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ABSTRACT: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis that progresses to destruction of cartilage and bone. Bone marrow (BM) cells have been shown to contribute to this pathogenesis. In this study, we compared differentially expressed molecules in BM cells from RA and osteoarthritis (OA) patients and analyzed abnormal regulatory networks to identify the role of BM cells in RA.
Gene expression profiles (GEPs) in BM-derived mononuclear cells from 9 RA and 10 OA patients were obtained by DNA microarray. Up- and down-regulated genes were identified by comparing the GEPs from the two patient groups. Bioinformatics was performed by Expression Analysis Systemic Explorer (EASE) 2.0 based on gene ontology, followed by network pathway analysis with Ingenuity Pathways Analysis (IPA) 7.5.
The BM mononuclear cells showed 764 up-regulated and 1,910 down-regulated genes in RA patients relative to the OA group. EASE revealed that the gene category response to external stimulus, which included the gene category immune response, was overrepresented by the up-regulated genes. So too were the gene categories signal transduction and phosphate metabolism. Down-regulated genes were dominantly classified in three gene categories: cell proliferation, which included mitotic cell cycle, DNA replication and chromosome cycle, and DNA metabolism. Most genes in these categories overlapped with each other. IPA analysis showed that the up-regulated genes in immune response were highly relevant to the antigen presentation pathway and to interferon signaling. The major histocompatibility complex (MHC) class I molecules, human leukocyte antigen (HLA)-E, HLA-F, and HLA-G, tapasin (TAP) and TAP binding protein, both of which are involved in peptide antigen binding and presentation via MHC class I molecules, are depicted in the immune response molecule networks. Interferon gamma and interleukin 8 were overexpressed and found to play central roles in these networks.
Abnormal regulatory networks in the immune response and cell cycle categories were identified in BM mononuclear cells from RA patients, indicating that the BM is pathologically involved in RA.
Arthritis research & therapy 06/2011; 13(3):R89. · 4.27 Impact Factor
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Takahiro Higashi,
Takeo Nakayama,
Shunichi Fukuhara,
Hisashi Yamanaka,
Tsuneyo Mimori,
Junnosuke Ryu,
Kazuo Yonenobu,
Norikazu Murata,
Hiroaki Matsuno,
Hajime Ishikawa, Takahiro Ochi
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ABSTRACT: To examine the views of rheumatology physicians concerning clinical practice guidelines in Japan, and changes to them following the dissemination of new guidelines for rheumatoid arthritis (RA) in 2004.
Two cross-sectional questionnaire surveys, the first conducted before publication of new evidence-based RA clinical practice guidelines and the second conducted after implementation.
Rheumatology-focused practices in Japan.
A random sample of physicians registered with the Japan Rheumatism Foundation who satisfied the registration criteria with regard to experience with RA care.
The percentage of guideline users increased from 48 to 60% following publication of the new RA guidelines in 2004 (P < 0.01). The majority agreed that clinical practice guidelines support decision-making in practice, although the proportion of supportive responses decreased slightly in the second survey, from 83 to 77% (P < 0.01) for decision-making, while concern about restricting physician autonomy increased from 18 to 22% (P = 0.01). While only 39% of physicians felt that clinical practice guidelines would contribute to malpractice litigation, the proportion of physicians who were concerned that clinical practice guidelines would be used to bring legal action against providers was larger than that who expected they would defend providers (58 vs 30%, P < 0.001).
Clinical practice guidelines are well accepted among Japanese rheumatology physicians, albeit that the proportion decreased slightly after the introduction of new guidelines. One reason for this may be concern about the use of the guidelines in malpractice litigation. To facilitate implementation, trends in physician support for the guidelines should be closely monitored.
International Journal for Quality in Health Care 04/2010; 22(2):78-85. · 1.96 Impact Factor
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ABSTRACT: Osteopontin (OPN) is expressed by fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), but its pathologic role is still obscure. The present study was undertaken to analyze the role of OPN in RA by focusing on its effects on cell-cell interactions between FLS and B lymphocytes.
FLS obtained from 10 patients with RA and 10 non-RA subjects and a B lymphocyte cell line were studied. The characteristics of OPN expression by FLS were analyzed by Western blotting, immunoprecipitation, and immunofluorescence studies. In cocultures of FLS and B lymphocytes, the effects of OPN on adhesion of B lymphocytes to FLS and the consequent production of interleukin-6 (IL-6) were analyzed in experiments involving overexpression and knockdown of OPN and inhibitory studies with an OPN-blocking antibody. In vivo, the expression of OPN in RA synovium was examined by immunohistochemistry.
A specifically modified 75-kd form of OPN was predominantly expressed in RA FLS, and this was associated with expression of >200-kd thrombin-cleaved OPN that was crosslinked with fibronectin and localized on the surface of the FLS. In FLS-B lymphocyte cocultures, 75-kd OPN-positive FLS produced a significantly higher amount of IL-6 than did 75-kd OPN-negative FLS. When the FLS were separated from B lymphocytes or cultured alone, the production of IL-6 was low and was not significantly different between these 2 culture conditions. Moreover, OPN overexpression enhanced production of IL-6 in 75-kd OPN-positive FLS-B lymphocyte cocultures. Addition of the OPN-blocking antibody inhibited the adhesion of B lymphocytes to FLS. Immunohistochemical analyses revealed that localization of IL-6-positive cells coincided with the sites at which OPN and B lymphocytes were colocalized.
Specifically modified 75-kd OPN was expressed by RA FLS. This form of OPN affected FLS-B lymphocyte interactions by supporting the adhesion of B lymphocytes to FLS and enhancing the production of IL-6.
Arthritis & Rheumatism 11/2009; 60(12):3591-601. · 7.87 Impact Factor
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Kosuke Ebina,
Kazuya Oshima,
Morihiro Matsuda,
Atsunori Fukuhara,
Kazuhisa Maeda,
Shinji Kihara,
Jun Hashimoto, Takahiro Ochi,
Nirmal K Banda,
Hideki Yoshikawa,
Iichiro Shimomura
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ABSTRACT: Adiponectin (APN) is a hormone released by adipose tissue with anti-inflammatory properties. The purpose of this study was to examine the therapeutic effects of systemic delivery of APN in murine arthritis model. Collagen-induced arthritis (CIA) was induced in male DBA1/J mice, and adenoviral vectors encoding human APN (Ad-APN) or beta-galactosidase (Ad-beta-gal) as control were injected either before or during arthritis progression. Systemic APN delivery at both time points significantly decreased clinical disease activity scores of CIA. In addition, APN treatment before arthritis progression significantly decreased histological scores of inflammation and cartilage damage, bone erosion, and mRNA levels of pro-inflammatory cytokines in the joints, without altering serum anti-collagen antibodies levels. Immunohistochemical staining showed significant inhibition of complement C1q and C3 deposition in the joints of Ad-APN infected CIA mice. These results provide novel evidence that systemic APN delivery prevents inflammation and joint destruction in murine arthritis model.
Biochemical and Biophysical Research Communications 12/2008; 378(2):186-91. · 2.48 Impact Factor
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Satoru Ishida,
Shoji Yamane,
Saori Nakano,
Toru Yanagimoto,
Yukie Hanamoto,
Miki Maeda-Tanimura,
Tomoko Toyosaki-Maeda,
Jun Ishizaki,
Yoshiyuki Matsuo,
Naoshi Fukui,
Tsunetoshi Itoh, Takahiro Ochi,
Ryuji Suzuki
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ABSTRACT: Formation of osteoclasts and consequent joint destruction are hallmarks of rheumatoid arthritis (RA). Here we show that LIGHT, a member of the tumour necrosis factor (TNF) superfamily, induced the differentiation into tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) of CD14(+) monocytes cocultured with nurse-like cells isolated from RA synovium, but not of freshly isolated CD14(+) monocytes. Receptor activator of nuclear factor-kappaB ligand (RANKL) enhanced this LIGHT-induced generation of TRAP-positive MNCs. The MNCs showed the phenotypical and functional characteristics of osteoclasts; they showed the expression of osteoclast markers such as cathepsin K, actin-ring formation, and the ability to resorb bone. Moreover, the MNCs expressed both matrix metalloproteinase 9 (MMP-9) and MMP-12, but the latter was not expressed in osteoclasts induced from CD14(+) monocytes by RANKL. Immunohistochemical analysis showed that the MMP-12-producing MNCs were present in the erosive areas of joints in RA, but not in the affected joints of osteoarthritic patients. These findings suggested that LIGHT might be involved in the progression of inflammatory bone destruction in RA, and that osteoclast progenitors might become competent for LIGHT-mediated osteoclastogenesis via interactions with synoviocyte-like nurse-like cells.
Immunology 12/2008; 128(1 Suppl):e315-24. · 3.32 Impact Factor
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Kosuke Ebina,
Atsunori Fukuhara,
Wataru Ando,
Makoto Hirao,
Tadashi Koga,
Kazuya Oshima,
Morihiro Matsuda,
Kazuhisa Maeda,
Tadashi Nakamura, Takahiro Ochi,
Iichiro Shimomura,
Hideki Yoshikawa,
Jun Hashimoto
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ABSTRACT: Adiponectin is a hormone released by adipose tissue with antidiabetic, antiatherogenic, and anti-inflammatory properties. The present observational study focused on the relation between serum adiponectin level and the disease severity of established rheumatoid arthritis (RA). Ninety patients with more than 5-year diagnosis of RA and 42 age- and BMI-matched control were enrolled. The severity of RA was evaluated according to the number of destructed joints of overall 68 joints on plain radiographs (37 patients had mild RA and 53 had severe RA). Serum adiponectin level was significantly higher in the severe RA group (17.7+/-6.7 microg/ml) than in the control (9.1+/-3.8 microg/ml) and mild RA groups (13.9+/-6.5 microg/ml) (control vs. mild RA group, P<0.001; mild RA vs. severe RA group, P<0.01). These results suggest that increased number of joint destruction is associated with hyperadiponectinemia in established RA patients.
Clinical Rheumatology 12/2008; 28(4):445-51. · 2.00 Impact Factor
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Konagi Tanaka,
Tatsuya Horikawa,
Satsuki Suzuki,
Kazutaka Kitaura,
Junko Watanabe,
Akito Gotoh,
Noriyuki Shiobara,
Tsunetoshi Itoh,
Shoji Yamane,
Ryuji Suzuki,
Naoshi Fukui, Takahiro Ochi
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ABSTRACT: To investigate whether the blockade of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) has any therapeutic effects on rheumatoid arthritis.
A functional blocking monoclonal antibody for SHPS-1 (anti-SHPS-1 mAb) was administered at various doses to collagen-induced arthritis (CIA) mice, and severity of the arthritis was evaluated by clinical and histological scores of the limbs. To clarify the mechanisms of action of the antibody, the serum concentration of anti-type II collagen antibody was measured in those mice, and in vitro experiments were conducted to determine the effects of the antibody on the induction of osteoclasts and the release of cytokines from mouse spleen cells.
Compared with mice given control IgG, the administration of anti-SHPS-1 mAb significantly reduced the severity of inflammation and destruction of bone and cartilage in CIA mice. This therapeutic effect was observed even when the antibody treatment was started after the onset of arthritis. The appearance of anti-type II collagen antibody in CIA mice was not altered by the antibody treatment. In in vitro experiments, the anti-SHPS-1 mAb significantly inhibited osteoclastogenesis of bone marrow cells, and significantly reduced the release of interleukin 1beta (IL-1beta), IL-2, IL-12, interferon-gamma, and tumor necrosis factor-alpha, but not that of IL-4 or IL-10, from the spleen cells after stimulation with concanavalin A.
Administration of a monoclonal antibody for SHPS-1 reduced the severity of arthritis in CIA mice. Regulation of biological functions of SHPS-1 may be a novel and potent strategy to treat patients with rheumatoid arthritis.
The Journal of Rheumatology 12/2008; 35(12):2316-24. · 3.69 Impact Factor
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ABSTRACT: To investigate the effects of LIGHT (lymphotoxin-like, exhibits inducible expression and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes) on the proliferation and gene expression of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).
We measured LIGHT levels in RA synovial fluids (SF) by ELISA, and compared them with those in osteoarthritis (OA) SF. Levels of LIGHT and its receptors in RA-FLS and synovium were assessed using real-time quantitative polymerase chain reaction (PCR). RA-FLS proliferation was examined by a bromodeoxyuridine assay. Expression of intercellular adhesion molecule-1 (ICAM-1) and several chemokines, such as interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1alpha (MIP-1alpha), was examined by real-time quantitative PCR, ELISA, and flow cytometry. The effects of LIGHT on nuclear factor-kappaB (NF-kappaB) activation were investigated using immunofluorescence and Western blotting.
LIGHT was upregulated in both SF and synovium of RA patients compared with OA patients. Herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTbetaR), but not LIGHT, were detected in RA-FLS. LIGHT significantly promoted RA-FLS proliferation and induced expression of MCP-1, IL-8, MIP-1alpha, and ICAM-1 by RA-FLS. As well, LTbetaR small interfering RNA (siRNA), but not HVEM siRNA, inhibited these effects of LIGHT. LIGHT induced IkappaBa degradation and NF-kappaB translocation, and a NF-kappaB inhibitor suppressed the effects of LIGHT on RA-FLS.
Our findings suggest that LIGHT signaling via LTbetaR plays an important role in the pathogenesis of RA by affecting key processes such as the proliferation and activation of RA-FLS. Regulation of LIGHT-LTbetaR signaling may represent a new therapeutic target for RA treatment.
The Journal of Rheumatology 07/2008; 35(6):960-8. · 3.69 Impact Factor
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ABSTRACT: In total hip arthroplasty (THA), the patient-specific bone geometry or the characteristics of the skeletal movement should be considered during treatment in order to prevent complications. In this paper, we propose a novel approach for the analysis of joints which combines the patient-specific virtual and physical simulation. The patient-specific anatomical structure and hip motion was obtained from CT and optical motion capture. The virtual simulation was conducted by integrating these data using virtual reality technique. The physical simulation was achieved by using plaster models of the patient's pelvis and femur and robotic manipulator. The plaster models were driven by two robotic manipulators to reproduce the hip motion. The accuracy of the robot movement was 0.245 mm over the working area according to the validation by an optical tracking system. By combining this system with linear actuators that reproduce the muscle functions, patient-specific muscle function can be simulated, thereby helping clinicians to diagnose and make a treatment plan.
Studies in health technology and informatics 02/2008; 132:339-44.
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Akihide Nampei,
Jun Hashimoto,
Junichiro Koyanagi,
Takeshi Ono,
Hideo Hashimoto,
Noriyuki Tsumaki,
Tetsuya Tomita,
Kazuomi Sugamoto,
Norihiro Nishimoto, Takahiro Ochi,
Hideki Yoshikawa
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ABSTRACT: To examine the clinical features of vertebral and non-vertebral fractures in patients with rheumatoid arthritis (RA), including insufficiency fractures, and to assess the risk factors for fracture, we prospectively studied 209 outpatients with rheumatoid arthritis for 1 year. The age, gender, Steinbrocker's functional class, glucocorticoid use, history of lower limb surgery, serum C-reactive protein (CRP), and use of bisphosphonates were evaluated. Examination for fractures was performed by radiography, computed tomography (CT), magnetic resonance imaging (MRI), and bone scanning. Thirty-three fractures occurred in 24 patients over the 1-year study period, and the incidence was 15.8 fractures per 100 patient-years. Fractures occurred at various sites. The majority (70%) was insufficiency fracture, and more than 50% caused ambulatory dysfunction. Radiographic findings were absent in 39% of the fractures at the onset of pain. The functional class and glucocorticoid dose were significantly associated with fracture development. This prospective study showed that the incidence of fractures, especially insufficiency fractures, was very high in patients with rheumatoid arthritis and that most of their fractures caused gait disturbance. Early intervention to prevent secondary osteoporosis is recommended to maintain the quality of life in patients with rheumatoid arthritis, especially those with functional impairment or undergoing glucocorticoid therapy.
Modern Rheumatology 02/2008; 18(2):170-6. · 1.58 Impact Factor
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Naoshi Fukui,
Yasuko Ikeda,
Toshiyuki Ohnuki,
Nobuho Tanaka,
Atsuhiko Hikita,
Hiroyuki Mitomi,
Toshihito Mori,
Takuo Juji,
Yozo Katsuragawa,
Seizo Yamamoto,
Motoji Sawabe,
Shoji Yamane,
Ryuji Suzuki,
Linda J Sandell, Takahiro Ochi
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ABSTRACT: To determine the change in metabolic activity of chondrocytes in osteoarthritic (OA) cartilage, considering regional difference and degree of cartilage degeneration.
OA cartilage was obtained from knee joints with end-stage OA, at both macroscopically intact areas and areas with various degrees of cartilage degeneration. Control cartilage was obtained from age-matched donors. Using laser capture microdissection, cartilage samples were separated into superficial, middle, and deep zones, and gene expression was compared quantitatively in the respective zones between OA and control cartilage.
In OA cartilage, gene expression changed markedly with the site. The expression of cartilage matrix genes was highly enhanced in macroscopically intact areas, but the enhancement was less obvious in the degenerated areas, especially in the upper regions. In contrast, in those regions, the expression of type III collagen and fibronectin was most enhanced, suggesting that chondrocytes underwent a phenotypic change there. Within OA cartilage, the expression of cartilage matrix genes was significantly correlated with SOX9 expression, but not with SOX5 or SOX6 expression. In OA cartilage, the strongest correlation was observed between the expression of type III collagen and fibronectin, suggesting the presence of a certain link(s) between their expression.
The results of this study revealed a comprehensive view of the metabolic change of the chondrocytes in OA cartilage. The change of gene expression profile was most obvious in the upper region of the degenerated cartilage. The altered gene expression at that region may be responsible for the loss of cartilage matrix associated with OA.
Arthritis & Rheumatism 02/2008; 58(1):154-63. · 7.87 Impact Factor
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Shoji Yamane,
Satoru Ishida,
Yukie Hanamoto,
Ken-Ichi Kumagai,
Riako Masuda,
Konagi Tanaka,
Noriyuki Shiobara,
Noriko Yamane,
Toshihito Mori,
Takuo Juji,
Naoshi Fukui,
Tsunetoshi Itoh, Takahiro Ochi,
Ryuji Suzuki
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ABSTRACT: The epidermal growth factor (EGF) and EGF receptor (EGFR) families play important roles in the hyperplastic growth of several tissues as well as tumor growth. Since synovial hyperplasia in rheumatoid arthritis (RA) resembles a tumor, involvement of the EGF/EGFR families in RA pathology has been implied. Although several reports have suggested that ErbB2 is the most important member of the EGFR family for the synovitis in RA, it remains unclear which members of the EGF family are involved. To clarify the EGF-like growth factors involved in the pathology of RA, we investigated the expression levels of seven major EGF-like growth factors in RA patients compared with those in osteoarthritis (OA) patients and healthy control subjects.
The expression levels of seven EGF-like growth factors and four EGFR-like receptors were measured in mononuclear cells isolated from bone marrow and venous blood, as well as in synovial tissues, using quantitative RT-PCR. Further evidence of gene expression was obtained by ELISAs. The proinflammatory roles were assessed by the growth-promoting and cytokine-inducing effects of the corresponding recombinant proteins on cultured fibroblast-like synoviocytes (FLS).
Among the seven EGF-like ligands examined, only amphiregulin (AREG) was expressed at higher levels in all three RA tissues tested compared with the levels in OA tissues. The AREG protein concentration in RA synovial fluid was also higher than that in OA synovial fluid. Furthermore, recombinant human AREG stimulated FLS to proliferate and produce several proinflammatory cytokines, including angiogenic cytokines such as interleukin-8 and vascular endothelial growth factor (VEGF), in a dose-dependent manner. The VEGF mRNA levels in RA synovia and VEGF protein concentrations in RA synovial fluid were significantly higher than those in the corresponding OA samples and highly correlated with the levels of AREG.
The present findings suggest that AREG functions to stimulate synovial cells and that elevated levels of AREG may be involved in the pathogenesis of RA.
Journal of Inflammation 02/2008; 5:5. · 2.26 Impact Factor
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Yoshikazu Nakajima,
Takahito Tashiro,
Nobuhiko Sugano,
Kazuo Yonenobu,
Tsuyoshi Koyama,
Yuki Maeda,
Yuichi Tamura,
Masanobu Saito,
Shin'ichi Tamura,
Mamoru Mitsuishi,
Naohiko Sugita,
Ichiro Sakuma, Takahiro Ochi,
Yoichiro Matsumoto
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ABSTRACT: A new method for fluoroscopic tracking of a proximal bone fragment in femoral fracture reduction is presented. The proposed method combines 2-D and 3-D image registration from single-view fluoroscopy with tracking of the head center position of the proximal femoral fragment to improve the accuracy of fluoroscopic registration without the need for repeated manual adjustment of the C-arm as required in stereo-view registrations. Kinematic knowledge of the hip joint, which has a positional correspondence with the femoral head center and the pelvis acetabular center, allows the position of the femoral fragment to be determined from pelvis tracking. The stability of the proposed method with respect to fluoroscopic image noise and the desired continuity of the fracture reduction operation is demonstrated, and the accuracy of tracking is shown to be superior to that achievable by single-view image registration, particularly in depth translation.
IEEE Transactions on Biomedical Engineering 10/2007; 54(9):1703-6. · 2.28 Impact Factor
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ABSTRACT: The effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on juxta-articular osteopenia and growth plate destruction adjacent to inflamed joints was investigated in rats with collagen-induced arthritis. Forty rats were assigned to the following six groups: (1) an untreated arthritis group; (2-5) arthritis rats receiving indomethacin (3 mg/kg per day), dexamethasone (0.2 mg/kg per day), or celecoxib (5 or 50 mg/kg per day), and (6) normal control rats. Drugs were administered for 2 weeks from the onset of arthritis. Then the hind paws were measured. Juxta-articular osteopenia and growth plate destruction adjacent to inflamed joints were also assessed using plain radiography, bone mineral density measurement, histology, and histomorphometry. Each treatment reduced inflammation, but only dexamethasone and high-dose celecoxib prevented bone loss adjacent to inflamed joints and significantly decreased bone resorption. In contrast, no treatment affected bone formation parameters. Growth plate destruction adjacent to inflamed joints was prevented by indomethacin, dexamethasone, and high-dose celecoxib. Although dexamethasone abolished inflammation, growth plate destruction was still observed. In conclusion, among the various drugs tested, only celecoxib had a preventive effect on both growth plate destruction and bone loss adjacent to inflamed joints in this arthritis model.
Modern Rheumatology 02/2007; 17(2):115-22. · 1.58 Impact Factor
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ABSTRACT: A system for evaluating the soft-tissue-generated forces at the hip joint was developed. The system enabled measurement of contact pressure distribution at hip joint surfaces, as well as evaluation of the artificial hip joint condition during total hip arthroplasty (THA). First, a pressure sensor module that forms part of the artificial joint was constructed. Eight small pressure sensors were installed in the spherical head component of the ball-and-socket joint. Next, software for recording and visualizing the detected pressures at 1-millisecond intervals was developed. The pressure distribution was displayed in real time via 3D computer graphics on a monitor. The system enabled intuitive recognition of the direction of soft-tissue-generated forces and pressure distribution in three dimensions. Accuracy tests were conducted using a high-accuracy 6-degree-of-freedom positioning device and digital force gauge. The error between the applied loads and measured forces was 3.42 +/- 3.26 N (mean +/- standard deviation) for each coordinate in 10 trials involving load application from 10 different directions. Next, a clinical evaluation was conducted during THA. The relative positions of the cup and stem component were measured using a surgical navigation system simultaneously with the pressure measurement. The system allowed real-time acquisition of information regarding the artificial hip joint, as well as comparison of the differences in the hip condition when several types of neck were used. Further improvements to the calibration method should enable more accurate measurements. We believe this system will be a useful tool for selecting an appropriate implant that fits a patient's hip joint or for estimating the risk of complications following surgery.
Computer Aided Surgery 02/2007; 12(1):53-9. · 0.30 Impact Factor
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ABSTRACT: A major question concerning the immunopathology of rheumatoid arthritis is why the disease is localized to particular joints. A possible explanation could be the presence within the synovium of cells that foster inflammation or easy accessibility of the synovium to migratory disease enhancing cells. Within both the bone marrow and the synovium, fibroblastic stromal cells play an important role in supporting the differentiation and survival of normal cells, and also contribute to the pathologic processes. Among fibroblastic stromal cells in synovial tissue and bone marrow, nurse-like cells are a unique population having the specific capacity to promote pseudoemperipolesis (adhesion and holding beneath) of lymphocytes, and also the ability to promote the growth and function of some populations of lymphocytes and monocytes. Nurse-like cells could therefore contribute to the immunopathogenesis of rheumatoid arthritis, and may contribute to the localization of inflammation within specific joints. The present review considers the evidence that supports these possibilities.
Arthritis research & therapy 02/2007; 9(1):201. · 4.27 Impact Factor
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Systems and Computers in Japan. 01/2007; 38:32-45.
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ABSTRACT: A method for automated determination of the distribution of hip joint cartilage thickness from in vivo magnetic resonance (MR) images is described. Three-dimensional (3-D) filtering techniques are combined with the shape constraint
of the ball and socket constitution of the hip joint to accurately detect and quantitate thin structures of cartilages. The
method consists of three steps: 3-D cartilage enhancement filtering, detection, and quantification. First, the cartilage and
articular space regions in MR images are effectively enhanced by 3-D radial directional second-derivative filtering based
on the sphere approximation of the hip joint. Next, the initial regions of the cartilages and articular space are detected
from the filtered images using thresholding and connectivity analysis. The boundaries of these regions provide the initial
descriptions for the subsequent refinement processes. Finally, the boundaries of cartilage regions are accurately localized
and quantitated three-dimensionally through subpixel edge searching. The effect of partial voluming on the accuracy of the
estimated thickness is evaluated by means of software simulation studies, and the usefulness of the method is demonstrated
through experiments using in vivo MR images of a normal volunteer and actual patients.
10/2006: pages 338-347;
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ABSTRACT: In articular chondrocytes, the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) induces the expression of bone morphogenetic protein-2 (BMP-2), a growth factor known to be involved in the induction of cartilage and bone. A study was performed to clarify the mechanism(s) underlying the induction of BMP-2 in chondrogenic ATDC5 cells and primary cultured adult human articular chondrocytes. In ATDC5 cells, the endogenous BMP-2 expression was consistently low throughout the process of chondrogenic differentiation, and TNF-alpha induced BMP-2 expression only after the cells acquired the chondrogenic phenotype. The results of nuclear run-off assay and cycloheximide treatment consistently indicated that ATDC5 cells acquire the capacity to synthesize BMP-2 mRNA in the nuclei during the differentiation process. In an attempt to explain the discrepancy between the active nuclear mRNA synthesis and the observed low expression level in differentiated ATDC5 cells, the stability of BMP-2 mRNA was evaluated, and the cells were found to regulate the expression of BMP-2 at the post-transcriptional level. Human chondrocytes were confirmed to have a similar post-transcriptional regulation. The result of 3'-rapid amplification of cDNA end revealed that both human and mouse BMP-2 mRNAs contain multiple pentameric AUUUA motifs in a conserved manner in the 3'-untranslated regions, and transient transfection experiments demonstrated that TNF-alpha increases the stability of BMP-2 mRNA through the pentameric motifs. Further experiments revealed that TNF-alpha modulates mRNA stability via p38 signal transduction pathway, whereas the cytokine also augmented the expression of BMP-2 through transcriptional up-regulation via the transcriptional factor NF-kappaB.
Journal of Biological Chemistry 10/2006; 281(37):27229-41. · 4.77 Impact Factor
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Nobuo Nakamura,
Yasunori Shimaoka,
Takahiro Tougan,
Hiroaki Onda,
Daisuke Okuzaki,
Hanjun Zhao,
Azumi Fujimori,
Norikazu Yabuta,
Ippei Nagamori,
Akie Tanigawa,
Jun Sato,
Takenori Oda,
Kenji Hayashida,
Ryuji Suzuki,
Masao Yukioka,
Hiroshi Nojima, Takahiro Ochi
[show abstract]
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ABSTRACT: We have comprehensively identified the genes whose expressions are augmented in bone marrow-derived mononuclear cells (BMMC) from patients with Rheumatoid Arthritis (RA) as compared with BMMCs from Osteoarthritis (OA) patients, and named them AURA after augmented in RA. Both stepwise subtractive hybridization and microarray analyses were used to identify AURA genes, which were confirmed by northern blot analysis and/or reverse transcription polymerase chain reaction (RT-PCR). We also assessed their expression levels in individual patients by quantitative real-time RT-PCR. Of 103 AURA genes we have identified, the mRNA levels of the following 10 genes, which are somehow related to immune responses, were increased in many of the RA patients: AREG (=AURA9), FK506-binding protein 5 (FKBP5 = AURA45), C-type lectin superfamily member 9 (CLECSF9 = AURA24), tyrosylprotein sulfotransferase 1 (TPST1 = AURA52), lymphocyte G0/G1 switch gene (G0S2 = AURA8), chemokine receptor 4 (CXCR4 = AURA86), nuclear factor-kappa B (NF-kappaB = AURA25) and two genes of unknown function (FLJ11106 = AURA1, BC022398 = AURA2 and XM_058513 = AURA17). Since AREG was most significantly increased in many of the RA patients, we subjected it to further analysis and found that AREG-epidermal growth factor receptor signaling is highly activated in synovial cells isolated from RA patients, but not in OA synoviocytes. We propose that the expression profiling of these AURA genes may improve our understanding of the pathogenesis of RA.
DNA Research 09/2006; 13(4):169-83. · 5.16 Impact Factor
