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1.  Tandem age-related lumbar and cervical intervertebral disc changes in asymptomatic subjects 
European Spine Journal  2012;22(4):708-713.
Purpose
To investigate the frequency of tandem lumbar and cervical intervertebral disc degeneration in asymptomatic subjects.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s00586-012-2500-z
PMCID: PMC3631032  PMID: 22990606
MRI; Disc degeneration; Lumbar spine; Cervical spine; Asymptomatic subjects
2.  Inflammatory cascades mediate synapse elimination in spinal cord compression 
Background
Cervical compressive myelopathy (CCM) is caused by chronic spinal cord compression due to spondylosis, a degenerative disc disease, and ossification of the ligaments. Tip-toe walking Yoshimura (twy) mice are reported to be an ideal animal model for CCM-related neuronal dysfunction, because they develop spontaneous spinal cord compression without any artificial manipulation. Previous histological studies showed that neurons are lost due to apoptosis in CCM, but the mechanism underlying this neurodegeneration was not fully elucidated. The purpose of this study was to investigate the pathophysiology of CCM by evaluating the global gene expression of the compressed spinal cord and comparing the transcriptome analysis with the physical and histological findings in twy mice.
Methods
Twenty-week-old twy mice were divided into two groups according to the magnetic resonance imaging (MRI) findings: a severe compression (S) group and a mild compression (M) group. The transcriptome was analyzed by microarray and RT-PCR. The cellular pathophysiology was examined by immunohistological analysis and immuno-electron microscopy. Motor function was assessed by Rotarod treadmill latency and stride-length tests.
Results
Severe cervical calcification caused spinal canal stenosis and low functional capacity in twy mice. The microarray analysis revealed 215 genes that showed significantly different expression levels between the S and the M groups. Pathway analysis revealed that genes expressed at higher levels in the S group were enriched for terms related to the regulation of inflammation in the compressed spinal cord. M1 macrophage-dominant inflammation was present in the S group, and cysteine-rich protein 61 (Cyr61), an inducer of M1 macrophages, was markedly upregulated in these spinal cords. Furthermore, C1q, which initiates the classical complement cascade, was more upregulated in the S group than in the M group. The confocal and electron microscopy observations indicated that classically activated microglia/macrophages had migrated to the compressed spinal cord and eliminated synaptic terminals.
Conclusions
We revealed the detailed pathophysiology of the inflammatory response in an animal model of chronic spinal cord compression. Our findings suggest that complement-mediated synapse elimination is a central mechanism underlying the neurodegeneration in CCM.
doi:10.1186/1742-2094-11-40
PMCID: PMC3975877  PMID: 24589419
cervical compressive myelopathy; tip-toe walking Yoshimura mice; complement activation classical pathway; synapse elimination
3.  Prevalence and characteristics of chronic musculoskeletal pain in Japan: A second survey of people with or without chronic pain 
Abstract
Background
An epidemiological survey conducted in Japan in fiscal year 2010 revealed a high prevalence of chronic musculoskeletal pain, low patient satisfaction with treatment, a high incidence of protracted treatment lasting a year or more, and reduced quality of life. To improve the current system for treating chronic musculoskeletal pain, it is important to identify risk factors, including patient characteristics, for developing chronic pain. Thus, we sought to determine the incidence of new chronic pain in the Japanese population, as well as the persistence rate, associated factors, and current state of treatment of chronic pain, by repeating a postal survey in a nationwide representative sample group first surveyed in 2010.
Methods
Among 11,507 participants in the 2010 epidemiological survey, 1,717 reported chronic pain and 6,283 reported no chronic pain. A repeat questionnaire, mailed to subjects in these 2 groups in fiscal year 2011, received replies from 85 % of those who reported pain and 76 % of those without pain in 2010.
Results
The incidence of new chronic pain was 11.1 %. Risk factors for developing chronic pain included working in a professional, managerial, or clerical/specialist occupation, being female, having a BMI ≥25; currently using alcohol or cigarettes; and having completed an education level of vocational school or higher. Persistent chronic pain was reported by 45.2 % of respondents. Those with severe (VAS score ≥7) and constant lower-back pain lasting more than 5 years had the highest risk of the pain persisting. More than 80 % respondents with persistent chronic pain had a history of treatment, and while about 30 % were still receiving treatment at the time of the survey, the other 50 % had discontinued treatment despite the persistence of pain because of a low degree of satisfaction with treatment.
Discussion
We identified risk factors related to the development of new chronic pain and the persistence of chronic pain. Countermeasures to prevent chronic pain could be especially important for the high-risk populations for understanding the pathology of chronic pain.
doi:10.1007/s00776-013-0525-8
PMCID: PMC3960485  PMID: 24504984
4.  Subluxation of the Palmar Radioulnar Ligament As a Cause of Blocked Forearm Supination: A Case of DRUJ Locking 
Journal of Wrist Surgery  2013;2(1):83-86.
We report a case of locking of the distal radioulnar joint (DRUJ) due to interposition of a flap of the palmar radioulnar ligament (RUL) torn from the triangular fibrocartilage complex (TFCC). We released the blockage by elevating the flap and partially resecting a portion of the triangular fibrocartilage (TFC) arthroscopically.
doi:10.1055/s-0032-1333065
PMCID: PMC3656574  PMID: 24436794
locking; distal radioulnar joint; triangular fibrocartilage complex; pronation contracture; radioulnar ligament
5.  Radiographic Parameter Analysis on Modified Sauvé-Kapandji Procedure 
Journal of Wrist Surgery  2013;2(1):19-26.
Purpose The Sauvé-Kapandji (S-K) procedure is now an established treatment option for symptomatic distal radioulnar joint (DRUJ) dysfunction. However, for patients with poor bone quality (frequently as a result of advanced-stage rheumatoid arthritis [RA]), the conventional S-K procedure is difficult to perform without reducing the radioulnar diameter of the wrist, which may result in a loss of grip strength and pain over the proximal ulnar stump. The purpose of this study was to review the radiographic outcomes of patients who underwent a modified S-K procedure that involves rotating the resected ulnar segment 90 degrees and using it to bridge the gap between the sigmoid notch and the ulnar head.
Methods The modified S-K procedure was performed in 29 wrists of 23 patients. Twenty-one patients had severe RA, while two had malunited radius fractures. The mean follow-up period was 43 months (range, 23 to 95). The radiographic evaluation included a measurement of the radioulnar width, the pseudarthrosis gap between the proximal and distal ulnar stump, the radioulnar distance, and the ulnar translation of the carpus.
Results The radioulnar width of the wrist, pseudarthrosis gap, and radioulnar distance were well maintained throughout the period. A postoperative loss in the radioulnar width of the wrists appeared to correlate with a postoperative additional ulnar translocation of the carpus.
Conclusion Narrowing of the radioulnar width of the wrist is a potential cause of progressive ulnar translocation of the carpus. The modified technique for the S-K procedure maintains the distal ulna in the proper position and provides sufficient ulnar support for the carpus. It is a useful reconstruction procedure in patients with severe RA with poor bone quality.
doi:10.1055/s-0032-1333061
PMCID: PMC3656575  PMID: 24436785
modified Sauvé-Kapandji; radiographic evaluation; distal radioulnar joint
6.  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.
Purpose
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.
Methods
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.
Results
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).
Conclusion
The new analysis method proposed here is useful for understanding the pathomechanisms of foraminal stenosis in DLS patients.
doi:10.1007/s00586-012-2408-7
PMCID: PMC3508233  PMID: 22743646
Degenerative lumbar scoliosis; Segmental deformity; Intervertebral foramina; Multidetector-row computed tomography
7.  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.
doi:10.1371/journal.pone.0080548
PMCID: PMC3838418  PMID: 24278289
8.  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
9.  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.
doi:10.1007/s00776-013-0474-2
PMCID: PMC3929026  PMID: 24132791
10.  IL-32-PAR2 axis is an innate immunity sensor providing alternative signaling for LPS-TRIF axis 
Scientific Reports  2013;3:2960.
Interleukin (IL)-32 is known to exert adujvant effects on innate immune response, however, receptors and downstream signaling pathways remain to be clarified. Here we found that IL-32γ upregulated serine protease activity of proteinase-3 (PR3), in turn triggering protease-activated receptor 2 (PAR2) signaling. Interestingly, silencing of PR3 or PAR2 using siRNA markedly diminished IL-32γ-induced TNFα and IFN-β mRNA expression. IL-32γ-PAR2 axis utilized TRIF and Ras-Raf-1 pathways. On stimulation with lipopolysaccharide (LPS), differential activation of protein kinase C isoforms modulated the balance between LPS-TLR4-TRIF and IL-32-PAR2-TRIF axes, because LPS was a strong inducer of IL-32γ. IL-32-PAR2-TRIF axis might serve not only as an extracellular sensor of bacterial and autologous proteases, but also as a modulator of innate and adaptive immunity during infection.
doi:10.1038/srep02960
PMCID: PMC3797434  PMID: 24129891
11.  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
12.  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
13.  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
14.  Secondary Aneurysmal Bone Cyst Following Chondroblastoma of the Patella 
Rare Tumors  2013;5(3):e43.
Aneurysmal bone cyst (ABC) is a rare benign cystic lesion of the bone that composes 1-2% of the entire bone tumors. Some are idiopathic, and some occur secondary to other tumors such as giant cell tumor and chondroblastoma. In this article, we report the clinical, radiographic, and histological findings of a secondary ABC following chondroblastoma of the patella with a review of the literature.
doi:10.4081/rt.2013.e43
PMCID: PMC3804818  PMID: 24179655
secondary aneurysmal bone cyst; chondroblastoma; patella
15.  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.
Background
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.
Methods/design
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.
Discussion
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
doi:10.1186/1745-6215-14-245
PMCID: PMC3750661  PMID: 23924165
Spinal cord injury; Surgery; Timing; Canal stenosis; Ossification of the posterior longitudinal ligament; Spondylosis; Spinal fracture; Bone injury
16.  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
17.  Acute respiratory failure due to hemothorax after posterior correction surgery for adolescent idiopathic scoliosis: a case report 
Background
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.
Conclusion
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.
doi:10.1186/1471-2474-14-132
PMCID: PMC3636110  PMID: 23577922
18.  PADI4 and HLA-DRB1 Are Genetic Risks for Radiographic Progression in RA Patients, Independent of ACPA Status: Results from the IORRA Cohort Study 
PLoS ONE  2013;8(4):e61045.
Introduction
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease influenced by both genetic and environmental factors, leading to joint destruction and functional impairment. Recently, a large-scaled GWAS meta-analysis using more than 37,000 Japanese samples were conducted and 13 RA susceptibility loci were identified. However, it is not clear whether these loci have significant impact on joint destruction or not. This is the first study focused on the 13 loci to investigate independent genetic risk factors for radiographic progression in the first five years from onset of RA.
Methods
Sharp/van der Heijde score of hands at 5-year disease duration, which represents joint damage, were measured retrospectively and used as an outcome variable in 865 Japanese RA patients. Genetic factors regarded as putative risk factors were RA-susceptible polymorphisms identified by the Japanese GWAS meta-analysis, including HLA-DRB1 (shared epitope, SE), rs2240340 (PADI4), rs2230926 (TNFAIP3), rs3093024 (CCR6), rs11900673 (B3GNT2), rs2867461 (ANXA3), rs657075 (CSF2), rs12529514 (CD83), rs2233434 (NFKBIE), rs10821944 (ARID5B), rs3781913 (PDE2A-ARAP1), rs2841277 (PLD4) and rs2847297 (PTPN2). These putative genetic risk factors were assessed by a stepwise multiple regression analysis adjusted for possible non-genetic risk factors: autoantibody positivity (anti-citrullinated peptide antibody [ACPA] and rheumatoid factor), history of smoking, gender and age at disease onset.
Results
The number of SE alleles (P = 0.002) and risk alleles of peptidyl arginine deiminase type IV gene (PADI4, P = 0.04) had significant impact on progressive joint destruction, as well as following non-genetic factors: ACPA positive (P = 0.0006), female sex (P = 0.006) and younger age of onset (P = 0.02).
Conclusions
In the present study, we found that PADI4 risk allele and HLA-DRB1 shared epitope are independent genetic risks for radiographic progression in Japanese rheumatoid arthritis patients. The results of this study give important knowledge of the risks on progressive joint damage in RA patients.
doi:10.1371/journal.pone.0061045
PMCID: PMC3620057  PMID: 23577190
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.
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
20.  Conditional Inactivation of TNFα-Converting Enzyme in Chondrocytes Results in an Elongated Growth Plate and Shorter Long Bones 
PLoS ONE  2013;8(1):e54853.
TNFα-converting enzyme (TACE) is a membrane-bound proteolytic enzyme with essential roles in the functional regulation of TNFα and epidermal growth factor receptor (EGFR) ligands. Previous studies have demonstrated critical roles for TACE in vivo, including epidermal development, immune response, and pathological neoangiogenesis, among others. However, the potential contribution of TACE to skeletal development is still unclear. In the present study, we generated a Tace mutant mouse in which Tace is conditionally disrupted in chondrocytes under the control of the Col2a1 promoter. These mutant mice were fertile and viable but all exhibited long bones that were approximately 10% shorter compared to those of wild-type animals. Histological analyses revealed that Tace mutant mice exhibited a longer hypertrophic zone in the growth plate, and there were fewer osteoclasts at the chondro-osseous junction in the Tace mutant mice than in their wild-type littermates. Of note, we found an increase in osteoprotegerin transcripts and a reduction in Rankl and Mmp-13 transcripts in the TACE-deficient cartilage, indicating that dysregulation of these genes is causally related to the skeletal defects in the Tace mutant mice. Furthermore, we also found that phosphorylation of EGFR was significantly reduced in the cartilage tissue lacking TACE, and that suppression of EGFR signaling increases osteoprotegerin transcripts and reduces Rankl and Mmp-13 transcripts in primary chondrocytes. In accordance, chondrocyte-specific abrogation of Egfr in vivo resulted in skeletal defects nearly identical to those observed in the Tace mutant mice. Taken together, these data suggest that TACE-EGFR signaling in chondrocytes is involved in the turnover of the growth plate during postnatal development via the transcriptional regulation of osteoprotegerin, Rankl, and Mmp-13.
doi:10.1371/journal.pone.0054853
PMCID: PMC3548805  PMID: 23349978
21.  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.
doi:10.1371/journal.pone.0054412
PMCID: PMC3544834  PMID: 23342154
22.  Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury 
Molecular Brain  2013;6:3.
Background
The transplantation of neural stem/progenitor cells (NS/PCs) at the sub-acute phase of spinal cord injury, but not at the chronic phase, can promote functional recovery. However, the reasons for this difference and whether it involves the survival and/or fate of grafted cells under these two conditions remain unclear. To address this question, NS/PC transplantation was performed after contusive spinal cord injury in adult mice at the sub-acute and chronic phases.
Results
Quantitative analyses using bio-imaging, which can noninvasively detect surviving grafted cells in living animals, revealed no significant difference in the survival rate of grafted cells between the sub-acute and chronic transplantation groups. Additionally, immunohistology revealed no significant difference in the differentiation phenotypes of grafted cells between the two groups. Microarray analysis revealed no significant differences in the expression of genes encoding inflammatory cytokines or growth factors, which affect the survival and/or fate of grafted cells, in the injured spinal cord between the sub-acute and chronic phases. By contrast, the distribution of chronically grafted NS/PCs was restricted compared to NS/PCs grafted at the sub-acute phase because a more prominent glial scar located around the lesion epicenter enclosed the grafted cells. Furthermore, microarray and histological analysis revealed that the infiltration of macrophages, especially M2 macrophages, which have anti-inflammatory role, was significantly higher at the sub-acute phase than the chronic phase. Ultimately, NS/PCs that were transplanted in the sub-acute phase, but not the chronic phase, promoted functional recovery compared with the vehicle control group.
Conclusions
The extent of glial scar formation and the characteristics of inflammation is the most remarkable difference in the injured spinal cord microenvironment between the sub-acute and chronic phases. To achieve functional recovery by NS/PC transplantation in cases at the chronic phase, modification of the microenvironment of the injured spinal cord focusing on glial scar formation and inflammatory phenotype should be considered.
doi:10.1186/1756-6606-6-3
PMCID: PMC3556141  PMID: 23298657
Spinal cord injury; Neural stem/progenitor cells; Cell transplantation; Chronic phase; Microenvironment
23.  MRI Characterization of Paranodal Junction Failure and Related Spinal Cord Changes in Mice 
PLoS ONE  2012;7(12):e52904.
The paranodal junction is a specialized axon-glia contact zone that is important for normal neuronal activity and behavioral locomotor function in the central nervous system (CNS). Histological examination has been the only method for detecting pathological paranodal junction conditions. Recently, diffusion tensor MRI (DTI) has been used to detect microstructural changes in various CNS diseases. This study was conducted to determine whether MRI and DTI could detect structural changes in the paranodal junctions of the spinal cord in cerebroside sulfotransferase knock-out (CST-KO) mice. Here, we showed that high-resolution MRI and DTI characteristics can reflect paranodal junction failure in CST-KO mice. We found significantly lower T1 times and significantly higher T2 times in the spinal cord MRIs of CST-KO mice as compared to wild-type (WT) mice. Spinal cord DTI showed significantly lower axial diffusivity and significantly higher radial diffusivity in CST-KO mice as compared to WT mice. In contrast, the histological differences in the paranodal junctions of WT and CST-KO mice were so subtle that electron microscopy or immunohistological analyses were necessary to detect them. We also measured gait disturbance in the CST-KO mice, and determined the conduction latency by electrophysiology. These findings demonstrate the potential of using MRI and DTI to evaluate white matter disorders that involve paranodal junction failure.
doi:10.1371/journal.pone.0052904
PMCID: PMC3531327  PMID: 23300814
24.  Pre-Evaluated Safe Human iPSC-Derived Neural Stem Cells Promote Functional Recovery after Spinal Cord Injury in Common Marmoset without Tumorigenicity 
PLoS ONE  2012;7(12):e52787.
Murine and human iPSC-NS/PCs (induced pluripotent stem cell-derived neural stem/progenitor cells) promote functional recovery following transplantation into the injured spinal cord in rodents. However, for clinical applicability, it is critical to obtain proof of the concept regarding the efficacy of grafted human iPSC-NS/PCs (hiPSC-NS/PCs) for the repair of spinal cord injury (SCI) in a non-human primate model. This study used a pre-evaluated “safe” hiPSC-NS/PC clone and an adult common marmoset (Callithrix jacchus) model of contusive SCI. SCI was induced at the fifth cervical level (C5), followed by transplantation of hiPSC-NS/PCs at 9 days after injury. Behavioral analyses were performed from the time of the initial injury until 12 weeks after SCI. Grafted hiPSC-NS/PCs survived and differentiated into all three neural lineages. Furthermore, transplantation of hiPSC-NS/PCs enhanced axonal sparing/regrowth and angiogenesis, and prevented the demyelination after SCI compared with that in vehicle control animals. Notably, no tumor formation occurred for at least 12 weeks after transplantation. Quantitative RT-PCR showed that mRNA expression levels of human neurotrophic factors were significantly higher in cultured hiPSC-NS/PCs than in human dermal fibroblasts (hDFs). Finally, behavioral tests showed that hiPSC-NS/PCs promoted functional recovery after SCI in the common marmoset. Taken together, these results indicate that pre-evaluated safe hiPSC-NS/PCs are a potential source of cells for the treatment of SCI in the clinic.
doi:10.1371/journal.pone.0052787
PMCID: PMC3531369  PMID: 23300777
25.  Up-Regulation of Imp3 Confers In Vivo Tumorigenicity on Murine Osteosarcoma Cells 
PLoS ONE  2012;7(11):e50621.
Osteosarcoma is a high-grade malignant bone tumor that manifests ingravescent clinical behavior. The intrinsic events that confer malignant properties on osteosarcoma cells have remained unclear, however. We previously established two lines of mouse osteosarcoma cells: AX cells, which are able to form tumors in syngeneic mice, and AXT cells, which were derived from such tumors and acquired an increased tumorigenic capacity during tumor development. We have now identified Igf2 mRNA-binding protein3 (Imp3) as a key molecule responsible for this increased tumorigenicity of AXT cells in vivo. Imp3 is consistently up-regulated in tumors formed by AX cells, and its expression in these cells was found to confer malignant properties such as anchorage-independent growth, loss of contact inhibition, and escape from anoikis in vitro. The expression level of Imp3 also appeared directly related to tumorigenic ability in vivo which is the critical determination for tumor-initiating cells. The effect of Imp3 on tumorigenicity of osteosarcoma cells did not appear to be mediated through Igf2-dependent mechanism. Our results implicate Imp3 as a key regulator of stem-like tumorigenic characteristics in osteosarcoma cells and as a potential therapeutic target for this malignancy.
doi:10.1371/journal.pone.0050621
PMCID: PMC3511546  PMID: 23226335

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