The Radiological Characteristics of Degenerative Cervical Kyphosis with Cervical Spondylotic Myelopathy.

Introduction: In this study, we aim to describe the radiological characteristics of degenerative cervical kyphosis (DCK) with cervical spondylotic myelopathy (CSM) and discuss the relationship between DCK and the pathogenesis of spinal cord dysfunction. Methods: In total, 90 patients with CSM hospitalized in our center from September 2017 to August 2022 were retrospectively examined in this study; they were then divided into the kyphosis group and the nonkyphosis group. The patients' demographics, clinical features, and radiological data were obtained, including gender, age, duration of illness, cervical Japanese Orthopaedic Association (JOA) score, cervical lordosis (CL), height of intervertebral space, degree of wedging vertebral body, degree of osteophyte formation, degree of disc herniation, degree of spinal cord compression, and anteroposterior diameter of the spinal cord. In the kyphosis group, kyphotic segments, apex of kyphosis, and segmental kyphosis angle were recorded. Radiological characteristics between the two groups were also compared. Correlation analysis was performed for different spinal cord compression types. Results: As per our findings, the patients in the kyphosis group showed more remarkable wedging of the vertebral body, more severe anterior compression of the spinal cord, and a higher degree of disc herniation, while the posterior compression of the spinal cord was relatively mild when compared with the nonkyphosis group. CL was related to the type of spinal cord compression, as cervical kyphosis is an independent risk factor for anterior spinal cord compression. Conclusions: DCK might play a vital role in the pathogenesis of spinal cord dysfunction. In patients with DCK, it was determined that the anterior column is less supported, and more severe anterior spinal cord compression is present. The anterior approach is supposed to be preferred for CSM patients with DCK.

HIF-1α-induced expression of the m6A reader YTHDF1 inhibits the ferroptosis of nucleus pulposus cells by promoting SLC7A11 translation.

The nucleus pulposus is in a hypoxic environment in the human body, and when intervertebral disc degeneration (IVDD) occurs, the hypoxic environment is disrupted. Nucleus pulposus cell (NPC) ferroptosis is one of the causes of IVDD. N6-methyladenosine (m6A) and its reader protein YTHDF1 regulate cellular activities by affecting RNA metabolism. However, the regulation of ferroptosis in NPCs by m6A-modified RNAs under hypoxic conditions has not been as well studied. In this study, through in vitro and in vivo experiments, we explored the underlying mechanism of HIF-1α and YTHDF1 in regulating ferroptosis in NPCs. The results indicated that the overexpression of HIF-1α or YTHDF1 suppressed NPC ferroptosis; conversely, the knockdown of HIF-1α or YTHDF1 increased ferroptosis levels in NPCs. Luciferase reporter assays and chromatin immunoprecipitation demonstrated that HIF-1α regulated YTHDF1 transcription by directly binding to its promoter region. Polysome profiling results showed that YTHDF1 promoted the translation of SLC7A11 and consequently the expression of the anti-ferroptosis protein GPX4 by binding to m6A-modified SLC7A11 mRNA. In conclusion, HIF-1α-induced YTHDF1 expression reduces NPC ferroptosis and delays IVDD by promoting SLC7A11 translation in a m6A-dependent manner.

ROS-Responsive Injectable Hydrogel Loaded with SLC7A11-modRNA Inhibits Ferroptosis and Mitigates Intervertebral Disc Degeneration in Rats.

Intervertebral disc degeneration (IVDD) is the primary cause of low back pain, with oxidative stress being a recognized factor that causes its development. Presently, low back pain imposes a significant global economic burden. However, the effectiveness of treatments for IVDD remains extremely limited. Therefore, this study aims to explore innovative and effective IVDD treatments by focusing on oxidative stress as a starting point. In this study, an injectable reactive oxygen species-responsive hydrogel (PVA-tsPBA@SLC7A11 modRNA) is developed, designed to achieve rapid loading and selective release of chemically synthesized modified mRNA (modRNA). SLC7A11 modRNA is specifically used to upregulate the expression of the ferroptosis marker SLC7A11. The local injection of PVA-tsPBA@SLC7A11 modRNA into the degenerated intervertebral disc (IVD) results in the cleavage of PVA-tsPBA, leading to the release of enclosed SLC7A11 modRNA. The extent of SLC7A11 modRNA release is directly proportional to the severity of IVDD, ultimately ameliorating IVDD by inhibiting ferroptosis in nucleus pulposus cells (NPCs). This study proposes an innovative system of PVA-tsPBA hydrogel-encapsulated modRNA, representing a potential novel treatment strategy for patients with early-stage IVDD.

Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission.

BACKGROUND: Cartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), is characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead to apoptosis during CEP degeneration and IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis and IVDD. Despite their major success in drug delivery, the full potential of exosomes remains untapped. MATERIALS AND METHODS: In vitro and in vivo models of CEP degeneration were established by using lipopolysaccharide (LPS). We designed genetically engineered exosomes (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on the surface and carrying the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). The affinity between CAP-Nrf2-Exos and CEP was evaluated by in vitro internalization assays and in vivo imaging assays. qRT‒PCR, Western blotting and immunofluorescence assays were performed to examine the expression level of Nrf2 and the subcellular localization of Nrf2 and Drp1. Mitochondrial function was measured by the JC-1 probe and MitoSOX Red. Mitochondrial morphology was visualized by MitoTracker staining and transmission electron microscopy (TEM). After subendplate injection of the engineered exosomes, the degree of CEP degeneration and IVDD was validated radiologically and histologically. RESULTS: We found that the cargo delivery efficiency of exosomes after cargo packaging was increased by surface modification. CAP-Nrf2-Exos facilitated chondrocyte-targeted delivery of Nrf2 and activated the endogenous antioxidant defence system in CEP cells. The engineered exosomes inhibited Drp1 S616 phosphorylation and mitochondrial translocation, thereby preventing mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was alleviated by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, the engineered exosomes successfully attenuated CEP degeneration and IVDD and exhibited better repair capacity than natural exosomes. CONCLUSION: Collectively, our findings showed that exosome-mediated chondrocyte-targeted delivery of Nrf2 was an effective strategy for treating CEP degeneration.

A Study on Interobserver and Intraobserver Reliability of the Huashan Radiologic Classification System for Cervical Spinal Cord Injury Without Fracture and Dislocation.

STUDY DESIGN: Observational study. OBJECTIVE: To assess the reproducibility and reliability of the system. BACKGROUND: The Huashan radiologic classification system for cervical spinal cord injury without fracture and dislocation (CSCIWFD) was recently proposed and found useful for clinical practice. PATIENTS AND METHODS: Patients diagnosed with CSCIWFD between 2015 and 2021 were recruited. Six spine surgeons from different institutions, three experienced and other inexperienced respectively, were trained as observers of the system, and these surgeons classified the recruited patients using the system. Then, 8 weeks later, they repeated the classification on the same patients in a different order. The interobserver and intraobserver agreement between the results was analyzed using percentage agreement, weighted kappa, and Cohen kappa (κ) statistics. RESULTS: A total of 60 patients were included in the analysis. Type I was the most frequent type (29 cases, 48.3%), followed by type II (13 cases, 21.7%), type III (12 cases, 20%), and type IV (6 cases, 10%). For all the observers, experienced observers, and inexperienced observers, the overall agreement percentages were 77.6% (κ = 0.78), 84.4% (κ = 0.84), and 72.8% (κ = 0.74), respectively, indicating substantial to nearly perfect interobserver reproducibility. A higher level of agreement was found for differentiating type I from other types, with the percentage agreement ranging from 87.8% to 94.4% (κ= 0.74-0.88). For distinguishing compression on the spinal cord (types I and II vs types III and IV) among the different groups of observers, the percentage agreement was 97.8% (κ = 0.94), indicating nearly perfect reproducibility. As for intraobserver agreement, the percentage agreement ranged from 86.7% to 96.7% (κ = 0.78-0.95), indicating at least substantial reliability. CONCLUSIONS: The Huashan radiologic classification system for CSCIWFD was easy to learn and apply in a clinical environment, showing excellent reproducibility and reliability. Therefore, it would be promising to apply and promote this system for the precise evaluation and personalized treatment strategy.

A Novel Cervical Sagittal Classification for Asymptomatic Population Based on Cluster Analysis.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To propose a novel cervical sagittal classification for asymptomatic people so as to deepen the understanding of cervical sagittal alignment. SUMMARY OF BACKGROUND DATA: Cervical spine sagittal morphology varies in people. There is a lack of widely-accepted cervical sagittal classification method. METHODS: In all, 183 asymptomatic subjects were included. A series of global and segmental cervical sagittal parameters were measured. Subjects with cervical lordosis (CL)<0 degrees were incorporated directly into the kyphosis (K) group. For subjects with CL ≥0 degrees, a two-step cluster analysis was used to arrive at the optimal number of clusters. The results of the expressions for the subtypes were derived by graphing. The 60 randomly selected lateral cervical spine films were evaluated by 4 spine surgeons at 4-week intervals using our classification method, the Toyama classification method and the Donk classification method. The 3 classification methods' reliability was expressed by the intra-group correlation coefficient (ICC), and convenience was expressed by the measuring time. Finally, the distribution of 4 subtypes was depicted, and sagittal parameters were compared among subtypes. RESULTS: Four subtypes of the cervical spine were suggested: Large lordosis (LL): CL≥-1.5×T1 slope (TS)+70°; Small lordosis (SL): -1.5×TS+50°≤CL<-1.5×TS+70°; Straight (S): 0°≤CL<-1.5×TS+50°; and K: CL<0°. The measuring time for our classification method was significantly less than the Toyama classification method (P<0.001). Our classification method showed high inter-observer reliability (ICC=0.856) and high to excellent intra-observer reliability (ICC between 0.851 and 0.913). SL was the most common type (37.7%). Men had more LL type and women had more S type and K type. The proportion of S and K increased with age. Cervical sagittal parameters were significantly different among the subtypes except for C4 vertebral body (VB) angle (P=0.546), C2-C7 SVA (P=0.628) and NT (P=0.816). CONCLUSIONS: We proposed a novel cervical sagittal classification for an asymptomatic population, which proved to be simple to implement with satisfactory reliability.

Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response.

Osteoarthritis (OA) progression is highly associated with chondrocyte mitochondrial dysfunction and disorders of catabolism and anabolism of the extracellular matrix (ECM) in the articular cartilage. The mitochondrial unfolded protein response (UPRmt), which is an integral component of the mitochondrial quality control (MQC) system, is essential for maintaining chondrocyte homeostasis. We successfully validated the pivotal role of activating transcription factor 5 (ATF5) in upregulating the UPRmt, mitigating IL-1ß-induced inflammation and mitochondrial dysfunction, and promoting balanced metabolism in articular cartilage ECM, proving its potential as a promising therapeutic target for OA. Modified mRNAs (modRNAs) have emerged as novel and efficient gene delivery vectors for nucleic acid therapeutic approaches. In this study, we combined Atf5-modRNA (modAtf5) with engineered exosomes derived from bone mesenchymal stem cells (ExmodAtf5) to exert cytoprotective effects on chondrocytes in articular cartilage via Atf5. However, the rapid localized metabolization of ExmodAtf5 limits its application. PLGA-PEG-PLGA (Gel), an injectable thermosensitive hydrogel, was used as a carrier of ExmodAtf5 (Gel@ExmodAtf5) to achieve a sustained release of ExmodAtf5. In vitro and in vivo, the use of Gel@ExmodAtf5 was shown to be a highly effective strategy for OA treatment. The in vivo therapeutic effect of Gel@ExmodAtf5 was evidenced by the preservation of the intact cartilage surface, low OARSI scores, fewer osteophytes, and mild subchondral bone sclerosis and cystic degeneration. Consequently, the combination of ExmodAtf5 and PLGA-PEG-PLGA could significantly enhance the therapeutic efficacy and prolong the exosome release. In addition, the mitochondrial protease ClpP enhanced chondrocyte autophagy by modulating the mTOR/Ulk1 pathway. As a result of our research, Gel@ExmodAtf5 can be considered to be effective at alleviating the progression of OA.

Evaluation of the modified MRI vertebral bone quality score for bone quality in lumbar degenerative disorders.

OBJECTIVE: The traditional VBQ scoring method may lead to overestimation due to the concentration of intravertebral fat and vascular structures in the posterior half of vertebral bodies, potentially resulting in false-positive outcomes. This study aims to modify the measurement method of VBQ score (Modified-VBQ) and evaluate its effectiveness in evaluating bone quality of lumbar degenerative diseases. METHODS: Retrospective analysis was conducted on clinical data from patients undergoing lumbar surgery for degenerative diseases between September 2022 and September 2023. Preoperative lumbar t1-weighted Magnetic resonance imaging was used for both modified and traditional VBQ scoring. Computed tomography (CT) images and dual-energy X-ray absorptiometry (DEXA) data were collected through the picture archiving and communication system. The effectiveness of the modified VBQ score was evaluated, considering P < 0.05 as statistically significant. RESULTS: The study included 212 patients, revealing a significant difference between the modified VBQ and VBQ scores (P < 0.0001). Notably, patients with a history of hyperlipidemia exhibited a significant difference between the two scores (P = 0.0037). The area under the ROC curve (AUC) for the modified VBQ was 0.86, surpassing the VBQ score (AUC = 0.74). Linear regression analysis demonstrated a moderate to strong correlation between the modified VBQ and DEXA T-score (r = - 0.49, P < 0.0001) and a high correlation with CT Hounsfield units (HU) values (r = - 0.60, P < 0.0001). CONCLUSION: The modified VBQ score provides a simple, effective, and relatively accurate means of assessing bone quality in lumbar degenerative diseases. Preoperative implementation of the modified VBQ score facilitates rapid screening for patients with abnormal bone quality.

Establishment of the Lunar Phase Morphological Classification for Cervical Spinal Canal.

STUDY DESIGN: Retrospective clinical trial. PURPOSE: To establish a morphological classification of the cervical spinal canal using its parameters. OVERVIEW OF LITERATURE: Cervical spine computed tomography (CT) data of 200 healthy volunteers in 2 years were analyzed. The morphology of the spinal cord was also analyzed. METHODS: The median sagittal diameter and transverse diameter of the spinal canal from C2 to C7 were measured on CT images. The ratio of the median sagittal diameter to the transverse diameter was calculated. Accordingly, the spinal canal shape of each segment was classified into four, and the specific criteria of lunar phase classification were determined through linear discriminant analysis based on the ratio of the median sagittal diameter to the transverse diameter. The inter-rater reliability of the classification was explored using Kappa coefficients. Finally, the morphology of the different segments of the cervical spinal canal in healthy volunteers was revised and compared. RESULTS: According to the ratio of the median sagittal diameter and the transverse diameter of the cervical spinal canal, the lunar phase classification of the cervical bony spinal canal was determined as follows: full-moon >0.65, 0.55< convex-moon ≤0.65, 0.46≤ quarter-moon ≤0.55, and residual-moon <0.46. The Kappa values of C2-C7 were 0.851, 0.958, 0.823, 0.927, 0.793, and 0.946, and the Kappa value of all C2-C7 segments was 0.854 that mainly presented two forms of full-moon (76.5%) and convex-moon (23.0%). A quarter-moon spinal canal was mainly distributed in C3, C4, C5, and C6; a residual-moon spinal canal was mainly distributed in C4 and C5; and the morphological distribution of C4 and C5 were similar (p>0.05). The frequency of the spinal canal of the residual-moon type was the highest, and the full-moon (6.5%) and residual-moon (7.5%) types of C7 were rare. CONCLUSIONS: The morphological classification of the cervical spinal canal was established to present anatomical variations. The classification showed good inter-rater reliability.

C4 constant vertebra: a novel benchmark of physiological cervical sagittal alignment.

BACKGROUND: Cervical sagittal alignment is essential, and there is considerable debate as to what constitutes physiological sagittal alignment. The purpose of this study was to identify constant parameters for characterizing cervical sagittal alignment under physiological conditions. METHODS: A cross-sectional study was conducted in which asymptomatic subjects were recruited to undergo lateral cervical spine radiographs. Each subject was classified according to three authoritative cervical sagittal morphology classifications, followed by the evaluation of variations in radiological parameters across morphotypes. Moreover, the correlations among cervical sagittal parameters, age, and cervicothoracic junction parameters were also investigated. RESULTS: A total of 183 asymptomatic Chinese subjects were enrolled with a mean age of 48.4 years. Subjects with various cervical sagittal morphologies had comparable C4 endplate slope angles under all three different typing systems. Among patients of different ages, C2-C4 endplate slope angles remained constant. Regarding the cervicothoracic junction parameters, T1 slope and thoracic inlet angle affected cervical sagittal parameters, including cervical lordosis and C2-7 sagittal vertical axis, and were correlated with the endplate slope angles of C5 and below and did not affect the endplate slope angles of C4 and above. In general, the slope of the C4 inferior endplate ranges between 13° and 15° under different physiological conditions. CONCLUSIONS: In the asymptomatic population, the C4 vertebral body maintains a constant slope angle under physiological conditions. The novel concept of C4 as a constant vertebra would provide a vital benchmark for diagnosing pathological sagittal alignment abnormalities and planning the surgical reconstruction of cervical lordosis.

MSC-Derived Exosomes Ameliorate Intervertebral Disc Degeneration By Regulating the Keap1/Nrf2 Axis.

Bone marrow mesenchymal stem cell derived exosomes (BMSC-exos) are a crucial means of intercellular communication and can regulate a range of biological processes by reducing inflammation, decreasing apoptosis and promoting tissue repair. The process of intervertebral disc degeneration (IVDD) is accompanied by increased reactive oxygen species (ROS) because of a decrease in the expression of Nrf2, a critical transcription factor that resists excessive ROS. Our study demonstrated that BMSC-exos decreased ROS production by inhibiting Keap1 and promoting Nrf2 expression, attenuating the apoptosis, inflammation, and degeneration of nucelus pulposus (NP) cells. BMSC-exos promoted an increase in Nrf2 and nuclear translocation, while NF-κB expression was downregulated during this process. Additionally, the expression of antioxidative proteins was elevated after treatment with BMSC-exos. In vivo, we found more NP tissue retention in the BMSC-exos-treated group, along with more expression of Nrf2 and antioxidant-related proteins. Our findings demonstrated for the first time that BMSC-exos could restore the down-regulated antioxidant response system in degenerating NP cells by modulating the Keap1/Nrf2 axis. BMSC-exos could be used as an immediate ROS modulator in the treatment of intervertebral disc degeneration. When BMSC-exos were uptaken by NPCs, the expression of Keap1 decreased and this led to increased expression of Nrf2. Nuclear translocation of Nrf2 then promoted the synthesis of antioxidants against ROS and inhibited NF-kB signalling. Cellular inflammation, apoptosis, and ECM-related indicators were further reduced. Together, the process of IVDD was alleviated.

N6-methyladenosine hypomethylation of circGPATCH2L regulates DNA damage and apoptosis through TRIM28 in intervertebral disc degeneration.

Circular RNAs (circRNAs) are a class of noncoding RNAs that have been found to be involved in intervertebral disc degeneration (IVDD) progression, and N6-methyladenosine (m6A) broadly exists in circRNAs. Here, we identified circGPATCH2L with a low m6A methylation level to be upregulated in degenerative nucleus pulposus tissues. Mechanistically, as a protein decoy for tripartite motif containing 28 (TRIM28) within aa 402-452 region, circGPATCH2L abrogates the phosphorylation of TRIM28 and inhibits P53 degradation, which contributes to DNA damage accumulation and cellular apoptosis and leads to IVDD progression. Moreover, m6A-methylated circGPATCH2L is recognised and endoribonucleolytically cleaved by a YTHDF2-RPL10-RNase P/MRP complex to maintain the physiological state of nucleus pulposus cells. Thus, our data show the physiological significance of m6A modification in regulating circRNA abundance and provide a potentially effective therapeutic target for the treatment of IVDD.

Use of MRI-based vertebral bone quality score (VBQ) of S1 body in bone mineral density assessment for patients with lumbar degenerative diseases.

PURPOSE: To evaluate the use of the modified and simplified vertebral bone quality (VBQ) method based on T1-weighted MRI images of S1 vertebrae in assessing bone mineral density (BMD) for patients with lumbar degenerative diseases. METHODS: We reviewed the preoperative data of patients with lumbar degenerative diseases undergoing lumbar spine surgery between January 2019 and June 2022 with available non-contrast T1-weighted magnetic resonance imaging (MRI), computed tomography (CT) images and dual-energy X-ray absorptiometry (DEXA). S1 vertebral bone quality scores (S1 VBQ) and S1 CT Hounsfield units were measured with picture archiving and communication system (PACS). One-way ANOVA was applied to present the discrepancy between the S1 VBQ of patients with normal bone density (T-score ≥ - 1.0), osteopenia (- 2.5 < T-score < - 1.0) and osteoporosis (T-score ≤ - 2.5). The receiver operating characteristic curve (ROC) was drawn to analyze the diagnostic performance of S1 VBQ in distinguishing low BMD. Statistical significance was set at p < 0.05. RESULTS: A total of 207 patients were included. The S1 VBQ were significantly different between groups (p < 0.001). Interclass correlation coefficient for inter-rater reliability was 0.86 (95% CI 0.78-0.94) and 0.94(95% CI 0.89-0.98) for intra-rater reliability. According to the linear regression analysis, the S1 VBQ has moderate-to-strong correlations with DEXA T-score (r = - 0.48, p < 0.001). The area under the ROC curve indicated a predictive accuracy of 82%. A sensitivity of 77.25% with a specificity of 70% could be achieved for distinguishing low BMD by setting the S1 VBQ cutoff as 2.93. CONCLUSIONS: The S1 VBQ was a promising tool in distinguishing poor bone quality in patients with lumbar degenerative diseases, especially in cases where the previously reported VBQ method based on L1-L4 was not available. S1 VBQ score could be useful as opportunistic assessment for screening and complementary evaluation to DEXA T-score before surgery.

Dihydroorotate dehydrogenase regulates ferroptosis in neurons after spinal cord injury via the P53-ALOX15 signaling pathway.

BACKGROUND: Spinal cord injury (SCI) is a highly disabling condition in spinal surgery that leads to neuronal damage and secondary inflammation. Ferroptosis is a non-apoptotic type of cell death that has only recently been identified, which is marked primarily by iron-dependent and lipid-derived reactive oxygen species accumulation, and accompanied by morphological modifications such as mitochondrial atrophy and increase in membrane density. Dihydroorotate dehydrogenase (DHODH) is a powerful inhibitor of ferroptosis and has been demonstrated to inhibit cellular ferroptosis in tumor cells, but whether it can inhibit neuronal injury following spinal cord injury remains ambiguous. METHODS: In this study, the effect of DHODH on neuronal ferroptosis was observed in vivo and in vitro using a rat spinal cord injury model and erastin-induced PC12 cells, respectively. A combination of molecular and histological approaches was performed to assess ferroptosis and explore the possible mechanisms in vivo and in vitro. RESULTS: First, we confirmed the existence of neuronal ferroptosis after spinal cord injury and that DHODH attenuates neuronal damage after spinal cord injury. Second, we showed molecular evidence that DHODH inhibits the activation of ferroptosis-related molecules and reduces lipid peroxide production and mitochondrial damage, thereby reducing neuronal ferroptosis. Further analysis suggests that P53/ALOX15 may be one of the mechanisms regulated by DHODH. Importantly, we determined that DHODH inhibits ALOX15 expression by inhibiting P53. CONCLUSIONS: Our findings reveal a novel function for DHODH in neuronal ferroptosis after spinal cord injury, suggesting a unique therapeutic target to alleviate the disease process of spinal cord injury.

Engineered exosomes enriched in netrin-1 modRNA promote axonal growth in spinal cord injury by attenuating inflammation and pyroptosis.

BACKGROUND: Spinal cord injury (SCI) brings a heavy burden to individuals and society, and there is no effective treatment at present. Exosomes (EX) are cell secreted vesicles containing molecules such as nucleic acids and proteins, which hold promise for the treatment of SCI. Netrin-1 is an axon guidance factor that regulates neuronal growth. We investigated the effects of engineered EX enriched in netrin-1 chemically synthetic modified message RNA (modRNA) in treating SCI in an attempt to find a novel therapeutic approach for SCI. METHODS: Netrin-1 modRNA was transfected into bone marrow mesenchymal stem cells to obtain EX enriched with netrin-1 (EX-netrin1). We built an inflammatory model in vitro with lipopolysaccharide (LPS) in vitro to study the therapeutic effect of EX-netrin1 on SCI. For experiments in vitro, ELISA, CCK-8 assay, immunofluorescence staining, lactate dehydrogenase release experiments test, real-time quantitative polymerase chain reaction, and western blot were conducted. At the same time, we constructed a rat model of SCI. MRI, hematoxylin-eosin and Nissl staining were used to assess the extent of SCI in rats. RESULTS: In vitro experiments showed that EX had no effect on the viability of oligodendrocytes and PC12 cells. EX-netrin1 could attenuate LPS-induced inflammation and pyroptosis and accelerate axonal/dentritic growth in PC12 cells/oligodendrocytes. In addition, netrin-1 could activate the PI3K/AKT/mTOR signalling pathway upon binding to its receptor unc5b. When Unc5b and PI3K were inhibited, the effect of EX-netrin1 was weakened, which could be reversed by PI3K or mTOR activator. Our in vivo experiments indicated that EX-netrin1 could promote recovery in rats with SCI. CONCLUSION: We found that EX-netrin1 regulated inflammation, pyroptosis and axon growth in SCI via the Unc5b/PI3K/AKT/mTOR pathway, which provides a new strategy for the treatment of SCI.

Sulforaphane Delays Intervertebral Disc Degeneration by Alleviating Endoplasmic Reticulum Stress in Nucleus Pulposus Cells via Activating Nrf-2/HO-1.

Intervertebral disc degeneration (IVDD) is one of the main causes of low back pain, which brings heavy burdens to individuals and society. The mechanism of IVDD is complex and diverse. One of the important reasons is that the abnormal accumulation of reactive oxygen species (ROS) in nucleus pulposus cells (NPCs) leads to endoplasmic reticulum stress (ERS), which causes increased apoptosis of NPCs. Nuclear factor E2-related factor 2 (Nrf-2) and its downstream antioxidant proteins are key molecular switches for sensing oxidative stress and regulating antioxidant responses in cells. Sulforaphane (SFN), a natural compound derived from Brassicaceae plants, is a Nrf-2 agonist that displays potent antioxidant potential in vitro and in vivo. Here, we used advanced glycation end products (AGEs) to construct an in vitro degeneration model of NPCs, and we found that AGEs elevated ROS level in NPCs and caused severe ERS and apoptosis. While SFN can promote the entry of Nrf-2 into the nucleus and increase the expression level of heme oxygenase 1 (HO-1) in vitro, thus clearing the accumulated ROS in cells and alleviating ERS and cell apoptosis. Moreover, the protection of SFN on NPCs was greatly attenuated after HO-1 was inhibited. We also used AGEs to construct a rat IVDD model. Consistent with the in vitro experiments, SFN could attenuate ERS in NPCs in vivo and delay disc degeneration in rats. This study found that SFN can be used as a new and promising agent for the treatment of IVDD.

Efficacy of Anterior Cervical Discectomy and Fusion for Female Patients with Hirayama Disease.

OBJECTIVE: To compare the preoperative and postoperative hand function and radiographic parameters in female patients with Hirayama disease (HD). METHODS: Consecutive female patients with HD undergoing anterior cervical discectomy and fusion were followed up. The postoperative hand functional data were obtained from the last follow-up, whereas the postoperative radiographic data were obtained from the examinations in 3- or 6-month follow-up after surgical treatments. The preoperative and postoperative data of hand functional and radiographic assessments were collected and compared between them. Logistic regression analysis was used to clear potential risk factors for surgical treatment. RESULTS: In all, 15 female patients with HD were included in the follow-up study over 9 years. Significant differences were found in total scores (P < 0.001) and all 6 dimensions, including function (P = 0.003), activities of daily life (P = 0.002), work (P = 0.003), satisfaction (P = 0.002), appearance (P = 0.005), and HD-specific hand symptoms (P = 0.001) in hand functional assessment. The comparison of C2-C7 Cobb angle was statistically different (P = 0.042) in radiographic assessments. The course of illness was of marginal significance (P = 0.065) with curative effect of surgical treatment in logistic regression analysis. CONCLUSIONS: Anterior cervical discectomy and fusion is an effective way to treat female patients with HD, and the course of illness may be correlated with the efficacy of surgery. For some female patients with HD with a clear diagnosis, early surgical treatment is worthy of clinical consideration.

The Influence of Roussouly Type on the Prevalence, Subtype, and Distribution Characteristics of Modic Changes in Patients with Lumbar Degenerative Disc Disease.

BACKGROUND: The relationship between Roussouly type and Modic changes (MC) is unknown. The aim of our study was to investigate the influence of Roussouly type on the characteristics of MC in patients with lumbar degenerative disc disease. METHODS: This cross-sectional observational study from Huashan Hospital included 270 patients with lumbar degenerative disc disease. Subjects were divided into 4 groups according to the Roussouly classification. Prevalence, subtype, and distribution characteristics of MC from L1-L2 upper end plate to L5-S1 lower end plate were compared between 4 Roussouly types. RESULTS: Of 270 patients, 65 (24.1%) were Roussouly type I, 115 (42.6%) were Roussouly type II, 55 (20.4%) were Roussouly type III, and 35 (13.0%) were Roussouly type IV. MC were present in 45.9% (n = 270) of patients, 12.7% (n = 2700) of end plates, and 11.8% (n = 1350) of intervertebral discs. The prevalence rate of MC by subtype and intervertebral disc among the 4 Roussouly types was statistically different (P < 0.05), and the prevalence rate of MC by intervertebral disc in Roussouly type I was statistically higher than the other 3 Roussouly types. In Roussouly types I and IV, the prevalence rate of MC at L4-L5 level showed no significant differences compared with those at upper lumbar levels, while in Roussouly types II and III, the prevalence rate of MC at L4-L5 level was significantly higher than those at upper lumbar levels. CONCLUSIONS: Roussouly types can influence prevalence, subtype, and distribution characteristics of MC in patients with lumbar degenerative disc disease.

Do patients with Hirayama disease require surgical treatment? A review of the literature.

The main clinic characteristic of Hirayama disease (HD) is atrophy of the distal muscles in the upper limbs. Recently, an increasing number of HD cases have been reported. Many HD patients have persistently progressive symptoms and conservative treatments failed. This article aims to review the current status of the field and summarizes the main surgical treatment options for patients with HD. A comprehensive search of the PubMed and the Web of Science databases was conducted from their inception to September 15th, 2022. Search terms included "juvenile muscular atrophy of upper extremity", "Hirayama disease" and "surgery". A total of 169 relevant publications were identified and 29 articles were finally reviewed. Current surgical treatments for HD are either anterior cervical surgery or posterior cervical surgery. The two approaches can effectively stop the disease. However, no studies have compared the advantages and limitations of the two surgical methods. The previous view that HD can be improved with conservative treatment has been challenged. In many studies, surgical treatment has been shown to improve the hand function in patients with HD. However, there is still controversy about the methods of anterior and posterior cervical surgery. Future research could focus on exploring the advantages and limitations of different surgeries.