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Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant driver of chronic liver disease globally and is associated with increased cardiovascular disease morbidity and mortality. However, the association between NAFLD and calcific aortic valve disease remains unclear. We aimed to prospectively investigate the association between NAFLD and incident aortic valve calcification (AVC), as well as its genetic relationship with incident calcific aortic valve stenosis (CAVS)., Methods: A post hoc analysis was conducted on 4226 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) database. We employed the adjusted Cox models to assess the observational association between NAFLD and incident AVC. Additionally, we conducted two-sample Mendelian randomization (MR) analyses to investigate the genetic association between genetically predicted NAFLD and calcific aortic valve stenosis (CAVS), a severe form of CAVD. We repeated the MR analyses by excluding NAFLD susceptibility genes linked to impaired very low-density lipoprotein (VLDL) secretion., Results: After adjustment for potential risk factors, participants with NAFLD had a hazard ratio of 1.58 (95% CI: 1.03-2.43) for incident AVC compared to those without NAFLD. After excluding genes associated with impaired VLDL secretion, the MR analyses consistently showed the significant associations between genetically predicted NAFLD and CAVS for 3 traits: chronic elevation of alanine aminotransferase (odds ratio = 1.13 [95% CI: 1.01-1.25]), imaging-based NAFLD (odds ratio = 2.81 [95% CI: 1.66-4.76]), and biopsy-confirmed NAFLD (odds ratio = 1.12 [95% CI: 1.01-1.24]). However, the association became non-significant when considering all NAFLD susceptibility genes., Conclusions: NAFLD was independently associated with an elevated risk of incident AVC. Genetically predicted NAFLD was also associated with CAVS after excluding genetic variants related to impaired VLDL secretion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hao, Zeng, Lin, Guo, Li, Yang, Gao and Li.)

Background: Ginkgo biloba L. preparations (GBLPs) are a class of Chinese herbal medicine used in the adjuvant treatment of ischemic stroke (IS). Recently, several systematic reviews (SRs) and meta-analyses (MAs) of GBLPs for IS have been published., Objective: This overview aims to assess the quality of related SRs and MAs., Search Strategy: PubMed, Embase, Cochrane Library, Web of Science, Chinese Biological Medicine, China National Knowledge Infrastructure, Wanfang, and Chinese Science and Technology Journals databases were searched from their inception to December 31, 2022., Inclusion Criteria: SRs and MAs of randomized controlled trials (RCTs) that explored the efficacy of GBLPs for patients with IS were included., Data Extraction and Analysis: Two independent reviewers extracted data and assessed the methodological quality, risk of bias (ROB), reporting quality, and credibility of evidence of the included SRs and MAs using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2), Risk of Bias in Systematic Reviews (ROBIS), the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), and the Grading of Recommendations Assessment, Development and Evaluation (GRADE), respectively. Additionally, descriptive analysis and data synthesis were conducted., Results: Twenty-nine SRs/MAs involving 119 outcomes were included in this review. The overall methodological quality of all SRs/MAs was critically low based on AMSTAR 2, and 28 had a high ROB based on the ROBIS. According to the PRISMA statement, the reporting items of the included SRs/MAs are relatively complete. The results based on GRADE showed that of the 119 outcomes, 8 were rated as moderate quality, 24 as low quality, and 87 as very low quality. Based on the data synthesis, GBLPs used in conjunction with conventional treatment were superior to conventional treatment alone for decreasing neurological function scores., Conclusion: GBLPs can be considered a beneficial supplemental therapy for IS. However, because of the low quality of the existing evidence, high-quality RCTs and SRs/MAs are warranted to further evaluate the benefits of GBLPs for treating IS. Please cite this article as: Meng TT, You YP, Li M, Guo JB, Song XB, Ding JY, Xie XL, Li AQ, Li SJ, Yin XJ, Wang P, Wang Z, Wang BL, He QY. Chinese herbal medicine Ginkgo biloba L. preparations for ischemic stroke: An overview of systematic reviews and meta-analyses. J Integr Med. 2024;22(2): 163-179., 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 © 2024. Published by Elsevier B.V.)

Background: Remnant cholesterol (RC) is implicated in the risk of cardiovascular disease. However, comprehensive population-based studies elucidating its association with aortic valve calcium (AVC) progression are limited, rendering its precise role in AVC ambiguous., Methods: From the Multi-Ethnic Study of Atherosclerosis database, we included 5597 individuals (61.8 ± 10.1 years and 47.5% men) without atherosclerotic cardiovascular disease at baseline for analysis. RC was calculated as total cholesterol minus high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), as estimated by the Martin/Hopkins equation. Using the adjusted Cox regression analyses, we examined the relationships between RC levels and AVC progression. Furthermore, we conducted discordance analyses to evaluate the relative AVC risk in RC versus LDL-C discordant/concordant groups., Results: During a median follow-up of 2.4 ± 0.9 years, 568 (10.1%) participants exhibited AVC progression. After adjusting for traditional cardiovascular risk factors, the HRs (95% CIs) for AVC progression comparing the second, third, and fourth quartiles of RC levels with the first quartile were 1.195 (0.925-1.545), 1.322 (1.028-1.701) and 1.546 (1.188-2.012), respectively. Notably, the discordant high RC/low LDL-C group demonstrated a significantly elevated risk of AVC progression compared to the concordant low RC/LDL-C group based on their medians (HR, 1.528 [95% CI 1.201-1.943]). This pattern persisted when clinical LDL-C threshold was set at 100 and 130 mg/dL. The association was consistently observed across various sensitivity analyses., Conclusions: In atherosclerotic cardiovascular disease-free individuals, elevated RC is identified as a residual risk for AVC progression, independent of traditional cardiovascular risk factors. The causal relationship of RC to AVC and the potential for targeted RC reduction in primary prevention require deeper exploration., (© 2023. The Author(s).)

Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri ( P. copri ) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo , accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri -derived LPS ( Pc -LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc -LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc -LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc -LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.

Background: It is unclear that paired-related homeobox 1 (PRRX1) induces epithelial-mesenchymal transition (EMT) in oesophageal cancer and the specific function of PRRX1 in oesophageal cancer metastasis., Aim: To assess the significance of PRRX1 expression and investigate the mechanism of EMT in oesophageal cancer metastasis., Methods: Detect the expression of PRRX1 by immunohistochemistry in oesophageal tumour tissues and adjacent normal oesophageal tissues; the PRRX1 short hairpin RNA (shRNA) or blank vector lentiviral gene delivery system was transfected into cells; cell proliferation assay, soft agar colony formation assays, cell invasion and migration assays and animal studies were used to observe cells biological characteristics In vitro and in vivo ; XAV939 and LiCl were used to alter the activity of Wnt/β-catenin pathway. Immunofluorescence staining and western blot analysis were used to detect protein expression of EMT markers and Wnt/β-catenin pathway., Results: PRRX1 is expressed at high levels in oesophageal cancer specimens and is closely related to tumour metastasis in patients with oesophageal cancer. Regulation of PRRX1 expression might exert obvious effects on cell proliferation, especially the migration and invasion of oesophageal cancer cells. Moreover, silencing PRRX1 expression using a shRNA produced the opposite effects. In addition, when PRRX1 was overexpressed, inhibition of the Wnt/β-catenin pathway with XAV939 negated the effect of PRRX1 on EMT, whereas when PRRX1 was downregulated, activation of the Wnt/β-catenin pathway with LiCl impaired the effect on EMT., Conclusion: PRRX1 is upregulated in oesophageal cancer is closely correlated with cancer metastasis. Additionally, PRRX1 induces EMT in oesophageal cancer metastasis through activation of Wnt/β-catenin signalling., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To evaluate the long-term efficacy and quality of life concerning sacrospinous ligament fixation (SSLF) using conventional instruments for Chinese women with symptomatic stage 2 and 3 apical prolapse., Methods: This single-arm prospective cohort study was conducted at our hospital between October 2011 and December 2018. Eligible participants were followed up over 3 years after surgery. The primary surgical outcome was composite surgical failure. Secondary outcomes included rate of satisfaction, quality of life (QoL) scores, and long-term complications., Results: Fifty-nine patients were enrolled (mean age 57.1 years), of whom 55 (93.22%) completed the 3-year follow up. At year 3, the composite failure rate was 21.34% (95% confidence interval [CI] 9.30%-31.79%), and satisfaction rate was 81.40% (95% CI 66.09%-91.08%). Right thigh pain and de novo dyspareunia occurred in 1.8% and 14.6% patients after year 1, respectively, but at year 3 there were no complications. Lower urinary tract symptoms were present in 5.5% of patients. Improvement was found in urinary symptoms and prolapse symptoms, but sexual function showed no significant change., Conclusions: Compared with results at year 1, complication rates of SSLF decreased at year 3. The composite failure rate was relatively low and satisfaction rate was relatively high at year 3. Prolapse and urinary symptoms improved significantly after surgery., (© 2023 International Federation of Gynecology and Obstetrics.)

Background: Hip fracture patients often have a large drop in hemoglobin (Hgb) concentration that is associated with the initial trauma. However, there is no study of a correlation between Hgb concentration at admission and short-term mortality. Thus, we evaluated a possible linear and nonlinear association between Hgb and mortalityfor older patients with hip fracture., Methods: Consecutive older patients who had hip fractures were screened between January 2015 and September 2019. Demographic and clinical characteristics were collected. Linear and nonlinear multivariate Cox regression models were used to identify association between Hgb at admission and mortality. All analyses were performed with EmpowerStats and R software., Results: Two thousand five hundred eighty-nine patients were included in the study. There were 849 men and 1740 women. The mean age was 79.6 ± 6.8 years. The mean follow-up was 39.0 months. Nine hundred seven (35.0%) patients died for all-cause reasons. The mean Hgb at admission was 11.07 ± 1.95 g/dL. Linear multivariate Cox regression models showed Hgb at admission was associated with mortality ([Hazard Ratio] HR 0.91, 95% CI 0.87-0.95, P < 0.0001) after adjusting for confounding factors. However, the linear association was unstable, and nonlinearity was found between Hgb at admission and mortality. The Hgb concentration of 9.8 g/dL was an inflection point. A Hgb at admission < 9.8 g/dL was associated with mortality (HR 0.81, 95% CI 0.74-0.89, P < 0.0001), whereas > 9.8 g/dL was not a risk factor for mortality (HR 0.98, 95% CI 0.92-1.04, P = 0.4730)., Conclusions: The Hgb concentration at admission was nonlinearly associated with mortality of older patients with hip fracture, and Hgb at admission < 9.8 g/dL was a risk predictor of 3-year mortality., Research Registration: ChiCTR2200057323., (© 2023. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

Aim: To investigate the changes in type II neuregulin-1 (NRG-1) during the regeneration process following autologous sciatic nerve transplantation in rats., Material and Methods: In total, 40 healthy male Sprague-Dawley (SD) rats of clean grade with body weights between 250 g and 300 g were randomly divided into an experimental and control group, with 20 rats per group. Five time points were set, including the 3 < sup > rd < /sup > , 7 < sup > th < /sup > , 14 < sup > th < /sup > , 21 < sup > st < /sup > and 28 < sup > th < /sup > days after surgery. In the experimental group, reversed autologous transplantation of the sciatic nerve was performed, while in the control group, the sciatic nerve was simply exposed without autologous transplantation. At the different time points, changes in the rat footprints were observed, the sciatic functional index (SFI) was calculated, changes in the regeneration of the myelin sheath at the nerve end after transplantation were observed by transmission electron microscopy, changes in type II NRG-1 protein expression were detected by a western blot analysis, and changes in type II NRG-1 mRNA expression were detected by real-time PCR., Results: The SFI in the experimental group was lower than that in the control group at all time points after surgery, and the SFI in the experimental group gradually increased; these differences were statistically significant (p < 0.05). The expression of type II NRG-1 protein in the experimental group was significantly increased on the 3rd day after nerve transplantation and peaked on the 7 < sup > th < /sup > day, which continued until the 28 < sup > th < /sup > day after surgery, indicating a significant difference from the control group (p < 0.01). NRG-1 mRNA expression was markedly increased on the 7th day after nerve transplantation, further increased, and peaked on the 14 < sup > th < /sup > day (p < 0.01). The area of medullated nerve fibers (?m2) in the experimental group significantly differed from that in the control group on the 7 < sup > th < /sup > , 14 < sup > th < /sup > , 21 < sup > st < /sup > and 28 < sup > th < /sup > days (p < 0.01), and the diameters of the axons in the experimental group notably differed from those in the control group on the 7 < sup > th < /sup > , 14 < sup > th < /sup > and 21 < sup > st < /sup > days (p < 0.01)., Conclusion: Type II NRG-1 expression peaked between the 3 < sup > rd < /sup > day and 14 < sup > th < /sup > day after autologous nerve transplantation and is likely involved in the regulation of myelin sheath regeneration during this period.

In recent years, extensive research has been focused on the field of single cell analysis. The isolation of single cells is the first step in this type of research. However, the techniques used for direct isolation and acquisition of single adherent cells are limited. Here, we present a method of obtaining selected single adherent cells using a separation device. Compared with other single cell isolation methods, this method has the advantages of simple operation, low cost, minimal cell damage, and preservation of cell morphology. Our methodology is, therefore, suitable for the collection of selected single adherent cells., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Wang-Ying Dai et al.)

Diabetic nephropathy (DN) is the most common chronic kidney disease. Accumulation of glucose and metabolites activates resident macrophages in kidneys. Resident macrophages play diverse roles on diabetic kidney injuries by releasing cytokines/chemokines, recruiting peripheral monocytes/macrophages, enhancing renal cell injuries (podocytes, mesangial cells, endothelial cells and tubular epithelial cells), and macrophage-myofibroblast transition. The differentiation and cross-talks of macrophages ultimately result renal inflammation and fibrosis in DN. Emerging evidence shows that targeting macrophages by suppressing macrophage activation/transition, and macrophages-cell interactions may be a promising approach to attenuate DN. In the review, we summarized the diverse roles of macrophages and the cross-talks to other cells in DN, and highlighted the therapeutic potentials by targeting macrophages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, You, Shao, Wu, Wang, Guo, Meng and Chen.)

Objective: To analyze the long-term outcomes of different secondary surgeries in women with recurrent stress urinary incontinence (SUI) after Burch colposuspension. Methods: Between February 2004 to February 2010, five women with recurrent SUI after Burch colposuspension in Peking Union Medical College Hospital were retrospectively followed up, and the long-term outcomes of secondary surgeries were analyzed. Subjective cures of Burch colposuspension and secondary surgeries were assessed by patients' self-reported incontinence symptoms and patient global impression of improvement questionnaire; objective cure, improvement or failure were determined by 1-hour pad test. Results: Three women underwent tension-free vaginal tape-retropubic (TVT) as the secondary surgery, one underwent tension-free vaginal tape-obturator (TVT-O), and one underwent single-incision tension-free vaginal tape-Secur (TVT-Secur). The follow-up period of five women was (14.6±2.4) years (range: 10.8 to 16.9 years). Three women undergoing TVT secondary surgery were subjectively cured; while the other two women undergoing TVT-O or TVT-Secur were not subjectively cured, but the woman undergoing TVT-O was objectively improved. Conclusions: It is feasible for women with recurrent SUI after Burch colposuspension to receive the secondary surgery. Our limited data suggests that TVT could be considered.

In order to enhance the role of Al in the materials, Al-substituted MnAlO catalysts were synthesized via the hydrothermal-redox method at different calcination temperatures for acetone oxidation. There were Al-substituted α-MnO 2 and amorphous aluminum oxide existed with homogeneous dispersion of elements in the catalysts. The surface property, reaction rate, CO 2 yield and water resistance of MnAlO catalysts were greatly affected by calcination temperatures. MnAlO-450 catalyst exhibited the best catalytic performance (acetone conversion of 90% at 165 °C) with CO 2 yield higher than 99.7%, which was mainly related to the weaker Mn-O bond strength, lower temperature reducibility and abundant Lewis acid sites. The acetone conversion of MnAlO-450 increased by as much as 16% in the presence of 1 vol% H 2 O compared to that in the absence of H 2 O at T 50 (the temperature for 50% conversion of acetone). The acceleration consumption of ethanol as the main by-product by H 2 O improved the catalytic performance. This work would shed light on the Al substitution based catalysts for OVOC oxidation with highly efficient and water resistance., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Conservative treatment is the recommended first-line treatment for degenerative disc diseases. Traction therapy has historically been one of the most common clinical methods to address this, but the clinical effect remains controversial., Methods: Forty-two six-month-old male Sprague-Dawley rats were randomly divided into six groups: the model group (Group A, four coccyx vertebrae (Co7-Co10) were fixed with customized external fixators, and the vertebral disc degeneration model was constructed by axial compression of the target segment Co8 - Co9 for 4 weeks), the experimental control group (Group B, after successful modeling, the external fixation device was removed and self-rehabilitation was performed) and four intervention groups (Groups C to F): Groups C and E: Co8 - Co9 vertebrae compressed for 4 weeks followed by two or 4 weeks of high tension traction (HTT), respectively, and Groups D and F: vertebrae compressed for 4 weeks followed by two or 4 weeks of low-tension traction (LTT), respectively. Imaging tests (X-ray and MRI) were performed to assess disc height and T2 signal intensity at each time point. After the experiment, the animals were euthanized, and the caudal vertebrae were collected for analysis of intervertebral disc histopathology, proteoglycan content, and micronanostructure of the annulus fibrosus, nucleus pulposus and bony endplate., Results: Signs of tissue regeneration were apparent in all four intervention groups. After two to 4 weeks of intervention (HTT and LTT), the morphology of pores in the bony endplate, their number, and diameter had recovered significantly compared with those in Group A. The LTT group was superior to the HTT group, and the 4w in situ group was significantly superior to the 2w group. Meanwhile, the histological scores of discs, the mean fibril diameter and modulus of annulus fibrosus were significantly improved compared with the control groups, and the LTT group was superior to HTT group., Conclusions: Low-tension traction better promotes active reconstruction of bony endplates and improves the elastic modulus and micro/nanostructure of the disc. Thus, it further promotes the regeneration and repair of intervertebral discs., (© 2022. The Author(s).)

Background: During total knee arthroplasty (TKA), surgeons mobilize the patella to facilitate clear visualization of the articular surfaces and allow better prosthesis placement. According to the manipulation, this manipulation can be divided into patellar eversion and noneversion. However, the effect of patellar eversion in TKA is controversial, with substantial variability in clinical practice. This systematic review is aimed at assessing the adverse effects of patellar eversion and patellar noneversion duration in TKA., Methods: This updated systematic literature review identified randomized controlled trials comparing patellar eversion and noneversion durations in TKA. Two investigators independently extracted data and evaluated the quality of the studies. A meta-analysis was performed using RevMan version 5.3., Results: Nine studies with a total of 608 patients (730 knees) were included. Of these, 374 knees were classified in the eversion group and 356 knees in the noneversion group. The quality of the studies was high. The results showed that patellar eversion could increase the postoperative complication rate (relative risk [RR] = 1.67; 95% confidence interval [CI], 1.09-2.54; P = 0.02) and postoperative pain before discharge (mean deviation [MD] = 0.19; 95% CI, 0.04-0.34; P = 0.01), compared to noneversion. Additionally, patellar eversion could prolong the time until the patient is able to raise the leg while straightened (MD = 0.42; 95% CI, 0.24-0.59; P < 0.00001) and increase the length of stay (MD = 0.65; 95% CI, 0.05-1.25; P = 0.03). However, patellar eversion did not influence postoperative pain at 1 year (MD = 0.02; 95% CI, -0.23-0.28; P = 0.85), operative time (MD = -2.66; 95% CI, -8.84-3.52; P = 0.40), recovery of quadriceps force throughout the follow-up period, and Insall-Salvati ratio (MD = -0.04; 95% CI, [-0.11-0.02]; P = 0.23)., Conclusions: The patellar eversion could increase the postoperative complication rate and postoperative pain. Current evidence supports the avoidance of patellar eversion in TKA. Further large-sample and long-term trials are required to validate these results., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Jun Wang et al.)

An immuno-separated assay for ochratoxin A detection coupled with a nano-affinity cleaning up for LC-confirmation was developed. Firstly, ochratoxin A was modified to quantum dot beads for immuno-fluorescent reporters. Secondly, Fe 3 O 4 magnetic nanoparticles were conjugated with protein G for immuno-magnetic adsorbents. The immuno-separation of fluorescent reporters by magnetic adsorbents could be completed by ochratoxin A, so the fluorescent reporters released from the immune complex indicate a linear correlation with the concentration of ochratoxin A. Furthermore, the immuno-separated ochratoxin A can be eluted from magnetic adsorbent for LC-conformation. The optimized assay showed results as follows: the quantitative range of the immuno-separated assay was 0.03-100 ng mL -1 of ochratoxin A. The recoveries for spiked samples ranged from 78.2% to 91.4%, with the relative standard deviation (RSD) being 11.9%~15.3%. Statistical analysis indicated no significant difference between the HPLC-FLD results based on commercial affinity column and by nano-affinity cleaning up.

Exercise can help inhibition of neuropathic pain (NP), but the related mechanism remains being explored. In this research, we performed the effect of swimming exercise on the chronic constriction injury (CCI) rats. Compared with CCI group, the mechanical withdrawal threshold of rats in the CCI-Swim group significantly increased on the 21st and 28th day after CCI surgery. Second-generation RNA-sequencing technology was employed to investigate the transcriptomes of spinal dorsal horns in the Sham, CCI, and CCI-Swim groups. On the 28th day post-operation, 306 intersecting long non-coding RNAs (lncRNAs) and 173 intersecting mRNAs were observed between the CCI vs Sham group and CCI-Swim vs CCI groups. Then, the biological functions of lncRNAs and mRNAs in the spinal dorsal horn of CCI rats were then analyzed. Taking the results together, this study could provide a novel perspective for the treatment for NP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Song, Zhang, Wang, Guo, Zheng, Yang, Su, Chen, Xie and Wang.)

Neuropathic pain (NP) is poorly managed, and in-depth mechanisms of gene transcriptome alterations in NP pathogenesis are not yet fully understood. To determine microRNA-related molecular mechanisms of NP and their transcriptional regulation in NP, PubMed, Embase, Web of Science and CINAHL Complete (EBSCO) were searched from inception to April 2021. Commonly dysregulated miRNAs in NP were assessed. The putative targets of these miRNAs were determined using TargetScan, Funrich, Cytoscape and String database. A total of 133 literatures containing miRNA profiles studies and experimentally verify studies were included. Venn analysis, target gene prediction analysis and functional enrichment analysis indicated several miRNAs (miR-200b-3p, miR-96, miR-182, miR-183, miR-30b, miR-155 and miR-145) and their target genes involved in known relevant pathways for NP. Targets on transient receptor potential channels, voltage-gated sodium channels and voltage-gated calcium channels may be harnessed for pain relief. A further delineation of signal processing and modulation in neuronal ensembles is key to achieving therapeutic success in future studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Su, Chen, Guo, Song, Yang, Chen and Wang.)

Importance: Therapeutic aquatic exercise is frequently offered to patients with chronic low back pain, but its long-term benefits are unclear., Objective: To assess the long-term effects of therapeutic aquatic exercise on people with chronic low back pain., Design, Setting, and Participants: This 3-month, single-blind randomized clinical trial with a 12-month follow-up period was performed from September 10, 2018, to March 12, 2019, and the trial follow-up was completed March 17, 2020. A total of 113 people with chronic low back pain were included in the experiment., Interventions: Participants were randomized to either the therapeutic aquatic exercise or the physical therapy modalities group. The therapeutic aquatic exercise group received aquatic exercise, whereas the physical therapy modalities group received transcutaneous electrical nerve stimulation and infrared ray thermal therapy. Both interventions were performed for 60 minutes twice a week for 3 months., Main Outcomes and Measures: The primary outcome was disability level, which was measured using the Roland-Morris Disability Questionnaire; scores range from 0 to 24, with higher scores indicating more severe disability. Secondary outcomes included pain intensity, quality of life, sleep quality, recommendation of intervention, and minimal clinically important difference. Intention-to-treat and per-protocol analyses were performed., Results: Of the 113 participants, 59 were women (52.2%) (mean [SD] age, 31.0 [11.5] years). Participants were randomly allocated into the therapeutic aquatic exercise group (n = 56) or the physical therapy modalities group (n = 57), and 98 patients (86.7%) completed the 12-month follow-up. Compared with the physical therapy modalities group, the therapeutic aquatic exercise group showed greater alleviation of disability, with adjusted mean group differences of -1.77 (95% CI, -3.02 to -0.51; P = .006) after the 3-month intervention, -2.42 (95% CI, -4.13 to -0.70; P = .006) at the 6-month follow-up, and -3.61 (95% CI, -5.63 to -1.58; P = .001) at the 12-month follow-up (P < .001 for overall group × time interaction). At the 12-month follow-up point, improvements were significantly greater in the therapeutic aquatic exercise group vs the physical therapy modalities group in the number of participants who met the minimal clinically important difference in pain (at least a 2-point improvement on the numeric rating scale) (most severe pain, 30 [53.57%] vs 12 [21.05%]; average pain, 14 [25%] vs 11 [19.30%]; and current pain, 22 [39.29%] vs 10 [17.54%]) and disability (at least a 5-point improvement on the Roland-Morris Disability Questionnaire) (26 [46.43%] vs 4 [7.02%]). One of the 56 participants (1.8%) in the therapeutic aquatic exercise group vs 2 of the 57 participants (3.5%) in the physical therapy modalities group experienced low back pain and other pains related to the intervention., Conclusions and Relevance: The therapeutic aquatic exercise program led to greater alleviation in patients with chronic low back pain than physical therapy modalities and had a long-term effect up to 12 months. This finding may prompt clinicians to recommend therapeutic aquatic exercise to patients with chronic low back pain as part of treatment to improve their health through active exercise rather than relying on passive relaxation., Trial Registration: Chinese Clinical Trial Registry: ChiCTR1800016396.

Neuropathic pain (NP) results from a lesion or disease of the nervous system and accompanied by chronic pain, leading a serious public health issue and economic burden. In terms of the NP mechanisms remaining poorly understood, circular RNAs (circRNAs), owing to their high stability and evolutionary conservation, are expected to be used as potential therapeutic targets or diagnostic biomarkers. In this review, we concisely discuss the characteristics and biological functions of circRNAs. As emerging evidence we reviewed, deregulation of circRNAs (e.g., circ-Filip1l, circHIPK3, ciRS-7, circRNA.2837, circ-Ankib1 and circAnks1a) were involved in NP development. It suggested that specific circRNAs modulated through sponging their target miRNAs and thus regulated the homologous downstream mRNAs and proteins in neuropathic pain. These findings provide a theoretical basis for circRNAs use as biomarkers and therapeutic targets in neuropathic pain., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Objective: Adding vitamin E to highly cross-linked polyethylene liners is frequently performed in clinical practice, aiming at reducing liner wear, increasing liner survival, and delaying revision surgery. This study is aimed at evaluating the revision rate, total femoral head penetration, and postoperative clinical function of highly cross-linked polyethylene liners with and without vitamin E in total hip arthroplasty., Methods: We conducted a systematic literature search to identify the use of highly cross-linked vitamin E liners compared to other liners in patients who received total hip arthroplasty (THA) before April 2021. The study quality assessment and data collection were conducted by two independent reviewers. Studies were artificially grouped, and vitamin E-enhanced liners (VE-PE) were compared with vitamin E-free liners (non-VE-PE). Analyses were executed using Review Manager version 5.4.1., Results: From the preliminary screening of 568 studies, fourteen studies met the research criteria. Compared to non-VE-PE, using VE-PE reduced the all-cause revision rate (odds ratio = 0.54; 95% confidence interval (CI) 0.40, 0.73; P < 0.0001). The total femoral head penetration of the VE-PE was lower than that of the non-VE-PE (mean difference = -0.10; 95% CI -0.17, -0.03; P = 0.007). However, there was no difference in clinical function, including the Harris Hip Score and EuroQol Five-Dimension Questionnaire scores., Conclusion: Compared to the liners without vitamin E, the addition of vitamin E to liners could reduce the all-cause revision rate by approximately 46% in the short-term follow-up. In addition, even though addition of vitamin E could also slow down femoral head penetration, there is no contribution to clinical function., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Qian-Yue Cheng et al.)

Most randomized trials for acute promyelocytic leukemia (APL) have investigated highly selected patients under idealized conditions, and the findings need to be validated in the real world. We conducted a population-based study of all APL patients in Zhejiang Province, China, with a total population of 82 million people, to assess the generalization of all-trans retinoic acid (ATRA) and arsenic as front-line treatment. The outcomes of APL patients were also analyzed. Between January 2015 and December 2019, 1,233 eligible patients were included in the final analysis. The rate of ATRA and arsenic as front-line treatment increased steadily from 66.2% in 2015 to 83.3% in 2019, with no difference among the size of the center (≥5 or <5 patients per year, p = 0.12) or age (≥60 or <60 years, p = 0.35). The early death (ED) rate, defined as death within 30 days after diagnosis, was 8.2%, and the 3-year overall survival (OS) was 87.9% in the whole patient population. Age (≥60 years) and white blood cell count (>10 × 10 9 /L) were independent risk factors for ED and OS in the multivariate analysis. This population-based study showed that ATRA and arsenic as front-line treatment are widely used under real-world conditions and yield a low ED rate and a high survival rate, which mimic the results from clinical trials, thereby supporting the wider application of APL guidelines in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhu, Ma, Yu, Ouyang, Luo, Pei, Xu, Hu, Mo, Xu, Lan, Shen, Shou, Qian, Feng, Zhao, Jiang, Hu, Zhang, Qian, Wu, Wu, Qiu, Li, Lang, Chen, Chen, Guo, Cao, Jiang, Xia, Le, Zhao, Huang, Zhang, Lv, Hua, Hong, Zheng, Wang, Hu, Chen, Zhang, Tao, Xie, Kuang, Luo, Su, Guo, Wu, Jiang, Zhang, Zhang, Chen, Xu, Guo, Tu, Hu, Yan, Yao, Lou, Jin and the APL Cooperative Group of Zhejiang Province.)

Musculoskeletal degenerative diseases (MSDDs) are pathological conditions that affect muscle, bone, cartilage, joint and connective tissue, leading to physical and functional impairments in patients, mainly consist of osteoarthritis (OA), intervertebral disc degeneration (IDD), rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are novel regulators of gene expression that play an important role in biological regulation, involving in chondrocyte proliferation and apoptosis, extracellular matrix degradation and peripheral blood mononuclear cell inflammation. Research on MSDD pathogenesis, especially on RA and AS, is still in its infancy and major knowledge gaps remain to be filled. The effects of lncRNA/circRNA-miRNA-mRNA axis on MSDD progression help us to fully understand their contribution to the dynamic cellular processes, provide the potential OA, IDD, RA and AS therapeutic strategies. Further studies are needed to explore the mutual regulatory mechanisms between lncRNA/circRNA regulation and effective therapeutic interventions in the pathology of MSDD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zheng, Song, Guo, Su, Chen, Yang, Chen and Wang.)

Objective: To investigate the clinical significance of serum S100 calcium-binding protein A10 (S100A10) levels in lung cancer., Methods: This prospective study enrolled patients with lung cancer, patients with benign lung nodules and healthy control subjects. Serum S100A10 levels and three biomarkers were measured and compared between the groups. Associations between serum S100A10 and clinical characteristics in patients with lung cancer were investigated. The diagnostic efficacy of serum S100A10 and carcinoembryonic antigen for lung cancer was calculated., Results: The study enrolled 82 patients with lung cancer, 21 with benign lung nodules and 50 healthy controls. Serum S100A10 levels were significantly higher in patients with lung cancer compared with patients with benign lung nodules and healthy control subjects. Serum S100A10 levels of patients with advanced lung cancer were significantly higher than those with early stage disease. Patients with lymph node metastases had significantly higher serum S100A10 levels than patients without lymph node metastases. The cut-off serum S100A10 value for lung cancer detection was 1.34 ng/ml, which had a sensitivity of 48.2%, a specificity of 76.2% and an area under the curve of 0.63., Conclusion: Serum S100A10 was significantly correlated with disease stage and lymph node metastasis. It has the potential to be a tumour biomarker for lung cancer.

Background: The progression of liver disorders is frequently associated with inflammatory bowel disease through the gut-liver axis. However, no direct evidence showed the mechanisms of ulcerative colitis (UC) in the development of liver fibrosis per se . Thus, this study aimed to evaluate the effects of UC on liver fibrosis and its potential mechanism in the experimental model. Methods: Male C57BL/6 mice were allocated into five groups ( n = 10 per group) to receive either drinking water (control), 2% dextran sulfate sodium (DSS), olive oil, carbon tetrachloride (CCl 4 ) or DSS + CCl 4 for 4 cycles. Blood was collected for biochemical analysis. Colons were excised for the evaluation of colon length and morphological score. Liver, colon, and mesenteric lymph nodes (MLNs) were collected for histopathological staining, expression analysis, and bacterial translocation assay to evaluate the inflammation, fibrosis, the activation of hepatic stellate cells (HSCs), and gut barrier function. Results: DSS caused severe colitis in mice treated or treated with CCl 4 , as evident from the elevation of disease activity index (DAI), histological abnormalities, and increased pro-inflammatory cytokines (TNF-α, IFN-γ, and IL-17A). Histopathological staining revealed that DSS treatment aggravated the CCl 4 -induced extracellular matrix deposition, liver fibrosis, and inflammation in mice. Additionally, biochemical and expression analysis indicated the DSS treatment caused the increase of hydroxyproline and pro-inflammatory cytokines, as well as the abnormal liver function indexes in CCl 4 -induced mice. Gut barrier function was impaired in DSS- and DSS + CCl 4 -treated mice, manifesting as the increase in bacterial translocation and lipopolysaccharide level, and the reduction in tight junction proteins (occluding, claudin-1 and ZO-1) expression. Further, the activations of HSCs and TLR4 signaling pathway were observed after DSS + CCl 4 treatment, presenting with the increase in expression of α-SMA, vimentin, TGF-β, collagen type I, collagen type II, TIMP-2, TLR4, TRAF6, and NF-κB p65, and a decrease in GFAP and MMP-2 expression. Conclusion: The present study verified that UC aggravated CCl 4 -induced liver injury, inflammation, and fibrosis in mice through the gut-liver axis. Gut barrier dysfunction in UC leads to bacterial translocation and elevated lipopolysaccharide, which may promote the activation of TLR4 signaling and HSCs in the liver., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Niu, Li, Guo, Song, Li and Zhang.)

Purpose: Endometriosis is a common chronic gynecological disease greatly affecting women health. Prior studies have implicated that dysferlin (DYSF) aberration might be involved in the pathogenesis of ovarian endometriosis. In the present study, we explore the potential presence of DYSF mutations in a total of 152 Han Chinese samples with ovarian endometriosis., Methods: We analyze the potential presence of DYSF mutations by direct DNA sequencing., Results: A total of seven rare variants/mutations in the DYSF gene in 10 out of 152 samples (6.6%) were identified, including 5 rare variants and 2 novel mutations. For the 5 rare variants, p.R334W and p.G941S existed in 2 samples, p.R865W, p.R1173H and p.G1531S existed in single sample, respectively; for the two novel mutations, p.W352* and p.I1642F, they were identified in three patients. These rare variants/mutations were absent or existed at extremely low frequency either in our 1006 local control women without endometriosis, or in the China Metabolic Analytics Project (ChinaMAP) and Genome Aggregation Database (gnomAD) databases. Evolutionary conservation analysis results suggested that all of these rare variants/mutations were evolutionarily conserved among 11 vertebrate species from Human to Fox. Furthermore, in silico analysis results suggested these rare variants/mutations were disease-causing. Nevertheless, we find no significant association between DYSF rare variants/mutations and the clinical features in our patients. To our knowledge, this is the first report revealing frequent DYSF mutations in ovarian endometriosis., Conclusion: We identified a high frequency of DYSF rare variants/mutations in ovarian endometriosis for the first time. This study suggests a new correlation between DYSF rare variants/mutations and ovarian endometriosis, implicating DYSF rare variants/mutations might be positively involved in the pathogenesis of ovarian endometriosis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

There is accumulating evidence showing that exercise therapy may play an active role in peripheral neuropathic pain (NP), but its mechanism is still unclear. Studies have found that microRNAs (miRNAs) may play a role in NP by regulating pain-related target genes. Therefore, we aimed to explore the changes of miRNA and mRNA of dorsal root ganglion (DRG) after NP in response to exercise with transcriptome technology. The chronic constriction injury (CCI) model was established, and rats were randomly allocated into three groups, namely, the sham-operated, CCI, and CCI-exercised groups. L4-L6 DRG tissue was taken for RNA-sequencing, and the differentially expressed genes (DEGs) were determined through bioinformatics analysis. Real-time PCR was used to confirm the accuracy. A total of 4 overlapping differentially expressed miRNAs and 186 overlapping differentially expressed mRNAs were identified in the two comparisons of the sham-operated group versus the CCI group and the CCI group versus the CCI-exercised group. Among these DEGs, miR-145-5p, miR-341, miR-300-5p, miR-653-5p, Atf3, Cacna2d1, Gal, and Ctss related to NP were validated by real-time PCR. DEGs between the CCI and CCI-exercised groups were enriched in HIF-1 signaling pathway, Rap1 signaling pathway, and neurotrophin signaling pathway. This study provides an understanding of the adaptive mechanisms after exercise of NP, and these DEGs in DRG might play a role in NP by stimulating the enriched pathways., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Jia-Bao Guo et al.)

Introduction: Diabetes mellitus is an expanding global health problem. Currently, the home management of diabetes is mainly led by a multidisciplinary team based on telemedicine. However, the role nurses play in it remains inconclusive. This study aimed to investigate the effectiveness of nurse-led web-based intervention on glycated haemoglobin, blood pressure and lipid profile in patients with type 2 diabetes., Methods: An exhaustive systematic literature search was undertaken using the following databases: PubMed, Web of Science, Embase, The Cochrane Central Register of Controlled Trials and CINAHL. Two investigators independently extracted data and assessed the quality of the studies by examining the risk of bias and using Modified Jadad Score system. We conducted a meta-analysis of randomized controlled trials that had been published from inception to July 2020, using Review Manager 5.3., Results: Eleven randomized controlled trials were selected that included 2063 participants. Meta-analyses results indicated significant effects on not only glycated haemoglobin (pooled mean difference (MD) = -0.40, 95% confidence interval (CI): -0.5 to -0.26, p  < 0.00001), but also on systolic blood pressure (pooled MD = -1.91, 95% CI: -3.73 to -0.09, p  = 0.04) and low density lipoprotein (pooled standardized MD = -0.29, 95% CI: -0.44 to -0.15, p  < 0.0001). There were no effects of nurse-led web-based intervention on fasting blood glucose, diastolic blood pressure, high density lipoprotein, body mass index and triglycerides., Discussion: Nurse-led web-based intervention is a promising way to complement routine clinical care. However, the specific intervention content and intervention media still need to carry out large-scale well-designed randomized controlled trials. Systematic review registration: PROSPERO CRD 42020204565.

Herein, a new "turn on" fluorescent probe C-1 is developed to specifically detect hydrazine using coumarin nucleus as the fluorophore and β-diketone as the recognition group. The probe shows high selectivity towards hydrazine over other common ions and amine-containing species, as well as good water solubility and quantitative detectability of hydrazine in concentration range of 1-200 μM. The detection limit is as low as 1.89 ppb, which is lower than the threshold set by EPA (10 ppb). Probe-coated filter papers are confirmed to detect gaseous hydrazine successfully through obvious fluorescence color changes. In addition, the probe has been verified to detect hydrazine in actual water environment and living cells., 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 © 2021 Elsevier B.V. All rights reserved.)

Accurately quantifying the impacts of environmental factors and canopy structure on stem sap flow is of great significance for deeply understanding water use strategies of trees in changing environment. The stem sap flow of Larix principis-rupprechtii plantation was observed using thermal diffusion probes from June to September of 2019 in the Xiangshuihe small watershed of Liupan Mountains, with the meteorological conditions, root-zone soil water content and canopy structure being simultaneously recorded. We first analyzed the relationships of sap flow rate ( J c ) to potential evapotranspiration (PET), relative extract water (REW) and canopy leaf area index (LAI), and then quantified their relative contribution to J c . The results showed that the response of J c to PET, LAI, and REW conformed to binomial, linearly increase and saturated exponential function, respectively. The J c model coupling multiple factors was established as a continuous multiplication of the response functions of J c to PET, REW and LAI, which had good simulation precision. PET was the main factor leading to the difference of J c in different weather conditions. The average contribution rate of PET had obvious difference in sunny (with a contribution rate of 40.3%), cloudy (4.3%), and rainy days (-26.3%). PET and LAI were the leading factors affecting the J c variation among months. The ranges of the contribution rates of PET and LAI were from -23.1% to 16.8% and from -12.3% to 11.0%, respectively. The J c model coupling the multi-factor effect developed in this study could be used to predict J c , and quantify the impacts of each leading factor, which had the potential to be an effective tool to analyze the water use of trees in the changing environment.

Androgen plays a significant role in the development and progression of prostate cancer (PCa), one of the commonest malignancies in the male urogenital system. Castration-resistant PCa (CRPC) is the end-result of the majority of prostate cancer cases treated by androgen deprivation therapy (ADT). Furthermore, the androgen axis is reactivated due to adaptive intratumoral androgen biosynthesis, which can be driven by adrenal androgens and /or by changes in the androgen receptor (AR) including AR gene amplification. At present, drugs targeting the androgen axis, such as abiraterone and enzalutamide, et al, are used for the first-line therapy for CRPC. Nevertheless, drug resistance and disease progression occur during the treatment of CRPC by anti-androgen therapy. Therefore, an insight into the mechanisms of drug resistance in anti-androgen therapy for CRPC may help surmount the drug reistance and improve the prognosis of the malignancy.

Up to 90% of the human genome is transcribed into Long-noncoding RNAs (lncRNAs) that longer than 200 nucleotides but do not code for proteins. LncRNAs play a vital role in a broad range of biological process, it's dysregulations and mutations are linked to the development and progression of various complex human diseases. Given the dramatic changes and growing scientific outputs in lncRNAs field, using a quantitative measurement to analyze and characterize the existing studies has become imperative.Bibliometric analysis is a widely used tool to assess the academic influence of a publication or a country in a specific field. However, a bibliometric analysis of the top 100 most-cited papers in lncRNAs area has not been conducted. Thus, we executed a bibliometric study to identify the authors, journals, countries and institutions that contributed most to the top 100 lncRNAs list, characterize the key words and focus of top 100 most-cited papers, and detect the factors related to their successful citation. This study provides a comprehensive list of the most influential papers on lncRNAs research and demonstrates the important advances in this field, which might be benefit to researchers in their paper publication and scientific cooperation.

Background: Low-tension traction is more effective than high-tension traction in restoring the height and rehydration of a degenerated disc and to some extent the bony endplate. This might better reshape the microenvironment for disc regeneration and repair. However, the repair of the combination of endplate sclerosis, osteophyte formation, and even collapse leading to partial or nearly complete occlusion of the nutrient channel is greatly limited., Purpose: To evaluate the effectiveness of low-intensity extracorporeal shock wave therapy (ESWT) combined with low tension traction for regeneration and repair of moderately and severely degenerated discs; to explore the possible mechanism of action., Study Design: Animal study of a rat model of degenerated discs., Methods: A total of thirty-five 6-month old male Sprague-Dawley rats were randomly assigned to one of five groups (n=7, each group). In Group A (model group), caudal vertebrae were immobilized using a custom-made external device to fix four caudal vertebrae (Co7-Co10) whereas Co8-Co9 underwent 4 weeks of compression to induce moderate disc degeneration. In Group B (experimental control group), as in Group A, disc degeneration was successfully induced after which the fixed device was removed for 8 weeks of self-recovery. The remaining three groups of rats represented the intervention Groups (C-E): after successful generation of disc degeneration in Group C (com - 4w/tra - 4w) and Group D (com - 4w/ESWT), as described for group A, low-tension traction (in-situ traction) or low-energy ESWT was administered for 4 weeks (ESWT parameters: intensity: 0.15 Mpa; frequency: 1 Hz; impact: 1,000 each time; once/week, 4 times in total); Group E (com - 4w/tra - 4w/ESWT): disc degeneration as described for group A, low-tension traction combined with low-energy ESWT was conducted (ESWT parameters as Group D). After experimentation, caudal vertebrae were harvested and disc height, T2 signal intensity, disc morphology, total glycosaminoglycan (GAG) content, gene expression, structure of the Co8-Co9 bony endplates and elastic moduli of the discs were measured., Results: After continuous low-tension traction, low energy ESWT intervention or combined intervention, the degenerated discs effectively recovered their height and became rehydrated. However, the response in Group D was weaker than in the other intervention groups in terms of restoration of intervertebral disc (IVD) height, whereas Group E was superior in disc rehydration. Tissue regeneration was evident in Groups C to E using different interventions. No apparent tissue regeneration was observed in the experimental control group (Group B). The histological scores of the three intervention groups (Groups C-E) were lower than those of Groups A or B (p<.0001), and the scores of Groups C and E were significantly lower than those of Group D (p<.05), but not Group C versus Group E (p>.05). Compared with the intervention groups (Groups C-E), total GAG content of the nucleus pulposus (NP) in Group B did not increase significantly (p>.05). There was also no significant difference in the total GAG content between Groups A and B (p>.05). Of the three intervention groups, the recovery of NP GAG content was greatest in Group E. The expression of collagen I and II, and aggrecan in the annulus fibrosus (AF) was up-regulated (p<.05), whereas the expression of MMP-3, MMP-13, and ADAMTS-4 was down-regulated (p<.05). Of the groups, Group E displayed the greatest degree of regulation. The trend in regulation of gene expression in the NP was essentially consistent with that of the AF, of which Group E was the greatest. In the intervention groups (Groups C-E), compared with Group A, the pore structure of the bony endplate displayed clear changes. The number of pores in the endplate in Groups C to E was significantly higher than in Group A (p<.0001), among which Group C versus Group D (p=.9724), and Group C versus Group E (p=.0116). There was no significant difference between Groups A and B (p=.5261). In addition, the pore diameter also increased, the trend essentially the same as that of pore density. There was no significant difference between the three intervention groups (p=.7213). It is worth noting that, compared with Groups A and B, peripheral pore density and size in Groups D and E of the three intervention groups recovered significantly. The elastic modulus and diameter of collagen fibers in the AF and NP varied with the type of intervention. Low tension traction combined with ESWT resulted in the greatest impact on the diameter and modulus of collagen fibers., Conclusions: Low energy ESWT combined with low tension traction provided a more stable intervertebral environment for the regeneration and repair of moderate and severe degenerative discs. Low energy ESWT promoted the regeneration of disc matrix by reducing MMP-3, MMP-13, and ADAMTS-4 resulting in inhibition of collagen degradation. Although axial traction promoted the recovery of height and rehydration of the IVD, combined with low energy ESWT, the micro-nano structure of the bony endplate underwent positive reconstruction, tension in the annulus of the AF and nuclear stress of the NP declined, and the biomechanical microenvironment required for IVD regeneration and repair was reshaped., (Copyright © 2020. Published by Elsevier Inc.)

Background: By blocking the cascade of reactions leading to intervertebral disc degeneration through immobilization-traction, a delay in intervertebral disc degeneration and its regeneration, to some extent, has been observed. However, the precise balance of regulation of the microenvironment of intervertebral disc biomechanics and coordination of the complex spatiotemporal reconstruction of the extracellular matrix have not yet been solved, and clinical results are far from successful., Purpose: In the present study, a mechanical degeneration model was constructed to evaluate the possibility and effectiveness of disc regeneration or repair through low-tension traction of degenerated discs so as to provide basic biomechanical information for clinical optimization of the traction device and to establish traction parameters for prevention and treatment of disc degeneration., Study Design: A macro-, micro-, and nano-level structural analysis of degenerative discs of rat tail before and after controlled traction., Methods: Six-month-old male Sprague-Dawley rats were randomly divided into seven groups: Group A: control group (instrumented with Kirschner [K]-wires only); Group B: Model group (caudal vertebrae immobilized using a custom-made external device to fix four caudal vertebrae [Co7-Co10], while Co8-Co9 vertebrae underwent 4 weeks of compression to induce disc degeneration); Group C: experimental control group (devices removed after the 4 week compression described in Group B, and recovered by themselves for 4 weeks). The remaining four groups represented intervention groups (Groups D and F: Co8-Co9 vertebrae compressed for 4 weeks followed by 2 or 4 weeks of in situ traction, respectively; Groups E and G: vertebrae compressed for 4 weeks followed by 2 or 4 weeks of excessive traction, respectively). X-ray and magnetic resonance imaging were performed at each time point to measure disc height and T2 signal intensity. At the end of the experiment, the animals were euthanized and tail vertebrae harvested for analysis of intervertebral disc histopathology, proteoglycan content, elastic modulus of fibers of the annulus fibrosus (AF) and nucleus pulposus (NP), and microstructure of the bony end plate., Results: After 2 to 4 weeks of continuous traction (in situ and excessive traction), the Co8-Co9 intervertebral disc space of rats in Groups D to G increased significantly compared with Groups B and C (p < .05). In addition, signs of tissue regeneration were apparent in all four intervention groups (D-G). In addition, histologic scores of the intervention groups (D-G) were significantly lower than those in the model and experimental control groups (Groups B and C, respectively), although no significant difference was found between those four groups. Compared with the model group (Group B), total proteoglycan content of the NP in the intervention groups (D-G) increased significantly (p < .05). After 2 to 4 weeks of intervention (in situ and excessive traction), the morphology of pores in the bony end plate, their number, and the diameter had recovered significantly compared with those in Group B. The in situ traction group was superior to the excessive traction group, and 4 weeks in situ group significantly superior to the 2 weeks group. In all intervention groups, in both the inner and outer AF, mean fibril diameter decreased significantly (p < .05), although they remained larger in the excessive traction group than that in the in situ traction group. Consistent with trend in collagen fiber diameter, the outer AF was stiffer than the inner, and the modulus of the AF in each intervention group not significantly different from that of the control group (Group A) except Group C. However, within the NP, the variation in trend in diameter and modulus of collagen fibers was essentially inconsistent with that of the AF., Conclusions: Degenerated discs exhibit greater reconstruction after low tension traction. It is clear that the intervertebral disc mechanical microenvironment depends to a greater extent on low-tension traction than high-tension traction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ganoderic acid A (GA) is one of the most abundant triterpenoids in Ganoderma lucidum, and has been proved to possess a wide range of beneficial health effects. The aim of the current study is to investigate the amelioration effects and mechanism of GA on improving hyperlipidemia in mice fed a high-fat diet (HFD). The results showed that GA intervention significantly inhibited the abnormal growth of body weight and epididymal white adipose tissue (eWAT), prevented the hypertrophy of epididymal adipocytes, and ameliorated the biochemical parameters of serum and liver related to lipid metabolism in HFD-fed mice. Histological analysis also showed that the excessive accumulation of lipid droplets in the liver induced by HFD-feeding was greatly alleviated by GA intervention. In addition, GA intervention also increased the level of short chain fatty acids (SCFAs) in the intestine and promoted the excretion of bile acids (BAs) through feces. High-throughput sequencing of bacterial full-length 16S rDNA revealed that daily supplementation with GA made significant structural changes in the gut microbial population of mice fed with HFD, in particular modulating the relative abundance of some function related microbial phylotypes. The relationships between lipid metabolic parameters and gut microbial phylotypes were also revealed by correlation analysis based on a heatmap and network. The result showed that 46 key gut microbial phylotypes (OTUs) were markedly correlated with at least one lipid metabolic parameter. Moreover, UPLC-QTOF/MS-based liver metabolomics showed that 111 biomarkers (47 up-regulated metabolites and 64 down-regulated metabolites) were significantly changed after high-dose GA intervention (75 mg kg -1 day -1 ), compared with the HFD-fed hyperlipidemic mice. Metabolic pathway enrichment analysis of the differential hepatic metabolites demonstrated that GA intervention had significant regulatory effects on primary bile acid biosynthesis, fatty acid biosynthesis, amino sugar and nucleotide sugar metabolism, inositol phosphate metabolism, and so on. In addition, GA intervention regulated the mRNA levels of hepatic genes involved in fatty acid metabolism and bile acid homeostasis. These findings present new evidence supporting that GA from G. lucidum has the potential to alleviate lipid metabolic disorders and ameliorate the imbalance of gut microflora in a positive way.

Background: Articular cartilage has a high-weight-bearing area and a low-weight-bearing area, the macroscopic elastic moduli of the two regions are different. Chondrocytes are affected by the applied force at the microscopic level. Currently, the modulus of the two areas at the micro and nano levels is unknown, and studies on the relationship between macro-, micro- and nano-scale elastic moduli are limited. Such information may be important for further understanding of cartilage mechanics. Moreover, the surface morphology, proteoglycan content, and micro and nano structure of the two areas, which influences the mechanical properties of cartilage should be discussed., Methods: Safranin-O/Fast Green staining was used to evaluate the surface morphology and semi-quantify proteoglycan content of porcine femoral head cartilage between the two weight-bearing areas. The unconfined compression test was used to determine the macro elastic modulus. Atomic force microscope was used to measure the micro and nano compressive elastic modulus as well as the nano structure. Scanning electron microscope was employed to evaluate the micro structure., Results: No significant differences in the fibrillation index were observed between two areas (P = 0.5512). The Safranin-O index of the high-weight-bearing area was significantly higher than that of the low-weight-bearing area (P = 0.0387). The compressive elastic modulus of the high-weight-bearing area at the macro and micro level was significantly higher than that of the low-weight-bearing area (P = 0.0411 for macro-scale, and P = 0.0001 for micro-scale), while no statistically significant differences were observed in the elastic modulus of collagen fibrils at the nano level (P = 0.8544). The density of the collagen fibers was significantly lower in the high-weight-bearing area (P = 0.0177). No significant differences were observed in the structure and diameter of the collagen fibers between the two areas (P = 0.7361)., Conclusions: A higher proteoglycan content correlated with a higher compressive elastic modulus of the high-weight-bearing area at the micro level than that of the low-weight-bearing area, which was consistent with the trend observed from the macroscopic compressive elastic modulus. The weight-bearing level was not associated with the elastic modulus of individual collagen fibers and the diameter at the nano level. The micro structure of cartilage may influence the macro- and micro-scale elastic modulus.

Background: To retrospectively investigate the clinical characteristics, initial treatment, relapse, therapy outcome, and prognosis of Chinese patients with primary testicular lymphoma (PTL) through analysis of the cases of our institute., Methods: From December 2008 to July 2018, all patients with PTL were included in this study. Kaplan-Meier method was used to estimate PFS and OS. The Cox proportional hazards model was used to compare the survival times for groups of patients differing in terms of clinical and laboratory parameters., Results: All 28 PTL patients (24 DLBCL, three NK/T lymphomas, and one Burkkit's lymphoma) with a median age of 65.5 years were included in this study. Six patients were observed recurrence among all the 22 individuals evaluated. Following orchiectomy and systemic chemotherapy, with or without intrathecal prophylaxis, complete response was achieved in 15 (68%) patients. For DLBCL patients, the median progression-free survival (PFS) was 44.63 months (95% CI 17.71-71.56 months), and the median overall survival (OS) was 77.02 months (95% CI, 57.35-96.69 months). For all the DLBCL patients, the 5-year PFS and 5-year OS were 35.4% (95%CI, 14.8-56.0%) and 53.4% (95%CI, 30.1-76.7%). Without further chemotherapy following orchiectomy (HR = 3.4, P = 0.03) were associated with inferior PFS of DLBCL patients. Advanced Ann Arbor stage (HR =5.9, P = 0.009) and high (international prognostic index, IPI) score: 3-5 (HR =3.9, P = 0.04) were correlated with shorter OS of DLBCL patients., Conclusion: This study confirms that PTL is an aggressive malignant with a poor prognosis. Limited Ann Arbor stage, further chemotherapy following orchiectomy, and low IPI score (less than 2) are correlated with superior survival for DLBCL patients.

The chromatin modifier enhancer of zeste homolog 2 (EZH2) methylates lysine 27 of histone H3 (H3K27) and regulates T cell differentiation. However, the potential role of EZH2 in the pathogenesis of rheumatoid arthritis (RA) remains elusive. We analyzed EZH2 expression in PBMC, CD4 + T cells, CD19 + B cell, and CD14 + monocytes from active treatment-naïve RA patients and healthy controls (HC). We also suppressed EZH2 expression using EZH2 inhibitor GSK126 and measured CD4 + T cell differentiation, proliferation and apoptosis. We further examined TGFβ-SMAD and RUNX1 signaling pathways in EZH2-suppressed CD4 + T cells. Finally, we explored the regulation mechanism of EZH2 by RA synovial fluid and fibroblast-like synoviocyte (FLS) by neutralizing key proinflammatory cytokines. EZH2 expression is lower in PBMC and CD4 + T cells from RA patients than those from HC. EZH2 inhibition suppressed regulatory T cells (Tregs) differentiation and FOXP3 transcription, and downregulated RUNX1 and upregulated SMAD7 expression in CD4 + T cells. RA synovial fluid and fibroblast-like synoviocytes suppressed EZH2 expression in CD4 + T cells, which was partially neutralized by anti-IL17 antibody. Taken together, EZH2 in CD4 + T cells from RA patients was attenuated, which suppressed FOXP3 transcription through downregulating RUNX1 and upregulating SMAD7 in CD4 + T cells, and ultimately suppressed Tregs differentiation. IL17 in RA synovial fluid might promote downregulation of EZH2 in CD4 + T cells. Defective EZH2 in CD4 + T cells might contribute to Treg deficiency in RA., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Immobilization can lead to intervertebral disc degeneration. The biomechanical characteristics of such discs have not so far been investigated at the micro- or nanoscale, the level at which cells sense and respond to the surrounding environment. This study aimed to characterize changes in the elastic modulus of the collagen fibrils in the nucleus pulposus at the nanoscale and correlate this with micro-biomechanical properties of the nucleus pulposus after immobilization, in addition to observation of tissue histology and its gene expressions. An immobilization system was used on the rat tail with an external fixation device. The elastic modulus was measured using both nano and micro probes for atomic force microscopy after 4 and 8 weeks of immobilization. Histology of the tissue was observed following hematoxylin and eosin staining. Gene expression in the annulus fibrosus tissue was quantified using real-time reverse transcription-polymerase chain reaction. The elastic modulus of the collagen fibrils in the nucleus pulposus at the nanoscale increased from 74.07 ± 17.06 MPa in the control to 90.06 ± 25.51 MPa after 8 weeks (P = 0.007), and from 33.51 ± 9.33 kPa to 43.18 ± 12.08 kPa at the microscale (P = 0.002). After immobilization for 8 weeks, a greater number of cells were observed by histology to be aggregated within the nucleus pulposus. Collagen II (P = 0.007) and aggrecan (P = 0.003) gene expression were downregulated whereas collagen I (P = 0.002), MMP-3 (P < 0.001), MMP-13 (P < 0.001) and ADAMTs-4 (P < 0.001) were upregulated. Immobilization not only influenced individual collagen fibrils at the nanoscale, but also altered the micro-biomechanics and cell response in the nucleus pulposus. These results suggest that significant changes occur in intervertebral discs at both scales after immobilization, a situation about which clinicians should be aware when immobilization has to be used clinically., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: Neutrophil infiltration in patients with sinonasal inverted papilloma (SNIP) is significantly high. Whether IL-17, which is a potent factor mediating neutrophilic inflammation, is involved in the neutrophilic phenotype of SNIP is investigated in the current study., Study Design: Laboratorial study., Participants: Nasal papilloma and inferior turbinate were collected from patients with SNIP (n = 50) and control subjects with septal deviation (n = 15)., Methods: IL-17 + cells were evaluated in tissues obtained from patients with SNIP and control subjects with septal deviation, by immunohistochemistry and flow cytometry., Main Outcome Measures: The IL-17 + cells were mainly localised in mononuclear cells and neutrophils, and were up-regulated in the SNIP samples compared with those in the controls. The IL-17 + T-cell subsets mainly included CD4+ (Th17, 60.0%) and CD8+ (Tc17, 30.0%), and both subsets were enhanced in the SNIP samples than controls. The total level of IL-17 + cells was significantly correlated with neutrophil infiltration in the SNIP tissues. Furthermore, the SNIP homogenates could significantly promote IL-17 production in peripheral blood mononuclear cells., Conclusions: An increase in IL-17 + cells is evident in SNIP and may be involved in neutrophil infiltration in local tissues. IL-17 could be a potential therapeutic target to relieve the neutrophilic pathological change in SNIP., (© 2019 John Wiley & Sons Ltd.)

Objectives The aim of our study was to ascertain the underlying role of microRNAs (miRNAs) in human intervertebral disc degeneration (IDD). Design Bioinformatic analysis from multiple databases. Methods Studies of the association of miRNAs and IDD were identified in multiple electronic databases. All potential studies were assessed by the same inclusion and exclusion criteria. We recorded whether miRNA expression was commonly increased or suppressed in the intervertebral disc tissues and cells of IDD subjects. We used String to identify biological process and cellular component pathways of differentially expressed genes. Results We included fifty-seven articles from 1,277 records in this study. This report identified 40 different dysregulated miRNAs in 53 studies, including studies examining cell apoptosis (26 studies, 49.06%), cell proliferation (15 studies, 28.3%), extracellular matrix (ECM) degradation (10 studies, 18.86%), and inflammation (five studies, 9.43%) in IDD patients. Three upregulated miRNAs (miR-19b, miR-32, miR-130b) and three downregulated miRNAs (miR-31, miR-124a, miR-127-5p) were considered common miRNAs in IDD tissues. The top three biological process pathways for upregulated miRNAs were positive regulation of biological process, nervous system development, and negative regulation of biological process, and the top three biological process pathways for downregulated miRNAs were negative regulation of gene expression, intracellular signal transduction, and negative regulation of biological process. Conclusions This study revealed that miRNAs could be novel targets for preventing IDD and treating patients with IDD by regulating their target genes. These results provide valuable information for medical professionals, IDD patients, and health care policy makers., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Atorvastatin (ATO) is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used to treat hypercholesterolemia. However, clinical application is limited by potential hepatotoxicity. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidants, and oxidative stress is implicated in statin-induced liver injury. This study investigated mechanisms of ATO-induced hepatotoxicity and potential mitigation by Nrf2 signaling. ATO reduced Nrf2 and antioxidant enzyme superoxide dismutase-2 (SOD2) expression in human hepatocarcinoma HepG2 cells. ATO also induced concentration-dependent HepG2 cell toxicity, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential (MMP) and cellular adenosine triphosphate (ATP). Further, ATO induced mitochondria-dependent apoptosis as indicated by increased Bax/Bcl-2 ratio, cleaved caspase-3, mitochondrial cytochrome c release and Annexin V-fluorescein isothiocyanate/propidium iodide staining. Tert-butylhydroquinone enhanced Nrf2 and SOD2 expression, and partially reversed ATO-induced cytotoxicity, ROS accumulation, MMP reduction, ATP depletion and mitochondria-dependent apoptosis. In conclusion, the present study demonstrates that ATO induces mitochondrial dysfunction and cell apoptosis in HepG2 cells, at least in part, via inhibition of the Nrf2 pathway. Nrf2 pathway activation is a potential prevention for ATO-induced liver injury., (© 2019 John Wiley & Sons, Ltd.)

Ca 2+ is an important microbial growth factor that can affect the activity, flocculation, and sedimentation of activated sludge. In order to study the roles of Ca 2+ in the activated sludge system, the activity changes of ammonium oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) were analyzed using the specific oxygen uptake rates (SOUR AOB and SOUR NOB ). The changes in composition and structure of extracellular polymeric substances (EPS) were analyzed using Fourier transform infrared spectroscopy (FTIR) and three-dimensional excitation emission fluorescence spectroscopy (3D-EEM). The effects of Ca 2+ on the nitrification activity and microbial metabolites were investigated. The results showed that when the Ca 2+ concentration increased from 0.45 mmol·L -1 to 3 mmol·L -1 , SOUR AOB and SOUR NOB increased from 6.3 mg·(g·h) -1 to 10.4 mg·(g·h) -1 and from 2.3 mg·(g·h) -1 to 3.7 mg·(g·h) -1 , respectively. The EPS concentrations increased from 68 mg·g -1 to 93 mg·g -1 , and the flocculation ability (FA) of the sludge was improved. When the Ca 2+ concentration was higher than 3 mmol·L -1 , SOUR AOB and SOUR NOB both decreased. The FA was maintained at about 30%, and the particle size of the sludge continued to increase. Based on FTIR analysis, the main components of EPS were always amino, amide Ⅰ, and carboxyl with an increase in Ca 2+ concentration. Based on EEM analysis, the composition of loosely-bound (LB)-EPS did not change, and humic acid substances appeared in the tightly-bound (TB)-EPS at low nitrification rates. Low concentrations of Ca 2+ promoted nitrification activity and flocculation of the sludge. However, high concentrations of Ca 2+ led to a decline in the sludge nitrification activity.

The molecular mechanisms underlying neuropathic pain (NP) remain poorly understood. Emerging evidence has suggested the role of microRNAs (miRNAs) in the initiation and development of NP, but the specific effects of miRNAs in NP are largely unknown. Here, we use network- and pathway-based methods to investigate NP-induced miRNA changes and their biological functions by conducting a systematic search through multiple electronic databases. Thirty-seven articles meet the inclusion criteria. Venn analysis and target gene forecasting are performed and the results indicate that 167 overlapping target genes are co-regulated by five down-regulated miRNAs (rno-miR-183, rno-miR-96, rno-miR-30b, rno-miR-150 and rno-miR-206). Protein-protein interaction network analysis shows that 77 genes exhibit interactions, with cyclic adenosine monophosphate (cAMP)-dependent protein kinase catalytic subunit beta (degree = 11) and cAMP-response element binding protein 1 (degree = 10) having the highest connectivity degree. Gene ontology analysis shows that these target genes are enriched in neuron part, neuron projection, somatodendritic compartment and nervous system development. Moreover, analysis of Kyoto Encyclopedia of Genes and Genomes reveals that three pathways, namely, axon guidance, circadian entrainment and insulin secretion, are significantly enriched. In addition, rno-miR-183, rno-miR-96, rno-miR-30b, rno-miR-150 and rno-miR-206 are consistently down-regulated in the NP models, thus constituting the potential biomarkers of this disease. Characterizing these miRNAs and their target genes paves way for their future use in clinical practice., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)