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1.  Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing osteosarcoma cells 
Cancer Science  2015;106(7):875-882.
Osteosarcoma (OS) is the most frequent primary solid malignant tumor of bone. Its prognosis remains poor in the substantial proportion of patients who do not respond to chemotherapy and novel therapeutic options are therefore needed. We previously established a mouse model that mimics the aggressive behavior of human OS. Enzyme-linked immunosorbent assay-based screening of such mouse tumor lysates identified platelet-derived growth factor–BB (PDGF-BB) as an abundant soluble factor, the gene for which was expressed dominantly in surrounding non-malignant cells of the tumor, whereas that for the cognate receptor (PDGF receptor β) was highly expressed in OS cells. Platelet-derived growth factor-BB induced activation of both MEK–ERK and phosphatidylinositol 3-kinase–protein kinase B signaling pathways and promoted survival in OS cells deprived of serum, and these effects were blocked by the PDGF receptor inhibitor imatinib. However, these actions of PDGF-BB and imatinib were mostly masked in the presence of serum. Whereas imatinib alone did not manifest an antitumor effect in mice harboring OS tumors, combined treatment with imatinib and adriamycin exerted a synergistic antiproliferative effect on OS cells in vivo. These results suggest that treatment of OS with imatinib is effective only when cell survival is dependent on PDGF signaling or when imatinib is combined with another therapeutic intervention that renders the tumor cells susceptible to imatinib action, such as by inducing cellular stress.
PMCID: PMC4520639  PMID: 25940371
Animal model; drug resistance; imatinib; osteosarcoma; platelet-derived growth factor (PDGF) signaling
2.  Arthroscopic Visualization of Abnormal Movement of Discoid Lateral Meniscus With Snapping Phenomenon 
Arthroscopy Techniques  2015;4(3):e235-e238.
Discoid lateral meniscus with snapping phenomenon is a rare pathologic condition. The purpose of this article is to present an arthroscopic technique for the treatment of discoid lateral meniscus with snapping phenomenon. The patient is placed in the supine position for confirmation of snapping. As the patient's knee bends, it can be confirmed by arthroscopy that the posterior horn of the discoid lateral meniscus moves posteriorly and the central portion of the discoid lateral meniscus moves anteriorly at the same time with snapping at deep flexion angles. The anterior segment of the discoid lateral meniscus is found to be redundant and is often folded. On the contrary, as the patient's knee extends, the central portion is returned to the original position accompanied by snapping at nearly full extension. After excision of the central portion, the movement of the meniscus is evaluated again and the disappearance of the snapping phenomenon can be confirmed. Although it includes limitations, this application is easy and would certainly help surgeons to treat snapping knee with discoid lateral meniscus.
PMCID: PMC4523719  PMID: 26258036
3.  Total En Bloc Spondylectomy for Locally Aggressive Vertebral Hemangioma Causing Neurological Deficits 
Case Reports in Orthopedics  2015;2015:724364.
Vertebral hemangiomas are common; however, aggressive vertebral hemangiomas with extraosseous extensions causing neurological deficits are rare. The treatment for this subtype of hemangioma remains controversial, since there are few reports on long-term clinical outcomes or tumor recurrence rates. We describe a case of aggressive vertebral hemangioma treated by total en bloc spondylectomy, with a literature review focusing on long-term recurrence. A 52-year-old male with a two-month history of numbness in the bilateral lower extremities was referred to our hospital. Imaging studies showed a tumor originating in the T9 vertebra and extending to the T8 and T10 vertebrae, with extraosseous extension causing spinal-cord compression. Ten months after onset, the patient presented with progressive paraparesis and hypalgesia. Total en bloc spondylectomy was performed, and pathology was consistent with cavernous hemangioma. Motor and sensory deficits improved significantly, and no signs of recurrence are seen at 2.5 years after operation. A review of literature revealed a recurrence rate of 12.7% (10/79 cases). The available evidence indicates satisfactory long-term outcomes for total tumor resection without adjuvant radiotherapy.
PMCID: PMC4397049  PMID: 25918662
4.  Controlling Immune Rejection Is a Fail-Safe System against Potential Tumorigenicity after Human iPSC-Derived Neural Stem Cell Transplantation 
PLoS ONE  2015;10(2):e0116413.
Our previous work reported functional recovery after transplantation of mouse and human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) into rodent models of spinal cord injury (SCI). Although hiPSC-NS/PCs proved useful for the treatment of SCI, the tumorigenicity of the transplanted cells must be resolved before they can be used in clinical applications. The current study sought to determine the feasibility of ablation of the tumors formed after hiPSC-NS/PC transplantation through immunoregulation. Tumorigenic hiPSC-NS/PCs were transplanted into the intact spinal cords of immunocompetent BALB/cA mice with or without immunosuppressant treatment. In vivo bioluminescence imaging was used to evaluate the chronological survival and growth of the transplanted cells. The graft survival rate was 0% in the group without immunosuppressants versus 100% in the group with immunosuppressants. Most of the mice that received immunosuppressants exhibited hind-limb paralysis owing to tumor growth at 3 months after iPSC-NS/PC transplantation. Histological analysis showed that the tumors shared certain characteristics with low-grade gliomas rather than with teratomas. After confirming the progression of the tumors in immunosuppressed mice, the immunosuppressant agents were discontinued, resulting in the complete rejection of iPSC-NS/PC-derived masses within 42 days after drug cessation. In accordance with the tumor rejection, hind-limb motor function was recovered in all of the mice. Moreover, infiltration of microglia and lymphocytes was observed during the course of tumor rejection, along with apoptosis of iPSC-NS/PC-generated cells. Thus, immune rejection can be used as a fail-safe system against potential tumorigenicity after transplantation of iPSC-NS/PCs to treat SCI.
PMCID: PMC4338009  PMID: 25706286
5.  Long-Term Safety Issues of iPSC-Based Cell Therapy in a Spinal Cord Injury Model: Oncogenic Transformation with Epithelial-Mesenchymal Transition 
Stem Cell Reports  2015;4(3):360-373.
Previously, we described the safety and therapeutic potential of neurospheres (NSs) derived from a human induced pluripotent stem cell (iPSC) clone, 201B7, in a spinal cord injury (SCI) mouse model. However, several safety issues concerning iPSC-based cell therapy remain unresolved. Here, we investigated another iPSC clone, 253G1, that we established by transducing OCT4, SOX2, and KLF4 into adult human dermal fibroblasts collected from the same donor who provided the 201B7 clone. The grafted 253G1-NSs survived, differentiated into three neural lineages, and promoted functional recovery accompanied by stimulated synapse formation 47 days after transplantation. However, long-term observation (for up to 103 days) revealed deteriorated motor function accompanied by tumor formation. The tumors consisted of Nestin+ undifferentiated neural cells and exhibited activation of the OCT4 transgene. Transcriptome analysis revealed that a heightened mesenchymal transition may have contributed to the progression of tumors derived from grafted cells.
Graphical Abstract
•Grafted iPSC (253G1)-derived neurospheres formed tumors after long-term observation•Activation of the OCT4 transgene is potentially related to tumor formation•Tumor progression may have been caused by mesenchymal transition of grafted cells•Integration-free iPSCs should be chosen to avoid transgene-induced tumorigenesis
Previously, Okano and colleagues reported the therapeutic potential of induced pluripotent stem cell (iPSC)-derived neurospheres for spinal cord injury. However, safety issues concerning iPSC-based therapy remain unresolved. In this article, they show that grafted human iPSC (253G1)-derived neurospheres formed undifferentiated neural tumors after long-term observation. The tumors exhibited activation of the OCT4 transgene and a heightened mesenchymal transition. Integration-free iPSCs should be chosen to avoid transgene-induced tumorigenesis.
PMCID: PMC4375796  PMID: 25684226
8.  The Mohawk homeobox transcription factor regulates the differentiation of tendons and volar plates 
Mohawk (Mkx) is a homeodomain-containing transcription factor that is expressed in various mesoderm-derived tissues, particularly in developing tendons. In this study, we investigate the exact expression pattern and functions of Mkx in forelimbs.
We analyzed the forelimbs of Mkx knockout mice (from embryonic day [E] 18.5 to postnatal day [P] 28-week) by using knocked-in Venus signals, Masson trichrome staining, and hematoxylin and eosin (H&E) staining.
We detected Venus signals in forelimb tendons, pulleys, and volar plates (VPs) in P21 mice. In-depth histological analysis showed that compared to the wild-type mice, the Mkx knockout mice showed significant hypoplasia in the flexor digitorum profundus (FDP) tendons from E18.5. The VPs and pulleys appeared normal until P0, however, by P14, they became increasingly thicker in Mkx-null mice compared to wild-type mice. The fiber alignment was particularly disrupted in VPs of Mkx-null mice.
These results suggest that Mkx is an important regulator of the differentiation of VPs and pulleys, as well as of tendon differentiation.
PMCID: PMC3943675  PMID: 24166359
9.  Acetabular labral tear complicating idiopathic osteonecrosis of the femoral head treated by labral repair with hip arthroscopy: a case report 
It has been well documented that labral tear is frequently associated with femoroacetabular impingement and dysplasia of the hip; however, there have been few reported cases of labral tear associated with idiopathic osteonecrosis of the hip. Here we report the case of a patient with labral tear associated with idiopathic osteonecrosis of the femoral head who was treated by hip arthroscopy, with a favorable short-term outcome.
Case presentation
Under the diagnosis of systemic lupus erythematosus, a 28-year-old Japanese woman was treated with the oral administration of steroid in 2007. A year after the treatment, she developed right hip joint pain and was diagnosed with idiopathic osteonecrosis of the femoral head at our institution. In November of 2011, she revisited our hospital when her right hip joint pain exacerbated and she became unable to walk. On the visit, the anterior impingement sign and Patrick test were positive. Radiography and magnetic resonance imaging in 2011 demonstrated neither spreading of the osteonecrosis area nor collapse of the femoral head in the right joint; however, magnetic resonance imaging showed a high-intensity area in the articular labrum in a T2-weighted image, leading to a diagnosis of labral tear. She underwent labral repair with hip arthroscopy in August of 2012. Now, 1 year after surgery, she does not feel any pain during walking and her modified Harris hip score has improved from 20 prior to surgery to 85.
The case indicated that it is important to be aware of the possibility of labral tear in patients with idiopathic osteonecrosis of the femoral head, when spreading of the osteonecrosis area or collapse of the femoral head has not been seen on magnetic resonance imaging.
PMCID: PMC4304144  PMID: 25404056
Hip arthroscopy; Idiopathic osteonecrosis; Labral tear
10.  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
11.  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
12.  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
13.  Massive hemothorax caused by Gelpi retractor during posterior correction surgery for adolescent idiopathic scoliosis: a case report 
Scoliosis  2014;9:17.
Background context
Gelpi retractors are used in surgery because they can reduce paravertebral muscle damage during retraction. No pleural injuries associated with their use in posterior spine surgery have been reported.
To describe a patient who suffered a massive postoperative hemothorax caused by a Gelpi retractor used during posterior correction surgery for adolescent idiopathic scoliosis (AIS).
Study design
Case report.
A case report of a rare hemothorax complication due to a Gelpi retractor is reported. The relevant literature was reviewed.
A 12-year-old girl with Lenke type 2 AIS, with curves of 60° at T2-7 and 75° at T7-L1, underwent posterior correction and fusion surgery using a segmental pedicle screw construct placed between T2 and L2. Although the patient’s vital signs were stable during and soon after the surgery, a chest x-ray taken one day later revealed a massive left hemothorax. Her hemoglobin concentration was decreased to 5.5g/dl, and SpO2 remained as low as 92% even with oxygen administration. Thoracoscopy revealed subpleural hemorrhaging at several points in the left upper intercostal area (T3-6), and a penetration of the pleura between the left 4th and 5th ribs. Active bleeding had already stopped. The tip of the Gelpi retractor appeared to have penetrated the pleura. A chest tube was placed in the patient to treat the hemothorax.
A pleural injury by the Gelpi retractor was determined to be the cause of the hemothorax in this case. The patient’s prominent thoracic hump may have increased the risk of such an injury because the tip of a Gelpi retractor might easily have become stuck in the intercostal space rather than the paravertebral muscles.
PMCID: PMC4406011  PMID: 25904971
14.  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
15.  An Osteoprotegerin Gene Polymorphism Is Associated with an Increased Risk of Hip Fracture in Japanese Patients with Rheumatoid Arthritis: Results from the IORRA Observational Cohort Study 
PLoS ONE  2014;9(8):e104587.
Patients with rheumatoid arthritis (RA) have a higher prevalence of osteoporosis and hip fracture than healthy individuals. Multiple genetic loci for osteoporotic fracture were identified in recent genome-wide association studies. The purpose of this study was to identify genetic variants associated with the occurrence of hip fracture in Japanese patients with RA.
DNA samples from 2,282 Japanese patients with RA were obtained from the DNA collection of the Institute of Rheumatology Rheumatoid Arthritis cohort (IORRA) study. Six single nucleotide polymorphisms (SNPs) that have been reported to be associated with fractures in recent studies were selected and genotyped. Forty hip fractures were identified with a maximum follow-up of 10 years. The genetic risk for hip fracture was examined using a multivariate Cox proportional hazards regression model.
The risk analyses revealed that patients who are homozygous for the major allele of SNP rs6993813, in the OPG locus, have a higher risk for hip fracture (hazard ratio [95% CI]  = 2.53 [1.29–4.95], P  = 0.0067). No association was found for the other SNPs.
Our results indicate that an OPG allele is associated with increased risk for hip fracture in Japanese patients with RA.
PMCID: PMC4126739  PMID: 25105978
16.  Cellular Composition and Organization of the Subventricular Zone and Rostral Migratory Stream in the Adult and Neonatal Common Marmoset Brain 
The adult subventricular zone (SVZ) of the lateral ventricle contains neural stem cells. In rodents, these cells generate neuroblasts that migrate as chains toward the olfactory bulb along the rostral migratory stream (RMS). The neural-stem-cell niche at the ventricular wall is conserved in various animal species, including primates. However, it is unclear how the SVZ and RMS organization in nonhuman primates relates to that of rodents and humans. Here we studied the SVZ and RMS of the adult and neonatal common marmoset (Callithrix jacchus), a New World primate used widely in neuroscience, by electron microscopy, and immunohistochemical detection of cell-type-specific markers. The marmoset SVZ contained cells similar to type B, C, and A cells of the rodent SVZ in their marker expression and morphology. The adult marmoset SVZ had a three-layer organization, as in the human brain, with ependymal, hypocellular, and astro-cyte-ribbon layers. However, the hypocellular layer was very thin or absent in the adult-anterior and neonatal SVZ. Anti-PSA-NCAM staining of the anterior SVZ in whole-mount ventricular wall preparations of adult marmosets revealed an extensive network of elongated cell aggregates similar to the neuroblast chains in rodents. Time-lapse recordings of marmoset SVZ explants cultured in Matrigel showed the neuroblasts migrating in chains, like rodent type A cells. These results suggest that some features of neurogenesis and neuronal migration in the SVZ are common to marmosets, humans, and rodents. This basic description of the adult and neonatal marmoset SVZ will be useful for future studies on adult neurogenesis in primates.
PMCID: PMC4096931  PMID: 21246550
common marmoset; subventricular zone; rostral migratory stream
17.  Computed tomography-guided resection of osteoid osteoma of the sacrum: a case report 
Osteoid osteoma is a benign tumor that usually occurs in the long bones of young adults. Its symptoms can be diverse depending on the location of the tumor and especially difficult to diagnose when occurring in an atypical location. Osteoid osteoma arising in the sacrum is extremely rare, and here, we present a case that was treated successfully in a minimally invasive fashion under computed tomography guidance.
Case presentation
A 25-year-old Asian man was referred to our institution due to persistent pain in the buttock after 12 months of conservative treatment. Computed tomography and magnetic resonance imaging scans revealed a ring-shaped radiolucency consistent with a nidus of osteoid osteoma in the sacrum. The lesion was subsequently resected under computed tomography guidance and the histological diagnosis was compatible with osteoid osteoma. His postoperative course was uneventful, and at two years after surgery our patient is symptom-free with no evidence of recurrence.
Computed tomography-guided resection of osteoid osteoma in the spinal column is feasible and accurate if there is adequate margin from vital organs. Although rare, it is important to always bear in mind the possibility of osteoid osteoma occurring in the sacrum when no other apparent lesion is detected.
PMCID: PMC4088307  PMID: 24942997
Osteoid osteoma; Sacrum; CT-guided resection
18.  Investigation of chronic musculoskeletal pain (third report): with special reference to the importance of neuropathic pain and psychogenic pain 
Journal of Orthopaedic Science  2014;19(4):667-675.
The previous epidemiological surveys conducted in Japan revealed that once the vicious cycle of chronic musculoskeletal pain begins, it is difficult to disrupt the cycle. This finding suggests the existence of problems with the conventional approaches to treatment of chronic musculoskeletal pain. The purpose of this study was to investigate the characteristics of patients with chronic musculoskeletal pain focusing on neuropathic and psychogenic pain.
The questionnaire was sent again to the 660 subjects found to have persistent chronic pain in the epidemiological surveys conducted in 2011. Responses were collected from 588 subjects (response rate 90 %).
Of the 588 responders, 365 (62 %) complained of persistent chronic pain. Among them, 128 (35 %) were still receiving treatment and 193 (53 %) had discontinued treatment. The degree of satisfaction with the treatment was low, and 66 % of the patients had switched the medical facility that they visited to receive treatment. The cited reasons for the change in the medical facility visited and discontinuation of treatment were “treatment was ineffective,” “I did not have sufficient time,” “I thought I could take care of it myself,” and “Treatment seemed to be unnecessary”. Involvement of neuropathic pain was suggested in 20 % of all the patients with chronic pain. As the PainDETECT Score rose, the Visual Analog Scale (VAS) score became higher and the change of medical facility for treatment also increased. The Pain Catastrophizing Scale score was correlated positively with the VAS score. The Hospital Anxiety and Depression Scale score was significantly correlated with the VAS score and the duration of pain.
The results of this survey indicated that the chronic course of musculoskeletal pain may be attributable to the following factors: (1) lack of appropriate treatment of neuropathic pain and psychogenic pain, and (2) insufficient awareness/knowledge among patients about chronic musculoskeletal pain.
PMCID: PMC4111854  PMID: 24737064
19.  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
20.  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
21.  A GC polymorphism associated with serum 25-hydroxyvitamin D level is a risk factor for hip fracture in Japanese patients with rheumatoid arthritis: 10-year follow-up of the Institute of Rheumatology, Rheumatoid Arthritis cohort study 
Vitamin D deficiency has been reported to be common in patients with rheumatoid arthritis (RA) who have a higher prevalence of osteoporosis and hip fracture than healthy individuals. Genetic variants affecting serum 25-hydroxyvitamin D (25(OH)D) concentration, an indicator of vitamin D status, were recently identified by genome-wide association studies of Caucasian populations. The purpose of this study was to validate the association and to test whether the serum 25(OH)D-linked genetic variants were associated with the occurrence of hip fracture in Japanese RA patients.
DNA samples of 1,957 Japanese RA patients were obtained from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort DNA collection. First, five single nucleotide polymorphisms (SNPs) that were reported to be associated with serum 25(OH)D concentration by genome-wide association studies were genotyped. The SNPs that showed a significant association with serum 25(OH)D level in the cross-sectional study were used in the longitudinal analysis of hip fracture risk. The genetic risk for hip fracture was determined by a multivariate Cox proportional hazards model in 1,957 patients with a maximum follow-up of 10 years (median, 8 years).
Multivariate linear regression analyses showed that rs2282679 in GC (the gene encoding group-specific component (vitamin D binding protein)) locus was significantly associated with lower serum 25(OH)D concentration (P = 8.1 × 10-5). A Cox proportional hazards model indicated that rs2282679 in GC was significantly associated with the occurrence of hip fracture in a recessive model (hazard ratio (95% confidence interval) = 2.52 (1.05-6.05), P = 0.039).
A two-staged analysis demonstrated that rs2282679 in GC was associated with serum 25(OH)D concentration and could be a risk factor for hip fracture in Japanese RA patients.
PMCID: PMC4060202  PMID: 24646907
22.  Computed tomography measurement of glenoid vault version as an alternative measuring method for glenoid version 
The conventional measuring method for glenoid version is greatly influenced by the scapular body shape that varies widely between patients. We postulated that the glenoid vault version could be more useful than the conventional glenoid version in clinical cases.
The purposes of this study were to compare the values of glenoid version measured with the conventional method to those with the vault method and to investigate the feasibility of the glenoid vault version.
Computed tomography scans of 150 normal shoulders and 150 arthritic shoulders were analyzed. Three-dimensionally corrected slices were reconstructed from the Digital Imaging and Communications in Medicine (DICOM) data, and glenoid version was measured with both the conventional and vault methods. After determining intra- and interrater reliabilities, differences in glenoid version values between the conventional and vault methods were assessed. In the normal shoulder group, side-to-side differences of glenoid version values were also evaluated in both methods.
Both measuring methods demonstrated high intra- and interrater reliabilities. The normal glenoid had 1.1° ± 3.2° retroversion with the conventional method and 8.9° ± 2.7° retroversion with the vault method. The average glenoid retroversion of arthritic shoulders was 10.8° ± 9.3° measured with the conventional method and 18.2° ± 9.1° with the vault method. The vault method showed significantly larger glenoid retroversion than the conventional method in both normal and arthritic shoulder groups. Both conventional glenoid retroversion and glenoid vault retroversion were significantly larger on dominant sides than on nondominant sides in the normal shoulders.
The glenoid vault version could be used as an alternative measuring method for glenoid version with high reliability. In clinical use, the glenoid vault version appears to be more useful than the conventional glenoid version to assess the severity of arthritis and difficulty of glenoid replacement. The glenoid vault is not symmetric, but usually retroverted in both normal and arthritic shoulders.
PMCID: PMC3995775  PMID: 24618285
Glenoid vault; Glenoid version; Glenoid retroversion; Shoulder arthroplasty; Glenoid component; Glenoid replacement; Glenoid morphology
23.  Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition 
Molecular Brain  2014;7:14.
Rats exhibit extremely limited motor function recovery after total transection of the spinal cord (SCT). We previously reported that SM-216289, a semaphorin3A inhibitor, enhanced axon regeneration and motor function recovery in SCT adult rats. However, these effects were limited because most regenerated axons likely do not connect to the right targets. Thus, rebuilding the appropriate connections for regenerated axons may enhance recovery. In this study, we combined semaphorin3A inhibitor treatment with extensive treadmill training to determine whether combined treatment would further enhance the “rewiring” of regenerated axons. In this study, which aimed for clinical applicability, we administered a newly developed, potent semaphorin3A inhibitor, SM-345431 (Vinaxanthone), using a novel drug delivery system that enables continuous drug delivery over the period of the experiment.
Treatment with SM-345431 using this delivery system enhanced axon regeneration and produced significant, but limited, hindlimb motor function recovery. Although extensive treadmill training combined with SM-345431 administration did not further improve axon regeneration, hindlimb motor performance was restored, as evidenced by the significant improvement in the execution of plantar steps on a treadmill. In contrast, control SCT rats could not execute plantar steps at any point during the experimental period. Further analyses suggested that this strategy reinforced the wiring of central pattern generators in lumbar spinal circuits, which, in turn, led to enhanced motor function recovery (especially in extensor muscles).
This study highlights the importance of combining treatments that promote axon regeneration with specific and appropriate rehabilitations that promote rewiring for the treatment of spinal cord injury.
PMCID: PMC4008261  PMID: 24618249
Axonal regeneration; Semaphorin3A; Inhibitor; Rehabilitation; Rewiring; Drug delivery system
24.  Inflammatory cascades mediate synapse elimination in spinal cord compression 
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.
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.
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.
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.
PMCID: PMC3975877  PMID: 24589419
cervical compressive myelopathy; tip-toe walking Yoshimura mice; complement activation classical pathway; synapse elimination
25.  Prevalence and characteristics of chronic musculoskeletal pain in Japan: A second survey of people with or without chronic pain 
Journal of Orthopaedic Science  2014;19(2):339-350.
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.
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.
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.
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.
PMCID: PMC3960485  PMID: 24504984

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