Tetsuya Tamaki

Pathomechanism of pain-related behavior produced by allografts of intervertebral disc in the rat

Study Design This study was designed to evaluate whether allografts of intervertebral disc materials produce hyperalgesia in the rat and whether an immune response, pH, or chemicals correlate with the induced hyperalgesia. Objective To elucidate the pathomechanisms of radicular pain secondary to lumbar disc herniation. Summary of Background Data It has been reported that a low pH, an autoimmune reaction, or chemical radiculitis is likely responsible for radicular pain associated with lumbar disc herniation. In animal studies, it has been shown that hyperalgesia (an increased sensitivity to painful stimuli) involves activation of phospholipase A2 and nitric oxide synthase. Methods Fat, nucleus pulposus, and anulus fibrosus were allografted into the epidural space at L6 in the rat. Withdrawal response thresholds to mechanical stimuli and withdrawal response latencies to thermal stimuli on the tail and pH in the applied tissues were measured after surgery. Interleukin‐1, phospholipase A2, and nitric oxide synthase were examined in the applied tissues using immunohistochemistry, nicotineamide adenine dinucleotide phosphate‐diaphorase histochemistry, and in situ hybridization. Results Allografted fat did not produce hyperalgesia. Allografts of nucleus pulposus and nucleus pulposus plus anulus fibrosis showed evidence of mechanical and thermal hyperalgesia, respectively. There were no observed changes in pH over time. Although interleukin‐1 was demonstrated in all applied tissues, phospholipase A2 was only observed around the applied nucleus pulposus and nucleus pulposus plus anulus fibrosus. Nitric oxide synthase was only markedly increased around the applied tissues. Conclusion The nucleus pulposus and anulus fibrosus produce different forms of hyperalgesia (mechanical vs. thermal) associated with different and distinct immunohistochemical changes. It is possible that radicular pain of a lumbar disc herniation results from chemicals, such as phospholiapse A2 and nitric oxide.

Early complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute cervical spinal cord injury.

Study Design A prospective, randomized, and double-blind study comparing high-dose methylprednisolone sodium succinate (MPSS) with placebo, in the treatment of patients with acute cervical spinal cord injury. Objectives To evaluate the complications of high-dose MPSS in patients with acute cervical spinal cord injury when administered within 8 hours of injury. Summary of Background Data High-dose therapy with MPSS has been demonstrated to improve the recovery of motor function in patients with acute cervical spinal cord injury. However, little is known about the follow-up complications. Methods Forty-six patients, 42 men and 4 women (mean age, 60.6 years; range, 18–84), were included in the study: 23 in the MPSS group and 23 in the placebo group. They were treated without surgery for spinal cord injury in the cervical spine, and were enrolled in the trial if a diagnosis had been made and treatment had begun within 8 hours. Complications of high-dose therapy with MPSS were compared with placebo treatment throughout the study period and up to 2 months after injury. Results The MPSS group had 13 patients (56.5%) with complications, whereas the placebo group had 8 (34.8%). The difference between the two groups was not statistically significant (P = 0.139). There were eight instances of pulmonary complication with MPSS (34.8%) and one instance (4.34%) with placebo (P = 0.009). There were four instances of gastrointestinal complication (17.4%) with MPSS and none with placebo (P = 0.036). Pulmonary (complications were more prevalent in patients aged more than 60 years (P = 0.029). Conclusion Aged patients with cervical spinal injury may be more likely to have pulmonary side effects (P = 0.029) after high-dose therapy with MPSS and thus deserve special care.

Hypertrophied ligamentum flavum in lumbar spinal canal stenosis : pathogenesis and morphologic and immunohistochemical observation

To investigate the pathogenesis of hypertrophy of the ligamentum flavum, 45 cases of lumbar canal stenosis were evaluated by computed tomography scan and pathologic and immunohistochemical studies. The ligamentum flavum along with the medial one-third of the superior facet was obtained an bloc to include the enthesis. Statistically significant differences in transverse area and thickness of the ligamentum flavum were evident compared to the control gourp (P<0.01). Pathogenesis of the hypertrophied ligamentum flavum was classified into three major groups: 1) fibrocartilage change due to proliferation of type II collagen, 2) ossification, and 3) calclum crystal depostion. It is stressed that marked proliferation of Type II collagen from the enthesis to the ligament side was revealed in the capsular portion of the hypertophied ligament.

Lumbar sagittal balance influences the clinical outcome after decompression and posterolateral spinal fusion for degenerative lumbar spondylolisthesis.

Study Design. This study was designed to assess both lumbar sagittal balance and clinical outcomes of decompression and posterolateral fusion for degenerative lumbar spondylolisthesis. As an index for the radiologic evaluation of sagittal alignment, the L1 axis S1 distance was used (i.e., the horizontal distance from the plumbline of the center in the L1 to the back corner of the S1). Objective. To determine whether lumbar sagittal balance affected the clinical outcome after posterolateral fusion. Summary of Background Data. Little is known about whether the sagittal vertical axis influences clinical outcomes in cases of degenerative lumbar spondylolisthesis. Methods. A retrospective review of 47 patients (15 men and 32 women), ranging in age from 41 to 79 years, was conducted. The mean follow-up period was 3.6 years. Relations among outcomes including the visual analog pain scale, recovery rate, L1 axis S1 distance, slippage, and lumbar lordosis were evaluated. Results. Recovery rates were 44% and 62% in patients whose preoperative L1 axis S1 distance, respectively, was more than 35 mm (Group A, n = 16) and less than 35 mm (Group B, n = 31) (P < 0.05). Follow-up assessment found a positive correlation between only lordosis and recovery rate. Severe low back pain and lower recovery rate were observed in patients with in situ fusion in Group A (n = 9), as compared with patients with reduced slippage in Group A (n = 7) and patients in Group B. Conclusions. Both preoperative L1 axis S1 distance and lordosis at follow-up assessment affected surgical outcome. Reduction of slippage may improve clinical outcomes of posterolateral fusion for degenerative lumbar spondylolisthesis with an L1 axis S1 distance more than 35 mm.

Possible mechanism of painful radiculopathy in lumbar disc herniation.

The pathophysiologic mechanisms of painful radiculopathy caused by a herniated intervertebral disc remain unknown. This study sought to determine whether the autologous intervertebral disc produces pain related behavior and whether pliospliolipase A, and nitric oxide are involved in the pathophysiologic mechanism producing the behavior. A rat model, in which autologous intervertebral discs were implanted on the nerve root in the lumbar spine, was used to measure hyperalgesia, which is a pain related behavior in the rat. In this experimental model, autologous nucleus pulposus and anulus fibrosus transplanted to lumbar nerve roots produced mechanical and thermal hyperalgesia, respectively. Epidural injection of a selective inhibitor for pliospholipase A, resulted in the disappearance of hypersensitivity to noxious mechanical stimuli. Thermal hyperalgesia produced by application of the anulus fibrosus was abated and abolished by epidural injections of saline and one of the inhibitors for nitric oxide synthase, respectively. The authors suggest that chemical mediators such as phospholipase A, and nitric oxide, induced by extruded or sequestrated intervertebral discs, are involved in the pathophysiologic mechanisms of painful radiculopathy in lumbar disc herniations. This study may be useful in attempting to develop new medical approaches for treatments of lumbar disc herniation.

A comparative study of surgical approaches for cervical compressive myelopathy.

Since 1986, the authors have used anterior decompression and fusion to treat patients with one-or two-level lesions without spinal canal stenosis (Group A) and laminoplasty for patients with more than three-level lesions or spinal canal stenosis (Group P). The aim of this study was to compare surgical outcomes of anterior and posterior approaches for patients with cervical myelopathy because of spondylosis and disc herniation and to determine the cause of poor neurologic recovery after surgery. One hundred thirty-six patients were followed up for an average of 5.6 years. There were no significant differences in gender, preoperative neurologic deficits, axial symptoms, or duration of symptoms before surgery between the two groups. Mean recovery rates for disc herniations were 71.1% and 71.9% in Groups A and P, respectively. For spondylosis, mean recovery rates were 49.0% and 58.6% in Groups A and P, respectively. There were no differences in recovery rate for patients with either spinal disorder between Groups A and P. The neurologic recovery of patients with kyphotic spinal cord was inferior to that of patients with lordotic or straight spinal cord. It is possible that acquisition and maintenance of lordosis result in improvement of clinical outcomes after surgery for patients with myelopathy.

Cyclic mechanical stretch stress increases the growth rate and collagen synthesis of nucleus pulposus cells in vitro.

STUDY DESIGN A rabbit model designed to investigate the effects of applied cyclic tensile stress on the cell division rate and the collagen synthesis in the rabbit nucleus pulposus cells in vitro. OBJECTIVE To evaluate the effects of mechanical stress on nucleus pulposus cells, thus adding to the understanding of the adaptation of the intervertebral disc to mechanical stress. SUMMARY OF BACKGROUND DATA Intervertebral disc cells in vivo are exposed to a multitude of physical forces during physical motion. Although it is known that in intervertebral disc disease, a common pathway of disc degeneration is mechanical stress on the nucleus pulposus or the anulus fibrosus or both, the underlying mechanism has been less well defined. METHODS Nucleus pulposus cells were isolated from 4-week-old Japanese white rabbits. These cells were subjected to the mechanical cyclic stretch stress using a computerized, pressure-operated instrument that physically deformed the cells. The DNA synthesis rate, collagen synthesis rate, and cell cycle progression were measured. RESULTS Cyclic tensile stretch increased the DNA synthesis rate in nucleus pulposus cells and in the population of cells in the S phase of the cell cycle during 1 to 2 days of subjugation to stress. Cyclic tensile stretch also increased collagenous protein synthesis in nucleus pulposus cells during 1 to 4 days of stress. CONCLUSIONS Mechanical stress on nucleus pulposus cells promotes the proliferation of cells and alters the properties of intervertebral disc cells. This study may reflect the adaptation of the intervertebral disc to increased motion and stress.

The role of phospholipase A2 and nitric oxide in pain-related behavior produced by an allograft of intervertebral disc material to the sciatic nerve of the rat

Study Design. To elucidate the pathomechanisms of radicular pain secondary to lumbar disc herniation. Objectives. To evaluate whether intervertebral disc material applied to the sciatic nerve produces hyperalgesia, and if the hyperalgesia is influenced by inhibitors of phospholipase A2 and nitric oxide synthase. Summary of Background Data. Previously, the authors reported that application of nucleus pulposus and anulus fibrosus material to the lumbar epidural space produces different forms of hyperalgesia (mechanical versus thermal), with different and distinct histologic changes. Additional pharmacologic studies showed that phospholipase A2 and nitric oxide are involved in the mechanisms that produce the mechanical and thermal hyperalgesia, respectively. Nω‐nitro‐L‐arginine methyl ester and mepacrine are relatively selective inhibitors of nitric oxide synthase and phospholipase A2, respectively. However, it is not known what the relation is between the hyperalgesia produced and the activation and involvement of phospholipase A2 and production of nitric oxide, or why the application of nucleus pulposus and nucleus pulposus with anulus fibrosus produces different types of hyperalgesia. Methods. Experiments were performed in five groups of rats: The control group (no treatment), the sham group (exposure of the sciatic nerve only), the fat group (allografted fat on the sciatic nerve), the nucleus pulposus group (allografted nucleus pulposus) and the nucleus pulposus + anulus fibrosus group (allografted nucleus pulposus and anulus fibrosus). Withdrawal threshold and latency from mechanical pressure and a radiant heat to hind paws were measured preoperatively and postoperatively. After local sciatic nerve administration of Nϑ‐nitro‐L‐arginine methyl ester or mepacrine into the operated site, sensitivities to noxious stimuli were reevaluated after treatment. Results. Only rats in the nucleus pulposus group showed evidence of mechanical hyperalgesia. However, injection of Nϑ‐nitro‐L‐arginine methyl ester resulted in evidence of mechanical hyperalgesia in the nucleus pulposus + anulus fibrosus group. Mechanical hyperalgesia was produced in the nucleus pulposus group and after injection of Nϑ‐nitro‐L‐arginine methyl ester in the nucleus pulposus + anulus fibrosus group, both of which returned to normal after mepacrine injection. There were no significant changes in sensitivity to thermal stimuli in any of the experimental groups. Conclusion. It appears that phospholipase A2 and nitric oxide play important but different roles in pathomechanisms of radicular pain in lumbar disc herniation.

Axial symptoms and cervical alignments after cervical anterior spinal fusion for patients with cervical myelopathy.

This retrospective clinical study was designed to examine the relation between cervical alignment and axial symptoms developing after cervical anterior spinal fusion. Sixty patients with myelopathy treated with cervical anterior spinal fusion were reviewed. For radiographic evaluation, lordosis, enlargement of the fused segments and neural foramen, radiographic union, and degeneration of adjacent segment were reviewed before or after surgery or both. Twenty-three patients had axial symptoms. Only local kyphosis and narrowing of the neural foramen at the fused segment were recognized more often in patients with axial symptoms than in those without such symptoms. No less than 2 mm and < or = 5 mm in enlargement of the anterior disc space immediately after surgery resulted in maintenance of cervical lordosis. These findings suggest that > or = 2 mm and < or = 5 mm in enlargement of anterior vertebral body height during operation results in prevention of axial symptoms.

MOLECULAR CLONING AND CHARACTERIZATION OF THE HUMAN P27KIP1 GENE PROMOTER

p27Kip1 is an inhibitor of multiple cyclin‐dependent kinases (cdk), and can arrest the cell‐cycle progression by inhibiting the phosphorylation of the retinoblastoma gene family products. Tumor formation in p27Kip1 knockout mice clearly shows that p27Kip1 plays an important role in inhibiting tumor formation and progression. To investigate the mechanism of transcriptional p27Kip1 gene expression, we isolated the genomic DNA fragment of the 5′ flanking region of the human p27Kip1 gene and characterized its promoter region. The human p27Kip1 promoter is TATA‐less, and the sequence is highly homologous to the murine p27Kip1 promoter sequence. In the promoter assay, deletion from −774 to −435 relative to the initiating codon resulted in a 15–20‐fold reduction of the p27Kip1 promoter activity, suggesting that the elements for basal promoter activity exist in this highly conserved 340 bp region, where putative CTF and ATF sites are conserved.