Regulating tumor microenvironments by a lymph node-targeting adjuvant via tumor-specific CTL-derived IFNγ.

Inducing tumor-specific T cell responses and regulating suppressive tumor microenvironments have been a challenge for effective tumor therapy. CpG (ODN), the Toll-like receptor 9 agonist, has been widely used as adjuvants of cancer vaccines to induce T cell responses. We developed a novel adjuvant to improve the targeting of lymph nodes. CpG were modified with lipid and glycopolymers by the combination of photo-induced RAFT polymerization and click chemistry, and the novel adjuvant was termed as lipid-glycoadjuvant@AuNPs (LCpG). OVA protein was used as model antigen and melanoma model was established to test the immunotherapy effect of the adjuvant. In tumor model, the antitumor effect and mechanism of LCpG on the response of CTLs were examined by flow cytometry and cell cytotoxicity assay. The effects of LCpG on macrophage polarization and Tregs differentiation in tumor microenvironment were also studied by cell depletion assay and cytokine neutralization assay. We also tested the therapeutic effect of the combination of the adjuvant and anti-PD-1 treatment. LCpG could be rapidly transported to and retained longer in the lymphoid nodes than unmodified CpG. In melanoma model, LCpG controlled both primary tumor and its metastasis, and established long-term memory. In spleen and tumor draining lymphoid nodes, LCpG activated tumor-specific Tc1 responses, with increased CD8+ T-cell proliferation, antigen-specific Tc1 cytokine production and specific-tumor killing capacity. In tumor microenvironments, antigen-specific Tc1 induced by the LCpG promoted CTL infiltration, skewed tumor associated macrophages to M1 phenotype, regulated Treg and induced proinflammatory cytokines production in a CTL-derived IFN-γ-dependent manner. In vivo cell depletion and adoptive transfer experiments confirmed that antitumor activity of LCpG included vaccine was mainly dependent on CTL-derived IFN-γ. The anti-tumor efficacy of LCpG was dramatically enhanced when combined with anti-PD1 immunotherapy. LCpG was a promising adjuvant for vaccine formulation which could augment tumor-specific Tc1 activity, and regulate tumor microenvironments.

Nimbolide targeting SIRT1 mitigates intervertebral disc degeneration by reprogramming cholesterol metabolism and inhibiting inflammatory signaling.

Inflammation, abnormal cholesterol metabolism, and macrophage infiltration are involved in the destruction of the extracellular matrix of the nucleus pulposus (NP), culminating in intervertebral disc degeneration (IDD). Whether nimbolide (Nim), a natural extract, can alleviate IDD is unclear. In this study, we demonstrated that Nim promotes cholesterol efflux and inhibits the activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways by activating sirtuin 1 (SIRT1) in nucleus pulposus cells (NPCs) during inflammation. Thus, Nim balanced matrix anabolism and catabolism of NPCs. However, the inhibition of SIRT1 significantly attenuated the effects of Nim. We also found that Nim promoted the expression of SIRT1 in RAW 264.7, which enhanced the proportion of M2 macrophages by facilitating cholesterol homeostasis reprogramming and impeded M1-like macrophages polarization by blocking the activation of inflammatory signaling. Based on these results, Nim can improve the microenvironment and facilitate matrix metabolism equilibrium in NPCs. Furthermore, in vivo treatment with Nim delayed IDD progression by boosting SIRT1 expression, modulating macrophage polarization and preserving the extracellular matrix. In conclusion, Nim may represent a novel therapeutic strategy for treating IDD.

Single-Cell Transcriptome Profiling Reveals Multicellular Ecosystem of Nucleus Pulposus during Degeneration Progression.

Although degeneration of the nucleus pulposus (NP) is a major contributor to intervertebral disc degeneration (IVDD) and low back pain, the underlying molecular complexity and cellular heterogeneity remain poorly understood. Here, a comprehensive single-cell resolution transcript landscape of human NP is reported. Six novel human NP cells (NPCs) populations are identified by their distinct molecular signatures. The potential functional differences among NPC subpopulations are analyzed. Predictive transcripts, transcriptional factors, and signal pathways with respect to degeneration grades are explored. It is reported that fibroNPCs is the subpopulation for end-stage degeneration. CD90+NPCs are observed to be progenitor cells in degenerative NP tissues. NP-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including granulocytic myeloid-derived suppressor cells (G-MDSCs). Integrin αM (CD11b) and oxidized low density lipoprotein receptor 1 (OLR1) as surface markers of NP-derived G-MDSCs are uncovered. The G-MDSCs are found to be enriched in mildly degenerated (grade II and III) NP tissues compared to severely degenerated (grade IV and V) NP tissues. Their immunosuppressive function and alleviation effects on NPCs' matrix degradation are revealed in vitro. Collectively, this study reveals the NPC-type complexity and phenotypic characteristics in NP, thereby providing new insights and clues for IVDD treatment.

Multifaceted glycoadjuvant@AuNPs inhibits tumor metastasis through promoting T cell activation and remodeling tumor microenvironment.

ABSTARCT: BACKGROUND: Cytosine-phosphate-guanine (CpG) dinucleotides has been used as adjuvants for cancer immunotherapy. However, unmodified CpG are not very efficient in clinical trials. Glucose, ligand of C-type lectin receptors (CLRs), can promote DC maturation and antigen presentation, which is the first step of induction of adaptive immune responses. Therefore, conjugation of type B CpG DNA to glucose-containing glycopolymers may enhance the therapeutic effects against tumor by CpG-based vaccine. METHODS: gCpG was developed by chemical conjugation of type B CpG DNA to glucose-containing glycopolymers. The therapeutic effects of gCpG-based vaccine were tested in both murine primary melanoma model and its metastasis model. RESULTS: gCpG based tumor vaccine inhibited both primary and metastasis of melanoma in mice which was dependent on CD8 + T cells and IFNγ. In tumor microenvironment, gCpG treatment increased Th1 and CTL infiltration, increased M1 macrophages, decreased Tregs and MDSCs populations, and promoted inflammatory milieu with enhanced secretion of IFNγ and TNFα. The anti-tumor efficacy of gCpG was dramatically enhanced when combined with anti-PD1 immunotherapy. CONCLUSIONS: We confirmed that gCpG was a promising adjuvant for vaccine formulation by activating both tumor-specific Th1 and Tc1 responses, and regulating tumor microenvironments.

Precise in-situ release of microRNA from an injectable hydrogel induces bone regeneration.

Critical bone defects are a common yet challenging orthopedic problem. Tissue engineering is an emerging and promising strategy for bone regeneration in large-scale bone defects. The precise on-demand release of osteogenic factors is critical for controlling the osteogenic differentiation of seed cells with the support of appropriate three dimensional scaffolds. However, most of the effective osteogenic factors are biomacromolecules with release behaviors that are difficult to control. Here, the cholesterol-modified non-coding microRNA Chol-miR-26a was used to promote the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Chol-miR-26a was conjugated to an injectable poly(ethylene glycol) (PEG) hydrogel through an ultraviolet (UV)-cleavable ester bond. The injectable PEG hydrogel was formed by a copper-free click reaction between the terminal azide groups of 8-armed PEG and dibenzocyclooctyne-biofunctionalized PEG, into which UV-cleavable Chol-miR-26a was simultaneously conjugated via a Michael addition reaction. Upon UV irradiation, Gel-c-miR-26a (MLCaged) released Chol-c-miR-26a selectively and exhibited significantly improved efficacy in bone regeneration compared to the hydrogel without UV irradiation and UV-uncleavable MLControl. MLCaged significantly enhanced alkaline phosphatase activity and promoted calcium nodule deposition in vitro and repaired critical skull defects in a rat animal model, demonstrating that injectable implantation with the precise release of osteogenic factors has the potential to repair large-scale bone defects in clinical practice. STATEMENT OF SIGNIFICANCE: Provide a novel and practical strategy via hydrogel for efficient delivery and precisely controlled release of miRNAs into bone defect sites. The hydrogel is formed by polyethylene glycol (PEG), which is crosslinked by 'click' reaction. Cholesterol-modified miR-26a loading on the hydrogel is covalently patterned onto the fibers of hydrogel through a UV light-cleavable linker, which prevents undesired release of miRNA. This hydrogel could realize the controlled release of miRNA under light regulation both in vitro and in vivo, thus realize bone regeneration.

Resveratrol protects human nucleus pulposus cells from degeneration by blocking IL-6/JAK/STAT3 pathway.

BACKGROUND: Nucleus pulposus cells' (NPCs') degeneration is mainly responsible for the intervertebral disc degeneration (IDD), which is closely related to inflammatory response. Among the major proinflammatory factors that are related to NPCs' degeneration, interleukin-6 (IL-6) and its downstream JAK/STAT3 pathway have received recent attention. The goal of our study is to figure out whether or how resveratrol (RSV) can protect NPCs from degeneration by affecting IL6/JAK/STAT3 pathway. METHODS: Different concentrations of RSV were added to NPCs' mediums. Cell viability was measured by MTT assay and crystal violet staining. Cell cycle and apoptosis were analyzed by flow cytometry. Protein expression level was determined by western blot. mRNA expression level was measured by qPCR. RESULTS: Our study showed that RSV improved NPCs' cell viability. It also inhibited cell apoptosis and cell cycle arrest, which were accompanied by the increased expression level of heat shock protein 90 (HSP90) and N-Cadherin. What' more, RSV also improved the NPCs' degeneration which was reflected in the increase of extracellular matrix (collagen II, Aggrecan). Moreover, RSV significantly attenuated the level of IL-6 secretion, which was accompanied by less phosphorylation of the transcription factors Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3). CONCLUSION: RSV exerted its protective effect on HNPCs' degeneration by improving cell survival and function. The possible mechanism may be associated with the suppression of JAK/STAT3 phosphorylation and the decreased IL-6 production, which could be explained by a blockage of the positive feedback control loop between IL-6 and JAK/STAT3 pathway.

Differential Diagnosis Strategy between Lower Extremity Arterial Occlusive Disease and Lumbar Disc Herniation.

Considering the increasingly incidence rate of lower extremity arterial occlusive disease and difficult to distinguish from lumbar disc herniation, it is very necessary to exclude lower extremity arterial occlusive disease resulting in lower limb symptoms from lumbar disc herniation. More importantly, who have a higher risk of combining with lower extremity arterial occlusive disease and misdiagnosed as lumbar disc herniation? Why those patients are easy to be misdiagnosed as lumbar disc herniation? It is worth analyzing and discussing. The risk factors including age, gender, the medical history of high blood pressure, diabetes, smoking and coronary, pulse pressure, lumbar disc herniation segment and type, ankle-brachial index, and straight leg raising test were observed. The Oswestry disability index and the Japanese Orthopedic Association score were collected preoperative, six months after posterior lumbar interbody fusion and six months after vascular interventional treatment to evaluate the symptoms relief and surgical efficacy. There was a statistically significant difference (P < 0.01) in pulse pressure, ankle-brachial index, central disc herniation, and straight leg raising test between two groups. There was a high risk to missed diagnosis of lower extremity arterial occlusive disease and misdiagnosed as lumbar disc herniation when patients are with a mild central lumbar disc herniation, higher pulse pressure, lower ankle-brachial index, and straight leg raising test negative. Therefore, sufficient history-taking and cautious physical examinations contributed to find risk factors and attach importance to such patients and, further, to exclude lower extremity arterial occlusive disease from lumbar disc herniation using lower extremity vascular ultrasound examination.

Tea Polyphenol Attenuates Oxidative Stress-Induced Degeneration of Intervertebral Discs by Regulating the Keap1/Nrf2/ARE Pathway.

OBJECTIVE: Intervertebral disc degeneration (IDD) and low back pain caused by IDD have attracted public attention owing to their extremely high incidence and disability rate. Oxidative stress is a major cause of IDD. Tea polyphenols (TP) are natural-derived antioxidants extracted from tea leaves. This study explored the protective role of TP on the nucleus pulposus cells (NPCs) of intervertebral discs and their underlying mechanism. METHODS: An in vitro model of H2O2-induced degeneration of NPCs was established. RT-qPCR and western blotting were used to detect the mRNA and protein expression of the targets. An in vivo model of IDD was established via acupuncture of the intervertebral disc. Radiological imaging and histological staining were performed to evaluate the protective role of TP. RESULTS: H2O2 contributed to NPC degeneration by inducing high levels of oxidative stress. TP treatment effectively increased the expression of nucleus pulposus matrix-associated genes and reduced the expression of degeneration factors. Further mechanistic studies showed that TP delayed H2O2-mediated NPC degeneration by activating the Keap1/Nrf2/ARE pathway. In vivo experiments showed that TP delayed the degeneration of NPCs in rats through the Keap1/Nrf2/ARE pathway. CONCLUSION: Our study confirmed that TP activates the Keap1/Nrf2/ARE pathway to exert an antioxidative stress role, ultimately delaying the degeneration of intervertebral discs.

Bioinformatics-Based Research on Key Genes and Pathways of Intervertebral Disc Degeneration.

OBJECTIVE: To find out the pathways and key genes and to reveal disc degeneration pathogenesis based on bioinformatic analyses. DESIGN: The GSE70362 dataset was downloaded from the GEO (Gene Expression Omnibus) database. Differentially expressed genes (DEGs) between the patients having disc degeneration and healthy controls were screened by Limma package in R language. Critical genes were identified by adopting gene ontologies (GOs), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein-protein interaction (PPI) networks. RESULTS: We identified 112 DEGs, including 60 genes which were upregulated and 52 that were downregulated. Analyses, such as GO and KEGG demonstrated that the DEGs got enriched in 4 biological processes and 2 signaling pathways, mainly related to disc degeneration. The PPI network analyses identified 5 key proteins, CCND1 (cyclin D1), GATA3, TNFSF11, LEF1, and DKK1 (Dickkopf related protein 1). CONCLUSION: In this study, the DEGs and pathways determined promoted us understand the disc degeneration mechanisms. Also, the study may contribute novel biomarkers for the diagnosis and prevention of disc degeneration, and seek new treatment methods to repair and even regenerate degenerative intervertebral disc.

FK506 Induces the TGF-ß1/Smad 3 Pathway Independently of Calcineurin Inhibition to Prevent Intervertebral Disk Degeneration.

BACKGROUND: Intervertebral disk (IVD) degeneration is the most common cause of lower back pain. Inhibiting inflammation is a key strategy for delaying IVD degeneration. Tacrolimus (FK506) is a potent immunosuppressive agent that is also beneficial to chondrocytes via alleviating inflammation. However, the potential function of FK506 in IVD and the underlying mechanisms remain unknown. The current study is aim at exploring the underlying mechanism of FK506 in preventing IVD degeneration. METHODS: Cell morphology was imaged using an optical microscope. mRNA levels of nucleus pulposus (NP) matrix components were determined by qRT-PCR, and protein expression NP matrix components was assessed by western blotting. A rat caudal IVD degeneration model was established to test for FK506 in vivo. RESULTS: FK506 improved the morphology of NP cells and the cell function at both the mRNA and protein level. FK506 could attenuate NP degeneration induced by IL-1ß. Furthermore, FK506 exerted its function via TGFß/Smad3 activation instead of through calcineurin inhibition. Inhibition of the TGF-ß pathway prevented the protective effect of FK506 on IVD degeneration. In an in vivo study, FK506 injection reversed the development of rat caudal IVD degeneration influenced by Smad3. CONCLUSION: Our current study demonstrates the positive effect of FK506 on delaying the degeneration of IVD via the TGFß/Smad3 pathway.

Calcitonin inhibits intervertebral disc degeneration by regulating protein kinase C.

Intervertebral disc degeneration (IVDD) is the most critical factor that causes low back pain. Molecular biotherapy is a fundamental strategy for IVDD treatment. Calcitonin can promote the proliferation of chondrocytes, stimulate the synthesis of matrix and prevent cartilage degeneration. However, its effect and the underlying mechanism for IVDD have not been fully revealed. Chondrogenic specific matrix components' mRNA expression of nucleus pulposus cell (NPC) was determined by qPCR. Protein expression of NPC matrix components and protein kinase C was determined by Western blotting. A rat caudal intervertebral disc degeneration model was established and tested for calcitonin in vivo. IL-1 induced NPC change via decreasing protein kinase C (PKC)-ε phosphorylation, while increasing PKC-δ phosphorylation. Calcitonin treatment could prevent or reverse IL-1-induced cellular change on PKC signalling associated with degeneration. The positive effect of calcitonin on IVDD in vivo was verified on a rat caudal model. In summary, this study, for the first time, elucidated the important role of calcitonin in the regulation of matrix components in the nucleus of the intervertebral disc. Calcitonin can delay degeneration of the intervertebral disc nucleus by activating the PKC-ε pathway and inhibiting the PKC-δ pathway.

Proximal femur lag screw placement based on bone mineral density determined by quantitative computed tomography.

Following internal fixations for intertrochanteric fractures in elderly patients, lag screws or screw blades frequently cut the femoral head, leading to surgical failure. The bone mineral density (BMD) at various parts of the proximal femur is significantly correlated with the holding force of the lag screw, which in turn is closely associated with the stability of the fixation. However, the appropriate placement of the lag screw has been controversial. As a novel detection method for BMD, quantitative computed tomography (QCT) may provide relatively accurate measurements of three-dimensional structures and may provide an easy way to determine the appropriate lag screw placement. A total of 50 elderly patients with intertrochanteric fractures were selected for the present study. The BMD of the proximal femur on the healthy side, including the femoral intertrochanter, neck and head, was measured using QCT. For testing, the femoral head was divided into medial, central and lateral sections. The BMD of the femoral head was determined to be the highest, while the BMD of the femoral neck was the lowest. In the femoral head, the central section had the highest BMD, while the lateral section had the lowest BMD. The present study used QCT to detect differences in the BMD at various regions of the proximal femur and provided a novel theoretical reference for the placement of lag screws. To obtain maximum holding power, the lag screw must be placed in the central section of the femoral head.

Surgical consideration for thoracolumbar burst fractures with spinal canal compromise without neurological deficit.

BACKGROUND: For thoracolumbar burst fractures with spinal canal compromise but no neurological deficit, is it necessary to perform additional laminectomy decompression after the currently accepted posterior pedicle-screw internal fixation? METHODS: Patients were divided into two groups: decompression group (Group A) and nondecompression group (Group B). A retrospective analysis of the posterior vertebral body height of the fractured vertebral body, the ratio of the volume of the spinal canal, and the change of the Cobb angle, relative to the corresponding preoperative values, was conducted to analyse the reasons for choosing different surgical methods. RESULTS: Compared the intraoperative findings after fixation with the preoperative data, in Group A, the posterior vertebral body height of the fractured vertebral body was not significantly restored, the volume ratio of the spinal canal was not significantly improved, and the Cobb angle was not significantly reduced (p â€‹> â€‹0.05). In comparison, in Group B, the posterior vertebral body height of the fractured vertebral body was significantly restored, the volume ratio of spinal canal was significantly increased, and the Cobb angle was significantly reduced (p â€‹< â€‹0.001). CONCLUSION: For patients with thoracolumbar burst fractures with spinal canal compromise but no neurological deficit, if when the posterior intraoperative fixation is performed, the spinal canal fracture is partially recovered, the posterior vertebral body height of the injured vertebrae is significantly restored, the spinal canal volume ratio is significantly increased, and the large kyphosis is corrected, then the indirect decompression without the posterior laminectomy can be performed. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study contributes to offer treatment â€‹consideration for â€‹patients with thoracolumbar burst fracture without neurological symptoms.

The protein tyrosine kinase inhibitor, Genistein, delays intervertebral disc degeneration in rats by inhibiting the p38 pathway-mediated inflammatory response.

The treatment for intervertebral disc degeneration (IDD) has drawn great attention and recent studies have revealed that the p38 MAPK pathway is a potential therapeutic target for delaying the degeneration of intervertebral discs. In this study, we analyzed a nature-derived protein tyrosine kinase inhibitor, Genistein, and its function in delaying IDD in rats both in vitro and in vivo via the p38 MAPK pathway. Nucleus pulposus cells treated with Genistein showed better function compared with untreated cells. Further study revealed that Genistein could play a protective role in IDD by inhibiting phosphorylation of p38, consequently inhibiting the p38 pathway-mediated inflammatory response. The rat IDD model also demonstrated that Genistein could effectively delay the degeneration of intervertebral disc tissue. The current study reveals new biological functions of Genistein, further demonstrates the effects of the p38 MAPK pathway on intervertebral disc degeneration, and deepens our understanding of the treatment and prevention of IDD.

Calcium Phosphate Cement Causes Nucleus Pulposus Cell Degeneration through the ERK Signaling Pathway.

While calcium phosphate cement (CPC) is recognized as one of the most likely substitutes for the conventional Polymethylmethacrylate (PMMA), there are very few studies about its intradiscal leakage consequences. Herein, the goal of our study was to examine the effect of CPC particles on the ERK (extracellular regulatory kinase) pathway in human nucleus pulposus cell (HNPC) degeneration. Different concentrations of CPC particles (0.00‰, 0.01‰, 0.05‰, 0.1‰ v/v) were added to human nucleus pulposus cell cultures. After 10 days of treatment, HNPC biological behaviors and degeneration degree were analyzed by CCK-8 assay, crystal violet staining, flow cytometer and western blot. The effect of CPC on the ERK pathway was also analyzed by western blot. After activating the ERK path by overexpressing Ras, HNPCs' biological behaviors and degeneration degree were analyzed again. We found that CPC particles had a negative effect on human nucleus pulposus cells (HNPCs), which are mainly reflected in cell growth and the cell cycle. After activation of the ERK signaling pathway, the negative effects of CPC on cell growth and the cell cycle were significantly reduced and the degeneration degree of HNPCs was reversed. CPC particles can probably block the activation of the ERK pathway, thus causing the HNPCs' degeneration.

IL-10 delays the degeneration of intervertebral discs by suppressing the p38 MAPK signaling pathway.

OBJECTIVES: The degeneration of intervertebral discs (IVD) is a risk factor for chronic low back pain. Anti-inflammation therapy could alleviate IVD degeneration. IL-10 is an important anti-inflammatory cytokine. However, the effect of IL-10 on IVD has not been fully revealed. The current study is to reveal the effect of IL-10 on IVD and its underlying mechanism. METHODS: IL-1ß was used to induce the degeneration of nucleus pulposus cells (NPCs). mRNA expression level was determined by qPCR. Protein expression level was determined by western blotting. Methylene blue was used to determined the expression of aggrecan. Immunocytochemical staining was used to determined the expression of collagen II. A rat caudal IVD degeneration model was established and used to evaluate the effect of IL-10 on IVD in vivo. RESULTS: IL10 could alleviated NPC degeneration in both morphology and extracellular matrix. IL-10 could increase the mRNA expression of Collagen II, Sox-9, but decrease the mRNA expression of IL-1ß, TNFα and Collagen X. IL-10 could also increase the protein level of Collagen II and aggrecan, but decrease that of Collagen X. Western blotting futher revealed the mechanism of the positive effect of IL-10 on IVD. IL-10 reduces phosphorylation level of p38 MAPK effectively. Rat caudal IVD degeneration model futher confirmed the positive effect of IL-10 on IVD degeneration and its mechanism in vivo. CONCLUSION: The current study demonstrates that exogenous IL-10 treatment can induce an anti-inflammatory response and inhibit p38 MAPK activation to delay IVD degeneration.

Melatonin Protects Intervertebral Disc from Degeneration by Improving Cell Survival and Function via Activation of the ERK1/2 Signaling Pathway.

Melatonin, a neuroendocrine hormone secreted by the pineal body, has a positive effect on intervertebral disc degeneration. The present study is aimed at investigating the biological role of melatonin in intervertebral disc degeneration and its underlying mechanism. A human nucleus pulposus cell (NPC) line was exposed to melatonin at different concentrations. Cell proliferation was measured by CCK-8 assay. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was performed to measure the protein expression of indicated genes. A rabbit model of intervertebral disc degeneration was established to detect the role and mechanism of melatonin on intervertebral disc degeneration. Our study showed that melatonin promoted NPC viability and inhibited cell arrest. Furthermore, melatonin treatment led to the upregulation of collagen II and aggrecan and downregulation of collagen X. Moreover, melatonin significantly elevated the activity of the ERK signaling pathway. Inhibition of the ERK1/2 signals reversed the role of melatonin in the regulation of NPCs both in vitro and in vivo. Melatonin increased NPC viability through inhibition of cell cycle arrest and apoptosis. Moreover, melatonin promoted the secretion of functional factors influencing the nucleus pulposus cell physiology and retarded cell degeneration. Our results suggest that melatonin activated the ERK1/2 signaling pathway, thereby affecting the biological properties of the intervertebral disc degeneration.

Distribution of Modic changes in patients with low back pain and its related factors.

BACKGROUND: To summarize the clinical distribution of Modic changes in patients with low back pain and explore the related factors. METHODS: A total of 153 patients were enrolled. Gender, age, disk degeneration, herniation, involved segments, lumbar lordosis angle, and endplate concave angle were recorded, respectively. Patients were divided into two or more groups according to a different classification. The relevant factors were studied with a multivariate logistic regression analysis to analyze their correlation. RESULTS: A total of 35 patients with type I changes, 110 patients with type II changes, and 8 patients with type III changes. In total, 204 disks were found with Modic changes, L1/2 (10 disks), L2/3 (18 disks), L3/4 (17 disks), L4/5 (76 disks), and L5/S1 (81 disks). Type I changes were distributed mainly under the age of 50. Multivariate regression showed that gender, age, disk degeneration, lumbar lordosis, L4/5 segment lordosis angle, and L5 lower endplate concave angle were related with different types of Modic changes. The regression equation Y = 2.410 - 1.361S - 0.633A - 0.654P + 1.106L - 0.990D (Y means type I changes, S means gender, A means age, P means disk degeneration, L means L4/5 segment lordosis angle, and D means L5 upper endplate concave angle). The OR values were S = 0.256, A = 0.531, P = 0.520, L = 3.022, D = 0.372, respectively. CONCLUSIONS: Type II changes are the most common, followed by type I. Modic changes mostly occur in L4/5 and L5/S1; young, male, lower-grade disk degeneration, normal physiological curvature of the lumbar spine, and normal endplate concave angle were associated with type I changes; gender and lumbar curvature were the most relevant factors for different types.

Selection of the Optimal Puncture Needle for Induction of a Rat Intervertebral Disc Degeneration Model.

BACKGROUND: The incidence of intervertebral disc (IVD) degeneration has increased in recent years. A simple, reliable, and reproducible animal model is critical for understanding the underlying mechanisms of IVD degeneration. The caudal discs of rats have been proposed as a common puncture model in which to induce IVD degeneration. However, there is still no consensus on the size of needle to be used. OBJECTIVES: The present study aimed to identify the appropriate needle size to establish an IVD degeneration model. STUDY DESIGN: A randomized, experimental trial. SETTING: Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, China. METHODS: Validity was verified by magnetic resonance imaging (MRI) and histology. RESULTS: From T2-weighted MRI imaging and histological examination, the IVD punctured by the 16-gauge needle degenerated acutely one week after the operation, whereas the 26-gauge needle puncture did no harm to the IVD. An 18-gauge needle showed a progressive degeneration in IVD. LIMITATIONS: The observation period was not very long (4 weeks). CONCLUSIONS: An 18-gauge needle can be used to induce IVD degeneration in rats. Therefore, an 18-gauge needle is the optimal selection to establish the degenerative IVD model on rats, whereas the 26-gauge needle failed to cause IVD degeneration. Thus, to study the prevention and treatment of IVD degeneration, a 26-gauge needle can be used for IVD injection of growth factors, plasmids, and drugs. A 16-gauge needle may be used to induce acute disc injury, but not IVD degeneration. KEY WORDS: Low back pain, degenerative intervertebral disc, animal model, puncture needle, rat model, optimal choice.

Therapeutic Efficacy Analysis of Talar Fracture Internal Fixation with Lateral Malleolar Osteotomy.

BACKGROUND There are many surgical treatment approaches for talar fractures. However, due to the unique anatomical and blood supply characteristics of the talus, the traditional approaches tend to lead to blood supply damage. In order to best preserve the blood supply of the talus, we proposed a surgical approach of internal fixation of the talar fracture with lateral malleolar osteotomy and analyzed its efficacy. MATERIAL AND METHODS Twenty-six patients with talar fractures underwent open reduction surgery between January 2010 and December 2016. Following the lateral malleolar osteotomy, the talus was fully exposed. After anatomical reduction, the talus was fixed with 2 screws, and the lateral malleolus was fixed with distending wires. The treatment effects were assessed in the follow-up. RESULTS All patients were followed for 7 to 22 months, for an average of 14.34 months. According to the Maryland Foot Score, 19 cases were excellent (90-100 points), 4 cases were good (85-90 points), and 3 cases were moderate (50-74 points). CONCLUSIONS Internal fixation of talar fractures with lateral malleolar osteotomy is a viable surgical approach to reduce injury to blood supply and maximize surgical exposure.