Binding and Activation of LRP1-Dependent Cell Signaling in Schwann Cells Using a Peptide Derived from the Hemopexin Domain of MMP-9.

Schwann cells (SCs) undergo phenotypic transformation and then orchestrate nerve repair following a peripheral nervous system injury. The low-density lipoprotein receptor-related protein-1 (LRP1) is significantly upregulated in SCs in response to acute injury, activating cJun and promoting SC survival. Matrix-metalloproteinase-9 (MMP-9) is an LRP1 ligand that binds LRP1 through its hemopexin domain (PEX) and activates SC survival signaling and migration. To identify novel peptide mimetics within the hemopexin domain of MMP-9, we examined the crystal structure of PEX, synthesized four peptides, and examined their potential to bind and activate LRP1. We demonstrate that a 22 amino acid peptide, peptide 2, was the only peptide that activated Akt and ERK1/2 signaling in SCs, similar to a glutathione s-transferase (GST)-fused holoprotein, GST-PEX. Intraneural injection of peptide 2, but not vehicle, into crush-injured sciatic nerves activated cJun greater than 2.5-fold in wild-type mice, supporting that peptide 2 can activate the SC repair signaling in vivo. Peptide 2 also bound to Fc-fusion proteins containing the ligand-binding motifs of LRP1, clusters of complement-like repeats (CCRII and CCRIV). Pulldown and computational studies of alanine mutants of peptide 2 showed that positively charged lysine and arginine amino acids within the peptide are critical for stability and binding to CCRII. Collectively, these studies demonstrate that a novel peptide derived from PEX can serve as an LRP1 agonist and possesses qualities previously associated with LRP1 binding and SC signaling in vitro and in vivo.

Axon-derived PACSIN1 binds to the Schwann cell survival receptor, LRP1, and transactivates TrkC to promote gliatrophic activities.

Schwann cells (SCs) undergo phenotypic transformation and then orchestrate nerve repair following PNS injury. The ligands and receptors that activate and sustain SC transformation remain incompletely understood. Proteins released by injured axons represent important candidates for activating the SC Repair Program. The low-density lipoprotein receptor-related protein-1 (LRP1) is acutely up-regulated in SCs in response to injury, activating c-Jun, and promoting SC survival. To identify novel LRP1 ligands released in PNS injury, we applied a discovery-based approach in which extracellular proteins in the injured nerve were captured using Fc-fusion proteins containing the ligand-binding motifs of LRP1 (CCR2 and CCR4). An intracellular neuron-specific protein, Protein Kinase C and Casein Kinase Substrate in Neurons (PACSIN1) was identified and validated as an LRP1 ligand. Recombinant PACSIN1 activated c-Jun and ERK1/2 in cultured SCs. Silencing Lrp1 or inhibiting the LRP1 cell-signaling co-receptor, the NMDA-R, blocked the effects of PACSIN1 on c-Jun and ERK1/2 phosphorylation. Intraneural injection of PACSIN1 into crush-injured sciatic nerves activated c-Jun in wild-type mice, but not in mice in which Lrp1 is conditionally deleted in SCs. Transcriptome profiling of SCs revealed that PACSIN1 mediates gene expression events consistent with transformation to the repair phenotype. PACSIN1 promoted SC migration and viability following the TNFα challenge. When Src family kinases were pharmacologically inhibited or the receptor tyrosine kinase, TrkC, was genetically silenced or pharmacologically inhibited, PACSIN1 failed to induce cell signaling and prevent SC death. Collectively, these studies demonstrate that PACSIN1 is a novel axon-derived LRP1 ligand that activates SC repair signaling by transactivating TrkC.

Quantitative evaluation of the lumbar ligamentum flavum using MRI T2-mapping: Efficacy of its clinical application in patients with lumbar spinal stenosis.

OBEJECTIVE: To perform a magnetic resonance imaging T2-mapping of the ligamentum flavum in healthy individuals and patients with lumbar spinal stenosis scheduled for surgery and compare the T2 relaxation times. SUBJECTS AND METHODS: The T2 relaxation time of the ligamentum flavum was compared among 3 groups, healthy young individuals (H group (age< 50)), healthy middle-aged and older individuals (H group (age≥50)), and patients with lumbar spinal stenosis (L group). Additionally, the thickness of the ligament was measured in the axial image plane, and the occupied area ratio of each fiber was measured by staining the surgically obtained ligament, and each was correlated with the T2 relaxation time. We also evaluated the adhesion of the ligamentum flavum with the dura mater during the surgery. RESULTS: The T2 relaxation times were significantly prolonged in H group (age ≥50) and L group (P < 0.001) compared to H group (age<50). The relationship between collagen fiber and T2 relaxation times was significantly positive (r = 0.720, P < 0.001). Moreover, the relaxation times were significantly prolonged in those with adhesion of the ligamentum flavum with the dura mater (P < 0.05). The cut-off for the relaxation time was 50 ms (sensitivity: 62.50%, false positive rate: 10.8%). CONCLUSION: Healthy middle-aged and older individuals and patients with lumbar spinal stenosis and adhesion of the ligamentum flavum with the dura mater have prolonged T2 relaxation times. Hence, the adhesion between the ligamentum flavum and dura mater should be considered in cases with a relaxation time ≥50 ms.

Objective Assessment of Sleep Disorders in Patients with Lumbar Spinal Stenosis Using Wearable Trackers.

Introduction: Low-back pain causes sleep disorders, which impairs the quality of life (QOL) of patients. Sleep disorders are associated with lumbar spinal stenosis (LSS); however, the postoperative effects of LSS surgery on sleep disorders are unknown. This study aimed to assess sleep disorders in patients with LSS using wearable activity trackers and determine whether surgery improves sleep quality. Methods: A total of 39 patients scheduled for LSS surgery (mean age 71.1±8.7 years; 22 men and 17 women) were studied. Sleep disorders in the participants were objectively evaluated using a wearable Motionlogger Micro system. Sleep efficiency (SEf), mean active count (MAC), and wake after sleep onset (WASO) were measured before and 6 months following surgery. Furthermore, the patient-based outcomes of pain and QOL-related scores were measured and compared with those of healthy participants. The group with improved SEf following surgery was designated as "nonpoor sleepers," whereas the group that did not exhibit improvements was designated as "poor sleepers." The two groups were compared based on patient factors, patient-based questionnaires, and sleep disorder measurements. Results: The SEf and WASO were significantly worse in patients with LSS compared with healthy participants (P<0.05). Furthermore, the SEf in patients with LSS was associated with the Oswestry Disability Index scores. No improvement was observed in the SEf, MAC, and WASO before and after surgery. Evaluation of each case revealed 21 and 12 cases of nonpoor and poor sleepers, respectively. Preoperative low-back pain was significantly associated with improvement in postoperative sleep quality. Conclusions: Sleep disorders in patients with LSS were evaluated, and improvement in sleep disorders following surgery was associated with the intensity of preoperative low-back pain. Sleep disorders are associated with QOL disorders, suggesting that focusing on the treatment of sleep disorders is important in the management of patients with LSS.

The impact of postoperative inclination of the joint line on clinical outcomes in total knee arthroplasty using a prosthesis with anatomical geometry.

The goal of this study was to investigate the impact of postoperative inclination of the joint line on clinical results after total knee arthroplasty (TKA) using a prosthesis with anatomical geometry. This study included 145 primary cruciate-retaining type of knee prosthesis with anatomical geometry. Three years postoperatively, clinical outcomes including the patient-reported outcomes (PROs) were recorded. Limb alignment was evaluated by the hip-knee-ankle (HKA) axis and inclination of the joint line was assessed by the joint line orientation angle (JLOA). Knees were divided into two groups according to the HKA: in-range (- 3 to 3°) and outlier group (< - 3° or > 3°) or the JLOA: in-range (2-4°) and outlier group (< 2° or > 4°), and clinical outcomes were compared between the groups. Postoperative Knee Society Function Score (KS-FS) was significantly higher in the HKA in-range group than the outlier group (p = 0.01). The Knee Society Knee Score and all subscales of the Knee injury Osteoarthritis Outcome Score were comparable between the groups. A multivariate analysis revealed a significant association between age at operation and postoperative KS-FS > of 80 points. Neither HKA in-range nor JLOA in-range were associated with the higher knee function. In conclusion, TKA-postoperative inclination of the joint line was not relevant to the short-term PROs. Treatment strategies that attempt to make joint line inclination in order to improve postoperative PROs should be avoided, and alignment goals such as kinematic alignment should be considered carefully.

Postoperative change in lumbopelvic alignment after short-segment transforaminal lumbar interbody fusion is related to preoperative postural difference in lumbar lordosis.

BACKGROUND: Postoperative changes in lumbar lordosis (LL) after transforaminal lumbar interbody fusion (TLIF) and the related factors are not well-understood. Recently, the preoperative difference in LL between standing and supine positions (DiLL) was proposed as a factor for predicting postoperative radiologic outcomes after short-segment TLIF. This study investigated the influence of DiLL on mid-term radiological outcomes after short-segment TLIF. METHODS: Sixty-six patients with lumbar degenerative disease treated with short-segment TLIF (1-2 levels) who underwent lumbar spine standing radiographs at 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, and 5 years postoperatively were divided into DiLL (+) and DiLL (-) groups (preoperative DiLL ≥0° and <0°, respectively). Associations between the postoperative change in LL and DiLL and clinical outcomes (Oswestry disability index (ODI) and Nakai score) were evaluated. RESULTS: Temporary restoration of LL (+4.5°) until 1 year postoperatively and a subsequent decrease in LL from 1 to 5 years postoperatively (-5.3°) was observed in the DiLL (+) group. No postoperative change in LL was observed in the DiLL (-) group. Postoperative changes in LL were mainly observed in non-fused segments. The postoperative change in LL (ΔLL) until 1 year postoperatively had a significant positive association with DiLL (p = 0.00028), whereas ΔLL from 1 to 5 years postoperatively showed a significant negative association with DiLL (p = 0.010) and a positive association with Nakai score (p = 0.028). ΔLL until 5 years postoperatively showed a significant positive association with postoperative ODI improvement (p = 0.011). CONCLUSIONS: DiLL (+) patients showed a specific time course with temporary LL restoration until 1 year postoperatively and a subsequent decrease in LL from 1 to 5 years postoperatively. Patients with larger postoperative increase in LL until 5 years postoperatively and lesser decrease in LL from 1 to 5 years postoperatively tended to show better mid-term clinical outcomes.

Lateral shift of the femoral condyle after total knee arthroplasty: simulation using 2D-templates of the medial pivot design on knee radiographs of young Japanese patients.

BACKGROUND: Total knee arthroplasty (TKA) is an established surgical treatment for advanced knee osteoarthritis by which patients can expect improvement of knee pain and function. Although many surgeons have investigated limb alignment after TKA, changes in coronal positional relation between the femur and tibia are not known well. METHODS: Radiographs of 105 knees of young Japanese patients between 20 and 49 years-old (60 men and 45 women) without osteoarthritic changes who received arthroscopic surgeries at our hospital were used in this study. Using 2D-templates of the medial pivot design (the FINE total knee), we simulated TKA on a SYNAPSE-PACS software. First, the femoral component was placed in normal knee alignment and then was merged to the medial concave of the insert where the tibial component was placed in neutral alignment. The length of the mediolateral shift of the femoral component was measured as an estimate of lateral shift of the femoral condyle, of which association with radiographic parameters including the femorotibial angle (FTA), lateral distal femoral angle (LDFA), and medial proximal tibial angle (MPTA) was analyzed. Subjects were classified into three groups according to the femoral component size that was chosen in simulation of TKA, and the lateral shift of the femoral condyle was compared between groups. RESULTS: The estimated mean lateral shift of the femoral condyle was 5.99 ± 1.98 mm and was greater in males than females (p < 0.05). Also, it was most highly correlated with the medial proximal tibial angle (MPTA) (r = - 0.553, p < 0.01). A group receiving larger component sizes significantly shifted more laterally compared with a group receiving smaller component sizes (p < 0.01). CONCLUSIONS: These results suggest that the coronal positional relation between the femur and tibia is altered and subsequent ligament imbalance may occur after mechanically aligned TKA using the medial pivot design.

Comparison of pain and discomfort in supine and lateral positions after surgery for lumbar degenerative disease: A prospective randomized controlled study.

INTRODUCTION: To compare postoperative pain and discomfort between supine and lateral positions after lumbar surgery, a prospective randomized controlled study was performed. METHODS: Forty-three patients with lumbar degenerative disease, treated by decompression (n = 23) or fusion surgery (n = 20), were randomly assigned to be placed in either the supine (supine group: n = 21) or lateral (lateral group: n = 22) position postoperatively, and asked to maintain their position until a day after the surgery. Postoperative back pain and discomfort (visual analog scale [VAS], 0-100 mm) and the number of patients who could maintain their position were examined. RESULTS: The VAS scores for back pain (supine: 64.9 ± 22.0, lateral: 55.7 ± 21.4) showed no significant difference between the positions. However, the supine group showed significantly more severe discomfort (75.6 ± 15.7) than the lateral group (64.9 ± 15.7, p = 0.039). Significantly fewer patients maintained their position in the supine group (28.2%) than in the lateral group (68.2%; p = 0.022). Among patients who underwent fusion surgery, significantly fewer patients maintained their position in the supine group (10.0%) than those in the lateral group (60.0%, p = 0.029). CONCLUSION: Postoperative discomfort was significantly reduced in the lateral position than in the supine position; thus, the lateral position is more suitable after lumbar surgery in terms of postoperative discomfort.

Changes in lumbar lordosis and predicted minimum 5-year surgical outcomes after short-segment transforaminal lumbar interbody fusion.

Although most patients who undergo transforaminal lumbar interbody fusion (TLIF) show favorable surgical results, some still have unfavorable results for various reasons. This study aimed to investigate the influence of differences in lumbar lordosis (LL) between the standing and supine positions (DiLL: supine LL-standing LL) on minimum 5-year surgical outcomes after short-segment TLIF. Ninety-one patients with lumbar degenerative disease who underwent short-segment TLIF (1-2 levels) were categorized based on preoperative differences in LL as DiLL (+) and DiLL (-). Comparison and correlation analyses were performed. The incidence of adjacent segment disease (ASD) by radiology (R-ASD) and symptomatic ASD (S-ASD), bony fusion rates, and pre- and postoperative clinical scores (visual analog scale [VAS]; Japanese Orthopaedic Association [JOA] score; Oswestry disability index (ODI); and Nakai's score) were evaluated. Postoperatively, VAS for low back pain (LBP) in the sitting position, JOA scores for LBP, lower leg pain, intermittent claudication, ODI, and Nakai's score were significantly worse in the DiLL (+) group than in the DiLL (-) group. DiLL values were significantly correlated with VAS for LBP, ODI, and Nakai's score, postoperatively. Positive DiLL values were associated with poorer postoperative outcomes. DiLL is a simple and useful method for predicting mid-term outcomes after TLIF.

Efficacy and Safety of Condoliase Disc Administration as a New Treatment for Lumbar Disc Herniation.

INTRODUCTION: Condoliase is a newly approved drug that improves symptoms associated with lumbar disk herniation (LDH) by intradiscal administration. This study aimed to evaluate the mid-term outcomes of condoliase injection, examine the adverse events, including cases that required surgery after condoliase administration, and verify cases in which condoliase could be effective. METHODS: We enrolled patients with LDH who were treated conservatively for at least six weeks and received condoliase. We assessed the visual analog scale (VAS) score, Japanese Orthopaedic Association Back Pain Evaluation Questionnaire, Oswestry Disability Index, disk height, and disk degeneration for up to 6 months, and we examined the complications. Furthermore, a 50% or more improvement in leg pain VAS score was considered effective. Factors related to symptom improvement were investigated by determining whether lower limb pain improved in six months. RESULTS: In total, 84 patients were recruited (52 men, 32 women; mean age, 44.2 ± 17.1 [16-86 years]). The duration of illness was 6.7 ± 6.8 (1.5-30) months. All patient-based outcomes significantly improved at 4 weeks after the administration compared with pretreatment. The intervertebral disc height decreased significantly at four weeks after condoliase administration compared with that before administration. Progression of intervertebral disc degeneration occurred in 50% of the patients. Eleven patients underwent herniotomy due to poor treatment effects. Moreover, treatment in 77.4% of the patients was considered effective. A logistic regression analysis revealed that L5/S1 disk administration (p = 0.029; odds ratio, 5.94; 95% confidence interval, 1.20-29.45) were significantly associated with clinical effectiveness. CONCLUSIONS: Condoliase disk administration improved pain and quality of life over time. Condoliase disk administration was more effective in L5/S1 intervertebral administration.

Association Between the Accumulation of Pentosidine at the Sciatic Nerve and Cutaneous Hindpaw Hypersensitivity in a Rat Ovariectomy Model.

Introduction Advanced glycation end-products (AGEs) have the potential to serve as biomarkers of aging and metabolic diseases; however, how their expression relates to clinical symptoms is not well defined. In this study, we sought to determine whether the accumulation of pentosidine, one type of AGE, at the peripheral nerve is associated with cutaneous pain or hypersensitivity caused by ovariectomy (OVX). Methods We assigned 12-week-old female Sprague Dawley rats into either the OVX group (n = 6) or the sham group (n = 6). Cutaneous hindpaw sensitivity to mechanical stimuli was measured with von Frey filaments, using Chaplan's adapted method, and the 50% withdrawal threshold was calculated. Then, the accumulation of pentosidine, which represents AGEs, was measured in sciatic nerve fibers after staining with an anti-pentosidine antibody. Results OVX rats showed significantly increased plantar hypersensitivity to mechanical stimuli compared to sham rats 8 weeks after OVX (P = 0.017). Pentosidine-positive sciatic nerves were detected at a higher rate in OVX rats than in sham rats (P = 0.035). The pentosidine positivity rate in sciatic nerve fibers showed a negative correlation with withdrawal threshold (P < 0.001). Conclusions This study showed that higher levels of pentosidine in sciatic nerve fibers are associated with higher plantar hypersensitivity. Accumulation of pentosidine at the sciatic nerve, caused by OVX, may result in cutaneous hindpaw hypersensitivity.

Usefulness of Simultaneous Magnetic Resonance Neurography and Apparent T2 Mapping for the Diagnosis of Cervical Radiculopathy.

STUDY DESIGN: Retrospective observational study. PURPOSE: We investigated the correlation between T2 relaxation times and clinical symptoms in patients with cervical radiculopathy caused by cervical disk herniation. OVERVIEW OF LITERATURE: There are currently no imaging modalities that can assess the affected cervical nerve roots quantitatively. METHODS: A total of 14 patients with unilateral radicular symptoms and five healthy subjects were subjected to simultaneous apparent T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement signaling (SHINKEI-Quant) using a 3-Tesla magnetic resonance imaging. The Visual Analog Scale (VAS) score for neck pain and upper arm pain was used to evaluate clinical symptoms. T2 relaxation times of the cervical dorsal root ganglia of the brachial plexus were measured bilaterally from C4 to C8 in patients with radicular symptoms and from C5 to C8 in healthy controls. The T2 ratio was calculated as the affected side to unaffected side. RESULTS: When comparing nerve roots bilaterally at each spinal level, no significant differences in T2 relaxation times were found between patients and healthy subjects. However, T2 relaxation times of nerve roots in the patients with unilateral radicular symptoms were significantly prolonged on the involved side compared with the uninvolved side (p<0.05). The VAS score for upper arm pain was not significantly correlated with the T2 relaxation times, but was positively correlated with the T2 ratio. CONCLUSIONS: In patients with cervical radiculopathy, the SHINKEI-Quant technique can be used to quantitatively evaluate the compressed cervical nerve roots. The VAS score for upper arm pain was positively correlated with the T2 ratio. This suggests that the SHINKEI-Quant is a potential tool for the diagnosis of cervical nerve entrapment.

Effects of the difference between lumbar lordosis in the supine and standing positions on the clinical outcomes of decompression surgery for lumbar spinal stenosis.

OBJECTIVE: The authors sought to evaluate the relationship between the difference in lumbar lordosis (DiLL) in the preoperative supine and standing positions and spinal sagittal alignment in patients with lumbar spinal stenosis (LSS) and to determine whether this difference affects the clinical outcome of laminectomy. METHODS: Sixty patients who underwent single-level unilateral laminectomy for bilateral decompression of LSS were evaluated. Spinopelvic parameters in the supine and standing positions were measured preoperatively and at 3 months and 2 years postoperatively. DiLL between the supine and standing positions was determined as follows: DiLL = supine LL - standing LL. On the basis of this determination patients were then categorized into DiLL(+) and DiLL(-) groups. The relationship between DiLL and preoperative spinopelvic parameters was evaluated using Pearson's correlation coefficient. In addition, clinical outcomes such as visual analog scale (VAS) and Oswestry Disability Index (ODI) scores between the two groups were measured, and their relationship to DiLL was evaluated using two-group comparison and multivariate analysis. RESULTS: There were 31 patients in the DiLL(+) group and 29 in the DiLL(-) group. DiLL was not associated with supine LL but was strongly correlated with standing LL and pelvic incidence (PI) - LL (PI - LL). In the preoperative spinopelvic alignment, LL and SS in the standing position were significantly smaller in the DiLL(+) group than in the DiLL(-) group, and PI - LL was significantly higher in the DiLL(+) group than in the DiLL(-) group. There was no difference in the clinical outcomes 3 months postoperatively, but low-back pain, especially in the sitting position, was significantly higher in the DiLL(+) group 2 years postoperatively. DiLL was associated with low-back pain in the sitting position, which was likely to persist in the DiLL(+) group postoperatively. CONCLUSIONS: We evaluated the relationship between DiLL and spinal sagittal alignment and the influence of DiLL on postoperative outcomes in patients with LSS. DiLL was strongly correlated with PI - LL, and in the DiLL(+) group, postoperative low-back pain relapsed. DiLL can be useful as a new spinal alignment evaluation method that supports the conventional spinal sagittal alignment evaluation.

Improvements in Intractable Lumbar and LowerExtremity Symptoms after Systemic Administration of Tocilizumab, an Anti-interleukin-6 Receptor Antibody.

STUDY DESIGN: Prospective cohort study (open-label, single-arm, and non-blinded). PURPOSE: This study aims to determine the effects of systemic administration of tocilizumab, an anti-interleukin-6 (IL-6) receptor antibody on refractory low back pain and leg symptoms. OVERVIEW OF LITERATURE: IL-6 overexpression is associated with neuropathic pain pathogenesis, which is potentially followed by chronic low back pain, including leg pain and numbness. This finding suggest that inhibition of IL-6 at the site of pain or in the transmission pathway could provide novel therapeutic targets for chronic low back pain. METHODS: This prospective, single-arm study included 11 patients (eight men; mean age, 62.7 years) with ≥3-months' chronic pain history due to lumbar disease. Subcutaneous TCZ injections were administered twice, at a 2-week interval. We evaluated low back pain, leg pain, and leg numbness using numeric rating scales and the Oswestry Disability Index (ODI; baseline and 6 months postinjection); serum IL-6 and tumor necrosis factor-α levels (baseline and 1 month postinjection); and clinical adverse events. RESULTS: Intractable symptoms reduced after TCZ administration. Low back pain improved for 6 months. Improvements in leg pain and numbness peaked at 4 and 1 month, respectively. Improvements in ODI were significant at 1 month and peaked at 4 months. Serum IL-6 was increased at 1 month. IL-6 responders (i.e., patients with IL-6 increases >10 pg/mL) showed particularly significant improvements in leg pain at 2 weeks, 1 month, and 2 months compared with nonresponders. We observed no apparent adverse events. CONCLUSIONS: Systemic TCZ administration improved symptoms effectively for 6 months, with peak improvements at 1-4 months and no adverse events. Changing serum IL-6 levels correlated with leg pain improvements; further studies are warranted to elucidate the mechanistic connections between lumbar disorders and inflammatory cytokines.

Nerve Growth Factor in Breast Cancer Cells Promotes Axonal Growth and Expression of Calcitonin Gene-related Peptide in a Rat Model of Spinal Metastasis.

BACKGROUND/AIM: Bone metastasis commonly causes severe pain. Nerve growth factor (NGF) contributes to pain, and promotes the production of pain-associated neuropeptides, such as calcitonin gene-related peptide (CGRP), from sensory nerve endings. We hypothesized that breast cancer cells have NGF levels that promote axonal growth from dorsal root ganglia (DRGs) neurons, and increase their CGRP production associated with pain from spinal metastases. MATERIALS AND METHODS: Expression of NGF by the cultured rat breast adenocarcinoma cell line CRL-1666 was determined using an enzyme-linked immunosorbent assay (ELISA). We constructed a rat model of spinal metastasis by implanting CRL-1666 into L6 vertebrae and determined the change in CGRP expression in DRG neurons innervating vertebrae immunohistochemically. RESULTS: NGF was expressed by CRL-1666. When DRG cells were co-cultured with CRL-1666, there were more CGRP-ir neurons and with a greater average length of axon growth than in cultures without CRL-1666 (p<0.05). In the rat model of metastasis, there were more CGRP-ir DRG neurons innervating vertebra treated with CRL-1666 than in vertebrae from sham surgery control rats (p<0.05). CONCLUSION: NGF from breast cancer may mediate spinal bone pain from metastasis via axonal growth and up-regulation of pain-associated neuropeptides.

Serum Reactive Oxygen Metabolites as a Predictor of Clinical Disease Activity Index, Simplified Disease Activity Index, and Boolean Remissions in Rheumatoid Arthritis Patients Treated With Biologic Agents.

Introduction Reactive oxygen metabolites (ROMs) are metabolite hydroperoxides in the blood, and their serum levels were associated with the disease activity score 28 (DAS28) in patients with rheumatoid arthritis (RA). In this study, we aimed to investigate whether ROMs would be predictive of the clinical disease activity index (CDAI) remission, simplified disease activity index (SDAI) remission, or Boolean remission. Materials and methods Fifty-one biologic agents (BA)-naïve RA patients were included in this observational study. Associations between ROMs, C-reactive protein, matrix metalloproteinase-3, DAS28-erythrocyte sedimentation rate (ESR), CDAI, SDAI, and health assessment questionnaire (HAQ) at 12 weeks and the DAS28, CDAI, SDAI, and Boolean remission rates at 52 weeks were investigated. Results The DAS28, CDAI, SDAI, and Boolean remission rates at 52 weeks were 66.7, 52.9, 54.9, and 54.9%, respectively. A multivariate logistic regression analysis revealed that ROMs and HAQ at 12 weeks were associated with the CDAI, SDAI, and Boolean remission at 52 weeks. Receiver operating characteristic analyses demonstrated that the cut-off value for CDAI, SDAI, and Boolean remission was 389.5 U.Carr. Conclusion Reactive oxygen metabolites at 12 weeks of initial treatment with BAs was a predictor for CDAI, SDAI, and Boolean remission at 52 weeks. Serum levels of ROMs may be a useful biomarker in the current treatment strategy aiming at early remission of RA.

Early mobilization reduces the medical care cost and the risk of disuse syndrome in patients with acute osteoporotic vertebral fractures.

STUDY DESIGN: A retrospective observational study. PURPOSE: To compare two conservative treatments for acute osteoporotic vertebral fractures (OVFs). OVERVIEW OF LITERATURE: Several studies have reported conservative treatments for OVFs in terms of using a brace, rehabilitation, and bed rest. However, there is no consensus about the conservative treatment for OVFs. METHODS: We evaluated 68 patients with acute OVF treated in our hospital from 2007 to 2011. Thirty-four patients treated in prolonged bed rest (PBR) regimen underwent rehabilitation wearing a Jewett's brace after three weeks of bed rest. In contrast, the other 34 patients underwent rehabilitation wearing a Jewett's brace as soon as possible, which we called a stir-up (SU) regimen. We compared two treatment groups for medical costs, hospital length of stay (LOS), pain according to the numeric rating scale (NRS), the activities of daily living (ADL), and imaging studies. RESULTS: The average hospital LOS was significantly shorter in patients treated by the SU regimen, which resulted in the medical costs reduction. There was no significant difference in the NRS through 6 months between the two groups. Although many patients in both groups experienced at least one level reduction in ADL at 6 months after the injury, patients in the SU group tended to maintain their pre-injury ADL, which almost agrees with past reports. In terms of imaging studies, patients in the PBR group showed milder vertebral compression rate over time. Pseudoarthrosis occurred in 2 patients in the SU group, who presented with mild pain, which had little influence on their daily lives. CONCLUSION: We compared two conservative treatments for OVFs. Early rehabilitation was useful treatment for OVFs to minimize the risk for disuse syndrome, maintain pre-injury ADL status, and reduce the medical costs.

Time-Course Changes in Bone Metabolism Markers and Density in Patients with Osteoporosis Treated with Romosozumab: A Multicenter Retrospective Study.

PURPOSE: In this multicenter retrospective observational study, we examined the early effects of romosozumab in patients with severe osteoporosis in terms of time-course changes in bone metabolism marker, improvement in bone density, and adverse effects. MATERIALS AND METHODS: Patients with severe osteoporosis were included. We investigated the progress of TRACP 5b and P1NP before and 1-2 months after the administration of romosozumab. We also investigated the bone density of lumbar spine, femoral neck, and the entire femur, measured by the DXA method, before and 5-7 months after the administration of romosozumab. RESULTS: A total of 70 patients (7 males and 63 females, age 75.0±3.6 years) participated in this study. Significant improvements in TRACP 5b and P1NP levels were observed before and 1-2 months after romosozumab administration. The average bone density of lumbar spine, femoral neck, and the entire femur were measured before and 5-7 months after romosozumab administration; and a significant increase only observed in the lumbar spine. CONCLUSION: Consistent with the findings of previous clinical studies, romosozumab has both bone formation-enhancing and bone resorption effects (dual effect). In addition, romosozumab also demonstrated improvement in bone density from the early phase after the administration, though the result was only seen in the lumbar spine.

Comparison between intervertebral oblique lumbar interbody fusion and transforaminal lumbar interbody fusion: a multicenter study.

This study aimed to perform a comparative analysis of postoperative results between lumbar degenerative spondylolisthesis (LDS) treated with oblique lateral interbody fusion (OLIF) and transforaminal lumbar interbody fusion (TLIF) from the Chiba spine surgery registry database. Sixty-five patients who underwent single-level OLIF (O group) for LDS with ≥ 3 years' follow-up were retrospectively reviewed. The control group comprised 78 patients who underwent single-level TLIF (T group). The analyzed variables included global alignment, radiological parameters of fused segments, asymptomatic and symptomatic ASD incidence, clinical outcomes at 3 years postoperatively using the Japanese Orthopedic Association Back Pain Evaluation Questionnaire data, visual analogue scale scores for low back pain, lower extremity pain, and lower extremity numbness. There was no significant change in global alignment between the two groups. The rate of improvement in anterior intervertebral disc height was not significantly different between the groups at 1-month postoperatively. However, at the final evaluation, the anterior intervertebral disc height and incidence of asymptomatic ASD were significantly higher in the O group. There was no significant difference in symptomatic ASD, reoperation cases, or clinical results between groups. Thus, single-level OLIF can maintain the corrected disc height, but as it has no effect on global alignment, its benefit is limited.

An Injectable Hyaluronic Acid Hydrogel Promotes Intervertebral Disc Repair in a Rabbit Model.

STUDY DESIGN: An in vivo model to study the effect of an injectable hyaluronic acid (HA) hydrogel following puncture-induced lumbar disc injury in rabbits. OBJECTIVES: The aim of this study was to determine the efficacy of an injectable HA hydrogel to maintain disc height and tissue hydration, promote structural repair, and attenuate inflammation and innervation in the lumbar discs. SUMMARY OF BACKGROUND DATA: Previously, we have demonstrated that HA hydrogel alleviated inflammation, innervation, and pain to promote disc repair. Nevertheless, the effect of an injectable HA hydrogel in the lumbar disc in a weight-bearing animal model was not performed. METHODS: We have adopted a surgically puncture-induced disc injury at lumbar levels in a rabbit model. The discs were grouped into sham, puncture with water injection, and puncture with HA hydrogel injection. Postoperatively, we measured changes in disc height using x-ray. We used magnetic resonance imaging to assess disc degeneration on tissue hydration after euthanasia. Post-mortem, we determined histological changes, innervation (PGP9.5) and inflammation (interleukin [IL]-6, IL-1ß, and tumor necrosis factor [TNF]-α) in the discs. RESULTS: We have demonstrated a significant reduction of disc height and T2/T1ρ mapping with histological evidence of degenerative discs, increase of innervation and inflammation in puncture-induced disc injury over time. In the HA hydrogel group, disc height was increased at weeks four and eight. A slight increase of T2 mapping, but significantly in T1ρ mapping, was observed in the HA hydrogel group at week 8. We observed homogenous NP distribution and organised AF lamellae at week eight and a slight reduced innervation score in the treatment group. HA hydrogel significantly downregulated IL-6 expression at day 1. This, however, was only slightly reduced for IL-1ß and TNF-α. CONCLUSION: An injectable HA hydrogel had the protective effects in suppressing the loss of disc height, promoting tissue hydration for structural repair, and attenuating inflammation and innervation to prevent further disc degeneration.Level of Evidence: N/A.