ADSC-Exos enhance functional recovery after spinal cord injury by inhibiting ferroptosis and promoting the survival and function of endothelial cells through the NRF2/SLC7A11/GPX4 pathway.

BACKGROUND: Spinal cord injury (SCI) is a devastating disease that causes major motor, sensory and autonomic dysfunctions. Currently, there is a lack of effective treatment. In this study, we aimed to investigate the potential mechanisms of Exosomes from adipose-derived stem cells (ADSC-Exos) in reducing ferroptosis and promoting angiogenesis after spinal cord injury. METHODS: We isolated ADSC-Exos, the characteristics of which were confirmed. In vitro, we tested the potential of ADSC-Exos to promote the survival and function of human brain microvascular endothelial cells (HBMECs) and analyzed the ferroptosis of HBMECs. In vivo, we established rat models of SCI and locally injected ADSC-Exos to verify their efficacy. RESULTS: ADSC-Exos can reduce reactive oxygen species (ROS) accumulation and cell damage induced by an excessive inflammatory response in HBMECs. ADSC-Exos inhibit ferroptosis induced by excessive inflammation and upregulate the expression of glutathione peroxidase 4(GPX4) in HBMECs. It can also effectively promote proliferation, migration, and vessel-like structure formation. In vitro, ADSC-Exos improved behavioral function after SCI and increased the number and density of blood vessels around the damaged spinal cord. Moreover, we found that ADSC-Exos could increase nuclear factor erythroid-2-related factor 2(NRF2) expression and nuclear translocation, thereby affecting the expression of solute carrier family 7 member 11(SLC7A11) and GPX4, and the NRF2 inhibitor ML385 could reverse the above changes. CONCLUSION: Our results suggest that ADSC-Exos may inhibit ferroptosis and promote the recovery of vascular and neural functions after SCI through the NRF2/SLC7A11/GPX4 pathway. This may be a potential therapeutic mechanism for spinal cord injury.

Association of PFN1 Gene Polymorphisms with Bone Mineral Density, Bone Turnover Markers, and Osteoporotic Fractures in Chinese Population.

Recent studies have discovered an association between the PFN1 gene and Paget's disease. However, it is currently unknown whether the PFN1 gene is related to osteoporosis. This study was performed to investigate the association of Single-Nucleotide Polymorphisms (SNPs) in the PFN1 gene with Bone Mineral Density (BMD) as well as bone turnover markers and osteoporotic fractures in Chinese subjects. A total of 2836 unrelated Chinese subjects comprising 1247 healthy subjects and 1589 osteoporotic fractures patients (Fracture group) were enrolled in this study. Seven tagSNPs (rs117337116, rs238243, rs6559, rs238242, rs78224458, rs4790714, and rs13204) of the PFN1 gene were genotyped. The BMD of the lumbar spine 1-4 (L1-4), femoral neck, and total hip as well as bone turnover markers, such as ß-C-Terminal telopeptide of type 1 collagen (ß-CTX) and Procollagen type 1 N-terminal Propeptide (P1NP), were measured. The association between 7 tagSNPs and BMD and bone turnover markers was analyzed in 1247 healthy subjects only. After age matching, we selected 1589 osteoporotic fracture patients (Fracture group) and 756 nonfracture controls (Control group, selected from 1247 healthy subjects) for a case-control study, respectively. For the case-control study, we used logistic regression to investigate the relationship between 7 tagSNPs and osteoporotic fractures risk. In the All group, the PFN1 haplotype GAT was associated with the ß-CTX (P = 0.007). In the Female group, the PFN1 haplotype GAT was associated with the ß-CTX (P = 0.005). In the Male group, the rs13204, the rs78224458, and the PFN1 haplotype GAC were associated with the BMD of the L1-4 (all P = 0.012); the rs13204, the rs78224458, and the PFN1 haplotype GAC were associated with the BMD of the femoral neck (all P = 0.012); the rs13204 and rs78224458 were associated with the BMD of the total hip (both P = 0.015); and the PFN1 haplotype GAT was associated with the ß-CTX (P = 0.013). In the subsequent case-control study, the rs13204 and rs78224458 in the male group were associated with the risk of L1-4 fracture (P = 0.016 and 0.010, respectively) and total hip fracture (P = 0.013 and 0.016, respectively). Our study reveals that PFN1 gene polymorphisms are associated with BMD in Chinese males and ß-CTX in Chinese people and confirmed the relationship between PFN1 gene polymorphisms and Chinese male osteoporotic fractures in a case-control study.

Curcumin improves age-related and surgically induced osteoarthritis by promoting autophagy in mice.

Reduced autophagy has been implied in chondrocyte death and osteoarthritis. Curcumin (Cur) owns therapeutic effect against osteoarthritis (OA) and enhances autophagy in various tumor cells. Whether the cartilage protection of curcumin is associated with autophagy promotion and the potential signaling pathway involved remains unclear. The present study aimed to investigate the role of autophagy in the anti-OA activity of curcumin using spontaneous and surgically induced OA mice model. Spontaneous and surgically induced OA mice model was established and treated with Cur. Articular cartilage destruction and proteoglycan loss were scored through Safranin O/Fast green staining. Apoptotic cell death was detected with TUNEL (terminal deoxynucleotidyl transferase-mediated dTUP-biotin nick end labeling assay) staining and Western blot for caspase-3, Bcl-2 associated X protein (Bax), and Bcl-2 (B-cell lymphoma-2). Light chain 3 (LC3) immunohistochemistry was used to evaluate autophagy. In vitro, primary chondrocytes were treated with interleukin 1 beta (IL-1ß) and Cur. Autophagy was inhibited using 3-methyladenine. Apoptosis and autophagy were detected using flow cytometry and Western blotting assay. Curcumin treatment enhanced autophagy, reduced apoptosis, and cartilage loss in both OA models. In vitro, curcumin treatment improved IL-1ß induced autophagy inhibition, cell viability decrease, and apoptosis. Mechanistically, in vivo studies suggested curcumin promoted autophagy through regulating Akt/mTOR pathway. In conclusion, our results demonstrate that curcumin-induced autophagy via Akt/mTOR signaling pathway contributes to the anti-OA effect of curcumin.

Transpseudarthrosis Osteotomy with Interbody Fusion for Kyphotic Spinal Pseudarthrosis in Ankylosing Spondylitis by a Single Posterior Approach: A Retrospective Study and a Brief Relevant Literature Review.

OBJECTIVE: To explore the safety and efficacy of transpseudarthrosis osteotomy with interbody fusion in the treatment of Ankylosing Spondylitis (AS) patients with kyphotic spinal pseudarthrosis by a single posterior approach. METHODS: Twelve consecutive patients with spinal pseudarthrosis underwent transpseudarthrosis osteotomy and interbody fusion with a polyetheretherketone (PEEK) cage by a single posterior approach. The operative time, intraoperative blood loss, and complications were recorded. Radiographic and clinical results were assessed preoperatively and at the final follow-up. RESULTS: The average operative time was 201.9 min and the mean blood loss was 817.5 ml. The visual analogue scale (VAS) improved significantly from 6.7 preoperatively to 1.1 at the final follow-up. The average correction of the segmental kyphosis at the level of the pseudarthrosis was 22.3°. Bony fusion was achieved in all patients, and there was no obvious loss of correction at follow-up. CONCLUSION: Transpseudarthrosis osteotomy at the level of the pseudarthrosis can be safely performed and surgical repair of pseudarthrosis with interbody fusion by a single posterior approach was feasible.

"Direct vision" operation of posterior atlantoaxial transpedicular screw fixation for unstable atlantoaxial fractures: A retrospective study.

BACKGROUND: The posterior screw fixation in atlas via posterior arch and lateral mass, also called C1 "pedicle" screw, combined with C2 pedicle screw fixiation has shown better biomechanical stability in unstable atlantoaxial fractures. However, its popularization has to fulfill the limitation imposed by anatomical characteristics. The aim of this study was to explore the manipulation, effect, and safety of the atlantoaxial transpedicular screw fixation under "direct vision" for the treatment of unstable atlantoaxial fracture. METHODS: All the patients diagnosed with unstable atlantoaxial fracture, who received surgery treatment of C1,C2 internal fixation from January 2012 to December 2014 were reviewed. Only these patients that were diagnosed with atlantoaxial unstability secondary to trauma and were treated with atlantoaxial transpedicular screw fixation under "direct vision" and iliac autograft were included. The safety of transpedicular screw placement, postoperative outcome, atlantoaxial stability, autograft fusion, and complications was observed and analyzed retrospectively. The pain visual analog scale (VAS) and the Japanese Orthopedic Association (JOA) score were used as surgical curative effect evaluation standards. RESULTS: We reviewed a total of 92 patients diagnosed with unstable atlantoaxial fracture, who received surgery treatment of C1,C2 internal fixation from January 2012 to December 2014, and 87 patients were treated with atlantoaxial transpedicular screw fixation under "direct vision" and were included this analysis. A total of 306 transpedicular screws in atlas and axis were placed successfully. All cases were followed-up >12 months. The overall breach rate was 11.36%. None of the breaches resulted in new-onset neurological sequela. The neurological status in cases with bilateral upper extremities numbness and lower extremities weakness had improved after surgery. At the latest follow-up, the neck VAS and JOA scores were significantly improved (P < .01) than those preoperatively. No cases demonstrated implantation failure and bone graft absorption on the postoperative x-ray films and CT scans. CONCLUSION: Atlantoaxial transpedicular screw fixation under "direct vision" and iliac autograft for the treatment of unstable atlantoaxial fracture has shown simple manipulation and efficient performance. Thus, the technique of C1-C2 fixation is feasible in treating unstable atlantoaxial fracture.

Multichannel polymer scaffold seeded with activated Schwann cells and bone mesenchymal stem cells improves axonal regeneration and functional recovery after rat spinal cord injury.

The adult mammalian CNS has a limited capacity to regenerate after traumatic injury. In this study, a combinatorial strategy to promote axonal regeneration and functional recovery after spinal cord injury (SCI) was evaluated in adult rats. The rats were subjected to a complete transection in the thoracic spinal cord, and multichannel scaffolds seeded with activated Schwann cells (ASCs) and/or rat bone marrow-derived mesenchymal stem cells (MSCs) were acutely grafted into the 3-mm-wide transection gap. At 4 weeks post-transplantation and thereafter, the rats receiving scaffolds seeded with ASCs and MSCs exhibited significant recovery of nerve function as shown by the Basso, Beattie and Bresnahan (BBB) score and electrophysiological test results. Immunohistochemical analyses at 4 and 8 weeks after transplantation revealed that the implanted MSCs at the lesion/graft site survived and differentiated into neuron-like cells and co-localized with host neurons. Robust bundles of regenerated fibers were identified in the lesion/graft site in the ASC and MSC co-transplantation rats, and neurofilament 200 (NF) staining confirmed that these fibers were axons. Furthermore, myelin basic protein (MBP)-positive myelin sheaths were also identified at the lesion/graft site and confirmed via electron microscopy. In addition to expressing mature neuronal markers, sparse MSC-derived neuron-like cells expressed choline acetyltransferase (ChAT) at the injury site of the ASC and MSC co-transplantation rats. These findings suggest that co-transplantation of ASCs and MSCs in a multichannel polymer scaffold may represent a novel combinatorial strategy for the treatment of spinal cord injury.

Surgical treatment of severe multilevel circumferential compressive myelopathy of the cervical spine: is circumferential procedure necessary?

OBJECTIVE: To determine the necessity of circumferential decompression and fusion in patients with severe multilevel cervical spondylotic myelopathy with circumferential cord compression. METHODS: This prospective study involved 51 patients with severe multilevel circumferential cervical myelopathy underwent two-stage circumferential procedure between July 2008 and June 2010. VAS scores, satisfaction surveys and JOA scores and imaging studies were obtained. Twenty-three patients (45.1%) underwent two-stage surgery (group A); the other 28 patients (54.9%) were satisfied with the outcomes after first-stage surgery, and the second-stage surgery was avoided (group B). Age, sex and symptom duration did not differ between the groups. RESULTS: Patients were followed up for 3-5 years (mean, 42.5 months). In group A, VAS and JOA scores significantly improved from 63.3 and 7.9 to 38.3 and 10.4, respectively, at 3 months after the first-stage operation and 10.2 and 12.7, respectively, at 3 months after the second-stage operation. In group B, the VAS and JOA scores significantly improved from 62.7 and 7.9 to 31.1 and 11.2 respectively, at 3 months and 18.2 and 12.4, respectively at 6 months. Patient satisfaction rate significantly increased from 43.5% after the first-stage operation to 82.6% after the second-stage operation in group A. In group B, this rate was 89.3%. In group A, cervical spine lordosis increased from 12.8° preoperatively to 18.5° (p < .0001) and 19.1° (p > .05) at 3 months after the first-stage and second-stage operations, respectively. In group B, lordosis significantly increased from 12.5° preoperatively to 18.8° at 3 months. The total complication rate did not significantly differ from the rates after a single surgery (either anterior or posterior). CONCLUSION: Only 45.1% patients required surgery via both approaches. Therefore, a two-stage procedure is a rational choice and safe procedure. If outcomes are unsatisfactory after the first-stage operation, a second-stage operation can be performed.

Percutaneous Vertebroplasty Versus Conservative Treatment in Aged Patients With Acute Osteoporotic Vertebral Compression Fractures: A Prospective Randomized Controlled Clinical Study.

STUDY DESIGN: A prospective randomized clinical trial. OBJECTIVE: In this study, we determine whether percutaneous vertebroplasty (PVP) offers extra benefits to aged patients with acute osteoporotic vertebral compression fractures (OVCFs) over conservative therapy (CV). SUMMARY OF BACKGROUND DATA: OVCFs are common in the aged population with osteoporosis. While the optimal treatment of aged patients with acute OVCFs remains controversial, PVP, a minimally invasive procedure, is a treatment option to be considered. METHODS: Patients aged at 70 years or above with acute OVCF and severe pain from minor or mild trauma were assigned randomly to PVP and CV groups. The primary outcome was pain relief as measured by VAS score in 1-year follow-up period. The second outcome was quality of life assessed with ODI and Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Patient satisfaction surveys were also recorded. RESULTS: A total of 135 patients were enrolled, and 107 (56 in PVP group; 51 in CV group) completed 1-year follow-up. In PVP group, the vertebroplasty procedure was performed at a mean of 8.4 ±â€Š4.6 days (range, 2-21 days) after onset. Vertebroplasty resulted in much greater pain relief than did conservative treatment at postoperative day 1 (P < 0.0001). At every time point of follow-up, pain relief and quality of life were significantly improved in PVP group than in CV group at 1 week, 1 month, 3 months, 6 months, and 1 year (all P < 0.0001). The final follow-up surveys indicated that patients in PVP group were significantly more satisfied with given treatment (P < 0.0001). In addition, lower rate of complications was observed in PVP group (P < 0.0001). CONCLUSION: In aged patients with acute OVCF and severe pain, early vertebroplasty yielded faster, better pain relief and improved functional outcomes, which were maintained for 1 year. Furthermore, it showed fewer complications than conservative treatment. LEVEL OF EVIDENCE: 2.

An RCT study comparing the clinical and radiological outcomes with the use of PLIF or TLIF after instrumented reduction in adult isthmic spondylolisthesis.

OBJECTIVE: We prospectively compared posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) used in adult isthmic spondylolisthesis (IS) after surgical reduction with pedicle screws. METHODS: Between January 2009 and December 2010, 66 adult patients with single-level IS were randomly assigned to two groups treated using the PLIF technique (PLIF group, n = 34) and the TLIF technique (TLIF group, n = 32). Both groups were followed up for an average of 30.5 months (range 24-48 months). Clinical outcomes were assessed using the visual analog scale (VAS), Oswestry disability index (ODI) and Japanese orthopedic association (JOA) scores. Radiographic outcomes included percentage of vertebral slippage, focal lordosis and disk height. Clinical and radiographic outcomes were compared between the two groups. RESULTS: The average operative time and blood loss during surgery were significantly more in PLIF group than in TLIF group. Spondylolisthesis, disk height and focal lordosis were significantly improved postoperatively in both groups. There was no obvious difference in clinical outcomes, as assessed using the VAS, ODI and JOA scores, and radiographic outcomes. In PLIF group, there were two cases of neuropathic pain after surgery. CONCLUSIONS: After instrumented reduction of adult IS, either PLIF or TLIF can provide good clinical and radiological outcomes. With a single cage, TLIF was superior to PLIF in terms of surgical time and blood loss, but these differences may not be clinically relevant.

Continuous irrigation and drainage for early postoperative deep wound infection after posterior instrumented spinal fusion.

STUDY DESIGN: A retrospective study of clinical cases. PURPOSE: To evaluate the efficacy of continuous irrigation and drainage for early postoperative deep wound infection after posterior instrumented spinal fusion. SUMMARY OF BACKGROUND DATA: Aggressive debridement and irrigation has been recommended to treat postoperative wound infections after instrumented spinal fusion. However, this method of management, indicating repeating visits to the operating room until the wound is clean enough for closure, often results in prolonged hospitalization, increased cost, and sometimes compromise of the desired outcome. We hypothesize that repeat visits to the operating room for debridements can be avoided by aggressive debridements and primary closure with continuous irrigation and drainage for postoperative wound infections. METHODS: From 2004 to 2009, 23 patients with early postoperative deep wound infections after spinal fusion with instrumentation were surgically treated with thorough debridement and primary closure with continuous irrigation and drainage. All patients were followed up for 30.6 months (range, 24-54 mo). RESULTS: The mean duration of irrigation was 12.0 days (range, 7-16 d). In 21 patients (91.3%), the wound healed after continuous irrigation. The removal of the instrumentation or cages was not required in any case. Spinal fusion was achieved in all cases, except 1, where the patient developed a pseudoarthrosis at the L4-L5 level after L4-S1 fusion. The mean ODI for these 23 patients improved significantly from 53.4±18.7 preoperatively to 18.3±11.2 at the final follow-up visit (P<0.001). The mean JOA scores increased significantly from 15.5±4.1 preoperatively to 24.3±3.8 at the final follow-up (P<0.001). CONCLUSIONS: Continuous irrigation and drainage is an effective and safe method for the treatment of early postoperative deep wound infection after posterior instrumented spinal fusion.

Single segment of posterior lumbar interbody fusion for adult isthmic spondylolisthesis: reduction or fusion in situ.

OBJECTIVE: We prospectively compared surgical reduction or fusion in situ with posterior lumbar interbody fusion (PLIF) for adult isthmic spondylolisthesis in terms of surgical invasiveness, clinical and radiographical outcomes, and complications. METHODS: From January 2006 to June 2008, 88 adult patients with isthmic spondylolisthesis who underwent surgical treatment in our unit were randomized to reduced group (group 1, n = 45) and in situ group (group 2, n = 43), and followed up for average 32.5 months (range 24-54 months). The clinical and radiographical outcomes were compared between the two groups. RESULTS: The average operative time and blood loss during surgery showed insignificant difference (p > 0.05) between two groups. The radiological outcomes were significantly better in group 1, but there was no significant difference between two groups of clinical outcomes, depicting as VAS, ODI, JOA and patients' satisfaction surveys. Incident rate of surgical complications was similar in two groups, but in group 1 the complication seemed more severe because of two patients with neurological symptoms. CONCLUSIONS: For the adult isthmic spondylolisthesis without degenerative disease in adjacent level, single segment of PLIF with pedicle screw fixation is an effective and safe surgical procedure regardless of whether additional reduction had been conducted or not. Better radiological outcome does not mean better clinical outcome.