TACAN Is an Ion Channel Involved in Sensing Mechanical Pain.

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elusive. Here we report identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, a nociceptor-specific inducible knockout of TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to painful mechanical stimuli but not to thermal or touch stimuli. We propose that TACAN is an ion channel that contributes to sensing mechanical pain.

Single-Cell RNA-Seq Analysis of Cells from Degenerating and Non-Degenerating Intervertebral Discs from the Same Individual Reveals New Biomarkers for Intervertebral Disc Degeneration.

In this study, we used single-cell transcriptomic analysis to identify new specific biomarkers for nucleus pulposus (NP) and inner annulus fibrosis (iAF) cells, and to define cell populations within non-degenerating (nD) and degenerating (D) human intervertebral discs (IVD) of the same individual. Cluster analysis based on differential gene expression delineated 14 cell clusters. Gene expression profiles at single-cell resolution revealed the potential functional differences linked to degeneration, and among NP and iAF subpopulations. GO and KEGG analyses discovered molecular functions, biological processes, and transcription factors linked to cell type and degeneration state. We propose two lists of biomarkers, one as specific cell type, including C2orf40, MGP, MSMP, CD44, EIF1, LGALS1, RGCC, EPYC, HILPDA, ACAN, MT1F, CHI3L1, ID1, ID3 and TMED2. The second list proposes predictive IVD degeneration genes, including MT1G, SPP1, HMGA1, FN1, FBXO2, SPARC, VIM, CTGF, MGST1, TAF1D, CAPS, SPTSSB, S100A1, CHI3L2, PLA2G2A, TNRSF11B, FGFBP2, MGP, SLPI, DCN, MT-ND2, MTCYB, ADIRF, FRZB, CLEC3A, UPP1, S100A2, PRG4, COL2A1, SOD2 and MT2A. Protein and mRNA expression of MGST1, vimentin, SOD2 and SYF2 (p29) genes validated our scRNA-seq findings. Our data provide new insights into disc cells phenotypes and biomarkers of IVD degeneration that could improve diagnostic and therapeutic options.

A roadmap to surgery in osteogenesis imperfecta: results of an international collaboration of patient organizations and interdisciplinary care teams.

Background and purpose - Involvement of patient organizations is steadily increasing in guidelines for treatment of various diseases and conditions for better care from the patient's viewpoint and better comparability of outcomes. For this reason, the Osteogenesis Imperfecta Federation Europe and the Care4BrittleBones Foundation convened an interdisciplinary task force of 3 members from patient organizations and 12 healthcare professionals from recognized centers for interdisciplinary care for children and adults with osteogenesis imperfecta (OI) to develop guidelines for a basic roadmap to surgery in OI.Methods - All information from 9 telephone conferences, expert consultations, and face-to-face meetings during the International Conference for Quality of Life for Osteogenesis Imperfecta 2019 was used by the task force to define themes and associated recommendations.Results - Consensus on recommendations was reached within 4 themes: the interdisciplinary approach, the surgical decision-making conversation, surgical technique guidelines for OI, and the feedback loop after surgery.Interpretation - The basic guidelines of this roadmap for the interdisciplinary approach to surgical care in children and adults with OI is expected to improve standardization of clinical practice and comparability of outcomes across treatment centers.

Toll-like receptor involvement in adolescent scoliotic facet joint degeneration.

Facet joint osteoarthritis is prevalent in young patients with adolescent idiopathic scoliosis (AIS) and might contribute to back pain. Toll-like receptors (TLR) have been linked to cartilaginous tissue degeneration but their involvement in facet joint osteoarthritis in AIS patients is still unknown. We compared baseline gene expression levels of TLRs -1, -2, -4, and -6 in scoliotic and non-scoliotic chondrocytes and found higher expression levels in scoliotic chondrocytes with significantly higher TLR2 levels. Furthermore, TLR expression correlated strongly and significantly with inflammatory and catabolic markers in scoliotic but not in non-scoliotic chondrocytes. TLR activation with a synthetic TLR2/6 agonist resulted in a robust induction and release of pro-inflammatory and catabolic factors which exacerbated proteoglycan loss in scoliotic but not in non-scoliotic cartilage. We also detected a higher abundance of alarmins including S100A8/9 and biglycan in scoliotic cartilage. Finally, the small-molecule antagonists Sparstolonin B and o-Vanillin reduced catabolism following induction with naturally occurring alarmins and the synthetic TLR2/6 agonist. The high baseline expression, robust responsiveness and strong and significant correlation with proteases and pro-inflammatory cytokines suggest that TLRs are key regulators of facet joint degeneration in AIS. Blocking their activity could therefore potentially modify disease progression.

Back pain in adolescents with idiopathic scoliosis: the contribution of morphological and psychological factors.

PURPOSE: To define the relationship between 3D radiological features, psychological factors, and back pain prevalence and intensity in patients with adolescent idiopathic scoliosis (AIS). METHODS: Consecutive AIS patients answered self-reported questionnaires and underwent simultaneous posterior-anterior and lateral scans of the spine (EOS Imaging, Paris, France). 3D reconstructions of the spine and pelvis reported 18 parameters in the coronal, sagittal, and axial plane. RESULTS: Hundred and twenty-four patients with AIS were included in the study. Overall, 90% of AIS patients reported having some back pain over the last 6 months and 85.8% over the last 30 days. Pain intensity in the last month was reported to be mild in 37.5%, moderate in 31.8%, moderate to severe in 24.3%, and severe in 6.54% of cases. Location of back pain was associated with location of main curve (P = 0.036). Low back pain was associated with higher lumbar apical AVR and lower lumbar lordosis (P < 0.05). Independent risk factors for back pain in AIS were pain catastrophizing (B = 0.061, P = 0.035), poorer self-reported state of mental health (B = - 0.872, P = 0.023), decreased thoracic kyphosis (B = - 0.033, P = 0.044) and greater pelvic asymmetry (B = 0.146, P = 0.047). There was a significant association between self-reported pain intensity in the last 24 h and levels of catastrophizing. Pain catastrophizing level influenced the relationship between deformity severity and pain intensity. In low catastrophizers, there was a significant association between greater deformity severity and higher pain levels. CONCLUSIONS: Back pain in AIS is multifactorial and associated with psychological and morphological parameters. Pain catastrophizing is an important construct in AIS-related pain and should be taken into consideration when evaluating these patients.

Adolescent idiopathic scoliosis: evaluating perioperative back pain through a simultaneous morphological and biomechanical approach.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) has been associated with diminished postural stability and a greater prevalence of back pain. Currently, the literature is lacking information on the effect of spinal fusion on both postural stability and its association with back pain. Our objectives were to evaluate the postsurgical effect of spinal morphological changes on static standing balance and assess the influence of these alterations on reported pain throughout the perioperative period. METHODS: Twenty consecutive AIS patients schedule to undergo spinal fusion surgery were recruited and followed prospectively at the Shriners Hospitals for Children-Canada. Data was collected at the preoperative, 6 weeks and 6 months postoperative visits. Spinal morphology data was collected through 3D reconstructed simultaneous standing biplanar radiographs using the SterEOS software. Postural balance was assessed through Moticon© sensor insoles and analyzed through their software. The data was simultaneously collected as part of the Global Biomechanical and morphological Assessment. Pain was evaluated through self-reported questionnaires. RESULTS: Morphological curve parameters were significantly reduced after surgery. Balance parameters did not change significantly throughout the perioperative period with the exception of the Center of Pressure of the left foot medial/lateral transient shift (P = 0.017) at 6 weeks. Of note, preoperative balance parameters were associated with the degree of right thoracic Cobb angles (P = 0.029 R = 0.528). Pain scores significantly improved 6 weeks and 6 months after the surgery. Pain intensity diminished in the thoracic and lumbar spine but worsen in the neck region at the 6 weeks and 6 months postoperative time points (P = 0.044). Greater residual Cobb angle difference between Mid thoracic and Thoracolumbar/Lumbar curves was associated with greater pain severity at 6 weeks postop (P < 0.005). In addition, greater residual thoracic deformity was associated with significant pain severity 6 months after surgery (P < 0.05). CONCLUSIONS: Improved spinal morphology of postsurgical AIS patients has no significant impact on their static standing balance. Suggesting that other factors apart from the spinal morphology may contribute to AIS patients' balance during stance. Although balance did not influence pain severity, spinal morphology and its correction appear to have influenced the intensity and location of back pain.

The Tampa Scale of Kinesiophobia: Structural Validation among Adolescents with Idiopathic Scoliosis Undergoing Spinal Fusion Surgery.

AIMS: Spinal fusion surgery is one of the most invasive orthopedic surgeries. Pain while moving or a fear of experiencing pain after surgery may delay return to function and cause prolonged disability. The purpose of the study was to examine the psychometric properties of the Tampa Scale of Kinesiophobia (TSK) in pediatric patients undergoing scoliosis surgery. METHODS: Fifty-five adolescents (10-18 years old) scheduled for spinal fusion surgery were enrolled. Participants completed the TSK questionnaire before surgery and six weeks after surgery. Reliability, exploratory and confirmatory factor analyses were performed on the two-factors TSK including activity avoidance (TSK-AA) and somatic focus (TSK-SF). RESULTS: Before and after surgery, all TSK-AA items conformed into the same factor component and revealed good internal reliability with Cronbach's alpha of .76 and .70 respectively. TSK-SF items were separated into different factor components and revealed poor reliability (.11 and .56). The TSK-AA also produced an adequate fit to the data, as reflected with several fit indices at both timepoints, respectively: χ2/df = 1.19 and 1.22; CFI=.96 and .94; and RMSEA=.06 and .06. CONCLUSIONS: The TSK-AA demonstrated good psychometric properties in patients undergoing scoliosis surgery, which provides empirical evidence for pediatrics. Its validation in distinct populations and settings is recommended prior to its use.

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs.

Nerve growth factor (NGF) contributes to the development of chronic pain associated with degenerative connective tissue pathologies, such as intervertebral disc degeneration and osteoarthritis. However, surprisingly little is known about the regulation of NGF in these conditions. Toll-like receptors (TLR) are pattern recognition receptors classically associated with innate immunity but more recently were found to be activated by endogenous alarmins such as fragmented extracellular matrix proteins found in degenerating discs or cartilage. In this study we investigated if TLR activation regulates NGF and which signaling mechanisms control this response in intervertebral discs. TLR2 agonists, TLR4 agonists, or IL-1ß (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1ß gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1ß treatment increased NGF protein secretion. TLR2 activation increased p38, ERK1/2, and p65 activity and increased p65 translocation to the cell nucleus. JNK activity was not affected by TLR2 activation. Inhibition of NF-κB, and to a lesser extent p38, but not ERK1/2 activity, blocked TLR2-driven NGF up-regulation at both the transcript and protein levels. These results provide a novel mechanism of NGF regulation in the intervertebral disc and potentially other pathogenic connective tissues. TLR2 and NF-κB signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-κB inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.

Partial recovery of abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment.

We previously reported that effective treatment of chronic low back pain (CLBP) reversed abnormal brain structure and functional MRI (fMRI) activity during cognitive task performance, particularly in the left dorsolateral prefrontal cortex (DLPFC). Here, we used resting-state fMRI to examine how chronic pain affects connectivity of brain networks supporting cognitive functioning and the effect of treatment in 14 CLBP patients and 16 healthy, pain-free controls (scans were acquired at baseline for all subjects and at 6-months post-treatment for patients and a matched time-point for 10 controls). The main networks activated during cognitive task performance, task-positive network (TPN) and task-negative network (TNN) (aka default mode) network, were identified in subjects' task fMRI data and used to define matching networks in resting-state data. The connectivity of these cognitive resting-state networks was compared between groups, and before and after treatment. Our findings converged on the bilateral insula (INS) as the region of aberrant cognitive resting-state connectivity in patients pretreatment versus controls. These findings were complemented by an independent, data-driven approach showing altered global connectivity of the INS. Detailed investigation of the INS confirmed reduced connectivity to widespread TPN and TNN areas, which was partially restored post-treatment. Furthermore, analysis of diffusion-tensor imaging (DTI) data revealed structural changes in white matter supporting these findings. The left DLPFC also showed aberrant connectivity that was restored post-treatment. Altogether, our findings implicate the bilateral INS and left DLPFC as key nodes of disrupted cognition-related intrinsic connectivity in CLBP, and the resulting imbalance between TPN and TNN function is partially restored with treatment.

Axial T1ρ MRI as a diagnostic imaging modality to quantify proteoglycan concentration in degenerative disc disease.

PURPOSE: The aim of the study was to investigate if axial T1ρ MR images had similar accuracy as established sagittal T1ρ MRI for the assessment of proteoglycan concentration and content in intervertebral degenerated discs (IDDs). METHODS: T1ρ and T2-weighted MR images of 12 intervertebral discs (IVDs) from 3 harvested human lumbar spines (levels L1-L2 to L5-S1) were grouped across their degenerative grade (Pfirrmann scores) and analyzed using a 3T MRI scanner in the axial and sagittal views. Post-processing of axial T1ρ-weighted images was performed using a Wiener filter. Median axial T1ρ values for traced regions of interest (ROIs) on color maps were compared against ROIs in the corresponding location in the sagittal plane of each disc. Assessment of sulfated glycosaminoglycans (GAGs) content was also performed. RESULTS: Comparison of post Wiener filtered mid-axial T1ρ values in the NP with corresponding mid-sagittal values revealed no statistical difference (P > 0.05). Higher axial T1ρ and biochemically measured GAGs content corresponded to a lower Pfirrmann grading of the IVDs. A strong association between the T1ρ values and the GAG contents was observed (r = 0.85, P = 0.0002). CONCLUSIONS: The axial T1ρ methodology was validated against sagittal T1ρ providing an augmented spatial representation of IVD and can facilitate localization of focal degeneration within IVDs. T1ρ values provided a better granularity assessment of degenerative disc disease as it correlated with proteoglycan concentration. Thus, Wiener filtering is an effective tool for removing noise from T1ρ-weighted axial MR images.

Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors.

Intervertebral disc degeneration (IVD) can result in chronic low back pain, a common cause of morbidity and disability. Inflammation has been associated with IVD degeneration, however the relationship between inflammatory factors and chronic low back pain remains unclear. Furthermore, increased levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are both associated with inflammation and chronic low back pain, but whether degenerating discs release sufficient concentrations of factors that induce nociceptor plasticity remains unclear. Degenerating IVDs from low back pain patients and healthy, painless IVDs from human organ donors were cultured ex vivo. Inflammatory and nociceptive factors released by IVDs into culture media were quantified by enzyme-linked immunosorbent assays and protein arrays. The ability of factors released to induce neurite growth and nociceptive neuropeptide production was investigated. Degenerating discs release increased levels of tumour necrosis factor-α, interleukin-1ß, NGF and BDNF. Factors released by degenerating IVDs increased neurite growth and calcitonin gene-related peptide expression, both of which were blocked by anti-NGF treatment. Furthermore, protein arrays found increased levels of 20 inflammatory factors, many of which have nociceptive effects. Our results demonstrate that degenerating and painful human IVDs release increased levels of NGF, inflammatory and nociceptive factors ex vivo that induce neuronal plasticity and may actively diffuse to induce neo-innervation and pain in vivo.

Markers of Tissue Deterioration and Pain on Earth and in Space.

Purpose: Pain is an understudied physiological effect of spaceflight. Changes in inflammatory and tissue degradation markers are often associated with painful conditions. Our aim was to evaluate the changes in markers associated with tissue deterioration after a short-term spaceflight. Patients and Methods: Plasma levels of markers for systemic inflammation and tissue degeneration markers were assessed in two astronauts before and within 24 h after the 17-day Axiom Space AX-1 mission. Results: After the spaceflight, C-reactive protein (CRP) was reduced in both astronauts, while INFγ, GM-CSF, TNFα, BDNF, and all measured interleukins were consistently increased. Chemokines demonstrated variable changes, with consistent positive changes in CCL3, 4, 8, 22 and CXCL8, 9, 10, and consistent negative change in CCL8. Markers associated with tissue degradation and bone turnover demonstrated consistent increases in MMP1, MMP13, NTX and OPG, and consistent decreases in MMP3 and MMP9. Conclusion: Spaceflight induced changes in the markers of systemic inflammation, tissue deterioration, and bone resorption in two astronauts after a short, 17-day, which were often consistent with those observed in painful conditions on Earth. However, some differences, such as a consistent decrease in CRP, were noted. All records for the effect of space travel on human health are critical for improving our understanding of the effect of this unique environment on humans.

Pharmacological Treatment of Degenerative Cervical Myelopathy: A Critical Review of Current Evidence.

Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults, representing substantial morbidity and significant financial and resource burdens. Typically, patients with progressive DCM will eventually receive surgical treatment. Nonetheless, despite advancements in pharmacotherapeutics, evidence for pharmacological therapy remains limited. Health professionals from various fields would find interest in pharmacological agents that could benefit patients with mild DCM or enhance surgical outcomes. This review aims to consolidate all clinical and experimental evidence on the pharmacological treatment of DCM. We conducted a comprehensive narrative review that presents all pharmacological agents that have been investigated for DCM treatment in both humans and animal models. Riluzole exhibits effectiveness solely in rat models, but not in treating mild DCM in humans. Cerebrolysin emerges as a potential neuroprotective agent for myelopathy in animals but had contradictory results in clinical trials. Limaprost alfadex demonstrates motor function improvement in animal models and exhibits promising outcomes in a small clinical trial. Glucocorticoids not only fail to provide clinical benefits but may also lead to adverse events. Cilostazol, anti-Fas ligand antibody, and Jingshu Keli display promise in animal studies, while erythropoietin, granulocyte colony-stimulating factor and limaprost alfadex exhibit potential in both animal and human research. Existing evidence mainly rests on weak clinical data and animal experimentation. Current pharmacological efforts target ion channels, stem cell differentiation, inflammatory, vascular, and apoptotic pathways. The inherent nature and pathogenesis of DCM offer substantial prospects for developing neurodegenerative or neuroprotective therapies capable of altering disease progression, potentially delaying surgical intervention, and optimizing outcomes for those undergoing surgical decompression.

Breast Hypertrophy: A Real Pain in the Back.

BACKGROUND: Bilateral breast hypertrophy comes with signs and symptoms ranging from mild to debilitating. Bilateral breast reduction (BBR) is one of the most frequently performed plastic surgery procedures, and its effects on parameters such as spinal balance, paraspinal muscle function, and physical performance have not been thoroughly evaluated. The objective of this study was to evaluate the effects of BBR using advanced spine imaging modalities, and pain resolution. METHODS: A prospective, observational, cohort study was carried out at the McGill University Health Centre. The following measures were recorded preoperatively and postoperatively for each patient: patient questionnaires (BREAST-Q and Pain), magnetic resonance imaging, and EOS low-radiation spinal scan. RESULTS: Significant postoperative pain reduction was recorded, and there was up to 148% improvement in physical tests. Improvement in all questionnaire and BREAST-Q categories was documented. Preoperative and postoperative magnetic resonance imaging did demonstrate a statistically significant absence of permanent anatomical skeletal sequelae. Postoperative improvement in thoracic kyphosis was documented. CONCLUSIONS: Quality-of-life scores are uniformly improved following BBR. Key findings following BBR include significant pain reduction and no evidence of spinal skeletal change. This is a finding of major importance in view of the practice of many insurance companies/third-party payer and health care systems that use the Schnur scale. The Schnur scale associates a weight for resection with body size that is not directly predictive of pain relief. This may indicate the need for more precise or different guidelines based on these quantitative findings. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The Psychosocial Characteristics and Somatosensory Function of Children and Adolescents Who Meet the Criteria for Chronic Nociplastic Pain.

Purpose: Nociplastic pain distinguishes individuals with pain and hypersensitivity in body regions with apparently normal tissues, without any signs of neuropathy, but with contribution of central and/or peripheral sensitization. There is a lack of literature describing nociplastic pain in the pediatric population. The objective of this study was to investigate the differences between pediatric patients with nociplastic pain compared with patients with non-nociplastic pain. Patients and Methods: This study included 414 pediatric patients followed at an interdisciplinary centre for complex pain. All patients underwent an exhaustive pain assessment consisting of face-to-face interviews, validated self-report questionnaires and quantitative sensory testing. Recently established criteria for chronic nociplastic pain, and quantitative sensory testing was used to describe and stratify our cohort. Results: One hundred and sixty-five patients (40%) were stratified as having possible nociplastic pain and two hundred and forty-nine (60%) patients, as non-nociplastic pain. Patients with nociplastic pain displayed pain hypersensitivity in the region of pain, more symptoms of panic and social phobia, and worse sleep quality than patients with non-nociplastic pain. The proportion of patients achieving a meaningful clinical outcome after completion of their treatment (medications, physiotherapy, psychology, nursing, social worker, and/or interventional procedures) was lower in patients with nociplastic pain (62%) than those without nociplastic pain (86%). Conclusion: Our results suggest that patients who meet the criteria for nociplastic pain can be identified in a population of children and adolescents being treated in a center for complex pain. Combining screening with validated questionnaires and quantitative sensory testing facilitates the phenotyping and graded severity of patients with nociplastic pain in daily clinical practice.

Validation of the Critical-Care Pain Observation Tool (CPOT) in pediatric patients undergoing orthopedic surgery.

Background: Postoperative pain cannot be measured accurately among many children with intellectual and developmental disabilities, resulting in underrecognition or delay in recognition of pain. The Critical-Care Pain Observation Tool (CPOT) is a pain assessment tool that has been widely validated in critically ill and postoperative adults. Aims: The objective of this study was to validate the CPOT for use with pediatric patients able to self-report and undergoing posterior spinal fusion surgery. Methods: Twenty-four patients (10-18 years old) scheduled to undergo surgery were consented to this repeated-measure, within-subject study. To examine discriminative and criterion validation, CPOT scores and patients' self-reports of pain intensity were collected prospectively by a bedside rater before, during, and after a nonnociceptive and nociceptive procedure on the day following surgery. Patients' behavioral reactions were video recorded at the bedside and retrospectively viewed by two independent video raters to examine interrater and intrarater reliability of CPOT scores. Results: Discriminative validation was supported with higher CPOT scores during the nociceptive procedure than during the nonnociceptive procedure. Criterion validation was supported with a moderate positive correlation between the CPOT scores and the patients' self-reported pain intensity during the nociceptive procedure. A CPOT cutoff score of ≥2 was associated with the maximum sensitivity (61.3%) and specificity (94.1%). Reliability analyses revealed poor to moderate agreement between bedside and video raters and moderate to excellent consistency within video raters. Conclusions: These findings suggest that the CPOT may be a valid tool to detect pain in pediatric patients in the acute postoperative inpatient care unit after posterior spinal fusion.

Contexte: La douleur postopératoire ne peut pas être mesurée avec précision chez de nombreux enfants atteints de déficience intellectuelle et développementale, entraînant ainsi une méconnaissance ou un retard dans la reconnaissance de la douleur. Le Critical-Care Pain Observation Tool (CPOT) est un outil d'évaluation de la douleur qui a été largement validé chez les adultes gravement malades et postopératoires.Objectifs: L'objectif de cette étude était de valider le CPOT pour une utilisation auprès de patients pédiatriques capables d'autoévaluation et subissant une chirurgie de fusion vertébrale postérieure.Méthodes: Dans le cadre d'une étude intra-sujet, un consentement à cette mesure répétée a été obtenu pour vingt-quatre patients (10­18 ans) devant subir une intervention chirurgicale. Pour examiner la validation discriminante et de critère, les scores CPOT et les autoévaluations des patients concernant l'intensité de la douleur ont été collectés de manière prospective par un évaluateur au chevet du patient avant, pendant et après une procédure non nociceptive et nociceptive le lendemain de la chirurgie. Les réactions comportementales des patients ont été enregistrées sur vidéo au chevet du patient et visionnées rétrospectivement par deux des évaluateurs vidéo indépendants pour examiner la fiabilité des scores CPOT inter-évaluateurs et intra-évaluateurs.Résultats: La validation discriminante a été confirmée par l'obtention de scores plus élevés à l'échelle CPOT pendant la procédure nociceptive que pendant la procédure non nociceptive. La validation de critère a été confirmée par une corrélation positive modérée entre les scores sur l'échelle CPOT et l'intensité de la douleur autoévaluée par les patients pendant la procédure nociceptive. Un score-seuil ≥ 2 sur l'échelle CPOT a été associé à la sensibilité et la spécificité maximales (61,3 % et 94,1 %, respectivement). Les analyses de fiabilité ont révélé une concordance faible à modérée entre les évaluateurs de chevet et les évaluateurs vidéo, et une cocordance modérée à excellente parmi les évaluateurs vidéo.Conclusions: Ces résultats indiquent que le CPOT peut être un outil valide pour détecter la douleur chez les enfants patients de l'unité de soins hospitaliers postopératoires aigus après une fusion rachidienne postérieure.

Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs.

BACKGROUND: Low back pain is a global health problem directly related to intervertebral disc (IVD) degeneration. Senolytic drugs (RG-7112 and o-Vanillin) target and remove senescent cells from IVDs in vitro, improving tissue homeostasis. One drawback of using a single senolytic agent is the failure to target multiple senescent antiapoptotic pathways. This study aimed to determine if combining the two senolytic drugs, o-Vanillin and RG-7112, could more efficiently remove senescent cells and reduce the release of inflammatory factors and pain mediators in cells from degenerating human IVDs than either drug alone. METHODS: Preliminary data evaluating multiple concentrations of o-Vanillin and RG-7112 led to the selection of four treatment groups. Monolayer and pellet cultures of cells from painful degenerate IVDs were exposed to TLR-2/6 agonist. They were then treated with the senolytics o-Vanillin and RG7112 alone or combined. p16ink4a, Ki-67, caspase-3, inflammatory mediators, and neuronal sprouting were assessed. RESULTS: Compared to the single treatments, the combination of o-Vanillin and RG-7112 significantly reduced the amount of senescent IVD cells, proinflammatory cytokines, and neurotrophic factors. Moreover, both single and combination treatments significantly reduced neuronal sprouting in rat adrenal pheochromocytoma (PC-12 cells). CONCLUSIONS: Combining o-Vanillin and RG-7112 greatly enhanced the effect of either senolytic alone. Together, these results support the potential of senolytics as a promising treatment for IVD-related low back pain.

Modulating the activity of human nociceptors with a SCN10A promoter-specific viral vector tool.

Despite the high prevalence of chronic pain as a disease in our society, there is a lack of effective treatment options for patients living with this condition. Gene therapies using recombinant AAVs are a direct method to selectively express genes of interest in target cells with the potential of, in the case of nociceptors, reducing neuronal firing in pain conditions. We designed a recombinant AAV vector expressing cargos whose expression was driven by a portion of the SCN10A (NaV1.8) promoter, which is predominantly active in nociceptors. We validated its specificity for nociceptors in mouse and human dorsal root ganglia and showed that it can drive the expression of functional proteins. Our viral vector and promoter package drove the expression of both excitatory or inhibitory DREADDs in primary human DRG cultures and in whole cell electrophysiology experiments, increased or decreased neuronal firing, respectively. Taken together, we present a novel viral tool that drives expression of cargo specifically in human nociceptors. This will allow for future specific studies of human nociceptor properties as well as pave the way for potential future gene therapies for chronic pain.

Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function.

Chronic pain is associated with reduced brain gray matter and impaired cognitive ability. In this longitudinal study, we assessed whether neuroanatomical and functional abnormalities were reversible and dependent on treatment outcomes. We acquired MRI scans from chronic low back pain (CLBP) patients before (n = 18) and 6 months after (spine surgery or facet joint injections; n = 14) treatment. In addition, we scanned 16 healthy controls, 10 of which returned 6 months after the first visit. We performed cortical thickness analysis on structural MRI scans, and subjects performed a cognitive task during the functional MRI. We compared patients and controls, as well as patients before versus after treatment. After treatment, patients had increased cortical thickness in the left dorsolateral prefrontal cortex (DLPFC), which was thinner before treatment compared with controls. Increased DLPFC thickness correlated with the reduction of both pain and physical disability. Additionally, increased thickness in primary motor cortex was associated specifically with reduced physical disability, and right anterior insula was associated specifically with reduced pain. Left DLPFC activity during an attention-demanding cognitive task was abnormal before treatment, but normalized following treatment. These data indicate that functional and structural brain abnormalities-specifically in the left DLPFC-are reversible, suggesting that treating chronic pain can restore normal brain function in humans.

Sprengel deformity: pathogenesis and management.

Sprengel deformity (ie, congenital elevation of the scapula) is a rare clinical entity. However, it is the most common congenital anomaly of the shoulder. Sprengel deformity is caused by abnormal descent of the scapula during embryonic development. Sprengel deformity is associated with cosmetic deformity and decreased shoulder function. Diagnostic confusion with limited scoliosis can be dangerous to the patient because it may delay proper treatment of other abnormalities that may be present with even mild cases. Sprengel deformity is commonly linked to a variety of conditions, including Klippel-Feil syndrome, scoliosis, and rib anomalies. Nonsurgical management can be considered for mild cases. Surgical management is typically warranted for more severe cases, with the goal of improving cosmesis and function. Surgical techniques are centered on resection of the protruding portion of the scapula and inferior translation of the scapula. Recent long-term studies indicate that patients treated surgically maintain improved shoulder function and appearance.