Aims. This study was performed to explore the effect of melatonin on pyroptosis in nucleus pulposus cells (NPCs) and the underlying mechanism of that effect. Methods. This experiment included three patients diagnosed with lumbar disc herniation who failed conservative treatment. Nucleus pulposus tissue was isolated from these patients when they underwent surgical intervention, and primary NPCs were isolated and cultured. Western blotting, reverse transcription polymerase chain reaction, fluorescence staining, and other methods were used to detect changes in related signalling pathways and the ability of cells to resist pyroptosis. Results. Western blot analysis confirmed the expression of cleaved CASP-1 and melatonin receptor (MT-1A-R) in NPCs. The cultured NPCs were identified by detecting the expression of CD24, collagen type II, and aggrecan. After treatment with hydrogen peroxide, the pyroptosis-related proteins NLR family pyrin domain containing 3 (NLRP3), cleaved CASP-1, N-terminal fragment of gasdermin D (GSDMD-N), interleukin (IL)-18, and IL-1β in NPCs were upregulated, and the number of propidium iodide (PI)-positive cells was also increased, which was able to be alleviated by pretreatment with melatonin. The protective effect of melatonin on pyroptosis was blunted by both the melatonin receptor antagonist luzindole and the nuclear factor erythroid 2–related factor 2 (Nrf2) inhibitor ML385. In addition, the expression of the transcription factor Nrf2 was up- or downregulated when the melatonin receptor was activated or blocked by melatonin or luzindole, respectively. Conclusion. Melatonin protects NPCs against reactive oxygen species-induced pyroptosis by upregulating the transcription factor Nrf2 via melatonin receptors. Cite this article: Bone Joint Res 2023;12(3):202–211

Aims. To investigate the correlations among cytokines and regulatory T cells (T-regs) in ankylosing spondylitis (AS) patients, and their changes after anti-tumour necrosis factor-α (TNF-α) treatment. Methods. We included 72 AS patients with detailed medical records, disease activity score (Bath Ankylosing Spondylitis Disease Activity Index), functional index (Bath Ankylosing Spondylitis Functional Index), and laboratory data (interleukin (IL)-2, IL-4, IL-10, TNF-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, ESR, and CRP). Their peripheral blood mononuclear cells (PBMCs) were marked with anti-CD4, anti-CD25, and anti-FoxP3 antibodies, and triple positive T cells were gated by flow cytometry as T-regs. Their correlations were calculated and the changes after anti-TNF-α therapy were compared. Results. The frequency of T-regs in PBMCs was positively correlated to ESR and CRP in AS (r = 0.35 and 0.43; p = 0.032 and 0.027, respectively), and there was also a significant correlation between serum level of TNF-α and CRP (p = 0.041). The frequency of T-regs in PBMCs positively correlated to serum levels of TNF-α, IL-10, and TGF-β, while IL-2, IL-4, and IFN-γ showed opposite results. After anti-TNF-α treatment, there were significantly lower serum levels of TNF-α, IL-10, TGF-β, and frequency of T-regs in PBMCs among these AS patients (p = 0.026, 0.032, 0.029, and 0.037, respectively). Conclusion. In AS patients, proinflammatory cytokine may give positive feedback to induce more T-reg production and anti-inflammatory cytokine secretion to suppress this inflammatory status, and they can be reversed by anti-TNF-α therapy. However, the detailed interactions among T-regs and complex cytokine networks in autoinflammatory diseases still need more studies and further functional assay. Cite this article: Bone Joint Res 2023;12(2):133–137

Introduction. Degenerative cervical myelopathy (DCM) is associated with progressive neurological deterioration. Surgical decompression can halt but not reverse this progression. The Modified Japanese Orthopaedic Assessment (MJOA) tool is recommended by international guidelines to grade disease severity into mild, moderate and severe, where moderate and severe are both recommended to undergo surgical intervention. During Covid-19 Nottingham University Hospitals (NUH) NHS Trust, identified DCM patients as high risk for sustaining permanent neurological damage due to surgical delay. The Advanced Spinal Practitioner (ASP) team implemented a surveillance project to evaluate those at risk. Methods. A spreadsheet was compiled of all DCM patients known to the service. Patients were telephoned (Oct-Nov 2021) by an ASP. MJOA score was recorded and those describing progressive deterioration were reviewed by the ASP team on a spinal same day emergency assessment unit. Incident forms were completed for clinical deterioration and recorded as severe harm. Acute, progressive neurological deterioration was fast tracked for emergency surgical decompression. Results. 45 patients were telephoned, 18 (40%) had deteriorated. Of the 18, 9 underwent urgent surgical decompression, 6 still await surgery and 3 continue to be monitored. Those who had deteriorated were sent a formal apology and duty of candour letter. Conclusion. It appears that patients with a diagnosis of DCM deteriorate over time. Delays to timely surgical intervention can have a deleterious effect on patient's neurological function. Baseline assessment should be clearly documented and scoring system such as MJOA considered for effective monitoring. Safety netting for deterioration should be standard practice, and a clear pathway for emergency presentation identified. Conflicts of interest: No conflicts of interest. Sources of funding: No funding obtained

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This study aimed, through bioinformatics analysis and in vitro experiment validation, to identify the key extracellular proteins of intervertebral disc degeneration (IDD).

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In this investigation, we administered oxidative stress to nucleus pulposus cells (NPCs), recognized DNA-damage-inducible transcript 4 (DDIT4) as a component in intervertebral disc degeneration (IVDD), and devised a hydrogel capable of conveying small interfering RNA (siRNA) to IVDD.

Purpose of study and background. Degeneration of the intervertebral disc is a strong contributor of low back pain. Studies have shown that both, mechanical unloading and overloading, lead to disc degeneration. This is intuitively clear if one considers that an intervertebral disc essentially is a poro-elastic material embedded with cells, which depend on fluid flow for the transport of nutrients and waste products. As such, mechanical loading is also required for regeneration. It is unclear, however, how much loading is beneficial or detrimental for the healthy or degenerated disc. Methods and Results. We developed a loaded disc culture system for the long-term study of disc physiology. This way we could control both the mechanical and biochemical conditions. If no loading was applied, about half of the cells died within a week. Cells died under a low dynamic loading regime after three weeks. A diurnal loading regime rescued cell viability, gene expression profile and mechanical behavior of the discs. Both static and dynamic overloading induced damage to the discs and led to catabolic and inflammatory gene expressions. Conclusion. Intervertebral discs need a certain dosage of mechanical loading to remain viable. Under overloading, cells deform, change gene expression and become degenerative. The matrix is also remodeled, thereby further decreasing the hydrostatic pressure on the cells and increasing their deformation. This induces a vicious circle of disc degeneration, which needs to be reversed in order to repair the disc. The loaded disc culture system also allows evaluating new therapies for disc degeneration. There are no conflicts of interest. Funded by ZonMW program “Alternatives for live animal testing”, grant #11400090;. BioMedical Materials Program, grant # P2.01 IDiDas; Dutch Arthritis Funds, personal grant KSE

Background and Purpose. Intervertebral disc (IVD) degeneration is a prominent cause of low back pain. IVD cells expressing angiopoietin-1 receptor Tie2 represent a progenitor cell population which decreases with progression of IVD degeneration. Homing of mesenchymal stem cells (MSCs) is a physiological mechanism aiming to enhance the regenerative capacity of the IVD. The purpose of this study was to assess the effect of MSC homing on the Tie2 positive IVD progenitor cell population, the IVD cell viability, and the proliferative phenotype of the IVD cells. Methods and Results. Human MSCs were isolated from bone marrow aspirates and labelled with fluorescent dye. Whole IVDs with endplates were harvested from bovine tails; MSCs were placed on the endplates. Human traumatic, degenerative and healthy IVD tissues were obtained from patients and organ donors. MSCs were added onto tissue samples. After 5 days, IVD cells were isolated. Percentages of Tie2 positive, DAPI positive (dead) and Ki-67 positive (proliferative) IVD cells were determined. MSC homing or co-culture significantly increased the proportion of Tie2 positive progenitor IVD cells in bovine and 7/10 human IVDs, decreased the fraction of dead IVD cells in bovine and 7/10 human IVDs, and induced a proliferative phenotype in bovine and 5/6 human IVDs. Conclusion. Stimulation of bovine and human IVDs by MSC homing resulted in an enhanced population of Tie2 positive IVD progenitor cells, induced a proliferative response and reduced IVD cell death. Hence, the interaction with recruited MSCs may contribute to an improved survival of IVD cells, helping to reverse or slow down an ongoing degenerative process. Conflicts of interest: The authors declare no conflicts of interest. Sources of funding: AO Foundation and AOSpine International

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To systematically evaluate whether bracing can effectively achieve curve regression in patients with adolescent idiopathic scoliosis (AIS), and to identify any predictors of curve regression after bracing.

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CRP is an acute-phase protein that is used as a biomarker to follow severity and progression in infectious and inflammatory diseases. Its pathophysiological mechanisms of action are still poorly defined. CRP in its pentameric form exhibits weak anti-inflammatory activity. The monomeric isoform (mCRP) exerts potent proinflammatory properties in chondrocytes, endothelial cells, and leucocytes. No data exist regarding mCRP effects in human intervertebral disc (IVD) cells. This work aimed to verify the pathophysiological relevance of mCRP in the aetiology and/or progression of IVD degeneration.

This prospective study of 136 children with progressive infantile scoliosis treated under the age of four years, and followed up for nine years, shows that the scoliosis can be reversed by harnessing the vigorous growth of the infant to early treatment by serial corrective plaster jackets. In 94 children (group 1), who were referred and treated in the early stages of progression, at a mean age of one year seven months (6 to 48 months) and with a mean Cobb angle of 32° (11° to 65°), the scoliosis resolved by a mean age of three years and six months. They needed no further treatment and went on to lead a normal life. At the last follow-up, their mean age was 11 years and two months (1 year 10 months to 25 years 2 months), 23 (24.5%) were at Risser stages 4 and 5 and 13 girls were post-menarchal. In 42 children (group 2), who were referred late at a mean age of two years and six months (11 to 48 months) and with a mean Cobb angle of 52° (23° to 92°), treatment could only reduce but not reverse the deformity. At the last follow-up, at a mean age of ten years and four months (1 year 9 months to 22 years 1 month), eight children (19%) were at Risser stages 4 and 5 and five girls were post-menarchal. Fifteen children (35.7%) had undergone spinal fusion, as may all the rest eventually

Introduction. Osteoporotic fracture reduces vertebral stiffness, and alters spinal load-sharing. Vertebroplasty partially reverses these changes at the fractured level, but is suspected to increase deformations and stress at adjacent levels. We examined this possibility. Methods. Twelve pairs of three-vertebra cadaver spine specimens (67-92 yr) were loaded to induce fracture. One of each pair underwent vertebroplasty with PMMA, the other with a resin (Cortoss). Specimens were then creep-loaded at 1.0kN for 1hr. In 15 specimens, either the uppermost or lowest vertebra was fractured, so that compressive stress distributions could be determined in the disc between adjacent non-fractured vertebrae. Stress was measured in flexion and extension, at each stage of the experiment, by pulling a pressure-transducer through the disc whilst under 1.0kN load. Stress profiles quantified intradiscal pressure (IDP), stress concentrations in the posterior annulus (SP. P. ), and compressive load-bearing by the neural arch (F. N. ). Elastic deformations in adjacent vertebrae were measured using a MacReflex tracking system during 1.0kN compressive ramp loading. Results. No differences were found between Cortoss and PMMA so data was pooled. Following fracture, IDP fell by 27% in extension (P=0.009), and SP. P. increased by 277% in flexion (P=0.016). F. N. increased from 17% to 30% of the applied load in flexion, and from 23% to 37% in extension (P<0.05). Vertebroplasty partially reversed these changes without inducing any increase in elastic deformation of the adjacent vertebrae. Conclusion. Vertebral fracture increases stress concentrations acting on the vertebral bodies and neural arches of adjacent (non-fractured) vertebrae, and these increases can be partially reversed by vertebroplasty

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The aim of the study was to determine if there was a direct correlation between the pain and disability experienced by patients and size of their disc prolapse, measured by the disc’s cross-sectional area on T2 axial MRI scans.

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The aim of this study was to assess the ability of morphological spinal parameters to predict the outcome of bracing in patients with adolescent idiopathic scoliosis (AIS) and to establish a novel supine correction index (SCI) for guiding bracing treatment.

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The outcome following the development of neurological complications after corrective surgery for scoliosis varies from full recovery to a permanent deficit. This study aimed to assess the prognosis and recovery of major neurological deficits in these patients, and to determine the risk factors for non-recovery, at a minimum follow-up of two years.

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Non-coding microRNA (miRNA) in extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) may promote neuronal repair after spinal cord injury (SCI). In this paper we report on the effects of MSC-EV-microRNA-381 (miR-381) in a rodent model of SCI.

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To describe the clinical, radiological, and functional outcomes in patients with isolated congenital thoracolumbar kyphosis who were treated with three-column osteotomy by posterior-only approach.

Purpose and Background:. The spread of upright MRi scanning is a relatively new development in the UK. However, there is a lack of information about whether weight bearing scans confer any additional useful information for low back conditions. Methods and Results:. Forty-five patient referrals to the upright MRI Department at the AECC for weight bearing lumbar spine scans between November 1. st. 2014 and June 30. th. 2015, and the resulting radiologists' reports were reviewed. Age, gender, clinical history, summary of findings, type of weight bearing scanning performed (sitting, standing, flexion, extension) were abstracted. All patients were scanned in a 0.5T Paramed MRopen scanner and all also received supine lumbar spine sagittal and axial scans. The patients comprised 18 females and 27 males, mean age 52 years, (SD 15.5). Thirty had leg pain, 6 of which was bilateral. In 15, a stenotic lesion was suspected. Other reasons for referral were; possible malignancy (1), effects of degenerative change (4), spondylolisthesis (2), fracture, (1), previous surgery (3), trauma (1), sacroiliitis (1) and instability (3). In 12/45 cases, reportable findings were more prominent, and sometimes only identifiable, on weight bearing scans, while in a further 4, the reverse was true. All but one of these involved disruption of the spinal or root canals. Eight of them also involved positional alignment. Conclusion:. In this case series nearly a third of referred patients had reportable findings relating to the spinal or nerve root canals that were differentiated by upright MRI scans

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Spinal deformity surgery carries the risk of neurological injury. Neurophysiological monitoring allows early identification of intraoperative cord injury which enables early intervention resulting in a better prognosis. Although multimodal monitoring is the ideal, resource constraints make surgeon-directed intraoperative transcranial motor evoked potential (TcMEP) monitoring a useful compromise. Our experience using surgeon-directed TcMEP is presented in terms of viability, safety, and efficacy.

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Inflammatory response plays a pivotal role in the pathophysiological process of intervertebral disc degeneration (IDD). A20 (also known as tumour necrosis factor alpha-induced protein 3 (TNFAIP3)) is a ubiquitin-editing enzyme that restricts nuclear factor-kappa B (NF-κB) signalling. A20 prevents the occurrence of multiple inflammatory diseases. However, the role of A20 in the initiation of IDD has not been elucidated. The aim of the study was to investigate the effect of A20 in senescence of TNF alpha (TNF-α)-induced nucleus pulposus cells (NPCs).

To establish the current practice of spinal cord monitoring in units carrying out scoliosis surgery in the UK. To illustrate the benefit of routinely monitoring motor evoked potentials (MEPs). Questionaire: Nationwide survey of spinal monitoring modalities used by spinal units carrying out deformity surgery. 10 out of 27 units routinely measure motor evoked potentials (MEPs), the remainder use only sensory potentials (SEPs). There is significant variability in use of monitoring around the UK and we have compared this to the practice elsewhere in the world. We report the case of a thirteen year old girl who underwent posterior instrumentation for correction of an idiopathic scoliosis. Intra-operatively there was a significant reduction in the amplitude of the MEPs without any corresponding change in the SEPs. These changes reversed when the correction was released. The surgery was abandoned and was carried out as a staged procedure, initially anteriorly then posteriorly. There was no loss of motor potentials during either operation and no post operative neurological abnormalities. We propose that the changes noted initially were due to transient ischaemia of the cord which would not have been detected without MEPs and may have led to long term sequelae. This highlights the safety benefit of routinely using MEPs in scoliosis surgery. Nationally there is wide variation in the monitoring of spinal cord function during scoliosis surgery. We feel that monitoring of motor potentials is a vital component in ensuring scoliosis surgery is as safe as possible