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Abstract Background Japanese encephalitis (JE) is a leading cause of childhood viral encephalitis both at global level and in China. Vaccination is recommended as a key strategy to control JE. In China most JE cases have been reported in southwest provinces, which include Yunnan. In this study, we quantify the epidemiological shift of JE in Yunnan Province from 2005 to 2017, covering before and after the introduction of JE vaccination into routine Expanded Program on Immunization (EPI) in 2007. Methods We used routinely collected data in the case-based JE surveillance system from 2005 through 2017 in Yunnan. Cases were reported from hospital and county-level Centers for Disease Control in line with the National JE Surveillance Guideline. Epidemiological data were extracted, analysed and presented in appropriate ways. Immunization coverage was estimated from actual JE doses administered and new births for each year. Results A total 4780 JE cases (3077 laboratory-confirmed, 1266 clinical and 437 suspected) were reported in the study period. Incidence of JE (per 100 000 population) increased from 0.95 in 2005 to 1.69 in 2007. With increase in vaccination coverage, incidence rates decreased steadily from 1.16 in 2009 to 0.17 in 2017. However, seasonality remained similar across the years, peaking in June–September. Banna (bordering Myanmar and Laos), Dehong (bordering Myanmar), and Zhaotong (an inland prefecture) had the highest incidence rates of 2.3, 1.9, and 1.6, respectively. 97% of all cases were among local residents. As vaccination coverage increased (and incidence decreased), proportion of JE cases among children

Fracture nonunion, a serious bone fracture complication, remains a challenge in clinical practice. Although the molecular pathogenesis of nonunion remains unclear, a better understanding may provide better approaches for its prevention, diagnosis and treatment at the molecular level. This review tries to summarise the progress made in studies of the pathogenesis of fracture nonunion. We discuss the evidence supporting the concept that the development of nonunion is related to genetic factors. The importance of several cytokines that regulate fracture healing in the pathogenesis of nonunion, such as tumour necrosis factor-α, interleukin-6, bone morphogenetic proteins, insulin-like growth factors, matrix metalloproteinases and vascular endothelial growth factor, has been proven in vitro, in animals and in humans. Nitric oxide and the Wnt signalling pathway also play important roles in the development of nonunion. We present potential strategies for the prevention, diagnosis and treatment of nonunion, and the interaction between genetic alteration and abnormal cytokine expression warrants further investigation. The translational potential of this article: A better understanding of nonunion molecular pathogenesis may provide better approaches for its prevention, diagnosis and treatment in clinical practice. Keywords: Cytokine, Gene, Molecular pathogenesis, Nonunion

Background/Aims: Newly identified IL-10-producing regulatory B cells (Bregs) have been shown to play an important role in the suppression of immune responses. Chronic immune activation participates in the pathogenesis of dilated cardiomyopathy (DCM) but whether Bregs are involved in its development remains unclear. We aimed to investigate the circulating frequency and function of Bregs in DCM. Methods: In total, 35 DCM patients (20 men and 15 women) and 44 healthy controls (23 men and 21 women) were included in the experiment, and the frequency of Bregs was detected using flow cytometry. Results: According to our results, the frequency of circulating IL-10-producing Bregs was significantly lower in DCM patients compared with healthy controls. Furthermore, the CD24hiCD27+ B cell subset in which IL-10-producing Bregs were mainly enriched from DCM patients showed impaired IL-10 expression and a decreased ability to suppress the TNF-α production of CD4+CD25- Tconv cells and to maintain Tregs differentiation. Correlation analysis showed that the frequency of IL-10-producing Bregs and the suppressive function of CD24hiCD27+ B cells were positively correlated with left ventricular ejection fraction and negatively correlated with NT-proBNP in DCM patients. Conclusions: In conclusion, the reduced frequency and impaired functions suggest a potential role of Bregs in the development of DCM.

Abstract Understanding the epidemiology and risk factors of adverse drug events (ADEs) in pediatric inpatient is essential if we are to prevent, reduce or ameliorate the harm experienced. The Global Trigger Tool (GTT) is a method of retrospective medical record review that measures harm in hospitalized children. We employed a three-stage retrospective chart review of random samples of 1800 pediatric inpatients discharged from January 2013 to December 2015. 31 kinds of pediatric-specific triggers were made based on the previous trigger tool studies developed for use in adult or pediatric. Positive predictive value (PPV) of individual triggers, as well as ADEs detection rates were calculated. Stepwise logistic regression was performed to investigate risk factors associated with ADEs. Of 1746 patients, detected in 221 patients (12.7%) with 247 ADEs. The PPV of the trigger tool was 13.3%. Of the 247 ADEs, 82.6% were identified as category E, 11.7% category F and 5.7% category H. The pediatric-focused trigger tool is a feasible and useful tool for detecting pediatric ADEs. Especially for patients who have had more drugs, more doses or more admissions which needs to be closely monitored as triggers to improve the safety.

Resistive switching characteristics of hafnium oxide are studied for possible nonvolatile memory device applications. The HfOx films with different oxygen contents are deposited by rf magnetron sputtering under different O2 flow rates. The films are amorphous, and the stoichiometric of the film is improved by increasing the O2 flow rate. Current-voltage characteristics of the TiN/HfOx/ITO device are investigated with 1 mA compliance. The bipolar resistive switching behavior is observed for the TiN/HfOx/ITO structure, and the resistive switching mechanism of the TiN/HfOx/ITO structure is explained by trap-controlled space charge limit current conduction. [ABSTRACT FROM AUTHOR]

The structural, electronic and mechanical properties of cubic SrHfO3 under hydrostatic pressure up to 70GPa are investigated using the first-principles density functional theory (DFT). The calculated lattice parameter, elastic constants and mechanical properties of cubic SrHfO3 at zero pressure are in good agreement with the available experimental data and other calculational values. As pressure increases, cubic SrHfO3 will change from an indirect band gap (Γ-R) compound to a direct band gap (Γ-Γ) compound. Charge densities reveal the coexistence of covalent bonding and ionic bonding in cubic SrHfO3. With the increase of pressure, both the covalent bonding (HfO) and ionic bonding (SrO) are strengthened. Cubic SrHfO3 is mechanically stable when pressure is lower than 55.1GPa, whereas that is instable when pressure is higher than 55.1GPa. With the increasing pressure, enthalpy, bulk modulus, shear modulus and Young's modulus increase, whereas the lattice parameter decreases. Moreover, cubic SrHfO3 under pressure has higher hardness and better ductility than that at zero pressure. [ABSTRACT FROM AUTHOR]

Background/Objective: As a widely used absorbable suture with antibacterial property, triclosan- coated polyglactin suture (Vicryl Plus) has been extensively utilized to reduce the occurrence rate of surgical site infections (SSIs) in orthopaedic surgery. However, the potential toxicity and side-effects of triclosan raised increasing concerns about its biological safety. This study aimed to investigate the antimicrobial activity and biocompatibility of quaternised chitosan-coated Vicryl suture (HV) both in vitro and in vivo. Methods: In this study, a modified chitosan derivate, (hydroxypropyltrimethyl ammonium chloride chitosan, HACC), was coated over the surface of the absorbable Vicryl suture. Two standard bacteria strains, Staphylococcus epidermidis (ATCC35984) and methicillin-resistant Staphylococcus aureus (ATCC43300), were selected to evaluate bacterial adhesion and biofilm formation on the sutures at 6, 24 and 48 h in vitro. Additionally, human skin-derived fibroblasts cells were used to test the cytocompatibility of the sutures. Furtherly, sutures contaminated with methicillin-resistant S. aureus were implanted subcutaneously in SD rats in order to confirm the in vivo antibacterial performance and biocompatibility. Results: We found that HACC-coated Vicryl suture (HV) exhibited significant anti-bacterial effects on the two tested strains. The bacterial attachment and biofilm formation on the surface of the HV sutures were found to be comparable to that of Vicryl Plus sutures (VP). Moreover, all the four tested sutures presented good cytocompatibility with human skin-derived fibroblasts cells. Histology and immunohistochemistry results indicated that the infections and inflammations were significantly inhibited around the HV and VP sutures. Conclusion: In general, the present study demonstrated that the quaternised chitosan coating is a flexible and cost-effective alternative strategy to prevent the suture related surgical site infections in orthopaedic practices.

Background/Objective: Plasma-sprayed titanium coating (TC) with rough surfaces has been successfully applied in hip or knee prostheses. This study aimed to investigate the osteoconduction and osseointegration of Type I collagen covalently immobilised on TC (TC-AAC) compared with those of TC. Methods: In vitro, the migration of human mesenchymal stem cells (hMSCs) on TC and TC-AAC was observed by scanning electron microscopy and visualised fluorescent live/dead assay. In vivo, a rabbit model with femur condyle defect was employed, and implants of TC and TC-AAC were embedded into the femur condyles. Results: Collagen immobilised on TC could promote hMSCs' migration into the porous structure of the TC. Micro computed tomography images showed that bone trabeculae were significantly more abundant around TC-AAC implants than around TC implants. Fluorescence micrographs indicated more active new-bone formation around implants in the TC-AAC group than in the TC group. The measurement of bone–implant contact on histological sections indicated significantly greater osteointegration around TC-AAC implants than around TC ones. Conclusion: Immobilised Type I collagen could improve the osteoconduction and osseointegration of TC implants.

Background/Aims: Recent studies have shown that circulating microRNAs (miRNAs) are emerging as promising biomarkers for cardiovascular diseases. This study aimed to determine whether miR-19b-3p, miR-134-5p and miR-186-5p can be used as novel indicators for acute myocardial infarction (AMI). Methods: To investigate the kinetic expression of the three selected miRNAs, we enrolled 18 patients with AMI and 20 matched controls. Plasma samples were collected from each participant, and total RNA was extracted. Quantitative real-time PCR and ELISA assays were used to investigate the expression of circulating miRNAs and cardiac troponin I (cTnI), respectively. Plasma samples from another age- and gender-matched cohort were collected to investigate the impact of medications for AMI on the expression of the selected miRNAs. Results: Levels of plasma miR-19b-3p, miR-134-5p and miR-186-5p were significantly increased in early stage of AMI. Plasma miR-19b-3p and miR-134-5p levels reached peak expression immediately after admission (T0), whereas miR-186-5p achieved peak expression at 4 h after T0. All of these times were earlier than the peak for cTnI (8 h after T0). In addition, all three miRNAs were positively correlated with cTnI. Receiver Operating Characteristic (ROC) analysis indicated that each single miRNA showed considerable diagnostic efficiency for predicting AMI. Furthermore, combining all three miRNAs in a panel increased the efficiency of distinguishing between patients with AMI and controls. Moreover, we found that heparin and medications for AMI did not impact the expression of these circulating miRNAs. Conclusion: Circulating miR-19b-3p, miR-134-5p and miR-186-5p could be considered promising novel diagnostic biomarkers for the early phase of AMI.

The thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3,628 CAD cases and 3,776 controls using common variants in the genes TSLP, interleukin 7 receptor (IL7R), and TSLPR. Three common variants in the TSLP/TSLPR axis were significantly associated with CAD in a Chinese Han population [rs3806933T in TSLP, Padj = 4.35 × 10−5, odds ratio (OR) = 1.18; rs6897932T in IL7R, Padj = 1.13 × 10−7, OR = 1.31; g.19646A>GA in TSLPR, Padj = 2.04 × 10−6, OR = 1.20]. Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence TSLP and IL7R expression, respectively. Furthermore, the “T” allele of rs3806933 might increase plasma TSLP levels (R2 = 0.175, P

Osteosarcoma is the most common bone cancer in children and adolescents. Tissue inhibitors of metalloproteinases (TIMPs)-3 inhibit matrix metalloproteinases to limit extracellular matrix degradation. Cisplatin is a widely used chemotherapeutic drug used to cure osteosarcoma. Interleukin (IL)-6 and TIMP3 play important roles in the drug resistance of osteosarcoma; however, their relationship in this process remains unclear. This study aimed to explore the role of TIMP3 in the cisplatin sensitivity of osteosarcoma and its underlying molecular mechanisms in vitro and in vivo. We compared TIMP3 expression levels between patients with cisplatin-sensitive and -insensitive osteosarcoma. TIMP3 was overexpressed or knocked down in the Saos2-lung cell line, which is a Saos2 subtype isolated from pulmonary metastases that has higher cisplatin chemoresistance than Saos2 cells. IL-6 expression, cell proliferation, sensitivity to cisplatin, migration, and invasion after TIMP3 overexpression or knockdown were determined. The same experiments were performed using MG63 and U2OS cells. Subsequently, luciferase-labeled Saos2-lung cells overexpressing TIMP3 were injected into the tibiae of nude mice treated with cisplatin. The results showed that IL-6 inhibited TIMP3 expression in Saos2 and Saos2-lung cells via signal transducer and activator of transcription 3 (STAT3) activation. STAT3 knockdown reversed the effect of IL-6. The expression of TIMP3 was higher in patients with cisplatin-sensitive osteosarcoma than in those with insensitive osteosarcoma. IL-6 expression was downregulated upon TIMP3 overexpression, and upregulated by TIMP3 knockdown. TIMP3 overexpression suppressed cell proliferation and enhanced cisplatin sensitivity by activating apoptosis-related signal pathways and inhibiting IL-6 expression in vitro and in vivo. In conclusion, cisplatin sensitivity correlated positively with TIMP3 expression, which is regulated by the IL-6/TIMP3/caspase pathway. The TIMP3 pathway could represent a target for new therapies to treat osteosarcoma.

Background: Interleukin (IL)-17A, a newly identified cytokine, may participate in the transition of a stable plaque into an unstable plaque. Macrophages play a critical role in the destabilization of atherosclerotic plaque. Methods: RAW 264.7 cells were stimulated with IL-17A. The mRNA expression of inflammatory cytokines was determined by RT-PCR. The cytokines production in the supernatants was measured by ELISA. Small interfering RNA (siRNA) was used to confirm that IL-17A-induced pro-inflammatory cytokines production via IL-17RA signaling. The western blot assay was used to detect the phosphorylation of MAPKinases including p38 and ERK1/2. The DNA binding activity of nuclear factor NF-κB and AP-1 were detected by EMSA. Results: IL-17A induced the production of pro-inflammatory cytokines in macrophages in a time- and dose-dependent manner, such as tumor necrosis factor (TNF)-a, IL-1ß, and IL-6. Meanwhile, IL-17A resulted in the phosphorylation of p38 and ERK1/2 and increased DNA-binding activity of NF-κB and AP-1. Pharmacological inhibitors of p38 and ERK1/2 partly attenuated IL-17A-induced TNF-a, IL-1ß, and IL-6 production. Either NF-κB inhibitor or AP-1 inhibitor also partly decreased the IL-17A-induced cytokine production. Conclusions: IL-17A induces pro-inflammatory cytokines production in macrophages via MAPKinases, NF-κB and AP-1 pathway.

Abstract T lymphocytes exhibit pro‐inflammatory or anti‐inflammatory activities in obesity and diabetes, depending on their subtypes. Guanidine‐rich immunosuppressive oligodeoxynucleotides (ODNs) effectively control Th1/Th2‐cell counterbalance. This study reveals a non‐toxic regulatory ODN (ODNR01) that inhibits Th1‐ and Th17‐cell polarization by binding to STAT1/3/4 and blocking their phosphorylation without affecting Th2 and regulatory T cells. ODNR01 improves glucose tolerance and insulin sensitivity in both diet‐induced obese (DIO) and genetically generated obese (ob/ob) mice. Mechanistic studies show that ODNR01 suppresses Th1‐ and Th17‐cell differentiation in white adipose tissue, thereby reducing macrophage accumulation and M1 macrophage inflammatory molecule expression without affecting M2 macrophages. While ODNR01 shows no effect on diabetes in lymphocyte‐free Rag1‐deficient DIO mice, it enhances glucose tolerance and insulin sensitivity in CD4+ T‐cell‐reconstituted Rag1‐deficient DIO mice, suggesting its beneficial effect on insulin resistance is T‐cell‐dependent. Therefore, regulatory ODNR01 reduces obesity‐associated insulin resistance through modulation of T‐cell differentiation.

In this study, we investigated the hypothesis that regulatory T cells (Treg) are involved in the immunomodulatory effects of statins on rheumatoid arthritis (RA) patients. The 12-week study cohort consisted of 55 RA patients and 42 control subjects allocated to either a group treated with atorvastatin (AT) (20 mg/day) or a non-AT group. Treg numbers, suppressive function, serum inflammatory markers, and disease activity were evaluated before and after the therapy. Furthermore, the effects of AT on the frequency and suppressive function of Treg were determined in vitro. Our data revealed that the suppressive function of Treg from RA patients significantly decreased compared with that of control subjects. AT significantly reduced erythrosedimentation, C-reactive protein, and disease activity. Concomitantly, Treg numbers and suppressive functions were significantly improved by AT. Consistent with the in vivo experiments, AT promoted the generation of Treg from primary T cells and enhanced preexisting Treg function in vitro. Moreover, we showed that PI3K-Akt-mTOR and ERK signal pathways were involved in the induction of Treg by AT. In conclusion, AT significantly increased Treg numbers and restored their suppressive function in the RA patients, and this may be relevant in the modulation of uncontrolled inflammation in this disorder.

Animal studies suggest that regulatory T (T(reg)) cells play a beneficial role in ventricular remodeling and our previous data have demonstrated defects of T(reg) cells in patients with chronic heart failure (CHF). However, the mechanisms behind T(reg-)cell defects remained unknown. We here sought to elucidate the mechanism of T(reg-)cell defects in CHF patients.We performed flow cytometry analysis and demonstrated reduced numbers of peripheral blood CD4(+)CD25(+)FOXP3(+)CD45RO(-)CD45RA(+) naïve T(reg) (nT(reg)) cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+)CD45RA(-) memory T(reg) (mT(reg)) cells in CHF patients as compared with non-CHF controls. Moreover, the nT(reg)/mT(reg) ratio (p