藤田 順之

Although the number of patients with intervertebral disc (IVD) degeneration is increasing in aging societies, its etiology and pathogenesis remain elusive and there is currently no effective treatment to prevent this undesirable condition. The unfolded protein response (UPR) is a cellular machinery that plays critical roles in handling endoplasmic reticulum (ER) stress, a condition caused by the accumulation of unfolded proteins in the ER lumen. This study aimed to elucidate the potential role of the UPR mediated by pancreatic endoplasmic reticulum kinase (PERK), one of the major ER stress sensors in mammalian cells, in the development of IVD degeneration. IVD degeneration was artificially induced in Wister rats by percutaneously puncturing the coccyx IVDs and human IVDs were collected from patients who underwent spinal surgery. Expression of the UPR target genes was elevated in degenerative IVDs in both humans and rats. The induction of ER stress in annulus fibrosus cells significantly increased the transcripts for tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in a nuclear factor (NF)-κB pathway-dependent manner. The expression of TNF-α and IL-6 was significantly reduced by treatment with a selective PERK inhibitor, GSK2606414, and by gene silencing against PERK and activating transcription factor 4 (ATF4) transcripts. Our findings indicate that the UPR mediated by the PERK pathway is causally related to the development of IVD degeneration, suggesting that PERK may be a potential molecular target for suppressing the degenerative changes in IVDs. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1334-1345, 2018.

STUDY DESIGN: Single-center retrospective analysis of consecutively collected data. OBJECTIVE: To determine the clinical characteristics of idiopathic spinal epidural lipomatosis (SEL). SUMMARY OF BACKGROUND DATA: SEL is associated with the overt accumulation of nonencapsulated adipose tissue in the epidural space, leading to spinal cord or nerve root compression. The etiology of this condition is currently not completely understood. METHODS: Data of 166 male patients who underwent primary surgery for lumbar spinal canal stenosis (LSS) from May 2013 to February 2016 were retrospectively reviewed. Participants were divided into three groups based on the degree of epidural lipomatous lesion. Patient data of age at surgery, body mass index, prevalence of common noncommunicable diseases, blood tests, arteriosclerotic index, and preoperative clinical scores (assessed using the Japanese Orthopedic Association Back Pain Evaluation Questionnaire) were evaluated. Multivariate analysis was performed to assess the potential associated factors for idiopathic SEL. RESULTS: Patients with LSS with severe SEL had a significantly higher body mass index and elevated serum levels of total cholesterol and triglyceride compared with those without SEL. Analysis of preoperative clinical scores revealed that patients with SEL experienced pain more frequently and showed less walking ability than did those without SEL. Multivariate analysis revealed that hyperlipidemia was significantly associated with idiopathic SEL (odds ratio = 3.74, 95% confidence interval = 1.31-10.64). CONCLUSION: Our data suggest that aberrant lipid metabolism is related to the pathogenesis of idiopathic SEL and that patients with LSS with idiopathic SEL have more severe pain than do those without SEL. LEVEL OF EVIDENCE: 3.

STUDY DESIGN: A propensity-matched comparison of risk factors for proximal junctional failure (PJF), which is a symptomatic proximal junctional kyphosis developing after corrective surgery for adult spinal deformity (ASD). OBJECTIVE: To elucidate the role of bone strength for developing PJF. SUMMARY OF BACKGROUND DATA: PJF, a devastating complication of corrective surgery for ASD, often recurs even after revision surgery. Most studies of risk factors for PJF are retrospective and have a selection bias in surgical strategy, making it difficult to identify modifiable PJF risk factors. METHODS: We conducted propensity-matched comparisons of 113 surgically treated ASD patients who were followed for at least 2 years, to elucidate whether low bone-mineral density (BMD) was a true risk factor for PJF in a uniform population from a multicenter database. Patients were grouped as having mildly low to normal BMD (M group; T-score≧ - 1.5) or significantly low BMD (S group; T-score <  -1.5), and were propensity-matched for age, upper and lower instrumented vertebrae, history of spine surgery, and Schwab-Scoliosis Research Society (SRS) ASD classification. PJF was defined as a ≥20° increase from the baseline proximal junction angle with a concomitant deterioration of at least one SRS-Schwab sagittal modifier grade, or any type of proximal junctional kyphosis requiring revision. RESULTS: PJF developed in 22 of 113 patients (19%). There were 48 propensity-matched patients in the M and S groups (24 in each) with similar parameters for age, body mass index, number of vertebrae involved, C7SVA, pelvic incidence  - LL, and SRS-Schwab type. In this propensity-matched population, the incidence of PJF was significantly higher in the S group (33% vs. 8%, P < 0.01, odds ratio 6.4, 95% CI: 1.2-32.3). CONCLUSION: Low BMD was a significant risk factor for PJF in this propensity-matched cohort (odds ratio 6.4). Surgeons should consider prophylactic treatments when correcting ASD in patients with low BMD. LEVEL OF EVIDENCE: 3.

BACKGROUND CONTEXT: The relationship between gait pattern and the level of upper instrumented vertebra (UIV) in surgically treated patients with adult spinal deformity (ASD) has not been fully documented. PURPOSE: This study aimed to assess the effect of UIV level for the gait pattern in ASD. STUDY DESIGN/SETTING: A prospective case series was carried out. PATIENT SAMPLE: Thirty surgically treated consecutive female ASD with lumbosacral fusion (age 67.0±8.4 years; body mass index 22.7±2.4 kg/m2; Cobb angle 49.9°±21.3°; coronal vertical axis 1.5±3.6 cm; C7 sagittal vertical axis [C7SVA] 9.3±5.3 cm; pelvic incidence-lumbar lordosis 35.4°±25.8°; and lean volume of the lower leg 5.5±0.9 kg) were categorized into upper thoracic [UT] group or lower thoracic [LT] group based on the level of UIV (UT; UIV T2-T5, LT; UIV T9-T11), and the gait pattern were compared before and after corrective spine surgery. OUTCOME MEASURES: Scoliosis Research Society Patient Questionnaire, Oswestry Disability Index, and force plate analysis were the outcome measures. METHODS: All subjects underwent gait analysis on a custom-built force plate. Dual-energy X-ray absorptiometry. Subjects were followed-up for at least 2 years postoperation. RESULTS: The UT group had larger baseline Cobb angle, whereas the LT group had larger C7SVA (UT vs. LT; Cobb angle: 59.2±22.9 vs. 44.6±17.4°, p=.03, C7SVA: 10.9±8.7 vs. 12.0±7.1 cm, p=.03). Preoperatively, no difference was found in gait velocity and stride between UT and LT group, whereas the right and left difference of step length was significantly large in UT group (velocity: 55.0±12.5 vs. 53.6±9.0 m/min, stride: 99.7±13.0 vs. 97.8±13.6 cm, step length; 10.4±4.9 vs. 5.6%±3.3%). Coronal and sagittal alignments were significantly improved in both groups (total; Cobb angle: 19.4°±10.6°, C7SVA: 5.3±2.9 cm, PI-LL: 12.1°±5.1°). Gait pattern, stride, and velocity all improved significantly after surgery (total; velocity: 62.3±8.9m/min, stride: 106.8±12.3 cm, p=.01). The knee angle at the heel contact phase and hip range of motion (ROM) were also significantly improved at postoperation (total; hip ROM: preoperation: 29.2°±9.1°, postoperation: 36.2°±4.8°, knee angle; preoperation: 10.6°±6.6°, postoperation: 4.4°±2.8°). No difference was observed for the pelvis and shoulder rotation on the horizontal plane at postoperation in both groups (total; pelvis rotation; preoperation: 7.4°±3.4°, postoperation: 7.9°±2.4°, shoulder rotation; preoperation: 7.4°±2.9°, postoperation: 8.7°±3.6°). The head vertical deviation was also not changed postoperatively in both groups (preoperation: 3.1±0.9 cm, postoperation: 3.1±0.8 cm). CONCLUSIONS: Both UT and LT groups achieved similar improvement of gait ability and pattern after surgery. Additional studies will be needed to further define the effect of UIV for the activity of daily living such as fast walking, stepping the stairs, or standing from the chair in ASDs.

INTRODUCTION: Multifocal primary melanoma of the spine is extremely rare. Here, we report a case of multifocal primary melanoma of the cervical spinal cord. CASE PRESENTATION: A 39-year-old man presented with a 1-year history of numbness of the upper extremities and back. Magnetic resonance imaging of the cervical spine suggested multifocal intradural extramedullary tumors at levels C2 and C4-C5. A diagnostic biopsy revealed a pathological diagnosis of malignant melanoma. Tumorectomy was then performed. The numbness in the patient's upper extremities improved, and he was discharged. As of 2 years after surgery, no signs of local or systemic recurrence have been noted. DISCUSSION: Primary melanoma of the spinal cord usually carries a poor prognosis. However, in this case, the outcome following tumorectomy has been highly favorable. We speculate that this is because the MIB-1 labeling index of the tumors was less than 1%.

INTRODUCTION: Post-transplant lymphoproliferative disorder (PTLD) is a condition associated with post-transplant immunosuppression that can develop in various organs, including the grafted one. However, it has rarely been reported in nerve tissue. We encountered an unexpected case of PTLD in the cauda equina of a kidney transplant recipient who was being treated with chronic immunosuppressive therapies. CASE PRESENTATION: The patient was a 39-year-old woman in whom lower limb muscle weakness appeared and progressed rapidly 10 years after kidney transplantation for glomerulonephritis. Magnetic resonance imaging (MRI) findings were suggestive of an intradural extramedullary tumor. Diagnosis of PTLD was established on open biopsy. Culprit immunosuppressants (tacrolimus, mycophenolate mofetil, and prednisolone) were discontinued, and rituximab and radiation therapy were started. The paraplegia gradually improved after drug discontinuation, and the lesion diminished in size 3 months after this series of treatment, and finally disappeared on MRI as of 1 year after treatment. DISCUSSION: PTLD in the cauda equina is extremely rare, and only one case involving the cauda equina has been reported previously. Biopsy should be performed initially for definitive diagnosis, after which the suspected culprit immunosuppressants should be immediately discontinued.

STUDY DESIGN: Multicenter retrospective study. BACKGROUND: Postoperative surgical site infection is one of the most serious complications following spine surgery. Previous studies do not appear to have investigated pyogenic discitis following lumbar laminectomy without discectomy. This study aimed to identify risk factors for postoperative pyogenic discitis following lumbar decompression surgery. METHODS: We examined data from 2721 patients undergoing lumbar laminectomy without discectomy in five hospitals from April 2007 to March 2012. Patients who developed postoperative discitis following laminectomy (Group D) and a 4:1 matched cohort (Group C) were included. Fisher's exact test was used to determine risk factors, with values of p < 0.05 considered statistically significant. RESULTS: The cumulative incidence of postoperative discitis was 0.29% (8/2721 patients). All patients in Group D were male, with a mean age of 71.6 ± 7.2 years. Postoperative discitis was at L1/2 in 1 patient, at L3/4 in 3 patients, and at L4/5 in 4 patients. Except for 1 patient with discitis at L1/2, every patient developed discitis at the level of decompression. The associated pathogens were methicillin-resistant Staphylococcus aureus (n = 3, 37.5%), methicillin-susceptible Staphylococcus epidermidis (n = 1, 12.5%), methicillin-sensitive S. aureus (n = 1, 12.5%), and unknown (n = 3, 37.5%). In the analysis of risk factors for postoperative discitis, Group D showed a significantly lower ratio of patients who underwent surgery in the winter and a significantly higher ratio of patients who had Modic type 1 in the lumbar vertebrae compared to Group C. CONCLUSIONS: Although further prospective studies, in which other preoperative modalities are used for the evaluation, is needed, our data suggest the presence of Modic type 1 as a risk factor for discitis following laminectomy. Latent pyogenic discitis should be carefully ruled out in patients with Modic type 1. If lumbar laminectomy is performed for such patients, more careful observation is necessary to prevent the development of postoperative discitis.

OBJECTIVE A number of studies have reported that surgery for cervical intramedullary tumors via the posterior approach can result in postoperative sagittal malalignment of the cervical spine; however, the risk factors remain unclear. The purpose of this study was to investigate the changes in cervical spinal alignment after surgery for cervical intramedullary tumors in adults and to elucidate the risk factors for cervical spinal sagittal misalignment. METHODS Data for the period from April 2001 to December 2011 for all adults who had undergone surgery for cervical intramedullary spinal cord tumors at a single institution were retrospectively analyzed to determine the postoperative changes in cervical spine alignment. Patients younger than 20 years of age and those who required postoperative radiotherapy were excluded from the study. Patients were divided into 2 groups according to tumor location: upper tumor (U) group, in which the central region of the tumor was above the C-5 level; and lower tumor (L) group, in which the central region of the tumor was at or below the C-5 level. Changes in alignment of the cervical spine were measured on plain lateral radiographs. Data on atrophy of the deep extensor muscles (DEMs), tumor location, detachment of the DEMs from the C-2 spinous process, the C2-7 angle before surgery, patient age at surgery, tumor histology, patient sex, tumor size, and number of laminae affected were reviewed for each patient, and the correlation of each of these factors with cervical spinal malalignment was evaluated using statistical analysis. RESULTS The 54 adults eligible for analysis had a mean age of 49.1 years. Ependymoma was the most common cervical intramedullary tumor (63.0%) in this series. In the tumor location U group, the kyphotic angle of the C2-7 spinal segments increased after surgery (-5.8° ± 2.8°). In contrast, in the L group, the C2-7 lordotic angle increased after surgery (6.4° ± 2.6°). In the univariate analysis, atrophy of the DEMs, detachment of the DEMs from the C-2 spinous process, and an upper cervical location of the tumor were identified as factors significantly correlated with the development of cervical spinal kyphosis after surgery. Multiple linear regression analysis revealed the following as risk factors for kyphotic change of the cervical spine after surgery: 1) atrophy of the DEMs after surgery (β = -0.54, p < 0.01), and 2) detachment of the DEMs from the C-2 spinous process (β = -0.37, p < 0.01). CONCLUSIONS Atrophy of the DEMs after surgery and detachment of the DEMs from the C-2 spinous process are directly related to the risk of cervical spinal kyphosis after surgery for cervical intramedullary tumors in adults. Therefore, preservation of the DEMs, especially those attached to the C-2 spinous process, is important for the prevention of kyphotic malalignment of the cervical spine after surgery for intramedullary tumors.

Adolescent idiopathic scoliosis (AIS) is a common spinal deformity affecting millions of children. Since treatment and prognosis of AIS depend on curve progression, identifying factors related to AIS curve progression is important in its management. Although several genetic loci for AIS occurrence are reported, no locus for curve progression has been identified. To identify genes associated with AIS progression, we conducted a genome-wide association study followed by a replication study using a total of 2,543 AIS subjects who were evaluated for the curve progression. We identified a significantly associated locus on chromosome 11q14.1 (P = 1.98 × 10-9, odds ratio = 1.56). In silico and in vitro analyses identified a functional variant, rs35333564 in MIR4300HG, the host gene of a microRNA, MIR4300. The genomic region containing rs35333564 had enhancer activity, which was decreased in its risk allele. Our data suggest that decrease of MIR4300 is related to AIS progression.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: This study was conducted to assess the invasiveness, efficacy, and safety of minimally invasive spine stabilization (MISt) for metastatic spinal tumor patients with short life expectancy. SUMMARY OF BACKGROUND DATA: Conventional open surgery for metastatic spinal tumors has the disadvantages of significant blood loss, potential infection, damage to back muscles, and extended hospital stays. The minimally invasive spine surgery has changed the treatment of metastatic spinal tumors radically and fundamentally. MATERIALS AND METHODS: We retrospectively reviewed data from 50 consecutive patients registered with the Keio Spine Research Group (KSRG) who underwent posterior palliative surgery for metastatic spinal tumors from January 2009 to June 2015. Of these, 25 patients underwent MISt surgery (M group), and 25 underwent conventional open surgery (C group). The patients were assessed by demographic data, surgical invasiveness, complications, pain improvement, and neurological recovery. RESULTS: The 2 groups did not differ significantly in baseline characteristics. The M group had significantly less blood loss (M, 340.1 mL; C, 714.3 mL; P=0.005), less postoperative drainage (M, 136.0 mL; C, 627.0 mL; P<0.001), lower rates of red blood cell transfusion (M, 3 cases; C, 10 cases; P=0.029), and a shorter postoperative period of bed rest (M, 2.0 d; C, 3.6 d; P<0.001), compared with the C group. The perioperative complication rates were significantly lower (P=0.012) in the M group (3 patients, 12%) than in the C group (11 patients, 44%). Neurological deficits and pain improved significantly and comparably in the 2 groups after surgery. CONCLUSIONS: MISt is a less invasive and effective alternative surgery to conventional open surgery for metastatic spinal tumors. MISt should be considered as a valid option for the treatment of metastatic spinal tumor patients with a short life expectancy. LEVEL OF EVIDENCE: Level 3.

PURPOSE: The aim of the present study was to investigate the factors associated with C5 palsy by focusing on radiological parameters using multivariable analysis. METHODS: The authors retrospectively assessed 190 patients with cervical spondylotic myelopathy treated by open-door laminoplasty. Four radiographic parameters-the number of expanded lamina, C3-C7 angle, lamina open angle and space anterior to the spinal cord-were evaluated to clarify the factors associated with C5 palsy. RESULTS: Of the 190 patients, 11 developed C5 palsy, giving an overall incidence of 5.8%. Although the number of expanded lamina, lamina open angle and space anterior to the spinal cord were significantly larger in C5 palsy group than those in non-palsy group, a multiple logistic regression analysis revealed that only the space anterior to the spinal cord (odds ratio 2.60) was a significant independent factor associated with C5 palsy. A multiple linear regression analysis indicated that the lamina open angle was associated with the space anterior to the spinal cord and the analysis identified the following equation: space anterior to the spinal cord (mm) = 1.54 + 0.09 × lamina open angle (degree). A cut-off value of 53.5° for the lamina open angle predicted the development of C5 palsy with a sensitivity of 72.7% and a specificity of 83.2%. CONCLUSIONS: The larger postoperative space anterior to the spinal cord, which was associated with the lamina open angle, was positively correlated with the higher incidence of C5 palsy.

Control of phosphate metabolism is crucial to regulate aging in mammals. Klotho is a well-known anti-aging factor that regulates phosphate metabolism: mice mutant or deficient in Klotho exhibit phenotypes resembling human aging. Here we show that ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is required for Klotho expression under phosphate overload conditions. Loss-of-function Enpp1 ttw/ttw mice under phosphate overload conditions exhibited phenotypes resembling human aging and Klotho mutants, such as short life span, arteriosclerosis and osteoporosis, with elevated serum 1,25(OH)2D3 levels. Enpp1 ttw/ttw mice also exhibited significantly reduced renal Klotho expression under phosphate overload conditions, and aging phenotypes in these mice were rescued by Klotho overexpression, a low vitamin D diet or vitamin D receptor knockout. These findings indicate that Enpp1 plays a crucial role in regulating aging via Klotho expression under phosphate overload conditions.

STUDY DESIGN: Laboratory study. OBJECTIVE: To elucidate the potential involvement of the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducers and activator of transcription (STAT3) pathway in the development of intervertebral disc (IVD) degeneration. SUMMARY OF BACKGROUND DATA: IL-6 plays a crucial role in IVD degeneration; however, the downstream intracellular signaling of IL-6 in the IVD is not fully understood. METHODS: The expression levels of IL-6 and suppressors of cytokine signaling 3 (SOCS3), a target gene of the IL-6/JAK/STAT3 pathway, were evaluated in rat and human degenerated IVD samples. The effects of IL-6 on primary rat annulus fibrosus (AF) cells were analyzed using quantitative PCR, immunocytochemistry, and Western blotting. The potential efficacy of a JAK inhibitor, CP690,550, in neutralizing the effect of IL-6 was evaluated in vitro. RESULTS: A high expression of IL-6 and SOCS3 was observed in both rat and human degenerated IVD samples. In rat AF cells, IL-6 markedly induced the phosphorylation of STAT3 and the expression of cyclooxygenase-2 and matrix metalloprotease-13. CP690,550 significantly suppressed the phosphorylation of STAT3 and offset the catabolic effect of IL-6 in rat AF cells. CONCLUSION: Our results suggest that the IL-6/JAK/STAT3 pathway is involved in the pathogenesis of IVD degeneration and that CP690,550 suppresses the catabolic effect of the IL-6 in the IVD. LEVEL OF EVIDENCE: N/A.

The pathomechanism of the ligamentum flavum (LF) hypertrophy in diabetic patients with lumbar spinal canal stenosis (LSCS) remains unclear. A cross-sectional study was undertaken to investigate the mechanism of LF hypertrophy in these patients. Twenty-four diabetic and 20 normoglycemic patients with LSCS were enrolled in the study. The structure of the LF in the study subjects was evaluated using histological and immunohistochemical methods, and the levels of sorbitol, pro-inflammatory cytokines, and the fibrogenic factor, TGF-β1, in the LF were analyzed. In vitro experiments were performed using NIH3T3 fibroblasts to evaluate the effect of high-glucose conditions and an aldose reductase inhibitor on the cellular production of sorbitol, pro-inflammatory factors, and TGF-β1. We found that the LF of diabetic patients exhibited significantly higher levels of sorbitol and pro-inflammatory cytokines, TGF-β1 and of CD68-positive staining than that of the normoglycemic subjects. The diabetic LF was significantly thicker than that of the controls, and showed evidence of degeneration. The high glucose-cultured fibroblasts exhibited significantly higher levels of sorbitol, pro-inflammatory factors, and TGF-β1 compared to the low glucose-cultured cells, and these levels were dose-dependently reduced by treatment with the aldose reductase inhibitor. Taken together, our data suggests that increased sorbitol levels in the LF of diabetic patients results in increased production of pro-inflammatory and fibrogenic factor, which contribute to LF hypertrophy, and could increase the susceptibility of diabetic patients to LSCS. Furthermore, aldose reductase inhibition effectively reduced the levels of sorbitol and sorbitol-induced pro-inflammatory factor expression in high glucose-cultured fibroblasts. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1058-1066, 2017.

BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) can cause myelopathy that is often managed surgically. Knowledge of predictors of surgical outcomes can provide decision support to surgeons. The aims of this study were to investigate the relationships between preoperative physical signs and postoperative functional outcomes in patients with OPLL and to clarify whether physical signs could predict functional outcomes. METHODS: Fifty-five patients with OPLL who had undergone cervical laminoplasty were included in this study. Six physical signs including hyperreflexia, Babinski sign, sensory disturbance, grip strength, 10-s grip and release test, and bladder dysfunction, and four other factors including age, duration of symptoms, history of minor trauma and preoperative Japanese Orthopaedic Association (JOA) score were investigated as potential predictive prognostic factors using both univariate and multivariate analyses. RESULTS: The mean recovery rate of JOA score was 62.5 ± 32.5%. The neurological recovery rate was negatively associated with age (P = 0.002), the duration of symptoms (P = 0.002) and Babinski sign (P = 0.007), whereas it was positively correlated with grip strength (P = 0.011). Multiple logistic regression analyses revealed that age (Odds ratio: 0.89, 95% CI: 0.81-0.99) and Babinski sign (Odds ratio: 0.18, 95% CI: 0.04-0.89) were factors associated with functional outcomes. CONCLUSIONS: Satisfactory functional outcomes could be expected for patients who are young and do not exhibit the Babinski sign, showing that the Babinski sign could be useful as an indicator of the window of opportunity for achieving satisfactory functional outcomes.

BACKGROUND AND PURPOSE: Adolescent idiopathic scoliosis (AIS) is a structural, lateral curvature with rotation of the spine that develops around puberty. The influence of this spinal deformity on three-dimensional trunk movements during gait has not yet been elucidated. The aim of this study was to determine the influence of spinal curve pattern (single thoracic curve vs. single lumbar curve) on trunk kinematics during gait. METHODS: Twenty-two patients with a single thoracic curve (Lenke type 1) and 17 patients with a single lumbar curve (Lenke type 5) were included in this study. Trunk symmetry in the sagittal, coronal, and transverse planes during gait was evaluated using an optoelectronic motion capture system. RESULTS: In the type 1 group, the trunk was significantly rotated towards the concave side in the transverse plane during gait (mean difference of transverse rotation angle between concave side load and the convex side load, 8.8±0.6°, p<0.01). In the type 5 group, the trunk was significantly rotated towards the convex side in the coronal plane throughout the stance phase of gait (mean difference of coronal inclination angle, 1.9±0.3°, p<0.05). CONCLUSIONS: The AIS patients with a single thoracic curve showed asymmetrical trunk movement in the transverse plane, and patients with a single lumbar curve showed asymmetrical trunk movement in the coronal plane. These results indicate that the spinal curve pattern influenced trunk kinematics, and suggest that the global postural control strategy of patients with AIS differs according to the curve pattern.

Extramedullary hematopoiesis (EMH) occasionally occurs in patients exhibiting hematological disorders with decreased hematopoietic efficacy. EMH is rarely observed in the spinal epidural space and patients are usually asymptomatic. In particular, in the patients with polycythemia vera, spinal cord compression due to EMH is extremely rare. We report a case of polycythemia vera, in which operative therapy proved to be an effective treatment for myelopathy caused by spinal EMH.

BACKGROUND: Although most pediatric Chance fractures (PCFs) can be treated successfully with casting and bracing, some PCFs cause progressive spinal deformities requiring surgical treatment. There are only few reports of asymmetrical osteotomy for PCF-associated spinal deformities. CASE PRESENTATION: We here report a case of a 10-year-old girl who suffered an L2 Chance fracture from an asymmetrical flexion-distraction force, accompanied by abdominal injuries. She was treated conservatively with a soft brace. However, a progressive spinal deformity became evident, and 10 months after the injury, examination showed segmental kyphoscoliosis with a Cobb angle of 36°, a kyphosis angle of 31°, and a coronal imbalance of 30 mm. Both the coronal and sagittal deformities were successfully corrected by asymmetrical pedicle subtraction osteotomy. CONCLUSIONS: Initial kyphosis and posterior ligament complex should be evaluated at some point when treating PCFs. Asymmetrical pedicle subtraction osteotomy can be a useful surgical option when treating rigid kyphoscoliosis associated with a PCF.

BACKGROUND: Postoperative coronal imbalance is a significant problem after selective thoracic fusion for primary thoracic and compensatory lumbar curves in adolescent idiopathic scoliosis (AIS). However, longitudinal studies on postoperative behavior of coronal balance are lacking. This multicenter retrospective study was conducted to analyze factors related to onset and remodeling of postoperative coronal imbalance after posterior thoracic fusion for Lenke 1C and 2C AIS. METHODS: Twenty-one Lenke 1C or 2C AIS patients, who underwent posterior thoracic fusion ending at L3 or above, were included with a minimum 2-year follow-up. The mean patients' age was 15.1 years at the time of surgery. Radiographic measurements were performed on Cobb angles of the main thoracic (MT) and thoracolumbar/lumbar (TLL) curves and coronal balance. Factors related to the onset of immediately postoperative coronal decompensation (IPCD) and postoperative coronal balance remodeling (PCBR), defined as an improvement of coronal balance during postoperative follow-up, were investigated using comparative and correlation analyses. RESULTS: Mean Cobb angles for the MT and TLL curves were 57.3° and 42.3° preoperatively and were corrected to 22.8° and 22.5° at final follow-up, respectively. Mean preoperative coronal balance of -3.8 mm got worse to -21.2 mm postoperatively, and regained to -12.0 mm at final follow-up. Coronal decompensation was observed in two patients preoperatively, in ten patients immediately postoperatively, and in three patients at final follow-up. The preoperative coronal balance and lowest instrumented vertebra (LIV) selection relative to stable vertebra (SV) were significantly different between patients with IPCD and those without. PCBR had significantly negative correlation with immediately postoperative coronal balance. CONCLUSIONS: IPCD after posterior thoracic fusion for Lenke 1C and 2C AIS was frequent and associated with preoperative coronal balance and LIV selection. However, most patients with IPCD regained coronal balance through PCBR, which was significantly associated with immediately postoperative coronal balance. A fixation more distal to SV shifted the coronal balance further to the left postoperatively.

CASE: A 12-year-old girl with Crouzon syndrome presented to our hospital with scoliosis (114°) and kyphosis from T8 to T12 (138°). After she had been in halo-gravity traction for 2 weeks, we performed posterior correction and fusion surgery from T3 to L3, with a posterior vertebral column resection of T10. She experienced postoperative respiratory failure and remained on a ventilator for 4 weeks. With rehabilitation, the respiratory function had recovered by postoperative week 8. At the 2-year follow-up, there was no loss of correction or any other complication. CONCLUSION: Serious perioperative respiratory complications may occur when a patient with Crouzon syndrome is treated surgically.

INTRODUCTION: Spinal lipoma and spinal arteriovenous fistula (sAVF) are different pathologies and their co-existence is extremely rare. Here we reported two cases of adult-onset sAVF occurring within a spinal lipoma and with review the literature in an attempt to identify the mechanisim of and optimal treatment of this condition. CASE PRESENTATION: Case 1 was a 51-year-old man who was treated by embolization of the feeding artery and ligation of the draining vein. Case 2 was a 53-year-old man who was treated by embolization and resection of the tumor containing the shunt zone. In both cases, symptoms improved after surgery. However, in Case 1, angiography at 1 month after the surgery revealed recurrence of the arteriovenous shunt. DISCUSSION: A literature search revealed only nine other similar case reports. All cases, including ours occurred in adults. In almost all cases, the shunt was located within the spinal lipoma. Pathologic examination revealed venous hypertension, but no evidence of congenital vascular malformation. Given that lipomas release angiogenic factors, the presence of a spinal lipoma may indicate its involvement in the development of acquired sAVF. Our two cases might represent a new subtype of sAVF. Based on our experiences, we recommend resection of the tumor containing the shunt for the management of sAVF.

STUDY DESIGN: Multicenter case-control study. OBJECTIVE: To characterize the pathogenesis of idiopathic spinal epidural lipomatosis (SEL). SUMMARY OF BACKGROUND DATA: SEL is often associated with the history of steroid use or endocrine disorders; however, the pathogenesis of idiopathic SEL remains poorly understood. METHODS: Sixteen patients who underwent lumbar decompression surgery due to severe idiopathic SEL were included in the study (L group, 15 men and 1 woman; mean age, 71.5 yrs). Fifteen patients without SEL, who underwent decompression surgery for lumbar canal stenosis, were selected as controls (C group, 14 men and 1 woman; mean age, 70.3 yrs). The following parameters were analyzed in these two groups: body mass index (BMI), medical history, histology, the size of adipocytes in the epidural fat (EF) tissues, and the expression level of the transcripts for adiponectin, leptin, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-8. RESULTS: The mean BMI of the L group was significantly higher than that of the C group (29.1 vs. 25.2 kg/m, P = 0.006), and there was a significant correlation between BMI and the width of EF in both groups. The average adipocyte size in the EF was significantly larger in the L group than in the C group (2846.8 vs. 1699.0 μm, P = 0.017). Furthermore, the expression levels of the transcripts for TNF-α and IL-1β in the L group were significantly higher than those in the C group [2.59-fold increase (P = 0.023) and 2.60-fold increase (P = 0.015), respectively]. CONCLUSION: Our data suggest that the pathogenesis of idiopathic SEL is associated with obesity. In addition, the increased expression of two major inflammatory cytokines in the EF in the L group may indicate that SEL is causally related to chronic inflammation. LEVEL OF EVIDENCE: 3.

Minimodeling is a type of focal bone formation that is characterized by the lack of precedent bone erosion by osteoclasts. Although this form of bone formation has been described for more than a decade, how anti-osteoporotic agents that are currently used in clinical practice affect the kinetics of minimodeling is not fully understood. We performed a bone morphometric analysis using human vertebral specimens collected from postmenopausal patients who underwent spinal surgery. Patients were divided into three groups according to osteoporosis medication; non-treated, Eldecalcitol (ELD, a vitamin D derivative that has recently been approved to treat patients with osteoporosis in Japan)-treated, and bisphosphonate-treated groups. Five to six patients were enrolled in each group. There was a trend toward enhanced minimodeling in ELD-treated patients and suppressed of it in bisphosphonate-treated patients compared with untreated patients. The differences of minimodeling activity between ELD-treated and bisphosphonate-treated patients were statistically significant. The present study suggests that ELD and bisphosphonates have opposite effects on minimodeling from one another, and show that minimodeling also takes place in vertebrae as has been described for the ilium and femoral head in humans.

Both bone and muscle volume is concomitantly reduced under immobilization conditions; however, no single drug is currently available to block these outcomes simultaneously. Bisphosphonates are utilized clinically to inhibit osteoclast-dependent bone resorption, but their effects on muscle are largely unknown. Here we show that skeletal muscle is a direct target of the bisphosphonate ibandronate (IBN) and that reduced muscle volume and induction of Atrogin-1 and MuRF1, both atrogenes, are significantly inhibited by IBN administration in vivo using a mouse model of muscle atrophy. IBN treatment also significantly blocked immobilization-induced bone loss in vivo. We also report that expression of Atrogin-1 and MuRF1 and accumulation of Smad2/3 proteins, which are upstream of atrogines, occurred following serum starvation of myogenic C2C12 cells in vitro, effects significantly inhibited by IBN treatment. Interestingly, IBN effects on C2C12 cells were abrogated by MG132, an ubiquitin/proteasome inhibitor, suggesting that IBN functions via the ubiquitin-proteasome system. Our findings lend new insight into the role of IBN in preventing muscle atrophy.

STUDY DESIGN: Case report and systematic review of the literature. OBJECTIVE: To describe a rare case of remodeling of the cervical facet joint after the microendoscopic resection of an osteoid osteoma. SUMMARY OF BACKGROUND DATA: Osteoid osteoma, the third most common benign bone tumor, is often treated by image-guided percutaneous removal of the nidus. However, percutaneous resection poses technical difficulties when the tumor is located near the spinal cord or nerve roots. To our knowledge, there are no reports describing postoperative remodeling of the cervical facet joint after surgical resection of an osteoid osteoma. METHODS: A 13-year-old boy was presented with neck pain that became worse at night. Computed tomography showed an osteoid osteoma in the right 7th cervical superior articular process. We successfully resected the nidus of the osteoid osteoma using minimally invasive microendoscopy. RESULTS: The patient was symptom-free at the 1-year follow up, and computed tomography images showed new bone formation at the C6/7 facet joint. CONCLUSION: This case indicates that microendoscopic resection is safe and effective for treating a cervical osteoid osteoma. This technique allowed total resection of the nidus with only minimal damage to the adjacent soft tissue and bone, and induced remodeling of the resection site.Level of Evidence: 4.

Intervertebral disc degeneration proceeds with age and is one of the major causes of lumbar pain and degenerative lumbar spine diseases. However, studies in the field of intervertebral disc biology have been hampered by the lack of reliable cell lines that can be used for in vitro assays. In this study, we show that a chordoma-derived cell line U-CH1-N cells highly express the nucleus pulposus (NP) marker genes, including T (encodes T brachyury transcription factor), KRT19, and CD24. These observations were further confirmed by immunocytochemistry and flow cytometry. Reporter analyses showed that transcriptional activity of T was enhanced in U-CH1-N cells. Chondrogenic capacity of U-CH1-N cells was verified by evaluating the expression of extracellular matrix (ECM) genes and Alcian blue staining. Of note, we found that proliferation and synthesis of chondrogenic ECM proteins were largely dependent on T in U-CH1-N cells. In accordance, knockdown of the T transcripts suppressed the expression of PCNA, a gene essential for DNA replication, and SOX5 and SOX6, the master regulators of chondrogenesis. On the other hand, the CD24-silenced cells showed no reduction in the mRNA expression level of the chondrogenic ECM genes. These results suggest that U-CH1-N shares important biological properties with notochordal NP cells and that T plays crucial roles in maintaining the notochordal NP cell-like phenotype in this cell line. Taken together, our data indicate that U-CH1-N may serve as a useful tool in studying the biology of intervertebral disc. © 2016 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 34:1341-1350, 2016.

BACKGROUND: In Japan, ossification of the posterior longitudinal ligament (OPLL) has been designated as an intractable disease by the Ministry of Health, Labour, and Welfare. Here we aimed to clarify the epidemiological characteristics of severe OPLL patients by analyzing a national registry of this disease that uses clinical investigation registration forms. METHODS: We retrospectively investigated clinical investigation registration forms for 24,502 patients with OPLL. We examined the sex distribution, age of disease onset, period from disease onset to registration, family history, site of ossification as determined by plain radiographs, Japanese Orthopaedic Association score, and number of OPLL surgeries. RESULTS: The male-to-female ratios were 2.7:1 and 1.9:1 for new and renewed registrations, respectively. The mean ages at disease onset were 61.1 and 59.7 years for new and renewed registrations, respectively. The mean periods from disease onset to registration were 2.6 and 8.4 years for new and renewed registrations, respectively. The percentages of new registrations with and without family history were 5.3% and 51.5%, respectively (unknown for 43.3%). Of the new registrations, 3511, 359, and 200 cases exhibited ossification in the cervical spine, thoracic spine, and lumbar spine, respectively; the corresponding numbers for renewed registrations were 13,710, 2484, and 1508. The Japanese Orthopaedic Association score was 9.9 ± 3.6 for new registrations, and the mean score recovery rate for renewed registrations was 6.0%. The number of OPLL surgeries was one or zero, two, three, four, or five for 21,785, 2167, 412, 99, and 39 patients, respectively, with 11.1% of all patients having undergone multiple surgeries. CONCLUSIONS: This study offers new insight into the epidemiological characteristics of severe OPLL. In particular, we found that the age of disease onset was higher than previously reported, the period from disease onset to registration (surgery) was relatively short, and about 90% of the patients required only a single surgery.

BACKGROUND: Although various risk factors have been reported for adjacent segment degeneration after lumbar fusion, the exact mechanisms and risk factors related to adjacent segment degeneration have not been clear. The present study was conducted to evaluate the risk factors for radiological adjacent segment degeneration in patients surgically treated for single-level L4 spondylolisthesis focusing on a single pathology, a specific fusion level, at a set interval. METHODS: We assessed preoperative and five-year postoperative radiographs for 72 patients who underwent L4-5 anterior or posterior lumbar interbody fusion for single-level L4 degenerative spondylolisthesis. Adjacent segment degeneration was defined as imaging evidence of one or more of the following conditions at L1-2, L2-3, or L3-4: 1) a loss of more than 20% of the preoperative disc height, 2) anterolisthesis or retrolisthesis greater than 3 mm, 3) or osteophyte formation greater than 3 mm. RESULTS: We found adjacent segment degeneration in 21 patients, with 31 discs affected. Multiple logistic regression analysis identified the following significant independent risk factors for adjacent segment degeneration: female gender (odds ratio 10.80; 95% confidence interval 1.20-96.89), posterior lumbar interbody fusion (odds ratio 7.70; 95% confidence interval 1.82-32.66), and pre-existing disc degeneration (odds ratio 12.29; 95% confidence interval 1.69-89.27). CONCLUSIONS: Female gender, posterior lumbar interbody fusion, and pre-existing disc degeneration were significant independent risk factors for radiologically diagnosed adjacent segment degeneration in patients treated for L4 degenerative spondylolisthesis by interbody lumbar fusion.

STUDY DESIGN: Retrospective study. OBJECTIVE: To examine the reliabilities of sagittal spino-pelvic alignment measurements using whole spine-pelvic and local pelvic radiographs and to determine whether spinal deformity affects these reliabilities. SUMMARY OF BACKGROUND DATA: Sagittal spino-pelvic alignment is important in adult spinal deformity patients (ASD). Spino-pelvic parameters are closely related to health-related quality of life and indispensable for surgical planning. However, few studies have focused on the reliability of these measurements. METHODS: Three spino-pelvic parameters, pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) were measured in 2 patient groups: 33 adult scoliosis (AS) and 33 nondeformity (ND) patients, using whole spine-pelvic lateral radiographs (whole spine radiographs) and local pelvic lateral radiographs (local pelvic radiographs), by 5 experienced spine surgeons. Intra- and interobserver reliabilities for each procedure were evaluated by intraclass correlation coefficients (ICC). The interobserver reliability differences between the 2 procedures were statistically evaluated. The difference between the largest and smallest measurements among the 5 observers was also evaluated in the AS and ND groups. RESULTS: Measurement of the 3 parameters using whole spine or local pelvic radiographs showed good to excellent intraobserver reliability (range of ICC: 0.820-0.935). The interobserver reliabilities of PI and PT from local pelvic radiographs were significantly higher than those from whole spine radiographs (P < 0.002). The intraobserver reliabilities of PI and PT from pelvic radiographs tended to be higher than those from whole spine radiographs, but the differences were not statistically significant. The reliability of SS was comparable between the 2 methods. The differences between the highest and lowest PI and PT measurements were smaller with the pelvic compared to whole spine radiographs. These findings were consistent in the AS and ND groups. CONCLUSION: Local pelvic radiography is more reliable than whole spine radiography for determining spino-pelvic parameters, and we recommend its use for evaluating ASD patients. LEVEL OF EVIDENCE: 3.

INTRODUCTION: Oxidative stress has been reported to be involved in numerous human diseases, including musculoskeletal disorders such as osteoarthritis. However, the interaction between intervertebral disc (IVD) degeneration and oxidative stress is not well understood. The purpose of the present study was to elucidate the contribution of oxidative stress to IVD degeneration and the efficacy of antioxidant treatment for degenerative discs. METHODS: The expression level of an oxidative stress marker, nitrotyrosine, was assessed by immunohistochemistry and Western blotting. For evaluating intracellular reactive oxygen species (ROS) levels and oxidative stress in rat annulus fibrosus (AF) cells, flow cytometry and luciferase assay with an OKD48 construct were performed. The grade of IVD degeneration was assessed by magnetic resonance imaging and histological analysis. RESULTS: A high frequency of nitrotyrosine-positive cells was observed in rat and human degenerative discs. mRNA expression of catabolic factors such as tumor necrosis factor-alpha (TNF-alpha), matrix metalloprotease-3 (MMP-3), and cyclooxygenase-2 (COX-2) was significantly induced by treatment with H2O2 or buthionine sulfoximine, whereas that of aggrecan, an important chondrogenic proteoglycan, was reduced in a dose-dependent manner. Treatment with mitogen-activated protein kinase (MAPK) inhibitors blocked the inductive effect of excessive ROS on COX-2 mRNA expression. Western blotting confirmed the phosphorylation of MAPKs in H2O2 and BSO-treated AF cells. Conversely, we showed that TNF-α induced oxidative stress with increased intracellular ROS levels in AF cells. Treatment with the antioxidant N-acetyl cysteine (NAC) abrogated the catabolic effect of excessive ROS and TNF-alpha in vitro. Finally, we showed that oral administration of NAC prevented IVD degeneration in rat degenerative model. CONCLUSIONS: A positive feedback loop was formed between excessive ROS and TNF-alpha in AF cells. Thus, oxidative stress contributes to the progression of IVD degeneration and NAC can be a therapeutic option for IVD degeneration.

PURPOSE: Minimally invasive spine stabilization (MISt) procedures, including MIS-transforaminal lumbar interbody fusion (MIS-TLIF), rely on precise placement of percutaneous pedicle screws (PPS). Serious intraoperative complications associated with PPS placement include great vessel and bowel injuries due to the guide-wire's anterior migration and penetration through the anterior aspect of the vertebral body. To address this issue, we developed a novel percutaneous guide wire (S-wire) and compared the biomechanical characteristics of S-wire and conventional wire in cadaveric spines, and to evaluate the S-wire's efficacy and safety in a clinical trial. METHODS: The S-wire is hollow, with braided wires extending at one tip. We compared the push-out and penetration forces of the S-wire and conventional wire in fresh cadaveric lumbar spines, from L1 to L5. RESULTS: Push-out forces caused the braided tip of the S-wire to bend or spread, and thus to resist anterior migration. The mean push-out forces for the S-wire and conventional wire were 15.5 ± 1.9 and 5.7 ± 0.8 N, respectively (P < .0001); the mean penetration forces were 69.1 ± 4.2 and 37.1± 4.8 N, respectively (P < .0005). There was no wire breakage or anterior-wall penetration in a clinical trial of 922 S-wires; interestingly, the pull-out force increased in 780 (84.6%) S-wires after placement. CONCLUSIONS: The mean push-out and penetration forces for the S-wire were approximately 3 and 2 times greater than those of conventional wire, respectively. The S-wire effectively prevented guide-wire anterior migration and penetration of the anterior vertebral-body wall. The S-wire device should effectively improve the safety of MISt procedures, including MIS-TLIF and percutaneous kyphoplasty in selected patient with osteoporosis.

OBJECT: The object of this study was to investigate correlations between sagittal spinopelvic alignment and improvements in clinical and quality-of-life (QOL) outcomes after lumbar decompression surgery for lumbar spinal canal stenosis (LCS) without coronal imbalance. METHODS: The authors retrospectively reviewed data from consecutive patients treated for LCS with decompression surgery in the period from 2009 through 2011. They examined correlations between preoperative or postoperative sagittal vertical axis (SVA) and radiological parameters, clinical outcomes, and health-related (HR)QOL scores in patients divided according to SVA. Clinical outcomes were assessed according to Japanese Orthopaedic Association (JOA) and visual analog scale (VAS) scores. Health-related QOL was evaluated using the Roland-Morris Disability Questionnaire (RMDQ) and the JOA Back Pain Evaluation Questionnaire (JOABPEQ). RESULTS: One hundred nine patients were eligible for inclusion in the study. Compared to patients with normal sagittal alignment prior to surgery (Group A: SVA < 50 mm), those with preoperative sagittal imbalance (Group B: SVA ≥ 50 mm) had significantly smaller lumbar lordosis and thoracic kyphosis angles and larger pelvic tilt. In Group B, there was a significant decrease in postoperative SVA compared with the preoperative SVA (76.3 ± 29.7 mm vs. 54.3 ± 39.8 mm, p = 0.004). The patients in Group B with severe preoperative sagittal imbalance (SVA > 80 mm) had residual sagittal imbalance after surgery (82.8 ± 41.6 mm). There were no significant differences in clinical and HRQOL outcomes between Groups A and B. Compared to patients with normal postoperative SVA (Group C: SVA < 50 mm), patients with a postoperative SVA ≥ 50 mm (Group D) had significantly lower JOABPEQ scores, both preoperative and postoperative, for walking ability (preop: 36.6 ± 26.3 vs. 22.7 ± 26.0, p = 0.038, respectively; postop: 71.1 ± 30.4 vs. 42.5 ± 29.6, p < 0.001) and social functioning (preop: 38.7 ± 18.5 vs. 30.2 ± 16.7, p = 0.045; postop: 67.0 ± 25.8 vs. 49.6 ± 20.0, p = 0.001), as well as significantly higher postoperative RMDQ (4.9 ± 5.2 vs. 7.9 ± 5.7, p = 0.015) and VAS scores for low-back pain (2.68 ± 2.69 vs. 3.94 ± 2.59, p = 0.039). CONCLUSIONS: Preoperative sagittal balance was not significantly correlated with clinical or HRQOL outcomes after decompression surgery in LCS patients without coronal imbalance. Decompression surgery improved the SVA value in patients with preoperative sagittal imbalance; however, the patients with severe preoperative sagittal imbalance (SVA > 80 mm) had residual imbalance after decompression surgery. Both clinical and HRQOL outcomes were negatively affected by postoperative residual sagittal imbalance.

Vertebral hemangiomas are common; however, aggressive vertebral hemangiomas with extraosseous extensions causing neurological deficits are rare. The treatment for this subtype of hemangioma remains controversial, since there are few reports on long-term clinical outcomes or tumor recurrence rates. We describe a case of aggressive vertebral hemangioma treated by total en bloc spondylectomy, with a literature review focusing on long-term recurrence. A 52-year-old male with a two-month history of numbness in the bilateral lower extremities was referred to our hospital. Imaging studies showed a tumor originating in the T9 vertebra and extending to the T8 and T10 vertebrae, with extraosseous extension causing spinal-cord compression. Ten months after onset, the patient presented with progressive paraparesis and hypalgesia. Total en bloc spondylectomy was performed, and pathology was consistent with cavernous hemangioma. Motor and sensory deficits improved significantly, and no signs of recurrence are seen at 2.5 years after operation. A review of literature revealed a recurrence rate of 12.7% (10/79 cases). The available evidence indicates satisfactory long-term outcomes for total tumor resection without adjuvant radiotherapy.

Intervertebral disc degeneration is the leading cause of chronic back pain. Recent studies show that raised level of SDC4, a cell-surface heparan sulfate (HS) proteoglycan, plays a role in pathogenesis of disc degeneration. However, in nucleus pulposus (NP) cells of the healthy intervertebral disc, the mechanisms that control expression of SDC4 and its physiological function are unknown. Hypoxia induced SDC4 mRNA and protein expression by ~2.4- and 4.4-fold (P<0.05), respectively, in NP cells. While the activity of the SDC4 promoter containing hypoxia response element (HRE) was induced 2-fold (P<0.05), the HRE mutation decreased the activity by 40% in hypoxia. Transfections with plasmids coding prolyl-4-hydroxylase domain protein 2 (PHD2) and ShPHD2 show that hypoxic expression of SDC4 mRNA and protein is regulated by PHD2 through controlling hypoxia-inducible factor 1α (HIF-1α) levels. Although overexpression of HIF-1α significantly increased SDC4 protein levels, stable suppression of HIF-1α and HIF-1β decreased SDC4 expression by 50% in human NP cells. Finally, suppression of SDC4 expression, as well as HS function, resulted in an ~2-fold increase in sex-determining region Y (SRY)-box 9 (Sox9) mRNA, and protein (P<0.05) and simultaneous increase in Sox9 transcriptional activity and target gene expression. Taken together, our findings suggest that in healthy discs, SDC4, through its HS side chains, contributes to maintenance of the hypoxic tissue niche by controlling baseline expression of Sox9.

同側THA・TKAを同時施行され、退院後に草取りをしたいと希望した患者(72歳女性)に対し、脱臼予防動作の指導を行った。その際、3つの動作方法を試み、各々のメリット/デメリットについて検討した。1つ目の方法は「四股立ち(股外転・外旋)」で、メリットは、両下肢支持での動作のため安定性が高いことと、移動が行いやすいこと、デメリットは腰部への負担が大きいことであった。2つ目は「椅子を使用する方法」で、メリットは下肢への負担が少ないことと安定性が高いこと、デメリットは不整地での移動が困難なことと、股関節の屈曲角度が大きくなり、可動域に制限のある患者では行いづらいことであった。3つ目は「患側を後ろに引く方法」で、メリットは脱臼肢位となりにくいこと、デメリットは健側中心の支持であるため支持性が低いことであった。これらの結果を踏まえ、草取りの場所や広さに応じて動作を使い分けるよう指導した。

We investigated TNF-α and IL-1β regulation of ADAMTS-4 expression in nucleus pulposus (NP) cells and its role in aggrecan degradation. Real-time quantitative RT-PCR, Western blotting, and transient transfections with rat NP cells and lentiviral silencing with human NP cells were performed to determine the roles of MAPK and NF-κB in cytokine-mediated ADAMTS-4 expression and function. ADAMTS4 expression and promoter activity increased in NP cells after TNF-α and IL-1β treatment. Treatment of cells with MAPK and NF-κB inhibitors abolished the inductive effect of the cytokines on ADAMTS4 mRNA and protein expression. Although ERK1, p38α, p38β2, and p38γ were involved in induction, ERK2 and p38δ played no role in TNF-α-dependent promoter activity. The inductive effect of p65 on ADAMTS4 promoter was confirmed through gain and loss-of-function studies. Cotransfection of p50 completely blocked p65-mediated induction. Lentiviral transduction with shRNA plasmids shp65, shp52, shIKK-α, and shIKK-β significantly decreased TNF-α-dependent increase in ADAMTS-4 and -5 levels and aggrecan degradation. Silencing of either ADAMTS-4 or -5 resulted in reduction in TNF-α-dependent aggrecan degradation in NP cells. By controlling activation of MAPK and NF-κB signaling, TNF-α and IL-1β modulate expression of ADAMTS-4 in NP cells. To our knowledge, this is the first study to show nonredundant contribution of both ADAMTS-4 and ADAMTS-5 to aggrecan degradation in human NP cells in vitro.

The objective of the study was to investigate if hypoxia-inducible factor (HIF)-1α and connective tissue growth factor (CCN2) form a regulatory network in hypoxic nucleus pulposus (NP) cells. A decrease in CCN2 expression and proximal promoter activity was observed in NP cells after hypoxic culture. Analysis of both human and mouse CCN2 promoters using the JASPAR core database revealed the presence of putative hypoxia response elements. Transfection experiments showed that both promoter activities and CCN2 expression decreases in hypoxia in a HIF-1α-dependent fashion. Interestingly, deletion analysis and mutation of the hypoxia responsive elements individually or in combination resulted in no change in promoter activity in response to hypoxia or in response to HIF-1α, suggesting an indirect mode of regulation. Notably, silencing of endogenous CCN2 increased HIF-1α levels and its target gene expression, suggesting a role for CCN2 in controlling basal HIF-1α levels. On the other hand, treatment of cells with rCCN2 resulted in a decrease in the ability of HIF-1α transactivating domain to recruit co-activators and diminished target gene expression. Last, knockdown of CCN2 in NP cells results in a significant decrease in GAG synthesis and expression of AGGRECAN and COLLAGEN II. Immunohistochemical staining of intervertebral discs of Ccn2 null embryos shows a decrease in aggrecan. These findings reveal a negative feedback loop between CCN2 and HIF-1α in NP cells and demonstrate a role for CCN2 in maintaining matrix homeostasis in this tissue.

OBJECTIVE: There is agreement that symptomatic sacral meningeal cysts with a check-valve mechanism and/or large cysts representing space-occupying lesions should be treated surgically. This study investigated factors indicating a need for surgical intervention and surgical techniques for sacral meningeal cysts with a check-valve mechanism. METHODS: In ten patients presenting with sciatica and neurological deficits, myelography, computed tomography (CT) myelography, and magnetic resonance imaging (MR imaging) detected sacral meningeal cysts with a check-valve mechanism. One patient had two primary cysts. Ten cysts were type 2 and one cyst was type 1. Nine of the ten patients had not undergone previous surgery, while the remaining case involved recurrent cyst. For the seven patients with normal (i.e., not huge or recurrent) type 2 cysts and no previous surgery (eight cysts), suture after collapse of the cyst wall was performed. For the recurrent type 2 cyst, duraplasty and suture with collapse of the cyst wall were performed to eliminate the check-valve mechanism. For the remaining type 2 cyst, a primary root was sacrificed because of the huge size of the cyst. For the type 1 cyst, the neck of the cyst was ligated. RESULTS: In all cases, chief complaints disappeared immediately postoperatively and no deterioration of clinical symptoms has been seen after a mean follow-up of 27 months. CONCLUSIONS: The presence or absence of a check-valve mechanism is very important in determining the need for surgical intervention for sacral meningeal cysts.

We describe a novel operative technique for patellar fracture. The patient is placed in the supine position for setup of both an image intensifier and arthroscopy. After routine intra-articular inspection with an arthroscope, an extra-articular space including the prepatellar bursa is developed. The space is created with a lifting hanger applied from a portal wherein an arthroscope can then afford both intra- and extra-articular observation of the articular and bony surface of the patella. By use of an image intensifier, the fracture can be treated and fixed in percutaneous fashion with the aid of an arthroscope. This new technique offers surgeons a magnified view of the patella, both intra- and extra-articularly, through a minimally invasive procedure. Although it includes inherent risks and limitations, this new application of arthroscopy would certainly help surgeons to treat patellar fracture.

Recent studies suggest a differential role of prolyl hydroxylase (PHD) isoforms in controlling hypoxia-inducible factor (HIF)-α degradation and activity in nucleus pulposus (NP) cells. However, the regulation and function of PHDs under inflammatory conditions that characterize disc disease are not yet known. Here, we show that in NP cells, TNF-α and IL-1β induce PHD3 expression through NF-κB. Lentiviral delivery of Sh-p65 and Sh-IKKβ confirms that cytokine-mediated PHD3 expression is NF-κB-dependent. It is noteworthy that although both cytokines induce HIF activity, mechanistic studies using Sh-HIF-1α and PHD3 promoter/enhancer constructs harboring well characterized hypoxia response element (HRE) show lack of HIF involvement in cytokine-mediated PHD3 expression. Loss-of-function studies clearly indicate that PHD3 serves as a co-activator of NF-κB signaling activity in NP cells; PHD3 interacts with, and co-localizes with, p65. We observed that when PHD3 is silenced, there is a significant decrease in TNF-α-induced expression of catabolic markers that include ADAMTS5, syndecan4, MMP13, and COX2, and at the same time, there is restoration of aggrecan and collagen type II expression. It is noteworthy that hydroxylase function of PHDs is not required for mediating cytokine-dependent gene expression. These findings show that by enhancing the activity of inflammatory cytokines, PHD3 may serve a critical role in degenerative disc disease.

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-1β 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.

The objective of our study was to examine the regulation of hypoxic expression of heat shock protein 70 (Hsp70) in nucleus pulposus cells and to determine if Hsp70 promoted hypoxia-inducible factor (HIF)-1α degradation. Rat nucleus pulposus cells were maintained in culture in either 21% or 1% oxygen. To determine the regulation of Hsp70 expression by tonicity enhancer binding protein (TonEBP) and HIF-1/2, loss-of-function and gain-of-function experiments and mutational analysis of the Hsp70 promoter were performed. Hypoxia increased Hsp70 expression in nucleus pulposus cells. Noteworthy, hypoxia increased TonEBP transactivation and mutation of TonE motifs blocked hypoxic induction of the Hsp70 promoter. In contrast, mutation of hypoxia response element (HRE) motifs coupled with loss-of-function experiments suggested that HIF-1 and HIF-2 suppressed Hsp70 promoter activity and transcription. Interestingly, HIF-α interferes with TonEBP function and suppresses the inductive effect of TonEBP on the Hsp70 promoter. In terms of Hsp70 function, when treated with Hsp70 transcriptional inhibitor, KNK437, there was an increase in HIF-1α protein stability and transcriptional activity. Likewise, when Hsp70 was overexpressed, the stability of HIF-1α and its transcriptional activity decreased. Hsp70 interacted with HIF-1α under hypoxic conditions and evidenced increased binding when treated with MG132, a proteasomal inhibitor. These results suggest that Hsp70 may promote HIF-1α degradation through the proteasomal pathway in nucleus pulposus cells. In hypoxic and hyperosmolar nucleus pulposus cells, Hsp70, TonEBP, and HIFs form a regulatory loop. We propose that the positive regulation by TonEBP and negative regulation of Hsp70 by HIF-1 and HIF-2 may serve to maintain Hsp70 levels in these cells, whereas Hsp70 may function in controlling HIF-1α homeostasis.

Studies of many cell types show that levels of hypoxia inducible factor (HIF)-1α and HIF-2α are primarily controlled by oxygen-dependent proteasomal degradation, catalyzed by HIF prolyl-hydroxylases (PHDs). However, in the hypoxic niche of the intervertebral disc, the mechanism of HIF-α turnover in nucleus pulposus cells is not yet known. We show that in nucleus pulposus cells HIF-1α and HIF-2α, degradation was mediated through 26S proteasome irrespective of oxygen tension. It is noteworthy that HIF-2α degradation through 26S proteasome was more pronounced in hypoxia. Surprisingly, treatment with DMOG, a PHD inhibitor, shows the accumulation of only HIF-1α and induction in activity of its target genes, but not of HIF-2α. Loss and gain of function analyses using lentiviral knockdown of PHDs and overexpression of individual PHDs show that in nucleus pulposus cells only PHD2 played a limited role in HIF-1α degradation; again HIF-2α degradation was unaffected. We also show that the treatment with inhibitors of lysosomal proteolysis results in a strong accumulation of HIF-1α and to a much smaller extent of HIF-2α levels. It is thus evident that in addition to PHD2 catalyzed degradation, the HIF-1α turnover in nucleus pulposus cells is primarily regulated by oxygen-independent pathways. Importantly, our data clearly suggests that proteasomal degradation of HIF-2α is not mediated by a classical oxygen-dependent PHD pathway. These results for the first time provide a rationale for the normoxic stabilization as well as the maintenance of steady-state levels of HIF-1α and HIF-2α in nucleus pulposus cells.

The interaction with bone marrow (BM) plays a crucial role in pathophysiological features of multiple myeloma (MM), including cell proliferation, chemoresistance, and bone lesion progression. To characterize the MM-BM interactions, we utilized an in vivo experimental model for human MM in which a GFP-expressing human MM cell line is transplanted into NOG mice (the NOG-hMM model). Transplanted MM cells preferentially engrafted at the metaphyseal region of the BM endosteum and formed a complex with osteoblasts and osteoclasts. A subpopulation of MM cells expressed VE-cadherin after transplantation and formed endothelial-like structures in the BM. CD138(+) myeloma cells in the BM were reduced by p53-dependent apoptosis following administration of the nitrogen mustard derivative bendamustine to mice in the NOG-hMM model. Bendamustine maintained the osteoblast lining on the bone surface and protected extracellular matrix structures. Furthermore, bendamustine suppressed the growth of osteoclasts and mesenchymal cells in the NOG-hMM model. Since VE-cadherin(+) MM cells were chemoresistant, hypoxic, and HIF-2α-positive compared to the VE-cadherin(-) population, VE-cadherin induction might depend on the oxygenation status. The NOG-hMM model described here is a useful system to analyze the dynamics of MM pathophysiology, interactions of MM cells with other cellular compartments, and the utility of novel anti-MM therapies.

Medial patellofemoral ligament (MPFL) reconstruction has become a common surgical procedure in the treatment of recurrent dislocation of the patella. A technique of MPFL reconstruction with the "hanger lifting procedure" using extra-articular arthroscopy is presented. After conventional intra-articular arthroscopy, an incision about 1 cm long is made at the superomedial edge of the patella. A bone tunnel is created with a guide pin and overdrilling method, from this portal to the subcutaneous surface of the patella. Using a semi-loop-shaped hanger, the harvested Gracillis tendon is passed through the bone tunnel using a passing pin. Under extra-articular arthroscopy with the "hanger lifting procedure", this tendon is then led back to the superomedial portal. Both ends of the Gracillis tendon are then led to the femoral fixation site posterosuperior to the medial epicondyle with a tendon passer, and fixed by an absorbable interference screw. This procedure can be performed under a minimum incision using a hanger, but control radiographs should be taken to confirm appropriate placement of bone tunnels.

We propose a unique arthroscopic technique, the "hanger-lifting procedure." Unlike conventional arthroscopy, the space in which the arthroscope is placed is not a joint space filled with water but a subcutaneous space filled with air. The space is kept lifted by a semi-loop-shaped hanger and a retraction system by use of a wire. In general, arthroscopes are unable to be applied outside the joint because of the lack of a cavity. However, this method can provide extra-articular visualization of the knee in addition to standard intra-articular visualization. This approach is useful for lateral release of the knee extensor and bipartite patellae, allowing direct vision from both outside and inside the joint. One possible complication is subcutaneous effusion or interstitial edema. Compressive dressings should be applied to prevent subcutaneous effusion after surgery. However, the combination of conventional arthroscopy by use of saline solution and the hanger-lifting technique by use of air arthroscopy can provide an excellent view inside and outside the joint. This technique may continue to evolve, and although some points in the technique can be improved, this method is useful in joint surgeries.

Regulation of dendritic cell (DC) function is critical for maintaining self-tolerance and preventing autoimmunity. The dendritic cell-specific transmembrane protein (DC-STAMP) plays a key role in cell-cell fusion of osteoclasts and foreign body giant cells, but though originally identified in DCs, its specific roles there remain undefined. Here, we report that aged DC-STAMP-deficient mice display several systemic autoimmune symptoms such as spontaneous lymphoproliferation, splenomegaly associated with infiltration of T cells in several organs and increased serum anti-double-stranded DNA antibody production. Although a lack of DC-STAMP did not inhibit DC differentiation or proliferation, antigen presentation activity of DC-STAMP-deficient DCs was significantly up-regulated in both class I and II pathways through increased phagocytotic activity compared with wild-type DCs, an activity likely leading to autoimmunity. Our results indicate that DC-STAMP is required for proper regulation of DC activity and maintenance of immune self-tolerance.