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The rapid development of photo‐synergistic transition metal catalytic systems has provided a green paradigm to complement thermal transition metal catalytic methods. However, the most commonly used iridium or ruthenium complexes involve expensive in nature, in contrast to the abundant copper elements in the earth's crust, which are highly valued for their unique electronic structure and light‐absorbing properties. Recently, the application of copper and photocatalytic synergistic strategies in radical cyclization reactions has progressed considerably, leading to a renaissance in the synthesis of functional natural products, drugs and their analogues, but summary work addressing this aspect has not been reported. In this review, we briefly analyze the effect of ligand choice on copper complexes and some inorganic copper salts and even on light sources. We then summarize the copper and photocatalytic synergistic strategies in radical cyclization reactions and classify them into three categories, C, N and O radicals, according to the class of the central atom of the radical in each work, and in each category will be elaborated in turn from coordination cyclization via Cu catalysts, direct radical cyclization and other cyclization mode. For individual more complex reactions, the mechanisms are explored and briefly discussed. [ABSTRACT FROM AUTHOR]

Aim: To evaluate real‐world abatacept retention and clinical outcomes in patients with rheumatoid arthritis in Taiwan. Methods: This prospective, observational study enrolled patients with rheumatoid arthritis aged ≥20 years who received abatacept in real‐world practice. The primary endpoint was the abatacept retention rate at 24 months. Patients were categorized into subgroups based on abatacept treatment status and previous biological disease‐modifying antirheumatic drug (bDMARD) therapy. Risk factors affecting abatacept retention were determined by regression analysis. Results: A total of 212 patients were enrolled. The overall abatacept retention rate at 24 months among all patients was 59.9% (95% confidence interval 53.0%–66.6%). Patients who were ongoing users of abatacept and bDMARD‐naïve had the highest retention rate (76.3%); of these, 31.6% achieved low disease activity or remission after 2 years. Previous treatment with bDMARDs was associated with an increased risk of abatacept discontinuation (hazard ratio 1.99; p =.002). The most common reasons for abatacept discontinuation were drug switch (11.3%) and loss to follow‐up (6.1%). Abatacept was well‐tolerated with no new safety signals. Conclusion: The 24‐month retention rate of abatacept was 59.9%; abatacept was associated with improved clinical outcomes and was well‐tolerated in the real‐world setting in Taiwan. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This prospective cohort study aims to identify the optimal measure of glycated hemoglobin (HbA1c) variability and to explore its relationship with the development of new diabetic sensorimotor polyneuropathy (DSPN) in individuals with type 2 diabetes mellitus, building upon previous cross-sectional studies that highlighted a significant association between HbA1c visit-to-visit variability and DSPN. Materials and Methods: In a prospective study, 321 participants diagnosed with type 2 diabetes mellitus underwent comprehensive clinical assessments, neurophysiologic studies, and laboratory evaluations at enrollment and follow-up. Various indices, including HbA1c standard deviation (HbA1c SD), coefficient of variation (HbA1c CV), HbA1c change score (HbA1c HVS), and average real variability (HbA1c ARV), were employed to calculate the visit-to-visit variability HbA1c based on 3 month intervals. The investigation focused on examining the associations between these indices and the development of new DSPN. Results: The average follow-up duration was 16.9 ± 6.9 months. The Cox proportional hazards model identified age (P = 0.001), diabetes duration (P = 0.024), and HbA1C ARV (P = 0.031) as the sole factors associated with the development of new DSPN. Furthermore, the cumulative risk of developing DSPN over 1 year demonstrated a significant association with HbA1C ARV (P = 0.03, log-rank test). Conclusions: Apart from age and diabetes duration, HbA1c variability emerged as a robust predictor for the occurrence of new DSPN. Among the various measures of HbA1c variability evaluated, HbA1c ARV demonstrated the highest potential as a reliable indicator for anticipating the onset of new DSPN. [ABSTRACT FROM AUTHOR]

Chemodivergent tandem radical cyclization offers exciting possibilities for the synthesis of structurally diverse cyclic compounds. Herein, we revealed a chemodivergent tandem cyclization of alkene‐substituted quinazolinones under metal‐ and base‐free conditions, this transformation is initiated by alkyl radicals produced from oxidant‐induced α‐C(sp3)−H functionalization of alkyl nitriles or esters. The reaction resulted in the selective synthesis of a series of mono‐ and di‐alkylated ring‐fused quinazolinones by modulating the loading of oxidant, reaction temperature, and reaction time. Mechanistic investigations show that the mono‐alkylated ring‐fused quinazolinones is constructed by the key process of 1,2‐hydrogen shift, whereas the di‐alkylated ring‐fused quinazolinones is mainly achieved through crucial steps of resonance and proton transfer. This protocol is the first example of remote second alkylation on the aromatic ring via α‐C(sp3)−H functionalization and difunctionalization achieved by association of two unsaturated bonds in radical cyclization. [ABSTRACT FROM AUTHOR]

A convenient and straightforward approach for the radical cascade cyclization/hydrolysis of CN‐containing 1,6‐enynes with simple ethers under metal‐ and base‐free conditions is described. This strategy provides a variety of valuable ethers‐substituted polyheterocycles via the construction of three C−C bonds, one C=O bond, and two new six‐membered rings within a single procedure. The resulting products can smoothly undergo follow‐up conversions to various useful scaffolds. The methodology shows excellent functional group tolerance, high step‐ and atom‐ economy, and mild reaction conditions, which can be further scaled up to gram quantity in a satisfactory yield. [ABSTRACT FROM AUTHOR]

Background: Genetic and epigenetic factors are strongly associated with the autoimmune disease rheumatoid arthritis (RA). Cyclic AMP response element modulator (CREM), a gene related to immune system regulation, has been implicated in various immune‐mediated inflammatory processes, although it remains unknown whether CREM is involved in RA. Methods: This study enrolled 278 RA patients and 262 controls. Three variants [rs12765063, rs17499247, rs1213386] were identified through linkage disequilibrium and expression quantitative trait locus analysis, and CREM transcript abundance was determined by quantitative real‐time polymerase chain reaction. The identified variants were genotyped using the TaqMan Allelic Discrimination assay, and CREM promoter methylation was assessed by bisulphite sequencing. Differences between groups and correlations between variables were assessed with Student's t‐tests and Pearson's correlation coefficients. Associations between phenotypes and genotypes were evaluated with logistic regression. Results: Rheumatoid arthritis patients exhibited increased CREM expression (p <.0001), which was decreased by methotrexate (p =.0223) and biologics (p =.0001), but could not be attributed to CREM variants. Interestingly, rs17499247 displayed a significant association with serositis (p =.0377), and rs1213386 increased the risk of lymphadenopathy (p =.0398). Furthermore, seven CpG sites showed decreased methylation in RA (p =.0477~ p <.0001). Conclusions: Collectively, our results indicate that CREM hypomethylation and CREM upregulation occur in RA and that CREM variants are involved in the development of serositis and lymphadenopathy in RA. This study highlights the novel roles of CREM in RA pathophysiology. [ABSTRACT FROM AUTHOR]

Introduction: The sural sensory nerve action potential (SNAP) amplitude is a measure of the number of axons. We tested the hypothesis that sural SNAP amplitude can be used as a marker in screening, severity evaluation, and follow-up of diabetic distal symmetrical polyneuropathy (DSPN).Methods: Patients with type 2 diabetes underwent nerve conduction studies and were followed for 6 years. Composite amplitude scores (CASs) were determined to evaluate DSPN severity.Results: Sural SNAP amplitudes were negatively correlated with CAS (r = -.790, P < .0001), and changes in sural SNAP amplitudes were negatively correlated with those of CAS after controlling for follow-up duration (r = -.531, P = .028).Discussion: When a patient's baseline sural SNAP amplitude is above zero, it can be used as one measure of DSPN in screening, severity evaluation, and follow-up. However, if the patient's sural SNAP value is zero, CAS can be used as a follow-up measure. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Clinical studies show that either heart rate variability (HRV) or electrochemical skin conductance (ESC) alone can serve as a simple and objective method for screening cardiovascular autonomic neuropathy (CAN). We tested the hypothesis that combining these two quantitative approaches can not only reinforce accuracy in CAN screening but also provide a better estimate of CAN severity in patients with type 2 diabetes (T2DM) who had already had CAN in outpatient clinics. Materials and Methods: Each patient received a complete battery of cardiovascular autonomic reflex tests (CARTs), with ESC measured by SUDOSCAN, time domain of HRV measured by standard deviation of all normal RR intervals (SDNN) and frequency domain of HRV (low frequency [LF], high frequency [HF], and LF/HF ratio), and peripheral blood studies for vascular risk factors. Severity of CAN was measured by CAN score. Results: The 90 T2DM patients included 50 males and 40 females. Those with more severe CAN had lower values in feet ESC (P = 0.023) and SDNN (P < 0.0001). Multiple linear regression analysis also showed that feet ESC and SDNN value (P = 0.003 and P < 0.0001) were significantly associated with CAN score. Combining SDNN and feet ESC also can increase the diagnostic accuracy of CAN with respective to sensitivity and specificity by using receiver operating characteristic analysis. Conclusions: Combining the results of SDNN and feet ESC can not only assess, but also quantitatively reflect the progress or improvement of autonomic nerve function (including sympathetic and parasympathetic activity) in patients with T2DM. [ABSTRACT FROM AUTHOR]

Although human leucocyte antigen (HLA)‐B27 is strongly associated with ankylosing spondylitis (AS), the association of unfolded protein response (UPR) induced by HLA‐B27 misfolding in AS remains controversial. Since dendritic cells (DCs) are crucial in induction of AS in HLA‐B27‐transgenic rats, and plasmacytoid DCs (pDCs) belong to one type of DCs, we here aim to study the relevance of pDCs and UPR in AS. Peripheral pDCs were isolated from 27 HLA‐B27(+) AS patients and 37 controls. The bone marrow (BM) and synovium of inflamed hips from AS patients and controls were obtained. We found a significantly higher frequency of pDCs in the peripheral blood, BM, or inflamed synovium of hips, which is associated with the enhanced expression of pDC trafficking molecules, CCR6 and CCL20 in the synovium of AS patients. Functional analysis further revealed that several inflammatory cytokines, including TNFα, IL‐6, and IL‐23, secreted by pDCs were significantly increased in AS patients as compared with those in controls. Remarkably, protein kinase RNA‐like endoplasmic reticulum kinase (PERK) pathway in UPR was up‐regulated in pDCs of AS patients. Notably, PERK inhibitor treatment significantly inhibited the enhanced cytokine production by pDCs of AS patients. Further, the extent of PERK activation was significantly associated with the increased disease severity of AS patients. Our data uncover the aberrant distribution and function of pDCs in AS patients. The up‐regulated PERK pathway in UPR of pDCs not only contributes to enhanced cytokine production of pDCs, but also is associated with increased disease activity of AS patients. [ABSTRACT FROM AUTHOR]

Objective: Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low‐density lipoprotein (LDL) levels. This study was undertaken to investigate the role of LDL composition in promoting early vascular aging in SLE patients. Methods: Plasma LDL from 45 SLE patients (SLE‐LDL) and from 37 normal healthy controls (N‐LDL) was chromatographically divided into 5 subfractions (L1–L5), and the subfraction composition was analyzed. Correlations between subfraction levels and signs of early vascular aging were assessed. Mechanisms of lipid‐mediated endothelial dysfunction were explored using in vitro assays and experiments in apoE−/− mice. Results: The L5 percentage was increased 3.4 times in the plasma of SLE patients compared with normal controls. This increased percentage of SLE‐L5 was positively correlated with the mean blood pressure (r = 0.27, P = 0.04), carotid intima‐media thickness (IMT) (right carotid IMT, r = 0.4, P = 0.004; left carotid IMT, r = 0.36, P = 0.01), pulse wave velocity (r = 0.29, P = 0.04), and blood levels of CD16+ monocytes (r = 0.35, P = 0.004) and CX3CL1 cytokines (r = 0.43, P < 0.001) in SLE patients. Matrix‐assisted laser desorption ionization–time‐of‐flight mass spectrometry analysis revealed that plasma levels of lysophosphatidylcholine (LPC) and platelet‐activating factor (PAF) were increased in SLE‐LDL and in the SLE‐L5 plasma subfraction. Injecting SLE‐LDL, SLE‐L5, or LPC into young, male apoE−/− mice caused increases in plasma CX3CL1 levels, aortic fatty‐streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall, whereas injection of N‐LDL or SLE‐L1 had negligible effects (n = 3–8 mice per group). In vitro, SLE‐L5 lipid extracts induced increases in CX3CR1 and CD16 expression in human monocytes; synthetic PAF and LPC had similar effects. Furthermore, lipid extracts of SLE‐LDL and SLE‐L5 induced the expression of CX3CL1 and enhanced monocyte–endothelial cell adhesion in assays with bovine aortic endothelial cells. Conclusion: An increase in plasma L5 levels, not total LDL concentration, may promote early vascular aging in SLE patients, leading to premature atherosclerosis. [ABSTRACT FROM AUTHOR]

Aim: To establish guidelines for the clinical management of axial spondyloarthritis that take into account local issues and clinical practice concerns for Taiwan. Method: Overarching principles and recommendations were established by consensus among a panel of rheumatology and rehabilitation experts, based on analysis of the most up‐to‐date clinical evidence and the clinical experience of panelists. All Overarching Principles and Recommendations were graded according to the standards developed by the Oxford Centre for Evidence Based Medicine, and further evaluated and modified using the Delphi method. Results: The guidelines specifically address issues such as local medical considerations, National Health Insurance reimbursement, and management of extra‐articular manifestations. Conclusion: It is hoped that this will help to optimize clinical management outcomes for axial spondyloarthritis in Taiwan. [ABSTRACT FROM AUTHOR]

Objective: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease bearing challenges in early diagnosis. To improve clinical diagnosis and management of axSpA, recommendations were developed with current axSpA classification criteria and recent advances in medical imaging applications. Methods: A systematic literature review was conducted by 10 rheumatologists and radiologists in Taiwan to retrieve research evidence on the utilization of imaging modalities, including conventional radiography (CR), magnetic resonance imaging (MRI), computed tomography (CT), ultrasound (US), quantitative sacroiliac scintigraphy (QSS), and dual‐energy X‐ray absorptiometry (DXA). The panel of experts proposed six key issues on the role of imaging in early diagnosis of axSpA, monitoring of disease activity and structural changes, predicting treatment effects, and assessing complications such as osteoporosis and spinal fracture. The consensus was established on the basis of research evidence, clinical experiences and expert opinions. For each recommendation statement, the level of evidence was evaluated, the strength of recommendation was graded and the final level of agreement was determined through voting. Results: In total, four overarching principles and 13 recommendations were formulated. These recommendations outlined different imaging approaches in the diagnosis and management of axSpA disease progression. Considering CT is easy to perform when MRI is less available in Taiwan, the expert panel proposed a concise and practical diagnostic scheme to strengthen the valuable role of MRI and CT in the diagnostic evaluation of axSpA without evident radiographic features. Conclusion: These modified recommendations provide guidance for rheumatologists, radiologists and healthcare professionals on timely diagnosis of axSpA and disease management with appropriate imaging modalities. [ABSTRACT FROM AUTHOR]

Macular fibrosis is a vital obstacle of vision acuity improvement of age‐related macular degeneration patients. This study was to investigate the effects of interleukin 2 (IL‐2) on epithelial‐mesenchymal transition (EMT), extracellular matrix (ECM) synthesis and transforming growth factor β2 (TGF‐β2) expression in retinal pigment epithelial (RPE) cells. 10 μg/L IL‐2 was used to induce fibrosis in RPE cells for various times. Western blot was used to detect the EMT marker α‐smooth muscle actin (α‐SMA), ECM markers fibronectin (Fn) and type 1 collagen (COL‐1), TGF‐β2, and the activation of the JAK/STAT3 and NF‐κB signaling pathway. Furthermore, JAK/STAT3 and NF‐κB signaling pathways were specifically blocked by WP1066 or BAY11‐7082, respectively, and the expression of α‐SMA, COL‐1, Fn and TGF‐β2 protein were detected. Wound healing and Transwell assays were used to measure cell migration ability of IL‐2 with or without WP1066 or BAY11‐7082. After induction of IL‐2, the expressions of Fn, COL‐1, TGF‐β2 protein were significantly increased, and this effect was correlated with IL‐2 treatment duration, while α‐SMA protein expression did not change significantly. Both WP1066 and BAY11‐7082 could effectively downregulate the expression of Fn, COL‐1 and TGF‐β2 induced by IL‐2. What's more, both NF‐κB and JAK/STAT3 inhibitors could suppress the activation of the other signaling pathway. Additionally, JAK/STAT3 inhibitor WP1066 and NF‐κB inhibitor BAY 11‐7082 could obviously decrease RPE cells migration capability induced by IL‐2. IL‐2 promotes cell migration, ECM synthesis and TGF‐β2 expression in RPE cells via JAK/STAT3 and NF‐κB signaling pathways, which may play an important role in proliferative vitreoretinopathy. [ABSTRACT FROM AUTHOR]

Aim: We report tofacitinib efficacy and safety in Asia‐Pacific patients who participated in the rheumatoid arthritis (RA) clinical development program. Method: This post‐hoc analysis included pooled data from patients with RA in the Asia‐Pacific region treated with tofacitinib with/without conventional synthetic disease‐modifying antirheumatic drugs in Phase (P)1, 2, 3, and long‐term extension (LTE) studies (one LTE ongoing; January 2016 data‐cut). Efficacy was assessed over 24 months in patients who received tofacitinib 5 (N = 397) or 10 (N = 382) mg twice daily or placebo (N = 243) in three P2 and five P3 studies. Endpoints included American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28‐4[ESR]) and Clinical Disease Activity Index (CDAI) remission rates, and change from baseline in Health Assessment Questionnaire‐Disability Index (∆HAQ‐DI). Safety data pooled over 92 months from one P1, four P2, six P3, and two LTE studies for all tofacitinib doses (N = 1464) included incidence rates (IRs) (patients with events/100 patient‐years) for adverse events (AEs) of special interest. Results: At month 3, patients receiving tofacitinib 5/10 mg twice daily improved vs placebo in ACR20 (69.2%/77.9% vs 27.5%), ACR50 (36.9%/44.4% vs 9.5%), and ACR70 (15.1%/22.4% vs 2.7%) responses, remission rates for DAS28‐4(ESR) (8.5%/18.5% vs 2.6%) and CDAI (6.1%/12.3% vs 0.5%), and ∆HAQ‐DI (−0.5/–0.6 vs −0.1); improvements were sustained through 24 months. IRs (95% CI) were 9.4 (8.5, 10.3) for serious AEs, 9.1 (8.3, 10.1) for discontinuations due to AEs, 3.7 (3.2, 4.3) for serious infections, 5.9 (5.2, 6.7) for herpes zoster, and 0.8 (0.6, 1.1) for malignancies (excluding non‐melanoma skin cancer). Conclusion: In Asia‐Pacific patients, tofacitinib improved signs/symptoms over 24 months. Safety over 92 months was generally consistent with global tofacitinib studies; however, infection IRs were higher in Asia‐Pacific patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Liquorice is the root of Glycyrrhiza glabra, which is a popular food in Europe and China that has previously shown benefits for skeletal fatigue and nutrient metabolism. However, the mechanism and active ingredients remain largely unclear. The aim of this study was to investigate the active ingredients of liquorice for muscle wasting and elucidate the underlying mechanisms.Experimental Approach: RNA-Seq and bioinformatics analysis were applied to predict the main target of liquorice. A machine learning model and a docking tool were used to predict active ingredients. Isotope labelling experiments, immunostaining, Western blots, qRT-PCR, ChIP-PCR and luciferase reporters were utilized to test the pharmacological effects in vitro and in vivo. The reverse effects were verified through recombination-based overexpression.Key Results: The liposoluble constituents of liquorice improved muscle wasting by inhibiting protein catabolism and fibre atrophy. We further identified FoxO1 as the target of liposoluble constituents of liquorice. In addition, hispaglabridin B (HB) was predicted as an inhibitor of FoxO1. Further studies determined that HB improved muscle wasting by inhibiting catabolism in vivo and in vitro. HB also markedly suppressed the transcriptional activity of FoxO1, with decreased expression of the muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1.Conclusions and Implications: HB can serve as a novel natural food extract for preventing muscle wasting in chronic kidney disease and possibly other catabolic conditions. [ABSTRACT FROM AUTHOR]

Aims: Osteoporosis is one of the consequences of aging, and it remains underdiagnosed and undertreated; this study aimed to present the characteristics and prevalence of osteoporosis in elderly men by conducting a nationwide survey in Taiwan. Methods: The participants were enrolled between 2008 and 2011, and bone mineral density (BMD) was measured via dual‐energy X‐ray absorptiometry for the hip (total), lumbar spine (L1‐4), and femoral neck (FN). Patients with rheumatoid arthritis, female patients, and those using steroids were excluded. Osteoporosis was defined as a T‐score at the FN of ≤−2.5. Results: This study included 3734 men of mean age 70.0 ± 9.3 years, accounting for the prevalence of osteoporosis at 9.7%. Participants with osteoporosis had a significantly older age, lower body weight, shorter height and more previous fractures than those without osteoporosis. The mean BMD at FN was 0.534 ± 0.056 and 0.791 ± 0.115 (g/cm2) in participants with and without osteoporosis, respectively (P < 0.001). The FN and hip (total) BMD showed a significant negative correlation with age (r = −0.234, P < 0.001) and (r = −0.003, P < 0.001), respectively, but not at L1‐4 (r = 0.00, P = 0.540). A history of fracture is the most important risk factor associated with male osteoporosis (odds ratio, 2.50; 95% CI, 1.49‐4.21; P = 0.006). Conclusions: The associated factors for male osteoporosis are aging, lower body weight, and a history of fracture; the BMDs at FN and hip (total), but not L1‐4, are inversely correlated with age. We recommend that BMD at the proximal femur be the preferred site to evaluate osteoporosis for elderly male subjects. [ABSTRACT FROM AUTHOR]

Aim: Gout is a common complication in kidney transplant recipients. This study evaluated the association between kidney transplant recipients and the long‐term risk of incident gout. Method: For this age‐matched and sex‐matched retrospective cohort study, the Catastrophic Illness Certificate Database and the National Health Insurance Research Database were combined between 1997 and 2010. The study included 5917 patients with kidney transplants and 23 668 matched kidney transplant‐free subjects. Hazard ratio (HR) for risk of incident gout was calculated using the Cox proportional hazards regression. Results: In this study, of the 5917 kidney transplant recipients, 521 (8.8%) had gout. The kidney transplant group had a higher risk of incident gout than those in the matched kidney transplant‐free group (adjusted HR = 1.55, 95% confidence intervals [CI] = 1.36‐1.77), particularly within 3 years following kidney transplant recipients (adjusted HR = 2.61, 95% CI = 2.13‐3.20). We observed that at the >3 to 6 years and the >6 to 9 years follow‐up, patients with kidney transplant did not have a significant association with risk of incident gout (adjusted HR = 0.92, P = 0.4806 and adjusted HR = 1.26, P = 0.1901, respectively). Conclusion: These findings revealed that risk of incident gout increased within 3 years following kidney transplant recipients and the individual's long‐term risk of incident gout between kidney transplant recipients and the general population remained similar. [ABSTRACT FROM AUTHOR]

Purpose: The use of biological agents has revolutionized the treatment of rheumatoid arthritis (RA). However, details of serial synovial changes in imaging evaluation are unclear. Using power Doppler (PD) ultrasound, this study aimed to evaluate the comparative efficacy of biologicals for patients with refractory RA, with the hope that these findings could aid in clinical decision making. Methods: Patients with RA who received abatacept, adalimumab or tocilizumab therapy were enrolled. All underwent gray scale synovial hypertrophy and PD assessments of the dominant wrist (dorsal aspect) at baseline and at 1, 3 and 6 months after therapy. A generalized estimating equation model was used to compare efficacy among the three drugs. Results: Of the 103 patients enrolled, 32 received adalimumab, 38 abatacept and 33 tocilizumab. There were no significant differences in age or sex among the three groups. All had a treatment response according to gray scale (P = 0.000) and PD (P = 0.001) synovitis scores. The tocilizumab group had a significantly lower synovial hypertrophy score at 6 months (P = 0.006), and the adalimumab group also had a lower score although without statistical significance (P = 0.043). The adalimumab group had a lower PD score than the other two groups (P < 0.05). Conclusion: In a 6‐month head‐to‐head comparison of patients with RA, tocilizumab and adalimumab had a greater effect on reducing synovial hypertrophy, while adalimumab had a greater effect in controlling inflammation in PD. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To evaluate etanercept in patients from Latin America, Central/Eastern Europe, and Asia with non‐radiographic axial spondyloarthritis (nr‐axSpA). Methods: A subset analysis was performed on nr‐axSpA patients from Argentina, Colombia, the Czech Republic, Hungary, Russia and Taiwan who were enrolled in EMBARK (NCT01258738). Patients received either etanercept 50 mg or placebo once weekly. The primary endpoint was proportion of patients achieving 40% improvement from baseline based on Assessment of SpondyloArthritis International Society (ASAS) criteria. Secondary endpoints included other efficacy assessments, health‐related quality of life (HRQoL) and safety. Results: Of the 117 patients in this subset, 59 were treated with etanercept and 58 received placebo. At week 12, numerically greater improvements from baseline were observed for all efficacy endpoints in etanercept‐treated patients compared with those receiving placebo. Statistically significant differences between the two treatment groups were observed for proportion of patients achieving ASAS40 (P = 0.0413, at week 8), ASAS5/6 (P = 0.0126), Ankylosing Spondylitis Disease Activity Score ‐ C‐reactive protein (CRP) inactive disease (P = 0.0093), Spondyloarthritis Research Consortium of Canada magnetic resonance imaging of sacroiliac joint scores (P = 0.0014), high‐sensitivity CRP (P=0.032), and erythrocyte sedimentation rate (P = 0.0082). Statistically significant improvements in the etanercept‐treated group compared with placebo group were observed for nocturnal back pain (P = 0.040), total back pain (P = 0.025), physician global assessment of disease (P = 0.023), and Work Productivity and Activity Impairment Questionnaire percent impairment while working (P = 0.047). Adverse events were similar between the two treatment groups. Conclusions: In this subset of patients with nr‐axSpA from Latin America, Central/Eastern Europe, and Asia, treatment with etanercept, compared with placebo, resulted in improved disease symptoms and patient HRQoL. Etanercept was well tolerated. [ABSTRACT FROM AUTHOR]

Objective: Past studies have shown common pathologic characteristics and shared immunologic features between polymyositis (PM) and amyotrophic lateral sclerosis (ALS). To explore the potential relationship between the 2 diseases, we performed a nationwide cohort study.Methods: We identified all newly diagnosed patients with PM from Taiwan's Registry of Catastrophic Illness Database between January 1, 1998 and December 31, 2011. Each PM patient was matched to ≤5 control patients from the National Health Insurance Research Database by sex, age, and entry date. Cumulative incidence of ALS was calculated by the Kaplan-Meier method and compared using the log rank test. Cox hazard regression was used to calculate the hazard ratio of ALS.Results: A total of 1,778 PM patients and 8,124 control patients were enrolled. PM patients had a higher cumulative incidence of ALS (P < 0.001). There was a positive correlation in being diagnosed with ALS in patients previously diagnosed with PM when stratified by sex. Consistent trends were conserved across different age strata. The strength of this association remained statistically significant after adjusting for sex, age, and concomitant autoimmune diseases (hazard ratio 25.72 [95% confidence interval 2.95-224.58]; P = 0.003).Conclusion: This study demonstrates that a diagnosis of PM increased the likelihood of a subsequent ALS diagnosis, independent of sex, age, and concomitant autoimmune diseases. Future studies are warranted to clarify the underlying biologic mechanisms and to translate them into clinical therapeutic options. [ABSTRACT FROM AUTHOR]

Aim The purpose of this study is to investigate the role of methylation in the histone deacetylases 6 ( HDAC6) promoter and HDAC6 messenger RNA ( mRNA) expression in the pathogenesis of systemic lupus erythematosus ( SLE). Method Direct bisulfite-polymerase chain reaction ( PCR) sequencing was performed to detect the HDAC6 promoter methylation in 33 patients with SLE and 35 healthy controls. The HDAC6 mRNA expression was measured in 93 SLE patients and 84 healthy controls by using the method of quantitative real-time PCR. Results This study demonstrated that the methylation rates at HDAC6-680, -660 and -658 were significantly increased in the SLE patients compared with healthy controls ( P = 0.041, 0.034 and 0.029, respectively). The SLE patients also had lower HDAC6 mRNA expression than the controls ( P = 0.031). However, there was no significant difference in HDAC6 mRNA expression between patients with active and inactive SLE. Conclusion The SLE patients had higher methylation in the HDAC6 promoter and lower HDAC6 mRNA expression than the controls. These changes may be related to the susceptibility of SLE. However, they are not associated with the disease activity of SLE. [ABSTRACT FROM AUTHOR]

In their original forms, carbon nanotubes (CNT) are spatially entangled. To make CNT papers (CNTPs), the CNT agglomerates must be dispersed and re-entangled into a planar sheet. The processing characteristics are very different from those of traditional buck-form nanocomposites. This article examines the processing, micro-structures, and failure behavior of the CNTP composites. The CNTPs were first made by a dispersion and filtering process. Then, an epoxy resin was added into the CNTP by using a vacuum bag method. Different CNT weights were employed to make the CNTPs with different thicknesses and areal weights. The CNTP allows direct resin impregnation along the thickness direction and avoids the difficulty of dispersing CNTs in the viscous resin. The CNT content can be much higher than that attainable in traditional bulk CNT composites. Both tensile and tearing tests were conducted, and the fracture behaviors were examined. POLYM. COMPOS., 37:1564-1571, 2016. © 2014 Society of Plastics Engineers [ABSTRACT FROM AUTHOR]

Aim Although F11 receptor (F11R), also named junctional adhesion molecular A ( JAM-A), participates in leukocyte migration, its role in autoimmune diseases has not been specifically disclosed. In this study, we examined the association of F11R expression with the development and clinical manifestations of rheumatoid arthritis ( RA). Method RNA from peripheral blood mononuclear cells (PBMCs) and DNA from the peripheral blood in RA patients and a healthy control group were extracted. F11R messenger RNA ( mRNA) expression was determined by quantitative real-time polymerase chain reaction. The F11R polymorphisms were determined by the TaqMan genotyping assay. Results There was more F11R mRNA expression in the PBMCs of RA patients than those of the control group ( P = 0.018). In F11R promoter −688 A > C, C carriers have lower titers of the anticyclic citrullinated peptide (anti-CCP) antibodies ( P = 0.002) and fewer positive rates of Schirmer's tests ( P = 0.009). The effect is independent of the existence of HLA-DR4. Different genotypes in F11R promoter −688 A > C and −436 A > G do not lead to changes of the gene expression in RA patients. Conclusion RA patients have higher mRNA expression of F11R. In RA patients, F11R −688 C may be a protective factor for the development of anti-CCP antibodies and positive rates of Schirmer's tests. [ABSTRACT FROM AUTHOR]

Chronic inflammation, coupled with alcohol, betel quid, and cigarette consumption, is associated with oral squamous cell carcinoma (OSCC). Interleukin-1 beta (IL-1β) is a critical mediator of chronic inflammation and implicated in many cancers. In this study, we showed that increased pro-IL-1β expression was associated with the severity of oral malignant transformation in a mouse OSCC model induced by 4-Nitroquinolin-1-oxide (4-NQO) and arecoline, two carcinogens related to tobacco and betel quid, respectively. Using microarray and quantitative PCR assay, we showed that pro-IL-1β was upregulated in human OSCC tumors associated with tobacco and betel quid consumption. In a human OSCC cell line TW2.6, we demonstrated nicotine-derived nitrosamine ketone (NNK) and arecoline stimulated IL-1β secretion in an inflammasome-dependent manner. IL-1β treatment significantly increased the proliferation and dysregulated the Akt signaling pathways of dysplastic oral keratinocytes (DOKs). Using cytokine antibodies and inflammation cytometric bead arrays, we found that DOK and OSCC cells secreted high levels of IL-6, IL-8, and growth-regulated oncogene-α following IL-1β stimulation. The conditioned medium of IL-1β-treated OSCC cells exerted significant proangiogenic effects. Crucially, IL-1β increased the invasiveness of OSCC cells through the epithelial-mesenchymal transition (EMT), characterized by downregulation of E-cadherin, upregulation of Snail, Slug, and Vimentin, and alterations in morphology. These findings provide novel insights into the mechanism underlying OSCC tumorigenesis. Our study suggested that IL-1β can be induced by tobacco and betel quid-related carcinogens, and participates in the early and late stages of oral carcinogenesis by increasing the proliferation of dysplasia oral cells, stimulating oncogenic cytokines, and promoting aggressiveness of OSCC. J. Cell. Physiol. 230: 875-884, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

An electrocardiogram (ECG) records changes in the electric potential of cardiac cells using a noninvasive method. Previous studies have shown that each person's cardiac signal possesses unique characteristics. Thus, researchers have attempted to use ECG signals for personal identification. However, most studies verify results using ECG signals taken from databases which are obtained from subjects under the condition of rest. Therefore, the extraction and analysis of a subject's ECG typically occurs in the resting state. This study presents experiments that involve recording ECG information after the heart rate of the subjects was increased through exercise. This study adopts the root mean square value, nonlinear Lyapunov exponent, and correlation dimension to analyse ECG data, and uses a support vector machine (SVM) to classify and identify the best combination and the most appropriate kernel function of a SVM. Results show that the successful recognition rate exceeds 80% when using the nonlinear SVM with a polynomial kernel function. This study confirms the existence of unique ECG features in each person. Even in the condition of exercise, chaotic theory can be used to extract specific biological characteristics, confirming the feasibility of using ECG signals for biometric verification. [ABSTRACT FROM AUTHOR]

Aim: Systemic lupus erythematosus (SLE) is an autoimmune disease that is associated with genetic and environmental factors and microbial infection. With respect to microbial infection, the Epstein-Barr virus (EBV) has been a widely discussed issue in recent decades. Human herpesvirus 8 (HHV-8) belongs to the same c-herpesvirus subfamily as EBV and is closely related to it. Until now, only one paper has reported the prevalence of HHV- 8 infection in SLE patients. The goal of this study was to detect the prevalence of HHV-8 infection in SLE patients to elucidate the relationship between HHV-8 and SLE. Methods: We assessed the seroprevalence of HHV-8 in SLE patients by immunofluorescence assay. In addition, we quantified the HHV-8 DNA in peripheral blood mononuclear cells (PBMCs) from SLE patients by real-time polymerase chain reaction (PCR). Results: The prevalence of HHV-8 antibodies in SLE and normal controls was 57.8% (26/45) and 19.2% (5/ 26), respectively. These data were highly significant (P = 0.001). No HHV-8 DNA was detected by real-time PCR in SLE patients' PBMCs. In addition, we analyzed the prevalence of HHV-8 infection in patients with rheumatoid arthritis and ankylosing spondylitis. There was no significant difference between the patients and normal controls. Conclusion: A high seroprevalence of HHV-8 infection was found in patients with SLE. The negative DNA load and high seropositive rate indicate that most patients might have latent infection. [ABSTRACT FROM AUTHOR]

Background The importance of basic surgical skills is entirely agreed among surgical educators. However, restricted by ethical issues, finance etc, the basic surgical skills training is increasingly challenged. Increasing cost gives an impetus to the development of cost-effective training models to meet the trainees' acquisition of basic surgical skills. In this situation, a cost-effective training framework was formed in our department and introduced here. Methods Each five students were assigned to a 'training unit'. The training was implemented weekly for 18 weeks. The framework consisted of an early, a transitional, an integrative stage and a surgical skills competition. Corresponding training modules were selected and assembled scientifically at each stage. The modules comprised campus intranet databases, sponge benchtop, nonliving animal tissue, local dissection specimens and simulating reality operations. The training outcomes used direct observation of procedural skills as an assessment tool. The training data of 50 trainees who were randomly selected in each year from 2006 to 2011 year, were retrospectively analysed. Results An excellent and good rate of the surgical skills is from 82 to 88%, but there is no significant difference among 6 years ( P > 0.05). The skills scores of the contestants are markedly higher than those of non-contestants ( P < 0.05). The average training cost per trainee is about $21.85-34.08. Conclusion The present training framework is reliable, feasible, repeatable and cost-effective. The skills competition can promote to improve the surgical skills level of trainees. [ABSTRACT FROM AUTHOR]

Background: It is known that quantification of bovine acute-phase proteins could routinely provide early diagnostic and prognostic information for monitoring herd health status. Objective: The aim of this study was to test the hypothesis that haptoglobin (Hp) and serum amyloid A (SAA) have the potential for indicating uterine infection, mainly due to subclinical endometritis, which can seriously influence the reproductive performance in dairy cows. Methods: A total of 264 serum samples were collected from 24 Holstein dairy cows at defined intervals from 1 week prepartum to 6 months postpartum. Clinically healthy animals (Group 1, n=6) were compared with 24 animals having acute puerperal metritis (Group 2, n=18) and with concentrations obtained from healthy heifers (baseline values, n=10). The concentrations of serum Hp and SAA were measured using a hemoglobin-binding assay and Western blot analysis, respectively. Reproductive performance was assessed as the number of days open and the conception rate at the end of the study. Results: Upper cut-off values for Hp and SAA concentrations in heifers were 130.9 μg/L and 51.9 μg/mL, respectively. Hp concentrations in Group 2 were significantly higher than those in Group 1 at all time points ( P<.001). Additionally, among the successfully pregnant animals, the number of days open was significantly higher in 6 cows with Hp >130.9 μg/mL (median=316 days) than in 11 cows with Hp ≤130.9 μg/mL (median=120 days) ( P=.0024). Conclusions: Serum Hp and SAA concentrations can be used to recognize uterine infection in postpartum cows. The association between elevated Hp values and number of days open suggests Hp may also be a useful indicator of poor prognosis for reproductive performance. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin," by H. Wang and colleagues in the 2015 issue.

Background: Rheumatoid arthritis (RA) is an autoimmune disease where both genetics and epigenetics are contributing factors. In order to discover genetic and epigenetic associations with RA and its phenotypes, we analysed RNA expression, DNA variations and DNA methylation of programmed cell death 1 (PDCD1) in a cohort of RA patients and healthy controls. Methods: RA patients (n = 206) and healthy controls (n = 234) were included for analysis of PDCD1 expression, PDCD1 polymorphisms and PDCD1 methylation. Differences in continuous variables between groups were compared by applying t tests. Associations between phenotypes and genotypes were evaluated with contingency tables. Sensitivity analyses were conducted to confirm the robustness of results, considering potential confounding factors and different treatment response definitions. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Results: Higher expression of PDCD1 was found in RA compared to controls (P < 0.001), with similar PDCD1 polymorphisms in RA and controls. rs36084323 decreased inadequate response to conventional synthetic disease‐modifying antirheumatic drugs (OR = 0.37, 95% CI = 0.19‐0.72, P = 0.003), and rs41386349 increased rheumatoid factor seropositivity (OR = 11.89, 95% CI = 1.57‐89.87, P = 0.003). Sensitivity analysis adjusting for further potential confounders and using different treatment response definition indicated similar results. Additionally, DNA methylation change at regulatory region of PDCD1 was detected in RA (P = 0.036). Conclusion: Altogether, this was the first study to suggest genetic and epigenetic changes of PDCD1 in RA subsets and RA. Independent prospective cohorts are awaited to address the implications of these genetic and epigenetic changes in disease pathogenesis and phenotypes of RA. [ABSTRACT FROM AUTHOR]