Advancing Spinal Cord Injury Bioimaging and Repair with Multifunctional Gold Nanodots Tracking.

High levels of reactive oxygen species (ROS) are known to play a critical role in the secondary cascade of spinal cord injury (SCI). The scavenging of ROS has emerged as a promising approach for alleviating acute SCI. Moreover, identifying the precise location of the SCI site remains challenging. Enhancing the visualization of the spinal cord and improving the ability to distinguish the lesion site are crucial for accurate and safe treatment. Therefore, there is an urgent clinical need to develop a biomaterial that integrates diagnosis and treatment for SCI. Herein, ultra-small-sized gold nanodots (AuNDs) were designed for dual-mode imaging-guided precision treatment of SCI. The designed AuNDs demonstrate two important functions. First, they effectively scavenge ROS, inhibit oxidative stress, reduce the infiltration of inflammatory cells, and prevent apoptosis. This leads to a significant improvement in SCI repair and promotes a functional recovery after injury. Second, leveraging their excellent dual-mode imaging capabilities, the AuNDs enable rapid and accurate identification of SCI sites. The high contrast observed between the injured and adjacent uninjured areas highlights the tremendous potential of AuNDs for SCI detection. Overall, by integrating ROS scavenging and dual-mode imaging in a single biomaterial, our work on functionalized AuNDs provides a promising strategy for the clinical diagnosis and treatment of SCI.

Associations of pyrethroid exposure with bone mineral density and osteopenia in adults.

INTRODUCTION: This study was to investigate the correlations between pyrethroid exposure and bone mineral density (BMD) and osteopenia. MATERIALS AND METHODS: This cross-sectional study included 1389 participants over 50 years of age drawn from the 2007-2010 and 2013-2014 National Health and Nutrition Examination Survey (NHANES). Three pyrethroid metabolites, 3-phenoxybenzoic acid (3-PBA), trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid (trans-DCCA), and 4-fluoro-3-phenoxybenzoic acid (4-F-3PBA) were used as indicators of pyrethroid exposure. Low BMD was defined as T-score < - 1.0, including osteopenia. Weighted multivariable linear regression analysis or logistic regression analysis was utilized to evaluate the correlation between pyrethroid exposure and BMD and low BMD. Bayesian kernel machine regression (BKMR) model was utilized to analyze the correlation between pyrethroids mixed exposure and low BMD. RESULTS: There were 648 (48.41%) patients with low BMD. In individual pyrethroid metabolite analysis, both tertile 2 and tertile 3 of trans-DCCA were negatively related to total femur, femur neck, and total spine BMD [coefficient (ß) = - 0.041 to - 0.028; all P < 0.05]. Both tertile 2 and tertile 3 of 4-F-3PBA were negatively related to total femur BMD (P < 0.05). Only tertile 2 [odds ratio (OR) = 1.63; 95% CI = 1.07, 2.48] and tertile 3 (OR = 1.65; 95% CI = 1.10, 2.50) of trans-DCCA was correlated with an increased risk of low BMD. The BKMR analysis indicated that there was a positive tendency between mixed pyrethroids exposure and low BMD. CONCLUSION: In conclusion, pyrethroids exposure was negatively correlated with BMD levels, and the associations of pyrethroids with BMD and low BMD varied by specific pyrethroids, pyrethroid concentrations, and bone sites.

Causal association of physical activity with low back pain, intervertebral disc degeneration and sciatica: a two-sample mendelian randomization analysis study.

Objective: Previous studies are insufficient to confirm a causal association between physical activity (PA) and low back pain (LBP), intervertebral disc degeneration (IDD), and sciatica. The present study used a two-sample Mendelian randomization (MR) analysis method to demonstrate whether or not there was a causal connection. Methods: First, four PA phenotypes were selected [accelerometer-based PA (average acceleration), accelerometer-based PA (acceleration fraction >425 mg), self-reported moderate-to-vigorous PA, and self-reported vigorous PA], setting thresholds for single nucleotide polymorphisms (SNPs) significantly concerned with PA p < 5 × 10-8, linkage disequilibrium (LD) r 2 < 0.01, genetic distance >5,000 kb, and F-value >10. SNPs associated with the outcome and confounding factors were then excluded using the PhenoScanncer database. Finally, after coordinating the genetic instruments from genome-wide association studies (GWAS) effect alleles for exposure and outcomes, multiplicative random effects inverse variance weighting (IVW), MR-Egger, weighted median method (WMM), and weighted mode method were used to assess exposure-outcome causality and perform sensitivity analysis on the estimated results. Results: The current study's IVW findings revealed proof of a causal connection between PA and LBP. While there was a positive causal tie between accelerometer-based PA (acceleration fraction >425 mg) and LBP [OR: 1.818, 95% CI:1.129-2.926, p = 0.012], there was a negative causal link between accelerometer-based PA (average acceleration) and LBP [OR: 0.945, 95% CI: 0.909-0.984, p = 0.005]. However causal relationship between PA and IDD or sciatica was not found. Conclusion: Increasing average PA but needing to avoid high-intensity PA may be an effective means of preventing low back pain. Although PA is not directly causally related to disc degeneration and sciatica, it can act through indirect pathways.

Immunogenic cell death-related classifications guide prognosis and immunotherapy in osteosarcoma.

Immunogenic cell death (ICD) is a form of cell death that stimulates the immune system to produce an immune response by releasing tumour-associated antigens and tumour-specific antigens and is considered to play an important role in tumour immunotherapy. In the present study, we identified two ICD-related subtypes in osteosarcoma (OS) by consensus clustering. The ICD-low subtype was associated with favourable clinical outcomes, abundant immune cell infiltration, and high activity of immune response signalling. We also established and validated an ICD-related prognostic model, which could not only be used to predict the overall survival of OS patients but was also found to be closely related to the tumour immune microenvironment of OS patients. Overall, we established a new classification system for OS based on ICD-related genes, which can be used to predict the prognosis of OS patients and to select appropriate immunotherapy drugs.

Identification of key genes involved in neural regeneration and the repairing effect of BDNF-overexpressed BMSCs on spinal cord ischemia-reperfusion injury in rats.

Bone marrow mesenchymal stem cells (BMSCs) can repair spinal cord ischemia-reperfusion injury (SCII); however, only a few BMSCs are usually located in the injured spinal cord. Since the brain-derived neurotrophic factor (BDNF) can promote neural development and maturation, we hypothesised that BDNF-overexpressed BMSCs can ameliorate SCII more effectively than BMSCs alone. To determine the effect of BDNF overexpression on SCII repair, BDNF-overexpressed BMSCs and BMSCs were transplanted into SCII rats. Our results revealed that BDNF-overexpressed BMSCs can better promote the recovery of damaged spinal cords than BMSCs alone. Gene chip detection of spinal cord tissues showed 803 differentially expressed genes in all groups. BTG anti-proliferation factor 2 (Btg2), FOS like 2 (Fosl2), early growth response protein 1 (Egr1), and serpin family E member 1 (Serpine1) were identified as key interrelated genes based on their expression trends, as validated via quantitative PCR and protein-protein interaction network analysis. A co-expression network was constructed to further explore the role of the candidate key genes using Pearson correlation analysis. Cluster 5 was identified as the key cluster using community discovery algorithms. Functional analysis of Cluster 5 genes revealed that this cluster was mainly involved in the stress-activated MAPK cascade, p38MAPK cascade, and apoptosis. Notably, Egr1 may play an important role in SCII repair as the top hub gene in Cluster 5. Therefore, the repair activity of transplanted BDNF-overexpressed BMSCs in SCII rats is better than that of BMSCs alone, which may be regulated by the interactions between Btg2, Fosl2, Egr1, Serpine1, and BDNF.

Immune mechanism of low bone mineral density caused by ankylosing spondylitis based on bioinformatics and machine learning.

Background and Objective: This study aims to find the key immune genes and mechanisms of low bone mineral density (LBMD) in ankylosing spondylitis (AS) patients. Methods: AS and LBMD datasets were downloaded from the GEO database, and differential expression gene analysis was performed to obtain DEGs. Immune-related genes (IRGs) were obtained from ImmPort. Overlapping DEGs and IRGs got I-DEGs. Pearson coefficients were used to calculate DEGs and IRGs correlations in the AS and LBMD datasets. Louvain community discovery was used to cluster the co-expression network to get gene modules. The module most related to the immune module was defined as the key module. Metascape was used for enrichment analysis of key modules. Further, I-DEGs with the same trend in AS and LBMD were considered key I-DEGs. Multiple machine learning methods were used to construct diagnostic models based on key I-DEGs. IID database was used to find the context of I-DEGs, especially in the skeletal system. Gene-biological process and gene-pathway networks were constructed based on key I-DEGs. In addition, immune infiltration was analyzed on the AS dataset using the CIBERSORT algorithm. Results: A total of 19 genes were identified I-DEGs, of which IFNAR1, PIK3CG, PTGER2, TNF, and CCL3 were considered the key I-DEGs. These key I-DEGs had a good relationship with the hub genes of key modules. Multiple machine learning showed that key I-DEGs, as a signature, had an excellent diagnostic performance in both AS and LBMD, and the SVM model had the highest AUC value. Key I-DEGs were closely linked through bridge genes, especially in the skeletal system. Pathway analysis showed that PIK3CG, IFNAR1, CCL3, and TNF participated in NETs formation through pathways such as the MAPK signaling pathway. Immune infiltration analysis showed neutrophils had the most significant differences between case and control groups and a good correlation with key I-DEG. Conclusion: The key I-DEGs, TNF, CCL3, PIK3CG, PTGER2, and IFNAR1, can be utilized as biomarkers to determine the risk of LBMD in AS patients. They may affect neutrophil infiltration and NETs formation to influence the bone remodeling process in AS.

Effectiveness and safety of decompression alone versus decompression plus fusion for lumbar spinal stenosis with degenerative spondylolisthesis: a systematic review and meta-analysis.

Background: There have been lingering controversies reported decompression and plus fusion. And the relative safety of fusion in addition to standard decompression remains unclear. This study aimed to assess the effectiveness and safety of decompression alone or combined with fusion in lumbar spinal stenosis (LSS) with degenerative spondylolisthesis (DS). Methods: In this systematic review and meta-analysis, we searched the databases of PubMed, Embase, Cochrane Library, and Web of Science for relevant literature from their inception to 28th December 2021. We identified the eligible studies based on the PICOS principles, populations (LSS with DS), interventions (decompression alone), controls (decompression combined with fusion), outcomes [overall reoperation rate, complications, Oswestry Disability Index (ODI), operative time, the amount of blood lost, length of stay (LOS), and visual analog scales (VAS)], study design (cohort studies). Quality assessment for individual study was performed with the Newcastle-Ottawa Scale (NOS). Results: In all, 12 articles involving a total of 14,693 patients were finally included in the study, the majority of patients underwent decompression alone (DA group: n=11,598) and the rest underwent decompression associated with fusion (FU group: n=3,095). The quality of most of the included studies was regarded as high quality. The results indicated that the FU group had a higher rate of complication [relative risk (RR): 1.770, 95% confidence interval (CI): 1.485 to 2.110], longer operative time [weighted mean difference (WMD): 51.037, 95% CI: 13.743 to 88.330], and increased blood loss (WMD: 258.354, 95% CI: 150.468 to 366.239) than the DA group (all P<0.05), with no significant differences for overall reoperation rate (RR: 0.879, 95% CI: 0.432 to 1.786), ODI (WMD: -2.569, 95% CI: -6.548 to 1.409), LOS (WMD: 3.838, 95% CI: -2.172 to 9.848), and VAS found between the two groups (P>0.05). Conclusions: In patients with LSS + DS, the effectiveness and safety of decompression alone may be superior to decompression plus fusion in terms of complication rate, operative time, and the amount of bleeding. However, more high-quality literature is needed in the future to confirm the best treatment choice for patients with LSS + DS.

The efficiency and safety of alendronate versus teriparatide for treatment glucocorticoid-induced osteoporosis: A meta-analysis and systematic review of randomized controlled trials.

BACKGROUND: Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis, alendronate (ALE) and teriparatide (TPTD) are widely used in the treatment of GIOP. However, which of these two drugs has a better curative effect needs the support of evidence-based medicine. METHODS: We searched PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar for randomized controlled trials of ALE and TPTD in the treatment of glucocorticoid-induced osteoporosis until February 2022. These patients included in the study took glucocorticoid doses greater than 7.5 mg/d for more than 3 months before treatment with ALE and TPTD. The risk ratio (RR) and its 95% confidence interval (CI) are used as the influence index of discontinuous data, and the standardized mean difference (SMD) and its 95% CI are used as the influence index of continuous data. RESULTS: A total of 4102 patients were enrolled in all 5 studies that met the admission criteria. We found that compared with ALE, TPTD could reduce the rate of new vertebral fracture (RR = 0.13, 95% CI: 0.05-0.34, P<0.00001). TPTD increased LS bone mineral density (BMD) (0.53, 95% CI 0.42-0.64, P<0.00001), TH BMD (0.17, 95% CI 0.05-0.28, P = 0.004) and FN BMD (0.17, 95% CI 0.05-0.29, P = 0.006) compared to ALE. However, there was no significant difference in the incidence of non-vertebral fracture and adverse events between the two groups. CONCLUSIONS: Compared with ALE, TPTD is an effective drug to reduce vertebral fracture risk in patients with GIOP. Furthermore, long-term use of TPTD can increase the bone mineral density of LS, FN, and TH.

Gold nanodots with stable red fluorescence for rapid dual-mode imaging of spinal cord and injury monitoring.

Spinal cord injury is one of the most devastating complications of spinal surgery, often resulting in numbness, pain or paralysis. Minor injuries in the spinal cord are hard to be identified and existing imaging modalities are unable to provide intraoperative monitoring. Monitoring pathological change at the site of injury is a key factor in staging and treatment decision making as well as prognosis of spinal cord injury. Herein, we offer the fluorescence imaging with intraoperative visualization and detection accuracy for bioimaging to resolve the problem. A novel red fluophore AuNDs caped with glutathione is prepared, which exhibits some advantages such as ultra-small size, negligible biotoxicity, superior water solubility and great biocompatibility. AuNDs fluorophore especially exhibit both of a remarkable photoluminescence stability and high attenuation coefficient to X-rays. In addition, AuNDs can be used as CT contrast agent for spinal cord, which avoid the high toxicity and weak CT signal of traditional iodine contrast. After intradural injection into the spinal cord, AuNDs are transported through the flow of cerebrospinal fluid and bound to the spinal cord parenchyma. not only the bioimage of the entire spinal cord can be achieved as quick as 15 min, but they are also particularly beneficial to long-term imaging of complex physiological environments in vivo, with negligible quenching. Comparing from the bright red fluorescence in adjacent normal spinal cord sites, there is almost no fluorescence in spinal cord at the areas of the injury. We suggest that AuNDs are unable to enter the injury sites of necrosis and ischemia, which promote a different contrast imaging from the normal one. The bright red fluorescence of the AuNDs significantly overcome the restriction of the blue autofluorescence of the biological tissues, providing a clear boundary for observation of the thin spinal cord injury. As a result, we developed the AuNDs with fluorescent and CT dual-mode bioimaging capability to clearly and effectively diagnose spinal cord injury, which are expected to provide a novel visualization imaging regent for clinical use.

Efficacy and safety of 18 anti-osteoporotic drugs in the treatment of patients with osteoporosis caused by glucocorticoid: A network meta-analysis of randomized controlled trials.

BACKGROUND: Glucocorticoids are widely used in a variety of diseases, especially autoimmune diseases and inflammatory diseases, so the incidence of glucocorticoid-induced osteoporosis is high all over the world. OBJECTIVES: The purpose of this paper is to use the method of network meta-analysis (NMA) to compare the efficacy of anti-osteoporosis drugs directly and indirectly, and to explore the advantages of various anti-osteoporosis drugs based on the current evidence. METHODS: We searched PubMed, Embase and Cochrane Library for randomized controlled trials (RCTs), of glucocorticoid-induced osteoporosis (GIOP) and compared the efficacy and safety of these drugs by NMA. The risk ratio (RR) and its 95% confidence interval (CI) are used as the influence index of discontinuous data, and the standardized mean difference (SMD) and its 95% CI are used as the influence index of continuous data. The statistical heterogeneity was evaluated by the calculated estimated variance (τ2), and the efficacy and safety of drugs were ranked by the surface under the cumulative ranking curve (SUCRA). The main outcome of this study was the incidence of vertebral fracture after taking several different types of drugs, and the secondary results were the incidence of non-vertebral fracture and adverse events, mean percentage change of lumbar spine (LS) and total hip (TH)bone mineral density (BMD) from baseline to at least 12 months. RESULTS: Among the different types of anti-GIOP, teriparatide (SUCRA 95.9%) has the lowest incidence of vertebral fracture; ibandronate (SUCRA 75.2%) has the lowest incidence of non-vertebral fracture; raloxifene (SUCRA 98.5%) has the best effect in increasing LS BMD; denosumab (SUCRA 99.7%) is the best in increasing TH BMD; calcitonin (SUCRA 92.4%) has the lowest incidence of serious adverse events. CONCLUSIONS: Teriparatide and ibandronate are effective drugs to reduce the risk of vertebral and non-vertebral fractures in patients with GIOP. In addition, long-term use of raloxifene and denosumab can increase the BMD of LS and TH.

Effect of non-invasive brain stimulation on neuropathic pain following spinal cord injury: A systematic review and meta-analysis.

BACKGROUND: In recent years, some studies indicated that repetitive transcranial magnetic stimulation (rTMS) could relieve neuropathic pain (NP) following a spinal cord injury (SCI), whereas some studies showed no pain relief effect. In addition, some studies showed the analgesic effect of transcranial direct current stimulation (tDCS) on NP post SCI, whereas other studies showed no effect. METHODS: We systematically searched on the PubMed, Web of Science, EMBASE, Medline, Google Scholar for studies exploring the analgesic effect of rTMS or tDCS on NP post SCI until November 2019. Meta-analysis was conducted to summarize results of these studies. RESULTS: The present quantitative meta-analysis indicated no significant difference in the effect of treatment on NP following SCI between rTMS and sham rTMS over the motor cortex at about 1 week after the end of the rTMS period (standardized mean difference (SMD) = 2.89, 95% confidence interval (CI) = -0.27 to 6.04). However, the study indicated that rTMS showed significantly better pain relief of treatment compared with sham rTMS between 2 and 6 weeks after the end of the rTMS period (SMD = 3.81, 95%CI: 0.80-7.52). However, no sufficient evidence could be provided to make a meta-analysis for the analgesic effect of tDCS on NP following SCI over the primary motor area (M1). CONCLUSIONS: In conclusion, the present meta-analysis suggested that rTMS did not show early analgesic effect on NP after SCI, but showed better middle-term analgesic effect, compared with sham rTMS. More large scale, blinded randomized controlled trials (RCTs) were needed to explore the analgesic effect of rTMS and tDCS on NP following SCI.