-binding globulin (SHBG, OR, 0.708; 95% CI, 0.555 to 0.903), estradiol (OR, 0.179; 95% CI, 0.042 to 0.751), tea intake (OR, 0.550; 95% CI, 0.345 to 0.878), alcoholic drinks per week (OR, 0.992; 95% CI, 0.987 to 0.997), and some physical activity (e.g., swimming, cycling, keeping fit, and bowling, OR, 0.054; 95% CI, 0.008 to 0.363) were significantly associated with a lower risk of urolithiasis. In the Multivariate Mendelian Randomization (MVMR) analyses, the significant causal associations between estradiol, SHBG, tea intake, and alcoholic drinks per week with urolithiasis were robust even after adjusting for potential confounding variables. However, the previously observed causal association between other exercises and urolithiasis was no longer significant after adjusting for these factors. Conclusions: The univariable and multivariable MR findings highlight the independent and significant roles of estradiol, SHBG, tea intake, and alcoholic drinks per week in the development of urolithiasis, which might provide a deeper insight into urolithiasis risk factors and supply potential preventative strategies. [ABSTRACT FROM AUTHOR]

Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome's pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease. A new mycn mutant zebrafish model of Feingold syndrome type 1 recapitulates many aspects of the human disease, including intestinal defects. This model provides insights into the mechanisms of the disorder, revealing altered mTOR signaling, changes in ribosomal biosynthesis and assembly, and decreased proliferation. Targeting TOR signaling ameliorated some of the intestinal pathologies. [ABSTRACT FROM AUTHOR]

Evapotranspiration (ET) plays an essential role in agricultural water resource management. Understanding regional agricultural water consumption characteristics can be improved by predicting ET using remote sensing. However, due to the lack of high-resolution images on clear-sky days or the limitation of ET reconstruction on cloudy-sky days, it remains challenging to continuously derive ET at the field scale. In this study, the Landsat and MODIS data were initially fused to obtain the Landsat-like vegetation index and land surface temperature on clear-sky days. Then the two-source energy balance (TSEB) model was applied to calculate the daily ET during the clear-sky. A canopy resistance-based gap-filling method was involved in reconstructing regional ET on cloudy days while considering different environmental factors. The estimations were validated by automatic weather system data (AWS) and eddy covariance (EC) measurements in Guantao County. The results demonstrated that the proposed scheme performed well in estimating cropland ET, with an RMSE of 0.86 mm·d−1 and an R2 of 0.65, and the NSE and PBias were 0.61 and -0.29%, respectively. The crop water consumption analysis revealed that the daily ET of winter wheat peaked during the maturation stage. Nevertheless, summer maize water consumption peaked in the middle of the growing season in this area. The temperature during the early development stage and the soil moisture in the mid and late growth stages had the greatest impact on the ET of winter wheat. During the entire growing period, soil moisture had the largest effect on the ET of summer maize. The findings showed that the TSEB model can be effectively applied to field-scale water consumption monitoring in North China through MODIS and Landsat data fusion and ET temporal reconstruction considering environmental factors. [ABSTRACT FROM AUTHOR]

Angiogenesis is vital during pregnancy for remodeling and enhancing vasodilation of maternal uterine arteries, and increasing uterine blood flow. Abnormal angiogenesis is associated with decreased uteroplacental blood flow and development of pregnancy disorders such as gestational hypertension, preeclampsia, fetal growth restriction, preterm delivery, stillbirth, and miscarriage. The mechanisms that contribute to normal angiogenesis remain obscure. Our previous studies demonstrated that expression of the angiotensin type 2 receptor (AT2R) is increased while the angiotensin type 1 receptor (AT1R) is unchanged in the endothelium of uterine arteries, and that AT2R-mediated pregnancy adaptation facilitates enhanced vasodilation and uterine arterial blood flow. However, the role of AT2R in regulating angiogenesis during pregnancy has never been studied. This study examines whether or not AT2R activation induces angiogenesis and, if so, what mechanisms are involved. To this end, we used primary human uterine artery endothelial cells (hUAECs) isolated from pregnant and nonpregnant women undergoing hysterectomy. The present study shows that Compound 21, a selective AT2R agonist, induced proliferation of pregnant-hUAECs, but not nonpregnant-hUAECs, in a concentration-dependent manner, and that this C21-induced mitogenic effect was blocked by PD123319, a selective AT2R antagonist. The mitogenic effects induced by C21 were inhibited by blocking JNK—but not ERK, PI3K, and p38—signaling pathways. In addition, C21 concentration dependently increased cell migration and capillary-like tube formation in pregnant-hUAECs. The membrane-based antibody array showed that C21 increased expression of multiple angiogenic proteins, including EGF, bFGF, leptin, PLGF, IGF-1, and angiopoietins. Our qPCR analysis demonstrates that C21-induced increase in expression of these angiogenic proteins correlates with a proportional increase in mRNA expression, indicating that AT2R activates angiogenic proteins at the transcriptional level. In summary, the present study shows that AT2R activation induces angiogenesis of hUAECs in a pregnancy-specific manner through JNK-mediated pathways with associated transcriptional upregulation of multiple proangiogenic proteins. [ABSTRACT FROM AUTHOR]

Varicella-zoster virus (VZV) is a medically important alphaherpesvirus that induces fusion of the virion envelope and the cell membrane during entry, and between cells to form polykaryocytes within infected tissues during pathogenesis. All members of the Herpesviridae, including VZV, have a conserved core fusion complex composed of glycoproteins, gB, gH and gL. The ectodomain of the primary fusogen, gB, has five domains, DI-V, of which DI contains the fusion loops needed for fusion function. We recently demonstrated that DIV is critical for fusion initiation, which was revealed by a 2.8Å structure of a VZV neutralizing mAb, 93k, bound to gB and mutagenesis of the gB-93k interface. To further assess the mechanism of mAb 93k neutralization, the binding site of a non-neutralizing mAb to gB, SG2, was compared to mAb 93k using single particle cryogenic electron microscopy (cryo-EM). The gB-SG2 interface partially overlapped with that of gB-93k but, unlike mAb 93k, mAb SG2 did not interact with the gB N-terminus, suggesting a potential role for the gB N-terminus in membrane fusion. The gB ectodomain structure in the absence of antibody was defined at near atomic resolution by single particle cryo-EM (3.9Å) of native full-length gB purified from infected cells and by X-ray crystallography (2.4Å) of the transiently expressed ectodomain. Both structures revealed that the VZV gB N-terminus (aa72-114) was flexible based on the absence of visible structures in the cryo-EM or X-ray crystallography data but the presence of gB N-terminal peptides were confirmed by mass spectrometry. Notably, N-terminal residues 109KSQD112 were predicted to form a small α-helix and alanine substitution of these residues abolished cell-cell fusion in a virus-free assay. Importantly, transferring the 109AAAA112 mutation into the VZV genome significantly impaired viral propagation. These data establish a functional role for the gB N-terminus in membrane fusion broadly relevant to the Herpesviridae. Author summary: Herpesviruses are ubiquitous infectious agents of medical and economic importance, including varicella-zoster virus (VZV), which causes chicken pox and shingles. A unifying theme of herpesviruses is their mechanism of entry into host cells, membrane fusion, via a core complex of virally expressed envelope glycoproteins gB, gH and gL. Of these, the primary fusogen, gB, is activated by the heterodimer gH-gL through an unknown mechanism and enables the virus envelope to merge with cell membranes to release the DNA containing capsid into the cytoplasm to initiate infection. By using a human antibody that neutralizes VZV we have recently demonstrated that the initiation of membrane fusion is associated with the crown region of gB. Here, we use cryogenic electron microscopy to compare the structure of this human neutralizing antibody, 93k, to a non-neutralizing antibody SG2. Surprisingly, both antibodies bind to the crown of gB with considerable overlap of their footprints on gB with one important exception, SG2 does not bind to a flexible region in the gB N-terminus. Mutations incorporated into this flexible region disrupts gB mediated membrane fusion and significantly impairs VZV propagation, identifying an Achilles heel in viral replication. [ABSTRACT FROM AUTHOR]

Background: Transcatheter aortic valve-in-valve (VIV) procedure is a safe alternative to conventional reoperation for bioprosthetic dysfunction. Balloon-expandable valve (BEV) and self-expanding valve (SEV) are the 2 major types of devices used. Evidence regarding the comparison of the 2 valves remains scarce. Methods: A systematic review and meta-analysis was conducted to compare the outcomes of BEV and SEV in transcatheter VIV for aortic bioprostheses dysfunction. A computerized search of Medline, PubMed, Embase, and Cochrane databases was performed. English-language journal articles reporting SEV or BEV outcomes of at least 10 patients were included. Results: In total, 27 studies were included, with 2,269 and 1,671 patients in the BEV and SEV groups, respectively. Rates of 30-day mortality and stroke did not differ significantly between the 2 groups. However, BEV was associated with significantly lower rates of postprocedural permanent pacemaker implantation (3.8% vs. 12%; P < 0.001). Regarding echocardiographic parameters, SEV was associated with larger postprocedural effective orifice area at 30 days (1.53 cm2 vs. 1.23 cm2; P < 0.001) and 1 year (1.55 cm2 vs. 1.22 cm2; P < 0.001). Conclusions: For patients who underwent transcatheter aortic VIV, SEV was associated with larger postprocedural effective orifice area but higher rates of permanent pacemaker implantation. These findings provide valuable information for optimizing device selection for transcatheter aortic VIV. [ABSTRACT FROM AUTHOR]

Objective: Whether the cardiovascular (CV) outcomes of second-generation limus-eluting stents (LESs) differ from those of paclitaxel-eluting stents (PESs) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) is still unclear. Methods: We used the Taiwan National Health Insurance Research Database to analyse data of 516 patients with AMI and CS diagnosed from January 2007 to December 2011. We used propensity score matching to adjust for the imbalance in covariate baseline values between these two groups. We evaluated clinical outcomes by comparing 197 subjects who used second-generation LESs to 319 matched subjects who used PESs. Results: The risk of the primary composite outcomes (i.e., myocardial infarction, coronary revascularisation or CV death) was significantly lower in the second-generation LES group than in the PES group [37.3% vs. 51.8%; hazard ratio (HR), 0.73; 95% CI: 0.56–0.95] at the 12-month follow-up. The patients who received second-generation LESs had a lower risk of coronary revascularisation (HR 0.62; 95% CI: 0.41–0.93) than those who used PESs. However, the risks of myocardial infarction (HR 0.56; 95% CI: 0.26–1.24), ischemic stroke (HR 0.73; 95% CI: 0.23–2.35), or CV death (HR 0.90; 95% CI: 0.63–1.28) were not significantly different between the two groups. Conclusions: Among patients with CS-complicating AMI, second-generation LES implantation significantly reduced the risk of coronary revascularisation and composite CV events compared to PES implantation at the 12-month follow-up. [ABSTRACT FROM AUTHOR]

Epigenetic predisposition is thought to critically contribute to adult-onset disorders, such as retinal neurodegeneration. The histone methyltransferase, enhancer of zeste homolog 2 (Ezh2), is transiently expressed in the perinatal retina, particularly enriched in retinal ganglion cells (RGCs). We previously showed that embryonic deletion of Ezh2 from retinal progenitors led to progressive photoreceptor degeneration throughout life, demonstrating a role for embryonic predisposition of Ezh2-mediated repressive mark in maintaining the survival and function of photoreceptors in the adult. Enrichment of Ezh2 in RGCs leads to the question if Ezh2 also mediates gene expression and function in postnatal RGCs, and if its deficiency changes RGC susceptibility to cell death under injury or disease in the adult. To test this, we generated mice carrying targeted deletion of Ezh2 from RGC progenitors driven by Math5-Cre (mKO). mKO mice showed no detectable defect in RGC development, survival, or cell homeostasis as determined by physiological analysis, live imaging, histology, and immunohistochemistry. Moreover, RGCs of Ezh2 deficient mice revealed similar susceptibility against glaucomatous and acute optic nerve trauma-induced neurodegeneration compared to littermate floxed or wild-type control mice. In agreement with the above findings, analysis of RNA sequencing of RGCs purified from Ezh2 deficient mice revealed few gene changes that were related to RGC development, survival and function. These results, together with our previous report, support a cell lineage-specific mechanism of Ezh2-mediated gene repression, especially those critically involved in cellular function and homeostasis. [ABSTRACT FROM AUTHOR]

Purpose: The prognostic value of serum cystatin-C (Cys-C) in renal cell carcinoma (RCC) remains unknown. The purpose of this study is to explore the prognostic value of Cys-C for RCC patients. Patients and methods: The levels of preoperative Cys-C, creatinine (CRE) and estimated glomerular filtration rate (e-GFR) were retrospectively collected in 325 RCC patients undergoing surgery. The cutoff values of Cys-C, CRE and e-GFR were determined by the standardized Cutoff Finder algorithm. The receiver operating characteristic (ROC) curve and pairwise comparison were performed to compare the three variables. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic value of serum Cys-C in RCC. Results: Based on the analysis of Cutoff Finder algorithm, ROC curve and pairwise comparison, the preoperative Cys-C was superior to CRE and e-GFR as a predictive factor in RCC. Multivariate Cox regression analyses showed that high preoperative Cys-C (>1.09 mg/L) was significantly associated with shorter overall survival (OS) in all RCC patients (hazard ratio [HR], 1.59; P = 0.012), patients at pT1-2 (P<0.001), pN0 (P<0.001) and pM0 stages (P<0.001). Moreover, Multivariate Cox regression analyses also showed that in the 306 patients without metastasis, high preoperative Cys-C was also associated with shorter disease-free survival (DFS) (HR, 3.50; P = 0.013). Conclusions: An elevated preoperative Cys-C level was demonstrated to be related with worse survival in patients with RCC. Measuring preoperative serum Cys-C might be a simple way for finding poor prognostic patients and patients with elevated preoperative Cys-C level should be more closely followed up. [ABSTRACT FROM AUTHOR]

Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of genetic disorders typically manifesting with tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, in some subtypes. Most HPS subtypes are associated with defects in Biogenesis of Lysosome-related Organelle Complexes (BLOCs), which are groups of proteins that function together in the formation and/or trafficking of lysosomal-related endosomal compartments. BLOC-2, for example, consists of the proteins HPS3, HPS5, and HPS6. Here we present an HPS patient with defective BLOC-2 due to a novel intronic mutation in HPS5 that activates a cryptic acceptor splice site. This mutation leads to the insertion of nine nucleotides in-frame and results in a reduced amount of HPS5 at the transcript and protein level. In studies using skin fibroblasts derived from the proband and two other individuals with HPS-5, we found a perinuclear distribution of acidified organelles in patient cells compared to controls. Our results suggest the role of HPS5 in the endo-lysosomal dynamics of skin fibroblasts. [ABSTRACT FROM AUTHOR]

Background: Prior studies have suggested intraaortic balloon pump (IABP) have a neutral effect on acute myocardial infarction (AMI) patients with cardiogenic shock (CS). However, the effects of IABP on patients with severe CS remain unclear. We therefore investigated the benefits of IABP in AMI patients with severe CS undergoing coronary revascularization. Methods and Results: This study identified 14,088 adult patients with AMI and severe CS undergoing coronary revascularization from Taiwan’s National Health Insurance Research Database between January 1, 1997 and December 31, 2011, dividing them into the IABP group (n = 7044) and the Nonusers group (n = 7044) after propensity score matching to equalize confounding variables. The primary outcomes included myocardial infarction(MI), cerebrovascular accidents or cardiovascular death. In-hospital events including dialysis, stroke, pneumonia and sepsis were secondary outcomes. Primary outcomes were worse in the IABP group than in the Nonusers group in 1 month (Hazard ratio (HR) = 1.97, 95% confidence interval (CI) = 1.84–2.12). The MI rate was higher in the IABP group (HR = 1.44, 95% CI = 1.16–1.79), and the cardiovascular death was much higher in the IABP group (HR = 2.07, 95% CI = 1.92–2.23). The IABP users had lower incidence of dialysis (8.5% and 9.5%, P = 0.04), stroke (2.6% and 3.8%, P<0.001), pneumonia (13.9% and 16.5%, P<0.001) and sepsis (13.2% and 16%, P<0.001) during hospitalization than Nonusers. Conclusion: The use of IABP in patients with myocardial infarction and severe cardiogenic shock undergoing coronary revascularization did not improve the outcomes of recurrent myocardial infarction and cardiovascular death. However, it did reduce the incidence of dialysis, stroke, pneumonia and sepsis during hospitalization. [ABSTRACT FROM AUTHOR]

Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided. [ABSTRACT FROM AUTHOR]

We describe an interdisciplinary comparison of the effects of acute and chronic alcohol exposure in terms of their disturbance of light, dark and color preferences and the occurrence of Parkinson-like behavior in zebrafish through computer visual tracking, data mining, and behavioral and physiological analyses. We found that zebrafish in anxiolytic and anxious states, which are induced by acute and chronic repeated alcohol exposure, respectively, display distinct emotional reactions in light/dark preference tests as well as distinct learning and memory abilities in color-enhanced conditional place preference (CPP) tests. Additionally, compared with the chronic alcohol (1.0%) treatment, acute alcohol exposure had a significant, dose-dependent effect on anxiety, learning and memory (color preference) as well as locomotive activities. Acute exposure doses (0.5%, 1.0%, and 1.5%) generated an “inverted V” dose-dependent pattern in all of the behavioral parameters, with 1.0% having the greatest effect, while the chronic treatment had a moderate effect. Furthermore, by measuring locomotive activity, learning and memory performance, the number of dopaminergic neurons, tyrosine hydroxylase expression, and the change in the photoreceptors in the retina, we found that acute and chronic alcohol exposure induced varying degrees of Parkinson-like symptoms in zebrafish. Taken together, these results illuminated the behavioral and physiological mechanisms underlying the changes associated with learning and memory and the cause of potential Parkinson-like behaviors in zebrafish due to acute and chronic alcohol exposure. [ABSTRACT FROM AUTHOR]

Introduction: The level of 9-month high-sensitivity C-reactive protein (hsCRP) in predicting cardiovascular outcomes is scanty in patients at 9 months after receiving drug-eluting stent (DES) implantations. This study aims to evaluate the relationship between 9-month follow-up hsCRP levels and long-term clinical outcomes in patients at 9 months after receiving DES. Methods: A total of 1,763 patients who received 9-month follow-up angiography were enrolled and grouped according to hsCRP level 9 months after the DES implantation: group I (718 patients, hsCRP<1.0 mg/L), group II (639 patients, 1.0≦hsCRP≦3.0 mg/L), and group III (406 patients, hsCRP>3.0 mg/L). Results: Group III patients had a lower cardiovascular event-free survival rate than group I or II patients during a follow-up of 64±45 months (64.5% vs. 71.6% vs. 72.8%, respectively, p = 0.012). Multivariate analysis showed that a follow-up hsCRP level <3.0 mg/L was an independent predictor of a major adverse cardiovascular event (cardiac death, reinfarction, target lesion revascularization, stenting in a new lesion, or coronary bypass surgery). Group III patients had a higher restenosis rate (11.3% vs. 5.8% vs. 6.6%, respectively, p = 0.002) and loss index (0.21±0.32 vs. 0.16±0.24 vs. 0.18±0.28, respectively, p = 0.001) than group I or II patients in 9-month follow-up angiography. Conclusions: A high 9-month follow-up hsCRP level is an independent predictor of long-term clinical cardiovascular outcomes in patients at 9 months after DES implantation. It is also associated with a higher restenosis rate, larger late loss and loss index at 9 months after DES implantation. [ABSTRACT FROM AUTHOR]

Background: Different locations and study periods were used in the assessment of the relationships between heatwaves and mortality. However, little is known about the comparability and consistency of the previous effect estimates in the literature. This study assessed the heatwave—mortality relationship using different study periods in the three largest Australian cities (Brisbane, Melbourne and Sydney). Methods: Daily data on climatic variables and mortality for the three cities were obtained from relevant government agencies between 1988 and 2011. A consistent definition of heatwaves was used for these cities. Poisson generalised additive model was fitted to assess the impact of heatwaves on mortality. Results: Non-accidental and circulatory mortality significantly increased during heatwaves across the three cities even with different heatwave definitions and study periods. Using the summer data resulted in the largest increase in effect estimates compared to those using the warm season or the whole year data. Conclusion: The findings may have implications for developing standard approaches to evaluating the heatwave-mortality relationship and advancing heat health warning systems. It also provides an impetus to methodological advance for assessing climate change-related health consequences. [ABSTRACT FROM AUTHOR]

Dystrobrevin-binding protein 1 (DTNBP1), a gene encoding dysbindin-1, has been identified as a susceptibility gene for schizophrenia. Functioning with partners in synapses or the cytoplasm, this gene regulates neurite outgrowth and neurotransmitter release. Loss of dysbindin-1 affects schizophrenia pathology. Dysbindin-1 is also found in the nucleus, however, the characteristics of dysbindin in the nucleus are not fully understood. Here, we found that dysbindin-1A is degraded in the nucleus via the ubiquitin-proteasome system and that amino acids 2-41 at the N-terminus are required for this process. By interacting with p65, dysbindin-1A promotes the transcriptional activity of NF-kappa B in the nucleus and positively regulates MMP-9 expression. Taken together, the data obtained in this study demonstrate that dysbindin-1A protein levels are highly regulated in the nucleus and that dysbindin-1A regulates transcription factor NF-kappa B activity to promote the expression of MMP-9 and TNF-α. [ABSTRACT FROM AUTHOR]

Background: The cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients after acute myocardial infarction (AMI) has so far remained uncertain. Methods: We analyzed data from the National Health Insurance Research Database (NHIRD), a government-operated, population-based database, from March 1st, 2009 to December 31st, 2011. Type 2 diabetic patients hospitalized for AMI were included in our study. We compared subjects using sitagliptin with comparison group to evaluate its cardiovascular safety and efficacy. The primary endpoint was a composite of cardiovascular death, myocardial infarction, and ischemic stroke. Results: We identified a total of 3,282 type 2 diabetic patients hospitalized for AMI (mean follow-up 1.15 years). Of these patients, 547 (16.7%) who were exposed to sitagliptin were defined as the sitagliptin group and 2,735 (83.3 %) who did not use sitagliptin were the comparison group. The incidence of primary composite cardiovascular outcomes was 9.50 per 100 person-years in the sitagliptin group and was 9.70 per 100 person-years in the comparison group (hazard ratio (HR), 0.97; 95% CI, 0.73–1.29, P=0.849). Compared to the non-sitagliptin group, the sitagliptin group had similar risks of all-cause mortality, hospitalization for heart failure (HF) or percutaneous coronary intervention (PCI) with a HR of 0.82 (95% CI, 0.61–1.11, P=0.195), 0.93 (95% CI, 0.67–1.29, P=0.660), and 0.93 (95% CI, 0.75–1.14, P=0.473), respectively. Conclusion: The use of sitagliptin in type 2 diabetic patients with recent AMI was not associated with increased risk of adverse cardiovascular events. [ABSTRACT FROM AUTHOR]

Background: Several risk factors for pacemaker (PM) related complications have been reported. However, no study has investigated the impact of lead characteristics on pacemaker-related complications. Methods and Results: Patients who received a new pacemaker implant from January 1997 to December 2011 were selected from the Taiwan National Health Insurance Database. This population was grouped according to the pacemaker lead characteristics in terms of fixation and insulation. The impact of the characteristics of leads on early heart perforation was analyzed by multivariable logistic regression analysis, while the impact of the lead characteristics on early and late infection and late heart perforation over a three-year period were analyzed using Cox regression. This study included 36,104 patients with a mean age of 73.4±12.5 years. In terms of both early and late heart perforations, there were no significant differences between groups across the different types of fixation and insulations. In the multivariable Cox regression analysis, the pacemaker-related infection rate was significantly lower in the active fixation only group compared to either the both fixation (OR, 0.23; 95% CI, 0.07–0.80; P = 0.020) or the passive fixation group (OR, 0.26; 95% CI, 0.08–0.83; P = 0.023). Conclusions: There was no difference in heart perforation between active and passive fixation leads. Active fixation leads were associated with reduced risk of pacemaker-related infection. [ABSTRACT FROM AUTHOR]

Vegetation patterns are strongly influenced by sand mobility in desert ecosystems. However, little is known about the spatial patterns of Artemisia ordosica, a dominant shrub in the Mu Us desert of Northwest China, in relation to sand fixation. The aim of this study was to investigate and contrast the effects of sand dune stabilization on the population and spatial distribution of this desert shrub. Spatial autocorrelation, semi-variance analysis, and point-pattern analysis were used jointly in this study to investigate the spatial patterns of A. ordosica populations on dunes in Yanchi County of Ningxia, China. The results showed that the spatial autocorrelation and spatial heterogeneity declined gradually, and the distance between the clustered individuals shortened following sand dune fixation. Seedlings were more aggregated than adults in all stage of dune stabilization, and both were more aggregated on shifting sand dunes separately. Spatial associations of the seedlings with the adults were mostly positive at distances of 0–5 m in shifting sand dunes, and the spatial association changed from positive to neutral in semi-fixed sand dunes. The seedlings were spaced in an almost random pattern around the adults, and their distances from the adults did not seem to affect their locations in semi-fixed sand dunes. Furthermore, spatial associations of the seedlings with the adults were negative in the fixed sand dune. These findings demonstrate that sand stabilization is an important factor affecting the spatial patterns of A. ordosica populations in the Mu Us desert. These findings suggest that, strong association between individuals may be the mechanism to explain the spatial pattern formation at preliminary stage of dune fixation. Sand dune stabilization can change the spatial pattern of shrub population by weakening the spatial association between native shrub individuals, which may affect the development direction of desert shrubs. [ABSTRACT FROM AUTHOR]

We have previously characterized human neuronal progenitor cells (hNP) that can adopt a retinal ganglion cell (RGC)-like morphology within the RGC and nerve fiber layers of the retina. In an effort to determine whether hNPs could be used a candidate cells for targeted delivery of neurotrophic factors (NTFs), we evaluated whether hNPs transfected with an vector that expresses IGF-1 in the form of a fusion protein with tdTomato (TD), would increase RGC survival in vitro and confer neuroprotective effects in a mouse model of glaucoma. RGCs co-cultured with hNPIGF-TD cells displayed enhanced survival, and increased neurite extension and branching as compared to hNPTD or untransfected hNP cells. Application of various IGF-1 signaling blockers or IGF-1 receptor antagonists abrogated these effects. In vivo, using a model of glaucoma we showed that IOP elevation led to reductions in retinal RGC count. In this model, evaluation of retinal flatmounts and optic nerve cross sections indicated that only hNPIGF-TD cells effectively reduced RGC death and showed a trend to improve optic nerve axonal loss. RT-PCR analysis of retina lysates over time showed that the neurotrophic effects of IGF-1 were also attributed to down-regulation of inflammatory and to some extent, angiogenic pathways. This study shows that neuronal progenitor cells that hone into the RGC and nerve fiber layers may be used as vehicles for local production and delivery of a desired NTF. Transplantation of hNPIGF-TD cells improves RGC survival in vitro and protects against RGC loss in a rodent model of glaucoma. Our findings have provided experimental evidence and form the basis for applying cell-based strategies for local delivery of NTFs into the retina. Application of cell-based delivery may be extended to other disease conditions beyond glaucoma. [ABSTRACT FROM AUTHOR]

Introduction: Carotid artery stenosis is one of the leading causes of ischemic stroke. Carotid artery stenting has become well-established as an effective treatment option for carotid artery stenosis. For this study, we aimed to determine the efficacy and safety of carotid stenting in a population-based large cohort of patients by analyzing the Taiwan National Healthcare Insurance (NHI) database. Methods: 2,849 patients who received carotid artery stents in the NHI database from 2004 to 2010 were identified. We analyzed the risk factors of outcomes including major adverse cardiovascular events including death, acute myocardial infarction, and cerebral vascular accidents at 30 days, 1 year, and overall period and further evaluated cause of death after carotid artery stenting. Results: The periprocedural stroke rate was 2.7% and the recurrent stroke rate for the overall follow-up period was 20.3%. Male, diabetes mellitus, and heart failure were significant risk factors for overall recurrent stroke (Hazard Ratio (HR) = 1.35, p = 0.006; HR = 1.23, p = 0.014; HR = 1.61, p < 0.001, respectively). The periprocedural acute myocardial infarction rate was 0.3%. Age and Diabetes mellitus were the significant factors to predict periprocedural myocardial infarction (HR = 3.06, p = 0.019; HR = 1.68, p < 0.001, respectively). Periprocedural and overall mortality rates were 1.9% and 17.3%, respectively. The most significant periprocedural mortality risk factor was acute renal failure. Age, diabetes mellitus, acute or chronic renal failure, heart failure, liver disease, and malignancy were factors correlated to the overall period mortality. Conclusion: Periprocedural acute renal failure significantly increased the mortality rate and the number of major adverse cardiovascular events, and the predict power persisted more than one year after the procedure. Age and diabetes mellitus were significant risk factors to predict acute myocardial infarction after carotid artery stenting. [ABSTRACT FROM AUTHOR]

The presence of cancer stem-like cells (CSCs) is one of the mechanisms responsible for chemoresistance that has been a major hindrance towards lung adenocarcinoma (LAD) treatment. Recently, we have identified microRNA (miR)-200b as a key regulator of chemoresistance in human docetaxel-resistant LAD cells. However, whether miR-200b has effects on regulating CSCs remains largely unclear and needs to be further elucidated. Here, we showed that miR-200b was significantly downregulated in CD133+/CD326+ cells that exhibited properties of CSCs derived from docetaxel-resistant LAD cells. Also, restoration of miR-200b could inhibit maintenance and reverse chemoresistance of CSCs. Furthermore, suppressor of zeste-12 (Suz-12) was identified as a direct and functional target of miR-200b, and silencing of Suz-12 phenocopied the effects of miR-200b on CSCs. Additionally, overexpression of histone deacetylase (HDAC) 1 was identified as a pivotal mechanism responsible for miR-200b repression in CSCs through a specificity protein (Sp) 1-dependent mechanism, and restoration of miR-200b by HDAC1 repression significantly suppressed CSCs formation and reversed chemoresistance of CSCs by regulating Suz-12-E-cadherin signaling. Also, downregulation of HDAC1 or upregulation of miR-200b reduced the in vivo tumorigenicity of CSCs. Finally, Suz-12 was inversely correlated with miR-200b, positively correlated with HDAC1 and up-regulated in docetaxel-resistant LAD tissues compared with docetaxel-sensitive tissues. Taken together, the HDAC1/miR-200b/Suz-12-E-cadherin signaling might account for maintenance of CSCs and formation of chemoresistant phenotype in docetaxel-resistant LAD cells. [ABSTRACT FROM AUTHOR]

Objective: It has been reported that IKAROS family of zinc finger 3 (IKZF3)-deficient mice spontaneously develop human systemic lupus erythematosus (SLE)-like phenotypes and produce anti-dsDNA Ab leading to immune complex-mediated glomerulonephritis. Polymorphism of the IKZF3 gene corresponds with the susceptibility to several immune-related diseases. Our intention was to establish an association between polymorphisms in the IKZF3 gene and SLE in the Chinese Han population. Methods: The study involved obtaining blood samples for DNA extraction and genotyping the 4 selected single-nucleotide polymorphisms (SNPs) in IKZF3, including rs12150079, rs9909593, rs907091, and rs2872507, by performing PCR restriction fragment length polymorphism analysis (PCR-RFLP). A group of 366 SLE patients were compared to 455 healthy controls. Results: A significant decrease in frequencies of the rs907091 CC genotype and C allele appeared in the SLE patients unlike that observed in the controls (p = 0.001 and 0.015, respectively). The frequencies of the rs12150079 genotype and allele were different between the SLE patients and the control individuals, although the significance was only marginal (p = 0.046 and 0.049, respectively). In addition, a significantly low frequency of the GGCG haplotype was observed in the SLE patients, suggesting that it may provide protection against SLE (p = 0.011). Conclusion: To the best of our knowledge, this is the first study to demonstrate an important association between polymorphisms in IKZF3 and SLE in the Chinese Han population. A strong association between rs907091 in the IKZF3 gene and SLE was identified. [ABSTRACT FROM AUTHOR]

Background: BRAF mutations have been well described in non-small cell lung cancer (NSCLC) for several years, but the clinical features of patients harboring BRAF mutations are still not well described. We performed a meta-analysis to identify common clinical features in NSCLC patients carrying BRAF mutations. Methods: We identified clinical studies that examined the association between BRAF mutations and features of NSCLC within PubMed, Embase and ISI Science Citation Index database up to October 2013. The effect size of clinical features was estimated by odds ratios (ORs) with 95% confidence interval (CI) for each study, using a fixed-effects or random-effects model. Results: Ten studies with a total of 5599 NSCLC patients were included. There was a 3% (170/5599) BRAF mutation rate. BRAF mutations in NSCLC were significantly associated with adenocarcinomas (ADCs) (compared with non-ADCs, OR = 4.96, 95%CI = 2.29–10.75). There were no significant differences in gender, smoking and stage in patients with and without BRAF mutations. The BRAFV600E mutation was more frequent in women than non-BRAFV600E mutations (OR = 0.27, 95%CI = 0.12–0.59), and was closely related to never smokers (OR = 0.14, 95%CI = 0.05–0.42). Conclusions: These findings have important implications for the prediction of the NSCLC sub-types more accurately combined with other genetic changes. [ABSTRACT FROM AUTHOR]

Genotyping of thiopurine S-methyltransferase (TPMT) is recommended for predicting the adverse drug response of thiopurines. In the current study, a novel version of allele-specific PCR (AS-PCR), termed competitive real-time fluorescent AS-PCR (CRAS-PCR) was developed to analyze the TPMT*2 genotype in ethnic Chinese. This technique simultaneously uses wild-type and mutant allele-specific scorpion primers in a single reaction. To determine the optimal conditions for both traditional AS-PCR and CRAS-PCR, we used the Taguchi method, an engineering optimization process that balances the concentrations of all components using an orthogonal array rather than a factorial array. Instead of running up to 264 experiments with the conventional factorial method, the Taguchi method achieved the same optimization using only 16 experiments. The optimized CRAS-PCR system completely avoided non-specific amplification occurring in traditional AS-PCR and could be performed at much more relaxed reaction conditions at 1% sensitivity, similar to traditional AS-PCR. TPMT*2 genotyping of 240 clinical samples was consistent with published data. In conclusion, CRAS-PCR is a novel and robust genotyping method, and the Taguchi method is an effective tool for the optimization of molecular analysis techniques. [ABSTRACT FROM AUTHOR]

Background: The recently solved solution structure of HCV (hepatitis C virus) p7 ion channel provides a solid structure basis for drug design against HCV infection. In the p7 channel the ligand amantadine (or rimantadine) was determined in a hydrophobic pocket. However the pharmocophore (−NH2) of the ligand was not assigned a specific binding site. Results: The possible binding sites for amino group of adamantane derivatives is studied based on the NMR structure of p7 channel using QM calculation and molecular modeling. In the hydrophobic cavity and nearby three possible binding sites are proposed: His17, Phe20, and Trp21. The ligand binding energies at the three binding sites are studied using high level QM method CCSD(T)/6–311+G(d,p) and AutoDock calculations, and the interaction details are analyzed. The potential application of the binding sites for rational inhibitor design are discussed. Conclusions: Some useful viewpoints are concluded as follows. (1) The amino group (−NH2) of adamantane derivatives is protonated (−NH3+), and the positively charged cation may form cation-π interactions with aromatic amino acids. (2) The aromatic amino acids (His17, Phe20, and Trp21) are the possible binding sites for the protonated amino group (−NH3+) of adamantane derivatives, and the cation-π bond energies are 3 to 5 times stronger than the energies of common hydrogen bonds. (3) The higher inhibition potent of rimantadine than amantadine probably because of its higher pKa value (pKa = 10.40) and the higher positive charge in the amino group. The potential application of p7 channel structure for inhibitor design is discussed. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. The B-type Raf proto-oncogene (BRAF) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade during CRC. The presence of BRAFV600E mutation can determine the response of a tumor to chemotherapy. However, the association between the BRAFV600E mutation and the clinicopathological features of CRC remains controversial. We performed a systematic review and meta-analysis to estimate the effect of BRAFV600E mutation on the clinicopathological characteristics of CRC. Methods: We identified studies that examined the effect of BRAFV600E mutation on CRC within the PubMed, ISI Science Citation Index, and Embase databases. The effect of BRAFV600E on outcome parameters was estimated by odds ratios (ORs) with 95% confidence intervals (CIs) for each study using a fixed effects or random effects model. Results: 25 studies with a total of 11,955 CRC patients met inclusion criteria. The rate of BRAFV600 was 10.8% (1288/11955). The BRAFV600E mutation in CRC was associated with advanced TNM stage, poor differentiation, mucinous histology, microsatellite instability (MSI), CpG island methylator phenotype (CIMP). This mutation was also associated with female gender, older age, proximal colon, and mutL homolog 1 (MLH1) methylation. Conclusions: This meta-analysis demonstrated that BRAFV600E mutation was significantly correlated with adverse pathological features of CRC and distinct clinical characteristics. These data suggest that BRAFV600E mutation could be used to supplement standard clinical and pathological staging for the better management of individual CRC patients, and could be considered as a poor prognostic marker for CRC. [ABSTRACT FROM AUTHOR]

Objective: β-blockers (BBs) with different pharmacological properties may have heterogeneous effects on sympathetic nervous activity (SNA) and central aortic pressure (CAP), which are independent cardiovascular factors for hypertension. Hence, we analyzed the effects of bisoprolol and atenolol on SNA and CAP in hypertensive patients. Methods: This was a prospective, randomized, controlled study in 109 never-treated hypertensive subjects randomized to bisoprolol (5 mg) or atenolol (50 mg) for 4–8 weeks. SNA, baroreflex sensitivity (BRS) and heart rate (HR) variability (HRV) were measured using power spectral analysis using a Finometer. CAP and related parameters were determined using the SphygmoCor device (pulse wave analysis). Results: Both drugs were similarly effective in reducing brachial BP. However, central systolic BP (−14±10 mm Hg vs −6±9 mm Hg; P<0.001) and aortic pulse pressure (−3±10 mm Hg vs +3±8 mm Hg; P<0.001) decreased more significantly with bisoprolol than with atenolol. The augmentation index at a HR of 75 bpm (AIxatHR75) was significantly decreased (29%±11% to 25%±12%; P = 0.026) in the bisoprolol group only. Furthermore, the change in BRS in the bisoprolol group (3.99±4.19 ms/mmHg) was higher than in the atenolol group (2.66±3.78 ms/mmHg), although not statistically significant (P>0.05). BRS was stable when RHR was controlled (RHR≤65 bpm), and the two treatments had similar effects on the low frequency/high frequency (HF) ratio and on HF. Conclusion: BBs seem to have different effects on arterial distensibility and compliance in hypertensive subjects. Compared with atenolol, bisoprolol may have a better effect on CAP. Trial Registration: ClinicalTrials.gov NCT01762436 [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Although its pathogenesis is still unclear, increasing evidence suggests that mitochondrial dysfunction induced by environmental toxins, such as mitochondrial complex I inhibitors, plays a significant role in the disease process. The microglia in PD brains are highly activated, and inflammation is also an essential element in PD pathogenesis. However, the means by which these toxins activate microglia is still unclear. In the present study, we found that rotenone, a mitochondrial complex I inhibitor, could directly activate microglia via the nuclear factor kappa B (NF-κB) signaling pathway, thereby inducing significantly increased expression of inflammatory cytokines. We further observed that rotenone induced caspase-1 activation and mature IL-1β release, both of which are strictly dependent on p38 mitogen-activated protein kinase (MAPK). The activation of p38 is associated with the presence of reactive oxygen species (ROS) produced by rotenone. Removal of these ROS abrogated the activation of the microglia. Therefore, our data suggest that the environmental toxin rotenone can directly activate microglia through the p38 MAPK pathway. [ABSTRACT FROM AUTHOR]

Previous studies of the conditional ablation of TGF-b activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells' increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-κB and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1's role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1's role in leukemogenesis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is the initial step of the atopic march: the progression from AD to allergic rhinitis and asthma. There is a close association between skin barrier abnormalities and the development of AD and the atopic march. One of cardinal features of AD is that the lesional skin of the majority of AD patients is chronically colonized with Staphylococcus aureus with half isolates producing superantigen enterotoxin B (SEB). Although diverse roles of SEB in the pathogenesis and severity of AD have been recognized, whether SEB contributes to the dermal inflammation that drives lung inflammation and airway hyperresponsiveness (AHR) has not been examined. Here we show a novel role of S. aureus superantigen SEB in augmenting allergen ovalbumin (Ova) induced atopic march through an IL-17A dependent mechanism. When mice epicutaneously (EC) sensitized with allergen Ova, addition of topical SEB led to not only augmented systemic Th2 responses but also a markedly exaggerated systemic Th17/IL-17 immune environment. The ability of SEB in enhancing Th17/IL-17 was mediated through stimulating lymphocytes in spleen and draining lymph nodes to promote IL-6 production. Epicutaneous sensitization of mice with a combination of Ova and SEB significantly enhanced Ova-induced AHR and granulocytic lung inflammation than Ova allergen alone. When IL-17A was deleted genetically, the effects of SEB on augmenting lung inflammation and AHR were markedly diminished. These findings suggest that chronic heavy colonization of enterotoxin producing S. aureus in the skin of patients with atopic dermatitis may have an important role in the development of atopic march via an IL-17A dependent mechanism [ABSTRACT FROM AUTHOR]

Background: Clopidogrel is a prodrug that undergoes in vivo bioactivation to show its antiplatelet effects. Recent studies have shown that cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogrel bioactivation. Here, we aim to determine the effects of genetic polymorphisms of CYP (CYP 2C19*2, CYP 2C19*3, and CYP 2C19*17), ABCB1 (ABCB1 3435C>T, ABCB1 129T>C, and ABCB1 2677G>T/A), and PON1 (PON1 Q192R, PON1 L55M, and PON1 108C.T) on the development of stent thrombosis (ST) in patients receiving clopidogrel after percutaneous coronary intervention (PCI). Methods and Results: We evaluated the incidence of ST (0.64%) in 4964 patients who were recruited in the CAPTAIN registry (Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions). The presence of genetic polymorphisms was assessed in 20 subjects who developed ST after aspirin and clopidogrel therapy and in 40 age- and sex-matched control subjects who did not develop ST, which was documented after 9 months of angiographic follow-up. ST was acute in 5 subjects, subacute in 7, late in 7, and very late in 1. The presence of CYP 2C19*2 allele was significantly associated with ST (adjusted odds ratio [ORadj]: 4.20, 95% confidence interval [CI], 1.263-9.544; P = 0.031). However, genetic variations in PON1 and ABCB1 showed no significant association with ST. Conclusion: We conclude that in a Taiwanese population, PON1 Q192R genotype is not associated with ST development after PCI. However, the presence of CYP 2C19*2 allele is a risk factor for ST development after PCI. [ABSTRACT FROM AUTHOR]

Interleukin-17F (IL-17F), produced by Th17 cells and other immune cells, is a member of IL-17 cytokine family with highest homology to IL-17A. IL-17F has been shown to have multiple functions in inflammatory responses. While IL-17A plays important roles in cancer development, the function of IL-17F in tumorigenesis has not yet been elucidated. In the current study, we found that IL-17F is expressed in normal human colonic epithelial cells, but this expression is greatly decreased in colon cancer tissues. To examine the roles of IL-17F in colon cancer, we have used IL-17F over-expressing colon cancer cell lines and IL-17F-deficient mice. Our data showed decreased tumor growth of IL-17F-transfected HCT116 cells comparing to mock transfectants when transplanted in nude mice. Conversely, there were increased colonic tumor numbers and tumor areas in Il-17f-/- mice than those from wild-type controls after colon cancer induction. These results indicate that IL-17F plays an inhibitory role in colon tumorigenesis in vivo. In IL-17F over-expressing tumors, there was no significant change in leukocyte infiltration; instead, we found decreased VEGF levels and CD31+ cells. While the VEGF levels were increased in the colon tissues of Il-17f-/- mice with colon cancer. Together, our findings demonstrate a protective role for IL-17F in colon cancer development, possibly via inhibiting tumor angiogenesis. [ABSTRACT FROM AUTHOR]

Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFa triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasLdeficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma. [ABSTRACT FROM AUTHOR]

Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNF \(\alpha\) triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma.

Background: BRAF mutations have been well described in non-small cell lung cancer (NSCLC) for several years, but the clinical features of patients harboring BRAF mutations are still not well described. We performed a meta-analysis to identify common clinical features in NSCLC patients carrying BRAF mutations., Methods: We identified clinical studies that examined the association between BRAF mutations and features of NSCLC within PubMed, Embase and ISI Science Citation Index database up to October 2013. The effect size of clinical features was estimated by odds ratios (ORs) with 95% confidence interval (CI) for each study, using a fixed-effects or random-effects model., Results: Ten studies with a total of 5599 NSCLC patients were included. There was a 3% (170/5599) BRAF mutation rate. BRAF mutations in NSCLC were significantly associated with adenocarcinomas (ADCs) (compared with non-ADCs, OR = 4.96, 95%CI = 2.29-10.75). There were no significant differences in gender, smoking and stage in patients with and without BRAF mutations. The BRAFV600E mutation was more frequent in women than non-BRAFV600E mutations (OR = 0.27, 95%CI = 0.12-0.59), and was closely related to never smokers (OR = 0.14, 95%CI = 0.05-0.42)., Conclusions: These findings have important implications for the prediction of the NSCLC sub-types more accurately combined with other genetic changes.

Genotyping of thiopurine S-methyltransferase (TPMT) is recommended for predicting the adverse drug response of thiopurines. In the current study, a novel version of allele-specific PCR (AS-PCR), termed competitive real-time fluorescent AS-PCR (CRAS-PCR) was developed to analyze the TPMT*2 genotype in ethnic Chinese. This technique simultaneously uses wild-type and mutant allele-specific scorpion primers in a single reaction. To determine the optimal conditions for both traditional AS-PCR and CRAS-PCR, we used the Taguchi method, an engineering optimization process that balances the concentrations of all components using an orthogonal array rather than a factorial array. Instead of running up to 264 experiments with the conventional factorial method, the Taguchi method achieved the same optimization using only 16 experiments. The optimized CRAS-PCR system completely avoided non-specific amplification occurring in traditional AS-PCR and could be performed at much more relaxed reaction conditions at 1% sensitivity, similar to traditional AS-PCR. TPMT*2 genotyping of 240 clinical samples was consistent with published data. In conclusion, CRAS-PCR is a novel and robust genotyping method, and the Taguchi method is an effective tool for the optimization of molecular analysis techniques.

Background: Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. The B-type Raf proto-oncogene (BRAF) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade during CRC. The presence of BRAFV600E mutation can determine the response of a tumor to chemotherapy. However, the association between the BRAFV600E mutation and the clinicopathological features of CRC remains controversial. We performed a systematic review and meta-analysis to estimate the effect of BRAFV600E mutation on the clinicopathological characteristics of CRC., Methods: We identified studies that examined the effect of BRAFV600E mutation on CRC within the PubMed, ISI Science Citation Index, and Embase databases. The effect of BRAFV600E on outcome parameters was estimated by odds ratios (ORs) with 95% confidence intervals (CIs) for each study using a fixed effects or random effects model., Results: 25 studies with a total of 11,955 CRC patients met inclusion criteria. The rate of BRAFV600 was 10.8% (1288/11955). The BRAFV600E mutation in CRC was associated with advanced TNM stage, poor differentiation, mucinous histology, microsatellite instability (MSI), CpG island methylator phenotype (CIMP). This mutation was also associated with female gender, older age, proximal colon, and mutL homolog 1 (MLH1) methylation., Conclusions: This meta-analysis demonstrated that BRAFV600E mutation was significantly correlated with adverse pathological features of CRC and distinct clinical characteristics. These data suggest that BRAFV600E mutation could be used to supplement standard clinical and pathological staging for the better management of individual CRC patients, and could be considered as a poor prognostic marker for CRC.

Pseudorabies virus (PRV) belongs to Alphaherpesvirinae subfamily that causes huge economic loss in pig industry worldwide. It has been recently demonstrated that many herpesviruses encode microRNAs (miRNAs), which play crucial roles in viral life cycle. However, the knowledge about PRV-encoded miRNAs is still limited. Here, we report a comprehensive analysis of both viral and host miRNA expression profiles in PRV-infected porcine epithelial cell line (PK-15). Deep sequencing data showed that the ∼4.6 kb intron of the large latency transcript (LLT) functions as a primary microRNA precursor (pri-miRNA) that encodes a cluster of 11 distinct miRNAs in the PRV genome, and 209 known and 39 novel porcine miRNAs were detected. Viral miRNAs were further confirmed by stem-loop RT-PCR and northern blot analysis. Intriguingly, all of these viral miRNAs exhibited terminal heterogeneity both at the 5' and 3' ends. Seven miRNA genes produced mature miRNAs from both arms and two of the viral miRNA genes showed partially overlapped in their precursor regions. Unexpectedly, a terminal loop-derived small RNA with high abundance and one special miRNA offset RNA (moRNA) were processed from a same viral miRNA precursor. The polymorphisms of viral miRNAs shed light on the complexity of host miRNA-processing machinery and viral miRNA-regulatory mechanism. The swine genes and PRV genes were collected for target prediction of the viral miRNAs, revealing a complex network formed by both host and viral genes. GO enrichment analysis of host target genes suggests that PRV miRNAs are involved in complex cellular pathways including cell death, immune system process, metabolic pathway, indicating that these miRNAs play significant roles in virus-cells interaction of PRV and its hosts. Collectively, these data suggest that PRV infected epithelial cell line generates a diverse set of host miRNAs and a special cluster of viral miRNAs, which might facilitate PRV replication in cells.

The increasing prevalence of insecticide resistance in Anopheles sinensis, a major vector of malaria in Jiangsu province in eastern China, threatens to compromise the successful use of insecticides in malaria control strategies. It is therefore vital to understand the insecticide resistance status of An. sinensis in the region. This study examined the nucleotide diversity of the para-sodium channel and knockdown resistance (kdr) in five field populations of adult An. sinensis mosquitoes collected in Jiangsu province, identifying the L1014F and L1014C substitutions for the first time. Competitive polymerase chain reaction (PCR) amplification of specific allele (cPASA) and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) for resistance diagnosis were developed and validated. Comparing the results with direct sequencing revealed that the PCR-RFLP method was more sensitive and specific whereas the cPASA method was more convenient and suitable. The significant positive correlation between kdr allele frequency and bioassay-based resistance phenotype demonstrates that the frequency of L1014F and L1014C substitutions in the kdr gene provides a useful molecular marker for monitoring beta-cypermethrin resistance in natural populations of An. sinensis. Our results point to the L1014F substitution as the key mutation associated with beta-cypermethrin resistance. The high resistance and mutation frequency detected in the five populations also suggest cross-resistance with other pyrethroids may occur in An. sinensis, highlighting the need for further surveys to map insecticide resistance in China and the adoption of a rational management of insecticide application for resistance management and mosquito vector control.

Background: Diseases of the kidneys and genitourinary tract are common health problems that affect people of all ages and demographic backgrounds. In this study, we compared the quantity and quality of nephrological and urological articles published in international journals from the three major regions of China: the mainland (ML), Hong Kong (HK), and Taiwan (TW)., Methods: Nephrological and urological articles originating from ML, TW, and HK that were published in 61 journals from 1999-2008 were retrieved from the PubMed database. We recorded the numbers of total articles, clinical trials, randomized controlled trials, case reports, impact factors (IF), citations, and articles published in the leading general-medicine journals. We used these data to compare the quantity and quality of publication output from the three regions., Results: The total number of articles increased significantly from 1999 to 2008 in the three regions. The number of articles from ML has exceeded that from HK since 2004, and surpassed that from TW in 2008. Publications from TW had the highest accumulated IF, total citations of articles, and the most articles published in leading general-medicine journals. However, HK publications had the highest average IF. Although ML produced the largest quantity of articles, it exhibited the lowest quality among the three regions., Conclusion: The number of nephrological and urological publications originating from the three major regions of China increased significantly from 1999 to 2008. The annual number of publications by ML researchers exceeded those from TW and HK. However, the quality of articles from TW and HK was higher than that from ML.