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Abstract While polymorphism is prevalent in crystalline solids, polyamorphism draws increasing interest in various types of amorphous solids. Recent studies suggested that supercooling of liquid phase-change materials (PCMs) induces Peierls-like distortions in their local structures, underlying their liquid-liquid transitions before vitrification. However, the mechanism of how the vitrified phases undergo a possible polyamorphic transition remains elusive. Here, using high-energy synchrotron X-rays, we can access the precise pair distribution functions under high pressure and provide clear evidence that pressure can reverse the Peierls-like distortions, eliciting a polyamorphic transition in GeTe and GeSe. Combined with simulations based on machine-learned-neural-network potential, our structural analysis reveals a high-pressure state characterized by diminished Peierls-like distortion, greater coherence length, reduced compressibility, and a narrowing bandgap. Our finding underscores the crucial role of Peierls-like distortions in amorphous octahedral systems including PCMs. These distortions can be controlled through pressure and composition, offering potentials for designing properties in PCM-based devices.

Abstract Background Tedizolid is a new oxazolidinone antibiotic with high potency for the treatment of infections caused by methicillin-resistant Staphylococcus aureus and other species. Case presentation Two patients with osteoarthritis (women aged 79 and 73 years, cases 1 and 2, respectively) infected with S. aureus were successfully treated with tedizolid after administration of 200 mg once daily via intravenous infusion. The synovial fluid and plasma concentrations of tedizolid during surgery in case 1 at day 7 were 2.1 and 1.6 µg/mL, respectively, yielding a ratio of synovial fluid/plasma of 130%. Those in case 2 at day 2 were 2.9 and 3.3 µg/mL, respectively, corresponding to a ratio of synovial fluid/plasma of 88%. Conclusions These results imply very similar concentrations of tedizolid in the synovial fluid and plasma of osteoarthritis patients with acute S. aureus infection.

Abstract Transient creep in olivine aggregates has been studied by stress‐relaxation experiments at pressures of 1.7–3.6 GPa and at temperatures of ≤1020 K in a DIA apparatus. Time‐dependent deformation of olivine at small strains (

Abstract We present the case of a 45‐year‐old man who underwent a screening total colonoscopy and developed delayed perforation after a cold snare polypectomy in the descending colon and sigmoid colon. The patient developed abdominal pain and was referred to our department for further evaluation and treatment. On clinical examination, we noted lower abdominal tenderness, mild rebound pain, and elevated levels of inflammatory markers. Abdominal contrast‐enhanced computed tomography confirmed the presence of free air in the abdomen. Since there were no signs of peritoneal inflammation and the vital signs were stable, we planned to perform endoscopic clip closure of the perforated area. The patient's symptoms improved with conservative management thereafter, including fasting, fluid replacement, and antibiotic administration. The patient was discharged on the 6th hospital day. In this case report, we discuss the usefulness of endoscopic clip closure in managing delayed perforation.

Abstract Objectives Previous studies of cold snare polypectomy (CSP) for sessile serrated lesions (SSLs) ≥10 mm were performed by experienced endoscopists, and therefore their skills might have significantly influenced results. In this study, we compared the efficacy and safety of CSP for SSLs ≥10 mm between experienced and trainee endoscopists. Methods In a 1:1 propensity score matched retrospective cohort study, we compared the complete resection rate, en‐bloc resection rate, adverse event rate, and procedure time between experienced and trainee groups. Thirteen endoscopists performed CSP, and we defined the experienced group as endoscopists with board certification from the Japan Gastroenterological Endoscopy Society. Results We examined 616 lesions with SSLs ≥10 mm resected by CSP between February 2018 and May 2022. We excluded 61 lesions from the analysis because they had simultaneously undergone hot snare polypectomy (n = 57) or had been taken over by experienced endoscopists from trainees in the CSP procedure (n = 4). Finally, we identified 217 propensity score‐matched pairs (n = 434). Between experienced and trainee groups, the results were complete resection rate (100 vs. 100%; p = 1.00), en‐bloc resection rate (73.2 vs. 75.6%; p = 0.24), adverse event rate (3.2 vs. 2.8%; p = 0.77), or procedure time (6.2 vs. 5.9 min; p = 0.64). Conclusions We have demonstrated the safety and efficacy of CSP for SSLs ≥10 mm performed by experienced and trainee endoscopists.

Abstract A 25‐year‐old man was referred to our center for investigation of a gastric submucosal tumor and an ulcer that had developed on its oral side. Endoscopic ultrasonography findings suggested the presence of an ectopic pancreas, and treatment with an oral proton pump inhibitor was planned for the ulcer. Over the subsequent 3 years, the patient endured recurring epigastric pain and episodes of passing black stools. Emergency endoscopy revealed that the morphology of the gastric submucosal tumor had transformed into a pedunculated polyp‐like morphology with a bleeding ulcer at the apex of the lesion. Endoscopic hemostasis using hemostatic forceps was performed. However, the patient continued to pass black stools. In light of the persistent symptoms and unique morphology of the lesion, endoscopic resection was attempted as a curative approach. The lesion was excised by hot snare polypectomy. Post‐treatment, the patient exhibited no signs of recurrence, marking a successful resolution. Three months later, a gastroduodenal endoscopy showed that the excised site had undergone scar formation without recurrence of the lesion. This case holds significant clinical value as it demonstrates the efficacy of a minimally invasive treatment strategy in managing repeated bleeding ulcerations of an ectopic pancreas, ultimately achieving a complete cure.

The BL09XU beamline of SPring-8 has been reorganized into a beamline dedicated for hard X-ray photoelectron spectroscopy (HAXPES) to provide advanced capabilities with upgraded optical instruments. The beamline has two HAXPES analyzers to cover a wide range of applications. Two sets of double channel-cut crystal monochromators with the Si(220) and (311) reflections were installed to perform resonant HAXPES analyses with a total energy resolution of less than 300 meV over a wide energy range (4.9–12 keV) while achieving a fixed-exit condition. A double-crystal X-ray phase retarder using diamond crystals controls the polarization state with a high degree of polarization over 0.9 in the wide energy range 5.9–9.5 keV. Each HAXPES analyzer is equipped with a focusing mirror to provide a high-flux microbeam. The design and performance of the upgraded instruments are presented.

Abstract Aim The overdose of caffeine, a cytochrome P450 1A2 probe, in young women has become a problem. The aim of this study was to evaluate possible drug interactions between intentionally overdosed caffeine (12 g) and oral contraceptive doses of ethinyl estradiol prescribed to a young woman in a suicide attempt. Methods The serum concentrations of caffeine in the patient and the time‐dependent ethinyl estradiol inhibition of caffeine oxidation in vitro were evaluated. Results The serum concentration of caffeine 4 h after overdose was 136 μg/mL; from the data obtained between 4 and 28 h after overdose, the half‐life was estimated to be 33 h, which is many times larger than the normal value. Prescribed ethinyl estradiol prolonged caffeine elimination in vivo and inhibited paraxanthine formation, as evidenced by the low serum concentrations. In human liver microsomes, ethinyl estradiol (50 nM) inhibited half of caffeine N3‐demethylation. Pre‐incubation of human liver microsomes with ethinyl estradiol resulted in a powerful time‐dependent inhibitory effect on caffeine N3‐demethylation in human liver microsomes. Conclusion These results suggest that a prescription history of contraceptives at clinical doses may have a strong effect on the pharmacokinetics of overdosed caffeine in young women, resulting in dangerous drug interactions.

Various coordinate systems have been used in tooth profile analysis for cylindrical gears. An effective approach to tooth profile expression using normal polar coordinates is proposed. In this expression, the intersection between the normal at any point on the tooth profile and the operating pitch circle is determined. Then the tooth profile is represented using the length of the normal from the point on the tooth profile to the intersection, inclination angle between the normal and the straight line connecting the center of gear, and coordinate value of the intersection. Using this expression method, the path of contact is represented in polar coordinates by the length of the normal and its inclination angle. The tooth profile of the gear generated is the shape obtained by transforming the path of contact using the coordinates of the points of intersection. By applying the normal polar coordinates to a gear with an arbitrary tooth profile, the analysis to obtain the tooth profile by generation can be handled relatively easily. This method also works effectively for the analysis of the interference problem on tooth profiles. The application of this method to the analysis of a specific non-involute tooth profile adopted in this paper showed that a range of profile shift without interference could be determined, and that the interference could be prevented by modifying the tooth profile of rack. Furthermore, the interference occurring in the middle of the non-involute tooth profile was the same type of interference as undercutting in involute gears.

Because treated sewage water contains nitrogen compounds such as NH4-N and NO2+3-N, nitrous oxide (N2O) which is one of the greenhouse gases is generated by nitrification and denitrification reactions in rivers. This study aimed to develop a method for estimating the amount of N2O generated from the nitrification of residual N compounds in treated sewage water by subtracting the amount of residual N2O dissolved in the treated sewage water. A year-round field survey of dissolved N2O (D-N2O) in the treated sewage water and river water showed that nitrification proceeded in the downstream direction in the rivers following the discharge of the treated sewage water, thereby generating N2O. The deaeration rate of N2O dissolved in the river water was obtained from a laboratory experiment. The N2O emission factor that can be applied to in-river nitrification of NH4-N contained in the treated sewage water was calculated to be 0.0025 kgN2O-N kgNH4-N-1. HIGHLIGHTS N2O emissions derived from the nitrification of treated sewage water in rivers were investigated in Japan.; The laboratory experiment revealed the deaeration rates for D-N2O present in the rivers and treated sewage water.; N2O emission factor was developed for the nitrification of treated sewage water in rivers.;

In Japan, the WET method for assessing the ecological effects of wastewater in a short-term chronic toxicity test employing aquatic creatures is now being explored for development. On the other hand, there is a johkasou, which is an individual decentralized wastewater treatment facility in Japan. However, the ecological impact of this johkasou treated water, has yet to be determined. Therefore, in this study, the tandoku-syori and gappei-syori johkasou treated water and greywater were collected from 120 sites in Saitama, and the algae growth inhibition effect of the johkasou treated water was evaluated in the algae growth inhibition test. As a result, tandoku-syori johkasou treated water had a stronger growth-inhibiting effect than gappei-syori johkasou treated water on algae. It was also confirmed that the effects of algae growth inhibition on greywater vary greatly from site to site. Differences were observed in water quality of the treated water between winter and summer, but no significant difference was observed in the inhibition of algae growth. The correlation between each sample’s water quality concentration and the inhibition of algae development in the sample water was confirmed to be low.

In this study, double-multilayer monochromators that generate intense, high-energy, pink X-ray beams are designed, installed and evaluated at the SPring-8 medium-length (215 m) bending-magnet beamline BL20B2 for imaging applications. Two pairs of W/B4C multilayer mirrors are designed to utilize photon energies of 110 keV and 40 keV with bandwidths of 0.8% and 4.8%, respectively, which are more than 100 times larger when compared with the Si double-crystal monochromator (DCM) with a bandwidth of less than 0.01%. At an experimental hutch located 210 m away from the source, a large and uniform beam of size 14 mm (V) × 300 mm (H) [21 mm (V) × 300 mm (H)] was generated with a high flux density of 1.6 × 109 photons s−1 mm−2 (6.9 × 1010 photons s−1 mm−2) at 110 keV (40 keV), which marked a 300 (190) times increase in the photon flux when compared with a DCM with Si 511 (111) diffraction. The intense pink beams facilitate advanced X-ray imaging for large-sized objects such as fossils, rocks, organs and electronic devices with high speed and high spatial resolution.

Abstract Chimeric TK-NOG mice with a humanized liver (normal Hu-liver) are a unique animal model for predicting drug metabolism in humans. However, residual mouse hepatocytes occasionally prevent the precise evaluation of human drug metabolism. Herein, we developed a novel humanized liver TK-NOG mouse with a conditional knockout of liver-specific cytochrome P450 oxidoreductase (POR cKO Hu-liver). Immunohistochemical analysis revealed only a few POR-expressing cells around the portal vein in POR cKO mouse livers. NADPH-cytochrome c reductase and cytochrome P450 (P450)-mediated drug oxidation activity in liver microsomes from POR cKO mice was negligible. After the intravenous administration of S-warfarin, high circulating and urinary levels of S-7-hydroxywarfarin (a major human metabolite) were observed in POR cKO Hu-liver mice. Notably, the circulating and urinary levels of S-4′-hydroxywarfarin (a major warfarin metabolite in mice) were much lower in POR cKO Hu-liver mice than in normal Hu-liver mice. POR cKO Hu-liver mice with minimal interference from mouse hepatic P450 oxidation activity are a valuable model for predicting human drug metabolism.

Abstract Background Little is known of whether Internet use is associated with physical activity among socially isolated older adults during the coronavirus disease 2019 (COVID-19) pandemic. This study investigated the association between Internet use and physical activity, and whether this association differs depending on social isolation among community-dwelling Japanese older adults. Methods A cross-sectional study was conducted with 1048 community-dwelling residents aged 65–90 years. Data were obtained using a self-reported questionnaire in August 2020. Physical activity was assessed using the International Physical Activity Questionnaire-Short Form. Multivariable logistic regression analyses were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between Internet use and moderate-to-vigorous physical activity (MVPA). Results Internet use showed a significant association with MVPA (OR = 1.42, 95% CI: 1.06–1.90) after adjusting for age, sex, self-reported socioeconomic status, and other health-related characteristics. When the results were stratified by social participation and living status, Internet use was associated with a significantly higher likelihood of MVPA among participants with no social participation (OR = 1.81, 95% CI: 1.03–3.17) and living with family (OR = 1.40, 95% CI: 1.02–1.93). Conclusion Internet use was associated with sufficient physical activity, and this association may differ depending on the social isolation among community-dwelling older adults in Japan.

Abstract Background Linezolid is a new oxazolidinone antibiotic used for infections caused by methicillin-resistant Staphylococcus and other species. Case presentation Two cases of knee osteoarthritis with acute infection were successfully treated using linezolid. The plasma and synovial fluid concentrations of linezolid in two patients [women aged 69 and 73 years (cases 1 and 2)] with knee osteoarthritis infected with Staphylococcus aureus were measured after they were administered 600 mg twice daily by intravenous infusion. The plasma linezolid concentrations during knee surgery in case 1 at day 5 and in case 2 at day 2 were 19.6 and 15.6 μg/mL, respectively. The synovial fluid concentrations of linezolid in samples taken during surgery in case 1 and case 2 were 14.9 and 17.0 μg/mL, respectively; these values corresponded to ratios of synovial fluid/plasma of 76 and 109%. Possible metabolite 2-hydroxylated linezolid potentially mediated by cytochrome P450 2 J2 was not detected in the plasma or synovial fluid samples under the current clinical setting after multiple doses. Conclusions These results implied nearly equivalent concentrations of linezolid in plasma and synovial fluid of clinical patients with knee osteoarthritis acutely infected with Staphylococcus aureus.

Understanding the structural origin of the anomalous properties of SiO2 liquid and glass at high pressures is fundamental in wide range of scientific fields. Here, the authors find experimental evidence of a bimodal behavior in the translational order of silicon’s second shell and breaking of local tetrahedral symmetry in SiO2 glass under pressure.

With the recent development of ultraviolet light emitting diodes (UV-LEDs), it is now possible to apply UV disinfection, previously used only for medium-to-large sized sewage treatment plants, to Johkasou wastewater, a household wastewater treatment system. However, it is known that coliforms that have been inactivated by UV irradiation regain their activity after of sunlight irradiation, etc. Therefore, in small Johkasou, where discharge channels are often open, photorecovery may occur immediately after UV disinfection. However, no studies have been conducted to investigate photorecovery by sunlight after UV disinfection of wastewater from small Johkasou. In this study, the relationship between the photorecovery of coliforms and the dose of sunlight after UV-LED irradiation of effluent in Johkasou was investigated. As a result, we identified the amount of sunlight that will maximize photoreactivation effect. We also clarified the suppressing effect of an excessive amount of sunlight on the photoreactivation phenomenon. Additionally, since it was confirmed that the photoreactivation effect was suppressed by a certain period of darkness following UV-LED irradiation, it was considered that the photoreactivation effect can also be suppressed by allowing wastewater to reside in darkness for the currently estimated residence time in a disinfection tank.

Abstract Background Caffeine (0.1 g) is used as a central nervous system stimulant and as a nontoxic phenotyping probe for cytochrome P450 1A2. However, an increasing number of suicide attempts by caffeine overdose have been recently reported. Case presentation A 25-year-old woman (body weight, 43 kg) who intentionally took an overdose of 5.9 g caffeine as a suicide attempt was emergently admitted to Kyoto Medical Center. The plasma concentrations of caffeine and its primary metabolite, N-demethylated paraxanthine, in the current case were 100 and 7.3 μg/mL, 81 and 9.9 μg/mL, 63 and 12 μg/mL, and 21 and 14 μg/mL, at 12, 20, 30, and 56 h after oral overdose, respectively. The observed apparent terminal elimination half-life of caffeine during days 1 and 2 of hospitalization was 27 h, which is several times longer than the reported normal value. This finding implied nonlinearity of caffeine pharmacokinetics over such a wide dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic model founded on a normal dose of 100 mg. Low serum potassium levels (2.9 and 3.5 mM) on days 1 and 2 may have been caused by the caffeine overdose in the current case. Conclusions The patient underwent infusion with bicarbonate Ringer’s solution and potassium chloride and was discharged on the third day of hospitalization despite taking a potentially lethal dose of caffeine. The virtual plasma exposures of caffeine estimated using the current simplified PBPK model were higher than the measured values. The present results based on drug monitoring data and additional pharmacokinetic predictions could serve as a useful guide in cases of caffeine overdose.

Abstract Background Loxoprofen is a propionic acid derivative and is the most widely prescribed non-steroidal anti-inflammatory drug in Japan. Loxoprofen is generally considered to be relatively nontoxic. Case presentation A 33-year-old man (body weight, 55 kg) who intentionally took an overdose of 100 tablets of loxoprofen (6000 mg) as a suicide attempt was emergently admitted to Kyoto Medical Center. On arrival, the patient was suffering disorders of consciousness. His plasma concentrations of loxoprofen and its reduced trans-alcohol metabolite were 52 and 24 μg/mL, 3.7 and 2.3 μg/mL, 0.81 and 0.54 μg/mL, and 0.015 and 0.011 μg/mL, respectively, at 4, 26, 50, and 121 h after the oral overdose. The observed apparent terminal elimination half-life of loxoprofen during days 1 and 2 of hospitalization was in the range 6–12 h, which is several times longer than the reported normal value. This finding implied nonlinearity of loxoprofen pharmacokinetics over the current 100-fold dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic (PBPK) model founded on data from a normal dose of 60 mg. The reasons for the delayed eliminations from plasma of loxoprofen and its trans-alcohol metabolite in this case are uncertain, but slight renal impairment (low eGFR values) developed on the second and third hospital days and could be a causal factor. Conclusions Because the patient’s level of consciousness had gradually improved, he was discharged on the fourth day of hospitalization. The virtual plasma exposures of loxoprofen and its reduced trans-alcohol metabolite estimated using the current simplified PBPK model were lower than the measured values in the overdose case. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide in cases of loxoprofen overdose.

Abstract Background Although the over-the-counter H1 receptor antagonist diphenhydramine is not a common drug of abuse, it was recently recognized as one of the substances causing acute poisoning in patients attempting suicide that led to admissions to our hospital emergency room. Case presentation Two patients [women aged 21 and 27 years (cases 1 and 2)] were emergently admitted after intentionally taking overdoses of 900 and 1200 mg diphenhydramine, respectively. The plasma diphenhydramine concentrations in case 1 were 977 and 425 ng/mL at 2.5 and 11.5 h after single oral overdose, and those in case 2 were 1320 and 475 ng/mL at 3 and 18 h after administration, respectively. We set up a simplified physiologically based pharmacokinetic (PBPK) model that was established using the reported pharmacokinetic data for a microdose of diphenhydramine. The two virtual plasma concentrations and the area under the curve (AUC) values extrapolated using the PBPK model were consistent with the observed overdose data. This finding implied linearity of pharmacokinetics over a wide dosage range for diphenhydramine. Conclusions The determined plasma concentrations of diphenhydramine of around 1000 ng/mL at ~ 3 h after orally administered overdoses in cases 1 and 2 may not have been high enough to cause hepatic impairment because levels of aspartate aminotransferase and alanine aminotransferase were normal; however, there was an increase in total bilirubin in case 1. Nonetheless, high virtual liver exposures of diphenhydramine were estimated by the current PBPK model. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide when setting the duration of treatment in cases of diphenhydramine overdose.

Abstract Background A chemopreventive effect of low-dose aspirin against colorectal tumors was previously found in participants of two Japanese multicenter, double-blind, randomized, placebo-controlled clinical trials investigating the effects of daily aspirin (100 mg/day) for 0.7–2 years on tumor recurrence in colorectal cancer patients whose tumors were excised endoscopically. Methods In the current study, chemopreventive data from single-center subsets having daily aspirin (100 mg/day) were reanalyzed with respect to variations in polymorphic cytochrome P450 2A6 (CYP2A6). From the J-CAPP study, 56 of 311 participants (47 men, 9 women; excluding patients with familial adenomatous polyposis) were genotyped for CYP2A6*1, *4 (whole-gene deletion), *7 (amino acid substitution), and *9 (upstream mutation), and from the J-FAPP IV study, 81 of 102 participants (43 men, 38 women; including patients with familial adenomatous polyposis) were also genotyped. Results The chemopreventive effects of daily aspirin were found to be inversely dependent on the predicted enzyme activity of the CYP2A6 phenotype [based on normal genotypes (CYP2A6*1/*1,*7,*9) and impaired genotypes (CYP2A6*4,*7,*9/*4,*7,*9 and CYP2A6*1/*4)] among a nonsmoker Japanese cohort without familial adenomatous polyposis. Conclusions The CYP2A6 wild-type allele could be a candidate biomarker for reduced chemopreventive effects of daily aspirin in a population with wide-ranging CYP2A6 phenotypes with a high frequency of impaired activities resulting from variations and whole-gene deletions. The CYP2A6 genotypes could be applicable to future personalized treatments for colorectal tumor chemoprevention with daily aspirin.

Abstract Background Combinations of antidepressant duloxetine (at doses of 40–60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt. Case presentation The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient’s plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model. Conclusion Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.

Abstract Background The anticoagulant edoxaban is used clinically at doses of 30–60 mg/day; however, we experienced a patient who had taken an overdose of edoxaban of 750 mg. We investigated the pharmacokinetics of edoxaban in this patient by using liquid chromatography–tandem spectrometry to estimate the follow-up period in emergency clinical practice with this medicine. Case presentation The patient was a 57-year-old woman (body weight, 69 kg) who had taken a single oral dose of 750 mg of edoxaban in a suicide attempt. She was emergently admitted to Kyoto Medical Center. The patient’s edoxaban plasma concentrations during ambulance transport (8 h after oral administration) were ~ 4900 ng/ml, and the concentration gradually decreased to ~ 10 ng/mL and to detectable but unmeasurable levels of ~ 1.0 ng/mL at 60 h and 100 h, respectively. The linear range of the relationship between the dose and plasma concentration was assumed to have been exceeded during the first 8 h; however, the measured elimination rate of edoxaban was similar to that visualized curves predicted by a simplified physiologically based pharmacokinetic model previously established. Conclusion Simplified physiologically based pharmacokinetic models for creating visualized curves have proven to be useful not only during drug discovery or chemical risk assessment but also in cases of medical poisoning. We used a physiologically based pharmacokinetic model previously established for edoxaban to predict the pharmacokinetics in the current case. It is hoped that the results of this study, which encompass drug monitoring data in the patient and visualized pharmacokinetic prediction, will serve as an index when setting the treatment and follow-up period in cases of drug overdose for medicines such as edoxaban in emergency clinical practice.

Abstract Purpose To retrospectively evaluate the mid-term outcome of transarterial embolization (TAE) of renal artery pseudoaneurysm (RAP) including arteriovenous fistula (AVF) after partial nephrectomy screened by early postoperative contrast-enhanced CT (CE-CT). Materials and methods Eighty-two patients (7.0%) who underwent TAE after partial nephrectomy were reviewed, from 1166 partial nephrectomies performed over 6 years. In 18 patients (22.0%), TAE was performed emergently on the median postoperative day (POD) seven. In the remaining patients, elective TAE was performed on the median POD six for RAP detected by early postoperative CE-CT or that emerged on follow-up CE-CT. Results In one patient (1.2%), TAE was performed twice because one of two RAPs could not be embolized during the first TAE, being successfully embolized at the second TAE after readmission with hematuria. Otherwise, no bleeding recurrence or RAPs were observed during the median 1354 follow-up days. Thus, the primary and secondary success rates of TAE were 98.8% (81 of 82 patients) and 100% (82 of 82 patients), respectively. On angiography, the average number of lesions was 1.7 ± 0.9 and the average RAP size was 12.8 ± 6.0 mm. The shapes of the lesions varied: oval-round 60, oval-round + AVF 36, irregular + AVF 14, AVF 12, irregular 10, disruption 4, and extravasation 3. No major complications were observed. The median inpatient days after TAE were two. No estimated glomerular filtration rate deterioration was observed (64.6 ± 18.6 vs. 64.2 ± 18.4 mL/min/1.73 m2, p = 0.902). Conclusion TAE is largely effective and safe for treating bleedings or RAPs, including AVFs, after partial nephrectomy, as screened by early postoperative CE-CT.

Anaerobic ammonia oxidation (anammox) bacteria are inhibited by heavy metals at high concentrations but require trace amounts of some heavy-metal elements for growth and activity maintenance. The present study evaluates the long-term limitation effects of Se(VI), Zn(II), and Ni(II) on the start-up period of an anammox reactor. To strictly limit the levels of heavy metals in the reactor, all tests used ultrapure water as the influent synthetic wastewater and all reactors were installed in a clean booth. The anammox biomass was maintained through the gel entrapment technique. In the absence of Se(VI) and Ni(II), the anammox reactor start-up was 18.9 kg-N (m3-carrier d)−1 (nitrogen conversion rate (NCR) per gel carriers), indicating that Se(VI) and Ni(II) are not required or need not be continuously added to maintain the anammox process. Under Zn(II) limitation, the anammox process failed to start-up and the NCR tended to decrease rapidly. After readdition of 0.005 mg L−1 of Zn(II), the NCR did not decline further and instead partially recovered at a very slow rate. The NCR was completely recovered after adding 0.020 mg L−1 of Zn(II). These results reveal that Zn(II) limitation seriously affects the start-up of the anammox process while Se(VI) and Ni(II) are not required or need not be continuously added to the anammox process.

Cerebral venous thrombosis (CVT) is a rare complication of ulcerative colitis (UC) that is potentially fatal once it occurs. This report describes a case of CVT that led to a diagnosis of UC. A 48-year-old woman was diagnosed with CVT due to paresthesia and weakness and was hospitalized for treatment. She developed bloody diarrhea on admission and was further diagnosed with UC based on endoscopic and pathologic findings. Treatment of UC with steroids and sulfasalazine was administered immediately. Her condition improved significantly within several days following treatment. After discharge, the patient experienced no recurrence of either CVT or UC flare-up over the last five years. This report describes CVT as an initial presentation of UC. This is also the first report of a long-term follow-up following successful treatment of CVT with concomitant UC.

Refineries, especially fluid catalytic cracking (FCC) units are required to increase propylene production because of changing demand from fuels to chemicals in recent years. We have found a promising FCC catalyst for such demand. The FCC catalyst with Al ion-exchanged USY zeolite (catalyst (Al)) has indicated the higher LPG yield without decreasing in the activity. The catalyst (Al) would be suppressing hydrogen transfer reactions between products or intermediates. Moreover, the olefins in the gasoline would be over-cracked to LPG over catalyst (Al) because of strong acidity of Al ion-exchanged USY.

Apparent permeability coefficients (Papp) across a human intestinal epithelial Caco-2 cell monolayer were measured for a range of industrial/drug chemicals. A predictive equation for determining in vitro Papp values of fifty-six substances was set up using multivariate regression analysis based on in silico-estimated physicochemical properties (molecular weights and water distribution coefficients for apical and basal pH environments) (r = 0.77, p

Abstract Background Osteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region. Case presentation A 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6 months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157 cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient. Conclusions Protein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.

Despite early bilateral cochlear implantation, children with congenital deafness do not develop accurate spatial hearing; we thus asked whether auditory brain networks are disrupted in these children. EEG responses were evoked unilaterally and bilaterally in 13 children with normal hearing and 16 children receiving bilateral cochlear implants simultaneously. Active cortical areas were estimated by the Time Restricted Artifact and Coherent source Suppression (TRACS) beamformer and connected cortical areas were identified by measuring coherence between source responses. A whole-brain analysis of theta band coherence revealed the strongest connections between the temporal areas in all conditions at early latencies. Stronger imaginary coherence in activity between the two auditory cortices to bilateral than unilateral input was found in children with normal hearing reflecting facilitation in the auditory network during bilateral hearing. The opposite effect, depressed coherence, was found during bilateral stimulation in children using cochlear implants. Children with cochlear implants also showed a unique auditory network in response to bilateral stimulation which was marked by increased connectivity between occipital and frontal areas. These findings suggest that cortical networks for sound processing are normally facilitated by bilateral input but are disrupted in children who hear through two independent cochlear implants. Efforts to improve hearing in children with congenital deafness must thus include corrections to potential mismatches in bilateral input to support brain development.

Lithium-ion batteries (LIBs) are expected to be main power sources of automobiles. Nevertheless, LIBs easily lead to serious incidents because LIBs have high energy density. For application to automobiles, the reliability of LIBs should be guaranteed against various external loads. Especially, static loads and cyclic loads are constantly applied on LIBs because of vibration and thermal stress induced in automobiles, and fatigue damage occurs in electrodes of the LIBs. In this respect, it is important to evaluate mechanical strength and mechanical fatigue property of electrodes, such as tensile strength and S-N curves. This study has proposed a simple evaluation method of the mechanical strength and the fatigue property of electrodes for LIBs by using mechanical models of the electrodes. The actual alignment of particles of active material is random, and mechanical models based on the actual alignment are too complex to derive the main factor of mechanics of the electrodes. The proposed models approximate the alignment of the particles as the body-centered cubic (bcc) and the face-centered cubic (fcc) which are the well-known crystal lattices. In order to verify the proposed method, static tensile tests and bending fatigue tests of negative electrodes for LIBs have been conducted. From the test results, the tensile strength of the negative electrodes estimated by the proposed models agree with the experimental values, and the difference between the bcc model and the fcc model is smaller than the variation of the experimental values. The estimation value of the stress that initiates a crack on the negative electrodes by 1 cycle agrees with the tensile strength. The number of cycles linearly increases in the log scale with the decrease of the stress amplitude, and the stress amplitude at the 106–107 cycles agrees with the half of the tensile strength.

Recently, a new rapid assay for the detection of tcdB gene of Clostridioides difficile was developed using the GENECUBE. The assay can directly detect the tcdB gene from stool samples without a purification in approximately 35 minutes with a few minutes of preparation process. We performed a prospective comparative study of the performance of the assay at eight institutions in Japan. Fresh residual stool samples (Bristol stool scale ≥5) were used and comparisons were performed with the BD MAX Cdiff assay and toxigenic cultures. For the evaluation of 383 stool samples compared with the BD MAX Cdiff assay, the sensitivity, and specificity of the two assays was 99.0% (379/383), 98.1% (52/53), 99.1% (327/330), respectively. In the comparison with toxigenic culture, the total, sensitivity, and specificity were 96.6% (370/383), 85.0% (51/60), and 98.8% (319/323), respectively. The current investigation indicated the GENECUBE Clostridioides difficile assay has equivalent performance with the BD MAX Cdiff assay for the detection of tcdB gene of C. difficile.

Purpose: Hydroxylation activity at the 6β-position of steroid hormones (testosterone, progesterone, and cortisol) by human cytochromes P450 (P450 or CYP) 3A4 and CYP3A5 and their molecular docking energy values were compared to understand the catalytic properties of the major forms of human CYP3A, namely, CYP3A4 and CYP3A5. Methods: Testosterone, progesterone, and cortisol 6β-hydroxylation activities of recombinant CYP3A4 and CYP3A5 were determined by liquid chromatography. Docking simulations of these substrates to the heme moiety of reported crystal structures of CYP3A4 (Protein Data Bank code ITQN) and CYP3A5 (6MJM) were conducted. Results: Michaelis constants (Km) for CYP3A5-mediated 6β-hydroxylation of testosterone and progesterone were approximately twice those for CYP3A4, whereas the value for cortisol 6β-hydroxylation mediated by CYP3A5 was similar to the value for that by CYP3A4. Maximal velocities (Vmax) of the three steroid hormones 6β-hydroxylation catalyzed by CYP3A5 were 30%-63% of those by CYP3A4. Thus, Vmax/ Km values of these hormones for CYP3A5 resulted in 22%-31% of those for CYP3A4. The differences in the docking energies between CYP3A4 and CYP3A5 for steroid hormones were slightly correlated to the logarithm of CYP3A5/CYP3A4 ratios for Km values (substrate affinity). Conclusions: The Vmax, rather than Km values, for CYP3A5-mediated 6β-hydroxylation of three steroid hormones were different from those for CYP3A4. Molecular docking simulations could partially explain the differences in the accessibility of substrates to the heme moiety of human CYP3A molecules, resulting in the enzymatic affinity of CYP3A4 and CYP3A5.

We pharmacologically characterized microminipigs as an in vivo experimental model by assessing cardiovascular effects of pilsicainide, verapamil and E-4031, which can preferentially inhibit cardiac Na+, Ca2+ and K+ channels, respectively. Intravenous infusion of 1 mg/kg of pilsicainide (n = 4), 0.1 mg/kg of verapamil (n = 4) and 0.01 followed by 0.1 mg/kg of E-4031 (n = 5) over 10 min decreased the heart rate, mean blood pressure and ventricular contractility. Moreover, pilsicainide prolonged the PR interval, QRS width and QTc; verapamil prolonged the PR interval, but shortened the QRS width and QTc; and E-4031 prolonged the QTc, whereas no substantial change was detected in the PR interval or QRS width. Peak plasma concentrations of pilsicainide, verapamil and E-4031 in microminipigs were 1.7–4.8 times higher than those expected in humans and dogs, possibly due to smaller effective volume of drug distribution. The extent of the drug-induced cardiovascular responses was generally greater in microminipigs than in humans and dogs, which could be explained by the following possibilities; namely unique pharmacokinetic profile, less great reflex-mediated increase of sympathetic tone and/or smaller repolarization reserve in microminipigs. These information may make it feasible to apply this new-type animal to a tool for assessing cardiac safety profiles of new chemical entities.

This data article contains a supplementary figure and validation data relating to the research article entitled “Genotyping of wild-type cytochrome P450 2A6 and whole-gene deletion using human blood samples and a multiplex real-time polymerase chain reaction method with dual-labeled probes” (Shimizu et al., Clinica Chimica Acta 441, 71–74, 2015), which presents a multiplex real-time polymerase chain reaction method with dual-labeled probes for human P450 2A6 wild-type and whole-gene deletion. Real-time methods have dramatically improved the speed of complex genetic diagnostics compared to conventional assays based on restriction enzyme digestion. Here, we show the basic assay validation data by single and multiplex determinations in comparison with commercial TaqMan copy number assays for P450 2A6.

Polymorphic human flavin-containing monooxygenase 3 (FMO3) is associated with the inherited disorder trimethylaminuria. Several FMO3 variants have been observed in a variety of ethnic groups, including a Japanese cohort suffering from trimethylaminuria. The aim of this study was to screen another self-reported Japanese trimethylaminuria cohort for novel FMO3 variants and to investigate these new variants. Subjects with low FMO3 metabolic capacities were identified by measuring the urinary trimethylamine and trimethylamine N-oxide concentrationsin171 Japanese volunteers. The FMO3 genes from these subjects and their family members were then sequenced. Heterozygotes or homozygotes for novel single-nucleotide polymorphisms c.20 T>C p.(Ile7Thr), c.122 G>A p.(Trp41Ter), c.127T>A p.(Phe43Ile), c.488 T>C p.(Leu163Pro), and c.1127G>A p.(Gly376Glu) and a heterozygote for the novel duplication c.850_860dupTTTAACGATGA p.(Glu287AspfsTer17) were identified. In addition, the known (but as yet uncharacterized) single-nucleotide polymorphism c.929 C>T p.(Ser310Leu) was found. Pedigree analysis revealed the p.(Ser310Leu) FMO3 allele in cis configuration with c.929 C>T p.(Glu158Lys). These variant FMO3 proteins recombinantly expressed in Escherichia coli membranes exhibited decreased N-oxygenation activities toward trimethylamine and benzydamine. Although the allele frequencies of these seven variants were low, the present results suggest that individuals homozygous or heterozygous for any of these novel missense or duplicationFMO3 variants or known nonsense mutations such as p.(Cys197Ter) may possess abnormal activities toward trimethylamine N-oxygenation.

Newly developed 3D scanning optical endoscopic probe consists of φ1.5mm quartz pipe and 2 micro motors that run inside and conduct helical 3D scanning. This research looks into the possibility of accurately measuring the inner wall of extremely small diameter object by combining 3D scanning endoscopic optical probe and OCT (optical coherence tomography). Conventionally, precision measurement of such extreme inner diameter size was not possible due to influence of what is called “fluctuation of light” and “mechanical run-out of the measuring instrument itself” in axial and radial direction. In the new method, the inner wall of quartz pipe is measured in advance by calibration work, and the inner wall of the object is measured based on the quartz pipe. Applying this method, we succeeded in measuring with standard variation 0.07μｍ(σ) repeatedly. This new method also features auto-correction of the incline angle between the optical probe and the measuring object by computing, which prevents setting error and variation.

Sign language is an essential medium for everyday social interaction for deaf people and plays a critical role in verbal learning. In particular, language development in those people should heavily rely on the verbal short-term memory (STM) via sign language. Most previous studies compared neural activations during signed language processing in deaf signers and those during spoken language processing in hearing speakers. For sign language users, it thus remains unclear how visuospatial inputs are converted into the verbal STM operating in the left-hemisphere language network. Using functional magnetic resonance imaging, the present study investigated neural activation while bilinguals of spoken and signed language were engaged in a sequence memory span task. On each trial, participants viewed a nonsense syllable sequence presented either as written letters or as fingerspelling (4-7 syllables in length) and then held the syllable sequence for 12 s. Behavioral analysis revealed that participants relied on phonological memory while holding verbal information regardless of the type of input modality. At the neural level, this maintenance stage broadly activated the left-hemisphere language network, including the inferior frontal gyrus, supplementary motor area, superior temporal gyrus and inferior parietal lobule, for both letter and fingerspelling conditions. Interestingly, while most participants reported that they relied on phonological memory during maintenance, direct comparisons between letters and fingers revealed strikingly different patterns of neural activation during the same period. Namely, the effortful maintenance of fingerspelling inputs relative to letter inputs activated the left superior parietal lobule and dorsal premotor area, i.e., brain regions known to play a role in visuomotor analysis of hand/arm movements. These findings suggest that the dorsal visuomotor neural system subserves verbal learning via sign language by relaying gestural inputs to the classical left-hemisphere language network.

A new in vivo proarrhythmia model of drug-induced long QT syndrome was developed using the Microminipig, an incredibly small minipig established by Fuji Micra Inc. (Shizuoka). The atrioventricular (AV) node of the Microminipig of either sex weighing approximately 6 – 7 kg was ablated under halothane anesthesia, and proper care was taken for them. Proarrhythmic effects of drugs were assessed at >2 months after the onset of AV block using a Holter recording system. Oral administration of dl-sotalol (10 mg/kg) to the AV-block Microminipig prolonged the QT interval; moreover, it frequently induced dangerous ventricular premature beats, whereas no arrhythmia was detected after the vehicle administration (n = 4). Such dl-sotalol–induced ventricular arrhythmias were not detected in the intact Microminipig with sinus rhythm, although significant QT prolongation was observed (n = 4). Thus, the sensitivity and specificity of the AV-block Microminipig for detecting the drug-induced long QT syndrome can be considered to be comparable to previously established AV-block animal models of dogs and monkeys. Keywords:: Microminipig, long QT syndrome, torsades de pointes, atrioventricular block, dl-sotalol

In this paper, a novel pendulum-type accelerometer based on hetero-core fiber optics has been proposed for structural health monitoring targeting large-scale civil infrastructures. Vibration measurement is a non-destructive method for diagnosing the failure of structures by assessing natural frequencies and other vibration patterns. The hetero-core fiber optic sensor utilized in the proposed accelerometer can serve as a displacement sensor with robustness to temperature changes, in addition to immunity to electromagnetic interference and chemical corrosions. Thus, the hetero-core sensor inside the accelerometer measures applied acceleration by detecting the rotation of an internal pendulum. A series of experiments showed that the hetero-core fiber sensor linearly responded to the rotation angle of the pendulum ranging within (−6°, 4°), and furthermore the proposed accelerometer could reproduce the waveform of input vibration in a frequency band of several Hz order.

In this study, a new three-dimensional micro vibration stage is developed, in which a doubly steric L-shaped clamped-free beam type vibrator is utilized. The developed three-dimensional micro vibration stage, which has very simple structure and is quite easily sterilized, is extended to control system of cell culture. Focusing on osteoblast character which is sensitive to external mechanical stimuli, a normal human osteoblast is chosen as a test subject. Dynamic stimulation is applied to the normal human osteoblast utilizing the developed three-dimensional vibration stage. In order to estimate effect of dynamic stimulation upon cultured cell, we define parameters of projected area and slenderness ratio of the cultured normal human osteoblast. Statically cultured cells of 4th and 6th passage were provided for experiments. It was observed that the projected area of normal human osteoblast increased, while the slenderness ratio decreased according to the number of cell passage increasing. Shape of the 6th passage of dynamically stimulated cells was not similar to that of same passage of control, but to that of 4th passage of control. From the viewpoint of morphology, the present study has shown the significant effect of dynamic stimulation upon cultured cells.

We reported that the introduction of polyethylene glycol (PEG) to poly-l-ornithine (PLO), which is an homopolymeric basic amino acid having absorption-enhancement ability, prolonged retention time in an in vitro inclined plate test, probably due to an increase in viscosity caused by PEGylation. The aim of the present study is to investigate whether the introduction of PEG chains to PLO improves intranasal retention and transnasal absorption in vivo. We performed intranasal administration experiments using PLO and PEG-PLO with a model drug, fluorescein isothiocyanate dextran (FD-4), in rats under closed and open systems. In the open system, transition of plasma FD-4 concentration after co-administration with unmodified PLO was low, and the area under the plasma concentration-time curve (AUC) decreased to about 60% of that in the closed system. In contrast, the AUC after co-administration with PEG-PLO in the open system was about 90% of that in the closed system, and the transition of plasma FD-4 concentration and FD-4 absorption profile were similar to those of the closed system. These findings indicate that introducing PEG chains to homopolymeric basic amino acids (HPBAAs) is a very useful method for developing a functional absorption enhancer that can exhibit an efficient in vivo absorption-enhancing effect.

The common marmoset (Callithrix jacchus) is a non-human primate that could prove useful as human pharmacokinetic and biomedical research models. The cytochromes P450 (P450s) are a superfamily of enzymes that have critical roles in drug metabolism and disposition via monooxygenation of a broad range of xenobiotics; however, information on some marmoset P450s is currently limited. Therefore, identification and quantitative analysis of tissue-specific mRNA transcripts, including those of P450s and flavin-containing monooxygenases (FMO, another monooxygenase family), need to be carried out in detail before the marmoset can be used as an animal model in drug development. De novo assembly and expression analysis of marmoset transcripts were conducted with pooled liver, intestine, kidney, and brain samples from three male and three female marmosets. After unique sequences were automatically aligned by assembling software, the mean contig length was 718 bp (with a standard deviation of 457 bp) among a total of 47,883 transcripts. Approximately 30% of the total transcripts were matched to known marmoset sequences. Gene expression in 18 marmoset P450- and 4 FMO-like genes displayed some tissue-specific patterns. Of these, the three most highly expressed in marmoset liver were P450 2D-, 2E-, and 3A-like genes. In extrahepatic tissues, including brain, gene expressions of these monooxygenases were lower than those in liver, although P450 3A4 (previously P450 3A21) in intestine and P450 4A11- and FMO1-like genes in kidney were relatively highly expressed. By means of massive parallel long-read sequencing and short-read technology applied to marmoset liver, intestine, kidney, and brain, the combined next-generation sequencing analyses reported here were able to identify novel marmoset drug-metabolizing P450 transcripts that have until now been little reported. These results provide a foundation for mechanistic studies and pave the way for the use of marmosets as model animals for drug development in the future.

Cynomolgus monkey and rhesus monkey are used in drug metabolism studies due to their evolutionary closeness and physiological resemblance to human. In cynomolgus monkey, we previously identified cytochrome P450 (P450 or CYP) 2C76 that does not have a human ortholog and is partly responsible for species differences in drug metabolism between cynomolgus monkey and human. In this study, we report characterization of CYP2C93 cDNA newly identified in cynomolgus monkey and rhesus monkey. The CYP2C93 cDNA contained an open reading frame of 490 amino acids approximately 84-86% identical to human CYP2Cs. CYP2C93 was located in the genomic region, which corresponded to the intergenic region in the human genome, indicating that CYP2C93 does not correspond to any human genes. CYP2C93 mRNA was expressed predominantly in the liver among 10 tissues analyzed. The CYP2C93 proteins heterologously expressed in Escherichia coli metabolized human CYP2C substrates, diclofenac, flurbiprofen, paclitaxel, S-mephenytoin, and tolbutamide. In addition to a normal transcript (SV1), an aberrantly spliced transcript (SV2) lacking exon 2 was identified, which did not give rise to a functional protein due to frameshift and a premature termination codon. Mini gene assay revealed that the genetic variant IVS2-1G>T at the splice site of intron 1, at least partly, accounted for the exon-2 skipping; therefore, this genotype would influence CYP2C93-mediated drug metabolism. SV1 was expressed in 6 of 11 rhesus monkeys and 1 of 8 cynomolgus monkeys, but the SV1 in the cynomolgus monkey was nonfunctional due to a rare null genotype (c.102T>del). These results suggest that CYP2C93 can play roles as a drug-metabolizing enzyme in rhesus monkeys (not in cynomolgus monkeys), although its relative contribution to drug metabolism has yet to be validated.

The main purpose of the present study is to envisage the molecular mechanism of inhibitory action of dehydrocostuslactone (DCE) and costunolide (CS), two naturally occurring sesquiterpene lactones, towards the activation of signal transducer and activator of transcription 3 (STAT3). We report that, in human THP-1 cell line, they inhibit IL-6-elicited tyrosine phosphorylation of STAT3 and its DNA binding activity with EC(50) of 10 µM with concomitant down-regulation of the phosphorylation of the tyrosine Janus kinases JAK1, JAK2 and Tyk2. Furthermore, these compounds that contain an α-β-unsaturated carbonyl moiety and function as potent Michael reaction acceptor, induce a rapid drop in intracellular glutathione (GSH) concentration by direct interaction with it, thereby triggering S-glutathionylation of STAT3. Dehydrocostunolide (HCS), the reduced form of CS lacking only the α-β-unsaturated carbonyl group, fails to exert any inhibitory action. Finally, the glutathione ethylene ester (GEE), the cell permeable GSH form, reverts the inhibitory action of DCE and CS on STAT3 tyrosine phosphorylation. We conclude that these two sesquiterpene lactones are able to induce redox-dependent post-translational modification of cysteine residues of STAT3 protein in order to regulate its function.