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Background and aims Older adults’ ever-improving health and changing lifestyles necessitate the development of a scale that can better measure their competence at a higher level. We developed the Japan Science and Technology Agency Index of Competence (JST-IC) via item analysis and assessed its psychometric properties. Methods Participants were 1306 community-dwelling older adults (623 men and 683 women, 74.0 ± 2.8 years old) who completed the 54-item draft JST-IC to determine their level of independence. Three procedures (including item selection, factor analyses, and reliability and validity analyses) were conducted to finalize the JST-IC and evaluate its psychometric properties. Results The item selection resulted in exclusion of 26 items for the following reasons: (a) 15 because of very high ratios (80% or more) of responders who answered “yes”, (b) one because of gender differences (phi coefficient = 0.34), (c) five because of their weak association with the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) (Pearson correlation coefficient of 0.30 or smaller), and (d) five because of redundancy of meaning with other items. Through factor analyses, we selected 16 items with a four-factor solution for the final version. JST-IC score exhibited a near-normal distribution and significant gender and age differences, and had moderate correlations with size of social network and level of subjective well-being and strong correlations with TMIG-IC score, physical fitness, and health literacy. Conclusions The JST-IC is useful for assessing competence at a higher level in community-dwelling older adults.

Factors affecting bone strength have not been elucidated in patients with rheumatoid arthritis (RA) undergoing silicone implant arthroplasty. In this observational study, we aimed to investigate factors affecting bone strength. We measured toughness in terms of bone strength, bone mineral density, and bone quality of 105 resected metacarpal heads (I:32, II:36, III:33, IV:2, V:2) obtained during silicone implant arthroplasty at the metacarpophalangeal (MP) joint in patients with RA. Bone strength was associated with all parameters in micro-computed tomography (µCT) and all parameters in bone histomorphometry, other than osteoid volume and osteoid surface. Clinical factors associated with bone strength included prednisolone (PSL) dose at the time of surgery, % young adult mean, T-score and the Rooney score. Bone volume fraction by µCT only influenced bone strength per multiple linear regression analysis. Compared to joints with higher bone strength, those with lower bone strength had a higher magnitude of implant subsidence, which assumed to the risk of reduced mobility and implant fracture after the operation. Suppressing the degradation of subchondral bone structures by continuously ameliorating disease activity without the use of PSL appeared to be crucial to maintain the radiological appearance of silicone implant arthroplasty at the MP joint.

Background Giant cell arteritis (GCA) is a primary large-vessel vasculitis (LVV) of unknown origin. Its management is a challenge due to the late onset of disease symptoms and frequent relapse; therefore, clarifying the pathophysiology of GCA is essential to improving treatment. This study aimed to identify the transition of molecular signatures in immune cells relevant to GCA pathogenesis by analyzing longitudinal transcriptome data in patients. Methods We analyzed the whole blood transcriptome of treatment-naive patients with GCA, patients with Takayasu arteritis (TAK), age-matched, old healthy controls (HCs), and young HCs. Characteristic genes for GCA were identified, and the longitudinal transition of those genes was analyzed using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). Results Repeated measures analysis of variance revealed 739 differentially expressed genes among all patients and HCs. Of the 739 genes, 15 were characteristically upregulated and 36 were downregulated in patients with GCA compared to those with TAK and HCs. Pathway enrichment analysis showed that downregulated genes in GCA were associated with B cell activation. CIBERSORT analysis revealed that upregulation of “M0-macrophages” and downregulation of B cells were characteristic of GCA. Upregulation of “M0-macrophages” reflects the activation of monocytes in GCA toward M0-like phenotypes, which persisted under 6 weeks of treatment. Combined treatment with prednisolone and an interleukin-6 receptor antagonist normalized molecular profiles more efficiently than prednisolone monotherapy. Conclusions Gene signatures of monocyte activation and B cell inactivation were characteristic of GCA and associated with treatment response.

A direct reductive homo-coupling of alkyl tosylates has been developed by employing a combination of nickel and nucleophilic cobalt catalysts. A single-electron-transfer-type oxidative addition is a pivotal process in the well-established nickel-catalyzed coupling of alkyl halides. However, the method cannot be applied to the homo-coupling of ubiquitous alkyl tosylates due to the high-lying σ*(C–O) orbital of the tosylates. This paper describes a Ni/Co-catalyzed protocol for the activation of alkyl tosylates on the construction of alkyl dimers under mild conditions.

The development of Th17 cells is a key event in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis (MS). Previous studies have demonstrated that an IL-6-dependent pathway is involved in the differentiation of Th17 cells from naïve CD4-positive T cells in vitro. However, the role of IL-6 in vivo in the development of Th17 cells in EAE has remained unclear. In the present study, we found that IL-6 blockade by treatment with an anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb) inhibited the development of EAE and inhibited the induction of myelin oligodendrocyte glycoprotein (MOG) peptide-specific CD4-positive, CD8-positive, and Th17 T cells, in inguinal lymph nodes. Thus, the protective effect of IL-6 blockade in EAE is likely to be mediated via the inhibition of the development of MOG-peptide-specific Th17 cells and Th1 cells, which in turn leads to reduced infiltration of T cells into the CNS. These findings indicate that anti-IL-6R mAb treatment might represent a novel therapy for human MS.

This study examined the impact of frailty on medical and long-term care expenditures in an older Japanese population. The subjects were those aged 75 years and over who responded to the survey (March 2018) in Bibai, Hokkaido, Japan (n=1,203) and have never received certification of long-term care insurance at the survey. We followed up 867 individuals (72.1%) until the end of December 2018 (10 month-period). We defined frailty as a state in performing 4 items and over of 15 items which were composed of un-intentional weight loss, history of falls, etc. Among 867 subjects, 233 subjects (26.9%) were judged to be frailty group, and 634 subjects (73.1%) non-frailty group. We compared period to the new certification of long-term care insurance (LTCI), accumulated medical and long-term care expenditures adjusted for age and gender between the two groups during the follow-up period. Cox proportional hazard models were used to examine the association between baseline frailty and the new certification of LTCI. The relative hazard ratio (HR) was higher in frailty group than non-frailty group (HR=3.51, 95% CI：1.30-9.45, P=.013). The adjusted mean accumulated medical and long-term care expenditures per capita during the follow-up were significantly (P=.002) larger for those in the frailty group (629,699 yen), while those in the non-frailty group were 450,995 yen. We confirmed strong economic impact of frailty in the elderly aged 75 or over in Japan.

Thiazolium carbene-catalyzed reactions of 1,2-diketones and 1,2,3-triketones with enones and ynones have been investigated. The diketones gave α,β-double acylation products via unique Breslow intermediates isolable as acid salts, whereas the triketones formed stable adducts with the NHC instead of the coupling products.

We studied the influence of IL-6 on chemokine production from peripheral blood mononuclear cells (PBMC), fibroblastic synovial cells and human umbilical vessel endothelial cells (HUVEC). Moreover, we examined the effect of IL-6 on the adhesion of U937 cells to HUVEC. For chemokine production, PBMC, fibroblastic synovial cells and HUVEC were cultured with IL-6 or IL-6 + soluble IL-6R (sIL-6R) for 24 h and then the production of MCP-1 and IL-8 were measured in supernatants. IL-6 and IL-6 + sIL-6R induced production of both MCP-1 and IL-8 in PBMC and synovial cells, respectively. In HUVEC, IL-6 + sIL-6R induced MCP-1 production, but inhibited IL-8 production. For adhesion molecule expression, the production of soluble form of adhesion molecules in HUVEC culture supernatant were measured by ELISA and the expression of adhesion molecules on cell surface were examined by flow cytometry analysis. Soluble ICAM-1 was detectable in IL-6 + sIL-6R-treated HUVEC and IL-6 + sIL-6R-induced ICAM-1 expression on cell membrane of HUVEC. In addition, U937 cells were added to HUVEC, which were pre-treated with IL-6 + sIL-6R for 24 h, and 3 h later attached U937 cells were counted. The adhesion of U937 cells to HUVEC was augmented when HUVEC was pretreated by IL-6 + sIL-6R. This adhesion was suppressed by anti-ICAM-1 antibody and anti-IL-6R antibody, but not by antibodies against VCAM-1 or E-selectin. In conclusion, IL-6 signaling plays an important role in inflammatory cell migration by increasing the rate of cell adhesion and by inducing chemokine production in inflamed joints.

Objectives Large vessel vasculitis (LVV) is characterised by a high relapse rate. Because accurate assessment of the LVV disease status can be difficult, an accurate prognostic marker for initial risk stratification is required. We conducted a comprehensive longitudinal investigation of next‐generation RNA‐sequencing data for patients with LVV to explore useful biomarkers associated with clinical characteristics. Methods Key molecular pathways relevant to LVV pathogenesis were identified by examining the whole blood RNA from patients with LVV and healthy controls (HCs). The data were examined by pathway analysis and weighted gene correlation network analysis (WGCNA) to identify functional gene sets that were differentially expressed between LVV patients and HCs, and associated with clinical features. We then compared the expression of the selected genes during week 0, week 6, remission and relapse. Results The whole‐transcriptome gene expression data for 108 samples obtained from LVV patients (n = 27) and HCs (n = 12) were compared. The pathway analysis and WGCNA revealed that molecular pathway related to interleukin (IL)‐1 was significantly upregulated in LVV patients compared with HCs, which correlated with the positron emission tomography vascular activity score, a disease‐extent score based on the distribution of affected arteries. Further analysis revealed that the expression levels of genes in the IL‐1 signalling pathway remained high after conventional treatment and were associated with disease relapse. Conclusion Upregulation of the IL‐1 signalling pathway was a characteristic of LVV patients and was associated with the extent of disease and a poor prognosis. In this study, we found that interleukin (IL)‐1 signalling was upregulated in large vessel vasculitis (LVV) and correlated with the disease‐extent score. IL‐1 signalling remained upregulated even after conventional treatment and was associated with disease relapse. Targeting IL‐1 signalling may be a promising therapeutic approach for LVV.

TNFα-induced adipose-related protein (TIARP) is a six-transmembrane protein expressed on macrophages, neutrophils and synoviocytes. We reported recently that mice deficient in TIARP (TIARP −/− ) spontaneously develop arthritis and are highly susceptible to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effects of TIARP on neutrophils and fibroblast-like synoviocytes (FLS) have not been elucidated. We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP −/− mice. Arthritis in TIARP −/− mice transferred with K/BxN serum was significantly exacerbated compared with WT mice. We characterized the differences in neutrophils between wild-type (WT) and TIARP −/− mice by DNA microarray. Overexpression of CXCR1 and CXCR2 was noted in TIARP −/− neutrophils. Neutrophils of TIARP −/− mice showed strong migration activity, which was markedly facilitated by CXCL2 in vitro and in vivo . Moreover, enhanced production of CXCL2 and IL-6 and cell proliferation was noted in TIARP −/− TNFα-stimulated FLS. Blockade of IL-6R significantly attenuated serum-transferred TIARP −/− arthritis with diminished neutrophil recruitment in joints. Our findings suggested that TIARP independently down-regulated CXCL2 and IL-6 production by FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, with resultant reduction of neutrophil migration into arthritic joints.