Takafumi Torigoshi

CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes

IntroductionInterleukin (IL)-6-type cytokines exert their effects through activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade. The JAK/STAT pathways play an important role in rheumatoid arthritis, since JAK inhibitors have exhibited dramatic effects on rheumatoid arthritis (RA) in clinical trials. In this study, we investigated the molecular effects of a small molecule JAK inhibitor, CP690,550 on the JAK/STAT signaling pathways and examined the role of JAK kinases in rheumatoid synovitis.MethodsFibroblast-like synoviocytes (FLS) were isolated from RA patients and stimulated with recombinant oncostatin M (OSM). The cellular supernatants were analyzed using cytokine protein chips. IL-6 mRNA and protein expression were analyzed by real-time PCR method and ELISA, respectively. Protein phosphorylation of rheumatoid synoviocytes was assessed by Western blot using phospho-specific antibodies.ResultsOSM was found to be a potent inducer of IL-6 in FLS. OSM stimulation elicited rapid phosphorylation of STATs suggesting activation of the JAK/STAT pathway in FLS. CP690,550 pretreatment completely abrogated the OSM-induced production of IL-6, as well as OSM-induced JAK/STAT, and activation of mitogen-activated kinases (MAPKs) in FLS.ConclusionsThese findings suggest that IL-6-type cytokines contribute to rheumatoid synovitis through activation of the JAK/STAT pathway in rheumatoid synoviocytes. Inhibition of these pro-inflammatory signaling pathways by CP690,550 could be important in the treatment of RA.

IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics

BackgroundHeparin-induced thrombocytopenia (HIT) is a thromboembolic complication that can occur with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Our objective was to determine and compare the incidence of IgG-class HIT antibodies in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) with different antithrombotic prophylaxis therapies and their contributions to the occurrence of venous thromboembolism (VTE).MethodsA prospective observational study was performed for 374 Japanese patients undergoing THA or TKA to determine the incidence of VTE. IgG-class anti-PF4/heparin antibodies were measured using IgG-specific EIA before and after the operation.ResultsIn the clinical outcome, the incidence of symptomatic deep vein thrombosis (DVT) was 15.0% (56/374, TKA; 35, THA; 21) and pulmonary emboli (PE) were not observed. The total seroconversion incidence of IgG-class PF4/heparin antibodies was 19.8% (74/374). The seroconversion incidence of IgG-class PF4/heparin antibodies was higher in patients receiving UFH (32.7%) compared to those receiving LMWH (9.5%) or fondaparinux (14.8%). Furthermore, the seroconversion incidence was significantly higher in patients undergoing TKA compared to those undergoing THA. Based on multivariate analysis, seroconversion of the IgG-class PF4/heparin antibodies was independent a risk factor for symptomatic DVT.ConclusionOur findings show that the seroconversion of IgG-class anti-PF4/heparin antibodies differed with various anti-thrombotic prophylaxis therapeutics and was associated with the risk of DVT in a subset of patients undergoing total joint arthroplasty (TKA and THA).

Clinical relevance of heparin-PF4 complex antibody in DVT after total joint replacement

BackgroundAntibodies to the heparin-platelet factor-4 (HPF-4) complex (HIT antibodies) have been observed in patients with heparin-induced thrombocytopenia (HIT). These antibodies are thought to be involved in thrombosis through activation of platelet/endothelial cells. This prospective study was conducted to determine the incidence of post-operative HIT antibodies to assess the associated risk of deep vein thrombosis (DVT) in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA).MethodsWe studied 104 patients who underwent unilateral primary TKA (n = 44) and primary THA (n = 60) with short-duration prophylaxis (1–2 days of a fixed dose of unfractionated heparin). HIT antibodies were assayed using a sandwich-type ELISA before the operation and after heparin treatment (post-operative day 7).ResultsIn the clinical outcome, the incidence of symptomatic DVT was 15.4% (16/104, TKA; 10, THA 6) and pulmonary embolism (PE) was not observed. The total seroconversion rate of HIT antibodies at post-operative day 7 was 34.6% (36/104). Among 36 seroconverted patients, 11 (30.6%) developed symptomatic DVT and 5 out of 68 of the non-seroconverted patients (7.4%) developed symptomatic DVT. The incidence for DVT was significantly higher in the seroconverted patients compared with that of the non-seroconverted patients (odds ratio 5.5, 95%CI: 1.7–17.6 p = 0.0028). Furthermore, in the patients with symptomatic DVT, the titer of HIT antibodies at post-operative day 7 was significantly higher compared with those without symptomatic DVT.ConclusionOur data therefore suggest that seroconversion for HIT antibodies generated by heparin is associated with a risk of DVT in patients undergoing total joint replacement.

Treatment for Chronic and Broad Osteomyelitis of Femor with Papineau's Method

今回我々は，長期間放置されていた大腿骨の慢性化膿性骨髄炎の3例に対し，Papineau法による治療を行い良好な治療成果が得られたので報告する．症例は男性2例，女性1例で，年齢は60歳～70歳（平均64.7歳）．骨髄炎罹患期間は23年～52年（平均38.0年）であった．第1相～第2相までの日数は平均47.3日，第2相～第3相までは平均28.0日で，入院期間は平均110.0日であった．病巣掻爬の範囲が約20cmに及ぶものが1例あったが，両側前後の腸骨からの骨移植でなんとか骨充填可能であった．第3相は3例とも創の縫縮のみで閉創可能で，再燃は認めていない．〈考察〉慢性化膿性骨髄炎に対してはPapineau法以外にもさまざまな治療法が施行されている．当院ではイリザロフによる仮骨延長法等も症例によっては施行しているが，患者の性格，年齢，罹患部位等を考慮すると，今回のようにPapineau法の有用性が改めて確認できた．

Septic Arthritis of the Knee Joint Followed by Common Cold in an Infant

We treated a comparatively rare case of septic arthritis of the knee joint followed by common cold in an infant, caused by β-lactamase-negative ampicillin-resistant H. influenzae (BLNAR). The patient was 9 months of age. Knee joint arthritis symptoms appeared following common cold and middle ear infection. We detected H. influenzae from the fluid of the knee joint, and from the effusion of the middle ear and throat. The results of bacteriological tests indicated BLNAR. It was treated by surgical drainage and antibiotics injection. BLNAR is rapidly increasing in recent years. BLNAR can therefore be suspected when infantile septic arthritis especially following common cold. In this case, it is very important to detect the joint fluid by bacteriological tests and carefully select the antibiotics to use without residual disability.

Clinical Results of Surgical Treatment for Rotator Cuff Tear in Tsushima

We treated rotator cuff tears surgically by the McLaughlin method on 14 cases from 1994 to 1997. They were followed up for an average of 26 months (range, 6 to 52). There were 11 were men and 5 were women. The average age of the patients was 58.1 years (range, 48 to 68). The clinical results were evaluated using the JOA score system and questionnaires on the patients satisfaction and problems and self score system (10 point method). The average JOA score was 96.1 points. The average 10 points score was 8.9 points.