The characteristics of the patients with radiologically severe cervical ossification of the posterior longitudinal ligament of the spine: A CT-based multicenter cross-sectional study.

BACKGROUND: Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by heterotopic bone formation in the posterior longitudinal ligament of the spine. We know that the size and distribution of the ossified lesions in patients with OPLL are different in each case. However, the characteristics of the patients with radiologically severe cervical OPLL remain unknown. METHODS: The participants of our study were symptomatic patients with cervical OPLL who were diagnosed by standard radiographs of the cervical spine. Whole-spine CT data and demographic data such as age and sex were obtained from 20 institutions belonging to the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament. According to the number of the levels involved by OPLL, we stratified the patients into two subgroups: severe group (S-group) and non-severe group (NS-group) to delineate the characteristics of radiologically severe patients with cervical OPLL. We also evaluated the most compressed level and the degree of occupying ratio of cervical spinal canal by OPLL at the most compressed level. RESULTS: A total of 234 patients with a mean age of 65 years were recruited. The S-group consisted of 48 patients (21%, 12 females and 36 males) and the NS-group consisted of 92 patients (79%, 22 females and 70 males). The mean age of males in the S-group (68 years old) was significantly higher than that of males in the NS-group (64 years old); however there was no significant difference in the mean age in females between the S-group (69 years old) and the NS-group (66 years old). No significant difference of body mass index, ossification of the nuchal ligament-positivity and presence of diabetes mellitus were found between the S- and the NS-group. CONCLUSIONS: It is likely that the manner of extension of cervical OPLL is different between male and female patients.

Co-existence of ossification of the nuchal ligament is associated with severity of ossification in the whole spine in patients with cervical ossification of the posterior longitudinal ligament -A multi-center CT study.

BACKGROUND: Previous studies have shown that patients with cervical ossification of the posterior longitudinal ligament (OPLL) often have co-existing ossification of the nuchal ligament (ONL). However, no studies have focused on ONL and its relevance to the severity of OPLL or ossification of other spinal ligaments, such as anterior longitudinal ligament (OALL), ligamentum flavum (OLF), and supraspinous/interspinous ligament (OSIL). METHODS: In this multicenter study, we investigated ossification of the spinal ligaments in the whole spine computed tomography (CT) images of 233 cervical OPLL patients. The severity of ossification was evaluated using ossification index for each spinal ligament, calculated as the sum of the level of ossification. We compared the severity of ossification in each spinal ligament between patients with ONL and those without ONL. Furthermore, we investigated how the number of segments, where ONL exists, affects the severity of ossification in each spinal ligament. RESULTS: One hundred thirty patients (55.8%) had co-existing ONL in the cervical OPLL patients included in this study. The ONL (+) group included more male and aged patients. The cervical ossification indexes of OPLL and OALL were higher in ONL (+) patients than in ONL (-) patients. The thoracolumbar ossification indexes of OALL and OSIL were also higher in ONL (+) patients. Logistic regression analysis revealed that age, gender and cervical OA-index were independent factors correlating to the existence of ONL. In the cervical spine, both the ossification indexes of OALL and OPLL increased as the levels of ONL increased. Similarly, in the thoracolumbar spine, both the ossification indexes of OALL and OSIL were increased as the levels of cervical ONL increased. In the multiple regression analysis, cervical OA-index and thoracolumbar OSI-index showed significant correlation with the number of ONL levels. CONCLUSIONS: Co-existence of ONL in cervical OPLL patients was associated with the severity of spinal hyperostosis especially in cervical OPLL, OALL, thoracolumbar OALL and OSIL.

Whole-Genome DNA Methylation Analyses Revealed Epigenetic Instability in Tumorigenic Human iPS Cell-Derived Neural Stem/Progenitor Cells.

Although human induced pluripotent stem cell (hiPSC) derivatives are considered promising cellular resources for regenerative medicine, their tumorigenicity potentially limits their clinical application in hiPSC technologies. We previously demonstrated that oncogenic hiPSC-derived neural stem/progenitor cells (hiPSC-NS/PCs) produced tumor-like tissues that were distinct from teratomas. To gain insight into the mechanisms underlying the regulation of tumorigenicity in hiPSC-NS/PCs, we performed an integrated analysis using the Infinium HumanMethylation450 BeadChip array and the HumanHT-12 v4.0 Expression BeadChip array to compare the comprehensive DNA methylation and gene expression profiles of tumorigenic hiPSC-NS/PCs (253G1-NS/PCs) and non-tumorigenic cells (201B7-NS/PCs). Although the DNA methylation profiles of 253G1-hiPSCs and 201B7-hiPSCs were similar regardless of passage number, the methylation status of the global DNA methylation profiles of 253G1-NS/PCs and 201B7-NS/PCs differed; the genomic regions surrounding the transcriptional start site of the CAT and PSMD5 genes were hypermethylated in 253G1-NS/PCs but not in 201B7-NS/PCs. Interestingly, the aberrant DNA methylation profile was more pronounced in 253G1-NS/PCs that had been passaged more than 15 times. In addition, we identified aberrations in DNA methylation at the RBP1 gene locus; the DNA methylation frequency in RBP1 changed as 253G1-NS/PCs were sequentially passaged. These results indicate that different NS/PC clones have different DNA methylomes and that DNA methylation patterns are unstable as cells are passaged. Therefore, DNA methylation profiles should be included in the criteria used to evaluate the tumorigenicity of hiPSC-NS/PCs in the clinical setting. Stem Cells 2017;35:1316-1327.

Distribution of ossified spinal lesions in patients with severe ossification of the posterior longitudinal ligament and prediction of ossification at each segment based on the cervical OP index classification: a multicenter study (JOSL CT study).

BACKGROUND: In patients with ossification of the posterior longitudinal ligament (OPLL) in the cervical spine, it is well known that the thoracic ossified lesions often coexist with the cervical lesions and can cause severe myelopathy. However, the prevalence of OPLL at each level of the thoracic and lumbar spinal segments is unknown. The aims of this study were to investigate how often OPLL occurs at each level in the thoracolumbar spine in patients with a radiological diagnosis of cervical OPLL and to identify the spinal levels most likely to develop ossification. METHODS: Data were collected from 20 institutions in Japan. Three hundred and twenty-two patients with a diagnosis of cervical OPLL were included. The OPLL index (OP index), defined as the sum of the vertebral body and intervertebral disc levels where OPLL is present, was used to determine disease severity. An OP index ≥20 was defined as severe OPLL. The prevalence of OPLL at each level of the thoracic and lumbar spinal segments was calculated. RESULTS: Women were more likely to have ossified lesions in the thoracolumbar spine than men. Severe OPLL was significantly more common in women than in men (20% vs. 4.5%). For thoracic vertebral OPLL, the most frequently affected was the T1 segment in both men and women, followed by the T1/2 and T3/4 intervertebral levels in men and women, respectively. Ossified lesions were frequently seen at the intervertebral and vertebral levels around the cervicothoracic and thoracolumbar junctions in men with severe OPLL, whereas OPLL was more diffusely distributed in the thoracic spine in women with severe OPLL. CONCLUSION: Thoracolumbar OPLL occurred most often at T1 in men and at T3/4 in women. In severe OPLL cases, although ossified lesions were frequently seen at the intervertebral and vertebral levels around the cervicothoracic and thoracolumbar junctions in men, OPLL could be observed more diffusely in the thoracic spine in women.

A screening method to distinguish syndromic from sporadic spinal extradural arachnoid cyst.

BACKGROUND: Spinal extradural arachnoid cyst (SEDAC) is a cystic lesion that protrudes into the epidural space from a small dural defect. Early diagnosis of SEDAC is important because its expansion causes neurological damage. Two types of SEDAC, syndromic and sporadic, are present. Syndromic SEDAC is inherited as a part of lymphedema-distichiasis syndrome caused by mutations in the FOXC2 gene; however, it is often mistaken as sporadic because of low penetrance. It is not reasonable to conduct a genetic testing for all SEDAC patients and their family members. The aim of this study is to establish an effective screening method to distinguish syndromic SEDAC from sporadic SEDAC. METHODS: We performed a retrospective review of medical records and imaging studies of 29 subjects who were diagnosed with SEDAC. Clinical features, family history and magnetic resonance imaging (MRI) were analyzed. Mutations in FOXC2 were examined by Sanger-sequencing of the entire coding region of the genes. SEDAC having a mutation in FOXC2 gene was defined with syndromic SEDAC. RESULTS: Eleven subjects had a heterozygous mutation in FOXC2. They were all familial and hence syndromic SEDAC. Only one proband had known family history of SEDAC at diagnosis. MRI findings and physical examinations, especially eye and leg examinations, were quite useful to screen syndromic SEDAC. Physical examination often showed accompanying lymphedema and distichiasis in syndromic SEDAC. Syndromic SEDAC tended to have multiple cysts out of the thoracolumbar area. CONCLUSIONS: We established an effective screening method based on physical examinations and MRI findings.

Application of q-Space Diffusion MRI for the Visualization of White Matter.

White matter abnormalities in the CNS have been reported recently in various neurological and psychiatric disorders. Quantitation of non-Gaussianity for water diffusion by q-space diffusional MRI (QSI) renders biological diffusion barriers such as myelin sheaths; however, the time-consuming nature of this method hinders its clinical application. In the current study, we aimed to refine QSI protocols to enable their clinical application and to visualize myelin signals in a clinical setting. For this purpose, animal studies were first performed to optimize the acquisition protocol of a non-Gaussian QSI metric. The heat map of standardized kurtosis values derived from optimal QSI (myelin map) was then created. Histological validation of the myelin map was performed in myelin-deficient mice and in a nonhuman primate by monitoring its variation during demyelination and remyelination after chemical spinal cord injury. The results demonstrated that it was sensitive enough to depict dysmyelination, demyelination, and remyelination in animal models. Finally, its utility in clinical practice was assessed by a pilot clinical study in a selected group of patients with multiple sclerosis (MS). The human myelin map could be obtained within 10 min with a 3 T MR scanner. Use of the myelin map was practical for visualizing white matter and it sensitively detected reappearance of myelin signals after demyelination, possibly reflecting remyelination in MS patients. Our results together suggest that the myelin map, a kurtosis-related heat map obtainable with time-saving QSI, may be a novel and clinically useful means of visualizing myelin in the human CNS. SIGNIFICANCE STATEMENT: Myelin abnormalities in the CNS have been gaining increasing attention in various neurological and psychiatric diseases. However, appropriate methods with which to monitor CNS myelin in daily clinical practice have been lacking. In the current study, we introduced a novel MRI modality that produces the "myelin map." The myelin map accurately depicted myelin status in mice and nonhuman primates and in a pilot clinical study of multiple sclerosis patients, suggesting that it is useful in detecting possibly remyelinated lesions. A myelin map of the human brain could be obtained in <10 min using a 3 T scanner and it therefore promises to be a powerful tool for researchers and clinicians examining myelin-related diseases.

Striking the balance between PTEN and PDK1: it all depends on the cell context.

The phosphatidyl-inosital-3 kinase (PI3K) signaling pathway is critical for normal brain development and function and is commonly hyperactivated in brain cancer. The PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor protein and phosphate-depended kinase 1 (PDK-1) are critical regulators of this pathway. In the July 15, 2009, issue of Genes & Development, Chalhoub and colleagues (pp. 1619-1624) demonstrate PDK1-dependent and PDK1-independent effects of conditional PTEN deletion in the brain, and they identify cell type-specific differences in feedback regulation of the PI3K pathway. These studies provide important insights as to how neurons and glia may differentially regulate PI3K signaling, yielding intriguing clues about targeting PTEN-deficient brain cancers.

A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma.

Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations that activate receptor tyrosine kinase (RTK) and Pi-3 kinase (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic glial tumors that display many features of human glioblastoma. In both human and Drosophila, activation of the RTK and PI3K pathways stimulates Akt signaling along with other as-yet-unknown changes that drive oncogenesis. We used this Drosophila glioblastoma model to perform a kinome-wide genetic screen for new genes required for RTK- and PI3K-dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian glioblastoma models and human tumors. Our results revealed that the atypical kinases RIOK1 and RIOK2 are overexpressed in glioblastoma cells in an Akt-dependent manner. Moreover, we found that overexpressed RIOK2 formed a complex with RIOK1, mTor, and mTor-complex-2 components, and that overexpressed RIOK2 upregulated Akt signaling and promoted tumorigenesis in murine astrocytes. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity in glioblastoma cells by inducing p53 activity through the RpL11-dependent ribosomal stress checkpoint. These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into defects underlying glioblastoma and related cancers and may reveal new therapeutic opportunities for these cancers.

PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.

Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it.

Prevalence and distribution of ossification of the supra/interspinous ligaments in symptomatic patients with cervical ossification of the posterior longitudinal ligament of the spine: a CT-based multicenter cross-sectional study.

BACKGROUND: Supra/interspinous ligaments connect adjacent spinous processes and act as a stabilizer of the spine. As with other spinal ligaments, it can become ossified. However, few report have discussed ossification supra/interspinous ligaments (OSIL), so its epidemiology remains unknown. We therefore aimed to investigate the prevalence and distribution of OSIL in symptomatic patients with cervical ossification of the posterior longitudinal ligament (OPLL). METHODS: The participants of our study were symptomatic patients with cervical OPLL who were diagnosed by standard radiographs of the cervical spine. The whole spine CT data as well as clinical parameters such as age and sex were obtained from 20 institutions belong to the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament (JOSL). The prevalence and distribution of OSIL and the association between OSIL and clinical parameters were reviewed. The sum of the levels involved by OPLL (OP-index) and OSIL (OSI-index) as well as the prevalence of ossification of the nuchal ligament (ONL) were also investigated. RESULTS: A total of 234 patients with a mean age of 65 years was recruited. The CT-based evidence of OSIL was noted in 68 (54 males and 14 females) patients (29%). The distribution of OSIL showed a significant thoracic preponderance. In OSIL-positive patients, single-level involvement was noted in 19 cases (28%), whereas 49 cases (72%) presented multi-level involvement. We found a significant positive correlation between the OP-index grade and OSI-index. ONL was noted at a significantly higher rate in OSIL-positive patients compared to negative patients. CONCLUSIONS: The prevalence of OSIL in symptomatic patients with cervical OPLL was 29%. The distribution of OSIL showed a significant thoracic preponderance.

Epidemiological survey of ossification of the posterior longitudinal ligament by using clinical investigation registration forms.

BACKGROUND: In Japan, ossification of the posterior longitudinal ligament (OPLL) has been designated as an intractable disease by the Ministry of Health, Labour, and Welfare. Here we aimed to clarify the epidemiological characteristics of severe OPLL patients by analyzing a national registry of this disease that uses clinical investigation registration forms. METHODS: We retrospectively investigated clinical investigation registration forms for 24,502 patients with OPLL. We examined the sex distribution, age of disease onset, period from disease onset to registration, family history, site of ossification as determined by plain radiographs, Japanese Orthopaedic Association score, and number of OPLL surgeries. RESULTS: The male-to-female ratios were 2.7:1 and 1.9:1 for new and renewed registrations, respectively. The mean ages at disease onset were 61.1 and 59.7 years for new and renewed registrations, respectively. The mean periods from disease onset to registration were 2.6 and 8.4 years for new and renewed registrations, respectively. The percentages of new registrations with and without family history were 5.3% and 51.5%, respectively (unknown for 43.3%). Of the new registrations, 3511, 359, and 200 cases exhibited ossification in the cervical spine, thoracic spine, and lumbar spine, respectively; the corresponding numbers for renewed registrations were 13,710, 2484, and 1508. The Japanese Orthopaedic Association score was 9.9 ± 3.6 for new registrations, and the mean score recovery rate for renewed registrations was 6.0%. The number of OPLL surgeries was one or zero, two, three, four, or five for 21,785, 2167, 412, 99, and 39 patients, respectively, with 11.1% of all patients having undergone multiple surgeries. CONCLUSIONS: This study offers new insight into the epidemiological characteristics of severe OPLL. In particular, we found that the age of disease onset was higher than previously reported, the period from disease onset to registration (surgery) was relatively short, and about 90% of the patients required only a single surgery.

Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma.

Despite recent advances in molecular classification, surgery, radiotherapy, and targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In this study, we have identified the tetraspan protein epithelial membrane protein-2 (EMP2) as a potential target for glioblastoma (GBM) killing. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. In GBM cells, EMP2 enhanced tumor growth in vivo in part by up-regulating αvß3 integrin surface expression, activating focal adhesion kinase and Src kinases, and promoting cell migration and invasion. Consistent with these findings, EMP2 expression significantly correlated with activated Src kinase in patient samples and promoted tumor cell invasion using intracranial mouse models. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents. These reagents were effective in killing GBM cells in vitro and in reducing tumor load in subcutaneous mouse models. These results support the role of EMP2 in the pathogenesis of GBM and suggest that anti-EMP2 treatment may be a novel therapeutic treatment.

Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240.

Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

A Novel Percutaneous Guide Wire (S-Wire) for Percutaneous Pedicle Screw Insertion: Its Development, Efficacy, and Safety.

PURPOSE: Minimally invasive spine stabilization (MISt) procedures, including MIS-transforaminal lumbar interbody fusion (MIS-TLIF), rely on precise placement of percutaneous pedicle screws (PPS). Serious intraoperative complications associated with PPS placement include great vessel and bowel injuries due to the guide-wire's anterior migration and penetration through the anterior aspect of the vertebral body. To address this issue, we developed a novel percutaneous guide wire (S-wire) and compared the biomechanical characteristics of S-wire and conventional wire in cadaveric spines, and to evaluate the S-wire's efficacy and safety in a clinical trial. METHODS: The S-wire is hollow, with braided wires extending at one tip. We compared the push-out and penetration forces of the S-wire and conventional wire in fresh cadaveric lumbar spines, from L1 to L5. RESULTS: Push-out forces caused the braided tip of the S-wire to bend or spread, and thus to resist anterior migration. The mean push-out forces for the S-wire and conventional wire were 15.5 ± 1.9 and 5.7 ± 0.8 N, respectively (P < .0001); the mean penetration forces were 69.1 ± 4.2 and 37.1± 4.8 N, respectively (P < .0005). There was no wire breakage or anterior-wall penetration in a clinical trial of 922 S-wires; interestingly, the pull-out force increased in 780 (84.6%) S-wires after placement. CONCLUSIONS: The mean push-out and penetration forces for the S-wire were approximately 3 and 2 times greater than those of conventional wire, respectively. The S-wire effectively prevented guide-wire anterior migration and penetration of the anterior vertebral-body wall. The S-wire device should effectively improve the safety of MISt procedures, including MIS-TLIF and percutaneous kyphoplasty in selected patient with osteoporosis.

Factors contributing to improvement of syringomyelia after foramen magnum decompression for Chiari type I malformation.

BACKGROUND: Although various surgical approaches have been proposed for treating syringomyelia associated with Chiari type I malformation, a standard method has yet to be established. we prospectively investigated the results of our surgical method: foramen magnum decompression combined with C1 laminectomy and excision of the outer layer of the dura mater. METHODS: Twenty patients underwent surgery between 2000 and 2010 at our hospital. After surgery, the size of the syrinx decreased in 11 patients (decreased group) but remained unchanged in nine patients (unchanged group). The following parameters were compared: age at the time of surgery, duration of morbidity, improvement of preoperative symptoms, morphological type and length of the syrinx, presence or absence of scoliosis, cervical alignment, basal and clivo-axial angles, and postoperative subarachnoid space at the foramen magnum level. RESULTS: Preoperative symptoms improved in all patients in the decreased group but in only one patient in the unchanged group. The average duration of morbidity was significantly shorter in the decreased group. Morphological examination revealed that the size of all central-type syrinxes decreased after surgery, whereas in all cases of deviated-type syrinx, size was unchanged. The average length of preoperative syrinx was significantly shorter in the decreased group. The postoperative subarachnoid space at the foramen magnum was enlarged in the entire decreased group, whereas residual narrowing of the space was observed in 44 % of patients in the unchanged group. No significant intergroup differences were observed in the other factors. CONCLUSIONS: In patients with syringomyelia, a longer and deviated type of syrinx, a longer duration of morbidity, and postoperative residual narrowing of the subarachnoid space are associated with a poor prognosis after the surgical procedure. The pathogenesis of syringomyelia is inconsistent, and the choice of surgical technique for each pathological condition is important.

High preoperative hemoglobin A1c is a risk factor for surgical site infection after posterior thoracic and lumbar spinal instrumentation surgery.

BACKGROUND: Diabetes mellitus (DM) is reported to be a risk factor for surgical site infection (SSI), which is a serious complication after spinal surgery. The effect of DM on SSI after instrumented spinal surgery remains to be clarified. The aim was to elucidate perioperative risk factors for infection at the surgical site after posterior thoracic and lumbar spinal arthrodesis with instrumentation in patients with DM. METHODS: Consecutive patients who underwent posterior instrumented thoracic and lumbar spinal arthrodesis during the years 2005-2011, who could be followed for at least 1 year after surgery, were included. These included 36 patients with DM (19 males and 17 females; mean age 64.3 years). The patients' medical records were retrospectively reviewed to determine the SSI rate. The characteristics of the DM patients were examined in detail, including the levels of serum glucose and HbA1c, which indicate the level of diabetes control. RESULTS: Patients with DM had a higher rate of SSI (6 of 36 patients, 16.7 %) than patients without DM (10 of 309 patients, 3.2 %). Although the perioperative serum glucose level did not differ between DM patients that did or did not develop SSI, the preoperative HbA1c value was significantly higher in the patients who developed SSI (7.6 %) than in those who did not (6.9 %). SSI developed in 0.0 % of the patients with controlled diabetes (HbA1c <7.0 %) and in 35.3 % of the patients with uncontrolled diabetes (HbA1c ≥7.0 %). CONCLUSIONS: DM patients whose blood glucose levels were poorly controlled before surgery were at high risk for SSI. To prevent SSI in DM patients, we recommend lowering the HbA1c to <7.0 % before performing surgery.

[Cervical spondylosis].

Japan has now become an aging society. In 2014, people aged more than 65 years old accounted for 25.1% of Japan's entire population. Aging is associated with an increased risk of problems related to the locomotive organs. Deterioration of locomotive ability causes falls or tumbles, which would be a threat to good health and longevity of aged people. To maintain the locomotive ability of the elderly, therefore, the Japanese Orthopaedic Association starts a campaign to promote awareness and prevention of "locomotive syndrome". Cervical spondylosis is a disorder for age-related wear affecting the disks and vertebrae of cervical spine. It would also be a cause of "locomotive syndrome". Here, we give an outline of this disease and introduce its diagnosis and treatment.

A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord.

Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI.

Spinal coronal profiles and proximal femur bone mineral density in adolescent idiopathic scoliosis.

PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation.

The phosphatase and tensin homolog (PTEN) is a tumor suppressor that is inactivated in many human cancers. PTEN loss has been associated with resistance to inhibitors of the epidermal growth factor receptor (EGFR), but the molecular basis of this resistance is unclear. It is believed that unopposed phosphatidylinositol-3-kinase (PI3K) activation through multiple receptor tyrosine kinases (RTKs) can relieve PTEN-deficient cancers from their "dependence" on EGFR or any other single RTK for survival. Here we report a distinct resistance mechanism whereby PTEN inactivation specifically raises EGFR activity by impairing the ligand-induced ubiquitylation and degradation of the activated receptor through destabilization of newly formed ubiquitin ligase Cbl complexes. PTEN-associated resistance to EGFR kinase inhibitors is phenocopied by expression of dominant negative Cbl and can be overcome by more complete EGFR kinase inhibition. PTEN inactivation does not confer resistance to inhibitors of the MET or PDGFRA kinase. Our study identifies a critical role for PTEN in EGFR signal termination and suggests that more potent EGFR inhibition should overcome resistance caused by PI3K pathway activation.