Safety and efficacy of anterior vertebral body tethering in the treatment of idiopathic scoliosis.

AIMS: Spinal fusion remains the gold standard in the treatment of idiopathic scoliosis. However, anterior vertebral body tethering (AVBT) is gaining widespread interest, despite the limited data on its efficacy. The aim of our study was to determine the clinical efficacy of AVBT in skeletally immature patients with idiopathic scoliosis. METHODS: All consecutive skeletally immature patients with idiopathic scoliosis treated with AVBT enrolled in a longitudinal, multicentre, prospective database between 2013 and 2016 were analyzed. All patients were treated by one of two surgeons working at two independent centres. Data were collected prospectively in a multicentre database and supplemented retrospectively where necessary. Patients with a minimum follow-up of two years were included in the analysis. Clinical success was set a priori as a major coronal Cobb angle of < 35° at the most recent follow-up. RESULTS: A total of 57 patients were included in the study. Their mean age was 12.7 years (SD 1.5; 8.2 to 16.7), with 95% being female. The mean preoperative Sanders score and Risser grade was 3.3 (SD 1.2), and 0.05 (0 to 3), respectively. The majority were thoracic tethers (96.5%) and the mean follow-up was 40.4 months (SD 9.3). The mean preoperative major curve of 51° (SD 10.9°; 31° to 81°) was significantly improved to a mean of 24.6° (SD 11.8°; 0° to 57°) at the first postoperative visit (45.6% (SD 17.6%; 7% to 107%); p < 0.001)) with further significant correction to a mean of 16.3° (SD 12.8°; -12 to 55; p < 0.001) at one year and a significant correction to a mean of 23° (SD 15.4°; -18° to 57°) at the final follow-up (42.9% (-16% to 147%); p < 0.001). Clinical success was achieved in 44 patients (77%). Most patients reached skeletal maturity, with a mean Risser score of 4.3 (SD 1.02), at final follow-up. The complication rate was 28.1% with a 15.8% rate of unplanned revision procedures. CONCLUSION: AVBT is associated with satisfactory correction of deformity and an acceptable complication rate when used in skeletally immature patients with idiopathic scoliosis. Improved patient selection and better implant technology may improve the 15.8% rate of revision surgery in these patients. Further scrutiny of the true effectiveness and long-term risks of this technique remains critical. Cite this article: Bone Joint J 2020;102-B(12):1703-1708.

Correction of complex lower limb angular deformities with or without length discrepancy in children using the TL-HEX hexapod system: comparison of clinical and radiographical results.

The aim of this study was to compare clinical and radiographical results for treatment of lower limb multiaxial deformities±limb length discrepancy (LLD) of at least 2 cm with the Truelok hexapod fixator system (TL-HEX). All consecutive cases of lower limb multiaxial deformities were included. Patients were divided in two groups: group 1, lower limb angular deformity+LLD less than 2 cm, and group 2, lower limb angular deformity+LLD of at least 2 cm. Only patients with age younger than or equal to 20 years and follow-up of 6 months after removal of the external fixator were included. A total of 27 (six femur and 39 tibia treated) and 20 patients (12 femur and 19 tibia) were enrolled in groups 1 and 2, respectively. Complete correction of the deformity was achieved in 90 and 96% of the patients in groups 1 and 2, respectively. There were no differences in terms of external fixator, maturation, and distraction indexes between the two groups and between different anatomical sites. Good to excellent functional results (ASAMI score) were obtained in 93% of patients in group 1 and 75% in group 2 (P=0.01). Complication rate was similar between the two groups (7.4 vs. 10%, respectively). Average follow-up after removal of the external fixator was 25.6 (range: 7.0-54.0) months. The TL-HEX external fixator system allows a predictable correction of complex lower limb deformities regardless of the presence of LLD. Although complication rate is similar between the two groups, lower functional outcomes can be expected in patients with significant preoperative LLD.

Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging.

Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/∆ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/∆ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/∆ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/∆ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1-/∆ mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1-/∆ and aged WT mice. Chronic treatment of Ercc1-/∆ mice with the mitochondrial-targeted radical scavenger XJB-5-131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline.

Assessing the Risk-Benefit Ratio of Scoliosis Surgery in Cerebral Palsy: Surgery Is Worth It.

BACKGROUND: The true benefits of scoliosis surgery in cerebral palsy (CP) remain uncertain. Our aims were to determine the benefits of spinal fusion according to health-related quality of life (HRQoL) improvement at long-term follow-up and to explore the effect of surgery-related complications on clinical outcomes. METHODS: The cases of consecutive patients who had Gross Motor Function Classification System (GMFCS) level-IV or V cerebral palsy with 5-year follow-up from a prospective, longitudinal, multicenter database were analyzed. Caregivers completed the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire and 4 Likert-type anchor questions preoperatively and at 1, 2, and 5 years of follow-up. Data on complications were collected prospectively. Preoperative CPCHILD scores were compared with postoperative scores at the 1, 2, and 5-year follow-up evaluations. Preoperative CPCHILD scores were compared with postoperative scores at the 1, 2, and 5-year follow-up evaluations using repeated-measures analysis of variance (ANOVA). Spearman correlation coefficient was used to explore the association between changes in the CPCHILD at 1, 2, and 5-year follow-up and the reported complications within the follow-up period. Similarly, a comparative analysis between the percentage distribution of the answers to the 4 anchor questions and the reported complications was also performed. RESULTS: Sixty-nine patients with a mean age (and standard deviation) of 13.4 ± 2.6 years at enrollment were analyzed. The major Cobb angle was a mean of 81.9° ± 26.7° preoperatively and improved to a mean of 28.7° ± 14.4° at 2 years and 30.7° ± 15.3° at 5 years postoperatively. Significant improvements in CPCHILD personal care, positioning, and comfort domains were noted at all time points. The mean increase in the total score was 7.19 (p < 0.001) at 1 year, and the score gain was maintained at 2 and 5 years postoperatively. The overall complication rate was 46.4% at 1 year, 1.4% between 1 and 2 years, and 4.3% at 2 to 5 years postoperatively, with surgical intervention required in 6 patients within 1 year and in 2 additional patients within 5 years following scoliosis surgery. There was no correlation between complications and CPCHILD scores postoperatively at all time points, with the only exception of a weak correlation (ρ = -0.450, p = 0.002) with CPCHILD comfort score at 1 year after surgery. CONCLUSIONS: Scoliosis surgery in patients with CP leads to a significant improvement in HRQoL, which is maintained 5 years following surgery. The substantial complication rate does not correlate with HRQoL changes postoperatively, suggesting that the benefits of surgery outweigh the risks in this fragile population. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A Detailed Comparative Analysis of Anterior Versus Posterior Approach to Lenke 5C Curves.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To prospectively compare radiographic, perioperative, and functional outcomes between anterior spinal instrumentation and fusion (ASIF) and posterior spinal instrumentation and fusion (PSIF) in Lenke 5C curves. SUMMARY OF BACKGROUND DATA: Historically, ASIF has been the treatment of choice for treatment of thoracolumbar adolescent idiopathic scoliosis. More recently, PSIF has gained popularity for its ease, versatility, and amount of correction achieved. Current literature lacks a prospective comparative analysis between these two approaches to better aid treating surgeons in decision making when treating Lenke 5C curves. METHODS: A prospective, longitudinal multicenter adolescent idiopathic scoliosis database was used to identify 161 consecutive patients with Lenke 5C curves treated by ASIF with a dual rod system, or PSIF with a pedicle screw-rod construct. Pre- and 2-year postoperative radiographic data, Scoliosis Research Society outcome scores, and perioperative comparisons were made between the two approaches. RESULTS: A total of 69 patients were treated with ASIF and 92 patients with PSIF. Curve extent, magnitude, stable, and end vertebrae distribution before surgery were similar between the two groups. At 2-year follow-up, there were no significant differences in percentage correction of the main curve (ASIF: 59.1%, PSIF: 59.6%), C7 decompensation (ASIF: -0.6 ±â€Š1.2, PSIF: -0.3 ±â€Š1.4 cm), length of hospital stay (ASIF: 5.6 days, PSIF: 5.7 days), postoperative day conversion to oral pain medication (ASIF: 3.2 days, PSIF: 3.2 days), and SRS outcome scores (P = 0.560) between the two groups. The number of levels fused was significantly lower in ASIF group (ASIF: 4.7, PSIF: 6.3; P < 0.001), but PSIF resulted in significantly less disc angulation below lowest instrumented vertebrae (ASIF: 3.4°, PSIF: 1.7°; P = 0.011), greater lumbar lordosis (P < 0.001), and greater % correction of lumbar prominence (P = 0.017). CONCLUSION: The amount of correction achieved was similar between ASIF and PSIF. ASIF resulted in shorter fusions (average 1.6 levels) compared with PSIF. This was at the expense of increased disc angulation below the lowest instrumented vertebrae, less lumbar lordosis, and a lower % correction of the lumbar prominence than PSIF. LEVEL OF EVIDENCE: 2.

Teriparatide anabolic therapy as potential treatment of type II dens non-union fractures.

Odontoid fractures account for 5% to 15% of all cervical spine injuries and 1% to 2% of all spine fractures. Type II fractures are the most common fracture pattern in elderly patients. Treatment (rigid and non-rigid immobilization, anterior screw fixation of the odontoid and posterior C1-C2 fusion) remains controversial and represents a unique challenge for the treating surgeon. The aims of treatment in the elderly is to quickly restore pre-injury function while decreasing morbidity and mortality associated with inactivity, immobilization with rigid collar and prolonged hospitalization. Conservative treatment of type II odontoid fractures is associated with relatively high rates of non-union and in a few cases delayed instability. Options for treatment of symptomatic non-unions include surgical fixation or prolonged rigid immobilization. In this report we present the case of a 73-year-old woman with post-traumatic odontoid non-union successfully treated with Teriparatide systemic anabolic therapy. Complete fusion and resolution of the symptoms was achieved 12 wk after the onset of the treatment. Several animal and clinical studies have confirmed the potential role of Teriparatide in enhancing fracture healing. Our case suggests that Teriparatide may have a role in improving fusion rates of C2 fractures in elderly patients.

Intrathecal baclofen pumps do not accelerate progression of scoliosis in quadriplegic spastic cerebral palsy.

PURPOSE: To compare scoliosis progression in quadriplegic spastic cerebral palsy with and without intrathecal baclofen (ITB) pumps. METHODS: A retrospective matched cohort study was conducted. Patients with quadriplegic spastic cerebral palsy, GMFCS level 5, treated with ITB pumps with follow-up >1 year were matched to comparable cases by age and baseline Cobb angle without ITB pumps. Annual and peak coronal curve progression, pelvic obliquity progression and need for spinal fusion were compared. RESULTS: ITB group: 25 patients (9 female), mean age at pump insertion 9.4 and Risser 0.9. Initial Cobb angle 25.6° and pelvic tilt 3.2°. Follow-up 4.3 (1.0-7.8) years. Cobb angle at follow-up 76.1° and pelvic tilt 18.9°. Non-ITB group: 25 patients (14 female), mean age at baseline 9.2 and Risser 1.0. Initial Cobb angle 29.7° and pelvic tilt 7.1°. Follow-up 3.5 (1.0-7.5) years. Cobb angle at follow-up 69.1° and pelvic tilt 21.0°. The two groups were statistically similar for baseline age, Cobb angle and Risser grade. Mean curve progression was 13.6°/year for the ITB group vs 12.6°/year for the non-ITB group (p = 0.39). Peak curve progression was similar between the groups. Pelvic tilt progression was comparable; ITB group 4.5°/year vs non-ITB 4.6°/year (p = 0.97). During follow-up 5 patients in the ITB group and 9 in the non-ITB group required spinal fusion surgery for curve progression (p = 0.35). CONCLUSIONS: Patients with quadriplegic spastic cerebral palsy with and without ITB pumps showed significant curve progression over time. ITB pumps do not appear to alter the natural history of curve progression in this population.

Correlation between preoperative spinopelvic alignment and risk of proximal junctional kyphosis after posterior-only surgical correction of Scheuermann kyphosis.

BACKGROUND CONTEXT: Surgical correction of Scheuermann kyphosis (SK) is challenging and plagued by relatively high rates of proximal junctional kyphosis and failure (PJK and PJF). Normal sagittal alignment of the spine is determined by pelvic geometric parameters. How these parameters correlate with the risk of developing PJK in SK is not known. PURPOSE: The study aimed to investigate the relationship between preoperative and postoperative spinopelvic alignment and occurrence of PJK and PJF. STUDY DESIGN/SETTING: This is a retrospective observational cohort study. PATIENT SAMPLE: The sample included 37 patients who underwent posterior correction of SK from January 2006 to December 2012. OUTCOME MEASURES: The outcome measure was correlation analysis between preoperative and postoperative spinopelvic alignment parameters and the development of PJK over the course of the study period. METHODS: Whole spine x-rays obtained before surgery, 3 months after surgery, and at the latest follow-up were analyzed. The following parameters were measured: thoracic kyphosis (TK), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). The development of PJK was considered the primary end point of the study. Patient population was split into a control and a PJK group; repeated-measures analysis of variance was used to assess group and time differences. RESULTS: Seven patients developed PJK over the study period. Although the severity of the preoperative deformity (TK) did not differ significantly between the two groups, preoperative PI was significantly higher in the PJK group (51.9°C±8.6°C vs. 42.7°C±8.8°C, p=.018). Postoperative correction of TK was similar between the two groups (39.3% and 41.2%, p=.678) and final LL did not differ as well (53.6°C±9.2°C vs. 51.3°C±11.5°C). However, because PJK patients had larger preoperative PI values, a significant deficit of LL was observed at final follow-up in this group compared with the control group (ΔLL -10.5°C±9.8°C vs. 0.6°C±10.5°C, p=.013). CONCLUSIONS: Scheuermann kyphosis patients who developed PJK appeared to have a significant postoperative deficit of LL (lumbopelvic mismatch). Lumbar lordosis decreases after surgery following correction of TK; therefore, TK correction should be planned according to preoperative PI values to avoid excessive reduction of LL in patients with higher PI values.

GH receptor isoforms and skeletal fragility in acromegaly.

OBJECTIVE: Acromegaly is associated with an increased prevalence of vertebral fractures (VFs) in close relationship with GH hypersecretion. Two isoforms of the GH receptor (GHR) have been identified; the two isoforms differ or not by the expression of the protein fragment encoded by exon 3 of the GHR gene. Deletion of the exon 3 may influence the functional properties of the GHR and affect fracture risk in acromegalic patients. DESIGN: A cross-sectional study was designed to investigate the association between the d3-GHR isoform and the prevalence of VFs in patients with acromegaly. METHODS: In this study, 109 acromegalic patients were included (M/F, 48/61): 73 with controlled/cured acromegaly and 36 with active disease. GHR genotype was assessed in each patient. All patients were evaluated for VFs and bone mineral density at lumbar spine and hip. Serum IGF1 levels and bone metabolism markers were measured. A multivariate analysis was performed to establish risk factors for VFs in our population. RESULTS: d3-GHR carriers showed an increased prevalence of VFs when compared with patients expressing full-length GHR (35/55 vs 12/54; P<0.001). The association between GHR deletion and VFs was demonstrated both in patients with active disease and in those with controlled/cured disease. Out of 35 patients who were prospectively evaluated, 13 (37.1%) developed incident VFs. The incidence of VFs was significantly higher in patients for whom the GHR gene has been deleted when compared with those harboring the fl gene (P=0.04). In multivariate analysis, male sex (odds ratio (OR), 3.250; P=0.041), IGF1 levels (OR, 1.183; P=0.031), length of active diseases (OR, 1.038; P=0.001), and d3-GHR genotype (OR, 3.060; P=0.015) were all confirmed as risk factors of VFs in our population. CONCLUSIONS: This study suggests for the first time that exon 3 deletion of GHR may predispose patients with active and controlled acromegaly to a higher risk of VFs.

Investigating the role of DNA damage in tobacco smoking-induced spine degeneration.

BACKGROUND CONTEXT: Tobacco smoking is a key risk factor for spine degeneration. However, the underlying mechanism by which smoking induces degeneration is not known. Recent studies implicate DNA damage as a cause of spine and intervertebral disc degeneration. Because tobacco smoke contains many genotoxins, we hypothesized that tobacco smoking promotes spine degeneration by inducing cellular DNA damage. PURPOSE: To determine if DNA damage plays a causal role in smoking-induced spine degeneration. STUDY DESIGN: To compare the effect of chronic tobacco smoke inhalation on intervertebral disc and vertebral bone in normal and DNA repair-deficient mice to determine the contribution of DNA damage to degenerative changes. METHODS: Two-month-old wild-type (C57BL/6) and DNA repair-deficient Ercc1(-/Δ) mice were exposed to tobacco smoke by direct inhalation (4 cigarettes/day, 5 days/week for 7 weeks) to model first-hand smoking in humans. Total disc proteoglycan (PG) content (1,9-dimethylmethylene blue assay), PG synthesis ((35)S-sulfate incorporation assay), aggrecan proteolysis (immunoblotting analysis), and vertebral bone morphology (microcomputed tomography) were measured. RESULTS: Exposure of wild-type mice to tobacco smoke led to a 19% increase in vertebral porosity and a 61% decrease in trabecular bone volume. Intervertebral discs of smoke-exposed animals also showed a 2.6-fold decrease in GAG content and an 8.1-fold decrease in new PG synthesis. These smoking-induced degenerative changes were similar but not worse in Ercc1(-/Δ) mice. CONCLUSIONS: Short-term exposure to high levels of primary tobacco smoke inhalation promotes degeneration of vertebral bone and discs. Disc degeneration is primarily driven by reduced synthesis of proteoglycans needed for vertebral cushioning. Degeneration was not exacerbated in congenic DNA repair-deficient mice, indicating that DNA damage per se does not have a significant causal role in driving smoke-induced spine degeneration.

Is posterior percutaneous screw-rod instrumentation a safe and effective alternative approach to TLSO rigid bracing for single-level pyogenic spondylodiscitis? Results of a retrospective cohort analysis.

BACKGROUND CONTEXT: Currently, treatment for patients diagnosed with noncomplicated (ie, known infectious agent, no neurologic compromise, and preserved spinal stability) pyogenic spondylodiscitis (PS) is based on intravenous antibiotics and rigid brace immobilization. Since January 2010, we started offering our patients percutaneous posterior screw-rod instrumentation as an alternative approach to rigid bracing. Supposed benefits of posterior percutaneous instrumentation over rigid bracing are earlier free mobilization, increased comfort, and faster recovery. PURPOSE: To evaluate safety and effectiveness of posterior percutaneous spinal instrumentation for single-level PS and compare clinical and quality-of-life outcomes with standard thoracolumbosacral orthosis (TLSO) rigid bracing. STUDY DESIGN/SETTING: Retrospective observational cohort study. PATIENT SAMPLE: Twenty-seven patients consecutively diagnosed with single-level noncomplicated lower thoracic or lumbar PS from January 2010 to December 2011. OUTCOME MEASURES: Healing rate, healing time, and changes in segmental kyphosis Cobb angle were compared in the two treatment groups. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete blood count at regular time points until complete healing were also obtained. Self-report measures included Visual Analog Scale (VAS), Short-Form 12 (SF-12), and EuroQol five-dimension (EQ-5D) questionnaires. METHODS: At enrollment, patients were offered to choose between 24/7 TLSO rigid bracing for 3 to 4 months and bridging posterior percutaneous screw-rod instrumentation followed by soft bracing for 4 weeks after surgery. All patients underwent antibiotic therapy accordingly to isolated infectious agents. Patients were seen in the clinic at 1, 3, 6, and 9 months, and ESR, CRP, complete blood count, VAS, SF-12, and EQ-5D questionnaires were obtained. Segmental kyphosis was measured at diagnosis and at 9 months follow-up. Two-way repeated-measures analysis of variance was used to assess group and time differences across time points. RESULTS: Fifteen patients chose conservative treatment, whereas 12 patients chose surgical treatment. Complete infection healing was achieved in all patients with no significant differences in healing time (p<.366). C-reactive protein and ESR levels decreased in both groups accordingly with positive response to therapy with no significant differences. Surgically treated patients had significantly lower VAS scores at 1 month (2.76±0.80 vs. 5.20±1.21, p<.001) and 3 months (2.31±0.54 vs. 2.85±0.54, p<.016) post-diagnosis over TLSO patients. Moreover, surgery patients also showed steeper and statistically significant improvements in SF-12 scores over TLSO patients at 1, 3, and 6 months post-diagnosis (p<.012); no significant differences were detected at the other time points. EuroQol five-dimension index was significantly higher in surgery patients at 1 month (0.764±0.043 vs. 0.458±0.197, p<.001) and 3 months (0.890±0.116 vs. 0.688±0.142, p<.001); no significant changes were observed in segmental pre- and posttreatment kyphosis between the two groups. No instrumentation-related complications were observed in any patient. CONCLUSIONS: Posterior percutaneous spinal instrumentation is a safe, feasible, and effective procedure in relieving pain, preventing deformity, and neurologic compromise in patients affected by noncomplicated lower thoracic (T9-T12) or lumbar PS. Posterior instrumentation did not offer any advantage in healing time over TLSO rigid bracing because infection clearance is strongly dependent on proper antibiotic therapy. Nevertheless, surgical stabilization was associated with faster recovery, lower pain scores, and improved quality of life compared with TLSO conservative treatment at 1, 3, and 6 months after treatment.

Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration.

Oxidative damage is a well-established driver of aging. Evidence of oxidative stress exists in aged and degenerated discs, but it is unclear how it affects disc metabolism. In this study, we first determined whether oxidative stress negatively impacts disc matrix metabolism using disc organotypic and cell cultures. Mouse disc organotypic culture grown at atmospheric oxygen (20% O(2)) exhibited perturbed disc matrix homeostasis, including reduced proteoglycan synthesis and enhanced expression of matrix metalloproteinases, compared to discs grown at low oxygen levels (5% O(2)). Human disc cells grown at 20% O(2) showed increased levels of mitochondrial-derived superoxide anions and perturbed matrix homeostasis. Treatment of disc cells with the mitochondria-targeted reactive oxygen species (ROS) scavenger XJB-5-131 blunted the adverse effects caused by 20% O(2). Importantly, we demonstrated that treatment of accelerated aging Ercc1(-/Δ) mice, previously established to be a useful in vivo model to study age-related intervertebral disc degeneration (IDD), also resulted in improved disc total glycosaminoglycan content and proteoglycan synthesis. This demonstrates that mitochondrial-derived ROS contributes to age-associated IDD in Ercc1(-/Δ) mice. Collectively, these data provide strong experimental evidence that mitochondrial-derived ROS play a causal role in driving changes linked to aging-related IDD and a potentially important role for radical scavengers in preventing IDD.

Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs.

Intervertebral disc degeneration (IDD) is the leading cause of debilitating spinal disorders such as chronic lower back pain. Aging is the greatest risk factor for IDD. Previously, we demonstrated IDD in a murine model of a progeroid syndrome caused by reduced expression of a key DNA repair enzyme. This led us to hypothesize that DNA damage promotes IDD. To test our hypothesis, we chronically exposed adult wild-type (Wt) and DNA repair-deficient Ercc1(-/Δ) mice to the cancer therapeutic agent mechlorethamine (MEC) or ionization radiation (IR) to induce DNA damage and measured the impact on disc structure. Proteoglycan, a major structural matrix constituent of the disc, was reduced 3-5× in the discs of MEC- and IR-exposed animals compared to untreated controls. Expression of the protease ADAMTS4 and aggrecan proteolytic fragments was significantly increased. Additionally, new PG synthesis was reduced 2-3× in MEC- and IR-treated discs compared to untreated controls. Both cellular senescence and apoptosis were increased in discs of treated animals. The effects were more severe in the DNA repair-deficient Ercc1(-/Δ) mice than in Wt littermates. Local irradiation of the vertebra in Wt mice elicited a similar reduction in PG. These data demonstrate that genotoxic stress drives degenerative changes associated with IDD.

NF-κB inhibition delays DNA damage-induced senescence and aging in mice.

The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.

ISSLS prize winner: inhibition of NF-κB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging.

STUDY DESIGN: NF-κB activity was pharmacologically and genetically blocked in an accelerated aging mouse model to mitigate age-related disc degenerative changes. OBJECTIVE: To study the mediatory role of NF-κB-signaling pathway in age-dependent intervertebral disc degeneration. SUMMARY OF BACKGROUND DATA: Aging is a major contributor to intervertebral disc degeneration (IDD), but the molecular mechanism behind this process is poorly understood. NF-κB is a family of transcription factors that play a central role in mediating cellular response to damage, stress, and inflammation. Growing evidence implicates chronic NF-κB activation as a culprit in many aging-related diseases, but its role in aging-related IDD has not been adequately explored. We studied the effects of NF-κB inhibition on IDD, using a DNA repair-deficient mouse model of accelerated aging (Ercc1 mice) previously been reported to exhibit age-related IDD. METHODS: Systemic inhibition of NF-κB activation was achieved either genetically by deletion of 1 allele of the NF-κB subunit p65 (Ercc1p65 mice) or pharmacologically by chronic intraperitoneal administration of the Nemo Binding Domain (8K-NBD) peptide to block the formation of the upstream activator of NF-κB, IκB Inducible Kinase (IKK), in Ercc1 mice. Disc cellularity, total proteoglycan content and proteoglycan synthesis of treated mice, and untreated controls were assessed. RESULTS.: Decreased disc matrix proteoglycan content, a hallmark feature of IDD, and elevated disc NF-κB activity were observed in discs of progeroid Ercc1 mice and naturally aged wild-type mice compared with young wild-type mice. Systemic inhibition of NF-κB by the 8K-NBD peptide in Ercc1 mice increased disc proteoglycan synthesis and ameriolated loss of disc cellularity and matrix proteoglycan. These results were confirmed genetically by using the p65 haploinsufficient Ercc1p65 mice. CONCLUSION: These findings demonstrate that the IKK/NF-κB signaling pathway is a key mediator of age-dependent IDD and represents a therapeutic target for mitigating disc degenerative diseases associated with aging.

Onset of a Charcot spinal arthropathy at a level lacking surgical arthrodesis in a paraplegic patient with traumatic cord injury.

The study design included a case report of Charcot spinal arthropathy treated with posterior and anterior spinal instrumentation. The objective of the study was to report an unusual case of Charcot spinal arthropathy as a late complication of traumatic spinal cord injury in a patient previously treated with a long posterior thoraco-lumbar instrumentation and postero-lateral fusion. A 33-year-old man with T10-T11 complete paraplegia presented with focal low back pain, kyphotic deformity of the lumbar region with L2-L3 fracture-dislocation and hardware failure. Our treatment consisted of a circumferential arthrodesis performed with a combined anterior and posterior approach. Spinal stabilization was achieved and the patient was pain free and able to resume a sitting posture. This report suggests that the development of a Charcot spine arthropathy must always be considered as a late complication of a spinal cord injury. Moreover, we would emphasize the fundamental role of a strict clinical and radiological follow-up in order to detect an early Charcot spine complication.