Depth sensitive sampling of implanted species in Genesis Collectors using UV laser ablation and SIMS

SIMS profiling of laser abalation pits in CVD diamond implanted with oxygen- 18 shows that homogenised 193nm excimer laser beam can successfully ablate a layer a few nm thick, removing surface contamination without signicant loss of implanted sample

Localization of Quaternary slip rates in an active rift in 10(5) years: an example from central Greece constrained by U-234-Th-230 coral dates from uplifted paleoshorelines

Mapping, dating, and modeling of paleoshorelines uplifted in the footwall of the 1981 Gulf of Corinth earthquake fault, Greece (Ms 6.9–6.7), are used to assess its slip rate history relative to other normal faults in the area and study strain localization. The 234U-230Th coral ages from Cladocora caespitosa date uplifted shoreface sediments, and paleoshorelines from glacioeustatic sea level highstands at 76, (possibly) 100, 125, 175, 200, 216, 240, and 340 ka. Uplifted Quaternary and Holocene paleoshorelines decrease in elevation toward the western tip of the fault, exhibiting larger tilt angles with age, showing that uplift is due to progressive fault slip. Since 125 ka, uplift rates varied from 0.25 to 0.52 mm/yr over a distance of 5 km away from the fault tip. Tilting was also occurring prior to 125 ka, but uplift rates were lower because the 125 ka paleoshoreline is at 77% of the elevation of the 240 ka paleoshoreline despite being nearly half its age. Comparison of paleoshoreline elevations and sedimentology with the Quaternary sea level curve shows that slip rates increased by a factor of 3.2 ± 0.2 at 175 ± 75 ka, synchronous with cessation of activity on a neighboring normal fault at 382–112 ka. We suggest that the rapid localization of up to 10–15 mm/yr of extension into the narrow gulf (∼30 km wide) resulted from synchronous fault activity on neighboring faults followed by localization rather than sequential faulting, with consequences for the mechanism controlling localization of extension

Integration of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus

Background and Objective: Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal–maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods: An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi®]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results: Tested approaches to predict placental t

Physiologically Based Pharmacokinetic Modeling to Characterize Acetaminophen Pharmacokinetics and N-Acetyl-p-Benzoquinone Imine (NAPQI) Formation in Non-Pregnant and Pregnant Women

Background and Objective: Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy. Methods: PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (Css,avg) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated. Results: PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest Css,avg in the third trimester (median [interquartile range]: 4.5 [3.8–5.1] mg/L), while Css,avg was 6.7 [5.9–7.4], 5.6 [4.7–6.3], and 4.9 [4.1–5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1–13.4%]), followed by the second (9.0% [7.5–11.0%]) and third trimester (8.2% [6.8–10.1%]), compared with non-pregnant women (7.7% [6.4–9.4%]). Conclusion: Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether pregnancy affects the toxicodynamics of NAPQI. Information on glutathione abundance during pregnancy and NAPQI in vivo data are required to further refine the presented model

A comprehensive review on non-clinical methods to study transfer of medication into breast milk – A contribution from the ConcePTION project

Breastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBP

Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice

<div><p>Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. <i>In utero</i> exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼70% of control and induced atrophic seminiferous tubules in ∼30% of the testes. When the <i>in utero</i> CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents <i>in utero</i> may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.</p></div

Uranium-series dating applications in natural environmental science

Uranium-series (U-series) analyses are an essential component of many research projects in Earth and environmental science, oceanography, hydrology and science-based archaeology. Topics range from magma chamber evolution and volcanic hazard prediction, global climatic change through dating of authigenic carbonate deposits, human evolution through dating of bone, to the study of groundwater evolution. The U-series decay chains contain many elements that can be fractionated in environmental and geological processes. Half-lives of radioactive isotopes of such elements range from seconds to many millennia and application depends on the natural timeframe of the process or the elapsed time. This review will be limited to some aspects of the 238U–234U–230Th–226Ra system with half-lives of 245 kyr, 76 kyr and 1.6 kyr, respectively. In environmental systems, fractionation of uranium and thorium is a very efficient process because thorium is extremely insoluble while hexavalent uranium in oxidising conditions is relatively soluble. Many authigenic precipitates of calcite contain virtually no thorium and inorganic precipitates have U/Ca ratios very similar to the ratio of dissolved uranium and calcium. Almost no radiogenic 230Th in the precipitate means that the radiogenic clock starts effectively at zero. However, pure authigenic precipitates are rare and many contain some allogenic material, mostly silicate with 238U in secular equilibrium with significant 230Th. Some of the characteristics of different types of samples and various methods to accommodate or correct for ‘inherited’ 230Th will be discussed. Authigenic material should remain a ‘closed system’ with respect to the relevant isotopes but that requirement is sometimes difficult to maintain because radioactive decay results in damage to the crystal lattice of the host mineral. Consequences of this ‘recoil effect’ and correction schemes will be discussed. Dating archaeological bone based on the systematics of diffusion and adsorption to effectively model ‘open system’ behaviour is also included