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Remodeling of the human bony skeleton is constantly occurring with up to 10% annual bone volume turnover from osteoclastic and osteoblastic activity. A shift toward resorption can result in osteoporosis and pathologic fractures, while a shift toward deposition is required after traumatic, or surgical injury. Spinal fusion represents one such state, requiring a substantial regenerative response to immobilize adjacent vertebrae through bony union. Autologous bone grafts were used extensively prior to the advent of advanced therapeutics incorporating exogenous growth factors and biomaterials. Besides cost constraints, these applications have demonstrated patient safety concerns. This study evaluated the regenerative ability of a nanostructured, magnesium-doped, hydroxyapatite/type I collagen scaffold (MHA/Coll) augmented by autologous platelet-rich plasma (PRP) in an orthotopic model of posterolateral lumbar spinal fusion. After bilateral decortication, rabbits received either the scaffold alone (Group 1) or scaffold with PRP (Group 2) to the anatomic right side. Bone regeneration and fusion success compared to internal control were assessed by DynaCT with 3-D reconstruction at 2, 4, and 6 weeks postoperatively followed by comparative osteogenic gene expression and representative histopathology. Both groups formed significantly more new bone volume than control, and Group 2 subjects produced significantly more trabecular and cortical bone than Group 1 subjects. Successful fusion was seen in one Group 1 animal (12.5%) and 6/8 Group 2 animals (75%). This enhanced effect by autologous PRP treatment appears to occur via astounding upregulation of key osteogenic genes. Both groups demonstrated significant gene upregulation compared to vertebral bone controls for all genes. Group 1 averaged 2.21-fold upregulation of RUNX2 gene, 3.20-fold upregulation of SPARC gene, and 3.67-fold upregulation of SPP1 gene. Depending on anatomical subgroup (cranial, mid, caudal scaffold portions), Group 2 had significantly higher average expression of all genes than both control and Group 1-RUNX2 (8.23-19.74 fold), SPARC (18.67-55.44 fold), and SPP1 (46.09-90.65 fold). Our data collectively demonstrate the osteoinductive nature of a nanostructured MHA/Coll scaffold, a beneficial effect of augmentation with autologous PRP, and an ability to achieve clinical fusion when applied together in an orthotopic model. This has implications both for future study and biomedical innovation of bone-forming therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Van Eps, Fernandez-Moure, Cabrera, Taraballi, Paradiso, Minardi, Wang, Aghdasi, Tasciotti and Weiner.)

Study Design: This was a systematic review and meta-analysis., Objective: This study aims to perform a systematic review and quantitative meta-analysis of patient-reported outcome measures after spinal fusion for adolescent idiopathic scoliosis (AIS)., Summary of Background Data: Radiographic correction of scoliosis is extensively reported in the literature but there is a need to study the impact of spinal fusion on patient-reported outcome measures. Prior reviews lacked homogeneity in outcome measures, did not perform quantitative meta-analysis of pooled effect size, or interpret the results in light of minimally clinically important difference thresholds., Materials and Methods: A systematic review of medical databases identified all studies that prospectively reported Scoliosis Research Society (SRS)-22 questionnaire data after spinal fusion for AIS. We screened 2314 studies for eligibility. Studies were included that reported preoperative and postoperative data at 24- or >60-month follow-up. Studies were excluded that failed to report means and SDs which were needed to calculate Cohen d effect sizes and 95% confidence intervals in estimating the magnitude and precision of the effect., Results: A total of 7 studies met eligibility criteria for inclusion in quantitative meta-analysis of effect sizes and 95% confidence intervals. Patients report large improvements in total score, self-image, and satisfaction; and moderate improvements in pain, function and mental health at 2 and 5 years after spinal fusion for AIS. All domains showed statistically significant improvement at all times except function at >60 months. All domains surpassed the minimally clinically important difference at all times except mental health., Conclusions: Moderate evidence suggests that spinal fusion improves quality of life for adolescents with idiopathic scoliosis in medium and long-term follow-up. Our results may help inform patient expectations regarding surgery., Ocemb Level of Evidence: Level I-systematic review and meta-analysis of prospective studies.

Purpose: Intervertebral disc degeneration is a major cause of back pain. Novel therapies for prevention or reversal of disc degeneration are needed. It is desirable for potential therapies to target both inflammation and matrix degeneration., Materials and Methods: The combined regenerative potential of link protein N-terminal peptide (LN) and fullerol on annulus fibrosus (AF) cells was evaluated in a 3D culture model., Results: Interleukin-1α (IL-1α)-induced AF cell degeneration was counteracted by fullerol, LN, and fullerol + LN, with the latter having the greatest effect on matrix production as evaluated by real-time polymerase chain reaction and glycosaminoglycan assay. IL-1α-induced increases in pro-inflammatory mediators (interleukin-6 and cyclooxygenase-2) and matrix metalloproteinases (MMP-1, -2, -9, and -13) were also counteracted by fullerol and LN., Conclusion: Our data demonstrate that LN and fullerol individually, and in combination, promote matrix production and have anti-inflammatory and anti-catabolic effects on AF cells.

Purpose: The purpose of this study was to examine the movement of the spinal cord and its relationship to the spinal canal in patients with mild spondylosis using kinetic magnetic resonance imaging (kMRI)., Methods: Weight-bearing, multiposition kMRI was performed on symptomatic patients through a full range of flexion-extension. A total of 52 study patients were selected based on the C2-C7 Cobb angle of sagittal alignment: lordotic (from 30 to 45 degrees). We evaluated dynamic changes in different parameters from flexion-extension: spinal canal diameter (CD), spinal cord diameter (SCD), space available for the cord, anterior space available for the cord (ASAC), posterior space available for the cord (PSAC), average distance between the anterior canal and the cord (d-value), and global angle for the spinal canal and cord., Results: The CD tended to decrease from flexion to extension from C3/C4 to C6/C7, however, there were no significant differences at the proximal and distal levels, C2/C3 and C7/T1. There were no significant differences of SCD between different postures. The SCD tended to decrease from C2/C3 to C7/T1. The ASAC followed the same pattern as CD-values. The ASAC was narrowest at C4/C5 and C5/C6. The PSAC tended to increase from C2/C3 to C7/T1. The spinal cord shifted anteriorly with extension and posteriorly with flexion. In addition, the spinal cord maintained its curve with the movement., Conclusions: The kinematics of spinal cord motion may be associated with the pathogenesis of cervical spondylotic myelopathy. However, the spinal cord maintains its curve with position changes. Consequently, different motions of the cervical spine may affect spinal cord migration and cause changes in ASAC and PSAC.

The present study aimed to evaluate the analgesic effect of the antioxidant nanoparticle fullerol in a mouse radiculopathy and a dorsal root ganglion (DRG) culture models. Intervertebral disk degeneration causes significant hyperalgesia and nerve inflammation. Pain sensitization and inflammatory reaction were counteracted by fullerol when disk material was bathed in 10 or 100μM of fullerol prior to implantation. Immunohistochemistry showed similar massive IBA1 positive macrophage infiltration surrounding implanted disk material among groups, but IL-1β and IL-6 expression was decreased in the fullerol treated group. In the DRG explant culture, after treatment with TNF-α, the expression of IL-1β, NLRP3, and caspase 1 was significantly increased but this was reversed by the addition of fullerol. In addition, fullerol also decreased the expression of substance P and CGRP in the cultured DRGs. Nanoparticle fullerol effectively counteracts pain sensitization and the inflammatory cascade caused by disk degeneration., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Growth factors are of great potential in regenerative medicine. However, their clinical applications are largely limited by the short in vivo half-lives and the narrow therapeutic window. Thus, a robust controlled release system remains an unmet medical need for growth-factor-based therapies. In this research, a nanoscale controlled release system (degradable protein nanocapsule) is established via in situ polymerization on growth factor. The release rate can be finely tuned by engineering the surface polymer composition. Improved therapeutic outcomes can be achieved with growth factor nanocapsules, as illustrated in spinal cord fusion mediated by bone morphogenetic protein-2 nanocapsules.

Study Design: This study was an in vivo kinematic magnetic resonance imaging analysis of cervical spinal motion in human subjects., Objective: The objective of the study was to identify associations between disk degeneration in the subaxial cervical spine and upper cervical spinal motion in patients with general age-related cervical spondylosis., Summary of Background Data: The kinematic relationship between the occipital-atlantoaxial complex and subaxial cervical spine in patients with cervical spondylosis and decreased cervical motion is not well understood., Methods: A total of 446 symptomatic patients who had neck pain with and without neurogenic symptoms were included in this study. Kinematic magnetic resonance imaging was performed with dynamic motion of the cervical spine in upright, weight-bearing neutral, flexion, and extension positions. Intervertebral disk degeneration for each segment from C2-3 to C7-T1 and sagittal angular motion between flexion and extension for each segment from Oc-C1 to C7-T1 was evaluated. Depending on the amount of sagittal subaxial angular motion, the patients were classified into 3 groups by sagittal angular motion using cutoff points based on tertile (<36-degree group: 149 cases; 36-47-degree group: 148 cases; and >47-degree group: 149 cases)., Results: A significant correlation was found between subaxial angular motion and intervertebral disk degeneration, indicating that the subaxial motion decreases according to the degree of disk degeneration. Mean angular motion of the occipital-atlantoaxial complex, especially of Oc-C1, was significantly higher in the <36-degree and 36-47-degree group than in the >47-degree group, whereas no significant difference was found at C1-C2., Conclusions: Our study demonstrates that decreased subaxial cervical spinal motion is associated with intervertebral disk degeneration in a symptomatic population. This decrease in mobility at the subaxial cervical spine is compensated for by an increase in angular mobility of the upper cervical spine at the occipital-atlantoaxial complex, especially at Oc-C1.

Study Design Retrospective cohort study. Objective The objective was to measure the change of flavum ligament diameter during positional changes of the cervical spine using kinetic magnetic resonance imaging (MRI) and to examine the correlational diameter changes of the flavum ligament, disk bulging, and the spinal canal from extension to flexion positions. Methods One hundred eight-nine patients underwent kinetic MRI in neutral, extension, and flexion positions. The diameters of cervical ligamentum flavum, disk bulging, and cervical spinal canal and the disk degeneration grade and Cobb angles were measured from C2-C3 to C7-T1. Results In all, 1,134 cervical spinal segments from 189 patients were included. There was a 0.26 ± 0.85-mm average increase in the diameter of the ligamentum flavum from flexion to extension, and 62.70% of the segments had increased ligamentum flavum diameter from flexion to extension. For all segments of the 189 patients, the cervical spinal canal diameters had an average decrease at the disk level of 0.56 ± 1.21 mm from flexion to extension. For all segments with cervical spinal canal narrowing ≥1 mm from flexion to extension view, the ligamentum flavum diameters at C3-C4 to C5-C6 had significant increases compared with patients with spinal canal narrowing < 1 mm (p < 0.05). For patients with ligamentum flavum hypertrophy of ≥1 mm from the flexion to extension view, the cervical spinal canal diameters at C2-C3, C4-C5, and C5-C6 had significant decreases compared with patients with ligamentum flavum hypertrophy of <1 mm (p < 0.05). Conclusion The "hidden" hypertrophy of ligamentum flavum was significant at C4-C5 and C5-C6 and significantly contributes to the stenosis of cervical spinal canal in the extension position.

Study Design Retrospective case series. Objectives The kinematics of the cervical spine has been investigated by many researchers. However, the occupancy of the disk bulges, spinal cord, ligamentum flavum, and the rest of the canal as well as the changes of these structures with motion have not yet been investigated. The goal of this study is to investigate these dynamic changes. Methods The kinetic magnetic resonance images of 248 patients (124 men and 124 women) were evaluated, and the occupancy of each structure for each cervical level at neutral, flexion, and extension were calculated. Results Whole canal anteroposterior (AP) diameters showed significant differences between neutral-extension and flexion-extension at the C4-C5 and C5-C6 levels (p < 0.05). The mean disk bulges showed significant differences between neutral-flexion and flexion-extension at the C4-C5, C5-C6, C6-C7, and C7-T1 levels (p < 0.01). The mean spinal canal AP diameter showed significant differences between flexion-extension and neutral-extension at the C3-C4, C4-C5, C5-C6, and C6-C7 levels (p < 0.05). There were significant differences between neutral-flexion at the C4-C5, C5-C6, and C6-C7 levels (p < 0.05). The mean thickness of the ligamentum flavum showed significant differences between flexion-extension at the C3-C4, C4-C5, C5-C6, and C6-C7 levels (p < 0.001). There were significant differences between neutral-extension at the C3-C4 and C5-C6 levels (p < 0.05). There were significant differences between neutral-flexion at the C5-C6 and C6-C7 levels (p < 0.05). The mean thickness of the spinal cord showed significant differences between neutral-flexion at the C2-C3 and C3-C4 levels (p < 0.05). There were significant differences between flexion-extension at the C3-C4 and C4-C5 levels (p < 0.01). The rest of the canal showed significant differences between neutral-extension and flexion-extension at the C3-C4, C4-C5, C5-C6, and C6-C7 levels (p < 0.005). There were significant differences between neutral-flexion at the C5-C6 and C6-C7 levels (p < 0.01). Conclusions The occupancy of each structure in the cervical spine for each level was revealed by this study. In addition, the dynamic changes in the cervical spine with flexion and extension were seen to have different characteristics for each level.

Study Design: Prospective in vivo rat tail model of disk degeneration comparing the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) injection over various time points and grades of degeneration., Objective: To evaluate the effect of timing and disk grade on rhBMP-2 injection in a rat tail model of disk degeneration., Summary of Background Data: rhBMP-2 stimulates the proliferation of intervertebral disk cells and the secretion of extracellular matrix. However, few in vivo studies have demonstrated whether rhBMP-2 also improves disk degeneration and the severity of disk degeneration beyond which disks cannot be recovered by rhBMP-2 treatment., Methods: Two coccygeal disks of each rodent subject were punctured percutaneously using an 18 G needle. At 4 weeks after the puncture, disks demonstrating induced degeneration were divided into 3 groups. Groups 1, 2, and 3 were treated with 7.5 μg rhBMP-2 or phosphate buffered saline by injection into the disk at 4, 6, and 8 weeks postpuncture, respectively. Plain radiographs and magnetic resonance images (MRIs) were obtained on the day of puncture and every 2 weeks thereafter until sacrifice. At 6 weeks after injection, each group was killed and examined with histologic and immunohistochemical analysis., Results: According to MRI disk grade evaluation of the degenerative disk, rhBMP-2 significantly improved degeneration grade in group 1 at 2 weeks after injection. According to radiographic disk height index, groups 1 and 2 showed a trend toward improvement at 2 weeks after rhBMP-2 injection. Chondrogenic differentiation was noted on immunohistochemical staining of many disks treated with rhBMP-2., Conclusions: rhBMP-2 injection of degenerated disks at 4 weeks postpuncture induced a transient improvement in disk grade on MRI and stimulated chondrogenic differentiation. These data suggest rhBMP-2 as a potential therapy for degenerative disk disease.

Osteogenic factors are often used in orthopedics to promote bone growth, improve fracture healing, and induce spine fusion. Osteogenic oxysterols are naturally occurring molecules that were shown to induce osteogenic differentiation in vitro and promote spine fusion in vivo. The purpose of this study was to identify an osteogenic oxysterol more suitable for clinical development than those previously reported, and evaluate its ability to promote osteogenesis in vitro and spine fusion in rats in vivo. Among more than 100 oxysterol analogues synthesized, Oxy133 induced significant expression of osteogenic markers Runx2, osterix (OSX), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN) in C3H10T1/2 mouse embryonic fibroblasts and in M2-10B4 mouse marrow stromal cells. Oxy133-induced activation of an 8X-Gli luciferase reporter, its direct binding to Smoothened, and the inhibition of Oxy133-induced osteogenic effects by the Hedgehog (Hh) pathway inhibitor, cyclopamine, demonstrated the role of Hh pathway in mediating osteogenic responses to Oxy133. Oxy133 did not stimulate osteogenesis via BMP or Wnt signaling. Oxy133 induced the expression of OSX, BSP, and OCN, and stimulated robust mineralization in primary human mesenchymal stem cells. In vivo, bilateral spine fusion occurred through endochondral ossification and was observed in animals treated with Oxy133 at the fusion site on X-ray after 4 weeks and confirmed with manual assessment, micro-CT (µCT), and histology after 8 weeks, with equal efficiency to recombinant human bone morphogenetic protein-2 (rhBMP-2). Unlike rhBMP-2, Oxy133 did not induce adipogenesis in the fusion mass and resulted in denser bone evidenced by greater bone volume/tissue volume (BV/TV) ratio and smaller trabecular separation. Findings here suggest that Oxy133 has significant potential as an osteogenic molecule with greater ease of synthesis and improved time to fusion compared to previously studied oxysterols. Small molecule osteogenic oxysterols may serve as the next generation of bone anabolic agents for therapeutic development., (© 2014 American Society for Bone and Mineral Research.)

The aim of this prospective cohort study was to investigate the effect of head and neck positioning on cerebral perfusion during shoulder arthroscopy in the beach chair position. Regional cerebral tissue oxygen saturation (rSO2) was monitored intraoperatively using near-infrared spectroscopy on 51 consecutive patients undergoing arthroscopic shoulder surgery in the beach chair position. The head of each subject was manipulated by the examiner and sequentially positioned for 45 seconds in terminal flexion, extension, bilateral rotation, and bilateral lateral bending. Decreases in rSO2 of 20% or greater from baseline were defined as a cerebral desaturation event (CDE). The association between head and neck position and cerebral perfusion was assessed. Eight percent of patients (4/51) experienced CDE during head and neck positioning. Body mass index was found to be a risk factor for CDE (p = .05). When comparing preoperative baseline rSO2 to intraoperative supine and intraoperative upright rSO2, there was no significant decrease in saturation levels for any of the six tested positions. Frequent intraoperative evaluations of the head and neck position as well as careful preoperative positioning may reduce the risk of position-related complications in patients undergoing elective shoulder arthroscopy in the beach chair position. In this study's patient population, however, head and neck position was not found to cause significant cerebral desaturation for the time period tested compared to preoperative baselines.

Study Design: Retrospective analysis of kinematic magnetic resonance images., Objective: To provide baseline data on the segmental angular and translational motion of the degenerated cervical spine by subtype of kyphotic cervical deformity and to elucidate the relationship between motion and degree of spinal cord compression., Summary of Background Data: Kyphotic deformities of the cervical spine are relatively common and are classified as either global or focal. Nevertheless, the effects of kyphotic subtype on cervical segmental motion and degree of spinal cord compression are unknown., Methods: A total of 1171 symptomatic patients (618 females, 553 males) underwent cervical kinematic magnetic resonance imaging in the neutral, flexion, and extension positions. Cervical spines demonstrating kyphosis were included and classified into 3 groups: (1) "global kyphotic deformity" (C-type) (n = 54); (2) "sigmoid deformity" (S-type) with kyphotic upper and lordotic lower cervical segments (n = 29); and (3) "reverse sigmoid deformity" (R-type) with lordotic upper and kyphotic lower cervical segments (n = 39). Translational motion, angular motion, and degree of spinal cord compression were evaluated for each cervical level along with the changes associated with flexion and extension., Results: In the C- and R-types, angular motion with extension was increased in the upper cervical spine, where there was kyphosis; when compared with the S-type, in which there was lordosis in the upper segments. The results were opposite for flexion angular motion. R-type displayed more translational motion at C3-C4 and C5-C6. Degree of static spinal cord compression of R-type was higher than the others at C3-C4. The dynamic spinal cord compression increased in extension more than flexion in all subtypes., Conclusion: Cervical spine studies that aim to investigate kyphotic deformities should make efforts to discern the different subtypes of kyphotic deformities to more accurately characterize and study the effects that the sagittal alignment has on the kinematics of the spine and the degree of spinal cord compression.

Study Design: Retrospective case series., Objective: To evaluate reoperations for lumbar adjacent segment pathology (ASP) during a 10-year period., Summary of Background Data: ASP after lumbar arthrodesis is an important clinical problem. There remains controversy, however, on the distribution of the most commonly affected levels., Methods: Thirty-one patients undergoing revision operation for ASP in the lumbar spine were included in this study. Patients' charts were evaluated for demographic data including age at index and revision operations, time to revision operation, and index and revision levels fused., Results: L4-L5 was the most commonly instrumented level in both single-level (n = 12), and multilevel (n = 13) index fusions. The mean length of time from the index operation to revision surgery was 81 months (range, 11-570 mo). Kaplan-Meier analysis predicted a disease-free survival rate of 32.3% at 5 years and of 12.9% at 10 years after the index operation. L3-L4 was the most commonly affected level by ASP with 75% (16/20) requiring reoperation. L2-L3 was the next most commonly affected level at 52% (14/27). The L5-S1 disk was relatively protected from ASP, with only 4/17 (24%) disks at risk developing ASP. A subgroup analysis of patients undergoing revision after a single-level L4-L5 arthrodesis revealed ASP at L3-L4 in 83% (10/12) of patients, compared with only 3/12 (25%) at L5-S1 (P < 0.05). Of all cases of ASP, the proximal segments were involved 90% of the time., Conclusion: ASP most commonly affects proximal levels in the lumbar spine. In this cohort of patients undergoing revision fusion for ASP, 90% of affected levels were rostral to the index level(s). In patients undergoing L4-L5 single-level arthrodesis, L3-L4 is at high risk, whereas L5-S1 is somewhat protected. Surgeons should pay particular attention to proximal levels when planning a lumbar arthrodesis, however, motion segments distal to fusion may not be as protected as previously thought., Level of Evidence: 4.

Background: Patients undergoing shoulder surgery in the beach chair position may be at increased risk for serious neurocognitive complications due to cerebral ischemia. We sought to define the incidence, patient risk factors, and clinical sequelae of intraoperative cerebral desaturation events., Methods: Regional cerebral tissue oxygen saturation (rSO2) was monitored intra-operatively using near-infrared spectroscopy (NIRS) on 50 consecutive patients. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was administered to each patient pre- and postoperatively. Intra-operative decreases in rSO2 of 20% or greater were defined as cerebral desaturation events (CDE). The association between intraoperative CDE and postoperative cognitive decline was assessed., Results: The incidence of intraoperative CDE in our series was 18% (9/50). Increased body mass index (BMI) was found to have a statistically significant association with intraoperative CDE (mean BMI 37.32 vs 28.59, P < .0001). There was no statistical significance in pre- vs postoperative RBANS either in composite scores or any of the sub-indices in either group., Conclusion: The degree and duration of cerebral ischemia required to produce neurocognitive dysfunction in this patient population remains undefined; however, cerebral oximetry with NIRS allows prompt identification and treatment of decreased cerebral perfusion decreasing the risk of this event. Increased BMI was found to be a statistically significant patient risk factor for the development of intra-operative CDE. The transient intra-operative CDEs were not associated with postoperative cognitive dysfunction in our patient series. We believe protocols aimed at detecting and reversing CDE minimize the risk of neurocognitive dysfunction and improve patient safety., (Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.)

Background Context: Lumbar foraminal stenosis is a common clinical problem and a significant cause of lower extremity radiculopathy. Minimal in vivo data exists quantifying changes in foraminal area (FA) as the spine moves from flexion to extension in the lumbar spine or on the relationship between FA and lumbar segmental angular motion, translational motion (TM), or disc bulge migration., Purpose: To use kinetic magnetic resonance imaging (kMRI) to evaluate changes in dimensions of lumbar neural foramina during weight bearing in neutral, flexion, and extension positions. To evaluate the relationship between foraminal stenosis and lumbar segmental angular motion, TM, and disc bulge migration., Study Design: A retrospective radiographic study., Patient Sample: Forty-five patients with a mean age of 44 years undergoing kMRI for symptoms of low back pain or radiculopathy., Outcome Measures: Magnetic resonance imaging measurements of FA, angular motion, TM, and disc bulge migration., Methods: Kinetic magnetic resonance imaging of the lumbar spine was reviewed in 45 patients with low back pain or radiculopathy, and parasagittal images were evaluated for changes in neural foraminal dimensions in various degrees of motion with weight bearing. The changes in foraminal dimension were correlated to the amount of segmental angular motion, TM, and disc bulge migration at each level. Neural foramina were also assessed qualitatively by Wildermuth criteria. Only those foramina that were clearly visualized with well-defined anatomic boundaries in all three positions were taken into consideration. Patients with previous surgery, tumor, and scoliosis were excluded from the study., Results: There was a significant decrease in the FA from flexion to neutral (p<.05) at all levels except L5-S1 and from neutral to extension at all levels (p<.05). The average percent decrease in FA was 30.0% with the greatest decrease from flexion to extension occurring at L2-L3 (167-107 mm(2)) and the smallest change occurring at L5-S1 (135-106 mm(2)) (p<.05). The magnitude of change in FA increased as angular motion at a segment increased. The mean change in FA was 32.3 mm(2) when angular motion was less than 5° and was 75.16 mm(2) when angular motion exceeded 15°. The extent of disc bulging posteriorly in the neural foramen was also correlated with the reduction in the FA from flexion to extension, but TM had no effect., Conclusions: Foraminal area decreased significantly in extension compared with flexion and neutral on MRI. Lumbar disc bulge migration and angular motion at each level contributed independently to the decrease in FA in extension, whereas TM had no effect on FA., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Study Design: Basic science rodent model of bone morphogenetic protein-2 (BMP-2) soft-tissue inflammation., Objective: This study investigated the anti-inflammatory effect of human dose equivalent (HDE) dexamethasone (DM) for treatment of BMP-2-related soft-tissue inflammation in a rodent model and suggests an appropriate dose for utilization in the clinical practice of spine surgeons., Summary of Background Data: BMP-2 is frequently used in spinal surgery to augment fusion. Yet, side effects of soft-tissue inflammation have been observed. DM decreases proinflammatory cytokine production and cellular immune response. However, the anti-inflammatory effects of HDE DM in a rodent model of BMP-2-associated soft-tissue inflammation have not been reported., Methods: Five, 10, and 15 mg of HDE DM were administered 3 times perioperatively to rodent cohorts receiving BMP-2 paraspinal implants and compared against BMP-2 only positive controls and phosphate buffer negative controls (n = 6 subjects per group). Histopathology, magnetic resonance imaging, and gross dissection were used as measures of cellular, edematous, and exudative inflammatory response. Serial killings were made on day 2 and day 7 postoperatively., Results: Magnetic resonance imaging volume rendering demonstrated inflammatory edema decreased by 49% from 605.4 mm to 304.03 mm in subjects treated with 5, 10, or 15 mg of HDE DM (P < 0.05). Histopathological analysis demonstrated inflammatory cross-sectional area decreased 28.8% from 1.84 mm to 1.31 mm in subjects treated with 5, 10 or 15 mg of HDE DM (P < 0.05). Immune cellular infiltration depth decreased 38.5% from 0.26 mm to 0.16 in subjects treated with 15 mg of HDE DM (P < 0.05). Gross anatomical inflammatory exudates were prevented in 100% of subjects treated with 10 or 15 mg of HDE DM (P < 0.05)., Conclusion: Low-dose DM administration is effective in controlling the cellular inflammation and edema resulting from BMP-2. Ten or 15 mg of DM might be considered by spine surgeons for controlling the inflammation and edema seen in spine surgery with BMP-2.

Transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMPs) have opposing but complementary functions in directing bone growth, repair, and turnover. Both are found in the bone matrix. Proteins that bind to and affect the activity of these growth factors will determine the relative abundance of the growth factors and, therefore, regulate bone formation. Secreted phosphoprotein 24 kD (Spp24) is a bone matrix protein that has been demonstrated to bind to and affect the activity of BMPs. The arginine-rich carboxy terminus of Spp24 is proteolytically processed to produce three other predictable truncation products (Spp18.1, Spp16.0, and Spp14.5). In this work, we report that kinetic data obtained by surface plasmon resonance demonstrate that Spp24 and the three C-terminal truncation products all bind to TGF-β1 and TGF-β2 with a similar but somewhat less affinity than they bind BMP-2; that, as in the case of BMP-2, the full-length (FL) form of Spp24 binds TGF-β with greater affinity than do the truncation products; that FL-Spp24 inhibits TGF-β2 induced bone formation in vivo, but Spp14.5 does not; and that co-administration of FL-Spp24 or Spp14.5 with TGF-β2 in vivo is associated with a reduction in the amount of cartilage, relative to new bone, present at the site of injection. This finding is consistent with the observation that low-dose TGF-β administration in vivo is associated with greater bone formation than high-dose TGF-β administration, and suggests that one function of Spp24 and its truncation products is to down-regulate local TGF-β activity or availability during bone growth and development. The similarities and differences of the interactions between Spp24 proteins and TGF-β compared to the interaction of the Spp24 proteins and BMPs have significant implications with respect to the regulation of bone metabolism and with respect to engineering therapeutic proteins for skeletal disorders.

Study Design: Retrospective analysis of kinetic magnetic resonance images., Objective: To define the prevalence of degenerative cervical spondylolisthesis in symptomatic patients and to analyze the motion characteristics and influence on the spinal canal at the affected level., Summary of Background Data: When compared with lumbar spondylolisthesis, there are few studies evaluating cervical spondylolisthesis, and the prevalence and motion characteristics of cervical spondylolisthesis are not well defined., Methods: Four hundred sixty-eight symptomatic patients underwent upright cervical kinetic magnetic resonance images in neutral, flexion, and extension positions. Segmental displacement and intervertebral angles were measured in 3 positions using computer analysis software. Spondylolisthesis was defined as the vertebral displacement more than 2 mm, and graded based on the magnitude into 2 groups at each level: grade 1 (2-3 mm), grade 2 (>3 mm). Instability was defined as segmental translational motion exceeding 3 mm., Results: Grade 1 and 2 spondylolisthesis at a minimum of 1 level were observed with a prevalence of 16.4% and 3.4% of all patients, respectively. The most affected levels were C4-C5 (6.2%) and C5-C6 (6.0%) followed by C3-C4 (3.6%) and C6-C7 (3.0%). Translational motion was greater in levels with grade 1 as compared with segments without spondylolisthesis, but there was no difference in angular motion between the 3 groups. Translational instability was observed with a prevalence of 16.7% in grade 2, 4.3% in grade 1, and 3.4% in segments without spondylolisthesis. Space available for the cord at the affected level was decreased and spinal cord compression grade was higher in grade 1 and grade 2 as compared with levels without spondylolisthesis., Conclusion: Cervical spondylolisthesis of at least 2 mm was observed in 20% of patients and was most common at C4-C5 and C5-C6. The presence of spondylolisthesis was associated with increased translational motion and decreased segmental spinal canal diameter., Level of Evidence: N/A.

The alignment and mobility of the cervical spine is influenced by factors related to the vertebral bodies, intervertebral discs, ligaments, facet joints, and muscles. Few reports have described the role played by the paraspinal muscles in cervical spine mobility. In this study, we investigate the relationship between fatty degeneration of the paraspinal muscles and cervical motion as assessed with kinetic magnetic resonance imaging (kMRI). One hundred eighty-eight symptomatic patients underwent cervical kMRI in neutral, flexion, and extension positions. We quantified cervical paraspinal muscle fatty infiltration and measured angular variation and translational motion at each cervical level, and the global Cobb angle. Cervical paraspinal muscle fatty degeneration demonstrated a pattern in which C3 and C7 had significantly more fatty infiltration than C4, C5, and C6. Additionally, when the normal group was compared with the fatty degeneration group with respect to angular variation, translational motion, and Cobb angle, no significant differences were found except in angular variation at the C3-C4 level. In conclusion, we found a significantly larger quantity of fatty degeneration in the paraspinal muscles at C3 and C7 than the middle cervical levels. Also, we demonstrate that fatty degeneration does not significantly affect cervical lordotic alignment or mobility characteristics.

Phospholipase C gamma 1 (PLC-gamma 1) hydrolyses phosphatidylinositol-4,5-bisphosphate to the second messengers inositol-1,4,5-trisphosphate and diacylglycerol. PLC-gamma 1 also has mitogenic activity upon growth-factor-dependent tyrosine phosphorylation; however, this activity is not dependent on the phospholipase activity of PLC-gamma 1, but requires an SH3 domain. Here, we demonstrate that PLC-gamma 1 acts as a guanine nucleotide exchange factor (GEF) for PIKE (phosphatidylinositol-3-OH kinase (PI(3)K) enhancer). PIKE is a nuclear GTPase that activates nuclear PI(3)K activity, and mediates the physiological activation by nerve growth factor (NGF) of nuclear PI(3)K activity. This enzymatic activity accounts for the mitogenic properties of PLC-gamma 1.

FKBP12, the 12-kDa FK506-binding protein, is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506, binds tightly to intracellular calcium release channels and to the transforming growth factor beta (TGF-beta) type I receptor. We now demonstrate that cells from FKBP12-deficient (FKBP12(-/-)) mice manifest cell cycle arrest in G(1) phase and that these cells can be rescued by FKBP12 transfection. This arrest is mediated by marked augmentation of p21(WAF1/CIP1) levels, which cannot be further augmented by TGF-beta1. The p21 up-regulation and cell cycle arrest derive from the overactivity of TGF-beta receptor signaling, which is normally inhibited by FKBP12. Cell cycle arrest is prevented by transfection with a dominant-negative TGF-beta receptor construct. TGF-beta receptor signaling to gene expression can be mediated by SMAD, p38, and ERK/MAP kinase (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathways. SMAD signaling is down-regulated in FKBP12(-/-) cells. Inhibition of ERK/MAP kinase fails to affect p21 up-regulation. By contrast, activated phosphorylated p38 is markedly augmented in FKBP12(-/-) cells and the p21 up-regulation is prevented by an inhibitor of p38. Thus, FKBP12 is a physiologic regulator of cell cycle acting by normally down-regulating TGF-beta receptor signaling.

FKBP12, a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin, is ubiquitously expressed and interacts with proteins in several intracellular signal transduction systems. Although FKBP12 interacts with the cytoplasmic domains of type I receptors of the transforming growth factor-beta (TGF-beta) superfamily in vitro, the function of FKBP12 in TGF-beta superfamily signalling is controversial. FKBP12 also physically interacts stoichiometrically with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine receptor (RyR1). In contrast, the cardiac ryanodine receptor, RyR2, appears to bind selectively the FKBP12 homologue, FKBP12.6. To define the functions of FKBP12 in vivo, we generated mutant mice deficient in FKBP12 using embryonic stem (ES) cell technology. FKBP12-deficient mice have normal skeletal muscle but have severe dilated cardiomyopathy and ventricular septal defects that mimic a human congenital heart disorder, noncompaction of left ventricular myocardium. About 9% of the mutants exhibit exencephaly secondary to a defect in neural tube closure. Physiological studies demonstrate that FKBP12 is dispensable for TGF-beta-mediated signalling, but modulates the calcium release activity of both skeletal and cardiac ryanodine receptors.