The collection of ultrafine silica particles (23nm in diameter) and oilwater emulsion (500nm in diameter) from low concentrated suspensions were studied by using an ecomaterial (slag fibers) -collector bed system. The collec tion efficiency was highly dependent on the sol's pH and less on the specific surface area ratio between collector and ultrafine particles. The highest collec tion efficiency was attained at pH 4 for silica and at pH 3 for oil-water emulsion. The experimental results were partially interpreted by the total interac tion potential theory. In the case of the collection of ultrafine silica a second. mechanism regarding flocculation by the dissolved fraction of the SF comple mented the DLVO theory. In the case of the collection of oil-water emulsion effects regarding the deformable character of the oil drops as well as the hydrodynamic effects derived from the high molecular weight of the oil comple mented the DLVO theory.

抄録全体を表示

Service, innovation is essential for the future of Japan. This prefatory note discusses service innovation, designing for service innovation, service sustainability, service arts, and my expectations for Japan and for this special issue. The main points are: (1) Service relationships should yield mutual value for all parties and solutions are needed in social, economic, and environmental areas throughout the world; (2) Service design needs to broaden its focus into complex service systems design; (3) The focus of service innovation should expand to include environmental sustainability; and (4) Service aesthetics stimulate and influence customer gratification with the service encounter and will become another view for service innovation. I believe Japan will become a world leader in service innovation because it has both ancient service understanding and modern service technology. The papers published in this special issue will contribute to achieving service innovations in Japan.

抄録全体を表示

A physical and chemical characterization to the slag fibers was carried out by several instrumental techniques. Its main components were Si, Mg and Al oxides. The distribution of these elements was constants and uniform in all slag fibers' body by its amorphous structure, which generates surface'sites with both positive and negative charges in aqueous solution, which is depending on the compound lacated in the site.
The dissolution behavior of the slag fibers was negligible in a wide range of pH (4 to 10) and temperature (25 to 95°C), which was an important collecting feature as ecomaterial. The slag fibers' dissolution at low and high pH was concordant with thermodynamic predictions. The differential dissolution by different elements of slag fibers produces a remarkably high difference between the point of zero charge (pH10.8) and isoelectric point (pH2.9) of this material.

抄録全体を表示

Chromosome numbers and karyotypic observations are reported for 22 species of Hesperiidae (Pyrginae and Hesperiinae) found in southwestern North America. Characteristic haploid numbers for certain genera are found: Amblyscirtes (N=29), Chiodes (N=31), Erynnis (N=30 or 31), Heliopetes (N=29 or 30), Panoquina (N=29), and Wallengrenia (N=28, 29, 30). Two genera with widely varying chromo-some numbers are Achalarus (N=16, 29) and Pyrgus (N=28, 32). The pheno-typically unusual Celotes nessus (Edwards) is shown to be cytogenetically distinct from all other Pyrginae with a haploid number of 13-14, the lowest number reported to date for the family Hesperiidae.

抄録全体を表示

Objectives: Evaluation of the pharmacokinetics of opicapone in the Wistar rat and the Cynomolgus monkey.

Methods: Opicapone disposition was evaluated in the Wistar rat and Cynomolgus monkey after intravenous (1 mg/kg) and oral administration (10 mg/kg) of [14C]-opicapone.

Results: Five to seven days after administration of [14C]-opicapone, more than 89.0% and more than 68% of opicapone related radioactivity had been excreted in rats and in monkeys, respectively. The radioactivity peaked in plasma at 4 and 0.25 h post-dosing in rats and monkeys, respectively, followed by a quick decline and a very slow terminal phase. Opicapone related radioactivity was mainly recovered in feces with very low levels (less than 10%) excreted in urine in both species, rat and monkey. Whole body autoradiography studies in rat following single oral administration of [14C]-opicapone (10 mg/kg), indicate that radioactivity was rapidly absorbed and distributed throughout the body. No quantifiable levels of radioactivity was detected in brain up to 24h. The high tissue to blood ratio of total radioactivity observed in liver and kidney at 48h post-dosing suggests a slower elimination of opicapone related radioactivity from these tissues. Following oral administration of 1000 mg/kg opicapone, opicapone-3-O-sulfate, opicapone-3-O-glucuronide and the N-oxide reduced form of opicapone were quantified in rat and monkey, with the exception of the N-oxide reduced form for which the AUC0-t was higher in monkeys, the exposure to opicapone and quantified metabolites were higher in rat. The relative abundancies of opicapone metabolites were diferente, however the metabolic profile was qualitatively similar in rat and monkey,

Conclusions: Opicapone was found to be rapidly absorbed and primarily excreted via feces in the Cynomolgus monkey and the Wistar rat. Although differences in relative abundances were observed, the metabolic profile of opicapone was qualitatively similar in rat and in monkey.

抄録全体を表示

Background: Opicapone is a high-affinity and long-acting third generation nitrocatechol COMT inhibitor for the adjunctive therapy in levodopa-treated Parkinson's disease (PD) patients.

Objectives: The aim of this study was to evaluate the effects of opicapone, as adjunctive therapy to levodopa, in reversing MPTP-induced Parkinson's-like syndrome in cynomolgus monkeys (Macaca Fascicularis).

Methods: Induction of a PD-like syndrome was performed by daily intravenous administrations of MPTP. Characterization of the animals included scoring with the Primate Parkinsonism Motor Rating Scale (PPMRS) and assessment of locomotor activity.

Results: MPTP produced a stable Parkinson's-like behavioural syndrome as evidenced by tremor, postural changes, rigidity, impaired movements and balance, (i.e., PPMRS scores between 10 and 15) and decreased locomotor activity (13% of their pre-MPTP values). Opicapone treatment per se, for 14 days, did not change either the PD-like symptoms or the decreased locomotor behaviour of the subjects. Ascending combinations of levodopa/benserazide dose-dependently decreased PPMRS reaching statistical significance for the levodopa/benserazide doses of 18/4.5 mg/kg and that effect was further enhanced in opicapone treated subjects. Similarly, levodopa/benserazide dose-dependently increased locomotor behaviour, reaching significance with levodopa/benserazide doses of 18/4.5 mg/kg. This increase was also potentiated in the presence of opicapone. Opicapone treated subjects as compared to those treated with vehicle, had significantly increased plasma levodopa levels (2-fold higher AUC) with no changes in Cmax while for 3-OMD, AUC and Cmax values were both significantly reduced 7-8 fold. Erythrocyte COMT activity was markedly reduced in opicapone treated subjects.

Conclusions: Opicapone inhibited erythrocyte COMT activity, increased plasma levodopa exposure and reduced plasma 3-OMD levels with a concomitant potentiation of the improvements in PD-like symptoms produced by levodopa/benserazide combinations.

抄録全体を表示

映画作家パトリシオ・グスマンは母国チリの記憶をテーマにこれまで数々の作品を発表してきた。グスマンの作品における記憶の表象を扱った先行研究の多くはピノチェト独裁時代の被害の記憶を扱う1990年以降の作品を対象にしている。そのため彼の初期代表作である『チリの闘い』は「記録」の側面が重視され、「記憶」の視点から検討されてこなかった。本論文は、人々の証言によって構成される「証言映画」として『チリの闘い』を捉えることで、この映画が映し出す特異な記憶の様態を明らかにするとともに、この作品から証言映画の系譜に新たな視点を導き出すことを目的とする。第1節では証言映画の系譜の整理として、「表象不可能」な被害の記憶について『ショア』が提起した1980年代以降の議論と、同時期にラテンアメリカで起こった「証言の文化」を結びつけ、その流れに1990年代以降のグスマンの作品を位置付ける。第2節では1960～1970年代のラテンアメリカ映画運動における証言映画の働きを分析し、1980年代以降の証言映画との差異と共通の問題点を明らかにする。両時期の証言映画がこれまで別々に論じられ、『チリの闘い』はそれらの時期のはざまに生まれた作品であることを示したうえで、第3節では『チリの闘い』の制作経緯や証言の構成を考察し、当時の闘争を物語る人々の証言が、グスマンの主観性と結びつきながら新たな協働の可能性へつながれていくことを明らかにする。

抄録全体を表示

Soluble oligomers of Ab (SOAb) are the toxic agent in the pathogenesis of AD with multiple toxic effects. The aim of this work was to evaluate the effects of SOAb on the expression and levels of P2X2R and its contribution on mitochondrial biogenesis and dynamics. Changes on P2X2R was measured and Mitochondrial biogenesis was evaluated by changes on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a), and by the silent mating type information regulation 2 homolog (SIRT1) protein. On the other hand, mitochondrial dynamics was evaluated by changes on the fusion protein Mitofusin 1 (Mfn1) and fission dynamin-related protein 1 (DRP1). P2X2R increase (after 24 h) its expression and functional activity on neurons (over 25%). Through western blot and immunofluorescence, we observed decreased SIRT1 after SOAb treatments (about 50%). Conversely, an increment of PGC-1a was detected after 5h incubations (218%), though reduced levels were obtained after 1 and 24 h treatments (30%, 42% respectively). The interaction between these two proteins after a 24 h SOAb exposure was lost, which correlates with a change in PGC-1a distribution, increasing in the cytoplasm (177%) and decreasing in the nucleus (38%). After 2 h incubations we observed a reduction in Mfn1 levels (42%), and an increase in DRP1 (198%); additionally, DRP1 presented a distribution shift on hippocampal neurons, increasing its immunoreactivity in neuronal processes. Changes regarding mitochondrial proteins correlate with an alteration of mitochondrial network morphology and this dysfunction can be associated to the P2X2R contribution. Finally, SOAb-induced imbalance on P2X2R, mitochondrial dynamics, and decreased mitochondrial biogenesis, thus blocking the pathway that lead to the cell to have functional mitochondrias.

抄録全体を表示

Background: Opicapone (OPC), a new once-daily catechol-O-methyltransferase (COMT) inhibitor [1], was shown to be effective in the treatment of motor fluctuations in Parkinson's disease patients receiving levodopa [2, 3].

Objectives: Here we report the data from phase 1 studies that led to the decision-making process for opicapone's bedtime regimen.

Methods: Five phase 1 studies were selected on the basis of concomitant, alone or 1-hour apart administration between oral single-doses of opicapone (25, 50 and 100mg) and immediate- (IR) or controlled-release (CR) levodopa/carbidopa (LC, 100/25) or levodopa/benserazide (LB, 100/25). Opicapone, levodopa, carbidopa and benserazide pharmacokinetic data was analyzed.

Results: In studies conducted with concomitant administration between opicapone and IR/CR LB, an increase in rate (as assessed by Cmax) and extent (as assessed by AUC) to levodopa and benserazide occurred at all doses of opicapone. The increase was statistically significant for IR formulation. Levodopa Cmax decreased when doses of opicapone increased. In studies conducted with concomitant administration between opicapone and IR/CR LC, a statistically significant increase in Cmax and AUC to levodopa, but not to carbidopa, occurred at all doses of opicapone. Levodopa Cmax decreased (more pronounced with CR formulation) when doses of opicapone increased. Finally, similar levodopa and carbidopa Cmax was observed when opicapone (50mg) was administered 1-hour apart from IR LC. In all studies, Cmax and AUC to opicapone increased in a dose-proportional manner but an important variability was observed between different levodopa formulations and the use of carbidopa or benserazide.

Conclusions: The pharmacokinetic data suggest a certain degree of interaction at absorption phase that was minimized by separating both administrations for at least 1-hour. Opicapone was developed as an add-on to levodopa and, taking into consideration that Parkinson's disease patients may well necessitate several daily doses of levodopa, a bedtime regimen for opicapone was proposed to better allow the physician to individually tailor the levodopa daily regimen without any concern of a potential absorption interaction.

References:

1-Kiss LE, et al. J Med Chem, 53,3396-3411,2010

2-Ferreira J, et al. Lancet Neurol, 15,154-165,2017

3-Lees A, et al. JAMA Neurol, 74,197-206,2017

抄録全体を表示

Gastric Cancer (GC) is the one of the most prevalent cancer and one of the leading causes of cancer-induced deaths. Previously, we have found that the mRNA for the purinergic P2Y2 receptor is significantly increased in GC samples as compared to adjacent healthy mucosa taken from patients diagnosed with GC. In this work, we studied in detail the purinergic signaling in the gastric adenocarcinoma-derived AGS cell line and compared to the non-tumoral epithelial cell line, GES-1. In AGS cells, we detected the expression of several purinergic receptors, and we found important differences in the expression pattern compared to GES-1 cells. Functional studies revealed a strong contribution of P2Y2 receptors in the increase in intracellular calcium, elicited by ATP, UTP and the specific agonist MRS2768. Purinergic responses were preserved in the absence of extracellular calcium and inhibited by the P2Y2 antagonists suramin and AR-C118925. In contrast, in GES-1 ATP induced significantly higher responses as compared to UTP and P2X receptor antagonists were able to partially block these responses. Proliferation studies showed that ATP regulates AGS cell proliferation in a biphasic manner, slightly increasing cell proliferation at 10 and 100 uM, but inhibiting at 300 uM ATP. On the other hand, 1-300 uM UTP, a selective P2Y2 agonist, increased concentration-dependently cell proliferation. The effects of UTP and were prevented by wide range and specific purinergic antagonists. In contrast in GES-1 cells ATP only decreased cell-proliferation in a concentration dependent manner and UTP had no effect. Notably, the application of purinergic antagonist alone was enough to change the rates of AGS cells proliferation, indicating that nucleotides released by the cells can signal through paracrine and autocrine mechanisms. Finally, in tumor-derived biopsies, we found that whereas the expression of P2Y2 is significantly increased, the expression of P2X4 is significantly decreased, as compared to healthy tissues. Taken together, these results demonstrate the involvement of different purinergic receptors and signaling in GC, and the pattern of expression changes in tumoral cells, and this change probably directs ATP and nucleotide signaling from an anti-proliferative effect in healthy cells to a proliferative effect in tumoral cells.

抄録全体を表示

Background: Opicapone is a high-affinity and long-acting third generation nitrocatechol COMT inhibitor for adjunctive therapy in levodopa-treated Parkinsons disease patients.

Objectives: Evaluate the effect of opicapone, a third generation COMT inhibitor, on metabolic enzymes and drug transporters in vitro to anticipate potential in vivo drug-drug interactions.

Methods: To assess the potential of opicapone to inhibit cytochrome P450, the rate of metabolite formation from selective CYP marker substrates by pooled human liver microsomes was measured in the presence of six concentrations (0, 0.03, 0.1, 0.3, 3 and 10 µg/mL) of opicapone. Opicapone was evaluated as substrate and/or inhibitors of SLC transporters OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1 and MATE2-K and of human ATP-binding cassette (ABC) transportes, P-gp, BCRP and BSEP, using vesicles or cell-lines overexpressing each transporters. The binding of [14C]-opicapone to human plasma was determined at the concentration of 0.3, 3 and 30 µg/ml.

Results: When tested against P450 cytochromes (CYP), opicapone were reversible inhibitors of CYP2C8 (IC50, 3.6 µg/ml) and CYP2C9 (IC50, 9.6 µg/ml, respectively). No metabolism dependent inhibition by opicapone was observed for any of the other tested CYPs. Opicapone was a substrate for the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) efflux transporters and for the organic anion transporting polypeptide transporter (OATP1B3). Opicapone showed moderate inhibition of bile salt export pump (BSEP), and organic anionic transporters (OAT1 and OAT3), but inhibited OATP1B1 and OATP1B3 at lower concentrations (IC50 values of 0.45 and 1.4 µg/ml, respectively). However, when the 99.9% binding of opicapone to human serum proteins is considered, the 1.55 µg/mL Cmax in humans receiving 50 mg/day of opicapone equates to 0.002 µg/mL of unbound material. This is 225-fold lower than the lowest IC50 against transporters (OATP1B1, OATP1B3) and metabolic enzymes (CYP2C8 and CYP2C9) measured in the present study.

Conclusions: Although opicapone inhibited select CYPs and transporters in vitro, because of its high protein binding, the observed in vitro effect upon these biological targets is highly unlikely to have any clinical impact. Nonetheless, caution is advised when co-administering CYP2C8, CYP2C9 or OATP1B1 substrates.

抄録全体を表示

An environmentally safe procedure has been developed for the extraction, separation and determination of metal ions using a monosegmented flow analysis technique that exploits an aqueous two-phase system (ATPS-MSFA). The ATPS-MSFA method was applied for the determination of cobalt, based on the reaction between Co(II) and KSCN, which produces a metallic complex that spontaneously partitions to the top phase of the ATPS composed of poly(ethylene oxide), ammonium sulfate and water. The linear range was 5.00 to 500 μmol kg⁻¹ (R = 0.9998; n = 13) with a coefficient of variation equal to 1.14% (n = 7). The method yielded a limit of detection and a limit of quantification of 2.17 and 7.24 μmol kg⁻¹, respectively. The ATPS-MSFA method was applied to the determination of cobalt in a nickel-cadmium battery sample and the results were validity with flame atomic absorption spectrometry using addition standard.

抄録全体を表示

Obesity is a major public health problem, both globally and in Japan. A nationwide approach targeting metabolic syndrome has routinely been conducted in Japan since April 2008; however, the obesity statistics have not improved. Promotion of physical activity is one anti-obesity strategy. Numerous observational studies have revealed inverse associations between obesity and physical activity; however, these results have not always been conducted as randomized controlled trials (RCTs) that can provide the highest level of evidence. Therefore, this review looks at RCTs in the field of obesity and physical activity worldwide. The Diabetes Prevention Program and the Look AHEAD study are representative RCTs in this field. A guideline for the management of overweight and obesity among U.S. adults has recently been updated using a systematic review of good- or fair-quality RCTs, but a comprehensive, systematic review of RCTs in Japan has not yet been undertaken. This review seeks to fill this gap. Overall, we only found 10 RCTs that met the three inclusion criteria ([1] intervention study on obesity, [2] overweight or obese Japanese participants, and [3] RCT) and did not meet the exclusion criterion (study protocol without results). Based on our review results, it is strongly suggested that more RCTs in this field be conducted in Japan.

抄録全体を表示