Yasuo Mikami

A functional SNP in CILP , encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease

Lumbar disc disease (LDD) is caused by degeneration of intervertebral discs of the lumbar spine. One of the most common musculoskeletal disorders, LDD has strong genetic determinants. Using a case-control association study, we identified a functional SNP (1184T → C, resulting in the amino acid substitution I395T) in CILP, which encodes the cartilage intermediate layer protein, that acts as a modulator of LDD susceptibility. CILP was expressed abundantly in intervertebral discs, and its expression increased as disc degeneration progressed. CILP colocalized with TGF-β1 in clustering chondrocytes and their territorial matrices in intervertebral discs. CILP inhibited TGF-β1–mediated induction of cartilage matrix genes through direct interaction with TGF-β1 and inhibition of TGF-β1 signaling. The susceptibility-associated 1184C allele showed increased binding and inhibition of TGF-β1. Therefore, we conclude that the extracellular matrix protein CILP regulates TGF-β signaling and that this regulation has a crucial role in the etiology and pathogenesis of LDD. Our study also adds to the list of connective tissue diseases that are associated with TGF-β.

A Functional Polymorphism in COL11A1, Which Encodes the α1 Chain of Type XI Collagen, Is Associated with Susceptibility to Lumbar Disc Herniation

Lumbar disc herniation (LDH), degeneration and herniation of the nucleus pulposus of the intervertebral disc (IVD) of the lumbar spine, is one of the most common musculoskeletal diseases. Its etiology and pathogenesis, however, remain unclear. Type XI collagen is important for cartilage collagen formation and for organization of the extracellular matrix. We identified an association between one of the type XI collagen genes, COL11A1, and LDH in Japanese populations. COL11A1, which encodes the alpha 1 chain of type XI collagen, was highly expressed in IVD, but its expression was decreased in the IVD of patients with LDH. The expression level was inversely correlated with the severity of disc degeneration. A single-nucleotide polymorphism (c.4603C-->T [rs1676486]) had the most significant association with LDH (P=3.3 x 10(-6)), and the transcript containing the disease-associated allele was decreased because of its decreased stability. These observations indicate that type XI collagen is critical for IVD metabolism and that its decrease is related to LDH.

Surgical results and related factors for ossification of posterior longitudinal ligament of the thoracic spine: A multi-institutional retrospective study

Study Design. Retrospective multi-institutional study Objective. To describe the surgical outcomes in patients with ossification of the posterior longitudinal ligament in the thoracic spine (T-OPLL) and to clarify factors related to the surgical outcomes. Summary of Background Data. Detailed analyses of surgical outcomes of T-OPLL have been difficult because of the rarity of this disease. Methods. The subjects were 154 patients with T-OPLL who were surgically treated at 34 institutions between 1998 and 2002. The surgical procedures were laminectomy in 36, laminoplasty in 51, anterior decompression via anterior approach in 25 and via posterior approach in 29, combined anterior and posterior fusion in 8, and sternum splitting approach in 5 patients. Instrumentation was conducted in 52 patients. Assessments were made on (1) The Japanese Orthopedic Association (JOA) scores (full score, 11 points), its recovery rates, (2) factors related to surgical results, and (3) complications and their consequences. Results. (1) The mean JOA score before surgery was 4.6 ± 2.0 and, 7.1 ± 2.5 after surgery. The mean recovery rate was 36.8% ± 47.4%. (2) The recovery rate was 50% or higher in 72 patients (46.8%). Factors significantly related to this were location of the maximum ossification (T1–T4) (odds ratio, 2.43–4.17) and the use of instrumentation (odds ratio, 3.37). (3) The frequent complications were deterioration of myelopathy immediately after surgery in 18 (11.7%) and dural injury in 34 (22.1%) patients. Conclusion. The factors significantly associated with favorable surgical results were maximum ossification located at the upper thoracic spine and use of instrumentation. T-OPLL at the nonkyphotic upper thoracic spine can be treated by laminoplasty that is relatively a safe surgical procedure for neural elements. The use of instrumentation allows correction of kyphosis or prevention of progression of kyphosis, thereby, enhancing and maintaining decompression effect, and its use should be considered with posterior decompression.

Association study of COL9A2 with lumbar disc disease in the Japanese population.

AbstractLumbar disc disease (LDD) is a common musculo-skeletal disease with strong genetic determinants. In a Finnish population, a single nucleotide polymorphism (SNP) causing an amino-acid substitution (Trp2 allele) in COL9A2, which encodes the α2 (IX) chain of type IX collagen, has been reported to associate with LDD. However, replication studies in different populations have produced controversial results. To further investigate the association of COL9A2 with LDD in Japanese, we examined SNPs in COL9A2, including Trp2, in 470 LDD patients (mean age 35) along with 658 controls (mean age 48). We identified a total of 43 sequence variations in COL9A2. Nine SNPs, including Trp2, were selected and genotyped. After Bonferronis correction, none of these SNPs showed association. Unlike observations in the Finnish population, Trp2 was common in Japanese, and no association with LDD was apparent. However, we did see association of a COL9A2 specific haplotype with LDD (P=0.025; permutation test); this association is more significant in patients with severe lumbar disc degeneration (P=0.011). Thus, the association of Trp2 with LDD was not replicated, but COL9A2 susceptibility allele(s) other than Trp2 may be present in Japanese LDD.

Is posterior spinal cord shifting by extensive posterior decompression clinically significant for multisegmental cervical spondylotic myelopathy

Study Design. Posterior cervical spinal cord shifting after selective single laminectomy associated with partial laminotomies was compared with that after bilateral open-door laminoplasty between the C3 and C7 levels in relation to the clinical results of each procedure. Objectives. To investigate the clinical significance of posterior spinal cord shifting after extensive cervical laminoplasty. Summary of Background Data. Current techniques used for cervical laminoplasty for multisegmental cervical spondylotic myelopathy (CSM) are consecutively performed between the C3 and C6 or C7 levels with expectation that the spinal cord will shift backward to keep it clear of anterior compression. However, the clinical significance of the posterior spinal cord shifting remains controversial, and there has been no report verifying it by comparing limited posterior decompression procedures with conventional extensive ones. Methods. Twenty-six patients with consecutive 2- to 3-level CSM who underwent selective laminoplasty (Group A) were enrolled in the study, and among 56 CSM patients who underwent bilateral open-door laminoplasty between the C3 and C7 levels, 25 who had consecutive 2- or 3- level stenosis identified by preoperative magnetic resonance imaging were used as controls (Group B). The recovery rate was calculated using preoperative and postoperative Japanese Orthopedic Association (JOA) scores for each patient, and for each patient’s magnetic resonance imaging, the postoperative cervical curvature index was obtained according to Ishihara’s method and the magnitude of postoperative backward shifting of the spinal cord was measured. Results. There was no significant difference between the subjects in Groups A and B with respect to the spinal curvature index, preoperative JOA scores, and recovery rate, but the magnitude of the postoperative posterior shifting of the spinal cord was greater for those in Group B than for those in Group A. There was no correlation between the recovery rate and posterior shifting of the spinal cord for each group, and no correlation was also found between the curvature index and posterior shifting of the spinal cord. Conclusions. The outcome of posterior decompression surgery for multisegmental CSM is not correlated with the magnitude of postoperative backward shifting of the spinal cord. Extensive and consecutive decompression performed in conventional cervical laminoplasties is therefore not always necessary for multisegmental CSM.

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

Classification of vertebral compression fractures in the osteoporotic spine

Objective: The purpose of this study was to clarify the relationship between initial radiographs of osteoporotic vertebral compression fractures (VCFs) and clinical results. Methods: Of the 135 VCFs in the elderly, 73 consecutive patients (84 vertebrae) were reviewed retrospectively. All patients were treated without rigid immobilization. The subjects consisted of 15 men and 58 women. The mean age was 75.0 years with a range from 61 to 91 years. The early radiographic features were classified into five types based on lateral radiographs. Radiographic results during follow-up were evaluated according to the number of collapsed vertebrae and vacuum clefts. Clinical results were evaluated by Visual Analog Scale and activities of daily living. Results: Of the five types, swelled-front-type, bow-shaped-type, and projecting-type fractures had a poor prognosis with late collapse and often showing a vacuum cleft. On the other hand, concave-type and dented-type fractures had a good prognosis and almost achieved fusion. Clinical results of 28 patients with vacuum clefts were fair at the final follow-up. Nineteen patients had little back pain, and nine patients experienced moderate back pain. Regarding the activities of daily living, four patients had difficulty walking.

Muscle-preserving interlaminar decompression for the lumbar spine: a minimally invasive new procedure for lumbar spinal canal stenosis.

Study Design. Outcomes of muscle-preserving interlaminar decompression (MILD) for the lumbar spine are reported. Objective. To verify the clinical findings of lumbar MILD. Summary of Background Data. A preliminary short-term follow-up study of lumbar MILD demonstrated satisfactory neural recovery and reduced invasiveness. Methods. The initial 105 consecutive patients with lumbar spinal canal stenosis were included in this study. A total of 210 intervertebral levels were decompressed. There were 48 women and 57 men, and the mean patient age was 68.8 years. The postoperative follow-up period ranged from 8 to 44 months (mean 21.3months). Eighty-one patients showed cauda equina claudication, and 75 patients complained of radicular pain. Preoperative imaging studies demonstrated that all patients had moderate-to-severe spinal canal stenosis, 75 patients had degenerative spinal canal stenosis, and the remaining 30 had degenerative spondylolisthesis. Pre- and postoperative Japanese Orthopedic Association scores, intraoperative blood loss, surgical complications, and postoperative ambulation were recorded. Results. One hundred five patients underwent lumbar MILD procedure for 210 interspinous levels, 42 patients for 2 levels, 37 patients for 1 level, 17 for 3 levels, 7 for 4 levels, and 2 for 5 levels. Cerebrospinal fluid leakage due to dural tear occurred in 2 patients. Expansion of the operative field was not necessary to repair the dura mater. The mean operation time was 104.9 minutes per level, and mean intraoperative blood loss was 29.4 g per level. Neurologic improvement was demonstrated in all patients. The mean recovery rate calculated with pre- and postoperative Japanese Orthopedic Association scores was 64.9%. Patients started to stand or walk an average of 2.5 days after surgery. None of the patients presented with wound infection. There was no neurologic complication in this series. Conclusion. In MILD for the lumbar spine, damage to the posterior stabilizing structures such as the intervertebral facet joints, paravertebral muscles, thoracolumbar fascia, supra- and interspinous ligaments, can be minimized, while preserving the function of the spinous processes as lever arms for lumbar extension.

Atlantoaxial subluxation in different intraoperative head positions in patients with rheumatoid arthritis

Background: Disorders of the cervical spine are often observed in patients with rheumatoid arthritis (RA). However, the best head position for RA patients with atlantoaxial subluxation in the perioperative period is unknown. This study investigated head position during general anesthesia for the patients with RA and proven atlantoaxial subluxation. Methods: During anesthesia of patients with RA and proven atlantoaxial subluxation, the authors used fluoroscopy to obtain a lateral view of the upper cervical spine in four different positions: the mask position, the intubation position, the flat pillow position, and the protrusion position. Copies of the still fluoroscopic images were used to determine the anterior atlantodental interval, the posterior atlantodental interval, and the angle of atlas and axis (C1–C2 angle). Results: The anterior atlantodental interval was significantly smaller in the protrusion position (2.3 mm) than in the flat pillow position (5.1 mm) (P < 0.05). The posterior atlantodental interval was significantly greater in the protrusion position (18.9 mm) than in the flat pillow position (16.2 mm) (P < 0.05). The C1–C2 angle was, on average, 9.3° greater in the protrusion position than in the flat pillow position (P < 0.05). Conclusion: This study showed that the protrusion position using a flat pillow and a donut-shaped pillow during general anesthesia reduced the anterior atlantodental interval and increased the posterior atlantodental interval in RA patients with atlantoaxial subluxation. This suggests that the protrusion position, which involves support of the upper cervical spine and extension at the craniocervical junction, might be advantageous for these patients.

Association of the tag SNPs in the human SKT gene (KIAA1217) with lumbar disc herniation.

Lumbar disc herniation (LDH) is one of the most common musculo‐skeletal diseases. Recent studies have indicated that LDH has strong genetic determinants, and several susceptibility genes have been reported to associate with LDH; however, its etiology and pathogenesis still remain unclear. KIAA1217 (alias SKT, the human homolog of murine Skt [Sickle tail]) is a good candidate for an LDH susceptibility gene because SKT is specifically expressed in nucleus pulposa of intervertebral discs (IVDs) in humans and mice, and SktGt mice, which are established through a large‐scale gene‐trap mutagenesis, exhibit progressive, postnatal onset abnormality of the IVDs. Here, we report the association of SKT with LDH. Using tag SNPs, we examined the association in two independent Japanese case‐control populations and found a significant association with SKT rs16924573 in the allele frequency model (p = 0.0015). The association was replicated in a Finnish case‐control population (p = 0.026). The combined p value of the two population by meta‐analysis is 0.00040 (OR, 1.34; 95% CI, 1.14–1.58). Our data indicate that SKT is involved in the etiology of LDH.