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Background Dual antiplatelet therapy (DAPT) is currently the standard treatment for the prevention of ischemic events after stent implantation. However, the optimal DAPT duration remains elusive for patients with chronic kidney disease (CKD). Therefore, we aimed to compare the effectiveness and safety between long-term and short-term DAPT after coronary stenting in patients with CKD. Methods This retrospective cohort study analyze data from the Taipei Medical University (TMU) Institutional and Clinical Database, which include anonymized electronic health data of 3 million patients that visited TMU Hospital, Wan Fang Hospital, and Shuang Ho Hospital. We enrolled patients with CKD after coronary stenting between 2008 and 2019. The patients were divided into the long-term (>6 months) and short-term DAPT group (≤ 6 months). The primary end point was major adverse cardiovascular events (MACE) from 6 months after the index date. The secondary outcomes were all-cause mortality and Thrombolysis in Myocardial Infarction (TIMI) bleeding. Results A total of 1899 patients were enrolled; of them, 1112 and 787 were assigned to the long-term and short-term DAPT groups, respectively. Long-term DAPT was associated with similar risk of MACE (HR: 1.05, 95% CI: 0.65–1.70, P = 0.83) compare with short-term DAPT. Different CKD risk did not modify the risk of MACE. There was also no significant difference in all-cause mortality (HR: 1.10, 95% CI: 0.75–1.61, P = 0.63) and TIMI bleeding (HR 1.19, 95% CI: 0.86–1.63, P = 0.30) between groups. Conclusions Among patients with CKD and coronary stenting, we found that long-term and short-term DAPT tied on the risk of MACE, all-cause mortality and TIMI bleeding.

ObjectivesMore and more evidence suggests oxidative stress and inflammation contribute importantly to subarachnoid hemorrhage (SAH)-induced cerebral vasospasm and secondary brain injury. Recent evidence indicates Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) increases the expression of antioxidant genes and decreases the expression of pro-inflammatory genes. This study examines the effects of an activator of Nfr2, RTA 408, on SAH-induced cerebral vasospasm and possible mechanism underlying its effect in a two-hemorrhage rodent model of SAH.MethodsWe randomly assigned 60 Sprague-Dawley male rats (350 to 420g) to five groups twelve rats each: one control group (no SAH), one untreated SAH only group and three RTA-408 treatment groups (SAH+ RTA 408 0.5 mg/kg/day, SAH+RTA 408 1 mg/kg/day and a SAH+RTA 408 1.5 mg/kg/day). The treatment groups were administered RTA 408 by intraperitoneal injection thirty min following first induction of SAH for seven days starting with first hemorrhage. Cerebral vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of Nrf2, NF-κB and iNOS in basilar artery and expressions of Nrf2, HO-1, NQO1 and Cleaved caspase-3 were evaluated. Tissue TNF-alpha was assessed by ELISA using the protein sampled from the dentate gyrus, cerebral cortex, and hippocampus.ResultsPrior to perfusion fixation, there were no significant physiological differences among the control and treated groups. RTA 408 treatment attenuated the morphological changes caused by cerebral vasospasm. It mitigated SAH-induced suppression of Nrf2 and increased expression of NF-κB and iNOS in the basilar artery. In dentate gyrus, it reversed SAH-decreases in Nrf2, HO-1, NQO-1 and cleaved caspase-3 and RTA 408 1.5 mg/kg/day reversed SAH increases in TNF-alpha.ConclusionIt was concluded that RTA 408 reversal vasospasm was achieved via increases in Nrf2 and decreases in NF-κB and iNOS. It exerted a neuron-protection effect by decreasing the apoptosis-related protein cleaved caspase-3 and decreasing the information cytokine TNF-alpha expression, which it achieved by increasing HO-1 and NQO-1 protein found downstream from Nrf2 and Nrf2. We believe that RTA 408 can potentially be used to manage of cerebral vasospasm and secondary brain injury following SAH.

Purpose The use of Virtual Reality (VR) in health professions education has increased dramatically in recent years, yet there is limited evidence of its impact on educational outcomes. The purpose of the study was to assess the impact of VR anatomy instruction on the ultrasound competency of novice learners participating in a ultrasonography workshop. Method We designed a VR-enhanced ultrasonography training program and utilized a plane transection tool to interact with a three-dimensional (3D) VR model of the human body which facilitated the 3D conceptualization of the spatial relationship of anatomical structures, leading to faster and better development of ultrasonographic competency. This was a randomized control study which enrolled third-year medical students (n = 101) without previous exposure to formal or informal ultrasonography training. The participants were randomly divided into an intervention and control group. We assessed participants’ competency through ultrasound performance stations on live subjects, we also measured anatomical and ultrasound image identification ability using multiple choice tests. Result Participants in the intervention group (median = 16; interquartile 13 to 19) had significantly higher scores in ultrasonography task performance tests than the control group (median = 10; interquartile 7 to 14; Mann-Whitney U = 595; P < 0.01). In sub-group analysis, the intervention group performed significantly better in the six out of ten ultrasound tasks. Participants in the intervention group also had greater improvement in ultrasonographic image identification MCQ tests than the control group (Mann-Whitney U = 914; P < 0.05). Conclusion This study suggests that VR-enhanced anatomical training could be of significant benefit in ultrasonography training by promoting a better understanding of the spatial relationships of anatomical structures and the development of early psychomotor skills transferable to the handling of ultrasonographic probes.

Background The optimal anticoagulant for end-stage renal disease patients for stroke prophylaxis is unknown. The efficacy and safety of warfarin in this population are debatable. In addition, real-world evidence of direct oral anticoagulants in patients with end-stage renal disease is limited. The aim of this study was to evaluate the clinical outcomes of rivaroxaban compared with warfarin in Taiwanese patients with end-stage renal disease with nonvalvular atrial fibrillation in a real-world setting. Methods and results This was a retrospective population-based cohort study conducted using Taiwan’s National Health Insurance Research Database. Patients with nonvalvular atrial fibrillation and end-stage renal disease who started on rivaroxaban or warfarin between February 2013 and September 2017 were eligible to participate in the study. The inverse probability of treatment weighting approach was used to balance baseline characteristics. Bleeding and thromboembolic outcomes were compared using competing risk analyses. The study population consisted of 3358 patients (173 and 3185 patients on rivaroxaban and warfarin, respectively). In the rivaroxaban group, 50.8%, 38.7%, and 10.4% of the patients received 10, 15, and 20 mg of the drug, respectively. The cumulative incidence of major bleeding was similar between the two groups; however, the gastrointestinal bleeding rate was lower in the rivaroxaban group (adjusted subdistribution hazard ratio [SHR]: 0.56, 95% confidence interval [CI]: 0.34–0.91) than in the warfarin group. Furthermore, the composite risk of ischemic stroke or systemic embolism was significantly lower in the rivaroxaban group (adjusted SHR: 0.36, 95% CI: 0.17–0.79). Similar findings were observed for patients who received 10 mg of rivaroxaban. Conclusions In Taiwanese patients with end-stage renal disease and nonvalvular atrial fibrillation, rivaroxaban may be associated with a similar risk of major bleeding but a lower risk of thromboembolism compared with warfarin. The potential benefit of 10 mg of rivaroxaban in this population requires further investigation.

The majority of compressive vertebral fractures in osteoporotic bone occur at the level of the thoracolumbar junction. Immediate decompression is often required in order to reduce the extent of neurological damage. This study evaluated four fixation methods for decompression in patients with thoracolumbar burst fractures, and presented the most suitable method for osteoporotic patients. A finite element model of a T7-L5 spinal segment was created and subjected to an L1 corpectomy to simulate a serious burst fracture. Five models were tested: a) intact spine; 2) two segment fixation (TSF), 3) up-three segment fixation (UTSF), below-three segment fixation (BTSF), and four segment fixation (FSF). The ROM, stiffness and compression ratio of the fractured vertebra were recorded under various loading conditions. The results of this study showed that the ROM of the FSF model was the lowest, and the ROMs of UTSF and BTSF models were similar but still greater than the TSF model. Decreasing the BMD to simulate osteoporotic bone resulted in a ROM for the four instrumented models that was higher than the normal bone model. Of all models, the FSF model had the highest stiffness at T12-L2 in extension and lateral bending. Similarly, the compression ratio of the FSF model at L1 was also higher than the other instrumented models. In conclusion, FSF fixation is suggested for patients with osteoporotic thoracolumbar burst fractures. For patients with normal bone quality, both UTSF and BTSF fixation provide an acceptable stiffness in extension and lateral bending, as well as a favorable compression ratio at L1.

[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetry in mice and monkeys. We also conducted a preliminary study of this imaging agent in humans. Using this one-pot two-step method, the radiochemical yield (RCY) of [18F]T807 was 20.5 ± 6.1% (n = 15) at the end of bombardment (EOB) in a synthesis time of 70±5 min. The chemical and radiochemical purities were >90% and the specific activities were 151 ± 52 GBq/μmol. The quality of [18F]T807 synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]T807 injection was stable at room temperature for up to 4 h after the end of synthesis (EOS). The estimated effective dose of the [18F]T807 injection extrapolated from monkeys was 19 μSv/MBq (n = 2), while the estimated effective doses of the [18F]T807 injection extrapolated from fasted and non-fasted mice were 123 ± 27 (n = 3) and 94 ± 19 (n = 4) μSv/MBq, respectively. This one-pot two-step automated method produced the [18F]T807 injection with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Thus, this method could fulfill the demand for the [18F]T807 injection in both preclinical and clinical studies of tauopathies, especially for nearby study sites without cyclotrons.

The unrivaled computing capabilities of modern GPUs meet the demand of processing massive amounts of data seen in many application domains. While traditional HPC systems support applications as standalone entities that occupy entire GPUs, there are GPU-based DBMSs where multiple tasks are meant to be run at the same time in the same device. To that end, system-level resource management mechanisms are needed to fully unleash the computing power of GPUs in large data processing, and there were some researches focusing on it. In our previous work, we explored the single compute-bound kernel modeling on GPUs under NVidia's CUDA framework and provided an in-depth anatomy of the NVidia's concurrent kernel execution mechanism (CUDA stream). This paper focuses on resource allocation of multiple GPU applications towards optimization of system throughput in the context of systems. Comparing to earlier studies of enabling concurrent tasks support on GPU such as MultiQx-GPU, we use a different approach that is to control the launching parameters of multiple GPU kernels as provided by compile-time performance modeling as a kernel-level optimization and also a more general pre-processing model with batch-level control to enhance performance. Specifically, we construct a variation of multi-dimensional knapsack model to maximize concurrency in a multi-kernel environment. We present an in-depth analysis of our model and develop an algorithm based on dynamic programming technique to solve the model. We prove the algorithm can find optimal solutions (in terms of thread concurrency) to the problem and bears pseudopolynomial complexity on both time and space. Such results are verified by extensive experiments running on our microbenchmark that consists of real-world GPU queries. Furthermore, solutions identified by our method also significantly reduce the total running time of the workload, as compared to sequential and MultiQx-GPU executions.

Tumor characteristics in computed tomography (CT) are correlated to pathologic presentation and survival. However, most studies have been based on thin slice thickness CT while lymph node metastatic pattern has remained unclear. The aim of this study was to analyze the correlation between image characteristics under 5 mm slice thickness and pathology findings in non small lung cancer patients who have received curative resection.From January 2010 to May 2014, 440 patients who underwent curative resection were included and medical records were reviewed retrospectively. The tumor size and consolidation tumor ratio were simultaneously evaluated and measured by a physician, a thoracic surgeon, and a radiologist. The correlation between image and pathology characteristics and its survival impact was analyzed.Tumor sizes, as measured by CT and by pathologic measurement were highly coincident. (p0.001) GGO predominant lesions were correlated to well-differentiated adenocarcinoma, (p0.001), and less tumor necrosis (p0.0001), lymphocyte infiltration (p = 0.0042) and tumor purity (p0.0001). In addition, less risk of visceral pleura (p0.0001) and angiolymphatic invasion, and fewer metastases to N1 lymph node (p = 0.004) involvement were identified. No lymph node metastasis (0/12) was identified in sub-centimeter pure GGO lesion. The consolidation tumor ratio could be used to differentiate patients' survival and excellent 5-year overall survival was identified in pure GGO lesion cases.No lymph node metastasis was identified in sub-centimeter pure GGO lesion. The consolidation tumor ratio could be used to differentiate patients' disease status and overall survival, while excellent 5-year overall survival was identified in cases with pure GGO lesion.

Several reports have indicated that hypoxia, GLI, and connective tissue growth factor (CTGF) contribute to pulmonary fibrosis in idiopathic pulmonary fibrosis. We investigated the participation of mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1)/MEK1/ERK1/GLI-1/2 and activator protein-1 (AP-1) signaling in hypoxia-induced CTGF expression in human lung fibroblasts. Hypoxia time-dependently increased CTGF expression, which was attenuated by the small interfering RNA (siRNA) of GLI-1 (GLI-1 siRNA) and GLI-2 (GLI-2 siRNA) in both human lung fibroblast cell line (WI-38) and primary human lung fibroblasts (NHLFs). Moreover, GLI-1 siRNA and GLI-2 siRNA attenuated hypoxia-induced CTGF-luciferase activity, and the treatment of cells with hypoxia induced GLI-1 and GLI-2 translocation. Furthermore, hypoxia-induced CTGF expression was reduced by an MEK inhibitor (PD98059), MEK1 siRNA, ERK inhibitor (U0126), ERK1 siRNA, and MEKK1 siRNA. Both PD98059 and U0126 significantly attenuated hypoxia-induced CTGF-luciferase activity. Hypoxia time-dependently increased MEKK1, ERK, and p38 MAPK phosphorylation. Moreover, SB203580 (a p38 MAPK inhibitor) also apparently inhibited hypoxia-induced CTGF expression. The treatment of cells with hypoxia induced ERK, GLI-1, or GLI-2 complex formation. Hypoxia-induced GLI-1 and GLI-2 translocation into the nucleus was significantly attenuated by U0126. In addition, hypoxia-induced ERK Tyr204 phosphorylation was impeded by MEKK1 siRNA. Moreover, hypoxia-induced CTGF-luciferase activity was attenuated by cells transfected with AP-1 site mutation in a CTGF construct. Exposure to hypoxia caused a time-dependent phosphorylation of c-Jun, but not of c-Fos. Chromatin immunoprecipitation (ChIP) revealed that hypoxia induced the recruitment of c-Jun, GLI-1, and GLI-2 to the AP-1 promoter region of CTGF. Hypoxia-treated cells exhibited an increase in α-smooth muscle actin (α-SMA) and collagen production, which was blocked by GLI-1 siRNA and GLI-2 siRNA. Overall, these data implied that the MEKK1/MEK1/ERK1/GLI-1/GLI-2, and AP-1 pathways mediated hypoxia-induced CTGF expression in human lung fibroblasts. Furthermore, GLI-1 and GLI-2 found to be involved in hypoxia-induced α-SMA and collagen expression.

Objective The relationship between chronic obstructive pulmonary disease (COPD) and diabetes remains incompletely understood. This study evaluated diabetes risk and post-diabetes outcomes in COPD patients with and without exacerbations. Methods We identified 4671 adults newly diagnosed with COPD exacerbations and 9342 adults newly diagnosed with COPD without exacerbations during 2000–2008 using Taiwan’s National Health Insurance Research Database. A comparison cohort of 18684 adults without COPD, matched by age and sex, was randomly selected from the same dataset for the control group. Diabetes events during 2000–2013 were ascertained from medical claims during the follow-up period. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of diabetes associated with COPD with or without exacerbations were calculated. We conducted another nested cohort study of 395516 patients with diabetes hospitalization during 2002–2013 and calculated adjusted odds ratios (ORs) and 95% CIs of histories of COPD and COPD exacerbations associated with adverse events after diabetes admission. Results During the follow-up period, the incidences of diabetes for patients without COPD and for patients with COPD without or with exacerbations were 3.4, 4.1 and 7.4 per 1000 person-years, respectively (P < 0.0001). Increased risk of diabetes for patients with COPD without exacerbations (HR 1.09, 95% CI 1.02–1.17) and COPD with exacerbations (HR 2.18, 95% CI 1.88–2.52) was noted. Post-diabetes pneumonia (OR 3.28, 95% CI 3.13–3.43), intensive care admission (OR 1.32, 95% CI 1.26–1.39) and mortality (OR 2.06, 95% CI 1.88–2.25) were associated with COPD exacerbations. Conclusion Prevention and intervention strategies for diabetes and post-diabetes outcomes are needed for this susceptible population.

β-amyloid peptide (Aβ) aggregation has been thought to be associated with the pathogenesis of Alzheimer’s disease. Recently, we showed that L17A/F19A substitutions may increase the structural stability of wild-type and Arctic-type Aβ40 and decrease the rates of structural conversion and fibril formation. However, the underlying mechanism for the increase of structural stability as a result of the alanine substitutions remained elusive. In this study, we apply nuclear magnetic resonance and circular dichroism spectroscopies to characterize the Aβ40 structure, demonstrating that L17A/F19A substitutions can augment the α-helicity of the residues located in the α/β-discordant segment (resides 15 to 23) of both wild-type and Arctic-type Aβ40. These results provide a structural basis to link the α-helicity of the α/β-discordant segment with the conformational conversion propensity of Aβ.

Micro-plasma is a possible alternative treatment for wound management. The effect of micro-plasma on wound healing depends on its composition and temperature. The authors previously developed a capillary-tube-based micro-plasma system that can generate micro-plasma with a high nitric oxide-containing species composition and mild working temperature. Here, the efficacy of micro-plasma treatment on wound healing in a laser-induced skin wound mouse model was investigated. A partial thickness wound was created in the back skin of each mouse and then treated with micro-plasma. Non-invasive methods, namely wound closure kinetics, optical coherence tomography (OCT), and laser Doppler scanning, were used to measure the healing efficiency in the wound area. Neo-tissue growth and the expressions of matrix metallopeptidase-3 (MMP-3) and laminin in the wound area were assessed using histological and immunohistochemistry (IHC) analysis. The results show that micro-plasma treatment promoted wound healing. Micro-plasma treatment significantly reduced the wound bed region. The OCT images and histological analysis indicates more pronounced tissue regrowth in the wound bed region after micro-plasma treatment. The laser Doppler images shows that micro-plasma treatment promoted blood flow in the wound bed region. The IHC results show that the level of laminin increased in the wound bed region after micro-plasma treatment, whereas the level of MMP-3 decreased. Based on these results, micro-plasma has potential to be used to promote the healing of skin wounds clinically.

Several reports have indicated that hypoxia, GLI, and connective tissue growth factor (CTGF) contribute to pulmonary fibrosis in idiopathic pulmonary fibrosis. We investigated the participation of mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1)/MEK1/ERK1/GLI-1/2 and activator protein-1 (AP-1) signaling in hypoxia-induced CTGF expression in human lung fibroblasts. Hypoxia time-dependently increased CTGF expression, which was attenuated by the small interfering RNA (siRNA) of GLI-1 (GLI-1 siRNA) and GLI-2 (GLI-2 siRNA) in both human lung fibroblast cell line (WI-38) and primary human lung fibroblasts (NHLFs). Moreover, GLI-1 siRNA and GLI-2 siRNA attenuated hypoxia-induced CTGF-luciferase activity, and the treatment of cells with hypoxia induced GLI-1 and GLI-2 translocation. Furthermore, hypoxia-induced CTGF expression was reduced by an MEK inhibitor (PD98059), MEK1 siRNA, ERK inhibitor (U0126), ERK1 siRNA, and MEKK1 siRNA. Both PD98059 and U0126 significantly attenuated hypoxia-induced CTGF-luciferase activity. Hypoxia time-dependently increased MEKK1, ERK, and p38 MAPK phosphorylation. Moreover, SB203580 (a p38 MAPK inhibitor) also apparently inhibited hypoxia-induced CTGF expression. The treatment of cells with hypoxia induced ERK, GLI-1, or GLI-2 complex formation. Hypoxia-induced GLI-1 and GLI-2 translocation into the nucleus was significantly attenuated by U0126. In addition, hypoxia-induced ERK Tyr204 phosphorylation was impeded by MEKK1 siRNA. Moreover, hypoxia-induced CTGF-luciferase activity was attenuated by cells transfected with AP-1 site mutation in a CTGF construct. Exposure to hypoxia caused a time-dependent phosphorylation of c-Jun, but not of c-Fos. Chromatin immunoprecipitation (ChIP) revealed that hypoxia induced the recruitment of c-Jun, GLI-1, and GLI-2 to the AP-1 promoter region of CTGF. Hypoxia-treated cells exhibited an increase in α-smooth muscle actin (α-SMA) and collagen production, which was blocked by GLI-1 siRNA and GLI-2 siRNA. Overall, these data implied that the MEKK1/MEK1/ERK1/GLI-1/GLI-2, and AP-1 pathways mediated hypoxia-induced CTGF expression in human lung fibroblasts. Furthermore, GLI-1 and GLI-2 found to be involved in hypoxia-induced α-SMA and collagen expression.

Background CpG islands have been demonstrated to influence local chromatin structures and simplify the regulation of gene activity. However, the accurate and rapid determination of CpG islands for whole DNA sequences remains experimentally and computationally challenging. Methodology/Principal Findings A novel procedure is proposed to detect CpG islands by combining clustering technology with the sliding-window method (PSO-based). Clustering technology is used to detect the locations of all possible CpG islands and process the data, thus effectively obviating the need for the extensive and unnecessary processing of DNA fragments, and thus improving the efficiency of sliding-window based particle swarm optimization (PSO) search. This proposed approach, named ClusterPSO, provides versatile and highly-sensitive detection of CpG islands in the human genome. In addition, the detection efficiency of ClusterPSO is compared with eight CpG island detection methods in the human genome. Comparison of the detection efficiency for the CpG islands in human genome, including sensitivity, specificity, accuracy, performance coefficient (PC), and correlation coefficient (CC), ClusterPSO revealed superior detection ability among all of the test methods. Moreover, the combination of clustering technology and PSO method can successfully overcome their respective drawbacks while maintaining their advantages. Thus, clustering technology could be hybridized with the optimization algorithm method to optimize CpG island detection. Conclusion/Significance The prediction accuracy of ClusterPSO was quite high, indicating the combination of CpGcluster and PSO has several advantages over CpGcluster and PSO alone. In addition, ClusterPSO significantly reduced implementation time.

Cortex Eucommiae is used worldwide in traditional medicine, various constituents of Cortex Eucommiae, such as chlorogenic acid (CGA), has been reported to exert anti-osteoporosis activity in China, but the mechanism about their contribution to the overall activity is limited. The aims of this study were to determine whether chlorogenic acid can prevent estrogen deficiency-induced osteoporosis and to analyze the mechanism of CGA bioactivity. The effect of CGA on estrogen deficiency-induced osteoporosis was performed in vivo. Sixty female Sprague-Dawley rats were divided randomly among a sham-operated group and five ovariectomy (OVX) plus treatment subgroups: saline vehicle, 17α-ethinylestradiol (E2), or CGA at 9, 27, or 45 mg/kg/d. The rats’ femoral metaphyses were evaluated by micro-computed tomography (μCT). The mechanism of CGA bioactivity was investigated in vitro. Bone mesenchymal stem cells (BMSCs) were treated with CGA, with or without phosphoinositide 3-kinase (PI3K) inhibitor LY294002. BMSCs proliferation and osteoblast differentiation were assessed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and alkaline phosphatase, with or without Shp2 interfering RNA (RNAi). The results display that CGA at 27 and 45 mg/kg/day inhibited the decrease of bone mineral density (BMD) that induced by OVX in femur (p< 0.01), significantly promoted the levels of bone turnover markers, and prevented bone volume fraction (BV/TV), connectivity density (CoonD), trabecular number (Tb.N), trabecular thickness (Tb.Th) (all p< 0.01) to decrease and prevented the trabecular separation (Tb.Sp), structure model index (SMI)(both p< 0.01) to increase. CGA at 1 or 10 μM enhanced BMSC proliferation in a dose-dependent manner. CGA at 0.1 to 10 μM increased phosphorylated Akt (p-Akt) and cyclin D1. These effects were reversed by LY294002. CGA at 1 or 10 μM increased BMSC differentiation to osteoblasts (p< 0.01), Shp2 RNAi suppressed CGA-induced osteoblast differentiation by decreasing Shp2, p-Akt, and cyclin D1. This study found that CGA improved the BMD and trabecular micro-architecture for the OVX-induced osteoporosis. Therefore, CGA might be an effective alternative treatment for postmenopausal osteoporosis. CGA promoted proliferation of osteoblast precursors and osteoblastic differentiation of BMSCs via the Shp2/PI3K/Akt/cyclin D1 pathway.

The goal of this study is to optimize a 32-channel head coil array for accelerated 3T human brain proton MRI using either a Cartesian or a radial k-space trajectory. Coils had curved trapezoidal shapes and were arranged in a circular symmetry (CS) geometry. Coils were optimally overlapped to reduce mutual inductance. Low-noise pre-amplifiers were used to further decouple between coils. The SNR and noise amplification in accelerated imaging were compared to results from a head coil array with a soccer-ball (SB) geometry. The maximal SNR in the CS array was about 120% (1070 vs. 892) and 62% (303 vs. 488) of the SB array at the periphery and the center of the FOV on a transverse plane, respectively. In one-dimensional 4-fold acceleration, the CS array has higher averaged SNR than the SB array across the whole FOV. Compared to the SB array, the CS array has a smaller g-factor at head periphery in all accelerated acquisitions. Reconstructed images using a radial k-space trajectory show that the CS array has a smaller error than the SB array in 2- to 5-fold accelerations.

Prostaglandin reductase 2 (PTGR2) is the enzyme that catalyzes 15-keto-PGE2, an endogenous PPARγ ligand, into 13,14-dihydro-15-keto-PGE2. Previously, we have reported a novel oncogenic role of PTGR2 in gastric cancer, where PTGR2 was discovered to modulate ROS-mediated cell death and tumor transformation. In the present study, we demonstrated the oncogenic potency of PTGR2 in pancreatic cancer. First, we observed that the majority of the human pancreatic ductal adenocarcinoma tissues was stained positive for PTGR2 expression but not in the adjacent normal parts. In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2. Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT) and cystathionine gamma-lyase (CTH), two important providers of intracellular cysteine for the generation of glutathione (GSH), which is widely accepted as the first-line antioxidative defense. The oxidative stress-mediated cell death after silencing of PTGR2 or addition of 15-keto-PGE2 was further abolished after restoring intracellular GSH concentrations and cysteine supply by N-acetyl-L-cysteine and 2-Mercaptomethanol. Our data highlight the therapeutic potential of targeting PTGR2/15-keto-PGE2 for pancreatic cancer.

Background and aim Hepatic decompensation is a severe on-treatment adverse event for chronic hepatitis C treated with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Till now, few papers regarding on-treatment hepatic decompensation have been reported. The study aims to analyze the general feature and predictive factors of on-treatment hepatic decompensation in hepatitis C virus (HCV) genotype 1b-infected patients with advanced fibrosis and compensated cirrhosis who receive treatment with PrOD. Methods A real-word cohort enrolled 189 HCV genotype 1b patients with advanced fibrosis and compensated cirrhosis treated with 12-week PrOD. Clinical and laboratory data were analyzed between patients with and without on-treatment hepatic decompensation. Results The sustained virologic response rate at 12 weeks after treatment was 97.3% in HCV subtype 1b patients with advanced fibrosis and cirrhosis. On-treatment hyperbilirubinemia (total bilirubin >2 mg/dL) occurred in 27 (14.3%) patients, and the incidence of the increase of total and direct form bilirubin was significantly different during treatment between patients with Child-Turcotte-Pugh score 5 and score 6. Five (18.5%) hyperbilirubinemia patients progressed to hepatic decompensation. Older age (adjusted OR: 1.2, 95% CI: 1.0–1.4) and albumin ≤3.6 g/dL (adjusted OR: 10.4, 95% CI: 1.3–81.2) may be two predictors for on-treatment hepatic decompensation by multivariate analysis. Conclusions PrOD is an effective direct-acting antiviral agent for antiviral therapy in HCV genotype 1b patients with advanced fibrosis and cirrhosis. Hyperbilirubinemia is possibly the early warning feature of on-treatment hepatic decompensation. This serious adverse event of on-treatment hepatic decompensation is not common. Older age and low baseline albumin level may be predictive factors.

Background Many modern molecular diagnostic assays targeting nucleic acids are typically confined to developed countries or to the national reference laboratories of developing-world countries. The ability to make technologies for the rapid diagnosis of infectious diseases broadly available in a portable, low-cost format would mark a revolutionary step forward in global health. Many molecular assays are also developed based on polymerase chain reactions (PCR), which require thermal cyclers that are relatively heavy (>20 pounds) and need continuous electrical power. The temperature ramping speed of most economical thermal cyclers are relatively slow (2 to 3°C/s) so a polymerase chain reaction can take 1 to 2 hours. Most of all, these thermal cyclers are still too expensive ($2k to $4k) for low-resource setting uses. Methodology/Principal Findings In this article, we demonstrate the development of a low-cost and rapid water bath based thermal cycler that does not require active temperature control or continuous power supply during PCR. This unit costs $130 to build using commercial off-the-shelf items. The use of two or three vacuum-insulated stainless-steel Thermos food jars containing heated water (for denaturation and annealing/extension steps) and a layer of oil on top of the water allow for significantly stabilized temperatures for PCR to take place. Using an Arduino-based microcontroller, we automate the “archaic” method of hand-transferring PCR tubes between water baths. Conclusions/Significance We demonstrate that this innovative unit can deliver high speed PCR (17 s per PCR cycle) with the potential to go beyond the 1,522 bp long amplicons tested in this study and can amplify from templates down to at least 20 copies per reaction. The unit also accepts regular PCR tubes and glass capillary tubes. The PCR efficiency of our thermal cycler is not different from other commercial thermal cyclers. When combined with a rapid nucleic acid detection approach, the thermos thermal cycler (TTC) can enable on-site molecular diagnostics in low-resource settings.

Multi-channel magnetocardiography (MCG) is a sensitive technique to map spatial ventricular repolarization with high resolution and reproducibility. Spatial ventricular repolarization heterogeneity measured by MCG has been shown to accurately detect and localize myocardial ischemia. Here, we explored whether these measurements correlated with cardiovascular risk factors in patients with type 2 diabetes. Two hundreds and seventy-seven type 2 diabetic patients without known coronary artery disease (CAD) and arrhythmia were recruited consecutively from the outpatient clinic of National Taiwan University Hospital. The spatially distributed QTc contour maps were constructed with 64-channel MCG using the superconducting quantum interference device (SQUID) system. Indices of myocardial repolarization heterogeneity including the smoothness index of QTc (SI-QTc) and QTc dispersion were derived and analyzed for association with conventional cardiovascular risk factors. SI-QTc correlated strongly with the QTc dispersion (r = 0.70, p

The aim of this study was to develop a simple and reliable high-performance chromatographic (HPLC) method for simultaneous analysis of adapalene and benzoyl peroxide in pharmaceutical formulation by response surface methodology (RSM). An optimized mobile phase composed of acetonitrile, tetrahydrofuran and water containing 0.1% acetic acid at a ratio of 25:50:25 by volume was successfully predicted by using RSM. An isocratic separation was achieved by using the condition. Furthermore, the analytical method was validated in terms of specificity, linearity, accuracy and precision in a range of 80% to 120% of the expected concentration. Finally, the method was successfully applied to the analysis of a commercial product.

Gramicidin A is an antimicrobial peptide that destroys gram-positive bacteria. The bactericidal mechanism of antimicrobial peptides has been linked to membrane permeation and metabolism disruption as well as interruption of DNA and protein functions. However, the exact bacterial killing mechanism of gramicidin A is not clearly understood. In the present study, we examined the antimicrobial activity of gramicidin A on Staphylococcus aureus using biochemical and biophysical methods, including hydroxyl radical and NAD+/NADH cycling assays, atomic force microscopy, and Fourier transform infrared spectroscopy. Gramicidin A induced membrane permeabilization and changed the composition of the membrane. The morphology of Staphylococcus aureus during gramicidin A destruction was divided into four stages: pore formation, water permeability, bacterial flattening, and lysis. Changes in membrane composition included the destruction of membrane lipids, proteins, and carbohydrates. Most interestingly, we demonstrated that gramicidin A not only caused membrane permeabilization but also induced the formation of hydroxyl radicals, which are a possible end product of the transient depletion of NADH from the tricarboxylic acid cycle. The latter may be the main cause of complete Staphylococcus aureus killing. This new finding may provide insight into the underlying bactericidal mechanism of gA.

3,4-Methylenedioxymethamphetamine (MDMA), also known as “Ecstasy”, is a common recreational drug of abuse. Several previous studies have attributed the central serotonergic neurotoxicity of MDMA to distal axotomy, since only fine serotonergic axons ascending from the raphe nucleus are lost without apparent damage to their cell bodies. However, this axotomy has never been visualized directly in vivo. The present study examined the axonal integrity of the efferent projections from the midbrain raphe nucleus after MDMA exposure using in vivo manganese-enhanced magnetic resonance imaging (MEMRI). Rats were injected subcutaneously six times with MDMA (5 mg/kg) or saline once daily. Eight days after the last injection, manganese ions (Mn2+) were injected stereotactically into the raphe nucleus, and a series of MEMRI images was acquired over a period of 38 h to monitor the evolution of Mn2+-induced signal enhancement across the ventral tegmental area, the medial forebrain bundle (MFB), and the striatum. The MDMA-induced loss of serotonin transporters was clearly evidenced by immunohistological staining consistent with the Mn2+-induced signal enhancement observed across the MFB and striatum. MEMRI successfully revealed the disruption of the serotonergic raphe-striatal projections and the variable effect of MDMA on the kinetics of Mn2+ accumulation in the MFB and striatum.

Vibrio parahaemolyticus is recognized as major cause of foodborne illness of global public health concern. This study collected 107 strains of V. parahaemolyticus during active surveillance of diarrheal diseases in hospitals in Zhoushan during 2013 to 2014 and investigated their serotypes, virulence genes (tdh, trh, and orf8), antimicrobial resistance, and genotypes. The dominant serotypes of the 107 clinical strains were O3:K6, O4:K8, and O4:KUT with 87.9% and 3.7% of the strains carrying the virulence genes tdh and trh, respectively. Molecular typing by pulsed-field gel electrophoresis indicated divergence among the clinical strains. Most isolates were sensitive to the common antimicrobial agents used against the Vibrio species except ampicillin. We conclude that continuous surveillance of V. parahaemolyticus in diarrhea patients is a public health priority and is useful for conducting risk assessment of foodborne illnesses caused by V. parahaemolyticus.

Cardiovascular diseases are the leading cause of death of death in Taiwan. Atherosclerosis can lead to serious problems, including heart attack, stroke, or even death. Coronary heart disease (CHD) occurs when plaque builds up in the coronary arteries to cause the ischemic heart disease which will enhance myocardial remodeling and also induce myocardial hypoxia. High density lipoprotein (HDL) has been proposed to have cardio-protective effects. Under hypoxic conditions (1%O2 for 24hr), in H9c2 cells, reactive oxygen species (ROS) is induced which leads to cardiomyocyte apoptosis and cardiac dysfunction. Therefore, the present study described the protective effect of HDL on hypoxia-induced cardiomyocyte damage. We investigated the NADPH oxidase-produced ROS-related signaling pathways and apoptosis in cardiomyocytes under hypoxia conditions. Results showed that the ROS mediated cardiac damage might occur via AT1 and PKC activation. Furthermore, hypoxia downregulated the survival protein (p-AKTser473) and anti-apoptotic protein (BCL2), whereas pro-apoptotic protein, Bax and caspase 3 were upregulated. These detrimental effects by ROS and apoptosis were prevented by HDL pretreatment. Our findings revealed the underlying molecular mechanism by which HDL suppresses the hypoxia-induced cardiomyocyte dysfunction. Further, we elucidated the role of HDL on preventing hypoxia induced cardiomyocyte apoptosis is mediated through the inhibition of NADPH oxidase-derived ROS.

Identifying drug-drug interaction (DDI) is an important topic for the development of safe pharmaceutical drugs and for the optimization of multidrug regimens for complex diseases such as cancer and HIV. There have been about 150,000 publications on DDIs in PubMed, which is a great resource for DDI studies. In this paper, we introduced an automatic computational method for the systematic analysis of the mechanism of DDIs using MeSH (Medical Subject Headings) terms from PubMed literature. MeSH term is a controlled vocabulary thesaurus developed by the National Library of Medicine for indexing and annotating articles. Our method can effectively identify DDI-relevant MeSH terms such as drugs, proteins and phenomena with high accuracy. The connections among these MeSH terms were investigated by using co-occurrence heatmaps and social network analysis. Our approach can be used to visualize relationships of DDI terms, which has the potential to help users better understand DDIs. As the volume of PubMed records increases, our method for automatic analysis of DDIs from the PubMed database will become more accurate.