ABSTRACT
BACKGROUND: Maternal obesity increases offspring propensity to metabolic dysfunctions and to non-alcoholic fatty liver disease (NAFLD), which may lead to cirrhosis or liver cancer. The circadian clock is a transcriptional/epigenetic molecular machinery synchronising physiological processes to coordinate energy utilisation within a 24-h light/dark period. Alterations in rhythmicity have profound effects on metabolic pathways, which we sought to investigate in offspring with programmed NAFLD. METHODS: Mice were fed a standard or an obesogenic diet (OD), before and throughout pregnancy, and during lactation. Offspring were weaned onto standard or an OD at 3 weeks postpartum and housed in 12:12 light/dark conditions. Biochemical and histological indicators of NAFLD and fibrosis, analysis of canonical clock genes with methylation status and locomotor activity were investigated at 6 months. RESULTS: We show that maternal obesity interacts with an obesogenic post-weaning diet to promote the development of NAFLD with disruption of canonical metabolic rhythmicity gene expression in the liver. We demonstrate hypermethylation of BMAL-1 (brain and muscle Arnt like-1) and Per2 promoter regions and altered 24-h rhythmicity of hepatic pro-inflammatory and fibrogenic mediators. CONCLUSIONS: These data implicate disordered circadian rhythms in NAFLD and suggest that disruption of this system during critical developmental periods may be responsible for the onset of chronic liver disease in adulthood.
Subject(s)
ARNTL Transcription Factors/metabolism , Circadian Rhythm , Liver/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Obesity/metabolism , Prenatal Exposure Delayed Effects/metabolism , Animals , Animals, Newborn , DNA Methylation , Disease Models, Animal , Female , Lactation , Liver/pathology , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/pathology , Period Circadian Proteins/metabolism , PregnancyABSTRACT
A randomized, open-label, 2-period crossover study was conducted to evaluate the bioequivalence of 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg (arm A, n = 42) and the oral bioavailability of the 150-mg tablet versus a 25-mg intravenous infusion (arm B, n = 20) in healthy subjects. The washout period was 2 weeks between treatments. Plasma concentrations of erlotinib and its active metabolite, OSI-420, were measured after each dose. The ratios of geometric means for AUC(0-infinity) and Cmax of erlotinib following 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg were (1 and 0.95) within the predefined bioequivalence range of 0.80 to 1.25. The mean absolute oral bioavailability, using compartmental analysis, was estimated as 59% (95% confidence interval, 55%-63%). Overall, 6 tablets of erlotinib 25 mg are bioequivalent to a single 150-mg tablet. Both intravenous and oral erlotinib were generally well tolerated with an estimated bioavailability of 59% following oral administration.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacokinetics , Quinazolines/pharmacokinetics , Administration, Oral , Adolescent , Adult , Biological Availability , Cross-Over Studies , Drug Monitoring , Erlotinib Hydrochloride , Female , Humans , Infusions, Intravenous , Male , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/blood , Quinazolines/administration & dosage , Quinazolines/blood , Sex Factors , Therapeutic EquivalencyABSTRACT
Deleterious trace impurities like Mn, Fe, Co, Ni, Zn, Bi and Pb in oxygen-free electronic copper (OFEC) were separated and determined by dynamic coating ion-interaction chromatography (IIC) with spectrophotometric detection using pre-column reaction methods. 4-(2-Thiazolylazo)resorcinol (TAR) was used as pre-column chelating agent. The requirements for sample preparation and the conditions for pre-column chelation reaction are discussed. The optimum conditions for the sensitive detection of these trace metal ions after ion-chromatographic separation are set. The ph of the chelating medium and the eluent, the concentration of TAR and the composition of the eluent were investigated. The detection limits achieved were 2.0, 2.8, 0.6, 0.8, 1.2, 2.6 and 3.0 ng for Mn, Fe, Co, Ni, Zn, Bi and Pb, respectively. The results obtained by IIC methods compare well with those of graphite furnace atomic-absorption spectrometry and the certified values of Mur Bundy Hamil (MBH Analytical Ltd, U.K.).
ABSTRACT
A flow-injection atomic absorption spectrometric method was developed for the determination of trace amounts of arsenic and selenium in proposed spinach and tomato leaves standard reference materials (SRM 1570a and SRM 1573a). The samples were digested with HNO(3), H(2)SO(4) and HClO(4) using reflux column. The experimental details for sample preparation and the flow injection hydride generation method are discussed. The effect of matrix and various acid concentrations on the extraction and absorbance was also studied. The method has detection limits of 0. 15 ng As/ml and 0.17 ng Se/ml. Standard Reference Materials (SRM 1571 and 1547) were analyzed and the results agreed well with the certified values.
ABSTRACT
A flow-injection, cold-vapor atomic absorption spectrophotometric method was developed for the determination of trace amounts of mercury in a proposed zinc ore concentrate Standard Reference Material (SRM 113b). The samples were digested with nitric and hydrochloric acids in closed Teflon digestion vessels. The experimental details for sample preparation and the flow injection method are discussed. The effect of matrix and various acid concentrations on the extraction and subsequent analysis of mercury were also studied. The method has a detection limit of 0.08 mug Hg/g in the sample. A certified reference material (CZN-1) was analyzed and the results obtained agreed well with the certified value.