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We investigate the stability of the polar surface of ZnO films grown homoepitaxially on atomically flat ZnO (000 1 ¯) O-face substrates by neodymium yttrium aluminum garnet (Nd:YAG) pulsed laser deposition (PLD). For films grown in the temperature range from 500 to 700 °C, ion scattering spectroscopy showed that the film surface termination was the same as the ZnO substrate. Even for a Mg0.2Zn0.8O/ZnO superlattice, no polarity reversal occurred, indicating that the ZnO (000 1 ¯) O-face is highly stable, despite the film surface sputtering caused by the high kinetic energy of the PLD plume generated by the Nd:YAG laser. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) is a personalized treatment approach that involves optimizing drug dosages based on patient-specific factors, such as drug plasma concentrations, therapeutic efficacy, or adverse reactions. The plasma concentration of drugs is determined using liquid chromatography/tandem mass spectrometry (LC-MS/MS) or various immunoassays. Compared with immunoassays, LC-MS/MS requires more pretreatment time as the number of samples increases. Recently, fully automated pretreatment LC-MS/MS systems have been developed to automatically perform whole-sample pretreatment for LC-MS/MS analysis. In this study, we developed a method for simultaneous concentration determination of five analytes (clozapine, mycophenolic acid, sunitinib, N-desethylsunitinib, and voriconazole) using LC-MS/MS for clinical TDM using a fully automated LC-MS/MS pretreatment system. In the developed method, the intra- and inter-assay relative error (RE) values ranged between −14.8% and 11.3%; the intra- and inter-assay coefficient of variation (CV) values were <8.8% and <10.5%, respectively. The analytes showed good stability, with RE values ranging between −13.6% and 10.9% and CV values <8.9%. Furthermore, the plasma concentrations in clinical samples using this method and the conventional manual pretreatment method showed similar results. Therefore, the method developed in this study could be considered a useful pretreatment method for routine TDM in patients. [ABSTRACT FROM AUTHOR]

Imaging tests, tumor marker (TM) screening, and biochemical tests provide a definitive diagnosis of hepatocellular carcinoma (HCC). However, some patients with HCC may present TM-negative results, warranting a need for developing more sensitive and accurate screening biomarkers. Various diseases exhibit increased blood levels of bile acids, biosynthesized from cholesterol in the liver, and they have been associated with HCC. Herein, we analyzed plasma bile acids using liquid chromatography/tandem mass spectrometry and integrated them with conventional biomarkers to develop a diagnostic screening model for HCC. Plasma samples were obtained from patients diagnosed with chronic hepatitis, hepatic cirrhosis (HC), and HCC. A QTRAP 6500 mass spectrometer and a Nexera liquid chromatograph with a YMC-Triart C18 analytical column were used. The mobile phase A was a 20 mmol/L ammonium formate solution, and mobile phase B was a methanol/acetonitrile mixture (1:1, v/v) with 20 mmol/L ammonium formate. After determining the concentrations of 32 bile acids, statistical analysis and diagnostic screening model development were performed. Plasma concentrations of bile acids differed between sample groups, with significant differences observed between patients with HC and HCC. By integrating bile acid results with conventional biochemical tests, a potential diagnostic screening model for HCC was successfully developed. Future studies should increase the sample size and analyze the data in detail to verify the diagnostic efficacy of the model. [ABSTRACT FROM AUTHOR]

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β‐hydroxycortisol, deoxycholic acid, and 1β‐hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography–tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three‐compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM. [ABSTRACT FROM AUTHOR]

Aim: Nucleos(t)ide analogs do not completely prevent hepatocellular carcinoma (HCC) in chronic hepatitis B virus infection. This study aimed to evaluate the dynamics of a non‐invasive liver fibrosis marker, the Fibrosis‐4 (FIB‐4) index, for predicting HCC development. Methods: Among a total of 882 chronically hepatitis B virus infection‐infected patients who were treated with nucleos(t)ide analogs, 472 patients without HCC history whose FIB‐4 at baseline and 1 year of treatment was obtained were evaluated for the incidence of HCC. Results: The median FIB‐4 was 2.00 at baseline and was significantly reduced to 1.58 at 1 year (P < 0.001), but the reduction was small at 2 years or later. When a receiver operating characteristic analysis of FIB‐4 was performed to predict HCC within 5 years, the area under the curve of FIB‐4 at 1 year was higher than that at baseline (0.676 vs. 0.599). The HCC incidence was significantly higher in patients with FIB‐4 ≥1.58 than in those with FIB‐4 <1.58 (14.8% vs. 3.6% at 10 years, P < 0.001). Additionally, an abnormal alanine aminotransferase (≥31 U/L) at 1 year was an independent risk for HCC. When a fibrosis and alanine aminotransferase‐1 (FAL‐1) score was evaluated as an applicable number of FIB‐4 ≥1.58, and alanine aminotransferase ≥31 as 0, 1, and 2, the HCC risk in patients with score 2 was significantly higher than in those with score 1 or score 0 (24.1% vs. 9.8% vs. 0.7% at 10 years, P < 0.001). Conclusions: FIB‐4 ≥1.58 and alanine aminotransferase ≥31 at 1 year of nucleos(t)ide analog was an independent risk factor for HCC development, and a score using these factors stratified the risk of HCC. [ABSTRACT FROM AUTHOR]

Flavonoids have garnered attention because of their beneficial bioactivities. However, some flavonoids reportedly interact with drugs via transporters and may induce adverse drug reactions. This study investigated the effects of food ingredients on organic anion-transporting polypeptide (OATP) 4C1, which handles uremic toxins and some drugs, to understand the safety profile of food ingredients in renal drug excretion. Twenty-eight food ingredients, including flavonoids, were screened. We used ascorbic acid (AA) to prevent curcumin oxidative degradation in our method. Twelve compounds, including apigenin, daidzein, fisetin, genistein, isorhamnetin, kaempferol, luteolin, morin, quercetin, curcumin, resveratrol, and ellagic acid, altered OATP4C1-mediated transport. Kaempferol and curcumin strongly inhibited OATP4C1, and the Ki values of kaempferol (AA(−)), curcumin (AA(−)), and curcumin (AA(+)) were 25.1, 52.2, and 23.5 µM, respectively. The kinetic analysis revealed that these compounds affected OATP4C1 transport in a competitive manner. Antioxidant supplementation was determined to benefit transporter interaction studies investigating the effects of curcumin because the concentration-dependent curve evidently shifted in the presence of AA. In this study, we elucidated the food–drug interaction via OATP4C1 and indicated the utility of antioxidant usage. Our findings will provide essential information regarding food–drug interactions for both clinical practice and the commercial development of supplements. [ABSTRACT FROM AUTHOR]

Niemann–Pick disease type C (NPC) is an autosomal recessive disorder with progressive neurodegeneration. Although the causative genes were previously identified, NPC has unclear pathophysiological aspects, and patients with NPC present various symptoms and onset ages. However, various novel biomarkers and metabolic alterations have been investigated; at present, few comprehensive proteomic alterations have been reported in relation to NPC. In this study, we aimed to elucidate proteomic alterations in NPC and perform a global proteomics analysis for NPC model cells. First, we developed two NPC cell models by knocking out NPC1 using CRISPR/Cas9 (KO1 and KO2). Second, we performed a label-free (LF) global proteomics analysis. Using the LF approach, more than 300 proteins, defined as differentially expressed proteins (DEPs), changed in the KO1 and/or KO2 cells, while the two models shared 35 DEPs. As a bioinformatics analysis, the construction of a protein–protein interaction (PPI) network and an enrichment analysis showed that common characteristic pathways such as ferroptosis and mitophagy were identified in the two model cells. There are few reports of the involvement of NPC in ferroptosis, and this study presents ferroptosis as an altered pathway in NPC. On the other hand, many other pathways and DEPs were previously suggested to be associated with NPC, supporting the link between the proteome analyzed here and NPC. Therapeutic research based on these results is expected in the future. [ABSTRACT FROM AUTHOR]

Introduction: The CAPTURE study estimated the global prevalence of established cardiovascular disease (CVD) and characterized the usage of glucose-lowering agents (GLAs) in adults with type 2 diabetes (T2D) across 13 countries. The purpose of this secondary analysis of data from the Japanese sites within CAPTURE (NCT03786406, NCT03811288) was to provide data about medication usage stratified by CVD status among Japanese participants with T2D. Materials and methods: Data on GLA usage (including those with proven cardiovascular [CV] benefits) in Japanese participants with T2D managed in clinics or hospitals were collected and stratified by CVD subgroups. Results: There were 800 Japanese participants in the CAPTURE study (n = 502 [no CVD group], n = 298 [CVD group], n = 268 [atherosclerotic CVD subgroup]). Oral antidiabetic agents and insulin were used by 88.5% and 23.4%, respectively, of participants overall. Among participants with established CVD, dipeptidyl peptidase-4 inhibitors (65.1%) were most frequently used, followed by biguanides (50.7%) and insulins (26.2%). The pattern was similar among participants with atherosclerotic CVD. A lower proportion of participants in the CVD group used glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) with proven CV benefits versus the no CVD group (GLP-1 RAs: 7.0% vs. 8.6%; SGLT-2is: 13.4% vs. 19.1%). Conclusion: This analysis of the CAPTURE study provided a comprehensive overview of prescription patterns for the treatment of T2D in Japan. Use of GLAs with proven CV benefit was low, even in participants with established CVD, which was comparable to the findings from the global cohort. [ABSTRACT FROM AUTHOR]

Background and Aim: Stimulant laxatives may cause electrolyte abnormalities, dehydration, and abdominal pain; their long‐term use can lead to tolerance and subsequent refractory constipation. We investigated the effectiveness, safety, and quality of life after switching from stimulant laxatives to lubiprostone in elderly patients with chronic constipation (CC). Methods: This multicenter, interventional, open‐label, single‐arm, before‐and‐after comparison study enrolled 99 Japanese patients aged 65–90 years with CC who took stimulant laxatives for ≥2 weeks prior to switching to lubiprostone monotherapy. Results: The mean ± SD spontaneous defecations at Week 1 of 7.8 ± 6.2 times/week was not significantly different from that at baseline (8.3 ± 4.7). Spontaneous defecations were significantly reduced at Weeks 2 (−1.5 ± 4.0, P < 0.001) and 4 (−1.5 ± 3.7, P < 0.001). The Bristol Stool Form Scale score did not change from baseline (4.7 ± 0.9) at Weeks 1 (4.5 ± 1.3) or 4 (4.3 ± 1.3), but it did at Week 2 (4.3 ± 1.5, P < 0.05). The Patient Assessment of Constipation Quality of Life questionnaire score increased (0.36 ± 0.07, P < 0.001) after 28 days. Nausea was the only symptom that worsened from baseline and was the most frequently reported adverse drug reaction (15.2%). Conclusion: Switching to lubiprostone monotherapy for CC was not associated with significant concerns in short‐term spontaneous defecation frequency and safety, but it might affect the efficacy and patient quality of life over 2 weeks. Careful treatment strategies facilitating gradual switching to lubiprostone monotherapy may be needed in patients using stimulant laxatives. [ABSTRACT FROM AUTHOR]

Drought is a serious abiotic stress that leads to decreased yield. In pot experiments, the reaction center chlorophyll of photosystem I (PSI) (P700) has been reported to be oxidized in response to drought stress. In the present study, we examined whether drought stress that decreases grain yield was detected by P700 oxidation in paddy-field-grown rice (Oryza sativa L.) plants. The P700 reduction and SPAD values were also evaluated. Drought stress was imposed by the prolonged mid-season drainage in 2019 and 2020. P700 oxidation was measured at saturated CO2 levels before heading. P700 oxidation was not stimulated in the 2019-drought plots. In contrast, P700 oxidation was stimulated in the 2020-drought plot. However, this phenomenon in 2020 was primarily accounted for by decreases in total leaf-N levels, as previously observed in the rice plants grown under low N availability. Rough rice yields and ratios of filled spikelets tended to decrease in the drought plots. Therefore, drought stress responsible for a decrease in grain yields could not be directly detected by P700 oxidation in paddy-field-grown rice plants, whereas the P700 oxidation responded to changes in total leaf-N levels due to the drought stress treatment. The same conclusion was drawn for the P700 reduction and SPAD value. [ABSTRACT FROM AUTHOR]

Background: Among congenital anomalies of the portal venous system, prepancreatic postduodenal portal vein (PPPV) is very rare and has only been reported to date. Herein, we report a case of PPPV identified in preoperative examinations for hepatocellular carcinoma and a literature review. Case presentation: A 63-year-old man was admitted to our hospital for treatment of a liver tumor. After examination, he was diagnosed with hepatocellular carcinoma with a diameter of 40 mm in segment 8. Contrast-enhanced computed tomography scan showed a portal vein passing between the duodenum and pancreas, hence called PPPV. At the hepatic hilus, the portal vein branched off in a complicated course with some porto-portal communications. We determined that anatomical resection with manipulation of the hepatic hilum in this case resulted in major vascular injury. Therefore, we performed partial liver resection, and the patient was discharged uneventfully on postoperative day 14. Conclusions: Although PPPV is an extremely rare congenital vascular variant, it is important to carefully identify vascular patterns preoperatively and to recognize the possibility of such an anomaly to avoid misidentification and inadvertent injuries during surgery. [ABSTRACT FROM AUTHOR]

Introduction: CAPTURE was a cross-sectional, non-interventional study (NCT03786406, NCT03811288) investigating the prevalence and characteristics of cardiovascular disease (CVD) in adults with type 2 diabetes (T2D) across 13 countries worldwide. Here we present the findings for Japan. Materials and methods: Data were collected from adults aged ≥ 20 years (aged ≥ 18 years in countries outside Japan) with T2D who were managed in clinics or hospitals in 2019. Standardized methodology was used for all countries. The prevalence of CVD and its subtypes was estimated, weighted by care setting (clinics versus hospitals). Results: Among participants from Japan (total: 800; clinics: 440; hospitals: 360), mean (standard deviation) age was 65.6 (11.2) years and glycated hemoglobin 7.2% (0.9). Sixty-seven percent of participants were male, 57.8% had diabetes duration > 10 years, 49.8% had body mass index ≥ 25 kg/m2 and 63.1% had hypertension. The weighted prevalences (95% confidence interval [CI]) of CVD and atherosclerotic CVD were 37.3% (34.2;40.3) and 33.5% (30.6;36.4), respectively. The prevalence (95% CI) of the most common subtypes of CVD was: carotid artery disease 20.5% (18.2;22.8), coronary heart disease 11.9% (9.7;14.1) and cerebrovascular disease 10.4% (8.3;12.5). Conclusions: These contemporary data from the CAPTURE study on CVD prevalence in adults with T2D in Japan show that approximately one in three adults with T2D had established CVD, which is comparable to the prevalence in the global study cohort. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Whether basal β‐cell proliferation during adulthood is involved in maintaining sufficient β‐cell mass, and if so, the molecular mechanism(s) underlying basal β‐cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in 'adaptive' β‐cell proliferation, which facilitates rapid increases in β‐cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of β‐cell FoxM1 in 'basal' β‐cell proliferation under normal conditions and in the maintenance of sufficient β‐cell mass as well as glucose homeostasis during adulthood. Materials and Methods: FoxM1 deficiency was induced specifically in β‐cells of 8‐week‐old mice, followed by analyzing its short‐ (2 weeks) and long‐ (10 months) term effects on β‐cell proliferation, β‐cell mass, and glucose tolerance. Results: FoxM1 deficiency suppressed β‐cell proliferation at both ages, indicating critical roles of FoxM1 in basal β‐cell proliferation throughout adulthood. While short‐term FoxM1 deficiency affected neither β‐cell mass nor glucose tolerance, long‐term FoxM1 deficiency suppressed β‐cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, the insulin secretory function was not impaired in islets isolated from mice subjected to long‐term β‐cell FoxM1 deficiency. Therefore, β‐cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long‐term β‐cell FoxM1 deficiency. Conclusions: Basal low‐level proliferation of β‐cells during adulthood is important for maintaining sufficient β‐cell mass and good glucose tolerance and β‐cell FoxM1 underlies this mechanism. Preserving β‐cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age. [ABSTRACT FROM AUTHOR]

Patients with liver diseases not only experience the adverse effects of liver-metabolized drugs, but also the unexpected adverse effects of renally excreted drugs. Bile acids alter the expression of renal drug transporters, however, the direct effects of bile acids on drug transport remain unknown. Renal drug transporter organic anion-transporting polypeptide 4C1 (OATP4C1) was reported to be inhibited by chenodeoxycholic acid. Therefore, we predicted that the inhibition of OATP4C1-mediated transport by bile acids might be a potential mechanism for the altered pharmacokinetics of renally excreted drugs. We screened 45 types of bile acids and calculated the IC50, Ki values, and bile acid–drug interaction (BDI) indices of bile acids whose inhibitory effect on OATP4C1 was >50%. From the screening results, lithocholic acid (LCA), glycine-conjugated lithocholic acid (GLCA), and taurine-conjugated lithocholic acid (TLCA) were newly identified as inhibitors of OATP4C1. Since the BDI index of LCA was 0.278, LCA is likely to inhibit OATP4C1-mediated transport in clinical settings. Our findings suggest that dose adjustment of renally excreted drugs may be required in patients with renal failure as well as in patients with hepatic failure. We believe that our findings provide essential information for drug development and safe drug treatment in clinics. [ABSTRACT FROM AUTHOR]

Background: Peritoneal dialysis (PD) catheter malposition is one of the complications of renal replacement therapy. This study aimed to determine the preoperative factors that cause PD catheter malposition. Methods: The prospective cohort study included patients who underwent PD catheter insertion surgery and had preoperative and postoperative computed tomography scans. We compared preoperative and intraoperative factors between the lower depth catheter group (group L) and upper depth catheter group (group U), and preoperative and intraoperative factors between the posterior catheter group (group P) and anterior catheter group (group A). In addition, PD catheter obstruction requiring surgical intervention in each group was followed up for 1 year. Results: A total of 150 patients were categorized into groups L (n = 77) and U (n = 73), or groups P (n = 107) and A (n = 43). Body mass index (BMI; P = 0.02), subcutaneous fat area (P = 0.02), and rate of previous abdominal surgery (P = 0.01) were significantly lower in group L than in group U. In terms of anterior catheter position, females had more-anterior catheter positions. The time to PD catheter obstruction requiring surgical intervention (P = 0.03) was significantly lower in group U than in group L. Conclusions: High BMI, high subcutaneous fat area, high subcutaneous fat thickness, and previous abdominal surgery were identified as preoperative factors that cause the PD catheter to have an upper depth. Female sex was a preoperative influencing factor for the anterior PD catheter position. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super‐aged' populations, such as Japan. This post‐hoc analysis assessed once‐weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. Materials and Methods: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once‐weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m2). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. Results: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8–73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20–168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups. Reductions from baseline in glycosylated hemoglobin ranged from –1.7 to –2.1 with semaglutide 0.5 mg, –1.8 to –2.4 with semaglutide 1.0 mg and –0.6 to –1.0 with comparators. Corresponding ranges for bodyweight (kg) were –1.0 to –2.5, –2.4 to –4.3 and 1.0 to –1.0 kg, respectively. The safety profile of semaglutide was broadly similar across BMI and age subgroups. Conclusions: In this post‐hoc analysis with modest subgroup numbers, once‐weekly semaglutide appeared consistently more efficacious versus comparators across age and BMI subgroups in Japanese patients, with a similar safety profile. [ABSTRACT FROM AUTHOR]

NaCT mediates citrate uptake in the liver cell line HepG2. When these cells were exposed to iron (Fe3+), citrate uptake/binding as monitored by the association of [14C]-citrate with cells increased. However, there was no change in NaCT expression and function, indicating that NaCT was not responsible for this Fe3+-induced citrate uptake/binding. Interestingly however, the process exhibited substrate selectivity and saturability as if the process was mediated by a transporter. Notwithstanding these features, subsequent studies demonstrated that the iron-induced citrate uptake/binding did not involve citrate entry into cells; instead, the increase was due to the formation of citrate-Fe3+ chelate that adsorbed to the cell surface. Surprisingly, the same phenomenon was observed in culture wells without HepG2 cells, indicating the adsorption of the citrate-Fe3+ chelate to the plastic surface of culture wells. We used this interesting phenomenon as a simple screening technique for new iron chelators with the logic that if another iron chelator is present in the assay system, it would compete with citrate for binding to Fe3+ and prevent the formation and adsorption of citrate-Fe3+ to the culture well. This technique was validated with the known iron chelators deferiprone and deferoxamine, and with the bacterial siderophore 2,3-dihydroxybenzoic acid and the catechol carbidopa. [ABSTRACT FROM AUTHOR]

Patients with a chronic hepatitis B virus (HBV) infection who are treated with nucleos(t)ide analogues (NAs) are still at risk for hepatocellular carcinoma (HCC), and it has been clinically questioned whether patients with a high risk of HCC can be identified efficiently. We aimed to clarify the risk factors associated with the development of HCC during NA therapies. A total of 611 chronically HBV-infected patients without a history of HCC, who were treated with NAs for more than 6 months (median 72 months), from 2000 to 2021, were included from 16 hospitals in the Tohoku district in Japan. Incidences of HCC occurrence were analyzed with clinical factors, including on-treatment responses. Alanine aminotransferase (ALT) normalization, based on the criteria of three guidelines, was analyzed with other parameters, including the age–male–ALBI–platelets (aMAP) risk score. During the observation period, 48 patients developed HCC, and the cumulative HCC incidence was 10.6% at 10 years. Non-achievement of ALT normalization at 1 year of therapy was mostly associated with HCC development when ALT ≤ 30 U/L was used as the cut-off (cumulative incidence, 19.9% vs. 5.3% at 10 years, p < 0.001). The effectiveness of the aMAP risk score at the start of treatment was validated in this cohort. A combination of an aMAP risk score ≥ 50 and non-achievement of ALT normalization could stratify the risk of HCC significantly, and notably, there was no HCC development in 103 patients without these 2 factors. In conclusion, non-achievement of ALT normalization (≤30 U/L) at 1 year might be useful in predicting HCC during NA therapies and, in combination with the aMAP risk score, could stratify the risk more precisely. [ABSTRACT FROM AUTHOR]

Niemann–Pick disease type C (NPC) is an autosomal recessive disease caused by a functional deficiency of cholesterol-transporting proteins in lysosomes, and exhibits various clinical symptoms. Since mitochondrial dysfunction in NPC has recently been reported, cholesterol catabolism to steroid hormones may consequently be impaired. In this study, we developed a comprehensive steroid hormone analysis method using liquid chromatography/tandem mass spectrometry (LC–MS/MS) and applied it to analyze changes in steroid hormone concentrations in NPC model cells. We investigated the analytical conditions for simultaneous LC–MS/MS analysis, which could be readily separated from each other and showed good reproducibility. The NPC phenotype was verified as an NPC model with mitochondrial abnormalities using filipin staining and organelle morphology observations. Steroid hormones in the cell suspension and cell culture medium were also analyzed. Steroid hormone analysis indicated that the levels of six steroid hormones were significantly decreased in the NPC model cell and culture medium compared to those in the wild-type cell and culture medium. These results indicate that some steroid hormones change during NPC pathophysiology and this change is accompanied by mitochondrial abnormalities. [ABSTRACT FROM AUTHOR]

Recent studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKIs) could improve treatment efficacy and safety. A simple analytical method using high‐performance LC/electrospray ionization–tandem mass spectrometry has been developed and validated for simultaneous quantification of BCR‐ABL and Bruton's TKIs used for chronic leukemia (imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib) in human plasma. Although these structures and physical properties are similar, owing to their different linear ranges, simultaneously determining the plasma levels of these five TKIs by applying optimal MS parameters remains difficult. A quantitative range exceeding 60,000‐fold was required, and the linear dynamic ranges of imatinib, bosutinib, and nilotinib were limited because of the presence of a saturated detection signal. In this study, we applied the in‐source collision‐induced dissociation technique to control the ion amounts in mass spectrometry. This new method allowed rapid determination within 5 min with simple pretreatment. The method was validated according to the US Food and Drug Administration guidelines. Moreover, all samples of patients with chronic leukemia were successfully measured and their values were within the linear range of measurement. Therefore, our high‐throughput analytical system is useful to measure the plasma concentrations of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in clinical practice. [ABSTRACT FROM AUTHOR]

Clozapine (CLZ) is a key drug in treatment‐resistant schizophrenia. Therapeutic drug monitoring (TDM) of CLZ and its metabolites, N‐desmethylclozapine and clozapine N‐oxide, is required to monitor and manage the risks of side effects. Although quantification methods for TDM have been developed for CLZ and its metabolites, they were not sufficiently accurate for the quantification of CLZ owing to the upper limits of the calibration curves. An analytical method using high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry was developed and validated for the simultaneous measurement of CLZ and its metabolites in human plasma. To expand the concentration range of the calibration curves, we used a linear range shift technique using in‐source collision‐induced dissociation (CID). Using our approach, the linearity and quantitative range were improved compared to those reported by previous studies, and were sufficient for TDM in clinical practice. The intra‐ and inter‐assay accuracy was 84.6%–114.8%, and the intra‐ and inter‐assay precisions were ≤9.1% and ≤9.9%, respectively. Moreover, all samples from patients with treatment‐resistant schizophrenia were successfully quantified. Therefore, our novel analytical method using in‐source CID had the appropriate performance to measure the plasma concentrations of CLZ and its metabolites for TDM in clinical practice. [ABSTRACT FROM AUTHOR]

Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients' condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP. Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487). [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (ICC) is primary cancer of the liver with poor prognosis because of its high potential for recurrence and metastasis. We experienced a rare case of ICC with hematogenous metastasis to the falciform ligament. We aimed to clarify the route of metastasis to the mesentery by increasing the accuracy of preoperative imaging and establish a hepatectomy to control cancer.Case Presentation: An 85-year-old woman was referred to our hospital for a detailed study of progressively increasing liver tumors. She had no subjective symptoms. Her medical history showed hypertension, aneurysm clipping for cerebral hemorrhage, and gallstones. A detailed physical examination and laboratory data evaluation included tumor markers but did not demonstrate any abnormalities. On computed tomography scan, contrast-enhanced ultrasound, and magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid, the tumor appeared to be located in liver segment IV, protruding outside the liver. It appeared to contain two distinct components; we suspected ICC in the intrahepatic tumor component. Laparoscopic observation revealed that the extrahepatic lesion was an intra-falciform ligament mass; laparoscopic left hepatectomy was performed. Microscopically, the main tumor in segment IV was 15 mm in diameter and was diagnosed as moderately and poorly differentiated ICC. The tumor of the intra-falciform ligament was not continuous with the main intrahepatic nodule and was also diagnosed as ICC with extensive necrosis. There were no infiltrates in the round ligament of the liver, and several tumor thrombi were found in the small veins of the falciform ligament.Conclusions: To date, there have been a few reports of metastases of primary liver cancer to the falciform ligament. At the time of preoperative imaging and pathological diagnosis, this case was suggestive of considering that the malignant liver tumor might be suspected of metastasizing to the falciform ligament. Our case improves awareness of this pathology, which can be useful in the future when encountered by hepatic specialists and surgeons. [ABSTRACT FROM AUTHOR]

Background: Pancreatic trauma is a rare condition with a wide presentation, ranging from hematoma or laceration without main pancreatic duct involvement, to massive destruction of the pancreatic head. The optimal diagnosis of pancreatic trauma and its management approaches are still under debate. The East Association of Surgery for Trauma (EAST) guidelines recommend operative management for high-grade pancreatic trauma; however, several reports have reported successful outcomes with nonoperative management (NOM) for grade III/IV pancreatic injuries. Herein, we report a case of grade IV pancreatic injury that was nonoperatively managed through endoscopic and percutaneous drainage.Case Presentation: A 47-year-old Japanese man was stabbed in the back with a knife; upon blood examination, both serum amylase and lipase levels were within normal limits. Contrast-enhanced computed tomography (CT) showed extravasation of the contrast medium around the pancreatic head and a hematoma behind the pancreas. Abdominal arterial angiography revealed a pseudo aneurysm in the inferior pancreatoduodenal artery, as well as extravasation of the contrast medium in that artery; coil embolization was thus performed. On day 12, CT revealed a wedge-shaped, low-density area in the pancreatic head, as well as consecutive pseudocysts behind the pancreas; thereafter, percutaneous drainage was performed via the stab wound. On day 22, contrast radiography through the percutaneous drain revealed the proximal and distal parts of the main pancreatic duct. The injury was thus diagnosed as a grade IV pancreatic injury based on the American Association for the Surgery of Trauma guidelines. On day 26, an endoscopic nasopancreatic drainage tube was inserted across the disruption; on day 38, contrast-enhanced CT showed a marked reduction in the fluid collection. Finally, on day 61, the patient was discharged.Conclusions: Although the EAST guidelines recommend operative treatment for high-grade pancreatic trauma, NOM with appropriate drainage by endoscopic and/or percutaneous approaches may be a promising treatment for grade III or IV trauma. [ABSTRACT FROM AUTHOR]

Hepatic epithelioid hemangioendothelioma (EHE) is a rare malignant tumor with unknown pathogenesis. Herein, we report a case of a hepatic EHE presenting synchronously with a hepatocellular carcinoma (HCC). To the best of our knowledge, this is the second case report of synchronous hepatic EHE and HCC. An 84-year-old man presented with back pain. During examination, a tumor in liver segment 3 was coincidentally detected. Tumor marker (carbohydrate antigen 19-9, alpha-fetoprotein, and protein induced by vitamin K absence or antagonist-II) levels were elevated. Contrast-enhanced computed tomography revealed perinodular enhancement in the arterial and portal phases. Another tumor was detected in liver segment 2, which was homogeneously enhanced in the arterial phase, followed by washout in the portal and late phases. Based on these imaging findings, we diagnosed the tumor in segment 3 as a solitary cholangiocellular carcinoma and the tumor in segment 2 as a solitary HCC. Lateral sectionectomy of the liver was performed. Microscopically, spindle-shaped and epithelioid cells were present in the tumor in segment 3. On immunohistochemistry, the tumor cells were positive for CD31 and CD34, focally positive for D2-40, and negative for AE1/AE3. Therefore, the tumor in segment 3 was ultimately diagnosed as an EHE and the tumor in segment 2 as a well-differentiated HCC. Preoperative diagnosis of EHE is difficult owing to the lack of specific findings. Intratumoral calcification, halo sign, and lollipop sign are occasionally found in EHE and are useful imaging findings for diagnosis. Clinical behavior is unpredictable, ranging from indolent growth to rapid progression. Clinical or pathological predictors of the course of EHE are urgently required. [ABSTRACT FROM AUTHOR]

This study examined whether forced postural change from prone to supine during toddlers' nap, a preventative measure taken in Japan for sudden unexplained death in childhood (SUDC), disturbs toddlers' sleep. When the "Back to Sleep" campaign (BSC) was introduced to Japan in 1996, its recommendations were also applied to infants aged 1 year old and over with the expectation that the BSC recommendations may also contribute to a decrease in the occurrence rate of SUDC. Since then, Japanese nurseries have routinely conducted sleeping position checks and positional adjustments of toddlers every 5–10 min during naps. A total of 52 toddlers (age 18.4 ± 3.3 months, means ± SD) were continuously monitored for 8 h during daytime at nursery schools for wake-sleep status and body position (prone, supine and lateral) with actigraphs and 3-orthogonal-axis accelerometers. Out of the 52 toddlers, 24 toddlers adopted prone positions during naps, which were adjusted by nursery staff back to supine. When nursery staff manually changed the toddlers position from prone to supine, the toddlers either did not wake or woke only briefly (3.1 ± 4.9 min) and returned to sleep soon after the positional change. Our study indicates that manual change of toddlers' sleeping position from prone to supine, a potential SUDC prevention method, does not disturb toddlers' sleep during their naps. [ABSTRACT FROM AUTHOR]

We report a case of a 64‐year‐old woman with a past medical history (PMH) of prosthetic valve replacement 7 months prior to admission, who presented with only right back pain. Physical examination revealed one conjunctival spot hemorrhage and a mild systolic murmur. Blood cultures were positive for methicillin‐resistant Staphylococcus epidermidis. Trans‐esophageal echocardiography revealed aortic valve vegetations; hence, a diagnosis of prosthetic valve endocarditis (PVE) was made. Clinical presentation of infective endocarditis varies and sometimes mimics that of polymyalgia rheumatica. The patient was diagnosed as PVE considering the whole clinical picture including the patient's PMH, physical examination, and blood cultures. [ABSTRACT FROM AUTHOR]

Purpose: A Na+-coupled transport system in mammalian cells is responsible for the uptake of oligopeptides consisting of 5 or more amino acids. Here we investigated if this transport system is expressed in brain cells and transports the 42-amino-acid β-amyloid peptide (Aβ1–42). Methods: The human and mouse neuronal cell lines SK-N-SH and HT22, human microglial cell line HMC-3, and human blood-brain barrier endothelial cell line hCMEC/D3 were used to monitor the uptake of [3H]-deltorphin II (a heptapeptide) and fluorescence-labeled Aβ1–42. Results: All four cell lines exhibited Na+-coupled uptake of deltorphin II. Aβ1–42 competed with deltorphin II for the uptake. Uptake of fluorescence-labeled Aβ1–42 was detectable in these cell lines, and the uptake was Na+-dependent and inhibitable by deltorphin II. The Na+-coupled uptake disappeared at high concentrations of Aβ1–42 due to oligomerization of the peptide. Exposure of the cells to excess iron abolished the uptake. In hCMEC/D3 cells cultured on Transwell filters, the uptake was localized preferentially to the abluminal membrane. Conclusion: A Na+-coupled transport system mediates the uptake of Aβ1–42 monomers in neuronal and microglial cells. The same system is also responsible for the uptake of Aβ1–42 from brain into blood-brain barrier endothelial cells. These findings have relevance to Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Metformin is the first-line treatment for type 2 diabetes. Inhibition of hepatic gluconeogenesis is the primary contributor to its anti-diabetic effect. Metformin inhibits complex I and α-glycerophosphate shuttle, and the resultant increase in cytoplasmic NADH/NAD+ ratio diverts glucose precursors away from gluconeogenesis. These actions depend on metformin-mediated activation of AMP kinase (AMPK). Here we report on a hitherto unknown mechanism. Metformin inhibits the expression of the plasma membrane citrate transporter NaCT in HepG2 cells and decreases cellular levels of citrate. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, elicits a similar effect. The process involves a decrease in maximal velocity with no change in substrate affinity. The decrease in NaCT expression is associated with decreased mRNA levels. AMPK inhibits mTOR, and the mTOR inhibitor rapamycin also decreases NaCT expression. The transcription factor downstream of AMPK that is relevant to cAMP signaling is CREB; decreased levels of phospho-CREB seem to mediate the observed effects of metformin on NaCT. Citrate is known to suppress glycolysis by inhibiting phosphofructokinase-1 and activate gluconeogenesis by stimulating fructose-1,6-bisphophatase; therefore, the decrease in cellular levels of citrate would stimulate glycolysis and inhibit gluconeogenesis. These studies uncover a novel mechanism for the anti-diabetic actions of metformin. [ABSTRACT FROM AUTHOR]

Background: Reactive lymphoid hyperplasia (RLH) of the liver is a benign disorder. It is usually observed in the skin, orbit, thyroid, lung, breast, or gastrointestinal tract, but rarely in the liver. Since the first report of RLH of the liver in 1981, only 75 cases have been described in the past literature. Herein, we report a case of RLH of the liver in a patient with autoimmune hepatitis (AIH), which was misdiagnosed as hepatocellular carcinoma (HCC) preoperatively and resected laparoscopically. Case presentation: A 43-year-old Japanese woman with autoimmune hepatitis was followed up for 5 years. During her medical checkup, a hypoechoic nodule in segment 6 of the liver was detected. The nodule had been gradually increasing in size for 4 years. Abdominal ultrasound (US) revealed a round, hypoechoic nodule, 12 mm in diameter. Contrast-enhanced computed tomography (CT) demonstrated that the nodule was slightly enhanced in the arterial dominant phase, followed by perinodular enhancement in the portal and late phases. A magnetic resonance imaging (MRI) scan showed low signal intensity on the T1-weighted image (T1WI) and slightly high signal intensity on the T2-weighted image (T2WI). The findings of the Gd-EOB-DTPA-enhanced MRI were similar to those of contrast-enhanced CT. Tumor markers were all within the normal range. The preoperative diagnosis was HCC and a laparoscopic right posterior sectionectomy was performed. Pathological examination revealed that the nodular lesion was infiltrated by small lymphocytes and plasma cells, and germinal centers were present. Immunohistochemistry was positive for B cell and T cell markers, indicating polyclonality. The final diagnosis was RLH of the liver. Conclusions: The pathogenesis of RLH of the liver remains unknown, and a definitive diagnosis based on imaging findings is extremely difficult. If a small, solitary nodule is found in female patients with AIH, the possibility of RLH of the liver should be considered. [ABSTRACT FROM AUTHOR]

Based on the evidence that hemochromatosis, an iron-overload disease, drives hepatocellular carcinoma, we hypothesized that chronic exposure to excess iron, either due to genetic or environmental causes, predisposes an individual to cancer. Using pancreatic cancer as our primary focus, we employed cell culture studies to interrogate the connection between excess iron and cancer, and combined in vitro and in vivo studies to explore the connection further. Ferric ammonium citrate was used as an exogenous iron source. Chronic exposure to excess iron induced epithelial-mesenchymal transition (EMT) in normal and cancer cell lines, loss of p53, and suppression of p53 transcriptional activity evidenced from decreased expression of p53 target genes (p21, cyclin D1, Bax, SLC7A11). To further extrapolate our cell culture data, we generated EL - Kras G12D ( EL-Kras ) mouse (pancreatic neoplastic mouse model) expressing Hfe +/+ and Hfe -/- genetic background. p53 target gene expression decreased in EL-Kras / Hfe -/- mouse pancreas compared to EL-Kras / Hfe +/+ mouse pancreas. Interestingly, the incidence of acinar-to-ductal metaplasia and cystic pancreatic neoplasms (CPN) decreased in EL-Kras / Hfe -/- mice, but the CPNs that did develop were larger in these mice than in EL-Kras / Hfe +/+ mice. In conclusion, these in vitro and in vivo studies support a potential role for chronic exposure to excess iron as a promoter of more aggressive disease via p53 loss and SLC7A11 upregulation within pancreatic epithelial cells. [ABSTRACT FROM AUTHOR]

Aim: Hepatitis B virus genotype B (HBV/B) has been reported to have less risk of liver cirrhosis and hepatocellular carcinoma (HCC), but long‐term observation has rarely been reported. We aimed to clarify the characteristics of HBV/B in nucleos(t)ide analog‐treated patients in an area where HBV/B is more prevalent than in other areas of Japan. Methods: A total of 498 chronically HBV‐infected patients treated with nucleos(t)ide analog (lamivudine, entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide fumarate) for >6 months (mean 70.6 months) were included from nine hospitals in northeast Japan. The frequencies of hepatitis B surface antigen loss and HCC occurrence were analyzed. Results: Among 427 patients whose genotype could be determined, 34.0% and 64.4% were infected with HBV/B and genotype C (HBV/C), respectively. The age of patients with HBV/B was significantly older than those with HBV/C (57.7 vs. 48.1). The cumulative rate of hepatitis B surface antigen loss was significantly higher in HBV/B than in HBV/C (3.6% vs. 0.7% at 10 years). Among 480 patients without HCC history, HCC occurrence was found in 40 patients (13.4% at 10 years). There was no cumulative rate difference of HCC occurrence among the genotypes, but after propensity score matching for age/sex, it was significantly lower in HBV/B than in HBV/C (5.3% vs. 18.5% at 10 years). Conclusions: Although a lower rate of HCC occurrence in HBV/B was shown by an age/sex‐matched analysis than that in HBV/C, patients with HBV/B were significantly older and had a comparative risk of HCC occurrence in nucleos(t)ide analog‐treated patients. [ABSTRACT FROM AUTHOR]

Psoriatic arthritis (PsA) is an inflammatory arthritis with as yet unclear pathophysiology. This retrospective, multicenter, cross‐sectional study was conducted in 19 facilities in western Japan and aimed to identify patients' characteristics and factors that affect the results of treatment with biologic agents. Of 2116 patients with psoriasis, 285 (13.5%) had PsA. Skin manifestations preceded joint manifestations in 69.8%, the onset was simultaneous in 17.2%, whereas PsA preceded skin manifestations in 2.5%. Peripheral arthritis was most common, occurring in 73.7%, compared with axial disease in 21.8%, enthesitis in 23.5% and dactylitis in 35.4%. Patients with severe skin manifestations were significantly younger at onset (P = 0.02) and more frequently had axial disease (P < 0.01). Biologic agents were used in 206 patients (72.3%), anti‐tumor necrosis factor (TNF)‐α antibodies being prescribed first to 157 of them. Anti‐TNF‐α antibodies were continued by 105 participants and discontinued by 47, the remaining five patients being lost to follow up. Patients who discontinued anti‐TNF‐α antibodies were significantly older than those who continued (55 vs 51 years, P = 0.04) and significantly older at onset of joint manifestations (50 vs 44 years, P = 0.01). Multivariate analysis revealed that patients over 50 years significantly more frequently terminated anti‐TNF‐α antibodies (P < 0.01). In conclusion, patients with PsA and severe skin manifestations have earlier onset and axial disease, which seriously impacts on quality of life. Anti‐TNF‐α antibodies were generally effective enough to continue but less so in patients aged over 50 years. Further detailed research is needed. [ABSTRACT FROM AUTHOR]

Many clinically approved protein kinase inhibitors stabilize an inactive conformation of their kinase target. Such inhibitors are generally highly selective compared to active conformation inhibitors, and consequently, general methods to identify inhibitors that stabilize an inactive conformation are much sought after. Here, we have applied a high‐throughput, second‐harmonic generation (SHG)‐based conformational approach to identify small molecule stabilizers of the inactive conformation of interleukin‐2‐inducible T‐cell kinase (ITK). A single‐site cysteine mutant of the ITK kinase domain was created, labeled with an SHG‐active dye, and tethered to a supported lipid bilayer membrane. Fourteen tool compounds, including stabilizers of the inactive and active conformations as well as nonbinders, were first examined for their effect on the conformation of the labeled ITK protein in the SHG assay. As a result, inactive conformation inhibitors were clearly distinguished from active conformation inhibitors by the intensity of SHG signal. Utilizing the SHG assay developed with the tool compounds described above, we identified the mechanism of action of 22 highly selective, inactive conformation inhibitors within a group of 105 small molecule inhibitors previously identified in a high‐throughput biochemical screen. We describe here the first use of SHG for identifying and classifying inhibitors that stabilize an inactive vs. an active conformation of a protein kinase, without the need to determine costructures by X‐ray crystallography. Our results suggest broad applicability to other proteins, particularly with single‐site labels reporting on specific protein movements associated with selectivity. [ABSTRACT FROM AUTHOR]

Purpose: Propofol is one of the most widely used fast-acting intravenously administered anesthetics. However, although large inter-individual differences in dose requirements and recovery time have been observed, there are few previous studies in which the association between several potential covariates, including genetic factors such as the UGT1A9 and CYP2B6 genotypes, and propofol pharmacokinetics was simultaneously examined. This study aimed to identify factors determining propofol pharmacokinetics.Methods: Eighty-three patients were enrolled, and their blood samples were collected 1, 5, 10, and 15 min after administering a single intravenous bolus of propofol at a dose of 2.0 ml/kg to measure propofol plasma concentration. Area under the time-plasma concentration curve from zero up to the last measurable time point (AUC15min) was determined from the concentration data. The inter-individual variability of the propofol pharmacokinetics was evaluated by investigating relationships between AUC15min and genotype of UGT1A9 and CYP2B6; clinical factors, such as age, sex, body mass index (BMI), and preoperative hematological examination; and hemodynamic variables measured by a pulse dye densitogram analyzer. The Spearman rank correlation coefficient and the Mann-Whitney U test were used for the statistical analysis of continuous and categorical values, respectively. Subsequently, clinical factors that had p values of < 0.05 in the univariate analysis were examined in a multivariate analysis using multiple linear regression analysis.Results: Age, BMI, indocyanine green disappearance ratio (K-ICG), hepatic blood flow (HBF), preoperative hemoglobin level, and sex were correlated with AUC15min (p < 0.05) in univariate analysis. Multivariate analysis performed to adjust for age, BMI, K-ICG, HBF, preoperative hemoglobin level, and sex revealed only BMI as an independent factor associated with AUC15min.Conclusions: This study demonstrated that BMI influences propofol pharmacokinetics after its administration as a single intravenous injection, while UGT1A9 and CYP2B6 SNPs, other clinical factors, and hemodynamic variables do not. These results suggest that BMI is an independent factor associated with propofol pharmacokinetics in several potential covariates.Clinical trials registration number: University Hospital Medical Information Network (UMIN000022948). [ABSTRACT FROM AUTHOR]

Purpose: Malignant bowel obstruction is a complication of colorectal carcinoma or metastasis from other carcinoma, and it causes significant damage on the condition of elderly patients; however, the self-expandable metallic stents (SEMSs) have been effectively used either for palliation or for bridging to the surgical procedure for this condition. The aim of this study was to investigate the factors influencing long-term outcomes of old-aged patients with SEMS for large bowel obstruction to develop the strategy for those patients in the community medicine. Methods: We performed a retrospective review of 42 patients with a median age of 83.0 years (range, 65-99 years), who underwent SEMS placement for malignant colorectal obstruction between 2006 and 2015 in our hospital. Univariate and multivariate logistic regressions were performed on data from the patients to assess the factors affecting 6-month survival without stent dysfunction. Results: The study population comprised 24 females (57.1%) and 18 males (42.9%). Of these, 38 patients (90.5%) received SEMS as palliation, whereas 4 patients (9.5%) underwent subsequent surgery. SEMSs were successfully inserted in 97.6% of patients. The median duration of follow-up was 205.0 days (range, 20-1377 days). On multivariate analysis, shorter stents (< 10 cm) yielded better outcomes than longer stents (≥ 10 cm) ( P = 0.041), and the Cox proportional hazard model also indicated that shorter stents ( P = 0.036) predicted longer event-free survival. Conclusions: Elderly patients with malignant bowel obstruction receiving shorter stents had longer event-free survival after stenting with better general condition. [ABSTRACT FROM AUTHOR]

1. The drug–drug interaction (DDI) mediated by organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and OATP2B1 has a major impact on the hepatic clearance of drugs. The effects of tyrosine kinase inhibitors (TKIs) on OATPs have not been well studied. In the present study, we evaluated the contribution of OATPs to the hepatic uptake of crizotinib and gefitinib and the interaction of those TKIs with OATPs to estimate DDIs. 2. To clarify whether crizotinib and gefitinib were substrates for OATPs, we performed uptake studies. We examined the effects of the TKIs on uptake of typical substrates and fluvastatin via OATPs. IC50and EC50values of the TKIs were calculated. 3. OATP1B3- and OATP2B1-mediated crizotinib uptake and OATP2B1-mediated gefitinib uptake were observed. Gefitinib accelerated OATP1B3-mediated [3H]TCA uptake and inhibited OATP2B1-mediated [3H]E3S uptake. On the other hand, gefitinib inhibited OATP1B1- and OATP2B1-mediated fluvastatin uptake. 4. We provided basic information to estimate the DDI on OATPs caused by TKIs. The DDI on OATPs caused by gefitinib could occur in a normal clinical situation. And the uptake of crizotinib into the intrahepatocellular environment via OATPs may induce DDI and liver damage. We therefore emphasize the necessity of careful use of TKIs. [ABSTRACT FROM AUTHOR]

Bile acids, the metabolites of cholesterol, are signaling molecules that play critical role in many physiological functions. They undergo enterohepatic circulation through various transporters expressed in intestine and liver. Human organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of bile acids such as taurocholic acid. However, the transport properties of individual bile acids are not well understood. Therefore, we selected HEK293 cells overexpressing OATP1B1 and OATP1B3 to evaluate the transport of five major human bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, lithocholic acid) together withtheir glycine and taurine conjugates via OATP1B1 and OATP1B3. The bile acids were quantified by liquid chromatography-tandem mass spectrometry. The present study revealed that cholic acid, chenodeoxyxcholic acid, and deoxycholic acid were transported by OATP1B1 and OATP1B3, while ursodeoxycholic acid and lithocholic acid were not significantly transported by OATPs. However, all the conjugated bile acids were taken up rapidly by OATP1B1 and OATP1B3. Kinetic analyses revealed the involvement of saturable OATP1B1- and OATP1B3-mediated transport of bile acids. The apparent Km values for OATP1B1 and OATP1B3 of the conjugated bile acids were similar (0.74–14.7 μM for OATP1B1 and 0.47–15.3 μM for OATP1B3). They exhibited higher affinity than cholic acid (47.1 μM for OATP1B1 and 42.2 μM for OATP1B3). Our results suggest that conjugated bile acids (glycine and taurine) are preferred to unconjugated bile acids as substrates for OATP1B1 and OATP1B3. [ABSTRACT FROM AUTHOR]

In the 2011 Tohoku Earthquake, many structures were destroyed by the tsunami whose magnitudes were much larger than the design level. Tsunami defense structures in coastal areas will need reinforcement in the future, and for that reason it is important to evaluate tsunami behavior and resulting tsunami force. This study analyzes tsunami transformation around a Haramachi thermal power station which suffered serious damage by the tsunami due to the 2011 Tohoku Earthquake and which has complex topography and building layout. A three-dimensional (3D) tsunami simulation is carried out for a surrounding region of the Haramachi thermal power station using boundary conditions of the water surface elevation and flow velocity obtained from a two-dimensional (2D) tsunami simulation by a nonlinear shallow water model. Using these boundary conditions, the computer fluid dynamic model FLUENT is employed to simulate the tsunami behavior around the Haramachi thermal power station. The validity of the predictions is examined by comparison with actual traces of tsunami inundation depths (I.D.). [ABSTRACT FROM AUTHOR]

Background Many poststroke patients suffer functional motor limitation of the affected upper limb, which is associated with diminished health-related quality of life. Aims The aim of this study is to conduct a randomized, multicenter, comparative study of low-frequency repetitive transcranial magnetic stimulation combined with intensive occupational therapy, NEURO ( Nov El intervention Using Repetitive TMS and intensive Occupational therapy) versus constraint-induced movement therapy in poststroke patients with upper limb hemiparesis. Methods In this randomized controlled study of NEURO and constraint-induced movement therapy, 66 poststroke patients with upper limb hemiparesis were randomly assigned at 2:1 ratio to low-frequency repetitive transcranial magnetic stimulation plus occupational therapy ( NEURO group) or constraint-induced movement therapy (constraint-induced movement therapy group) for 15 days. Fugl- Meyer Assessment and Wolf Motor Function Test and Functional Ability Score of Wolf Motor Function Test were used for assessment. Results No differences in patients' characteristics were found between the two groups at baseline. The Fugl- Meyer Assessment score was significantly higher in both groups after the 15-day treatment compared with the baseline. Changes in Fugl- Meyer Assessment scores and Functional Ability Score of Wolf Motor Function Test were significantly higher in the NEURO group than in the constraint-induced movement therapy group, whereas the decrease in the Wolf Motor Function Test log performance time was comparable between the two groups (changes in Fugl- Meyer Assessment score, NEURO: 5·39 ± 4·28, constraint-induced movement therapy: 3·09 ± 4·50 points; mean ± standard error of the mean; P < 0·05) (changes in Functional Ability Score of Wolf Motor Function Test, NEURO: 3·98 ± 2·99, constraint-induced movement therapy: 2·09 ± 2·96 points; P < 0·05). Conclusions The results of the 15-day rehabilitative protocol showed the superiority of NEURO relative to constraint-induced movement therapy; NEURO improved the motion of the whole upper limb and resulted in functional improvement in activities of daily living. [ABSTRACT FROM AUTHOR]