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1.  C1 posterior arch screw as an auxiliary anchor in posterior reconstruction for atlantoaxial dislocation associated with type II odontoid fracture: a case report and review of the literature 
SpringerPlus  2014;3:672.
Although pedicle or lateral mass screws are usually chosen to fix atlantoaxial (C1-C2) instability, there is an increased risk for vertebral artery (VA) injury when used in patients with bone or arterial anomalies or osteoporotic bone. Here we report the C1 posterior arch screw as a new technique for upper cervical fixation.
Case description
A 90-year-old man complained of upper cervical pain after falling in his house. The initial computed tomography (CT) scan showed C1-C2 posterior dislocation with a type II odontoid fracture. The patient underwent C2 fracture reduction and posterior C1-C2 fixation. On the right side of C1, because lateral mass screw placement could cause injury to the dominant VA considering a risk in oldest-old osteoporotic patients, a posterior arch screw was chosen instead as an auxiliary anchor. An intralaminar screw was placed on the right side of C2 because a high-riding VA was observed. A lateral mass screw and a pars interarticularis screw were placed on the left side of C1 and C2, respectively. Ten months later, the odontoid fracture had healed, with normal anatomical alignment. Although the patient experienced slight weakness when spreading his bilateral fingers, his overall condition was good.
Discussion and evaluation
We have presented a novel technique using C1 posterior arch screws for the fixation of a C1-C2 dislocation. Such a screw is an alternative to the C1 lateral mass screw in patients who are at risk for a VA injury because of anomalous bone and arterial structures or poor bone quality.
Although there have been few comparable studies, and the long-term outcome is unknown, fixation with a posterior arch screw could be a beneficial choice for surgeries involving the upper cervical region.
PMCID: PMC4234742  PMID: 25485206
Posterior arch screw; Atlantoaxial dislocation; Odontoid fracture; Vertebral artery injury
2.  The Vitamin D Analogue ED71 but Not 1,25(OH)2D3 Targets HIF1α Protein in Osteoclasts 
PLoS ONE  2014;9(11):e111845.
Although both an active form of the vitamin D metabolite, 1,25(OH)2D3, and the vitamin D analogue, ED71 have been used to treat osteoporosis, anti-bone resorbing activity is reportedly seen only in ED71- but not in 1,25(OH)2D3 -treated patients. In addition, how ED71 inhibits osteoclast activity in patients has not been fully characterized. Recently, HIF1α expression in osteoclasts was demonstrated to be required for development of post-menopausal osteoporosis. Here we show that ED71 but not 1,25(OH)2D3, suppress HIF1α protein expression in osteoclasts in vitro. We found that 1,25(OH)2D3 or ED71 function in osteoclasts requires the vitamin D receptor (VDR). ED71 was significantly less effective in inhibiting M-CSF and RANKL-stimulated osteoclastogenesis than was 1,25(OH)2D3 in vitro. Downregulation of c-Fos protein and induction of Ifnβ mRNA in osteoclasts, both of which reportedly block osteoclastogenesis induced by 1,25(OH)2D3 in vitro, were both significantly higher following treatment with 1,25(OH)2D3 than with ED71. Thus, suppression of HIF1α protein activity in osteoclasts in vitro, which is more efficiently achieved by ED71 rather than by 1,25(OH)2D3, could be a reliable read-out in either developing or screening reagents targeting osteoporosis.
PMCID: PMC4222951  PMID: 25375896
3.  Postoperative shoulder imbalance in Lenke Type 1A adolescent idiopathic scoliosis and related factors 
The purpose of this study was to investigate the occurrence and factors associated with postoperative shoulder imbalance (PSI) in Lenke type 1A curve.
This study included 106 patients with Lenke Type 1A curve who were followed up more than two years after posterior correction surgery. Pedicle screw (PS) constructs were used in 84 patients, and hybrid constructs in 22. The upper instrumented vertebra was rostral to the upper-end vertebra (UEV) in 70 patients, at UEV in 26, and below UEV in 10. The clavicle angle and T1 tilt angle were measured as PSI indicators, and correlations between radiographic parameters of shoulder balance and other radiographic parameters and associations between PSI and clinical parameters were investigated. For statistical analyses, paired and unpaired t-tests were used.
The mean Cobb angles of the main and proximal thoracic curves were 54.6 ± 9.5 and 26.7 ± 7.9 degrees before surgery, 14.5 ± 7.5, and 14.9 ± 7.1 at follow-up. Clavicle angle and T1 tilt angle were −2.9 ± 2.8 and −2.6 ± 6.3 before surgery, 2.4 ± 2.8 and 4.4 ± 4.3 immediately after surgery, and 1.8 ± 2.1 and 3.4 ± 5.5 at follow-up. Twenty patients developed distal adding-on. Clavicle angle at follow-up correlated weakly but significantly with preoperative clavicle angle (r = 0.34, p = 0.001) and with the correction rates of the main thoracic curve (r = 0.34, p = 0.001); it correlated negatively with the proximal curve spontaneous correction rate (r = −0.21, p = 0.034). The clavicle angle at follow-up was significantly larger in patients with PS-only constructs (PS 2.1 degrees vs. hybrid 0.9, p = 0.02), and tended to be smaller in patients with distal adding-on (adding-on 1.1 vs. non adding-on 2.0, p = 0.09).
PSI was more common with better correction of the main curve (using PS constructs), in patients with a larger preoperative clavicle angle, and with a larger and more rigid proximal curve. Distal adding-on may compensate for PSI.
PMCID: PMC4230354  PMID: 25373492
Lenke type 1A; Postoperative shoulder imbalance; Adolescent idiopathic scoliosis
4.  Spinal coronal profiles and proximal femur bone mineral density in adolescent idiopathic scoliosis 
European Spine Journal  2013;22(11):2433-2437.
Although the occurrence and progression of AIS has been linked to low bone mineral density (BMD), the relationships between spinal curvature and bilateral differences in proximal femur BMD are controversial. Few correlation studies have stratified patients by curve type. The purpose of this study was to evaluate the relationships between spinal coronal profile and bilateral differences in proximal femur BMD in patients with adolescent idiopathic scoliosis (AIS).
This study included 67 patients with AIS who underwent posterior correction and fusion surgery between January 2009 and October 2011. The mean age at the time of surgery was 17.4 ± 4.1 years. Bilateral proximal femur BMD was measured before surgery by dual-energy X-ray absorptiometry. We compared the proximal femur BMDs by determining the bilateral BMD ratio (left proximal femur BMD divided by that of the right). We evaluated correlations between coronal parameters, obtained from preoperative radiographs, and the BMD ratio using Pearson’s correlation analysis.
Patients with Lenke type 1 curve (48; all with a right convex curve) had a mean bilateral proximal femur BMD ratio of 1.00 ± 0.04. Patients with Lenke type 5 curve (19; all with a left convex curve) had a mean bilateral proximal femur BMD ratio of 0.94 ± 0.04, indicating that the BMD in the proximal femur on the right side (concave) was greater than that in the left (convex). Coronal balance was significantly correlated with the BMD ratio in both the Lenke type 1 and type 5 groups, with a correlation coefficient of 0.46 and 0.50, respectively.
The bilateral proximal femur BMD ratio was significantly correlated with the coronal balance in AIS patients. When the C7 plumb line was shifted toward one side, the BMD was greater in the contralateral proximal femur.
PMCID: PMC3886500  PMID: 23764767
Adolescent idiopathic scoliosis; Bone mineral density; Proximal femur
5.  A Novel Mouse Model of Soft-Tissue Infection Using Bioluminescence Imaging Allows Noninvasive, Real-Time Monitoring of Bacterial Growth 
PLoS ONE  2014;9(9):e106367.
Musculoskeletal infections, including surgical-site and implant-associated infections, often cause progressive inflammation and destroy areas of the soft tissue. Treating infections, especially those caused by multi-antibiotic resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) remains a challenge. Although there are a few animal models that enable the quantitative evaluation of infection in soft tissues, these models are not always reproducible or sustainable. Here, we successfully established a real-time, in vivo, quantitative mouse model of soft-tissue infection in the superficial gluteus muscle (SGM) using bioluminescence imaging. A bioluminescent strain of MRSA was inoculated into the SGM of BALB/c adult male mice, followed by sequential measurement of bacterial photon intensity and serological and histological analyses of the mice. The mean photon intensity in the mice peaked immediately after inoculation and remained stable until day 28. The serum levels of interleukin-6, interleukin-1 and C-reactive protein at 12 hours after inoculation were significantly higher than those prior to inoculation, and the C-reactive protein remained significantly elevated until day 21. Histological analyses showed marked neutrophil infiltration and abscesses containing necrotic and fibrous tissues in the SGM. With this SGM mouse model, we successfully visualized and quantified stable bacterial growth over an extended period of time with bioluminescence imaging, which allowed us to monitor the process of infection without euthanizing the experimental animals. This model is applicable to in vivo evaluations of the long-term efficacy of novel antibiotics or antibacterial implants.
PMCID: PMC4153648  PMID: 25184249
6.  Surgeons' Exposure to Radiation in Single- and Multi-Level Minimally Invasive Transforaminal Lumbar Interbody Fusion; A Prospective Study 
PLoS ONE  2014;9(4):e95233.
Although minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) has widely been developed in patients with lumbar diseases, surgeons risk exposure to fluoroscopic radiation. However, to date, there is no studies quantifying the effective dose during MIS-TLIF procedure, and the radiation dose distribution is still unclear. In this study, the surgeons' radiation doses at 5 places on the bodies were measured and the effective doses were assessed during 31 consecutive 1- to 3-level MIS-TLIF surgeries. The operating surgeon, assisting surgeon, and radiological technologist wore thermoluminescent dosimeter on the unshielded thyroid, chest, genitals, right middle finger, and on the chest beneath a lead apron. The doses at the lens and the effective doses were also calculated. Mean fluoroscopy times were 38.7, 53.1, and 58.5 seconds for 1, 2, or 3 fusion levels, respectively. The operating surgeon's mean exposures at the lens, thyroid, chest, genitals, finger, and the chest beneath the shield, respectively, were 0.07, 0.07, 0.09, 0.14, 0.32, and 0.05 mSv in 1-level MIS-TLIF; 0.07, 0.08, 0.09, 0.18, 0.34, and 0.05 mSv in 2-level; 0.08, 0.09, 0.14, 0.15, 0.36, and 0.06 mSv in 3-level; and 0.07, 0.08, 0.10, 0.15, 0.33, and 0.05 mSv in all cases. Mean dose at the operating surgeon's right finger was significantly higher than other measurements parts (P<0.001). The operating surgeon's effective doses (0.06, 0.06, and 0.07 mSv for 1, 2, and 3 fusion levels) were low, and didn't differ significantly from those of the assisting surgeon or radiological technologist. Revision MIS-TLIF was not associated with higher surgeons' radiation doses compared to primary MIS-TLIF. There were significantly higher surgeons' radiation doses in over-weight than in normal-weight patients. The surgeons' radiation exposure during MIS-TLIF was within the safe level by the International Commission on Radiological Protection's guidelines. The accumulated radiation exposure, especially to surgeon's hands, should be carefully monitored.
PMCID: PMC3988176  PMID: 24736321
7.  Tandem age-related lumbar and cervical intervertebral disc changes in asymptomatic subjects 
European Spine Journal  2012;22(4):708-713.
To investigate the frequency of tandem lumbar and cervical intervertebral disc degeneration in asymptomatic subjects.
We evaluated magnetic resonance imaging (MRI) results from 94 volunteers (48 men and 46 women; mean age 48 years) for age-related intervertebral disc degeneration in the lumbar and cervical spine.
MRI indicated degenerative changes in the lumbar spine in 79 subjects (84 %), with decreased disc signal intensity in 74.5 %, posterior disc protrusion in 78.7 %, anterior compression of the dura in 81.9 %, disc space narrowing in 21.3 %, and spinal canal stenosis in 12.8 %. These findings were more common in older subjects at caudal levels. MRI showed degenerative changes in both the lumbar and cervical spine in 78.7 % of the volunteers.
Degenerative findings in both the lumbar and cervical spine, suggesting tandem disc degeneration, was common in asymptomatic subjects. These results provide normative data for evaluating patients with degenerative lumbar and cervical disc diseases.
PMCID: PMC3631032  PMID: 22990606
MRI; Disc degeneration; Lumbar spine; Cervical spine; Asymptomatic subjects
8.  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.
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.
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.
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.
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.
PMCID: PMC3929037  PMID: 24317702
9.  Morphometric analysis of the lumbar intervertebral foramen in patients with degenerative lumbar scoliosis by multidetector-row computed tomography 
European Spine Journal  2012;21(12):2594-2602.
How the lumbar neural foramina are affected by segmental deformities in patients in whom degenerative lumbar scoliosis (DLS) is unknown. Here, we used multidetector-row computed tomography (MDCT) to measure the morphology of the foramina in three dimensions, which allowed us to elucidate the relationships between foraminal morphology and segmental deformities in DLS.
In 77 DLS patients (mean age, 69.4) and 19 controls (mean age, 69), the foraminal height (FH), foraminal width (FW), posterior disc height (PDH), interval between the pedicle and superior articular process (P-SAP), and cross-sectional foraminal area (FA) were measured on reconstructed MDCT data, using image-editing software, at the entrance, minimum-area point, and exit of each foramen. The parameters of segmental deformity included the intervertebral wedging angle and anteroposterior and lateral translation rate, measured on radiographs, and the vertebral rotation angle, measured using reconstructed MDCT images.
The FH, PDH, P-SAP, and FA were smaller at lower lumbar levels and on the concave side of intervertebral wedging (p < 0.05). In the DLS patients, the FH, P-SAP, and FA were significantly smaller than for the control group at all three foraminal locations and every lumbar level (p < 0.05). Intervertebral wedging strongly decreased the FA of the concave side (p < 0.05). Anteroposterior translation caused the greatest reduction in P-SAP (p < 0.05). Vertebral rotation decreased the P-SAP and FA at the minimum-area point on the same side as the rotation (p < 0.05).
The new analysis method proposed here is useful for understanding the pathomechanisms of foraminal stenosis in DLS patients.
PMCID: PMC3508233  PMID: 22743646
Degenerative lumbar scoliosis; Segmental deformity; Intervertebral foramina; Multidetector-row computed tomography
10.  FOXC2 Mutations in Familial and Sporadic Spinal Extradural Arachnoid Cyst 
PLoS ONE  2013;8(11):e80548.
Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater. Most cases are sporadic; however, three familial SEDAC cases have been reported, suggesting genetic etiological factors. All familial cases are associated with lymphedema-distichiasis syndrome (LDS), whose causal gene is FOXC2. However, FOXC2 mutation analysis has been performed in only 1 family, and no mutation analysis has been performed on sporadic (non-familial) SEDACs. We recruited 17 SEDAC subjects consisting of 2 familial and 7 sporadic cases and examined FOXC2 mutations by Sanger sequencing and structural abnormalities by TaqMan copy number assay. We identified 2 novel FOXC2 mutations in 2 familial cases. Incomplete LDS penetrance was noted in both families. Four subjects presented with SEDACs only. Thus, SEDAC caused by the heterozygous FOXC2 loss-of-function mutation should be considered a feature of LDS, although it often manifests as the sole symptom. Seven sporadic SEDAC subjects had no FOXC2 mutations, no symptoms of LDS, and showed differing clinical characteristics from those who had FOXC2 mutations, suggesting that other gene(s) besides FOXC2 are likely to be involved in SEDAC.
PMCID: PMC3838418  PMID: 24278289
11.  Comparative study of spinopelvic sagittal alignment between patients with and without degenerative spondylolisthesis 
European Spine Journal  2012;21(11):2181-2187.
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.
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).
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.
PMCID: PMC3481103  PMID: 22639298
Spinopelvic sagittal alignment; Pelvic incidence; Lumbar spinal canal stenosis; Degenerative spondylolisthesis; Percentage of vertebral slip
12.  Updates on surgical treatments for pediatric scoliosis 
Scoliosis in children poses serious problems including respiratory problems, trunk imbalance, and depression, as well as detracting from the child’s appearance. Scoliosis can also contribute to back pain later in life. Advanced surgical techniques allow for good correction and maintenance of progressive curves, and growth-sparing treatments are now available for patients with early-onset scoliosis (EOS). Posterior corrective surgeries using pedicle screw (PS) constructs, which allow curves to be corrected in three dimensions, has become the most popular surgical treatment for scoliosis. Several navigation systems and probes have been developed to aid in accurate PS placement. For thoracolumbar and lumbar curves, anterior surgery remains the method of choice. Growth-sparing techniques for treating EOS include growing rods, the Shilla method, anterior stapling, and vertical expandable prosthetic titanium rib, which was originally designed to treat thoracic insufficiency syndrome. However, these advanced surgical techniques do not always offer a perfect solution for pediatric scoliosis, and they are associated with complications such as infections and problems with instrumentation. Surgeons have developed several techniques in efforts to address these complications. We here review historic and recent advances in the surgical treatment of scoliosis in children, the problems associated with various techniques, and the challenges that remain to be overcome.
PMCID: PMC3929026  PMID: 24132791
13.  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.
PMCID: PMC3809787  PMID: 24216480
14.  Increase in spinal longitudinal length by correction surgery for adolescent idiopathic scoliosis 
European Spine Journal  2012;21(10):1920-1925.
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.
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.
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.
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.
PMCID: PMC3463697  PMID: 22310882
Adolescent idiopathic scoliosis; Posterior correction with fusion surgery; Anterior correction with fusion surgery; Spinal length
15.  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.
PMCID: PMC3762929  PMID: 24023777
16.  Optimal treatment for Spinal Cord Injury associated with cervical canal Stenosis (OSCIS): a study protocol for a randomized controlled trial comparing early versus delayed surgery 
Trials  2013;14:245.
The optimal management of acute cervical spinal cord injury (SCI) associated with preexisting canal stenosis remains to be established. The objective of this study is to examine whether early surgical decompression (within 24 hours after admission) would result in greater improvement in motor function compared with delayed surgery (later than two weeks) in cervical SCI patients presenting with canal stenosis, but without bony injury.
OSCIS is a randomized, controlled, parallel-group, assessor-blinded, multicenter trial. We will recruit 100 cervical SCI patients who are admitted within 48 hours of injury (aged 20 to 79 years; without fractures or dislocations; American Spinal Injury Association (ASIA) grade C; preexisting spinal canal stenosis). Patients will be enrolled from 36 participating hospitals across Japan and randomly allocated in a 1:1 ratio to either early surgical decompression (within 24 hours after admission) or delayed surgery following at least two weeks of conservative treatment. The primary outcomes include: 1) the change from baseline to one year in the ASIA motor score; 2) the total score of the Spinal Cord Independence Measure and 3) the proportion of patients who are able to walk without human assistance. The secondary outcomes are: 1) the health-related quality of life as measured by the Medical Outcomes Study Short Form 36 and the EuroQol 5 Dimension; 2) the Neuropathic Pain Symptom Inventory and 3) the walking status as evaluated with the Walking Index for Spinal Cord Injury II. The analysis will be on an intention-to-treat basis. The primary analysis will be a comparison of the primary and secondary outcomes one year after the injury.
The results of this study will provide evidence of the potential benefit of early surgical decompression compared to the current ‘watch and wait’ strategy.
Trial registration
UMIN000006780; NCT01485458
PMCID: PMC3750661  PMID: 23924165
Spinal cord injury; Surgery; Timing; Canal stenosis; Ossification of the posterior longitudinal ligament; Spondylosis; Spinal fracture; Bone injury
17.  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.
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).
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.
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.
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.
PMCID: PMC3366141  PMID: 22438165
Adolescent idiopathic scoliosis; Apical vertebral rotation; Correction loss; Coronal correction
18.  Acute respiratory failure due to hemothorax after posterior correction surgery for adolescent idiopathic scoliosis: a case report 
Although posterior correction and fusion surgery using pedicle screws carries the risk of vascular injury, a massive postoperative hemothorax in a patient with adolescent idiopathic scoliosis (AIS) is quite rare. We here report a case of a 12-year-old girl with AIS who developed a massive postoperative hemothorax.
Case presentation
The patient had a double thoracic curve with Cobb angles of 63° at T2-7 and 54° at T7-12. Posterior correction and fusion surgery was performed using a segmental pedicle screw construct placed between T2 and T12. Although the patient's respiration was stable during the surgery, 20 minutes after removing the trachea tube, the patient’s pulse oximetry oxygen saturation suddenly decreased to 80%. A contrast CT scan showed a massive left hemothorax, and a drainage tube was quickly inserted into the chest. The patient was re-intubated and a positive end-expiratory pressure of 5 cmH2O applied, which successfully stopped the bleeding. The patient was extubated 4 days after surgery without incident. Based on contrast CT scans, it was suspected that the hemothorax was caused by damage to the intercostal arteries or branches during pedicle probing on the concave side of the upper thoracic curve. Extensive post-surgical blood tests, echograms, and CT and MRI radiographs did not detect coagulopathy, pulmonary or vascular malformation, or any other possible causative factors.
This case underscores the potential risk of massive hemothorax related to thoracic pedicle screw placement, and illustrates that for this serious complication, respiratory management with positive airway pressure, along with a chest drainage tube, can be an effective treatment option.
PMCID: PMC3636110  PMID: 23577922
19.  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.
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 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.
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.
PMCID: PMC3265587  PMID: 21858566
Cervical spine; Anterior decompression and fusion; MRI; Posterior extensor muscle
20.  Systemic Overexpression of TNFα-converting Enzyme Does Not Lead to Enhanced Shedding Activity In Vivo 
PLoS ONE  2013;8(1):e54412.
TNFα-converting enzyme (TACE/ADAM17) is a membrane-bound proteolytic enzyme with a diverse set of target molecules. Most importantly, TACE is indispensable for the release and activation of pro-TNFα and the ligands for epidermal growth factor receptor in vivo. Previous studies suggested that the overproduction of TACE is causally related to the pathogenesis of inflammatory diseases and cancers. To test this hypothesis, we generated a transgenic line in which the transcription of exogenous Tace is driven by a CAG promoter. The Tace-transgenic mice were viable and exhibited no overt defects, and the quantitative RT-PCR and Western blot analyses confirmed that the transgenically introduced Tace gene was highly expressed in all of the tissues examined. The Tace-transgenic mice were further crossed with Tace−/+ mice to abrogate the endogenous TACE expression, and the Tace-transgenic mice lacking endogenous Tace gene were also viable without any apparent defects. Furthermore, there was no difference in the serum TNFα levels after lipopolysaccharide injection between the transgenic mice and control littermates. These observations indicate that TACE activity is not necessarily dependent on transcriptional regulation and that excess TACE does not necessarily result in aberrant proteolytic activity in vivo.
PMCID: PMC3544834  PMID: 23342154
21.  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.
PMCID: PMC3175907  PMID: 21431426
Extensor muscle; Cervical spine; Longitudinal study; Magnetic resonance imaging (MRI); Asymptomatic subjects
22.  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.
PMCID: PMC3264289  PMID: 22104103
23.  Vertebral derotation in adolescent idiopathic scoliosis causes hypokyphosis of the thoracic spine 
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.
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.
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°).
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.
PMCID: PMC3441743  PMID: 22691717
24.  Disc degeneration of cervical spine on MRI in patients with lumbar disc herniation: comparison study with asymptomatic volunteers 
European Spine Journal  2010;20(4):585-591.
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.
PMCID: PMC3065617  PMID: 21127918
Lumbar disc herniation; Asymptomatic volunteers; MRI; Cervical spine; Disc degeneration
25.  Long-term surgical outcomes of idiopathic spinal cord herniation 
Journal of Orthopaedic Science  2011;16(4):347-351.
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.
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.
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.
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.
PMCID: PMC3140945  PMID: 21544598

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