Age-related decline in melatonin contributes to enhanced osteoclastogenesis via disruption of redox homeostasis.

BACKGROUND: Increased oxidative stress contributes to enhanced osteoclastogenesis and age-related bone loss. Melatonin (MT) is an endogenous antioxidant and declines with aging. However, it was unclear whether the decline of MT was involved in the enhanced osteoclastogenesis during the aging process. METHODS: The plasma level of MT, oxidative stress status, bone mass, the number of bone marrow-derived monocytes (BMMs) and its osteoclastogenesis were analyzed in young (3-month old) and old (18-month old) mice (n = 6 per group). In vitro, BMMs isolated from aged mice were treated with or without MT, followed by detecting the change of osteoclastogenesis and intracellular reactive oxygen species (ROS) level. Furthermore, old mice were treated with MT for 2 months to investigate the therapeutic effect. RESULTS: The plasma level of MT was markedly lower in aged mice compared with young mice. Age-related decline in MT was accompanied by enhanced oxidative stress, osteoclastogenic potential and bone loss. MT intervention significantly suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, decreased intracellular ROS and enhanced antioxidant capacity of BMMs from aged mice. MT supplementation significantly attenuated oxidative stress, osteoclastogenesis, bone loss and deterioration of bone microstructure in aged mice. CONCLUSIONS: These results suggest that age-related decline of MT enhanced osteoclastogenesis via disruption of redox homeostasis. MT may serve as a key regulator in osteoclastogenesis and bone homeostasis, thereby highlighting its potential as a preventive agent for age-related bone loss.

Tanshinone IIA attenuates osteoarthritis via inhibiting aberrant angiogenesis in subchondral bone.

Excessive angiogenesis in subchondral bone is a pathological feature of osteoarthritis (OA). Tanshinone IIA (TIIA), an active compound found in Salvia miltiorrhiza, demonstrates significant anti-angiogenic properties. However, the effect of TIIA on abnormal subchondral angiogenesis in OA is still unclear. This study aims to investigate the mechanism of TIIA in modulating subchondral bone angiogenesis during OA and assess its therapeutic potential in OA. Our findings demonstrate that TIIA attenuated articular cartilage degeneration, normalized subchondral bone remodeling, and effectively suppressed aberrant angiogenesis within subchondral bone in monosodium iodoacetate (MIA)-induced OA mice. Additionally, the angiogenesis capacity of primary CD31hiEmcnhi endothelial cells was observed to be significantly reduced after treatment with TIIA in vitro. Mechanically, TIIA diminished the proportion of hypertrophic chondrocytes, ultimately leading to a substantial reduction in the secretion of vascular endothelial growth factor A (VEGFA). The supernatant of hypertrophic chondrocytes promoted the tube formation of CD31hiEMCNhi endothelial cells, whereas TIIA inhibited this process. Furthermore, TIIA effectively suppressed the expression of vascular endothelial growth factor receptor 2 (VEGFR2) along with its downstream MAPK pathway in CD31hiEmcnhi endothelial cells. In conclusion, our data indicated that TIIA could effectively inhibit the abnormal angiogenesis in subchondral bone during the progression of OA by suppressing the VEGFA/VEFGR2/MAPK pathway. These findings significantly contribute to our understanding of the abnormal angiogenesis in OA and offer a promising therapeutic target for OA treatment.

N-acetyl-L-cysteine attenuates oxidative stress-induced bone marrow endothelial cells apoptosis by inhibiting BAX/caspase 3 pathway.

Bone marrow endothelial cells (BMECs) play a crucial role in the maintenance of bone homeostasis. The decline in BMECs is associated with abnormal bone development and loss. At present, the mechanism of age-related oxidative stress enhancement in BMEC dysfunction remains unclear. Our experiment explored injury caused by oxidative stress enhancement in BMECs both in vivo and in vitro. The BMECs, indicators of oxidative stress, bone mass, and apoptosis-related proteins were analyzed in different age groups. We also evaluated the ability of N-Acetyl-L-cysteine (NAC) attenuate oxidative stress injury in BMECs. NAC treatment attenuated reactive oxygen species (ROS) overgeneration and apoptosis in BMECs in vitro and alleviated the loss of BMECs and bone mass in vivo. In conclusion, this study could improve our understanding of the mechanism of oxidative stress-induced BMECs injury and whether NAC has therapeutic potential in senile osteoporosis.

CircRBM23 regulates the switch between osteogenesis and adipogenesis of mesenchymal stem cells via sponging miR-338-3p.

BACKGROUND: The disruption of the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) in bone marrow contributes to the adipocytes accumulation and bone loss, which leads to the development of osteoporosis (OP). The circular RNA (circRNA), circRBM23, was generated from the RNA binding motif protein 23 (RBM23) gene. It was reported that circRBM23 was down-regulated in OP patients, but it remains unknown whether its down-regulation is involved in the lineage switch of MSCs. OBJECTIVE: We aimed to explore the role and mechanism of circRBM23 in regulating the switch between osteogenic and adipogenic differentiation of MSCs. METHODS: The expression and function of circRBM23 in vitro were detected by qRT-PCR, alizarin red staining, and oil Red O staining. The interactions between circRBM23 and microRNA-338-3p (miR-338-3p) were analyzed by RNA pull-down assay, FISH, and dual-luciferase reporter assay. MSCs treated with lentivirus overexpression of circRBM23 was applied for both in vitro and in vivo experiments. RESULTS: CircRBM23 was expressed at lower levels in OP patients. Besides, circRBM23 was up-regulated during osteogenesis and down-regulated during adipogenesis of MSCs. CircRBM23 could promote the osteogenic differentiation but inhibit the adipogenic differentiation of MSCs. Mechanistically, circRBM23 acted as a sponge for microRNA-338-3p (miR-338-3p) to enhance the expression of RUNX family transcription factor 2 (RUNX2). CONCLUSIONS: Our research indicates that circRBM23 could promote the switch from adipogenic to osteogenic differentiation of MSCs via sponging miR-338-3p. It might improve the understanding of the lineage switch of MSCs and provide a potential target for diagnosing and treating OP.

Ferroptosis-associated DNA methylation signature predicts overall survival in patients with head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common cancer characterized by late diagnosis and poor prognosis. The aim of this study was to identify a novel ferroptosis-related DNA methylation signature as an alternative diagnosis index for patients with HNSCC. METHODS: Methylome and transcriptome data of 499 HNSCC patients, including 275 oral squamous cell carcinoma (OSCC) samples, were obtained from The Cancer Genome Atlas (TCGA). An additional independent methylation dataset of 50 OSCC patients from the NCBI Gene Expression Omnibus (GEO) database was used for validation. As an index of ferroptosis activity, the ferroptosis score (FS) of each patient was inferred from the transcriptome data using single-sample gene set enrichment analysis. Univariate, multivariate, and LASSO Cox regression analyses were used to select CpG sites for the construction of a ferroptosis-related DNA methylation signature for diagnosis of patients. RESULTS: We initially inferred the FS of each TCGA HNSCC patient and divided the samples into high- and low-FS subgroups. Results showed that the high-FS subgroup displayed poor overall survival. Moreover, 378 differentially methylated CpG sites (DMCs) were identified between the two HNSCC subgroups, with 16 selected to construct a 16-DNA methylation signature for risk prediction in HNSCC patients using the LASSO and multivariate Cox regression models. Relative operating characteristic (ROC) curve analysis showed great predictive efficiency for 1-, 3-, and 5-year HNSCC survival using the 16-DNA methylation signature. Its predictive efficiency was also observed in OSCC patients from the TCGA and GEO databases. In addition, we found that the signature was associated with the fractions of immune types in the tumor immune microenvironment (TIME), suggesting potential interactions between ferroptosis and TIME in HNSCC progression. CONCLUSIONS: We established a novel ferroptosis-related 16-DNA methylation signature that could be applied as an alternative tool to predict prognosis outcome in patients with HNSCC, including OSCC.

Identification of an immune-related signature indicating the dedifferentiation of thyroid cells.

BACKGROUND: Immune cells account for a large proportion of the tumour microenvironment in anaplastic thyroid carcinomas (ATCs). However, the expression pattern of immune-related genes (IRGs) in ATCs is unclear. Our study aimed to identify an immune-related signature indicating the dedifferentiation of thyroid cells. METHODS: We compared the differences in thyroid differentiation score (TDS), infiltration of immune cells and enriched pathways between ATCs and papillary thyroid carcinomas (PTCs) or normal thyroid tissues in the Gene Expression Omnibus database. Univariate and multivariable Cox analyses were used to screen prognosis-associated IRGs in The Cancer Genome Atlas database. After constructing a risk score, we investigated its predictive value for differentiation and survival by applying receiver operating characteristic and Kaplan-Meier curves. We further explored its associations with important immune checkpoint molecules, infiltrating immune cells and response to immunotherapy. RESULTS: Compared with PTCs or normal thyroid tissues, ATCs exhibited lower TDS values and higher enrichment of immune cells and activation of the inflammatory response. The quantitative analyses and immunohistochemical staining validated that most ATC cell lines and ATC tissues had higher expression of MMP9 and lower expression of SDC2 than normal thyroid samples and PTC. Higher risk scores indicates dedifferentiation and a worse prognosis. Additionally, the risk score was positively correlated with the immune checkpoint molecules PDL1, CTLA4, IDO1, and HAVCR2 and infiltration of multiple immune cells. Importantly, we found that the samples with higher risk scores tended to have a better response to immunotherapy than those with lower scores. CONCLUSION: Our findings indicate that the risk score may not only contribute to the determination of differentiation and prognosis of thyroid carcinomas but also help the prediction of immune cells infiltration and immunotherapy response.

Identification and validation of an immune-related prognostic signature and key gene in papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer. The effect of traditional anti-tumor therapy is not ideal for the patients with recurrence, metastasis and radioiodine resistance. The abnormal expression of immune-related genes (IRGs) has critical roles in the etiology of PTC. However, the effect of IRGs on PTC prognosis remains unclear. METHODS: Based on The Cancer Genome Atlas (TCGA) and ImmPort databases, we integrated IRG expression profiles and progression-free intervals (PFIs) of PTC patients. First, we identified the differentially expressed IRGs and transcription factors (TFs) in PTC. Subsequently, an IRG model that can predict the PFI was constructed by using univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses of the differentially expressed IRGs in the TCGA. Additionally, a protein-protein interaction (PPI) network showed the interactions between the differentially expressed genes (DEGs), and the top 30 genes with the highest degree were extracted from the network. Then, the key IRG was identified by the intersection analysis of the PPI network and univariate Cox regression, which was verified the differential expression of by western blotting and immunohistochemistry (IHC). ssGSEA was performed to understand the correlation between the key IRG expression level and immune activity. RESULTS: A total of 355 differentially expressed IRGs and 43 differentially expressed TFs were identified in PTC patients. Then, eight IRGs were finally utilized to construct an IRG model. The respective areas under the curve (AUCs) of the IRG model reached 0.948, 0.820, and 0.831 at 1, 3 and 5 years in the training set. In addition, lactotransferrin (LTF) was determined as the key IRG related to prognosis. The expression level of LTF in tumor tissues was significantly lower than that in normal tissues. And the results of ssGSEA showed the expression level of LTF is closely related to immune activity. CONCLUSIONS: These findings show that the prognostic model and key IRG may become promising molecular markers for the prognosis of PTC patients.

The combination of contrast-enhanced ultrasonography with blue dye for sentinel lymph node detection in clinically negative node breast cancer.

PURPOSE: The aim of this prospective study was to evaluate the value of the combination of contrast-enhanced ultrasonography (CEUS) and blue dye (BD) for SLN detection in patients with clinically negative node breast cancer. METHODS: Patients with clinically negative node breast cancer were randomized into two cohorts for SLN biopsy (SLNB): the combination method cohort using CEUS and BD together, and the single BD method cohort. Standard axillary lymph node dissection was performed if any of the SLNs confirmed positive by pathology. The identification rate, the number of SLNs removed and recurrence-free survival (RFS) rates were evaluated between two cohorts. In addition, we assessed the sensitivity, specificity, accuracy, false-negative rate of CEUS for diagnosis of SLNs based on patterns of CEUS enhancement. RESULTS: 144 consecutive patients with clinically negative node breast cancer were randomized into two cohorts. Each cohort consisted of 72 cases. In the combination method cohort, contrast-enhanced lymphatic vessels were clearly visualized and SLNs were accurately localized in 72 cases. The identification rate and the mean number of SLNs detected by the combination method were 100% (72/72) and 3.26 (1-9), respectively. In contrast, in the single BD method cohort, SLNs in 69 cases were successfully identified. The identification rate and the mean number of SLNs using BD alone were 95.8% (69/72) and 2.21 (1-4), respectively. According to patterns of CEUS enhancement, the sensitivity, specificity, accuracy, and the FNR of CEUS for SLN diagnosis were 69.2%, 96.6%, 91.7%, and 30.8%, respectively. After a median follow-up of 50 months for the combination method cohort and 51 months for the blue dye alone cohort, five patients in the combination method cohort and nine in the blue dye alone cohort had recurrence. RFS rates showed no significant difference (P = 0.26) between two cohorts. CONCLUSION: The combination of CEUS and BD is more effective than BD alone for SLNB in clinically negative node patients with an identification rate as high as 100%. Use of BD and CEUS in combination may provide the possibility of a non-radioactive alternative method for SLNB in centers without access to radioisotope.

Adaptor protein LNK promotes anaplastic thyroid carcinoma cell growth via 14-3-3 ε/γ binding.

BACKGROUND: Rapid progression contributes to treatment failure in anaplastic thyroid carcinoma (ATC) patients. In a preliminary study, we demonstrated that some hematopoietic factors may be involved in the progression of ATC. The adaptor protein LNK, which is a negative regulator of hematopoietic cytokine signalling, has been studied extensively in malignant hematopoietic cells. However, there are few studies on LNK in solid tumours. METHODS: Real-time PCR, immunohistochemistry (IHC) and western blot analysis of LNK were performed on ATC cells, differentiated thyroid cancer (DTC) cells and normal thyroid cells. In vitro assays (including pull-down, liquid chromatography-mass spectrometry (LC-MS), co-IP, MTT and colony formation) were performed to validate the effect of LNK on ATC progression and elucidate the molecular mechanisms. RESULTS: Compared with DTC cells and normal thyroid cells, ATC cells exhibit overexpression of LNK. In addition, LNK overexpression results in increased proliferation of ATC cells. Conversely, LNK knockdown significantly suppresses ATC cell proliferation. LC-MS identified the 14-3-3 ε/γ protein as a LNK binding partner. Finally, the results indicate that LNK overexpression significantly enhances the anti-apoptotic ability of ATC cells via the Akt-NFκB-Bcl-2/Bcl-xL pathway and that the oncogenic effect of LNK largely depends on 14-3-3 ε/γ binding. CONCLUSIONS: The present study elucidated the important role of LNK in the growth of ATC opposite to its behaviour in the hematopoietic system and indicates that LNK is a potential target for the treatment of ATC.

Straighter low lumbar curvature in isthmic spondylolisthesis at L4.

BACKGROUND: This study was conducted to compare differences in imaging features and clinical symptoms between patients with single-level isthmic spondylolisthesis (IS) at L4 and at L5 and to investigate the correlation between imaging and clinical parameters. METHODS: This cross-sectional study evaluated patients with single-level IS who were enrolled between June 2011 and June 2018. A total of 139 patients, 44 in the L4 IS group and 95 in the L5 IS group, met the study criteria and were included. Imaging and clinical parameters obtained from the two groups were compared and analyzed. RESULTS: Patients in the L4 IS group had smaller lower lumbar lordosis (LLL) (27.1 ± 8.2 vs. 30.9 ± 9.3, P = 0.021) and were of older age (58.5 ± 8.7 vs. 52.8 ± 10.1, P < 0.01) than those in the L5 IS group. As per the Roussouly classification system, most patients with L4 IS were classified as Type 2 (43.2%), whereas most patients with L5 IS fell under Type 3 (44.2%). In the L5 IS group, pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), and L5 incidence (L5I) were positively associated with slippage rate (SR), but the lumbosacral angle (LSA) was negatively associated with SR (P < 0.01). In the L4 IS group, only L5I showed a positive association with SR (P < 0.01). More significant associations were found among sagittal lumbo-pelvic parameters in the L5 IS group, but none were found between SR and Oswestry Disability Index (ODI) in either group. CONCLUSIONS: When compared with patients with L5 IS, patients with L4 IS were of older age and had straighter low lumbar curvature when they were obviously symptomatic. PI was an important parameter for patients with L5 IS while for those with L4 IS, L5I deserved more attention for its significantly positive correlation with the degree of slippage.

Prospective comparison of indwelling cannulas drain and needle aspiration for symptomatic seroma after mastectomy in breast cancer patients.

AIMS: Postoperative seroma is the most frequent sequelae after mastectomy and axillary surgery with no optimal regimens for seroma resolution recommended in routine clinical. Indwelling cannulas with needle and catheter have been widely used in long-term medication therapies, but evidence of indwelling cannulas in seroma management after mastectomy is lacking. The purpose of this study is to evaluate the feasibility of indwelling cannulas in seroma management after mastectomy. METHODS: Patients who underwent modified radical mastectomy (MRM) and developed symptomatic seroma after removal of the drains between August 2017 and December 2018, were randomized into two groups either indwelling cannulas drain of seroma (Group A) or needle aspiration of seroma (Group B). We prospectively compared the number of visits for seroma, the time from removal of the drain to the final seroma resolution and the cost between the methods. RESULTS: A total of 860 patients underwent MRM between August 2017 and December 2018, among which 86 patients who developed symptomatic seroma after removal of the drains, were randomized into two groups either Group A or Group B. The number of visits for seroma in Group A was 2.35 ± 0.69 times, which was less than those in Group B (4.86 ± 1.06 times). Similarly, the time of drain removal to final seroma resolution in Group A was 4.65 ± 0.78 days, which was shorter than 7.09 ± 1.54 in Group B. In Group A, the total mean cost per patient (25.81 ± 7.71 RMB) was less than the total mean cost per patient (49.30 ± 9.85 RMB) in Group B. Cost savings were noted with using indwelling cannulas in seroma management. CONCLUSION: It is feasible to drain indwelling cannulas drain for postmastectomy seroma, with less visits for patients, rapid seroma resolution and less cost. Indwelling cannulas can be an efficient, cost effective solution to treat symptomatic seroma after breast surgery.

Advanced oxidation protein products induce chondrocyte death through a redox-dependent, poly (ADP-ribose) polymerase-1-mediated pathway.

This study aimed to investigate the effect of AOPPs on apoptosis in human chondrocytes. Chondrocytes were treated with AOPPs. Cell death, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, reactive oxygen species (ROS) generation, and the expression of apoptotic proteins were detected in vitro. AOPPs levels were detected by colorimetric method. The results in vitro demonstrated that AOPPs induced cell death in human chondrocyte through a redox-dependent pathway, including RAGE-mediated, NADPH oxidase-dependent ROS generation, and poly (ADP-ribose) polymerase-1 (PARP-1) activation. Targeting AOPPs-induced cellular mechanisms might emerge as a promising therapeutic option for patients with RA.

Differences in Clinicopathological Characteristics and Prognosis Between Primary and Postirradiation Tongue Squamous Cell Carcinoma.

PURPOSE: Many cases of postirradiation oral carcinoma have been reported, but its prognosis and optimal treatment modalities are not clear. Thus, the clinicopathologic characteristics and prognosis between postirradiation tongue squamous cell carcinoma (PTSCC) and primary tongue squamous cell carcinoma (TSCC) were compared. PATIENTS AND METHODS: A retrospective cohort study was conducted to assess patients with PTSCC or TSCC. The primary predictor variable was tumor type. The primary outcome variable was prognosis, and the additional outcome variables were clinicopathologic characteristics. Survival analysis was performed, and Kaplan-Meier analysis was conducted to compare the effects of clinicopathologic factors on survival using SPSS 18.0. Moreover, the Cox model was applied in multivariate analysis. RESULTS: The sample was composed of 449 patients with PTSCC (n = 68; 47 men and 21 women; age range, 31 to 72 yr) and TSCC (n = 381; 247 men and 134 women; age range, 20 to 86 yr). Patients with PTSCC were found to have a substantially poorer prognosis and several specific clinicopathologic characteristics compared with patients with TSCC. CONCLUSION: Patients with PTSCC had several unique biological tumor characteristics and a poorer prognosis than patients with TSCC. Thus, different surgical strategies should be used to treat patients with PTSCC.

Advanced oxidation protein products induce chondrocyte apoptosis via receptor for advanced glycation end products-mediated, redox-dependent intrinsic apoptosis pathway.

Pro-inflammatory cytokine-induced chondrocyte apoptosis is a primary cause of cartilage destruction in the progression of rheumatoid arthritis (RA). Advanced oxidation protein products (AOPPs), a novel pro-inflammatory mediator, have been confirmed to accumulate in patients with RA. However, the effect of AOPPs accumulation on chondrocyte apoptosis and the associated cellular mechanisms remains unclear. The present study demonstrated that the plasma formation of AOPPs was enhanced in RA rats compared with normal. Then, chondrocyte were treated with AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. Exposure of chondrocyte to AOPPs activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased expression of NADPH oxidase subunits, which was mediated by receptor for advanced glycation end products (RAGE), but not scavenger receptor CD36. Moreover, AOPPs challenge triggered NADPH oxidase-dependent ROS generation which induced mitochondrial dysfunction and endoplasmic reticulum stress resulted in activation of caspase family that eventually lead to apoptosis. Lastly, blockade of RAGE, instead of CD36, largely attenuated these signals. Our study demonstrated first time that AOPPs induce chondrocyte apoptosis via RAGE-mediated and redox-dependent intrinsic apoptosis pathway in vitro. These data implicates that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Targeting AOPPs-triggered cellular mechanisms might emerge as a promising therapeutic option for patients with RA.

Color Doppler Sonographic and Cadaveric Study of the Arterial Vascularity of the Lateral Upper Arm Flap.

OBJECTIVES: To determine the importance of adequate preoperative assessment with color Doppler sonography to assist in the successful transfer of lateral upper arm flaps by studying the lateral upper arm flap with color Doppler sonography and analyzing the anatomic features of the radial collateral artery. METHODS: A clinical case-control study was performed. The radial collateral artery was studied with color Doppler sonography in 15 healthy volunteers. The origins, courses, variations, and locations of the perforators of the radial collateral artery were recorded. The results and data from the color Doppler sonographic investigation were compared with an anatomic study that was performed on 22 adult cadaveric upper limb specimens. RESULTS: The volunteer group (14 of 15 volunteers) and the cadaveric group (19 of 22 upper arm specimens) clearly showed that the branch pattern of the arterial supply was as follows: brachial artery → deep brachial artery → radial collateral artery → posterior radial collateral artery → myocutaneous perforator. Variations in the origin of the radial collateral artery were identified in 1 volunteer bilaterally and in 3 upper arm specimens. The diameters of the artery and vein measured at the distal insertion of the deltoid and the origin of the deep brachial artery were not significantly different between the volunteer and cadaver groups (P > .05). Due to the difference in measuring methods, the length of the vascular pedicles was significantly different between the groups (P < .05). CONCLUSIONS: Color Doppler sonography can facilitate the preoperative assessment of the origin, course, variations, and locations of the radial collateral artery and therefore may increase the success rate of lateral upper arm flap transfer.

Reoperation After Cervical Disc Arthroplasty Versus Anterior Cervical Discectomy and Fusion: A Meta-analysis.

BACKGROUND: Anterior cervical discectomy and fusion is a standard surgical treatment for cervical radiculopathy and myelopathy, but reoperations sometimes are performed to treat complications of fusion such as pseudarthrosis and adjacent-segment degeneration. A cervical disc arthroplasty is designed to preserve motion and avoid the shortcomings of fusion. Available evidence suggests that a cervical disc arthroplasty can provide pain relief and functional improvements similar or superior to an anterior cervical discectomy and fusion. However, there is controversy regarding whether a cervical disc arthroplasty can reduce the frequency of reoperations. QUESTIONS/PURPOSES: We performed a meta-analysis of randomized controlled trials (RCTs) to compare cervical disc arthroplasty with anterior cervical discectomy and fusion regarding (1) the overall frequency of reoperation at the index and adjacent levels; (2) the frequency of reoperation at the index level; and (3) the frequency of reoperation at the adjacent levels. METHODS: PubMed, EMBASE, and the Cochrane Register of Controlled Trials databases were searched to identify RCTs comparing cervical disc arthroplasty with anterior cervical discectomy and fusion and reporting the frequency of reoperation. We also manually searched the reference lists of articles and reviews for possible relevant studies. Twelve RCTs with a total of 3234 randomized patients were included. Eight types of disc prostheses were used in the included studies. In the anterior cervical discectomy and fusion group, autograft was used in one study and allograft in 11 studies. Nine of 12 studies were industry sponsored. Pooled risk ratio (RR) and associated 95% CI were calculated for the frequency of reoperation using random-effects or fixed-effects models depending on the heterogeneity of the included studies. A funnel plot suggested the possible presence of publication bias in the available pool of studies; that is, the shape of the plot suggests that smaller negative or no-difference studies may have been performed but have not been published, and so were not identified and included in this meta-analysis. RESULTS: The overall frequency of reoperation at the index and adjacent levels was lower in the cervical disc arthroplasty group (6%; 108/1762) than in the anterior cervical discectomy and fusion group (12%; 171/1472) (RR, 0.54; 95% CI, 0.36-0.80; p = 0.002). Subgroup analyses were performed according to secondary surgical level. Compared with anterior cervical discectomy and fusion, cervical disc arthroplasty was associated with fewer reoperations at the index level (RR, 0.50; 95% CI, 0.37-0.68; p < 0.001) and adjacent levels (RR, 0.52; 95% CI, 0.37-0.74; p < 0.001). CONCLUSIONS: Cervical disc arthroplasty is associated with fewer reoperations than anterior cervical discectomy and fusion, indicating that it is a safe and effective alternative to fusion for cervical radiculopathy and myelopathy. However, because of some limitations, these findings should be interpreted with caution. Additional studies are needed. LEVEL OF EVIDENCE: Level I, therapeutic study.

Risk factors for bone cement leakage in percutaneous vertebroplasty: a retrospective study of four hundred and eighty five patients.

PURPOSE: Percutaneous vertebroplasty (PVP) is a common procedure in spine surgery. Bone cement leakage is the most common complication related to this procedure. The purpose of this study was to assess the incidence and risk factors for cement leakage after PVP. METHODS: A total of 485 patients who underwent PVP between August 2003 and August 2013 were enrolled in the study. Clinical and radiological characteristics, including age, gender, diagnosis, operated level, surgical approach, type of anesthesia, volume of bone cement, fracture type, and fracture severity, were considered as potential risk factors. Cement leakage was assessed based on post-operative imaging examination. Six types of leakage were defined and risk factors for each type were analyzed. RESULTS: The incidence of leakage was 58.2 %. Binary logistic analysis revealed that larger volume of bone cement (P < 0.001) and higher fracture severity grade (P < 0.001) were the strongest independent risk factors. Univariate analysis and multinomial logistic analysis showed that surgical approach (P < 0.001), gender (P = 0.016), and operated level (P = 0.032) were additional risk factors for leakage. Further analysis showed that more bone cement was used in bilateral than unilateral approaches, that men had larger volumes of bone cement injected than women, and that more bone cement was injected into lumbar vertebrae than thoracic vertebrae. Therefore, these risk factors (surgical approach, gender, and operated level) could be attributed to excess bone cement usage. CONCLUSIONS: Cement leakage is very common with PVP. Higher fracture severity grade and larger volume of bone cement were the two strongest independent risk factors for leakage.

Advanced Oxidation Protein Products as a Novel Marker of Oxidative Stress in Postmenopausal Osteoporosis.

BACKGROUND: Advanced oxidation protein products (AOPPs) are acknowledged as a novel marker of oxidation-mediated protein damage. This study aimed to investigate the plasma levels of AOPPs in postmenopausal osteoporotic women, and to determine the relationship between AOPPs accumulation and lumbar bone mineral destiny (BMD) or bone turnover markers. MATERIAL AND METHODS: Lumbar BMD was measured by dual-energy X-ray absorptiometry. Plasma AOPPs levels as a marker of protein oxidation damage and malondialdehyde (MDA) levels as a marker of lipid peroxidation were measured by spectrophotometry. The concentrations of 2 specific markers of bone turnover, bone-specific alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase5b, (TRACP 5b) were quantified using ELISA kits. RESULTS: We recruited 60 postmenopausal women meeting osteoporosis (OP) diagnostic criteria of World Health Organization (WHO) and 60 postmenopausal women without OP. Plasma levels of AOPPs (P<0.001), BALP (P<0.001) and TRACP 5b (P<0.001) were statistically significantly increased in the postmenopausal osteoporotic women compared with controls, but there was no statistically significant difference in MDA (P=0.124) between the 2 groups. Plasma AOPPs levels were negatively correlated with lumbar BMD and positively correlated with bone turnover markers both in postmenopausal osteoporotic women and in all subjects. However, plasma MDA levels were not correlated with lumbar BMD or bone turnover markers. CONCLUSIONS: In postmenopausal osteoporotic women elevated AOPPs is associated with reduced BMD and increased bone turnover markers. Because AOPPs is stable and easy to detect it may be used as a simple plasma marker to predict the severity of postmenopausal OP.

Loss of SIL1 Affects Actin Dynamics and Leads to Abnormal Neural Migration.

SIL1 is a nucleotide exchange factor for the molecular chaperone protein Bip in the endoplasmic reticulum that plays a crucial role in protein folding. The Sil1 gene is currently the only known causative gene of Marinesco-Sjögren syndrome (MSS). Intellectual developmental disability is the main symptom of MSS, and its mechanism has not been fully elucidated. Studies have shown that mutations in the Sil1 gene can delay neuronal migration during cortical development, but the underlying molecular mechanisms remain unclear. To further identify potential molecules involved in the regulation of central nervous system development by SIL1, we established a cortical neuron model with SIL1 protein deficiency and used proteomic analysis to screen for differentially expressed proteins after Sil1 silencing, followed by GO functional enrichment and protein‒protein interaction (PPI) network analysis. We identified 68 upregulated and 137 downregulated proteins in total, and among them, 10 upregulated and 3 downregulated proteins were mainly related to actin cytoskeleton dynamics. We further validated the differential changes in actin-related molecules using qRT‒PCR and Western blotting of a Sil1 gene knockout (Sil1-/-) mouse model. The results showed that the protein levels of ACTN1 and VIM decreased, while their mRNA levels increased as a compensatory response to protein deficiency. The mRNA and protein levels of IQGAP1 both showed a secondary increase. In conclusion, we identified ACTN1 and VIM as the key molecules regulated by SIL1 that are involved in neuronal migration during cortical development.

Accumulation of ß-aminoisobutyric acid mediates hyperalgesia in ovariectomized mice through Mas-related G protein-coupled receptor D signaling.

Hyperalgesia is typified by reduced pain thresholds and heightened responses to painful stimuli, with a notable prevalence in menopausal women, but the underlying mechanisms are far from understood. ß-Aminoisobutyric acid (BAIBA), a product of valine and thymine catabolism, has been reported to be a novel ligand of the Mas-related G protein coupled receptor D (MrgprD), which mediates pain and hyperalgesia. Here, we established a hyperalgesia model in 8-week-old female mice through ovariectomy (OVX). A significant increase in BAIBA plasma level was observed and was associated with decline of mechanical withdrawal threshold, thermal and cold withdrawal latency in mice after 6 weeks of OVX surgery. Increased expression of MrgprD in dorsal root ganglion (DRG) was shown in OVX mice compared to Sham mice. Interestingly, chronic loading with BAIBA not only exacerbated hyperalgesia in OVX mice, but also induced hyperalgesia in gonadally intact female mice. BAIBA supplementation also upregulated the MrgprD expression in DRG of both OVX and intact female mice, and enhanced the excitability of DRG neurons in vitro. Knockout of MrgprD markedly suppressed the effects of BAIBA on hyperalgesia and excitability of DRG neurons. Collectively, our data suggest the involvement of BAIBA in the development of hyperalgesia via MrgprD-dependent pathway, and illuminate the mechanisms underlying hyperalgesia in menopausal women.