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Objective To establish a method to culture synovial tissue explants from patients with rheumatoid arthritis (RA). Methods Synovial tissue explants obtained from 10 patients with RA were cultured at the air–liquid interface or were submerged in culture medium. As a control, synovial explants were engrafted subcutaneously into SCID mice. The synovial explants were harvested at different time points, and histologic or flow cytometric analysis was performed. Cytokine levels in the culture supernatants were measured by enzyme-linked immunosorbent assay. Infliximab was added to the air–liquid interface culture to evaluate the effect of tumor necrosis factor α blockade on inflammatory cytokine production. Results The histologic features of RA synovitis, including a hyperplastic lining layer and the presence of cellular infiltrate in the sublining layer, were maintained in synovial tissue explants in air–liquid interface culture. In synovial grafts harvested from SCID-HuRAg mice, the cellular infiltrate was well maintained in the sublining, but the lining layer was lost. Viable CD4+ T cells and macrophages were abundant after air–liquid interface culture but were virtually absent after submerged culture. Furthermore, synovial tissue explants in air–liquid interface culture produced interleukin-6 (IL-6) and IL-8 for a prolonged period of time. The addition of infliximab effectively reduced cytokine production. Conclusion RA synovial explants can be maintained for weeks using an air–liquid interface culture. This simple culture system might be useful for analyzing the pathogenesis of RA synovitis and for developing antirheumatic drugs.

To retrospectively evaluate the long-term results of cementless total hip arthroplasty (THA) in patients with rheumatoid arthritis (RA) and postoperative patient mortality after THA.This study included 191 hips in 149 RA patients who underwent cementless THA between 1998 and 2005. Mean age at surgery was 54.2 years, and mean follow-up was 12.6 years. Implant and patient survivorships were determined using the Kaplan-Meier method, and the associated influencing factors were determined.Implant survivals at 17 years were 99.5% for stems, 93.9% for cups, and 90.8% for liners. Among the liners used, THAs with highly cross-linked polyethylene showed better survivals compared with those with conventional polyethylene and alumina-bearing surface (93.4%, 90.9%, and 52.2%, respectively). A total of 64 deaths occurred; 45 patients died within 10 years and 19 patients died between 10 and 17 years. Malignancy (25.0%) was the leading cause of death, followed by pneumonia (20.8%) and sepsis (20.8%). The patient survival rate was 36.9% at 17 years after THA. Multivariate analysis exhibited that older age at operation and greater dose of concomitant corticosteroid resulted in shorter patient survivals.Cementless THA worked well in patients with RA. Mortality remained high among RA patients who needed THA.

Background Despite recent advancements in rheumatoid arthritis (RA) pharmacotherapy, surgeons still encounter severely damaged knees. The purpose of the present study was to analyze the mid-term clinical results of total knee arthroplasty (TKA) with metal block augmentation and stem extension. Methods A total of 26 knees in 21 patients who underwent primary TKA with metal block augmentation and stem extension were retrospectively reviewed. All patients with a mean age of 63 years had RA for a mean duration of 15 years. Functional and radiographic results as well as complications were evaluated at the mean follow-up period of 6 years after TKA. Eight knees were lost follow-up after the two-year evaluation. Results Tibial bone defects with average depth of 19 mm were preoperatively recognized in all 26 knees. The postoperative joint line was reconstructed on average 11 mm above the fibular head using average thickness of 11 mm tibial inserts and 9 mm metal blocks with stem extension. Significant improvements (p

The role of secondary amyloidosis in determining the prognosis of dialyzed patients with rheumatoid arthritis (RA) was examined in 22 patients with a mean age of 60.1 years included 21 renal amyloidosis. RA duration until the start of dialysis was 19.5 +/- 7.2 years and the observation period after introduction 27.1 +/- 26.4 months. Of the 14 dead cases, four died due to sepsis, three due to gastrointestinal tract bleeding, two due to congestive heart failure, and eight cases died within 5 months after starting dialysis. When comparing the eight survivors and the nine non-survivors who died within 2 years after the start of dialysis, the former patients showed significantly higher serum albumin, and lower electrocardiogram score and cardiothoracic ratios at the time of introduction to dialysis. The careful prevention and treatment of infection, cerebrovascular and/or gastrointestinal tract complications seem to be necessary to improve the prognosis of RA patients after the initiation of renal replacement therapy.

Fifty-seven primary cementless total hip arthroplasties (THAs) were performed in 48 patients with rheumatoid arthritis. The average length of follow-up was 2.4 years (range; 1.1 to 4.4 years).The average age of these 48 patients at the time of surgery was 56.9 years (range; 36 to 78 years). In all patients Kyocera Per Fix HA prosthesis was used.Clinical evaluation based on the JOA score indicated significant improvement from 36.8 points preoperatively to 67.4 points postoperatively. Three patients (5%) complained of thigh pain. There was no evidence of roentgenographic failure such as femoral component subsidence, loosening or osteolysis. Spot welds contacting the porous surfaces were observed in 52 hips (91%). None of the hips showed radiolucent lines adjacent to the porous-surfaced portion of the stems. All femoral components showed bone ingrown fixation. These findings suggest that cementless stem may be successful in rheumatoid patients.

Granulocyte macrophage colony-stimulating factor (GM-CSF), an immunomodulatory cytokine, is an emerging therapeutic target of rheumatoid arthritis (RA).1 Although GM-CSF is produced by various types of cells, including synovial fibroblasts, the importance of GM-CSF-producing CD4 T cells in the pathogenesis of RA was reported.2 Moreover, GM-CSF has been shown to be the critical effector cytokine produced by interleukin (IL)-23-stimulated Th17 cells in mice, leading to the prevailing notion that GM-CSF is a Th17-related cytokine.3 However, in humans, a distinct subset of CD4 T cells that produce only GM-CSF has recently been identified.4 The ‘GM-CSF-only’ T cells are characterised by the lack of lineage defining cytokines (interferon (IFN)-γ, IL-17 and IL-4) and are regulated independently of the master transcriptional regulators, T-bet, RORγt or GATA3. Furthermore, in contrast to mice, GM-CSF production by human CD4 T cells was promoted in Th1 conditions and was also detected in Th1 cells. At present, it is unclear which helper CD4 T cell subsets produce GM-CSF in human RA joints. Therefore, in this study, we performed multicolour flow cytometric analysis of cytokine production in CD4 T cells from patients with RA. Lymphocytes in the peripheral blood (PB) and in joints from the same patients were analysed to compare the profiles of cytokine production. Synovial fluid (SF) samples were obtained from seven patients by arthrocentesis, while synovial membrane (SM) samples were obtained from seven other patients who underwent joint replacement surgery. The mean age and disease duration of the patients was 63.5±15.5 and 16.5±10.1 years, respectively. Twelve patients (86%) were positive for RF and/or anti-CCP2 antibody, and the mean C reactive protein level was 1.2±1.1 mg/dL. In total, 11 (79%), 10 (71%) and 4 (29%) patients received …

To establish a method to culture synovial tissue explants from patients with rheumatoid arthritis (RA).Synovial tissue explants obtained from 10 patients with RA were cultured at the air-liquid interface or were submerged in culture medium. As a control, synovial explants were engrafted subcutaneously into SCID mice. The synovial explants were harvested at different time points, and histologic or flow cytometric analysis was performed. Cytokine levels in the culture supernatants were measured by enzyme-linked immunosorbent assay. Infliximab was added to the air-liquid interface culture to evaluate the effect of tumor necrosis factor α blockade on inflammatory cytokine production.The histologic features of RA synovitis, including a hyperplastic lining layer and the presence of cellular infiltrate in the sublining layer, were maintained in synovial tissue explants in air-liquid interface culture. In synovial grafts harvested from SCID-HuRAg mice, the cellular infiltrate was well maintained in the sublining, but the lining layer was lost. Viable CD4+ T cells and macrophages were abundant after air-liquid interface culture but were virtually absent after submerged culture. Furthermore, synovial tissue explants in air-liquid interface culture produced interleukin-6 (IL-6) and IL-8 for a prolonged period of time. The addition of infliximab effectively reduced cytokine production.RA synovial explants can be maintained for weeks using an air-liquid interface culture. This simple culture system might be useful for analyzing the pathogenesis of RA synovitis and for developing antirheumatic drugs.

We report a case of Ewing's sarcoma treated by free auto-fibular grafts. A 13-year-old girl experienced pain in her left leg. A plain radiograph showed thickened cortex over almost the entire tibia. The light microscopic features of a biopsy sample were those of a small round cell tumor. The patient received combined intensive multidrug chemotherapy before surgery. Local wide resection with reconstruction using a free auto-fibular bone graft and a intramedullary nail was performed. Plain radio-graph made one month after grafting showed fusion of the fibula. The patient was able to walk without any support in daily life 12 months after surgery.

Although associations between the expression of particular HLA genes and the susceptibility to specific autoimmune diseases has been known for some time, the role that these HLA molecules play in the autoimmune response is unclear. Through the establishment of a chimeric HLA-DR/I-E transgene, we have examined the function of the rheumatoid arthritis (RA) susceptibility allele HLA-DR4 (DRB1*0401) in presenting antigenic peptides derived from the model Ag, type II collagen (CII), and in mediating an autoimmune response. As a transgene, the chimeric DR4 molecule conferred susceptibility to an autoimmune arthritis induced by immunization with human CII or bovine CII. These mice developed an inflammatory, autoimmune arthritis that was similar both histologically and in severity to that previously described for the collagen-induced arthritis model. The DR4-mediated autoimmune arthritis was accompanied by T cell and B cell responses to both the immunogen and the autoantigen, murine CII. The DR4-restricted T cell response to human CII was focused on an immunodominant determinant within CII263–270 and a minor determinant within CII286–300, the same CII determinants recently identified for yet another RA susceptibility allele, HLA-DR1 (DRB1*0101). Thus these data demonstrate that, like HLA-DR1, HLA-DR4 is capable of binding peptides derived from human CII and therefore probably plays a role in the autoimmune response to human CII observed in RA patients.

Panspinal canal stenosis is a well known complication of Achondroplasia. It can be difficult to decide which level is primarily responsible for this stenosis and the most suitable treatment. A 19-year-old woman who suffered from Achondroplasia with ossification of the yellow ligament is described. We performed laminectomy (Th8-L2) and PLF (L1-3) with instrumentation (Th12-L3). We found that 8 of 34. Achondropl astic patients had suffered from ossification of their yellow ligaments. We consider that there could be a relationship between Achondroplasia and ossification of the yellow ligament with reference to its static and dynamic factors in Achondro-plastic spinal stucture.

We reviewed 28 cases with serious blood dyscrasias who underwent orthopaedic surgery, and studied their perioperative management. 10 of the 28 cases were suffering from fractures. 5, 4, 3, and, 3 cases were suffering form tumors, lumber degenerative disorders, infection, and osteonecrosis of the femoral head, respectively. Acute leukemia was the major combined blood disease, which occurred in 9 cases. Idiopathic thrombocytopenic purpura (ITP) was found in 5 cases. We preoperatively gave platelet transfusions to the patients, if laboratory data showed their platelet counts were under 5×104/mm3. High-dose gammaglobulin therapy was an effective treatment for ITP. We managed to achieve platelet counts of over 5×104/mm3 in all patients. Leukocyte poor red cells were used for blood transfusion, if necessary, to avoid graft versus host disease. In all cases, the perioperative course was uneventful.

We report on 10 cases with lateral lumber disc herniation who were surgically treated. Of these, 9 were male and 1 female ranging in age from 19-73 years (mean; 48.7 years). The level of herniation was L3/4 in 2, L4/5 in 5, L5/S1 in 3 cases. All patients complained of severe pain in lower extremities. Axial, sagittal, coronal views of MRI and selective root block were useful for accurate diagnosis of lateral herniation.Facetectomy with posterolateral fusion in 7 cases, osteoplastic hemilaminectomy in 2 cases, and lateral fenestration in 1 case were performed.Excellent and good results were achieved in all cases.

Secondary hyperparathyroidism is a well-known complication of renal failure. A rare manifestation of secondary hyperparathyrodism is the “Brown tumor” of bone. A 44-year-old woman who suffered from a pathological fracture due to Brown tumor is described. We perform osteosynthesis soon after injury allowing the patent to move by herself and significantly improving her quality of life. We consider that it is necessary to prepare bone cement, bank bone to support the weakness of bone structure.

Studies in vitro have suggested that a species barrier exists in functional interaction between human histocompatibility leukocyte antigen (HLA) class II and mouse CD4 molecules. However, whether mouse CD4+ T cells restricted by HLA class II molecules are generated in HLA class II transgenic mice and respond to peptide antigens across this barrier has remained unclear. In an analysis of T cell responses to synthetic peptides in mice transgenic for HLA-DR51 and -DQ6, we found that DR51 and DQ6 transgenic mice acquired significant T cell response to influenza hemagglutinin-derived peptide 307-319 (HA 307) and Streptococcus pyogenes M12 protein-derived peptide 347-397 (M6C2), respectively. Inhibition studies with several monoclonal antibodies showed that transgenic HLA class II molecules presented these peptides to mouse CD4+ T cells. Furthermore, T cell lines specific for HA 307 or M6C2 obtained from the transgenic mice could respond to the peptide in the context of relevant HLA class II molecules expressed on mouse L cell transfectants that lack the expression of mouse MHC class II. These findings indicate that interaction between HLA class II and mouse CD4 molecules is sufficient for provoking peptide-specific HLA class II-restricted T cell responses in HLA class II transgenic mice.

Antigenicity of peptic extract from type 12 group A streptococci (PEAST12) for T cells was examined in major histocompatibility complex (MHC) class II transgenic mice. PEAST12 was mitogenic for murine T cells when antigen-presenting cells were obtained from human MHC (HLA)-DQ4 alpha beta transgenic mice or from DQ6 alpha beta transgenic mice but was not mitogenic in DR alpha transgenic, DR51 alpha beta transgenic, E alpha transgenic, or nontransgenic mice. In addition, PEAST12 showed mitogenicity for murine T cells in DQ4 alpha singly transgenic mice but not in DQ4 beta singly transgenic mice. T-cell stimulation by PEAST12 was unrestricted by but dependent on the expression of HLA-DQ molecules on antigen-presenting cells, and PEAST12 selectively activated T-cell receptor V beta 11-, V beta 15-, and V beta 18-positive T cells in mice. We propose that PEAST12 contains a superantigen which binds preferentially to the alpha-chain of HLA-DQ molecules. The well-known phenomenon that peptic extracts from group A streptococci are mitogenic in humans but not in mice is likely due to structural differences in MHC class II molecules between these two species of mammals.

To clarify the histological and biological features of tenosynovitis accompanying rheumatoid arthritis (RA).Synovial tissue was obtained from the wrist joint and extensor tendon of the digits of six RA patients and the sections were examined by haematoxylin and eosin staining and immunohistochemical analysis. RA tenosynovitis exhibited the typical histological features of RA joint synovitis, including hyperplasia of the synovial lining and infiltration of leucocytes, largely CD4+ T cells and CD68+ macrophages. Notably, there was a significant correlation in the number of CD4+ T cells and CD68+ macrophages between the tenosynovium and joint synovium in each individual. Real-time reverse transcriptase-polymerase chain reaction analysis revealed similar mRNA expression patterns of various inflammatory mediators in tenosynovitis and joint synovitis. It was also observed that synovial fibroblasts isolated from the tenosynovium behaved in a manner similar to those isolated from the joint synovium with regard to proliferation and the production of inflammatory mediators.The histopathological features of RA tenosynovitis were indistinguishable from those of joint synovitis. Therefore, it is suggested that the ongoing inflammation is driven by similar mechanisms in the tenosynovium and joint synovium and that RA is probably a tissue-specific disease which targets systemic synovial tissues.

A rare case of renal tubular acidosis associated with hypoparathyroidism is reported. A 38-year-old man came to our department suffering from pain in his left thigh. Upon X-ray examination, subtrochanteric fracture of the left femur, osteosclerosis of spine and tubular bone, and basal ganglia calcification were seen. Upon biochemical examination, hypokalemia, hypocalcemia, hyperchloremia and metabolic acidosis were found. From the finding of NH4Cl loading test and biocarbonate loading test, this case was diagnosed as distal renal tubular acidosis. The finding of the i-PTH and Ellsworth-Howard test suggested that this case was associated with idiopathic hypoparathyroidism. The fracture was treated successfully with osteosynthesis.

Three patients with long-standing (over 30 years duration) chronic osteomyelitis were treated in our clicic between 1987 and 1989. These patients were 66, 71 and 79 year-old men and the length of follow-up averaged 11 months.All these osteomyelitis were hematogenous in origin. Localizations were 1 femur, 1 tibia and 1 hip joint. The First case was treated with mid-thigh amputation, because of a squamous cell carcinoma originated from the fistula. The second case was treated with curettage and bone graft (auto-bone and hydroxyapatite). The third case was treated with curettage and petrolatum-packing (three times), followed bone graft and skin-muscular rotation flap. All cases have had good clinical courses.

Background Although a substantial percentage of patients with rheumatoid arthritis (RA) experience low back pain, the characteristics of lumbar spine pathology in RA patients has been poorly investigated. In our institutions, lumbar spine radiographs indicated scoliosis in 26 patients. The present study aimed to clarify the characteristics of lumbar scoliosis in RA patients. Methods This is a retrospective study of 26 RA patients with lumbar scoliosis. Patient characteristics such as disease duration, disease stage and class according to Steinbrocker's classification, and medication for RA and osteoporosis were reviewed. Radiologic evaluation of scoliosis was performed at two different time points by measuring Cobb angles. The progression of scoliosis per year was calculated by dividing the change in Cobb angles by the number of years. Apical vertebral rotation, lateral listhesis, and the level of the intercrestal line at the first observation were also measured. The correlation between different factors and changes in the Cobb angles per year was analyzed. Results Majority of the patients had a long disease duration and were classified as stage 3 or 4 according to Steinbrocker's classification. During the observation period, most patients were treated with glucocorticoids. Unlike the previous studies on degenerative scoliosis, apical vertebral rotation, lateral listhesis, and the level of the intercrestal line at initial observation were not significantly related to the progression of scoliosis. Initial Cobb angles were inversely related to the progression of scoliosis. Patients who were treated with bisphosphonates showed slower progression of scoliosis. Conclusions Our results indicate that the characteristics of lumbar scoliosis in RA patients differ from those of degenerative lumbar scoliosis. Bone fragility due to the long disease duration, poor control of disease activity, and osteoporosis is possibly related to its progression.

We have established a set of transgenic mouse lines in which the HLA-DRA gene was expressed in different cell types. In one line (DR alpha-24), DR alpha E beta b molecules were expressed on thymic medullary and cortical epithelial cells and all lineages of bone marrow-derived antigen-presenting cells (APC) except for thymic macrophages. By contrast, expression of the molecules in another line (DR alpha-30) was found on thymic medullary and cortical epithelial cells but not on bone marrow-derived APC in the thymus and periphery. To evaluate the role of thymic epithelial cells in acquisition of T cell tolerance, comparative analysis of DR alpha-24 and DR alpha-30 was performed. In DR alpha-30, T cells expressing TcR V beta 5 and V beta 11 were eliminated to comparable levels to those in DR alpha-24, suggesting that expression of the DR alpha E beta b molecules on thymic epithelial cells are sufficient for clonal deletion of the self-superantigen-reactive T cells. In addition, CD4+ T cells from DR alpha-30 as well as those from DR alpha-24 were tolerant to DR alpha-derived peptide/I-Ab complex expressed on spleen cells from DR alpha-24 even in the presence of exogenous interleukin-2. These observations suggest that expression of the DR alpha chain in thymic epithelial cells could induce T cell tolerance directed toward naturally processed DR alpha-derived peptide bound to I-Ab molecules, probably via clonal deletion of the self-reactive T cells.

We have established a strain of transgenic mice in which the HLA-DRA gene was integrated into the X-chromosome and the xenogeneic mixed isotype molecule, DR alpha E beta b, was expressed in a cell type-specific manner, although the transgenic DRA gene contained only 268 base pairs of the 5'-flanking region. The DR alpha E beta b molecules expressed in the transgenic mice functioned as major histocompatibility complex (MHC) class II to select T-cell repertoire, and to stimulate mixed lymphocyte reaction. In female transgenic mice homozygous for HLA-DRA (DR alpha-B6-F-homo) and male transgenic mice (DR alpha-B6-M), DR alpha E beta b molecules were expressed in almost all of the MHC class II Ab-positive cells. In contrast, the expression of DR alpha E beta b molecules in female transgenic mice hemizygous for HLA-DRA (DR alpha-B6-F-hemi) was found only in part of the Ab positive cells, and the proportion of cells expressing the DR alpha E beta b molecules varied due to random inactivation of one of the X-chromosomes. Clonal deletions of the T cells and mature thymocytes bearing Tcrb-V5 and Tcrb-V11, which are eliminated from the peripheral repertoire in mice expressing self-superantigen and MHC class II E molecules, were incomplete in DR alpha-B6-F-hemi as compared with those in DR alpha-B6-F-homo, and were correlated with the proportion of DR alpha E beta b-positive spleen cells. These observations suggested that the number of bone marrow-derived cells expressing DR alpha E beta b molecules was critical for clonal deletions of Tcrb-V5+ and Tcrb-V11+ T cells in the thymus.

A case of spinal cord compression by an osteochondroma with multiple osteochondromas was reported.A 10-year-old boy was admitted to our hospital with 6-month history of spastic gait in the right leg.Neurological examination demonstrated mild weakness of the right lower extremity. There were relative hyper-reflexes in the right leg. Plain roentgenograms were unremarkable. Myelography and enhanced computerized tomography showed extradural spinal cord compression at the 3rd thracic level by a bone tumor. But magnetic resonance imaging showed high density area form C7 to Th6 in addition to the Th3 tumor image. We puzzled these data.We performed surgical removal of this tumor by laminectomy of Th3 and Th4. The high density area of MRI was recognized to be proliferative fatty tissue. Pathologic examination revealed that it was typical of osteochondroma. He could walk normally 3 months postoperatively.