Cyclosporine A attenuates the natriuretic action of loop diuretics by inhibition of renal COX-2 expression

Cyclosporine A attenuates the natriuretic action of loop diuretics by inhibition of renal COX-2 expression.BackgroundIt is known that inhibition of cyclooxygenase (COX) impairs the renal actions of loop diuretics. Recently, we found that cyclosporine A (CsA) inhibits renal COX-2 expression. Therefore, we examined the interferences of CsA with the renal actions of loop diuretics.MethodWe investigated the renal effects of furosemide administration (12mg/day subcutaneously) in male Sprague-Dawley rats receiving in addition vehicle, CsA (15mg/kg × day), rofecoxib (10mg/kg × day), or a combination of both.ResultsCsA, rofecoxib, and their combination lowered the furosemide-induced increase of prostaglandin E2 (PGE2) and of 6-keto prostaglandin F1α (6-keto PGF1α) excretion by 55% and by 70%. They also lowered furosemide stimulated renal excretion of sodium and water by about 65% and 60%. Basal as well as furosemide-induced stimulation of plasma renin activity (PRA) and of renal renin mRNA was further enhanced by CsA. In contrast, rofecoxib attenuated the furosemide-induced rise of PRA and of renin mRNA, both in the absence and in the presence of CsA. In addition, the increase in plasma 6-keto PGF1α levels by furosemide was further enhanced by CsA and was attenuated by rofecoxib.ConclusionTaken together, our data suggest that CsA acts as an antinatriuretic, likely by the inhibition of COX-2–mediated renal prostanoid formation. Since the furosemide-induced stimulation of the renin system is not attenuated by CsA but by COX-2 inhibition, we speculate that extrarenal COX-2–derived prostanoids may be involved in the stimulation of the renin system by CsA and by loop diuretics

Experimental investigation of fibre reinforced plastics with hybrid layups under high-velocity impact loads

This paper deals with experimental investigations concerning energy dissipation capacity of different kinds of reinforcement fibres in monolithic and hybrid layups under high-velocity impact loads. The investigated kinds of fibres are carbon, glass and basalt fibres. Therefore test panels, using the same thermoset resin, were built up and cured by autoclave processing. The fibre volume content of the test panels has been determined. Furthermore the influence of a separating layer at selected positions in the hybrid stacked panels was investigated. The results show the influence and the energy dissipation capacity of each single kind of fibreand the enhanced properties for the hybrid layups by hybrid stacking sequences and the use of a separating core material

Paclitaxel-loaded biodegradable ROS-sensitive nanoparticles for cancer therapy

Source at https://doi.org/10.2147/IJN.S208938. Background: Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, trigger biodegradation of polymer-based nanoparticles (NPs) bearing pinacol-type boronic ester groups. These NPs may selectively release their cargo, in this case paclitaxel (PTX), at the high levels of ROS present in the intracellular environment of inflamed tissues and most tumors. Purpose: The main objective was to determine anti-tumor efficacy of PTX-loaded ROS-sensitive NPs and to examine whether macrophage infiltration had any impact on treatment efficacy. Methods: NPs were synthesized and their characteristics in the presence of H2O2 were demonstrated. Both confocal microscopy as well as flow cytometry approaches were used to determine degradation of ROS-sensitive NPs. HeLa cells were cultured in vitro and used to establish tumor xenografts in nude mice. In vivo experiments were performed to understand toxicity, biodistribution and anti-tumor efficacy of the NPs. Moreover, we performed immunohistochemistry on tumor sections to study infiltration of M1 and M2 subsets of macrophages. Results: We demonstrated that PTX delivered in NPs containing a ROS-sensitive polymer exhibits a better anti-tumor efficacy than PTX in NPs containing ROS-non-sensitive polymer, free PTX or Abraxane® (nab-PTX). The biodistribution revealed that ROS-sensitive NPs exhibit retention in liver, spleen and lungs, suggesting a potential to target cancer metastasizing to these organs. Finally, we demonstrated a correlation between infiltrated macrophage subsets and treatment efficacy, possibly contributing to the efficient anti-tumor effects. Conclusion: Treatment with ROS-sensitive NPs containing PTX gave an improved therapeutic effect in HeLa xenografts than their counterpart, free PTX or nab-PTX. Our data revealed a correlation between macrophage infiltration and efficiency of the different antitumor treatments, as the most effective NPs resulted in the highest infiltration of the anti-tumorigenic M1 macrophages

The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans

Transcription of the ribosomal RNA precursor by RNA polymerase (Pol) I is a major determinant of cellular growth, and dysregulation is observed in many cancer types. Here, we present the purification of human Pol I from cells carrying a genomic GFP fusion on the largest subunit allowing the structural and functional analysis of the enzyme across species. In contrast to yeast, human Pol I carries a single-subunit stalk, and in vitro transcription indicates a reduced proofreading activity. Determination of the human Pol I cryo-EM reconstruction in a close-to-native state rationalizes the effects of disease-associated mutations and uncovers an additional domain that is built into the sequence of Pol I subunit RPA1. This “dock II” domain resembles a truncated HMG box incapable of DNA binding which may serve as a downstream transcription factor–binding platform in metazoans. Biochemical analysis, in situ modelling, and ChIP data indicate that Topoisomerase 2a can be recruited to Pol I via the domain and cooperates with the HMG box domain–containing factor UBF. These adaptations of the metazoan Pol I transcription system may allow efficient release of positive DNA supercoils accumulating downstream of the transcription bubble

Behavioral new Keynesian models : a literature review

Treball de Fi de Grau en Economia. Curs 2019-2020Tutora: Rosemarie NagelThe present paper tries to fill the gap of a missing up-to-date literature review of the most vanguard Behavioral New Keynesian (BNK) macroeconomic models. BNK models differ from traditional New Keynesian (NK) models insofar, as they challenge the notion of fully rational expectations of economic agents and introduce some kind of bounded rationality in the model. The models reviewed include Adaptive Learning by De Grauwe (2012), Level K by Mauersberger et al. (2020) and Sparse Dynamics by Gabaix (2019). The paper especially highlights different implications for monetary policy by critically comparing the heterodox BNK models to a standard version of the mainstream NK model. In doing so, it detects so far unidentified links and gaps in the current literature

Characteristics of critical incident reporting systems in primary care: an international survey

Aim: The aim of the study was to support the development of future critical incident reporting systems (CIRS) in primary care by collecting information on existing systems. Our focus was on processes used to report and analyse incidents, as well as strategies used to overcome difficulties. Methods: Based on literature from throughout the world, we identified existing CIRS in primary care. We developed a questionnaire and sent it to operators of a purposeful sample of 17 CIRS in primary care. We used cross-case analysis to compare the answers and pinpoint important similarities and differences in the CIRS in our sample. Results: Ten CIRS operators filled out the questionnaire, and 9 systems met the inclusion criteria. The sample of CIRS came from 8 different countries and was rather heterogeneous. The reporting systems invited a broad range of professions to report, with some also including reports by patients. In most cases, reporting was voluntary and conducted via an online reporting form. Reports were analysed locally, centrally, or both. The various CIRS used interesting ideas to deal with barriers. Some, for example, used confidential reporting modes as a compromise between anonymity and the need for follow-up investigations, whereas others used smartphone applications and call centres to speed up the reporting process. Conclusion: We found multiple CIRS that have operated in primary care for many years, have received a high number of reports and were largely developed in accordance with recommendations found in literature. Although primary care in Germany differs from other countries, these CIRS could serve as an inspiration for CIRS in German primary care.Ziel: Das Ziel dieser Arbeit war es, die Weiterentwicklung von Fehlerberichtssystemen (critical incident reporting systems = CIRS) in der Primärversorgung zu unterstützen. Zu diesem Zweck wurden Informationen über bereits existierende internationale Systeme erfasst. Die Schwerpunkte der Untersuchung waren dabei Berichts- und Analyseprozesse, sowie Strategien zur Überwindung von Schwierigkeiten in den Abläufen. Methodik: Durch eine Literaturrecherche wurden CIRS der Primärversorgung weltweit identifiziert. Ein neu konzipierter Fragebogen wurde einer bewussten Auswahl („purposeful sample“) von 17 CIRS der Primärversorgung zugesandt. In einer fallübergreifenden Auswertung („cross-case analysis“) wurden die Antworten der Systeme verglichen, sowie wichtige Gemeinsamkeiten und Unterschiede innerhalb der Stichprobe analysiert. Ergebnisse: Zehn CIRS Betreiber füllten den Fragebogen aus und neun Systeme erfüllten die Einschlusskriterien. Die Systeme stammten aus acht verschiedenen Ländern. Die Stichprobe war eher heterogen. Grundsätzlich konnten jeweils Angehörige verschiedener Gesundheitsberufe Ereignisse berichten. Bei einigen Systemen war das Berichtsformular auch für Patienten zugänglich. In den meisten Fällen war das Berichten freiwillig und wurde durch ein Online-Formular ermöglicht. Die Berichte wurden lokal, zentral oder in einer Mischform aus beidem bearbeitet. Die verschiedenen CIRS nutzten kreative Ansätze, um Barrieren gegenüber dem Berichten eines Fehlers zu überwinden. Einige nutzten beispielsweise vertrauliche Berichtsmodalitäten als Kompromiss zwischen Anonymität und der Notwendigkeit, Nachuntersuchungen zu ermöglichen. Andere nutzten Apps und Call-Center, um den Berichtsprozess zu beschleunigen. Schlussfolgerung: Wir konnten mehrere CIRS identifizieren, die seit vielen Jahren in der Primärversorgung aktiv sind, eine hohe Zahl an Berichten erfasst haben, und im Einklang mit den Empfehlungen aus der Literatur stehen. Obwohl die ambulante Versorgung in Deutschland einige Unterschiede zu anderen Ländern aufweist, können diese CIRS als Inspiration für deutsche Systeme der ambulanten Versorgung dienen