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Background: Restless legs syndrome (RLS) is frequent in patients with hemodialysis (HD) and occurs predominantly in its most severe forms. The study was conducted to evaluate the efficacy and safety of acupuncture for RLS in patients with end-stage renal disease (ESRD) at hospital-based HD center. Methods: This single-blind, randomized controlled trial was performed on patients with HD and RLS who were randomly assigned to the experimental group and control group. Data were collected using the International Restless Legs Syndrome Rating Scale (IRLSRS), Insomnia Severity Index (ISI), and heart rate variability (HRV) records at baseline, after the therapeutic course (12 times/4 weeks), and 1-week follow-up. Result: A total of 47 patients were evaluated with IRLSRS score from 11 to 30 in this study. There were 41 patients enrolled in the study based on inclusion/exclusion criteria and allocated randomly into two groups. A total of 35 participants completed the trial, including 18 subjects in the experimental group and 17 subjects in the control group. The comparison of IRLSRS and ISI showed a significant reduction between two groups after acupuncture treatment ( p = 0.002, p = 0.003). The ISI after 1-week follow-up also revealed significant decrease ( p = 0.003). This HRV results showed that high frequency (HF%) increased significantly ( p = 0.021) and low frequency (LF%) decreased significantly in the acupuncture group ( p = 0.021). The generalized estimating equation showed that the IRLSRS improved by 2.902 points ( p < 0.001) in the acupuncture group compared with the control group and by 1.340 points ( p = 0.003) after 1-week follow-up. There were no adverse effects observed during HD in this study. Discussion: The authors conclude that acupuncture could effectively improve the symptoms of RLS significantly. The results from this study provide clinical evidence on the efficacy and safety of acupuncture to treat the patients with RLS at the HD center.

This report develops a point-of-use chemical trigger and applies it to a dual-functional chemical encryption chip that enables manual and digital identification with enhanced coding security levels suitable for on-site information verification. The concept relies on conducting continuous chemical synthesis and chromatographic separation of specified compounds on a paper device in a straightforward sketch. In addition to single-step chemical reactions, cascade syntheses and operations involving components of distinct mobilities are also demonstrated. The condensation of dione and hydrazine is first demonstrated on a linear paper reactor, where precursors can mix to react, followed by final product separation under optimized conditions. This linear paper reactor design can also support a multistep cascade Wittig reaction by controlling the relative mobility of reactants, intermediates, and final products. Furthermore, a three-dimensional paper reactor with appropriate mobile phases helps to initiate complex solvent system-driven azide-alkyne cycloaddition. By the use of a three-dimensional device design for spatially limited interdevice reactant transportation, reactants crossing designated boundaries trigger confined chemical reactions at specific positions. Accumulation of repetitive reactions leads to successful product gradient generation and mixing effects, representing a fully controllable intersubstrate chemical operation on the platform. Standing on initiating desired chemical reactions at particular interface regions, integration of appropriate selective reaction area, numerical digits overlay, color diversity, and mobile recognition realizes this dual-functional multicoding encryption process., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Tongue diagnosis in traditional Chinese medicine (TCM) provides clinically important, objective evidence from direct observation of specific features that assist with diagnosis. However, the current interpretation of tongue features requires a significant amount of manpower and time. TCM physicians may have different interpretations of features displayed by the same tongue. An automated interpretation system that interprets tongue features would expedite the interpretation process and yield more consistent results., Materials and Methods: This study applied deep learning visualization to tongue diagnosis. After collecting tongue images and corresponding interpretation reports by TCM physicians in a single teaching hospital, various tongue features such as fissures, tooth marks, and different types of coatings were annotated manually with rectangles. These annotated data and images were used to train a deep learning object detection model. Upon completion of training, the position of each tongue feature was dynamically marked., Results: A large high-quality manually annotated tongue feature dataset was constructed and analyzed. A detection model was trained with average precision (AP) 47.67%, 58.94%, 71.25% and 59.78% for fissures, tooth marks, thick and yellow coatings, respectively. At over 40 frames per second on a NVIDIA GeForce GTX 1060, the model was capable of detecting tongue features from any viewpoint in real time., Conclusions/significance: This study constructed a tongue feature dataset and trained a deep learning object detection model to locate tongue features in real time. The model provided interpretability and intuitiveness that are often lacking in general neural network models and implies good feasibility for clinical application., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Interleukin-17 (IL-17) is a pro-inflammatory cytokine that plays a vital role in the promotion of tumorigenesis in various cancers, including colorectal cancer (CRC). Based on current evidence, IL-17 binds to interleukin-17 receptor A (IL-17RA); however, the role of IL-17RA has not been elucidated in previous studies on CRC. In this study, we explored the role of IL-17RA in human CRC tissues and the progression of CRC in humans and mice., Methods: The expressions of IL-17RA and epithelial-mesenchymal transition (EMT)-related genes were examined in CRC cells and tissue samples by quantitative real-time polymerase chain reaction. The role of IL-17RA in pathogenesis and prognosis was evaluated using a Chi-squared test, Kaplan-Meier analysis, univariate, and multivariate Cox regression analysis in 133 CRC patients. A tumor-bearing mice model was executed to evaluate the role of IL-17RA in tumor growth, vascularity and population of infiltrating immune cells., Results: IL-17RA expression was found to be significantly higher in CRC tissues than in adjacent normal tissues. The expression of IL-17RA in Stage IV patients was significantly higher than that in Stages I and II patients. Patients with high IL-17RA expression exhibited significantly worse overall and CRC-specific survival than those with low IL-17RA expression. Functional assessment suggested that the knockdown of IL-17RA expression distinctly suppressed cellular proliferation, migration, invasion, and EMT-related gene expression. In a tumor-bearing mouse model, decreased IL-17RA expression significantly repressed tumor growth and vascularity and reduced the population of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)., Conclusion: Reduced IL-17RA expression also suppressed cellular proliferation, migration, and invasion, and the expression of EMT genes. Knockdown of IL-17RA inhibited tumor growth and vascularity and decreased the population of Tregs and MDSCs in mouse tumors. Overall, IL-17RA expression was identified to be independently associated with the prognosis of patients with CRC., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

In this study, we explored a concise and mild synthetic route to produce novel C-14 arylcarbamate derivatives of andrographolide, a known anti-inflammatory and anticancer natural product. Upon assessing their anti-cancer efficacy against pancreatic ductal adenocarcinoma (PDAC) cells, some derivatives showed stronger cytotoxicity against PANC-1 cells than andrographolide. In addition, we demonstrated one derivative, compound 3m, effectively reduced the expression of oncogenic p53 mutant proteins (p53 R273H and p53 R248W ), proliferation, and migration in PDAC lines, PANC-1 and MIA PaCa-2. Accordingly, the novel derivative holds promise as an anti-cancer agent against pancreatic cancer. In summary, our study broadens the derivative library of andrographolide and develops an arylcarbamate derivative of andrographolide with promising anticancer activity against PDAC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Nursing home-associated pneumonia (NHAP) is a common type of infection among long-term care residents. Moreover, the mortality of NHAP is also higher than community-acquired pneumonia (CAP). In traditional Chinese medicine (TCM), the decoctions of Banxia Houpo Tang (BHT) and Ding Chuan Tang (DCT) are two formulas supporting the lungs' natural defense systems, helps to expel mucus and promote detoxification., Aim of the Study: We designed a concentrated Chinese herbal extract formula called BDT1, that combines the compounds of BHT and DCT. In this study, we evaluated the safety and efficacy of BDT1 for NHAP prevention in high-risk older residents in the nursing home., Materials and Methods: In this randomized, double-blind, placebo-controlled trial, 160 participants aged over 65 years old living in the nursing home were randomly assigned 1:1 to the BDT1 and placebo group. Besides regular medicine, participants received either BDT1 or a placebo for 12 consecutive weeks. The primary outcome was the hospitalization rate for pneumonia in the intervention period and half-year follow-up. The microscopic examination of Gram-stained sputum was also evaluated before and after the trial. Data were analyzed by using the Chi-square test and Wilcoxon Signed Ranks Test with SPSS., Results: A total of 160 participants were enrolled into two study groups in this study, which was completed with 143 participants analyzed, including 70 subjects in the BDT1 group and 73 subjects in the placebo group. After the 12-week medical treatment, the hospitalization rate for pneumonia was 10.0% and 34.2% in the BDT1 and placebo group respectively. The risk of pneumonia in half a year was lower in the BDT1 group (adjusted hazard ratio = 0.422, 95% CI = 0.226-0.791). Compared to the placebo group, the level of Gram-negative bacilli in the BDT1 group is significantly declined in sputum samples (p < 0.05)., Conclusion: In conclusion, the cumulative incidence of pneumonia and related-hospitalization rates declined significantly after 12-weeks of BDT1 treatment. Besides, Chinese herbal medicine BDT1 is a safe therapy without hepatotoxicity or nephrotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In Taiwan, the Integrated Home Care (IHC) project was introduced for medically compromised patients living at home receiving Home Health Care (HHC) in 2016. The focus of the project was on organizing care teams and managing care for patients. The aim of this study was to investigate the benefits and impacts of IHC in Taiwan. The primary outcome measure was the mortality rate of patients who received IHC versus those who did not receive IHC (non-IHC). The secondary outcomes were medical utilization and expenditure. The results showed that IHC was associated with a statistically significant reduction in mortality compared to non-IHC for home-dwelling patients over 90-, 180-, and 365-days periods. Additionally, IHC users were less likely to be hospitalized and had shorter hospitalization times compared to non-IHC users. Furthermore, IHC was found to reduce medical expenditure compared to non-IHC.

Early prognosis of cancer recurrence remains difficult partially due to insufficient and ineffective screening biomarkers or regimes. This study evaluated the rare circulating tumor microemboli (CTM) from liquid biopsy individually and together with circulating tumor cells (CTCs) and serum CEA/CA19-9 in a panel, on early prediction of colorectal cancer (CRC) recurrence. Stained CTCs/CTM were detected by a microfluidic chip-based automatic rare-cell imaging platform. ROC, AUC, Kaplan-Meier survival, and Cox proportional hazard models regarding 4 selected biomarkers were analyzed. The relative risk, odds ratio, predictive accuracy, and positive/negative predictive value of biomarkers individually and in combination, to predict CRC recurrence were assessed and preliminarily validated. The EpCAM + Hochest + CD45 - CTCs/CTM could be found in all cancer stages, where more recurrences were observed in late-stage cases. Significant correlations between CTCs/CTM with metastatic stages and clinical treatment were illustrated. CA19-9 and CTM could be seen as independent risk factors in patient survivals, while stratified patients by grouped biomarkers on the Kaplan-Meier analyses presented more significant differences in predicting CRC recurrences. By monitoring the panel of selected biomarkers, disease progressions of 4 CRC patients during follow-up visits after first treatments within 3 years were predicted successfully. This study unveiled the value of rare CTM on clinical studies and a panel of selected biomarkers on predicting CRC recurrences in patients at the early time after medical treatment, in which the CTM and serum CA19-9 could be applied in clinical surveillance and CRC management to improve the accuracy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A thermally stable, fluorous sulfur-containing boronic acid catalyst has been developed and was shown to efficiently promote dehydrative condensation between carboxylic acids and amines under environmentally friendly conditions. The methodology can be applied to aliphatic, aromatic and heteroaromatic acids as well as primary and secondary amines. N -Boc protected amino acids were also successfully coupled in good yields with very little racemization. The catalyst could be reused four times with no significant loss of activity., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Circulating tumor cells (CTCs) have been investigated as a potential biomarker for predicting prognosis and monitoring therapeutic responses in colorectal cancer (CRC). However, the sensitivity of CTCs detection is low, thus limiting the clinical utility of CTCs. We aim to examine the clinicopathological parameters that improve prognosis prediction for CRC using CTCs as a biomarker., Methods: We enumerated CTCs in 186 CRC patients and associated the number of CTCs with the clinicopathological features and overall survival (OS) using a univariate and multivariate Cox regression model and Kaplan-Meier survival analysis., Results: The presence of CTCs from 186 CRC patients was significantly associated with stage, preoperational carcinoembryonic antigen (CEA), and CA19-9 levels. Using Kaplan-Meier survival and Cox regression analysis, patients with five or more CTCs exhibited significantly worse OS compared to patients with fewer than five CTCs. The combination of CTCs with tumor marker CEA has a better OS prediction than individual CTCs or CEA and serves as a more effective prediction model in patients with CRC., Conclusion: We identified that patients with more than five CTCs exhibited significantly worse OS. Additionally, patients with the normal level of CEA, but who also had more than five CTCs trended towards a worse OS., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Ethnopharmacological Relevance: Helminthostachys zeylanica (HZ), which is also called "Dao-Di-U-Gon" in Taiwan, has anti-inflammatory and antiedema effects and is commonly used to treat edema in patients with fractures. The ugonin K component of HZ can induce osteogenesis and promote bone mineralization, its therapeutic effect, however, its therapeutic effect remains unclear. Therefore, the purpose of the present study was to investigate the effect of HZ on functional recovery in patients with ankle fractures requiring surgical treatment., Methods: A double-blinded, randomized, controlled study was conducted. A total of 45 patients with ankle fractures requiring surgical treatment were assigned to either the control group (n = 23 patients), which received the oral administration of HZ placebo 1.0 g t.i.d. for 42 days continuously, or to the treatment group (22 patients), which received HZ for 42 days., Results: The serum amino-terminal propeptide of type 1 procollagen (PINP) levels were similar in the first assessment (V1) between the control (45.90 ± 16.31 ng/mL) and treatment groups (52.61 ± 21.02 ng/mL; p = 0.240); the differences in PINP level between the third assessment (V3) and V1 were greater in the treatment group (35.84 ± 24.56 ng/mL) than in the control group (16.34 ± 11.97 ng/mL; p = 0.002). Radiographic healing time (RHT) was 9.09 ± 1.15 weeks in the treatment group, which was shorter than the 9.91 ± 0.79 weeks (p = 0.012) in the control group., Conclusion: Oral administration of HZ for 42 days can increase serum PINP level and reduce the RHT. Therefore, HZ can be used to treat patients with ankle fractures requiring surgical treatment. However, a larger sample size is needed in future studies., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Endometriosis is a hormone-associated disease which has been considered as the precursor for certain types of ovarian cancer. In recent years, emerging evidence demonstrated potent roles of lncRNA in regulating cancer development. Since endometriosis shares several features with cancer, we investigated the possible involvement of cancer-related lncRNAs in endometriosis, including UCA1, GAS5 and PTENP1. By using massARRAY system, we investigated certain genetic variations in cancer-related lncRNAs that can change the thermo-stability, leading to up-regulation or down-regulation of those lncRNAs. Our data indicated three risk genetic haplotypes in UCA1 which can stabilize the RNA structure and increase the susceptibility of endometriosis. Of note, such alterations were found to be associated with long-term pain and infertility in patients. It has been known that UCA1 can function as a ceRNA to sponge and inhibit miRNAs, resulting in loss-of-control on downstream target genes. Gene network analyses revealed fatty acid metabolism and mitochondria beta-oxidation as the major pathways associated with altered UCA1 expression in endometriosis patients. Our study thus provides evidence to highlight functional/epigenetic roles of UCA1 in endometriosis development via regulating fatty acid metabolism in women., Competing Interests: Competing interests: The authors declare no conflict of interest

Tripeptidyl peptidase II (TPPII or TPP2) degrades N-terminal tripeptides from proteins and peptides. Studies in both humans and mice have shown that TPPII deficiency is linked to cellular immune-senescence, lifespan regulation and the aging process. However, the mechanism of how TPPII participates in these processes is less clear. In this study, we established a chemical probe-based assay and found that although the mRNA and protein levels of TPPII were not altered during senescence, its enzymatic activity was reduced in senescent human fibroblasts. We also showed that elevation of the levels of the serine protease inhibitor serpinB2 reduced TPPII activity in senescent cells. Moreover, suppression of TPPII led to elevation in the amount of lysosomal contents as in well as TPPI (TPP1) and β-galactosidase activities, suggesting that lysosome biogenesis is induced to compensate for the reduction of TPPII activity in senescent cells. Together, this study discloses a critical role of the serpinB2-TPPII signaling pathway in proteostasis during senescence. Since serpinB2 levels can be increased by a variety of cellular stresses, reduction of TPPII activity through activation of serpinB2 might represent a common pathway for cells to respond to different stress conditions. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Insufficient prognosis of local recurrence contributes to the poor progression-free survival rate and death in colorectal cancer (CRC) patients. Various biomarkers have been explored in predicting CRC recurrence. This study investigated the expressions of plasma/exosomal microRNA-21 (miR-21) in 113 CRC patients by qPCR, their values of predicting CRC recurrence, and the possibility to improve the prognostic efficacy in early CRC recurrence in stratified patients by combined biomarkers including circulating miR-21s, circulating tumour cells/microemboli (CTCs/CTM), and serum carcinoembryonic antigen (CEA)/carbohydrate antigen 19-9 (CA19-9). Expressions of plasma and exosomal miR-21s were significantly correlated (p < 0.0001) in all and late-stage patients, presenting similar correlations with other biomarkers. However, stage IV patients stratified by a high level of exosomal miR-21 and stage I to III patients stratified by a high level of plasma miR-21 displayed significantly worse survival outcomes in predicting CRC recurrence, suggesting their different values to predict CRC recurrence in stratified patients. Comparable and even better performances in predicting CRC recurrence in late-stage patients were found by CTCs/CTM from our blood samples as sensitive biomarkers. Improved prognosing efficacy in CRC recurrence and better outcomes to significantly differentiate recurrence in stratified patients could be obtained by analysing combined biomarkers.

The propagation of the hepatitis C virus (HCV) is regulated in part by the phosphorylation of its nonstructural protein NS5A that undergoes sequential phosphorylation on several highly conserved serine residues and switches from a hypo- to a hyperphosphorylated state. Previous studies have shown that NS5A sequential phosphorylation requires NS3 encoded on the same NS3-NS4A-NS4B-NS5A polyprotein. Subtle mutations in NS3 without affecting its protease activity could affect NS5A phosphorylation. Given the ATPase domain in the NS3 COOH terminus, we tested whether NS3 participates in NS5A phosphorylation similarly to the nucleoside diphosphate kinase-like activity of the rotavirus NSP2 nucleoside triphosphatase (NTPase). Mutations in the NS3 ATP-binding motifs blunted NS5A hyperphosphorylation and phosphorylation at serines 225, 232, and 235, whereas a mutation in the RNA-binding domain did not. The phosphorylation events were not rescued with wild-type NS3 provided in trans . When provided with an NS3 ATPase-compatible ATP analog, N 6 -benzyl-ATP-γ-S, thiophosphorylated NS5A was detected in the cells expressing the wild-type NS3-NS5B polyprotein. The thiophosphorylation level was lower in the cells expressing NS3-NS5B with a mutation in the NS3 ATP-binding domain. In vitro assays with a synthetic peptide and purified wild-type NS3 followed by dot blotting and mass spectrometry found weak NS5A phosphorylation at serines 222 and 225 that was sensitive to an inhibitor of casein kinase Iα but not helicase. When casein kinase Iα was included in the assay, much stronger phosphorylation was observed at serines 225, 232, and 235. We concluded that NS5A sequential phosphorylation requires the ATP-binding domain of the NS3 helicase and that casein kinase Iα is a potent NS5A kinase. IMPORTANCE For more than 20 years, NS3 was known to participate in NS5A sequential phosphorylation. In the present study, we show for the first time that the ATP-binding domain of NS3 is involved in NS5A phosphorylation. In vitro assays showed that casein kinase Iα is a very potent kinase responsible for NS5A phosphorylation at serines 225, 232, and 235. Our data suggest that ATP binding by NS3 probably results in conformational changes that recruit casein kinase Iα to phosphorylate NS5A, initially at S225 and subsequently at S232 and S235. Our discovery reveals intricate requirements of the structural integrity of NS3 for NS5A hyperphosphorylation and HCV replication.

Background and Aim: Stroke is a major cause of disability worldwide, and ischemic stroke is the most common type of stroke. The prevention and treatment of ischemic stroke remain a challenge worldwide. Traditional Chinese medicine (TCM) is often sought to provide an alternative therapy for the prevention and rehabilitation intervention of ischemic stroke in Taiwan. Therefore, this study explored the pivotal variables of tongue diagnosis among acute ischemic stroke and healthy participants in middle and older age., Experimental Procedure: This was a cross-sectional and case-controlled study. Data were collected from 99 patients with acute ischemic stroke and 286 healthy participants who received tongue diagnoses at Changhua Christian Hospital (CCH) from September 1, 2014, to December 31, 2016. Tongue features were extracted using the automatic tongue diagnosis system. Nine tongue features, including tongue shape, tongue color, fur thickness, fur color, saliva, tongue fissures, ecchymoses, teeth marks, and red spots were analyzed., Results and Conclusion: Objective image analysis techniques were used to identify significant differences in the many tongue features between patients with acute ischemic stroke and individuals without stroke. According to the logistic regression analysis, pale tongue color (OR:5.501, p  = 0.001), bluish tongue color (OR:4.249, p  = 0.014), ecchymoses (OR:1.058, p  < 0.001), and tongue deviation angle (OR:1.218, p  < 0.001) were associated with significantly increased odds ratios for acute ischemic stroke. The research revealed that tongue feature abnormalities were significantly related to the occurrence of ischemic stroke., Competing Interests: The authors declare that they have no more conflict and financial interests., (© 2022 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Diabetic nephropathy (DN), a principal diabetic microvascular complication, is a chronic inflammatory immune disorder. A gastro-resistant peptide mcIRBP-9 from Momordica charantia has shown modulation of blood glucose homeostasis in diabetic mice. Here we conducted a long-term experiment to evaluate the therapeutic effects and mechanisms of mcIRBP-9 on DN. Type 2 diabetic mice ( db / db mice) were orally given mcIRBP-9 once daily for 12 consecutive weeks. The amelioration of DN was evaluated by renal function indexes, vascular leakage, and pathological lesions. Possible effective mechanisms of mcIRBP-9 on DN were analyzed by gene expression profiles. A pharmacokinetic study in rats was carried out to evaluate the oral bioavailability of mcIRBP-9. Our data showed that mcIRBP-9 was able to enter systemic circulation in rats after oral administration. In comparison with mock, long-term administration of mcIRBP-9 significantly decreased blood glucose (572.25 ± 1.55 mg dL -1 vs. 213.50 ± 163.39 mg dL -1 ) and HbA1c levels (13.58 ± 0.30% vs. 8.23 ± 2.98%) and improved the survival rate (85.7% vs. 100%) in diabetic mice. mcIRBP-9 ameliorated DN by reducing renal vascular leakage and histopathological changes. mcIRBP-9 altered the pathways involved in inflammatory and immune responses, and the nuclear factor-κB played a central role in the regulation of mcIRBP-9-affected pathways. Moreover, mcIRBP-9 improved the inflammatory characteristic of DN in diabetic and non-diabetic mice. In conclusion, mcIRBP-9 displayed a novel anti-inflammatory activity and exhibited a reno-protective ability in addition to controlling the blood glucose and HbA1c levels. These findings suggested the role of mcIRBP-9 from M. charantia as a nutraceutical agent for diabetes and subsequent DN.

Diabetic nephropathy is an inflammatory immune disorder accompanying diabetes. A trypsin inhibitor of Momordica charantia , mcIRBP, is an abundant 68 amino acid residue protein that interacts with the insulin receptor. Here the long-term effects of mcIRBP on the improvement of diabetic nephropathy were determined. Type 2 diabetic mice ( db / db ) were given mcIRBP administered orally for 12 consecutive weeks. Histological changes relating to the kidney were evaluated using Periodic Acid Schiff and Sirius Red staining. The mcIRBP-affected gene expression profile in the kidney was determined using RNA-Seq. The renoprotective mechanism of mcIRBP was elucidated based on ex vivo imaging and immunohistochemistry staining. Data showed that the administration of mcIRBP significantly decreased fasting blood glucose and glycated hemoglobin A1c (HbA1c) levels by 61% and 27.92%, respectively, suggesting that mcIRBP exhibited HbA1c-lowering abilities in diabetic mice. RNA sequencing (RNA-Seq) analysis showed that the majority of the mcIRBP-affected biological pathways were associated with inflammation and immunity, and the nuclear factor-κB (NF-κB) signaling pathway was significantly affected by mcIRBP. Ex vivo imaging showed that mcIRBP significantly decreased NF-κB-driven bioluminescence in the kidney by 46 ± 23%. The levels of the renal function indices, Evans blue dye content, fibrosis lesions, and cytokine expression were significantly decreased by mcIRBP, suggesting that mcIRBP improved vascular leakage and the pathological and inflammatory characteristics of diabetic nephropathy. This is the first study reporting that, in addition to blood glucose regulation, mcIRBP can act as a novel renoprotective and anti-inflammatory polypeptide, thereby improving diabetic nephropathy in db / db mice. In addition, this study suggested that there was a potential medicinal use of mcIRBP for the management of diabetes and its complications.

Infection-induced chronic inflammation is common in patients with endometriosis. Although microbial communities in the reproductive tracts of patients have been reported, little was known about their dynamic profiles during disease progression and complication development. Microbial communities in cervical mucus were collected by cervical swabs from 10 healthy women and 23 patients, and analyzed by 16S rRNA amplicon sequencing. The abundance, ecological relationships and functional networks of microbiota were characterized according to their prevalence, clinical stages, and clinical features including deeply infiltrating endometriosis (DIE), CA125, pain score and infertility. Cervical microbiome can be altered during endometriosis development and progression with a tendency of increased Firmicutes and decreased Actinobacteria and Bacteroidetes . Distinct from vaginal microbiome, upregulation of Lactobacillus , in combination with increased Streptococcus and decreased Dialister , was frequently associated with advanced endometriosis stages, DIE, higher CA125 levels, severe pain, and infertility. Significantly, reduced richness and diversity of cervical microbiome were detected in patients with more severe clinical symptoms. Clinical treatments against infertility can partially reverse the ecological balance of microbes through remodeling nutrition metabolism and transport and cell-cell/cell-matrix interaction. This study provides a new understanding on endometriosis development and a more diverse cervical microbiome may be beneficial for patients to have better clinical outcomes.

Introduction: Breast cancer (BC) is the most common cancer in women and patients with BC often undergo complex treatment. In Taiwan, nearly 80% of patients with BC seek traditional Chinese medicine (TCM) during adjuvant chemotherapy to relieve discomfort and side effects. This study investigated tongue features and pattern differentiation through noninvasive TCM tongue diagnosis in patients with BC., Materials and Methods: This cross-sectional, case-controlled, retrospective observational study collected patient data through a chart review. The tongue features were extracted using the automatic tongue diagnosis system (ATDS). Nine tongue features, including tongue shape, tongue color, fur thickness, fur color, saliva, tongue fissures, ecchymoses, teeth marks, and red dots, were analyzed. Results and Discussion . Objective image analysis techniques were used to identify significant differences in the many tongue features between BC patients and non-BC individuals. A significantly larger proportion of patients with BC had a small tongue ( p < 0.001), pale tongue ( p < 0.001), thick fur ( p < 0.001), yellow fur ( p < 0.001), wet saliva ( p < 0.001), thick tongue fur ( p < 0.001), fissures ( p =0.040), and ecchymoses in the heart-lung area ( p =0.013). According to logistic regression, small tongue shape, pale tongue color, yellow fur color, wet saliva, and the amounts of fissures were associated with a significantly increased odds ratio for BC., Conclusions: This study showed significant differences in tongue features, such as small tongue shape, pale tongue color, thick fur, yellow fur color, wet saliva, fissure, and ecchymoses in the heart-lung area in patients with BC. These tongue features would imply yin deficiency, deficiencies of blood, stagnation of heat, and phlegm/blood stasis in TCM theory. There is a need to investigate effective and safe treatment to enhance the role of TCM in integrated medical care for patients with BC., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Po-Chi Hsu et al.)

It is necessary to control contact force through modulation of joint stiffness in addition to the position of our limb when manipulating an object. This is achieved by contracting the agonist muscles in an appropriate magnitude, as well as, balancing it with contraction of the antagonist muscles. Here we develop a decoding technique that estimates both the position and torque of a joint of the limb in interaction with an environment based on activities of the agonist-antagonistic muscle pairs using electromyography in real time. The long short-term memory (LSTM) network that is capable of learning time series of a longtime span with varying time lags is employed as the core processor of the proposed technique. We tested both the unidirectional LSTM network and bidirectional LSTM network. A validation was conducted on the wrist joint moving along a given trajectory under resistance generated by a robot. The decoding approach provided an agreement of greater than 93% in kinetics (i.e. torque) estimation and an agreement of greater than 83% in kinematics (i.e. angle) estimation, between the actual and estimated variables, during interactions with an environment. We found no significant differences in performance between the unidirectional LSTM and bidirectional LSTM as the learning device of the proposed decoding method.

Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM 2.5 ) using negative binomial regression. The prevalence of CAO was not independently associated with PM 2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised., Competing Interests: Competing interests: RN reports grants and personal fees from Boehringer Ingelheim, AstraZeneca and Novartis outside the submitted work. EDB reports personal fees from Novartis, AstraZeneca, Orion, Menarirni, Boehringer Ingelheim and ALK outside the submitted work. KM reports grants from GlaxoSmithKline during the conduct of the study. TW reports grants from Boehringer Ingelheim and Pfizer during the conduct of the study. FM reports fees from Medycyba Praktyczna, Sandoz and Chiesi outside the submitted work. DM reports salary and shares from GlaxoSmithKline outside the submitted work. IH reports grants from Boehringer Ingelheim during the conduct of the study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Abstract: Sarcopenia, characterized by a decline of skeletal muscle mass, has emerged as an important prognostic factor for cancer patients. Trunk computed tomography (CT) is a commonly used modality for assessment of cancer disease extent and treatment outcome. CT images can also be used to analyze the skeletal muscle mass filtered by the appropriate range of Hounsfield scale. However, a manual depiction of skeletal muscle in CT scan images for assessing skeletal muscle mass is labor-intensive and unrealistic in clinical practice. In this paper, we propose a novel U-Net based segmentation system for CT scan of paravertebral muscles in the third and fourth lumbar spines. Since the number of training samples is limited (i.e., 1024 CT images only), it is well-known that the performance of the deep learning approach is restricted due to overfitting. A data augmentation strategy to enlarge the diversity of the training set to boost the performance further is employed. On the other hand, we also discuss how the number of features in our U-Net affects the performance of the semantic segmentation. The efficacies of the proposed methodology based on w/ and w/o data augmentation and different feature maps are compared in the experiments. We show that the Jaccard score is approximately 95.0% based on the proposed data augmentation method with only 16 feature maps used in U-Net. The stability and efficiency of the proposed U-Net are verified in the experiments in a cross-validation manner., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Intradialytic hypotension (IDH) may lead to a poor life quality and was associated with cardiovascular mortality in patients under hemodialysis. This study investigated the autonomic nerve and cardiovascular function in the IDH episodes.In this case-control study, 70 end stage renal disease patients (198 visits) were recruited. Pulse wave analysis and heart rate variability were evaluated before hemodialysis. Two definitions of IDH were confirmed by medical records. IDH-f indicated a drop of systolic blood pressure or mean arterial pressure, accompanied with symptoms; IDH-n indicated a low nadir systolic pressure during the hemodialysis. All parameters were evaluated for the possible predisposing factors under each definition.A total of 24 IDH-f and 37 IDH-n were noted in 177 visits. For both definitions, central pulse pressure seemed to be a consistent predisposing factor. Furthermore, lower sympathetic activity (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.35-0.87), lower pulse pressure (OR 0.95; 95% CI 0.92-0.98), and higher augmentation index (OR 17.36; 95% CI 1.48-204.10) were the possible predisposing factors for IDH-f. On the contrary, lower mean arterial pressure (OR 0.87; 95% CI 0.78-0.98) was identified as the possible factor for IDH-n.It was suggested that the lower central pulse pressure and sympathetic activity might be involved in the development of IDH., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

HOTAIR is a well-known long non-coding RNA (lncRNA) involved in various cellular signaling, whereas its functional impacts on endometriosis development are still largely unknown. To this end, six potential functional single nucleotide polymorphisms (SNPs) in HOTAIR, with minor allele frequencies more than 10% in Han population and altered net energy of RNA structures larger than 0.5 kcal/mol, were selected for genotyping study. The study included 207 endometriosis patients and 200 healthy women. Genetic substitutions at rs1838169 and rs17720428 were frequently found in endometriosis patients, and rs1838169 showed statistical significance (p = 0.0174). The G-G (rs1838169-rs17720428) haplotype showed the most significant association with endometriosis (p < 0.0001) with enhanced HOTAIR stability, and patients who harbor such haplotype tended to show higher CA125. Data mining further revealed higher mRNA HOTAIR levels in the endometria of patients with severe endometriosis which consistently showed reduced HOXD10 and HOXA5 levels. HOTAIR knockdown with specific shRNAs down-regulated cell proliferation and migration with the induction of HOXD10 and HOXA5 expression in human ovarian clear cancer cells. Our study therefore provided evidence to indicate a prominent role of HOTAIR in promoting endometriosis, which could be used as a potential target for clinical applications., Competing Interests: The authors have declared that no competing interests exist.

Background: Traditional Chinese medicine (TCM) tongue diagnosis plays an important role in differentiation of symptoms because the tongue reflects the physiological and pathological condition of the body. The automatic tongue diagnosis system (ATDS), which noninvasively captures tongue images, can provide objective and reliable diagnostic information. Chronic kidney disease (CKD) currently is an important global public health problem and contributor to morbidity and mortality from non-communicable diseases. Thus, it is interesting to analyze and probe the relationship between tongue examination and CKD., Methods: This protocol is a cross-sectional, case-controlled observational study investigating the usefulness of the ATDS in clinical practice by examining its efficacy as a diagnostic tool for CKD. Volunteers over 20 years old with and without CKD will be enrolled. Tongue images will be captured and the patients divided into 2 groups: CKD group and healthy group. Nine primary tongue features will be extracted and analyzed, including tongue shape, tongue color, tooth mark, tongue fissure, fur color, fur thickness, saliva, ecchymosis, and red dots., Result: The results of this study will systematically evaluate tongue manifestations of patients and examine its efficacy as an early detection and diagnosis of CKD., Discussion: The aim of this protocol is to investigate discriminating tongue features to distinguish between CKD and normal people, and establish differentiating index to facilitate the noninvasive detection of CKD., Trial Registries: ClinicalTrials.gov; Identifier: NCT04708743., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Restless legs syndrome (RLS) is frequent in dialysis patients and occurs predominantly in its most severe forms. The aim of the present study was to evaluate the effects of electroacupuncture (EA) in hemodialysis patients with RLS by heart rate variability (HRV) monitor., Methods: One hundred twelve subjects who were hemodialysis patients with RLS will be divided into 2 groups: experimental and control. Each subject will receive the treatment relevant to their group 2 times a week for 4 weeks. After 4 weeks of treatment the subject will enter a 2-week washout period, after which the subjects will switch groups. Measurements will include HRV recordings, International Restless Legs Syndrome Rating Scale (IRLSRS) and Insomnia Severity Index (ISI)., Result: The results of this study will systematically evaluate the effectiveness and safety of electoracupuncture intervention for hemodialysis patients with RLS., Discussion: This study is the first investigation to analyze the relationship between EA and the change of HRV by an objective monitor. If the findings of the current trial are positive, this study will also help support an effective, safe and cheap approach to clinical treatment of this challenging disorder, help foster improved understanding the relationship between autonomic nervous system and RLS, and ultimately contribute to elucidate the mechanisms of EA., Trial Registration: ClinicalTrials.gov Identifier: NCT04356794; registration date: April 22, 2020.

The coronavirus disease 2019 (COVID-19) pandemic caused by 2019 novel coronavirus (2019-nCoV) has been a crisis of global health, whereas the effective vaccines against 2019-nCoV are still under development. Alternatively, utilization of old drugs or available medicine that can suppress the viral activity or replication may provide an urgent solution to suppress the rapid spread of 2019-nCoV. Andrographolide is a highly abundant natural product of the medicinal plant, Andrographis paniculata, which has been clinically used for inflammatory diseases and anti-viral therapy. We herein demonstrate that both andrographolide and its fluorescent derivative, the nitrobenzoxadiazole-conjugated andrographolide (Andro- NBD), suppressed the main protease (M pro ) activities of 2019-nCoV and severe acute respiratory syndrome coronavirus (SARS-CoV). Moreover, Andro-NBD was shown to covalently link its fluorescence to these proteases. Further mass spectrometry (MS) analysis suggests that andrographolide formed a covalent bond with the active site Cys 145 of either 2019-nCoV M pro or SARS-CoV M pro . Consistently, molecular modeling analysis supported the docking of andrographolide within the catalytic pockets of both viral M pro s. Considering that andrographolide is used in clinical practice with acceptable safety and its diverse pharmacological activities that could be beneficial for attenuating COVID-19 symptoms, extensive investigation of andrographolide on the suppression of 2019-nCoV as well as its application in COVID-19 therapy is suggested., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The preparation of natural product-inspired nucleoside analogs using solution-phase parallel synthesis is described. The key intermediates containing alkyne and N-protected amino moieties were developed to allow for further skeleton and substituent diversity using click chemistry and urea or amide bond formation. Rapid purification was accomplished using solid-phase extraction. The obtained library comprised 80 molecules incorporating two diversity positions and one chiral center, each of which was efficiently prepared in good purity and acceptable overall yield. A bacterial morphology study was also performed.

All daily physiological activities have some effects on the body, and traditional Chinese medicine believes that pulse diagnosis can reflect the circulation of qi and blood throughout the body. This study aimed to explore the effects of five physiological activities, namely, sleep, exercise, ingestion, defecation, and shower, on pulse waves of the radial artery. Thirty test subjects were recruited for the study, and a wearable pulse signal measurement device was used for self-measurement of radial artery pulses before and after various physiological activities. All collected data were subjected to fast Fourier analysis, which transformed each wave from its time domain to frequency domain of 10 harmonics to describe the changes in pulse waves. The results were as follows: exercise and sleep had larger but opposite effects on the pulse waves; defecation and sleep relaxed the body and had the same trend of effect on the pulse waves. Both exercise and ingestion require energy to proceed, and both exert a burden on the body, and the pulse waves showed the same trend of changes. In contrast, shower had a little effect on the pulse waves. Preliminary observation in this study showed that relaxation of the body could increase high-level harmonics, whereas stress could increase low-level harmonics. Further studies are warranted to unravel the physiological significance of this finding., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Pan-Jen Chen et al.)

Background: Acute abdomen is a common disease in the emergency department (ED) and usually results in huge medical expenditure. To relieve abdominal pain effectively and reduce bed occupancy rate in emergency rooms, electroacupuncture is a practical method in the treatment of abdominal pain., Methods/design: Five hundred patients will be randomly and evenly divided into experimental and control groups. Both groups should have their basic information taken and their bilateral acupuncture points ( Hegu (LI 4), Neiguan (PC6), Zusanli (ST 36), Shangjuxu (ST37), Xiajuxu (ST39), Taichong (LR3), and Taibai (SP3)) will be intervened by electroacupuncture or vaccaria Seeds, in this clinical study. Electroacupuncture has been introduced to this experiment as an auxiliary technique. The experimental group will receive real electroacupuncture, but the control group will receive a placebo electroacupuncture in which transcutaneous electrical nerve stimulation will not be turned on. After the intervention, we will evaluate the difference in abdominal pain, the length of stay at the emergent observation ward, and the proportion of revisits with abdominal pain., Discussion: In Taiwan, medical expenditure is increasing annually because of the higher bed occupancy caused by acute abdominal pain in the hospital. We expect that the combined treatment of electroacupuncture and modern medical treatment will not only reduce bed occupancy and the length of ED stay but also effectively decrease the rate of readmission and revisits by 72 h. By means of electroacupuncture, the spiraling cost of health care can eventually be reduced., Trial Registration: ClinicalTrials.gov identifier: NCT03199495. Registered on 27 June 2017.

This study, an important groundwork for clinical tongue diagnosis and future traditional Chinese medicine (TCM) research, tested the hypothesis that some tongue features vary significantly between different gender and age groups by utilizing an automatic tongue diagnosis system (ATDS).A cross-sectional study of 1487 participants from a community-based population was performed. Study subjects with ages ranging from 20 to 92 were categorized into 3 groups: <40, 40 to 64, and ≥65 years old, and the subjects were also stratified according to gender. Tongue images were collected at the end of each normal health examination routine to further derive the relevant tongue features of every participant by using the ATDS developed by our team. There were a total of nine tongue features that were identified: tongue shape, tongue color, fur thickness, fur color, saliva, tongue fissure, ecchymosis, teeth mark, and red dot. The corresponding tongue features, demography, and physical/laboratory examination data were compared between different gender and age groups.Our study showed that, compared to females, males had enlarged tongue shape, thicker fur, more fissures and fewer teeth marks (all P < .001), and also had more red tongue color (P = .019), normal saliva (P = .001), more red dots (P = .005) and yellower fur (P = .014). In females, increasing age was associated with more enlarged tongue shape, thicker fur, yellower fur, more saliva, fissures and fewer teeth marks (all P < .001), more ecchymoses (P = .009), and more red tongue color (P = .023). These associations of age with more fissures, fewer teeth marks, fewer red dots (P < .001), median tongue shape (P = .029), and wet saliva (P = .014) were also evident in males, but other relationships were not clearly evident.Even though most of the common tongue features derived from a community-based population are consistent with TCM theory, yet some significantly gender- and age-dependent tongue characteristics were identified. These disparities in tongue features associated with gender or age shall be prudently taken into consideration in clinical tongue diagnosis and future TCM research.

High compliance with methadone maintenance therapy (MMT) is crucial to successful opioid abstinence in addicts. However, MMT has numerous side effects, including reductions in quality of life and quality of sleep. Many studies have demonstrated that electroacupuncture relieves withdrawal symptoms in opioid addicts. The present study was a case-control study. From January 2015 to September 2016, 106 patients undergoing MMT at a medical center in central Taiwan were recruited and separated into an electroacupuncture treatment group and a control group. Electroacupuncture was performed for 15 minutes twice weekly for 4 weeks. The electroacupuncture treatment group was discovered to have improved quality of life, especially in terms of vitality and mental health. Although electroacupuncture did not significantly improve sleep quality, we found that sleep quality was significantly improved once methadone dosage had been reduced. Electroacupuncture can improve quality of life in patients undergoing MMT. If methadone dosage can be reduced and electroacupuncture can be employed, both sleep and life quality can be improved., Competing Interests: The authors declare that they have no conflicts of interest.

Diabetes mellitus (DM) is a public problem closely associated with numerous oral complications, such as coated tongue, xerostomia, salivary dysfunction, etc. Tongue diagnosis plays an important role in clinical prognosis and treatment of diabetes in the traditional Chinese medicine (TCM). This study investigated discriminating tongue features to distinguish between type 2 DM and non-DM individuals through non-invasive TCM tongue diagnosis.The tongue features for 199 patients with type 2 DM, and 372 non-DM individuals, serving as control, are extracted by the automatic tongue diagnosis system (ATDS). A total of 9 tongue features, namely, tongue shape, tongue color, fur thickness, fur color, saliva, tongue fissure, ecchymosis, teeth mark, and red dot. The demography, laboratory, physical examination, and tongue manifestation data between 2 groups were compared.Patients with type 2 DM possessed significantly larger covering area of yellow fur (58.5% vs 22.5%, P < .001), thick fur (50.8% vs 29.2%, P < .001), and bluish tongue (P < .001) than those of the control group. Also, a significantly higher portion (72.7% vs 55.2%, P < .05) of patients with long-term diabetics having yellow fur color than the short-term counterparts was observed.The high prevalence of thick fur, yellow fur color, and bluish tongue in patient with type 2 DM revealed that TCM tongue diagnosis can serve as a preliminary screening procedure in the early detection of type 2 DM in light of its simple and non-invasive nature, followed by other more accurate testing process. To the best of our knowledge, this is the first attempt in applying non-invasive TCM tongue diagnosis to the discrimination of type 2 DM patients and non-DM individuals.

Increased matrix metalloproteinase 1 (MMP-1) expression is a feature of photo-aged skin. We investigated the effects of baicalein and sulphoraphane on ultraviolet B (UVB) irradiation-induced MMP-1 expression and apoptosis using human dermal fibroblasts. UVB irradiation not only increased MMP-1 expression, but also caused apoptosis. Both baicalein and sulphoraphane protected cells from UVB irradiation-induced apoptosis, but only baicalein inhibited MMP-1 expression. UVB irradiation activated 12-lipoxygenase, and its product, 12-hydroxyeicosatetraenoic acid, activated TRPV1 channels. The resulting UVB irradiation-induced Ca 2+ increase was blocked by the 12-lipoxygenase inhibitor baicalein and the TRPV1 blocker capsazepine, but not by the Nrf2 inducer sulphoraphane. UVB irradiation also increased ROS generation and decreased Nrf2 protein levels. UVB irradiation-induced MMP-1 expression was blocked by the Ca 2+ chelator BAPTA, by capsazepine and by TRPV1 silencing. However, induction was unaffected by the antioxidant N-acetylcysteine. ERK phosphorylation and JNK phosphorylation were induced by UVB irradiation, but only ERK phosphorylation was Ca 2+ sensitive. Increased MMP-1 expression was blocked by PD98059, but not by SP600125. Thus, increased MMP-1 expression is mediated by increased cytosolic Ca 2+ and ERK phosphorylation. UVB irradiation-induced ROS generation is also Ca 2+ sensitive, and UVB irradiation-induced apoptosis is caused by increased ROS. Thus, baicalein, by blocking the UVB irradiation-induced cytosolic Ca 2+ increase, protects cells from UVB irradiation-induced MMP-1 expression and apoptosis. In contrast, sulphoraphane, by decreasing cellular ROS, protects cells from only UVB-induced apoptosis. Thus, targeting 12-lipoxygenase may provide a therapeutic approach to improving the health of photo-aged human skin., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Copper is more likely than iron to generate reactive oxygen species (ROS) in a redox reaction due to its higher electrochemical reactivity. This study examined the effect of a newly synthesized Cu 2+ binding compound, (E)-2-(4-(dimethylamino)phenylimino)methyl)quinolin-8-ol (DPMQ), on ultraviolet B (UVB) irradiation-induced cytotoxicity in human dermal fibroblasts. DPMQ induced Cu 2+ influx as effectively as disulfiram, a Cu 2+ ionophore anticancer drug. However, disulfiram induced ROS generation, mitochondrial dysfunction, and apoptosis in fibroblasts in a Cu 2+ -dependent manner, whereas DPMQ was not only nontoxic, but protected cells against UVB irradiation-induced apoptosis in a Cu 2+ -independent manner. UVB irradiation induced a Ca 2+ -dependent increase in ROS generation, a decrease in Nrf2 levels, and activation of the mitochondrial apoptotic pathway, and these effects were prevented by DPMQ, which also increased Nrf2 nuclear translocation in a Cu 2+ -independent manner. UVB irradiation activated 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid (12-HETE), a product of 12-lipoxygenase, activated the TRPV1 channel. DMPQ did not act as a Ca 2+ chelator, but inhibited the cytosolic Ca 2+ increase induced by 12-HETE or capsaicin, but not that induced by bradykinin or ATP. Blockade of Ca 2+ influx by pharmacological inhibition or silencing of the TRPV1 channel or chelation of cytosolic Ca 2+ inhibited the UVB irradiation-induced Nrf2 reduction, ROS generation, mitochondrial dysfunction, and apoptosis. Taken together, our results suggest that Ca 2+ influx via the TRPV1 channel is responsible for UVB irradiation-induced cytotoxicity and that DPMQ protects cells against UVB irradiation by inhibiting the TRPV1 channel and stabilizing Nrf2, and could thus be a potentially useful compound for the treatment of free radical-induced diseases., (© 2018 Wiley Periodicals, Inc.)

The allocation of mental workload is critical to maintain cognitive-motor performance under various demands. While mental workload has been investigated during performance, limited efforts have examined it during cognitive-motor learning, while none have concurrently manipulated task difficulty. It is reasonable to surmise that the difficulty level at which a skill is practiced would impact the rate of skill acquisition and also the rate at which mental workload is reduced during learning (relatively slowed for challenging compared to easier tasks). This study aimed to monitor mental workload by assessing cortical dynamics during a task practiced under two difficulty levels over four days while perceived task demand, performance, and electroencephalography (EEG) were collected. As expected, self-reported mental workload was reduced, greater working memory engagement via EEG theta synchrony was observed, and reduced cortical activation, as indexed by progressive EEG alpha synchrony was detected during practice. Task difficulty was positively related to the magnitude of alpha desynchrony and accompanied by elevations in the theta-alpha ratio. Counter to expectation, the absence of an interaction between task difficulty and practice days for both theta and alpha power indicates that the refinement of mental processes throughout learning occurred at a comparable rate for both levels of difficulty. Thus, the assessment of brain dynamics was sensitive to the rate of change of cognitive workload with practice, but not to the degree of difficulty. Future work should consider a broader range of task demands and additional measures of brain processes to further assess this phenomenon., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

A novel ERP approach was proposed to index variations in mental workload, particularly in attentional reserve, which is complementary to EEG spectral content thought to reflect mental effort. To our knowledge, no study has assessed mental effort and attentional reserve simultaneously in EEG gel-based and, importantly, dry systems, which are particularly well suited for real-world settings. Therefore, by systematically considering ERP, EEG spectral, and importantly the combination of both, this study examined if a small set of dry EEG electrodes could detect changes in both spectral and ERP metrics to assess the mental workload under various challenges with a similar fidelity to their gel-based counterparts in a laboratory setting. By employing both EEG gel-based and dry systems, the ERP and spectral markers were computed while participants executed a visuomotor task under three levels of challenge. For both EEG systems, more challenging levels of difficulty were associated with concomitant changes in ERP amplitude, and spectral power reflected a reduction of the attentional reserve and an increase in cognitive-motor effort, respectively. Those variations in attentional reserve and cognitive-motor effort collectively indexed mental workload with nearly identical fidelity for both gel-based and dry EEG systems. These findings promise to assess the mental workload in situations where the use of dry EEG systems could be advantageously employed to examine human cognitive-motor performance., (© 2018 Society for Psychophysiological Research.)

While the concepts of cognitive workload and attentional reserve have been thought to have an inverse relationship for some time, such a relationship has never been empirically tested. This was the purpose of the present study. Aspects of the electroencephalogram were used to assess both cognitive workload and attentional reserve. Specifically, spectral measures of cortical activation were used to assess cognitive workload, while amplitudes of the event-related potential from the presentation of unattended "novel" sounds were used to assess attentional reserve. The relationship between these two families of measures was assessed using canonical correlation. Twenty-seven participants performed a flight simulator task under three levels of challenge. Verification of manipulation was performed using self-report measures of task demand, objective task performance, and heart rate variability using electrocardiography. Results revealed a strong, negative relationship between the spectral measures of cortical activation, believed to be representative of cognitive workload, and ERP amplitudes, believed to be representative of attentional reserve. This finding provides support for the theoretical and intuitive notion that cognitive workload and attentional reserve are inversely related. The practical implications of this result include improved state classification using advanced machine learning techniques, enhanced personnel selection/recruitment/placement, and augmented learning/training., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background . Patients suffering from stroke exhibit different levels of capability in retroflex tongues, in our clinical observation. This study aims to derive the association of tongue retroflexibility with the degree of severity for stroke patients. Methods . All ischemic stroke patients were collected from August 2010 to July 2013 in the Stroke Center, Changhua Christian Hospital, Taiwan. All participants underwent medical history collection and clinical examination, including tongue images captured by ATDS. Statistical analysis was performed to compare the differences of ischemic stroke patients with and without retroflex tongue. Result . Among the total of 308 cases collected, 123 patients cannot retroflex their tongues, that is, the non-RT group. The length of stay in the non-RT group, 32.0 ± 21.5, was longer than those of the RT counterparts, 25.9 ± 14.4 ( p value: 0.007). The NIHSS on admission, 14.1 ± 7.8 versus 8.9 ± 5.2, was higher and the Barthel Index upon admission, 18.6 ± 20.7 and 35.0 ± 24.2, was lower for the non-RT patients than that of the RT counterparts. Also, the non-RT patients account for 60.2% and 75.6% for Barthel Index ≤ 17 and NIHSS ≥ 9, respectively. Conclusion . The stroke patients in non-RT group showed significantly poor prognosis and were more serious in the degree of severity and level of autonomy than RT group, indicating that the ability to maneuver tongue retroflex can serve as a simple, reliable, and noninvasive means for the prognosis of ischemic stroke patients., Competing Interests: All authors declare that they have no conflict of interests.

Diabetes mellitus (DM) is associated with a state of chronic hyperglycemia with a highly increased risk of vascular complications. The current study aimed to investigate microcirculation abnormalities in patients with type 2 DM and those with pre-DM using nailfold videocapillaroscopy (NVC) and evaluate the possible correlation with microvascular complications.A total of 115 patients with type 2 DM, 41 patients with pre-DM, and 37 healthy subjects without diabetes were enrolled. All subjects underwent NVC to evaluate capillary density, length, morphology, distribution, presence of enlarged loops or hemorrhages, and blood flow. NVC score was used to quantitate the aforementioned characteristics.Patients with type 2 DM showed significantly increased alterations including reduced capillary length (29.6%), irregular distribution (35.7%), and abnormal morphology (59.1%), while the corresponding NVC scores were comparable to those of control subjects. In addition, subjects with pre-DM had a significantly higher NVC score and greater alterations in distribution (26.8%) and morphology (48.8%) than control subjects. NVC score was positively correlated with diabetic peripheral neuropathy (DPN) and the number of microvascular complications.NVC identified a high frequency of microcirculation abnormalities in subjects with pre-DM or type 2 DM compared to those in the control group. NVC score was also capable of detecting microvascular complications in patients with type 2 DM and was correlated with DPN and the number of microvascular complications., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Diabetes mellitus (DM) is a hypercoagulable state and is associated with highly increased risk of vascular complications. In the theory of traditional Chinese medicine (TCM), these vascular complications are classified as blood stasis. Diagnosis of the tongue plays an important role in TCM; a bluish tongue, petechiae, and engorged sublingual collateral vessels are manifestations of blood stasis. This study aimed to characterize the tongue manifestations of blood stasis and derive a relationship between blood stasis and vascular disorders in patients with type 2 DM., Method: We conducted a cross-sectional study of 140 patients with type 2 DM, and compared demography, laboratory, physical examination, ankle brachial index(ABI), brachial-ankle pulse wave velocity (ba-PWV), and tongue manifestation datas. An automatic tongue diagnosis system was used to capture tongue images and characterize clinical tongue manifestations., Results: A bluish or petechiae tongue was assoicated with a significant decrease in high-density lipoprotein level, and bluish tongue was associated with significant increase in blood triglyceride in patients with type 2 DM. On assessing arterial stiffness, patients with a petechiae tongue had a higher ba-PWV for both sides (L:1938.41 ± 469.54 cm/sec v.s.1723.99 ± 302.16, p = 0.02; R:1937.28 ± 405.55 v.s.1741.99 ± 325.82, p = 0.03)., Conclusion: Blood stasis, particularly a tongue with petechiae, may be associated with arterial stiffness in patients with type 2 DM. Furthermore, tongue diagnosis could detect blood stasis relevant to DM and could serve as a feasible predictor for DM.

Shaking the tea leaves is the key manipulation to making oolong tea. It contributes to the formation of flavor and fragrance in oolong tea. The dynamic variations of catechins and volatile organic compounds (VOCs) during the shaking process were investigated. The results showed that the contents of epicatechin, epigallocatechin, epicatechin gallate (ECG), and epigallocatechin gallate (EGCG) first decreased after the shaking and then increased to the initial value before the next shaking. Geraniol, linalool and its oxides, and phenylethyl alcohol showed similar variations. The contents of trans-β-ocimene, 1H-indole, and 3-hexenyl hexanoate increased after the second or third shaking (the late fermentation stage). However, the contents of aldehydes showed an opposite trend to other VOCs. The abundance of phenylethyl alcohol was positively related to the content of ECG and EGCG ​during fermentation, whereas the abundance of cis-3-hexenal was negatively related to the content of ECG. The correlations between catechin and VOCs indicated that shaking affected the chemical transformation of the compounds in oolong tea., (Copyright © 2016. Published by Elsevier B.V.)

Andrographolide (ANDRO) is a lactone diterpenoid compound present in the medicinal plant Andrographis paniculata which is clinically applied for multiple human diseases in Asia and Europe. The pharmacological activities of andrographolide have been widely demonstrated, including anti-inflammation, anti-cancer and hepatoprotection. However, the pharmacological mechanism of andrographolide remains unclear. Therefore, further characterization on the kinetics and molecular targets of andrographolide is essential. In this study, we described the synthesis and characterization of a novel fluorescent andrographolide derivative (ANDRO-NBD). ANDRO-NBD exhibited a comparable anti-cancer spectrum to andrographolide: ANDRO-NBD was cytotoxic to various types of cancer cells and suppressed the migration activity of melanoma cells; ANDRO-NBD treatment induced the cleavage of heat shock protein 90 (Hsp90) and the downregulation of its client oncoproteins, v-Src and Bcr-abl. Notably, ANDRO-NBD showed superior inhibitory effects to andrographolide in all anticancer assays we have performed. In addition, ANDRO-NBD was further used as a fluorescent probe to investigate the uptake kinetics, cellular distribution and molecular targets of andrographolide. Our data revealed that ANDRO-NBD entered cells rapidly and its fluorescent signal could be detected in nucleus, cytoplasm, mitochondria, and lysosome. Moreover, we demonstrated that ANDRO-NBD was covalently bound to several putative target proteins of andrographolide, including NF-κB and hnRNPK. In summary, we developed a fluorescent andrographolide probe with comparable bioactivity to andrographolide, which serves as a powerful tool to explore the pharmacological mechanism of andrographolide.

Metabolic syndrome is a morbid condition, which is manifested by central obesity, abnormal glucose tolerance, lipodystrophy, and hypertension. Traditional Chinese medicine (TCM) clarifies that obesity is classified as phlegm-dampness. It is often accompanied with qi stagnation and blood stasis. One hundred and two overweight adults, who did not receive lipid-lowering drugs, were enrolled for analysis. The exclusion criteria were adults having malignancy disease, DM, and renal disease or who were pregnant or lactating. The study was divided into two groups: metabolic syndrome group (MetS) and nonmetabolic syndrome group (nMetS). The modern tongue analysis and heart rate variability devices for data analysis and Council on Nutrition Appetite Questionnaire (CNAQ) for appetite evaluation were used. Obesity patients with metabolic syndrome obviously have lower CNAQ score. The 6 items of CNAQ between two groups have significant difference in variation (P < 0.001). The nMetS average was above 28 scores (96%) and the MetS was all in 17-28 scores. The tongue appearance showed that MetS group have white coating different from the nMetS group with white and yellow coating (P < 0.05). However the HRV is not different from nMetS group significantly. Our results try to explore the relationship between the TCM pattern, nutrition appetite, and heart rate variability in metabolic syndrome patients.