Effects of fluticasone propionate on arachidonic acid metabolites in BAL-fluid and methacholine dose-response curves in non-smoking atopic asthmatics

Hyperresponsiveness of the airways to nonspecific stimuli is a characteristic feature of asthma. Airway responsiveness is usually characterized in terms of the position and shape of the dose–response curve to methacholine (MDR). In the study we have investigated the influence of fluticasone propionate (FP), a topically active glucocorticoid, on arachidonic acid (AA) metabolites in broncho-alveolar lavage (BAL) fluid (i.e. TxB2, PGE2, PGD2, 6kPGF1α and LTC4) on the one hand and MDR curves on the other hand. The effect of FP was studied in a randomized, double-blind, placebo-controlled design in 33 stable nonsmoking asthmatics; 16 patients received FP (500 μg b.i.d.) whereas 17 patients were treated with placebo. We found that the forced expiratory volume in 1s (FEV1 % predicted) increased, the log2PC20 methacholine increased and the plateau value (% fall in FEV1) decreased after a 12 week treatment period. No changes in AA-metabolites could be determined after treatment except for PGD2 which decreased nearly significantly (p = 0.058) within the FP treated group, whereas the change of PGD2 differed significantly (p = 0.05) in the FP treated group from placebo. The levels of the other AA metabolites (i.e. TxB2, PGE2, 6kPGF1α and LTC4) remained unchanged after treatment and were not significantly different from the placebo group. Our results support the hypothesis that although FP strongly influences the position, the shape and also the maximum response plateau of the MDR curve, this effect is not mainly achieved by influence on the level of AA metabolites. Other pro-inflammatory factors may be of more importance for the shape of the MDR curve. It is suggested that these pro-inflammatory factors are downregulated by FP

Combining functional weed ecology and crop stable isotope ratios to identify cultivation intensity: a comparison of cereal production regimes in Haute Provence, France and Asturias, Spain

This investigation combines two independent methods of identifying crop growing conditions and husbandry practices—functional weed ecology and crop stable carbon and nitrogen isotope analysis—in order to assess their potential for inferring the intensity of past cereal production systems using archaeobotanical assemblages. Present-day organic cereal farming in Haute Provence, France features crop varieties adapted to low-nutrient soils managed through crop rotation, with little to no manuring. Weed quadrat survey of 60 crop field transects in this region revealed that floristic variation primarily reflects geographical differences. Functional ecological weed data clearly distinguish the Provence fields from those surveyed in a previous study of intensively managed spelt wheat in Asturias, north-western Spain: as expected, weed ecological data reflect higher soil fertility and disturbance in Asturias. Similarly, crop stable nitrogen isotope values distinguish between intensive manuring in Asturias and long-term cultivation with minimal manuring in Haute Provence. The new model of cereal cultivation intensity based on weed ecology and crop isotope values in Haute Provence and Asturias was tested through application to two other present-day regimes, successfully identifying a high-intensity regime in the Sighisoara region, Romania, and low-intensity production in Kastamonu, Turkey. Application of this new model to Neolithic archaeobotanical assemblages in central Europe suggests that early farming tended to be intensive, and likely incorporated manuring, but also exhibited considerable variation, providing a finer grained understanding of cultivation intensity than previously available

A thematic analysis into the experiences of people with a mild intellectual disability during the COVID-19 lockdown period

Background. The COVID-19 pandemic is expected to have a substantial impact on people with an intellectual disability. The goal of the current study was to explore the experiences and needs of people with a mild intellectual disability during the COVID-19 lockdown period in the Netherlands. Method. A descriptive qualitative methodology was conducted, using semi-structured individual interviews with six people with a mild intellectual disability. Data were analysed thematically. Results. Three overarching themes were found: (i) Missing social contact and having people close; (ii) Being housebound has changed my daily life; and (iii) Hard to understand the preventive measures. Conclusions. Important insights into the experiences and needs of people with a mild intellectual disability during the COVID-19 lockdown period were gained. These insights are valuable with respect to a potential second COVID-19 wave or a future infection-outbreak

Некоторые особенности структурной динамики межсекторальных ресурсных потоков в научной системе Украины

Представлен анализ динамики финансирования научно-технической деятельности в аспекте основных источников средств и исполнителей за весь период независимости Украины. Изложен авторский подход к оцениванию роли государства и других экономических субъектов, который адаптирует требования международных учетных стандартов к реалиям отечественной экономики.Представлено аналіз динаміки фінансування науково-технічної діяльності в аспекті головних джерел коштів та виконавців за весь період незалежності України. Викладено авторський підхід до оцінювання ролі держави та інших економічних суб’єктів, що адаптує вимоги міжнародних облікових стандартів до реалій вітчизняної економіки.An analysis of the R&D funding dynamics in terms of main funding sources and performers over the period of the Ukrainian independence is given. The author’s approach to evaluating the role of the government and other economic entities, which adapts the requirements of international accounting standards to the realities of the national economy, is shown

Abrasion in pyroclastic flows

The relative size of glass rims coating crystals in the matrix ash provides a semi-quantitative measure of abrasion of ash grains in pyroclastic flows. Median abrasion indices (= areacrystal / areaglass rim) are 8.4 to 18.5 in Laacher See pyroclastic flow units but only 4 to 6.3 in assocciated fallout, showing stronger abrasion of ash particles in the pyroclastic flows. All pyroclasts undergo strong attrition in the vent but clasts in pyroclastic flows undergo a second major phase of abrasion during high-energy near-vent flow. Abrasion of ash particles is weaker during lower-energy higher-strength motion further downstream, suggesting that high contents of fine ash in distal deposits are due to diminishing elutriation rather than high rate of attrition

Revisiting and modelling the woodland farming system of the early Neolithic Linear Pottery Culture (LBK), 5600–4900 B.C

International audienceThis article presents the conception and the conceptual results of a modelling representation of the farming systems of the Linearbandkeramik Culture (LBK). Assuming that there were permanent fields (PF) then, we suggest four ways that support the sustainability of such a farming system over time: a generalized pollarding and coppicing of trees to increase the productivity of woodland areas for foddering more livestock, which itself can then provide more manure for the fields, a generalized use of pulses grown together with cereals during the same cropping season, thereby reducing the needs for manure. Along with assumptions limiting bias on village and family organizations, the conceptual model which we propose for human environment in the LBK aims to be sustainable for long periods and can thereby overcome doubts about the PFs hypothesis for the LBK farming system. Thanks to a reconstruction of the climate of western Europe and the consequent vegetation pattern and productivity arising from it, we propose a protocol of experiments and validation procedures for both testing the PFs hypothesis and defining its eco-geographical area

Domestication as innovation : the entanglement of techniques, technology and chance in the domestication of cereal crops

The origins of agriculture involved pathways of domestication in which human behaviours and plant genetic adaptations were entangled. These changes resulted in consequences that were unintended at the start of the process. This paper highlights some of the key innovations in human behaviours, such as soil preparation, harvesting and threshing, and how these were coupled with genetic ‘innovations’ within plant populations. We identify a number of ‘traps’ for early cultivators, including the needs for extra labour expenditure on crop-processing and soil fertility maintenance, but also linked gains in terms of potential crop yields. Compilations of quantitative data across a few different crops for the traits of nonshattering and seed size are discussed in terms of the apparently slow process of domestication, and parallels and differences between different regional pathways are identified. We highlight the need to bridge the gap between a Neolithic archaeobotanical focus on domestication and a focus of later periods on crop-processing activities and labour organization. In addition, archaeobotanical data provide a basis for rethinking previous assumptions about how plant genetic data should be related to the origins of agriculture and we contrast two alternative hypotheses: gradual evolution with low selection pressure versus metastable equilibrium that prolonged the persistence of ‘semi-domesticated’ populations. Our revised understanding of the innovations involved in plant domestication highlight the need for new approaches to collecting, modelling and integrating genetic data and archaeobotanical evidence

Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (C <sub>max</sub> ) and trough concentration (C <sub>trough</sub> ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19

Divergent mathematical treatments in utility theory

In this paper I study how divergent mathematical treatments affect mathematical modelling, with a special focus on utility theory. In particular I examine recent work on the ranking of information states and the discounting of future utilities, in order to show how, by replacing the standard analytical treatment of the models involved with one based on the framework of Nonstandard Analysis, diametrically opposite results are obtained. In both cases, the choice between the standard and nonstandard treatment amounts to a selection of set-theoretical parameters that cannot be made on purely empirical grounds. The analysis of this phenomenon gives rise to a simple logical account of the relativity of impossibility theorems in economic theory, which concludes the paper