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IFN regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PML-promoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference–mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression. [Cancer Res 2007;67(23):11133–40]

Supplementary Figures 1-4 from Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells

The purpose of this study was to identify the criteria for atlantoaxial (AA) fusion by comparing follow-up lateral radiographs and computed tomography (CT) images. We retrospectively analyzed data from 161 consecutive patients undergoing AA fusion. Patients with a minimum of 1 year of CT follow-up after AA fusion surgery using C2 pedicle screws or translaminar screws (C2TLS) were included. Patients were followed up radiographically at 3, 6, and 12 months after surgery, and dynamic lateral radiographs were also evaluated. A total of 49 patients were analyzed, with a mean CT image follow-up of 41.6 ± 37.6 months. Thirty eight patients had C2 pedicle screw placement, and 11 patients underwent planned C2TLS. AA fusion with bridging bone mass formation was achieved in 45/49 (91.8%) patients. Screw halos were observed in 14/49 (28.6%) patients. Among them, final fusion failure occurred in 2 (14.3%) patients. The last follow-up CT showed no difference in the fusion failure rate according to the presence or absence of a screw halo (no halo, 5.7%; halo, 14.3%; P = .33). The differences in C1-2 segmental angles (SA) in flexion-extension dynamic lateral radiographs were 1.99 ± 1.62° in the fusion group and 4.37 ± 2.13° in the non-fusion group (P = .01). The likelihood of fusion failure increased when the SA gap was greater than 2.62° (P = .05). C2TLS placement had a significantly higher incidence of screw halos. However, the halo sign was not significantly related to final bone fusion. Bone fusion could be predicted when the SA gap of C1-2 was less than 2.62° on the dynamic radiograph.

Ligamentum flavum hypertrophy (LFH) is a known contributor to lumbar spinal canal stenosis (LSCS). However, the clinical significance and quantitative role of LFH compared to other components, such as disc bulging and facet hypertrophy, have not yet been examined. We investigated the correlation between the quantitative radiological factors, clinical symptoms, and outcomes in patients with LSCS. In total, 163 patients diagnosed with single-level (L4-L5) stenosis were included. The patients were divided into 2 groups according to claudication severity:100 m for mild (n = 92) and100 m for severe (n = 71). The visual analog scale (VAS) was used to quantify back and leg pain, and the Oswestry Disability Index (ODI) and Short form-36 (SF-36) physical component summary (PCS) scores, and Macnab criteria were evaluated as clinical factors 6 months after treatment. We measured the baseline canal cross-sectional area, ligamentum flavum (LF) area, disc herniation area, dural sac area, fat area, and LF thickness using MRI. A comparative analysis was performed to evaluate the association between radiologic and clinical factors. Additionally, further comparative analyses between the types of surgeries were performed. Among various radiologic factors, the baseline LF thickness (odds ratio [OR] 1.73; 95% confidence interval [CI] 1.25-2.41) was the only major contributing factor to the severity of claudication in the multivariate logistic regression analysis. The types of surgery (decompression alone vs fusion) did not significantly differ in terms of their clinical outcomes, including back and leg VAS, ODI, SF-36 PCS, and satisfaction with the MacNab classification. LF thickness is a major factor contributing to claudication severity.

Objective: Intractable back pain and radicular pain after lumbosacral spine surgery are challenges for surgeons because the pathophysiology of failed back surgery syndrome (FBSS) remains unknown. Various medications, exercise, reoperation, spinal cord stimulation, and various interventional treatments, such as epidural injection, and radiofrequency treatment, have been suggested as treatment options. However, the clinical outcomes for each treatment are unclear. Methods: We retrospectively evaluated clinical outcomes of consecutive FBSS patients who underwent revision operation or radiofrequency treatment from 2014 to 2017, who previously showed response to nerve block. Pain was analyzed preoperatively and 1 month, 6 months, and 12 months postoperatively using a visual analogue scale (VAS). Short Form 36 (SF-36) health survey and Oswestry Disability Index (ODI) scores were assessed preoperatively and 12 months postoperatively. Results: A total of 70 patients was included in the present study (33 males, 37 females). When comparing preoperative and postoperative 12-month results, back pain VAS score decreased from 5.5 to 4.2 for revision operation and from 5.1 to 4.7 for radiofrequency treatment. Leg pain VAS score decreased from 6.5 to 4.02 for revision operation and 6.2 to 4.3 for radiofrequency treatment. ODI score decreased from 70.9 to 36.1 for revision operation and 70.2 to 36.1 for radiofrequency treatment. SF-36 score increased from 28.9 to 64.1 for revision operation and from 29.6 to 59.6 for radiofrequency treatment. Differences between treatments were not statistically significant after 12 months (p>0.05) but were at 1 month (p=0.01). Conclusion: Compared with revision operation, radiofrequency treatment is not inferior on early clinical outcome (up to 1 year following the treatment) in terms of pain relief, functional capacity, patient satisfaction, and quality of life in patients with FBSS. Radiofrequency treatment can be considered in patients who are not good candidates for surgical treatment based on imaging results or underlying diseases and who are responsive to diagnostic/therapeutic nerve blocks.

Ligamentum flavum hypertrophy (LFH) is the most important component of lumbar spinal canal stenosis. Although the pathophysiology of LFH has been extensively studied, no method has been proposed to prevent or treat it. Since the transforming growth factor‐β (TGF‐β) pathway is known to be critical in LFH pathology, we investigated whether LFH could be prevented by blocking or modulating the TGF‐β mechanism. Human LF cells were used for the experiments. First, we created TGF‐β receptor 1 (TGFBR1) knock out (KO) cells with CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 biotechnology and treated them with TGF‐β1 to determine the effects of blocking the TGF‐β pathway. Subsequently, we studied the effect of CCN5, which has recently been proposed to modulate the TGF‐β pathway. To assess the predisposition toward fibrosis, α‐smooth muscle actin (αSMA), fibronectin, collagen‐1, collagen‐3, and CCN2 were evaluated with quantitative real‐time polymerase chain reaction, western blotting, and immunocytochemistry. The TGFBR1 KO LF cells were successfully constructed with high KO efficiency. In wild‐type (WT) cells, treatment with TGF‐β1 resulted in the overexpression of the messenger RNA (mRNA) of fibrosis‐related factors. However, in KO cells, the responses to TGF‐β1 stimulation were significantly lower. In addition, CCN5 and TGF‐β1 co‐treatment caused a notable reduction in mRNA expression levels compared with TGF‐β1 stimulation only. The αSMA protein expression increased with TGF‐β1 but decreased with CCN5 treatment. TGF‐β1 induced LF cell transdifferentiation from fibroblasts to myofibroblasts. However, this cell transition dramatically decreased in the presence of CCN5. In conclusion, CCN5 could prevent LFH by modulating the TGF‐β pathway. © 2019 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2634–2644, 2019

The generation of induced neural stem cells (iNSCs) from somatic cells using defined factors provides new avenues for basic research and cell therapies for various neurological diseases, such as Parkinson’s disease, Huntington’s disease, and spinal cord injuries. However, the transcription factors used for direct reprogramming have the potential to cause unexpected genetic modifications, which limits their potential application in cell therapies. Here, we show that a combination of four chemical compounds resulted in cells directly acquiring a NSC identity; we termed these cells chemically-induced NSCs (ciNSCs). ciNSCs expressed NSC markers (Pax6, PLZF, Nestin, Sox2, and Sox1) and resembled NSCs in terms of their morphology, self-renewal, gene expression profile, and electrophysiological function when differentiated into the neuronal lineage. Moreover, ciNSCs could differentiate into several types of mature neurons (dopaminergic, GABAergic, and cholinergic) as well as astrocytes and oligodendrocytes in vitro. Taken together, our results suggest that stably expandable and functional ciNSCs can be directly reprogrammed from mouse fibroblasts using a combination of small molecules without any genetic manipulation, and will provide a new source of cells for cellular replacement therapy of neurodegenerative diseases.

The sacral spinal epidural space is an uncommon site for primary malignant lymphomas, presenting with symptoms associated with cauda equina compression. Especially, lumbo-sacral epidural lymphoma has been reported to be very rare. We present a rare case of 29-year-old male with sacral spinal epidural malignant lymphoma. The patient complained of tingling sensation in his buttocks that was radiating to his calf. The neurological examination was normal. Magnetic resonance imaging (MRI) with contrast showed a well-defined extradural mass lesion at the mid L5 to mid S2 level. The lesion was iso- to hypointense on T1 and T2 weighted images and showed homogenous enhancement and a focal enhancement in the L5 vertebral body on post-contrast images. The patient underwent a L5-S2 laminectomy and subtotal excision of the lesion. Intra-operatively, the lesion was extradural and not densely adherent to the dura; the lesion was friable, not firm, fleshy, brownish and hypervascular. The histologic diagnosis was grade 2 non-Hodgkin's follicular lymphoma. Even though the primary spinal epidural non-Hodgkin's lymphoma is a very rare disease, clinicians should take it into consideration in the differential diagnosis of patients with spinal epidural tumor.

Benign Metastasizing Leiomyoma (BML) is a rare disease that results from metastasis of uterine leiomyoma to distant sites with benign pathologic features. Spine BML is very rare so the information of its features and pathophysiology is seldom known. We experienced a case of 42-year-old woman who presented with right buttock and leg pain with paresthesia. She had a surgical history of uterine myomectomy. Magnetic resonance imaging (MRI) of the lumbar spine revealed a well-circumscribed mass lesion in the posterior compartment of the L4 vertebral body, with extension into the ventral epidural space and both foramina. The mass showed hypointensity on T1-, T2-weighted images and strong homogeneous enhancement on gadolinium enhanced T1-weighted images. Tumor removal was conducted, and permanent biopsy revealed the mass as leiomyoma. Nine previous spine BML reports, which are known for all, were reviewed along with our case. We collated the clinical information and MRI findings of spine BML to figure out its common denominators. Premenopausal women, previous history of uterine myoma, myomectomy/hysterectomy, and lung BML seemed to be predisposing clinical factors. For the imaging findings, posterior vertebral body invasion with bony destruction, neural foramen invasion, and canal encroachment were shown as common denominators. Especially in MRI findings, low T1 and T2 signal intensities with strong homogeneous enhancement were their common features. We gathered the fragmentary information of the spine BML for the first time, especially the MRI findings. Although spine BML is rare, it surely exists. Accordingly, spine surgeons should be suspicious of spine BML given its typical clinical history and MRI findings.

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner.

Microsurgical bilateral decompression via a unilateral approach for lumbar spinal stenosis is a less invasive technique compared to conventional laminectomy. Although many technical reports have demonstrated acceptable overall surgical outcomes for this approach, no studies have attempted to clarify the clinical outcomes thereof in regard to anatomical variance of the spinal canal. This study was conducted to analyze the clinical outcomes of microsurgical bilateral decompression via a unilateral approach according to spinal canal morphology in degenerative lumbar spinal stenosis. Between January 2008 and December 2009, 144 patients with single-level spinal lumbar stenosis underwent microsurgical bilateral decompression via a unilateral approach by a single surgeon. Patients were categorized into three groups according to spinal canal shape: round (n = 42), oval (n = 36), and trefoil (n = 66), and clinical parameters were assessed both before and after surgery with 2–3 years of follow-up. Mean visual analog scale (VAS) and Oswestry disability index (ODI) decreased after surgery, respectively, from 8.1 and 59.8 % to 2.1 and 19.1 % in the round shaped spinal canal group, from 7.2 and 47.1 % to 2.2 and 15.1 % in the oval shaped spinal canal group, and from 6.8 and 53.6 % to 3.6 and 33.3 % in the trefoil shaped spinal canal group. In all groups, VAS and ODI scores significantly improved postoperatively (p

Majority of the previous studies compared lumbar spinal stenosis (LSS) and lumbar disc herniation (LDH) patients for analyses of LFH. However, the separation of normal/hypertrophied LF has often been ambiguous and the severity of hypertrophic activity differed. Here, we present a novel analysis scheme for LFH in which myofibroblast is proposed as a major etiological factor for LFH study. Seventy-one LF patient tissue samples were used for this study. Initially, mRNA levels of the samples were assessed by qRT-PCR: angiopoietin-like protein-2 (ANGPTL2), transforming growth factor-beta1 (TGF-β1), vascular endothelial growth factor (VEGF), interleukin-6, collagen-1, 3, 4, 5, and 11, and elastin. Myofibroblasts were detected by immune stain using α-smooth muscle actin (αSMA) as a marker. To study the myofibroblast in TGF-β pathway, LF tissues were analyzed for protein levels of αSMA/TGF-β1 by Western blot. In addition, from LF cells cultured with exogenous TGF-β1 conditioned medium, expression of αSMA/collagen-1 was assessed and the cell morphology was identified. The comparative analysis of mRNA expression levels (LSS vs LDH) failed to show significant differences in TGF-β1 (p = 0.08); however, we found a significant positive correlation among ANGPTL2, VEGF, TGF-β1, and collagen-1 and 3, which represent common trends in hypertrophic activity (p

Onyx embolization is one of the standard treatments for brain arteriovenous malformations (AVMs) and is a promising method for spinal AVMs as well. Its advantages have been emphasized, and few complications have been reported with Onyx embolization in spinal AVMs. Here, we report an incidental anterior spinal artery (ASA) occlusion due to Onyx reflux during embolization of a spinal type II AVM.A 15-year-old boy presented with weakness in both upper and lower extremities. Magnetic resonance imaging and spinal angiogram revealed a spinal type II AVM with two feeders including the right vertebral artery (VA) and the right deep cervical artery.Onyx embolization was performed gradually from the VA to the deep cervical artery and an unexpected Onyx reflux to the ASA was observed during the latter stage deep cervical artery embolization. Post-operative quadriplegia and low cranial nerves (CN) dysfunction were observed. Rehabilitation treatment was performed and the patient showed marked improvement of neurologic deterioration at 1-year follow-up.Onyx is an effective treatment choice for spinal AVMs. However, due to the small vasculature of the spine compared to the brain, the nidus is rapidly packed with a small amount of Onyx, which allows Onyx reflux to unexpected vessels. Extreme caution is required and dual-lumen balloon catheter could be considered for Onyx embolization in spinal AVMs treatment.

Objective To assess the clinical and radiological factors as predictors for successful outcomes in lumbar disc herniation (LDH) treatment. Methods Two groups of patients with single level LDH (L4–5) requiring treatment were retrospectively studied. The surgery group (SG) included 34 patients, and 30 patients who initially refused the surgery were included in the nerve blocks group (NG). A visual analogue scale (VAS) for leg and back pain and motor deficit were initially evaluated before procedures, and repeated at 1, 6, and 12 months. Radiological factors including the disc herniation length, disc herniation area, canal length-occupying ratio, and canal area-occupying ratio were measured and compared. Predicting factors of successful outcomes were determined with multivariate logistic regression analysis after the optimal cut off values were established with a receiver operating characteristic curve. Results There was no significant demographic difference between two groups. A multivariate logistic regression analysis with radiological and clinical (12 months follow-up) data revealed that the high disc herniation length with cutoff value 6.31 mm [odds ratio (OR) 2.35; confidence interval (CI) 1.21–3.98] was a predictor of successful outcomes of leg pain relief in the SG. The low disc herniation length with cutoff value 6.23 mm (OR 0.05; CI 0.003–0.89) and high baseline VAS leg (OR 12.63; CI 1.64–97.45) were identified as predictors of successful outcomes of leg pain relief in the NG. Conclusion The patients with the disc herniation length larger than 6.31 mm showed successful outcomes with surgery whereas the patients with the disc herniation length less than 6.23 mm showed successful outcomes with nerve block. These results could be considered as a radiological criteria in choosing optimal treatment options for LDH.

We report two cases of cervical spinal epidural abscess (SEA), which are related to anterior cervical surgeries. The first case reveals a late postoperative infection without any predisposing factor. The second case reveals combined complication of infection and instrument failure (artificial disc). Both two cases manifested ascending infections that are unusual courses of anterior cervical infections. The abscess extended upwards and, finally, caused life threatening bacterial meningitis. We suggest aggressive surgical interventions with anti-bacterial therapies in such cases.

Objective Understanding the microanatomy of the proximal middle cerebral artery (M1) and its early branches is very important for aneurysm surgery in this region. However, few articles provide detailed descriptions of such aneurysms. We report the angiographic characteristics of a series of M1 aneurysms and our experience with M1 aneurysm surgery. Materials and methods Twenty-three patients with 25 (combined) M1 aneurysms presented to our institution from January 2001 to December 2006. We examined the general characteristics and angiographic features of the M1 aneurysms, such as site, size, direction, and their association with early branches. Results Of the 23 patients with M1 aneurysms, 13 were women and 10 were men. Nineteen of the aneurysms had ruptured prior to presentation. Multiple aneurysms were observed in 10 of the patients. Angiography showed that 14 of the aneurysms were less than 5 mm in size, and most of the aneurysmal projections were superior. Eighteen of the aneurysms involved early frontal branches and three involved the lenticulostriate arteries. Postoperative infarction was seen in eight patients. Five of the eight patients showed either no or slight neurological deficits at the follow-up visit. One patient, however, suffered from hemiparesis and aphasia that corresponded to the vascular territory of the early frontal branches and lenticulostriate arteries. Two patients had a total MCA infarction and a posterior fossa infarction, respectively. Conclusions This study highlights the need for the critical management of M1 aneurysms, taking into consideration the size and number of aneurysms. By performing careful angiographic investigation of the aneurysm and related early arterial branches of M1, postoperative complications may be minimized.

A 13-year-old boy presented with a rare spontaneous spinal chronic subdural hematoma (SCSDH) with no associated trauma or medical problems manifesting as back and bilateral lower extremity pain persisting for 10 days. Neurological examination revealed mild weakness and paresthesia in both lower extremities. Magnetic resonance (MR) imaging performed 1 week after the appearance of symptoms revealed a chronic subdural hematoma at the thoracolumbosacral region. Follow-up MR imaging performed 1 week later showed significant resolution of the hematoma without the need for surgery. The patient was discharged with only conservative management. This case of spontaneous SCSDH with rapid spontaneous remission in a child not associated with coagulopathy indicates that aggressive surgical treatment should be delayed as long as possible in pediatric patients because the spinal structure is still developing.

A 65-year-old woman presented with a thrombosed giant pericallosal artery aneurysm manifesting as headache and memory loss that developed over a 2-year period. Computed tomography (CT), magnetic resonance (MR) imaging, and conventional and CT angiography could not establish the differential diagnosis. Open craniotomy revealed the mass as thrombosed giant aneurysm from the pericallosal artery. Direct clipping with thrombectomy was performed successfully with an uneventful postoperative course. Thrombosed giant aneurysm of the distal anterior cerebral artery should be considered in the differential diagnosis of an unusual mass in the mid-frontal area, particularly in the presence of inconclusive angiographic and MR imaging findings.

We have established several glioma-relevant oncogene-engineered cancer cells to reevaluate the oncogene-selective cytotoxicity of previously well-characterized anticancer drugs, such as etoposide, doxorubicin, staurosporine, and carmustine. Among several glioma-relevant oncogenes (activated epidermal growth factor receptor, Ras, and Akt, as well as Bcl-2 and p53DD used in the present study), the activated epidermal growth factor receptor, Ras, and Akt exerted oncogenic transformation of Ink4a/Arf−/− murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr)–transduced Ink4a/Arf−/− astrocytes and U87MG cells in a dose- and time-dependent manner. Etoposide-selective cytotoxicity in the Akt-myr–transduced cells was shown to be caused by nonapoptotic cell death and occurred in a p53-independent manner. Etoposide caused severe reactive oxygen species (ROS) accumulation preferentially in the Akt-myr–transduced cells, and elevated ROS rendered these cells highly sensitive to cell death. The etoposide-selective cell death of Akt-myr–transduced cells was attenuated by pepstatin A, a lysosomal protease inhibitor. In the present study, we show that etoposide might possess a novel therapeutic activity for oncogenic Akt-transduced cancer cells to kill preferentially through ROS-mediated damage. [Mol Cancer Ther 2007;6(8):2178–87]

Spinal cord injury (SCI) can cause irreversible damage to neural tissues. However, there is currently no effective treatment for SCI. The therapeutic potential of adipose-derived mesenchymal stem cells (ADMSCs) has been emerged.We evaluated the effects and safety of the intrathecal transplantation of autologous ADMSCs in patients with SCI. Participants/Interventions: Fourteen patients with SCI were enrolled (12 for ASIA A, 1 for B, and 1 for D; duration of impairments 3-28 months). Six patients were injured at cervical, 1 at cervico-thoracic, 6 at thoracic, and 1 at lumbar level. Autologous ADMSCs were isolated from lipoaspirates of patients' subcutaneous fat tissue and 9 × 10ASIA motor scores were improved in 5 patients at 8 months follow-up (1-2 grades at some myotomes). Voluntary anal contraction improvement was seen in 2 patients. ASIA sensory score recovery was seen in 10, although degeneration was seen in 1. In somatosensory evoked potential test, one patient showed median nerve improvement. There was no interval change of MRI between baseline and 8 months post-transplantation. Four adverse events were observed in three patients: urinary tract infection, headache, nausea, and vomiting.Over the 8 months of follow-up, intrathecal transplantation of autologous ADMSCs for SCI was free of serious adverse events, and several patients showed mild improvements in neurological function. Patient selection, dosage, and delivery method of ADMSCs should be investigated further.

OBJECTIVE: We compared the clinical and radiographic outcomes of stand-alone polyetheretherketone (PEEK) cage and Zero-Profile anchored spacer (Zero-P) for single level anterior cervical discectomy and fusion (ACDF). METHODS: We retrospectively reviewed 121 patients who underwent single level ACDF within 2 years (Jan 2011-Jan 2013) in a single institute. Total 50 patients were included for the analysis who were evaluated more than 2-year follow-up. Twenty-nine patients were allocated to the cage group (m : f=19 : 10) and 21 for Zero-P group (m : f=12 : 9). Clinical (neck disability index, visual analogue scale arm and neck) and radiographic (Cobb angle-segmental and global cervical, disc height, vertebral height) assessments were followed at pre-operative, immediate post-operative, post-3, 6, 12, and 24 month periods. RESULTS: Demographic features and the clinical outcome showed no difference between two groups. The change between final follow-up (24 months) and immediate post-op of Cobb-segmental angle (p=0.027), disc height (p=0.002), vertebral body height (p=0.033) showed statistically better outcome for the Zero-P group than the cage group, respectively. CONCLUSION: The Zero-Profile anchored spacer has some advantage after cage for maintaining segmental lordosis and lowering subsidence rate after single level anterior cervical discectomy and fusion.

Genomic instability and apoptosis evasion are hallmarks of cancer, but the molecular mechanisms governing these processes remain elusive. Here, we found that survivin, a member of the apoptosis-inhibiting gene family, and aurora B kinase, a chromosomal passenger protein, were co-overexpressed in the various glioblastoma cell lines and tumors. Notably, exogenous introduction of the aurora B in human BJ cells was shown to decrease cell growth and increase the senescence-associated beta-galactosidase activity by activation of p53 tumor suppressor. However, aurora B overexpression failed to inhibit cell proliferation in BJ and U87MG cells transduced with dominant-negative p53 as well as in p53(-/-) mouse astrocytes. Aurora B was shown to increase centrosome amplification in the p53(-/-) astrocytes. Survivin was shown to induce anchorage-independent growth and inhibit anti-proliferation and drug-sensitive apoptosis caused by aurora B. Overexpression of both survivin and aurora B further accelerated the proliferation of BJ cells. Taken together, the present study indicates that survivin should accelerate tumorigenesis by inhibiting the anti-proliferative effect of p53 tumor suppressor that is activated by aurora B in normal and glioblastoma cells containing intact p53.

OBJECTIVE: The objective of this study was to evaluate the clinical significance of the transforaminal ligaments (TFLs) in relation to the area of the lumbar intervertebral foramen (IVF) by analyzing cadaveric spines. METHODS: One hundred ninety-eight cadaveric lumbar IVFs were studied, and the existence and type of TFLs were identified. All IVFs were photographed, and the images were saved. The areas of the IVFs and TFLs were measured with the Scion Image for Windows image analysis program. RESULTS: TFLs were found in 82.8% of the IVFs. The oblique inferior transforaminal ligament was the most common. The mean area of the IVFs was 155.8 ± 51.1 mm2, and the mean area occupied by the TFLs was 46.3 ± 37.6 mm2. The mean percentage of the IVF area occupied by the TFLs was 28.5 ± 18.8%. CONCLUSION: TFLs are common structures in the IVF and may reduce the space available for the spinal nerve root within the IVF. In this circumstance, any compromise of the IVF may impinge on the nerve root.

A 56-year-old man presented with a meningioma associated with hyperostotic bone containing little tumor cell infiltration. The patient presented with a growing mass on his right forehead and exophthalmos. Computed tomography (CT) taken 4 years previously revealed only hyperostosis without intracranial lesion. Repeat CT revealed an enhanced intracranial mass with overlying diffuse hyperostosis extending extracranially. The tumor and affected bone were widely removed. Histological examination confirmed rhabdoid meningioma in the intracranial and extracranial lesion. However, most of the hyperostotic bone showed no tumor cell infiltration. The cause of hyperostosis associated with meningioma is unclear, but tumor invasion is the generally accepted cause. In this case, hyperostosis occurred without tumor cell infiltration so another mechanism was probably involved. The extracranial extension occurred despite the disproportionately small tumor without global tumor cell infiltration of the bone or bony erosion.

In order to verify the biological aspects of 'autogeneic' bone marrow stromal cells (BMSC) transplantation for neurological disorders, we aimed our study towards the assessment of the survival, distribution, and differentiation of autologous BMSC in the central nervous system (CNS). We harvested rat BMSC from femur bones, and the nuclei were then fluorescently labeled by a 24-h co-culture with bis-benzimide. These BMSC were stereotactically injected into the striatum (n=6) or thoracic cord (n=8) of each animal. We evaluated the distribution and differentiation of 'autogeneic' BMSC in the brain and spinal cord after 4 weeks, using the immunohistochemistry technique. We found some injected cells in the ipsilateral striatum, hippocampus, neocortex, and bilateral corpus callosum, and approximately 20% and 15% of the engrafted cells expressed neuronal and astrocytic markers, respectively. Other injected cells were distributed in the dorsal funiculus and adjacent gray matter, and about 10% and 15% of these cells expressed neuronal and astrocytic markers, respectively. Although the precise mechanism of BMSC transdifferentiation still remains unclear, the present results show that 'autogeneic' BMSC could highly differentiate into their own CNS neural cells, suggesting that they are surrounded by favorable conditions.

There is increasing evidence that bone marrow stromal cells (BMSC) have the potential to migrate into the injured neural tissue and to differentiate into the CNS cells, indicating the possibility of autograft transplantation therapy. The present study was aimed to clarify whether the mouse BMSC can migrate into the lesion and differentiate into the CNS cells when transplanted into the mice subjected to focal cerebral infarct or spinal cord injury. The BMSC were harvested from mice and characterized by flow cytometry. Then, the BMSC were labeled by bis-benzimide, a nuclear fluorescence dye, over 24 h, and were stereotactically transplanted into the brain or spinal cord of the mice. The cultured BMSC expressed low levels of CD45 and high levels of CD90 and Sca-1 on flow cytometry. A large number of grafted cells survived in the normal brain 4 weeks after transplantation, many of which were located close to the transplanted sites. They expressed the neuronal marker including NeuN, MAP2, and doublecortin on fluorescent immunohistochemistry. However, when the BMSC were transplanted into the ipsilateral striatum of the mice subjected to middle cerebral artery occlusion, many of the grafted cells migrated into the corpus callosum and injured cortex, and also expressed the neuronal markers 4 weeks after transplantation. In particular, NeuN was very useful to validate the differentiation of the grafted cells, because the marker was expressed in the nuclei and was overlapped with bis-benzimide. Similar results were obtained in the mice subjected to spinal cord injury. However, many of the transplanted BMSC expressed GFAP, an astrocytic protein, in injured spinal cord. The present results indicate that the mouse BMSC can migrate into the CNS lesion and differentiate into the neurons or astrocytes, and that bis-benzimide is a simple and useful marker to label the donor cells and to evaluate their migration and differentiation in the host neural tissues over a long period.

A 68-year-old woman presented to the emergency department for evaluation of bilateral leg weakness. On admission, she had paraparesis with incomplete sensory deficit. Magnetic resonance (MR) imaging of the thoracolumbar spine revealed spontaneous spinal epidural hematoma (SSEH) compressing the spinal cord. The patient was taken to the operating room for urgent surgical decompression and evacuation of the SSEH. After the surgery, she woke up with complete paraplegia. Postoperative MR imaging showed the spinal cord was edematous, with minimal remnant hematoma. MR imaging after 1 month clearly showed anterior spinal artery thrombosis. No significant neurological improvement occurred during the 3-month follow up. Surgeons should consider the possibility of this devastating complication before aggressive and early surgical intervention in a patient with SSEH causing cord compression and neurological deficit.

Background context Muscle needling therapy is common for chronic pain management, but the development of unusual complications such as hemiplegia is not well understood. Purpose We report on three cases with hemiplegia after cervical paraspinal muscle needling and propose possible explanations for these unusual complications. Study design Case report. Methods The authors retrospectively reviewed the medical charts from a decade (2002-2013) at Korea University Hospital. The records were systematically searched, and the cases with hemiplegia (grade Results A 54-year-old woman, a 38-year-old woman, and a 60-year-old man with hemiplegia by cervical subdural or epidural hematoma after cervical posterior paraspinal muscle needling without direct invasion (intramuscular stimulation, acupuncture, or intramuscular lidocaine) were observed. All patients were taken for emergent decompressive laminectomy, and their postoperative motor function improved substantially. Conclusion Spinal hematoma after muscle needling is unusual but was thought to result after a rupture of the epidural or subarachnoid veins by a sharp increase in blood pressure delivered in the intraabdominal or intrathoracic areas after needling therapy.

Background Ossification of the posterior longitudinal ligament (OPLL) of the spine is considered a multifactorial and polygenic disease. We aimed to investigate the association between four single nucleotide polymorphisms (SNPs) of pre-miRNAs [miR-146aC>G (rs2910164), miR-149T>C (rs2292832), miR-196a2T>C (rs11614913), and miR-499A>G (rs3746444)] and the risk of cervical OPLL in the Korean population. Methods The genotypic frequencies of these four SNPs were analyzed in 207 OPLL patients and 200 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Findings For four SNPs in pre-miRNAs, no significant differences were found between OPLL patients and controls. However, subgroup analysis based on OPLL subgroup (continuous: continuous type plus mixed type, segmental: segmental and localized type) showed that miR-499GG genotype was associated with an increased risk of segmental type OPLL (adjusted odds ratio = 4.314 with 95% confidence interval: 1.109–16.78). In addition, some allele combinations (C-T-T-G, G-T-T-A, and G-T-C-G of miR-146a/-149/-196a2/-499) and combined genotypes (miR-149TC/miR-196a2TT) were associated with increased OPLL risk, whereas the G-T-T-G and G-C-C-G allele combinations were associated with decreased OPLL risk. Conclusion The results indicate that GG genotype of miR-499 is associated with significantly higher risks of OPLL in the segmental OPLL group. The miR-146a/-149/-196a2/-499 allele combinations may be a genetic risk factor for cervical OPLL in the Korean population.

We report a case of intracranial dissemination developing approximately 4 months after partial removal of a spinal cord anplastic astrocytoma in a 22-year-old male. He presented with paraplegia on initial admission at a local hospital. Spinal magnetic resonance (MR) images disclosed multiple intramedullary lesions at the T3-11. The tumor was partially removed. The final histologic diagnosis was anaplastic astrocytoma. Four months after the operation, he was admitted with the symptoms of headache and deterioration of consciousness. MR images showed enhanced lesions in the anterior horn of the left lateral ventricle, and septum pellucidum. He underwent computed tomography-guided stereotactic biopsy and histological appearance was consistent with anaplastic astrocytoma. The clinical course indicates that the tumor originated in the spinal cord and extended into the subarachnoid space, first the spinal canal and later intracranial.

Objective. Recent reports have indicated that bone marrow stromal cells (BMSCs) have the potential to improve neurological function when transplanted into models of central nervous system (CNS) disorders, including traumatic spinal cord injury. In this study, the authors aimed to clarify the underlying mechanism through which BMSCs supported CNS regeneration in the spinal cord. Methods. The authors topically applied mouse BMSCs expressing green fluorescence protein (0.4-4 × 104 cells) on the organotypic spinal cord slice culture prepared from 6-day-old rat pups (n = 17). They were co-cultured for 3 weeks after the slice culture started, and the behavior of the applied BMSCs was serially observed using a fluorescence bioimaging technique. The authors completed a histological analysis at the end of the co-cultures and evaluated the profiles of the cultured BMSCs using microarray and immunocytochemistry techniques. Results. The fluorescence bioimaging showed that the BMSCs survived and made a cluster on the slice during the experiments. They also induced a morphological change in the slice within 48 hours of co-culture. Immunohistochemistry analysis showed that the BMSCs promoted a marked neurite extension toward their cluster and some of the BMSCs expressed Tuj-1, an early neuronal marker. Analysis by microarray and immunocytochemistry revealed that BMSCs highly expressed the matrix metalloproteinases (MMPs), stromal cell—derived factor-1, and its specific receptor CXCR4. Conclusions . These findings suggest that the donor BMSCs can support CNS regeneration due to their acquisition of a suitable environment for differentiation and promotion of neurite extension via MMPs and chemokines.

A 13-year-old boy presented with a rare spontaneous spinal chronic subdural hematoma (SCSDH) with no associated trauma or medical problems manifesting as back and bilateral lower extremity pain persisting for 10 days. Neurological examination revealed mild weakness and paresthesia in both lower extremities. Magnetic resonance (MR) imaging performed 1 week after the appearance of symptoms revealed a chronic subdural hematoma at the thoracolumbosacral region. Follow-up MR imaging performed 1 week later showed significant resolution of the hematoma without the need for surgery. The patient was discharged with only conservative management. This case of spontaneous SCSDH with rapid spontaneous remission in a child not associated with coagulopathy indicates that aggressive surgical treatment should be delayed as long as possible in pediatric patients because the spinal structure is still developing.

A 65-year-old woman presented with a thrombosed giant pericallosal artery aneurysm manifesting as headache and memory loss that developed over a 2-year period. Computed tomography (CT), magnetic resonance (MR) imaging, and conventional and CT angiography could not establish the differential diagnosis. Open craniotomy revealed the mass as thrombosed giant aneurysm from the pericallosal artery. Direct clipping with thrombectomy was performed successfully with an uneventful postoperative course. Thrombosed giant aneurysm of the distal anterior cerebral artery should be considered in the differential diagnosis of an unusual mass in the mid-frontal area, particularly in the presence of inconclusive angiographic and MR imaging findings.

IFN regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PML-promoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference–mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression. [Cancer Res 2007;67(23):11133–40]

Here, we show that H-ras(V12) causes the p53-knockout mouse astrocytes (p53-/- astrocytes) to be transformed into brain cancer stem-like cells. H-ras(V12) triggers the p53-/- astrocytes to express a Nestin and a Cd133, which are expressed in normal and cancer neural stem cells. H-ras(V12) also induces the formation of a single cell-derived neurosphere under neural stem cell culture conditions. Furthermore, H-ras(V12)-overexpressing p53-/- astrocytes (p53-/-ast-H-ras(V12)) possess an in vitro self-renewal capacity, and are aberrantly differentiated into Tuj1-positve neurons both in vitro and in vivo. Amongst a variety of Ras-mediated canonical signaling pathways, we demonstrated that the MEK/ERK signaling pathway is responsible for neurosphere formation in p53-deficient astrocytes, whereas the PI3K/AKT signaling pathway is involved in oncogenic transformation in these cells. These findings suggest that the activation of Ras signaling pathways promotes the generation of brain cancer stem-like cells from p53-deficient mouse astrocytes by changing cell fate and transforming cell properties.

A 68-year-old woman presented to the emergency department for evaluation of bilateral leg weakness. On admission, she had paraparesis with incomplete sensory deficit. Magnetic resonance (MR) imaging of the thoracolumbar spine revealed spontaneous spinal epidural hematoma (SSEH) compressing the spinal cord. The patient was taken to the operating room for urgent surgical decompression and evacuation of the SSEH. After the surgery, she woke up with complete paraplegia. Postoperative MR imaging showed the spinal cord was edematous, with minimal remnant hematoma. MR imaging after 1 month clearly showed anterior spinal artery thrombosis. No significant neurological improvement occurred during the 3-month follow up. Surgeons should consider the possibility of this devastating complication before aggressive and early surgical intervention in a patient with SSEH causing cord compression and neurological deficit.