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Tristetraprolin (TTP) is an intracellular protein that modulates the production of cytokines, including TNFα, by binding to and destabilizing the mRNAs of these cytokines. Therefore, differences in TTP gene expression may affect the severity of inflammatory diseases, such as rheumatoid arthritis (RA). We searched for polymorphisms in the human TTP gene and for this purpose, we sequenced the entire TTP gene in 20 Japanese individuals (ten with RA and ten healthy volunteers) and found one single nucleotide polymorphism (SNP) in the promoter region. We analyzed this SNP (A/G) by restriction fragment length polymorphism method in 155 RA patients and 100 control subjects. While the frequency of A allele in this SNP was similar in RA patients (74.5%) and controls (76.0%), the disease duration in RA patients with genotype GG was shorter than that of patients with genotypes AA/AG and RA patients with genotype GG had a higher probability of being treated with infliximab. We studied the difference in promoter activity between the two alleles by luciferase assay and found that the promoter activity of TTP promoter region with allele A was around two-fold higher than that with allele G. We conclude that this SNP in the promoter region of the TTP gene mildly affects promoter activity, and thus, may influence the disease activity of inflammatory disorders including RA. [ABSTRACT FROM AUTHOR]

Abstract: We recorded clear transients in the electric and magnetic fields upon sudden slip in stick–slip experiments on dry, cylindrically shaped, quartz-free rock specimens of basalt and peridotite with a 30° saw-cut (representing a fault) at confining pressures of up to 120 MPa. The amplitudes of the measured electric field signals were always higher at the electrode pair oriented parallel to the strike of the fault than at the pair oriented perpendicular. This anisotropy suggests a preferred electric polarization normal to the slip surface. The transients in the electric and magnetic fields were observed only when the fault slip occurred by stick–slip mode, not by a stable mode of the sliding, and the amplitudes of the electric field signals increased with increasing stress drop. It is suggested that the generation process of the electromagnetic signals is closely related to the characteristic behavior of the fault at the time of the initiation of slip during stick–slip events, probably with respect to the intensity of the signals. We propose that one or both of the following two processes characteristic of the fault at the time of the initiation of slip during stick–slip events are essential for the generation of detectable electromagnetic signals: rapid slip along the simulated fault and separation of the rock masses across the fault. [Copyright &y& Elsevier]

Interleukin-17 is a proinflammatory cytokine. Recent animal studies have shown that IL-17 plays a role in the initiation and progression of arthritis. However, whether IL-17 has a prominent role in human rheumatoid arthritis (RA) or not remains unclear. Here we investigated the role of IL-17 in patients with RA. cDNA was prepared from knee joint synovial tissues of RA ( n = 11) and osteoarthritic (OA, n = 10) patients and PBMC of RA ( n = 52) and healthy subjects ( n = 34). IL-17 gene expression level was measured by real-time PCR, and was compared with various clinical parameters. IL-17 gene expression in synovial tissues of RA was similar to that in OA. IL-17 gene expression level in PBMC of RA patients was significantly higher than in the control. The response (changes in DAS) to two-week treatment with anti-TNF-α blockers (infliximab or etanercept) did not correlate with changes in IL-17 gene expression levels. The IL-17/TNF-α gene expression ratio at baseline (before treatment) tended to be lower in responders to the treatment. Expression of IL-17 gene in PBMC may be associated with the inflammatory process of RA. IL-17/TNF-α expression ratio is a potentially suitable marker of response to anti-TNF-α therapy. [ABSTRACT FROM AUTHOR]

The article presents a study which aimed to understand the posttransciptional control of tumor necrosis factor α (TNFα) production in patients with rheumatoid arthritis (RA) and to identify parameters that may predict the efficacy of anti-TNFα therapy. The study found that differences in androgen-binding protein (ABP) gene expression may affect TNFα gene expression. It also found that a higher T cell intracellular antigen 1 (TIA-1): Hu antigen R (HuR) expression ratio might correlate with the response to infliximab therapy.

Antibodies against prothrombin are detected by enzyme immunoassays (EIA) in sera of patients with antiphospholipid syndrome (APS). However, there are two methods for antiprothrombin EIA; one that uses high binding plates (aPT-A), and another that utilizes phosphatidylserine bound plates (aPS/PT). We aimed to evaluate and compare aPT-A and aPS/PT in a clinical setting. We performed EIA for anti-PT, anti-PS/PT, IgG, and IgM anticardiolipin antibodies (aCL), and IgG β2-glycoprotein I-dependent aCL (aβ2GPI/CL) with serum samples from 139 systemic lupus erythematosus (SLE) patients (16 with history of at least one thrombotic episode) and 148 controls. We observed that: (1) although titers of anti-PT and anti-PS/PT were significantly related with each other ( P < 0.0001, ρ = 0.548), titer of anti-PT and anti-PS/PT differed greatly in some samples; (2) odds ratio and 95% confidence interval for each assay was 3.556 (1.221–10.355) for aPT-A, 4.591 (1.555–15.560) for aPS/PT, 4.204 (1.250–14.148) for IgG aCL, 1.809 (0.354–9.232) for IgM aCL, and 7.246 (2.391–21.966) for aβ2GPI/CL. We conclude that, while all EIA performed in this study except IgM aCL are of potential value in assessing the risk of thrombosis, aPS/PT and aβ2GPI/CL seemed to be highly valuable in clinical practice, and that autoantibodies detected by anti-PT and anti-PS/PT are not completely identical. [ABSTRACT FROM AUTHOR]

Abstract: Mannose binding lectin (MBL) is a serum protein with structure and functions similar to those of complement factor C1q, and is a key molecule in innate immunity. Interestingly, absence or extremely low concentration of serum MBL (MBL deficiency) seems to be a risk factor for occurrence of autoimmune diseases, in particular systemic lupus erythematosus. In addition, individuals with MBL deficiency are at risk of infection when in immunocompromised conditions. The concentration of serum MBL is greatly influenced by relatively common single nucleotide polymorphisms of the MBL gene. Therefore, typing of the MBL gene, or measurement of serum MBL may be valuable for determining the risk of infections in patients with systemic autoimmune diseases, who frequently undergo immunosuppressive therapies. MBL deficiency may also be a risk factor for atherosclerosis and arterial thrombosis, both being common complications of autoimmune diseases. On the other hand, MBL may be pathological in tissue injuries, and the precise roles of MBL in autoimmune diseases, and the value of MBL gene typing or serum MBL measurement in a clinical setting are yet to be clarified. Recently, presence of anti-MBL autoantibodies in sera of SLE patients has been reported. The significance of this autoantibody remains to be elucidated. [Copyright &y& Elsevier]

Our purpose was to investigate a possible relationship between occurrence of type I diabetes and polymorphism of the mannose binding lectin gene. Polymorphism of codon 54 of the mannose binding lectin (MBL) gene, whose presence of the minority allele leads to significant reduction of serum MBL concentration, was investigated in 128 Japanese patients with type I diabetes and 78 healthy volunteers by restriction fragment length polymorphism method. Frequencies of the minority allele were compared between the patient group and the control group. Frequency of the minority allele was 24.2% in the patient group and 19.9% in the control group. The probability of being heterozygous or homozygous for the minority allele was 41.4% in the patient group and 33.3% in the control group. Patients with DRB1*0405-DQB1*0401 and/or DRB1*0901-DQB1*0303 haplotypes, the two major type I diabetes&ndash;prone human leukocyte antigen haplotypes, showed a slightly higher probability of being heterozygous or homozygous for allele B of the MBL gene. Possession of the minority allele of the MBL gene may be a minor risk factor for having type I diabetes. [Copyright &y& Elsevier]

Examines the nearshore flow velocity of the tsunami caused by the Southwest Hokkaido earthquake. Overview of advancing direction of tsunami; Tsunami disasters in Aonae District, Okushiri Island, Japan; In situ strength tests; Calculation of fluid velocity; Discussion.

We previously reported that peripheral blood mononuclear cells from HLA-DRB1*0101 Japanese patients with rheumatoid arthritis (RA) were highly reactive to 256–271 peptide of type II collagen (CII). In this report, we tried to regulate the CII reactivity of T cells from RA patients with HLA-DRB1*0101 by altered peptide ligand (APL), which is a single amino acid substitution of the T-cell epitope on CII 256–271 peptide. Antagonistic activity of 21 APLs was assessed using three different T-cell lines. Results showed that 262 (G→A) APL of CII 256–271 exhibited antagonistic activity in all T-cell lines and it was suggested that the application of CII APL might be a new therapeutic strategy in the regulation of RA. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the lack of relationship between mannose-binding lectin variant alleles and risk of arterial thrombosis in Japanese patients with systemic lupus erythemosus.

Vitrinite reflectance (R o ) and Raman spectra of carbonaceous material (RSCM) are both widely used as indicators of the maximum attained temperatures in sedimentary and metamorphic rocks. However, the potential of these methods to estimate temperature increases associated with fault slip has not been closely studied. To examine this issue, friction experiments were conducted on a mixture of powdered clay-rich fault material and carbonaceous material (CM) at slip rates of 0.15 mm/s and 1.3 m/s in nitrogen (N 2 ) gas with or without distilled water. After the experiments, we measured R o and RSCM and compared to those in starting material. The results indicate that when fault material suffers rapid heating at >500 °C in ∼9 s at 1.3 m/s, R o and the intensity ratio of D1 and D2 Raman bands of CM (I D2 /I D1 ) markedly increase. Comminution with very small temperature rise in ∼32 min at 0.15 mm/s is responsible for very limited changes in R o and I D2 /I D1 . Our results demonstrate that R o and RSCM could be useful for the detection of frictional heating on faults when the power density is ≥0.52 MW/m 2 . However, the conventionally used R o and RSCM geothermometers are inadequate for the estimation of peak temperature during seismic fault slip. The reaction kinetics incorporating the effects of rapid heating at high slip rates and studies of the original microtexture and composition of CM are required to establish a reliable thermometer for frictional heating on faults. [ABSTRACT FROM AUTHOR]

The question of whether coseismic ruptures along megasplay faults in accretionary prisms (i.e., large landward-dipping thrust faults branching from the plate boundary) reach the seafloor is critical for assessing the risk of tsunami disaster. However, samples from active megasplay faults have not previously been available. Here we present geochemical and mineralogical data of megasplay fault samples obtained from the shallow (<300 m below seafloor) portion of the megasplay fault that coincides with the rupture area of the A.D. 1944 Tonankai earthquake in the Nankai Trough. The megasplay fault zone is characterized by localized shear zones of brecciated host rocks. A prominent slip zone, here termed "dark gouge," was discovered within one of the shear zones. Compared to the surrounding breccias, the dark gouge is chemically enriched in Al and K, and depleted in Ca and Sr. It is also characterized by higher illite content in illite-smectite mixed-layer clays. These chemical and mineralogical features may reflect a transformation in clay mineralogy caused by frictional heating, and suggest that the seismic slip can propagate to very shallow levels along megasplay fault systems. [ABSTRACT FROM AUTHOR]

The article discusses the study which aims to evaluate the significance of single-nucleotide polymorphisms (SNP) in the genetic backgroud of Japanese patients. The study explores the population attributable risk percentage compared with Caucasians of replication of the systemic lupus erythematosus. The finding of the study reveals the contribution of the region to the genetic predisposition to SNP in Japan compared with Caucasians.

The article investigates the lineage of glucose-6-phosphate isomerase (GPI)-specific CD4+ T cell involved in GPI-induced rheumatoid arthritis (RA). According to the authors, the interleukin (IL)-6/IL-17 system may be involved in the generation of RA, particularly in the early phase. They explain that the conclusion is based on the fact that treatment with a humanized anti-IL-6R monoclonal antibody has proven to be effective in RA patients, thereby demonstrating an involvement for the system.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of several autoantibodies. Among the multiple factors involved in SLE development, apoptotic defects and impaired clearance of cellular debris have gained considerable interest, as they contribute to autoantigen overload. Several molecules of the innate immunity, also participate in the removal of damaged and apoptotic cells. Among them are C1q, C-reactive protein (CRP), serum amyloid P protein (SAP), mannose-binding lectin (MBL), and apolipoprotein A1 (APO A1). To evaluate the prevalence of autoantibodies against CRP, SAP, MBL, APO A1, and C1q among SLE patients, and their relationship with disease activity, a total of 150 SLE patients were screened for the presence of elevated antibody titers against C1q, CRP, SAP, MBL, and APO A1, utilizing the enzyme-linked immunosorbent assay (ELISA) method. Disease activity was assessed using the ECLAM or SLEDAI scores. The study population comprised two groups of patients: 100 patients with quiescent disease (median ECLAM score 2) comprised the first group, and 50 patients with active disease (median SLEDAI score 16) comprised group 2. Elevated titers of anti-CRP antibodies were significantly elevated only in group 1 (10% versus 4% of controls). Antibodies against SAP were evaluated only among patients in group 1, and were found at a significant high prevalence (20%). Elevated titers of anti-MBL antibodies were significantly elevated only in group 1 (15% versus 3.6%); and antibodies directed against APO A1 were significantly elevated in 21% of group 1, and 50% of group 2 patients. Elevated titers of anti-C1q were evaluated only in group 2, and were found at a significant prevalence of 66%. Significant correlation with disease activity was found only for anti-APO A1 antibodies, and only in group 1. Several patients harbored more than one of the autoantibodies tested. In patients with SLE, autoantibodies directed against protective molecules, that is, acute-phase proteins involved in the disposal of cellular and nuclear debris, can be detected. These autoantibodies may play a pathogenic role in the development or perpetuation of autoimmunity in SLE. [ABSTRACT FROM AUTHOR]

A 54-year-old woman complaining of muscle weakness and weight loss was admitted to our hospital with suspected polymyositis. Muscle biopsy revealed Langhans-type giant cells and noncaseating granulomas. Therefore, sarcoid myositis was diagnosed. The patient was treated with prednisolone, and the symptoms improved gradually. Generally, sarcoidosis is identified clinically in patients with foggy vision or mediastinal lymphadenopathy, but muscular weakness may be an infrequently observed initial symptom. Sarcoidosis should be considered in the differential diagnosis of polymyositis. [ABSTRACT FROM AUTHOR]

The CD40–CD154 interaction is an attractive target for therapeutic intervention in various autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, and myasthenia gravis. In this study, to develop a new disruption strategy of the CD40–CD154 interaction, we screened for peptides with inhibitory effects on such ligation. 2 × 1011 phage display libraries displaying liner peptides of 12-mer amino acids were screened by CD40-Ig binding assay and eight phages which expressed a different respective peptide (40BP-1 to -8) were able to specifically bind to CD40. Competitive inhibition analyses showed that 3 of the 8 peptides (40BP-N1-1 – APELPNMTPSWT; 40BP-N1-2 – APRPHTSYSPLP; and 40BP-N1-3 – GMTAPPPPRLTQ) blocked CD40–CD154 interaction when used at high concentrations. A consensus sequence (APxPPxxT) was conserved in these three peptides. These peptides may constitute a useful and novel strategy for the inhibition of the interaction between CD40 and CD154 molecules. [ABSTRACT FROM AUTHOR]

Abstract: Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) solely induce arthritis in mice. High titers of anti-GPI Abs are found in some patients with rheumatoid arthritis (RA), but their pathogenic role remains elusive. The aim of this study was to evaluate the pathogenic role of anti-GPI Abs in cynomolgus monkeys. IgG fractions were separated from sera of anti-GPI Abs-positive RA patients and healthy subjects and directly injected into the metacarpophalangeal joints of 4 cynomolgus monkeys. At day 16, the joints were harvested and examined histologically and immunohistochemically. The expression of C5a receptor (C5aR) molecule in the synovium was quantified by real-time PCR using cDNA from monkey joints. In monkey joints, IgG including anti-GPI Abs resulted in recruitment of granulocytes and mononuclear cells, strong deposition of human IgG on the articular surface, and overexpression of C5aR, but no joint swelling. No infiltrated cells or IgG deposition were observed in monkeys injected with IgGs from healthy subjects. Our results suggest that IgG fraction from RA patients including anti-GPI Abs may play a crucial role in the generation of synovitis in monkeys, although the pathogenesis of anti-GPI Abs in RA patients is still uncertain. [Copyright &y& Elsevier]

Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) are known to be arthritogenic in mice. These Abs are elevated in several forms of arthritic condition in humans, although their prevalence in rheumatoid arthritis (RA) patients is still in debate. Some RA patients have increased levels of anti-GPI Abs, but their clinical manifestation and relevance to other Abs are not clearly elucidated. The aims of this study were to explore the clinical and hematological characteristics of RA with anti-GPI Abs, and to compare their prevalence in RA patients, systemic lupus erythematosus (SLE) patients, and healthy subjects (HS) in a Japanese population. Anti-GPI Abs were positive in 16 patients with RA (12%, n = 137), in 10 patients with SLE (8%, n = 131), and in 6 HS (4%, n = 139). C-reactive protein (CRP), immunoglobulin G, and the antinuclear antibody titer were higher in anti-GPI-positive patients than in those who were negative ( P = 0.049, P = 0.0003, and P = 0.002, respectively). Moreover, the positivity of anti-GPI Abs was correlated with CRP more than with rheumatoid factor in RA patients. It is unclear whether anti-GPI Abs can predict the progress of disease, but the prevalence of these Abs was higher in active RA patients with severe arthritis, suggesting that anti-GPI Abs may be related to the pathogenesis of severe forms of arthritis. [ABSTRACT FROM AUTHOR]

Glucose-6-phosphate isomerase (GPI), recognized as an autoantigen in the K/BxN arthritis model, is a ubiquitous cytoplasmic enzyme. Anti-GPI antibodies (Abs) are also detected in the serum of patients with arthritic diseases including rheumatoid arthritis (RA). So far, 24 GPI variants have been reported and most of these variants relate to non-spherocytic hemolytic disease. To understand the mechanisms of anti-GPI Ab production, cDNAs from peripheral blood mononuclear cells of subjects with or without anti-GPI Abs were cloned and sequenced. We identified 39 new GPI variants (57–1596bp). The frequency of GPI variants in healthy control subjects (HS) with anti-GPI Abs (27/73, 31.5%) was significantly higher than that in anti-GPI Ab-negative HS (5/78, 6.4%, p<0.001). The frequency of GPI variants in anti-GPI Ab-positive RA patients (22/77, 28.6%) was more significantly higher than in anti-GPI Ab-negative patients (1/63, 1.6%, p<0.0001). Our results suggest that GPI variants may play a crucial role in the production of autoantibodies against ubiquitous GPI autoantigens. [Copyright &y& Elsevier]