Human Hepatocyte Growth Factor Promotes Functional Recovery in Primates after Spinal Cord Injury

Many therapeutic interventions for spinal cord injury (SCI) using neurotrophic factors have focused on reducing the area damaged by secondary, post-injury degeneration, to promote functional recovery. Hepatocyte growth factor (HGF), which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We previously reported that introducing exogenous HGF into the injured rodent spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, that study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF) intrathecally. Motor function was assessed using an original open field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. In vivo magnetic resonance imaging showed significant preservation of the intact spinal cord parenchyma. rhHGF-treatment did not give rise to an abnormal outgrowth of calcitonin gene related peptide positive fibers compared to the control group, indicating that this treatment did not induce or exacerbate allodynia. This is the first study to report the efficacy of rhHGF for treating SCI in non-human primates. In addition, this is the first presentation of a novel scale for assessing neurological motor performance in non-human primates after contusive cervical SCI

Noninvasive technique to evaluate the muscle fiber characteristics using q-space imaging

Background Skeletal muscles include fast and slow muscle fibers. The tibialis anterior muscle (TA) is mainly composed of fast muscle fibers, whereas the soleus muscle (SOL) is mainly composed of slow muscle fibers. However, a noninvasive approach for appropriately investigating the characteristics of muscles is not available. Monitoring of skeletal muscle characteristics can help in the evaluation of the effects of strength training and diseases on skeletal muscles. Purpose The present study aimed to determine whether q-space imaging can distinguish between TA and SOL in in vivo mice. Methods In vivo magnetic resonance imaging of the right calves of mice (n = 8) was performed using a 7-Tesla magnetic resonance imaging system with a cryogenic probe. TA and SOL were assessed. q-space imaging was performed with a field of view of 10 mm x 10 mm, matrix of 48 x 48, and section thickness of 1000 mu m. There were ten b-values ranging from 0 to 4244 s/mm(2), and each b-value had diffusion encoding in three directions. Magnetic resonance imaging findings were compared with immunohistological findings. Results Full width at half maximum and Kurtosis maps of q-space imaging showed signal intensities consistent with immunohistological findings for both fast (myosin heavy chain II) and slow (myosin heavy chain I) muscle fibers. With regard to quantification, both full width at half maximum and Kurtosis could represent the immunohistological findings that the cell diameter of TA was larger than that of SOL (P < 0.01). Conclusion q-space imaging could clearly differentiate TA from SOL using differences in cell diameters. This technique is a promising method to noninvasively estimate the fiber type ratio in skeletal muscles, and it can be further developed as an indicator of muscle characteristics.journal articl

Long-term surgical outcomes of idiopathic spinal cord herniation

AbstractBackgroundBecause of the lack of long-term postoperative follow-up studies of idiopathic spinal cord herniation (ISCH), there is little information about the long-term effectiveness and complications of the dural defect enlargement in patients with ISCH. The purpose of this study is to determine the long-term effectiveness of this procedure.MethodsSixteen patients with ISCH were treated surgically by enlargement of the dural defect. The patient's neurological status and surgical outcome were evaluated by the JOA scores for thoracic myelopathy and the recovery rate (mean follow-up period 9.6 years). Correlations between the surgical outcomes and patients' age and duration of disease were assessed retrospectively. The patients were also divided into two groups based on the location of the dural defect: the ventro-lateral (VL) group and the ventral (V) group. The difference in the duration of disease, preoperative JOA score, and the recovery rate were compared between the two groups.ResultsThere was no recurrence of ISCH after surgery. The mean recovery rate was 42.6%. There was a significant correlation between the patient's age and the recovery rate, and between the duration of disease and the recovery rate. The median recovery rate was significantly lower in the V group than in the VL group. There were no complications related to CSF leakage after surgery.ConclusionsLong-term surgical outcomes of enlargement of the dural defect for ISCH were stable and favorable without recurrences or any complications. This procedure should be considered for patients with ISCH before their neurological deficit worsens, especially for the patients in whom the dural defect is located at the ventral part of the dural canal

Effects of Bone Cross-Link Bridging on Fracture Mechanism and Surgical Outcomes in Elderly Patients with Spine Fractures

Study Design This study adopted a cross-sectional study design. Purpose This study was designed to investigate the effects of bone cross-link bridging on fracture mechanism and surgical outcomes in vertebral fractures using the maximum number of vertebral bodies with bony bridges between adjacent vertebrae without interruption (maxVB). Overview of Literature The complex interplay of bone density and bone bridging in the elderly can complicate vertebral fractures, necessitating a better understanding of fracture mechanics. Methods We examined 242 patients (age >60 years) who underwent surgery for thoracic to lumbar spine fractures from 2010 to 2020. Subsequently, the maxVB was classified into three groups: maxVB (0), maxVB (2–8), and maxVB (9–18), and parameters, including fracture morphology (new Association of Osteosynthesis classification), fracture level, and neurological deficits were compared. In a sub-analysis, 146 patients with thoracolumbar spine fractures were classified into the three aforementioned groups based on the maxVB and compared to determine the optimal operative technique and evaluate surgical outcomes. Results Regarding the fracture morphology, the maxVB (0) group had more A3 and A4 fractures, whereas the maxVB (2–8) group had less A4 and more B1 and B2 fractures. The maxVB (9–18) group exhibited an increased frequency of B3 and C fractures. Regarding the fracture level, the maxVB (0) group tended to have more fractures in the thoracolumbar transition region. Furthermore, the maxVB (2–8) group had a higher fracture frequency in the lumbar spine area, whereas the maxVB (9–18) group had a higher fracture frequency in the thoracic spine area than the maxVB (0) group. The maxVB (9–18) group had fewer preoperative neurological deficits but a higher reoperation rate and postoperative mortality than the other groups. Conclusions The maxVB was identified as a factor influencing fracture level, fracture type, and preoperative neurological deficits. Thus, understanding the maxVB could help elucidate fracture mechanics and assist in perioperative patient management

Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury

Abstract Background The transplantation of neural stem/progenitor cells (NS/PCs) at the sub-acute phase of spinal cord injury, but not at the chronic phase, can promote functional recovery. However, the reasons for this difference and whether it involves the survival and/or fate of grafted cells under these two conditions remain unclear. To address this question, NS/PC transplantation was performed after contusive spinal cord injury in adult mice at the sub-acute and chronic phases. Results Quantitative analyses using bio-imaging, which can noninvasively detect surviving grafted cells in living animals, revealed no significant difference in the survival rate of grafted cells between the sub-acute and chronic transplantation groups. Additionally, immunohistology revealed no significant difference in the differentiation phenotypes of grafted cells between the two groups. Microarray analysis revealed no significant differences in the expression of genes encoding inflammatory cytokines or growth factors, which affect the survival and/or fate of grafted cells, in the injured spinal cord between the sub-acute and chronic phases. By contrast, the distribution of chronically grafted NS/PCs was restricted compared to NS/PCs grafted at the sub-acute phase because a more prominent glial scar located around the lesion epicenter enclosed the grafted cells. Furthermore, microarray and histological analysis revealed that the infiltration of macrophages, especially M2 macrophages, which have anti-inflammatory role, was significantly higher at the sub-acute phase than the chronic phase. Ultimately, NS/PCs that were transplanted in the sub-acute phase, but not the chronic phase, promoted functional recovery compared with the vehicle control group. Conclusions The extent of glial scar formation and the characteristics of inflammation is the most remarkable difference in the injured spinal cord microenvironment between the sub-acute and chronic phases. To achieve functional recovery by NS/PC transplantation in cases at the chronic phase, modification of the microenvironment of the injured spinal cord focusing on glial scar formation and inflammatory phenotype should be considered.</p

MRI characterization of paranodal junction failure and related spinal cord changes in mice.

The paranodal junction is a specialized axon-glia contact zone that is important for normal neuronal activity and behavioral locomotor function in the central nervous system (CNS). Histological examination has been the only method for detecting pathological paranodal junction conditions. Recently, diffusion tensor MRI (DTI) has been used to detect microstructural changes in various CNS diseases. This study was conducted to determine whether MRI and DTI could detect structural changes in the paranodal junctions of the spinal cord in cerebroside sulfotransferase knock-out (CST-KO) mice. Here, we showed that high-resolution MRI and DTI characteristics can reflect paranodal junction failure in CST-KO mice. We found significantly lower T1 times and significantly higher T2 times in the spinal cord MRIs of CST-KO mice as compared to wild-type (WT) mice. Spinal cord DTI showed significantly lower axial diffusivity and significantly higher radial diffusivity in CST-KO mice as compared to WT mice. In contrast, the histological differences in the paranodal junctions of WT and CST-KO mice were so subtle that electron microscopy or immunohistological analyses were necessary to detect them. We also measured gait disturbance in the CST-KO mice, and determined the conduction latency by electrophysiology. These findings demonstrate the potential of using MRI and DTI to evaluate white matter disorders that involve paranodal junction failure