NOD2 attenuates osteoarthritis via reprogramming the activation of synovial macrophages.

OBJECTIVE: Synovial inflammation, which precedes other pathological changes in osteoarthritis (OA), is primarily initiated by activation and M1 polarization of macrophages. While macrophages play a pivotal role in the inflammatory process of OA, the mechanisms underlying their activation and polarization remain incompletely elucidated. This study aims to investigate the role of NOD2 as a reciprocal modulator of HMGB1/TLR4 signaling in macrophage activation and polarization during OA pathogenesis. DESIGN: We examined NOD2 expression in the synovium and determined the impact of NOD2 on macrophage activation and polarization by knockdown and overexpression models in vitro. Paracrine effect of macrophages on fibroblast-like synoviocytes (FLS) and chondrocytes was evaluated under conditions of NOD2 overexpression. Additionally, the in vivo effect of NOD2 was assessed using collagenase VII induced OA model in mice. RESULTS: Expression of NOD2 was elevated in osteoarthritic synovium. In vitro experiments demonstrated that NOD2 serves as a negative regulator of HMGB1/TLR4 signaling pathway. Furthermore, NOD2 overexpression hampered the inflammatory paracrine effect of macrophages on FLS and chondrocytes. In vivo experiments revealed that NOD2 overexpression mitigated OA in mice. CONCLUSIONS: Supported by convincing evidence on the inhibitory role of NOD2 in modulating the activation and M1 polarization of synovial macrophages, this study provided novel insights into the involvement of innate immunity in OA pathogenesis and highlighted NOD2 as a potential target for the prevention and treatment of OA.

Application of vertebral body compression osteotomy in pedicle subtraction osteotomy on ankylosing spondylitis kyphosis: Finite element analysis and retrospective study.

Background: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease, with pathological characteristics of bone erosion, inflammation of attachment point, and bone ankylosis. Due to the ossified intervertebral disc and ligament, pedicle subtraction osteotomy (PSO) is one of the mainstream surgeries of AS-related thoracolumbar kyphosis, but the large amount of blood loss and high risk of instrumental instability limit its clinical application. The purpose of our study is to propose a new transpedicular vertebral body compression osteotomy (VBCO) in PSO to reduce blood loss and improve stability. Methods: A retrospective analysis was performed on patients with AS-related thoracolumbar kyphosis who underwent one-level PSO in our hospital from February 2009 to May 2019. A total of 31 patients were included in this study; 6 received VBCO and 25 received eggshell vertebral body osteotomy. We collected demographic data containing gender and age at diagnosis. Surgical data contained operation time, estimated blood loss (EBL), and complications. Radiographic data contained pre-operative and follow-up sagittal parameters including chin brow-vertical angle (CBVA), global kyphosis (GK), thoracic kyphosis (TK), and lumbar lordosis (LL). A typical case with L2-PSO was used to establish a finite element model. The mechanical characteristics of the internal fixation device, vertebral body, and osteotomy plane of the two osteotomy models were analyzed under different working conditions. Results: The VBCO could provide comparable restoring of CBVA, GK, TK, and LL in the eggshell osteotomy procedure (all p > 0.05). The VBCO significantly reduced EBL compared to those with eggshell osteotomy [800.0 ml (500.0-1,439.5 ml) vs. 1,455.5 ml (1,410.5-1,497.8 ml), p = 0.033]. Compared with the eggshell osteotomy, VBCO showed better mechanical property. For the intra-pedicular screw fixation, the VBCO group had a more average distributed and lower stress condition on both nails and connecting rod. VBCO had a flattened osteotomy plane than the pitted osteotomy plane of the eggshell group, showing a lower and more average distributed maximum stress and displacement of osteotomy plane. Conclusion: In our study, we introduced VBCO as an improved method in PSO, with advantages in reducing blood loss and providing greater stability. Further investigation should focus on clinical research and biomechanical analysis for the application of VBCO.

Value of Evoked Potential Changes Associated with Neck Extension Prior to Cervical Spine Surgery.

Background: Multimodal intraoperative monitoring (MIOM) is a useful tool to warn surgeons to intervene for intraoperative spinal cord injury in cervical spine surgery. However, the value of MIOM remains controversial before cervical spine surgery. Objective: To explore the value of MIOM in early detecting spinal cord injury associated with neck extension before cervical spine surgery. Methods and Materials: Data of 191 patients receiving cervical spine surgery with the MIOM were enrolled from June 2014 to June 2020. The subjects were divided into a group of evoked potentials (EP) changes and a group of no EP changes for analysis according to the monitoring alerts or not. Results: Five (2.62%) patients showed EP changes associated with neck extension during intubation or positioning. After early different interventions, such as repositioning and timely surgical decompression, none or transient postoperative neurological deficits were observed in four cases, and only one case was with permanent neurological deficits. The average preoperative Japanese Orthopaedic Association (JOA) scores of the group with EP changes were lower than those of the group with no EP changes (P = 0.037 < 0.05). There was no statistical significance in gender, average age, mean Pavlov ratio, and the minimum Palov ratio between the two groups (P > 0.05). Conclusions: The MIOM could identify spinal cord injury associated with neck extension before cervical spine surgery. Active and effective interventions could prevent or reduce permanent postoperative neurological deficits. Severe spinal cord compression might be a risk factor for EP changes.

Special type of distal junctional failure exhibits pelvic incidence changes: sacroiliac joint-related pain following lumbar spine surgery.

Background: Currently, change in pelvic incidence (PI) in patients after spinal surgery have not been associated with clear clinical symptoms. This study sought to compare changes in the sagittal parameters of different patients before and after thoracolumbar spine surgery, the relationship between PI change and sacroiliac joint pain (SIJP) after surgery was clarified, and the correlation between PI change and sacroiliac joint (SIJ) activity was verified. Methods: This study retrospectively analyzed the data of patients who underwent thoracolumbar fusion at Sun Yat-sen Memorial Hospital from January 2019 to June 2021. The spinal and pelvic parameters [including pelvic tilt (PT), sacral slope (SS), PI, lumbar lordosis (LL) angle, etc.] of 409 patients with standard standing lateral radiographs before and after surgery were compared and analyzed. Postoperative follow-up of all patients with standardized SIJP assessment. The incidence of postoperative SIJP, and its correlation with sagittal parameters of the spine and pelvis, surgical methods, and the basic characteristics of patients were analyzed. The Chi-square test was used for categorical variables, the independent-sample t-test was used for generally conformed normally distributed continuous variables. Risk factors associated with the development of SIJP were analyzed using logistics regression. Correlations among SS, PI, and the 4 other sagittal parameters were analyzed using the Pearson correlation coefficient (r). Results: Postoperative PI changes tended to be larger in the lowest instrumented vertebra (LIV) (L4 and above: 1.63°; L5: 2.43°; S1: 3.83°; P<0.05) and longer fixed segment. The risk factors for SIJP included a PI >4° [odds ratio (OR) =13.051; P<0.001], LIV S1 (OR =3.378; P=0.023), and fixed total segment ≥3 (OR =2.632; P=0.038). ∆PI was significantly correlated with ∆SS in patients with non-S1 distal fixation vertebrae (R2=0.388; P<0.01), but no such correlation was found in patients with S1 distal fixation vertebrate. Conclusions: Changes in PI values after thoracolumbar spine surgery can correctly reflect the motion state of the SIJ. Excessive changes in PI (>4°) are similar to the mechanism of distal junctional kyphosis (DJK), while such changes make patients prone to SIJP following lumbar spine surgery.

The Difference of Sagittal Correction of Adult Subaxial Cervical Spine Surgery According to Age: A Retrospective Study.

OBJECTIVE: At present, the true sagittal alignment of the cervical spine is uncertain, resulting in no standard reference for subaxial cervical surgery. So, we aimed to explore the age difference of normal cervical sagittal alignment and to further investigate the mid-and long-term changes of sagittal alignment after subaxial cervical spine surgery. MATERIALS AND METHODS: This was a retrospective study and 1223 asymptomatic volunteers and 79 patients undergoing subaxial cervical spine surgery were retrospectively reviewed in total. Asymptomatic volunteers and patients were divided into six subgroups: 20-29, 30-39, 40-49, 50-59, 60-69 and ≥70 groups. The age difference and trend with age of cervical sagittal parameters of asymptomatic volunteers were assessed by cervical lateral radiography and analyzed by ANOVA test, and the regression equation of C2-7 Cobb was established via multiple linear regression. Based on the C2-7 Cobb regression equations of different ages, the theoretical value, deviation value, loss value of the C2-7 Cobb, and JOA recovery rate of patients were calculated, and the correlation among the loss value, deviation value of the C2-7 Cobb, and JOA recovery rate of the 79 patients was evaluated by Pearson correlation analysis. RESULTS: For the asymptomatic volunteers, the C0-2 Cobb decreased gradually with increasing age. The C2-7 Cobb, C2-7 SVA, T1S, NT, and TIA increased gradually with increasing age. The CBVA fluctuated with increasing age. T1S demonstrated a moderate correlation with C2-7 Cobb (r = 0.60, p < 0.01); C0-2 Cobb, C2-7 SVA, CBVA, and TIA demonstrated a fair correlation with C2-7 Cobb (r = -0.30, -0.33, 0.41, 0.40, p < 0.01); age demonstrated a poor correlation with C2-7 Cobb (r = 0.19, p < 0.01). The regression equations of C2-7 Cobb were established using C0-2 Cobb, C2-7 SVA, CBVA, and T1S. For the patients with subaxial cervical spine surgery, the loss of C2-7 Cobb was moderately correlated with the deviation of C2-7 Cobb (r = 0.33, p < 0.01). CONCLUSION: The age difference of cervical sagittal alignment was obvious, and the C2-7 Cobb increased with age especially. The closer the postoperative C2-7 Cobb was to the theoretical value of corresponding age, the smaller the loss of correction angle was, and the better the mid- and long-term outcomes. The personalized sagittal reconstruction should be performed according to age difference for subaxial cervical spine surgery.

Retraction Notice to: Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1.

[This retracts the article DOI: 10.1016/j.omtn.2019.11.015.].

Posterior wedge osteotomy assisted by O-arm navigation for treating ankylosing spondylitis with thoracolumbar fractures: an early clinical evaluation.

BACKGROUND: To explore the feasibility and efficiency of posterior wedge osteotomy assisted by O-arm navigation treatment of ankylosing spondylitis (AS) patients with thoracolumbar fracture. METHODS: This is a case series study. A total of 16 cases of AS accompanied by thoracolumbar fractures from January 2012 to July 2015 were retrospectively analyzed. All patients underwent "posterior wedge osteotomy assisted by O-arm navigation". The operation time, blood loss volume, preoperative and postoperative visual analogue scale (VAS), American Spinal Injury Association (ASIA) classification, and spinal imaging parameters [Cobb angle, C7 plumb line (C7PL), and jaw-brow angle] were collected and analyzed. RESULTS: The operative time consumption was 120-350 mins and the intra-operative blood loss volume was 200-800 mL. No obvious postoperative complications occurred in any participants. The back pain of all participants was relieved, and the neurological functions of eight participants with spinal cord injury (SCI) were recovered in varying degrees except for one patient with severe SCI. The spinal deformities of the participants were corrected to varying degrees. The fracture sites of 16 participants were all healed, and there was no loosening or detachment of internal fixation during the 6-month follow-up period. CONCLUSIONS: Posterior wedge osteotomy assisted by O-arm navigation was shown to be a safe and effective method to treat AS accompanied by thoracolumbar fractures. This treatment strategy can accurately decompress and reduce the fracture and significantly correct the kyphosis, with good surgical effect.

RAB5C, SYNJ1, and RNF19B promote male ankylosing spondylitis by regulating immune cell infiltration.

BACKGROUND: This study aimed to identify the key genes related to male ankylosing spondylitis (AS) and to analyze the role of immune cell infiltration in the pathological process of this disease. METHODS: The AS dataset was downloaded from the Gene Expression Omnibus (GEO) public database, and the data of male healthy controls (M_HC) and male AS patients (M_AS) were extracted. R software was used to identify differentially expressed genes (DEGs). Functional and pathway enrichment analysis of the DEGs was performed. A protein-protein interaction (PPI) network was constructed, and the hub genes were screened out. All expression profile data were analyzed by weighted correlation network analysis (WGCNA) to screen out the hub genes, which were then intersected with the hub genes from the PPI network to obtain the key genes. Finally, the difference in immune cell infiltration in the two sets of samples was evaluated with CIBERSORT, and the correlation between the key genes and infiltrating immune cells was analyzed. RESULTS: A total of 689 DEGs were obtained, of which 395 genes were up-regulated and 294 genes were down-regulated. Functional and pathway enrichment analysis showed that DEGs were mainly enriched in pathways related to immune response. Based on the PPI analysis, five clusters with high scores were selected. Through WGCNA, 14 gene modules were obtained. The green module with the highest correlation was selected and intersected with the cluster previously obtained to obtain three key genes, RAB5C, SYNJ1, and RNF19B. Immune infiltration analysis found that monocytes and gamma delta T cells may be involved in the process of AS. Also, RAB5C, SYNJ1, and RNF19B are all related to increased levels of monocytes and macrophages. CONCLUSIONS: RAB5C, SYNJ1, and RNF19B are key DEGs expressed in M_AS and may play a role in the disease's occurrence and development through regulating immune cell functions.

Use of zero-profile device for contiguous three-level anterior cervical discectomy and fusion: comparison with cage and plate construct.

OBJECTIVE: The aim of this study was to compare a traditional cervical cage with a zero-profile (ZP) fixation device in patients who underwent three-level anterior cervical decompression and fusion (ACDF) in terms of patient-reported outcomes (visual analog scale [VAS], Japanese Orthopaedic Association [JOA], and Neck Disability Index [NDI] scores), radiographic findings (sagittal alignment 2 years after surgery and likelihood of fusion), and complications. METHODS: This study was a retrospective case series. Between January 2012 and December 2016, 58 patients with cervical spondylotic myelopathy (CSM) who required three-level ACDF procedures, as identified by spinal surgeons, were treated with three-level ACDF and an anterior cage-plate construct (ACPC) (n = 38) or a three-level stand-alone ZP device (n = 20). On the basis of patient choice, patients were divided into two groups (ACPC group and ZP group). All patients completed a minimum of 2 years of follow-up. Patient-reported outcome scores included VAS, JOA, and NDI scores. The radiographic findings included sagittal alignment and likelihood of fusion 2 years after surgery. Data related to patient-reported outcomes and sagittal alignment were collected preoperatively, postoperatively, and at the final follow-up. Intraoperative and postoperative complications were also documented and analyzed. RESULTS: The clinical outcomes, including VAS, JOA, and NDI scores, showed improvement in both groups, and no significant difference was observed between the two groups. Sagittal alignment and height of the fused segments were restored in all patients. However, the authors found no differences between the ZP and ACPC groups, and the groups exhibited similar fusion rates. The authors found no differences in complications, including dysphagia, adjacent-segment degeneration, and postoperative hematoma, between the groups. CONCLUSIONS: Use of ZP implants yielded satisfactory long-term clinical and radiological outcomes that were similar to those of the standard ACPC. Additionally, the rates of complications between the groups were not significantly different. Although the best surgical option for multilevel CSM remains controversial, the results of this work suggest that ACDF with the ZP device is feasible, safe, and effective, even for multilevel CSM.

Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1.

Accumulating evidence suggests long non-coding RNAs (lncRNAs) play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Here, we aimed to define the role of HOXA transcript at the distal tip (HOTTIP) in RA pathogenesis in relation to SFRP1 methylation and Wnt signaling pathway. HOTTIP was found highly expressed, and SFRP1 was hypermethylated in RA synovial fibroblasts (RASFs). Next, gain- or loss-of-function experiments were conducted in RASFs to explore the effects of HOTTIP on the biological behaviors of RASFs. Silencing of HOTTIP or overexpression of SFRP1 inhibited RASF proliferation, invasion, and migration, while enhancing apoptosis. The relationship among HOTTIP, SFRP1, and Dnmt3b was determined using methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), RNA pull-down, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays. The regulatory mechanisms of HOTTIP/Dnmt3b/SFRP1 were explored by altering their expression in RASFs. It was noted that HOTTIP could induce SFRP1 promoter methylation through recruitment of Dnmt3b and activate the Wnt signaling pathway. Finally, a rat RA model was established in order to evaluate the in vivo effects of HOTTIP and SFRP1, which suggested that HOTTIP silencing or SFRP1 elevation inhibited the progression of RA in vivo. Our key findings demonstrate the anti-inflammatory ability of HOTTIP silencing in RA through SFRP1 promoter demethylation. These findings support HOTTIP as a candidate anti-arthritis target.

ß1,4-galactosyltransferase-I protects chondrocytes against TNF-induced apoptosis by blocking the TLR4 signaling pathway.

Osteoarthritis (OA) is the most common degenerative disease of the cartilage and is characterized by inflammation of the synovial membrane and subchondral osteosclerosis. ß1,4-galactosyltransferase-I (ß1,4-GalT-I) is a crucial regulator of inflammation based on its role in the stimulation and sustenance of inflammation in OA. In the present study, we aimed at elucidating the expression pattern and potential biological activity of ß1,4-GalT-I in chondrocytes isolated from OA patients. Chondrocytes were isolated from the cartilage and cultured. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to analyze ß1,4-GalT-I expression. Isolated chondrocytes were stimulated with tumor necrosis factor (TNF). Our results indicate significantly enhanced expression of ß1,4-GalT-I in cultivated chondrocytes upon stimulation with TNF. ß1,4-GalT-I inhibited the inflammation and cell death triggered by TNF. In addition, ß1,4-GalT-Iinhibited the expression of Toll-like receptor 4 (TLR4) and phosphorylation of p65 and IKK. In conclusion, our findings suggest the protective effect of ß1,4-GalT-I in chondrocytes against OA induced by TNF based on its ability to block the TLR4 signaling pathway. Our results also indicate significant contribution of ß1,4-GalT-I towards the anti-inflammation in the cartilage of patients suffering from OA.

RGS1 silencing inhibits the inflammatory response and angiogenesis in rheumatoid arthritis rats through the inactivation of Toll-like receptor signaling pathway.

Emerging evidence shows that rheumatoid arthritis (RA) progression can be induced by the activation of Toll-like receptor (TLR) signaling pathway. Regulator of G-protein signaling 1 (RGS1) is observed to be a candidate biomarker for arthritis. Accordingly, the present study aims to determine the potential effects of RGS1 mediating TLR on RA. A rat model of collagen-induced arthritis (CIA) was established to mimic the features of RA by injection of bovine type II collagen. The rats with CIA were treated with short hairpin RNA (shRNA) against RGS1 or TLR pathway activator Poly I:C to elucidate the role of RGS1 in RA progression. The inflammatory factors were measured, and the thoracic gland and spleen indexes as well as the vascular density were determined. The expression levels of RGS1, TLR3, vascular endothelial growth factor (VEGF), metalloproteinase-2 (MMP-2), MMP-9, and interleukin 1 receptor-associated kinase-4 (IRAK4) were determined. RGS1 was robustly increased in RA. The TLR signaling pathway was suppressed by RGS1 silencing. shRNA-mediated depletion of RGS1 was shown to significantly enhance thoracic gland index and inhibit the serum levels of TNF-α, IL-1ß, and IL-17, spleen index, vascular density, and the expression levels of TLR3, VEGF, MMP-2, MMP-9, and IRAK4. However, when the rats with CIA were treated with Poly I:C, the trend of effects was opposite. These findings highlight that functional suppression of RGS1 inhibits the inflammatory response and angiogenesis by inactivating the TLR signaling pathway in rats with CIA, thereby providing a novel therapeutic target for RA treatment.

Prediction modeling using EHR data: challenges, strategies, and a comparison of machine learning approaches.

BACKGROUND: Electronic health record (EHR) databases contain vast amounts of information about patients. Machine learning techniques such as Boosting and support vector machine (SVM) can potentially identify patients at high risk for serious conditions, such as heart disease, from EHR data. However, these techniques have not yet been widely tested. OBJECTIVE: To model detection of heart failure more than 6 months before the actual date of clinical diagnosis using machine learning techniques applied to EHR data. To compare the performance of logistic regression, SVM, and Boosting, along with various variable selection methods in heart failure prediction. RESEARCH DESIGN: Geisinger Clinic primary care patients with data in the EHR data from 2001 to 2006 diagnosed with heart failure between 2003 and 2006 were identified. Controls were randomly selected matched on sex, age, and clinic for this nested case-control study. MEASURES: Area under the curve (AUC) of receiver operator characteristic curve was computed for each method using 10-fold cross-validation. The number of variables selected by each method was compared. RESULTS: Logistic regression with model selection based on Bayesian information criterion provided the most parsimonious model, with about 10 variables selected on average, while maintaining a high AUC (0.77 in 10-fold cross-validation). Boosting with strict variable importance threshold provided similar performance. CONCLUSIONS: Heart failure was predicted more than 6 months before clinical diagnosis, with AUC of about 0.76, using logistic regression and Boosting. These results were achieved even with strict model selection criteria. SVM had the poorest performance, possibly because of imbalanced data.

Prospective study of the association between abandoned dwellings and testosterone level on the development of behaviors leading to cannabis use disorder in boys.

BACKGROUND: The role of testosterone in the development of behaviors presaging cannabis use and subsequently cannabis use disorder was investigated in a prospective study of 208 boys. It was theorized that adverse neighborhood correlates with testosterone level that in turn potentiates behaviors predisposing to cannabis consumption and subsequently diagnosis of cannabis use disorder. METHODS: Proportion of boarded-up dwellings in the 1990 census tract and testosterone level were recorded at baseline (ages 10-12), followed by assessments of assaultiveness and testosterone level (ages 12-14), social dominance/norm-violating behavior (SDNVB) (age 16), cannabis use (age 19), and cannabis use disorder (age 22). RESULTS: Percent of vacant dwellings correlates with testosterone level that in turn predicts assaultive behavior sequentially leading to SDNVB, cannabis use, and cannabis use disorder. Externalizing behaviors and cannabis use disorder are not directly predicted by neighborhood quality. CONCLUSIONS: Elevated testosterone level intermediates the association between neighborhood adversity and aggressive socially deviant behaviors presaging cannabis use and cannabis use disorder.