Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese.

The primary aim of this study was to investigate the association of polymorphisms of TRAF1-C5, a newly identified rheumatoid arthritis (RA) risk locus in Caucasians, with susceptibility to RA and systemic lupus erythematosus (SLE) in Japanese populations. Gene expression levels of TRAF1 and C5 to assess the functional significance of genotypes were also analysed. A multicentre association study consisting of 4 RA case-control series (4397 cases and 2857 controls) and 3 SLE case-control series (591 cases and 2199 shared controls) was conducted. Genotyping was performed using TaqMan genotyping assay for two single nucleotide polymorphisms (SNPs) that showed the best evidence of association in the previous Caucasian studies. Quantifications of TRAF1 and C5 expression were performed with TaqMan expression assay. Significant differences in allele frequency for both SNPs were observed between RA and control subjects (combined odds ratio = 1.09), while no significant difference was detected between patients with SLE and controls. Interestingly, alleles rs3761847 A and rs10818488 G had increased the risk for RA in the present study, while they decreased the risk in the original studies. A significant difference was found between risk allele carriers and non-carriers of rs10818488 for the expression level of TRAF1 in phorbol myristate acetate-stimulated lymphoblastoid cell lines (p = 0.04). Association of TRAF1-C5 locus with RA susceptibility was detected in the Japanese populations with modest magnitude, while no significant association was observed for SLE. Significant positive effect of genotype on the expression of TRAF1 might support the genetic association between TRAF1 and RA.


Fresh stress fractures of lumbar pedicles in an adolescent male ballet dancer: case report and literature review.

Stress fracture in the pars interarticularis is a common cause of low back pain in young athletes. Pedicle stress fractures have also been reported in adolescent sport players, and most of them were associated with contralateral spondylolysis. Only a few cases with bilateral pedicle stress fractures have been reported. We report a 14-year-old ballet dancer with fresh bilateral pedicle fractures treated conservatively, together with a review of the literature.

Archives of Orthopaedic and Trauma Surgery


Conservative treatment of lumbar spondylolysis in childhood and adolescence: the radiological signs which predict healing.

It has been noted that bony union of a pars defect can be achieved in children if they wear a trunk brace. Our aim was to evaluate how the stage of the defect on CT and the presence or absence of high signal change in the adjacent pedicle on T2-weighted MRI were related to bony healing. We treated 23 children conservatively for at least three months. There were 19 boys and four girls with a mean age of 13.5 years (7 to 17). They were asked to refrain from sporting activity and to wear a Damen soft thoracolumbosacral type brace. There were 41 pars defects in 23 patients. These were classified as an early, progressive or terminal stage on CT. The early-stage lesions had a hairline crack in the pars interarticularis, which became a gap in the progressive stage. A terminal-stage defect was equivalent to a pseudarthrosis. On the T2-weighted MR scan the presence or absence of high signal change in the adjacent pedicle was assessed and on this basis the defects were divided into high signal change-positive or -negative. Healing of the defect was assessed by CT. In all, 13 (87%) of the 15 early defects healed. Of 19 progressive defects, only six (32%) healed. None of the seven terminal defects healed. Of the 26 high signal change-positive defects 20 (77%) healed after conservative treatment whereas none of the high signal change-negative defects did so. We concluded that an early-stage defect on CT and high signal change in the adjacent pedicle on a T2-weighted MR scan are useful predictors of bony healing of a pars defect in children after conservative treatment.

The Journal of Bone and Joint Surgery. British Volume


Cervical and upper thoracic screwing for spinal fusion: strategy for its safe insertion to avoid major complications.

There are several screwing techniques to attain cervical fusion such as pedicle screw, lateral mass screw, facet screw, transarticular and laminar screw. Each screwing technique has advantages and disadvantages. In this study, we introduce our strategy for safe screwing and its clinical results. Our strategy is as follows: lateral mass screw for C1, 3, 4, 5, 6 and pedicle screw for C2, 7, and thoracic level. When the C2 pedicle is thinner than 3.5 mm, we use C2 laminar screws. We do not use Magerl transarticular screw or facet screw; 146 screws were inserted in 17 patients. There were no major complications such as spinal cord and nerve root injury. We did not observe vertebral arterial injury either. Of the 146 screws, 141 (97.0%) were accurately inserted. As for lateral mass screwing by Roy-Camille's technique and C2 laminar screwing, all screws were inserted in the appropriate site (100%) without any complications. Five pedicle screws were misplaced. Of the 57 pedicle screws, 5 showed a minor tear of the wall at C7, Th1 and Th3, the success rate for all pedicle screws was 91%. All showed solid fusion. For cervical screwing the most important aspect should be safety to avoid severe morbidity. Our strategy, which consists in the combined use of pedicle, lateral mass and laminar screwing, is safe and reliable.


Newly occurred L4 spondylolysis in the lumbar spine with pre-existence L5 spondylolysis among sports players: case reports and biomechanical analysis.

STUDY DESIGN: Case series and a biomechanical study using a finite element (FE) analysis. OBJECTIVES: To report three cases with multi-level spondylolysis and to understand the mechanism biomechanically. BACKGROUND: Multi-level spondylolysis is a very rare condition. There have been few reports in the literature on multi-level spondylolysis among sports players. METHODS: We reviewed three cases of the condition, clinically. These patients were very active young sports players and had newly developed fresh L4 spondylolysis and pre-existing L5 terminal stage spondylolysis. Thus, we assumed that L5 spondylolysis may have increased the pars stress at the cranial adjacent levels, leading to newly developed spondylolysis at these levels. Biomechanically, we investigated pars stress at L4 with or without spondylolysis at L5 using the finite element technique. RESULTS: L4 pars stress decreased in the presence of L5 spondylolysis, which does not support our first hypothesis. CONCLUSIONS: It seems that multi-level spondylolysis may occur due to genetic and not biomechanical reasons.


Altered fracture callus formation in chondromodulin-I deficient mice.

Chondromodulin-I (Chm-I) is a glycoprotein that stimulates the growth of chondrocytes and inhibits angiogenesis in vitro. Mice lacking the Chm1 gene show abnormal bone metabolism and pathological angiogenesis in cardiac valves in the mature stage although they develop normally without aberrations in endochondral bone formation during embryogenesis or in cartilage development during growth. These findings indicate that Chm-I is critical under conditions of stress such as bone repair through endochondral ossification of a fracture callus. We carried out the present study to examine the expression and role of Chm-I in bone repair using a stabilized tibial fracture model, and compared fracture healing in Chm1 knockout (Chm1(-/-)) mice with that in wild-type mice. Chm-I mRNA and protein localized in the external cartilaginous callus in the reparative phase of fracture healing. Radiological examination showed a delayed union in Chm1(-/-) mice although the fracture site was covered with both external and internal calluses. Chm1 null mutation reduced external cartilaginous callus formation as judged by marked decrease of type X collagen alpha 1 (Col10a1) expression and the total amount of cartilage matrix. Interestingly, the majority of chondrocytes in the periosteal callus failed to differentiate into mature chondrocytes in Chm1(-/-) mice, while the hypertrophic maturation of chondrocytes between the cortices was not affected. These results suggest that Chm-I is involved in hypertrophic maturation of periosteal chondrocytes. Although a direct effect of Chm-I on bones is still unclear, bony callus formation was increased while external cartilaginous callus decreased in Chm1(-/-) mice. We conclude that in the absence of Chm1, predominant primary bone healing occurs due to an indirect effect induced by reduction of cartilaginous callus rather than to a direct effect on osteogenic function, resulting in a delayed union.


Therapeutic effects of one-year alendronate treatment in three cases of osteoporosis with parietal thinning of skull.

We studied the therapeutic effects of one-year alendronate treatment in three cases (two males and one female) of osteoporosis with parietal thinning of skull. Plain radiography and three dimensional computed tomography revealed asymmetric external thinning of the posteromedial part of the bilateral parietal bones. Technetium-99m methylenediphosphate bone scintigraphy did not show any changes in these three cases. Pretreatment levels of urinary type I collagen cross-linked N-telopeptides (NTX) in all three cases were high compared to the normal range. Pretreatment levels of serum bone-specific alkaline phosphatase (BAP) in the two male patients were high in contrast to the normal values in the female patient. Pretreatment mean bone mineral density (BMD) values of the 2nd to 4th lumbar vertebrae (L2-4BMD), head BMD, femoral neck BMD, and whole body BMD of all three patients were low compared with the respective normal ranges. One-year alendronate treatment decreased both urinary NTX and serum BAP in all three cases to normal values. Treatment also increased the whole body BMD in all three cases, the L2-4BMD of the female patient, the femoral neck BMD of the female patient and one male patient, and the head BMD of the female patient when compared to pretreatment levels.

The Journal of Medical Investigation : JMI


Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population.

OBJECTIVE: STAT4 encodes a transcriptional factor that transmits signals induced by several key cytokines, and it might be a key molecule in the development of autoimmune diseases. Recently, a STAT4 haplotype was reported to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in Caucasian populations. This was replicated in a Korean RA population. Interestingly, the degree of risk of RA susceptibility with the STAT4 haplotype was similar in the Caucasian and Korean populations. The present study was undertaken to investigate the effect of STAT4 on susceptibility to RA and SLE in the Japanese. METHODS: We performed an association study using 3 independent Japanese RA case-control populations (total 3,567 cases and 2,199 controls) and 3 independent Japanese SLE populations (total 591 cases). All samples were genotyped using the TaqMan fluorogenic 5' nuclease assay for single-nucleotide polymorphism (SNP) rs7574865, which tags the susceptibility haplotype. The association of the SNP with disease susceptibility in each case-control study was calculated using Fisher's exact test, and the results were combined, using the Mantel-Haenszel method, to obtain combined odds ratios (ORs). RESULTS: We observed a significant association of the STAT4 polymorphism with susceptibility to both RA and SLE. The combined ORs for RA and SLE, respectively, were 1.27 (P = 8.4 x 10(-9)) and 1.61 (P = 2.1 x 10(-11)) for allele frequency distribution; these ORs were quite similar to those previously observed in the Caucasian population. CONCLUSION: We conclude that STAT4 is associated with RA and SLE in the Japanese. Our results indicate that STAT4 is a common genetic risk factor for autoimmune diseases, with similar strength across major racial groups.


Pseudoaneurysm of the thoracoabdominal aorta caused by the severe migration of an anterior spinal device. A case report.

Case report. To describe the case of pseudoaneurysm of the thoracoabdominal aorta caused by the severe migration of an anterior spinal device 5 years after surgery. Case report. A 70-year-old woman was referred to us because of migrated anterior spinal devices and a pseudoaneurysm of the thoracoabdominal aorta. This patient had undergone anterior corpectomy and spinal fusion from Th12 to L2 because of delayed palsy after a burst fracture using a smooth rod Kaneda device (SRK) with bioactive ceramic (apatite-wollastonite containing glass ceramic) at a local hospital. She had persistent low back pain after the surgery. Five years after the initial surgery, the patient was referred to us because of increasing of her low back pain and the migrated SRK devices shown on plain X-ray films. An enhanced computed tomography scan taken in our hospital clearly showed a pseudoaneurysm of the thoracoabdominal aorta surrounding the SRK devices. The pseudoaneurysm was resected, the aortic defect was repaired with an artificial patch, and the migrated SRK devices were removed. The pseudoaneurysm of the aorta can occur secondary to a migrated anterior spinal fixation device and can be successfully treated by revision anterior surgery with vascular repair and implant removal.


Lack of association of genetic variation in chromosome region 15q14-22.1 with type 2 diabetes in a Japanese population.

BACKGROUND: Chromosome 15q14-22.1 has been linked to type 2 diabetes (T2D) and its related traits in Japanese and other populations. The presence of T2D disease susceptibility variant(s) was assessed in the 21.8 Mb region between D15S118 and D15S117 in a Japanese population using a region-wide case-control association test. METHODS: A two-stage association test was performed using Japanese subjects: The discovery panel (Stage 1) used 372 cases and 360 controls, while an independent replication panel (Stage 2) used 532 cases and 530 controls. A total of 1,317 evenly-spaced, common SNP markers with minor allele frequencies > 0.10 were typed for each stage. Captured genetic variation was examined in HapMap JPT SNPs, and a haplotype-based association test was performed. RESULTS: SNP2140 (rs2412747) (C/T) in intron 33 of the ubiquitin protein ligase E3 component n-recognin 1 (UBR1) gene was selected as a landmark SNP based on repeated significant associations in Stage 1 and Stage 2. However, the marginal p value (p = 0.0043 in the allelic test, OR = 1.26, 95% CI = 1.07-1.48 for combined samples) was weak in a single locus or haplotype-based association test. We failed to find any significant SNPs after correcting for multiple testing. CONCLUSION: The two-stage association test did not reveal a strong association between T2D and any common variants on chromosome 15q14-22.1 in 1,794 Japanese subjects. A further association test with a larger sample size and denser SNP markers is required to confirm these observations.


Os odontoideum in achondroplasia: a case report.

The neurological complication in achondroplasia has been focused on the foramen magnum stenosis. We report the combination of os odontoideum in a patient with achondroplasia.

Journal of Pediatric Orthopaedics. Part B


Minimally invasive excision of lumbar epidural lipomatosis using a spinal endoscope.

In this report, we describe the case of a patient with a long-term radiculopathy due to epidural lipomatosis at the L3-4 intervertebral disc level. The fatty tissue was located on the dorsal side of the dural sac in the spinal canal and compressed the dural sac. The fatty tissue was removed endoscopically. After surgery, the symptoms disappeared, and neurological deficits normalized. We would like to state that epidural lipomatosis is a good candidate for minimally invasive endoscopic surgery because of its anatomic location.


Myelopathy in a 6-year-old girl caused by neurofibromatosis Type 1: a case report

Even when there is radiological evidence of spinal involvement, young patients with neurofibromatosis Type 1 (NF-1) seldom have symptoms. We report the case of a child who developed rapidly progressive myelopathy. To describe a technique used to prevent postoperative spinal deformity and instability, after removal of a dumbbell-shaped tumor in a 6-year-old child. Case report. A 6-year-old female. Retrospective case review. The patient underwent a resection of the cervical dumbbell tumor using an osteoplastic laminectomy technique to prevent postoperative spinal deformity. At 2-year follow-up, there was no clinical or radiographic evidence of complications or spinal kyphotic deformity. The case of a 6-year-old girl with cervical myelopathy caused by NF-1 was reported. The tumor was removed after osteoplastic laminectomy, which could prevent postoperative kyphotic deformity.


Conservative treatment for osteochondrosis of the humeral capitellum.

BACKGROUND: Conservative treatment is recommended for the early stage of osteochondrosis of the humeral capitellum. However, the outcome of conservative treatment has not been well documented. HYPOTHESIS: Osteochondrosis of the humeral capitellum detected at an early stage responds well to conservative treatment. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: We retrospectively reviewed 176 patients with osteochondrosis of the humeral capitellum. There were 134 lesions that were stage I (radiolucent area) in patients with a mean age of 11.5 years and 42 lesions that were stage II (nondisplaced fragments) in patients with a mean age of 13.9 years based on anteroposterior radiographs of the elbow in 45 degrees of flexion. Conservative treatment was performed on 101 patients. The remaining 75 patients did not follow the authors' advice. Conservative treatment consisted of discontinuation of heavy use of the elbow for at least 6 months. Follow-up radiographs were taken at 1-month intervals. At a mean follow-up of 24 months, all patients were evaluated clinically and radiographically. RESULTS: Conservative management produced healing in 90.5% of stage I lesions and 52.9% of stage II lesions. The mean period required for healing was 14.9 months in stage I and 12.3 months in stage II. Sixty-six of 84 (78.6%) stage I patients and 9 of 17 (52.9%) stage II patients returned to competitive-level baseball. Of the 75 patients who did not follow our advice, healing was observed in 17 (22.7%). The healing rate was higher for the 101 patients who followed our advice as opposed to the 75 patients who did not. CONCLUSION: Osteochondrosis of the humeral capitellum can be successfully treated conservatively if treatment is begun in an early stage of the disease.


Treatment of dysplastic osteoarthritis with labral tear by Chiari pelvic osteotomy: outcomes after more than 10 years follow-up.

The presence of a damaged labrum is one of many factors influencing the outcomes of Chiari pelvic osteotomy. However, there are few previous papers describing the long-term outcomes of Chiari pelvic osteotomy with labrectomy. The purpose of this study was to evaluate the long-term clinical and radiological outcomes of Chiari pelvic osteotomy for dysplastic hips with labral tears. We compared outcomes between labrectomy (+) and labrectomy (-) groups. Chiari pelvic osteotomies were performed by one surgeon on 34 dysplastic hips with labral tears between 1983 and 1996, in which labrectomy was performed on 23 hips but not on 11 hips. Three patients undergoing labrectomy were lost to follow-up evaluation within 5 years after surgery. The average age of the remaining 31 patients was 35.5 years (range, 16-54 years). The clinical and radiographic surveillance averaged 16.0 years (range, 10-23.3 years). In all patients, pain disappeared after the operation. At the end of the study, 8 of the 31 patients displayed clinical deterioration. Progression of osteoarthritis (OA) was observed in 11 hips. Patients with poor results have not opted for revision surgery except for one patient. In the labrectomy (+) group, 10 of the 20 hips showed progression of OA and the clinical outcomes of 6 patients deteriorated. In the labrectomy (-) group, 1 of the 11 hips showed progression of OA and 2 patients deteriorated clinically. Radiological outcomes differed significantly between the two groups. Labrectomy accompanying Chiari pelvic osteotomy is an acceptable procedure for relieving pain caused by the damaged labrum, but the outcomes have a tendency to deteriorate after 10 or more years postoperatively.

Archives of Orthopaedic and Trauma Surgery


Continuous local infusion of fibroblast growth factor-2 enhances consolidation of the bone segment lengthened by distraction osteogenesis in rabbit experiment.

Experimental tibial lengthening was achieved in 61 rabbits to examine the effect of continuous local infusion of recombinant human fibroblast growth factor-2 (rhFGF-2) on bone healing of the lengthened segment. The tibial diaphysis was separated by osteotomy and was subjected to slow progressive distraction (rate: 0.35 mm/12 h) using a monolateral external fixator. There were a lag phase for 1 week, a distraction phase for 2 weeks, and a consolidation phase for 5 weeks in this experiment. At various stages of distraction, rhFGF-2 was infused continuously for 2 weeks into the lengthened segment (rate: 14.28 microg/60 microl/day) using an osmotic pump implanted under the skin. Bone healing was significantly accelerated when rhFGF-2 was infused in the beginning of consolidation phase, but not in the distraction phase or in the lag phase. Infusion of normal saline (N/S) using the same osmotic pump had no effect. Dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (pQCT) studies demonstrated that rhFGF-2-treated tibia had increased bone mineral density (BMD), bone mineral content (BMC) and cortical bone thickness (CBT) when compared with N/S-treated tibia. Three-point bending test demonstrated that rhFGF-2-treated bone had significantly stronger mechanical properties than N/S-treated bone. Finally, distribution of the infused materials was checked by using Indian ink or radio-opaque. The dyes distributed widely but exclusively in the lengthened segment. Based on these results, we conclude that direct delivery of rhFGF-2 into the lengthened segment can shorten the consolidation phase of limb lengthening and the method is applicable to the clinical treatment.


Replication of reported genetic associations of PADI4, FCRL3, SLC22A4 and RUNX1 genes with rheumatoid arthritis: results of an independent Japanese population and evidence from meta-analysis of East Asian studies.

We conducted population-based association tests for the four selected SNPs (rs2240340/padi4_94, rs7528684/fcrl3_3, rs3792876/slc2F2 and rs2268277/runx1) previously reported to be associated with rheumatoid arthritis (RA). The study population consisted of 950 unrelated Japanese subjects with RA and 507 controls, none of whom had previously been tested for these variants. Only the SNP rs2240340/padi4_94 was modestly associated with RA [allele odds ratio (OR) 1.22, 95% confidence interval (CI) 1.04-1.43, P=0.012]. The most significant association effect was found for genotype contrast between minor and major allele homozygotes (OR 1.53, 95% CI 1.10-2.12, P=0.010). No other SNPs showed a statistically significant association with RA in our population. Meta-analysis of published studies and our new data confirmed a highly significant association between PADI4 gene SNPs and increased risk of RA in East Asian populations (allele fixed-effects summary OR 1.31, 95% CI 1.22-1.41, P<0.0001). We found some evidence for an association of either rs7528684/fcrl3_3 or rs3792876/slc2F2 with RA; however, because the magnitudes of effects were apparently much weaker than those reported in the initial positive reports, and there were substantial levels of inter-study OR heterogeneity, we concluded that additional studies are needed to fully understand the present results.


Radiological features of lumbar spinal lesions in patients with rheumatoid arthritis with special reference to the changes around intervertebral discs.

Compared with the cervical spine, little attention has been paid to rheumatoid arthritis (RA)-related lumbar disorders. Only a few articles have described the status of the lumbar spine affected by RA based on plain X-ray films and magnetic resonance imaging (MRI). To describe the features and prevalence of radiological changes of the lumbar spine of patients with RA and to clarify the correlations of such features with disease activity. Transverse radiological study. We radiographically examined 104 patients with RA whose age ranged from 21 to 78 years (mean, 51.0). In each, the duration of RA exceeded 10 years (mean, 17.7 years). Clinical outcomes included Ochi's classification, Lansbury index, C-reactive protein (CRP) (mg/dL), rheumatoid factor (RF) (U/mL), and platelet (count/mm). Radiological outcomes included radiography and MRI. One hundred four RA patients were included in this study regardless of the presence/absence of low back pain. We examined discs from L1-2 to L5-S, including endplates, in each patient on plain X-ray films and magnetic resonance images and used a comprehensive grading system to evaluate each feature of the lumbar spine affected by RA based on the present findings and published reports. The correlations of these radiological features with RA activity and Ochi's classification were examined. To quantify disease activity, we determined the Lansbury index, serum CRP (mg/dL), RF (U/mL), and platelet count (count/mm) at the time of radiological examinations. Of the 104 patients, 47 (45.2%) exhibited a lumbar lesion. There were two types of lumbar disc lesions related to RA: disc narrowing and disc ballooning. The Lansbury index of patients with the most severe lesions was significantly higher than that of patients with less severe lesions (p<.01). The frequency of lumbar involvement also increased as the number of affected peripheral joints increased, and Ochi's classification appeared to be useful in predicting the occurrence of lumbar lesions. Of 104 patients, 47 (45.2%) exhibited abnormalities on X-ray films and MRI. There were two types of disorders, disc narrowing and disc ballooning. Both the Lansbury index and Ochi's classification reflected the severity of lumbar lesions in RA patients.


Continuous infusion of insulin-like growth factor-I into the epiphysis of the tibia.

We have developed a method to promote longitudinal bone growth at the level of a specific growth-plate (GP) in young rabbits. Insulin-like growth factor-I (IGF-I) was continuously infused by means of an osmotic pump into the bone marrow cavity of the proximal epiphysis of the tibia. Radiological measurement showed a 2-mm overgrowth of the tibia after 4 weeks of treatment, while histological analysis demonstrated a 15% increase in the thickness of the selected GP. The local infusion of IGF-I increased the numbers of both proliferative and hypertrophic chondrocytes and promoted hyperplasia of bony trabeculae within the epiphysis. The distribution of material infused locally into the epiphysis was simulated by the infusion of Indian ink using the same methodology (osmotic pump) as that for IGF-I. Most of the dye remained within the bone marrow cavity of the epiphysis, but a portion infiltrated into the GP, reaching the deep layer of the physeal chondrocytes and primary spongiosa of the metaphysis. These results suggest that the method reported here is a valid one for delivering cytokines or growth factors to the selected GP and for controlling the growth and differentiation of physeal chondrocytes.


Vertebral rounding deformity in pediatric spondylolisthesis occurs due to deficient of endochondral ossification of the growth plate: radiological, histological and immunohistochemical analysis of a rat spondylolisthesis model.

A study using rat spondylolisthesis models. To clarify pathomechanism of vertebral rounding deformity in pediatric spondylolisthesis. For high-grade slippage, rounding of sacrum surface associated with L5 spondylolisthesis is reported to be the most responsible risk factor. However, the exact pathomechanism of the rounding deformity is yet to be clarified. Spondylolisthesis rat model (4-week-old) was used. Radiographs were taken weekly for 5 weeks after the surgery. The lumbar spines were harvested for histology. Hematoxylin and eosin, alcian blue staining, and tartrate-resistant acid phosphatase staining were used. Immunohistochemically, the growth plate cartilage was studied for type II and X collagen. A modified bone histomorphometric analysis was also performed. Radiographs showed slippage 1 week after surgery. Rounding deformity was obvious 2 weeks after surgery. The rounding deformity progressed with time. Three weeks after surgery, the specific columns of growth plate were unclear at the anterior corner, which corresponded to the rounding surface observed on radiographs. Instead, a huge mass of cartilage was observed at that site. Tartrate-resistant acid phosphatase-positive cells were observed in the vicinity of the growth plate except in relation with the anterior corner. The growth plate and cartilage mass at the anterior corner stained positive for type II collagen. Chondrocytes in the hypertrophied layer stained positively for type X collagen; however, staining was faint at the anterior corner. The results suggested that the chondrocytes at the anterior did not form, morphologically and functionally, the normal growth plate. From histomorphometrical analysis, the normal posterior growth plate made endochondral bone growth in 510 +/- 20 microm for a week, whereas the anterior corner in 200 +/- 15 microm. Deficient endochondral ossification of the growth plate in the anterior upper corner of the vertebra could be the pathomechanism of the rounding deformity of the sacrum.


Pathomechanism of loss of elasticity and hypertrophy of lumbar ligamentum flavum in elderly patients with lumbar spinal canal stenosis.

A histologic, biologic, and immunohistochemical assessment using human samples of lumbar ligamentum flavum. To clarify the pathomechanism of loss of elasticity and hypertrophy of the lumbar ligamentum flavum (LF) in the elderly population. The most common spinal disorder in elderly patients is lumbar spinal canal stenosis, causing low back and leg pain, and paresis. Canal narrowing, in part, results from hypertrophy of the LF. Although histologic and biologic literature on this topic is available, the pathomechanism of loss of elasticity and hypertrophy of the LF is still unknown. One fetus, 5 young, and 5 elderly LF were obtained for histologic study. Hematoxylin and eosin, Alcian blue, Masson Trichrome, and Elastica Van Gieson stains were performed for each LF. Nine LF were collected and were used for biologic study of real time RT-PCR to quantitatively measure mRNA expression of Type I collagen and elastin in each LF. In the LF of the fetus, elastic fibers accounted for about 75% of the entire area. In the dural aspect of the LF in the young and elderly group, the ratio was also around 75%; however, the ratio of the dorsal aspect decreased with age. Almost half of the area showing loss of elastic fibers was shown to be converted to cartilaginous tissue producing Type II collagen and proteoglycan by Alcian blue and Type II collagen immunohistochemistry. The area, which did not stain black with EV nor blue with AB stain, was positively stained blue with T stain, indicating scarring. The area of the normal dural layer was 18.0 +/- 2.3 and 33.8 +/- 4.3 (mm2), for young and elderly group, respectively. Accordingly, it was 3.2 +/- 0.8 and 18.0 +/- 10.2 (mm2), for the dorsal abnormal layer. Elastin mRNA showed a relatively strong correlation (r = 0.44) with age; however, the slope was very gentle. Type I collagen mRNA showed a very strong correlation (r = 0.80) with age. The slope was steeper, and the value reached at 1000% (10-fold) around 65 years old when compared with the LF from younger patient. Elastin mRNA showed a weak correlation (r = 0.36) with thickness, and the slope was gentle. Type I collagen mRNA showed relatively strong correlation (r = 0.52) with thickness. The slope was steeper, and the line reached at 1000% (10-fold) around 6.5 (mm) when compared with a thin LF. Decreased elasticity of LF in the elderly is due to the loss of elastic fibers and a concomitant increase of collagenous fibers in the dorsal aspect. LF hypertrophy could be due to the thickening of the normal elastic layer as well as of the abnormal collagenous layer.


Intraneural heterotopic ossification of a digital nerve.

The Journal of Hand Surgery, European Volume


Callus formation during healing of the repaired tendon-bone junction. A rat experimental model.

This study was undertaken to elucidate the mechanism of biological repair at the tendon-bone junction in a rat model. The stump of the toe flexor tendon was sutured to a drilled hole in the tibia (tendon suture group, n = 23) to investigate healing of the tendon-bone junction both radiologically and histologically. Radiological and histological findings were compared with those observed in a sham control group where the bone alone was drilled (n = 19). The biomechanical strength of the repaired junction was confirmed by pull-out testing six weeks after surgery in four rats in the tendon suture group. Callus formation was observed at the site of repair in the tendon suture group, whereas in the sham group callus formation was minimal. During the pull-out test, the repaired tendon-bone junction did not fail because the musculotendinous junction always disrupted first. In order to understand the factors that influenced callus formation at the site of repair, four further groups were evaluated. The nature of the sutured tendon itself was investigated by analysing healing of a tendon stump after necrosis had been induced with liquid nitrogen in 16 cases. A proximal suture group (n = 16) and a partial tenotomy group (n = 16) were prepared to investigate the effects of biomechanical loading on the site of repair. Finally, a group where the periosteum had been excised at the site of repair (n = 16) was examined to study the role of the periosteum. These four groups showed less callus formation radiologically and histologically than did the tendon suture group. In conclusion, the sutured tendon-bone junction healed and achieved mechanical strength at six weeks after suturing, showing good local callus formation. The viability of the tendon stump, mechanical loading and intact periosteum were all found to be important factors for better callus formation at a repaired tendon-bone junction.

The Journal of Bone and Joint Surgery. British Volume


Locking of the metacarpophalangeal joint as a result of the shape of the metacarpal head in achondroplasia.

A 21 year-old woman with achondroplasia exhibited locking of the metacarpophalangeal joint of the right index finger which required surgery to release the joint. Locking was confirmed to be due to entrapment of the fan-like part of the radial collateral ligament on a metacarpal head prominence arising from epiphysial thickening.


Correction of deformity and shortening due to post traumatic epiphyseal arrest by distraction osteogenesis.

Growth arrest in the epiphyseal plate during childhood often causes both periarticular deformities and limb length discrepancy, leading to compartmental osteoarthrosis and gait disturbance or spinal disorders, respectively. Distraction osteogenesis using external fixators with hinge systems appears to be useful for the simultaneous correction of deformity and shortening. In this paper, we evaluated cases of lower limbs with periarticular deformities and limb length discrepancy after epiphyseal plate injury that has been treated by distraction osteogenesis using external fixators. This is the first report regarding the outcomes of distraction osteogenesis for a group of patients having deformity and limb length discrepancy due to traumatic arrest of the physis. Successful outcomes may promise the use of this method as the first choice for the treatment of growth disorders after the arrest of the epiphyseal plate in the lower limbs. However, treatment under 20 years of age may provide a better outcome with a lower incidence of complications.

Archives of Orthopaedic and Trauma Surgery


SNPs in the KCNJ11-ABCC8 gene locus are associated with type 2 diabetes and blood pressure levels in the Japanese population.

Many genetic association studies support a contribution of genetic variants in the KCNJ11-ABCC8 gene locus to type 2 diabetes (T2D) susceptibility in Caucasians. In non-Caucasian populations, however, there have been only a few association studies, and discordant results were obtained. Herein, we selected a total of 31 SNPs covering a 211.3-kb region of the KCNJ11-ABCC8 locus, characterized the patterns of linkage disequilibrium (LD) and haplotype structure, and performed a case-control association study in a Japanese population consisting of 909 T2D patients and 893 control subjects. We found significant associations between eight SNPs, including the KCNJ11 E23K and ABCC8 S1369A variants, and T2D. These disease-associated SNPs were genetically indistinguishable because of the presence of strong LD, as found previously in Caucasians. For the KCNJ11 E23K variant, the most significant association was obtained under a dominant genetic model (OR 1.32, 95% CI 1.09-1.60, P = 0.004). A meta-analysis of East Asian studies, comprising a total of 3,357 T2D patients (77.4% Japanese) and 2,836 control subjects (77.8% Japanese), confirmed the significant role of the KCNJ11 E23K variant in T2D susceptibility. Furthermore, we found evidence suggesting that the KCNJ11 E23K genotype is independently associated with higher blood-pressure levels.


Lumbar radiculopathy caused by extradural rheumatoid nodules. A case report.

The authors report on a 51-year-old woman with a 9-year history of rheumatoid arthritis (RA) who presented with symptomatic rheumatoid nodules in the lumbar extradural region with compression on the L-5 nerve roots bilaterally. She had also suffered from dysesthesia in the right lower leg and intermittent claudication. Magnetic resonance imaging revealed masses compressing the dural sac, and on lumbar myelography and computed tomography myelography a filling defect at L4-5 was revealed, which was compressing the dural sac posterolaterally on both sides. The masses were surgically removed. On histological examination the typical characteristics of rheumatoid nodules were found. Soon after the operation all of the patient's symptoms disappeared. There have been few reports on extradural rheumatoid nodules. Patients with RA usually complain of articular symptoms, and in fact the patient in the present study had been referred to the authors' institution for total hip arthroplasty. However, various symptoms other than those arising from articular lesions were found clinically. The authors believe that if patients with RA are also examined for extraarticular lesions, it is likely that these will be more frequently detected.


PKC412 (CGP41251) modulates the proliferation and lipopolysaccharide-induced inflammatory responses of RAW 264.7 macrophages.

PKC412 (CGP41251) is a multitarget protein kinase inhibitor with anti-tumor activities. Here, we investigated the effects of PKC412 on macrophages. PKC412 inhibited the proliferation of murine RAW 264.7 macrophages through induction of G2/M cell cycle arrest and apoptosis. At non-toxic drug concentrations, PKC412 significantly suppressed the lipopolysaccharide (LPS)-induced release of TNF-alpha and nitric oxide, while instead enhancing IL-6 secretion. PKC412 attenuated LPS-induced phosphorylations of MKK4 and JNK, as well as AP-1 DNA binding activities. Furthermore, PKC412 suppressed LPS-induced Akt and GSK-3beta phosphorylations. These results suggest that the anti-proliferative and immunomodulatory effects of PKC412 are, at least in part, mediated through its interference with the MKK4/JNK/AP-1 and/or Akt/GSK-3beta pathways. Since macrophages contribute significantly to the development of both acute and chronic inflammation, PKC412 may have therapeutic potential and applications in treating inflammatory and/or autoimmune diseases.

Biochemical and Biophysical Research Communications


Unilateral chronic insufficiency of anterior cruciate ligament decreases bone mineral content and lean mass of the injured lower extremity.

We studied the effects of unilateral chronic anterior cruciate ligament (ACL) injury on bone size, bone mineral content (BMC), bone mineral density (BMD), soft tissue composition and muscle strength of the injured lower extremity in Japanese 21 men and 12 women aged 15 to 39 years. Bone area, BMD, BMC, lean mass and fat mass of lower extremity were measured using dual energy X-ray absorptiometry. The isometric and isokinetic muscle strength was assessed by an isokinetic machine.BMC, lean mass, circumference of the thigh and circumference of the lower leg of the injured lower extremity were significantly smaller than those of the intact lower extremity (p=0.0002, p<0.0001, p<0.0001, p=0.0131). In contrast, fat mass and %Fat of the injured lower extremity was significantly greater than that of the intact lower extremity (p=0.0301, p<0.0001). Bone area and BMD did not produce significant difference. These findings suggest that chronic insufficiency of ACL decreases BMC and lean mass of the injured lower extremity.

The Journal of Medical Investigation : JMI


Distinct expression of mast cell tryptase and protease activated receptor-2 in synovia of rheumatoid arthritis and osteoarthritis.

The objective of this study is to examine the differential expression of mast cell tryptase and its receptor, protease-activated receptor-2 (PAR-2), in the synovium and synovial fluid of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Biochemical and immunohistochemical analyses were performed to determine whether the trypsin-like protease in the synovium is identical to mast cell tryptase. The effects of mast cell tryptase on the proliferation of synovial fibroblast-like cells (SFCs) and the release of IL-8 thereof were evaluated by the [3H]-thymidine incorporation and ELISA, respectively. The trypsin-like protease in the synovium of RA patients was identical to human mast cell tryptase, which was composed of two subunits: 33 and 34 kDa. The 33- and 34-kDa proteins are different glycosylated forms of the 31-kDa protein, which was unglycosylated. Mast cell tryptase activity in RA synovial fluid was significantly higher than that in OA synovial fluid, while their activities and expression in the synovium were similar. Expression of PAR-2 mRNA in the synovium was higher in RA than in OA. Mast cell tryptase containing the unglycosylated 31-kDa subunit was the predominant form in synovial fluid. RA patients had higher amounts of this subunit in their synovial fluid than OA patients. Mast cell tryptase and PAR-2 activating peptide stimulated the proliferation of SFCs and release of IL-8 from these cells. Mast cell tryptase secretion into RA synovial fluid is higher than OA synovial fluid. Mast cell tryptase in synovial fluid stimulates the proliferation of SFCs and the release of pro-inflammatory cytokines via PAR-2, which may contribute to exacerbation of synovitis in RA.


Minimally invasive endoscopic removal of herniated nucleus pulposus that had migrated to the S1 nerve root foramen.

In this report, we described an adult case with a lumbar herniated nucleus pulposus that had migrated to the S1 nerve root foramen from L5-S1 disc space. Endoscopically, the migrated mass was successfully removed after laminectomy at the S1 with a small skin incision of 20 mm in length. Unlike the other levels, the intraforaminally migrated mass along the S1 root can be excised without any removal of the facet joints; therefore, additional spinal fusion is not necessary. Thus, an S1 foraminal migrated mass can be a good surgical candidate for minimally invasive endoscopic surgery.


Study on factors related to loss of lower extremity muscle mass in elderly acute stroke patients

The present study investigated the factors contributing to the loss of upper and lower extremity muscle mass in three elderly stroke patients with right hemiplegia in whom our rehabilitation program could not be performed at 1‐2 weeks after onset. The results revealed common factors such as prolonged accurate microinjection of hypotensive agents, severe hemiplegia(Brunnstrom stage I or Ⅱ), diarrhea and delayed initiation of tube feeding at 3 to 8 days after onset. With regard to individual differences, while all patients were recovering in bed, the degree of decrease in muscle mass varied among patients because they moved their extremities differently.

JNI : The Journal of Nursing Investigation


Surgical outcomes after treatment of fractures in femur and tibia in pycnodysostosis.

Pycnodysostosis is a rare hereditary disease, characterized by systemic bone sclerosis. The most important orthopedic problem in this condition is the recurrent pathological fracture of long bones. In this paper, the surgical results for fractures of six limbs (three femurs and three tibias) in five cases of pycnodysostosis are reported. Five limbs achieved fracture union and union is developing in one tibia after intramedullary nail (IM) nailing or Ilizarov external fixation (IEF), although fracture line tends to persist for longer periods of time. One femoral fracture was treated by IM nailing, and one femoral and one tibial fracture were treated by IEF leading to final bone union. One femoral and one tibial fracture were initially treated by IEF, and were treated by IM nailing after re-fracture. One tibial fracture was initially treated by IEF leading to a failure of union, and was converted to IM nailing. All cases are able to walk; one case requires a single crutch. Infection was noted in two limbs after IM nailing following IEF. Fixation with IM nail was effective in preventing re-fracture as well as in alignment correction. Although the surgical technique is more difficult, IM nailing in the initial surgery may be a better choice for achieving successful union while reducing the risk of re-fracture or infection.

Archives of Orthopaedic and Trauma Surgery


Effects of intervention with back-lying exercises with bent knees pointing upwards to prevent disuse muscle atrophy in patients with post-stroke hemiplegia

The present study measured lower extremity muscle mass using DXA (Dual energy X-ray Absorptiometry) in order to verify the effectiveness of intervention with a series of movements, including lying hip raise exercise with bent knees pointing upwards, among bedridden patients with post-stroke hemiplegia in the acute post-stroke period. Subjects in the intervention group were required to perform 10 repetitions of a series of back-lying exercises once a day with researchers, in addition to the exercises performed by those in a control group. The first measurement of muscle mass was conducted at three to five days after onset, and the second measurement was conducted seven days after the first. Muscle mass in the lower extremities was reduced by approximately 600g (decrease rate : 9%)on the paralyzed side and by 280g on the non-paralyzed side(decrease rate: 5%)in one week in the Brunnstrom stage ≤ II subgroup(site of measurement : lower extremities) (n＝8) of the control group (n＝23). The decrease in muscle mass in the Brunnstrom stage ≤ II subgroup (n＝4) of the intervention group (n＝15) was approximately 260g on the paralyzed side (decrease rate : 5%) and approximately 280g (decrease rate : 5%)on the non-paralyzed side. Thus, muscle mass decreased on both sides, and this occurred regardless of degree of paralysis. Comparison of the Brunnstrom stage ≥ III subgroups between the control and intervention groups also confirmed that the decease in muscle mass was smaller in the latter group. Thus, it was confirmed that back-lying exercises combining lower extremity movements, including hip raises with bent knees pointing upwards, prevented the decrease in lower extremity muscle mass on the paralyzed side in post-stroke patients. The present study also suggests that these exercise movements can be applied to preventive care for bedridden patients with other severe diseases.


Differences of therapeutic effects on regional bone mineral density and markers of bone mineral metabolism between alendronate and alfacalcidol in Japanese osteoporotic women.

We studied the differences of therapeutic effects on regional bone mineral density (BMD) and markers of bone mineral metabolism between alendronate and alfacalcidol in Japanese osteoporotic women. Ninety-two Japanese women suffering from primary osteoporosis without osteoporotic fractures, aged 55 to 81 years, were divided into two groups: women treated orally with alendronate for one-year (5mg/day) (alendronate group, n=35) and women treated orally with alfacalcidol for one year (0.5 microg/day) (alfacalcidol group, n=57). The mean BMD of the 2nd to 4th lumbar vertebrae (L2-4BMD) and regional BMD were measured using dual energy X-ray absorptiometry. In the alendronate group, the percentage changes of L2-4BMD, lumbar spine BMD, thoracic spine BMD, pelvis BMD in the alendronate group were 106.3+/-4.6%, 104.2+/-6.6%, 107.1+/-10.4%, 107.1+/-10.5%, respectively. The percentage changes of L2-4BMD and regional BMD except for head BMD in the alendronate group were significantly greater than those in the alfacalcidol group. In the alfacalcidol group, L2-4BMD, thoracic spine BMD and lumbar spine BMD were maintained at respective pretreatment levels, whereas other regional BMD were decreased. Both serum bone-specific alkaline phosphatase and urinary type I collagen cross-linked N-telopeptide of the alendronate group were decreased, whereas these markers of bone mineral metabolism of alfacalcidol group were increased compared with the respective pre-treatment levels. The results suggest that one-year treatment with alendronate increased L2-4BMD, lumbar spine BMD, thoracic spine BMD and pelvis BMD, and that markers of both bone formation and bone resorption were decreased following one-year treatment with alendronate.


Minimally invasive technique for direct repair of the pars defects in young adults using a spinal endoscope. A technical note.

Pars defect (spondylolysis) of the lumbar spine can cause chronic low back pain, and it sometimes requires surgical intervention. Direct repair is selected for the surgery if young adult patients do not present significant disc degeneration and lumbar instability. In order to lessen damages of back muscles during surgery, we added the use of a spinal endoscope to the "Buck's screwing procedure" the direct repair. There are four steps in this procedure: 1) identification of the defect, 2) curettage (refresh) of the defect, 3) percutaneous insertion of the annulated screws and 4) cancellous bone grafting. All these steps can be done endoscopically. We treated 3 young adults--a baseball player, a professional cycle-racer and a sculptor--using this endoscopic procedure. There were no complications during or after the operation. Union was obtained in all defects within 3 months, and they returned to their previous activities within 6 months after the surgery.


Genetic association between the PRKCH gene encoding protein kinase Ceta isozyme and rheumatoid arthritis in the Japanese population.

Analyses of families with rheumatoid arthritis (RA) have suggested the presence of a putative susceptibility locus on chromosome 14q21-23. This large population-based genetic association study was undertaken to examine this region. A 2-stage case-control association study of 950 unrelated Japanese patients with RA and 950 healthy controls was performed using >400 gene-based common single-nucleotide polymorphisms (SNPs). Multiple SNPs in the PRKCH gene encoding the eta isozyme of protein kinase C (PKCeta) showed significant single-locus disease associations, the most significant being SNP c.427+8134C>T (odds ratio 0.72, 95% confidence interval 0.62-0.83, P = 5.9 x 10(-5)). Each RA-associated SNP was consistently mapped to 3 distinct regions of strong linkage disequilibrium (i.e., linkage disequilibrium or haplotype blocks) in the PRKCH gene locus, suggesting that multiple causal variants influence disease susceptibility. Significant SNPs included a novel common missense polymorphism of the PRKCH gene, V374I (rs2230500), which lies within the ATP-binding site that is highly conserved among PKC superfamily members. In circulating lymphocytes, PRKCH messenger RNA was expressed at higher levels in resting T cells (CD4(+) or CD8(+)) than in B cells (CD19(+)) or monocytes (CD14(+)) and was significantly down-regulated through immune responses. Our results provide evidence of the involvement of PRKCH as a susceptibility gene for RA in the Japanese population. Dysregulation of PKCeta signal transduction pathway(s) may confer increased risk of RA through aberrant T cell-mediated autoimmune responses.


Chronic osteomyelitis of the tibia resembling benign bone tumors.


The alpha2 type IX collagen tryptophan polymorphism is associated with the severity of disc degeneration in younger patients with herniated nucleus pulposus of the lumbar spine.

Tryptophan alleles in COL9A2 (Trp2) and COL9A3 (Trp3) have been linked to lumbar disc diseases in the Finnish population. Although such diseases consist of various pathogenetically different conditions, detailed analysis of each has not been well documented. The aim of this study was to clarify whether the collagen IX tryptophan alleles influence the symptomatic degeneration of the lumbar disc in Japanese patients with herniated nucleus pulposus. We performed a prospective study of 84 patients who underwent lumbar discectomy. The degree of disc degeneration was evaluated by magnetic resonance images in relation to the collagen IX genotype. Twenty patients (21.4%) had the Trp2 allele and no patients had the Trp3 allele. Patients under 40 years with the Trp2 allele showed more severe disc degeneration at the surgical level than did those without the Trp2 allele (odds ratio 6.00, P=0.043). In contrast, patients aged 40 years or over did not show significant association between disc degeneration and collagen IX genotype. Our results suggest that the Trp2 allele is an age-dependent risk factor for the severity of disc degeneration in younger patients with symptomatic herniated nucleus pulposus of the lumbar spine.


Extension of contained rupture of an abdominal aortic aneurysm into a lumbar intervertebral disc. Case report.

Chronic contained rupture of an abdominal aortic aneurysm (AAA) is a rare event, making its diagnosis difficult. A delayed diagnosis and delayed surgical repair compromise the outcome. In this paper the authors report the case of a chronic contained rupture of an AAA causing spinal destruction, in which diagnosis was difficult because the lesion produced symptoms mimicking those of pyogenic spondylitis.


Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population.

In order to identify type 2 diabetes disease susceptibility gene(s) in a Japanese population, we applied a region-wide case-control association test to the 20.4 Mb region between D3S1293 and D3S2319 on chromosome 3p24.3-22.1, supported by linkage to type 2 diabetes and its related traits in Japanese and multiple populations. We performed a two-stage association test using 1,762 Japanese persons with 485 gene-centric, evenly spaced, common single nucleotide polymorphism (SNP) markers with minor allele frequency >0.1. For mouse studies, total RNA was extracted from various organs of BKS.Cg-+Lepr(db)/+Lepr(db) and control mice, and from MIN6, NIH3T3 and C2C12 cell lines. We detected a landmark SNP375 (A/G) (rs2051211, p = 0.000046, odds ratio = 1.33, 95% CI 1.16-1.53) in intron 5 of the endonuclease G-like 1 (ENDOGL1) gene. Systematic dense SNPs approach identified a susceptibility linkage disequilibrium (LD) block of 116.5 kb by |D'|, an LD units map and a critical region of 2.1 kb by r (2) in ENDOGL1. A haplotype-based association test showed that an at-risk haplotype is associated with disease status (p = 0.00001). The expression of ENDOGL1 was rather ubiquitous with relatively abundant expression in the brain and also in a pancreatic islet beta cell line. Mouse Endogl1 expression increased in pancreatic islets of hyperglycaemic BKS.Cg-+Lepr(db)/+Lepr(db) mice compared with that in control mice. Based on the population genetics, fine mapping of LD block and haplotype analysis, we conclude that ENDOGL1 is a candidate disease-susceptibility gene for type 2 diabetes in a Japanese population. Further analysis in a larger sample size is required to substantiate this conclusion.


Ubiquitin ligase gene expression in healthy volunteers with 20-day bedrest.

In animal models, several ubiquitin ligases play an important role in skeletal muscle atrophy caused by unloading. In this study we examined protein ubiquitination and ubiquitin ligase gene expression in quadriceps femoris muscle from healthy volunteers after 20-day bedrest to clarify ubiquitin-dependent proteolysis in human muscles after unloading. During bedrest, thickness and cross-sectional area of the quadriceps femoris muscle decreased significantly by 4.6% and 3.7%, respectively. Ubiquitinated proteins accumulated in these atrophied human muscles. A real-time reverse transcription-polymerase chain reaction system showed that bedrest significantly upregulated expression of two ubiquitin ligase genes, Cbl-b and atrogin-1. We also performed DNA microarray analysis to examine comprehensive gene expression in the atrophied muscle. Bedrest mainly suppressed the expression of muscle genes associated with control of gene expression in skeletal muscle. Our results suggest that, in humans, Cbl-b- or atrogin-1-mediated ubiquitination plays an important role in unloading-induced muscle atrophy, and that unloading stress may preferentially inhibit transcriptional responses in skeletal muscle.


Changes in lower extremity muscle mass among bedridden patients with post-stroke hemiplegia in the acute post-stroke period

The present study analyzed16patients who were bedridden for one week immediately after onset of post-stroke hemiplegia. We used DXA(dual energy X-ray absorptiometry)to determine changes in muscle mass in the lower extremities on both paralyzed and non-paralyzed sides. The first measurement was conducted 3 to 5 days after the onset, and the second measurement was conducted 7 days after the first. Muscle mass in the lower extremities was reduced by approximately 600g (9%) on the paralyzed side with and by 200g on the non-paralyzed side (3%) in the Brunnstrom stage≤II group (n＝5). Although the decrease of muscle mass in the Brunnstrom stage≥III group(n＝11, relatively slight degree of functional motion impairment)was not significant, a decrease of approximately 300g (decrease rate : 5%)was observed on the paralyzed side and approximately 100g (decrease rate : 1．5%)was seen on the non-paralyzed side. Hence, muscle mass declined on both sides, and this occurred regardless of degree of paralysis. The findings suggested that conventional range of motion exercises, functional position maintenance, and postural changes are inadequate to prevent disuse muscle atrophy in post-stroke patients ; thus, it is necessary to develop a new rehabilitation program which adopts different exercises such as trunk motion, even for patients in the acute stage after stoke onset.

JNI : The Journal of Nursing Investigation


Treatment of relapsed idiopathic clubfoot by complete subtalar release combined with the Ilizarov method.

This study presents the clinical and radiographic outcomes of 6 feet (4 patients) with relapsed idiopathic clubfoot that were treated with a combination of subtalar release and the Ilizarov method. The mean patient age at the time of the surgery was 7.4 years (range, 4.5-10.5 years), and the mean follow-up was 5.1 years (range, 2.0-7.3 years). All cases achieved a plantigrade foot, better walking ability, and parental satisfaction with the result. Ankle joint range of motion increased from a mean of 17 degrees (range, 10-30 degrees) preoperatively to 45 degrees (range, 35-65 degrees) at final follow-up. The talocalcaneal angle improved from a mean of 26 degrees (range, 15-34 degrees) preoperatively to 55 degrees (range, 47-65 degrees) at follow-up. The mean tibiocalcaneal angle improved from 95 degrees (range, 87-115 degrees) preoperatively to 80 degrees (77-83 degrees) at follow-up, whereas the talometatarsal angle improved from a preoperative mean of -19 degrees (range, -35 to -10 degrees) to 3.5 degrees (range, -5 to 7 degrees) at follow-up. Recurrence was observed in only 1 foot with forefoot adductus, caused by a pin tract infection and early fixator removal. These cases suggest the Ilizarov method combined with subtalar release are beneficial for the treatment of relapsed idiopathic clubfoot.


High-grade slippage of the lumbar spine in a rat model of spondylolisthesis: effects of cyclooxygenase-2 inhibitor on its deformity.

Radiographic and histologic evaluation of spondylolisthesis in a rat model. To investigate the effects of etodolac, a cox-2 inhibitor, on the severity of spondylolisthesis in a 4-week-old rat model. Spondylolisthesis occurs associated with spondylolysis in some pediatric patients. In such patients, the percent of forward slippage varies individually ranging between 0% and 100%. The factors determining the severity of forward slippage have not been clarified as yet. In earlier studies, we found that growth plate stress fracture was the basic lesion and that slippage was a consequence of the stress fracture. Hence, we hypothesized that the capacity of bone healing might be an important determinant of the degree of forward slippage. A lumbar spine slippage model was prepared in 4-week-old rats with vertebral physis fracture. To disrupt the fracture healing, the cyclooxygenase-2 (cox-2) inhibitor etodolac was used, and its effects on slippage and deformity were evaluated radiologically and histologically. In the etodolac group, forward slip significantly increased (P < 0.05) to the Meyerding Grade III while in the control rats it was Grade I or II. Bone remodeling of the vertebral body was suppressed by etodolac. Histologically, epiphyseal separation with slippage was observed in all the control and etodolac-treated rats. However, in the etodolac-treated group, the epiphyseal plate was greatly separated and did not present periosteal thickening at the physis fracture site. Vertebral forward slippage occurred in young rats after epiphyseal separation. In the etodolac group, slippage increased as deterioration of the bone healing capacity increased. Poor bony healing is suggested as one of the determinants of high-grade spondylolisthesis in children and adolescents.


A novel type of EWS-CHOP fusion gene in myxoid liposarcoma.

The cytogenetic hallmark of myxoid type and round cell type liposarcoma consists of reciprocal translocation of t(12;16)(q13;p11) and t(12;22)(q13;q12), which results in fusion of TLS/FUS and CHOP, and EWS and CHOP, respectively. Nine structural variations of the TLS/FUS-CHOP chimeric transcript have been reported, however, only two types of EWS-CHOP have been described. We describe here a case of myxoid liposarcoma containing a novel EWS-CHOP chimeric transcript and identified the breakpoint occurring in intron 13 of EWS. Reverse transcription-polymerase chain reaction and direct sequence showed that exon 13 of EWS was in-frame fused to exon 2 of CHOP. Genomic analysis revealed that the breaks were located in intron 13 of EWS and intron 1 of CHOP.

Biochemical and Biophysical Research Communications


The alpha 2 type IX collagen gene tryptophan polymorphism is not associated with rheumatoid arthritis in the Japanese population

The aim of this study was to investigate whether the alpha 2 type IX collagen (COL9A2) polymorphism that introduces tryptophan residue into the collagen triple-helix is a marker of susceptibility to, or severity of, rheumatoid arthritis (RA). The study included 749 Japanese patients with RA. One hundred twenty-four unrelated healthy individuals served as the control subjects. The relationship between the COL9A2 gene polymorphism and clinical manifestations of RA was evaluated. For the number of subjects positive for COL9A2 tryptophan polymorphism, there was no statistically significant difference between RA patients and normal controls. Furthermore, we did not detect any association of COL9A2 tryptophan polymorphism with disease status, least erosive subset, more erosive subset, or mutilating disease. The lack of association of COL9A2 tryptophan polymorphism with RA and the clinical findings in our study implies that the polymorphism may not function as a candidate gene marker for screening RA patients.


A remarkable large hamartoma around the knee in a patient with tuberous sclerosis.


MRI Characteristics of Parosteal Lipomas Associated with the HMGA2-LPP Fusion Gene.

The magnetic resonance (MR) characteristics of parosteal lipomas with the HMGA2-LPP fusion transcripts are described. The expression of HMGA2-LPP fusion transcripts was determined using the reverse transcription-polymerase chain reaction method. MR images of two cases with the fusion transcripts, a 56-year-old man and a 50-year-old woman, revealed heterogeneous high signal intensities on T1- and T2-weighted images, showing heterogeneous curvilinear enhancement on fat-suppressed T1-weighted images after Gd-DTPA injection, which resembled those of well-differentiated liposarcomas. Since the HMGA2-LPP fusion transcripts are exclusively detectable in benign mesenchymal tumors, testing HMGA2-LPP expression may be useful for differential diagnosis in cases of radiologically-suspected well-differentiated liposarcomas.


JRAB/MICAL-L2 is a junctional Rab13-binding protein mediating the endocytic recycling of occludin.

The dynamic turnover of tight junctions (TJs) is essential for epithelial-mesenchymal transitions and/or mesenchymal-epithelial transitions during epithelial morphogenesis. We previously demonstrated that Rab13 specifically mediates the endocytic recycling of occludin. Here, we identified MICAL-L2 (molecule interacting with CasL-like 2) as a novel Rab13-binding protein. Immunoprecipitation and immunofluorescence microscopy showed that MICAL-L2 specifically bound to the GTP-bound form of Rab13 via its C terminus, which contained a coiled-coil domain, and localized at TJs in epithelial MTD-1A cells. Recycling assay demonstrated that a MICAL-L2 mutant lacking the Rab13-binding domain (MICAL-L2-N) specifically inhibited the endocytic recycling of occludin but not transferrin receptor. Ca2+ switch assay further revealed that MICAL-L2-N as well as Rab13 Q67L inhibited the recruitment of occludin to the plasma membrane, the development of transepithelial electrical resistance, and the formation of a paracellular diffusion barrier. MICAL-L2 was displaced from TJs upon actin depolymerization and was distributed along radiating actin cables and stress fibers in Ca2+-depleted MTD-1A and fibroblastic NIH3T3 cells, respectively. These results suggest that MICAL-L2 mediates the endocytic recycling of occludin and the formation of functional TJs by linking Rab13 to actin cytoskeleton. We rename MICAL-L2 as JRAB (junctional Rab13-binding protein).


Sp1 Family of Transcription Factors Regulates the Human 2(XI) Collagen Gene (COL11A2) in Saos-2 Osteoblastic Cells.

Genes encoding type XI collagen, normally associated with chondrogenesis, are also expressed by osteoblasts. By studying Saos-2 cells, we showed that the transcription factors, Sp1, Sp3, and Sp7 (Osterix), regulate COL11A2 expression through its proximal promoter. The findings indicate both ubiquitous and osteoblast-specific mechanisms of collagen gene regulation. Type XI collagen is essential for skeletal morphogenesis. Collagen XI gene regulation has been studied in chondrocytes but not in osteoblasts. We cultured Saos-2 cells, a human osteosarcoma-derived line of osteoblasts, and analyzed them for alpha2(XI) protein and COL11A2 regulatory mechanisms. Although types I and V were the dominant collagens deposited by Saos-2 cells, they expressed COL11A2 mRNA, and alpha2(XI) chains were present in the extracellular matrix. The COL11A2 promoter region (from -149 to -40) containing three Sp1 binding sites was required for promoter activity in transient transfection assays. All three Sp1 sites were critical for binding by nuclear proteins in electrophoretic mobility shift assays. Further analysis using consensus oligonucleotides and specific antibodies as well as chromatin immunoprecipitation assay implicated Sp1 and Sp3 in binding to this promoter region. Overexpressing Sp1 or Sp3 significantly increased COL11A2 promoter activity and endogenous COL11A2 gene expression, an effect that was suppressed by the Sp1-binding inhibitor mithramycin A. Further experiments showed that Sp1, Sp3, CREB-binding protein (CBP), p300, and histone deacetylase (HDAC) were physically associated and HDAC inhibitors (trichostatin A or NaB) upregulated COL11A2 promoter activity and endogenous gene expression. Another Sp1 family member, Sp7 (Osterix), was expressed in Saos-2 cells, but not in chondrocytes, and was shown by chromatin immunoprecipitation to occupy the COL11A2 promoter. Overexpressing Sp7 increased COL11A2 promoter activity and endogenous gene expression, an effect also blocked by mithramycin A. Using siRNA to knockdown Sp1, Sp3, or Sp7, it was shown that depression of any of them decreased COL11A2 promoter activity and endogenous gene expression. Finally, primary cultures of osteoblasts expressed COL11A2 and Sp7, upregulated COL11A2 promoter activity and endogenous gene expression when Sp1, Sp3, or Sp7 were overexpressed, and downregulated them when Sp1, Sp3, or Sp7 were selectively depressed. The results establish that Sp1 proteins regulate COL11A2 transcription by binding to its proximal promoter and directly interacting with CBP, p300, and HDAC.


Ubiqitin Ligase Cbl-b Downregulates Bone Formation Through Suppression of IGF-I Signaling in Osteoblasts During Denervation

Unloading can prevent bone formation by osteoblasts. To study this mechanism, we focused on a ubiquitin ligase, Cbl-b, which was highly expressed in osteoblastic cells during denervation. Our results suggest that Cbl-b may mediate denervation-induced osteopenia by inhibiting IGF-I signaling in osteoblasts. Unloading, such as denervation (sciatic neurectomy) and spaceflight, suppresses bone formation by osteoblasts, leading to osteopenia. The resistance of osteoblasts to growth factors contributes to such unloading-mediated osteopenia. However, a detailed mechanism of this resistance is unknown. We first found that a RING-type ubiquitin ligase, Cbl-b, was highly expressed in osteoblastic cells after sciatic neurectomy in mice. In this study, we reasoned that Cbl-b played an important role in the resistance of osteoblasts to IGF-I. Cbl-b-deficient (Cbl-b(-/-)) or wildtype (Cbl-b(+/+)) mice were subjected to sciatic neurectomy. Bone formation in these mice was assessed by calcein labeling and histomorphometric analyses. We examined IGF-I signaling molecules in femora of these mice by Western blot and immunohistochemical analyses. We also examined the mitogenic response of Cbl-b-overexpressing or -deficient osteoblastic cells to various growth factors. In Cbl-b(+/+) mice, denervation decreased femur mass and bone formation, whereas it increased the expression of Cbl-b protein in osteoprogenitor cells and in osteocalcin-positive cells (osteoblastic cells) in hindlimb bone. In contrast, in Cbl-b(-/-) mice, bone mass and bone formation were sustained during denervation. Denervation inhibited the mitogenic response of osteoprogenitor cells most significantly to IGF-I. Therefore, we focused on Cbl-b-mediated modification of IGF-I signaling. Denervation decreased the amounts of insulin receptor substrate-1 (IRS-1), phosphatidly inositol 3-phosphate kinase (PI3K), and Akt-1 proteins in femora of Cbl-b(+/+) mice, whereas the amounts of these IGF-I signaling molecules in femora of Cbl-b(-/-) mice were constant after denervation. On a cellular level, primary osteoblastic cells from Cbl-b(-/-) mice were more stimulated to proliferate by IGF-I treatment compared with those from Cbl-b(+/+) mice. Furthermore, overexpression of Cbl-b increased ubiquitination and degradation of IRS-1 in primary Cbl-b(-/-) osteoblastic cells, leading to their impaired mitogenic response to IGF-I. These results suggest that Cbl-b induces resistance of osteoblasts to IGF-I during denervation by increasing IRS-1 degradation and that Cbl-b-mediated modification of IGF-I signaling may contribute to decreased bone formation during denervation.


Effects of monofilament nylon coated with basic fibroblast growth factor on endogenous intrasynovial flexor tendon healing.

We developed a monofilament nylon thread that can release various growth factors to enhance intrinsic reparative processes after flexor tendon injury. We evaluated the properties of this thread in vitro and in vivo. Nylon threads were coated with gelatin that subsequently was cross-linked in glutaraldehyde. The thread was soaked in basic fibroblast growth factor (bFGF) solution (400 microg/mL). Exogenous bFGF in the thread was released constantly over the course of 1 week. The biologic activity of bFGF and the biomechanical strength of the thread were examined in vitro and its efficacy was investigated in an in vivo rabbit tendon repair model after early flexion exercises. The sutured sites were examined histologically (hematoxylin-eosin, immunohistochemistry, in situ hybridization), biochemically (Western blot test), and biomechanically (ultimate load) after surgery. This gelatin-coated thread absorbed iodine 125-labeled bFGF in a time-dependent manner. The total amount of bFGF absorbed by the thread within the tendon tissue was between 3 and 15 mug depending on the concentration of bFGF solution. Basic fibroblast growth factor protein was delivered selectively-not in the surrounding scar but in the repaired tendon-for 3 weeks. Histologic analysis showed that the cellular density at the repaired site increased in accordance with the expression of bFGF messenger RNA and protein in the tendon. Endogenous bFGF expression seemed to be enhanced transiently by exogenous bFGF during the first few weeks. The epitenon showed a vigorous fibroblastic response to the coated thread and the ultimate load also was increased significantly at 3 weeks after surgery. This bFGF-coated nylon suture gave excellent results in delivering a drug selectively to tendon; it also induced an increase of biomechanical strength and a thickening of the epitenon layer in vivo during a 3-week period, thereby accelerating cellular proliferation, initially peripherally and later centrally. This system may become a therapeutic tool to be used in hand surgery.


Metaphyseal Dysplasia of Braun-Tinschert Type: Report of a Japanese Girl.

We report on a 7-year-old Japanese girl with metaphyseal dysplasia (MD) of Braun-Tinschert type, a recently recognized, autosomal dominant sclerosing bone dysplasia. All individuals with the disorder from four families in the literature originated from a small town in Bohemia or its vicinity. The occurrence of the disorder in a Japanese girl indicates that it is not restricted to Germans. The radiographic hallmarks of the disorder include metaphyseal undermodeling (Erlenmeyer-flask deformity); osteosclerosis of the chondroosseous junctions, metaphyseal cortices, and epiphyseal margins; and exostosis-like bone excrescences at the metaphyseal-diaphyseal junctions. In the girl we described, the latter two findings were conspicuous at age 4 years, but became less prominent with increasing age. The metaphyseal trabeculae were somewhat coarse. The humeri exhibited varus deformity, and the ulnae and fibulae mild bowing. The mean bone mineral density of the lumbar spine was lower than that of age-matched controls. The patient exhibited premature loss of primary teeth, likely to be a sign of increased periodontal bone resorption. Markers of bone formation and resorption were both increased, an indication of a high rate of bone turnover.

American Journal of Medical Genetics. Part A.


Extruded lumbar osseous endplate causing long-term radiculopathy in an adult: an endoscopic excision.

In this report, we described an adult case that had a long-term radiculopathy due to an extruded osseous endplate of the lumbar spine at the L5-S1 intervertebral disc level. The osseous material inside the extruded material was not absorbed, and it had continued compressing the nerve root for one year. Endoscopically, the bony fragment was successfully removed. After the surgery, the patient's symptom disappeared, and neurological deficits became normalized. In conclusion, we propose that surgical intervention should be taken into account for the treatment of HNP, when the extruded material contains bony fragment such as osseous endplate.


MRI signal changes of the pedicle as an indicator for early diagnosis of spondylolysis in children and adolescents. A clinical and biomechanical study.

Clinical review of pediatric patients with lumbar spondylolysis and biomechanical analysis using finite-element lumbar spine model. To evaluate the usefulness of the signal changes observed on MR images of the pedicle for the early diagnosis of spondylolysis, and to investigate the pathomechanism of the signal changes based on the stresses in pedicles, as predicted using finite-element analyses. Furthermore, to evaluate the usefulness of the signal change to predict the bony healing following conservative treatment. Since early-stage spondylolysis can achieve osseous healing conservatively, it is important to diagnose this disorder as early as possible. Presently, there is no well-established, noninvasive, and reliable diagnostic tool for the early diagnosis. Thirty-seven pediatric patients with spondylolysis were included. Sixty-eight defects were examined and their stages as revealed on CT scans were recorded. High signal changes (HSC) of the pedicles on axial T2-weighted MRI were compared with the CT-based stages of the defect. Among them, 16 patients, including 15 boys and 1 girl, were treated conservatively for at least a 3-month period. Bony healing of the fracture site was evaluated on CT, and the results were compared between two groups with or without HSC at the initial consultation. Using a three-dimensional nonlinear finite-element model of the L3-L5 segment, stress distributions in the pars and pedicle regions were analyzed in response to 400 N compression and 10.6 Nm moment. Based on CTs, 68 pars defects were classified as follows: 8 very early, 24 late-early, 16 progressive, and 20 terminal stages. All defects in very early and late-early stages (100%) showed HSC on T2-weighted MRI at the ipsilateral pedicle. Among 16 progressive stages, eight (50%) showed HSC, while no defects of the terminal stage (0%) were found to have HSC. In total, 29 pars defects were treated conservatively out of 16 patients. In 19 of the HSC positive defects, 15 (79%) showed bony healing after the conservative treatment, whereas none of the 10 HSC negative defects (0%) showed any healing. The results were statistically significant at P < 0.05 (chi). Stress results from the finite-element model indicated that pars interarticularis showed the highest value in all loading modes, and the pedicle showed the second highest. The correlation between the high stresses in the pedicle and the corresponding HSC suggest that signal changes in MRI could be used as an indicator for early diagnosis of spondylolysis. The HSC of the pedicle provided useful information to diagnose early stage spondylolysis. Furthermore, the HSC may be a good indicator as to whether a bony union will result from conservative treatment.


Association of single nucleotide polymorphisms in the suppressor of cytokine signaling 2 (SOCS2) gene with type 2 diabetes in the Japanese.

Several previous linkage scans in type 2 diabetes (T2D) families indicated a putative susceptibility locus on chromosome 12q15-q22, while the underlying gene for T2D has not yet been identified. We performed a region-wide association analysis on 12q15-q22, using a dense set of >500 single-nucleotide polymorphisms (SNPs), in 1492 unrelated Japanese individuals enrolled in this study. We identified an association between T2D and a haplotype block spanning 13.6 kb of genomic DNA that includes the entire SOCS2 gene. Evolutionary-based haplotype analysis of haplotype-tagging SNPs followed by a "sliding window" haplotypic analysis indicated SNPs that mapped to the 5' region of the SOCS2gene to be associated with T2D with high statistical significance. The SOCS2 gene was expressed ubiquitously in human and murine tissues, including pancreatic beta-cell lines. Adenovirus-mediated expression of the SOCS2 gene in MIN6 cells or isolated rat islets significantly suppressed glucose-stimulated insulin secretion. Our data indicate that SOCS2 may play a role in susceptibility to T2D in the Japanese.


Distinct gene expression profiles in the femora of rats exposed to spaceflight, tail-suspension and dnervation.


High tibial osteotomy for osteoarthritis of the knee with varus deformity utilizing the hemicallotasis method.

A hemicallotasis method has been developed utilizing an external fixator as high tibial osteotomy (HTO), and satisfactory results of this method with the external fixator have been reported. This external fixator has a universal joint that moves in all directions. We have recently designed a hemicallotasis device for this operation. HTO for the knee with varus deformity utilizing the hemicallotasis method was performed on 44 knees. The patients had a mean age at operation of 65 years (range 49-82 years), a mean follow-up period of 68 months (range 36-119 months), and a mean preoperative knee score of 66 points (range 27-90 points). The operated knees had a mean knee score at the final follow-up of 86 points (range 51-98 points), but the mean range of knee motion was not changed as follows. Before surgery, the mean flexion was 129 degrees (range 90-150 degrees) and the mean extension was -5 degrees (range -30 to 0 degrees), whereas at the final follow-up, the corresponding values were 127 degrees (range 85-150 degrees) and -4 degrees (range -25 to 0 degrees), respectively. Radiographically, the femorotibial joint was classified as grade 2 in 9 knees, grade 3 in 21 knees, and grade 4 in 14 knees according to the classification of osteoarthritis (Kellgren and Laurence). The patellofemoral joint was also classified as grade 1 in 39 knees, grade 2 in 2 knees, and grade 3 in 3 knees. The mean femorotibial angle was 184 degrees (4 degrees varus) before surgery, 169 degrees (11 degrees valgus) after pin extraction, and was maintained at the final follow-up. The complications of this method were relatively few and consisted of pin-tract infection (8 knees), deep vein thrombosis (3 knees), and delayed union (2 knees). No peroneal nerve palsy or compartment syndrome was encountered. No knee was converted to total arthroplasty. However, administration of analgesics was necessary in ten knees at the final follow-up. The hemicallotasis method easily determined the angle of correction even in the knees with ligamentous laxity. Nevertheless, one of the major demerits of this method was a longer period of application of the external fixator. The level of evidence was level IV (case series).

Archives of Orthopaedic and Trauma Surgery


A Leiomyoma Arising from the Deep Palmar Arterial Arch.

Vascular leiomyomas, or angioleiomyomas, are benign tumours originating from smooth non-striated muscle. Leiomyomas in the hand are uncommon and their pre-operative diagnosis is difficult. We report a 65 year-old woman who developed a vascular leiomyoma arising from the deep palmar arterial arch.

The Journal of Hand Surgery, British and European Volume


Intrafamilial phenotypic diversity in multiple epiphyseal dysplasia associated with a COL9A2 mutation (EDM2)

We describe a Japanese family with an autosomal dominant multiple epiphyseal dysplasia (MED EDM2) showing significant phenotypic diversity among the five affected members. Genomic analysis for COL9A2 identified an Ex3-1A>G heterozygous mutation, which has been proved to result in skipping of exon 3. The proband was a 9-year-old boy, who presented with ulnar club hands due to severe epiphyseal dysplasia in the distal ulnae. Radiological examination showed multiple epiphyseal dysplasias, predominantly involving the knee and the wrist. The hip appeared almost normal. The malalignment of the wrist was successfully treated with a limb lengthening procedure. The phenotype of the asymptomatic 12-year-old brother was similar to, but milder than, that of the proband. The asymptomatic 39-year-old mother, the 35-year-old uncle, and the 65-year-old grandmother with bilateral painful knees showed radiographically mild and severe osteoarthritis of the knee, respectively, and none of them had wrist deformity.


Intrapatellar tendon lipoma with chondro-osseous differentiation: detection of HMGA2-LPP fusion gene transcript.

A 54 year old man developed an unusual lipoma in the patellar tendon, consisting of a fibro-adipose component and a chondro-osseous component. The fibro-adipose component contained mature adipocytes, lipoblasts, and fibroblasts; the chondro-osseous component showed typical endochondral bone formation. Molecular analysis showed that the identical HMGA2-LPP fusion transcript-characteristic of lipoma, parosteal lipoma, and pulmonary chondroid hamartoma-was detectable in the both components.


Treatment of knee osteoarthritis associated with extraarticular varus deformity of the femur: staged total knee arthroplasty following corrective osteotomy.


No evidence for association of ENPP1(PC-1)K121Q variant with risk of Type 2 diabetes in a Japanese population.

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1, also known as PC-1) inhibits insulin signal transduction pathway(s). Previous studies have demonstrated the K121Q variant of the ENPP1 gene to have a significant functional role in determining susceptibility to insulin resistance and type 2 diabetes (T2D). To assess whether the K121Q variant has any impact on T2D in Japanese, we undertook an extensive case-control association study using a total of 911 unrelated Japanese T2D patients and 876 control subjects. No significant difference was observed in either genotype distribution (P=0.95) or allele frequency (P=0.83) between T2D and control groups. Notably, the frequency of the ancestral Q121 allele, which is also present in other primates, was quite high in African-Americans, and showed a marked ethnic variation (77.3% in African-Americans, 16.7% in European Americans, 10.5% in Japanese and 4.2% in Han Chinese). Consequently, the pairwise F(ST )value (a classic measure of genetic distance between pairs of population) showed highly significant differentiations between African-American and non-African-American populations (F(ST)>0.3). Our results indicated that the K121Q variant of the ENPP1 gene has very little, if any, impact on T2D susceptibility in Japanese, but may play a role in the inter-ethnic variability in insulin resistance and T2D.


Bisphosphonate Modulates Morphological and Mechanical Properties in Distraction Osteogenesis through Inhibition of Bone Resorption.

Despite the general clinical acceptance of distraction osteogenesis and much attention to bone formation in this method, little is recognized about activated bone resorption in the regenerated bone. The purpose of this study was to demonstrate the simultaneously activated bone resorption with activated bone formation and to investigate the role and efficacy of bisphosphonate in distraction osteogenesis. Left tibiae of 54 immature rabbits were lengthened for 3 weeks at a rate of 0.7 mm/day after a 1-week lag. Regenerated bone was quantitatively investigated by radiographic bone density, bone histomorphometry, and three-point bending testing. Animals received either vehicle or nitrogen-containing bisphosphonate (N-BP), YM529/ONO5920 at doses of 0.4 mg/kg/w or 0.004 mg/kg/w for 6 weeks. Regenerated bone of the vehicle group showed a radiologically characteristic zone structure containing the osteopenic zones adjacent to the sclerotic zones. The regenerated bone of the 0.4-mg/kg/w group showed no osteopenic zones during the course and eventually became homogeneously radiodense. The bone volume corresponding to the osteopenic zone of this group was 5.6-fold greater compared with that of the vehicle group. The lengthened bone strength of this group was 3.3-fold greater in ultimate force than that of the vehicle group and equivalent to the contralateral tibia. The 0.004-mg/kg/w group had no substantial differences compared with the vehicle group, despite radiological enhancement of the mineralized front as well as somewhat delayed bone resorption. These results demonstrate that not only bone formation but also bone resorption is highly activated in the regenerated bone, implying high bone turnover. Sufficient N-BP caused a notable modulation in morphological properties of the regenerated bone through inhibition of highly activated bone resorption and eventually increased mechanical properties.


Overexpression of HMGA2-LPP fusion transcripts promotes expression of the alpha 2 type XI collagen gene.

In a subset of human lipomas, a specific t(3;12) chromosome translocation gives rise to HMGA2-LPP fusion protein, containing the amino (N)-terminal DNA binding domains of HMGA2 fused to the carboxyl (C)-terminal LIM domains of LPP. In addition to its role in adipogenesis, several observations suggest that HMGA2-LPP is linked to chondrogenesis. Here, we analyzed whether HMGA2-LPP promotes chondrogenic differentiation, a marker of which is transactivation of the alpha 2 type XI collagen gene (Col11a2). Real-time PCR analysis showed that HMGA2-LPP and COL11A2 were co-expressed. Luciferase assay demonstrated that either of HMGA2-LPP, wild-type HMGA2 or the N-terminal HMGA2 transactivated the Col11a2 promoter in HeLa cells, while the C-terminal LPP did not. RT-PCR analysis revealed that HMGA2-LPP transcripts in lipomas with the fusion were 591-fold of full-length HMGA2 transcripts in lipomas without the fusion. These results indicate that in vivo overexpression of HMGA2-LPP promotes chondrogenesis by upregulating cartilage-specific collagen gene expression through the N-terminal DNA binding domains.

Biochemical and Biophysical Research Communications


Preservation of C7 spinous process does not influence the long-term outcome after laminoplasty for cervical spondylotic myelopathy.

Axial pain is one of the major complications after laminoplasty, and preservation of C7 spinous process during the procedure can reduce the axial pain. However, it has not been elucidated whether laminoplasty preserving the C7 spinous process can maintain neurological improvement for a long time. The purpose of our retrospective study was to investigate the long-term neurological outcome after open-door laminoplasty preserving the C7 spinous process for cervical spondylotic myelopathy (CSM). Clinical and radiological outcomes were analysed in 42 patients who underwent open-door laminoplasty preserving C7 spinous process and followed up for more than 5 years. Neurological function was evaluated by means of the Japanese Orthopaedic Association (JOA) scoring system for cervical myelopathy. Axial pain was assessed using a visual analog scale (VAS) at the last examination. Alignment and motion of the cervical spine were measured from radiographs, and magnetic resonance imaging (MRI) was used to evaluate postoperative compression at C7. The mean JOA score was 9.4 before surgery and 12.0 at the latest follow-up. The mean VAS score in 26 patients score was 9.7/100. No compression of the spinal cord was observed in any MRI at the latest follow-up. Preservation of the C7 spinous process does not influence the long-term outcome of CSM after laminoplasty. Although we did not have a comparative group, the procedure described here should be considered as the solution.


Total hip arthroplasty in osteopetrosis using computer-assisted fluoroscopic navigation.

Hybrid total hip arthroplasty with computer-assisted fluoroscopic navigation was performed on a patient with osteoarthritis due to an autosomal dominant form of osteopetrosis. The surgical procedures were difficult because the bone was extremely hard and brittle with obliteration of the medullary cavity. Especially, preparation of a femoral canal for the stem was technically challenging and required changes from a conventional surgical procedure. Therefore, we used a computer-assisted fluoroscopic navigation system to create the femoral cavity for the stem, and an accurate placement of the prosthesis was achieved. Navigation guidance can be a useful tool when performing arthroplasty in patients with hip osteoarthritis associated with osteopetrosis.


Asynchronous progressive diaphyseal dysplasia.

We report the case of a 42-year-old Japanese woman with unusual diaphyseal dysplasia of bilateral femora. Radiographs showed thickening and sclerosis of the cortex with resultant enlargement of the diaphysis, unclear demarcation of the surface of the cortex, and no periosteal reaction. These changes were found on the left femur at the first presentation, and those on the right femur developed within several years. Although this patient partly presented characteristics of Ribbing disease and Camurati-Engelmann disease, the focal involvement of bilateral femora suggested an unknown pathogenesis.


Bone Tumor of the Distal Femur in a 67-Year-Old Woman

Clinical Orthopaedics and Related Research


The intramedullary gradual elongation nail:Application for femoral shaft non-union


Osteoactivin upregulates expression of MMP-3 and MMP-9 in fibroblasts infiltrated into denervated skeletal muscle in mice

In this study, we examined pathophysiological roles of osteoactivin, a functionally unknown type I membrane glycoprotein, in mouse skeletal muscle atrophied by denervation (sciatic neurectomy). Denervation increased the amounts of osteoactivin, vimentin, matrix metalloproteinase-3 (MMP-3), and MMP-9 in mouse gastrocnemius muscle. Interestingly, immunohistochemical analysis revealed that vimentin, MMP-3, and MMP-9 were mainly present in fibroblast-like cells infiltrated into denervated mouse gastrocnemius muscle, whereas osteoactivin was expressed in the sarcolemma of myofibers adjacent to the fibroblast-like cells. On the basis of these findings, we reasoned that osteoactivin in myocytes was involved in activation of the infiltrated fibroblasts. To address this issue, we examined effects of osteoactivin on expression of MMPs in fibroblasts in vitro and in vivo. Overexpression of osteoactivin in NIH-3T3 fibroblasts induced expression of MMP-3, but not in mouse C(2)C(12) myoblasts, indicating that osteoactivin might functionally target fibroblasts. Treatment with recombinant mouse osteoactivin increased the amounts of collagen type I, MMP-3, and MMP-9 in mouse NIH-3T3 fibroblasts. The upregulated expression of these fibroblast marker proteins was significantly inhibited by heparin, but not by an integrin inhibitor, indicating that a heparin-binding motif in the extracellular domain might be an active site of osteoactivin. In osteoactivin-transgenic mice, denervation further enhanced expression of MMP-3 and MMP-9 in fibroblasts infiltrated into gastrocnemius muscle, compared with wild-type mice. Our present results suggest that osteoactivin might function as an activator for fibroblasts infiltrated into denervated skeletal muscles and play an important role in regulating degeneration/regeneration of extracellular matrix.

American Journal of Physiology, Cell Physiology


Cyclooxygenase-2 inhibitor delays fracture healing in rats

Cyclooxigenase-2 (COX-2) inhibitors have been reported to delay fracture healing. To investigate the major inhibitory period of COX-2 inhibitors in fracture healing, we administrated etodolac, a COX-2-specific inhibitor, to a rat fracture model by altering the period of administration from early to late. After closed fractures had been created at the middle of the femoral shafts in 12-week-old Wister rats, a standardized dose of etodolac was administrated in three ways: group I received it for 3 weeks, group II for just the first week after operation, and group III for just the third (final) week. Group IV was the vehicle control group. Bone maturation was estimated by radiographic scoring system, and mechanically by a three-point bending test. In both the radiographic and mechanical studies, groups I and II showed lower scores than group IV, indicating that even a short period of administration of a COX-2-specific inhibitor in the early phase of fracture healing creates a risk of delayed healing. blacksquare, square, filled.