Construct prognostic models of multiple myeloma with pathway information incorporated.

Multiple myeloma (MM) is a hematological disease exhibiting aberrant clonal expansion of cancerous plasma cells in the bone marrow. The effects of treatments for MM vary between patients, highlighting the importance of developing prognostic models for informed therapeutic decision-making. Most previous models were constructed at the gene level, ignoring the fact that the dysfunction of the pathway is closely associated with disease development and progression. The present study considered two strategies that construct predictive models by taking pathway information into consideration: pathway score method and group lasso using pathway information. The former simply converted gene expression to sample-wise pathway scores for model fitting. We considered three methods for pathway score calculation (ssGSEA, GSVA, and z-scores) and 14 data sources providing pathway information. We implemented these methods in microarray data for MM (GSE136324) and obtained a candidate model with the best prediction performance in interval validation. The candidate model is further compared with the gene-based model and previously published models in two external data. We also investigated the effects of missing values on prediction. The results showed that group lasso incorporating Vax pathway information (Vax(grp)) was more competitive in prediction than the gene model in both internal and external validation. Immune information, including VAX pathways, seemed to be more predictive for MM. Vax(grp) also outperformed the previously published models. Moreover, the new model was more resistant to missing values, and the presence of missing values (<5%) would not evidently deteriorate its prediction accuracy using our missing data imputation method. In a nutshell, pathway-based models (using group lasso) were competitive alternatives to gene-based models for MM. These models were documented in an R package (https://github.com/ShuoStat/MMMs), where a missing data imputation method was also integrated to facilitate future validation.

The predictive value of albumin to alkaline phosphatase ratio for vertebral refractures in postmenopausal women.

INTRODUCTION: To investigate the clinical value of serum albumin to alkaline phosphatase ratio (AAPR) in predicting the risk of osteoporotic vertebral refractures group (OVRFs) after percutaneous vertebral augmentation (PVA) in postmenopausal women. MATERIALS AND METHODS: This is a retrospective case-control study including a series of postmenopausal women patients with osteoporotic vertebral fracture (OVF) and underwent PVA. Patients were divided into OVRFs and non-OVRFs. COX model was used to evaluate the correlation between preoperative AAPR and OVRFs after PVA. The receiver operating characteristic (ROC) curve and Kaplan-Meier method were used to analyze the predictive value of AAPR for the incidence of OVRFs. RESULTS: A total of 305 patients were included in the final study, and the incidence of postoperative OVRFs was 28.9%. Multivariate COX analysis showed that advanced age (HRs = 1.062, p = 0.002), low BMI (HRs = 0.923, p = 0.036), low AAPR (HRs = 0.019, p = 0.001), previous fall history (HRs = 3.503, p = 0.001), denosumab treatment (HRs = 0.409, p = 0.007), low L3 BMD (HRs = 0.977, p = 0.001) and low L3 paravertebral muscle density (PMD)value (HRs = 0.929, p = 0.001)) were closely related to the incidence of OVRFs. The area under the curve (AUC) of AAPR for predicting OVRFs was 0.740 (p < 0.001), and the optimal diagnostic cut-off value was 0.49. Kaplan-Meier curve analysis showed that low AAPR group (< 0.49) was significantly associated with lower OVRFs-free survival (p = 0.001; log-rank test). CONCLUSION: AAPR is an independent risk factor for OVRFs after PVA in postmenopausal women, and it can be used as an effective index to predict OVRFs.

The efficacy of nutritional screening indexes in predicting the incidence of osteosarcopenia and major osteoporotic fracture in the elderly.

INTRODUCTION: The effect of nutritional status on osteosarcopenia (OS) and major osteoporotic fracture (MOF) among the elderly is still unclear. So we aimed to compare the efficacy of the Mini-Nutrition Assessment-Short Form (MNA-sf), the Geriatric Nutritional Risk Index (GNRI) and Controlling Nutritional Status (CONUT) for predicting OS and MOF among the elderly. MATERIALS AND METHODS: A total of 409 participants were enrolled in this prospective study. Blood biochemical indexes, nutritional status, and bone- and muscle-related examinations were assessed at initial visit to the outpatient. Participants were divided into 4 groups: (1) control; (2) osteopenia/osteoporosis; (3) sarcopenia; (4) osteosarcopenia, and then followed for 5 years, recording the occurrence time of MOF. RESULTS: The frequency values of osteopenia/osteoporosis, sarcopenia, and OS, at baseline, were respectively 13.4, 16.1, and 12% among the study samples. Correlation analysis showed that nutritional status scores were associated with body mass index, handgrip strength, albumin, bone mineral density, and physical functions. According to multivariate models, poor nutritional status was significantly associated with a higher risk of OS and MOF (P < 0.05). Survival analysis showed that the MOF rate in malnutrition group was significantly higher than normal nutrition group (P < 0.05). The receiver operator characteristic curve shows that the value of MNA-sf to diagnose OS and MOF is greater (P < 0.05). CONCLUSION: The poor nutritional status was associated with a higher risk of both OS and MOF. MNA-sf showed a superior diagnostic power for OS and MOF among the elderly. Early nutrition assessments and interventions may be key strategies to prevent OS and fractures.

α-Ketoglutaric acid ameliorates intervertebral disk degeneration by blocking the IL-6/JAK2/STAT3 pathway.

Intervertebral disk degeneration (IVDD) is the major cause of low back pain. Alpha-ketoglutaric acid (α-KG), an important intermediate in energy metabolism, has various functions, including epigenetic regulation, maintenance of redox homeostasis, and antiaging, but whether it can ameliorate IVDD has not been reported. Here, we examined the impacts of long-term administration of α-KG on aging-associated IVDD in adult rats. In vivo and in vitro experiments showed that α-KG supplementation effectively ameliorated IVDD in rats and the senescence of nucleus pulposus cells (NPCs). α-KG supplementation significantly attenuated senescence, apoptosis, and matrix metalloproteinase-13 (MMP-13) protein expression, and it increased the synthesis of aggrecan and collagen II in IL-1ß-treated NPCs. In addition, α-KG supplementation reduced the levels of IL-6, phosphorylated JAK2 and STAT3, and the nuclear translocation of p-STAT3 in IL-1ß-induced degenerating NPCs. The effects of α-KG were enhanced by AG490 in NPCs. The underlying mechanism may involve the inhibition of JAK2/STAT3 phosphorylation and the reduction of IL-6 expression. Our findings may help in the development of new therapeutic strategies for IVDD.NEW & NOTEWORTHY Alpha-ketoglutaric acid (α-KG) exerted its protective effect on nucleus pulposus cells' (NPCs) degeneration by inhibiting the senescence-associated secretory phenotype and extracellular matrix degradation. The possible mechanism may be associated with negatively regulating the JAK2/STAT3 phosphorylation and the decreased IL-6 expression, which could be explained by a blockage of the positive feedback control loop between IL-6 and JAK2/STAT3 pathway.

Multi-longitudinal mode laser beat-frequency optical fiber vibration sensing system based on an FM radio module.

A multi-longitudinal mode (MLM) laser beat-frequency optical fiber vibration sensor using a frequency modulation (FM) radio integrated circuit module as the FM demodulation scheme is presented and demonstrated. To the best of our knowledge, this is the first case where a fiber-optic sensing system is combined with an FM radio module, and dynamic sensing is well achieved. As the carrier of the vibration source, the beat-frequency signal (BFS) generated by the MLM laser is transmitted to the FM radio module for FM and demodulation. The experimental results show that the system can successfully detect the vibration signal in the frequency range of 20 Hz to 18 kHz and accurately demodulate the waveform and amplitude of the vibration signal source. The minimum shape variable detected by the system is 20.67 nm, based on the performance of the commercial FM radio module itself, which can effectively solve the problem of detecting tiny vibration. The idea of the optical fiber vibration sensing system is extremely innovative, with high sensitivity, high signal-to-noise ratio (SNR), good stability, and strong resistance to electromagnetic interference.

Relay Selection for Dual-Hop Cooperative Ambient Backscatter Communication Systems.

Previous works only focus on the optimization design for the dual-hop cooperative ambient backscatter communication (AmBC) system with single-relay selection. The impact of relay selection on the outage performance of dual-hop cooperative AmBC systems is still missing. Motivated by this, in this paper, we investigate the outage performance of a dual-hop cooperative AmBC system with single-relay selection, where the backscatter link shares the receiver with the cellular link and the harmful direct-link interference (DLI) is mitigated by using successive interference cancellation (SIC). In the system considered, the selected relay has dual functions. One is to forward message for the cellular link, and the other is to act as the radio-frequency (RF) source for the backscatter device (BD). Specifically, after proposing two novel single-relay selection schemes (RSSs), namely reactive RSS and proactive RSS, we derive the closed-form outage probability (OP) expressions for both RSSs, which can be performed in a distributed manner. To gain more insights, the asymptotic OPs at high signal-to-noise ratio (SNR) are explored and the outage performance comparison between the reactive RSS and proactive RSS are also provided. Results show that the proposed reactive RSS is outage-optimal among all possible single-relay selection schemes. The theoretical analysis is validated by Monte Carlo simulations. The results also show that the relay selection scheme, the number of relays, the location of BD, and the reflection coefficient of BD have great impact on the outage performance of cooperative AmBC systems.

Computed tomography-based paravertebral muscle density predicts subsequent vertebral fracture risks independently of bone mineral density in postmenopausal women following percutaneous vertebral augmentation.

BACKGROUND: The risk of subsequent vertebral fractures (SVF) after the primary vertebral fracture cannot be explained by lower bone mineral density (BMD) alone. Computed tomography (CT) measurements of paravertebral muscle density (PMD) are recognized radiographic markers used to predict physical function, fragile fractures. AIMS: This study aims to investigate the relationship between PMD and the risk of SVF in cohorts of postmenopausal women, and to determine if combining both PMD and BMD measures derived from CT can improve the accuracy of predicting SVF. METHODS: This study enrolled 305 postmenopausal women between the ages of 50 and 88 for 3 years of follow-up studies. Trabecular attenuation (Hounsfield units, HU) was measured at L1 level and muscle attenuation of paravertebral muscle at L3 level on preoperative lumbar CT scans to determine the L1 BMD and L3 PMD. Kaplan-Meier analysis was applied to evaluate SVF-free survival. The hazard ratios (HRs) of PMD for SVF events were estimated with the Cox proportional hazards model. The predictive values of L1 BMD and L3 PMD for SVF were quantified using the Receiver-Operating Characteristic (ROC) curve. RESULT: During the 3 years of follow-up studies, 88 patients (28.9%) suffered an SVF. ROC curve analysis demonstrated that an L3 PMD threshold of 32 HU had a sensitivity of 89.8% and a specificity of 62% for the prediction of SVF. Kaplan-Meier analysis showed that L3 PMD ≤ 32 HU was significantly associated with lower SVF-free survival (p < 0.001; log-rank test). After adjusting for age, BMI, diabetes, postoperative osteoporosis treatment, handgrip strength, L1 BMD, multivariate analyses also indicated a persistent modest effect of L3 PMD on SVF-free survival. The area under the ROC curve of L3 PMD and L1 BMD, combined to predict the risk of SVF, was 0.790, which was significantly higher than the value for L1 BMD alone (0.735). L3 PMD and L1 BMD significantly improved the accuracy of SVF risk prediction compared with L1 BMD alone, which was confirmed by reclassification improvement measures. The inclusion of handgrip strength and postoperative osteoporosis treatment in the model further improved SVF prediction accuracy, and PMD remained significant in the model. CONCLUSION: Decreased L3 PMD is an independent risk predictor of SVF. Combined CT-based L1 BMD and L3 PMD can significantly improve the accuracy of predicting the risk of SVF in postmenopausal women who have suffered prior osteoporotic vertebral fractures.

Nutritional deficiency induces nucleus pulposus cell apoptosis via the ATF4-PKM2-AKT signal axis.

BACKGROUND: The intervertebral disc is the largest avascular tissue in the human body. The nucleus pulposus (NP) consumes glucose and oxygen to generate energy to maintain cellular metabolism via nutrients that diffuse from the cartilage endplate. The microenvironment in the intervertebral disc becomes nutritionally deficient during degeneration, and nutritional deficiency has been shown to inhibit the viability and proliferation of NP cells. METHODS: To investigate the molecular mechanism by which nutritional deficiency reduces viability and decreases proliferation, we created an in vitro model by using decreasing serum concentration percentages. RESULTS: In this study, we found that nutritional deficiency reduced NP cell viability and increased cell apoptosis and that the upregulation of ATF4 expression and the downregulation of PKM2 expression were involved in this process. Moreover, we found that PKM2 inhibition can reduce the cell apoptosis induced by ATF4 silence under nutritional deficiency. CONCLUSION: Our findings revealed that PKM2 inhibition reduces the cell apoptosis induced by ATF4 silence under nutritional deficiency by inhibiting AKT phosphate. Revealing the function and mechanism of NP cell development under nutritional deficiency will provide new insights into the etiology, diagnosis, and treatment of intervertebral disc and related diseases.

Association between handgrip strength and subsequent vertebral-fracture risk following percutaneous vertebral augmentation.

INTRODUCTION: The aim of this study was to investigate the association between handgrip strength (HGS) and the risk of subsequent vertebral fracture (SVF) after percutaneous vertebral augmentation (PVA). MATERIALS AND METHODS: A total of 340 patients aged over 50 years with osteoporotic vertebral fracture were enrolled in this 3-year follow-up investigation. HGS was measured with a hand-held dynamometer before PVA. Female patients and male patients were grouped using the HGS threshold recommended by the Asian Working Group for Sarcopenia (AWGS). Kaplan-Meier analysis was used to evaluate SVF-free survival. The hazard ratios (HRs) of HGS for SVF events were estimated with the Cox proportional hazards model. RESULTS: During the follow-up period, a total of 93 patients (27.4%) experienced SVF. Kaplan-Meier analysis showed that the HGS of female patients < 18.0 kg and male patients < 28 kg was significantly associated with lower SVF-free survival (female patients: p < 0.001, male patients: p = 0.038; log-rank test). Among women, each 1-kg increase in HGS was associated with a 9% lower risk of SVF (HR 0.91, p = 0.035) after adjustment for potential risk factors. Among men, although the associations between low HGS and increased risk of SVF were significant in the crude model (HR 0.79, p < 0.001), this significance disappeared after adjustment for bone mineral density of the femoral neck. CONCLUSIONS: Low HGS was significantly associated with lower SVF-free survival among elderly patients who underwent single-level PVA for osteoporotic vertebral fracture.

Estimation of the ideal correction of lumbar lordosis to prevent reoperation for symptomatic adjacent segment disease after lumbar fusion in older people.

BACKGROUND: Symptomatic adjacent segment disease (ASDis) is a major complication following spinal fusion. Sagittal spinopelvic imbalance may contribute to the development of ASDis. However, the exact ideal correction of lumbar lordosis (LL) is unknown for different ages of people to prevent ASDis. The purpose of this study was to estimate the ideal correction of LL required to prevent symptomatic ASDis requiring revision surgery in patients of various ages, and to determine the radiographic risk factors for ASDis. METHODS: 468 patients who underwent lumbar fusion between January 2014 and December 2016, were enrolled in the present study. The patients were classified into the ASDis and N-ASD group. These two matched groups were compared regarding surgery-related factors and radiographic features. Multivariate logistic regression analysis was used to evaluate the risk factors for ASDis. RESULTS: Sixty-two patients (13.25%) underwent reoperation for ASDis during a mean follow-up duration of 38.07 months. Receiver operating characteristic curve analysis showed that the postoperative LL - preoperative LL (△LL) cutoff value was 11.7°for the development of ASDis. Logistic regression analysis revealed that the risk factors for symptomatic ASDis were a smaller LL angle, △LL > 12°, and PI-LL > 10° (p <  0.05). For patients > 60 years, the incidence of ASDis was higher in patients with a LL correction of ≥10° and a lumbar-pelvic mismatch (PI-LL) of > 20°. CONCLUSIONS: The significant predictors of the occurrence of ASDis were a smaller LL angle, △LL > 12°, and PI-LL > 10°. However, in patients older than 60 years, the incidence of ASDis after lumbar fusion was higher in those with a LL correction of ≥10° and PI-LL of > 20°. More attention should be paid to patient age and the angle of correction of LL before lumbar fusion.

Preoperative vitamin D status and its effects on short-term clinical outcomes in lumbar spine surgery.

BACKGROUND: Many studies have found that vitamin D deficiency has a high incidence rate worldwide, but we found few studies on the role of vitamin D in spinal degenerative diseases. We investigated the determinants of preoperative vitamin D deficiency and its effects on postoperative outcomes among patients undergoing elective lumbar spine surgery. METHODS: 360 patients treated from July 2017 to July 2018 were retrospectively identified for inclusion. The patients' fasting serum levels of 25(OH)D, N-terminal midfragment of osteocalcin (N-MID), and ß typeⅠcollagen carboxyl terminal peptide (ß-CTX) were measured by electrochemiluminescence before the operation. The visual analogue scale (VAS), Japanese Orthopaedic Association (JOA) and Oswestry Disability Index scores (ODI) were used to evaluate the clinical outcomes. Standard demographic data and all perioperative complications occurring within 3 months follow-up after operation were recorded. RESULTS: The mean serum level of 25(OH)D was 20.81 ± 8.55 ng/mL, the rates of deficiency (<20 ng/ml) was 53.6%. The abnormal proportion of N-MID and ß-CTX were 8.61% and 34.44%, bone turnover markers serum level was higher in older age groups (p < 0.05). Female sex (p < 0.001), a high body mass index (BMI) (p = 0.012), lack of vitamin D supplementation (p = 0.018), smoking (p = 0.033), moderate (p < 0.001) to severe pain (p = 0.005) were significant predictors of vitamin D deficiency after the multivariate analysis. The VAS, JOA and ODI scores showed significantly better outcomes compared to deficient group at post-operative and final follow-up (p < 0.05). CONCLUSION: Vitamin D deficiency was common in patients undergoing elective lumbar spine surgery. Female sex, high BMI, lack of vitamin D supplementation, smoking and moderate to severe pain were risk factors for vitamin D deficiency. Moreover, preoperative hypovitaminosis D (<20 ng/ml) was correlated with worse surgical outcomes in short-term.

Does the C3/4 disc play a role in cervical spondylosis with dizziness? A retrospective study.

PURPOSE: To investigate the effect of C3/4 disc degeneration on cervical spondylosis with dizziness (CSD) and to assess the curative effect of anterior cervical decompression and fusion (ACDF) in patients with CSD. METHOD: Four hundred nineteen patients who underwent ACDF for treatment of myelopathy or radiculopathy were divided into dizziness and non-dizziness group. The visual analog scale (VAS) score and Japanese Orthopaedic Association (JOA) score were used to determine the intensity of dizziness and neurological symptoms, respectively. Cervical disc degeneration was evaluated using Miyazaki's classification system. Some parameters were measured using cervical radiographs. The surgical effects on CSD were compared between surgery with and without C3/4 level. Multivariate logistic regression analysis was used to determine the risk factors for CSD. RESULTS: The pre-operative incidence of CSD was 33.9%. Women were more likely to develop dizziness than men (p < 0.05), CSD was significantly associated with C3/4 disc degeneration (69.7%, p < 0.001), and smokers were more subject to dizziness (p < 0.05). Regression analysis showed that female (OR = 1.611, p = 0.031), smoking (OR = 1.719, p = 0.032), Miyazaki grade of C3/4 ≥ IV (OR = 2.648, p < 0.001), and instability on C3/4 (OR = 1.672, p = 0.024) were risk factors for CSD. Treatment of CSD by ACDF involving C3/4 was more effective than not involving C3/4 (efficacy rate, 73.2% vs 51.7%, p < 0.05). CONCLUSION: The CSD is a common clinical manifestation in elderly patients, especially patients with cervical spondylosis at the C3/4 level. Female, smoking, instability on C3/4, and C3/4 Miyazaki grade ≥ IV could be considered significant risk factors for CSD. CSD is more likely to be alleviated by ACDF involving C3/4.

Sagittal imbalance, muscle atrophy, and osteoporosis: risk factors for revision posterior lumbar fusion surgery in patients with Parkinson's disease.

OBJECTIVE: The aim of our study was to evaluate features and complications of patients with Parkinson's disease (PD) who underwent posterior lumbar fusion surgery for lumbar degenerative diseases (LDD), as well as the risk factors for revision. METHODS: Between January 2010 and December 2016, 132 patients were retrospectively identified for inclusion. Patients were divided into a 29 revision PD group and a 103 non-revision PD group. Patient factors included bone mineral density (BMD) and severity of PD using the Hoehn and Yahr staging system. Surgical factors included surgical levels and fusion methods. Radiographic measurements included pre-operative spinopelvic parameters, paraspinal muscle atrophy, and fatty infiltration. Logistic regression analysis was used to determine independent predictors for revision posterior lumbar fusion. RESULTS: The average age of the PD patients was 67.96 years, and the follow-up time was 49.01 months. R-PD patients accounted for 21.97% of all PD patients who underwent lumbar fusion surgery. Multivariable analysis indicated that low BMD (p = 0.012), fatty infiltration (p = 0.038), a smaller relative cross-sectional area (rCSA) of the paraspinal muscle (p = 0.008), larger pelvic incidence-lumbar lordosis (PI-LL) (p = 0.01), and sagittal vertical axis (SVA) (p = 0.004) were significant independent risk factors for revision posterior lumbar fusion in PD patients. CONCLUSION: PD patients with low pre-operative BMD, fatty infiltration, a smaller rCSA of the paraspinal muscle, and larger PI-LL and SVA had a higher rate of revision lumbar fusion. Maintaining sagittal balance, functional exercises, and anti-osteoporosis treatment were important in preventing complications in PD patients.

LncRNA MEG3 negatively modified osteosarcoma development through regulation of miR-361-5p and FoxM1.

This study was aimed to figure out whether long noncoding RNA MEG3/miR-361-5p/FoxM1 signaling would contribute to improved proliferation and metastasis of osteosarcoma cells. We altogether collected 204 pairs of osteosarcoma tissues and adjacent normal tissues, and obtained four human osteosarcoma cell lines. Then pcDNA3.1-MEG3, si-MEG3, miR-361-5p mimic, miR-361-5p inhibitor, pcDNA3.1-FoxM1, si-FoxM1, and negative control (NC) were, respectively, transfected into the osteosarcoma cells. Furthermore, real time polymerase chain reaction was utilized to determine the mRNA expressions of maternally expressed gene 3 (MEG3) and miR-361-5p, and western blot analysis was applied for determining the FoxM1 expression. Besides, dual luciferase reporter gene assay was adopted to verify if MEG3 can be directly targeted by miR-361-5p. Finally, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, colony formation assay, flow cytometry, wound healing assay, and transwell assay were conducted to investigate the influence of MEG3, miR-361-5p, and FoxM1 expressions on the viability, proliferation, apoptosis, migration, and invasion of osteosarcoma cells. MEG3 and miR-361-5p were observed to be significantly downregulated within both osteosarcoma tissues and cell lines, whereas FoxM1 was upregulated in osteosarcoma tissues and cell lines (p < 0.05). MEG3 directly bound to miR-361-5p, and significantly upgraded its expression (p < 0.05). The upregulated MEG3 and miR-361-5p or the downregulated FoxM1 appeared to substantially inhibit proliferation, migration, and invasion of osteosarcoma cells (p < 0.05). Finally, the proliferation, migration, invasion, and motility of osteosarcoma cells within the miR-NC + pcDNA3.1-FoxM1 group and pcDNA + pcDNA-FoxM1 group were markedly promoted when compared with the miR-361-5p mimic group and pcDNA3.1-MEG3 group (p < 0.05). The MEG3/miR-361-5p/FoxM1 axis could potentially serve as therapeutic targets or diagnostic biomarkers for osteosarcoma.

Oxidative damage induces apoptosis and promotes calcification in disc cartilage endplate cell through ROS/MAPK/NF-κB pathway: Implications for disc degeneration.

Cartilage endplate (CEP) cell calcification and apoptosis play a vital role in the intervertebral disc degeneration (IVDD). Oxidative stress is a key factor in inducing programmed cell death and cartilage calcification. However, the cell death and calcification of cartilage endplate cells under oxidative stress have never been described. The present study investigated the apoptosis and calcification in the cartilage endplate cell under oxidative stress induced by H2O2 to understand the underlying mechanism of IVDD. The cartilage endplate cells isolated from human lumbar discs were subjected to different concentrations of H2O2 for various time periods. The cell viability was determined by CCK-8 assay, whereas Western blot, immunofluorescence, and Alcian blue, Alizarin red, and Von Kossa staining evaluated the apoptosis and calcification. The level of mitochondria-specific reactive oxygen species (ROS) was quantified with an oxygen radical-sensitive probe-MitoSOX. The potential signaling pathways were investigated by Western blot after the addition of N-acetyl-l-cysteine (NAC). We found that the oxidative stress induced by H2O2 increased the apoptosis and subsequently the calcification in the cartilage endplate cells through the ROS/p38/ERK/p65 pathway. The apoptosis and the calcification of the cartilage endplate cells induced by H2O2 can be abolished by NAC. These results suggested that regulating the apoptosis and the calcification in the cartilage endplate cells under oxidative stress should be advantageous for the survival of cells and might delay the process of disc degeneration.

Leptin regulates disc cartilage endplate degeneration and ossification through activation of the MAPK-ERK signalling pathway in vivo and in vitro.

Recent findings demonstrate that leptin plays a significant role in chondrocyte and osteoblast differentiation. However, the mechanisms by which leptin acts on cartilage endplate (CEP) cells to give rise to calcification are still unclear. The aim of this study was to evaluate the effects of leptin that induced mineralization of CEP cells in vitro and in vivo. We constructed a rat model of lumbar disc degeneration and determined that leptin was highly expressed in the presence of CEP calcification. Rat CEP cells treated with or without leptin were used for in vitro analysis using RT-PCR and Western blotting to examine the expression of osteocalcin (OCN) and runt-related transcription factor 2 (Runx2). Both OCN and Runx2 expression levels were significantly increased in a dose- and time-dependent manner. Leptin activated ERK1/2 and STAT3 phosphorylation in a time-dependent manner. Inhibition of phosphorylated ERK1/2 using targeted siRNA suppressed leptin-induced OCN and Runx2 expression and blocked the formation of mineralized nodules in CEP cells. We further demonstrated that exogenous leptin induced matrix mineralization of CEP cells in vivo. We suggest that leptin promotes the osteoblastic differentiation of CEP cells via the MAPK/ERK signal transduction pathway and may be used to investigate the mechanisms of disc degeneration.

Comparison of unilateral versus bilateral pedicle screw fixation in degenerative lumbar diseases: a meta-analysis.

PURPOSE: Traditionally, lumbar spinal surgery is performed with bilateral pedicle screw fixation to provide stability as the fusion heals. However, many studies have reported that unilateral pedicle screw fixation is as effective as bilateral constructs. To compare the clinical outcomes, complications, and surgical trauma between the two techniques for treatment of degenerative lumbar diseases, we conducted a meta-analysis. METHODS: We searched MEDLINE, EMBASE, PubMed, Google Scholar, and Cochrane databases for relevant controlled studies up to August 2013 that compared unilateral with bilateral fixation for the treatment of degenerative lumbar diseases. We independently performed title/abstract screening and full-text screening. A random effects model was used for heterogeneous data; otherwise, a fixed effect model was used, pooling data using mean difference (MD) for continuous outcomes and odds ratio (OR) for dichotomous outcomes. RESULTS: A total of 12 articles (865 participants) were eligible. Overall, there were significant differences between the two groups for blood loss (MD = -171.73, 95 % CI = -281.70 to -61.76; p = 0.002), operation time (MD = -66.02, 95 % CI = -115.52 to -16.51; p = 0.009), and fusion rate (OR = 0.50, 95 % CI = 0.26-0.96; p = 0.004). However, there were no significant differences in hospital stay (MD = -4.44, 95 % CI = -13.37 to 4.50), ODI (MD = -0.09, 95 % CI = -0.59 to 0.42; p = 0.74), JOA (MD = 0.18, 95 % CI = -0.77 to 1.14; p = 0.71), VAS (MD = -0.04, 95 % CI = -0.16 to 0.08; p = 0.49), SF-36 (PF: MD = -1.11, 95 % CI = -4.38 to 2.17, p = 0.51; GH: MD = 1.22, 95 % CI = -2.17 to 4.60, p = 0.48; MH: MD = -0.22, 95 % CI = -3.83 to 3.38, p = 0.90) and complications (OR = 1.15, 95 % CI = 0.72-1.85; p = 0.56). CONCLUSIONS: This meta-analysis shows that there was significantly less blood loss in unilateral group and less operating time; however, the fusion rate was significantly higher in the bilateral group. The outcomes of hospital stay, ODI, JOA, VAS, SF-36 score, and complications are similar in the two groups.

Fusion techniques for adult isthmic spondylolisthesis: a systematic review.

INTRODUCTION: Various fusion techniques have been used to treat lumbar spine isthmic spondylolisthesis (IS) in adults, including anterior lumbar interbody fusion (ALIF), posterior lumbar interbody fusion (PLIF), transforaminal lumbar interbody fusion (TLIF), posterolateral fusion (PLF), and circumferential fusion. The objective of this study was to evaluate which fusion technique provides the best clinical and radiological outcome for adult lumbar IS. MATERIALS AND METHODS: A systematic review was performed. MEDLINE databases and reference lists of selected articles were searched. Inclusion criteria stated that the studies had to be controlled and that they compared clinical and radiological outcomes of various fusion techniques for treating adult IS. Exclusion criteria were use of only one treatment and non-English language articles. Two reviewers independently extracted relevant data from each included study. Statistical comparisons were made when appropriate. RESULTS: Nine studies that compared two surgical approaches to IS were included in this systematic review. Three were prospective studies, and six were retrospective studies. Two studies compared ALIF with instrumented PLF and ALIF with percutaneous pedicle screw fixation, two studies compared ALIF and TLIF, and five studies compared PLIF and PLF. ALIF was superior to other techniques regarding restoration of disc height, segmental lordosis, and whole lumbar lordosis. TLIF had lower complication rates. ALIF combined with PLF showed lower nonfusion rates than other techniques. However, there were no significant differences in clinical outcomes between any two techniques. CONCLUSION: Compared to other fusion techniques, TLIF shows fewer complications, ALIF shows better sagittal alignment, and circumferential fusion showed better fusion rates. It was difficult to make recommendations about the optimal approach because of the methodological variance in the publications.

Anterior cervical discectomy and fusion with a zero-profile VA spacer device: a clinical and radiological study with two-year follow-up.

STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to compare clinical and radiological outcomes of the anterior cervical discectomy and fusion (ACDF) with a novel zero-profile variable-angle (Zero-P VA) spacer and a traditional poly-ether-ether-ketone (PEEK) cage and plate system in cases pertaining to cervical radiculopathy/myelopathy. There are two conventional types of ACDF procedures aimed at treating symptomatic cervical spondylosis. The first one involves an uninstrumented "stand-alone" approach utilizing bone graft/cage, while the second incorporates bone graft/cage in conjunction with a front plate positioned before the vertebral bodies. Both procedures have their own inherent advantages and disadvantages. The Zero-P VA spacer, however, represents a unique synthesis by amalgamating the advantages of both traditionally typical procedures. Notably, this spacer can potentially circumvent the issue related to prevertebral soft-tissue disturbance and reduce the occurrence of dysphagia. METHODS: Using our surgical database, the authors systematically conducted a retrospective analysis encompassing all patients who underwent single-level ACDF between January 2018 and January 2019, with a minimum two-year follow-up. Patients either received a Zero-P VA implant or PEEK cage coupled with plating. The Japanese Orthopedic Association (JOA) score and Visual Analogue Scale (VAS) for arm and neck pain were documented. Dysphagia was evaluated using the Eating Assessment Tool-10 (ETA-10). Additional parameters such as cervical alignment, fusion rate and the incidence of postoperative complications were assessed. RESULTS: According to the outcomes of the statistical analysis, there was no substantial disparity that emerged in the advancements observed in the JOA and VAS metrics between the two study cohorts. Noteworthy, however, the ETA-10 scores were statistically significantly reduced in the Zero-P VA group compared to the cage and plating group (p < 0.05). At the final follow-up, there were no statistically significant differences in the height of the operated segment, Cobb angle of the fused segment, C2-C7 Cobb angle and fusion rate between the two groups (p > 0.05). However, postoperative complications were slightly lower in patients with the Zero-P VA group (7.69%) as compared to the cage and plating group (16.67%). CONCLUSION: The clinical outcomes observed with the Zero-P VA spacer used for single-level ACDF were found to be satisfactory. The performance of this device is comparable or even superior to the traditional cage and plating method in preventing postoperative dysphagia and mitigating potential complications associated with the use of a plate.

Inhibition of Mettl3 ameliorates osteoblastic senescence by mitigating m6A modifications on Slc1a5 via Igf2bp2-dependent mechanisms.

Age-related osteoporosis is characterized by a marked decrease in the number of osteoblasts, which has been partly attributed to the senescence of cells of the osteoblastic lineage. Epigenetic studies have provided new insights into the mechanisms of current osteoporosis treatments and bone repair pathophysiology. N6-methyladenosine (m6A) is a novel transcript modification that plays a major role in cellular senescence and is essential for skeletal development and internal environmental stability. Bioinformatics analysis revealed that the expression of the m6A reading protein Igf2bp2 was significantly higher in osteoporosis patients. However, the role of Igf2bp2 in osteoblast senescence has not been elucidated. In this study, we found that Igf2bp2 levels are increased in ageing osteoblasts induced by multiple repetition and H2O2. Increasing Igf2bp2 expression promotes osteoblast senescence by increasing the stability of Slc1a5 mRNA and inhibiting cell cycle progression. Additionally, Mettl3 was identified as Slc1a5 m6A-methylated protein with increased m6A modification. The knockdown of Mettl3 in osteoblasts inhibits the reduction of senescence, whereas the overexpression of Mettl3 promotes the senescence of osteoblasts. We found that administering Cpd-564, a specific inhibitor of Mettl3, induced increased bone mass and decreased bone marrow fat accumulation in aged rats. Notably, in an OVX rat model, Igf2bp2 small interfering RNA delivery also induced an increase in bone mass and decreased fat accumulation in the bone marrow. In conclusion, our study demonstrated that the Mettl3/Igf2bp2-Slc1a5 axis plays a key role in the promotion of osteoblast senescence and age-related bone loss.