IDN5706 Inhibits Synovial Inflammation via Inducing M2 Polarization of Synovial Macrophages in Osteoarthritis Rats.

INTRODUCTION: IDN5706 is a tetrahydro derivative of hyperforin. In this study, we aimed to explore the effect of IDN5706 on synovial macrophages in osteoarthritis (OA) rats and the underlying mechanisms. METHODS: OA rats were employed for the in vivo experiments, and RAW264.7 cells were employed for the in vitro experiments. Histopathological changes in synovium were examined using hematoxylin-eosin staining. Cell apoptosis in synovium was assessed by TUNEL staining. Macrophage polarization was determined by immunohistochemical analysis and flow cytometry. The mRNA expression and protein level of genes were detected by qRT-PCR and Western blot. The efferocytosis of macrophages was assessed by flow cytometry. RESULTS: IDN5706 reversed the increased CD86-positive cells (M1 macrophages) and decreased CD206-positive cells (M2 macrophages), both in synovium and synovial fluid of OA rats. The in vitro experiments further confirmed the promotion effect of IDN5706 on M2 macrophages, accompanied by the elevated Arg-1 and reduced iNOS. Also, the upregulated p-mTOR in synovium and synovial fluid of OA rats were reversed by IDN5706, and the decreased M1 macrophages and increased M2 macrophages induced by IDN5706 were reversed by the mTOR activator. IDN5706 enhanced the efferocytosis of IL-4-treated RAW264.7 cells, and the animal experiments further revealed the involvement of efferocytosis in the improvement of OA by IDN5706. CONCLUSIONS: IDN5706 enhanced the efferocytosis of synovial macrophages by inducing M2 polarization via inhibiting p-mTOR, thus suppressing synovial inflammation and OA development, providing a theoretical basis for IDN5706 as a clinical drug for inflammatory diseases.

Inhibition of NUCB2 suppresses the proliferation, migration, and invasion of rheumatoid arthritis synovial fibroblasts from patients with rheumatoid arthritis in vitro.

Rheumatoid arthritis (RA) is an autoimmune polyarthritis in which synovial fibroblasts (SF) play a major role in cartilage and bone destruction through tumorlike proliferation, migration, and invasion. Nesfatin-1, an 82-amino-acid-long peptide discovered by Oh-I in 2006, is derived from the precursor protein nucleobindin-2 (NUCB2). NUCB2/nesfatin-1 promotes cell proliferation, migration, and invasion in various tumors. We have previously shown that increased nesfatin-1 levels in the synovium may be associated with disease severity in patients with RA. However, the effect of NUCB2 on the tumorlike transformation of RASF has not yet been reported. The expression of NUCB2 mRNA in the synovium of RA and non-RA patients was further confirmed using three individual datasets from the NCBI GEO database. Gene set enrichment analysis (GSEA) was employed to explore the association between NUCB2 mRNA and RA-related gene signatures or signaling pathways in the GSE77298 dataset. Cell proliferation, migration, and invasion abilities were determined using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and transwell assays, respectively. The results showed that the levels of NUCB2 mRNA in the synovium were significantly elevated in patients with RA. Moreover, GSEA showed that high expression of NUCB2 mRNA was related to gene signatures, including those involved in the cell cycle, DNA replication, extracellular matrix-receptor interaction, and focal adhesion. Furthermore, the results of CCK-8 and EdU assays indicated that inhibition of NUCB2 markedly repressed RASF proliferation. Additionally, the results of wound healing and transwell assays demonstrated that inhibition of NUCB2 significantly suppressed the migratory and invasive abilities of RASFs. Our findings are the first to demonstrate that the inhibition of NUCB2 suppresses the proliferation, migration, and invasion of RASFs in vitro.

ECM-Mimicking Hydrogels Loaded with Bone Mesenchymal Stem Cell-Derived Exosomes for the Treatment of Cartilage Defects.

It is well-established that treating articular cartilage injuries is clinically challenging since they lack blood arteries, nerves, and lymphoid tissue. Recent studies have revealed that bone marrow stem cell-derived exosomes (BMSCs-Exos) exert significant chondroprotective effects through paracrine secretions, and hydrogel-based materials can synergize the exosomes through sustained release. Therefore, this research aims to synthesize an ECM (extracellular matrix)-mimicking gelatin methacryloyl (GelMA) hydrogel modified by gelatin combined with BMSCs-derived exosomes to repair cartilage damage. We first isolated and characterized exosomes from BMSCs supernatant and then loaded the exosomes into GelMA hydrogel to investigate cartilage repair effects in in vitro and in vivo experiments. The outcomes showed that the GelMA hydrogel has good biocompatibility with a 3D (three-dimensional) porous structure, exhibiting good carrier characteristics for exosomes. Furthermore, BMSCs-Exos had a significant effect on promoting chondrocyte ECM production and chondrocyte proliferation, and the GelMA hydrogel could enhance this effect through a sustained-release effect. Similarly, in vivo experiments showed that GelMA-Exos promoted cartilage regeneration in rat joint defects and the synthesis of related cartilage matrix proteins.

High levels of TDO2 in relation to pro-inflammatory cytokines in synovium and synovial fluid of patients with osteoarthritis.

BACKGROUND: Tryptophan 2,3-dioxygenase (TDO2) is the primary enzyme that catabolizes tryptophan to kynurenine. Numerous studies have suggested that TDO2 is involved in inflammation-related diseases. However, its role in osteoarthritis (OA) has not yet been investigated. The aim of the present study was to explore the levels of TDO2 in the synovium and synovial fluid (SF) of patients with OA and its correlation with clinical manifestations and levels of pro-inflammatory cytokines.  METHODS : Synovium and SF samples were collected from patients with OA and patients with joint trauma (controls) during surgery. An enzyme-linked immunosorbent assay (ELISA) was used to measure TDO2, interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) levels in the synovium and SF. Diagnostic performance of TDO2 in the synovium to discriminate between controls and OA patients was assessed using receiver operating characteristic (ROC) curve analysis. Correlations between TDO2 levels, OA clinical features, and pro-inflammatory cytokines were evaluated using Pearson correlation analysis. Effects of IL-1ß or TNF-α stimulation on TDO2 expression in OA-fibroblast-like synoviocytes (OA-FLS) were also examined. RESULTS: The levels of TDO2, IL-1ß, and TNF-α in the synovium of patients with OA were found to be significantly higher than those in controls. ROC curve analysis revealed an area under the curve (AUC) of 0.800 with 64.3% sensitivity and 85.0% specificity of TOD2 in the synovium, which enabled discriminating patients with OA from controls. Moreover, protein expression of TDO2 was upregulated to a greater extent in OA-FLS than in normal synovial fibroblasts (NSF). Furthermore, the levels of TDO2 showed significantly positive correlation with IL-1ß and TNF-α levels in the synovium and SF. TDO2 levels in the synovium were also positively correlated with the Kellgren-Lawrence score. Additionally, TDO2 protein expression was significantly increased in IL-1ß‒ or TNF-α‒stimulated OA-FLS than in control FLS. CONCLUSION: These data indicate that highTDO2 levels in the synovium can be correlated with pro-inflammatory cytokines and severity of OA.

Geniposide alleviates VEGF-induced angiogenesis by inhibiting VEGFR2/PKC/ERK1/2-mediated SphK1 translocation.

BACKGROUND: Rheumatoid arthritis (RA) is an angiogenesis-dependent disease caused by the imbalance of pro- and anti-angiogenic factors. More effective strategies to block synovial angiogenesis in RA should be studied. Geniposide (GE), a natural product isolated from the fruit of Gardenia jasminoides Ellis (GJ), is reported to have anti-inflammatory, anti-angiogenic and other pharmacological effects. However, the underlying mechanism through which GE affects synovial angiogenesis in RA remains unclear. PURPOSE: In this research, we aimed to elucidate the effect and potential mechanisms of GE on angiogenesis in RA. MATERIALS AND METHODS: Synovial angiogenesis in patients with RA and a rat model of adjuvant arthritis (AA) was detected by hematoxylin and eosin (HE) staining, immunohistochemistry (IHC), and western blottiing. The biological functions of vascular endothelial cells (VECs) and sphingosine kinase 1 (SphK1) translocation were checked by CCK-8, EdU, Transwell, tube formation, co-immunoprecipitation assays, and laser scanning confocal microscopy. The effect of the SphK1 gene on angiogenesis was assessed by transfection of SphK1-siRNA in cells and mices. The effect of GE on VEGF-induced angiogenesis was measured by Matrigel plug assay in a mouse model of AA. RESULTS: GE effectively inhibited synovial angiogenesis and alleviated the disease process. SphK1, as a new regulatory molecule, has a potentially important relationship in regulating VEGF/VEGFR2 and S1P/S1PR1 signals. SphK1 translocation was activated via the VEGFR2/PKC/ERK1/2 pathway and was closely linked to the biological function of VECs. GE significantly reduced SphK1 translocation, thereby ameliorating the abnormal biological function of VECs. Furthermore, after transfection of SphK1 siRNA in VECs and C57BL/6 mice, silencing SphK1 caused effectively attenuation of VEGF-induced VEC biological functions and angiogenesis. In vivo, the Matrigel plug experiment indicated that GE significantly inhibited pericyte coverage, basement membrane formation, vascular permeability, and fibrinogen deposition. CONCLUSIONS: Our findings suggest that GE inhibited VEGF-induced VEC biological functions and angiogenesis by reducing SphK1 translocation. Generally, studies have revealed that GE down-regulated VEGFR2/PKC/ERK1/2-mediated SphK1 translocation and inhibited S1P/S1PR1 signaling activation, thereby alleviating VEGF-stimulated angiogenesis. The above evidences indicated that angiogenesis inhibition may provide a new direction for RA treatment.

Circular RNA hsa_circ_0005567 overexpression promotes M2 type macrophage polarization through miR-492/SOCS2 axis to inhibit osteoarthritis progression.

Synovial macrophage polarization is essential for osteoarthritis (OA) development. Our study aims to investigate the underlying function and the molecular mechanisms of hsa_circ_0005567 in macrophage polarization. Circular RNA (CircRNA), microRNA (miRNA), and mRNA expression levels were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR). RNA pull down, luciferase reporter were employed to test the interaction between miR-492 and hsa_circ_0005567/suppressors of cytokine signaling 2 (SOCS2). Ectopic overexpression was used to evaluate the function of hsa_circ_0005567. The supernatant of THP-1 cells was used to incubate chondrocytes. Cell Counting Kit-8 (CCK-8) and flow cytometry were conducted to determine cell viability, proportion of M1 or M2 macrophages and apoptotic rate. The results showed that the hsa_circ_0005567 expression level was downregulated in the synovial tissues of osteoarthritis patients. Overexpression of hsa_circ_0005567 inhibited M1 macrophage polarization, and promoted M2 macrophage polarization. Hsa_circ_0005567 was proved to be a molecular sponge for miR-492, and SOCS2 was verified as the target of miR-492. MiR-492 mimic could reverse the effect of hsa_circ_0005567 overexpression on macrophage polarization. Besides, the supernatant from LPS-treated THP-1 macrophage significantly decreased chondrocytes cell viability and increased cell apoptosis ratio, which was reversed by hsa_circ_0005567 overexpression. In conclusion, hsa_circ_0005567 overexpression promoted M2 macrophage polarization through miR-492/SOCS2 axis to reduced chondrocyte apoptosis, which could inhibit osteoarthritis progression.

Elevated Nesfatin-1 Level in Synovium and Synovial Fluid is Associated with Pro-Inflammatory Cytokines in Patients with Rheumatoid Arthritis.

BACKGROUND: Adipocytokines have been proven to be involved in the progression of autoimmune diseases, including rheumatoid arthritis (RA). Nesfatin-1, a newly discovered adipokine, has recently been reported to possess potent anti-inflammatory, antiapoptotic, and antioxidative properties. However, its role in RA has not yet been reported. Therefore, this study aimed to determine nesfatin-1 levels in the synovium and synovial fluid (SF) of patients with RA and examine their correlation with clinical manifestations and proinflammatory cytokine levels. METHODS: Synovium and SF samples were collected from patients with RA and non-RA patients during joint surgery. Immunohistochemistry was used to measure nesfatin-1 protein expression in the synovium. Enzyme-linked immunosorbent assay was used to measure nesfatin-1, interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) levels in the synovium and SF. Pearson correlation analysis was used to evaluate the correlations between nesfatin-1 levels, RA clinical features, and proinflammatory cytokines. The diagnostic value of synovium nesfatin-1 for RA was assessed using receiver operating characteristic (ROC) curve analysis. RESULTS: The results showed that nesfatin-1, IL-1ß, and TNF-α levels in the synovium were significantly higher in patients with RA than in controls, with age and body mass index as covariates. Moreover, the results of Pearson correlation analysis showed that nesfatin-1 levels were positively correlated with IL-1ß and TNF-α levels in the synovium of patients with RA. Furthermore, there was a positive relationship between synovium nesfatin-1 levels and rheumatoid factor in patients with RA. Additionally, the results of the ROC curve analysis revealed an area under the curve of 0.733 with 77.5% sensitivity and 60.0% specificity for synovium nesfatin-1 in discriminating patients with RA from controls. CONCLUSION: These findings suggest that increased nesfatin-1 levels in the synovium may be associated with proinflammatory cytokines and RA severity.

Hsa_circ_0005567 Activates Autophagy and Suppresses IL-1ß-Induced Chondrocyte Apoptosis by Regulating miR-495.

Excessive chondrocyte apoptosis is mostly responsible for the progression of osteoarthritis (OA). It has been shown that circular RNAs (circRNAs) are differentially expressed in OA cartilage and participate in various pathological processes during OA. Here, this study was designed to explore the effect and molecular mechanism of hsa_circ_0005567 on IL-1ß-induced chondrocyte apoptosis. The results showed that hsa_circ_0005567 knockdown aggravated the IL-1ß-induced chondrocyte apoptosis. In contrast, hsa_circ_0005567 overexpression attenuated the IL-1ß-induced chondrocyte apoptosis, but this effect could be abrogated by 3-methyladenine (an inhibitor of autophagy), suggesting that hsa_circ_0005567 overexpression inhibited chondrocyte apoptosis by inducing autophagy. Furthermore, hsa_circ_0005567 competitively bound to miR-495 and derepressed the expression of ATG14, an early autophagy marker that was a direct target of miR-495. Moreover, both miR-495 mimic and ATG14 knockdown counteracted the autophagy-promoting and anti-apoptotic effects of hsa_circ_0005567 overexpression in IL-1ß-treated chondrocytes. Taken together, hsa_circ_0005567 activates autophagy by regulating the miR-495/ATG14 axis and thereby suppresses IL-1ß-induced chondrocyte apoptosis. These findings suggest that hsa_circ_0005567 may serve as a therapeutic target for the treatment of OA.

Influence of inflammatory arthritis on leukocyte esterase strip results in the diagnosis of periprosthetic joint infection.

BACKGROUND: The leukocyte esterase (LE) strip is considered as a helpful method to detect infection, which might be influenced by other inflammatory diseases. This study aims to explore whether the centrifugation of synovial fluid could influence the positive result of LE strip caused by inflammatory arthritis during the diagnosis of periprosthetic joint infection (PJI). METHODS: From March 2016 to December 2018, 64 patients who were diagnosed as PJI or aseptic arthritis and another 20 patients with inflammatory arthritis were enrolled in our study. After synovial fluid samples were obtained, the LE strip test was performed with and without centrifugation. Then clinicians read the color changes 3 min after the samples were dropped and classify the results based on the instruction of strip. The differences between septic and aseptic arthritis patients and septic and inflammatory arthritis patients were analyzed. RESULTS: Among the included 21 PJI samples, 19 of them showed positive results (++) of LE strip before centrifugation. After centrifugation, two samples changed from two-positive (++) to one-positive (+), which is also considered as positive. Before centrifugation, 29 of the LE strip tests in the aseptic arthritis group (43 samples included) were ++ or +. After centrifugation, 16 of the samples yielded negative results. Among 20 samples with inflammatory arthritis, LE strip of 18 samples were positive (++ or +) before centrifugation, among which only 3 samples remained as positive after centrifugation. CONCLUSION: LE strip test results could be influenced by inflammatory arthritis during the diagnosis of PJI. Centrifugation should be performed for LE strip tests to determine whether the result is a true positive or a false positive influenced by inflammatory arthritis.

A sensitive LC-MS/MS method to determine ginkgolide B in human plasma and urine: application in a pharmacokinetics and excretion study of healthy Chinese subjects.

1. Ginkgolide B (GB), the most active of the ginkgolides, has been developed as a new drug for the treatment of vascular insufficiency; however, the pharmacokinetics of GB remain unclear. Here, we investigated the pharmacokinetics and urine excretion properties of GB in healthy Chinese subjects administered single- and multiple-dose injectable GB based on a new LC-MS/MS method.2. GB pharmacokinetics were found to be dose-dependent from 20 to 60 mg. GB reached a steady state by day 6 with once-daily dosing at 40 mg. Systemic exposure to GB, as characterised by AUC0-∞, indicated accumulation following repeated once-daily dosing for seven consecutive days. The mean urinary cumulative excretion rate of GB in response to 20, 40, and 60 mg GB was 41.9 ± 18.5%, 32.9 ± 12.2%, and 43.9 ± 8.5%, respectively.3. Dose-proportional pharmacokinetics of GB were observed after intravenous administration in healthy subjects. A gradual reduction in the volume of distribution and slight change in mean resistance time led us to conjecture the limited accumulation of GB based on distribution equilibrium in vivo.4. This comprehensive study of the clinical pharmacokinetics of GB will provide useful information for its application and further development.

Long noncoding RNA ZBED3-AS1 induces the differentiation of mesenchymal stem cells and enhances bone regeneration by repressing IL-1ß via Wnt/ß-catenin signaling pathway.

Bone regeneration, as a physiological process of bone formation, is regulated by multiple cytokines. Long noncoding RNAs are involved in the progress of bone formation. The present study investigated role by which ZBED3-AS1 acts to control the differentiation of mesenchymal stem cells (MSCs) and bone regeneration. Bioinformatics prediction and dual luciferase reporter gene assay identified putative ZBED3-AS1 binding sites on the 3'-untranslated region of interleukin-1ß (IL-1ß). Then, RNA immunoprecipitation and chromatin immunoprecipitation assays confirmed that ZBED3-AS1 could regulate the expression of IL-1ß by binding to the transcription factor CREB. Notably, ZBED3-AS1 was shown to negatively regulate IL-1ß expression. After model establishment in rats simulating bone injury, MSCs were isolated and delivered with ZBED3-AS1, Si-ZBED3-AS1, Si-IL-1ß, or DKK (inhibitor of Wnt/ß-catenin signaling pathway) to identify their roles in osteogenic differentiation by evaluating MSC colony formation and proliferation. Then, number of mineralized nodules, alkaline phosphatase (ALP) activity and osteocalcin (OCN) expression, and expression of osteogenesis-related genes were determined. Overexpression of ZBED3-AS1 or silencing of IL-1ß was shown to accelerate ectopic osteogenesis, as reflected by increasing the number of mineralized nodules, ALP activity, and OCN expression, and promoting MSC colony formation and proliferation. Additionally, ZBED3-AS1 activated the Wnt/ß-catenin signaling pathway by negatively regulating IL-1ß. IL-1ß inhibited osteogenic differentiation by suppressing the Wnt/ß-catenin signaling pathway. Furthermore, the effect of ZBED3-AS1 and IL-1ß on osteogenic differentiation was confirmed in vivo. Taken together, upregulation of ZBED3-AS1 could restore differentiation of MSCs and enhance bone regeneration via activation of Wnt/ß-catenin signaling pathway by repressing IL-1ß.

Tetrahydrohyperforin prevents articular cartilage degeneration and affects autophagy in rats with osteoarthritis.

Osteoarthritis (OA) is a highly prevalent disease, which is associated with extracellular matrix degradation and cell death in articular cartilage. The aim of the present study was to identify whether tetrahydrohyperforin (IDN5706) ameliorates the degeneration of articular cartilage and affects autophagy in OA. The rat model of experimental OA was induced by intra-articular injection of collagenase solution. IDN5706 was administered intragastrically to rats for 6 weeks. Histopathological changes in articular cartilage were examined using hematoxylin and eosin (H&E) and safranin O staining, and Mankin scoring systems. The effect of IDN5706 on autophagy was examined using western blotting. ELISA was performed to detect cartilage inflammation. H&E and safranin O staining, Mankin scores, and electron microscopy indicated that IDN5706 could lessen the degeneration of articular cartilage in OA rats. In addition, western blotting revealed that IDN5706 treatment may activate the suppressed autophagy in OA rats. In conclusion, the present study demonstrated that IDN5706 was able to reduce the severity of experimental OA, alleviate the degeneration of articular cartilage, and affect autophagy in OA model rats.

Anti-Osteoarthritic and Anti-Inflammatory Activities of Diazine: In Vitro and In Vivo Studies.

BACKGROUND The present study evaluated the effects of diazine (DZN) on collagenase-induced osteoarthritis (OA) in rats. MATERIAL AND METHODS OA was produced via intra-articular injections of collagenase type II into the knee joint. The rats were then treated with DZN (25, 50, or 100 mg/kg, p.o.) for three weeks. At the end of the protocol, all rats were evaluated for paw latency, paw edema, and knee swelling. Additionally, serum concentrations of glycosaminoglycan (GAG), alkaline phosphatase (ALP), and C-reactive protein (CRP) were determined. X-rays were performed to estimate radiological and histopathological changes in the knee joint. The expressions of antioxidant enzymes, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) were estimated in the synovial tissues. RESULTS DZN treatment attenuated inflammation in osteoarthritic rats, as evidenced by decreases in paw edema and knee swelling and enhanced paw latency compared to the negative control group. Additionally, there were significant decreases in the serum levels of CRP and GAG and increases in ALP in the DZN-treated groups compared to the negative control group. The radiological and histopathological results showed that DZN protected against cartilage damage in the knee joint. Additionally, MMP levels decreased and there were significant reductions in the expressions of antioxidant enzymes and TIPMs in the DZN-treated groups compared to the negative control group. CONCLUSIONS The present findings demonstrated the chondroprotective effects of DZN via its modulation of the expressions of TIMP-1 and MMPs in the synovial tissues of osteoarthritic rats.

Comparison of tranexamic acid pharmacokinetics after intra-articular and intravenous administration in rabbits.

Tranexamic Acid (TXA) is commonly administered in total knee arthroplasty for reducing blood loss. There has been a growing interest in the topical use of TXA except intravenous use for prevention of bleeding in TKA. The aim of this study was to develop and validate a HPLC-MS method to detect TXA and apply to compare the pharmacokinetic profile of TXA after intravenous (IV) and topical intra-articular (IA) application of TXA at a dose of 20 mg/kg in rabbits. In order to prove intra-articular administration is better than that of intravenous administration from the point of rabbit pharmacokinetic. Two groups of rabbits (n=6/group) respectively received TXA intra-articularly or intravenously. Blood samples were collected at scheduled time. The concentration of TXA in plasma was determined by a validated HPLC-MS method. Excellent linearity was found between 0.015 and 70.0µg/ml with a lower limit of quantitation (LLOQ) of 0.015µg/ml (r>0.99); moreover, all the validation data including accuracy and precision (intra- and inter-day) were all within the required limits. The pharmacokinetic parameters in IA and IV group were: Cmax: 30.65±3.31 VS 54.05± 6.21µg/ml (p<0.01); t1/2: 1.26±0.05 VS 0.68±0.13h (p<0.05); AUC0-t: 42.98±7.73 VS 23.39±4.14µg/ml• h (p<0.01), time above the minimum effective concentration (%T > MEC): 1.5-2.2 VS 0.7-1.2h (p<0.05). HPLC-MS method is suitable for TXA pharmacokinetic studies. The results demonstrated that topical intra-articular application of TXA showed a reduced peak plasma concentration and prolonged therapeutic drug level compared with intravenous TXA from the point of rabbit pharmacokinetic.

A predictive model to estimate the pretest probability of metastasis in patients with osteosarcoma.

Osteosarcomas (OSs) represent a huge challenge to improve the overall survival, especially in metastatic patients. Increasing evidence indicates that both tumor-associated elements but also on host-associated elements are under a remarkable effect on the prognosis of cancer patients, especially systemic inflammatory response. By analyzing a series prognosis of factors, including age, gender, primary tumor size, tumor location, tumor grade, and histological classification, monocyte ratio, and NLR ratio, a clinical predictive model was established by using stepwise logistic regression involved circulating leukocyte to compute the estimated probabilities of metastases for OS patients. The clinical predictive model was described by the following equations: probability of developing metastases = ex/(1 + ex), x = -2.150 +  (1.680 × monocyte ratio) + (1.533 × NLR ratio), where is the base of the natural logarithm, the assignment to each of the 2 variables is 1 if the ratio >1 (otherwise 0). The calculated AUC of the receiver-operating characteristic curve as 0.793 revealed well accuracy of this model (95% CI, 0.740-0.845). The predicted probabilities that we generated with the cross-validation procedure had a similar AUC (0.743; 95% CI, 0.684-0.803). The present model could be used to improve the outcomes of the metastases by developing a predictive model considering circulating leukocyte influence to estimate the pretest probability of developing metastases in patients with OS.

[Research progress of difference between high-flexion prosthesis and conventional prosthesis in total knee arthroplasty].

OBJECTIVE: To summarize the research progress of the difference between high-flexion prosthesis and conventional prosthesis in total knee arthroplasty, so as to offer a reference for clinical choice of prosthesis. METHODS: The relevant literature on high-flexion prosthesis and conventional prosthesis in recent years was extensively reviewed and analyzed. RESULTS: There are some controversies in range of motion and complications between high-flexion prosthesis and conventional prosthesis; while no obvious difference is found in knee function and satisfaction. CONCLUSION: Comprehensive evaluation should be considered when high-flexion prosthesis is selected; and the effectiveness needs further follow-up.

[RESEARCH PROGRESS OF GENDER-SPECIFIC PROSTHESIS].

OBJECTIVE: To summarize the research progress of the design and effectiveness of gender-specific prosthesis in total knee arthroplasty (TKA). METHODS: The relevant literature on gender-specific prosthesis in recent years was extensively reviewed and analyzed. RESULTS: Gender-specific prosthesis is designed according to the female knee joint anatomical characteristics. In theory, it should obtain better effectiveness. But a large number of clinical studies have shown that the knee function, pain, and satisfaction has no obvious advantage when compared with conventional prosthesis after TKA for female patient. CONCLUSION: Comprehensive evaluation should be considered when gender-specific is selected; and the effectiveness needs further follow-up.