Strontium Ranelate Ameliorates Intervertebral Disc Degeneration via Regulating TGF-ß1/NF-κB Axis.

Intervertebral disc degeneration (IVDD) is a prevalent and debilitating condition characterized by chronic back pain and reduced quality of life. Strontium ranelate (SRR) is a compound traditionally used for treating osteoporosis via activating TGF-ß1 signaling pathway. Recent studies have proved the anti-inflammatory effect of SRR on chondrocytes. Although the exact mechanism of IVDD remains unclear, accumulating evidences have emphasized the involvement of multifactorial pathogenesis including inflammation, oxidative stress damage, and etc. However, the biological effect of SRR on IVDD and its molecular mechanism has not been investigated. Firstly, this study proved the decreased expression of Transforming Growth Factor-beta 1(TGF-ß1) in degenerated human intervertebral disc tissues. Subsequently, we confirmed for the first time that SRR could promote cell proliferation, mitigate inflammation and oxidative stress in human nucleus pulposus cells in vitro via increasing the expression of TGF-ß1 and suppressing the Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB) pathway. The molecular docking result proved the interaction between SRR and TGF-ß1 protein. To further verify this interaction, gain- and loss- of function experiments were conducted. We discovered that both TGF-ß1 knockdown and overexpression influenced the activation of the NF-κB pathway. Taken together, SRR could mitigate IL-1ß induced-cell dysfunction in human nucleus pulposus cells by regulating TGF-ß1/NF-κB axis in vitro. Finally, the in vivo therapeutic effect of SRR on IVDD was confirmed. Our findings may contribute to the understanding of the complex interplay between inflammation and degenerative processes in the intervertebral disc and provide valuable insights into the development of targeted treatment-based therapeutics for IVDD.

How cervical curvature changes after ACAF and ACDF: a radiological retrospective study.

To assess changes in cervical curvature and demonstrate the feasibility of using ACAF technology to restore lordosis, imaging data from patients undergoing multilevel ACAF and ACDF surgeries were retrospectively analyzed. Forty-seven patients receiving multilevel ACAF and ACDF were included in the study. Total cervical curvature and anterior, middle, and posterior column curvature, spinal canal diameter, cervical range of motion, and surgical complications were measured and analyzed by non-parametric or chi-square tests before and after surgery. The Spearman correlation between imaging data was analyzed. Compared with ACDF, the operation time of the ACAF group was longer, the cervical motion was larger, the median and change value of the middle column curvature was larger, and the change value of the posterior column curvature was smaller (P < 0.05). The postoperative differences in cervical lordosis angle, vertebral canal diameter, and middle and posterior column curvature in the ACAF group were significantly greater than those in the ACDF group (p = 0.015). The expansion of vertebral canal diameter was significantly correlated with the difference in curvature between the middle and posterior columns (r = 0.523, P < 0.01), and the curvature of the anterior column was correlated with that of the middle and posterior columns (P < 0.05). The curvature change of the anterior column is closely related to the curvature change of the middle column and the posterior column. Compared with ACDF, ACAF expands the diameter and volume of the spinal canal by increasing the curvature of the middle column and reducing the anterior movement of the posterior column.

Effects of "fixation-fusion" sequence of lumbar surgery on surgical outcomes for patients with lumbar spinal stenosis: study protocol for a multicenter randomized controlled trial.

BACKGROUND: New-onset neurological symptoms such as numbness and pain in lower extremities might appear immediately after conventional lumbar interbody fusion (LIF) surgery performed in patients with lumbar spinal stenosis. METHODS AND ANALYSIS: This is a multicenter, randomized, open-label, parallel-group, active-controlled trial investigating the clinical outcomes of modified LIF sequence versus conventional LIF sequence in treating patients with lumbar spinal stenosis. A total of 254 eligible patients will be enrolled and randomized in a 1:1 ratio to either modified LIF sequence or conventional LIF sequence group. The primary outcome measure is the perioperative incidence of new-onset lower extremity neurological symptoms, including new adverse events of pain, numbness, and foot drop of any severity. Important secondary endpoints include visual analogue scale (VAS) pain score and lumbar Japanese Orthopaedic Association (JOA) recovery rate. Other safety endpoints will also be evaluated. The safety set used for safety data analysis by the actual surgical treatment received and the full analysis set for baseline and efficacy data analyses according to the intent-to-treat principle will be established as the two analysis populations in the study. CONCLUSION: This study is designed to investigate the clinical outcomes of modified LIF sequences in patients with lumbar spinal stenosis. It aims to provide clinical evidence that the modified "fixation-fusion" sequence of LIF surgery is effective in treating lumbar spinal stenosis. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx ID: ChiCTR2100048507.

A retrospective study on application of a classification criterion based on relative intervertebral tension in spinal fusion surgery for lumbar degenerative diseases.

BACKGROUND: As an important part of spinal fusion procedure, the selection of fusion cage size is closely related to the curative effect of the surgery. It mainly depends on the clinical experience of surgeons, and there is still a lack of objective standards. The purpose of this study is to propose the concept of relative intervertebral tension (RIT) for the first time and its grading standards to improve the surgical procedures of lumbar interbody fusion. METHODS: This retrospective study was conducted from January 2018 to July 2019. A total of 83 eligible patients including 45 men and 38 women with lumbar degenerative disease underwent transforaminal lumbar interbody fusion (TLIF) were included in this study. A total of 151 fusion segments were divided into group A, group B and group C according to the grading standards of RIT. In addition, parameters of intervertebral space angle (ISA), intervertebral space height (ISH), intervertebral space foramen (IFH), fusion rates, cage-related complications and cage heights were also compared among the three groups. RESULTS: The ISA in group A was the smallest among three groups in contrast with group C with largest ISA at the final follow-up(P < 0.05). The group A presented the smallest ISH and IFH values(P < 0.05), compared with group B with the largest ISH and IFH values(P < 0.05). These two parameters in the group C were in-between. The fusion rates of group A, group B and group C were 100%, 96.3% and 98.8% at the final follow-up, respectively. No statistical difference in fusion rates and cage-related complications occurred among the three groups(P > 0.05), and a certain correlation between ISH and RIT was also observed. CONCLUSIONS: The concept of RIT and the application of its clinical grading standards could simplify the surgical procedures of spinal fusion and reduce cage-related complications.

A meta-analysis of risk factors for non-superficial surgical site infection following spinal surgery.

BACKGROUND: Surgical site infection (SSI) is the most common complications in spinal surgery. In SSI, non-superficial surgical site infections are more likely to result in poor clinical outcomes. It has been reported that there are multiple factors contributing to postoperative non-superficial SSI, but still remains controversial. Therefore, the aim of this meta-analysis is to investigate the potential risk factors for non-superficial SSI following spinal surgery. METHODS: A systematic database search of PubMed, Embase, Web of Science, Cochrane Library and Clinical Trials was performed for relevant articles published until September 2022. According to the inclusion and exclusion criteria, two evaluators independently conducted literature screening, data extraction and quality evaluation of the obtained literature. The Newcastle-Ottawa Scale (NOS) score was used for quality evaluation, and meta-analysis was performed by STATA 14.0 software. RESULTS: A total of 3660 relevant articles were initially identified and 11 articles were finally included in this study for data extraction and meta-analysis. The results of meta-analysis showed that the diabetes mellitus, obesity, using steroids, drainage time and operative time were related to the non-superficial SSI. The OR values (95%CI) of these five factors were 1.527 (1.196, 1.949); 1.314 (1.128, 1.532); 1.687(1.317, 2.162); 1.531(1.313, 1.786) and 4.255(2.612, 6.932) respectively. CONCLUSIONS: Diabetes mellitus, obesity, using steroids, drainage time and operative time are the current risk factors for non-superficial SSI following spinal surgery. In this study, operative time is the most important risk factor resulting in postoperative SSI.

Anterior controllable antidisplacement and fusion surgery for the treatment of extensive cervico-thoracic ossification of posterior longitudinal ligament with severe myelopathy: case report and literature review.

OPLL generally occurs in the cervical spine and involves no more than three vertebral segments, while extensive OPLL that involves the cervico-thoracic spine and spans over multiple segments is rare. Surgically it is difficult to achieve a satisfactory clinical outcome without surgical complications via the traditional anterior or posterior approaches. We report the first application of Anterior controllable antidisplacement and fusion (ACAF) in treating extensive cervico-thoracic OPLL. A 45-year old patient experienced severe walking disturbance, bladder and bowel dysfunction for 5 months after a fall. His preoperative Japanese Orthopedic Association (JOA) score was 8 of 17. Preoperative CT and MRI demonstrated a K-line (-) and mixed-type extensive OPLL from C2 to T2, causing significant cord compression. After ACAF surgery, neurological symptoms improved immediately without postoperative complications. Postoperative CT and MRI scanning showed restoration of spinal canal cross section and cord decompression. At 6 months he was able to stand and walk again without assistance and urinary bladder and bowel function returned to normal completely. At 15 months his JOA score was 14 of 17. ACAF surgery provides a promising alternative for the treatment of extensive cervico-thoracic OPLL.

Development and Validation of a Novel Nomogram to Predict the Risk of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) has been a complex disorder resulted from genetic and environmental risk factors. The aim of this study was to identify the risk factors associated with IVDD in orthopaedic patients and develop a prediction model for predicting the risk of IVDD. A total of 309 patients were retrospectively included in the study and randomly divided into the training group and the validation group. The least absolute shrinkage and selection operator regression (LASSO) and the univariate logistic regression analysis were used to optimize factors selection for the IVDD risk model. Multivariable logistic regression analysis was used to establish a predicting nomogram model incorporating the factors. In addition, discrimination, calibration, and clinical usefulness of the nomogram model were evaluated via the C-index, receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA). Then, based on the results above, the relationship between IVDD and angiotensin II (AngII) level in peripheral blood was examined prospectively. The predictors of the nomogram include age, sex, hypertension, diabetes, gout, working posture, and exercising hours per week. The C-index values of the training and validation groups were 0.916 (95% CI, 0.876-0.956) and 0.949 (95% CI, 0.909-0.989), respectively, which indicated that the model displayed good discrimination. In addition, the area under the curve (AUC) values of the ROC curve of the training and the validation group were 0.815 (95% CI, 0.759-0.870) and 0.805 (95% CI, 0.718-0.892), respectively, revealing the satisfactory discrimination performance of the model. The prospective investigation showed that the average AngII level in the degenerated group (97.62 ± 44.02 pg/mL) was significantly higher than that in the nondegenerated group (52.91 ± 9.01 pg/mL) (p < 0.001). This present study explored the risk factors for IVDD and established a prediction model, which would effectively predict the risk of IVDD. In addition, based on the prediction model, AngII was revealed to be a potentially auxiliary clinical diagnostic marker for IVDD.

Vericiguat Modulates Osteoclast Differentiation and Bone Resorption via a Balance between VASP and NF-κB Pathways.

Bone homeostasis has been a dynamic equilibrium between osteoclasts (OCs) and osteoblasts (OBs). However, excessive activation of OCs could disturb the bone homeostasis. As a result, effective medical interventions for patients are greatly demanding. NO/guanylate cyclase (GC)/cGMP signaling cascade has been previously reported to regulate bone metabolism, and GC plays a significantly critical role. Vericiguat, as a novel oral soluble guanylate cyclase (sGC) stimulator, has been firstly reported in 2020 to treat patients with heart failure. Nevertheless, the biological effects of Vericiguat on the function of OCs have not yet been explored. In this present study, we found that Vericiguat with the concentration between 0 and 8 µM was noncytotoxic to bone marrow-derived monocyte-macrophage lineage (BMMs). Vericiguat could enhance the differentiation of OCs at concentration of 500 nM, whereas it inhibited OC differentiation at 8 µM. In addition, Vericiguat also showed dual effects on OC fusion and bone resorption in a dose-dependent manner. Furthermore, a molecular assay suggested that the dual regulatory effects of Vericiguat on OCs were mediated by the bidirectional activation of the IκB-α/NF-κB signaling pathway. Taken together, our present study demonstrated the dual effects of Vericiguat on the formation of functional OCs. The regulatory effects of Vericiguat on OCs were achieved by the bidirectional modulation of the IκB-α/NF-κB signaling pathway, and a potential balance between the IκB-α/NF-κB signaling pathway and sGC/cGMP/VASP may exist.

Urodynamic evaluation of bladder function in patients with urinary incontinence secondary to congenital tethered cord syndrome after homogeneous spinal-shortening axial decompression procedure.

OBJECTIVE: To evaluate the effect of homogeneous spinal-shortening axial decompression procedure (HSAD) on bladder function in patients with spina bifida tethered syndrome. METHODS AND MATERIALS: Patients with tethered spinal cord syndrome were collected prospectively, and all patients were treated with lumbar HSAD. Patients' urodynamic evaluation mainly included detrusor function, sphincter function, sphincter coordination (Ig TLR, ratio of tension and loose of urethral sphincter), and bladder compliance. Meanwhile, all patients were followed up with ICI-Q-SF, SF-12, and Rantala scores. RESULTS: Twenty-four patients were included, with the average age of 27 ± 16 years. At the final follow-up, patients' detrusor function, sphincter function, sphincter coordination, and bladder compliance, were all improved dramatically (all P < 0.01). The preoperative SF-12 score, ICQ, and Rantala score were [52.16 ± 5.64, 14.11 ± 5.25, 7.84 ± 4.87], whereas the postoperative mean was [33.53 ± 3.53, 9.05 ± 4.89, 15 ± 3.77] (P < 0.01, respectively). According to objective evaluation, 16.7% of them recovered to normal. According to the subjective evaluation, 25% of the patients returned to normal. Only one patient (4.2%) deteriorated. Limitations include none-randomized controlled design and limited patient samples. CONCLUSIONS: The HSAD can significantly restore the bladder function in patients with long-term urinary incontinence.

The clinical effectiveness and complications of lumbar selective fenestration and concave-side fusion (LSFCF) in degenerative lumbar scoliosis (DLS) combined with lumbar spinal stenosis (LSS).

PURPOSE: This retrospective study was performed to analyze the clinical effects and complications of LSFCF in the surgical treatment of DLS combined with lumbar spinal stenosis (LSS). METHODS: A total of 26 eligible patients (mean age, 64.73 y; 17 men, 9 women) with DLS combined with LSS were included and LSFCF surgery was performed. An independent spine surgeon retrospectively reviewed the medical records and radiographs of all patients to evaluate surgical data and surgery-related complications. Preoperative, postoperative, and follow-up questionnaires were obtained to assess clinical outcomes. RESULTS: The average follow-up period of this study was 20.14 ± 5.21 months. The operation time and blood loss of patients underwent LSFCF were 129.33 ± 15.74 min and 356.13 ± 21.28 ml. The clinical effects of all patients in terms of visual analogue scale (VAS) and Oswestry disability index (ODI) have been significantly improved at the final follow-up postoperatively (P < 0.05). Complications such as infection, cerebrospinal fluid leakage, nerve injury, and internal fixation failure, etc. were not observed during the follow-up period. CONCLUSION: The LSFCF surgery is a safe and effective treatment for DLS patients combined with LSS.

The clinical application of individualized three-dimensional printing guiding template for assisting scaphoid fracture fixation through dorsal approach.

The purpose is to introduce a novel scaphoid screw placement surgery based on a novel three-dimensional (3D) printing guiding template through dorsal approach, and to evaluate the clinical feasibility and accuracy. The diagnose of scaphoid fracture was confirmed by Computed Tomography (CT) scanning, and subsequently the CT scanning data was input into a three-dimension imaging system(Hongsong software, China). An individualized 3D skin surface template with a guiding hole was printed. We put the template to the correct position on patient's wrist. Fluoroscopy was used to confirm the accurate position after drilling of Kirschner wire according to the prefabricated holes of template. Finally, the hollow screw was inserted through the wire. The operations were performed successfully without incision and complications. The operation time was below 20 minutes and the blood loss was below 1ml. The intraoperative fluoroscopy demonstrated good position of the screws. Postoperative imaging showed that the screws were considered to be placed perpendicularly to the fracture plane in the scaphoid. Three months after the operation, the patients acquired good recovery of the motor function of their hands. This present study suggested that the computer-assisted 3D printing guiding template is effective, reliable, and minimally invasive for the treatment of type B scaphoid fracture through dorsal approach.

TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice.

Congenital vertebral malformations (CVMs) are associated with human TBX6 compound inheritance that combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. <50%) as a potential mechanism of TBX6-associated CVMs. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found that 10 (9.3%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. For in vivo functional verification and genetic analysis of TBX6 compound inheritance, we generated both null and hypomorphic mutations in mouse Tbx6 using the CRISPR-Cas9 method. These Tbx6 mutants are not identical to the patient variants at the DNA sequence level, but instead functionally mimic disease-associated TBX6 variants. Intriguingly, as anticipated by the compound inheritance model, a high penetrance of CVM phenotype was only observed in the mice with combined null and hypomorphic alleles of Tbx6. These findings are consistent with our experimental observations in humans and supported the dosage effect of TBX6 in CVM etiology. In conclusion, our findings in the newly collected human CVM subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVMs, potentially via a gene dosage-dependent mechanism. Furthermore, mouse Tbx6 mutants mimicking human CVM-associated variants will be useful models for further mechanistic investigations of CVM pathogenesis in the cases associated with TBX6.

Increased hemoglobin and heme in MALDI-TOF MS analysis induce ferroptosis and promote degeneration of herniated human nucleus pulposus.

BACKGROUND: Neovasculogenesis is characteristic of herniated lumbar discs, in which extruded nucleus pulposus is prone to heme iron-induced cytotoxicity (increased oxidative stress causing ferroptosis). However, recent analyses of neovascularization are very complicated, and the mechanism of action is rarely reported. METHODS: Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) was performed to analyze human herniated and nonherniated nucleus pulposus. Then, the clinical relevance of the MALDI-TOF MS results and Pfirrmann classification of the degenerative nucleus pulposus were analyzed. To explore the mechanism, the heme-induced ferroptosis effect was evaluated at both the tissue and cell levels using high-resolution MALDI-TOF MS and molecular biology methods. RESULTS: The spectra revealed that hemoglobin (Hb) and heme signals were greatly increased, thus serving as predictors of vasculogenesis in herniated nucleus pulposus. The clinical relevance analysis demonstrated that the intensity of Hb and heme peaks was closely related to the Pfirrmann classification of degenerative nucleus pulposus. Mechanistically, increased heme catabolism and downregulation of glutathione peroxidase 4 (GPX4) levels were detected in herniated nucleus pulposus, reflecting iron-dependent cell death or ferroptosis. Iron levels was also increased in herniated nucleus pulposus compared with that in nonherniated nucleus pulposus. Furthermore, accuracy mass measurements confirmed that the levels of ferroptosis-related metabolites, such as glutathione, arachidonic acid (AA), sphinganine, polyunsaturated fatty acid (PUFA), and tricarboxylic acid (TCA) cycle metabolites, were significantly different between herniated and nonherniated tissues, indicating that the interior of the herniated tissues is a pro-oxidant environment. Moreover, heme-induced ferroptosis was verified in human nucleus pulposus cells (HNPCs), and the underlying mechanism might be associated with the Notch pathway. CONCLUSIONS: Neovascularization in herniated nucleus pulposus may expose tissues to high levels of heme, which can induce cytotoxicity and ferroptosis within tissues and accelerate the progressive degeneration of herniated nucleus pulposus. This study is beneficial for understanding the pathological mechanism of herniated nucleus pulposus and facilitating the development of nonoperative interventions for treating lumbar disc herniation (LDH).

Long noncoding RNA AC092155 facilitates osteogenic differentiation of adipose-derived stem cells through the miR-143-3p/STMN1 axis.

BACKGROUND: Numerous studies have demonstrated that long noncoding RNAs (lncRNAs) induce osteogenesis in adipose-derived stem cells (ADSCs). This study aimed to explore the role of lncRNAs AC092155 in promoting osteogenic differentiation of ADSCs. METHODS: MicroRNA (miRNA) and lncRNA sequencing were performed in ADSCs that underwent normal or osteogenic induction. Differentially expressed miRNAs and lncRNAs were identified using R software. The relative expression levels of lncRNA AC092155, miR-143-3p, and STMN1 during the process of osteogenic induction were determined by real-time polymerase chain reaction (RT-PCR). ADSCs were then transfected with agomiR-143-3p and pcDNA3.1-sh-lncRNA AC092155. Alkaline phosphatase (ALP) and alizarin red staining (ARS) were used to confirm the regulatory function of the lncRNA AC092155/miR-143-3p/STMN1 axis in osteogenic differentiation of ADSCs. RESULTS: lncRNA AC092155 was significantly upregulated in ADSCs following induction in the osteogenic medium. lncRNA AC092155 and STMN1 mimics increase the markers of osteogenic differentiation in the early and late phases, which was reflected in increased ALP activity as well as the higher deposition of calcium nodules. An miR-143-3p mimic showed the opposite effect. Luciferase reporter gene analysis demonstrated that lncRNA AC092155 directly targets miR-143-3p. Moreover, the lncRNA AC092155/miR-143-3p/STMN1 regulatory axis was found to activate the Wnt/ß-catenin signaling pathway. CONCLUSIONS: lncRNA AC092155 contributes to the osteogenic differentiation of ADSCs. The lncRNA AC092155/miR-143-3p/STMN1 axis may be a new therapeutic target for bone-related diseases.

Increased TBX6 gene dosages induce congenital cervical vertebral malformations in humans and mice.

BACKGROUND: Congenital vertebral malformations (CVMs) manifest with abnormal vertebral morphology. Genetic factors have been implicated in CVM pathogenesis, but the underlying pathogenic mechanisms remain unclear in most subjects. We previously reported that the human 16p11.2 BP4-BP5 deletion and its associated TBX6 dosage reduction caused CVMs. We aim to investigate the reciprocal 16p11.2 BP4-BP5 duplication and its potential genetic contributions to CVMs. METHODS AND RESULTS: Patients who were found to carry the 16p11.2 BP4-BP5 duplication by chromosomal microarray analysis were retrospectively analysed for their vertebral phenotypes. The spinal assessments in seven duplication carriers showed that four (57%) presented characteristics of CVMs, supporting the contention that increased TBX6 dosage could induce CVMs. For further in vivo functional investigation in a model organism, we conducted genome editing of the upstream regulatory region of mouse Tbx6 using CRISPR-Cas9 and obtained three mouse mutant alleles (Tbx6up1 to Tbx6up3 ) with elevated expression levels of Tbx6. Luciferase reporter assays showed that the Tbx6up3 allele presented with the 160% expression level of that observed in the reference (+) allele. Therefore, the homozygous Tbx6up3/up3 mice could functionally mimic the TBX6 dosage of heterozygous carriers of 16p11.2 BP4-BP5 duplication (approximately 150%, ie, 3/2 gene dosage of the normal level). Remarkably, 60% of the Tbx6up3/up3 mice manifested with CVMs. Consistent with our observations in humans, the CVMs induced by increased Tbx6 dosage in mice mainly affected the cervical vertebrae. CONCLUSION: Our findings in humans and mice consistently support that an increased TBX6 dosage contributes to the risk of developing cervical CVMs.

An open-label randomized multi-Centre study to evaluate anterior controllable Antedisplacement and fusion versus posterior Laminoplasty in patients with cervical ossification of the posterior longitudinal ligament: study design and analysis plan (STAR).

BACKGROUND: In treating patients with cervical ossification of the posterior longitudinal ligament (COPLL), a novel surgery technique - anterior controllable antedisplacement and fusion (ACAF) suggested promising clinical benefits in recent exploratory studies. METHODS: This is a multicentre, randomized, open-label, parallel-group, active controlled trial that will compare the clinical benefits of ACAF versus conventional posterior laminoplasty (LAMP) in severe COPLL patients. A total of 164 patients will be enrolled and randomized in a 1:1 ratio to either ACAF or LAMP group. The primary efficacy measure is cervical- Japanese Orthopaedic Association (C-JOA) recovery rate at 12 months post operation, which is to be derived by Hirabayashi's method from JOA data (range, 0 [worst] to 17 [normal condition]). Other important secondary efficacy endpoints include visual analogue scale (VAS) pain score (range, 0 [no pain] to 10 [most severe]), 10-item neck disability index (NDI, a total range of 0 to 50 points, the highest index the worst) and 6-level Nurick disability grade (range, 0 [mild] to 5 [severe]). Safety endpoints including adverse events, perioperative complications, and adverse events of special interest will also be assessed in this study. Full analysis set for baseline and efficacy data analyses according to the intention-to-treat principle will be established as the primary analysis population. Analysis of covariance (ANCOVA) will be used to analyze the C-JOA recovery rate, with random stratification factors (if appropriate) and the treatment group as fixed factors, and the baseline level of C-JOA score as covariate. DISCUSSION: This study is designed to demonstrate the clinical benefits of ACAF as compared to conventional LAMP in COPLL patients. It will provide clinical evidence that the novel surgery technique - ACAF might be more favorable in treating patients with severe cervical ossification of the posterior longitudinal ligament. (Words: 290). TRIAL REGISTRATION: ClinicalTrials.gov number, NCT04968028 .

Clinical impact and imaging results after a modified procedure of ACDF: a prospective case-controlled study based on ninety cases with two-year follow-up.

STUDY DESIGN: This is a prospective case-controlled study. BACKGROUND: To analyze the postoperative axial pain and cage subsidence of patients presenting with cervical spondylotic myelopathy (CSM) after a modified procedure of ACDF (mACDF). METHODS: Ninety patients with CSM were prospectively collected from 2014 to 2018. The patients were divided into spread group and non-spread group (48:42 ratio) according to the cage placement with or without releasing the Caspar cervical retractor after decompression. Spread group received conventional ACDF and non-spread group received mACDF. Patients were followed-up for at least 24 months after surgery. Radiologic data, including height of intervertebral space and Cobb Angle, were collected. Nervous system function was obtained using JOA scores, and level of pain was assessed using VAS scores. RESULTS: A total of 90 patients were enrolled and the patients were divided into spread group (n = 48) and none-spread group(n = 42). Cage subsidence of (spread group vs none-spread group) was (0.82 ± 0.68 vs 0.58 ± 0.81) mm, (0.64 ± 0.77 vs 0.34 ± 0.46) mm, (0.48 ± 0.43 vs 0.25 ± 0.28) mm, and (0.45 ± 0.47 vs 0.17 ± 0.32) mm at 3 months, 6 months, 12 months and 24 months, respectively. The period exhibiting the most decrease of the height of intervertebral space was 3 months postoperatively. However, there was no statistical difference in the height of intervertebral space, JOA or VAS scores at the final follow-up between the two groups. CONCLUSIONS: The mACDF can avoid excessive distraction by releasing the Caspar Cervical retractor, restore the "natural height" of cervical vertebra, relieve immediate pain after surgery, and prevent rapid Cage subsidence and the loss of cervical curvature.

Expression of Nogo-A in dorsal root ganglion in rats with cauda equina injury.

OBJECTIVE: To investigate the expression of Nogo-A in dorsal root ganglion (DRG) in rats with cauda equina injury and the therapeutic effects of blocking Nogo-A and its receptor. METHODS AND MATERIALS: Fifty-eight male Sprague-Dawley rats were divided randomly into either the sham operation group (n = 24) or the cauda equina compression (CEC) control group (n = 34). Behavioral, histological, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were conducted to assess the establishment of the model. The dynamic expression change of Nogo-A was evaluated using real time-qPCR. Immunofluorescence was used to evaluate the expression of Nogo-A in the DRG and cauda equina. Furthermore, 20 male Sprague-Dawley rats were equally divided into 4 groups, including the sham group, the CEC group, the NEP1-40 (the NgR antagonist peptide) treatment group, and the JTE-013 (the S1PR2 antagonist) treatment group. Behavioral assessments and western blotting were used to evaluate the therapeutic effect of cauda equina injury via blocking Nogo-A and its receptor. RESULTS: Tactile allodynia and heat hyperalgesia in the CEC model developed as soon as 1 day after surgery and recovered to normal at 7 days, which was followed by the downregulation of Nogo-A in DRG neurons. However, the locomotor function impairment in the CEC model showed a different prognosis from the sensory function, which was consistent with the expression change of Nogo-A in the spinal cord. Immunofluorescence results also demonstrated that Nogo A-positive/NF200-negative neurons and axons increased in the DRG and cauda equina 7 days after surgery. Surprisingly, Schwann cells, which myelinate axons in the PNS, also expressed considerable amounts of Nogo-A. Then, after blocking the Nogo-A/NgR signaling pathway by NEP1-40, significant improvement of mechanical allodynia was identified in the first 2 days after the surgery. Western blotting suggested the NEP1-40 treatment group had lower expression of cleaved caspase-3 than the CEC and JTE-013 treatment group. CONCLUSION: Neuronal Nogo-A in the DRG may be involved in regeneration and play a protective role in the CEC model. Whereas Nogo-A, released from the injured axons or expressed by Schwann cells, may act as an inhibiting factor in the process of CEC repairment. Thus, blocking the Nogo-A/NgR signaling pathway can alleviate mechanical allodynia by apoptosis inhibition.

Analysis of the spinal cord angle for severe cervical ossification of the posterior longitudinal ligament: comparison between anterior controllable antedisplacement and fusion (ACAF) and posterior laminectomy.

OBJECTIVE: To investigate the changes of spinal cord angle between anterior controllable antedisplacement and fusion (ACAF) and posterior laminectomy in treating severe ossification of the posterior longitudinal ligament (OPLL). PATIENTS AND METHODS: Seventy-one patients with cervical OPLL were enrolled. Patients in this study were divided into group A and group P. Japanese Orthopaedic Association (JOA) score was utilized to evaluate the neurological function. Radiological assessments included the spinal cord angle, Cobb angle, and area of the spinal cord. Surgery-related complications were also recorded. RESULTS: At the final follow-up, patients in group A had better recovery of local and whole cord angle, and the area of the cord than those in group P (all p < 0.05). A strong correlation between the change of local cord angle and the recovery of the spinal cord area was observed (r = - 0.867, p < 0.05). In addition, patients in group P had worse Cobb angle (9.15° ± 1.10°) than in group A (18.58° ± 0.73°) (p < 0.05). The final mean JOA score and its improvement rate were better in the group A than in group P (p < 0.05). During the follow-up, 15.15% patients in group P experienced surgery-related complications and 7.89% in group A. CONCLUSION: This present study revealed that ACAF can achieve better recovery of the expansion of the spinal cord, spinal cord alignment, and Cobb angle, with better postoperative JOA score and less complications, compared with posterior laminectomy in treating severe cervical OPLL. These slides can be retrieved under Electronic Supplementary Material.

Reliability and validity of multi-shot DWI in diagnosis of cervical spondylotic myelopathy: a study based on 3-T MRI.

OBJECTIVE: To investigate whether multi-shot diffusion-weighted imaging (ms-DWI) could be applied in diagnosis and quantitative evaluation of cervical spondylotic myelopathy (CSM). METHODS: Thirty-three normal volunteers and 78 patients with CSM were included in this study. The apparent diffusion coefficient (ADC) values were measured at C2-C7 levels on sagittal section ADC map. The intraclass correlation coefficient (ICC) and Bland and Altman plot and Spearman coefficient were used to quantify the reproducibility of test and retest and inter-rater reliability. Pearson correlations were calculated to compare lADC and rADC versus mJOA and NDI scores. Receiver operating characteristic curve and the area under the curve (AUC) were applied to evaluate the diagnostic reliability. RESULTS: There was no statistically significant difference between ADC values obtained from normal volunteers at C2-C7 levels (P < 0.05). The ICC and spearman coefficient of lADC and rADC indicated excellent test-retest and inter-rater reliability. The mean lADC and rADC were significantly higher from patients than that from volunteers (all P < 0.01). The lADC had moderate to good correlations with mJOA and NDI (all P < 0.0001). Moreover, rADC had good to excellent correlations with mJOA and NDI (all P < 0.0001). Comparing AUCs, rADC was significantly superior in diagnosis which participants were CSM than lADC (P = 0.0118). CONCLUSION: The ms-DWI could be applied in diagnosis and quantitive assessment of CSM according to lADC and rADC. A new parameter, rADC, could be served as a diagnostic indice for CSM, which may quantitively reflect the severity of CSM. These slides can be retrieved under Electronic Supplementary Material.