Carbonate Concretions in the Karlicher Loess Profile, Rheinland

A loess profile near the town of Karlich in the Rhein-land of Western Germany contains various forms of carbonate which are described in detail. A systematic relationship concerning a transition from finely divided grains of carbonate to large complex concretions is given. The stratigraphic presence of three distinct zones of carbonate concretions and the results of analysis for carbonate content in the entire profile are presented as additional evidence for a ternary (and possibly a quaternary) climatic differentiation of the most recent glacial stage in the Middle Rhein region

Kalium-Argon-Daten zum Alter des Laacher Vulkanismus, der Rheinterrassen und der Eiszeiten

Die Vulkanite des Laacher-See-Gebietes in der Eifel können mit den Terrassenbildungen des Rheines zeitlich korreliert und ihre Föderfolge auf diese Weise stratigraphisch festgelegt werden. Dadurch bietet sich eine Möglichkeit, die K-Ar-Datierungsmethode an Proben von pleistozänem Alter zu testen und zu prüfen, ob die physikalisch bestimmte Sequenz mit der geologischen übereinstimmt. Datierungen wurden vorgenommen an 13 Sanidinen, 7 Biotiten, 2 Augiten und 14 Gesteinen der Eifel, ferner als Ergänzung an 6 Gesteinen der Umgebung von Agde, Dept. Hérault, Südfrankreich. Die meisten Datierungen ergaben geologisch wahrscheinliche Alter. Sie reichen in der Eifel von 570.10³a bis 100.10³a, bei Agde von 1400.10³a bis 640.10³a. Diffusionsexperimente an Sanidinen und Biotiten zeigten, daß das atmosphärische Argon durch Ausheizen nicht zufriedenstellend entfernt werden kann, ohne daß radiogenes Argon verloren geht. Eine Kontrollprobe des abgeheizten radiogenen Gases mit radioaktivem Ar(39) wurde getestet und erwies sich als nützliche Korrekturgröße.researc

A physiologically based pharmacokinetic model of voriconazole integrating time-dependent inhibition of CYP3A4, genetic polymorphisms of CYP2C19 and predictions of drug-drug interactions

Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim(R). The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C-max), and trough concentrations for multiple dosings (C-trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregateC(max)ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregateC(max)ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to <5-6 mg/L forC(trough), while 400 mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model. Conclusions Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.Peer reviewe

Aeolianite and barrier dune construction spanning the last two glacial-interglacial cycles from the southern Cape coast, South Africa

The southern Cape region of South Africa has extensive coastal aeolianites and barrier dunes. Whilst previously reported, limited knowledge of their age has precluded an understanding of their relationship with the climatic and sea-level fluctuations that have taken place during the Late Quaternary. Sedimentological and geomorphological studies combined with an optical dating programme reveal aeolianite development and barrier dune construction spanning at least the last two glacial–interglacial cycles. Aeolianite deposition has occurred on the southern Cape coast at ca 67–80, 88–90, 104–128, 160–189 and >200 ka before the present. Using this and other published data coupled with a better understanding of Late Quaternary sea-level fluctuations and palaeocoastline configurations, it is concluded that these depositional phases appear to be controlled by interglacial and subsequent interstadial sea-level high stands. These marine transgressions and regressions allowed onshore carbonate-rich sediment movement and subsequent aeolian reworking to occur at similar points in the landscape on a number of occasions. The lack of carbonates in more recent dunes (Oxygen Isotope Stages 1/2 and 4/5) is attributed not to leaching but to changes to carbonate production in the sediment source area caused by increased terrigenous material and/or changes in the balance between the warm Agulhas and nutrient-rich Benguela ocean current

Physiologically based pharmacokinetic modeling of tacrolimus for food-drug and CYP3A drug-drug-gene interaction predictions

The immunosuppressant and narrow therapeutic index drug tacrolimus is metabolized mainly via cytochrome P450 (CYP) 3A4 and CYP3A5. For its pharmacokinetics (PK), high inter- and intra-individual variability can be observed. Underlying causes include the effect of food intake on tacrolimus absorption as well as genetic polymorphism in the CYP3A5 gene. Furthermore, tacrolimus is highly susceptible to drug–drug interactions, acting as a victim drug when coadministered with CYP3A perpetrators. This work describes the development of a whole-body physiologically based pharmacokinetic model for tacrolimus as well as its application for investigation and prediction of (i) the impact of food intake on tacrolimus PK (food–drug interactions [FDIs]) and (ii) drug–drug(−gene) interactions (DD[G]Is) involving the CYP3A perpetrator drugs voriconazole, itraconazole, and rifampicin. The model was built in PK-Sim® Version 10 using a total of 37 whole blood concentration–time profiles of tacrolimus (training and test) compiled from 911 healthy individuals covering the administration of tacrolimus as intravenous infusions as well as immediate-release and extended-release capsules. Metabolism was incorporated via CYP3A4 and CYP3A5, with varying activities implemented for different CYP3A5 genotypes and study populations. The good predictive model performance is demonstrated for the examined food effect studies with 6/6 predicted FDI area under the curve determined between first and last concentration measurements (AUClast) and 6/6 predicted FDI maximum whole blood concentration (Cmax) ratios within twofold of the respective observed ratios. In addition, 7/7 predicted DD(G)I AUClast and 6/7 predicted DD(G)I Cmax ratios were within twofold of their observed values. Potential applications of the final model include model-informed drug discovery and development or the support of model-informed precision dosing

A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug–Drug Interactions

Background: Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates.Objective: This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug–drug interactions (DDIs) with CYP3A4 substrates in more detail.Methods: In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration–time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim®. The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration–time curve (AUC), maximum concentration (Cmax), and trough concentrations for multiple dosings (Ctrough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration–time datasets over the full range of recommended intravenous and oral dosing regimens.Results: The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate Cmax ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate Cmax ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1–2 mg/L to Conclusions: Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug’s PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.</p

Methods for measuring gas emissions from naturally ventilated livestock buildings: Developments over the last decade and perspectives for improvement

[EN] The objectives of this paper are: 1) to give an overview of the development of methods for measuring emission rates from naturally ventilated livestock buildings over the last decade, 2) to identify and evaluate strengths and weaknesses, 3) to summarise and conclude the current state-of-art of available measurement concepts and their perspectives for improvement. The methods reviewed include determination of concentration and air exchange rate separately, tracer gas ratio, passive flux samplers, flux chambers, and combined downwind measurement and dispersion modelling. It is concluded that passive flux samplers, flux chambers and combined measurement and dispersion modelling are useful, but for limited fields of application only and require further development and validation against reference methods. The most robust method to investigate emission rates available at this stage is the tracer gas ratio method, but improvements are required. They include more detailed estimates of CO2 release rates (when using CO2 as a tracer) and research into optimising dosing performance of tracer gas release systems. The reliability of tracer gas ratio methods applied in buildings with large ventilation openings needs to be improved by a more profound understanding of tracer-pollutant ratios and their spatial variability, and the development of improved sampling methods for concentration ratios. There is a need for a field reference method against which other methods can be evaluated. None of the diicussed measurement methods can be marked as a solid reference for all conditions; tracer gas ratio methods are the most likely candidate but need further improvement. (C) 2012 IAgrE. Published by Elsevier Ltd. All rights reserved.The contribution to this paper of N. Ogink and J. Mosquera was financially supported by the Netherlands Ministry of Infrastructure and Environment.Ogink, NWM.; Mosquera, J.; Calvet Sanz, S.; Zhang, G. (2013). Methods for measuring gas emissions from naturally ventilated livestock buildings: Developments over the last decade and perspectives for improvement. Biosystems Engineering. 116(3):297-308. https://doi.org/10.1016/j.biosystemseng.2012.10.005S297308116

Assessment of Vascular Dysfunction in Patients Without Obstructive Coronary Artery Disease: Why, How, and When.

Ischemic heart disease secondary to coronary vascular dysfunction causes angina and impairs quality of life and prognosis. About one-half of patients with symptoms and signs of ischemia turn out not to have obstructive coronary artery disease, and coronary vascular dysfunction may be relevant. Adjunctive tests of coronary vasomotion include guidewire-based techniques with adenosine and reactivity testing, typically by intracoronary infusion of acetylcholine. The CorMicA (Coronary Microvascular Angina) trial provided evidence that routine management guided by an interventional diagnostic procedure and stratified therapy improves angina and quality of life in patients with angina but no obstructive coronary artery disease. In this paper, the COVADIS study group provide a comprehensive review of why, how, and when coronary vascular dysfunction should be assessed invasively. They discuss the rationale through a shared understanding of vascular pathophysiology and clinical evidence. They propose a consensus approach to how an interventional diagnostic procedure is performed with focus on practical aspects. Finally, the authors discuss the clinical scenarios in patients with stable and acute coronary syndromes in which measurement of coronary vascular function may be helpful for patient care