Causal relationship of interferon-γ and interleukin-18 upstream of intervertebral disc degeneration pathogenesis: a two-sample Mendelian randomization study.

Introduction: Intervertebral disc degeneration (IVDD) is a complex disease caused by genetic and environmental factors, but its pathogenesis is still unclear. Although studies of inflammatory cytokines have been used in recent years to unravel the biological mechanisms of a variety of diseases, such analyses have not yet been applied to IVDD. Therefore, we used a Mendelian Randomization approach to explore the potential mechanisms underlying the pathogenesis of IVDD. Methods: We obtained GWAS data from publicly available databases for inflammatory cytokines and IVDD, respectively, and explored the causal relationship between individual inflammatory cytokines and IVDD using instrumental variable (IV) analysis. We primarily used IVW methods to assess causality, while sensitivity, heterogeneity and multidirectionality analyses were performed for positive results (p < 0.05). All analyses were performed using R software. Results: In our study, we performed a two-sample MR analysis of 41 inflammatory cytokines to identify metabolites causally associated with IVDD. Ultimately, 2 serum metabolites associated with IVDD were identified (pval<0.05), IFN-γ and IL-18. sensitivity, heterogeneity, and Pleiotropy test analyses were performed for all results. Conclusion: Our study identified a causal relationship between IFN-γ and IL-18 and IVDD. It is valuable for the monitoring and prevention of IVDD and the exploration of targeted drugs. However, more evidence is needed to validate our study.

S100A9 Induces Macrophage M2 Polarization and Immunomodulatory Role in the Lesion Site After Spinal Cord Injury in Rats.

Immune response is pivotal in the secondary injury of spinal cord injury (SCI). Polarization of macrophages (MΦ) influences the immune response in the secondary injury, which is regulated by several immune-related proteins. M2Φ plays the immunomodulatory role in the central nervous system. This study used bioinformatic analysis and machine algorithms to screen hub immune-related proteins after SCI and experimentally investigate the role of the target protein in the M2Φ polarization and immunomodulation in rats and in vitro after SCI. We downloaded GSE151371 and GSE45006, hub immune-related genes were screened using machine learning algorithms, and the expression of S100A9 was verified by datasets. Allen's weight-drop injury SCI model in Sprague-Dawley rat and bone marrow-derived rat MΦ with myelin debris model were used to study the effects of S100A9 on M2Φ polarization and immunomodulation at the lesion site and in vitro. Bioinformatic analysis showed that S100A9 acts as a hub immune-related gene in the SCI patients and rats. S100A9 increased at the lesion site in SCI rats, and its inhibition reduced CD206 and ARG-1 expression. Exogenous S100A9 promoted CD206 and ARG-1 expression in MΦ. S100A9 also increased the expression of PD-L1 and decreased MHC II at the lesion site in SCI rats and MΦ with myelin debris, and enhanced mitochondrial activity in rat MΦ with myelin debris. In conclusion, S100A9 is an indispensable factor in the immune process in secondary injury following SCI.

Inhibition of HMGB1 Attenuates Spinal Cord Edema by Reducing the Expression of Na+-K+-Cl- Cotransporter-1 and Na+/H+ Exchanger-1 in Both Astrocytes and Endothelial Cells After Spinal Cord Injury in Rats.

Sodium/water transport through Na+-K+-Cl- cotransporter-1 (NKCC1) and sodium/hydrogen exchanger-1 (NHE1) in both astrocytes and endothelial cells is critical to cytotoxic and ionic edema following spinal cord injury (SCI). High-mobility group box-1 (HMGB1) promotes spinal cord edema after SCI. Accordingly, we sought to identify both the role of HMGB1 and the mechanism of its effect on NKCC1 and NHE1 expression in astrocytes and endothelial cells as well as the role of the regulation of spinal cord edema after SCI. An SCI model was generated in adult female rats using a heavy falling object, and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model was generated in rat spinal cord astrocytes and microvascular endothelial cells. The inhibition of HMGB1 reduced NKCC1 and NHE1 expression in the spinal cord of SCI rats, in cultured spinal cord astrocytes, and in cultured microvascular endothelial cells. The effects of HMGB1 on NKCC1 and NHE1 expression were mediated-at least in part-by activation of the Toll-like receptor 4 (TLR4)-Toll/interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-nuclear factor-kappa B (NF-κB) signaling pathway. The inhibition of NKCC1 or NHE1 decreased the spinal cord water content in rats following SCI, increased the Na+ concentration in the medium of cultured astrocytes after OGD/R, and reduced the astrocytic cell volume and AQP4 expression. These results imply that HMGB1 inhibition results in a reduction in NKCC1 and NHE1 expression in both astrocytes and microvascular endothelial cells and thus decreases spinal cord edema after SCI in rats and that these effects occur through the HMGB1-TLR4-TRIF-NF-κB signaling pathway.

Therapeutic effects and long-term outcomes of HMGB1-targeted therapy in rats and mice with traumatic spinal cord injury: A systematic review and meta-analysis.

Background: To date, the clinical need for therapeutic methods to prevent traumatic spinal cord injury (TSCI) progression and improve functional recovery has not been met. High mobility group box-1 (HMGB1) is released by necrotic neurons or secreted by glial cells after TSCI and plays an important role in pathophysiology. Objective: The purpose of this study was to evaluate the effects of HMGB1-targeted therapy on locomotor function recovery, inflammation reduction, edema attenuation, and apoptosis reduction in rat and mouse models of TSCI. Methods: We reviewed the literature on HMGB1-targeted therapy in the treatment and prognosis of TSCI. Twelve articles were identified and analyzed from four online databases (PubMed, Web of Science, Cochrane Library and Embase) based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and strict inclusion criteria. Results: The methodological quality of the 12 articles was poor. The results of the meta-analysis showed that compared with the SCI group, the treatment group had significantly increased locomotor function scores after SCI [n = 159, standardized mean difference (SMD) = 2.31, 95% confidence interval (CI) (1.52, 3.10), P < 0.00001], and the change in locomotor function scores was significantly increased in both the drug and anti-HMGB1 Ab groups (P < 0.000001 and P < 0.000001). A subgroup analysis showed significant differences (P > 0.05) between the drug group [(SMD) = 1.95, 95% CI (0.95, 2.94), P = 0.0001] and the anti-HMGB1 Ab group [(SMD) = 2.89, 95% CI (1.66, 4.13), P < 0.00001]. Compared with the SCI group, HMGB1 expression was significantly diminished [n = 76, SMD = -2.31, 95% CI (-3.71, -0.91), P = 0.001], TNF-α levels were significantly reduced [n = 76, SMD = -2.52, 95% CI (-3.77, -1.27), P < 0.0001], water content was significantly reduced [n = 44, SMD = -3.94, 95% CI (-6.28, -1.61), P = 0.0009], and the number of apoptotic cells was significantly diminished [n = 36, SMD = -3.31, 95% CI (-6.40, -0.22), P = 0.04] in the spinal cord of the treatment group. Conclusion: HMGB1-targeted therapy improves locomotor function, reduces inflammation, attenuates edema, and reduces apoptosis in rats and mice with TSCI. Intrathecal injection of anti-HMGB1 Ab 0-3 h after SCI may be the most efficacious treatment. Systematic review registration: PROSPERO, identifier: CRD42022326114.

Clinical efficacy and safety of posterior minimally invasive surgery in cervical spondylosis: a systematic review.

BACKGROUND: Posterior minimally invasive surgery has been increasingly used in in recent years for the clinical treatment of cervical spondylosis. However, this treatment remains challenging and has not been comprehensively reported. The aim of this study was to provide a systematic review of posterior minimally invasive treatment for cervical spondylosis to demonstrate the clinical efficacy and safety of this procedure. METHOD: We collected information from patients with myelopathy or radiculopathy cervical spondylosis who underwent posterior minimally invasive surgery and verified the clinical efficacy and safety of these surgeries with different measurement indicators from five electronic databases: the Nurick, visual analog scale score, Japanese Orthopaedic Association (JOA) score, Neck Disability Index (NDI), EuroQol Five Dimensions Questionnaire (EQ-5D) score, Short-Form Health Survey Physical Component Summary (SF12-PCS) questionnaire score, Short-Form Health Survey Mental Component Summary (SF12-MCS) questionnaire score, and the MOS item short form health survey (HF-36) score. The decompression effect, cervical spine stability, average surgery time, surgical blood loss volume, length of hospital stay, and related complications were included in the descriptive analysis. Reporting of this protocol followed the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines checklist. RESULTS: We identified 14 observational studies of cervical spondylosis with 479 patients, mainly including 197 cases of myelopathy and 207 cases of radiculopathy. Channel and endoscopic techniques were used. This study was certified by PROSPERO: CRD42021290074. Significant improvements in the quantitative indicators (Neck-VAS in 9 studies, JOA in 7 studies, NDIs in 5 studies, Nurick, ARM-VAS, and EQ-5D in 2 studies each, and the SF12-PCS, SF12-MCS, and HF-36 in 1 study each) were observed between pre- and postoperation (P < 0.05), and satisfactory clinical significance was acquired in the descriptive indicators [average surgery time (94.56 ± 37.26 min), blood loss volume (68.78 ± 103.31 ml), average length of stay (2.39 ± 1.20 d), and cervical spine stability after surgery]. Additionally, we showed that there was a 4.9% postoperative complication rate and the types of complications that may occur. CONCLUSION: Posterior minimally invasive surgery is an effective and safe method for the treatment of cervical spondylosis and is a recommended optional surgical procedure for single-segment myelopathy and radiculopathy.

Low cervical vertebral CT value increased early subsidence of titanium mesh cage after anterior cervical corpectomy and fusion.

STUDY DESIGN: This study was a retrospective review. OBJECTIVE: To study the predictive effect of Hounsfield units (HU) value in the cervical vertebral body derived from computed tomography (CT) on the early titanium mesh cage (TMC) subsidence after anterior cervical corpectomy and fusion (ACCF). METHODS: This retrospective study was conducted on patients who underwent ACCF at one institution between January 2014 and December 2018. We collected date included age, gender, body mass index (BMI), disease type, surgical segment, whether merge ACDF, HU value of the vertebral body and endplate, vertebral body height loss, cervical lordosis angle, and cervical sagittal alignment. VAS, JOA, and NDI were used to assess clinical efficacy. Univariate analysis was performed to screen the influencing factors of TMC subsidence, and then logistic regression was used to find out the independent risk factors. The ROC curve and area under curve (AUC) were used to analyze the HU value to predict the TMC subsidence. RESULTS: A total of 85 patients who accepted ACCF were included in this study, and early titanium mesh cage subsidence was demonstrated in 29 patients. The subsidence rate was 34.1%. The JOA, VAS, and NDI scores significantly improved in both groups after the operation. Between the subsidence and non-subsidence groups, there were significant differences in age, intervertebral distraction height, and HU value in both upper and lower vertebral body and endplate. The logistic regression analysis proved that the HU value of the lower vertebral body was an independent risk of TMC subsidence, the AUC was 0.866, and the most appropriate threshold of the HU value was 275 (sensitivity: 87.5%, specificity: 79.3%). CONCLUSION: Preoperative cervical CT value is an independent correlative factor for early TMC subsidence after ACCF, and patients with a low CT value of the inferior vertebral body of the operative segment have a higher risk of TMC subsidence in the early postoperative period. TRIAL REGISTRATION: This study is undergoing retrospective registration.

One-stage tracheostomy during surgery reduced early pulmonary infection and mechanical ventilation length in complete CSCI patients.

Objective: Complete cervical spinal cord injury (CSCI) is a devastating injury that usually requires surgical treatment. Tracheostomy is an important supportive therapy for these patients. To evaluate the effectiveness of early one-stage tracheostomy during surgery compared with necessary tracheostomy after surgery, and to identify clinical factors for one-stage tracheostomy during surgery in complete cervical spinal cord injury. Design: Data from 41 patients with complete CSCI treated with surgery were retrospectively analyzed. Participants and interventions: Ten patients (24.4%) underwent one-stage tracheostomy during surgery, thirteen (31.7%) underwent tracheostomy when necessary after surgery, and eighteen (43.9%) did not have a tracheostomy. Main results: One-stage tracheostomy during surgery significantly reduced the development of pneumonia at 7 days after tracheostomy (p = 0.025), increased the PaO2 (p < 0.05), and decreased the length of mechanical ventilation (p = 0.005), length of stay (LOS) in the intensive care unit (ICU) (p = 0.002), hospital LOS (p = 0.01) and hospitalization expenses compared with necessary tracheostomy after surgery (p = 0.037). A high neurological level of injury (NLI) (NLI C5 and above), a high PaCO2 in the blood gas analysis before tracheostomy, severe breathing difficulty, and excessive pulmonary secretions were the statistically significant factors for one-stage tracheostomy during surgery in the complete CSCI patients, but no independent clinical factor was found. Conclusions: In conclusion, one-stage tracheostomy during surgery reduced the number of early pulmonary infections and the length of mechanical ventilation, ICU LOS, hospital LOS and hospitalization expenses, and one-stage tracheostomy should be considered when managing complete CSCI patients by surgical treatment.