Persistent Orthostatic Hypotension Following Surgery for Adult Spinal Deformity: Prevalence, Risk Factors, and Cardiovascular Evaluation.

STUDY DESIGN: Retrospective case-control study. PURPOSE: To understand the prevalence of persistent orthostatic hypotension (POH), as well as its risk factors and cardiovascular pathology, in patients receiving surgery for the adult spinal deformity (ASD). OVERVIEW OF LITERATURE: Although reports of the incidence of and risk factors for POH in different spinal disorders have recently been published, we are not aware of the comprehensive evaluation of POH following surgery for ASD. METHODS: We examined medical records from a single central database for 65 patients receiving surgical treatment for ASD. Statistical comparisons were made between patients who experienced postoperative POH and those who did not, by examining patient and operative characteristics, such as age, sex, comorbidities, functional status, preoperative neurological function, vertebral fractures, three-column osteotomy, total operative time, estimated blood loss, length of stay, and radiographic parameters. The determinants of POH were assessed using multiple logistic regression. RESULTS: We showed that postoperative POH was a complication of ASD surgery, with a 9% incidence rate. Patients with POH were statistically considerably more likely to require supported walkers due to partial paralysis and to have comorbidities including diabetes and neurodegenerative disease (ND). Furthermore, ND was an independent risk factor for postoperative POH (odds ratio, 4.073; 95% confidence interval, 1.094-8.362; p =0.020). Moreover, perioperative evaluation of the inferior vena cava showed that patients with postoperative POH had preoperative congestive heart failure and had hypovolemia lower postoperative diameter of the inferior vena cava than patients without POH. CONCLUSIONS: Postoperative POH is a potential complication of ASD surgery. The most pertinent risk factor is having an ND. According to our study, patients who have surgery for ASD may experience alterations in their hemodynamics.

Three-dimensional phase-contrast magnetic resonance imaging for the detention of a small communicating defect in a patient with a spinal extradural arachnoid cyst: illustrative case.

BACKGROUND: Spinal extradural arachnoid cysts are thought to be pouches that communicate with the intraspinal subarachnoid space through a dural defect. The treatment for these cysts is resection of the cyst wall followed by obliteration of the communicating defect, which is often elusive. OBSERVATIONS: The authors report the case of a 22-year-old man with an extradural arachnoid cyst with claudication and progressive motor weakness. Regular magnetic resonance imaging (MRI) and computed tomography did not reveal the location of the defect in the cyst. However, three-dimensional (3D) phase-contrast MRI clearly indicated the location of the defect and the flow of cerebrospinal fluid into the cyst. These findings allowed the authors to perform the least invasive surgery; the patient recovered motor function and could walk more smoothly. LESSONS: 3D phase-contrast MRI can reveal a subtle dural defect in patients with spinal extradural arachnoid cysts.

Improvement of Coxarthrosis Due to Realignment of Pelvic Retroversion Following Spinal Corrective Surgery: A Case Report.

CASE: A 70-year-old woman presented with severe trunk deformity, gait disturbance, and bilateral hip pain. Radiography and magnetic resonance imaging revealed severe spinal kyphosis, bilateral osteoarthritis of the hip joints, and lumbar canal stenosis. A 2-stage corrective surgery for the treatment of spinal kyphosis was performed. Subsequently, the spinopelvic alignment changed remarkably. The spinal symptoms and radiographic parameters improved postoperatively, and bilateral hip pain and range of motion also showed improvement. CONCLUSION: Corrective surgery for the treatment of degenerative spinal kyphosis affected the spinopelvic alignment, and the symptoms of simultaneous coxarthrosis also improved after the corrective surgery.

Clinical application of diffusion tensor tractography to postoperative C5 palsy.

STUDY DESIGN: Diagnostic study. OBJECTIVE: Although C5 palsy is a well-known potential complication after cervical procedure, the exact pathophysiology remains uncertain. Diffusion tensor tractography (DTT) has recently been proposed as a useful tool to examine quantitatively and non-invasively the pathology of spinal cord disorders. The purpose of this study is to determine the clinical interest of DTT in patients with C5 palsy after cervical laminoplasty. SETTING: Single university hospital. METHODS: Five patients with C5 palsy out of 108 patients after cervical laminoplasty were subjected to DTT using a 1.5 Tesla magnetic resonance imaging in our hospital between 2010 and 2012. For the tractography, two regions of interest (ROI) were placed at the C5 segmental level and the bilateral C4/5 intervertebral foramen level. RESULTS: The postoperative number of tract fibers at the C5 segmental spinal cord level was significantly increased compared to the preoperative number, despite the C5 palsy. Analyses of two ROIs (at the C5 segmental level and the C4/5 intervertebral foramen level) showed that the number of tract fibers at the palsy side was significantly decreased compared to the intact side. Furthermore, in the patient who spontaneously recovered from C5 palsy within postoperative 6 months, a gradual augmentation of tract fibers was identified at the palsy side. CONCLUSIONS: Our findings suggest that DTT can document C5 palsy in detail, as the anatomical region between C5 segmental level and C4/5 intervertebral foramen level was potentially damaged in patients with C5 palsy after laminoplasty.

The Amelioration of Pain-Related Behavior in Mice with Chronic Spinal Cord Injury Treated with Neural Stem/Progenitor Cell Transplantation Combined with Treadmill Training.

Progress in regenerative medicine is realizing the possibility of neural regeneration and functional recovery in spinal cord injury (SCI). Recently, rehabilitation has attracted much attention with respect to the synergistic promotion of functional recovery in combination with neural stem/progenitor cell (NS/PC) transplantation, even in the chronic refractory phase of SCI. Nevertheless, sensory disturbance is one of the most prominent sequelae, even though the effects of combination or single therapies have been investigated mostly in the context of motor recovery. To determine how combination therapy with treadmill training (TMT) and NS/PC transplantation affects the manifestation of thermal allodynia and tactile hyperalgesia in chronic phase SCI, four groups of SCI mice were used to assess pain-related behavior and histological changes: combined transplantation and TMT therapy, transplantation only, TMT only, and control groups. Thermal allodynia and coarse touch-pressure hyperalgesia exhibited significant recovery in the combined therapy group in comparison with controls, whereas there were no significant differences with fine touch-pressure hyperalgesia and motor function. Further investigation revealed fewer fibers remaining in the posterior funiculus, which contained the tracts associated with the two modalities showing less recovery; that is, touch-pressure hyperalgesia and motor function. A significant correlation was only observed between these two modalities. Although no remarkable histological recovery was found within the lesion epicenter, changes indicating amelioration of pain were observed in the lumbar enlargement of the combination therapy group. Our results suggest that amelioration of thermal allodynia and tactile hyperalgesia can be brought about by the additive effect of NS/PC transplantation and TMT. The degree of recovery seems dependent on the distribution of damage.

Discography aids definitive diagnosis of posterior epidural migration of lumbar disc fragments: case report and literature review.

BACKGROUND: Posterior epidural migration of lumbar disc fragments (PEMLDF) is extremely rare. It is often confused with other posterior lesions and is usually diagnosed intraoperatively. We here describe the use of preoperative discography in the diagnosis of PEMLDF. CASE PRESENTATION: A 78-year-old man presented with acute low back pain, gait disturbance, and paresthesia in both legs. Magnetic resonance imaging showed a mass located posteriorly and laterally to the left aspect of the dural sac at the L3 level. The initial diagnosis indicated PEMLDF, malignancy, spontaneous hematoma, or epidural abscess. L3/4 discography clearly showed leakage of the contrast medium into the posterior dural space, indicating PEMLDF. The lesion was identified intraoperatively as a herniated-disc fragment, consistent with the preoperative discography. CONCLUSION: PEMDLF is difficult to diagnose preoperatively. Discography is useful for the definitive diagnosis of PEMDLF prior to surgery.

Enhanced Functional Recovery from Spinal Cord Injury in Aged Mice after Stem Cell Transplantation through HGF Induction.

The number of elderly patients with spinal cord injury (SCI) is increasing worldwide, representing a serious burden for both the affected patients and the community. Previous studies have demonstrated that neural stem cell (NSC) transplantation is an effective treatment for SCI in young animals. Here we show that NSC transplantation is as effective in aged mice as it is in young mice, even though aged mice exhibit more severe neurological deficits after SCI. NSCs grafted into aged mice exhibited better survival than those grafted into young mice. Furthermore, we show that the neurotrophic factor HGF plays a key role in the enhanced functional recovery after NSC transplantation observed in aged mice with SCI. The unexpected results of the present study suggest that NSC transplantation is a potential therapeutic modality for SCI, even in elderly patients.

Grafted Human iPS Cell-Derived Oligodendrocyte Precursor Cells Contribute to Robust Remyelination of Demyelinated Axons after Spinal Cord Injury.

Murine- and human-induced pluripotent stem cell-derived neural stem/progenitor cells (iPSC-NS/PCs) promote functional recovery following transplantation into the injured spinal cord in rodents and primates. Although remyelination of spared demyelinated axons is a critical mechanism in the regeneration of the injured spinal cord, human iPSC-NS/PCs predominantly differentiate into neurons both in vitro and in vivo. We therefore took advantage of our recently developed protocol to obtain human-induced pluripotent stem cell-derived oligodendrocyte precursor cell-enriched neural stem/progenitor cells and report the benefits of transplanting these cells in a spinal cord injury (SCI) model. We describe how this approach contributes to the robust remyelination of demyelinated axons and facilitates functional recovery after SCI.

Controlling immune rejection is a fail-safe system against potential tumorigenicity after human iPSC-derived neural stem cell transplantation.

Our previous work reported functional recovery after transplantation of mouse and human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) into rodent models of spinal cord injury (SCI). Although hiPSC-NS/PCs proved useful for the treatment of SCI, the tumorigenicity of the transplanted cells must be resolved before they can be used in clinical applications. The current study sought to determine the feasibility of ablation of the tumors formed after hiPSC-NS/PC transplantation through immunoregulation. Tumorigenic hiPSC-NS/PCs were transplanted into the intact spinal cords of immunocompetent BALB/cA mice with or without immunosuppressant treatment. In vivo bioluminescence imaging was used to evaluate the chronological survival and growth of the transplanted cells. The graft survival rate was 0% in the group without immunosuppressants versus 100% in the group with immunosuppressants. Most of the mice that received immunosuppressants exhibited hind-limb paralysis owing to tumor growth at 3 months after iPSC-NS/PC transplantation. Histological analysis showed that the tumors shared certain characteristics with low-grade gliomas rather than with teratomas. After confirming the progression of the tumors in immunosuppressed mice, the immunosuppressant agents were discontinued, resulting in the complete rejection of iPSC-NS/PC-derived masses within 42 days after drug cessation. In accordance with the tumor rejection, hind-limb motor function was recovered in all of the mice. Moreover, infiltration of microglia and lymphocytes was observed during the course of tumor rejection, along with apoptosis of iPSC-NS/PC-generated cells. Thus, immune rejection can be used as a fail-safe system against potential tumorigenicity after transplantation of iPSC-NS/PCs to treat SCI.

Control of the Survival and Growth of Human Glioblastoma Grafted Into the Spinal Cord of Mice by Taking Advantage of Immunorejection.

Recent studies have demonstrated that transplantation of induced pluripotent stem cell-derived neurospheres can promote functional recovery after spinal cord injury in rodents, as well as in nonhuman primates. However, the potential tumorigenicity of the transplanted cells remains a matter of apprehension prior to clinical applications. As a first step to overcome this concern, this study established a glioblastoma multiforme xenograft model mouse. The feasibility of controlling immune suppression to ablate the grafted cells was then investigated. The human glioblastoma multiforme cell line U251 MG was transplanted into the intact spinal cords of immunodeficient NOD/SCID mice or into those of immunocompetent C57BL/6J H-2kb mice treated with or without immunosuppressants [FK506 plus anticluster of differentiation (CD) 4 antibody (Ab), or FK506 alone]. In vivo bioluminescent imaging was used to evaluate the chronological survival of the transplanted cells. The graft survival rate was 100% (n = 9/9) in NOD/SCID mice, 0% (n = 6/6) in C57BL/6J mice without immunosuppressant treatment, and 100% (n = 37/37) in C57BL6/J mice with immunosuppressant treatment. After confirming the growth of the grafted cells in the C57/BL6J mice treated with immunosuppressants, immune suppression was discontinued. The grafted cells were subsequently rejected within 3 days in C57BL/6J mice treated with FK506 alone, as opposed to 26 days in C57BL/6J mice treated with FK506 plus anti-CD4 Ab. Histological evaluation confirmed the ablation of the grafted cells. Although this work describes a xenograft setting, the results suggest that this immunomodulatory strategy could provide a safety lock against tumor formation stemming from transplanted cells.

Inflammatory cascades mediate synapse elimination in spinal cord compression.

BACKGROUND: Cervical compressive myelopathy (CCM) is caused by chronic spinal cord compression due to spondylosis, a degenerative disc disease, and ossification of the ligaments. Tip-toe walking Yoshimura (twy) mice are reported to be an ideal animal model for CCM-related neuronal dysfunction, because they develop spontaneous spinal cord compression without any artificial manipulation. Previous histological studies showed that neurons are lost due to apoptosis in CCM, but the mechanism underlying this neurodegeneration was not fully elucidated. The purpose of this study was to investigate the pathophysiology of CCM by evaluating the global gene expression of the compressed spinal cord and comparing the transcriptome analysis with the physical and histological findings in twy mice. METHODS: Twenty-week-old twy mice were divided into two groups according to the magnetic resonance imaging (MRI) findings: a severe compression (S) group and a mild compression (M) group. The transcriptome was analyzed by microarray and RT-PCR. The cellular pathophysiology was examined by immunohistological analysis and immuno-electron microscopy. Motor function was assessed by Rotarod treadmill latency and stride-length tests. RESULTS: Severe cervical calcification caused spinal canal stenosis and low functional capacity in twy mice. The microarray analysis revealed 215 genes that showed significantly different expression levels between the S and the M groups. Pathway analysis revealed that genes expressed at higher levels in the S group were enriched for terms related to the regulation of inflammation in the compressed spinal cord. M1 macrophage-dominant inflammation was present in the S group, and cysteine-rich protein 61 (Cyr61), an inducer of M1 macrophages, was markedly upregulated in these spinal cords. Furthermore, C1q, which initiates the classical complement cascade, was more upregulated in the S group than in the M group. The confocal and electron microscopy observations indicated that classically activated microglia/macrophages had migrated to the compressed spinal cord and eliminated synaptic terminals. CONCLUSIONS: We revealed the detailed pathophysiology of the inflammatory response in an animal model of chronic spinal cord compression. Our findings suggest that complement-mediated synapse elimination is a central mechanism underlying the neurodegeneration in CCM.

Distinct roles of endogenous vascular endothelial factor receptor 1 and 2 in neural protection after spinal cord injury.

Secondary degeneration after spinal cord injury (SCI) is caused by increased vascular permeability, infiltration of inflammatory cells, and subsequent focal edema. Therapeutic interventions using neurotrophic factors have focused on the prevention of such reactions to reduce cell death and promote tissue regeneration. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. However, the effect of VEGF on SCI remains controversial. VEGF signaling is primarily regulated through two primary receptors, VEGF receptor 1 (VEGF-R1) and VEGF receptor 2 (VEGF-R2). The purpose of this study was to examine the effects of intraperitoneal administration of VEGF-R1- and VEGF-R2-neutralizing antibodies on a mouse model of SCI. VEGF-R1 blockade, but not VEGF-R2 blockade, decreased the permeability and infiltration of inflammatory cells, and VEGF-R2 blockade caused a significant increase in neuronal apoptosis in the acute phase of SCI. VEGF-R2 blockade decreased the residual tissue area and the number of neural fibers in the chronic phase of SCI. VEGF-R2 blockade worsened the functional recovery and prolonged the latency of motor evoked potentials. These data suggest that endogenous VEGF-R2 plays a crucial role in neuronal protection after SCI.

Transplantation of neural stem/progenitor cells at different locations in mice with spinal cord injury.

Transplantation of neural stem/progenitor cells (NS/PCs) promotes functional recovery after spinal cord injury (SCI); however, few studies have examined the optimal site of NS/PC transplantation in the spinal cord. The purpose of this study was to determine the optimal transplantation site of NS/PCs for the treatment of SCI. Wild-type mice were generated with contusive SCI at the T10 level, and NS/PCs were derived from fetal transgenic mice. These NS/PCs ubiquitously expressed ffLuc-cp156 protein (Venus and luciferase fusion protein) and so could be detected by in vivo bioluminescence imaging 9 days postinjury. NS/PCs (low: 250,000 cells per mouse; high: 1 million cells per mouse) were grafted into the spinal cord at the lesion epicenter (E) or at rostral and caudal (RC) sites. Phosphate-buffered saline was injected into E as a control. Motor functional recovery was better in each of the transplantation groups (E-Low, E-High, RC-Low, and RC-High) than in the control group. The photon counts of the grafted NS/PCs were similar in each of the four transplantation groups, suggesting that the survival of NS/PCs was fairly uniform when more than a certain threshold number of cells were transplanted. Quantitative RT-PCR analyses demonstrated that brain-derived neurotropic factor expression was higher in the RC segment than in the E segment, and this may underlie why NS/PCs more readily differentiated into neurons than into astrocytes in the RC group. The location of the transplantation site did not affect the area of spared fibers, angiogenesis, or the expression of any other mediators. These findings indicated that the microenvironments of the E and RC sites are able to support NS/PCs transplanted during the subacute phase of SCI similarly. Optimally, a certain threshold number of NS/PCs should be grafted into the E segment to avoid damaging sites adjacent to the lesion during the injection procedure.

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

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.

In vivo tracing of neural tracts in tiptoe walking Yoshimura mice by diffusion tensor tractography.

STUDY DESIGN: Basic imaging experiment. OBJECTIVE: To determine whether in vivo diffusion tensor tractography (DTT) can be used to evaluate the axonal disruption of the chronically compressed spinal cord in tiptoe walking Yoshimura (twy) mice. SUMMARY OF BACKGROUND DATA: In cervical ossification of the posterior longitudinal ligament, axonal disruption results in motor and sensory functional impairment. Twy mice develop spontaneous calcification in the cervical ligaments, which causes chronic compression of the spinal cord. DTT is emerging as a powerful tool for tracing axonal fibers in vivo. METHODS: Five twy mice were subjected to DTT at 6, 15, and 20 weeks of age. Magnetic resonance imaging was performed using a 7.0-Tesla magnet (Biospec 70/16; Billerica, MA) with a CryoProbe. Diffusion tensor images were analyzed using TrackVis (Massachusetts General Hospital, MA). Motor performance was evaluated by Rotarod treadmill test and Digigait analysis. Histological analysis was performed by hematoxylin-eosin staining and immunostaining for RT-97 and SMI-31. RESULTS: High resolution DTT of twy mice in vivo was successful. A lower number of RT-97- or SMI-31-positive fibers were associated with more severe spinal cord compression, which was determined by observing the ligamentous calcification at the C2-C3 level in each twy mouse. The severity of canal stenosis based on magnetic resonance images was strongly correlated with the axial area of the spinal cord. The tract fiber (TF) ratio (the number of TFs at the C2-C3 level/the number of TFs at the C0-C1 level) was strongly correlated with the RT-97/SMI-31-positive area and with motor function (rotarod latency, stride length). Furthermore, a two-part linear regression analysis showed that canal stenosis around 50% to 60% caused a sharp decrease in the TF ratio before the deterioration of motor function. CONCLUSION: We conclude that DTT could be useful for detecting the early changes associated with the compressed spinal cord in cervical ossification of the posterior longitudinal ligament.

Neural stem cells directly differentiated from partially reprogrammed fibroblasts rapidly acquire gliogenic competency.

Neural stem cells (NSCs) were directly induced from mouse fibroblasts using four reprogramming factors (Oct4, Sox2, Klf4, and cMyc) without the clonal isolation of induced pluripotent stem cells (iPSCs). These NSCs gave rise to both neurons and glial cells even at early passages, while early NSCs derived from clonal embryonic stem cells (ESCs)/iPSCs differentiated mainly into neurons. Epidermal growth factor-dependent neurosphere cultivation efficiently propagated these gliogenic NSCs and eliminated residual pluripotent cells that could form teratomas in vivo. We concluded that these directly induced NSCs were derived from partially reprogrammed cells, because dissociated ESCs/iPSCs did not form neurospheres in this culture condition. These NSCs differentiated into both neurons and glial cells in vivo after being transplanted intracranially into mouse striatum. NSCs could also be directly induced from adult human fibroblasts. The direct differentiation of partially reprogrammed cells may be useful for rapidly preparing NSCs with a strongly reduced propensity for tumorigenesis.

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.

Significance of remyelination by neural stem/progenitor cells transplanted into the injured spinal cord.

Previous reports of functional recovery from spinal cord injury (SCI) in rodents and monkeys after the delayed transplantation of neural stem/progenitor cells (NS/PCs) have raised hopes that stem cell therapy could be used to treat SCI in humans. More research is needed, however, to understand the mechanism of functional recovery. Oligodendrocytes derived from grafted NS/PCs remyelinate spared axons in the injured spinal cord. Here, we studied the extent of this remyelination's contribution to functional recovery following contusive SCI in mice. To isolate the effect of remyelination from other possible regenerative benefits of the grafted cells, NS/PCs obtained from myelin-deficient shiverer mutant mice (shi-NS/PCs) were used in this work alongside wild-type NS/PCs (wt-NS/PCs). shi-NS/PCs behaved like wt-NS/PCs in vitro and in vivo, with the exception of their myelinating potential. shi-NS/PC-derived oligodendrocytes did not express myelin basic protein in vitro and formed much thinner myelin sheaths in vivo compared with wt-NS/PC-derived oligodendrocytes. The transplantation of shi-NS/PCs promoted some locomotor and electrophysiological functional recovery but significantly less than that afforded by wt-NS/PCs. These findings establish the biological importance of remyelination by graft-derived cells for functional recovery after the transplantation of NS/PCs into the injured spinal cord.

[Case of nephrotic syndrome due to AL-type primary amyloidosis associated with renal cell carcinoma].

An 80-year-old man was admitted because of appetite loss, mild proteinuria, and leg edema. A computed tomography examination revealed a tumor in his left kidney, and a left nephrectomy was performed. The tumor was histologically diagnosed as a clear cell type renal cell carcinoma, and hematoxylin eosin staining of the non-tumor region of the resected kidney showed an almost normal morphology. Three months later, he was readmitted because of the development of nephrotic syndrome with a urinary protein excretion of 4.2 g/day, a serum total protein concentration of 5.0 g/dL, a serum albumin concentration of 2.4 g/dL, a serum total cholesterol concentration of 214 mg/dL, and generalized edema. A full examination revealed no evidence of metastasis or recurrence of the renal cell carcinoma or any other malignant tumor. Congo red staining and immunohistochemical staining were performed using the non-tumor region of his resected kidney, and the presence of amyloid deposits in the microvascular walls and glomeruli that did not disappear when treated with potassium permanganate was disclosed. In this manner, the patient was diagnosed as having AL-type primary amyloidosis. Bence-Jones proteinuria and gastric amyloidosis were also observed, but a bone marrow examination showed no signs of multiple myeloma. Previous studies have reported an association between renal cell carcinoma and renal amyloidosis, mainly AA-type secondary amyloidosis. To our knowledge, only two cases of renal cell carcinoma associated with primary amyloidosis have been previously reported. Therefore, the present patient not only represents a rare case of renal cell carcinoma associated with primary amyloidosis, but also reminds us that careful histological examination of the non-tumor region of the resected kidney is needed to evaluate the proteinuria associated with renal cell carcinoma, particularly in elderly patients.