Xylosyltransferase-1 expression is refractory to inhibition by the inflammatory cytokines tumor necrosis factor α and IL-1ß in nucleus pulposus cells: novel regulation by AP-1, Sp1, and Sp3.

We investigated whether expression of xylosyltransferase-1 (XT-1), a key enzyme in glycosaminoglycan biosynthesis, is responsive to disk degeneration and to inhibition by the inflammatory cytokines tumor necrosis factor α and IL-1ß in nucleus pulposus (NP) cells. Analysis of human NP tissues showed that XT-1 expression is unaffected by degeneration severity; XT-1 and Jun, Fos, and Sp1 mRNA were positively correlated. Cytokines failed to inhibit XT-1 promoter activity and expression. However, cytokines decreased activity of XT-1 promoters containing deletion and mutation of the -730/-723 bp AP-1 motif, prompting us to investigate the role of AP-1 and Sp1/Sp3 in the regulation of XT-1 in healthy NP cells. Overexpression and suppression of AP-1 modulated XT-1 promoter activity. Likewise, treatment with the Sp1 inhibitors WP631 and mithramycin A or cotransfection with the plasmid DN-Sp1 decreased XT-1 promoter activity. Inhibitors of AP-1 and Sp1 and stable knockdown of Sp1 and Sp3 resulted in decreased XT-1 expression in NP cells. Genomic chromatin immunoprecipitation analysis showed AP-1 binding to motifs located at -730/-723 bp and -684/-677 bp and Sp1 binding to -227/-217 bp and -124/-114 bp in XT-1 promoter. These results suggest that XT-1 expression is refractory to the disease process and to inhibition by inflammatory cytokines and that signaling through AP-1, Sp1, and Sp3 is important in the maintenance of XT-1 levels in NP cells.

CCN2 suppresses catabolic effects of interleukin-1ß through α5ß1 and αVß3 integrins in nucleus pulposus cells: implications in intervertebral disc degeneration.

The objective of the study was to examine the regulation of CCN2 by inflammatory cytokines, IL-1ß, and TNF-α and to determine whether CCN2 modulates IL-1ß-dependent catabolic gene expression in nucleus pulposus (NP) cells. IL-1ß and TNF-α suppress CCN2 mRNA and protein expression in an NF-κB-dependent but MAPK-independent manner. The conserved κB sites located at -93/-86 and -546/-537 bp in the CCN2 promoter mediated this suppression. On the other hand, treatment of NP cells with IL-1ß in combination with CCN2 suppressed the inductive effect of IL-1ß on catabolic genes, including MMP-3, ADAMTS-5, syndecan 4, and prolyl hydroxylase 3. Likewise, silencing of CCN2 in human NP cells resulted in elevated basal expression of several catabolic genes and inflammatory cytokines like IL-6, IL-4, and IL-12 as measured by gene expression and cytokine protein array, respectively. Interestingly, the suppressive effect of CCN2 on IL-1ß was independent of modulation of NF-κB signaling. Using disintegrins, echistatin, and VLO4, peptide inhibitors to αvß3 and α5ß1 integrins, we showed that CCN2 binding to both integrins was required for the inhibition of IL-1ß-induced catabolic gene expression. It is noteworthy that analysis of human tissues showed a trend of altered expression of these integrins during degeneration. Taken together, these results suggest that CCN2 and inflammatory cytokines form a functional negative feedback loop in NP cells that may be important in the pathogenesis of disc disease.

Minimally invasive versus open posterior lumbar interbody fusion: a systematic review.

BACKGROUND: Although conventional open posterior lumbar interbody fusion (open PLIF) is efficacious in management of lumbar spinal instability, concerns exist regarding lengthy hospital stays, blood loss, and postoperative complications. Minimally invasive posterior lumbar interbody fusion (MIS PLIF) may be able to address these concerns, but the research on this topic has not been systematically reviewed. QUESTIONS/PURPOSES: We performed a systematic review to determine whether MIS PLIF or open PLIF results in (1) better perioperative parameters, including blood loss, operative times, and length of hospital stay; (2) improved patient-reported outcome scores; and (3) improved disc distraction and (4) frequency of reoperation and complications when compared with open PLIF procedures. METHODS: A literature search of the MEDLINE database identified seven studies that met our inclusion criteria. A total of seven articles were included; quality was assessed using the Methodological Index for Non-Randomised Studies (MINORS) scale. Descriptive statistics were used to describe the included articles. RESULTS: In most studies, MIS PLIF was associated with decreased blood loss and shorter hospital stay but longer operative times. MIS PLIF resulted in better patient-related outcomes when compared with open PLIF in two studies in the short term, but most of the studies in this review found no short-term differences, and there was no difference at long-term followup in any studies. There was no significant difference in disc distraction. Both techniques appeared to have similar complication rates and reoperation rates. CONCLUSIONS: Based on the available evidence, which we restricted to prospective and retrospective studies with control groups, but did not include any well-designed randomized trials, MIS PLIF might lead to better perioperative parameters, but there was little evidence for improved patient-reported outcomes in the MIS groups. Randomized controlled trials are needed to compare these two surgical techniques.

Cervical laminectomy width and spinal cord drift are risk factors for postoperative C5 palsy.

BACKGROUND: Cervical laminectomy and fusion (CLF) is a treatment option for multilevel cervical spondylotic myelopathy. Postoperative C5 nerve palsy is a possible complication of CLF. It has been suggested that C5 nerve palsy may be due to posterior drift of the spinal cord related to a wide laminectomy trough. PURPOSE: To test the hypothesis that excessive spinal cord drift into a wide laminectomy trough is associated with C5 palsy. STUDY DESIGN: Retrospective case-control study. PATIENT SAMPLE: Seventeen patients with C5 palsy, 8 patients as control group. OUTCOME MEASURES: Spinal cord positional measurements on magnetic resonance imaging (MRI). METHODS: All patients who underwent elective CLF for cervical spondylotic myelopathy or ossified posterior longitudinal ligament using posterior instrumentation between 2004 and 2008 were included. Patients who underwent CLF for trauma, infection, or tumors were excluded. Clinical and radiographic outcomes were assessed by chart review (minimum of 1 y follow-up). Patients who developed a new postoperative C5 nerve palsy underwent repeat MRI. The control group also underwent CLF, did not develop a neurological deficit, and received a postoperative MRI for evaluation of possible infection. MRI measurements included the width of the laminectomy trough, the distance from the posterior vertebral body or disk to the anterior spinal cord, the width of the spinal cord herniated into the laminectomy defect, and C2-7 sagittal alignment. Preoperative radiographic measurements included preoperative vertebral body diameter, spinal canal diameter, and sagittal vertical offset. RESULTS: There were seventeen patients with C5 nerve root palsy and 8 patients without C5 nerve root palsy. There were no baseline differences in fusion levels, instrumentation used, patient age, or sex. MRI measurements revealed an increase in mean postoperative cord drift in patients with C5 palsy at C3 (4.2 vs. 2.2 mm, P=0.002), C4 (4.6 vs. 2.8 mm, P=0.056), C5 (5.1 vs. 2.4 mm, P=0.011), and C6 (5.2 vs. 2.4 mm, P=0.003). There was a significant increase in C5 laminectomy trough width among patients with postoperative C5 palsy (17.9 vs. 15.2 mm, P=0.032), but there was no difference in sagittal alignment. CONCLUSIONS: A wider laminectomy at C5 was associated with an increased risk of postoperative C5 palsy. Increased preoperative spinal canal diameter is also associated with increased risk of C5 palsy. In addition, patients who experienced C5 nerve palsy had a significantly greater posterior spinal cord drift. Strategies to reduce postoperative laminectomy trough width and spinal cord drift may reduce the risk of postoperative C5 palsy.

Expression of prolyl hydroxylases (PHDs) is selectively controlled by HIF-1 and HIF-2 proteins in nucleus pulposus cells of the intervertebral disc: distinct roles of PHD2 and PHD3 proteins in controlling HIF-1α activity in hypoxia.

Adaptive response to hypoxia in nucleus pulposus cells of the intervertebral disc is regulated by the hypoxia-inducible factors, HIF-1α and HIF-2α. Moreover, oxygen-dependent turnover of HIF-1α in these cells is controlled by the prolyl-4-hydroxylase domain (PHD) family of proteins. Whether HIF homologues control expression of PHDs and whether PHDs control hypoxia-inducible factor (HIF) turnover and/or activity under hypoxia is not known. Here, we show that in nucleus pulposus cells, hypoxia robustly induces PHD3 expression and, to a lesser extent, of PHD2 and PHD1. Reporter analysis shows that the hypoxic induction of the PHD2 promoter is HIF-1α dependent, whereas PHD3 promoter/enhancer activity is dependent on both HIF-1α and HIF-2α. Lentiviral delivery of HIF-1α, ShHIF-1α, and ShHIF-1ß confirmed these observations. Noteworthy, HIF-1α maintains basal expression of PHD1 in hypoxia at the posttranscriptional level. Finally, loss of function studies using lentiviral transduction of ShPHDs clearly shows that even at 1% O(2), PHD2 selectively degrades HIF-1α. In contrast, in hypoxia, PHD3 enhances HIF-1α transcriptional activity without affecting protein levels. To correlate these observations with disc disease, a condition characterized by tissue vascularization, we analyzed human tissues. Increased PHD1 mRNA expression but decreased PHD2 and PHD3 expression is observed in degenerate tissues. Interestingly, the hypoxic responsiveness of all the PHDs is maintained in isolated nucleus pulposus cells regardless of the disease state. We propose that PHD2 and PHD3 can be used as a biomarker of tissue oxygenation in the disc and that, as such, it may have important clinical implications.

Smad3 controls ß-1,3-glucuronosyltransferase 1 expression in rat nucleus pulposus cells: implications of dysregulated expression in disc disease.

OBJECTIVE: To study the regulation of expression of ß-1,3-glucuronosyltransferase 1 (GlcAT-1), an important regulator of glycosaminoglycan (GAG) synthesis, by Smad3 in nucleus pulposus (NP) cells. METHODS: GlcAT-1 expression was examined in rat NP and anulus fibrosus (AF) cells treated with transforming growth factor ß (TGFß). The effects of Smad signaling and Smad suppression on GlcAT-1 were examined in rat NP cells. GlcAT-1 expression was analyzed in the discs of Smad3-null mice and in degenerated human NP tissue. RESULTS: TGFß increased the expression of GlcAT-1 in rat NP but not rat AF cells. Suppression of GlcAT-1 promoter activity was evident with dominant-negative ALK-5 (DN-ALK-5). Cotransfection with Smad3 strongly induced promoter activity independent of TGFß. Bioinformatics analysis indicated the presence of several Smad binding sites in the promoter; deletion analysis showed that the region between -274 and -123 bp was required for Smad3 response. DN-Smad3, Smad 3 small interfering RNA, and Smad7 strongly suppressed basal as well as TGFß-induced promoter activity. Induction of promoter activity by Smad3 was significantly blocked by DN-Smad3; Smad7 had a very small effect. Lentiviral transduction of NP cells with short hairpin RNA Smad3 resulted in a decrease in GlcAT-1 expression and accumulation of GAG. Compared to wild-type mice, significantly lower expression of GlcAT-1 was seen in the discs of Smad3-null mice. Analysis of degenerated human NP tissue specimens showed no positive correlation between GlcAT-1 and TGFß expression. Moreover, isolated cells from degenerated human tissue showed a lack of induction of GlcAT-1 expression following TGFß treatment, suggesting an altered response. CONCLUSION: Our findings demonstrate that in healthy NP cells, the TGFß-Smad3 axis serves as a regulator of GlcAT-1 expression. However, an altered responsiveness to TGFß during disc degeneration may compromise GAG synthesis.

Short-Segment versus Long-Segment Spinal Fusion Constructs for the Treatment of Adult Degenerative Scoliosis: A Comparison of Clinical Outcomes.

OBJECTIVE: To compare clinical outcomes of patients diagnosed with degenerative scoliosis undergoing short-segment versus long-segment spinal fusion. METHODS: A retrospective cohort study was conducted of patients with degenerative thoracolumbar scoliosis undergoing elective spinal fusion at a single academic medical center. Cohorts were divided into short-segment (<3) or long-segment (≥3) groups. RESULTS: A total of 197 patients (122 short, 75 long) were included. Patients undergoing short-segment fusion more frequently presented with radiculopathy (P < 0.001) and had greater baseline visual analog scale (VAS) leg scores (P < 0.001). Patients with long-segment fusions had longer hospital length of stay (short, 3.82 ± 2.98 vs. long, 7.40 ± 6.85 days; P < 0.001), lower home discharge rates (short, 80.3% vs. long, 51.8; P = 0.003), higher revision surgery rates (short, 10.77% vs. long, 25.3%; P = 0.012), and greater percentage curve correction (short, 37.3% ± 25.9% vs. long, 45.1% ± 23.9%; P = 0.048). No significant differences were noted in postoperative complication rates (short, 1.64% vs. long, 5.33%; P = 0.143). At 1 year, patients with long fusions had worse ΔOswestry Disability Index (ODI) (P = 0.024), ΔVAS leg score (P = 0.002), and VAS leg minimum clinically important difference % (P = 0.003). Multivariate regression found that short-segment fusions were associated with greater improvements in ODI (P = 0.029), Physical Component Summary-12 (P = 0.024), and VAS leg score at 1 year (P = 0.002). CONCLUSIONS: Patients undergoing short-segment fusions more frequently presented with radiculopathy and had higher preoperative VAS leg scores compared with those receiving long constructs. Short-construct fusions in appropriately selected patients may provide satisfactory improvements in patient-reported outcome measures, particularly ΔODI and ΔVAS leg score, and mitigate hospital length of stay, revision surgery rates, and nonhome discharge.

TNF-α and IL-1ß promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc.

Elevated levels of TNF-α, IL-1ß and a resultant increase in ADAMTS (a disintegrin-like and metalloprotease with thrombospondin type I motifs) expression is seen during disc degeneration. However, if these pro-inflammatory cytokines control ADAMTS activity is not definitively known. The goal of the investigation was to study if TNF-α and IL-1ß regulate syndecan-4 (SDC4) expression, and if SDC4 was responsible for promoting aggrecan degradation through controlling ADAMTS activity in nucleus pulposus cells of the intervertebral disc. Cytokine treatment increased SDC4 expression and promoter activity. Use of inhibitor, SM7368 and co-transfections with IκBα, RelA/p50 showed that NF-κΒ regulated both basal and cytokine-dependent SDC4 transcription. SDC4 promoter harboring RelA binding site mutation was unresponsive to the cytokines. Moreover, cytokines failed to increase SDC4 promoter activity in RelA-null cells. Cytokines increased ADAMTS-4/5 expression and aggrecan degradation and promoted SDC4 interaction with ADAMTS-5. Treatment with heparinase-III and p-nitrophenyl-ß-D-xylopyranoside (PNPX), an inhibitor of heparan sulfate synthesis and transfection with SDC4-shRNA partially blocked cytokine mediated aggrecan degradation. Analysis of human tissues showed increased aggrecan degradation with a concomitant increase in SDC4 and ADAMTS-5 protein expression with severity of disc disease. Likewise, SDC4, TNF-α, IL-1ß, ADAMTS-4, and ADAMTS-5 mRNA expression increased in degenerate tissues. We conclude that in nucleus pulposus, TNF-α and IL-1ß regulate SDC4 expression, which plays a key role in pathogenesis of degenerative disc disease by promoting aggrecan degradation by ADAMTS-5.

Hypoxia activates the notch signaling pathway in cells of the intervertebral disc: implications in degenerative disc disease.

OBJECTIVE: To investigate whether hypoxia regulates Notch signaling, and whether Notch plays a role in intervertebral disc cell proliferation. METHODS: Reverse transcription-polymerase chain reaction and Western blotting were used to measure expression of Notch signaling components in intervertebral disc tissue from mature rats and from human discs. Transfections were performed to determine the effects of hypoxia and Notch on target gene activity. RESULTS: Cells of the nucleus pulposus and annulus fibrosus of rat disc tissue expressed components of the Notch signaling pathway. Expression of Notch-2 was higher than that of the other Notch receptors in both the nucleus pulposus and annulus fibrosus. In both tissues, hypoxia increased Notch1 and Notch4 messenger RNA (mRNA) expression. In the annulus fibrosus, mRNA expression of the Notch ligand Jagged1 was induced by hypoxia, while Jagged2 mRNA expression was highly sensitive to hypoxia in both tissues. A Notch signaling inhibitor, L685458, blocked hypoxic induction of the activity of the Notch-responsive luciferase reporters 12xCSL and CBF1. Expression of the Notch target gene Hes1 was induced by hypoxia, while coexpression with the Notch-intracellular domain increased Hes1 promoter activity. Moreover, inhibition of Notch signaling blocked disc cell proliferation. Analysis of human disc tissue showed that there was increased expression of Notch signaling proteins in degenerated discs. CONCLUSION: In intervertebral disc cells, hypoxia promotes expression of Notch signaling proteins. Notch signaling is an important process in the maintenance of disc cell proliferation, and thus offers a therapeutic target for the restoration of cell numbers during degenerative disc disease.

Antidepressants and the risk of abnormal bleeding during spinal surgery: a case­control study.

INTRODUCTION: Antidepressant medications are widely used by patients requiring spinal surgery. In spite of a generally favorable safety profile of newer antidepressants, several prior studies have suggested an association between use of serotonergic antidepressants and excessive bleeding. This study was designed to determine if there was any association between antidepressant use and the risk of excessive intraoperative blood loss during spinal surgery, and whether particular types of antidepressants were specifically associated with this increased blood loss. MATERIALS AND METHODS: A retrospective case control study was conducted utilizing a population of 1,539 patients who underwent elective spinal fusion by a single surgeon at one medical center. Of the included patients, 213 used antidepressant medication and 1,326 patients did not use any type of antidepressant medication. Of patients taking antidepressants, 37 patients were excluded based on exclusion criteria, leaving 176 patients suitable for inclusion. The study group (176 patients) consisted of all patients who used an antidepressant medication for at least a 2-week period prior to spinal surgery. A control group of 352 patients were assembled from a random sample of 1,326 patients operated on by the same surgeon during the same time period in a two-to-one ratio with study group. Intraoperative blood loss was the primary outcome variable and was compared between the study and control group and between individuals in the study group taking serotonergic (SSRIs or SNRIs) or non-serotonergic antidepressants. Other variables, including length of hospital stay and surgical category, were also collected and analyzed separately. RESULTS: Overall, the mean blood loss (BL) for the antidepressant group was 298 cc, 23% more than the 241 cc lost by the procedure- and level-matched control group (p = 0.01). Patients taking serotonergic antidepressants also had statistically significant higher blood loss than the matched control group as a whole (334 vs. 241 cc, p = 0.015). This difference was also found in subgroups of patients who underwent anterior cervical discectomy and fusion, lumbar instrumented fusion, or anterior/posterior lumbar fusion. Blood loss was also higher in the subgroup of patients taking bupropion (708 cc, p = 0.023) compared with the control group. The mean length of hospital stay was 33.3% greater in patients on antidepressant medications compared to patients not taking an antidepressant (mean of 4 vs. 3 days, respectively, p = 0.0001). Antidepressant medications may be associated with increased intraoperative blood loss during spinal surgery, although the magnitude of the increased blood loss may not be clinically significant in all cases. The increase was greatest in patients undergoing anterior/posterior lumbar fusions, in whom the intraoperative blood loss was 2.5 times greater than that in the matched control group. CONCLUSION: Clinicians treating patients who are planning to undergo elective spinal surgery and are on an antidepressant medication should be aware of this potential effect and should consider tapering off the serotonergic antidepressant prior to surgery.

Perioperative Chanage in Cervical Lordosis and Health-Related Quality-of-Life Outcomes.

BACKGROUND: Surgeons have scrutinized spinal alignment and its impact on improving clinical outcomes following anterior cervical discectomy and fusion (ACDF). The primary analysis of this study examines the relationship between change in perioperative cervical lordosis (CL) and health-related quality-of-life (HRQOL) outcomes after ACDF. Secondary analysis evaluates the effects of fusion construct length on outcomes in patients grouped by preoperative cervical alignment. METHODS: A retrospective cohort study was performed on an institutional database including patients who underwent 1- to 3-level ACDF. C2-C7 CL was measured preoperatively and at final follow-up. For primary analysis, patients were classified based on their perioperative cervical lordotic correction: (1) kyphotic, (2) maintained, and (3) restored. For secondary analysis, patients were categorized based on their preoperative C2-C7 CL: (1) kyphotic, (2) neutral, and (3) lordotic. Demographics and perioperative change in patient-reported outcome measures were compared between groups. RESULTS: A total of 308 patients were included. A significant difference was noted among maintained, restored, and kyphotic groups in terms of delta physical compositeshort form-12 score (ΔPCS-12) (9.0 vs 10.3 vs 1.5; P = 0.04) and delta visual analog scale score (ΔVAS) for arm pain (-0.9 vs -3.8 vs -0.6; P = 0.03). Regression analysis revealed significantly greater improvement of PCS-12 (ß: 8.6; P = 0.03) and VAS arm (ß: -2.0; P = 0.03) scores in restored patients compared with kyphotic patients. The length of fusion construct in patients grouped by preoperative cervical alignment had no significant impact on the clinical outcomes on regression analysis. CONCLUSIONS: Significantly greater PCS-12 and VAS arm improvement were seen in patients whose cervical sagittal alignment was restored to neutral/lordotic compared with those who remained kyphotic. Multivariate analysis demonstrated no association between construct length and perioperative outcomes. CLINICAL RELEVANCE: The results of this study highlight the importance of sagittal alignment and restoration of CL after short-segment ACDF. Irrespective of preoperative sagittal alignment, the length of ACDF fusion construct does not have a significant impact on clinical outcomes.

The Impact of the Affordable Care Act on Outpatient Spine Trauma Consult Follow-up.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: The objective of this study was to assess the impact of the Affordable Care Act (ACA) on spine trauma patient follow-up. SUMMARY OF BACKGROUND DATA: Although damage to the spinal column accounts for a small proportion of all traumatic injuries, it results in a significant burden on the patient, provider, and health care system. Postoperative follow-up is essential to direct rehabilitation, prevent early deterioration, and manage complications early in the postoperative period. Previous studies have established the role of insurance coverage on follow-up compliance, however, the impact of the ACA on follow-up has been scant. MATERIALS AND METHODS: A retrospective cohort study was performed upon institutional review board approval of spine trauma patients consulted by orthopedic spine or neurosurgery from January 2013 to December 2013 (pre-ACA) and January 2015 to December 2015 (post-ACA). Patient demographics, surgical case characteristics, and follow-up compliance were assessed via manual chart review. Multivariate regression analysis was used to identify predictors of follow-up in the overall cohort, as well as within nonoperative and operative patients. RESULTS: A total of 827 patients were included in the final analysis after inclusion and exclusion criteria. Overall, patient follow-up significantly increased after implementation of the ACA (P<0.001), with pre-ACA follow-up at 35.0% (144/411) and post-ACA follow-up at 50.0% (208/516). Multivariate regression analysis further corroborated these findings, showing post-ACA status associated with a 1.66-fold higher likelihood of follow-up. Among nonoperative patients, the ACA failed to make a significant difference in follow-up (P=0.56), however, patients treated operatively showed a significantly higher likelihood of follow-up (odds ratio=2.92, P<0.001). CONCLUSIONS: Postoperative follow-up is an essential part of patient care, aiding in improving clinical outcomes and limiting the economic burden on the health care system. This study suggests that passage of the ACA significantly improved patient follow-up for operatively managed patients but not for nonoperatively managed patients. LEVEL OF EVIDENCE: Level III.

Does the Size or Location of Lumbar Disc Herniation Predict the Need for Operative Treatment?

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The goal of this study was to determine whether the absolute size (mm2), relative size (% canal compromise), or location of a single-level, lumbar disc herniation (LDH) on axial and sagittal cuts of magnetic resonance imaging (MRI) were predictive of eventual surgical intervention. METHODS: MRIs of 89 patients were reviewed, and patients were split into groups based on type of management received (34 nonoperative vs 55 microdiscectomy). Radiographic characteristics-including size of disc herniation (mm2), size of spinal canal (mm2), location of herniation on axial (central, paracentral, foraminal) and sagittal (disc level, suprapedicle, pedicle, infrapedicle) planes, and type of herniation (bulge, protrusion, extrusion, sequestration)-were measured by 2 independent, orthopedic spine fellows and compared between groups via univariate and multivariate analyses. RESULTS: The operative group showed a significantly higher percentage of canal compromise (39.5% vs 31.1%, P = .001) compared to the nonoperative group. Multiple logistic regression analysis showed higher odds of eventual operative intervention for a disc protrusion (odds ratio [OR] 6.30 [1.99, 19.86], P = .002) or disc extrusion (OR 11.5 [1.63, 81.2], P = .014) for Rater 1 and a higher odds of eventual surgical management for a paracentral location for both Rater 1 and Rater 2 (OR = 3.39 [1.25, 9.22], P = .017, and OR = 5.46 [1.77, 16.8], P = .003, respectively). CONCLUSIONS: Disc herniations in a paracentral location were more likely to undergo operative treatment than those more centrally located, on axial MRI views.

Discharge Disposition and Clinical Outcomes After Spine Surgery.

OBJECTIVE: Spinal decompression with or without fusion is one of the most commonly performed procedures in spine surgery. However, there is limited evidence on the effect of discharge environment on outcomes after surgery. The purpose of this study is to identify the effects of discharge disposition setting on clinical outcomes after spine surgery. METHODS: Patients who underwent lumbar decompression, lumbar decompression and fusion, or posterior cervical decompression and fusion surgery were retrospectively identified. All clinical and demographic data were obtained from electronic health records. Surgical outcomes included wound complications, revision surgery, "30-day" readmission (0-30 d), and "90-day" readmission (31-90 d). Discharge disposition was stratified into home/self-care, acute inpatient rehabilitation, and subacute rehabilitation. Patient-reported outcome measures including VAS Back, VAS Leg, VAS Neck, VAS Arm, PCS-12 and MCS-12, ODI, and NDI were compared between patient discharge disposition settings using the Mann-Whitney U test. Pearson's chi-square analysis was used to assess for differences in wound complications, revision surgery, 30-day readmission, or 90-day readmission rates. Multivariate logistic regression incorporating age, sex, body mass index (BMI), Charlson Comorbidity Index (CCI), and discharge disposition was used to determine independent predictors of wound complications. RESULTS: A total of 637 patients were included in the study. A significant difference (P = 0.03) was found in wound complication based on discharge disposition, with subacute disposition having the highest proportion of wound complications (6.1%) and home disposition having the lowest (1.5%). There were no significant differences in the rates of revision surgery, 30-day readmission, or 90-day readmission between groups. Subacute rehabilitation (odds ratio: 3.67, P = 0.047) and CCI (odds ratio 1.49, P = 0.01) were independent predictors of wound complications. Significant improvement in PROMs was seen across all postacute discharge dispositions. Baseline (P = 0.02) and postoperative (P = 0.02) ODI were significantly higher among patients discharged to an acute facility (49.4 and 32.0, respectively) compared to home (42.2 and 20.0) or subacute (47.4 and 28.4) environments. CONCLUSION: Subacute rehabilitation disposition and CCI are independent predictors of wound complications after spinal decompression surgery. Patients undergoing spine surgery have similar readmission and revision rates and experience similar clinical improvement across all postacute discharge dispositions.

The Impact of Upper Cervical Spine Alignment on Patient-reported Outcome Measures in Anterior Cervical Decompression and Fusion.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: To determine the extent to which the upper cervical spine compensates for malalignment in the subaxial cervical spine, and how changes in upper cervical spine sagittal alignment affect patient-reported outcomes. SUMMARY OF BACKGROUND DATA: Previous research has investigated the relationship between clinical outcomes and radiographic parameters in the subaxial cervical spine following anterior cervical discectomy and fusion (ACDF). However, limited research exists regarding the upper cervical spine (occiput to C2), which accounts for up to 40% of neck movement and has been hypothesized to compensate for subaxial dysfunction. MATERIALS AND METHODS: Patients undergoing ACDF for cervical radiculopathy and/or myelopathy at a single center with minimum 1-year follow-up were included. Radiographic parameters including cervical sagittal vertical axis, C0 angle, C1 inclination angle, C2 slope, Occiput-C1 angle (Oc-C1 degrees), Oc-C2 degrees, Oc-C7 degrees, C1-C2 degrees, C1-C7 degrees, and C2-C7 degrees cervical lordosis (CL) were recorded preoperatively and postoperatively. Delta (Δ) values were calculated by subtracting preoperative values from postoperative values. Correlation analysis as well as multiple linear regression analysis was used to determine relationships between radiographic and clinical outcomes. Alpha was set at 0.05. RESULTS: A total of 264 patients were included (mean follow-up 20 mo). C2 slope significantly decreased for patients after surgery (Δ=-0.8, P =0.02), as did parameters of regional cervical lordosis (Oc-C7 degrees, C1-C7 degrees, and C2-C7 degrees; P <0.001, <0.001, and 0.01, respectively). Weak to moderate associations were observed between postoperative CL and C1 inclination ( r =-0.24, P <0.001), Oc-C1 degrees ( r =0.59, P <0.001), and C1-C2 degrees ( r =-0.23, P <0.001). Increased preoperative C1-C2 degrees and Oc-C2 degrees inversely correlated with preoperative SF-12 Mental Composite Score (MCS-12) scores ( r =-0.16, P =0.01 and r =-0.13, P =0.04). Cervical sagittal vertical axis was found to have weak but significant associations with Short Form-12 (SF-12) Physical Composite Score (PCS-12) ( r =-0.13, P =0.03) and MCS-12 ( r =0.12, P =0.05). CONCLUSION: No clinically significant relationship between upper cervical and subaxial cervical alignment was detected for patients undergoing ACDF for neurological symptoms. Upper cervical spine alignment was not found to be a significant predictor of patient-reported outcomes after ACDF. LEVEL OF EVIDENCE: Level III.

The impact of preoperative neurological symptom severity on postoperative outcomes in cervical spondylotic myelopathy.

Study Design: The study design is a retrospective cohort study. Objective: To compare patient-reported outcomes between patients with mild versus moderate-to-severe myelopathy following surgery for cervical spondylotic myelopathy (CSM). Summary of Background Data: Recent studies have demonstrated that decompression for CSM leads to improved quality of life when measured by patient-reported outcomes. However, it is unknown if preoperative myelopathy classification is predictive of superior postoperative improvements. Materials and Methods: A retrospective review of patients treated surgically for CSM at a single institution from 2014 to 2015 was performed. Preoperative myelopathy severity was classified according to the modified Japanese Orthopaedic Association (mJOA) scale as either mild (≥15) or moderate-to-severe (<15). Other outcomes included neck disability index (NDI), 12-item short-form survey (SF-12), and visual analog scale (VAS) for arm and neck pain. Differences in outcomes were tested by linear mixed-effects models followed by pairwise comparisons using least square means. Multiple linear regression determined whether any baseline outcomes or demographics predicted postoperative mJOA. Results: There were 67 patients with mild and 50 patients with moderate-to-severe myelopathy. Preoperatively, patients with moderate-to-severe myelopathy reported significantly worse outcomes compared to the mild group for NDI, Physical Component Score (PCS-12), and VAS arm (P = 0.031). While both groups experienced improvements in NDI, PCS-12, VAS Arm and Neck after surgery, only the moderate-to-severe patients achieved improved mJOA (+3.1 points, P < 0.001). However, mJOA was significantly worse in the moderate-to-severe when compared to the mild group postoperatively (-1.2 points, P = 0.017). Both younger age (P = 0.017, ß-coefficient = -0.05) and higher preoperative mJOA (P < 0.001, ß-coefficient = 0.37) predicted higher postoperative mJOA. Conclusions: Although patients with moderate-to-severe myelopathy improved for all outcomes, they did not achieve normal absolute neurological function, indicating potential irreversible spinal cord changes. Early surgical intervention should be considered in patients with mild myelopathy if they seek to prevent progressive neurological decline over time.

Risk Factors for 30-day and 90-day Readmission After Lumbar Decompression.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To assess readmission rates and risk factors for 30-day and 90-day readmission after elective lumbar decompression at a single institution. SUMMARY OF BACKGROUND DATA: Hospital readmission is an undesirable aspect of interventional treatment. Studies evaluating readmissions after elective lumbar decompression typically analyze national databases, and therefore have several drawbacks inherent to their macroscopic nature that limit their clinical utility. METHODS: Patients undergoing primary one- to four-level lumbar decompression surgery were retrospectively identified. Demographic, surgical, and readmission data within "30-days" (0-30 days) and "90-days" (31-90 days) postoperatively were extracted from electronic medical records. Patients were categorized into four groups: (1) no readmission, (2) readmission during the 30-day or 90-day postoperative period, (3) complication related to surgery, and (4) Emergency Department (ED)/Observational (OBs)/Urgent (UC) care. RESULTS: A total of 2635 patients were included. Seventy-six (2.9%) were readmitted at some point within the 30- (2.3%) or 90-day (0.3%) postoperative periods. Patients in the pooled readmitted group were older (63.1 yr, P  < 0.001), had a higher American Society of Anesthesiologists (ASA) grade (31.2% with ASA of 3, P = 0.03), and more often had liver disease (8.1%, P = 0.004) or rheumatoid arthritis (12.0%, P = 0.02) than other cohorts. A greater proportion of 90-day readmissions and complications had surgical-related diagnoses or a diagnosis of recurrent disc herniation than 30-day readmissions and complications (66.7% vs. 44.5%, P = 0.04 and 33.3% vs. 5.5%, P < 0.001, respectively). Age (Odds ratio [OR]: 1.02, P = 0.01), current smoking status (OR: 2.38, P < 0.001), longer length of stay (OR: 1.14, P < 0.001), and a history of renal failure (OR: 2.59, P = 0.03) were independently associated with readmission or complication. CONCLUSION: Increased age, current smoking status, hospital length of stay, and a history of renal failure were found to be significant independent predictors of inpatient readmission or complication after lumbar decompression.

Impact of the Affordable Care Act on Insurance Status of Spine Patients Presenting to the Emergency Department.

Although the Affordable Care Act (ACA) has been shown to broadly affect access to care, there is little data examining the change in insurance status with regard to nonelective spinal trauma, infection, and tumor patients. The purpose of this study is to evaluate the changes in insurance status before and after implementation of the ACA in patients who present to the emergency room of a single, level 1 trauma and regional spinal cord injury center. Patient demographic and hospital course information were derived from consult notes and electronic medical record review. Spinal consults between January 1, 2013, and December 31, 2015, were initially included. Consults between January 1 and December 31, 2014, were subsequently removed to obtain two separate cohorts reflecting one calendar year prior to ("pre-ACA") and following ("post-ACA") the effective date of implementation of the ACA on January 1, 2014. Compared with the pre-ACA cohort, the post-ACA cohort had a significant increase in insurance coverage (95.0% versus 83.9%, P < 0.001). Post-ACA consults had a significantly shorter length of stay compared with pre-ACA consults (7.94 versus 9.19, P < 0.001). A significantly greater percentage of the post-ACA cohort appeared for clinical follow-up subsequent to their initial consultation compared to the pre-ACA cohort (49.5% versus 35.3%, P < 0.001). Spinal consultation after the implementation of the ACA was found to be a significant positive predictor of Medicaid coverage (odds ratio = 1.96 [1.05, 3.82], P = 0.04) and a significant negative predictor of uninsured status (odds ratio = 0.28 [0.16, 0.47], P < 0.001). Increase in overall insurance coverage, increase in patient follow-up after initial consultation, and decrease in hospital length of stay were all noted after the implementation of the ACA for spinal consultation patients presenting to the emergency department.

Hypoxia-inducible factor regulation of ANK expression in nucleus pulposus cells: possible implications in controlling dystrophic mineralization in the intervertebral disc.

OBJECTIVE: Since nucleus pulposus cells reside under conditions of hypoxia, we determined if the expression of ANK, a pyrophosphate transporter, is regulated by the hypoxia-inducible factor (HIF) proteins. METHODS: Quantitative reverse transcription-polymerase chain reaction and Western blot analyses were used to measure ANK expression in nucleus pulposus cells from rats and humans. Transfections were performed to determine the effect of HIF-1/2 on ANK promoter activity. RESULTS: ANK was expressed in embryonic and mature rat discs. Oxygen-dependent changes in ANK expression in nucleus pulposus cells were minimal. However, silencing of HIF-1α and HIF-2α resulted in increased ANK expression and up-regulation of promoter activity. HIF-mediated suppression of ANK was validated by measuring promoter activity in HIF-1ß-null embryonic fibroblasts. Under conditions of hypoxia, there was induction of promoter activity in the null cells as compared with the wild-type cells. Overexpression of HIF-1α and HIF-2α in nucleus pulposus cells resulted in a significant suppression of ANK promoter activity. Since the ANK promoter contains 2 hypoxia-responsive elements (HREs), we performed site-directed mutagenesis and measured promoter activity. We found that HIF-1 can bind to either of the HREs and can suppress promoter activity; in contrast, HIF-2 was required to bind to both HREs in order to suppress activity. Finally, analysis of human nucleus pulposus tissue showed that while ANK was expressed in normal tissue, there was increased expression of ANK along with alkaline phosphatase in the degenerated state. CONCLUSION: Both HIF-1 and HIF-2 serve as negative regulators of ANK expression in the disc. We propose that baseline expression of ANK in the disc serves to prevent mineral formation under physiologic conditions.

Regulation of CCN2/connective tissue growth factor expression in the nucleus pulposus of the intervertebral disc: role of Smad and activator protein 1 signaling.

OBJECTIVE: To investigate transforming growth factor beta (TGFbeta) regulation of connective tissue growth factor (CTGF) expression in cells of the nucleus pulposus of rats, mice, and humans. METHODS: Real-time reverse transcription-polymerase chain reaction and Western blot analyses were used to measure CTGF expression in the nucleus pulposus. Transfections were used to measure the effects of Smads 2, 3, and 7 and activator protein 1 (AP-1) on TGFbeta-mediated CTGF promoter activity. RESULTS: CTGF expression was lower in neonatal rat discs than in skeletally mature rat discs. An increase in CTGF expression and promoter activity was observed in rat nucleus pulposus cells after TGFbeta treatment. Deletion analysis indicated that promoter constructs lacking Smad and AP-1 motifs were unresponsive to treatment. Analysis showed that full-length Smad3 and the Smad3 MH-2 domain alone increased CTGF activity. Further evidence of Smad3 and AP-1 involvement was seen when DN-Smad3, SiRNA-Smad3, Smad7, and DN-AP-1 suppressed TGFbeta-mediated activation of the CTGF promoter. When either Smad3 or AP-1 sites were mutated, CTGF promoter induction by TGFbeta was suppressed. We also observed a decrease in the expression of CTGF in discs from Smad3-null mice as compared with those from wild-type mice. Analysis of human nucleus pulposus samples indicated a trend toward increasing CTGF and TGFbeta expression in the degenerated state. CONCLUSION: TGFbeta, through Smad3 and AP-1, serves as a positive regulator of CTGF expression in the nucleus pulposus. We propose that CTGF is a part of the limited reparative response of the degenerated disc.