The stroke-like episodes in MELAS may reflect neuronal hyperexcitability, which increases energy demand and creates energy imbalance between energy requirement and adequate availability of adenosine triphosphate due to oxidative phosphorylation defect particularly in the susceptible neuronal population, causing cortical necrosis. The episodic nature of stroke-like episodes is unexplained.

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 ؋ 10 ؊9 ) and 1.61 (P ‫؍‬ 2.1 ؋ 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.

These data suggest that the use of TNF blockers is a likely cause of SSI and DVT development in RA patients following major orthopaedic surgery.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is the leading cause of myelopathy in Japan and is diagnosed by ectopic bone formation in the paravertebral ligament. OPLL is a systemic high bone mass disease with a strong genetic background. To detect genes relevant to the pathogenesis of OPLL, we performed a cDNA microarray analysis of systematic gene expression profiles during the osteoblastic differentiation of ligament cells from OPLL patients (OPLL cells), patients with a disorder called ossification of yellow ligament (OYL), and non-OPLL controls together with human mesenchymal stem cells (hMSCs) after stimulating them with osteogenic differentiation medium (OS). Twenty-four genes were up-regulated during osteoblastic differentiation in OPLL cells. Zinc finger protein 145 (promyelotic leukemia zinc finger or PLZF) was one of the highly expressed genes during osteoblastic differentiation in all the cells examined. We investigated the roles of PLZF in the regulation of osteoblastic differentiation of hMSCs and C2C12 cells. Small interfering RNA-mediated gene silencing of PLZF resulted in a reduction in the expression of osteoblast-specific genes such as the alkaline phosphatase, collagen 1A1 (Col1a1), Runx2/core-binding factor 1 (Cbfa1), and osteocalcin genes, even in the presence of OS in hMSCs. The expression of PLZF was unaffected by the addition of bone morphogenetic protein 2 (BMP-2), and the expression of BMP-2 was not affected by PLZF in hMSCs. In C2C12 cells, overexpression of PLZF increased the expression of Cbfa1 and Col1a1; on the other hand, the overexpression of CBFA1 did not affect the expression of Plzf. These findings indicate that PLZF plays important roles in early osteoblastic differentiation as an upstream regulator of CBFA1 and thereby might participate in promoting the ossification of spinal ligament cells in OPLL patients.Ossification of the posterior longitudinal ligament of the spine (OPLL) 1 is a common hyperostotic disorder among Japanese and other Asian populations with a prevalence of 2-4% of the general population (1). OPLL patients show ectopic bone formation in the posterior longitudinal ligament, which compresses the spinal cord leading to various neurological symptoms. Despite the late onset (average age of onset is 50 years), OPLL has a strong genetic background as shown in classical epidemiological studies and by an estimate of relative risk to siblings of ϳ10 (2, 3). Because genetic factors appear to play crucial roles in the etiology of OPLL, genetic screenings to identify susceptibility are important. To date, we have performed genetic linkage and linkage disequilibrium studies to identify the causalities of OPLL and have successfully identified collagen 11A2 (COL11A2) and collagen 6A1 (3-6). We also demonstrated that an intron 6 (Ϫ4a) polymorphism of COL11A2 affects the splicing of exon 6 in ligament cells from OPLL patients (5). Although the identification of genetic factors of OPLL has important implications, the overall picture of the molecul...

High tibial valgus osteotomy (HTO) is an established treatment for medial-compartment osteoarthritis of the knee. We have combined medial open and lateral closed-wedge HTO (hybrid closed-wedge HTO) to overcome the limitations of traditional closed-wedge HTO. Our new hybrid procedure has the following advantages: (1) the bone block removed is smaller in size; (2) the procedure yields optimal geometric characteristics for bone healing; (3) there is no step-off at the lateral osteotomy site; (4) the lateral cortex of the proximal and distal fragments is attached firmly by the oblique osteotomy; and (5) early full weight-bearing walking is possible. This procedure is effective in treating medial-compartment osteoarthritis accompanied by patellofemoral osteoarthritis. The indications for this procedure include a willingness and ability to comply with the postoperative rehabilitation program; a diagnosis of either medialcompartment osteoarthritis or complicated patellofemoral osteoarthritis; and preferably, an age of 70 years or younger, although this is not a strict constraint. Patients are permitted to stand using both legs on the day after surgery and walk with full weight bearing within 2 weeks of undergoing our novel HTO procedure. We describe the details of this surgical technique and the postoperative rehabilitation program for the patients who undergo this treatment.H igh tibial valgus osteotomy (HTO) is an established surgical procedure to correct varus malalignment in patients with medial-compartment osteoarthritis (OA) of the knee.1,2 There are 2 main types of HTO surgery: lateral closed-wedge high tibial valgus osteotomy (CWHTO) 3 and medial open-wedge high tibial valgus osteotomy (OWHTO). 4 At present, an increasing number of surgeons use OWHTO because it is comparatively simpler. OWHTO is most effective during the early or middle stages of knee OA but is not expected to have a beneficial impact if the knee OA is accompanied by a severe deformity or in cases of patellofemoral joint OA.There are several disadvantages to traditional CWHTO including lateral-offset increases due to horizontal osteotomy and loss of the large bone block below the lateral tibial plateau. Discrepancies in the leg length arise after CWHTO because the operative side is shortened. 5,6 It also takes a relatively long time to achieve bone union at the osteotomy site after CWHTO because of discrepancies between the area on the proximal and distal fragments. This creates difficulties in maintaining alignment until bone union is acquired. Full weight bearing is also difficult until the osteotomy site is united, and a long leg cast or knee brace is thus needed for CWHTO patients.Optimal postoperative rehabilitation after knee surgery is needed to enable walking with full weight without any support as soon as possible. This, in turn, will prevent the aggravation of osteoporosis, the deterioration of physical function, and the onset of deep vein thrombosis after surgery. We describe a new surgical procedure combining OWHTO and C...

Because COL6A1 could be a susceptibility to the occurrence of DISH and OPLL in the Japanese population, we consider that COL6A1 could be responsible for the hyperostotic state, leading to ectopic bone formation in the spinal ligament.

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.

To better understand the molecular pathogenesis of OPLL (ossification of the posterior longitudinal ligament) of the spine, an ectopic bone formation disease, we performed cDNA microarray analysis on cultured ligament cells from OPLL patients. We found that TSG-6 (tumour necrosis factor alpha-stimulated gene-6) is down-regulated during osteoblastic differentiation. Adenovirus vector-mediated overexpression of TSG-6 inhibited osteoblastic differentiation of human mesenchymal stem cells induced by BMP (bone morphogenetic protein)-2 or OS (osteogenic differentiation medium). TSG-6 suppressed phosphorylation and nuclear accumulation of Smad 1/5 induced by BMP-2, probably by inhibiting binding of the ligand to the receptor, since interaction between TSG-6 and BMP-2 was observed in vitro. TSG-6 has two functional domains, a Link domain (a hyaluronan binding domain) and a CUB domain implicated in protein interaction. The inhibitory effect on osteoblastic differentiation was completely lost with exogenously added Link domain-truncated TSG-6, while partial inhibition was retained by the CUB domain-truncated protein. In addition, the inhibitory action of TSG-6 and the in vitro interaction of TSG-6 with BMP-2 were abolished by the addition of hyaluronan. Thus, TSG-6, identified as a down-regulated gene during osteoblastic differentiation, suppresses osteoblastic differentiation induced by both BMP-2 and OS and is a plausible target for therapeutic intervention in OPLL.