白内障手術既往のある高齢者は視力と独立して高い認知機能を維持する : 平城京コホート研究横断解析

Cataract surgery improves visual acuity and drastically increases the capacity for light reception to the retina. Although previous studies suggested that both light exposure and visual acuity were associated with cognitive function, the relationships between cataract surgery, visual acuity, and cognitive function have not been evaluated in large populations. In this cross-sectional study, we measured cognitive function using the Mini-Mental State Examination and best-corrected visual acuity in pseudophakic (previous cataract surgery) and phakic (no previous cataract surgery) elderly individuals. Of 945 participants (mean age 71.7 years), 166 (17.6%) had pseudophakia and 317 (33.5%) had impaired cognitive function (score ≤26). The pseudophakic group showed significantly better visual acuity than the phakic group (p = 0.003) and lower age-adjusted odds ratio (ORs) for cognitive impairment (OR 0.66; p = 0.038). Consistently, in multivariate logistic regression models, after adjusting for confounding factors, including visual acuity and socioeconomic status, ORs for cognitive impairment were significantly lower in the pseudophakic group than in the phakic group (OR 0.64; 95% confidence interval 0.43-0.96; p = 0.031). This association remained significant in sensitivity analysis, excluding participants with low cognitive score ≤23 (n = 36). In conclusion, in a general elderly population, prevalence of cognitive impairment was significantly lower in pseudophakic individuals independently of visual acuity. The association was also independent of several major causes of cognitive impairment such as aging, gender, obesity, socioeconomic status, hypertension, diabetes, sleep disturbances, depressive symptoms, and physical inactivity.博士（医学）・甲第666号・平成29年3月15日© Mary Ann Liebert, Inc.This is a non-final version of an article published in final form in "http://dx.doi.org/10.1089/rej.2015.1718

Gut microbial metabolites of linoleic acid are metabolized by accelerated peroxisomal β-oxidation in mammalian cells

Microorganisms in animal gut produce unusual fatty acids from the ingested diet. Two types of hydroxy fatty acids (HFAs), 10-hydroxy-cis-12-octadecenoic acid (HYA) and 10-hydroxy-octadecanoic acid (HYB), are linoleic acid (LA) metabolites produced by Lactobacillus plantarum. In this study, we investigated the metabolism of these HFAs in mammalian cells. When Chinese hamster ovary (CHO) cells were cultured with HYA, approximately 50% of the supplemented HYA disappeared from the dish within 24 hours. On the other hand, the amount of HYA that disappeared from the dish of peroxisome (PEX)-deficient CHO cells was lower than 20%. Significant amounts of C2- and C4-chain-shortened metabolites of HYA were detected in culture medium of HYA-supplemented CHO cells, but not in medium of PEX-deficient cells. These results suggested that peroxisomal β-oxidation is involved in the disappearance of HYA. The PEX-dependent disappearance was observed in the experiment with HYB, but not with LA. We also found that HYA treatment up-regulates peroxisomal β-oxidation activity of human gastric MKN74 cells and intestinal Caco-2 cells. These results indicate a possibility that HFAs produced from gut bacteria affect lipid metabolism of host via modulation of peroxisomal β-oxidation activity

Long-term maintenance of the mucosal healing induced by azacitidine therapy in a patient with intestinal Behçet's-like disease accompanied with myelodysplastic syndrome involving trisomy 8

ArticleImmunological medicine. 42(3): 135-141 (2019)journal articl

Diagnostic approach for patients with unidentified fever according to the classical criteria of fever of unknown origin in the field of autoimmune disorders

ArticleImmunological medicine. 42(4): 176-184 (2019)journal articl

ディジタル ライブラリ ニオケル リレキ コジン ジョウホウ ノ ホゴ オヨビ リヨウ

電子図書館サービスの多くは、従来からある図書館サービスを電子的に行うことにより、図書館員が行う作業の効率化や資料への効率的なアクセスを実現するものであり、新たなサービスを提供するものは少ない。筆者らの研究グループは新たな電子図書館サービス構築を目指し研究を進めており、その過程で個人情報を含んだ貸出履歴をサービスに使うことの是非が大きな問題点として浮上した。本稿では、図書館の役割や利用者の個人情報について考察し、新たな電子図書館のサービスによる利便性向上と個人情報保護を両立するモデルを提案する

T細胞活性化によるアセチルコリン受容体の発現抑制機構の検討

T細胞にはムスカリン性およびニコチン性アセチルコリン受容体（mAChRおよびnAChR）が発現している。T細胞のAChRは、細胞傷害性の増強、細胞分裂の促進、細胞内cGMP濃度の上昇などの生理的役割を担っている。本研究では、T細胞の活性化がAChRの遺伝子発現に及ぼす影響および発現調節メカニズムを検討した。マウス脾臓細胞あるいは脾臓細胞から単離したCD4陽性T細胞において、2 日間の抗CD3/CD28抗体刺激は、M1-M5 mAChR mRNAおよびα4、α7、β2 nAChR mRNAの発現を減少させた。この減少作用には、nuclear factor-κBが関与していることが明らかとなった。さらに、2 日間の抗CD3/CD28抗体刺激は、mAChRあるいはnAChRの活性化による細胞内Ca2＋濃度上昇を抑制した。以上の結果より、T細胞の活性化は受容体発現を減少させることによりAChに対する反応性を低下させることが明らかとなった。すなわち、T細胞の活性化は、mAChRおよびnAChRを介した細胞障害性の増強や細胞分裂促進などの生理作用を低下させる可能性が示唆された。Muscarinic and nicotinic acetylcholine receptors（mAChR and nAChR）are expressed in immune cells including T cells. AChR of T cells plays physiological roles such as the enhancement of cytotoxicity, the promotion of cell division, the elevation of intracellular cGMP concentration. In this study, the effect of T cell activation on the expression of AChR and the mechanism of its expression were examined. In CD4-positive T cells or CD4-negative cells isolated from mouse spleen cells, anti-CD3/CD28 antibody stimulation for 2 days reduced the expression of M1-M5 mAChR mRNAs and α4, α7, β 2 nAChR mRNAs. It was revealed that nuclear factor-κB is involved in this decreasing action. Furthermore,stimulation of intracellular Ca2＋ concentration by activation of mAChR or nAChR was suppressed by stimulation with anti-CD3/CD28 antibody for 2 days. From the above results, it was revealed that activation of T cells reduces the reactivity to ACh by decreasing AChR expression. That is, it was suggested that differentiation of T cells may decrease physiological effects such as enhancement of cytotoxicity and promotion of cell division via mAChR and nAChR.論

Improved renal survival in Japanese children with IgA nephropathy

Since the beginning of the 1990s, Japanese medical practitioners have extensively prescribed angiotensin-converting enzyme (ACE) inhibitors for children with mild IgA nephropathy (IgA-N) and steriods for those with severe IgA-N. We have performed a retrospective cohort study to clarify whether the long-term outcome has improved in Japanese children with IgA-N. Renal survival was defined as the time from onset to end-stage renal disease (ESRD). We divided the study period into two time periods based on the occurrence of the initial renal biopsy:1976–1989 and 1990–2004. Actuarial survivals were calculated by Kaplan–Meier method, and comparisons were made with the logrank test. The Cox proportional hazard model was used for multivariate analysis. Between 1976 and 2004, 500 children were diagnosed as having IgA-N in our hospitals. The actuarial renal survival from the time of apparent disease onset was 96.4% at 10 years, 84.5% at 15 years and 73.9% at 20 years. Renal survival in the 1990–2004 period was significantly better than that in 1976–1989 (p = 0.008), and a marked improvement in renal survival in patients with severe IgA-N was also observed (p = 0.0003). Multivariate analysis indicated that diagnosis year was a significant factor for ESRD-free survival independently of baseline characteristics. The results of this study show that there has been an improvement in terms of renal survival in Japanese children with IgA-N

Haplotypes and a Novel Defective Allele of CES2 Found in a Japanese Population

ABSTRACT: Human carboxylesterase 2 (hCE-2) is a member of the serine esterase superfamily and is responsible for hydrolysis of a wide variety of xenobiotic and endogenous esters. hCE-2 also activates an anticancer drug, irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin, CPT-11), into its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). In this study, a comprehensive haplotype analysis of the CES2 gene, which encodes hCE-2, in a Japanese population was conducted. Human carboxylesterases are members of the serine esterase superfamily and are responsible for hydrolysis of a wide variety of xenobiotic and endogenous esters. They metabolize esters, thioesters, carbamates, and amides to yield soluble acids and alcohols or amines Although both hCE-1 and hCE-2 show broad substrate specificities, hCE-2 is relatively specific for heroin, cocaine (benzoyl ester), 6-acetylmorphine, procaine, and oxybutynin 1865 camptothecin (SN-38), a topoisomerase inhibitor, by carboxylesterases Previously, 12 exons and their flanking regions of CES2 were sequenced from 153 Japanese subjects, who received irinotecan or steroidal drugs, and 12 novel SNPs, including the nonsynonymous SNP, 100CϾT (Arg 34 Trp), and the SNP at the splice acceptor site of intron 8 (IVS8-2AϾG) were found Materials and Methods Chemicals. Irinotecan, SN-38, and SN-38G were kindly supplied by Yakult Honsha Co. Ltd. (Tokyo, Japan). Patients. A total of 262 Japanese subjects analyzed in this study consisted of 85 patients with allergies who received steroidal drugs and 177 patients with cancer who received irinotecan. The ethical review boards of the National Cancer Center, National Center for Child Health and Development, and National Institute of Health Sciences approved this study. Written informed consent was obtained from all participants. DNA Sequencing. Total genomic DNA was extracted from blood leukocytes or Epstein-Barr virus-transformed lymphocytes and used as a template in the polymerase chain reaction (PCR). Sequence data of the CES2 gene from 72 patients and 81 cancer patients were described previously Linkage Disequilibrium and Haplotype Analyses. LD analysis was performed by the SNPAlyze software (version 5.1; Dynacom Co., Yokohama, Japan), and a pairwise two-dimensional map between SNPs was obtained for the DЈ and rho square (r 2 ) values. All allele frequencies were in HardyWeinberg equilibrium. Some haplotypes were unambiguously assigned in the subjects with homozygous variations at all sites or a heterozygous variation at only one site. Separately, the diplotype configurations (combinations of haplotypes) were inferred by LDSUPPORT software, which determines the posterior probability distribution of the diplotype configuration for each subject on the basis of estimated haplotype frequencies Administration of Irinotecan and Pharmacokinetic Analysis. The demographic data and eligibility criteria for 177 cancer patients who received irinotecan in the National Cancer Center Hospitals (Tokyo and Chiba, Japan) were described elsewhere Each patient received a 90-min i.v. infusion at doses of 60 to 150 mg/m 2 , which varied depending on regimens/coadministered drugs: i.e., irinotecan dosages were 100 or 150 mg/m 2 for monotherapy and combination with 5-FU, 150 mg/m 2 for combination with mitomycin C (MMC), and 60 (or 70) mg/m 2 for combination with platinum anticancer drugs. Heparinized blood was collected before administration of irinotecan and at 0 min (end of infusion), 20 min, 1 h, 2 h, 4 h, 8 h, and 24 h after infusion. Plasma concentrations of irinotecan, SN-38, and SN-38G were determined as described previously Expression of Wild-Type and Variant CES2 Proteins in COS-1 Cells. Expression of wild-type and variant CES2 proteins in COS-1 cells was examined as described previously and ZERO-Dscan software (Raytest, Straubenhardt, Germany). The relative expression levels are shown as the means Ϯ S.D. of three separate transfection experiments. Determination of CES2 mRNA by Real-Time RT-PCR. Total RNA was isolated from transfected COS-1 cells using the RNeasy Mini Kit (QIAGEN, Tokyo, Japan). After RNase-free DNase treatment of samples to minimize plasmid DNA contamination, first-strand cDNA was prepared from 1 g of total RNA using the High-Capacity cDNA Archive Kit (Applied Biosystems, Foster City, CA) with random primers. Real-time PCR assays were performed with the ABI7500 Real Time PCR System (Applied Biosystems) using the TaqMan Gene Expression Assay for CES2 (Hs01077945_m1; Applied Biosystems) according to the manufacturer's instructions. The relative mRNA levels were determined using calibration curves obtained from serial dilutions of the pooled wild-type CES2 cDNA. Samples without reverse transcriptase were routinely included in the RT-PCR reactions to measure possible contributions of contaminating DNA, which was usually less than 1% of the mRNA-derived amplification. Transcripts of ␤-actin were quantified as internal controls using TaqMan ␤-Actin Control Reagent (Applied Biosystems), and normalization of CES2 mRNA levels were based on ␤-actin concentrations. Enzyme Assay. CPT-11 hydrolyzing activity of the postmitochondrial supernatants (microsomal fraction plus cytosol) was assayed over the substrate concentration range of 0.25 to 50 M as described previously Statistical Analysis. Statistical analysis of the differences in the AUC ratios among CES2 diplotypes, coadministered drugs. or irinotecan dosages was performed using the Kruskal-Wallis test, Mann-Whitney test, or Spearman rank correlation test (Prism 4.0, GraphPad Software, Inc., San Diego, CA). The t test (Prism 4.0) was applied to the comparison of the average values of protein expression and mRNA levels between wild-type and variant CES2. Results CES2 Variations Detected in a Japanese Population. Previously, the promoter region, all 12 exons, and their flanking introns of the CES2 gene were sequenced from 72 allergic patients and 81 cancer patients and resulted in the identification of 12 novel SNPs The nonsynonymous SNP 424GϾA (V142M) reported by our group LD and Haplotype Analysis. Using the detected SNPs, LD analysis was performed, and the pairwise values of r 2 and DЈ were obtained. A perfect linkage (r 2 ϭ 1.00) was observed between SNPs Ϫ363CϾG and IVS10-87GϾA. A close association (r 2 ϭ 0.85) was found between SNPs IVS10-108GϾA and 1749AϾG. Other associations were much lower (r 2 Ͻ 0.1). Therefore, the entire CES2 gene was analyzed as one LD block. The determined/inferred haplotypes are summarized i

2016～2017年度 関西大学研究拠点形成支援経費研究成果報告書

目次 ・研究成果の概要 ・第一論文 「信頼の革新、間メディア・クラックおよびリアルな共同の萌芽」（与謝野有紀） ・第二論文 「絵画鑑賞の社会・心理学的要因に関する計量的検討」（林直保子・与謝野有紀） ・第三論文 「全天球映像と球面ディスプレイを用いたインタラクティブコンテンツの開発 － 古墳をテーマとした地域連携事業への展開－ 」（林武文・堀雅洋・井浦崇・平尾修悟） ・第四論文 「展示解説におけるストーリー性が来館動機に及ぼす影響について－ 古代史系博物館での学習支援を目指して－ 」（井上卓也・田中孝治・池田満・堀雅洋） ・第五論文 「吹田の人形芝居・出口座の公演音声・映像資料について― 解題と考察」（菅原慶乃） ・第六論文 「長澤蘆雪と大坂画壇」（中谷伸生） ・第七論文 「『忠臣規矩順従録』小攷」（山本卓） ・第八論文 「古今和歌集の「誹諧」と「俳諧」」（山本登朗） ・謝辞 【付録】 「『隣女和歌集』巻一の基礎的考察」（坂本美樹） 「新出資料・林原美術館所蔵『隣女和歌集』(巻一)三本の紹介」（坂本美樹） 第一論文は、当該書籍に収録された論文の最終稿を東京大学出版会の許可を得て掲載しています。 第三論文は、著作権の関係により非公開としております。 第四論文は、知識共創フォーラムの許可を得て掲載しています。 第八論文は、当該資料に収録された論文の最終稿を臨川書店の許可を得て掲載しています