Endoplasmic reticulum stress-mediated autophagy alleviates lipopolysaccharide-induced nucleus pulposus cell pyroptosis by inhibiting CHOP signaling in vitro.

Pyroptosis, a newly discovered pro-inflammatory programmed necrosis of cells, serves as an initiating and promoting event that leads to intervertebral disc (IVD) degeneration (IDD). Endoplasmic reticulum stress (ERS) and autophagy are vital regulatory mechanisms of cellular homeostasis, which is also closely related to IDD. However, the role and relationship of ERS and autophagy in the pyroptosis of nucleus pulposus cell (NPC) are not well understood. In this research, we aimed to elucidate the role and mechanism of ERS-C/EBP homologous protein (CHOP) in lipopolysaccharide (LPS)-induced cell pyroptosis and determine its interaction with autophagy. ERS and autophagy inducers or inhibitors were used or not in the preconditioning of rat NPCs. Cell viability, pyroptosis-related protein expression, caspase-1 activity assay, and enzyme-linked immunosorbent assay were performed to observe rat NPC pyroptosis after the treatment of LPS. Activation of the ERS pathway and autophagy were assessed by quantitative real-time PCR, western blot analyses, and immunofluorescence staining assay to classify the molecular mechanisms. Our results showed that LPS stimulation induced NPC pyroptosis with concomitant activation of the ERS-CHOP pathway and initiated autophagy. Activation of the ERS-CHOP pathway exacerbated rat NPC pyroptosis, whereas autophagy inhibited cell pyroptosis. LPS-induced cell pyroptosis and CHOP upregulation were negatively regulated by autophagy. LPS-induced autophagy was depressed by the ERS inhibitor but aggravated by the ERS inducer. Taken together, our findings suggested that LPS induced NPC pyroptosis by activating ERS-CHOP signaling and ERS mediated LPS-induced autophagy, which in turn alleviated NPC pyroptosis by inhibiting CHOP signaling.

Is unilateral-approach full-endoscopic lumbar fusion effective for single-level lumbar spondylolisthesis with bilateral symptoms? A preliminary report of 43 CT analysis.

PURPOSE: To investigate the clinical results and radiological parameters changes after unilateral-approach endoscopic lumbar interbody fusion (Endo-LIF) for lumbar spondylolisthesis with bilateral symptoms. METHODS: 43 single-level lumbar spondylolisthesis patients with bilateral lower limb symptoms were included from June 2020 to May 2022. All patients underwent unilateral-approach Endo-LIF and postoperative computed tomography. Radiological parameters including disk height (DH), degree of upper vertebral slip (DUVS), and foramen intervertebral parameters including bilateral foraminal height (FH), contralateral foraminal areas (FA) were evaluated. The clinical outcomes including low back pain and bilateral leg pain were evaluated using Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI) before and after surgery. RESULTS: All cases were successfully completed surgery and followed for average 15.16 ± 5.2 months. DH (44% ± 11%) and DUVS were significantly improvement postoperatively compared with preoperatively (p < 0.05). Statistically significant increases in bilateral FH (25% ± 11% on the surgical side, 17% ± 8% on the contralateral side) and contralateral FA (26% ± 6%) were observed (p < 0.05). The VAS and the ODI scores were significantly decreased in comparison with the preoperative scores (p < 0.05). CONCLUSION: Unilateral-approach with contralateral indirect decompression in Endo-LIF can acquire satisfactory clinical outcomes. Therefore, unilateral-approach Endo-LIF may be a promising option for lumbar spondylolisthesis with bilateral symptoms.

Instrumented fusion versus instrumented non-fusion following expansive open-door laminoplasty for multilevel cervical ossification of the posterior longitudinal ligament.

PURPOSE: To compare the outcomes of expansive open-door laminoplasty with instrumented fusion (ELIF) and expansive open-door laminoplasty with instrumented non-fusion (ELINF) for multilevel cervical ossification of the posterior longitudinal ligament (OPLL). METHODS: Patients who underwent ELIF or ELINF due to multilevel cervical OPLL from June 2013 to June 2019 were identified. Clinical and radiological outcomes were compared between the two groups. RESULTS: A total of 78 patients were enrolled in this study with a minimum follow-up of 24 months, including 42 patients in the ELIF group and 36 patients in the ELINF group. At the final follow-up, sagittal vertical axis (SVA) and C2-C7 Cobb angle in the ELIF group were significantly better than those in the ELINF group, and cervical range of movement (ROM) in the ELIF group decreased significantly than that in the ELINF group. The incidence of OPLL progression at the final follow-up was 4.76% (2/42) in the ELIF group and 27.78% (10/36) in the ELINF group. Postoperative Japanese Orthopaedic Association (JOA) score, neck disability index (NDI), and visual analog scale (VAS) score improved significantly in each group, but JOA score and recovery rate (RR) in the ELIF group were significantly better than those in the ELINF group at the final follow-up. When K-line was positive, the difference in the final JOA score between the two groups was not significant, but the RR in the ELIF group was significantly better than that in the ELINF group. When K-line was negative, the final JOA score and RR in the ELIF group were significant higher than those in the ELINF group. CONCLUSIONS: ELIF and ELINF were two effective surgical procedures for treating multilevel cervical OPLL. However, ELIF was superior to ELINF due to better postoperative JOA score and RR, significant improvement of C2-C7 Cobb angle and maintenance of SVA, and suppressant effect on OPLL progression, especially for patients with K-line ( - ) OPLL.

Unfolded protein response alleviates acid-induced premature senescence by promoting autophagy in nucleus pulposus cells.

Acid-induced cellular senescence is a critical underlying mechanism of intervertebral disc (IVD) degeneration (IDD). Acid stimulation activates a variety of biological changes including autophagy, endoplasmic reticulum stress, and related unfolded protein response (UPR), which are important regulators of cellular senescence. However, the precise mechanism of acid-mediated UPR and autophagy in nucleus pulposus cell (NPC) senescence has not been fully elucidated. In this study, we used acid to mimic the acidic microenvironment of IVD, and rat NPCs were cultured with or without autophagy or UPR signaling small-interfering RNAs. The related proteins and genes were assessed by immunofluorescence staining assay, Western blot analyses, and quantitative real-time polymerase chain reaction to monitor the activation of these signals and classify the molecular mechanisms underlying the correlation between autophagy and UPR pathway. Cell cycle analyses, senescence-associated ß-galactosidase staining, gene expression, and immunoblotting analyses were performed to observe NPC senescence. Results showed that acid stimulation not only induced NPC senescence, but also initiated UPR and autophagy. Silencing the binding immunoglobulin protein signaling of UPR or autophagy signaling promoted rat NPC senescence. Knock-down of the UPR also blocked NPC autophagy. Taken together, UPR inhibits NPC senescence under acidic condition by activating autophagy. Hence, UPR-dependent autophagy could be an effective biologic target for the treatment of IDD in the future.

Radiological risk factors for recurrent lumbar disc herniation after percutaneous transforaminal endoscopic discectomy: a retrospective matched case-control study.

PURPOSE: To investigate radiological risk factors for recurrent lumbar disc herniation (rLDH) after percutaneous transforaminal endoscopic discectomy (PTED). METHODS: Patients who underwent PTED due to a single-level L4-L5 or L5-S1 disc herniation from January 2013 to May 2019 were enrolled in this study. A matched case-control design was carried out in a single institution. Cases were defined as those who developed rLDH, and controls were matched from those patients without rLDH according to corresponding clinical characteristics. The radiological parameters were compared between two groups. The radiological risk factors for rLDH after PTED were identified by univariate and multivariate logistic regression analysis. RESULTS: A total of 2186 patients who underwent PTED at L4-L5 or L5-S1 level were enrolled in this study. Sixty-eight patients were diagnosed with rLDH, and 136 patients were selected from the remaining 2118 nonrecurrent patients as matched controls. Univariate analysis demonstrated that herniation type (P = 0.009), surgical-level disc degeneration (P < 0.001), adjacent-level disc degeneration (P = 0.017), disc height index (DHI) (P = 0.003), and sagittal range of motion (sROM) (P < 0.001) were significantly related to rLDH. Multiple logistic regression analysis showed that low grade of surgical-level disc degeneration (P < 0.001), senior grade of adjacent-level disc degeneration (P < 0.001), a high DHI (P = 0.012), and a large sROM (P < 0.001) were the radiological independent risk factors. CONCLUSION: This study showed that low grade of surgical-level disc degeneration, senior grade of adjacent-level disc degeneration, a high DHI, and a large sROM were the radiological independent risk factors for rLDH after PTED.

Prediction Model and Risk Factor Analysis of Adjacent Segment Disease After L4-5 Transforaminal Lumbar Interbody Fusion Through Preoperative Radiographic Features.

STUDY DESIGN: A retrospective study. OBJECTIVE: To investigate the risk of adjacent segment disease (ASD) after L4-5 transforaminal lumbar interbody fusion (TLIF) in patients diagnosed with lumbar spinal stenosis (LSS), a prediction model for ASD is established and validated. METHODS: A retrospective study was carried out on a sample of 290 patients who underwent L4-5 TLIF at Zhongda Hospital, Southeast University, from January 2015 to January 2021. The study collected baseline data and preoperative radiographic features of L3-4 and L5-S1. The determination of the outcome variable was based on X-ray results spanning over 24 months and JOA scores. Multivariate logistic regression was used to identify the risk factors in constructing a nomogram. RESULTS: Independent risk factors for L3-4 degeneration after TLIF included osteoarthritis of L3-4 facet joints, L3-4 foraminal stenosis, L4 upper endplate osteochondritis, L3-4 local lordosis angle, and L3-4 spinal stenosis. Independent risk factors for L5-S1 degeneration after TLIF included osteoarthritis of L5-S1 facet joints, L5-S1 intervertebral disc degeneration, L5-S1 spinal stenosis, L5-S1 coronal imbalance, and S1 upper endplate osteochondritis. A predictive model was developed. The AUC for the prediction models at L3-4 and L5-S1 were .945 and .956. The calibration curve demonstrated good consistency between the predicted and actual probabilities. The DCA curve indicated the clinical benefit and practical value of this predictive model. CONCLUSION: This study established nomograms for postoperative degeneration at L3-4 and L5-S1 based on selected preoperative radiographic features. These models provide a valuable auxiliary decision-making system for clinicians and aid in early surgical decisions.

Which Criterion for Wound Drain Removal is Better Following Posterior 1-Level or 2-Level Lumbar Fusion With Instrumentation: Time Driven or Output Driven?

STUDY DESIGN: Case-control study. OBJECTIVES: To compare the outcomes of 2 different criteria (time driven and output driven) for wound drain removal and identify which one is better. METHODS: 743 patients who underwent posterior lumbar fusion with instrumentation involving 1 or 2 motion segments were enrolled in this study. Based on the different criteria for drain removal, the patients were divided into 2 groups. The drains were discontinued by time driven (postoperative day 2) in group I and output driven (<50 ml per day) in group II. Demographic characteristics, perioperative parameters and clinical outcomes were compared between the 2 groups. RESULTS: The demographic characteristics in both groups were comparable. The postoperative drain output, total blood loss, postoperative timing of ambulation, and postoperative duration of hospital stay in group I were lower than those in group II (P < 0.001). There was a higher proportion of patients requiring postoperative blood transfusion in group II, but not to a level of statistical significance (P = 0.054). There was no statistical significant difference in the incidence of surgical site infection (SSI) or symptomatic spinal epidural hematoma (SEH) between the 2 groups (P > 0.05). CONCLUSIONS: This study reveals that there are more benefits of wound drain removal by time driven than that by output driven for patients undergoing posterior 1-level or 2-level lumbar fusion with instrumentation, including less postoperative drain output, less total blood loss, earlier postoperative timing of ambulation and less postoperative duration of hospital stay without increasing the incidence of postoperative SSI or symptomatic SEH.

Underlying Mechanisms and Related Diseases Behind the Complex Regulatory Role of NOD-Like Receptor X1.

Among nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), NOD-like receptor X1 (NLRX1) is the only known NLR family member that is targeted to the mitochondria, which contains a C-terminal leucine-rich repeat domain, a central conserved nucleotide-binding domain, and an unconventional N-terminal effector domain. It is unique due to several atypical features, such as mitochondrial localization, noninflammasome forming, and relatively undefined N-terminal domain. NLRX1 has multiple functions, including negative regulation of type-I interferon signaling, attenuation of proinflammatory nuclear factor kappa B (NF-κB) signaling, autophagy induction, modulation of reactive oxygen species production, cell death regulation, and participating in cellular senescence. In addition, due to its diverse functions, NLRX1 has been associated with various human diseases, including respiratory, circulatory, motor, urinary, nervous, and digestive systems, to name but a few. However, the exact regulatory mechanisms of NLRX1 are still unclear in many related diseases since conflicting and controversial topics on NLRX1 in the previous studies remain. In this review, we review recent research advances on the underlying mechanisms and related disorders behind the complex regulatory role of NLRX1, which may provide a promising target to prevent and/or treat the corresponding diseases.

Intraoperative Endplate Injury Following Transforaminal Lumbar Interbody Fusion.

OBJECTIVE: To investigate the incidence, distribution characteristics, risk factors, and clinical outcomes of intraoperative endplate injury (EI) following transforaminal lumbar interbody fusion. METHODS: Patients who underwent single-level transforaminal lumbar interbody fusion from January 2018 to December 2020 were included. The patients were separated into EI and non-EI groups based on computed tomography obtained immediately postoperatively. Demographic, clinical, and radiographic parameters of all patients were analyzed. Clinical outcomes were evaluated by visual analog scale for low back pain and Oswestry Disability Index. RESULTS: This study enrolled 576 patients. Rates of EI were 19.6% (113/576) of patients and 9.9% (114/1152) of endplates. The rate of superior EI was significantly higher than that of inferior EI. The results showed that older age, lower disc height index, and taller cage height were independent risk factors for intraoperative EI. Postoperative drain output, total blood loss, postoperative duration of drainage tube, and postoperative hospital stay in the EI group were significantly greater than in the non-EI group. There were no statistical differences in Oswestry Disability Index and visual analog scale scores at the same time point between the groups. CONCLUSIONS: Rates of EI were 19.6% of patients and 9.9% of endplates. Superior endplates were more susceptible to injury than inferior endplates. Older age, lower disc height index, and taller cage height were independent risk factors for intraoperative EI. Clinical outcomes were not affected by intraoperative EI during early postoperative follow-up.

The use of incisional vacuum-assisted closure system following one-stage incision suture combined with continuous irrigation to treat early deep surgical site infection after posterior lumbar fusion with instrumentation.

BACKGROUND: Previous reports concerning deep surgical site infection (SSI) after posterior spinal instrumentation treated with vacuum-assisted closure (VAC) system indicated that most patients must suffer from a delayed incision suture. To date, there are no published reports about the application of incisional VAC following a one-stage incision suture in the treatment of spinal infections. The purpose of this study was to evaluate the feasibility and efficacy of using an incisional VAC system following a one-stage incision suture combined with continuous irrigation to treat early deep SSI after posterior lumbar fusion with instrumentation. METHODS: Twenty-one patients who were identified as early deep SSI after posterior lumbar fusion with instrumentation were treated by incisional VAC following a one-stage incision suture combined with continuous irrigation at our spine surgery center between January 2014 and March 2020. Detailed data from medical records were collected and analyzed, including age, gender, primary diagnosis, original operation, number of VAC dressing changes, duration of continuous irrigation, hospital stay, risk factors for infection, bacteria type, and laboratory data. Clinical efficacy was assessed using the pre- and postoperative visual analog scale (VAS) for back pain and Kirkaldy-Willis functional criteria by regular follow-up. RESULTS: All the patients were cured and retained implants with an average of 1.9 times of VAC dressing replacement, and an average of 10.2 days of continuous irrigation. There were significant differences between pre-operation and post-operation in ESR, CRP, and VAS score of back pain, respectively (P < 0.05). The satisfactory rate was 90.5% according to Kirkaldy-Willis functional criteria. One patient developed a back skin rash with itching around the wound because of long-time contact with the VAC dressing. There was no recurrent infection or other complications during follow-up. CONCLUSIONS: Our preliminary results support that the treatment protocol is feasible and effective to treat early deep SSI following posterior lumbar fusion with instrumentation.

A Novel Technique for Treating Early Deep Surgical Site Infection After Posterior Lumbar Fusion with Instrumentation.

OBJECTIVE: To introduce a novel technique of using incisional vacuum-assisted closure (VAC) after 1-stage incision suture combined with closed suction irrigation system (CSIS) for treating early deep surgical site infection (SSI) after posterior lumbar fusion with instrumentation and to compare it with traditional CSIS. METHODS: This was a retrospective study. Patients with early deep SSI after posterior lumbar fusion with instrumentation from January 2013 to May 2020 who were treated by meticulous debridement followed by either CSIS or incisional VAC after 1-stage incision suture combined with CSIS were identified. The demographic characteristics, treatment features, and outcomes were analyzed and compared between the 2 treatment methods. RESULTS: A total of 48 patients (48/5016, 0.96%) developed early deep SSI, 46 of whom were enrolled in this study. This included 24 patients in the CSIS group (group 1) and 22 patients in the incisional VAC after 1-stage incision suture combined with CSIS group (group 2). All patients received follow-up, with an average of 19.7 months (range, 13-30 months). There were no significant differences in demographic characteristics in both groups (P > 0.05). The number of VAC foam dressing or ordinary dressing changes (P < 0.001), number of debridements (P = 0.028), intravenous antibiotic duration (P = 0.042), oral antibiotic duration (P = 0.019), and hospital stay (P = 0.029) in group 1 were significantly higher than those in group 2. The irrigation duration in group 1 was significantly shorter than that in group 2 (P = 0.007). All patients were eventually cured with satisfactory outcomes. CONCLUSIONS: Compared with CSIS, incisional VAC after 1-stage incision suture combined with CSIS may be recommended considering that it has fewer dressing changes, fewer debridements, longer irrigation duration, shorter duration of antibiotic use, shorter hospital stay, and more convenient nursing care.

Risk Factors for Increased Surgical Drain Output After Transforaminal Lumbar Interbody Fusion.

OBJECTIVE: To investigate the risk factors for increased surgical drain output after transforaminal lumbar interbody fusion (TLIF). METHODS: Patients who underwent TLIF in a single center from June 2017 to January 2020 were included in this study. They were divided into the increased surgical drain output group and no increased surgical drain output group according to the boundary of the median drain output. Patients' demographic and clinical parameters were compared between the 2 groups. Risk factors for increased surgical drain output were identified by univariate and multivariate logistic regression analysis. RESULTS: This study enrolled 368 patients who underwent TLIF. Among them, 187 patients had increased surgical drain output (drain output ≥50th percentile or 480 mL). Univariate analysis showed that age (P < 0.001), smoking status (P = 0.002), number of fused levels (P < 0.001), intraoperative blood loss (P < 0.001), intraoperative end plate injury (P < 0.001), administration of tranexamic acid (TXA) (P = 0.002), and surgical duration (P < 0.001) were significantly associated with increased surgical drain output. Multiple logistic regression analysis revealed that older age (P = 0.001), smoking (P = 0.005), more fused levels (P < 0.001), and intraoperative end plate injury (P = 0.017) were the independent risk factors, while administration of TXA (P = 0.012) was a protective factor. CONCLUSIONS: This study showed that older age, smoking, more fused levels, and intraoperative end plate injury were the independent risk factors, while administration of TXA was a protective factor for increased surgical drain output after TLIF.

Outcomes of Microendoscopic Discectomy and Percutaneous Transforaminal Endoscopic Discectomy for the Treatment of Lumbar Disc Herniation: A Comparative Retrospective Study.

STUDY DESIGN: Retrospective, case control evaluation of 86 patients who underwent microendoscopic discectomy (MED) and percutaneous transforaminal endoscopic discectomy (PTED) for the treatment of lumbar disc herniation (LDH). PURPOSE: To evaluate the safety and the outcomes of MED and PTED for the treatment of LDH. OVERVIEW OF LITERATURE: MED and PTED are minimally invasive surgical techniques for lower back pain. Studies to date have shown that MED and PTED are safe and effective treatment modalities for LDH. METHODS: A retrospective study was performed in patients with LDH treated with MED (n=50) and transforaminal endoscopic discectomy (PTED; n=36) in our hospital. All patients were followed-up with self-evaluation questionnaires, Oswestry disability index (ODI), medical outcomes study 36-item short form health survey and MacNab criteria. All the patients in both groups were followed up to 12 months after the operation. RESULTS: ODI questionnaire responses were not statistically different between the MED and PTED groups (53.00 vs. 48.72) before treatment. Average scores and minimal disability after 5 days to 12 months of follow-up were 4.96 in the MED group and 3.61 in the PTED group. According to MacNab criteria, 92.0% of the MED group and 94.4% of the PTED group had excellent or good results with no significant difference. CONCLUSIONS: There was no significant difference between MED and PTED outcomes. Further large-scale, randomized studies with long-term follow-up are needed.

Effects of hydroxyapatite-containing composite nanofibers on osteogenesis of mesenchymal stem cells in vitro and bone regeneration in vivo.

Among a variety of polymers, poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), a microbial polyester, with biodegradable, nonantigenic, and biocompatible properties, is attracting more and more attention in tissue engineering. Hydroxyapatite (HA), similar to the mineral component of natural bone, is known to be osteoconductive, nontoxic, and noninflammatory. In this study, aligned and random-oriented PHBV nanofibrous scaffolds loaded with HA nanoparticles were fabricated through electrospinning technique. Mesenchymal stem cells (MSCs) derived from rat bone marrow were used to investigate the effects of HA and orientation of fibers on cell proliferation and differentiation in vitro. Cell proliferation tested with CCK-8 assay indicated that the MSCs attached and proliferated more favorably on random-oriented PHBV nanofibrous meshes without HA. After one, two and four weeks of cell seeding, osteogenic markers including alkaline phosphate (ALP), osteocalcin (OCN), and mineralized matrix deposits were detected, respectively. The results indicated that the introduction of HA could induce MSCs to differentiate into osteoblasts. Moreover, 3D PHBV/HA scaffolds made from aligned and random-oriented nanofibers were implanted into critical-sized rabbit radius defects and exhibited significant effects on the repair of critical bone defects, implying their promising applications in bone tissue engineering.

Stabilization of unstable pelvic fractures with a novel internal-external fixator.

An internal-external fixator for stabilization in three cases with unstable pelvic fractures were reported. Compared with external fixation, the internal-external fixator, which is placed in the subcutaneous layer, decreased the risk of pin-track infection, pin site pain, and bowel obstruction; meanwhile, it had the advantage of external fixation: it was easy to apply, controlled damage, and resulted in minimal injury.