Study on the causal relationship between educational attainment and delirium: A two-sample Mendelian randomization study.

This study aimed to investigate whether there is a causal relationship between educational attainment and delirium at the genetic level using the Mendelian randomization method, and provide new evidence for studies in this field. We found a causal relationship between educational attainment and delirium at the genetic level after excluding confounders using Mendelian randomization. The inverse variance weighting method of random effects was the main analysis method. The weighted median and Mendelian Randomization-Egger methods, as well as simple, and weighted modes were used as supplementary analysis methods. Additionally, horizontal pleiotropy tests were conducted, including the Mendelian Randomization-Egger intercept test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. Cochran's Q statistic was used to assess the size of heterogeneity. We retrieved all second single nucleotide polymorphism features and performed multivariate Mendelian randomization to adjust for the effect of potential confounders on our results. The inverse variance weighting suggested a negative correlation between genetically predicted educational attainment and delirium (0.67[0.49-0.92], p = 0.013); Mendelian Randomization Pleiotropy RESidual Sum and Outlier (0.67[0.49-0.92], p = 0.013) and multivariate Mendelian randomization (0.52[0.33-0.82], p = 0.005) results were generally consistent with the inverse variance weighting method. The Mendelian Randomization-Egger, simple, and weighted mode results were consistent with the inverse variance weighting results. Our results were not affected by pleiotropy or heterogeneity (p > 0.05, for both pleiotropy and heterogeneity). In addition, the "leave-one-out" analysis showed that the results of our Mendelian randomization analysis were not influenced by individual single nucleotide polymorphisms. Studies have found a causal relationship between educational attainment and delirium at the genetic level; higher educational attainment may be a protective factor against delirium. Clinically, more attention should be paid to patients at a high risk of delirium with low educational attainment.

A bidirectional Mendelian randomized study of classical blood lipids and venous thrombosis.

There is still some controversy about the relationship between lipids and venous thrombosis (VTE). A bidirectional Mendelian randomization (MR) study was conducted to clarify the causal relationship between three classical lipids (low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides (TGs)) and venous thromboembolism (VTE) (deep venous thrombosis (DVT) and pulmonary embolism (PE)). Three classical lipids and VTE were analysed by bidirectional Mendelian randomization (MR). We used the random effect inverse variance weighted (IVW) model as the main analysis model and the weighted median method, simple mode method, weighted mode method and MR-Egger methods as supplementary methods. The leave-one-out test was used to determine the influence of outliers. The heterogeneity was calculated by using Cochran Q statistics in the MR-Egger and IVW methods. The intercept term in the MR‒Egger regression was used to indicate whether horizontal pleiotropy affected the results of the MR analysis. In addition, MR-PRESSO identified outlier single-nucleotide polymorphisms (SNPs) and obtained a stable result by removing outlier SNPs and then performing MR analysis. When we used three classical lipids (LDL, HDL and TGs) as exposure variables, no causal relationship between them and VTE (DVT and PE) was found. In addition, we did not find significant causal effects of VTE on the three classical lipids in reverse MR analysis. There is no significant causal relationship between three classical lipids (LDL, HDL and TGs) and VTE (DVT and PE) from a genetic point of view.

Does Having Rheumatoid Arthritis Increase the Dose of Depression Medications? A Mendelian Randomization Study.

BACKGROUND: Rheumatoid arthritis (RA) increases the risk of depression. However, studies on the effects of RA on the dose of depression medications are limited. Therefore, in this study, we used two-sample Mendelian randomization (MR) to explore whether RA increases the dose of depression medications and gain a more comprehensive understanding of the relationship between RA and depression. METHODS: Two-sample MR was used to evaluate the causal effect of RA on the dose of depression medications. The aggregated data on RA originated from extensive genome-wide association studies (GWASs) of European descent (14,361 cases and 42,923 controls). The summary GWAS data for the dose of depression medications were derived from the FinnGen consortium (58,842 cases and 59,827 controls). Random effects inverse-variance weighted (IVW), MR-Egger regression, weighted median, and fixed effects IVW methods were used for the MR analysis. Random effects IVW was the primary method. The heterogeneity of the MR results was detected using the IVW Cochran's Q test. The pleiotropy of the MR results was detected using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. Finally, a leave-one-out analysis was performed to determine whether the MR results were affected by a specific single-nucleotide polymorphism (SNP). RESULTS: The primary method, random effects IVW, revealed that genetically predicted RA had a positive causal association with the dose of depression medications (Beta, 0.035; 95% confidence interval (CI), 0.007-0.064; p = 0.015). The IVW Cochran's Q test results revealed no heterogeneity in the MR analysis (p > 0.05). The MR-Egger regression and MR-PRESSO tests revealed that there was no pleiotropy in our MR analysis. The leave-one-out analysis confirmed that a single SNP did not affect the MR results, indicating the study's robustness. CONCLUSION: Using MR techniques, we discovered that having RA increases the dose of depression medications; however, the exact mechanisms and pathways still need to be further explored.

Causal relationship between osteoporosis and osteoarthritis: A two-sample Mendelian randomized study.

Introduction: At present, clinical studies have confirmed that osteoporosis (OP) has an inverse relationship with osteoarthritis (OA), but it has not been proven from the point of view of genetics, so our study hopes to clarify the potential effect of OP on OA at the level of gene prediction through two-sample Mendelian randomization (MR) analysis. Methods: A two-sample MR was adopted to research the causal relationship of OP with OA (including total OA, knee OA and hip OA). All data come from a public shared database. Such traditional methods as simple and weighted models, inverse variance weighted, weighted median, and Mendelian Randomization (MR-Egger) regression were employed to assess the causal effect of OP on OA. We used the Pleiotrophy RESidual Sum and Outlier (MR-PRESSO) method and MR-Egger method to study sensitivity. The leave-one-out test is used to determine the influence of outliers. The heterogeneity was calculated by using Cochran Q statistics and MR-Egger regression in the inverse variance-weighted (IVW) method. P > 0.05 indicates that there is a large heterogeneity. MR-Robust Adjustment Profile Score (RAPS) is stable to both systematic and specific multiplicity, so we used MR-RAPS as a supplementary method to verify the results of IVW. Results: According to the results of IVW, we found that there was a causal relationship between OP and total OA, and OP reduced the incidence of total OA (beta=-0.285, OR=0.751, P value< 0.016). The MR estimation of the causal effect of OP on knee OA suggested that the genetic prediction of OP was negatively correlated with knee osteoarthritis (KOA) (IVW: beta=-6.11, OR=0.002, P value< 0.016). The IVW results suggested that OP was causally related to hip OA, and OP had a protective effect on hip OA (beta=-5.48, OR=4.15e-3, P value= 3.99e-3). Except for heterogeneity in the analysis of OP and knee OA, there was no horizontal pleiotropy or heterogeneity in the other analyses. Conclusion: We explored the causal relationship between OP and OA through a two-sample MR analysis and found that OP can reduce the incidence of OA (including knee OA and hip OA).

The role of oxidative stress in the development of knee osteoarthritis: A comprehensive research review.

Knee osteoarthritis (KOA) is one of the most common degenerative diseases, and its core feature is the degeneration and damage of articular cartilage. The cartilage degeneration of KOA is due to the destruction of dynamic balance caused by the activation of chondrocytes by various factors, with oxidative stress playing an important role in the pathogenesis of KOA. The overproduction of reactive oxygen species (ROS) is a result of oxidative stress, which is caused by a redox process that goes awry in the inherent antioxidant defence system of the human body. Superoxide dismutase (SOD) inside and outside chondrocytes plays a key role in regulating ROS in cartilage. Additionally, synovitis is a key factor in the development of KOA. In an inflammatory environment, hypoxia in synovial cells leads to mitochondrial damage, which leads to an increase in ROS levels, which further aggravates synovitis. In addition, oxidative stress significantly accelerates the telomere shortening and ageing of chondrocytes, while ageing promotes the development of KOA, damages the regulation of redox of mitochondria in cartilage, and stimulates ROS production to further aggravate KOA. At present, there are many drugs to regulate the level of ROS, but these drugs still need to be developed and verified in animal models of KOA. We discuss mainly how oxidative stress plays a part in the development of KOA. Although the current research has achieved some results, more research is needed.

Gene Set Enrichment Analysis Detected Immune Cell-Related Pathways Associated with Primary Sclerosing Cholangitis.

Aim: To explore various immune cell-related causal pathways for primary sclerosing cholangitis (PSC). Methods: Immune cell-related pathway association study was conducted via integrative analysis of PSC GWAS summary and five immune cell-related eQTL datasets. The GWAS summary data of PSC was driven from 4,796 PSC cases and 19,955 healthy controls. The eQTL datasets of CD4+ T cells, CD8+ T cells, B cells, natural killer cells (NK), monocytes, and peripheral blood cells (PB) were collected from recently eQTL study. The PSC GWAS summary dataset was first aligned with eQTL datasets of six blood cells to obtain the GWAS summary data at overlapped eQTL loci, separately. For each type of cell, the obtained PSC GWAS summary dataset of eQTLs was subjected to pathway enrichment analysis. 853 biological pathways from Kyoto Encyclopedia of Genes and Genomes, BioCarta, and Reactome pathway databases were analyzed. Results: We identified 36 pathways for B cells, 33 pathways for CD4+ T cells, 28 pathways for CD8+ T cells, 33 pathways for monocytes (MN), 35 pathways for NK cells, and 33 for PB cells (all empirical P values <5.0 × 10-5). Comparing the pathway analysis results detected 25 pathways shared by five immune cells, such as KEGG_CELL_ADHESION_MOLECULES_CAMS (P value <5.0 × 10-5) and REACTOME_MHC_CLASS_II_ANTIGEN_ PRESENTATION (P value <5.0 × 10-5). Several cell-specific pathways were also identified, including BIOCARTA_INFLAM_PATHWAY (P value <5 × 10-5) for B cell. Conclusion: Our study holds potential to identify novel candidate causal pathways and provides clues for revealing the complex genetic mechanism of PSC.

Immunomodulatory role of T helper cells in rheumatoid arthritis : a comprehensive research review.

Rheumatoid arthritis (RA) is an autoimmune disease that involves T and B cells and their reciprocal immune interactions with proinflammatory cytokines. T cells, an essential part of the immune system, play an important role in RA. T helper 1 (Th1) cells induce interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and interleukin (IL)-2, which are proinflammatory cytokines, leading to cartilage destruction and bone erosion. Th2 cells primarily secrete IL-4, IL-5, and IL-13, which exert anti-inflammatory and anti-osteoclastogenic effects in inflammatory arthritis models. IL-22 secreted by Th17 cells promotes the proliferation of synovial fibroblasts through induction of the chemokine C-C chemokine ligand 2 (CCL2). T follicular helper (Tfh) cells produce IL-21, which is key for B cell stimulation by the C-X-C chemokine receptor 5 (CXCR5) and coexpression with programmed cell death-1 (PD-1) and/or inducible T cell costimulator (ICOS). PD-1 inhibits T cell proliferation and cytokine production. In addition, there are many immunomodulatory agents that promote or inhibit the immunomodulatory role of T helper cells in RA to alleviate disease progression. These findings help to elucidate the aetiology and treatment of RA and point us toward the next steps. Cite this article: Bone Joint Res 2022;11(7):426-438.

The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes.

BACKGROUND: Heat shock protein family A member 5 (HSPA5), a recently identified suppressor of ferroptosis, was reported to potentially regulating osteoarthritis. However, the exact role of HSPA5 and how its expression was regulated in osteoarthritis are largely unclear. METHODS: Rat primary chondrocytes were treated with 10 ng/mL IL-1ß for 24 h and incubated with ferrostatin-1 (a ferroptosis inhibitor). Cell viability, production of TNF-α, ROS and MDA, expression levels of collagen II, MMP13, GPX4, and SND1, and Fe2+ concentration were detected. Gain- and loss-of-function manipulations were performed to investigate the effect of HSPA5 on chondrocyte functions, and SND1 shRNA (sh-SND1) was transfected into IL-1ß-treated primary chondrocytes alone or together with sh-HSPA5. Furthermore, the interaction between HSPA5 and GPX4 and the regulation of HSPA5 on GPX4 were explored. Finally, SND1 was knocked down in the rats with osteoarthritis, and the histopathology, expression of HSPA5-GPX4 axis, and levels of oxidative stress markers were evaluated. RESULTS: IL-1ß treatment could enhance extracellular matrix (ECM) degradation (collagen II reduced and MMP13 increased), promote ferroptosis, manifested by decreased cell viability, increased levels of TNF-α, ROS, MDA, and Fe2+ concentrations, and decreased level of GPX4 protein, and increase SND1 expression in chondrocytes, which could be reversed by ferrostatin-1. Knockdown of SND1 enhanced ECM degradation and suppressed ferroptosis IL-1ß-treated chondrocytes, which could be eliminated by knockdown of HSPA5. SND1 bound with HSPA5 at the 3'UTR and destabilized the HSPA5 mRNA. HSPA5 protein directly bound with GPX4 protein and positively regulate its expression. HSPA5 overexpression suppressed IL-1ß-induced chondrocyte ferroptosis, while this effect was counteracted by GPX4 silencing. Knockdown of SND1 upregulated HSPA5 and GPX4 in rat cartilage, inhibited inflammatory damage and ferroptosis, and alleviated OA progression. CONCLUSION: The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes.

Quantitative Proteomic Analysis of Synovial Tissue Reveals That Upregulated OLFM4 Aggravates Inflammation in Rheumatoid Arthritis.

Tandem mass tag (TMT)-coupled liquid chromatography coupled with tandem mass spectrometry is a powerful method to investigate synovial tissue protein profiles in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Protein was isolated from synovial tissue samples of 22 patients and labeled with a TMT kit. Over 500 proteins were identified as the differential expression protein on comparing RA and OA synovial tissue, including 239 upregulated and 271 downregulated proteins. Data are available via ProteomeXchange with identifier PXD027703. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that the majority participated in the developmental processes and protein processing in the endoplasmic reticulum. Olfactomedin 4 (OLFM4), a secreted glycoprotein, in joint inflammation of RA was explored. OLFM4 was upregulated in RA synovial tissue samples. In fibroblast-like synoviocytes (FLS), inflammation cytokines, TNF-α, interleukin (IL)-1ß, and LPS can upregulate OLFM4. After OLFM4 knockdown under TNF-α stimulation, RA FLS proliferation was inhibited and the expression of CXCL9, CXCL11, and MMP-1 was decreased. Overall, the RA synovial tissue protein expression profile by proteomic analysis shows some unique targets in RA pathophysiology, and OLFM4 in FLS plays an important role in RA joint inflammation. OLFM4 can be a promising therapeutic target in RA synovial tissue.

Integrative Analysis of MicroRNA and mRNA Sequencing Data Identifies Novel Candidate Genes and Pathways for Developmental Dysplasia of Hip.

OBJECTIVE: Our aim is to explore the candidate pathogenesis genes and pathways of developmental dysplasia of hip (DDH). DESIGN: Proliferating primary chondrocytes from hip cartilage were used for total RNA extraction including 5 DDH patients and 5 neck of femur fracture (NOF) subjects. Genome-wide mRNA and microRNA (miRNA) were then sequenced on the Illumina platform (HiSeq2500). Limma package was used for difference analysis of mRNA expression profiles. edgeR was used for difference analysis of miRNA expression profiles. miRanda was used to predict miRNA-target genes. The overlapped DDH associated genes identified by mRNA and miRNA integrative analysis were further compared with the differently expressed genes in hip osteoarthritis (OA) cartilage. RESULTS: Differential expression analysis identified 1,833 differently expressed mRNA and 186 differently expressed miRNA for DDH. Integrative analysis of mRNA and miRNA expression profiles identified 175 overlapped candidate genes (differentially expressed genes, DEGs) for DDH, such as VWA1, TMEM119, and SCUBE3. Further gene ontology enrichment analysis detected 111 candidate terms for DDH, such as skeletal system morphogenesis (P = 4.92 × 10-5) and skeletal system development (P = 8.85 × 10-5). Pathway enrichment analysis identified 14 candidate pathways for DDH, such as Hedgehog signaling pathway (P = 4.29 × 10-5) and Wnt signaling pathway (P = 4.42 × 10-2). Among the identified DDH associated candidate genes, we also found some genes were detected in hip OA including EFNA1 and VWA1. CONCLUSIONS: We identified multiple novel candidate genes and pathways for DDH, providing novel clues for understanding the molecular mechanism of DDH.

Elevated IL-22 in psoriasis plays an anti-apoptotic role in keratinocytes through mediating Bcl-xL/Bax.

IL-22 is known to mediate inflammation in psoriasis, while IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling. However, the function of IL-22 in regulating apoptosis in psoriasis remains poorly understood. In this study, we found that IL-22/IL-22R1 in lesional skin and IL-22 in serum from psoriatic patients were highly upregulated compared with healthy controls, while IL-22BP was not changed. Correlations between IL-22/IL-22R1 levels and the thickness of psoriatic lesions suggested that IL-22 might positively regulate abnormal hyperplasia in psoriasis. Apoptotic keratinocytes were increased only in stratum corneum, but not in spinous and basal layers of psoriasis. Moreover, IL-22 promoted cell viability in human epidermal keratinocytes (HEKs). The apoptosis induced by TNF-α and IFN-γ was inhibited in HEKs treated with IL-22, since that IL-22 upregulated Bcl-xL and downregulated Bax production in HEKs in the presence of TNF-α and IFN-γ. In addition, IL-22BP could counteract the anti-apoptotic effect of IL-22. Our finding demonstrates that IL-22 might play an anti-apoptosis role on keratinocytes to balance cell proliferation and apoptosis in psoriatic epidermis.

Fabellar prevalence, degeneration and association with knee osteoarthritis in the Chinese population.

The fabella is a sesamoid bone of the knee that can degenerate in some patients with osteoarthritis. The purpose of this study was to examine the prevalence and degeneration grades of fabellae in the Chinese population and to analyse their relationships with subject ages and knee osteoarthritis grades. The anteroposterior and lateral knee roentgenograms of 1150 subjects were recruited from the institutional database. The Kellgren-Lawrence scoring system was used to evaluate knee osteoarthritis. The degeneration grades of fabellae were scored in lateral roentgenograms by screening their shapes, sizes, subchondral sclerosis and osteophyte formation. The prevalence and degeneration of fabellae among ages, genders and knee sides were analysed by the Pearson Chi-Square test, and their relationships with knee osteoarthritis were analysed by the Spearman nonparametric correlation test. The overall prevalence of fabellae was 48.6% in 1359 knees. There was no significant difference in fabellar prevalence between the two sides (χ² = 0.025, P = 0.87437) and genders (χ² = 3.647, P = 0.05617), while the prevalence increased with the increasing ages of the subjects (χ² = 213.868, P < 0.001). The fabellar degeneration grades were correlated with age (r = 0.5288, P < 0.001) and knee osteoarthritis scores (r = 0.6892, P < 0.001). These results suggested that the fabellar prevalence and degeneration grades were correlated with age and knee osteoarthritis scores.

Increased expression of Th17 cytokines and interleukin-22 correlates with disease activity in pristane-induced arthritis in rats.

The objective of this study was to identify the key changed subtype of T helper cells (Th cells) and their cytokines in pristane-induced arthritis (PIA) in rats. The severity of arthritis was evaluated by body weight, clinical score, the perimeter of ankle and mid-paw and histological assessment of ankle joints. Cytokines of Th1, Th2 and Th17 were determined in the spleen and inguinal lymph nodes at 28 days after pristane injection by real-time qPCR. The mRNA levels of IL-22 receptors, IL-22R1 and IL-22BP, in the spleen were quantified by real-time qPCR. Additionally, IL-22 expression in synovial membrane was detected by Western blotting, and serum IL-22 concentration was determined by ELISA. Correlation between IL-22 concentration and clinical score was analyzed. By screening the cytokines of Th1, Th2 and Th17 expression profile, we found that the mRNA levels of Th17 cytokines were significantly increased in PIA rats. Particularly, a significant increase in the protein expression of IL-22 was determined in synovial membrane and serum from PIA rats, and correlated with clinical score. We conclude that IL-22 expression level was increased and correlated with disease severity, which indicated that IL-22 may play an important role in development of PIA, and was helpful to explorer the pathogenesis of rheumatoid arthritis.

IL­22 expression is increased variedly in the initial phase, onset and chronic phase of a pristane­induced arthritis rat model.

The aim of the present study was to investigate the expression pattern of T helper (Th) 17 and Th22 cell-related factors in a pristane­induced arthritis (PIA) rat model. PIA rats were divided into the initial phase group [day (D) 6 post­pristane injection], the onset of clinical arthritis group (D12), the acute arthritis group (D26) and the chronic arthritis group (D70). Rats injected with saline alone were used as the control group. The mRNA expression levels of interleukin (IL)­17A, IL­17F, interferon (IFN)­Î³, IL­22, IL­22 receptor (R) 1, IL­22 binding protein (BP) and RAR­related orphan receptor α were examined in the spleen and/or synovium of the various phases of PIA rats by reverse transcription­quantitative polymerase chain reaction analysis. The results demonstrated that, in the spleen, IL­22 exhibited an increasing trend in both the initial phase and the onset of disease, while the ratio of IL­22R1/IL­22BP increased in both phases, compared with the control group. During the acute arthritis phase, IL­17F and IFN­Î³ were significantly increased and IL­17A exhibited an increasing tendency in the synovium, compared with the control group. In the chronic phase, IL­22, IL­22R1 and IFN­Î³ were increased in the spleen, while IL­22 exhibited an increasing trend in the synovium. In addition, immunohistochemistry analysis was used to evaluate the expression of IL­17A, IL­21, IL­22 and IL­22R1 in the ankle joints of D26 PIA rats. IL­17A was mainly expressed in infiltrated inflammatory cells in the synovium. IL­21 and IL­22 were both expressed in the inflammatory cells and in the articular chondrocyte of the proliferative zone. IL­22R1 was expressed in proliferating synovial cells. In conclusion, Th17 and Th22­related factor expression varied in different disease progression phases and in different tissues in PIA rats. IL­22 expression exhibited an increasing trend in the initial phase and the onset phase of arthritis and increased significantly with progression to chronic arthritis in the PIA rat model. It is thought that IL­22 may serve an important role in the pathological process of PIA, particularly in the chronic fluctuation phase. Therefore, it may be a candidate molecule for the treatment of rheumatoid arthritis.

Preoperative chlorhexidine reduces the incidence of surgical site infections in total knee and hip arthroplasty: A systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aims to assess the incidences of surgical site infection of patients who applied preadmission chlorhexidine skin preparation, versus those who applied the traditional skin preparation before undergoing total knee and hip arthroplasty. METHODS: A systematic search is carried out through Medline (1966-2016.11), PubMed (1966-2016.11), Embase (1980-2016.11), ScienceDirect (1985-2016.11) and the Cochrane Library. Only high quality studies are identified. Meta-analysis is conducted with the use of Stata 11.0 software. RESULTS: One RCT and five retrospective studies, published between 2010 and 2016, are included in the present meta-analysis. The present meta-analysis indicates that there are significant differences in surgical site infection rate (RD = -0.02, 95% CI: -0.02 to -0.01, P < 0.00001), revision surgery rate (RD = -0.01, 95% CI: -0.01 to -0.01, P < 0.00001) and length of stay (MD = -0.29, 95% CI: -0.48 to -0.11, P = 0.002) between groups. CONCLUSION: Preoperative chlorhexidine skin preparation appears to reduce the risk of infection, the incidence of revision surgery, and the length of stay for patients undergoing total knee and hip arthroplasty. No adverse effects, such as DVT or PE, appear to be related to chlorhexidine preparation. Due to the limited quality of the evidence currently available, high quality RCTs with better study designs, larger sample sizes and longer follow-ups are needed.

[Morphology characteristics of sural bean bone and it's role in knee joint diseases].

Fabella is a common sesamoid bone. In recent years, people have paid more attention to its anatomic location, distribution characteristics in crow, importance in stabilizing knee joint and related diseases. This article reviews the anatomy, distribution and the relationship between the calf bone and the knee joint diseases, so as to strengthen the attention of the bones in the diagnosis and treatment of knee diseases.

[Clinical observation of 15° face-changing acetabular cup in total hip replacement for the treatment of developmental dysplasia of hip].

OBJECTIVE: To explore early clinical effect of acetabular cup in total hip replacement for the treatment of Crowe II developmental dysplasia of hip. METHODS: Eighteen patients (18 hips) with Crowe type II developmental dysplasia of hip were treated with total hip replacement from September 2001 to July 2013. Among them,including 13 males and 5 females aged from 42 to 60 years old with an average of 47.6 years old; the courses of diseases ranged from 9 to 22 years with an average of 13.5 years. All the patients had hip joint pain, limb shortening and limited hip function before operation. Harris score of hip joint were used to evaluate recovery of function at 1 day and 12 months after operation. Prosthetic coverage of acetabular cup at 1 week after operation was observed by using radiography. RESULTS: Eighteen patients (18 hips) were followed up from 12 to 24 months with an average 17 months. All incisions were healed at stage I. No deep vein thrombosis, hip dislocation, periprosthetic joint infection and prosthesis loosening were occurred. No revision surgery during follow-up period. Prosthetic coverage of acetabular cup was more than 80% at 1 week after operation. Harris score were increased from 42.67 ± 5.06 before operation to 94.79 ± 3.27 at 12 months after operation (t = -45.269, P < 0.001). CONCLUSION: For type Crowe II developmental dysplasia of hip patients, 15° face-changing acetabular cups in THR could obtain higher actebular component coverage rate and satisfactory early clinical effects.

Association between genetic variants of DVWA and osteoarthritis of the knee and hip: a comprehensive meta-analysis.

Recently, double von Willebrand factor domain A (DVWA) gene, a previously unknown gene, was revealed to contain several single nucleotide polymorphisms (SNPs) that showed consistent association with knee osteoarthritis (OA) in Japanese and Chinese cohorts. However, subsequent studies failed to confirm this result in several different populations. To deal with the issues raised by inconsistent results among those studies, we investigated the association between DVWA and OA using meta-analytic techniques, combining all published data up to December 2014. 10 independent samples from 4 teams contributed data for a possible association between SNP rs7639618 and knee or hip OA. The total number of cases and controls of this SNP was respectively 4,142 versus 6,575 for knee OA, and 2,325 versus 2,914 for hip OA. A trend of significant association was observed in the combined population with knee OA (P=0.06), and a significant difference was identified between patients with knee OA and controls for the G-allele of rs7639618 (P=0.02). Together with the reported functional studies, our results indicate that DVWA may have a small but strong effect on the susceptibility to knee OA, at least in Asian population. Further functional studies are needed to determine the underlying variation of DVWA and to relate this to the pathophysiology of OA.

Overexpression of heparan sulfate 6-O-sulfotransferase-2 enhances fibroblast growth factor-mediated chondrocyte growth and differentiation.

In our previous study, we reported that heparan sulfate 6-O-sulfotransferase­2 (HS6ST2) plays an important role in the cartilage of patients with osteoarthritis and Kashin-Beck disease and that it regulates aggrecan (Acan) metabolism and the viability of chondrocytes. However, its role in chondrocyte differentiation remains poorly understood. In the present study, we aimed to investigate the role of HS6ST2 in chondrocyte differentiation in vitro using mouse prechondrocytic cells. We found that the overexpression or silencing of HS6ST2 significantly enhanced or abrogated the effects of fibroblast growth factor (FGF)­2 on chondrocyte growth, respectively. We found that the overexpression of HS6ST2 significantly induced the expression of Acan as well as the amount of total proteoglycans in the prechondrocytic cells in the presence of FGF­2, whereas the silencing of HS6ST2 caused the opposite effect. Furthermore, the expresssion of FGF­2­induced sex­determining region Y­type high mobility group box protein 9 (SOX9), a major transcription factor for chondrocyte proliferation and differentiation, was also enhanced or blocked by HS6ST2 overexpression or HS6ST2 knockdown, respectively. Additionally, Wnt/ß­catenin signaling, which inhibited chondrocyte proliferation and differentiation, was suppressed by HS6ST2. Taken together, these data suggest that HS6ST2 plays an important role in regulating chondrocyte growth and differentiation by modulating FGF­2 signaling, thus indicating that it may be a potential and valuable molecular target for the treatment of skeletal dysplasias, such as dwarfism.

The elevated expression of Th17-related cytokines and receptors is associated with skin lesion severity in early systemic sclerosis.

OBJECTIVE: The objective was to survey the expression and localization of Th17-related cytokines and their correlation with skin lesion severity in early systemic sclerosis (SSc). METHODS: The mRNA expression was detected by real-time quantitative polymerase chain reaction (RT-qPCR) from 21 SSc patients and 12 healthy controls (HC). The protein expression was examined by immunohistochemistry (IHC) and Western blotting. RESULTS: The RT-qPCR analysis showed a significantly higher expression of IL-17A, IL-21, IL-22, IL-26, IL-17RA, IL-21R, and IL-22R1 mRNA; consistently, the IHC analysis showed an over-expression of IL-17RA, IL-21R and IL-22R1 and the Western blotting analysis showed an over-expression of IL-17A, IL-21, IL-21R and IL-22R1 in early SSc skin lesions. The mRNA levels of IL-21 were higher in diffuse cutaneous than limited cutaneous SSc lesions. The mRNA expression of IL-26, IL-22, IL-22R1, mRNA and protein expression of IL-17A, IL-21, IL-21R were positively correlated with the modified Rodnan skin score of SSc. In addition, the mRNA levels of ICAM-1 were positively correlated with IL-17A/IL-17RA, and VEGFA and IL-4 were both positively correlated with IL-21/IL-21R, while TGF-ß were moderately negatively correlated with IL-22/IL-22R1. CONCLUSIONS: Th17 cytokines contribute to progression in early SSc skin lesions. IL-21/IL-21R could act as potential biomarkers presenting early SSc skin lesions severity.