Ambient temperature and mortality: An international study in four capital cities of East Asia

Extreme ambient temperature has been associated with increased daily mortality across the world. We describe the ambient temperature-mortality association for four capital cities in East Asia, Seoul, Beijing, Tokyo, and Taipei, and identify a threshold temperature for each city and the percent increase in mortality. We adapted generalized linear modeling with natural cubic splines (GLM + NS) to examine the association between daily mean apparent temperature (AT) and total mortality, as well as mortality due to respiratory (RD) and cardiovascular (CVD) causes in a threshold model. We conducted a time-series analysis adjusting for day of the week and long-term time trend. The study period differed by city. The threshold temperature for all seasons was estimated to be 30.1-33.5 °C, 31.3-32.3 °C, 29.4-30.8 °C, and 25.2°-31.5 °C for Seoul, Beijing, Tokyo, and Taipei, respectively, on the same day. For the mean daily AT increase of 1 °C above the thresholds in Seoul, Tokyo, and Taipei, estimated percentage increases in daily total mortality were 2.7 (95% confidence interval (CI) = 2.2-3.1), 1.7 (95% CI = 1.5-2.0), and 4.3 (95% CI = 2.9-5.7), respectively. Beijing provided no total mortality counts. Estimated percentage increases were 2.7-10.5 for RD mortality, 1.1-9.3 for CVD mortality in 4 cities. This study identified increased mortality due to exposure to elevated AT. The importance of effects of AT and city-specific threshold temperatures suggests that analyses of the impact of climate change should take regional differences into consideration.     

Yeast on the milky way: genetics,physiology and biotechnology of Kluyveromyces lactis

The milk yeast Kluyveromyces lactis has a life cycle similar to that of Saccharomyces cerevisiae and can be employed as a model eukaryote using classical genetics, such as the combination of desired traits, by crossing and tetrad analysis. Likewise, a growing set of vectors, marker cassettes and tags for fluorescence microscopy are available for manipulation by genetic engineering and investigating its basic cell biology. We here summarize these applications, as well as the current knowledge regarding its central metabolism, glucose and extracellular stress signalling pathways. A short overview on the biotechnological potential of K. lactis concludes this review. Copyright © 2013 John Wiley & Sons, Ltd.     

Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth.     

Minor Role of Mitochondrial Respiration for Fatty-Acid Induced Insulin Secretion

An appropriate insulin secretion by pancreatic beta-cells is necessary to maintain glucose homeostasis. A rise in plasma glucose leads to increased metabolism and an elevated cytoplasmic ATP/ADP ratio that finally triggers insulin granule exocytosis. In addition to this triggering pathway, one or more amplifying pathways—activated by amino acids or fatty acid—enhance secretion by promoting insulin granule recruitment to, and priming at, the plasma membrane. The aim of this study was to clarify the impact of the mitochondrial respiratory activity on fatty acid-induced insulin secretion that was assessed by an extracellular flux analyzer. Treatment of isolated mouse islets with glucose (20 mM) increased insulin secretion 18-fold and correlated with ATP-synthesizing respiration. Furthermore, oxygen consumption rate (OCR) significantly increased by 62% in response to glucose, whereas the addition of palmitate resulted only in a minor increase of OCR at both 2.8 mM (11%) and 20 mM glucose (21%). The addition of palmitate showed a pronounced increase of coupling efficiency (CE) at 2.8 mM glucose but no further insulin secretion. However, treatment with palmitate at 20 mM glucose increased insulin secretion about 32-fold accompanied by a small increase in CE. Thus, fatty acid induced respiration has a minor impact on insulin secretion. Our data clearly demonstrate that fatty acids in contrast to glucose play a minor role for respiration-mediated insulin secretion. In the presence of high glucose, fatty acids contribute partially to amplifying pathways of insulin secretion by further increasing mitochondrial activity in the islets of Langerhans.     

Modeling Human Liver Biology Using Stem Cell-Derived Hepatocytes

Stem cell-derived hepatocytes represent promising models to study human liver biology and disease. This concise review discusses the recent progresses in the field, with a focus on human liver disease, drug metabolism and virus infection.     

Pharmacokinetics of progesterone in lactating dairy cows: Gaining some insights into the metabolism from kinetic modeling

Progesterone pharmacokinetics were analyzed for plasma hormone concentrations ranging from linear to saturated metabolism in lactating Holstein cows with differing daily milk yields. The adequacy of 2-coupled first-order (bi-exponential equation), hyperbolic (Michaelis-Menten equation), and sigmoidal (Hill equation) kinetic models to describe the experimental progesterone pharmacokinetic profiles was examined on a statistical basis. After nonlinear regression and statistical analysis of the data-fitting capability, a simple one-compartment model based on Hill equation proved to be most adequate. This model indicates an enzyme-catalyzed metabolism of progesterone involving cooperative substrate-binding sites, resulting from allosteric effects that yield a sigmoidal saturation rate curve. Kinetic parameters were estimated for 2 groups of lactating Holstein cows with different daily milk yields. We found, for the first time, a remarkable quantitative agreement of the Hill coefficient value with that reported in pharmacokinetic studies involving cytochrome P450, family 3, subfamily A (CYP3A)-mediated reactions in other mammals, humans included. It seems that positive cooperativity makes enzymes much more sensitive to plasma progesterone concentration, and their activities can undergo significant changes in a narrow range of concentration as characteristic of sigmoidal behavior. Therefore, the values of classical pharmacokinetic parameters, such as the elimination constant, half-life, and clearance rate, were found to be highly dependent on the plasma progesterone concentration.     

In Vitro and In Vivo Metabolism of the Radiolytic Compound 2-Dodecylcyclobutanone

ABSTRACT: Our knowledge about the metabolism of alkylcyclobutanones (2-ACBs) is limited, and the lack of literature on the metabolism of 2-ACBs causes consumers to doubt the safety of irradiated foods. The objectives of this study were to evaluate the metabolism of 2-dodecylcyclobutanone (2-DCB) and identify any possible metabolite. The 2-DCB was mixed with rat S9 (postmitochondrial supernatant fraction) and β-nicotinamide adenine dinucleotide phosphate (NADPH) in phosphate buffer (pH 7.4) and incubated for 2 h at 37 °C. Then, the incubation mixture was mixed with sodium sulfate and extracted with n-hexane by using a Soxhlet apparatus. The hexane extract was concentrated under nitrogen and injected into the gas chromatography-mass spectrometry (GC-MS) machine running in selective ion monitoring mode (SIM) to measure 2-DCB concentration. The hexane extract from the in vitro and in vivo studies was also derivatized with a silylation reagent and injected into a GC-MS running in full scan mode. The average percentage of 2-DCB recovered from the test incubations was 23%, compared with 50% from the controls. The GC-MS chromatograms of the derivatized samples showed a unique peak in the in vitro test incubations and in the hexane extract of the rat feces that were given 2-DCB. This peak was later identified as 2-doecylcyclobutanol.