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1.  Breast carcinoma metastasis to meningioma in the thoracic spine: A case report and review of the literature 
Systemic metastasis to a primary tumor of the central nervous system is uncommon. Breast carcinomas metastasizing to a possibly preexisting meningioma in the spine are reported very rarely.
Study design
Case report.
A 69-year-old female was referred to us with progressive gait disturbance. She had undergone a total mastectomy for carcinoma of the right breast 11 years previously. A magnetic resonance imaging of the thoracic spine showed an intra- and extradural spinal cord tumor. The patient underwent resection of the tumor via laminectomy from T2 to T4. After the operation, the patient's neurological status improved significantly, and she was able to walk without assistance. Histological examination showed the tumor to be a fibrous-type meningioma within a metastatic breast cancer tumor. The patient underwent 40 Gy radiation treatment for local control of the tumor. However, the tumor recurred locally 7 months after the surgery. The patient died of carcinomatous pleurisy 13 months after the surgery.
This case illustrates that a primary meningioma in the thoracic spine can be a recipient of breast cancer metastasis, which may alter the treatment strategy.
PMCID: PMC4397206  PMID: 24617535
Breast carcinoma; Metastasis; Meningioma; Thoracic spine
2.  Grafted Human iPS Cell-Derived Oligodendrocyte Precursor Cells Contribute to Robust Remyelination of Demyelinated Axons after Spinal Cord Injury 
Stem Cell Reports  2015;6(1):1-8.
Murine- and human-induced pluripotent stem cell-derived neural stem/progenitor cells (iPSC-NS/PCs) promote functional recovery following transplantation into the injured spinal cord in rodents and primates. Although remyelination of spared demyelinated axons is a critical mechanism in the regeneration of the injured spinal cord, human iPSC-NS/PCs predominantly differentiate into neurons both in vitro and in vivo. We therefore took advantage of our recently developed protocol to obtain human-induced pluripotent stem cell-derived oligodendrocyte precursor cell-enriched neural stem/progenitor cells and report the benefits of transplanting these cells in a spinal cord injury (SCI) model. We describe how this approach contributes to the robust remyelination of demyelinated axons and facilitates functional recovery after SCI.
Graphical Abstract
•hiPSC-OPC-enriched NS/PCs differentiate into mature oligodendrocytes in vivo•Grafted hiPSC-OPCs-derived mature oligodendrocytes contribute to remyelination•Transplanted hiPSC-OPC-enriched NS/PCs enhance functional recovery following SCI•Transplanted hiPSC-OPC-enriched NS/PCs promote axonal growth of host neurons
In this article, Okano and colleagues show that the benefits of transplanting human-induced pluripotent stem cell-derived oligodendrocyte precursor cell-enriched neural stem/progenitor cells, describing how this approach contributes to the robust remyelination of demyelinated axons and facilitates functional recovery after spinal cord injury.
PMCID: PMC4719132  PMID: 26724902
3.  Novel MR imaging method – MAVRIC – for metal artifact suppression after joint replacement in musculoskeletal tumor patients 
Standard imaging modality for the follow-up after prosthetic replacements for musculoskeletal tumor patients has been conventional radiography. This technique is effective in detecting subtle changes in bone adjacent to metal implants, but in many cases, radiographs do not lead to definitive diagnosis of postoperative adverse events such as acute infection, local recurrence of soft tissue tumor or soft tissue local recurrence of osseous sarcoma. Conventional MRI sequences have not been effective due to metal artifacts. In this study, we tried to elucidate the effectiveness of metal artifact suppression using novel sequence, multiacquisition variable-resonance image combination (MAVRIC), after musculoskeletal tumor surgeries.
We retrospectively analyzed 5 cases of malignant bone and soft tissue sarcoma patients who were reconstructed with metal prosthesis after wide resection of tumors. Images obtained using MAVRIC and short tau inversion recovery (STIR) were compared side by side. The paired MAVRIC and STIR images were qualitatively compared independently by two specialists for 4 parameters: visualization of bone - implant interface, visualization of surrounding soft tissues, image blurring, and overall image quality. Quantitatively, paired images were reviewed to identify the slice where the metal artifact was maximal, and a region of interest encompassing the implant and surrounding artifact was drawn using Advantage Workstation (GE Healthcare, Japan).
There were no local recurrences that were detected. By utilizing MAVRIC, visualization of the bone - implant interface and visualization of the surrounding soft tissue were significantly improved in MAVRIC compared to STIR. Although blurring was worse on the MAVRIC acquisitions, the overall image quality was still better on MAVRIC. Quantitatively, the area of metal artifact measured using MAVRIC was markedly less compared to STIR (61.4 cm2 vs 135.9 cm2).
Despite the relatively small number of cases in the present study, our observation strongly suggests that MAVRIC is able to improve the quality of images by decreasing the artifact caused by endoprosthesis, frequently utilized in reconstruction of musculoskeletal tumor patients. Further installments of conventional imaging sequences with the addition of gadolinium - enhancement will enable increased accuracy in diagnosing local recurrences of sarcoma patients.
PMCID: PMC4670533  PMID: 26637412
MRI; MAVRIC; Metal artifact
4.  Identification of HOXD4 Mutations in Spinal Extradural Arachnoid Cyst 
PLoS ONE  2015;10(11):e0142126.
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 and leads to neurological disturbances. We previously showed that familial SEDAC is caused by FOXC2 mutation; however, the causal gene of sporadic SEDAC has not been identified. To identify the causal gene of sporadic SEDAC, we performed whole exome sequencing for 12 subjects with sporadic SEDAC and identified heterozygous HOXD4 loss-of-function mutations in three subjects. HOXD4 haplo-insufficiency causes SEDAC and a transcriptional network containing HOXD4 and FOXC2 is involved in the development of the dura mater and the etiology of SEDAC.
PMCID: PMC4636324  PMID: 26545093
5.  Excessive reactive oxygen species are therapeutic targets for intervertebral disc degeneration 
Oxidative stress has been reported to be involved in numerous human diseases, including musculoskeletal disorders such as osteoarthritis. However, the interaction between intervertebral disc (IVD) degeneration and oxidative stress is not well understood. The purpose of the present study was to elucidate the contribution of oxidative stress to IVD degeneration and the efficacy of antioxidant treatment for degenerative discs.
The expression level of an oxidative stress marker, nitrotyrosine, was assessed by immunohistochemistry and Western blotting. For evaluating intracellular reactive oxygen species (ROS) levels and oxidative stress in rat annulus fibrosus (AF) cells, flow cytometry and luciferase assay with an OKD48 construct were performed. The grade of IVD degeneration was assessed by magnetic resonance imaging and histological analysis.
A high frequency of nitrotyrosine-positive cells was observed in rat and human degenerative discs. mRNA expression of catabolic factors such as tumor necrosis factor-alpha (TNF-alpha), matrix metalloprotease-3 (MMP-3), and cyclooxygenase-2 (COX-2) was significantly induced by treatment with H2O2 or buthionine sulfoximine, whereas that of aggrecan, an important chondrogenic proteoglycan, was reduced in a dose-dependent manner. Treatment with mitogen-activated protein kinase (MAPK) inhibitors blocked the inductive effect of excessive ROS on COX-2 mRNA expression. Western blotting confirmed the phosphorylation of MAPKs in H2O2 and BSO-treated AF cells. Conversely, we showed that TNF-α induced oxidative stress with increased intracellular ROS levels in AF cells. Treatment with the antioxidant N-acetyl cysteine (NAC) abrogated the catabolic effect of excessive ROS and TNF-alpha in vitro. Finally, we showed that oral administration of NAC prevented IVD degeneration in rat degenerative model.
A positive feedback loop was formed between excessive ROS and TNF-alpha in AF cells. Thus, oxidative stress contributes to the progression of IVD degeneration and NAC can be a therapeutic option for IVD degeneration.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0834-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4635526  PMID: 26542776
Intervertebral disc degeneration; Oxidative stress; Reactive oxygen species; Antioxidant
6.  IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis 
The Journal of Clinical Investigation  2015;125(8):3269-3279.
The unfolded protein response (UPR) is a cellular adaptive mechanism that is activated in response to the accumulation of unfolded proteins in the endoplasmic reticulum. The inositol-requiring protein-1α/X-box–binding protein–mediated (IRE1α/XBP1-mediated) branch of the UPR is highly conserved and has also been shown to regulate various cell-fate decisions. Herein, we have demonstrated a crucial role for the IREα/XBP1-mediated arm of the UPR in osteoclast differentiation. Using murine models, we found that the conditional abrogation of IRE1α in bone marrow cells increases bone mass as the result of defective osteoclastic bone resorption. In osteoclast precursors, IRE1α was transiently activated during osteoclastogenesis, and suppression of the IRE1α/XBP1 pathway in these cells substantially inhibited the formation of multinucleated osteoclasts in vitro. We determined that XBP1 directly binds the promoter and induces transcription of the gene encoding the master regulator of osteoclastogenesis nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Moreover, activation of IRE1α was partially dependent on Ca2+ oscillation mediated by inositol 1,4,5-trisphosphate receptors 2 and 3 (ITPR2 and ITPR3) in the endoplasmic reticulum, as pharmacological inhibition or deletion of these receptors markedly decreased Xbp1 mRNA processing. The present study thus reveals an intracellular pathway that integrates the UPR and osteoclast differentiation through activation of the IRE1α/XBP1 pathway.
PMCID: PMC4563737  PMID: 26193638
7.  Langerhans Cell Histiocytosis of the Clavicle in an Adult: A Case Report and Review of the Literature 
Case Reports in Oncology  2015;8(3):426-431.
Langerhans cell histiocytosis (LCH) usually occurs in children under the age of 10 years with a predilection for the skull, spine, rib and humerus. Solitary LCH occurring in an adult clavicle is uncommon with limited reports to date. The lesion in our patient was curetted with the intent to make a diagnosis, which subsequently lead to the remission of the symptom and the disease. At the final follow-up after 1 year, no local recurrence or metastasis is observed.
PMCID: PMC4649755  PMID: 26600774
Langerhans cell histiocytosis; Clavicle; Adult
8.  Successful Treatment with Pazopanib for Multiple Lung Metastases of Inguinal Epithelioid Sarcoma: A Case Report 
Case Reports in Oncology  2015;8(3):378-384.
Epithelioid sarcoma is a rare soft tissue sarcoma and usually resistant to chemotherapy. It has high rates of local recurrence and distant metastasis, and the prognosis after metastasis is poor. We report a case of multiple lung metastases of an epithelioid sarcoma originating in the inguinal area that we treated with the multikinase inhibitor pazopanib. The patient was a 38-year-old male who began to experience discomfort in his left inguinal area. Magnetic resonance imaging showed a tumor extended from the medial aspect of the wing of the left ilium along the iliopsoas muscle to its site of insertion on the femur. The histopathological diagnosis with a biopsy was proximal-type epithelioid sarcoma. Although a positron emission tomography examination showed fluorodeoxyglucose accumulation in the left inguinal tumor, there was no distant metastasis. Wide resection by a combined iliac resection procedure was performed. Twelve months after surgery, computed tomography revealed multiple nodules and a diagnosis of bilateral multiple lung metastases was made. Treatment with pazopanib 800 mg was started. After 2.5 months of treatment, a clear reduction in the size of the pulmonary metastases was shown. Thirty months after the start of pazopanib treatment, most of the metastases have disappeared, and no development of new lesions has been seen. Therefore, it appeared that pazopanib was capable of serving as one of the choices of therapeutic agents that should be taken into consideration for the treatment of advanced epithelioid sarcoma.
PMCID: PMC4608657  PMID: 26500539
Epithelioid sarcoma; Treatment; Multikinase inhibitor; Pazopanib
9.  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
10.  Three-Component O-Demethylase System Essential for Catabolism of a Lignin-Derived Biphenyl Compound in Sphingobium sp. Strain SYK-6 
Applied and Environmental Microbiology  2014;80(23):7142-7153.
Sphingobium sp. strain SYK-6 is able to assimilate lignin-derived biaryls, including a biphenyl compound, 5,5′-dehydrodivanillate (DDVA). Previously, ligXa (SLG_07770), which is similar to the gene encoding oxygenase components of Rieske-type nonheme iron aromatic-ring-hydroxylating oxygenases, was identified to be essential for the conversion of DDVA; however, the genes encoding electron transfer components remained unknown. Disruption of putative electron transfer component genes scattered through the SYK-6 genome indicated that SLG_08500 and SLG_21200, which showed approximately 60% amino acid sequence identities with ferredoxin and ferredoxin reductase of dicamba O-demethylase, were essential for the normal growth of SYK-6 on DDVA. LigXa and the gene products of SLG_08500 (LigXc) and SLG_21200 (LigXd) were purified and were estimated to be a trimer, a monomer, and a monomer, respectively. LigXd contains FAD as the prosthetic group and showed much higher reductase activity toward 2,6-dichlorophenolindophenol with NADH than with NADPH. A mixture of purified LigXa, LigXc, and LigXd converted DDVA into 2,2′,3-trihydroxy-3′-methoxy-5,5′-dicarboxybiphenyl in the presence of NADH, indicating that DDVA O-demethylase is a three-component monooxygenase. This enzyme requires Fe(II) for its activity and is highly specific for DDVA, with a Km value of 63.5 μM and kcat of 6.1 s−1. Genome searches in six other sphingomonads revealed genes similar to ligXc and ligXd (>58% amino acid sequence identities) with a limited number of electron transfer component genes, yet a number of diverse oxygenase component genes were found. This fact implies that these few electron transfer components are able to interact with numerous oxygenase components and the conserved LigXc and LigXd orthologs are important in sphingomonads.
PMCID: PMC4249175  PMID: 25217011
11.  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
12.  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
13.  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
14.  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
15.  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
16.  Focal Transplantation of Human iPSC-Derived Glial-Rich Neural Progenitors Improves Lifespan of ALS Mice 
Stem Cell Reports  2014;3(2):242-249.
Transplantation of glial-rich neural progenitors has been demonstrated to attenuate motor neuron degeneration and disease progression in rodent models of mutant superoxide dismutase 1 (SOD1)-mediated amyotrophic lateral sclerosis (ALS). However, translation of these results into a clinical setting requires a renewable human cell source. Here, we derived glial-rich neural progenitors from human iPSCs and transplanted them into the lumbar spinal cord of ALS mouse models. The transplanted cells differentiated into astrocytes, and the treated mouse group showed prolonged lifespan. Our data suggest a potential therapeutic mechanism via activation of AKT signal. The results demonstrated the efficacy of cell therapy for ALS by the use of human iPSCs as cell source.
Graphical Abstract
•Transplantation of human iPSC-derived cells to spinal cord of ALS model mice•Transplanted glial-rich NPCs attenuated non-cell autonomous neurodegeneration•Feasibility study for ALS transplantation is presented
Transplantation research as ALS therapy is an important issue. In this study, Inoue and colleagues transplanted glial-rich neural progenitors derived from human iPSCs into the lumbar spinal cord of ALS mice. The transplanted cells differentiated into astrocytes, and the treated mouse group showed prolonged lifespan via increased neurotrophic factors and activation of AKT signal. Human iPSCs could be a promising resource for ALS transplantation therapy.
PMCID: PMC4175543  PMID: 25254338
17.  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
18.  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
19.  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
20.  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
21.  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
22.  Successful treatment in a case of Propionibacterium acnes-associated sarcoidosis with clarithromycin administration: a case report 
Sarcoidosis is recognized as a multiorgan disorder characterized by the presence of non-caseating granulomas in the involved tissues. It has been suggested that sarcoidosis might be due to the exposure to infectious or non-infectious agents in genetically susceptible individuals. In particular, Propionibacterium acnes and Mycobacterium tuberculosis have been considered causative microorganisms. We report a case of P. acnes-associated sarcoidosis in which a drastic improvement was achieved with clarithromycin administration. A possible mechanism of clarithromycin action is discussed.
Case presentation
A 78-year-old Japanese-Mongoloid woman with P. acnes-associated sarcoidosis presented with a persisting fever, joint pains and generalized lymph node swelling. The diagnosis of sarcoidosis was confirmed by pathological and immunohistochemical studies of a biopsied lymph node. In this case, an oral administration of clarithromycin was applied. Soon after the initiation of this treatment her symptoms as well as lymph node swelling disappeared. The clarithromycin treatment was discontinued 3.5 months after its initiation. She is currently in good condition. The pathological analysis of her lymph node, which was obtained during the clarithromycin treatment, suggested an apoptosis-inducing effect of clarithromycin on the sarcoid granulomas.
Clarithromycin was found to be effective for treating sarcoidosis and seems to have important pharmacological effects such as immunosuppression, immunomodulation and induction of apoptosis in addition to its antimicrobial role. In this case, apoptosis in the sarcoid granulomas induced by clarithromycin administration might have resulted in satisfactory improvement.
PMCID: PMC3916803  PMID: 24428939
Apoptosis; Clarithromycin (CAM); Propionibacterium acnes (P. acnes); Sarcoid granuloma; Sarcoidosis; Treatment
23.  Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells 
Cell Research  2012;23(1):70-80.
Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the induced pluripotent stem (iPS) cells and reprograming technologies in medical science. While iPS cells are expected to open a new era providing enormous opportunities in biomedical sciences in terms of cell therapies and regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this review, the pre-clinical investigations of cell therapy for spinal cord injury (SCI) using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo, are outlined. We also wish to discuss the strategy for the first human trails of iPS cell-based cell therapy for SCI patients.
PMCID: PMC3541652  PMID: 23229514
neural stem/progenitor cell; induced pluripotnet stem cell; spinal cord injury; transplantation
24.  Novel Method for Analyzing Locomotor Ability after Spinal Cord Injury in Rats: Technical Note 
Neurologia Medico-Chirurgica  2013;53(12):907-913.
In the research for the treatment of spinal cord injury (SCI), the evaluation of motor function in model rats must be as objective, noninvasive, and ethical as possible. The maximum speed and acceleration of a mouse measured using a SCANET system were previously reported to vary significantly according to severity of SCI. In the present study, the motor performance of SCI model rats was examined with SCANET and assessed for Basso-Beattie-Bresnahan (BBB) score to determine the usefulness of the SCANET system in evaluating functional recovery after SCI. Maximum speed and acceleration within the measurement period correlated significantly with BBB scores. Furthermore, among several phased kinematic factors used in BBB scores, the capability of “plantar stepping” was associated with a drastic increase in maximum speed and acceleration after SCI. Therefore, evaluation of maximum speed and acceleration using a SCANET system is a useful method for rat models of SCI and can complement open field scoring scales.
PMCID: PMC4508735  PMID: 24097095
acceleration; locomotor ability; hindlimb function; speed; spinal cord injury
25.  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

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