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1.  An outcome measure for patients with cervical myelopathy: the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ): an average score of healthy volunteers 
Journal of Orthopaedic Science  2013;19(1):33-48.
Background
An outcome measure to evaluate the neurological function of patients with cervical myelopathy was proposed by the Japanese Orthopaedic Association (JOA score) and has been widely used in Japan. However, the JOA score does not include patients’ satisfaction, disability, handicaps, or general health, which can be affected by cervical myelopathy. In 2007, a new outcome measure, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ), which is a self-administered questionnaire, was developed. However, the influence of age and gender on the scores has not been fully examined. The purpose of this study was to establish the standard value of the JOACMEQ by age using healthy volunteers.
Methods
This study was conducted in 23 university hospitals and their affiliated hospitals from September to December 2011. The questionnaire included 24 questions for evaluation of physical function of the cervical spine and spinal cord. A total of 1,629 healthy volunteers were recruited for the study. The ages ranged from 20 to 89 years old.
Results
The volunteers comprised 798 men and 831 women. In the elderly healthy volunteers, the JOACMEQ scores decreased with age. In general, the scores for cervical spine function and upper/lower extremity function were retained up to the 60s, then decreased in the 70s and 80s. The scores for quality of life were retained up to the 70s; however, the score for bladder function was retained up to the 40s, then declined with age from the 50s to 80s.
Conclusion
The standard values of the JOACMEQ by age were established. Differences in the scores were found among different generations. Patients with cervical myelopathy should be evaluated with this new self-administered questionnaire taking into account the standard values according to different ages.
doi:10.1007/s00776-013-0494-y
PMCID: PMC3929037  PMID: 24317702
2.  Comparative study of spinopelvic sagittal alignment between patients with and without degenerative spondylolisthesis 
European Spine Journal  2012;21(11):2181-2187.
Introduction
To date, few studies have focused on spinopelvic sagittal alignment as a predisposing factor for the development of degenerative spondylolisthesis (DS). The objectives of this study were to compare differences in spinopelvic sagittal alignment between patients with or without DS and to elucidate factors related to spinopelvic sagittal alignment.
Materials and methods
A total of 100 patients with or without DS who underwent surgery for lumbar spinal canal stenosis were assessed in this study. Fifty patients with DS (DS group) and 50 age- and gender-matched patients without DS (non-DS group) were enrolled. Spinopelvic parameters including pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), L4 slope, L5 slope, thoracic kyphosis (TK), lumbar lordosis (LL) and sagittal balance were compared between the two groups. In the DS group, the percentage of vertebral slip (% slip) was also measured.
Results
Several spinopelvic parameters, PI, SS, L4 slope, L5 slope, TK and LL, in the DS group were significantly greater than those in the non-DS group, and PI had positive correlation with % slip (r = 0.35, p < 0.05). Degrees of correlations among spinopelvic parameters differed between the two groups. In the DS group, PI was more strongly correlated with SS (r = 0.82, p < 0.001) than with PT (r = 0.41, p < 0.01). In the non-DS group, PI was more strongly correlated with PT (r = 0.73, p < 0.001) than with SS (r = 0.38, p < 0.01).
Conclusions
Greater PI may lead to the development and the progression of vertebral slip. Different compensatory mechanisms may contribute to the maintenance of spinopelvic sagittal alignment in DS and non-DS patients.
doi:10.1007/s00586-012-2374-0
PMCID: PMC3481103  PMID: 22639298
Spinopelvic sagittal alignment; Pelvic incidence; Lumbar spinal canal stenosis; Degenerative spondylolisthesis; Percentage of vertebral slip
3.  Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant 
The Journal of Clinical Investigation  2013;123(11):4909-4917.
Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.
doi:10.1172/JCI69277
PMCID: PMC3809787  PMID: 24216480
4.  Increase in spinal longitudinal length by correction surgery for adolescent idiopathic scoliosis 
European Spine Journal  2012;21(10):1920-1925.
Purpose
One of the downsides of spinal correction surgery for adolescent idiopathic scoliosis (AIS) is the cessation of spinal longitudinal growth within the fused levels in growing children. However, the surgery itself has the potential to increase spinal longitudinal length by correcting the curvature. The purpose of this study was to evaluate the correlation between curve correction and increased spinal longitudinal length by corrective surgery for AIS.
Methods
This study included 208 consecutive patients (14 male, 194 female) with AIS who underwent posterior or anterior correction and fusion surgeries. Mean age at the time of surgery was 15.7 ± 3.3 years (range 10–20 years). Patients with hyperkyphosis of more than 40° were excluded. All patients had main curves in the thoracic spine (Lenke type 1 or 2). Forty-three patients underwent anterior spinal correction and fusion (ASF) and 164 underwent posterior spinal correction and fusion (PSF). The mean preoperative height was 154.7 ± 6.9 cm (range 133–173 cm). Pre and postoperative PA standing X-ray films were used to measure the Cobb angle and spinal length between the end vertebrae of the main thoracic curve, and between T1 and L5. The patients were divided into ASF and PSF groups, within which correlations between the Cobb angle correction and spinal length increase were evaluated.
Results
In the ASF group, the mean preoperative Cobb angle of the main thoracic curve was 54.9 ± 8.3° (range 41–83°) and it was corrected to 19.7 ± 9.5° (range 0–47°) with a mean correction of 35.2 ± 11.1° (range 10–74°) after surgery. The mean increase in the length of the main thoracic curve was 1.5 ± 4.6 mm (range −8 to 13 mm), and the mean increase in T1–L5 length was 16.6 ± 7.7 mm (range −3 to 51 mm). Significant correlation between the correction of the Cobb angle and increase in T1–L5 length was observed, with a correlation coefficient of 0.44. In the PSF group, the mean preoperative Cobb angle of the main thoracic curve was 58.8 ± 11.6° (range 36–107°) and it was corrected to 17.1 ± 7.6° (range 10–49°), with a mean correction of 41.7 ± 10.2° (range 21–73°) after surgery. The mean increase in the length of the main thoracic curve was 14.0 ± 5.2 mm (range 0–42 mm), and the mean increase in T1–L5 length was 32.4 ± 10.8 mm (10–61 mm). Correlation between the correction of the Cobb angle and increase in T1–L5 length was high, with a correlation coefficient of 0.64. The increase in T1–L5 length could be calculated by the following formula based on linear regression analysis: increase in T1–L5 length (mm) = correction of the Cobb angle (º) × 0.77.
Conclusion
Spinal longitudinal length was significantly increased after surgery in both the ASF and PSF groups. Correction of the Cobb angle and increase in T1–L5 length were highly correlated with each other, especially in the PSF group.
doi:10.1007/s00586-012-2163-9
PMCID: PMC3463697  PMID: 22310882
Adolescent idiopathic scoliosis; Posterior correction with fusion surgery; Anterior correction with fusion surgery; Spinal length
5.  Identification of a Susceptibility Locus for Severe Adolescent Idiopathic Scoliosis on Chromosome 17q24.3 
PLoS ONE  2013;8(9):e72802.
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting around 2% of adolescents worldwide. Genetic factors play an important role in its etiology. Using a genome-wide association study (GWAS), we recently identified novel AIS susceptibility loci on chromosomes 10q24.31 and 6q24.1. To identify more AIS susceptibility loci relating to its severity and progression, we performed GWAS by limiting the case subjects to those with severe AIS. Through a two-stage association study using a total of ∼12,000 Japanese subjects, we identified a common variant, rs12946942 that showed a significant association with severe AIS in the recessive model (P = 4.00×10−8, odds ratio [OR] = 2.05). Its association was replicated in a Chinese population (combined P = 6.43×10−12, OR = 2.21). rs12946942 is on chromosome 17q24.3 near the genes SOX9 and KCNJ2, which when mutated cause scoliosis phenotypes. Our findings will offer new insight into the etiology and progression of AIS.
doi:10.1371/journal.pone.0072802
PMCID: PMC3762929  PMID: 24023777
6.  Loss of apical vertebral derotation in adolescent idiopathic scoliosis: 2-year follow-up using multi-planar reconstruction computed tomography 
European Spine Journal  2012;21(6):1111-1120.
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).
Methods
Twenty-seven AIS patients treated by segmental pedicle screw (PS) constructs were included in this study. Correction in the axial plane was evaluated using the “relative apical vertebral rotation angle” (rAVR), defined as the difference between the axial rotation angles of the upper instrumented vertebra and the apical vertebra on reconstructed axial CT images. The Cobb angle of the main curve and apical vertebral translation was measured to evaluate the coronal correction. Thoracic kyphosis was also measured for the evaluation of sagittal profile. Measurements were performed before surgery, and 1 week and 2 years after surgery. The relationships between the correction losses and skeletal maturity, and variety of spinal constructs were also evaluated.
Results
The mean preoperative Cobb angle of the major curve was 59.1° ± 11.2° before and 13.0° ± 7.2° immediately after surgery. Two years later, the mean Cobb angle had increased significantly, to 15.5° ± 7.8°, with a mean correction loss of 2.5° ± 1.5° (p < 0.001). The mean preoperative rAVR of 28.5° ± 8.4° was corrected to 15.8° ± 7.8° after surgery. It had increased significantly to 18.5 ± 8.4 by 2 years after surgery, with a mean correction loss of 2.7° ± 1.0° (p < 0.001). The mean correction losses for both the Cobb angle and rAVR were significantly greater in the skeletally immature patients. The significant correlations were recognized between the correction losses and the proportion of multi-axial screws, and the materials of constructs.
Conclusions
Statistically significant loss of correction in the Cobb angle and apical vertebral axial rotation angle (AVR) were recognized 2 years after surgery using PS constructs. The correction losses, especially AVR, were more evident in the skeletally immature patients, and in patients treated with more multi-axial screws and with titanium constructs rather than with stainless constructs.
doi:10.1007/s00586-012-2274-3
PMCID: PMC3366141  PMID: 22438165
Adolescent idiopathic scoliosis; Apical vertebral rotation; Correction loss; Coronal correction
7.  HIF-1α AND HIF-2α DEGRADATION IS DIFFERENTIALLY REGULATED IN NUCLEUS PULPOSUS CELLS OF THE INTERVERTEBRAL DISC 
Studies of many cell types show that level of HIF-1α and HIF-2α is primarily controlled by oxygen-dependent proteasomal degradation, catalyzed by HIF prolyl-hydroxylases (PHDs). However, in 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. Noteworthy, HIF-2α degradation through 26S proteasome was more pronounced in hypoxia. Surprisingly, treatment with DMOG, a PHD inhibitor, shows 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 demonstrate 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, 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 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.
doi:10.1002/jbmr.538
PMCID: PMC3260409  PMID: 21987385
intervertebral disc; nucleus pulposus; cartilage; hypoxia; HIF; prolyl hydroxylase
8.  Changes in the cross-sectional area of deep posterior extensor muscles of the cervical spine after anterior decompression and fusion: 10-year follow-up study using MRI 
European Spine Journal  2011;21(2):304-308.
Purpose
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.
Methods
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.
Results
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 mm2 in the first MR study (P = 0.63), and 4,616.7 ± 1,086.0 and 5,036.7 ± 1,105.6 mm2 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 mm2, P = 0.14). The mean change in the cross-sectional area had no significant correlation with clinical symptoms, including neck pain or JOA score.
Conclusions
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.
doi:10.1007/s00586-011-1978-0
PMCID: PMC3265587  PMID: 21858566
Cervical spine; Anterior decompression and fusion; MRI; Posterior extensor muscle
9.  Lumbar spinal stenosis associated with peripheral arterial disease: a prospective multicenter observational study 
Journal of Orthopaedic Science  2012;17(6):673-681.
Background
Intermittent claudication is a common symptom of both lumbar spinal stenosis (LSS) and peripheral arterial disease (PAD) in middle-aged and elderly people. However, the prevalence and clinical characteristics of LSS with PAD (LSSPAD) have not been investigated in a multicenter study. The aim of this study was to investigate the prevalence and clinical characteristics of LSS associated with PAD.
Methods
570 patients diagnosed with LSS using a clinical diagnostic support tool and MRI at 64 facilities were enrolled. We evaluated each patient’s medical history, physical findings, ankle brachial index, Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) score, and the Short Form 36 (SF-36) score. Statistical analyses were performed to compare LSSPAD patients and LSS patients without PAD using the t test, Mann–Whitney’s U test, and multivariate recurrence analysis. p values of <0.05 were considered statistically significant.
Results
The LSSPAD group comprised 38 patients (6.7 %); 20 (3.5 %) had pre-diagnosised PAD while 18 (3.2 %) had undetected PAD. The clinical characteristics of these patients were advanced age, diabetes, and a history of ischemic heart disease and cerebrovascular disorder. 570 patients enrolled, and 448 (78.6 %) of those patients were followed up at three months after enrollment. Pain in buttocks and legs improved less in the LSSPAD group than in the LSS group (p < 0.05). Improvements in the “general health” score in SF-36 were lower in the LSSPAD group than in the LSS group (p < 0.05).
Conclusions
Advanced age, diabetes, and a history of cerebrovascular disorder and ischemic heart disease were associated with LSSPAD. Because LSSPAD patients show less improvement in QOL than patients with LSS but without PAD do, clinicians should consider the coexistence of PAD in LSS patients.
doi:10.1007/s00776-012-0311-z
PMCID: PMC3513595  PMID: 23053583
10.  Cross-sectional area of posterior extensor muscles of the cervical spine in asymptomatic subjects: a 10-year longitudinal magnetic resonance imaging study 
European Spine Journal  2011;20(9):1567-1573.
There has been no prospective study on age-related changes of the extensor muscles of the cervical spine in healthy subjects. This study was conducted to elucidate any association between the changes in cross-sectional area of the extensor muscles of the cervical spine on MRIs and cervical disc degeneration or the development of clinical symptoms. Sixty-two subjects who underwent MR imaging by a 1.5-Tesla machine between 1993 and 1996 as asymptomatic volunteers in a previous study were recruited again 10 years later for this follow-up study. The mean interval between the studies was 11.0 ± 0.7 years. The cross-sectional areas of the multifidus, semispinalis cervicis, semispinalis capitis, and splenius capitis at C3–C4, C4–C5, and C5–C6 intervertebral levels were measured on T2-weighted axial images using Image J 1.42. The mean cross-sectional areas of the deep extensor muscles were 1,396.8 ± 337.6 mm2 at the C3–C4 level, 1,514.7 ± 381.0 mm2 at the C4–C5 level, and 1,542.8 ± 373.5 mm2 at the C5–C6 level in the previous investigation. The cross-sectional areas were 1,498.7 ± 374.4 mm2 at the C3–C4 level, 1,569.9 ± 390.9 mm2 at the C4–C5 level, and 1,599.6 ± 364.3 mm2 at the 10-year follow-up. An increase in the cross-sectional area of the muscles was more frequently observed in subjects in their tens to thirties in the initial study, while a decrease was more frequently observed in those in their forties and older in the initial study. Disc degeneration was not correlated with a change in extensor muscle volume. Development of shoulder stiffness during follow-up was significantly negatively correlated with a change in the cross-sectional area of the deep extensor muscles.
doi:10.1007/s00586-011-1774-x
PMCID: PMC3175907  PMID: 21431426
Extensor muscle; Cervical spine; Longitudinal study; Magnetic resonance imaging (MRI); Asymptomatic subjects
11.  Establishment of a Real-Time, Quantitative, and Reproducible Mouse Model of Staphylococcus Osteomyelitis Using Bioluminescence Imaging 
Infection and Immunity  2012;80(2):733-741.
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.
doi:10.1128/IAI.06166-11
PMCID: PMC3264289  PMID: 22104103
13.  Vertebral derotation in adolescent idiopathic scoliosis causes hypokyphosis of the thoracic spine 
Background
The purpose of this study was to test the hypothesis that direct vertebral derotation by pedicle screws (PS) causes hypokyphosis of the thoracic spine in adolescent idiopathic scoliosis (AIS) patients, using computer simulation.
Methods
Twenty AIS patients with Lenke type 1 or 2 who underwent posterior correction surgeries using PS were included in this study. Simulated corrections of each patient’s scoliosis, as determined by the preoperative CT scan data, were performed on segmented 3D models of the whole spine. Two types of simulated extreme correction were performed: 1) complete coronal correction only (C method) and 2) complete coronal correction with complete derotation of vertebral bodies (C + D method). The kyphosis angle (T5-T12) and vertebral rotation angle at the apex were measured before and after the simulated corrections.
Results
The mean kyphosis angle after the C + D method was significantly smaller than that after the C method (2.7 ± 10.0° vs. 15.0 ± 7.1°, p < 0.01). The mean preoperative apical rotation angle of 15.2 ± 5.5° was completely corrected after the C + D method (0°) and was unchanged after the C method (17.6 ± 4.2°).
Conclusions
In the 3D simulation study, kyphosis was reduced after complete correction of the coronal and rotational deformity, but it was maintained after the coronal-only correction. These results proved the hypothesis that the vertebral derotation obtained by PS causes hypokyphosis of the thoracic spine.
doi:10.1186/1471-2474-13-99
PMCID: PMC3441743  PMID: 22691717
14.  Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization 
The Journal of Experimental Medicine  2011;208(11):2175-2181.
The mobilization of hematopoietic stem cells does not require osteoclasts, which may even have an inhibitory effect.
Hematopoietic stem cells (HSCs) are maintained in a specific bone marrow (BM) niche in cavities formed by osteoclasts. Osteoclast-deficient mice are osteopetrotic and exhibit closed BM cavities. Osteoclast activity is inversely correlated with hematopoietic activity; however, how osteoclasts and the BM cavity potentially regulate hematopoiesis is not well understood. To investigate this question, we evaluated hematopoietic activity in three osteopetrotic mouse models: op/op, c-Fos-deficient, and RANKL (receptor activator of nuclear factor kappa B ligand)-deficient mice. We show that, although osteoclasts and, by consequence, BM cavities are absent in these animals, hematopoietic stem and progenitor cell (HSPC) mobilization after granulocyte colony-stimulating factor injection was comparable or even higher in all three lines compared with wild-type mice. In contrast, osteoprotegerin-deficient mice, which have increased numbers of osteoclasts, showed reduced HSPC mobilization. BM-deficient patients and mice reportedly maintain hematopoiesis in extramedullary spaces, such as spleen; however, splenectomized op/op mice did not show reduced HSPC mobilization. Interestingly, we detected an HSC population in osteopetrotic bone of op/op mice, and pharmacological ablation of osteoclasts in wild-type mice did not inhibit, and even increased, HSPC mobilization. These results suggest that osteoclasts are dispensable for HSC mobilization and may function as negative regulators in the hematopoietic system.
doi:10.1084/jem.20101890
PMCID: PMC3201203  PMID: 22006978
17.  Identification of Nocobactin NA Biosynthetic Gene Clusters in Nocardia farcinica▿ §  
Journal of Bacteriology  2010;193(2):441-448.
We identified the biosynthetic gene clusters of the siderophore nocobactin NA. The nbt clusters, which were discovered as genes highly homologous to the mycobactin biosynthesis genes by the genomic sequencing of Nocardia farcinica IFM 10152, consist of 10 genes separately located at two genomic regions. The gene organization of the nbt clusters and the predicted functions of the nbt genes, particularly the cyclization and epimerization domains, were in good agreement with the chemical structure of nocobactin NA. Disruptions of the nbtA and nbtE genes, respectively, reduced and abolished the productivity of nocobactin NA. The heterologous expression of the nbtS gene revealed that this gene encoded a salicylate synthase. These results indicate that the nbt clusters are responsible for the biosynthesis of nocobactin NA. We also found putative IdeR-binding sequences upstream of the nbtA, -G, -H, -S, and -T genes, whose expression was more than 10-fold higher in the low-iron condition than in the high-iron condition. These results suggest that nbt genes are regulated coordinately by IdeR protein in an iron-dependent manner. The ΔnbtE mutant was found to be impaired in cytotoxicity against J774A.1 cells, suggesting that nocobactin NA production is required for virulence of N. farcinica.
doi:10.1128/JB.00897-10
PMCID: PMC3019813  PMID: 21097631
18.  Long-term surgical outcomes of idiopathic spinal cord herniation 
Journal of Orthopaedic Science  2011;16(4):347-351.
Background
Because of the lack of long-term postoperative follow-up studies of idiopathic spinal cord herniation (ISCH), there is little information about the long-term effectiveness and complications of the dural defect enlargement in patients with ISCH. The purpose of this study is to determine the long-term effectiveness of this procedure.
Methods
Sixteen patients with ISCH were treated surgically by enlargement of the dural defect. The patient’s neurological status and surgical outcome were evaluated by the JOA scores for thoracic myelopathy and the recovery rate (mean follow-up period 9.6 years). Correlations between the surgical outcomes and patients’ age and duration of disease were assessed retrospectively. The patients were also divided into two groups based on the location of the dural defect: the ventro-lateral (VL) group and the ventral (V) group. The difference in the duration of disease, preoperative JOA score, and the recovery rate were compared between the two groups.
Results
There was no recurrence of ISCH after surgery. The mean recovery rate was 42.6%. There was a significant correlation between the patient’s age and the recovery rate, and between the duration of disease and the recovery rate. The median recovery rate was significantly lower in the V group than in the VL group. There were no complications related to CSF leakage after surgery.
Conclusions
Long-term surgical outcomes of enlargement of the dural defect for ISCH were stable and favorable without recurrences or any complications. This procedure should be considered for patients with ISCH before their neurological deficit worsens, especially for the patients in whom the dural defect is located at the ventral part of the dural canal.
doi:10.1007/s00776-011-0065-z
PMCID: PMC3140945  PMID: 21544598
19.  Kyphectomy for severe kyphosis with pyogenic spondylitis associated with myelomeningocele: a case report 
Scoliosis  2011;6:5.
A 32-year-old woman was referred to our hospital for a refractory ulcer on her back. She had a history of myelomeningocele with spina bifida that was treated surgically at birth. The ulcer was located at the apex of the kyphosis. An X-ray film revealed a kyphosis of 154° between L1 and 3 and a scoliosis of 60° between T11 and L5. Computed tomography, magnetic resonance imaging and laboratory data indicated the presence of a pyogenic spondylitis at L2/3. To correct the kyphosis and remove the infected vertebrae together with the skin ulcer, kyphectomy was performed. Pedicle screws were inserted from T8 to T12 and from L4 to S1. The dural sac was transected and ligated at L2, followed by total kyphectomy of the L1-L3 vertebrae. The spinal column was reconstructed by approximating the ventral wall of the T12 vertebral body and the cranial endplate of the L4 vertebra. Postoperatively, the kyphosis was corrected to 61° and the scoliosis was corrected to 22°. In the present case, we treated the skin ulcer and pyogenic spondylitis successfully by kyphectomy, thereby, preventing recurrence of the ulcer and infection, and simultaneously obtaining sufficient correction of the spinal deformity.
doi:10.1186/1748-7161-6-5
PMCID: PMC3080349  PMID: 21477271
20.  Severe progressive scoliosis due to huge subcutaneous cavernous hemangioma: A case report 
Scoliosis  2011;6:3.
Cavernous hemangioma consists mainly of congenital vascular malformations present before birth and gradually increasing in size with skeletal growth. A small number of patients with cavernous hemangioma develop scoliosis, and surgical treatment for the scoliosis in such cases has not been reported to date. Here we report a 12-year-old male patient with severe progressive scoliosis due to a huge subcutaneous cavernous hemangioma, who underwent posterior correction and fusion surgery. Upon referral to our department, radiographs revealed a scoliosis of 85° at T6-L1 and a kyphosis of 58° at T4-T10. CT and MR images revealed a huge hemangioma extending from the subcutaneous region to the paraspinal muscles and the retroperitoneal space and invading the spinal canal. Posterior correction and fusion surgery using pedicle screws between T2 and L3 were performed. Massive hemorrhage from the hemangioma occurred during the surgery, with intraoperative blood loss reaching 2800 ml. The scoliosis was corrected to 59°, and the kyphosis to 45° after surgery. Seven hours after surgery, the patient suffered from hypovolemic shock and disseminated intravascular coagulation due to postoperative hemorrhage from the hemangioma. The patient developed sensory and conduction aphasia caused by cerebral hypoxia during the shock on the day of the surgery. At present, two years after the surgery, although the patient has completely recovered from the aphasia. This case illustrates that, in correction surgery for scoliosis due to huge subcutaneous cavernous hemangioma, intraoperative and postoperative intensive care for hemodynamics should be performed, since massive hemorrhage can occur during the postoperative period as well as the intraoperative period.
doi:10.1186/1748-7161-6-3
PMCID: PMC3065437  PMID: 21414205
21.  Does the sagittal alignment of the cervical spine have an impact on disk degeneration? Minimum 10-year follow-up of asymptomatic volunteers 
European Spine Journal  2009;18(11):1644-1651.
There have been few studies that investigated and clarified the relationships between progression of degenerative changes and sagittal alignment of the cervical spine. The objective of the study was to longitudinally evaluate the relationships among progression of degenerative changes of the cervical spine with age, the development of clinical symptoms and sagittal alignment of the cervical spine in healthy subjects. Out of 497 symptom-free volunteers who underwent MRI and plain radiography of the cervical spine between 1994 and 1996, 113 subjects (45 males and 68 females) who responded to our contacts were enrolled. All subjects underwent another MRI at an average of 11.3 years after the initial study. Their mean age at the time of the initial imaging was 36.6 ± 14.5 years (11–65 years). The items evaluated on MRI were (1) decrease in signal intensity of the intervertebral disks, (2) posterior disk protrusion, and (3) disk space narrowing. Each item was evaluated using a numerical grading system. The subjects were divided into four groups according to the age and sagittal alignment of the cervical spine, i.e., subjects under or over the age of 40 years, and subjects with the lordosis or non-lordosis type of sagittal alignment of the cervical spine. During the 10-year period, progression of decrease in signal intensity of the disk, posterior disk protrusion, and disk space narrowing were recognized in 64.6, 65.5, and 28.3% of the subjects, respectively. Progression of posterior disk protrusion was significantly more frequent in subjects over 40 years of age with non-lordosis type of sagittal alignment. Logistic regression analysis revealed that stiff shoulder was closely correlated with females (P = 0.001), and that numbness of the upper extremity was closely correlated with age (P = 0.030) and male (P = 0.038). However, no significant correlation between the sagittal alignment of the cervical spine and clinical symptoms was detected. Sagittal alignment of the cervical spine had some impact on the progression of degenerative changes of the cervical spine with aging; however, it had no correlation with the occurrence of future clinical symptoms.
doi:10.1007/s00586-009-1095-5
PMCID: PMC2899405  PMID: 19609784
Cervical spine; Magnetic resonance imaging (MRI); Sagittal alignment; Aging; Asymptomatic volunteers
22.  The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis 
Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte–induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets ‘osteoclastic’ molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1–Bcl6–osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies.
doi:10.1084/jem.20091957
PMCID: PMC2856022  PMID: 20368579
23.  JOA Back Pain Evaluation Questionnaire: initial report 
Journal of Orthopaedic Science  2007;12(5):443-450.
Background
There is no widely accepted objective evaluation for lumbar spine disorders. New outcome measures should be patient-oriented and should measure symptoms and self-reported functional status in multiple dimensions. The aim of this study was to identify items to be included in the disease-specific quality of life (QOL) questionnaire for the assessments of patients with lumbar spine disorders.
Methods
The draft of the QOL questionnaire that consisted of a total of 60 items, including 24 items derived from the Japanese version of the Roland Morris Disability Questionnaire (RDQ) and 36 items derived from the Japanese version of Short Form 36 (SF-36), were administered to patients and controls. After obtaining written informed consent, the following data were collected from the patient group (n = 328) and the control group (n = 213): (1) background characteristics, including age, diagnosis, Japanese Orthopaedic Association (JOA) score, and finger to floor distance; (2) responses to the questionnaire; (3) the identification rate by discrimination analysis to select the candidates for adoption and by adopting explanatory variables. The items to be excluded were determined by examining the explanatory variables, which were selected after the discrimination analysis, by setting the candidate to-be-excluded items as an objective variable.
Results
Based on the distribution of the responses, two items, RDQ-15 and RDQ-19, were excluded. From the results of the correlation coefficient calculation for each question in the patient group, 33 items were excluded and 27 candidate items were adopted. Based on the adoption explanatory variable used in the discrimination analysis, 25 of the 27 candidate items for adoption were accepted.
Conclusions
This study identified the 25 specific questionnaire items that should be included in the questionnaire to evaluate QOL of patients with various lumbar spine disorders.
doi:10.1007/s00776-007-1162-x
PMCID: PMC2782112  PMID: 17909929
24.  Japanese Orthopaedic Association Back Pain Evaluation Questionnaire. Part 2. Verification of its reliability 
Journal of Orthopaedic Science  2007;12(6):526-532.
Background
The project to develop a new Japanese Orthopaedic Association (JOA) score rating system for low back disorders, the JOA Back Pain Evaluation Questionnaire (JOABPEQ), is currently in progress. Part 1 of the study selected 25 “candidateȝ items for use on the JOABPEQ. The purpose of this current Part 2 of the study was to verify the reliability of the questionnaire.
Methods
A total of 161 patients with low-back disorders of any type participated in the study. Each patient was interviewed twice at an interval of 2 weeks using the same questionnaire. The reliability of the questionnaire was evaluated by determining the extension of the kappa and weighted kappa coefficients.
Results
Both kappa and weighted kappa were more than 0.50 for all but one item, which was 0.48. The lower 95% confidence interval exceeded 0.4 in all but two items, which was 0.39. This implied that the test–retest reliability of JOABPEQ was acceptable as a measure of outcome.
Conclusions
The tentative questionnaire of the JOABPEQ with 25 items was confirmed to be reliable enough to describe the quality of life of patients who suffer low back disorders.
doi:10.1007/s00776-007-1168-4
PMCID: PMC2780682  PMID: 18040634
25.  Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire: Part 3. Determination of reliability 
Journal of Orthopaedic Science  2007;12(4):321-326.
Background
The manner of measuring the outcome of cervical myelopathy must be patient-oriented and have sufficient reliability and validity. The current Japanese Orthopaedic Association (JOA) scoring system for cervical myelopathy is widely used but has not met this requirement. The first- and second-round surveys established 24 items for inclusion on a new questionnaire for cervical myelopathy. The purpose of this study (the third-round survey A) was to confirm the reproducibility of patient responses to the selected questions.
Methods
A total of 201 patients with cervical myelopathy and with no change of symptoms between the two interviews were included. Each patient was interviewed twice using the same questionnaire at an interval of 4 weeks. The reliability of the questionnaire was evaluated by determining the extension of the weighted kappa coefficients.
Results
The weighted kappa coefficient for each item was >0.4, confirming that the test–retest reliability was acceptable.
Conclusions
The newly developed JOA Cervical Myelopathy Evaluation Questionnaire was proven to have sufficient reliability.
doi:10.1007/s00776-007-1131-4
PMCID: PMC2779404  PMID: 17657550

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