Objectives. Pulsed electromagnetic field (PEMF) stimulation was evaluated after anterior cervical discectomy and fusion (ACDF) procedures in a randomized, controlled clinical study performed for United States Food and Drug Administration (FDA) approval. PEMF significantly increased fusion rates at six months, but 12-month fusion outcomes for subjects at elevated risk for pseudoarthrosis were not thoroughly reported. The objective of the current study was to evaluate the effect of PEMF treatment on subjects at increased risk for pseudoarthrosis after ACDF procedures. Methods. Two evaluations were performed that compared fusion rates between PEMF stimulation and a historical control (160 subjects) from the FDA investigational device exemption (IDE) study: a post hoc (PH) analysis of high-risk subjects from the FDA study (PH PEMF); and a multicentre, open-label (OL) study consisting of 274 subjects treated with PEMF (OL PEMF). Fisher’s exact test and multivariate logistic regression was used to compare fusion rates between PEMF-treated subjects and historical controls. Results. In separate comparisons of PH PEMF and OL PEMF groups to the historical control group, PEMF treatment significantly (p < 0.05, Fisher’s exact test) increased the fusion rate at six and 12 months for certain high-risk subjects who had at least one clinical risk factor of being elderly, a nicotine user, osteoporotic, or diabetic; and for those with at least one clinical risk factor and who received at least a two- or three-level arthrodesis. Conclusion. Adjunctive PEMF treatment can be recommended for patients who are at high risk for pseudoarthrosis. Cite this article: D. Coric, D. E. Bullard, V. V. Patel, J. T. Ryaby, B. L. Atkinson, D. He, R. D. Guyer. Pulsed electromagnetic field stimulation may improve fusion rates in cervical arthrodesis in high-risk populations. Bone Joint Res 2018;7:124–130. DOI: 10.1302/2046-3758.72.BJR-2017-0221.R1

This review provides a concise outline of the advances made in the care of patients and to the quality of life after a traumatic spinal cord injury (SCI) over the last century. Despite these improvements reversal of the neurological injury is not yet possible. Instead, current treatment is limited to providing symptomatic relief, avoiding secondary insults and preventing additional sequelae. However, with an ever-advancing technology and deeper understanding of the damaged spinal cord, this appears increasingly conceivable. A brief synopsis of the most prominent challenges facing both clinicians and research scientists in developing functional treatments for a progressively complex injury are presented. Moreover, the multiple mechanisms by which damage propagates many months after the original injury requires a multifaceted approach to ameliorate the human spinal cord. We discuss potential methods to protect the spinal cord from damage, and to manipulate the inherent inhibition of the spinal cord to regeneration and repair. Although acute and chronic SCI share common final pathways resulting in cell death and neurological deficits, the underlying putative mechanisms of chronic SCI and the treatments are not covered in this review.

Objectives. This study aims to investigate whether bacteria are present in intervertebral discs (IVDs) and their influence. Causality between chronic infection of the IVD and its degenerative process gained great interest recently. Granville Smith et al. (2021) identified 36 articles from 34 research studies investigating bacteria in IVDs, from these 27 studies found, Cutibacterium acnes being the most abundant. However, whether bacteria identified were present in vivo or if they represent contamination remains unclear. Methods. Human IVD tissue was fixed in paraffin and Immunohistochemical stained for Gram-positive bacteria. NP cells in monolayer have been stimulated with LPS (0.1–50 µg/ml) and Peptidoglycan (0.1–50 µg/ml) for 24, 48 and 72 hrs to investigate their influence. The concentration of proinflammatory and catabolic cytokines in the media is being measured using ELISA. RNA extracted and RT-qPCR utilised for factors associated with disc degeneration matrix genes, matrix degrading enzymes, cytokines, neurotrophic factors and angiogenic factors. Results. Bacteria were detected within IVD tissue. Bacteria was internalized by the NP cells and influenced the nuclei morphology. Preliminary results of the exposure of NP cells to bacterial components demonstrate that ADAMTS4 as well as IL-8 were showed an increase in gene expression after LPS and peptidoglycan treatment compared to the non-treated control. Underlining these results, IL-8 protein was increased in treated groups, whereas peptidoglycan treated groups showed a dose dependence. Conclusion. This study demonstrates that Gram positive bacteria are present within the IVD. The exposure of NP cells to peptidoglycans indicates that bacterial components trigger a stress response. Conflicts of Interest: No conflict of interest. Sources of Funding: This project is part of the Disc4All Training network to advance integrated computational simulations in translational medicine, applies to intervertebral disc degeneration and funded by Horizon 2020 (H2020-MSCA-ITN-ETN-2020 GA: 955735)

Study purpose and background. Novel regenerative therapies have the potential to restore function and relieve pain in patients with low back pain (LBP) caused by intervertebral disc (IVD) degeneration. We have previously shown that stimulation of adipose-derived stem cells (ASCs) with growth differentiation factor-6 (GDF6) promotes differentiation into nucleus pulposus (NP) cells of the IVD, which have potential for IVD regeneration. We have also shown that GDF6 stimulation activates the Smad1/5/8 and ERK1/2 signalling cascades. The aim of this study was to progress our understanding of the immediate/early response mechanisms in ASCs (N=3) which may direct GDF6-induced differentiation. Methods and results. RNAseq was used to perform transcriptome-wide analysis across a 12-hour time course, post-stimulation. Gene ontology analysis revealed greater transcription factor and biological processes activity at 2hrs than at the 6hr and 12hr time points, where molecular and cellular activities appeared to stabilise. Interestingly, a number of lineage determining genes were identified as differentially expressed and work is ongoing to investigate whether the early response genes are maintained throughout differentiation, or whether they are responsible for early NP lineage commitment. Conclusion. This study is the first transcriptome-wide analysis on GDF6-mediated stimulation of ASCs, elucidating important early response mechanisms involved in directing appropriate differentiation. Identification of additional key markers and signalling pathways of differentiation will allow improved selection of ASCs for IVD regeneration. ‘No conflicts of interest’. Funding sources: NIHR Manchester Biomedical Research Centre and The RoseTrees Trust

Background. Signalling by growth differentiation factor 6 (GDF6/BMP13) has been implicated in the development and maintenance of healthy NP cell phenotypes and GDF6 mutations are associated with defective vertebral segmentation in Klippel-Feil syndrome. GDF6 may thus represent a promising biologic for treatment of IVD degeneration. This study aimed to investigate the effect of GDF6 in human NP cells and critical signal transduction pathways involved. Methods. BMP receptor expression profile of non-degenerate and degenerate human NP cells was determined through western blot, immunofluorescence and qPCR. Phosphorylation statuses of Smad1/5/9 and non-canonical p38 MAPK and Erk1/2 were assessed in the presence/absence of pathway blockers. NP marker and matrix degrading enzyme gene expression was determined by qPCR following GDF6 stimulation. Glycosaminoglycan and collagen production were assessed through DMMB-assay and histochemical staining. Results. NP cells expressed all GDF6 receptor subunits, with receptor subunits BMPR-1A and BMPR2 displaying the highest expression and highest binding affinity. GDF6 stimulation significantly upregulated the expression of NP specific marker genes but had no significant effect on the expression of matrix degrading enzymes. Total glycosaminoglycan and collagen production was also significantly increased following GDF6 stimulation. Smad1/5/9, p38 MAPK and Erk1/2 pathways were phosphorylated following GDF6 stimulation and could be effectively blocked. Conclusions. These findings enhance our understanding of both the effects of GDF6 in NP cells and the mechanisms of GDF6 signal transduction that are critical to promote NP phenotype and cellular function. This knowledge is important for the effective use of GDF6 as a therapeutic molecule for treatment of IVD degeneration. Conflicts of interest. No conflicts of interest. Sources of funding. We would like to acknowledge UKRMP Acellular Hub, MRC, NIHR Musculoskeletal BRU and The Rosetrees Trust for funding this research

Background. Degeneration of the intervertebral disc (IVD) is a leading cause of lower back pain, and a significant clinical problem. Inflammation mediated by IL-1β and TNF-α drives IVD degeneration through promoting a phenotypic switch in the resident nucleus pulposus (NP) cells towards a more catabolic state, resulting in extracellular matrix degradation. Bone marrow mesenchymal stem cells (MSCs) produce bioactive factors that modulate local tissue microenvironments and their anti-inflammatory potential has been shown in numerous disease models. Thus MSCs offer a potential therapy for IVD degeneration. In a clinical setting, adipose-derived stem cells (ASCs) might represent an alternative and perhaps more appealing cell source. However, their anti-inflammatory properties remain poorly understood. Methods. Here we assess the anti-inflammatory properties of donor-matched human ASCs and MSCs using qPCR and western blotting. Results. We demonstrate that stimulating ASCs or MSCs with IL-1β and/or TNF-α elicits a strong anti-inflammatory response with increased expression of IL-1 receptor antagonist (IL-1Ra), cyclooxygenase-2 (COX-2) and the tissue protective protein tumour-necrosis factor stimulated gene-6 (TSG-6). ASCs produced significantly higher levels of IL-1Ra and TSG-6 than their matched MSCs at both gene and protein levels, indicating that ASCs are potentially a more potent anti-inflammatory cell type. This anti-inflammatory response was also observed upon co-culture with degenerate NP cells without exogenous cytokine. Signalling analyses suggested this difference between cell types might be mediated through differences in the activation of inflammation-associated transcription factors. Conclusion. These data indicate that the anti-inflammatory properties of ASCs may be useful in developing future therapies for IVD degeneration. No conflicts of interest. Sources of funding: EPSRC-MRC Centre for Doctoral Training in Regenerative Medicine (EP/L014904/1)

Background. Currently, there is a focus on the development of cell based therapies to treat intervertebral disc (IVD) degeneration, particularly for regenerating/repairing the central region, the nucleus pulposus (NP). Recently, we demonstrated that GDF6 promotes NP-like differentiation in mesenchymal stem cells (MSCs). However, bone marrow- (BM-MSCs) and adipose- (Ad-MSCs) showed differential responses to GDF6, with Ad-MSCs adopting a more NP-like phenotype. Here, we investigated GDF6 signalling in BM-MSCs and Ad-MSCs, with the aim to improve future IVD stem cell therapies. Methods. GDF6 receptor expression in patient-matched BM-MSCs and Ad-MSCs (N=6) was profiled through western blot and immunocytochemistry (ICC). GDF6 signal transduction was investigated through stimulation with 100 ng ml. −1. GDF6 for defined time periods. Subsequently smad1/5/9 phosphorylation and alternative non-smad pathway activation (phospho-p38; phospho-Erk1/2) was analysed (western blot, ELISA). Their role in inducing NP-like gene expression in Ad-MSCs was examined through pathway specific inhibitors. Results. Western blot and ICC established that BMPR profiles differed between MSC populations; specifically, BMPR2 (a GDF6 receptor) expression, was significantly higher in Ad-MSCs (p<0.05). ELISA and western blot analysis showed that smad1/5/9 phosphorylation was significantly higher in Ad-MSCs following GDF6 stimulation (p<0.05). GDF6 stimulation also phosphorylated p38 and Erk1/2 pathways. Blocking of both smad and non-smad pathways resulted in variation of GDF6 induced NP-like gene expression. Conclusions. The upregulation of BMPR2 in Ad-MSCs and corresponding differences in smad1/5/9 and non-smad pathway phosphorylation in response to GDF6 indicates an enhanced discogenic potential in Ad-MSCs, suggesting they may be more suitable for GDF6 mediated cellular IVD regeneration. Conflicts of interest. No conflicts of interest. Sources of funding. We would like to acknowledge UKRMP Acellular Hub, MRC, NIHR Musculoskeletal BRU and The Rosetrees Trust for funding this research

Aims

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.

Aims

The prevalence of scoliosis is not known in patients with idiopathic short stature, and the impact of treatment with recombinant human growth hormone on those with scoliosis remains controversial. We investigated the prevalence of scoliosis radiologically in children with idiopathic short stature, and the impact of treatment with growth hormone in a cross-sectional and retrospective cohort study.

Aims

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.

Introduction. Musculoskeletal diseases are the biggest cause of morbidity worldwide, with low back pain (LBP) being the leading cause. Forty percent of LBP cases are caused by disease of shock absorbers in the spine known as intervertebral discs (IVDs). The IVDs enable the spine to twist and bend, whilst absorbing load during normal daily activities. The durability of this tissue is sustained by the cells of the spine and so during disease or mechanical damage these cells can behave abnormally further damaging the disc and stimulating local nerves causing extreme pain. Degradation of the intervertebral disc (IVD) currently has no preventative treatment; an injectable hydrogel biomaterial could reinforce disc mechanical properties and promote tissue regeneration. Methods and Results. We present an injectable range of hydrogel biomaterials made from water, clay and polymer that set at 37°C. The materials were made at 80°C polymerised in water and stored at 70°C to remain liquid. The physical properties of the materials were assessed using various methods, including mechanical assessment using temperature-controlled rheometry to monitor the liquid-hydrogel transition. Conclusion. Results showed that by changing three factors within the formulation we can produce a range of materials with suitable mechanical and morphological properties for a variety of tissues of the spine. These types of biomaterials have the potential to provide the first efficacious early-mid stage treatment for IVD disease and reduce the cost of LBP on our health services. Conflicts of interest: CS and CLM are named inventors on the patent for NPgel/BGel. Funded by the Medical Research Council and Versus Arthritis UK: SNiPER

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This study was performed to explore the effect of melatonin on pyroptosis in nucleus pulposus cells (NPCs) and the underlying mechanism of that effect.

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The aim of this study was to investigate the incidence and characteristics of instrumentation failure (IF) after total en bloc spondylectomy (TES), and to analyze risk factors for IF.

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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).

We recorded compound muscle action potentials (CMAPs) from the diaphragm in 15 normal volunteers, nine patients with lesions of the lower cervical cord (C5 to C8), one completely quadriplegic patient (C6) and seven patients with lesions at a higher cervical level (C1 to C4). Transcranial magnetic stimulation and electrical stimulation of the phrenic nerve were carried out. When the centre of the coil was placed on the interauricular line at a point 3 cm lateral to the vertex on the scalp, the CMAPs from the diaphragm had the largest amplitude and the shortest latency. There was no difference in the mean latency of the CMAPs recorded by transcranial magnetic stimulation in the normal volunteers and in the patients with lesions of the lower cervical cord. In the quadriplegic patient, the latency of the CMAPs was not delayed, but was prolonged in the patients with lesions at a higher level. Those evoked by electrical stimulation of the phrenic nerve were not prolonged in the patients with higher lesions. Our findings suggest that the prolongation of the latency by transcranial magnetic stimulation reflects dysfunction of the higher cervical cord. The combination of transcranial magnetic stimulation and electrical stimulation of the phrenic nerve can detect the precise level of the lesion in the motor tract to the diaphragm

Previous research has suggested that when subjected to painful lumbar stimulation, chronic low back pain (CLBP) patients with illness behaviour (IB) are unable to effectively engage a sensory modulation system utilised by patients without IB. 1. Furthermore, reduced insular cortex volume in CLBP patients with IB, may compound this problem. 2. . Pain Management Programs (PMP) has demonstrated reductions in IB and disability associated with chronic pain conditions. This current study aims to assess whether the pattern of cerebral response to pain in IB patients could be normalised by participation in a PMP. 12 patients with CLBP and IB (>4/5 Waddell signs present) were recruited prior to attending a 16-day PMP. FMRI scanning occurred prior to (PrePMP) and upon completion of the PMP (PostPMP). 8 healthy volunteers (HC) were scanned once. As in previous research, painful stimuli consisted of intense electrical stimulation delivered bilaterally to the lower back. The presentation of 3 colours indicated the likelihood of receiving 10second stimulation to the lower back (Always, Never and Maybe). IB scores were significantly reduced PostPMP (p <0.05). FMRI group activation maps for the Always condition revealed PostPMP patients increased activation in posterior regions, areas similarly activated by HC. For the Maybe condition, compared to PrePMP group, HC demonstrated greater activation in precuneus and middle and inferior frontal regions. Compared to their pre-treatment selves, PostPMP patients demonstrated increased activation in posterior and frontal regions. The results demonstrate that completion of a 16-day PMP leads to alteration in the brain's response to painful low back stimulation in CLBP patients with IB. Increased activation is seen in regions associated with the top-down modulation of pain. The response is similar to that seen in HC, and greater than before PMP confirming that the PMP process facilitates the utilisation of more normal coping pathways in response to CLBP

The aim of this study was to evaluate the feasibility of using the intact S1 nerve root as a donor nerve to repair an avulsion of the contralateral lumbosacral plexus. Two cohorts of patients were recruited. In cohort 1, the L4–S4 nerve roots of 15 patients with a unilateral fracture of the sacrum and sacral nerve injury were stimulated during surgery to establish the precise functional distribution of the S1 nerve root and its proportional contribution to individual muscles. In cohort 2, the contralateral uninjured S1 nerve root of six patients with a unilateral lumbosacral plexus avulsion was transected extradurally and used with a 25 cm segment of the common peroneal nerve from the injured leg to reconstruct the avulsed plexus. The results from cohort 1 showed that the innervation of S1 in each muscle can be compensated for by L4, L5, S2 and S3. Numbness in the toes and a reduction in strength were found after surgery in cohort 2, but these symptoms gradually disappeared and strength recovered. The results of electrophysiological studies of the donor limb were generally normal. . Severing the S1 nerve root does not appear to damage the healthy limb as far as clinical assessment and electrophysiological testing can determine. Consequently, the S1 nerve can be considered to be a suitable donor nerve for reconstruction of an avulsed contralateral lumbosacral plexus. Cite this article: Bone Joint J 2015; 97-B:358–65

Aims

With resumption of elective spine surgery services in the UK following the first wave of the COVID-19 pandemic, we conducted a multicentre British Association of Spine Surgeons (BASS) collaborative study to examine the complications and deaths due to COVID-19 at the recovery phase of the pandemic. The aim was to analyze the safety of elective spinal surgery during the pandemic.

Objectives. In order to elucidate the influence of sympathetic nerves on lumbar radiculopathy, we investigated whether sympathectomy attenuated pain behaviour and altered the electrical properties of the dorsal root ganglion (DRG) neurons in a rat model of lumbar root constriction. Methods. Sprague-Dawley rats were divided into three experimental groups. In the root constriction group, the left L5 spinal nerve root was ligated proximal to the DRG as a lumbar radiculopathy model. In the root constriction + sympathectomy group, sympathectomy was performed after the root constriction procedure. In the control group, no procedures were performed. In order to evaluate the pain relief effect of sympathectomy, behavioural analysis using mechanical and thermal stimulation was performed. In order to evaluate the excitability of the DRG neurons, we recorded action potentials of the isolated single DRG neuron by the whole-cell patch-clamp method. Results. In behavioural analysis, sympathectomy attenuated the mechanical allodynia and thermal hyperalgesia caused by lumbar root constriction. In electrophysiological analysis, single isolated DRG neurons with root constriction exhibited lower threshold current, more depolarised resting membrane potential, prolonged action potential duration, and more depolarisation frequency. These hyperexcitable alterations caused by root constriction were significantly attenuated in rats treated with surgical sympathectomy. Conclusion. The present results suggest that sympathectomy attenuates lumbar radicular pain resulting from root constriction by altering the electrical property of the DRG neuron itself. Thus, the sympathetic nervous system was closely associated with lumbar radicular pain, and suppressing the activity of the sympathetic nervous system may therefore lead to pain relief