Titanium-coated PEEK Versus Uncoated PEEK Cages in Lumbar Interbody Fusion: A Systematic Review and Meta-analysis of Randomized Controlled Trial.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: This study was performed to compare the fusion and subsidence rate of titanium-coated polyetheretherketone (Ti-PEEK) versus polyetheretherketone (PEEK) cages after lumbar fusion and to investigate the clinical effect on patient-reported outcomes (PROMs). SUMMARY OF BACKGROUND DATA: Ti-PEEK cages have been developed to combine the advantages of both titanium alloy and PEEK, but whether they are superior to uncoated PEEK cages in bone fusion is still inconclusive. METHODS: PubMed, EMBASE, ISI Web of Science, CENTRAL, and CNKI were searched to identify randomized controlled trials that compared the efficacy of Ti-PEEK and PEEK cages in lumbar fusion. Difference in fusion rate and subsidence rate was indicated by risk ratio and its associated 95% confidence interval (95% confidence interval). Mean difference was calculated for Oswestry Disability Index and visual analogue scale for low back pain. Subgroup analysis was performed by time course after the surgery. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to evaluate the certainty of evidence. RESULTS: Four randomized controlled trials involving 325 patients (160 patients in Ti-PEEK group and 165 patients in PEEK group) that underwent lumbar fusion were included by our current study. Low to moderate evidence suggested that Ti-PEEK and PEEK cages exhibited equivalent fusion rate and subsidence rate at any follow-up time. Low to moderate evidence suggested that there was no difference in PROMs except for visual analogue scale measured at 6 months (mean difference: -0.57, 95% confidence interval -0.94, -0.21; P =0.002) but the difference was not clinically relevant according to the minimal clinically important difference. CONCLUSION: Low to moderate evidence showed that Ti-PEEK and PEEK had equivalent effect in bone fusion and cages subsidence at any follow-up time after lumbar fusion surgeries. Low to moderate evidence showed no clinically important difference in PROMs.

A Novel Low Air Pressure-Assisted Approach for the Construction of Cells-Decellularized Tendon Scaffold Complex.

OBJECTIVE: The goal of this study was to develop a decellularized tendon scaffold (DTS) and repopulate it with adipose-derived stem cells (ADSCs) assisted by low air pressure (LP). METHODS: The porcine superficial flexor tendons were processed into the DTSs using a combination of physical, chemical, and enzymatic treatments. The effectiveness of decellularization was verified by histological analysis and DNA quantification. The properties of the DTSs were evaluated by quantitative analysis of biochemical characterization, porosimetry, in vitro biocompatibility assessment, and biomechanical testing. Subsequently, the ADSCs-DTS complexes were constructed via cell injection assisted by LP or under atmospheric pressure. The differences in cell distribution, biomechanical properties, and the total DNA content were compared by histological analysis, biomechanical testing, and DNA quantification, respectively. RESULTS: Histological analysis confirmed that no cells or condensed nuclear materials were retained within the DTSs with widened interfibrillar space. The decellularization treatment resulted in a significant decrease in the content of DNA and glycosaminoglycans, and a significant increase in the porosity. The DTSs were cytocompatible in vitro and did not show reduced collagen content and inferior biomechanical properties compared with the fresh-frozen tendons. The assistance of LP promoted the broader distribution of cells into the adjacent interfibrillar space and cell proliferation in DTSs. The biomechanical properties of the scaffolds were not significantly affected by the recellularization treatments. CONCLUSION: A novel LP-assisted approach for the construction of cells-DTS complex was established, which could be a methodological foundation for further bioreactor and in vitro studies.

The efficacy of platelet rich plasma on anterior cruciate ligament reconstruction: a systematic review and meta-analysis.

Anterior cruciate ligament (ACL) rupture is a common musculoskeletal injury, most frequently affecting young and physically active patients. Platelet-rich plasma (PRP) has been widely used in ACL reconstruction to augment the graft healing. However, high-level studies addressing its clinical efficacy could not reach a consensus. In this study, we assess the efficacy of PRP on pain relief, functional improvement along with radiological changes in patients who underwent ACL reconstruction. We performed comprehensive literature search and included 17 RCTs containing 970 participants who underwent ACL reconstruction. The combined data showed significant difference between PRP and control with regard to VAS score (MD: -1.12, 95% CI -1.92, -0.31; P = .007), subjective IKDC score (MD: 6.08, 95% CI 4.39, 7.77; P < .00001) and Lysholm score (MD: 8.49, 95% CI 1.63, 15.36; P = .02) by postoperative 6 months, but only pain reduction was deemed clinically important. At the end of one year's follow-up, no clinically meaningful improvement in VAS (MD: -0.47, P = .04), subjective IKDC score (MD: 3.99, P = .03), Lysholm score (MD: 2.30, P = .32), objective IKDC score (RR: 1.03, P = .09) and knee joint laxity (MD: 0.17, P = .28) was seen. In terms of radiological findings, about one-third of the studies favored PRP to facilitate the graft healing, improve the harvest site morbidity and prevent tunnel widening. In summary, moderate quality of evidence suggested that PRP could provide short-term but not long-term clinically important pain reduction.

Physalin A Inhibits MAPK and NF-κB Signal Transduction Through Integrin αVß3 and Exerts Chondroprotective Effect.

Osteoarthritis (OA) is a common articular ailment presented with cartilage loss and destruction that is common observed in the elderly population. Physalin A (PA), a natural bioactive withanolide, exerts anti-inflammatory residences in more than a few diseases; however, little is known about its efficacy for OA treatment. Here, we explored the therapeutic effects and potential mechanism of PA in mouse OA. After the in vitro administration of PA, the expression of inflammation indicators including inducible nitric oxide synthase and cyclooxygenase-2 was low, indicating that PA could alleviate the IL-1ß-induced chondrocyte inflammation response. Moreover, PA reduced IL-1ß-induced destruction of the extracellular matrix by upregulating the gene expression of anabolism factors, including collagen II, aggrecan, and sry-box transcription factor 9, and downregulating the gene expression of catabolic factors, including thrombospondin motif 5 and matrix metalloproteinases. In addition, the chondroprotective effect of PA was credited to the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, in vivo experiments showed that intra-articular injection of PA could alleviate cartilage destruction in a mouse OA model. However, the anti-inflammatory, anabolism enhancing, catabolism inhibiting, and MAPK and NF-κB signaling pathway inhibiting properties of PA on IL-1ß-induced chondrocytes could be reversed when integrin αVß3 is knocked down by siRNA. In conclusion, our work demonstrates that PA exhibits a chondroprotective effect that may be mediated by integrin αVß3. Thus, PA or integrin αVß3 might be a promising agent or molecular target for the treatment of OA.

COL12A1 rs970547 Polymorphism Does Not Alter Susceptibility to Anterior Cruciate Ligament Rupture: A Meta-Analysis.

Objective: Currently available evidence regarding the association between collagen type XII α1 (COL12A1) polymorphism and risk of anterior cruciate ligament rupture (ACLR) remains elusive. The aim of our present study was to assess the association between COL12A1 rs970547 polymorphism and ACLR risk. Methods: Five online databases, namely, PubMed, EMBASE, ISI Web of Science, CENTRAL, and CNKI, were searched from their inception data up to December 2020 to identify relative observational studies. The methodological quality of each individual study was evaluated using the Newcastle-Ottawa Scale (NOS). The "model-free approach" was employed to estimate the magnitude of effect of COL12A1 rs970547 polymorphism on ACLR, and the association was expressed using odds ratio (OR) and its associated 95% confidence interval (95% CI). Subgroup analysis was performed by ethnicity and sex of included subjects. Results: Eight studies involving 1,477 subjects with ACLR and 100,439 healthy controls were finally included in our study. The methodological quality of included studies was deemed moderate to high based on NOS scores. The "model-free" approach suggested no genotype differences between ACLR and healthy control for the rs970547 polymorphism, but we still used the allele model to present the combined data. Under the random-effect model, there was no significant difference in the frequency of effecting allele between ACLR and control (OR: 0.91, 95% CI 0.77, 1.08; p = 0.28). Stratified analysis by sex and ethnicity also showed no difference in allele frequency. Conclusion: The findings of this current meta-analysis suggested that rs970547 was not associated with ACLR risk in male, female, and the overall population among Asians or Caucasians.

No Association Between G1246A Polymorphism in HCRTR2 Gene and Risk of Cluster Headache: Evidence From an Updated Meta-Analysis of Observational Studies.

Background: The hypocretin receptor 2 (HCRTR2) gene may play a pathological role in cluster headache (CH). However, the conclusions of published reports on the relationship between the G1246A polymorphism (rs2653349) in the HCRTR2 gene and risk of CH remain controversial. This purpose of this article is to comprehensively study the current evidence and assess the association between G1246A polymorphism (rs2653349) in the HCRTR2 gene and risk of CH. Materials and Methods: Four electronic databases-ISI Web of Science, CNKI, PubMed, and EMBASE-were comprehensively searched on August 2020 to find and pinpoint all observational articles related to this study. The association between G1246A polymorphism in the HCRTR2 gene and risk of CH under five different genetic models was evaluated based on the summary odds ratio and corresponding 95 confidence interval (95% CI). Methodological quality was assessed based on the Newcastle-Ottawa Scale (NOS). To assist the analysis, RevMan 5.3 software was used to perform subgroup and sensitivity analyses. Egger's and Begg's tests were then conducted to evaluate and assess publication bias. Finally, a meta-regression was carried out by residual (restricted) maximum likelihood (REML). Results: Eight observation studies containing 3,161 healthy controls and 1,964 patients with CH were identified and to be used for the meta-analysis. With methodological quality NOS assessment, the incorporated studies showed an average score of 6.4 stars. The pooled data didn't support the association between G1246A polymorphism in the HCRTR2 gene and CH vulnerability in the overall population (OR: 0.85, 95% CI 0.69, 1.03; p = 0.10). Subgroup analysis by ethnicity showed no significant association between G1246A and CH in either Caucasians (OR: 0.89, 95% CI 0.77, 1.01; p = 0.08) or Asians (OR: 1.65, 95% CI 0.80, 3.41; p = 0.18). The robustness of the conclusion was tested and confirmed with the leave-one-out sensitivity analysis. Meta-regression analysis showed that chronological order of publication appeared to be significantly associated with the heterogeneity (t = 2.47, p = 0.039; residual I 2 = 0%, adjusted R 2 = 100%). Conclusion: Our present study showed that the G1246A polymorphism in the HCRTR2 gene did not appear to be an accomplice and associated with CH predisposition among either the Asian or Caucasian population.

Elevated expression of FREM1 in breast cancer indicates favorable prognosis and high-level immune infiltration status.

Breast cancer (BC) poses one of the major threats to female's health worldwide. Immune infiltration in BC is a key representative of the tumor microenvironment and has been proven highly relevant for prognosis. The role of the FREM1 (FRAS1-Related Extracellular Matrix 1) gene in carcinoma has not studied, moreover, the underlying mechanism remains largely unknown. This study aims to investigate the expression profile and potential action of FREM1 on BC progression. We applied series of bioinformatic methods as well as immunohistochemistry (IHC) and immunofluorescence (IF) to analyze FREM1 expression profile, its relationship with clinicopathological characteristics, impact on clinical outcomes, relevant functions, correlation with immune infiltration in BC. The results demonstrated that FREM1 had a dramatically reduced expression in BC tissues, possessed an inverse correlation with stage, age, and metastasis, and exhibited a higher level in invasive lobular breast carcinoma than in ductal one. Furthermore, decreased FREM1 expression was often associated with estrogen receptor (ER)/progesterone receptor (PR) negative and triple negative breast carcinoma (TNBC) status while human epidermal growth factor 2 (Her-2) positive status, and considerably correlated with a worse overall survival (OS) and recurrence-free survival (RFS). Meanwhile, the univariate/multivariate Cox model revealed that low-FREM1 expression can be an independent prognostic factor for BC. Additionally, FREM1 was mainly involved in the cell metabolism and immune cells infiltration. Moreover, IHC and IF demonstrated a positive correlation of its expression with the immune infiltrating levels of CD4+ , CD8+ T cells, and CD86+ M1 macrophages while a negative correlation with CD68+ pan-macrophages and CD163+ M2 macrophages. These findings suggest that FREM1 can be a potential biomarker for evaluating the immune infiltrating status, and the BC prognosis.

The Association Between Foxp3 Polymorphisms and Risk of Graves' Disease: A Systematic Review and Meta-Analysis of Observational Studies.

Purpose: This systematic review and meta-analysis was carried out with the aim of investigating the relationship between Foxp3 polymorphisms (rs3761547, r3761548, and rs3761549) and the risk of Graves' disease (GD). Methods: Four online database including PubMed, EMBASE, ISI Web of Science, and CNKI were searched to identify observational studies that evaluated the association between Foxp3 polymorphisms and risk of GD. The strength of associations was indicated as odds ratio (OR) and corresponding 95% confidence interval (95%CI) under the allelic model. The Newcastle-Ottawa Scale was used to assess the methodological quality. Pre-specified subgroup analysis and sensitivity analysis were performed using RevMan 5.3 software. Publication bias was detected by Egger's and Begg's tests. Results: Eight case control studies involving 3,104 GD patients and 3,599 healthy controls were included. The methodological quality of included studies was considered to be moderate to high. The results of our meta-analysis supported no association of rs3761547 and risk of GD in Asians (OR: 1.07, 95%CI 0.97, 1.19, P = 0.18). Evidence for rs3761547 and GD risk among Caucasians was still limited because only one study reported marginally increased risk of GD with the minor allele of rs3761547 (P = 0.04). The variant allele of both rs3761548 (OR: 1.31, 95%CI 1.04, 1.64; P = 0.02) and rs3761549 (OR: 1.30, 95%CI 1.03, 1.64; P = 0.03) was associated with increased risk of GD among Asians, but neither polymorphism turned out to be related with GD among Caucasians. Conclusion: Rs3761548 and rs3761549 polymorphisms in Foxp3 were associated with risk of GD among Asians, possibly due to suppressed function of regulatory T cells and augmented autoimmune response. Their genetic effect among Caucasians remained to be confirmed by future large-scale and well-designed studies.

Association of ITGAV polymorphisms and risk of rheumatoid arthritis: evidence from a meta-analysis.

OBJECTIVE: Currently published papers regarding the relationship between integrin alpha V (ITGAV) gene polymorphisms and rheumatoid arthritis (RA) are contradictory. The aim of this meta-analysis was to evaluate the associations between the ITGAV gene polymorphisms and RA risk. METHODS: Comprehensive literature search based on four electronic databases was applied to retrieve all related data. Two independent reviewers screened each article for eligibility according to the predetermined inclusion criteria. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess associations between ITGAV gene polymorphisms and RA. RESULTS: Six articles involving 5794 RA patients and 5297 healthy controls were included in this meta-analysis. The combined data indicated that rs3911238, rs3738919, rs3768777, and rs10174098 in ITGAV gene were not associated with RA risk in the overall population. However, stratification analysis by ethnicity suggested that rs3768777 was related with risk of RA among Caucasian population (OR 3.51, 95%CI 2.06, 5.97; P < 0.0001), but not among Asian population (OR 1.06, 95%CI 0.67, 1.69; P = 0.81). CONCLUSIONS: Our meta-analysis confirmed that the ITGAV gene rs3768777 polymorphisms might be a risk factor among Caucasians. However, larger-scale studies in Caucasian population are still warranted to confirm the findings of our study.

Omega-3 Polyunsaturated Fatty Acid Supplementation for Reducing Muscle Soreness after Eccentric Exercise: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: This systematic review and meta-analysis was performed to determine the effectiveness of Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplement on muscle soreness after eccentric exercise. METHODS: PubMed, EMBASE, CENTRAL, and ISI Web of Science were searched to identify randomized controlled trials (RCTs) that assessed the efficacy of n-3 PUFA on muscle soreness after eccentric exercise. Mean difference (MD) and the associated 95% confidence interval (95% CI) were calculated by RevMan 5.3 to indicate delayed onset muscle soreness (DOMS) that measured two days after eccentric trainings. Subgroup analyses according to duration and daily dosage of n-3 PUFA supplements before eccentric exercises were performed to determine whether these factors will influence the overall effect size. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the certainty of evidence. The protocol of this systematic review and meta-analysis was registered at PROSPERO (CRD42018085869). RESULTS: 12 RCTs containing 145 subjects and 156 controls were included in this study. Meta-analysis revealed a significantly decreased DOMS (MD -0.93; 95% CI -1.44, -0.42; P = 0.0004) in n-3 PUFA supplement groups, while no significant differences in isometric muscle strength and range of motion (ROM) were detected. However, the pooled effect size for DOMS was lower than the minimal clinically important difference (MCID) of 1.4 on the 10-unit VAS, suggesting that the effect size of less muscle soreness with n-3 PUFA supplements did not appear to be clinically relevant. CONCLUSION: There is low-quality evidence that n-3 PUFA supplementation does not result in a clinically important reduction of muscle soreness after eccentric exercise. Isometric muscle soreness and range of motion were not improved by n-3 PUFA supplementation either (low-quality evidence). To further elucidate the overall role of n-3 PUFA on muscle damage in this area, large-scale RCTs are still needed.

Intravenous parecoxib for early postoperative cognitive dysfunction in elderly patients: evidence from a meta-analysis.

BACKGROUND: Inflammation plays a key role in the etiology and pathology of postoperative cognitive dysfunction (POCD). Cyclooxygenase (COX)-2 inhibitor parecoxib is used for the treatment of acute pain due to its potent anti-inflammatory and analgesic effects. Herein, we evaluated the efficacy and safety of parecoxib on early POCD in geriatric patients. OBJECTIVE: This study was performed to evaluate the efficacy and safety of parecoxib for early postoperative cognitive dysfunction (POCD) in elderly patients. METHODS: Comprehensive literature search based on six electronic databases was applied to retrieve all related randomized controlled trials (RCTs). Two independent reviewers screened each article for eligibility according to the predetermined inclusion criteria. The Cochrane's Tool was applied to evaluate the methodological quality of included studies. RevMan 5.3 was used to conduct meta-analysis. RESULTS: Eight RCTs comprising a total of 1106 subjects prepared for orthopedic surgical operation were selected. All the identified RCTs were conducted in China. The methodological qualities of included studies were judged to be medium to high. The integrated data showed that perioperative intravenous parecoxib could remarkably reduce the incidence of POCD with improved Mini-Mental State Examination (MMSE) score. Parecoxib could significantly reduce the concentrations of interleukin-6, but results regarding the changes in tumor necrosis factor-alpha, C-reactive protein, and S100ß levels remained inconsistent. CONCLUSION: Perioperative parecoxib administration is effective in reducing the incidence of POCD and improving the MMSE score compared with control. However, the beneficial effect of parecoxib has been tested only in the Chinese population. Future RCTs in western countries with larger-scale and more comprehensive neurological tests are needed.

TMEM158 May Serve as a Diagnostic Biomarker for Anaplastic Thyroid Carcinoma: An Integrated Bioinformatic Analysis.

Anaplastic thyroid carcinoma (ATC) is a rare but extremely lethal malignancy. However, little is known about the pathogenesis of ATC. Given its high mortality, it is critical to improve our understanding of ATC pathogenesis and to find new diagnostic biomarkers. In the present study, two gene microarray profiles (GSE53072 and GSE65144), which included 17 ATC and 17 adjacent non-tumorous tissues, were obtained. Bioinformatic analyses were then performed. Immunohistochemistry (IHC) and receiver operating characteristic (ROC) curves were then used to detect transmembrane protein 158 (TMEM158) expression and to assess diagnostic sensitivity. A total of 372 differentially expressed genes (DEGs) were identified. Through protein-protein interaction (PPI) analysis, we identified a significant module with 37 upregulated genes. Most of the genes in this module were related to cell-cycle processes. After co-expression analysis, 132 hub genes were selected for further study. Nine genes were identified as both DEGs and genes of interest in the weighted gene co-expression network analysis (WGCNA). IHC and ROC curves confirmed that TMEM158 was overexpressed in ATC tissue as compared with other types of thyroid cancer and normal tissue samples. We identified 8 KEGG pathways that were associated with high expression of TMEM158, including aminoacyl-tRNA biosynthesis and DNA replication. Our results suggest that TMEM158 may be a potential oncogene and serve as a diagnostic indicator for ATC.

Maternal occupational exposure to chemicals in the textile factory during pregnancy is associated with a higher risk of polydactyly in the offspring.

Background: The number of children with polydactyly seen in our clinic is increasing. In addition to genetic factors, an influence of environmental effects during pregnancy is becoming increasingly apparent; however, epidemiological data on these effects are lacking.Methods: This hospital-based, case-control study enrolled 143 patients with polydactyly and 286 control patients with no genetic diseases, to evaluate the association between maternal exposure to a textile factory environment during pregnancy and the likelihood of giving birth to a child with polydactyly.Results: Maternal exposure to a textile factory environment during pregnancy was associated with an increased risk of giving birth to a child with polydactyly (exposure to textile factory environment: unadjusted odds ratio (OR) = 3.31, 95% confidence interval (CI) = 1.75-6.27, p = .0002; work seniority of exposed occupation: unadjusted OR 1.28, 95% CI = 1.13-1.47, p = .0002). Covariate screening indicated that certain risk factors (family monthly income per capita, mother's emotional state during pregnancy, colporrhagia, passive smoking, smoking, and history of consanguineous marriage) were potential confounding factors. After adjusting for these variables, the OR of exposure to a textile factory environment remained significant (exposure to textile factory environment: adjusted OR = 3.08, 95% CI = 1.32-7.19, p = .0094; work seniority of exposed occupation: adjusted OR = 1.58, 95% CI = 1.20-2.08, p = .0010). The risk of polydactyly increased with the number of years of employment.Conclusions: Maternal exposure to a textile factory environment appears to be a risk factor for polydactyly in newborns.

APRISMA-compliant systematic review and meta-analysis determining the association of miRNA polymorphisms and risk of congenital heart disease.

PURPOSE: Recent genetic association studies showed conflicting results on the relationship of miRNA single-nucleotide polymorphisms (SNPs) and congenital heart disease (CHD) risk. The purpose of the present systematic review was to collect the current available evidences to evaluate the association between miRNA polymorphisms and CHD risk. METHODS: Four electronic databases including PubMed, EMBASE, ISI Web of Science, and CENTRAL were extensively searched for relevant studies published before February, 2019. Observational studies determining the association between miRNA polymorphisms and risk of CHD were included. Risk of bias was evaluated using the Newcastle-Ottawa Scale by 2 independent researchers. Major characteristics of each study and estimation of effect size of individual locus polymorphism were summarized. In addition, meta-analysis was performed to quantify the associations between miRNA polymorphisms and CHD risk. RESULTS: Nine studies containing 6502 CHD patients and 6969 healthy controls were included in this systematic review. Ten loci in 9 miRNAs were reported. Only rs11614913 in miR-196a2 was determined to have significant associations with CHD susceptibility, which was supported by meta-analysis (CC vs CT+TT: odds ratio 1.54, 95% confidence interval 1.30, 1.82; P < .00001). A strong evidence indicated lack of association between rs2910164 in miR-146a and CHD. Limited or conflicting evidences were found for the associations of the other variants (rs11134527, rs139365823, rs76987351, rs3746444, rs4938723, rs2292832, rs41291957, rs895819) and risk of CHD. CONCLUSIONS: Locus polymorphisms in miRNAs are not generally associated with CHD. Only rs11614913 was found to have significant associations with CHD. Further studies will be needed, using larger populations of different ethnicities, to obtain a better understanding of these associations.

Decreased RIPK1 expression in chondrocytes alleviates osteoarthritis via the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop.

Osteoarthritis (OA) is the most common degenerative joint disease and involves the loss of articular cartilage integrity, formation of articular osteophytes, remodeling of subchondral bone, and synovitis. Knockdown of receptor interacting serine/threonine kinase (RIPK) 1 leads to anti-inflammatory and anti-apoptotic effects. However, the involvement of RIPK1 in the pathogenesis of OA is unclear. Here, we evaluated the effect of RIPK1 on chondrocytes and elaborated the underlying molecular mechanism. Knockdown of RIPK1 protected chondrocytes against inflammation and apoptosis induced by interleukin (IL)-1ß in vitro and in vivo. RIPK1 was required for myeloid differentiation primary response 88 (MyD88)- and TIR-domain-containing adapter-inducing interferon b (TRIF)-mediated production of matrix metalloproteinases (MMPs) in OA. Moreover, overexpression of RIPK1 promoted the expression of tumor necrosis factor receptor-associated factor 2 (TRAF2), which blocked the expression and phosphorylation of RIPK1. Upregulation of TRAF2 decreased the expression of TRIF, MyD88, and MMPs in chondrocytes. Furthermore, knockdown of RIPK1 blocked activation of the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling pathways. In summary, knockdown of RIPK1 alleviated OA in a manner mediated by the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop and activation of the NF-κB and JNK signaling pathways.

Effects of intensity of electroacupuncture on chronic pain in patients with knee osteoarthritis: a randomized controlled trial.

BACKGROUND: Conditioned pain modulation (CPM) is impaired in people with chronic pain such as knee osteoarthritis (KOA). The purpose of this randomized, controlled clinical trial was to investigate whether strong electroacupuncture (EA) was more effective on chronic pain by strengthening the CPM function than weak EA or sham EA in patients with KOA. METHODS: In this multicenter, three-arm parallel, single-blind randomized controlled trial, 301 patients with KOA were randomly assigned. Patients were randomized into three groups based on EA current intensity: strong EA (> 2 mA), weak EA (< 0.5 mA), and sham EA (non-acupoint). Treatments consisted of five sessions per week, for 2 weeks. Primary outcome measures were visual analog scale (VAS), CPM function, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Three hundred one patients with KOA were randomly assigned, among which 271 (90.0%) completed the study (mean age 63.93 years old). One week of EA had a clinically important improvement in VAS and WOMAC but not in CPM function. After 2 weeks treatment, EA improved VAS, CPM, and WOMAC compared with baseline. Compared with sham EA, weak EA (3.8; 95% CI 3.45, 4.15; P < .01) and strong EA (13.54; 95% CI 13.23, 13.85; P < .01) were better in improving CPM function. Compared with weak EA, strong EA was better in enhancing CPM function (9.73; 95% CI 9.44, 10.02; P < .01), as well as in reducing VAS and total WOMAC score. CONCLUSION: EA should be administered for at least 2 weeks to exert a clinically important effect on improving CPM function of KOA patients. Strong EA is better than weak or sham EA in alleviating pain intensity and inhibiting chronic pain. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry ( ChiCTR-ICR-14005411 ), registered on 31 October 2014.

Peimine suppresses interleukin­1ß­induced inflammation via MAPK downregulation in chondrocytes.

Osteoarthritis (OA) is the most common type of degenerative joint disease and secreted inflammatory molecules serve a pivotal role in it. Peimine has been reported to have anti­inflammatory activity. In order to investigate the potential therapeutic role of Peimine in OA, mouse articular chondrocytes were treated with IL­1ß and different doses of Peimine in vitro. The data revealed that Peimine not only suppressed IL­1ß­induced production of nitric oxide (NO) and prostaglandin E2, but also reduced the protein levels of inducible NO synthase (iNOS) and cyclooxygenase­2 (COX­2). In addition, Peimine inhibited the IL­1ß­induced mRNA expression of matrix metalloproteinase (MMP)­1, MMP­3, MMP­9, MMP­13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)­4 and ADAMTS­5. Furthermore, Peimine inhibited IL­1ß­induced activation of the mitogen­activated protein kinase (MAPK) pathway. The protective effect of Peimine on IL­1ß­treated chondrocytes was attenuated following activation of the MAPK pathway, as demonstrated by the increased expression levels of MMP­3, MMP­13, ADAMTS­5, iNOS and COX­2 compared with the Peimine group. The in vivo data suggested that Peimine limited the development of OA in the mouse model. In general, the data indicate that Peimine suppresses IL­1ß­induced inflammation in mouse chondrocytes by inhibiting the MAPK pathway, suggesting a promising therapeutic role for Peimine in the treatment of OA.

Necrostatin-1 Attenuates Trauma-Induced Mouse Osteoarthritis and IL-1ß Induced Apoptosis via HMGB1/TLR4/SDF-1 in Primary Mouse Chondrocytes.

Necrostatin-1 (Nec-1) is a specific small molecule inhibitor of receptor-interacting protein kinase 1 (RIPK1) that specifically inhibits phosphorylation of RIPK1. RIPK1 regulates inflammation and cell death by interacting with receptor-interacting serine/threonine protein kinases 3(RIPK3). We hypothesized that Nec-1 may have anti-inflammatory efficacy in patients with osteoarthritis (OA), as the pathophysiology of OA involves the activation of inflammation-related signaling pathways and apoptosis. In this study, we explored the effects of Nec-1 on interleukin (IL)-1ß-induced inflammation in mouse chondrocytes and the destabilised medial meniscus (DMM) mouse model. Inhibiting RIPK1 with Nec-1 dramatically suppressed catabolism both in vivo and in vitro, but did not inhibit changes in subchondral bone. Nec-1 abolished the in vitro increases in matrix metalloproteinase (MMP) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTs5) expression induced by IL-1ß. However, adding high-mobility group box 1 (HMGB1) partially abrogated this effect, indicating the essential role of HMGB1 and Nec-1 in the protection of primary chondrocytes. Furthermore, Nec-1 decreased the expression of Toll-like receptor 4 (TLR4) and stromal cell-derived factor-1 (SDF-1), and attenuated the interaction between TLR4 and HMGB1. Western blot results suggested that Nec-1 significantly suppressed IL-1ß-induced NF-κB transcriptional activity, but not MAPK pathway. Micro-computed tomography, immunohistochemical staining, and Safranin O/Fast Green staining were used in vivo to assess the degree of destruction of OA cartilage. The results show that NEC-1 can significantly reduce the degree of destruction of OA cartilage. Therefore, Nec-1 may be a novel therapeutic candidate to treat OA.

The association between TNF-α 238A/G and 308A/G polymorphisms and juvenile idiopathic arthritis: An updated PRISMA-compliant meta-analysis.

OBJECTIVE: A previous meta-analysis concluded that TNF-α 238A/G and TNF-α 308A/G polymorphisms were not associated with the risk of juvenile idiopathic arthritis (JIA) in the overall population or Caucasian subjects. With the publication of a fair number of studies on the association between TNF-α polymorphisms and JIA in recent years, we conducted this updated meta-analysis to make a more accurate evaluation of such relationship. METHODS: We adopted PubMed, EMBASE, ISI Web of Science and CNKI to identify observational studies that addressed the association between TNF-α polymorphisms and risk for JIA. The allelic effect of variant A for the risk of JIA was expressed as odds ratio (OR) along with the associated 95% confidence interval (95% CI). Meta-analyses were performed by pooling ORs and 95%CI from included studies using RevMan 5.3 software. The stratified-analysis based on ethnicity was performed to confirm the ethnicity-dependent effect on the relationship. RESULTS: A total of 15 case-control studies including 2845 patients in JIA groups and 4771 patients in control groups were included in our study. The findings indicated a statistically significant association between the A allele of the TNF-alpha 238A/G polymorphism and the decreased JIA risk in Caucasians (P = .0002). The study in Iranian showed similar results (P = .0002) whereas the studies in other ethnicities failed to replicate this finding: Han (P = .29), Mexican (P = .64) and Turkish population (P = .32). TNF-α 308A/G was not statistically associated with JIA in overall subjects or Caucasians. CONCLUSION: Our study confirmed the protective role of the A allele in TNF-α 238A/G but not TNF-α 308A/G against the occurrence of JIA in the Caucasian population. To exactly validate the correlation between TNF-α polymorphisms and JIA in other ethnic backgrounds, additional studies are required.

Association of the WNT3 polymorphisms and non-syndromic cleft lip with or without cleft palate: evidence from a meta-analysis.

OBJECTIVE: This meta-analysis was conducted with the aim of investigating the association between WNT3 gene polymorphisms and non-syndromic cleft lip (CL) with or without cleft palate (NSCL/P) predisposition. METHODS: A comprehensive literature search was performed in six online databases including PubMed, Embase, ISI Web of Science, CENTRAL, CNKI, and Wanfang from inception up to June 2018 without language restriction. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated under allele model of inheritance to indicate the association between WNT3 polymorphisms and NSCL/P. Risk of bias was assessed through the Newcastle-Ottawa scale (NOS). Predetermined stratified and sensitivity analyses were performed using the RevMan 5.3 software, publication bias were evaluated by Egger's and Begg's tests. RESULTS: Seven case-control studies comprising 1617 NSCL/P patients and 2143 healthy controls were identified and included in the present study, a total of eight loci were investigated in the present study: rs3809857 was significantly associated with NSCL/P vulnerability (G compared with T, OR = 1.34, 95%CI: 1.15-1.56, P=0.0001), a significant association between rs9890413 polymorphism and NSCL/P susceptibility (A compared with G, OR = 1.25, 95%CI: 1.06-1.47, P=0.007) was detected as well. Since only few studies reported detailed data about the association between rs142167, rs7207916, rs199498, rs111769, rs12452064, rs11653738, and NSCL/P risk, these results were not combined using meta-analysis. CONCLUSION: Based on the findings of our current study, the rs3809857 and rs9890413 polymorphisms of WNT3 appeared to be associated with NSCL/P. Limited evidence is found to support the association between other WNT3 polymorphisms and risk of NSCL/P.