Halo vest fixation effectively maintains cervical alignment through intraoperative repositioning in patients with cervical spine instability.

Introduction: The objective of this study was to examine if halo vest fixation provides sufficient stabilization of cervical spine alignment to endorse its use through intraoperative positional changes in patients with cervical spine instability. Methods: The subjects of this study were 14 patients with cervical spine instability who were immobilized in halo vests until they underwent subsequent internal fixation surgery. After induction of anesthesia, the patients in halo vests were repositioned from the supine position to the prone position. The halo ring was fixed to the surgical table and the dorsal struts and vest were removed for surgery. Radiographs obtained in the preoperative sitting position and intraoperative prone position were compared for the following measures of cervical alignment: O-C2 angle, C2-C6 angle, pharyngeal inlet angle (PIA), atlantodental interval (ADI), Redlund-Johnell (R-J) value as a measure of O-C2 length, O-C6 length, and O-C2 length/O-C6 length (%). Results: There were no significant differences in O-C2 angle, C2-C6 angle, PIA, ADI, or O-C2 length/O-C6 length (%). However, the R-J value and O-C6 length were significantly higher in the intraoperative prone position than in the preoperative sitting position. None of the patients presented with any complications, including dysphagia or neurological deterioration. Conclusions: Our results suggest that when patients are repositioned to the prone position while immobilized in halo vests, the cervical spine is distracted in the cephalocaudal direction across all cervical segments but the cervical alignment is sufficiently maintained. Halo vests are a highly effective external fixation method for patients with cervical spine instability, allowing for a safe repositioning to the prone position for surgery while preserving cervical alignment and preventing neurological deterioration.

Intraoperative Radiation Exposure from O-arm-based 3D Navigation in Spine Surgery.

Introduction: Intraoperative three-dimensional (3D) imaging guide technology, such as the O-arm surgical imaging system, is a beneficial tool in spinal surgery that provides real-time 3D images of a patient's spine. This study aims to determine the exposure dose from intraoperative O-arm imaging. Methods: A consecutive retrospective review of all patients undergoing spinal surgery was conducted between June 2019 and August 2022. Demographic and operative data were collected from electronic medical records. Results: Intraoperative O-arm imaging was conducted in 206 (12.9%) of 1599 patients, ranging from one to 4 scans per patient (1.17±0.43 scans). Single O-arm imaging enabled navigation of seven vertebrae in the cervical spine, seven in the thoracic spine, five in the thoracolumbar spine, and four in the lumbar spine on average. The number of O-arm shots per surgery was 1.15±0.36, 1.06±0.24, 1.61±0.7, and 1.07±0.25 for cervical, thoracic, thoracolumbar, and lumbar spinal cases, respectively. The exposure doses represented by dose length products in single O-arm imaging were 377±19 mGy-cm, 243±22 mGy-cm, 378±38 mGy-cm, and 258±11 mGy-cm for cervical, thoracic, thoracolumbar, and lumbar spine cases, respectively. We observed a weak positive correlation between the number of fused spinal levels and the exposure dose. Conclusions: Intraoperative radiation exposure from O-arm imaging was lower than the national diagnostic reference levels in Japan established based on the International Commission on Radiological Protection publication, demonstrating its safety from the standpoint of radiological protection in most cases. In surgeries with a large range of fixations, such as corrective deformity surgery, the number of imaging sessions and the amount of intraoperative radiation exposure would increase, leading surgeons to pay attention to the risk of radiation in spinal surgery.

Zinc deficiency impairs axonal regeneration and functional recovery after spinal cord injury by modulating macrophage polarization via NF-κB pathway.

Background: Spinal cord injury (SCI) is a devastating disease that results in permanent paralysis. Currently, there is no effective treatment for SCI, and it is important to identify factors that can provide therapeutic intervention during the course of the disease. Zinc, an essential trace element, has attracted attention as a regulator of inflammatory responses. In this study, we investigated the effect of zinc status on the SCI pathology and whether or not zinc could be a potential therapeutic target. Methods: We created experimental mouse models with three different serum zinc concentration by changing the zinc content of the diet. After inducing contusion injury to the spinal cord of three mouse models, we assessed inflammation, apoptosis, demyelination, axonal regeneration, and the number of nuclear translocations of NF-κB in macrophages by using qPCR and immunostaining. In addition, macrophages in the injured spinal cord of these mouse models were isolated by flow cytometry, and their intracellular zinc concentration level and gene expression were examined. Functional recovery was assessed using the open field motor score, a foot print analysis, and a grid walk test. Statistical analysis was performed using Wilcoxon rank-sum test and ANOVA with the Tukey-Kramer test. Results: In macrophages after SCI, zinc deficiency promoted nuclear translocation of NF-κB, polarization to pro-inflammatory like phenotype and expression of pro-inflammatory cytokines. The inflammatory response exacerbated by zinc deficiency led to worsening motor function by inducing more apoptosis of oligodendrocytes and demyelination and inhibiting axonal regeneration in the lesion site compared to the normal zinc condition. Furthermore, zinc supplementation after SCI attenuated these zinc-deficiency-induced series of responses and improved motor function. Conclusion: We demonstrated that zinc affected axonal regeneration and motor functional recovery after SCI by negatively regulating NF-κB activity and the subsequent inflammatory response in macrophages. Our findings suggest that zinc supplementation after SCI may be a novel therapeutic strategy for SCI.

Human Spinal Oligodendrogenic Neural Progenitor Cells Enhance Pathophysiological Outcomes and Functional Recovery in a Clinically Relevant Cervical Spinal Cord Injury Rat Model.

Traumatic spinal cord injury (SCI) results in the loss of neurons, oligodendrocytes, and astrocytes. Present interventions for SCI include decompressive surgery, anti-inflammatory therapies, and rehabilitation programs. Nonetheless, these approaches do not offer regenerative solutions to replace the lost cells, fiber tracts, and circuits. Neural stem/progenitor cell (NPC) transplantation is a promising strategy that aims to encourage regeneration. However, NPC differentiation remains inconsistent, thus, contributing to suboptimal functional recovery. As such, we have previously engineered oligodendrogenically biased NPCs (oNPCs) and demonstrated their efficacy in a thoracic model of SCI. Since the majority of patients with SCI experience cervical injuries, our objective in the current study was to generate human induced pluripotent stem cell-derived oNPCs (hiPSC-oNPCs) and to characterize these cells in vitro and in vivo, utilizing a clinically relevant rodent model of cervical SCI. Following transplantation, the oNPCs engrafted, migrated to the rostral and caudal regions of the lesion, and demonstrated preferential differentiation toward oligodendrocytes. Histopathological evaluations revealed that oNPC transplantation facilitated tissue preservation while diminishing astrogliosis. Moreover, oNPC transplantation fostered remyelination of the spared tissue. Functional analyses indicated improved forelimb grip strength, gait, and locomotor function in the oNPC-transplanted rats. Importantly, oNPC transplantation did not exacerbate neuropathic pain or induce tumor formation. In conclusion, these findings underscore the therapeutic potential of oNPCs in promoting functional recovery and histopathological improvements in cervical SCI. This evidence warrants further investigation to optimize and advance this promising cell-based therapeutic approach.

Time Course and Characteristics of the Nutritional Conditions in Acute Traumatic Cervical Spinal Cord Injury.

Introduction: This retrospective cohort study aimed to examine the nutritional time course and elucidate the critical period of undernutrition following acute traumatic cervical spinal cord injury (CSCI). Methods: The study was performed at a single facility that treated spinal cord injuries. We examined individuals with acute traumatic CSCI admitted to our hospital within 3 days of injury. Both prognostic nutritional index (PNI) and controlling nutritional status (CONUT) scores, which objectively reflect nutritional and immunological conditions, were assessed at admission and 1, 2, and 3 months after the injury. The American Spinal Injury Association impairment scale (AIS) categorizations and severity of dysphagia were evaluated at these time points. Results: A total of 106 patients with CSCI were evaluated consecutively for 3 months after injury. Individuals with AIS categorizations of A, B, or C at 3 days after injury were significantly more undernourished than those with an AIS categorization of D at 3 months after injury, indicating that individuals with mild paresis better maintained their nutritional condition after injury. Nutritional conditions, as assessed by both PNI and CONUT scores, improved significantly between 1 and 2 months after injury, whereas no significant differences were found between admission and 1 month after injury. Nutritional status and dysphagia were significantly correlated at each time point (p<0.001), indicating that swallowing dysfunction is an important factor associated with malnutrition. Conclusions: Nutritional conditions showed significant gradual improvements from 1 month after the injury. We must pay attention to undernutrition, which is associated with dysphagia, especially in individuals with severe paralysis during the acute phase following injury.

Incidence and risk factors of pneumonia following acute traumatic cervical spinal cord Injury.

OBJECTIVES: To elucidate the incidence and risk factors for pneumonia after acute traumatic cervical spinal cord injury (CSCI). DESIGN: Retrospective cohort study.Setting: Spinal injuries center in Japan.Participants: Of 184 individuals who were admitted within 2 weeks after acute traumatic cervical spinal injuries, 167 individuals who met the criteria were included in this study.Interventions: The occurrence of pneumonia, degree of dysphagia using the Dysphagia Severity Scale, patient age, history of smoking, presence of tracheostomy, vital capacity, level of injury, and the American Spinal Injury Association Impairment Scale (AIS) 2 weeks after injury were assessed.Outcomes: Incidence of pneumonia were analyzed. Moreover, the risk factors of pneumonia were evaluated using logistic regression analysis. RESULTS: From the 167 individuals who met the criteria, 30 individuals (18%) had pneumonia; in 26 (87%) of these individuals, pneumonia was aspiration related, defined as Dysphagia Severity Scale ≤ 4. The median occurrence of aspiration pneumonia was 11.5 days after injury. A logistic regression analysis revealed that severe AIS and severe Dysphagia Severity Scale scores were significant risk factors of pneumonia after CSCI. CONCLUSIONS: It was highly likely that the pneumonias following CSCI were related to aspiration based on the Dysphagia Severity Scale. In addition, most of the patients developed aspiration pneumonia within 1 month after injury. Aspiration and severe paralysis were significant risk factors for pneumonia. The treatment of dysphagia in the acute phase should be considered an important indicator to prevent pneumonia.

Significance of the neurological level of injury as a prognostic predictor for motor complete cervical spinal cord injury patients.

Objective: To investigate the usefulness of the combination of neurological findings and magnetic resonance imaging (MRI) as a prognostic predictor in patients with motor complete cervical spinal cord injury (CSCI) in the acute phase.Design: A cross-sectional analysisSetting: Department of Orthopaedic Surgery, Spinal Injuries CenterParticipants/Methods: Forty-two patients with an initial diagnosis of motor complete CSCI (AIS A, n = 29; AIS B, n = 13) within 72 h after injury were classified into the recovery group (Group R) and the non-recovery group (Group N), based on the presence or absence of motor recovery (conversion from AIS A/B to C/D) at three months after injury, respectively. The Neurological Level of Injury (NLI) at the initial diagnosis was investigated and the presumptive primary injured segment of the spinal cord was inferred from MRI performed at the initial diagnosis. We investigated whether or not the difference between the presumptive primary injured segment and the NLI exceeded one segment. The presence of a difference between the presumptive primary injured segment and the NLI was compared between Groups R and N.Results: The number of cases with the differences between the presumptive primary injured segment and the NLI was significantly higher in Group N than in Group R.Conclusion: The presence of differences between the presumptive primary injured segment and the NLI might be a poor improving prognostic predictor for motor complete CSCI. The NLI may be useful for predicting the recovery potential of patients with motor complete CSCI when combined with the MRI findings.

Long-term outcomes of spinal meningioma resection with outer layer of dura preservation technique.

Spinal meningioma is a common benign intradural spinal tumor. It has been reported that the local recurrence rate after surgical resection increases with longer follow-up duration. Simpson grade 1 resection could reduce the risk of recurrence, but this procedure needs dural reconstruction, which would cause cerebrospinal fluid (CSF) leakage or iatrogenic spinal cord injury. Saito et al. reported dura preservation technique to reduce the risk of CSF leakage, in which the meningioma together with the inner layer of the dura is removed and the outer layer is preserved for simple dural closure. The long-term outcomes with this technique have never been investigated. In this study, we retrospectively analyzed the data of 38 surgically treated patients (dura preservation technique, 12 patients; Simpson grade 2 resection, 26 patients) to assess the long-term recurrence rate (mean, 121.5 months; range, 60-228 months). The local recurrence rate in the dura preservation group was 8.3% (1 of 12 cases), which was similar to that in Simpson grade 2 resection group (2 of 26 cases [7.7%]). Although this case series did not indicate the significant difference in the recurrence rates between the dura preservation group and Simpson grade 2 group, we consider that this technique still has advantages for surgically less invasiveness in terms of dural reconstruction which is necessary for Simpson grade 1 and higher possibility of complete resection of tumors compared with Simpson grade 2 resection.

Regeneration of Spinal Cord Connectivity Through Stem Cell Transplantation and Biomaterial Scaffolds.

Significant progress has been made in the treatment of spinal cord injury (SCI). Advances in post-trauma management and intensive rehabilitation have significantly improved the prognosis of SCI and converted what was once an "ailment not to be treated" into a survivable injury, but the cold hard fact is that we still do not have a validated method to improve the paralysis of SCI. The irreversible functional impairment of the injured spinal cord is caused by the disruption of neuronal transduction across the injury lesion, which is brought about by demyelination, axonal degeneration, and loss of synapses. Furthermore, refractory substrates generated in the injured spinal cord inhibit spontaneous recovery. The discovery of the regenerative capability of central nervous system neurons in the proper environment and the verification of neural stem cells in the spinal cord once incited hope that a cure for SCI was on the horizon. That hope was gradually replaced with mounting frustration when neuroprotective drugs, cell transplantation, and strategies to enhance remyelination, axonal regeneration, and neuronal plasticity demonstrated significant improvement in animal models of SCI but did not translate into a cure in human patients. However, recent advances in SCI research have greatly increased our understanding of the fundamental processes underlying SCI and fostered increasing optimism that these multiple treatment strategies are finally coming together to bring about a new era in which we will be able to propose encouraging therapies that will lead to appreciable improvements in SCI patients. In this review, we outline the pathophysiology of SCI that makes the spinal cord refractory to regeneration and discuss the research that has been done with cell replacement and biomaterial implantation strategies, both by itself and as a combined treatment. We will focus on the capacity of these strategies to facilitate the regeneration of neural connectivity necessary to achieve meaningful functional recovery after SCI.

Macrophage centripetal migration drives spontaneous healing process after spinal cord injury.

Traumatic spinal cord injury (SCI) brings numerous inflammatory cells, including macrophages, from the circulating blood to lesions, but pathophysiological impact resulting from spatiotemporal dynamics of macrophages is unknown. Here, we show that macrophages centripetally migrate toward the lesion epicenter after infiltrating into the wide range of spinal cord, depending on the gradient of chemoattractant C5a. However, macrophages lacking interferon regulatory factor 8 (IRF8) cannot migrate toward the epicenter and remain widely scattered in the injured cord with profound axonal loss and little remyelination, resulting in a poor functional outcome after SCI. Time-lapse imaging and P2X/YRs blockade revealed that macrophage migration via IRF8 was caused by purinergic receptors involved in the C5a-directed migration. Conversely, pharmacological promotion of IRF8 activation facilitated macrophage centripetal movement, thereby improving the SCI recovery. Our findings reveal the importance of macrophage centripetal migration via IRF8, providing a novel therapeutic target for central nervous system injury.

Progression of local kyphosis after conservative treatment for compressive cervical spine fracture with spinal cord injury.

INTRODUCTION: Compressive-flexion type cervical spine fracture is typically accompanied by apparent dislocation of the facet joints, undesirable cervical alignment, and devastating neurological dysfunction, which provides strong rationale for rendering prompt operative treatment. However, the validity of conservative treatment for compressive-flexion cervical spine injury in cases with preserved congruity of the facet joints has yet to be elucidated. The purpose of this study is to evaluate the long-term outcome of cervical alignment following conservative treatment for compressive-flexion cervical spine injury with preserved congruity of the facet joints. METHODS: A total of 662 patients who experienced spinal cord injury from 2007 to 2017 were included and underwent retrospective review in a single institute. Thirteen patients were identified as receiving conservative therapy following compressive-flexion cervical spine fractures with spinal cord injury. Clinical and radiological results were collected, including vertical fractures of the vertebral column, laminar fractures, progression of local kyphosis, and neurological status. The degree of the local cervical kyphosis was evaluated with two methods: the posterior tangent method and the endplate method. RESULTS: All 13 patients were male, and the mean age at the time of injury was 28.4 years. The mean follow-up period was 3 years. Although none of the patients presented neurological deterioration after the injury, the degree of local kyphosis was increased at the time of final follow-up compared to what was observed at the time of injury. Patient age at the time of injury and concurrent vertical fracture of vertebral body could have been influencing factors for the progression of the kyphosis. While laminar fracture affected the kyphosis at the time of injury, it was not a strong influencing factor of the overall progression of local kyphosis. CONCLUSIONS: The conservative option for the compressive-flexion cervical injury allowed us to treat without exacerbating neurological symptoms as long as the facet joints are preserved. However, in terms of cervical alignment, surgical stabilization may have been desirable for these patients. Notably, the younger patients and the patients with vertical fracture of the cervical vertebral column in this type of injury required closer observation to help prevent the progression of local kyphosis.

Human Oligodendrogenic Neural Progenitor Cells Delivered with Chondroitinase ABC Facilitate Functional Repair of Chronic Spinal Cord Injury.

Treatment of chronic spinal cord injury (SCI) is challenging due to cell loss, cyst formation, and the glial scar. Previously, we reported on the therapeutic potential of a neural progenitor cell (NPC) and chondroitinase ABC (ChABC) combinatorial therapy for chronic SCI. However, the source of NPCs and delivery system required for ChABC remained barriers to clinical application. Here, we investigated directly reprogrammed human NPCs biased toward an oligodendrogenic fate (oNPCs) in combination with sustained delivery of ChABC using an innovative affinity release strategy in a crosslinked methylcellulose biomaterial for the treatment of chronic SCI in an immunodeficient rat model. This combinatorial therapy increased long-term survival of oNPCs around the lesion epicenter, facilitated greater oligodendrocyte differentiation, remyelination of the spared axons by engrafted oNPCs, enhanced synaptic connectivity with anterior horn cells and neurobehavioral recovery. This combinatorial therapy is a promising strategy to regenerate the chronically injured spinal cord.

Periostin Promotes Fibroblast Migration and Inhibits Muscle Repair After Skeletal Muscle Injury.

BACKGROUND: Skeletal muscle injury (SMI) can cause physical disability due to insufficient recovery of the muscle. The development of muscle fibrosis after SMI has been widely regarded as a principal cause of this failure to recover. Periostin (Postn) exacerbates tissue fibrosis in various organs. We investigated whether Postn is involved in the pathophysiology after SMI. METHODS: Partial laceration injuries of the gastrocnemius were created in wild-type (WT) and Postn knockout (Postn) mice. We examined the expression of the Postn gene before and after SMI. Regeneration and fibrosis of skeletal muscle were evaluated by histological analyses, and recovery of muscle strength was measured by physiological testing. Immunohistochemistry was used to examine the number and proliferative potential of infiltrating fibroblasts in injured muscle. A trans-well migration assay was used to assess the migration capability of fibroblasts. Control immunoglobulin G (IgG) or Postn-neutralizing antibody (Postn-nAb) was injected into injured muscle at 7 and 14 days after injury (dpi). We evaluated the effects of Postn-nAb on muscle repair after SMI. RESULTS: The expression of Postn was dramatically upregulated after SMI. Compared with WT mice, Postn mice had improved muscle recovery and attenuated fibrosis as well as a significantly reduced number of infiltrating fibroblasts. The proliferative potential of these fibroblasts in WT and Postn mice was comparable at 14 dpi; however, the migration capability of fibroblasts was significantly enhanced in the presence of Postn (mean, 258%; 95% confidence interval, 183% to 334%). Moreover, the administration of Postn-nAb inhibited fibroblast infiltration and promoted muscle repair after SMI. CONCLUSIONS: Postn exacerbates fibrotic scar formation through the promotion of fibroblast migration into injured muscle after SMI. Treatment with Postn-nAb is effective for attenuating fibrosis and improving muscle recovery after SMI. CLINICAL RELEVANCE: Our findings may provide a potential therapeutic strategy to enhance muscle repair and functional recovery after SMI.

Macrophage Infiltration Is a Causative Factor for Ligamentum Flavum Hypertrophy through the Activation of Collagen Production in Fibroblasts.

Ligamentum flavum (LF) hypertrophy causes lumbar spinal canal stenosis, leading to leg pain and disability in activities of daily living in elderly individuals. Although previous studies have been performed on LF hypertrophy, its pathomechanisms have not been fully elucidated. In this study, we demonstrated that infiltrating macrophages were a causative factor for LF hypertrophy. Induction of macrophages into the mouse LF by applying a microinjury resulted in LF hypertrophy along with collagen accumulation and fibroblasts proliferation at the injured site, which were very similar to the characteristics observed in the severely hypertrophied LF of human. However, we found that macrophage depletion by injecting clodronate-containing liposomes counteracted LF hypertrophy even with microinjury. For identification of fibroblasts in the LF, we used collagen type I α2 linked to green fluorescent protein transgenic mice and selectively isolated green fluorescent protein-positive fibroblasts from the microinjured LF using laser microdissection. A quantitative RT-PCR on laser microdissection samples revealed that the gene expression of collagen markedly increased in the fibroblasts at the injured site with infiltrating macrophages compared with the uninjured location. These results suggested that macrophage infiltration was crucial for LF hypertrophy by stimulating collagen production in fibroblasts, providing better understanding of the pathophysiology of LF hypertrophy.

Periostin Promotes Scar Formation through the Interaction between Pericytes and Infiltrating Monocytes/Macrophages after Spinal Cord Injury.

Scar formation is a prominent pathological feature of traumatic central nervous system (CNS) injury, which has long been implicated as a major impediment to the CNS regeneration. However, the factors affecting such scar formation remain to be elucidated. We herein demonstrate that the extracellular matrix protein periostin (POSTN) is a key player in scar formation after traumatic spinal cord injury (SCI). Using high-throughput RNA sequencing data sets, we found that the genes involved in the extracellular region, such as POSTN, were significantly expressed in the injured spinal cord. The expression of POSTN peaked at 7 days after SCI, predominantly in the scar-forming pericytes. Notably, we found that genetic deletion of POSTN in mice reduced scar formation at the lesion site by suppressing the proliferation of the pericytes. Conversely, we found that recombinant POSTN promoted the migration capacity of the monocytes/macrophages and increased the expression of tumor necrosis factor-α from the monocytes/macrophages in vitro, which facilitated the proliferation of pericytes. Furthermore, we revealed that the pharmacological blockade of POSTN suppressed scar formation and improved the long-term functional outcome after SCI. Our findings suggest a potential mechanism whereby POSTN regulates the scar formation after SCI and provide significant evidence that POSTN is a promising therapeutic target for CNS injury.

Experimental Mouse Model of Lumbar Ligamentum Flavum Hypertrophy.

Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in elderly people, with the number of LSCS patients increasing due to the aging of the population. The ligamentum flavum (LF) is a spinal ligament located in the interior of the vertebral canal, and hypertrophy of the LF, which causes the direct compression of the nerve roots and/or cauda equine, is a major cause of LSCS. Although there have been previous studies on LF hypertrophy, its pathomechanism remains unclear. The purpose of this study is to establish a relevant mouse model of LF hypertrophy and to examine disease-related factors. First, we focused on mechanical stress and developed a loading device for applying consecutive mechanical flexion-extension stress to the mouse LF. After 12 weeks of mechanical stress loading, we found that the LF thickness in the stress group was significantly increased in comparison to the control group. In addition, there were significant increases in the area of collagen fibers, the number of LF cells, and the gene expression of several fibrosis-related factors. However, in this mecnanical stress model, there was no macrophage infiltration, angiogenesis, or increase in the expression of transforming growth factor-ß1 (TGF-ß1), which are characteristic features of LF hypertrophy in LSCS patients. We therefore examined the influence of infiltrating macrophages on LF hypertrophy. After inducing macrophage infiltration by micro-injury to the mouse LF, we found excessive collagen synthesis in the injured site with the increased TGF-ß1 expression at 2 weeks after injury, and further confirmed LF hypertrophy at 6 weeks after injury. Our findings demonstrate that mechanical stress is a causative factor for LF hypertrophy and strongly suggest the importance of macrophage infiltration in the progression of LF hypertrophy via the stimulation of collagen production.

The feasibility of in vivo imaging of infiltrating blood cells for predicting the functional prognosis after spinal cord injury.

After a spinal cord injury (SCI), a reliable prediction of the potential functional outcome is essential for determining the optimal treatment strategy. Despite recent advances in the field of neurological assessment, there is still no satisfactory methodology for predicting the functional outcome after SCI. We herein describe a novel method to predict the functional outcome at 12 hours after SCI using in vivo bioluminescence imaging. We produced three groups of SCI mice with different functional prognoses: 50 kdyn (mild), 70 kdyn (moderate) and 90 kdyn (severe). Only the locomotor function within 24 hours after SCI was unable to predict subsequent functional recovery. However, both the number of infiltrating neutrophils and the bioluminescence signal intensity from infiltrating blood cells were found to correlate with the severity of the injury at 12 hours after SCI. Furthermore, a strong linear relationship was observed among the number of infiltrating neutrophils, the bioluminescence signal intensity, and the severity of the injury. Our findings thus indicate that in vivo bioluminescence imaging is able to accurately predict the long-term functional outcome in the hyperacute phase of SCI, thereby providing evidence that this imaging modality could positively contribute to the future development of tailored therapeutic approaches for SCI.

Engrafted Neural Stem/Progenitor Cells Promote Functional Recovery through Synapse Reorganization with Spared Host Neurons after Spinal Cord Injury.

Neural stem/progenitor cell (NSPC) transplantation is a promising therapeutic strategy for spinal cord injury (SCI). However, the efficacy of NSPC transplantation on severe SCI is poorly understood. We herein show that NSPC transplantation promotes functional recovery after mild and moderate SCI, but not after severe SCI. In severe SCI mice, there were few remaining host neurons within the range of NSPC engraftment; thus, we examined whether the co-distribution of transplant and host is a contributory factor for functional improvement. A cellular selective analysis using laser microdissection revealed that drug-induced host neuronal ablation considerably decreased the synaptogenic potential of the engrafted NSPCs. Furthermore, following host neuronal ablation, neuronal retrograde tracing showed less propriospinal relay connections bridging the lesion after NSPC transplantation. Our findings suggest that the interactive synaptic reorganization between engrafted NSPCs and spared host neurons is crucial for functional recovery, providing significant insight for establishing therapeutic strategies for severe SCI.

Therapeutic activities of engrafted neural stem/precursor cells are not dormant in the chronically injured spinal cord.

The transplantation of neural stem/precursor cells (NSPCs) is a promising therapeutic strategy for many neurodegenerative disorders including spinal cord injury (SCI) because it provides for neural replacement or trophic support. This strategy is now being extended to the treatment of chronic SCI patients. However, understanding of biological properties of chronically transplanted NSPCs and their surrounding environments is limited. Here, we performed temporal analysis of injured spinal cords and demonstrated their multiphasic cellular and molecular responses. In particular, chronically injured spinal cords were growth factor-enriched environments, whereas acutely injured spinal cords were enriched by neurotrophic and inflammatory factors. To determine how these environmental differences affect engrafted cells, NSPCs transplanted into acutely, subacutely, and chronically injured spinal cords were selectively isolated by flow cytometry, and their whole transcriptomes were compared by RNA sequencing. This analysis revealed that NSPCs produced many regenerative/neurotrophic molecules irrespective of transplantation timing, and these activities were prominent in chronically transplanted NSPCs. Furthermore, chronically injured spinal cords permitted engrafted NSPCs to differentiate into neurons/oligodendrocytes and provided more neurogenic environment for NSPCs than other environments. Despite these results demonstrate that transplanted NSPCs have adequate capacity in generating neurons/oligodendrocytes and producing therapeutic molecules in chronic SCI microenvironments, they did not improve locomotor function. Our results indicate that failure in chronic transplantation is not due to the lack of therapeutic activities of engrafted NSPCs but the refractory state of chronically injured spinal cords. Environmental modulation, rather modification of transplanting cells, will be significant for successful translation of stem cell-based therapies into chronic SCI patients.

Clinical outcome for patients with dedifferentiated chondrosarcoma: a report of 9 cases at a single institute.

BACKGROUND: Dedifferentiated chondrosarcomas consist of two distinguishable components: low-grade chondrosarcoma components and high-grade dedifferentiated components. MATERIALS AND METHODS: Nine cases (4 males, 5 females) of dedifferentiated chondrosarcoma were treated in our institute. The average age was 58.6 (range, 37-86) years. The tumor location was the long bone in 7 cases (femur, n=5; humerus, n=1; tibia, n=1) and the pelvic bone in 2 cases. The average time from appearance of symptoms to treatment was 9.4 (range, 1-40) months. RESULTS AND DISCUSSION: On plain radiographs, matrix mineralization was seen in all 9 cases (100%). Bone destruction was observed in 5 of 9 cases (56%), while pathological fracture was seen in one femur case (11%). Lung metastasis was observed in all cases (initially in 5 cases; during the treatment course in 4 cases). Surgery was performed in 8 cases, with local recurrence occurring in 2 of those cases (time to recurrence, 2 and 10 months). Chemotherapy was administered in 4 cases, but did not result in significant improvement. All 9 cases died of lung metastases, with a median survival time of 10 (range, 3.4-18.8) months. The presence of initial metastasis at diagnosis was a significant unfavorable prognostic factor. CONCLUSION: The prognosis of dedifferentiated chondrosarcoma is dismal. With the lack of convincing evidence of the benefit of chemotherapy, complete surgical excision is the initial recommended treatment.