Kazunori Yone

Strain on intervertebral discs after anterior cervical decompression and fusion.

STUDY DESIGN An analysis of the change in strain distribution of intervertebral discs present after anterior cervical decompression and fusion by an original method. The analytical results were compared to occurrence of herniation of the intervertebral disc on magnetic resonance imaging. OBJECTIVES To elucidate the influence of anterior cervical decompression and fusion on the unfused segments of the spine. SUMMARY OF BACKGROUND DATA There is no consensus regarding the exact significance of the biomechanical change in the unfused segment present after surgery. METHODS Ninety-six patients subjected to anterior cervical decompression and fusion for herniation of intervertebral discs were examined. Shear strain and longitudinal strain of intervertebral discs were analyzed on pre- and postoperative lateral dynamic routine radiography of the cervical spine. Thirty of the 96 patients were examined by magnetic resonance imaging before and after surgery, and the relation between alteration in strains and postsurgical occurrence of disc herniation was examined. RESULTS In the cases of double- or triple-level fusion, shear strain of adjacent segments had increased 20% on average 1 year after surgery. Thirteen intervertebral discs that had an abnormally high degree of strain showed an increase in longitudinal strain after surgery. Eleven (85%) of the 13 discs that showed an abnormal increase in longitudinal strain had herniation in the same intervertebral discs with compression of the spinal cord during the follow-up period. Relief of symptoms was significantly poor in the patients with recent herniation. CONCLUSIONS Close attention should be paid to long-term biomechanical changes in the unfused segment.

Treatment of spinal cord injury by transplantation of fetal neural precursor cells engineered to express BMP inhibitor

Spontaneous recovery after spinal cord injury is limited. Transplantation of neural precursor cells (NPCs) into lesioned adult rat spinal cord results in only partial functional recovery, and most transplanted cells tend to differentiate predominantly into astrocytes. In order to improve functional recovery after transplantation, it is important that transplanted neural precursor cells appropriately differentiate into cell lineages required for spinal cord regeneration. In order to modulate the fate of transplanted cells, we advocate transplanting gene-modified neural precursor cells. We demonstrate that gene modification to inhibit bone morphogenetic protein (BMP) signaling by noggin expression promoted differentiation of neural precursor cells into neurons and oligodendrocytes, in addition to astrocytes after transplantation. Furthermore, functional recovery of the recipient mice with spinal cord injury was observed when noggin-expressing neural precursor cells were transplanted. These observations suggest that gene-modified neural precursor cells that express molecules involved in cell fate modulation could improve central nervous system (CNS) regeneration.

Genetic mapping of ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is recognized as a common disorder among Japanese and throughout Asia. Estimates of its prevalence are in the range of 1. 9%-4.3%. Although its etiology is thought to involve a multiplicity of factors, epidemiological and family studies strongly implicate genetic susceptibility in the pathogenesis of OPLL. In this study we report an identification of a predisposing locus for OPLL, on chromosome 6p, close to the HLA complex. The evidence for this localization is provided by a genetic-linkage study of 91 affected sib pairs from 53 Japanese families. In this sib-pair study, D6S276, a marker lying close to the HLA complex, gives evidence for strongly significant linkage (P = .000006) to the OPLL locus. A candidate gene in the region, that for collagen 11A2, was analyzed for the presence of molecular variants in affected probands. Of 19 distinct variants identified, 4 showed strong statistical associations with OPLL (highest P = .0004). These observations of linkage and association, taken together, show that a genetic locus for OPLL lies close to the HLA region, on chromosome 6p.

Preoperative and postoperative magnetic resonance image evaluations of the spinal cord in cervical myelopathy.

To evaluate the morphologic changes of the spinal cord in patients with cervical myelopathy due to cervical spondylosis and ossification of the posterior longitudinal ligament, the authors measured the thickness and signal intensity of the cervical cord with magnetic resonance imaging in healthy adults and patients with cervicla myelopathy, and compared these findings. In patients with cervical myelopathy, the preoperative and postoperative magnetic resonance imaging findings were compared with the severity of myelopathy and postoperative results. In healthy adults, the anteroposterior diameter of the cervical cord wad 7.8 mm at the C3 level and decreased at lower levels. In the patients with cervical myelopathy, the preoperative spinal anteroposterior diameter was significantly reduced at various levels corresponding to the stenosis site within the vertebral canal. In the group with ossification of the posterior longitudinal ligament, the minimal anteroposterior diameter of the cervical cord tended to decrease with increasing severity of myelopathy. However no relationship was observed between the two parameters in the cervical spondylotic myelopathy group. In the group with ossification of the posterior longitudinal ligament, surgical results were good when the postoperative anteroposterior diameter was increased, whereas in the cervical spondylotic myelopathy group there was no relationship between the parameters. In the patients with myelopathy, a high intensity area was observed in about 40% of all patients before operation and about 30% after operation. However, the presence or absence of a high intensity area did not correlate with the severity of myelopathy or with surgical results in the group with ossification of the posterior longitudinal ligament and the cervical spondylotic myelopathy groups.

Indication of fusion for lumbar spinal stenosis in elderly patients and its significance.

Study Design Selection of surgical therapy for lumbar canal stenosis in elderly patients is discussed. Decompression alone and decompression with fusion were evaluated. Objectives To determine the indication of decompression with fusion for lumbar spinal stenosis in elderly patients. Summary of Background Data Although there is no objection to posterior decompression, which is regarded as the first choice of surgical therapy for lumbar spinal stenosis in the elderly, it is debatable whether or not fusion should be used with decompression. Methods The presence or absence of instability was defined by Posners method from preoperative plain radiographic lateral findings. Thirty-four elderly patients with lumbar canal stenosis were studied. Seventeen of the 34 patients were found to have instability. Ten of the 17 patients with spinal instability underwent decompression and instrumented fusion. The seven remaining patients with spinal instability underwent decompression alone. The 17 patients without spinal instability were treated by decompression alone. Preoperative symptoms, postoperative results, and changes in radiographic findings were compared among the three groups. Results The group treated by decompression and fusion showed the best results. The group treated by decompression in the presence of instability showed the worst results by the Japanese Orthopaedic Association back scores. Good results can be obtained by decompression alone only if the patients do not have instability as defined by Posner. Conclusions The definition of instability by Posners method proved useful for selecting elderly patients with instability for fusion treatment. Fusion with instrumentation should be performed on elderly patients with instability after decompression.

Traumatic injury-induced BMP7 expression in the adult rat spinal cord

It has been reported that bone morphogenetic proteins (BMPs) are involved in the generation of the central nervous system during development. However, the roles of BMPs in mature spinal cord have not been clarified. We examined the expression of BMP7 mRNA before and after traumatic injury of the adult rat spinal cord. BMP7 mRNA was already detectable at a relatively low level in uninjured spinal cord, but was dramatically increased after injury. Semiquantitative RT-PCR study further confirmed upregulation of BMP7 mRNA in injured spinal cord. In situ hybridization indicated that expression of BMP7 mRNA was present only in glial cells in uninjured spinal cord. After injury, the number of BMP7-expressing glial cells was increased, BMP7 expression also became apparent in motor neurons. It has been suggested that BMPs promote survival of subventricular zone cells in adult rats. Thus, our results suggest that increase in the expression of BMP7 promotes survival of neurons and glial cells after acute traumatic injury. In contrast, there is increasing evidence that BMPs inhibit neurogenesis and alternatively promote gliogenesis of neural progenitors, which are also present in adult spinal cord, suggesting that injury-upregulated BMP7 may regulate differentiation of glial cells from neural progenitors and may induce gliosis after central nervous system injury.

Induction of apoptosis signal regulating kinase 1 (ASK1) after spinal cord injury in rats: possible involvement of ASK1-JNK and -p38 pathways in neuronal apoptosis.

The aims of this study were to clarify the mechanism of cell death by apoptosis in the spinal cord after traumatic injury, and to examine the role of the mitogen-activated protein kinase (MAPK) pathways in the transmission of apoptosis signals. The rat spinal cord, experimentally injured by extradural static weight-compression, was studied by hematoxylin and eosin staining, Nissl-staining, terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick-end labeling (TUNEL) staining, and immunostaining using polyclonal antibodies against Apoptosis Signal-regulating Kinase 1 (ASK1), c-Jun N-terminal kinase (JNK), and p38 MAPK. TUNEL-positive cells were present at all stages studied until 7 days after injury, and percentage positivity for these cells was maximal at 3 days after injury. Electron microscopic analysis revealed the occurrence of apoptosis in both neuronal cells and glial cells. TUNEL-positive glial cells were stained by oligodendrocyte-specific maker. Expression of ASK1 was maximal at 24 h after injury in the gray matter and at 3 days after injury in the white matter. Following the expression of ASK1, activated forms of JNK and p38 were observed in apoptotic cells detected by the TUNEL method. Colocalization of ASK1 and activated JNK or activated p38 was observed in the same cell. These findings suggest the involvement of the stress-activated MAPK pathways including ASK1 in the transmission of apoptosis signals after spinal cord injury.

Mechanism of Destructive Pathologic Changes in the Spinal Cord Under Chronic Mechanical Compression

Study Design. A histologic and histochemical study was performed both in the autopsy of a human patient with cervical spinal cord compression caused by ossification of the posterior longitudinal ligament and in a tiptoe-walking Yoshimura mouse model of progressive cervical cord compression. Objectives. To clarify the mechanism of destructive pathologic changes in the spinal cord under chronic mechanical compression. Summary of Background Data. Under chronic compression, the spinal cord exhibits destructive changes considered to be causes of profound and irreversible motor paresis. Recently, some investigators have found that apoptosis in acute spinal cord injury induces both secondary degeneration at the site of injury and chronic demyelination of tracts away from the site of injury. However, the mechanism responsible for these destructive spinal cord changes under chronic compression remains unclear. Methods. The spinal cord was examined histologically, and an attempt was made to detect apoptotic cells using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling in both the autopsy of a human patient and tiptoe-walking mice exhibiting spinal cord compression. Results. Apoptotic cells were observed in the chronically compressed spinal cord in both the autopsy of a human patient and model mice. In tiptoe-walking mice exhibiting spinal cord compression, descending degeneration in the anterior and lateral columns and ascending degeneration in the posterior column were observed. The distribution of oligodendrocytes with positive results from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling was similar to that for degeneration of the long tracts. Conclusions. Spinal cord cell apoptosis may produce destructive changes in the spinal cord under chronic compression, with a resulting irreversible neurologic deficit.

High mobility group box 1 is upregulated after spinal cord injury and is associated with neuronal cell apoptosis.

Study Design. Cerebrocortical culture and rat spinal cord injury (SCI) model were used to examine the expression of high mobility group box 1 (HMGB1), TNF-&agr;, and Rage by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical examination. In addition, relationship between upregulation of HMGB1 and neural cells apoptosis was evaluated after SCI. Objective. To evaluate the upregulation of HMGB1, TNF-&agr;, and Rage after SCI. Summary of Background Data. It is known that the mode of delayed neuronal cell death after SCI is apoptosis. Apoptotic cell death is influenced by several injury-promoting factors which include pro-inflammatory cytokines. Inhibition of apoptosis promotes neurologic improvement following SCI. However, the factors which transmit inflammatory signaling following SCI have not yet been clarified in detail. HMGB1 was reported as an important mediator of inflammation. We examined the expression of HMGB1, TNF-&agr; and Rage following acute SCI. Methods. Expression of HMGB1, TNF-&agr; and Rage was examined by RT-PCR and immunohistochemical examination. Apoptotic cell death was evaluated by TUNEL methods. Results. HMGB1 was exported from nuclei to cytoplasm in active caspase-3 positive apoptotic cell in vitro. In addition, HMGB1, TNF-&agr;, and Rage was expressed in same cell after NMDA treatment. RT-PCR revealed that expression of HMGB1 and TNF-&agr; was upregulated following SCI. Immunohistochemical examination revealed that the numbers of HMGB1-, TNF-&agr;-, and Rage-positive cells were increased following SCI. The number of TUNEL-positive cells was significantly increased at 12 hours after injury, and was maximal at 72 hours after injury. However, HMGB1- and TNF-&agr;-positive cells were maximal in number 48 hours after injury, while Rage-positive cells were maximal in number at 24 hours after injury. These data suggest that HMGB1, TNF-&agr;, and Rage were upregulated following SCI but preceding the apoptotic cell death. Conclusion. Our findings suggest that HMGB1 play a role in the induction of apoptosis via inflammatory reaction.

Changes in nitric oxide and expression of nitric oxide synthase in spinal cord after acute traumatic injury in rats.

The aim of this study was to observe the time course of NO production and NOS expression in the spinal cord following acute traumatic injury. Rat spinal cord was injured by extradural static weight-compression, which resulted in an incomplete transverse spinal cord lesion with paralysis of the lower extremities. Using this model, measurement of NO by microdialysis and Griess reaction and histological and immunohistochemical examinations using polyclonal antibodies to nNOS and iNOS were performed from immediately to 14 days after injury. In injured cord, the amount of NO markedly increased immediately after injury and gradually decreased between 1 and 12 h after injury. A second wave of increase in NO level was observed at 24 h and 3 days after injury. Histologically, hematomas and necrotic changes were observed after injury and demyelination of nerve fibers increased with time in the compressed segment. Immunohistochemically, the number of cells with expression of nNOS was increased immediately to 12 h after injury. Expression of iNOS was observed from 12 h to 3 days after injury. These findings suggested that the initial maximal increase of NO production might be caused mainly by nNOS and that the second wave of increase in NO might be due mainly to iNOS.