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The purpose of this study was to examine drug absorption profile utilizing human intestinal tissues from ulcerative colitis (UC) patients and to compare with normal tissues from intestinal cancer patients. Human intestinal tissues from UC and cancer patients mounted in a mini-Ussing chamber were used to evaluate the permeation of drugs, including FD-4, a very low permeable marker, rebamipide, a low permeable marker, and metoprolol, a high permeable marker. The transport index, an index of sum of permeated and tissue-accumulated molecules, of the model drugs was in accordance with their absorption rank order, and was almost kept constant irrespective of autopsy grade based on tissue fibrosis. On the other hand, UC tissues of grade 2 showed the decreased Xcorr, an index of permeated amount of molecules and increased Tcorr, an index of tissue-accumulated molecules for every tested compound. Our finding of the transport characteristics in intestinal tissues of severe UC patients in mini-Ussing chamber system demonstrated that autopsy grade of UC patients did not drastically change membrane permeability of the tested compounds. Furthermore, it was suggested that morphological changes of intestinal tissues caused by fibrosis led to limited permeation and subsequently increased accumulation with little change of total absorption.

Our previous study in rats demonstrated that the metabolic pathways of DS-8500a, a novel GPR119 agonist, include cleavage pathways: reductive cleavage of the oxadiazole ring in the liver and hydrolysis of the amide side chain. In the present study, in vivo metabolic profiling in humans and monkeys after the oral administration of two

The effect of external additives on the synthesis of fumed TiO2 with a high rutile structure content was studied. The focus of this investigation was on the external additive species, agglomerates of the fumed TiO2 before and after the thermal treatment. The transformation ratio from the anatase to rutile structure of the thermally-treated fumed TiO2 was investigated as a function of the fumed TiO2 agglomerate before the thermal treatment. Small agglomerated powders resulted in a decrease of transformation temperature. Two novel results were obtained in this investigation. One was a new fumed TiO2 with a 100% rutile structure having an excellent dispersibility being successfully synthesized by the thermal treatment of AEROXIDE® TiO2 P 25 with a small portion of AEROSIL® R 972. The other was the remarkable acceleration of the transformation from the anatase to rutile structure and grain growth/sintering of the thermally-treated fumed TiO2 observed at a relatively low thermal treatment temperature by the oxidation reaction of calcium stearate as an external additive.

Background The real‐world safety and efficacy of uninterrupted anticoagulation treatment with edoxaban (EDX) or warfarin (WFR) during the peri‐procedural period of catheter ablation (CA) for atrial fibrillation (AF) are yet to be investigated. Methods We conducted a two‐center experience, observational study to retrospectively investigate consecutive patients who underwent CA for AF and received EDX or WFR. We examined the incidence of thromboembolic and bleeding complications during the peri‐procedural period. Results The EDX and WFR groups included 153 and 103 patients, respectively (total: 256 patients). Demise or thromboembolic events did not occur in either of the groups. The incidence of major bleeding in the EDX and WFR groups was 0.7% and 2.9%, respectively. The total incidence of major/minor bleeding in the EDX and WFR groups was 7.8% and 8.7%, respectively. Of note, the incidence of bleeding complications in the uninterrupted WFR strategy group was markedly high in patients with an estimated glomerular filtration rate (eGFR), Patients with severely impaired renal function and/or a higher bleeding risk during uninterrupted therapy with Warfarin were at a prominent risk of bleeding complications. Therefore, utmost attention should be paid in the treatment of these patients to prevent bleeding complications.

The synthesis of a porous-type of TiO2 with rutile structure was studied. The focuses were on the thermal treatment temperature and time. AEROXIDE® TiO2 P 25, as a fumed TiO2, was thermally treated in a vertical-type tubular furnace by the natural dropping method. Even though the thermal treatment time was less than 1 s, a drastic increase of polymorphism from anatase structure to rutile structure was observed. The relationships between the rutile structure transformation ratio and surface area of obtained porous type of TiO2 were investigated depending on the thermal treatment temperature. The porous-type of fumed TiO2 showed high dispersibility in the sedimentation test although is showed large particle size.

A new diatom species Gomphosphenia biwaensis Ohtsuka & D.Nakai was described from the south basin of Lake Biwa in Central Japan. Scanning electron microscopy revealed that the fine structure of this species is typical of the genus Gomphosphenia, although the striae are composed of a few areolae unlike Gomphosphenia lingulatiformis, the type species of the genus. Based on light micrographs of more than 100 specimens, the radii of the head pole, foot pole, and each valve side of these specimens were measured within a range that can be approximated by an arc, as well as the valve length, width, and stria density. The morphometric data were log-transformed and orthogonalized using principal component analysis based on the correlation coefficient, and the first principal component was eliminated to remove the effect of size differences. The second and subsequent principal components approximately followed a multivariate normal distribution. Morphometric data of the specimens from the other samples from Lake Bi...

The continuing investigation of SAR of 3-aminothieno[2,3-b]pyridine-2-carboxamide derivatives has been described. In this study, C4-piperidine derivatives with polar functional groups were synthesized to develop orally available bone anabolic agents. The optimized compound 9o (DS96432529), which exhibited the best PK profile and high in vitro activity, showed the highest in vivo efficacy in this series. Moreover, significant synergistic effects were observed following co-administration of DS96432529 and alendronate or parathyroid hormone. The mechanism of action is most likely mediated through CDK8 inhibition.

1. Effect of IL-6, a pro-inflammatory cytokine, on efflux transport of rebamipide, an antiulcer drug, was investigated in Caco-2 cells. 2. Rebamipide had a greater basal-to-apical than apical-to-basal transport rate. Efflux transport of rebamipide was inhibited by cyclosporine A, a P-gp inhibitor, and probenecid, which is a general MRP inhibitor, but not by Ko143, a BCRP inhibitor. 3. By the addition of IL-6, mannitol transport was slightly increased in a concentration-dependent manner in both directions of absorption and efflux. The addition of IL-6 did not change efflux transport of rebamipide even though efflux transport of digoxin, a typical substrate of P-gp, was significantly decreased by the addition of IL-6, indicating decrease of the function of P-gp. 4. Therefore, it was suggested that increase of MRP(s)-mediated transport compensates for the decrease of P-gp mediated transport of rebamipide. These findings suggested that rebamipide absorption is unlikely to be changed in IBD patients.

The purpose of the present study was to investigate the relationship between students' trust in their friends and their school adjustment. Junior high school students (N=563) completed a questionnaire. The results were as follows: First, exploratory factor analysis of the scale for students' trust in their friends revealed 3 factors: "sense of security in friends," "distrust toward friends," and "sense of dependability toward friends." Second, the scores on "sense of security in friends," "distrust toward friends," and "sense of dependability toward friends" were significantly different according to the students' grade level and students' gender. Finally, students' trust in their friends was correlated with their school adjustment, and the correlation differed according to the students' grade level and students' gender. Copyright © 2016 by Japan Society of Personality Psychology 本研究では，量的研究が限られている中学生の友人に対する信頼感の因子構造を実証的に明らかにし，友人に対する信頼感が生徒の学校適応感とどのように関連するかを検討した。中学生563名を対象に調査を実施した。第一に，生徒の友人に対する信頼感尺度（STS尺度）を作成し，信頼性と妥当性を検討した。その結果，（1）STS尺度は「友人への安心感」「友人への不信」「友人への頼もしさの感覚」の3因子構造からなり，信頼性と妥当性があること，（2）STS尺度の得点は，1年生が3年生に比べ，女子が男子に比べ高く，学年差・性差があることが明らかになった。また，生徒の友人に対する信頼感が生徒の学校適応感に及ぼす影響を検討したところ，（3）「友人への安心感」「友人への不信」「友人への頼もしさの感覚」のそれぞれが生徒の学校適応感に異なる影響を及ぼしていること，（4）また，その関連の様相も生徒の学年別，性別によって異なる可能性が示唆された。 Copyright © 2016 日本パーソナリティ心理学会 Language: ja

Telomeres maintain the integrity of chromosome ends and telomere length is an important marker of aging. The epidemiological studies suggested that many types of stress including psychosocial stress decrease telomere length. However, it remains unknown how various stresses induce telomere shortening. Here, we report that the stress-responsive transcription factor ATF7 mediates TNF-α–induced telomere shortening. ATF7 and telomerase, an enzyme that elongates telomeres, are localized on telomeres via interactions with the Ku complex. In response to TNF-α, which is induced by various stresses including psychological stress, ATF7 was phosphorylated by p38, leading to the release of ATF7 and telomerase from telomeres. Thus, a decrease of ATF7 and telomerase on telomeres in response to stress causes telomere shortening, as observed in ATF7-deficient mice. These findings give credence to the idea that various types of stress might shorten telomere.

Organic anion transporting polypeptide (OATP) 1B1 and 1B3 are key molecules that are involved in hepatic uptake related to drug elimination, and OATP-mediated drug interactions are of clinical concern. In this study, with an aim to determine a cutoff value for the potential involvement of OATP, we collected data on the distribution of 12 human OATP and 24 non-OATP radiolabeled substrates in rats. The OATP substrates exhibited a higher tissue-to-plasma ratio (Kp) in the liver than that in the other tissues. As an index of liver-specific distribution, a hepatic Kp ratio (the ratio of Kp in the liver to that in other tissues) was introduced, and a hepatic Kp ratio

To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.

Nowadays, as the widespread of smart-phones that equipped with Wi-Fi modules, many researchers have studied Wi-Fi based indoor positioning techniques. The existing method makes use of the Wi-Fi received signal strength (RSS) information that collected from several places indoors in advance to estimate the position of a mobile device by referring to a fingerprinting algorithm. Based on the existing method, this paper addresses a high-precision collaborative indoor positioning method. We first estimate the position coordinates of neighbor mobile devices and the distances between the devices by using the Wi-Fi and Bluetooth sensors on them. Then, by making use of the position and distance information, we utilize the spring model to correct the positioning errors. In addition, we performed the evaluation experiment in a real indoor environment, and confirmed the feasibility of our proposed method.

We investigate the inhibitory effect of marketed drugs for treatment of inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) on the uptake transporters of peptide transporter 1 (PEPT1), which are up-regulated under the inflamed condition. The uptake transport of glycylsarcosine, a typical substrate for PEPT1, was reduced to 60% only by 5-aminosalicylate at the clinically relevant concentration among tested marketed drugs in PEPT1 transfected HEK293 cell lines. These findings suggest that the inhibition of PEPT1, which were up-regulated in inflamed or non-inflamed site on UC and CD patients, contribute to the clinical effect of commercially available drugs for IBD patients through the inhibition of uptake of antigenic proinflammatory oligopeptides such as formyl-methionine (Met)-leucine (Leu)-phenylalanine (Phe) via PEPT1.

Human in vitro and dog in vitro/in vivo researches indicate that the drug-drug interaction (DDI) of decreased plasma valproic acid (VPA) concentration by co-administration of carbapenem antibiotics is caused by inhibition of acylpeptide hydrolase (APEH)-mediated VPA acylglucuronide (VPA-G) hydrolysis by carbapenems. In this study, we investigated VPA disposition and APEH activities in TK-NOG chimeric mice, whose livers were highly replaced with human hepatocytes, to evaluate the utility of this animal model and the clinical relevance of the DDI mechanism.VPA and VPA-G concentrations in plasma, urinary excretion of VPA-G and APEH activity in humanized livers were measured after co-administration of VPA with meropenem (MEPM) to chimeric mice.After co-administration with MEPM to the chimeric mice, plasma VPA concentration more rapidly decreased than without the co-administration. An increase in plasma AUC and urinary excretion of VPA-G was also observed. APEH activity in humanized livers was strongly inhibited even at 24 h after co-administration of MEPM to the chimeric mice.The DDI of VPA with carbapenems was successfully observed in chimeric mice with humanized livers. The DDI was caused by long-lasting inhibition of hepatic APEH-mediated VPA-G hydrolysis by carbapenems, which strongly supports the APEH-mediated mechanism of the clinical DDI. This is the first example showing the usefulness of chimeric mice with humanized livers for evaluation of a DDI via non-cytochrome P450 enzyme.

The Western Ontario Rotator Cuff Index (WORC) is a self-report, disease-specific, quality-of-life assessment tool. Good reliability and validity have been demonstrated with several language versions of the WORC. In this study, the WORC was translated into Japanese, and its reproducibility and validity for use in Japanese patients with rotator cuff disorder were determined.The translated version of the WORC was certified by the developer of the original version. Of 78 consecutive Japanese patients with rotator cuff disorder, 75 completed the following questionnaires: the WORC; the Disabilities of the Arm, Shoulder, and Hand (DASH); and the Short Form 36 (SF-36). In total, 50 patients completed the WORC twice within 2-14 days. Internal consistency, test-retest reliability, absolute reliability, and construct validity were assessed.Cronbach's alpha coefficients ranged from 0.78-0.95, and intraclass correlation coefficients ranged from 0.72-0.84 for the total score as well as scores on all WORC domains. A fixed bias was revealed between the test and retest for the total score and scores of some domains. Limits of agreement (LOA) ranged from -19.0-27.9% for the total score on the WORC. Furthermore, the WORC scores correlated with those of DASH (r = 0.63-0.78) and SF-36 (r = -0.24 to -0.69).Good test-retest reliability and construct validity were demonstrated for the Japanese WORC, but relatively high absolute measurement errors were observed. LOA values must be considered when using the WORC for individual patients with rotator cuff disorder.

A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3-b]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduction of cyclic amino groups to the C4-position of the thienopyridine ring improved the activity. Especially, N-phenyl-homopiperazine derivatives were found to be strong enhancers of ALPase among this new series. Furthermore, 3-amino-4-(4-phenyl-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide (15k) was orally administered to ovariectomized (OVX) rats over 6 weeks for evaluating the effects on areal bone mineral density (aBMD), and statistically significant improvements in aBMD were observed from the dosage of 10 mg/kg/day.

In a line production system of a factory, a worker repetitively performs predefined operation processes. This paper tries to recognize work by factory workers in an unsupervised manner. Specifically, we propose an unsupervised measurement method for estimating lead time (duration) of each period of an operation process using a wrist-worn accelerometer because the lead time greatly affects productivity of the line production system. Our proposed method automatically finds a frequent sensor data segment as a "motif" that occurs once in each operation period using only prior knowledge about predefined standard lead time of the operation process, and uses the occurrence intervals of the motif to estimate the lead time. We evaluated our method using real factory data and the estimation error was only about 3.5%.

This paper presents a new method for monitoring and managing factory workers of assembly works by using a wearable sensors. In line production systems, a worker repetitively performs predefined operation processes. Since the delay of a worker's process influences the entire line production system, measuring and managing cycle time of each worker's operation process is important. This study tries to measure cycle time of a worker using a wearable sensor in unsupervised manner.

1. In prior studies, it has been shown that tivantinib is extensively metabolized in humans to many oxidative metabolites and glucuronides. In order to identify the responsible enzymes, we investigated the in vitro metabolism of tivantinib and its four major circulating metabolites. 2. The primary isoforms involved in the elimination of tivantinib were CYP2C19 and CYP3A4/5. CYP2C19 showed catalytic activity for the formation of M5 (hydroxylated metabolite), but not for M4 (a stereoisomer of M5), whereas CYP3A4/5 catalyzed the formation of both metabolites. For the elimination of M4, M5 and M8 (keto-metabolite), CYP3A4/5 was the major cytochrome P450 isoform and UGT1A9 was mainly involved in the glucuronidation of M4 and M5. 3. ADH4 was identified as one of the major alcohol dehydrogenase isoforms contributing to the formation of M6 (sequential keto-metabolite of M4 and M5) and M8. The substrate preference of ADH for M4, and not M5, was observed in the formation of M6. 4. In conclusion, CYP2C19, CYP3A4/5, UGT1A9 and ADH4 were the primary drug metabolizing enzymes involved in the in vitro metabolism of tivantinib and its metabolites. The stereoselective hydroxylation by CYP2C19 and substrate stereoselectivity of ADH4-catalyzed oxidation in the in vitro metabolism of tivantinib was discovered.

Laninamivir octanoate (LO) (Inavir; Daiichi Sankyo, Japan) is an ester prodrug of the neuraminidase inhibitor laninamivir. We previously reported that a prolonged high retention of laninamivir in mouse respiratory tissues was achieved by intranasal administration of LO. In this study, we evaluated intrapulmonary pharmacokinetics both in vivo and in vitro to investigate the potential mechanism involved in such a preferable retention. After intranasal administration of LO to mice (0.5 μmol/kg), the drug was distributed from the airway space into the lungs, and laninamivir remained in the lung at 24 hours postdose (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid. The laninamivir was localized mainly on the epithelial cells of airway tracts, determined by microautoradiography using (14)C-labeled LO. In mouse airway epithelial cells, the cellular uptake and hydrolysis of LO were observed over incubation time without any apparent saturation at the highest concentration tested (1000 μM). Furthermore, after additional incubation in drug-free medium, the intracellular laninamivir was released very slowly into the medium with an estimate rate constant of 0.0707 h(-1), which was regarded as a rate-limiting step in the cellular retention. These results demonstrated that the prolonged high retention of laninamivir in the respiratory tissues was attributed to a consecutive series of three steps: uptake of LO into the airway epithelial cells, hydrolysis of LO into laninamivir by intracellular esterase(s), and limited efflux of the generated laninamivir due to its poor membrane permeability. This prodrug approach could be useful for lung-targeting drug delivery.