Effects of interleukin-6 signal inhibition on Treg subpopulations and association of Tregs with clinical outcomes in rheumatoid arthritis.

OBJECTIVES: Anti-IL-6 receptor antibodies are clinically efficacious in the management of rheumatoid arthritis (RA) with an associated increase in regulatory T cells (Tregs); however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyze the relationship between these Treg subsets and the clinical outcome of RA. METHODS: We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52. RESULTS: The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs, and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period. CONCLUSIONS: Blocking IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favorable treatment course, and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.

Ethynyl-B(dan) in [3+2] Cycloaddition and Larock Indole Synthesis: Synthesis of Stable Boron-Containing Heteroaromatic Compounds.

The cycloaddition of nitrile oxides with ethynyl-B(dan) (dan=naphthalene-1,8-diaminato) allowed the facile preparation of diverse isoxazolyl-B(dan) compounds, all of which displayed excellent protodeborylation-resistant properties. The dan-installation on the boron center proves vital to the high stability of the products as well as the perfect regioselectivity arising from hydrogen bond-directed orientation in the cycloaddition. The diminished boron-Lewis acidity of ethynyl-B(dan) also renders it amenable to azide-alkyne cycloaddition, Larock indole synthesis and related heteroannulations. The obtained boron-containing triazole, indoles, benzofuran and indenone exhibit sufficient resistance toward protodeborylation. Despite the commonly accepted transmetalation-inactive property derived from the diminished Lewis acidity, the synthesized heteroaryl-B(dan) compound was still found to be convertible to the oligoarene via sequential Suzuki-Miyaura coupling.

Complexation-Triggered Fluctuation of π-Conjugation on an Antiaromatic Dicyanoanthracene Dianion.

The formation of Lewis pairs is an important chemical concept. Recently, the complexation of Lewis acidic tris(pentafluorophenyl)borane with Lewis basic moieties and subsequent reduction has emerged as a fascinating strategy for designing novel reactions and structures. The impact of the complexation and subsequent reduction of antiaromatic systems bearing Lewis base moieties has been investigated. We found how Lewis adduct formation stabilizes an antiaromatic system consisting of 9,10-dicyanoanthracene and tris(pentafluorophenyl)borane by using synthesis, X-ray crystallography, spectroscopic analysis, and quantum chemical calculations.

Efficient one-pot synthesis of dan-substituted organo- and silyl-boron compounds.

Direct, transition metal-free B(dan)-installation into organic frameworks has been developed. Heteroaryl-H bonds were transformable into the respective heteroaryl-B(dan) bonds through deprotonation. The resulting heteroaryl-B(dan) compounds, which are otherwise difficult to access, can undergo the direct Suzuki-Miyaura coupling. The method was demonstrated to apply to a silicon nucleophile, giving Lewis acidity-diminished stable silyl-B(dan) and -B(aam) in one pot.

Self-Regulated Pathway-Dependent Chirality Control of Silver Nanoclusters.

Imparting chirality affords additive values, functions and responsiveness in molecular systems including nanoscale materials. Here, we report pathway-dependent chirality control in silver nanoclusters (NCs). The use of enantiomeric ligand, α-dihydrolipoic acid (DHLA), for the synthesis of Ag NCs leads to the preferential formation of one-handed chiral Ag29 (DHLA)12 NCs with intrinsic chirality in the exterior shell composed of a silver-dithiolate framework. Small Lewis base molecules such as pyridine bind to silver atoms in the shell of NC as a guest. The guest binding reverses the relative stability between the right- and left-handed NCs upon a steric interaction with the chiral ligand DHLA in the exterior shell in a kinetic manner, leading to unprecedented chirality inversion in the synthesis of NCs. This mechanism is further extended to the self-regulation or self-replication of chirality through interNC interactions dependent on the concentration in the synthesis of NCs.

Borylation and Stannylation Reactions with Tuning of Lewis Acidity.

A B(dan) moiety (dan=naphthalene-1,8-diaminato) of diminished boron-Lewis acidity has efficiently been installed into organic frameworks by three-component carboboration of alkenes under copper catalysis, where a Cu-B(dan) species, generated by chemoselective σ-bond metathesis between a copper catalyst and an unsymmetrical diboron [(pin)B-B(dan)], acts as a key intermediate. The Cu-B(dan) species has also turned out to serve as a B(dan) nucleophile to afford various dan-substituted organoboranes via borylative substitution of carbon electrophiles. Furthermore, borylation reactions with another Lewis acidity-diminished boron unit, B(aam) (aam=anthranilamidato), have become feasible by use of (pin)B-B(aam) or H-B(aam). The resulting dan/aam-substituted organoboranes have been demonstrated to undergo direct cross-coupling without prior acidic deprotection, regardless of their diminished boron-Lewis acidity. Synthesis of diverse organostannanes based upon copper-catalyzed carbostannylation and borylstannylation, in which Lewis acidity increment of a tin center facilitates the progress in some cases, have also been described.

Ni/Co-Catalyzed Homo-Coupling of Alkyl Tosylates.

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.

Assessing competence at a higher level among older adults: development of the Japan Science and Technology Agency Index of Competence (JST-IC).

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.

[Methods of coping with musculoskeletal pain among community-dwelling elderly individuals].

Objectives　Musculoskeletal pain impairs vital function and results in a requirement for long-term care. According to studies in other countries, a program that aims at reducing pain through instructions for pain-coping should be implemented. In Japan, a study on pain-coping has recently been initiated; however, the methods of coping with pain that are implemented by community-dwelling elderly individuals have not been evaluated. This study aimed to clarify the methods currently used for coping with musculoskeletal pain and to examine their association with the state of pain among community-dwelling elderly individuals.Methods　A survey was performed by sending questionnaires by mail to 2,281 community-dwelling elderly individuals. Responses were obtained from 1,835 people. The survey items consisted of questions about basic attributes and pain. A total of 16 questionnaire items regarding the methods of coping with pain were used for measuring pain-coping that community-dwelling elderly individuals use. The methods of coping with pain were classified into various types by factor analysis. The scores were calculated by type and their association with the state of pain was analyzed using one-way analysis of variance.Results　As a result of the factor analysis, methods of coping with pain were classified into five categories: "treatment in hospitals," "daily active coping," "restriction of daily behavior," "self-therapy," and "rest." From one-way analysis of variance for the site of pain, there was a significant difference between the "treatment in hospitals" and "restriction of daily behavior" categories. Among both scores, a higher score was observed in subjects with pain in both the lower back and the knee, compared to those with only pain in the lower back or the knee. Among the number of the sites, there was a significant difference between the "treatment in hospitals," "restriction of daily behavior," and "self-therapy" categories; subjects exhibiting two or more sites of pain showed a higher score than those exhibiting one site of pain. For pain duration, there was a significant difference between the "treatment in hospitals," "restriction of daily behavior," and "self-therapy" categories; subjects who had experienced pain for 5 years or longer had a higher score than those who had experienced pain for less than 6 months.Conclusion　We found that five types of methods of coping with pain ("treatment in hospitals," "daily active coping," "restriction of daily behavior," "self-therapy," and "rest") were used by community-dwelling elderly individuals and that "treatment in hospitals" and "restriction of daily behavior" were the most common strategies among elderly individuals with pain.

Obesity does not diminish the efficacy of IL-6 signalling blockade in mice with collagen-induced arthritis.

OBJECTIVES: Obese rheumatoid arthritis patients often have higher disease activity and a poorer response to treatment than do non-obese patients. The present study aims to clarify the influence of obesity on the action of IL-6 and to evaluate the efficacy of IL-6 signalling blockade in arthritis with obesity. METHODS: Mice were fed a high-fat diet for 5 weeks, and the influence of this diet on macrophages and type II collagen-induced arthritis was investigated. RESULTS: The mice fed the high-fat diet showed greater expression of macrophage marker F4/80, not only in subcutaneous fat but also in knee synovium and the calcaneal region, than did the mice fed a normal diet. Furthermore, macrophages isolated from mice on the high-fat diet tended to show higher expression of cyclooxygenase-2 following IL-6 stimulation than did macrophages from mice fed the normal diet. Moreover, mice fed the normal or high-fat diet were immunised with type II collagen, and were treated with anti-mouse IL-6 receptor antibody (MR16-1). The anti-arthritis effect of MR16-1 was not reduced in mice fed the high-fat diet compared to mice fed the normal diet (inhibition ratio: 87% vs. 62%). Furthermore, at the peak of arthritis, cyclooxygenase-2 expression in the calcaneal region of mice fed the high-fat diet was higher than that in the mice fed the normal diet. CONCLUSIONS: These results suggested that a high-fat diet induces inflammatory changes in the synovium. We demonstrated that IL-6 signalling blockade by an anti-IL-6 receptor antibody can be effective in treating arthritis, even with obesity.

NHC-catalyzed cleavage of vicinal diketones and triketones followed by insertion of enones and ynones.

Thiazolium carbene-catalyzed reactions of 1,2-diketones and 1,2,3-triketones with enones and ynones have been investigated. The diketones gave α,ß-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.

Copper Catalysis for Synthesizing Main-Group Organometallics Containing B, Sn or Si.

A copper complex has proven to be a potent catalyst for forming a C-B bond via diborylation of arynes and alkynes, affording vic-diborylarenes and vic-diborylalkenes with high efficiency. A boryl-substituted organocopper species, which is intermediately generated in the diborylation, has been found to be captured by a tin or a carbon electrophile, leading to three-component borylstannylation or carboboration, in which C-B and C-Sn (or C) bonds are constructed simultaneously. Furthermore, reducing the Lewis acidity of the boron center with 1,8-diaminonaphthalene decisively alters the regiochemical behavior of the borylcopper species, enabling the installation of a boryl moiety to occur at an internal carbon of terminal alkynes in borylstannylation and protoboration. Copper catalysis for C-Sn and C-Si bond-forming processes via distannylation, hydrostannylation and silylstannylation, as well as silver catalysis for a C-B bond-forming reaction, is also described.

Anti-interleukin-6 receptor antibody prevents systemic bone mass loss via reducing the number of osteoclast precursors in bone marrow in a collagen-induced arthritis model.

Systemic bone loss is a hallmark of rheumatoid arthritis (RA). Inflammatory cytokines such as interleukin (IL)-6 promote bone resorption by osteoclasts. Sphingosine-1-phosphate (S1P) controls the migration of osteoclast precursor cells (OCPs) between the blood and bone marrow, in part via S1P receptors (S1PR1 and S1PR2) expressed on the surface of OCPs. OCPs (CD11b(+) Gr-1(low+med) ) isolated from bone marrow of DBA/1J mice were stimulated with IL-6. S1P-directed chemotaxis of OCPs was evaluated using a transwell plate. mRNA expression of S1PR1 and S1PR2 was measured. DBA/1J mice were immunized with bovine type II collagen (days 0 and 21) and anti-mouse IL-6 receptor antibody (MR16-1) was administered on days 0 and/or 21. Trabecular bone volume was analysed using micro-computed tomography. The percentage of OCPs in tibial bone marrow and S1PR1 and S1PR2 mRNA expression in OCPs were measured. IL-6 stimulation significantly decreased S1P-directed chemotaxis of OCPs. IL-6 induced S1PR2 mRNA expression, but not S1PR1 mRNA expression, in OCPs. Bone volume was significantly lower in arthritic mice than in non-arthritic control mice on day 35. Treatment of immunized mice with MR16-1 significantly inhibited bone loss. In MR16-1-treated mice, the percentage of OCPs and expression of S1PR2 mRNA was each decreased compared with arthritic mice on day 14, but not on day 35. IL-6 increased the number of OCPs in tibial bone marrow via up-regulating S1PR2, thus playing a crucial role in systemic bone loss induced by inflammation.

[A 10-year community intervention for disability prevention and changes in physical, nutritional, psychological and social functions among community-dwelling older adults in Kusatsu, Gunma Prefecture, Japan].

OBJECTIVES: We reported previously that a 10-year community intervention for disability prevention successfully extended healthy life expectancy at 70 years and decreased the enrollment rate of the Long-Term Care Insurance in Kusatsu, Gunma Prefecture, Japan. In order to clarify functional factors that contributed to healthy aging, this study examined changes in physical, nutritional, psychological and social functions in older adults who participated in annual health checkups over the period. METHODS: Data sources were participants in annual health checkups conducted from 2002 to 2012 and respondents to biannual monitoring surveys conducted from 2003 to 2011. The target population was all older adults aged 70 years and over living in Kusatsu. The average participation rate over the period was 34.7% for the annual health checkups and 95.0% for the monitoring surveys. First, we examined the representativeness of the participants in annual health checkups by comparing them with the responders to monitoring surveys in terms of their higher-level functional capacity, as measured by the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) (Analysis 1). Second, we examined changes in the physical (4 measures), nutritional (3 measures), and psychological and social (4 measures) functions of participants in annual health checkups over the period. In this analysis, we standardized the data for each year on 11 measures to a mean of 0 and a standard deviation of 1.0 using the 2002 data as the standard, and conducted statistical tests for the slopes of the linear approximate equation (intercept=0) (Analysis 2). RESULTS: In Analysis 1, the TMIG-IC scores for participants in the annual health checkups were significantly higher in both sexes than were those for responders to the monitoring surveys. However, there were no significant year×group interactions in the scores. The difference in scores between the two groups was small for participants in their seventies, but large for participants in their eighties or over. Analysis 2 showed that all physical functions improved significantly over the period in both sexes, and the slopes of the linear approximate equation were steeper for maximal and usual gait speeds (slope=0.050 and 0.048, respectively, in men; 0.067 and 0.060, respectively, in women) than for other measures. In women, in addition to physical function, scores on the Mini-Mental State Examination (slope=0.053), Geriatric Depression Scale (slope=0.027), and Social Roll Scale (slope=0.019) also increased significantly. CONCLUSION: Although participants in annual health checkups were biased toward better functioning, the degree of the bias did not change significantly over the period. During the same period, physical function for both sexes, and psychological and social functions for women, improved significantly. It may be concluded that functional improvement in older adults contributed to the healthy longevity in Kusatsu.

Copper-catalyzed silylation of aryl and alkenyl triflates with silylboronic esters avoiding base-mediated borylation.

Silylation of aryl and alkenyl triflates is found to occur readily with silylboronic esters as a silicon source under copper catalysis. The silyl moieties are exclusively installed into the organic frameworks through the preferential generation of a silylcopper species, wherein base-mediated direct borylation is totally suppressed. The combined use of tri-n-butylphosphine and 4,4'-diphenyl-2,2'-bipyridine as a ligand combination turned out to be indispensable for achieving the high catalytic activity.

Immunoprotective effects of oral intake of heat-killed Lactobacillus pentosus strain b240 in elderly adults: a randomised, double-blind, placebo-controlled trial.

Oral intake of Lactobacillus pentosus strain b240 (b240) has been shown to enhance the secretion of salivary secretory IgA in elderly adults. However, its clinical benefits remain to be determined. We tested the hypothesis that b240 exerts a protective effect against the common cold in elderly adults. The design of the present study was a randomised, double-blind, placebo-controlled trial (RCT) with parallel three-group comparison. For this purpose, 300 eligible elderly adults were randomly allocated to one of three groups, namely a placebo, low-dose or high-dose b240 group. Participants in the low-dose and high-dose b240 groups were given tablets containing 2 × 10(9) or 2 × 10(10) cells, respectively, of heat-killed b240, while those in the placebo group were given tablets without b240. Each group consumed their respective tablets once daily for 20 weeks. The common cold was assessed on the basis of a diary. Change in quality of life was evaluated using the SF-36. Of the total participants, 280 completed the 20-week RCT. The accumulated incidence rate of the common cold was 47·3, 34·8 and 29·0 % for the placebo, low-dose b240 and high-dose b240 groups, respectively (P for trend = 0·012). Lower incidence rates were consistently observed throughout the experimental period in the b240 groups (log-rank test, P= 0·034). General health perception, as determined by the SF-36®, dose-dependently increased in the b240 groups ( P <0·025). In conclusion, oral intake of b240 significantly reduced the incidence rate of the common cold in elderly adults, indicating that b240 might be useful in improving resistance against infection through mucosal immunity.

[Validity of the "Kaigo-Yobo Check-List" as a frailty index].

OBJECTIVES: A frailty index for Japanese older people is not yet available. This study examined the validity of "Kaigo-Yobo Check-List" (CL) as a frailty index. METHODS: The study site was Kusatsu town, Gunma prefecture. Out of 612 older persons aged 65 years and over who undertook a comprehensive geriatric assessment in 2007, results from 526 who had no missing data were used to examine the cross-sectional relationship between frailty as defined by Fried's criteria (= external criteria) and CL scores in order to evaluate concurrent and construct validity. Further, 916 older individuals aged 70 years and over who responded to the baseline survey in 2001 were followed for the subsequent 4 years and 4 months regarding the onset of ADL disability, service use under the Long Term Care Insurance program, and mortality. We examined the predictive validity of the CL for such adverse outcomes after adjustment for gender, age, and comorbidity. RESULTS: The CL (cut-off point = 3/4) discriminated frailty from non-frailty at the sensitivity of 70.0% and specificity of 89.3%. The higher the CL score, the higher the prevalence of frailty; the trend was highly significant (P < 0.001). The Multitrail Multimethod Model showed that there were significant associations among three components of CL (homeboundness, falling, and lower nutrition) and four out of five components of Fried's frailty criteria (shrinking, exhaustion, low activity, and slowness), whereas those components of the CL did not have an association with the weakness component of Fried's frailty criteria. As compared with older persons who had CL scores of 3 points or below, those who had CL scores of 4 or more points had a significantly higher risk for developing adverse outcomes. Multivariate-adjusted odds ratios for ADL disability at 2 and 4 years after baseline were 5.25 (95% confidence interval, 2.79-9.89) and 3.42 (1.79-6.54), respectively. Likewise, multivariate-adjusted hazard ratios for the onset of service use under the Long Term Care Insurance program and mortality during the follow-up period of 4 years and 4 months were 3.50 (2.41-5.07) and 2.43 (1.70-3.47), respectively. Although the construct validity remained inconclusive, the "Kaigo-Yobo Check-List" showed CONCLUSION: good concurrent and predictive validity as a frailty index. Since it comprises 15 easy-to-answer questions, it could be widely used for research on frailty and its preventive intervention.

Computed ammonia affinity for evaluating Lewis acidity of organoboronates and organoboronamides.

Lewis acidity of organoboronates [B(pin), B(neop), B(cat), B(eg), B(nad)] and organoboronamides [B(dan), B(aam), B(mdan)] has been found to be unifiedly evaluated by computed ammonia affinity (AA), while other methods [LUMO energies, global electrophilicity index (GEI), fluoride ion affinity (FIA)] were only partially applicable. The relationships between the AA values and such structural characters including the B-X bond lengths, the X-B-X angles, and the changes in the B-X bond lengths in the formation of the ammonia adducts were also described.

Selective S-Arylation of Sulfenamides with Arynes: Access to Sulfilimines.

Sulfilimines, the aza analogues of sulfoxides, are of increasing interest in medicinal and agrochemical research programs. However, the development of efficient routes for their synthesis has remained relatively unexplored. In this study, we report a transition metal-free, selective S-arylation reaction between sulfenamides and arynes, enabling the facile preparation of structurally diverse sulfilimines under mild and redox-neutral conditions in good yields. The application value of our method was further demonstrated by scale-up synthesis, downstream derivatization, and robustness screen.

Longitudinal monitoring of circulating immune cell phenotypes in anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a necrotizing multiorgan autoimmune disease that affects small- to medium-sized blood vessels. Despite the improvements in treatments, half of the patients with AAV still experience disease relapses. In this review, we focus on peripheral leukocyte properties and phenotypes in patients with AAV. In particular, we explore longitudinal changes in circulating immune cell phenotypes during the active phase of the disease and treatment. The numbers and phenotypes of leukocytes in peripheral blood were differs between AAV and healthy controls, AAV in active versus inactive phase, AAV in treatment responders versus non-responders, and AAV with and without severe infection. Therefore, biomarkers detected in peripheral blood immune cells may be useful for longitudinal monitoring of disease activity in AAV.