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Introduction Long-term follow-up studies focusing on the posterior extensor muscles in patients suffering from whiplash injury are scarce. The purpose of this study was to elucidate the changes in the posterior extensor muscles 10 years after whiplash injury. Methods Twenty-three patients who had suffered from whiplash injury in 1994–1996 and had undergone MRI using a 1.5-T superconductive imager participated in this follow-up study (13 males, 10 females, mean age 51.8 years, mean follow-up 11.5 years). In addition, 60 healthy volunteers who had undergone MRI in the same period were included as controls (36 males, 24 females, mean age 47.8 years, mean follow-up 11.1 years). All participants underwent follow-up MRI. The cross-sectional areas of the deep posterior muscles (CSA) including the multifidus, semispinalis cervicis, semispinalis capitis, and splenius capitis were digitally measured at C3-4, C4-5, and C5-6 using NIH image. The long-term changes in the CSA were compared between the two groups. In addition, correlations between the CSA and cervical spine-related symptoms were evaluated. Results The mean total CSA per patient (the sum of the area from C3-4 to C5-6) was 4811.6 ± 878.4 mm 2 in the whiplash patients and 4494.9 ± 1032.7 mm 2 in the controls at the initial investigation ( p = 0.20), and 5173.4 ± 946.1 mm 2 and 4713.0 ± 1065.3 mm 2 at the follow-up ( p = 0.07). The mean change in CSA over time was 361.8 ± 804.9 mm 2 in the whiplash patients and 218.1 ± 520.7 mm 2 in the controls ( p = 0.34). Ten whiplash patients (43.5%) had neck pain and 11 (47.8%) had shoulder stiffness. However, there was no difference in the change in CSA over time between the symptomatic and asymptomatic patients. Conclusions There was no significant difference in the change in CSA between whiplash patients and healthy volunteers after a 10-year follow-up period. In both groups, the cross-sectional area slightly increased at follow-up. In addition, there was no association between the change in CSA and clinical symptoms such as neck and shoulder pain. These results suggest that whiplash injury is not associated with symptomatic atrophy of the posterior cervical muscles over the long term.

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% O2, 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.

We conducted a prospective follow-up MRI study of originally asymptomatic healthy subjects to clarify the development of Modic changes in the cervical spine over a ten-year period and to identify related factors. Previously, 497 asymptomatic healthy volunteers with no history of cervical trauma or surgery underwent MRI. Of these, 223 underwent a second MRI at a mean follow-up of 11.6 years (10 to 12.7). These 223 subjects comprised 133 men and 100 women with a mean age at second MRI of 50.5 years (23 to 83). Modic changes were classified as not present and types 1 to 3. Changes in Modic types over time and relationships between Modic changes and progression of degeneration of the disc or clinical symptoms were evaluated. A total of 31 subjects (13.9%) showed Modic changes at follow-up: type 1 in nine, type 2 in 18, type 3 in two, and types 1 and 2 in two. Modic changes at follow-up were significantly associated with numbness or pain in the arm, but not with neck pain or shoulder stiffness. Age (≥ 40 years), gender (male), and pre-existing disc degeneration were significantly associated with newly developed Modic changes. In the cervical spine over a ten-year period, type 2 Modic changes developed most frequently. Newly developed Modic changes were significantly associated with age, gender, and pre-existing disc degeneration.

Study design Retrospective case series. Objective To evaluate the treatment strategies for spinal meningioma. Summary of background data Although previous studies have demonstrated favorable surgical outcomes for spinal meningioma, with a low incidence of tumor recurrence, few have examined long-term surgical outcomes. Methods The influence of patient age, surgical margin status (Simpson grade), tumor location, and histological subtype on tumor recurrence were examined retrospectively. In addition, the resected dura mater from Simpson grade I cases was examined for invasive tumor cells and compared with the presence or absence of a dural tail sign on magnetic resonance image. Results Complete resection (Simpson grades I and II) was performed in 62 patients. Among them, the tumor recurrence rate was 9.7%, all in patients who underwent grade II resection for ventral spinal lesions. The mean duration to reoperation in these patients was 12.2 ± 5.2 years. Of the 6 patients who underwent incomplete resection (Simpson grade III/IV), all required reoperation for tumor recurrence or regrowth, 5 years later on average. Patients younger than 50 years at the initial surgery had a significantly higher recurrence rate than those aged 50 years or older. Histologic examination of 43 dura mater specimens from Simpson grade I-resection patients revealed tumor cell invasion between the inner and outer layers in 15 patients. This invasion was noted in 8 (29%) of 28 patients who were negative for the dural tail sign on magnetic resonance image, and in 7 (47%) of 15 patients who showed a positive dural tail sign. The MIB-1 index reached about 10% for dumbbell-type meningiomas invading the vertebral body; these were associated with repeated recurrence and unfavorable prognosis. Conclusion Long-term follow-up after surgery for meningiomas indicated that Simpson grade I resection should be selected whenever practicable when treating younger patients or dumbbell-type meningiomas. Tumors recurred at 12 years, on average, in approximately 30% of patients who underwent grade II resection.

Purpose The objective of this study was to evaluate 2 years post-surgical loss of three-dimensional correction in adolescent idiopathic scoliosis (AIS) patients using multi-planar reconstruction computed tomography (CT).

Osteosarcoma is the most frequent, nonhematopoietic, primary malignant tumor of bone. Histopathologically, osteosarcoma is characterized by complex mixtures of different cell types with bone formation. The role of environmental factors in the formation of such a complicated tissue structure as osteosarcoma remains to be elucidated. Here, a newly established murine osteosarcoma model was used to clarify the roles of environmental factors such as fibroblast growth factor-2 (Fgf2) or leukemia-inhibitory factor (Lif) in the maintenance of osteosarcoma cells in an immature state. These factors were highly expressed in tumor environmental stromal cells, rather than in osteosarcoma cells, and they potently suppressed osteogenic differentiation of osteosarcoma cells in vitro and in vivo. Further investigation revealed that the hyperactivation of extracellular signal–regulated kinase (Erk)1/2 induced by these factors affected in the process of osteosarcoma differentiation. In addition, Fgf2 enhanced both proliferation and migratory activity of osteosarcoma cells and modulated the sensitivity of cells to an anticancer drug. The results of the present study suggest that the histology of osteosarcoma tumors which consist of immature tumor cells and pathologic bone formations could be generated dependent on the distribution of such environmental factors. The combined blockade of the signaling pathways of several growth factors, including Fgf2, might be useful in controlling the aggressiveness of osteosarcoma. Mol Cancer Res; 10(3); 454–68. ©2012 AACR.

Study design Retrospective case series of chronic atlantoaxial rotatory fixation (AARF) treated by a novel closed reduction method (remodeling therapy) and review of the literature. Objective To describe clinical features of chronic AARF and the rationale of the remodeling therapy. Summary of background data Treatment strategy for chronic recurrent AARF remains controversial. Posterior C1-C2 arthrodesis has been widely used for recurrent unstable AARFs after the closed reduction, and a variety of posterior fusion techniques have been advocated. In contrast, several investigators reported a chronic AARF case treated by a simple traction or closed reduction followed by cervical immobilization. Previously, we have found that a deformity of the superior C2 facet joint (C2 facet deformity) on three dimensional computed tomography (3D CT) reconstructions is a risk factor for recurrent subluxation. In addition, the remodeling of this C2 facet deformity by careful closed manipulation followed by halo fixation (remodeling therapy) could prevent the recurrence of subluxation. Methods Twelve children with chronic AARF who sustained torticollis for an average of 4.4 months after the onset were referred to our clinic. The mean age at the initial visit was 7.8 years. All patients underwent the remodeling therapy as reported previously. Radiographic findings and clinical courses were retrospectively reviewed. Treatment methodology, pearls, and pitfalls of the remodeling therapy were discussed with review of the literature. Results 3D CT images before reduction revealed persistent atlantoaxial subluxation and the C2 facet deformity in the dislocated side in all cases. Follow-up 3D CT scans demonstrated the remodeling of the C2 facet deformity at an average of 2.4 months after successful reduction of subluxation. Neither recurrence of symptoms nor subluxation was observed at a mean follow-up of 42 months in any case. The cervical range of motion was 73.9° at the dislocated and 83.5° at the contra-dislocated side from the midline. Conclusion Chronic irreducible and recurrent unstable AARF should be initially managed by remodeling therapy using the facet deformity sign as a clinical index, if the C1 and C2 have not been osseously fused.

Study design Review article. Objective To discuss the history, indication, surgical outcomes, prognostic factors, and complications of laminoplasty for ossification of the posterior longitudinal ligament (OPLL) of the cervical spine. Summary of background data OPLL usually requires surgery, which often involves indirect decompression by the posterior approach. Of the posterior procedures for OPLL, laminoplasty is the favored treatment. Here, we review the previously published literature on laminoplasty for OPLL. Methods PubMed and previously published English and Japanese book chapters were searched for posterior procedures for treating OPLL. Results There is a large body of literature on OPLL and its treatment. Based on a review of the literature, the history, indication, surgical outcomes, prognostic factors, and complications of laminoplasty for OPLL were examined. The results showed that long-term outcomes of both the open-door and double-door types of laminoplasty are favorable, although late neurological deterioration occurs in some patients. Preoperative kyphosis of the cervical spine and severe (>60%) compromise of the spinal canal by OPLL appear to be the limiting factors for the indication of laminoplasty. Complications of laminoplasty include segmental motor palsy, lamina closure, and axial symptoms. Conclusion Laminoplasty is a feasible surgical option for OPLL if candidate patients are appropriately selected.

Synovial sarcoma is an aggressive soft tissue sarcoma with only a modest response to conventional cytotoxic agents. In the present study, we evaluated the potential antitumor effects of a novel anti-angiogenesis agent, pazopanib, against synovial sarcoma cells. We found that pazopanib directly inhibited the growth of synovial sarcoma cells by inducing G1 arrest. Multiplex analyses revealed that the PI3K-AKT pathway was highly suppressed in pazopanib-sensitive synovial sarcoma cells. Furthermore, administration of pazopanib highly suppressed the tumor growth in a xenograft model. Taken together, these results suggest pazopanib as a possible agent against synovial sarcoma and may warrant further clinical studies.

Anaplastic transformation of differentiated thyroid carcinoma (DTC) is a rare event with a poor clinical outcome. It usually occurs in the primary site or in regional lymph nodes, but rarely in distant metastatic lesions.A 55-year-old woman with persistent pain in the left hip joint visited our hospital. She had a history of DTC that had been surgically removed 12 years earlier. Clinical images showed a tumorous mass in the left pelvis, indicative of bone metastasis. The patient underwent surgery to remove the tumor and remained stable until local recurrence was found 5 weeks after the surgery. The patient subsequently underwent radiation therapy; however, she died of respiratory failure due to lung metastases 2 months after the surgery for the recurrent lesion. The surgical specimens were diagnosed as anaplastic thyroid carcinoma, indicating that anaplastic transformation of thyroid follicular carcinoma occurred in the metastatic skeletal lesion. In addition, the patient had an unusually high white blood cell count throughout the course. Based on elevated serum granulocyte colony-stimulating factor (G-CSF) levels and positive immunostaining for G-CSF in the surgical specimens, the patient was diagnosed with paraneoplastic leukocytosis.To our knowledge, this is the first case of anaplastic transformation of DTC arising in a metastatic bone lesion described in the literature. In addition, the present case also exhibited severe leukocytosis accompanied by elevated serum G-CSF levels. Clinicians should be aware of the possibility of this occurring in their patients with DTC, as this development calls for a rapid change from observational follow-up to aggressive treatment.

Osteomyelitis remains a serious problem in the orthopedic field. There are only a few animal models in which the quantity and distribution of bacteria can be reproducibly traced. Here, we established a real-time quantitative mouse model of osteomyelitis using bioluminescence imaging (BLI) without sacrificing the animals. A bioluminescent strain of Staphylococcus aureus was inoculated into the femurs of mice. The bacterial photon intensity (PI) was then sequentially measured by BLI. Serological and histological analyses of the mice were performed. The mean PI peaked at 3 days, and stable signals were maintained for over 3 months after inoculation. The serum levels of interleukin-6, interleukin-1β, and C-reactive protein were significantly higher in the infected mice than in the control mice on day 7. The serum monocyte chemotactic protein 1 level was also significantly higher in the infected group at 12 h than in the control group. A significantly higher proportion of granulocytes was detected in the peripheral blood of the infected group after day 7. Additionally, both acute and chronic histological manifestations were observed in the infected group. This model is useful for elucidating the pathophysiology of both acute and chronic osteomyelitis and to assess the effects of novel antibiotics or antibacterial implants.

Several biomarkers have been used to evaluate osteoarthritis of the limb joints. Here we evaluated the use of serum cartilage metabolites as biomarkers for degenerative lumbar scoliosis (DLS). Fifty-two DLS patients with Cobb angle > 10° were compared with 19 control patients. Serum levels of hyaluronic acid (HA), keratan sulfate (KS), cartilage oligomeric matrix protein (COMP), collagen type II cleavage (C2C), and procollagen type II C-propeptide (CPII) were measured. Serum levels of KS (DLS 1.20 ± 0.44 µg/ml vs. control 0.98 ± 0.33 µg/ml), CPII (DLS 1905.1 ± 948.2 ng/ml vs. control 1223.6 ± 884.4 ng/ml), and C2C (DLS 219.1 ± 59.2 ng/ml vs. control 177.7 ± 71.7 ng/ml) were significantly higher in DLS. There were no significant differences in the levels of HA or COMP. There was a significant positive correlation between the Cobb angle and CPII in DLS. This is the first study to evaluate the cartilage biomarkers in DLS. The results suggest DLS patients have higher levels of type II collagen synthesis and degradation, indicated by elevated serum CPII and C2C, respectively. As type II collagen is a major component of collagens in the nucleus pulposus and facet joint cartilages, its enhanced turnover may be related to the development and progression of DLS.

A case of radial and volar perilunate trans-scaphoid fracture dislocation in which the proximal fragment of the scaphoid was dislocated dorsally is presented.

Myxoid/round cell liposarcoma (MRCL), unlike other soft tissue sarcomas, has been associated with unusual pattern of metastasis to extrapulmonary sites. In an attempt to elucidate the clinical features of MRCL with metastatic lesions, 58 cases, from the medical database of Keio University Hospital were used for the evaluation. 47 patients (81%) had no metastases, whereas 11 patients (11%) had metastases during their clinical course. Among the 11 patients with metastatic lesions, 8 patients (73%) had extrapulmonary metastases and 3 patients (27%) had pulmonary metastases. Patients were further divided into three groups; without metastasis, with extrapulmonary metastasis, and with pulmonary metastasis. When the metastatic patterns were stratified according to tumor size, there was statistical significance between the three groups ( ). The 8 cases with extrapulmonary metastases were all larger than 10 cm. Similarly, histological grading had a significant impact on metastatic patterns ( ). 3 cases with pulmonary metastatic lesions were all diagnosed as high grade. In conclusion, large size and low histological grade were significantly associated with extrapulmonary metastasis.

Background Quantification of intervertebral disc degeneration based on intensity of the nucleus pulposus in magnetic resonance imaging (MRI) often uses the mean intensity of the region of interest (ROI) within the nucleus pulposus. However, the location and size of ROI have varied in different reports, and none of the reported methods can be considered fully objective. Purpose To develop a more objective method of establishing ROIs for quantitative evaluation of signal intensity in the nucleus pulposus using T2-weighted MRI. Material and Methods A 1.5-T scanner was used to obtain T2-weighted mid-sagittal images. A total of 288 intervertebral discs from 48 patients (25 men, 23 women) were analyzed. Mean age was 47.4 years (range, 17-69 years). All discs were classified into five grades according to Pfirrmann et al. Discs in grades I and II were defined as bright discs, and discs in grades IV and V were defined as dark discs. Eight candidate methods of ROI determination were devised. The method offering the highest degree of discrimination between bright and dark discs was investigated among these eight methods. Results The method with the greatest degree of discrimination was as follows. The quadrangle formed by anterior and posterior edges of the upper and lower end plates in contact with the intervertebral disc to be measured was defined as the intervertebral area. A shape similar to the intervertebral area but with one-quarter the area was drawn. The geometrical center of the shape was matched to the center of intensity, and this shape was then used as the ROI. Satisfactory validity and reproducibility were obtained using this method. Conclusion The present method offers adequate discrimination and could be useful for longitudinal tracking of intervertebral disc degeneration with sufficient reproducibility.

The effects of surgical approaches and patellar positions on joint gap measurement during total knee arthroplasty (TKA) remain unclear. We hypothesized that joint gap changes with different knee flexion angles would not be consistent within four different approaches and two different patellar positions.This study enrolled 80 knees undergoing posterior-stabilized TKA. For 60 varus knees, parapatellar, midvastus, and subvastus approaches were used in 20 knees each. For 20 valgus knees, a lateral subvastus approach was used. Component gap length and inclination were measured intra-operatively using a specific tensor device under 40 lb with the patella reduced or shifted laterally, at 0°, 45°, 90°, and 135° of knee flexion.Mean gap lengths at 45° and 90° of knee flexion were significantly larger with the parapatellar approach than with midvastus or lateral subvastus approaches (P0.05). Regarding gap inclination, varus angle increased linearly through the entire arc of flexion in all four approaches. When the patella was shifted laterally, gap lengths at 45°, 90°, and 135° were significantly reduced compared with those for the patella reduced in the subvastus approach, whereas gap length was constant in the parapatellar approach, regardless of patellar position.Joint gap kinematics was not consistent within four different approaches and two different patellar positions. Relatively large gaps at 45° and 90° were unique features for the parapatellar approach. Surgeons should be aware that the flexion gap is reduced when the patella is shifted laterally in vastus medialis-preserving approaches such as the subvastus approach.II.

Previous reports of functional recovery from spinal cord injury (SCI) in rodents and monkeys after the delayed transplantation of neural stem/progenitor cells (NS/PCs) have raised hopes that stem cell therapy could be used to treat SCI in humans. More research is needed, however, to understand the mechanism of functional recovery. Oligodendrocytes derived from grafted NS/PCs remyelinate spared axons in the injured spinal cord. Here, we studied the extent of this remyelination's contribution to functional recovery following contusive SCI in mice. To isolate the effect of remyelination from other possible regenerative benefits of the grafted cells, NS/PCs obtained from myelin-deficient shiverer mutant mice (shi-NS/PCs) were used in this work alongside wild-type NS/PCs (wt-NS/PCs). shi-NS/PCs behaved like wt-NS/PCs in vitro and in vivo, with the exception of their myelinating potential. shi-NS/PC-derived oligodendrocytes did not express myelin basic protein in vitro and formed much thinner myelin sheaths in vivo compared with wt-NS/PC-derived oligodendrocytes. The transplantation of shi-NS/PCs promoted some locomotor and electrophysiological functional recovery but significantly less than that afforded by wt-NS/PCs. These findings establish the biological importance of remyelination by graft-derived cells for functional recovery after the transplantation of NS/PCs into the injured spinal cord. STEM CELLS 2011;29:1983–1994.

The purpose of this study was to evaluate the prevalence of anterior knee pain in anatomic double-bundle anterior cruciate ligament (ACL) reconstruction and to identify critical factors affecting postoperative anterior knee pain development.Subjects comprised 171 patients (171 knees) who underwent anatomic double-bundle ACL reconstruction with a follow-up period of ≥2 years. The procedure used bone-patellar tendon-bone plus gracilis tendon (BTB-G) in 56 knees, semitendinosus tendon (ST) in 71 knees, and ST-G in 44 knees. Clinical results and prevalence and severity of anterior knee pain were assessed at 3 months and 2 years postoperatively. Clinical variables influencing anterior knee pain development at each postoperative period were subjected to univariate analysis, followed by logistic regression analysis to identify risk factors for anterior knee pain.Overall prevalences of anterior knee pain at 3 months and 2 years postoperatively were 42.0 and 11.1%, respectively. Use of BTB-G graft represented the highest prevalence of anterior knee pain between the 3 different grafts (P = 0.001); however, this statistical significance disappeared at 2 years postoperatively. Prevalence of postoperative extension deficit was significantly higher in anterior knee pain-positive cohort than in anterior knee pain-negative cohort at 3 months postoperatively. Level of quadriceps strength was significantly lower, and Lysholm score was significantly worse in anterior knee pain-positive cohort than in anterior knee pain-negative cohort at 2 years postoperatively. According to logistic regression analysis, knee extension deficit was a predisposing factor for the development of anterior knee pain at 3 months postoperatively (odds ratio, 2.76; P = 0.004); however, there was no significant predisposing factor for anterior knee pain at 2 years postoperatively.Knee extension deficit was an important predisposing factor for postoperative anterior knee pain in the early postoperative period, and anterior knee pain was associated with impaired quadriceps function and inferior subjective results over 2 years postoperatively. Early recovery of full extension may prevent postoperative development of anterior knee pain and achieve successful outcomes for ACL reconstruction.Retrospective comparative study, Level III.

Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in the elderly, and ligamentum flavum (LF) hypertrophy is an important cause of LSCS. Matrix metalloproteinase 13 (MMP13) can degrade fibrillar collagens and elastic microfibrils, and is involved in inflammation and fibrosis. The purpose of this study was to compare the expression of MMP13 in the LF from LSCS patients with diabetes mellitus [DM (+)] with that in the LF from patients without DM [DM (-)] and to analyze the relationship among DM, MMP13 expression, and LF hypertrophy.LFs from 11 DM (+) and 24 DM (-) LSCS patients were analyzed in this study. Histology analysis using hematoxylin and eosin and Masson's trichrome stain was performed for each LF. The expression of MMP13 was analyzed by quantitative real-time PCR. The thickness of LF was measured by CT.In the LF from DM (+) LSCS patients, the elastic fibers were more disorganized and had lower volumes than in the LF from DM (-) LSCS patients, while more fibrotic tissue was observed in the LF from DM (+) than from DM (-) LSCS patients. MMP13 expression was significantly higher in the LF from DM (+) LSCS patients (0.46 ± 0.61 vs. 0.05 ± 0.09, P = 0.002). The LF from the DM (+) LSCS patients was significantly thicker than that from the DM (-) LSCS patients (5.0 ± 0.9 vs. 3.1 ± 0.8 mm, P0.01), and the thickness was correlated with the expression of MMP13 (correlation coefficient = 0.43, P = 0.01, Pearson's correlation test).DM-related MMP13 expression can be one of the factors contributing to fibrosis and hypertrophy of the LF. Further research on the mechanism of this process may lead to new therapies for LF hypertrophy.

Shiro Ikegawa and colleagues identify common variants near LBX1 associated with adolescent idiopathic scoliosis. LBX1 encodes a homeobox protein expressed in the dorsal spinal cord and skeletal muscle that may contribute to scoliosis risk by altering somatosensory function. Adolescent idiopathic scoliosis is a pediatric spinal deformity affecting 2–3% of school-age children worldwide1. Genetic factors have been implicated in its etiology2. Through a genome-wide association study (GWAS) and replication study involving a total of 1,376 Japanese females with adolescent idiopathic scoliosis and 11,297 female controls, we identified a locus at chromosome 10q24.31 associated with adolescent idiopathic scoliosis susceptibility. The most significant SNP (rs11190870; combined P = 1.24 × 10−19; odds ratio (OR) = 1.56) is located near LBX1 (encoding ladybird homeobox 1). The identification of this susceptibility locus provides new insights into the pathogenesis of adolescent idiopathic scoliosis.

Objective Vascular endothelial growth factor 165 (VEGF165) and its receptors, including neuropilin 1 (NRP-1), are overexpressed in human osteoarthritic (OA) articular cartilage, although their functional roles in the cartilage are not fully understood. An axon-guidance molecule, semaphorin 3A (Sema3A), which binds to NRP-1, acts as an antagonist of VEGF signaling in endothelial cells. The aim of this study was to examine the expression of Sema3A and the functions of the VEGF165/Sema3A/NRP-1 axis in OA cartilage. Methods The expression of Sema3A in OA and normal cartilage samples was examined by real-time polymerase chain reaction and immunohistochemical analyses. Functional analyses of VEGF165 and Sema3A were carried out using OA chondrocytes in culture. The migration activity of chondrocytes was examined in a monolayer wound assay. The effects of Sema3A on VEGF165-induced up-regulation of matrix metalloproteinases (MMPs) and intracellular signaling were also studied in cultured chondrocytes. Results Sema3A expression was significantly elevated in OA cartilage as compared to normal cartilage. Sema3A immunoreactivity directly correlated with the Mankin score and with chondrocyte cloning. VEGF165 promoted the migration of chondrocytes, and this activity was suppressed by VEGF receptor 2 tyrosine kinase inhibitors. Sema3A antagonized the chondrocyte migration promoted by VEGF165, and the activity was blocked by a selective inhibitor of, or small interfering RNA for, Sema3A. VEGF165-induced overexpression of MMPs and phosphorylation of ERK and focal adhesion kinase in chondrocytes were inhibited by Sema3A. Conclusion Our findings provide the first evidence that Sema3A is overexpressed, with a direct correlation with cloning, in OA cartilage and that it suppresses the VEGF165-promoted migration of chondrocytes. Our findings also suggest that Sema3A plays a role in chondrocyte cloning through inhibition of cell migration in OA cartilage.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.

Object The object of this study was to investigate failures after spinal reconstruction following total en bloc spondylectomy (TES), related factors, and sequelae arising from such failures in patients with malignant spinal tumors. Methods Fifteen patients (12 males and 3 females, with a mean age of 46.5 years) with malignant spinal tumors who underwent TES and survived for more than 1 year were included in this analysis (mean follow-up 41.5 months). Seven patients had primary tumors, including giant cell tumors in 4 patients, chordoma in 2, and Ewing sarcoma in 1. Eight patients had metastatic tumors, including thyroid cancer in 6 and renal cell cancer and malignant fibrous histiocytoma in 1 patient each. Seven patients without prominent paravertebral extension of the tumor were treated using a posterior approach alone, and 8 patients who exhibited prominent anterior or anterolateral extension of the tumors into the thoracic or abdominal cavity were treated using a combined anterior and posterior approach. Spinal reconstruction after tumor resection was performed using a combination of anterior structural support and posterior instrumentation. The relationship between instrumentation failure and clinical and radiographic factors, including age, sex, history of previous surgery, preoperative radiotherapy, tumor histology, tumor level, surgical approach, number of resected vertebrae, rod diameter, number of instrumented vertebrae, and cage subsidence, was investigated. Results Six patients (40%) with spinal instrumentation failure were identified: rod breakage occurred in 3 patients, and breakage of both the rod and the cage, combined cage breakage and screw back-out, and endplate fracture arising from cage subsidence occurred in 1 patient each. All of these patients experienced acute or chronic back pain, but only 1 patient with a tumor recurrence experienced neurological deterioration upon instrumentation failure. Cage subsidence (≥ 5 mm), preoperative irradiation, and the number of instrumented vertebrae (≤ 4 vertebrae) were significantly related to late instrumentation failure. Conclusions Late instrumentation failure was a frequent complication after TES. Although patients with instrumentation failure experienced back pain, the neurological sequelae were not catastrophic. For prevention, meticulous preparation of the graft site and a longer posterior fixation should be considered.

To evaluate changes in the transverse area of deep posterior muscles of the cervical spine 10 years after anterior cervical decompression and fusion (ACDF), in comparison with healthy volunteers.Thirty-one patients (22 males, 9 females, mean age at follow-up 59.3 years, mean follow-up 12.1 years) who had undergone preoperative MRI and non-instrumented ACDF within levels C3-4 to C5-6 were enrolled. 32 asymptomatic volunteers (17 males, 15 females; mean age, 54.7 years; mean follow-up, 11.7 years) who underwent MRI between 1993 and 1996 served as controls. Follow-up MRI was performed on both patients and control subjects, and the cross-sectional areas of deep posterior muscles were measured digitally at levels C3-4, 4-5, and 5-6.The mean total cross-sectional area in the ACDF and control groups was 4,693.6 ± 1,140.9 and 4,825.8 ± 1,048.2 mm(2) in the first MR study (P = 0.63), and 4,616.7 ± 1,086.0 and 5,036.7 ± 1,105.6 mm(2) at follow-up (P = 0.13). The total cross-sectional area in the ACDF group slightly decreased, while that in the control group increased (-77.1 ± 889.7 vs. 210.9 ± 622.0 mm(2), P = 0.14). The mean change in the cross-sectional area had no significant correlation with clinical symptoms, including neck pain or JOA score.ACDF patients did not show a marked decrease in the cross-sectional area of the deep posterior cervical muscles, but as compared with control subjects there was a slight decrease. A decrease in the cross-sectional area of these muscles after ACDF may not result in the axial symptoms as seen in patients treated by posterior surgery.

To evaluate the morphologic characteristics of the thoracic pedicle with regard to safe free-hand thoracic pedicle screw placement, based on multi-planar reconstruction CT images. Thirty adolescent idiopathic scoliosis (AIS) patients who had undergone posterior corrective surgery for major thoracic curve were included in this study. Reconstructed CT axial images at each thoracic vertebra were used to measure: (1) the shortest distance from an entry point to the ventral cortex of the lamina (critical distance), and (2) the distance from the entry point to the tangent of the spinal canal at the medial wall of the pedicle (safe distance). The critical length was defined as the distance between the critical distance and the safe distance. The distance from the entry point to the medial wall breach site (breach distance) was measured on post-operative CT images. The mean critical distance was 9.3 ± 1.1 mm. The critical distance of vertebrae from different levels was relatively constant, between 8.1 and 10.1 mm. The mean safe distance was 15.2 ± 1.3 mm. The safe distance of vertebrae from different levels was also relatively constant, between 14.5 and 16 mm. The mean critical length was 5.9 ± 1.0 mm. The critical length of vertebrae between T3 and T12 was relatively constant, ranging from 5 to 6.5 mm. The mean breach distance was 12.3 ± 1.3 mm and the each breach always recognized between the critical distance and the safe distance. The risk of pedicle medial wall perforation increases as the pedicle probe advances beyond the critical distance of 8–10 mm from the entry point, while it decreases entering into the safe distance at 14.5–16 mm. These parameters were relatively constant even in the most rotated vertebrae at T9 or those with the narrowest pedicle at T7 or T4.

To clarify the mechanism of osteoporosis in adolescent idiopathic scoliosis (AIS), we investigated radiological and histological changes in the cervical vertebrae of a chicken thoracic scoliosis model. Forty newly hatched broiler chicks were randomly divided into four equal groups: sham-operated chickens serving as control (CON), pinealectomized chickens (PNX), sham-operated (CON + MLT) and pinealectomized chickens (PNX + MLT) that received intraperitoneal administration of melatonin. Pinealectomy was performed at the age of 3 days, and the chickens were killed at 2 months of age. Postmortem X-rays were examined for the presence of scoliosis, and micro-computed tomography (micro-CT) images were taken to evaluate the microstructure of the cervical vertebrae. Histological specimens of the scanned cervical vertebra were prepared, and a midsagittal section was stained with hematoxylin and eosin and tartrate-resistant acid phosphatase to evaluate the numbers of osteoblasts and osteoclasts, respectively. Scoliosis developed at the thoracic spine in all chickens of the PNX and in two of the PNX + MLT group. Micro-CT data revealed that chickens in the PNX group had a greater degree of generalized osteoporosis compared with the other birds. The number of osteoblasts was significantly decreased in the PNX group, while no significant difference was observed among chickens in the numbers of osteoclasts. Our results suggest that melatonin deficiency reduces osteoblast proliferation and leads to the development of scoliosis and osteoporosis. The restoration of melatonin prevented the development of scoliosis and osteoporosis, indicating that melatonin levels may be crucial to the development of deformity and osteoporosis in AIS.

BackgroundThis cross-sectional study was conducted to obtain epidemiologic data on chronic musculoskeletal pain in the Japanese people, and with it a better understanding of the actual conditions and problems involved.MethodsA questionnaire covering basic information, chronic musculoskeletal pain, daily life, quality of life, and social loss was prepared and mailed to 11507 individuals aged 18 years or older. Subjects were selected randomly nationwide in accordance with the demographic composition of Japan.ResultsThe prevalence of chronic musculoskeletal pain was 15.4%. The prevalence was highest in people in their 30s to 50s. Pain occurred most frequently in the low back, neck, shoulder, and knee. Among symptomatic subjects, 42% sought treatment, by visiting a medical institution (19%), taking folk remedies (20%), or both (3%). Treatment was generally prolonged, with 70% of those treated reporting treatment durations of more than a year. Although 69% reported that their symptoms had improved, 30% reported unchanged or aggravated symptoms and dissatisfaction with treatment. Among symptomatic subjects, a high percentage of both men and women had lost jobs, left school, been absent from work or school, or had changed jobs. Basic activities of daily living (ADL) were disturbed in men, and the instrumental ADL (IADL) score was low in women. SF-36 scale scores were significantly lower in every area for subjects with chronic pain.ConclusionsChronic musculoskeletal pain does not necessarily improve even with prolonged treatment. It adversely affects daily life and both physical and mental health. Because those suffering pain often increasingly need assistance in daily activities, people around them are also affected. The therapeutic system and treatment procedures for chronic musculoskeletal pain merit prompt review.

We report the case of a 43-year-old man with steroid-induced osteonecrosis of the distal humerus in both arms. Costal osteochondral autografts were used to restore both joints with satisfactory outcomes.

Osteoid osteoma is a relatively common benign bone tumor first described by Jaffe [1]. It most frequently arises in the long bones and exhibits a characteristic X-ray appearance, that is, a small radiolucent zone surrounded by reactive circumferential sclerosis (nidus) [2, 3]. Nocturnal pain, which can be alleviated by aspirin, is one of the characteristic clinical manifestations of this bone tumor [4]. Although it is relatively rare, osteoid osteoma can also arise in the intra-articular regions, and we found 14 such cases arising in the knee joint in the literature [5–18]. Patients with intra-articular osteoid osteoma often present with joint pain, intracapsular effusion, restricted motion, and muscle atrophy in the affected limb, which can be mistaken for more common entities, such as traumatic or degenerative pathologies of the joint. Furthermore, X-ray examination often fails to show the characteristic nidus that is typically seen in extra-articular osteoid osteoma and therefore can result in a delayed diagnosis. We herein present a case of intra-articular osteoid osteoma arising in the knee joint, which was successfully treated by arthroscopy, and review the reported cases of intra-articular osteoid osteoma arising in the knee.

The role of the AP-1 transcription factor Fra-1 (encoded by Fosl1) in inflammatory responses associated with lung disease is largely unknown. Here, we show that Fra-1 overexpression in mice reduced proinflammatory cytokine production in response to injection of lipopolysaccharide (LPS), a Toll-like receptor (TLR)-ligand. Unexpectedly, Fra-1 transgenic mice died rapidly following LPS treatment, showing severe interstitial lung disease and displaying massive accumulation of macrophages and overproduction of several chemokines, including macrophage chemoattractant protein-1 (MCP-1, encoded by Ccl2). To assess the clinical relevance of Fra-1 in lung pathology, mice were treated with the anticancer drug gefitinib (Iressa), which can lead to interstitial lung disease in patients. Gefitinib-treated mice showed increased Fosl1 and Ccl2 expression and developed interstitial lung disease in response to LPS, endogenous TLR ligands and chemotherapy. Moreover, deletion of Fra-1 or blocking MCP-1 receptor signaling in mice attenuated gefitinib-enhanced lethality in response to LPS. Importantly, human alveolar macrophages showed enhanced LPS-induced FOSL1 and CCL2 expression after gefitinib treatment. These results indicate that Fra-1 is an important mediator of interstitial lung disease following gefitinib treatment.

Background Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis and marfanoid habitus. The clinical findings of SGS include neurological, cardiovascular, connective tissue, and skeletal abnormalities. Among these skeletal findings, developmental scoliosis is recognized in half of all patients with SGS. However, no earlier reports have described the surgical treatment of scoliosis associated with SGS. Methods Four patients (2 boys and 2 girls; mean age at the time of surgery, 7.3±4.4 y) with SGS who underwent surgical treatment for progressive scoliosis were reviewed. The radiologic findings, operative findings, and perioperative complications were evaluated. Results The mean preoperative Cobb angle was 102.8±16.9 degrees. The curve patterns were a double curve in 2 cases and a triple curve in 2 cases. Local kyphosis at the thoracolumbar area was recognized in all the cases with a mean kyphosis angle of 49±16 degrees. Growing rod procedures were performed in 2 patients, and posterior correction and fusion were performed in 2 patients. The mean correction rate was 45% in the patients who underwent the growing rod procedures at the time of growing rod placement and 51% in the patients who underwent posterior correction and fusion. Dislodgement of the proximal anchors occurred in 3 of the 4 patients. One patient developed pseudoarthrosis. Two patients developed deep wound infections, and implant removal was necessary in 1 patient. Conclusions Surgical treatment for scoliosis in patients with SGS was associated with a high incidence of perioperative and postoperative complications including implant dislodgements and deep wound infections attributable to poor bone quality and a thin body habitus, which are characteristic clinical features of this syndrome. Careful preoperative surgical planning and postoperative care are critical for the surgical treatment of scoliosis associated with SGS, especially in infants requiring multiple surgeries. Level of Evidence Level IV.

Adolescent idiopathic scoliosis (AIS) is a spinal deformity most commonly arising in apparently healthy girls around puberty. AIS has a strong genetic predisposition. Several genetic associations between AIS and single nucleotide polymorphisms (SNPs) have been reported; common SNPs in the genes for matrilin 1 (MATN1), melatonin receptor 1B (MTNR1B), tryptophan hydroxylase 1 (TPH1), and insulin-like growth factor 1 (IGF1) are reported to be associated with AIS in Chinese. However, these associations have not been replicated so far. To confirm the associations, we compared these SNPs with AIS predisposition and curve severity in a population of Japanese females consisting of 798 AIS patients and 1,239 controls. All the subjects were genotyped using the PCR-based Invader assay. We found no association of any of the SNPs with AIS predisposition or curve severity. Considering the statistical power and sample size of the present study, we concluded that these SNPs are not associated with either AIS predisposition or curve severity in Japanese. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1055–1058, 2011

We have reviewed 38 surgically treated cases of spontaneous posterior interosseous nerve palsy in 38 patients with a mean age of 43 years (13 to 68) in order to identify clinical factors associated with its prognosis. Interfascicular neurolysis was performed at a mean of 13 months (1 to 187) after the onset of symptoms. The mean follow-up was 21 months (5.5 to 221). Medical Research Council muscle power of more than grade 4 was considered to be a good result. A further 12 cases in ten patients were treated conservatively and assessed similarly. Of the 30 cases treated surgically with available outcome data, the result of interfascicular neurolysis was significantly better in patients < 50 years old (younger group (18 nerves); good: 13 nerves (72%), poor: five nerves (28%)) than in cases > 50 years old (older group (12 nerves); good: one nerve (8%), poor: 11 nerves (92%)) (p < 0.001). A pre-operative period of less than seven months was also associated with a good result in the younger group (p = 0.01). The older group had a poor result regardless of the pre-operative delay. Our recommended therapeutic approach therefore is to perform interfascicular neurolysis if the patient is < 50 years of age, and the pre-operative delay is < seven months. If the patient is > 50 years of age with no sign of recovery for seven months, or in the younger group with a pre-operative delay of more than a year, we advise interfascicular neurolysis together with tendon transfer as the primary surgical procedure.

A butterfly vertebra is a congenital anomaly often associated with a series of syndromic diseases and is often recognized incidentally without any presenting symptoms. The authors report the case of a 13-year-old girl with lumbar scoliosis and mild spondylolisthesis associated with a butterfly vertebra at L-6 causing radiculopathy. The L-5 and L-6 nerve roots were entrapped at the intervertebral foramina between L-5 and the butterfly vertebra (L-6) and between L-6 and S-1 in the concave side. To decompress and preserve the two nerve roots, correct the deformity, and obtain a solid bone fusion, surgery involving the thorough removal of the facet joints between L-5 and L-6 and between L-6 and S-1 in the concave side was performed, with a partial resection of the butterfly vertebra and the placement of a titanium mesh cage between the L-5 and S-1 pedicles dorsal to the nerve roots. Complete pain relief and correction of the deformity with solid bone fusion was obtained after a 2-year follow-up period.

Object To reduce intraoperative damage to the posterior supporting structures of the lumbar spine during decompressive surgery for lumbar canal stenosis (LCS), lumbar spinous process–splitting laminectomy (LSPSL or split laminectomy) was developed. This prospective, randomized, controlled study was conducted to clarify whether the split laminectomy decreases acute postoperative wound pain compared with conventional laminectomy. Methods Forty-one patients with LCS were enrolled in this study. The patients were randomly assigned to either the LSPSL group (22 patients) or the conventional laminectomy group (19 patients). Questionnaires regarding wound pain (intensity, depth, and duration) and activities of daily living (ADL) were administered at postoperative days (PODs) 3 and 7. Additionally, the authors evaluated the pre- and postoperative serum levels of C-reactive protein and creatine phosphokinase, the amount of pain analgesics used during a 3-day postoperative period, and the muscle atrophy rate measured on 1-month postsurgical MR images. Results Data obtained in patients in the LSPSL group and in 16 patients in the conventional laminectomy group were analyzed. The mean visual analog scale for wound pain on POD 7 was significantly lower in the LSPSL group (16 ± 17 mm vs 34 ± 31 mm, respectively; p = 0.04). The mean depth-of-pain scores on POD 7 were significantly lower in the LSPSL group than in the conventional group (0.9 ± 0.6 vs 1.7 ± 0.8, respectively; p = 0.013). On POD 3, the mean serum creatine phosphokinase level was significantly lower in the LSPSL group (126 ± 93 U/L) than in the other group (207 ± 150 U/L) (p = 0.02); on POD 7, the mean serum C-reactive protein level was significantly lower in the LSPSL group (1.1 ± 0.6 mg/dl) than in the conventional laminectomy group (1.9 ± 1.5 mg/dl) (p = 0.04). The number of pain analgesics taken during the 3-day postoperative period was lower in the LSPSL group than in the conventional laminectomy group (1.7 ± 1.3 tablets vs 2.3 ± 2.4 tablets, respectively; p = 0.22). The mean muscle atrophy rate was also significantly lower in the LSPSL group (24% ± 15% vs 43% ± 22%; p = 0.004). Conclusions Lumbar spinous process–splitting laminectomy for the treatment of LCS reduced acute postoperative wound pain and prevented postoperative muscle atrophy compared with conventional laminectomy, possibly because of minimized damage to the paraspinal muscles.

Adolescent idiopathic scoliosis (AIS) is a common disorder with a strong genetic predisposition. Associations between AIS and common single nucleotide polymorphisms (SNPs) in estrogen receptor genes have been reported. rs9340799 in the gene for estrogen receptor α (ESR1) is reported to be associated with curve severity in Japanese and with AIS predisposition and curve severity in Chinese. In addition, rs1256120 in the gene for estrogen receptor β (ESR2) is reported to be associated with AIS predisposition and curve severity in Chinese. However, the sample sizes of these previous studies were small, and the associations of these SNPs have not been replicated. To examine the association between AIS and estrogen receptor genes, we investigated the association of rs9340799 and rs1256120 with AIS predisposition and curve severity using a large Japanese population, consisting of 798 AIS patients and 637 sex-matched controls. We found no association of either SNP with AIS predisposition or curve severity in the Japanese population. Considering the statistical power of the present study and the limitations of the previous reports, we conclude that the associations of rs9340799 and rs1256120 with AIS predisposition and curve severity are negative.

An association between progression of cervical disc degeneration and that of lumbar disc degeneration has been considered to exist. To date, however, this association has not yet been adequately studied. Age-related changes in the cervical intervertebral discs were evaluated by magnetic resonance imaging (MRI) in patients with lumbar disc herniation, and compared with the MRI findings of healthy volunteers without lower back pain. The purpose of this study was to clarify whether the prevalence of asymptomatic cervical disc degeneration is higher in patients with lumbar disc herniation than in healthy volunteers. The study was conducted on 51 patients who were diagnosed as having lumbar disc herniation and underwent cervical spine MRI. The patients consisted of 34 males and 17 females ranging in age from 21–83 years (mean 46.9 ± 14.5 years) at the time of the study. The control group was composed of 113 healthy volunteers (70 males and 43 females) aged 24–77 years (mean 48.9 ± 14.7 years), without neck pain or low back pain. The percentage of subjects with degenerative changes in the cervical discs was 98.0% in the lumbar disc herniation group and 88.5% in the control group (p = 0.034). The presence of lumbar disc herniation was associated significantly with decrease in signal intensity of intervertebral disc and posterior disc protrusion in the cervical spine. None of the MRI findings was significantly associated with the gender, smoking, sports activities, or BMI. As compared to healthy volunteers, patients with lumbar disc herniation showed a higher prevalence of decrease in signal intensity of intervertebral disc and posterior disc protrusion on MRI of the cervical spine. The result of this study suggests that disc degeneration appears to be a systemic phenomenon.

With increasing confidence and surgical experience, minimally invasive surgery (MIS) in total knee arthroplasty (TKA) is now being applied to more complicated cases. The present study assessed the feasibility of MIS-TKA using a lateral approach for valgus knees. Subjects comprised 26 patients with valgus knees who underwent MIS-TKA using a lateral subvastus approach. Five cases required a 1-cm snip of vastus lateralis obliquus, to shift the patella medially without eversion. Clinical scores and radiographic parameters of lateral MIS-TKA were examined and compared with those of 26 medial MIS-TKAs matched for preoperative patient characteristics. The lateral MIS-TKA group showed slightly longer operative time and larger skin incision than the medial MIS-TKA group. Nevertheless, myoglobin index and pain on a visual analog scale on postoperative day 7 were significantly lower in the lateral MIS-TKA group than in the medial MIS-TKA group. Postoperative improvement of clinical scores was quite comparable between lateral and medial MIS-TKA groups. Radiographic assessment revealed that tibiofemoral mechanical axis aligned within ±3° from ideal in 24 of 26 patients after lateral MIS-TKA. MIS technique-related complications occurred in only 1 patient presenting with subsidence of the tibial component, due to malpositioning of the tibial component. From the perspectives of postoperative pain, clinical scores, radiographic accuracy, and postoperative complication rate, lateral MIS-TKA achieved comparable or superior results to medial MIS-TKA. This technique may offer a promising technical option that can be utilized for most patients with valgus knee deformity.

Object The optimal management of malignant astrocytomas remains controversial, and the prognosis of these lesions has been dismal regardless of the administered treatment. In this study the authors investigated the surgical outcomes of cordotomy in patients with thoracic malignant astrocytomas to determine the effectiveness of this procedure. Methods Cordotomy was performed in 5 patients with glioblastoma multiforme (GBM) and 2 with anaplastic astrocytoma (AA). A Kaplan-Meier survival analysis was performed, and the associations of the resection level with survival and postoperative complications were retrospectively examined. Results Cordotomy was performed in a single stage in 2 patients with GBM and in 2 stages in 3 patients with GBM and 2 patients with AA. In the 2 patients with GBM, cordotomy was performed 2 and 3 weeks after a partial tumor resection. In the 2 patients with AA, the initial treatment consisted of partial tumor resection and subtotal resection combined with radiotherapy, and rostral tumor growth and progressive paralysis necessitated cordotomy 2 and 28 months later. One patient with a secondary GBM underwent cordotomy; the GBM developed 1 year after subtotal resection and radiotherapy for a WHO Grade II astrocytoma. Four patients died 4, 5, 24, and 42 months after the initial operation due to CSF dissemination, and 3 patients (2 with GBM and 1 with AA) remain alive (16, 39, and 71 months). No metastasis to any other organs was noted. Conclusions One-stage cordotomy should be indicated for patients with thoracic GBM or AA presenting with complete paraplegia preoperatively. In patients with thoracic GBM, even if paralysis is incomplete, cordotomy should be performed before the tumor disseminates through the CSF. Radical resection should be attempted in patients with AA and incomplete paralysis. If the tumor persists, radiotherapy and chemotherapy are indicated, and cordotomy should be reserved for lesions growing progressively after such second-line treatments.

Study Design. Prospective clinical series. Objective. To determine how many thoracic scoliotic pedicles have cancellous versus cortical versus absent channels. Summary of Background Data. Although morphologic evaluations of thoracic pedicles have been well reported, the results do not practically reflect clinical findings during actual pedicle screw placement. We propose a novel pedicle channel classification describing the osseous anatomy encountered during pedicle probe insertion. Methods. We noted 4 pedicle types in 53 consecutive scoliosis patients. Type A: pedicle probe smoothly inserted without difficulty; the morphology is described as a "Large Cancellous Channel." Type B: pedicle probe inserted snugly with increased force; described as a "Small Cancellous Channel." Type C: pedicle probe cannot be manually pushed but must be tapped with a mallet down the pedicle into the body; described as a "Cortical Channel." Type D: pedicle probe cannot locate a channel thus necessitating a "juxtapedicular" screw position; described as a "Slit/Absent Channel." The average age at time of surgery was 23.4 ± 16.7 years. Diagnoses included idiopathic scoliosis (n = 38) and syndromic scoliosis (n = 15). The average main thoracic Cobb angle was 73° ± 26°. Evaluation of pedicle morphology of the 4 types was also performed in 21 consecutive cases of adolescent idiopathic scoliosis using preoperative computed tomography images. Results. A total of 1021 pedicles with screws placed were evaluated. The average percent per type was as follows: 61.0% type A; 29.2% type B, 6.8% type C, and 3.0% type D. On the convexity, 98.2% of pedicles were type A or B versus 81.5% on the concavity (P < 0.05). There were significant differences between adolescent versus adult idiopathic scoliosis (P = 0.007), and syndromic scoliosis versus adult idiopathic scoliosis (P = 0.017) regarding pedicle morphologic proportions. There was a significant tendency toward a decrease in the proportion of type A pedicles, an increase in the proportion of type B pedicles as the Cobb angle increased (P < 0.0001). Evaluation based on 312 thoracic pedicles in 21 consecutive adolescent idiopathic scoliosis patients using preoperative computed tomography axial images confirmed assumptions of the 4 pedicle types. Conclusion. We propose a classification for pedicle channels describing the osseous anatomy encountered during pedicle probe insertion. Based on the classification, surprisingly, we found during surgery that 90% of thoracic pedicles had a cancellous channel, whereas 7% had a cortical channel and only 3% had an absent channel.

Introduction: The purpose of this study was to elucidate the feasibility of microendoscopic discectomy (MED) for the treatment of lumbar disc herniation in elderly patients over the age of 65. Methods: The elderly group consisted of 44 patients (27 men and 17 women; mean age, 69.6 years; mean follow-up, 27.7 months) with sciatic pain caused by lumbar disc herniation who were treated using MED. The younger group was comprised of 44 sex-matched patients younger than 65 years. The younger group also had lumbar disc herniation treated with MED and served as the control group. The clinical outcomes were evaluated using the Japanese Orthopaedic Association score for low back pain (JOA score). Results: The results revealed that the good surgical outcomes achieved in the younger group were also achieved in the elderly group (JOA scores: 14.8 ± 4.1 in the younger group before surgery versus 13.0 ± 3.2 in the elderly group; 26.0 ± 2.4 at follow-up versus 25.5 ± 2.7; recovery rates of JOA scores: 78.3 ± 17.8% versus 77.9 ± 16.6%, respectively). The mean surgical time was 78.3 ± 31.0 min in the elderly group and 69.2 ± 22.9 min (P=0.12) in the younger group; the blood loss was 33.9 ± 71.9 cc and 28.0 ± 37.8 cc (P=0.63), respectively. Complications included a dural tear in two elderly patients, and postoperative discitis and hematoma in one elderly patient each: all of these complications were managed successfully. Conclusion: The results of this study demonstrated that MED is a feasible minimally invasive surgical option for elderly patients with lumbar disc herniation.

Object The aim in this study was to evaluate the efficacy of the ball tip technique in placing thoracic pedicle screws (TPSs), as compared with the conventional freehand technique, in both a cadaveric study and a clinical study of patients with adolescent idiopathic scoliosis. Although posterior spinal surgery using TPSs has been widely applied, these screws are associated with the potential risk of vascular, pulmonary, or neurological complications. To further enhance the accuracy and safety of TPS placement, the authors developed the ball tip technique. Methods After creating an appropriate starting point for probe insertion, a specially designed ball tip probe consisting of a ball-shaped tip with a flexible metal shaft is used to make a guide hole into the pedicle. Holding the probe with the fingertips while using an appropriate amount of pressure or by tapping it gently and continuously with a hammer, one can safely insert the ball tip probe into the cancellous channel in the pedicle. In a cadaveric study, 5 spine fellows with similar levels of experience in placing TPSs applied the ball tip or the conventional technique to place screws in 5 cadavers with no spinal deformities. The incidence of misplaced screws was evaluated by dissecting the spines. In a clinical study, 40 patients with adolescent idiopathic scoliosis underwent posterior surgery with TPS placement via the ball tip or conventional technique (20 patients in each treatment group). The accuracy of the TPS placements was evaluated on postoperative axial CT scanning. Results In the cadaveric study, 100 TPSs were evaluated, and the incidence of misplaced screws was 14% in the ball tip group and 34% in the conventional group (p = 0.0192). In the clinical study, 574 TPSs were evaluated. One hundred seventy-one intrapedicular screws (67%) were recognized in the conventional group and 288 (90%) in the ball tip group (p < 0.01). In the conventional and ball tip groups, the respective numbers of TPSs with a pedicle breach of ≤ 2 mm were 20 (8%) and 15 (5%), those with a pedicle breach of > 2 mm were 32 (13%) and 9 (3%; p < 0.01), and those located in the costovertebral joints were 32 (13%) and 7 (2%). Conclusions In both cadaveric and clinical studies the ball tip technique enhanced the accuracy of TPS placement as compared with the conventional freehand technique. Thus, the ball tip technique is useful for the accurate and safe placement of TPSs in deformed spines.

We previously reported the beneficial effect of administering an anti-mouse IL-6 receptor antibody (MR16-1) immediately after spinal cord injury (SCI). The purpose of our present study was to clarify the mechanism underlying how MR16-1 improves motor function after SCI. Quantitative analyses of inflammatory cells using flow cytometry, and immunohistochemistry with bone marrow-chimeric mice generated by transplanting genetically marked purified hematopoietic stem cells, revealed that MR16-1 dramatically switched the central player in the post-traumatic inflammation, from hematogenous macrophages to resident microglia. This change was accompanied by alterations in the expression of relevant cytokines within the injured spinal cord; the expression of recruiting chemokines including CCL2, CCL5, and CXCL10 was decreased, while that of Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), a known mitogen for microglia, was increased. We also showed that the resident microglia expressed higher levels of phagocytic markers than the hematogenous macrophages. Consistent with these findings, we observed significantly decreased tissue damage and reduced levels of myelin debris and Nogo-A, the axonal growth inhibitor, by MR16-1 treatment. Moreover, we observed increased axonal regeneration and/or sprouting in the MR16-1-treated mice. Our findings indicate that the functional improvement elicited by MR16-1 involves microglial functions, and provide new insights into the role of IL-6 signaling in the pathology of SCI.

Purpose The purpose of this study was to investigate the clinical results of single-stage revision anterior cruciate ligament reconstruction (ACLR) after synthetic ligament failure. Methods The subjects comprised 20 patients who underwent revision ACLR after synthetic ligament failure. All revisions were performed with bone–patellar tendon–bone graft, and bone tunnel expansion after removal of synthetic materials was treated with bone plugs sized and trimmed as necessary to fill the bone tunnels. Clinical results were assessed at a mean of 2.8 years postoperatively, followed by comparison with the results of 20 primary ACLRs selected as case-matched controls. Assessment included the Lysholm score, International Knee Documentation Committee (IKDC) evaluation, instrumented laxity testing, and radiologic examination. Results Bone tunnel enlargement to 11 mm in diameter or greater was found in 10 of 20 revision ACLRs. However, favorable anteroposterior stability was obtained at final follow-up (1.4 ± 2.0 mm in revision ACLR group and 1.5 ± 1.5 mm in primary ACLR group). The overall Lysholm score improved significantly from preoperatively to final follow-up, but the revision ACLR group showed significantly worse results for the pain parameter than the primary ACLR group. The final IKDC results also showed significant postoperative improvement, but the number of cases with grade C was significantly higher in the revision ACLR group than in the primary ACLR group, which was attributed to radiologically confirmed osteoarthritis in the revision ACLR group. Conclusions Single-stage revision ACLR with bone–patellar tendon–bone graft after synthetic ligament failure yielded favorable results in terms of IKDC grade, Lysholm score, and anteroposterior stability, despite enlarged bone tunnels after removal of synthetic material. Inferior results for the radiologic and pain parameters of the IKDC and Lysholm scores were attributed to osteoarthritic changes inherent to the revision ACLR group. Level of Evidence Level III, therapeutic case-control study.

Background: A variety of osteotomies has been proposed to correct posttraumatic cubitus varus deformity as well as any associated hyperextension and/or rotational deformities. However, lateral closing-wedge osteotomy and step-cut osteotomy, both of which have been used extensively with satisfactory outcomes, correct only in the coronal plane. To date, no direct comparison has been made between three-dimensional and simple coronal plane osteotomies. Methods: Between 1983 and 2007, we treated eighty-six elbows with a posttraumatic varus deformity. We classified patients who underwent three-dimensional osteotomies as Group I and those who underwent simple coronal plane osteotomies as Group II, and we compared the outcomes between the groups. Clinical evaluation included an assessment of the carrying angle and measurement of the passive range of motion before surgery and at the time of the final follow-up. To evaluate the remodeling capacity of the bone to recover elbow flexion in Group II, we assessed the range of motion before surgery and at the time of the final follow-up in patients who were less than ten years old and those who were more than ten years old. Results: There was no significant difference between the groups with regard to the carrying angle or the elbow range of motion, either before surgery or at the time of the final follow-up. However, Group I had more significant loss of correction (p = 0.018). In Group II, elbow motion reached the physiological range by the time of the final follow-up in patients who were less than ten years old. Conclusions: For osteotomies to correct cubitus varus deformity, correction of internal rotation is not needed. With a three-dimensional osteotomy, it is difficult to maintain correction and to acquire the planned carrying angle because of the small area of bone contact. It is necessary to correct hyperextension in patients older than ten years of age, as after that age bone remodeling is not expected to increase elbow flexion. Level of Evidence: Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence.

Various types of induced pluripotent stem (iPS) cells have been established by different methods, and each type exhibits different biological properties. Before iPS cell-based clinical applications can be initiated, detailed evaluations of the cells, including their differentiation potentials and tumorigenic activities in different contexts, should be investigated to establish their safety and effectiveness for cell transplantation therapies. Here we show the directed neural differentiation of murine iPS cells and examine their therapeutic potential in a mouse spinal cord injury (SCI) model. “Safe” iPS-derived neurospheres, which had been pre-evaluated as nontumorigenic by their transplantation into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse brain, produced electrophysiologically functional neurons, astrocytes, and oligodendrocytes in vitro. Furthermore, when the safe iPS-derived neurospheres were transplanted into the spinal cord 9 d after contusive injury, they differentiated into all three neural lineages without forming teratomas or other tumors. They also participated in remyelination and induced the axonal regrowth of host 5HT + serotonergic fibers, promoting locomotor function recovery. However, the transplantation of iPS-derived neurospheres pre-evaluated as “unsafe” showed robust teratoma formation and sudden locomotor functional loss after functional recovery in the SCI model. These findings suggest that pre-evaluated safe iPS clone-derived neural stem/progenitor cells may be a promising cell source for transplantation therapy for SCI.

Summary Objective The role of postmenopause on the pathogenesis of cartilage degeneration has been an open question. We assessed cartilage degeneration in estrogen receptor (ER)α null mice and examined the role of glucocorticoid receptor-interacting protein 1 (GRIP1) in the ERα-dependent transcription of a type II collagen gene ( col2a1 ) with special reference to a crosstalk with the transforming growth factor (TGF)-β signaling pathway. Methods The vertebral cartilaginous endplate from female ERα null mice was subjected to histological analyses. Col2a1 expression of primary chondrocytes (PCs) obtained from ERα null mice after 17β-estradiol (E 2 ) and TGF-β1 stimulation was examined by reverse transcription polymerase chain reaction (RT-PCR). Estrogen response element (ERE) or col2a1 promoter–enhancer luciferase reporter system was used to investigate the crosstalk among ERα, GRIP1, and MKK6. Col2a1 expression and glycosaminoglycan (GAG) content were measured in ATDC5 cells treated with GRIP1 small interfering RNA (siRNA). Results ERα deficiency clearly accelerated impairment of the vertebral cartilaginous endplate. E 2 and TGF-β1 stimulation increased col2a1 expression in PC from wild-type mice, but not that from ERα null mice. The same stimulation increased the col2a1 promoter–enhancer reporter activity, and the elevated activity was decreased by dominant-negative ERα and p38 mitogen-activated protein kinase (MAPK) inhibitor. GRIP1 increased the E 2 -dependent ERE activation in the presence of ERα and constitutive-active MKK6. GRIP1 siRNA repressed col2a1 expression and GAG production in ATDC5 cells. Conclusions Crosstalks between ERα/GRIP1 and TGF-β/MKK6/p38 MAPK pathway have protective roles on cartilage metabolism via regulating the extracellular matrices expression. The finding may lead to the development of a novel therapeutic approach for cartilage degeneration.