-
ELife Jun 2024Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying...
Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation, and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain.
Topics: Animals; Mice; Osteoclasts; Cellular Senescence; Sensory Receptor Cells; Disease Models, Animal; Male; Nerve Growth Factor; Netrin-1; Mice, Inbred C57BL
PubMed: 38896465
DOI: 10.7554/eLife.92889 -
BioRxiv : the Preprint Server For... Jun 2024In most complex nervous systems there is a clear anatomical separation between the nerve cord, which contains most of the final motor outputs necessary for behaviour,...
In most complex nervous systems there is a clear anatomical separation between the nerve cord, which contains most of the final motor outputs necessary for behaviour, and the brain. In insects, the neck connective is both a physical and information bottleneck connecting the brain and the ventral nerve cord (VNC, spinal cord analogue) and comprises diverse populations of descending (DN), ascending (AN) and sensory ascending neurons, which are crucial for sensorimotor signalling and control. Integrating three separate EM datasets, we now provide a complete connectomic description of the ascending and descending neurons of the female nervous system of and compare them with neurons of the male nerve cord. Proofread neuronal reconstructions have been matched across hemispheres, datasets and sexes. Crucially, we have also matched 51% of DN cell types to light level data defining specific driver lines as well as classifying all ascending populations. We use these results to reveal the general architecture, tracts, neuropil innervation and connectivity of neck connective neurons. We observe connected chains of descending and ascending neurons spanning the neck, which may subserve motor sequences. We provide a complete description of sexually dimorphic DN and AN populations, with detailed analysis of circuits implicated in sex-related behaviours, including female ovipositor extrusion (DNp13), male courtship (DNa12/aSP22) and song production (AN hemilineage 08B). Our work represents the first EM-level circuit analyses spanning the entire central nervous system of an adult animal.
PubMed: 38895426
DOI: 10.1101/2024.06.04.596633 -
BioRxiv : the Preprint Server For... Jun 2024Chondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post myocardial infarction (MI), causing regional hypo-innervation that is...
UNLABELLED
Chondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post myocardial infarction (MI), causing regional hypo-innervation that is associated with supersensitivity of β-adrenergic receptors and increased arrhythmia susceptibility. To investigate the role of CSPGs and hypo-innervation in the heart of larger mammals, we used a rabbit model of reperfused MI and tested electrophysiological responses to sympathetic nerve stimulation (SNS). Innervated hearts from MI and sham rabbits were optically mapped using voltage and Ca -sensitive dyes. SNS was performed with electrical stimulation of the spinal cord and β-adrenergic responsiveness was tested using isoproterenol. Sympathetic nerve density and CSPG expression were evaluated using immunohistochemistry. CSPGs were robustly expressed in the infarct and border zone of all MI hearts, and the presence of CSPGs was associated with reduced sympathetic nerve density in the infarct vs. remote region. Action potential duration (APD) dispersion and susceptibility to ventricular tachycardia/fibrillation (VT/VF) were increased with SNS in MI hearts but not in sham. SNS decreased APD in MI but not sham hearts, while isoproterenol decreased APD in both groups. Isoproterenol also shortened Ca transient duration (CaTD ) in both groups but to a greater extent in MI hearts. Our data suggest sympathetic remodeling post-MI is similar between species, with CSPGs associated with sympathetic hypo-innervation. Despite a reduction in sympathetic nerve density, the infarct region of MI hearts remained responsive to both physiological SNS and isoproterenol, potentially through preserved or elevated β-adrenergic responsiveness, which may underly increased APD dispersion and susceptibility for VT/VF.
NEW & NOTEWORTHY
Here we show that CSPGs are present in the infarcts of rabbit hearts with reperfused MI, where they are associated with reduced sympathetic nerve density. Despite hypo-innervation, sympathetic responsiveness is maintained or enhanced in MI rabbit hearts, which also demonstrate increased APD dispersion and tendency for arrhythmias following sympathetic modulation. Together, this study indicates that the mechanisms of sympathetic remodeling post-MI are similar between species, with hypo-innervation likely associated with enhanced β-adrenergic sensitivity.
PubMed: 38895350
DOI: 10.1101/2024.06.05.597494 -
BioRxiv : the Preprint Server For... Jun 2024Depletion or inhibition of core stress granule proteins, G3BP1 in mammals and TIAR-2 in , increases axon regeneration in injured neurons that show spontaneous...
Depletion or inhibition of core stress granule proteins, G3BP1 in mammals and TIAR-2 in , increases axon regeneration in injured neurons that show spontaneous regeneration. Inhibition of G3BP1 by expression of its acidic or 'B-domain' accelerates axon regeneration after nerve injury bringing a potential therapeutic intervention to promote neural repair in the peripheral nervous system. Here, we asked if G3BP1 inhibition is a viable strategy to promote regeneration in the injured mammalian central nervous system where axons do not regenerate spontaneously. G3BP1 B-domain expression was found to promote axon regeneration in both the mammalian spinal cord and optic nerve. Moreover, a cell permeable peptide to a subregion of G3BP1's B-domain (rodent G3BP1 amino acids 190-208) accelerated axon regeneration after peripheral nerve injury and promoted the regrowth of reticulospinal axons into the distal transected spinal cord through a bridging peripheral nerve graft. The rodent and human G3BP1 peptides promoted axon growth from rodent and human neurons cultured on permissive substrates, and this function required alternating Glu/Asp-Pro repeats that impart a unique predicted tertiary structure. These studies point to G3BP1 granules as a critical impediment to CNS axon regeneration and indicate that G3BP1 granule disassembly represents a novel therapeutic strategy for promoting neural repair after CNS injury.
PubMed: 38895344
DOI: 10.1101/2024.06.07.597743 -
JOR Spine Jun 2024Numerous investigations have suggested links between circulating inflammatory proteins (CIPs) and spinal degenerative diseases (SDDs), but causality has not been proven....
BACKGROUND
Numerous investigations have suggested links between circulating inflammatory proteins (CIPs) and spinal degenerative diseases (SDDs), but causality has not been proven. This study used Mendelian randomization (MR) to investigate the causal associations between 91 CIPs and cervical spondylosis (CS), prolapsed disc/slipped disc (PD/SD), spinal canal stenosis (SCS), and spondylolisthesis/spondylolysis.
METHODS
Genetic variants data for CIPs and SDDs were obtained from the genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary method, analyzing the validity and robustness of the results through pleiotropy and heterogeneity tests and performing reverse MR analysis to test for reverse causality.
RESULTS
The IVW results with Bonferroni correction indicated that beta-nerve growth factor (β-NGF), C-X-C motif chemokine 6 (CXCL6), and interleukin-6 (IL-6) can increase the risk of CS. Fibroblast growth factor 19 (FGF19), sulfotransferase 1A1 (SULT1A1), and tumor necrosis factor-beta (TNF-β) can increase PD/SD risk, whereas urokinase-type plasminogen activator (u-PA) can decrease the risk of PD/SD. FGF19 and TNF can increase SCS risk. STAM binding protein (STAMBP) and T-cell surface glycoprotein CD6 isoform (CD6 isoform) can increase the risk of spondylolisthesis/spondylolysis, whereas monocyte chemoattractant protein 2 (MCP2) and latency-associated peptide transforming growth factor beta 1 (LAP-TGF-β1) can decrease spondylolisthesis/spondylolysis risk.
CONCLUSIONS
MR analysis indicated the causal associations between multiple genetically predicted CIPs and the risk of four SDDs (CS, PD/SD, SCS, and spondylolisthesis/spondylolysis). This study provides reliable genetic evidence for in-depth exploration of the involvement of CIPs in the pathogenic mechanism of SDDs and provides novel potential targets for SDDs.
PubMed: 38895179
DOI: 10.1002/jsp2.1346 -
Cureus Jun 2024We present a case report of diagnosis of cervical spine multiple sclerosis by a chiropractic physician. This unique case contributes an account of a challenging...
We present a case report of diagnosis of cervical spine multiple sclerosis by a chiropractic physician. This unique case contributes an account of a challenging differential diagnosis to the literature. A 30-year-old male presented with a three-year history of diffuse left upper extremity motor strength deficits and paresthesia (numbness and tingling). The patient had seen multiple physicians for these symptoms with no diagnosis of multiple sclerosis and no advanced imaging. The differential diagnosis included lower cervical spine nerve root compression or neurological disorders such as amyotrophic lateral sclerosis, cerebral lesion, motor neuropathy, multiple sclerosis, or spinal cord lesion. MRI of the cervical spine with and without IV contrast revealed evidence of spinal cord multiple sclerosis. The patient was referred to a neurologist where the diagnosis of multiple sclerosis was confirmed. A 10-year follow-up showed the patient was controlling his condition with medications and had no disability. This case underscores the importance for physicians to consider neurological conditions and advanced imaging in the presence of diffuse motor strength deficits and paresthesia in the absence of injury, pain, or any other symptoms.
PubMed: 38894936
DOI: 10.7759/cureus.62618 -
Journal of Pain Research 2024An early-stage, multi-centre, prospective, randomised control trial with five-year follow-up was approved by Health Research Authority to compare the efficacy of a... (Clinical Trial)
Clinical Trial
24-Month Outcomes of Indirect Decompression Using a Minimally Invasive Interspinous Fixation Device versus Standard Open Direct Decompression for Lumbar Spinal Stenosis: A Prospective Comparison.
PURPOSE
An early-stage, multi-centre, prospective, randomised control trial with five-year follow-up was approved by Health Research Authority to compare the efficacy of a minimally invasive, laterally implanted interspinous fixation device (IFD) to open direct surgical decompression in treating lumbar spinal stenosis (LSS). Two-year results are presented.
PATIENTS AND METHODS
Forty-eight participants were randomly assigned to IFD or decompression. Primary study endpoints included changes from baseline at 8-weeks, 6, 12 and 24-months follow-ups for leg pain (visual analogue scale, VAS), back pain (VAS), disability (Oswestry Disability Index, ODI), LSS physical function (Zurich Claudication Questionnaire), distance walked in five minutes and number of repetitions of sitting-to-standing in one minute. Secondary study endpoints included patient and clinician global impression of change, adverse events, reoperations, operating parameters, and fusion rate.
RESULTS
Both treatment groups demonstrated statistically significant improvements in mean leg pain, back pain, ODI disability, LSS physical function, walking distance and sitting-to-standing repetitions compared to baseline over 24 months. Mean reduction of ODI from baseline levels was between 35% and 56% for IFD (p<0.002), and 49% to 55% for decompression (p<0.001) for all follow-up time points. Mean reduction of IFD group leg pain was between 57% and 78% for all time points (p<0.001), with 72% to 94% of participants having at least 30% reduction of leg pain from 8-weeks through 24-months. Walking distance for the IFD group increased from 66% to 94% and sitting-to-standing repetitions increased from 44% to 64% for all follow-up time points. Blood loss was 88% less in the IFD group (p=0.024) and operating time parameters strongly favoured IFD compared to decompression (p<0.001). An 89% fusion rate was assessed in a subset of IFD participants. There were no intraoperative device issues or re-operations in the IFD group, and only one healed and non-symptomatic spinous process fracture observed within 24 months.
CONCLUSION
Despite a low number of participants in the IFD group, the study demonstrated successful two-year safety and clinical outcomes for the IFD with significant operation-related advantages compared to surgical decompression.
PubMed: 38894862
DOI: 10.2147/JPR.S453343 -
Frontiers in Genetics 2024Injuries to the spinal cord nervous system often result in permanent loss of sensory, motor, and autonomic functions. Accurately identifying the cellular state of spinal...
Injuries to the spinal cord nervous system often result in permanent loss of sensory, motor, and autonomic functions. Accurately identifying the cellular state of spinal cord nerves is extremely important and could facilitate the development of new therapeutic and rehabilitative strategies. Existing experimental techniques for identifying the development of spinal cord nerves are both labor-intensive and costly. In this study, we developed a machine learning predictor, ScnML, for predicting subpopulations of spinal cord nerve cells as well as identifying marker genes. The prediction performance of ScnML was evaluated on the training dataset with an accuracy of 94.33%. Based on XGBoost, ScnML on the test dataset achieved 94.08% 94.24%, 94.26%, and 94.24% accuracies with precision, recall, and F1-measure scores, respectively. Importantly, ScnML identified new significant genes through model interpretation and biological landscape analysis. ScnML can be a powerful tool for predicting the status of spinal cord neuronal cells, revealing potential specific biomarkers quickly and efficiently, and providing crucial insights for precision medicine and rehabilitation recovery.
PubMed: 38894722
DOI: 10.3389/fgene.2024.1413484 -
Sensors (Basel, Switzerland) May 2024This study investigated the reliability of measuring the median nerve cross-sectional area (CSA) at the carpal tunnel inlet using a handheld ultrasound device (HUD)...
This study investigated the reliability of measuring the median nerve cross-sectional area (CSA) at the carpal tunnel inlet using a handheld ultrasound device (HUD) compared to a standard ultrasound system, focusing on intra- and inter-operator reproducibility among novice and expert operators. Employing a prospective cross-sectional design, 37 asymptomatic adults were assessed using both devices, with measurements taken by an expert with over five years of experience and a novice with less than six months. The CSA was determined using manual tracing and ellipse methods, with reproducibility evaluated through intraclass correlation coefficients (ICCs) and agreement assessed via Bland-Altman plots. Results showed a high degree of agreement between the devices, with excellent intra-operator reproducibility (ICC > 0.80) for the expert, and moderate reproducibility for the novice (ICCs ranging from 0.539 to 0.841). Inter-operator reliability was generally moderate, indicating acceptable consistency across different experience levels. The study concludes that HUDs are comparable to standard ultrasound systems for assessing median nerve CSA in asymptomatic subjects, with both devices providing reliable measurements. This supports the use of HUDs in diverse clinical environments, particularly where access to traditional ultrasound is limited. Further research with a larger sample and symptomatic patients is recommended to validate these findings.
Topics: Humans; Median Nerve; Ultrasonography; Male; Female; Adult; Reproducibility of Results; Cross-Sectional Studies; Middle Aged; Prospective Studies; Carpal Tunnel Syndrome
PubMed: 38894235
DOI: 10.3390/s24113444 -
International Journal of Molecular... May 2024Glutamate functions as the major excitatory neurotransmitter for primary sensory neurons and has a crucial role in sensitizing peripheral nociceptor terminals producing...
Glutamate functions as the major excitatory neurotransmitter for primary sensory neurons and has a crucial role in sensitizing peripheral nociceptor terminals producing sensitization. Glutaminase (GLS) is the synthetic enzyme that converts glutamine to glutamate. GLS-immunoreactivity (-ir) and enzyme activity are elevated in dorsal root ganglion (DRG) neuronal cell bodies during chronic peripheral inflammation, but the mechanism for this GLS elevation is yet to be fully characterized. It has been well established that, after nerve growth factor (NGF) binds to its high-affinity receptor tropomyosin receptor kinase A (TrkA), a retrograde signaling endosome is formed. This endosome contains the late endosomal marker Rab7GTPase and is retrogradely transported via axons to the cell soma located in the DRG. This complex is responsible for regulating the transcription of several critical nociceptive genes. Here, we show that this retrograde NGF signaling mediates the expression of GLS in DRG neurons during the process of peripheral inflammation. We disrupted the normal NGF/TrkA signaling in adjuvant-induced arthritic (AIA) Sprague Dawley rats by the pharmacological inhibition of TrkA or blockade of Rab7GTPase, which significantly attenuated the expression of GLS in DRG cell bodies. The results indicate that NGF/TrkA signaling is crucial for the production of glutamate and has a vital role in the development of neurogenic inflammation. In addition, our pain behavioral data suggest that Rab7GTPase can be a potential target for attenuating peripheral inflammatory pain.
Topics: Animals; Ganglia, Spinal; Nerve Growth Factor; Signal Transduction; Glutaminase; Rats; Receptor, trkA; Inflammation; Rats, Sprague-Dawley; Male; Neurons; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins
PubMed: 38892241
DOI: 10.3390/ijms25116053