Lateral Mass Intrapedicular Screw Fixation for Subaxial Cervical Spines: A Short- to Medium-Term Retrospective Follow-Up Study of 20 Cases.

BACKGROUND: Lateral mass intrapedicular screw(LMIS) fixation was introduced in 2021 as an alternative method for the fixation of subaxial cervical spines for the treatment of various cervical spine disease. The objective of this study is to provide a short- to medium-term result of the 20 patients who underwent cervical spine fixation using LMIS. METHODS: Twenty patients with varying cervical spine pathology who underwent cervical spine fixation using LMIS in a 21-month period were included in the study. Postoperative computed tomography (CT) imaging was used to evaluate the screw placement. RESULTS: A total of 105 screws were used. The average screw size used was 3.5 × 14 mm. The average screw angle in the axial plane was 18 degrees. Five screws had breached the inner cortex of the vertebral canal. None of the patients had any postsurgical neurologic deficit. Fifteen screws did not reach the pedicle. Intraoperative fixation was excellent and no screw showed signs of loosening in the subsequent follow-up imaging. CONCLUSION: LMIS is a good alternative to the commonly used methods for subaxial cervical spine fixation and is worth considering in many patients.

Lestaurtinib induces DNA damage that is related to estrogen receptor activation.

A number of chemicals in the environment pose a threat to human health. Recent studies indicate estradiol induces DNA damage through the activation of the estrogen receptor alpha (ERα). Given that many environmental chemical compounds act like hormones once they enter the human body, it is possible that they induce DNA damage in the same way as estradiol, which is of great concern to females with the BRCA1 mutation. In this study, we developed an antibody-based high content method measuring γH2AX, a biomarker for DNA damage, to test a subset of 907 chemical compounds in MCF7 cells. The assay was optimized for a 1536 well plate format and had a satisfactory assay performance with Z-factor of 0.67. From the screening, we identified 128 compounds that induce γH2AX expression in the cells. These compounds were further examined for their γH2AX induction in the presence of an ER inhibitor, tamoxifen. After tamoxifen treatment, four compounds induced less γH2AX expression compared to those without tamoxifen treatment, suggesting these compounds induced γH2AX that is related to ERα activation. These four compounds were chosen for further studies to assess their ERα activating capability and c-MYC induction. Only lestaurtinib, a selective tyrosine kinase inhibitor, induced ERα activation, which was confirmed by both ERα beta-lactamase reporter gene assay and molecular docking analysis. Lestaurtinib also increased c-MYC expression, a target gene of ERα signaling, measured by the quantitative PCR method. This data suggests that lestaurtinib acts as a DNA damage inducer that is related to ERα activation.

A non-invasive system to monitor in vivo neural graft activity after spinal cord injury.

Expectations for neural stem/progenitor cell (NS/PC) transplantation as a treatment for spinal cord injury (SCI) are increasing. However, whether and how grafted cells are incorporated into the host neural circuit and contribute to motor function recovery remain unknown. The aim of this project was to establish a novel non-invasive in vivo imaging system to visualize the activity of neural grafts by which we can simultaneously demonstrate the circuit-level integration between the graft and host and the contribution of graft neuronal activity to host behaviour. We introduced Akaluc, a newly engineered luciferase, under the control of enhanced synaptic activity-responsive element (E-SARE), a potent neuronal activity-dependent synthetic promoter, into NS/PCs and engrafted the cells into SCI model mice. Through the use of this system, we found that the activity of grafted cells was integrated with host behaviour and driven by host neural circuit inputs. This non-invasive system is expected to help elucidate the therapeutic mechanism of cell transplantation treatment for SCI.

LOTUS overexpression via ex vivo gene transduction further promotes recovery of motor function following human iPSC-NS/PC transplantation for contusive spinal cord injury.

Functional recovery is still limited mainly due to several mechanisms, such as the activation of Nogo receptor-1 (NgR1) signaling, when human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PC) are transplanted for subacute spinal cord injury (SCI). We previously reported the neuroprotective and regenerative benefits of overexpression of lateral olfactory tract usher substance (LOTUS), an endogenous NgR1 antagonist, in the injured spinal cord using transgenic mice. Here, we evaluate the effects of lentiviral transduction of LOTUS gene into hiPSC-NS/PCs before transplantation in a mouse model of subacute SCI. The transduced LOTUS contributes to neurite extension, suppression of apoptosis, and secretion of neurotrophic factors in vitro. In vivo, the hiPSC-NS/PCs enhance the survival of grafted cells and enhance axonal extension of the transplanted cells, resulting in significant restoration of motor function following SCI. Therefore, the gene transduction of LOTUS in hiPSC-NS/PCs could be a promising adjunct for transplantation therapy for SCI.

Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells.

The transplantation of neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) has beneficial effects on spinal cord injury (SCI). However, while there are many subtypes of NPCs with different regional identities, the subtype of iPSC-derived NPCs that is most appropriate for cell therapy for SCI has not been identified. Here, we generated forebrain- and spinal cord-type NPCs from human iPSCs and grafted them onto the injured spinal cord in mice. These two types of NPCs retained their regional identities after transplantation and exhibited different graft-host interconnection properties. NPCs with spinal cord regional identity but not those with forebrain identity resulted in functional improvement in SCI mice, especially in those with mild-to-moderate lesions. This study highlights the importance of the regional identity of human iPSC-derived NPCs used in cell therapy for SCI.

Ring-shaped meniscus formation may arise from the regenerative response to meniscectomy during growth spurts: A case report.

INTRODUCTION: Ring-shaped meniscus is very rare and generally considered to be a congenital malformation. Here, we report a case of newly formed ring-shaped meniscus-like tissue following arthroscopic partial meniscectomy for a complete discoid lateral meniscus. PRESENTATION OF CASE: A 14-year-old boy underwent arthroscopic partial meniscectomy for complete discoid lateral meniscus of the left knee. The growth plates were present at the surgery. Although pain improved immediately after surgery, he reported left knee pain at the 7-month follow-up. Magnetic resonance imaging revealed a bucket-handle tear of the lateral meniscus and a second arthroscopic surgery was performed. During arthroscopy, we found that the anterior and posterior horns of the lateral meniscus were connected by meniscus-like tissue forming a ring-shaped meniscus and the newly formed interhorn meniscal bridge was resected. Histological evaluation indicated that the newly formed tissue was meniscus-like tissue that had appeared secondary to tissue repair. He visited our hospital at 16 years old, after the growth plates had closed, complaining of right knee pain. Arthroscopic partial meniscectomy was performed for complete discoid lateral meniscus of the right knee. As of two years after this surgery, no morphological changes have been observed. DISCUSSION: Although the exact mechanisms of meniscus-like tissue formation remain unclear, the growth spurt may promote the mechanisms of tissue repair, forming ring-shaped meniscus-like tissue. CONCLUSION: This is the first case of ring-shaped meniscus-like tissue forming after partial resection of a complete discoid lateral meniscus. Ring-shaped meniscus-like tissue can develop in growing patients.

The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury.

Treatment options for chronic spinal cord injury (SCI) remain limited due to unfavourable changes in the microenvironment. Gene therapy can overcome these barriers through continuous delivery of therapeutic gene products to the target tissue. In particular, adeno-associated virus (AAV) vectors are potential candidates for use in chronic SCI, considering their safety and stable gene expression in vivo. Given that different AAV serotypes display different cellular tropisms, it is extremely important to select an optimal serotype for establishing a gene transfer system during the chronic phase of SCI. Therefore, we generated multiple AAV serotypes expressing ffLuc-cp156, a fusion protein of firefly luciferase and Venus, a variant of yellow fluorescent protein with fast and efficient maturation, as a reporter, and we performed intraparenchymal injection in a chronic SCI mouse model. Among the various serotypes tested, AAVrh10 displayed the highest photon count on bioluminescence imaging. Immunohistological analysis revealed that AAVrh10 showed favourable tropism for neurons, astrocytes, and oligodendrocytes. Additionally, with AAVrh10, the area expressing Venus was larger in the injury epicentre and extended to the surrounding tissue. Furthermore, the fluorescence intensity was significantly higher with AAVrh10 than with the other vectors. These results indicate that AAVrh10 may be an appropriate serotype for gene delivery to the chronically injured spinal cord. This promising tool may be applied for research and development related to the treatment of chronic SCI.

Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury.

Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain "tumorigenic" cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic-severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270.

Optimized Screw Trajectory for Lumbar Cortical Bone Trajectory Pedicle Screws Based on Clinical Outcome: Evidence Favoring the Buttress Effect Theory.

BACKGROUND: Cortical bone trajectory (CBT) is a relatively new technique for pedicle screw insertion in the field of spine surgery. Previous studies have demonstrated the significantly better pullout and toggle characteristics the new method offers, and it appears to have certain advantages over the widely used traditional trajectory. The mechanism of the pullout and toggle characteristics still remains unknown. PURPOSE: To report the medium- to long-term follow-up findings of patients who underwent posterior lumbar interbody fusion or posterior lumbar fusion (PLIF/PLF) at our institution and to discuss the ideal screw trajectory when using this technique. STUDY DESIGN: Retrospective radiologic study. METHODS: Fifty-five patients who underwent PLIF/PLF for lumbar spondylosis using the new technique between January 2011 and January 2016 were included. Clinical outcome was assessed using the Japanese Orthopaedic Association scores for low back pain and visual analog scale scores. Screw loosening was evaluated via the presence of a translucent zone surrounding the pedicle screw using plain X-radiography (Xp). The screw trajectory was evaluated by measuring the rostral range (RR) and the lateral range score (LRS). The RR is the angle between the line drawn along the distal end plate of the vertebra and the line drawn along the screw on the lateral view. The LRS is the score given depending on the position of the tip of the screw seen on the Xp taken in the anteroposterior (AP) view. The pedicle ring is equally divided into the medial third (zone A), central third (zone B), and the lateral third (zone C) by four vertical lines. A score of 0 to 3 points is given depending on the position of the tip of the screw: 0, outside the pedicle ring; 1, zone A; 2, zone B; and 3, zone C. RESULTS: Bone fusion was recorded in 49 patients (49/55 patients). The total number of screws with a visible translucent zone on Xp was 26 (26/242 screws). When the screws are inserted at a more acute angle in the lateral view (low RR) or when the screws are directed more medially (low LRS), the risk of developing a translucent zone around the pedicle screw increased. CONCLUSION: With CBT, the pedicle screws are inserted from the pars interarticularis that is rich in cortical bone, strong enough to withstand the substantial forces usually encountered in the region. Our clinical data suggest that the optimal screw trajectory is one where the screw is inserted at an angle > 22.55 degrees (high RR) on the lateral view Xp and where the tip of the screw is directed toward the lateral third of the pedicle on the AP Xp. We believe the naturally occurring buttress effect that exists in the vertebra may give CBT a mechanical and anatomical advantage over the traditional screw trajectory.

Fail-Safe System against Potential Tumorigenicity after Transplantation of iPSC Derivatives.

Human induced pluripotent stem cells (iPSCs) are promising in regenerative medicine. However, the risks of teratoma formation and the overgrowth of the transplanted cells continue to be major hurdles that must be overcome. Here, we examined the efficacy of the inducible caspase-9 (iCaspase9) gene as a fail-safe against undesired tumorigenic transformation of iPSC-derived somatic cells. We used a lentiviral vector to transduce iCaspase9 into two iPSC lines and assessed its efficacy in vitro and in vivo. In vitro, the iCaspase9 system induced apoptosis in approximately 95% of both iPSCs and iPSC-derived neural stem/progenitor cells (iPSC-NS/PCs). To determine in vivo function, we transplanted iPSC-NS/PCs into the injured spinal cord of NOD/SCID mice. All transplanted cells whose mass effect was hindering motor function recovery were ablated upon transduction of iCaspase9. Our results suggest that the iCaspase9 system may serve as an important countermeasure against post-transplantation adverse events in stem cell transplant therapies.

Bilateral fracture of the superior articular process of S1 - An unusual fracture seen in a speed skater.

Background Fractures of the superior articular process are rarely seen in clinical practice. Repetitive spinal movements may lead to fractures of the pars interarticularis, resulting in spondylolysis. Traumatic spinal fractures often involve the vertebral body, transvers and/or the spinous processes. The superior articular processes, however, are seldom involved in both traumatic and stress-induced fractures. Purpose The purpose of this report is to present an unusual case of symptomatic bilateral fracture of the superior articular process of the sacrum in a 21-year-old speed skater. Study design This is a case report. Methods The patient was admitted for close observation after complaining of excruciating lower back pain and bilateral dysesthesia along the L5 nerve root. Post-myelography computed tomography (CT) revealed a bilateral facet joint deformity at L5/S1 and a bilateral fracture of the superior articular process of the sacrum. A facet joint block at the L5/S1 joint alleviated the pain, and a nerve root block at the L5 nerve root improved the dysesthesia. The patient underwent an L5/S1 decompression, whereby the nonunion bone fragments were removed, followed by a posterior lumbar inter-body fusion (PLIF) at L5/S1. Results The patient showed immediate improvement and returned to training six months post-operatively. Conclusion We have presented a case of bilateral fractures of the superior articular process of the sacrum in a speed skater. His presenting symptoms were similar to those found in patients with spondylolysis and the etiology appears to be similar. Surgical treatment was opted given his symptomatic relief from nerve root and facet joint blocks.

An Intramedullary Osteolipoma of the Upper Thoracic Spinal Cord: A Case Report.

CASE: We present a rare case of an intramedullary osteolipoma without any extramedullary connections or coexisting spinal dysraphism. A 48-year-old woman presented with back pain and pain around the lateral aspect of the left thigh. Magnetic resonance imaging (MRI) revealed a heterogeneous hyperintense and hypointense region on T1 and T2-weighted imaging. A cavernous hemangioma was suspected, and the patient was admitted for surgical resection. The histological diagnosis was an intramedullary osteolipoma. CONCLUSION: MRI with fat suppression and computed tomography are recommended for the diagnosis of an intramedullary osteolipoma, but a definitive diagnosis requires histological examination.