Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m²); normal (18.5-22.9 kg/m²); overweight (23-24.9 kg/m²); and obese (25+ kg/m²). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.     

Changes in levels of hepatitis B virus markers in patients positive for low-titer hepatitis B surface antigen

Aim: Recently, patients positive for the low-titer hepatitis B surface antigen (HBsAg) have been found occasionally owing to the increase in the accuracy of detection methods. The aim of this study is to clarify the clinical status of acute hepatitis B virus (HBV) infection in patients positive for low-titer HBsAg. Method: Eight patients, who were positive for HBsAg at low titers and diagnosed as having acute HBV infection, were enrolled in this study. Assays of HBsAg, hepatitis B core antibody (anti-HBc), hepatitis B e-antigen (HBeAg), hepatitis B e-antibody (anti-HBe), hepatitis B surface antibody (anti-HBs) and HBV DNA, and biochemical tests were basically conducted every 4 weeks for at least 24 weeks. Result: The average cut-off index of HBsAg was 8.7 ± 9.6 (range, 1.0–25.7). All the patients were negative for anti-HBc, HBeAg, anti-HBe and HBV DNA on their initial visit. The genotype of HBV could be determined in four patients: two were infected with genotype B/HBV, one was infected with genotype A/HBV, and the remaining patient was infected with genotype C/HBV. Although HBsAg clearance was observed within 4 months in all the patients, none of the other HBV markers seroconverted during the observation period. Conclusion: HBV infection terminating with seronegativity for HBV markers may occur in transient HBV infection.     

Exploratory Research on Determinants of Place of Death in a Large-scale Cohort Study: The JPHC Study

BackgroundThe place of death and related factor, such as diseases, symptoms, family burden, and cost, has been examined, but social background and lifestyle were not considered in most studies. Here, we assessed factors that are associated with the place of death using the largest cohort study in Japan.MethodsA total of 17,781 deaths from the cohort study were assessed. The study database was created from the Japan Public Health Center-based Prospective Study (JPHC Study), in which demographic data were collected from Japanese Vital Statistics. Adjusted odds ratios for home death were calculated using logistic regression.ResultsMultivariate analysis adjusted for various factors showed that unmarried status (odds ratio [OR] 2.4; 95% confidence interval [CI], 2.0–2.9), unemployed male (OR 1.3; 95% CI, 1.1–1.5), and high drinking level in male (OR 1.3; 95% CI, 1.1–1.6) were associated with home death. Regarding the cause of death, cardiovascular disease (OR 3.3; 95% CI, 2.9–3.8), cerebrovascular disease (OR 1.9; 95% CI, 1.6–2.2), and external factors (OR 4.1; 95% CI, 3.5–4.8) were significantly associated with home death, compared with cancer. The risk of death at home was significantly higher among unmarried subjects stratified by cause of death (cardiovascular disease: OR 3.2; 95% CI, 2.2–4.7; cerebrovascular disease: OR :5.1; 95% CI, 2.9–9.1; respiratory disease: OR 3.4; 95% CI, 1.6–7.6; and external factors: OR 2.3; 95% CI, 1.4–3.7), but for cancer, the risk of death at home tended to be higher among married participants.ConclusionThis study found that various factors are associated with home death using the largest cohort study in Japan. There is a high possibility of home deaths in people with fewer social connections and in those with diseases leading to sudden death.Key words: place of death, large-cohort study, factors influencing home death     

Female reproductive factors and risk of all-cause and cause-specific mortality among women: The Japan Public Health Center–based Prospective Study (JPHC study)

Purpose

We investigated the association between reproductive history and mortality from all and major causes among Japanese women.

Dietary Acrylamide Intake and the Risk of Pancreatic Cancer: The Japan Public Health Center-Based Prospective Study

Acrylamide is a probable carcinogen in humans. Few studies have assessed dietary acrylamide intake and the risk of pancreatic cancer; however, these studies are based on Western populations. Our purpose was to investigate the association of dietary acrylamide intake with the risk of pancreatic cancer utilizing data from the Japan Public Health Center-based Prospective Study. We evaluated the data of 89,729 participants aged 45–74 years, who replied to a questionnaire on past medical history and lifestyle habits from 1995–1998. Dietary acrylamide intake was estimated utilizing a validated food frequency questionnaire. We calculated the hazard ratios and 95% confidence intervals by using Cox proportional-hazards regression models. The average follow-up was 15.2 years, and 576 cases of pancreatic cancer were diagnosed. In the multivariate-adjusted model, an association between dietary acrylamide intake and pancreatic cancer risk was not demonstrated (hazard ratio for the highest vs. lowest quartile = 0.83, 95% confidence interval: 0.65–1.05, p for trend = 0.07). Furthermore, in the analyses stratified by sex, smoking status, coffee consumption, green tea consumption, alcohol consumption, and body mass index, no significant association was detected. Dietary acrylamide intake was not associated with the pancreatic cancer risk in Japanese individuals.     

Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13

Abstract

1.?The polycyclic hydrocarbons (PAHs), pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene, were found to induce Type I binding spectra with human cytochrome P450 (P450) 2A13 and were converted to various mono- and di-oxygenated products by this enzyme.

2.?Pyrene was first oxidized by P450 2A13 to 1-hydroxypyrene which was further oxidized to di-oxygenated products, i.e. 1,8- and 1,6-dihydroxypyrene. Of five other human P450s examined, P450 1B1 catalyzed pyrene oxidation to 1-hydroxypyrene at a similar rate to P450 2A13 but was less efficient in forming dihydroxypyrenes. P450 2A6, a related human P450 enzyme, which did not show any spectral changes with these four PAHs, showed lower activities in oxidation of these compounds than P450 2A13.

3.?1-Nitropyrene and 1-acetylpyrene were also found to be efficiently oxidized by P450 2A13 to several oxygenated products, based on mass spectrometry analysis.

4.?Molecular docking analysis supported preferred orientations of pyrene and its derivatives in the active site of P450 2A13, with lower interaction energies (U values) than observed for P450 2A6 and that several amino acid residues (including Ala-301, Asn-297 and Ala-117) play important roles in directing the orientation of these PAHs in the P450 2A13 active site. In addition, Phe-231 and Gly-329 were found to interact with pyrene to orient this compound in the active site of P450 1B1.

5.?These results suggest that P450 2A13 is one of the important enzymes that oxidizes these PAH compounds and may determine how these chemicals are detoxicated and bioactivated in humans.     

Identification of putative substrates for cynomolgus monkey cytochrome P450 2C8 by substrate depletion assays with 22 human P450 substrates and inhibitors

Cynomolgus monkeys are widely used in drug developmental stages as non‐human primate models. Previous studies used 89 compounds to investigate species differences associated with cytochrome P450 (P450 or CYP) function that reported monkey specific CYP2C76 cleared 19 chemicals, and homologous CYP2C9 and CYP2C19 metabolized 17 and 30 human CYP2C9 and/or CYP2C19 substrates/inhibitors, respectively. In the present study, 22 compounds selected from viewpoints of global drug interaction guidances and guidelines were further evaluated to seek potential substrates for monkey CYP2C8, which is highly homologous to human CYP2C8 (92%). Amodiaquine, montelukast, quercetin and rosiglitazone, known as substrates or competitive inhibitors of human CYP2C8, were metabolically depleted by recombinant monkey CYP2C8 at relatively high rates. Taken together with our reported findings of the slow eliminations of amodiaquine and montelukast by monkey CYP2C9, CYP2C19 and CYP2C76, the present results suggest that these at least four chemicals may be good marker substrates for monkey CYP2C8. Copyright © 2016 John Wiley & Sons, Ltd.     

Human plasma concentrations of herbicidal carbamate molinate extrapolated from the pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and physiologically based pharmacokinetic modeling

To predict concentrations in humans of the herbicidal carbamate molinate, used exclusively in rice cultivation, a forward dosimetry approach was carried out using data from lowest-observed-adverse-effect-level doses orally administered to rats, wild type mice, and chimeric mice with humanized liver and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated hydroxylation of molinate, but rat livers additionally produced molinate sulfoxide and an unidentified metabolite. Adjusted animal biomonitoring equivalents for molinate and its primary sulfoxide from animal studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. The slower disposition of molinate and accumulation of molinate sulfoxide in humans were estimated by modeling after single and multiple doses compared with elimination in rodents. The results from simplified PBPK modeling in combination with chimeric mice with humanized liver suggest that ratios of estimated parameters of molinate sulfoxide exposure in humans to those in rats were three times as many as general safety factor of 10 for species difference in toxicokinetics. Thus, careful regulatory decision is needed when evaluating the human risk resulting from exposure to low doses of molinate and related carbamates based on data obtained from rats.     

Single Ingestion of Trehalose Enhances Prolonged Exercise Performance by Effective Use of Glucose and Lipid in Healthy Men

Trehalose increases blood glucose levels slowly and induces a slight insulin response. The present study aimed to study the effect of trehalose on prolonged exercise performance. The participants were 12 healthy men (age: 21.3 ± 0.9 y). After an overnight fast (12 h), they first exercised with a constant load (intensity: 40% V˙O₂peak) for 60 min using a bicycle ergometer. They continued to exercise with a constant load (40% V˙O₂peak) for 30 min between four sets of the 30-s Wingate test. After the 1st set, each participant ingested 500 mL water (control), 8% glucose, or 8% trehalose in three trials. These three trials were at least one week apart and were conducted in a double-blind and randomized crossover manner. Blood was collected for seven biochemical parameters at 12 time points during the experiment. The area under the curve of adrenaline after ingestion of trehalose was significantly lower than that for water and tended to be lower than that for glucose in the later stage of the exercise. Lower secretion of adrenaline after a single dose of 8% trehalose during prolonged exercise reflected the preservation of carbohydrates in the body in the later stage of the exercise. In conclusion, a single ingestion of trehalose helped to maintain prolonged exercise performance.     

Dosimetry of radon progeny deposited on skin in air and thermal water

It is held that the skin dose from radon progeny is not negligibly small and that introducing cancer is a possible consequence under normal circumstances as there are a number of uncertainties in terms of related parameters such as activity concentrations in air and water, target cells in skin, skin covering materials, and deposition velocities. An interesting proposal has emerged in that skin exposure to natural radon-rich thermal water as part of balneotherapy can produce an immune response to induce beneficial health effects. The goal of this study was to obtain generic dose coefficients with a focus on the radon progeny deposited on the skin in air or water in relation to risk or treatment assessments. We thus first estimated the skin deposition velocities of radon progeny in air and thermal water based on data from the latest human studies. Skin dosimetry was then performed under different assumptions regarding alpha-emitting source position and target cell (i.e. basal cells or Langerhans cells). Furthermore, the impact of the radon progeny deposition on effective doses from all exposure pathways relating to ‘radon exposure’ was assessed using various possible scenarios. It was found that in both exposure media, effective doses from radon progeny inhalation are one to four orders of magnitude higher than those from the other pathways. In addition, absorbed doses on the skin can be the highest among all pathways when the radon activity concentrations in water are two or more orders of magnitude higher than those in air.