Therapeutic concentrations of cyclosporine A, but not FK506, increase P-glycoprotein expression in endothelial and renal tubule cells

Therapeutic concentrations of cyclosporine A, but not FK506, increase P-glycoprotein expression in endothelial and renal tubule cells.BackgroundThe immunosuppressive drugs cyclosporine A (CsA) and tacrolimus (FK506) are extruded from cells by the multidrug resistance P-glycoprotein (P-gp), an efflux pump for drugs and xenobiotics, which may limit their therapeutic effectiveness and/or incidence of toxic side effects. In the present study, we investigated the effect of therapeutic concentrations of CsA and FK506 on the expression of P-gp in cultured endothelial and proximal tubule cells.MethodsP-gp expression in human arterial endothelial (HAEC) and rat proximal tubule cells (RPTC) was determined by immunoblotting and immunocytochemistry, and correlated with P-gp-mediated transport by measuring the intracellular accumulation of the fluorescent probe calcein.ResultsFollowing incubation of HAEC with therapeutic concentrations of 0.1 to 1.6 μm CsA up to seven days, P-gp expression increased in a time- and concentration-dependent manner, maximally to 291 ± 42% of controls with 0.8 μm CsA for seven days. Similar effects of CsA were observed in RPTC. In contrast, therapeutic concentrations of FK506 (0.01 to 0.2 μm up to 7days) did not change P-gp expression in either cell type, though at higher, supratherapeutic concentrations of FK506 (0.6 to 1.2 μm) P-gp expression was also increased. Immunocytochemistry revealed increased P-gp expression in the plasma membrane of HAEC and RPTC treated with 0.8 μm CsA, which was reflected by a decrease of P-gp-mediated accumulation of calcein in both cell types.ConclusionsThe data suggest that the induction of P-gp expression in HAEC and RPTC at concentrations of CsA or FK506 above 0.5 μm is part of the protective answer of cells to toxic concentrations of the drugs and could therefore interfere with the therapeutic effectiveness of CsA in vivo

Performance-Detective: Automatic Deduction of Cheap and Accurate Performance Models

The many configuration options of modern applications make it difficult for users to select a performance-optimal configuration. Performance models help users in understanding system performance and choosing a fast configuration. Existing performance modeling approaches for applications and configurable systems either require a full-factorial experiment design or a sampling design based on heuristics. This results in high costs for achieving accurate models. Furthermore, they require repeated execution of experiments to account for measurement noise. We propose Performance-Detective, a novel code analysis tool that deduces insights on the interactions of program parameters. We use the insights to derive the smallest necessary experiment design and avoiding repetitions of measurements when possible, significantly lowering the cost of performance modeling. We evaluate Performance-Detective using two case studies where we reduce the number of measurements from up to 3125 to only 25, decreasing cost to only 2.9% of the previously needed core hours, while maintaining accuracy of the resulting model with 91.5% compared to 93.8% using all 3125 measurements

Quantitative and qualitative estimation of atherosclerotic plaque burden in vivo at 7T MRI using Gadospin F in comparison to en face preparation evaluated in ApoE KO

Background The aim of the study was to quantify atherosclerotic plaque burden by volumetric assessment and T1 relaxivity measurement at 7T MRI using Gadospin F (GDF) in comparison to en face based measurements. Methods and results 9-weeks old ApoE-/- (n = 5 for each group) and wildtype mice (n = 5) were set on high fat diet (HFD). Progression group received MRI at 9, 13, 17 and 21 weeks after HFD initiation. Regression group was reswitched to chow diet (CD) after 13 weeks HFD and monitored with MRI for 12 weeks. MRI was performed before and two hours after iv injection of GDF (100 μmol/kg) at 7T (Clinscan, Bruker) acquiring a 3D inversion recovery gradient echo sequence and T1 Mapping using Saturation Recovery sequences. Subsequently, aortas were prepared for en face analysis using confocal microscopy. Total plaque volume (TPV) and T1 relaxivity were estimated using ImageJ (V. 1.44p, NIH, USA). 2D and 3D en face analysis showed a strong and exponential increase of plaque burden over time, while plaque burden in regression group was less pronounced. Correspondent in vivo MRI measurements revealed a more linear increase of TPV and T1 relaxivity for regression group. A significant correlation was observed between 2D and 3D en face analysis (r = 0.79; p<0.001) as well as between 2D / 3D en face analysis and MRI (r = 0.79; p<0.001; r = 0.85; p<0.001) and delta R1 (r = 0.79; p<0.001; r = 0.69; p<0.01). Conclusion GDF-enhanced in vivo MRI is a powerful non-invasive imaging technique in mice allowing for reliable estimation of atherosclerotic plaque burden, monitoring of disease progression and regression in preclinical studies

Ernst Denert Award for Software Engineering 2019

This open access book provides an overview of the dissertations of the five nominees for the Ernst Denert Award for Software Engineering in 2019. The prize, kindly sponsored by the Gerlind & Ernst Denert Stiftung, is awarded for excellent work within the discipline of Software Engineering, which includes methods, tools and procedures for better and efficient development of high quality software. An essential requirement for the nominated work is its applicability and usability in industrial practice. The book contains five papers describing the works by Sebastian Baltes (U Trier) on Software Developers’Work Habits and Expertise, Timo Greifenberg’s thesis on Artefaktbasierte Analyse modellgetriebener Softwareentwicklungsprojekte, Marco Konersmann’s (U Duisburg-Essen) work on Explicitly Integrated Architecture, Marija Selakovic’s (TU Darmstadt) research about Actionable Program Analyses for Improving Software Performance, and Johannes Späth’s (Paderborn U) thesis on Synchronized Pushdown Systems for Pointer and Data-Flow Analysis – which actually won the award. The chapters describe key findings of the respective works, show their relevance and applicability to practice and industrial software engineering projects, and provide additional information and findings that have only been discovered afterwards, e.g. when applying the results in industry. This way, the book is not only interesting to other researchers, but also to industrial software professionals who would like to learn about the application of state-of-the-art methods in their daily work

Characterization of gastrointestinal transit and luminal conditions in pigs using a telemetric motility capsule

Within preclinical research, the pig has become an important model in regulatory toxicology and pharmacokinetics, to assess oral dosage forms and to compare different formulation strategies. In addition, there are emerging application of the pig model to asses clinical dosing conditions in the fasted and fed state. In this study, the gastrointestinal transit conditions in male landrace pigs were studied with a telemetric motility capsule under fasted and postprandial conditions. The whole gut transit time (WGTT) was determined by administering a SmartPill® capsule to four landrace pigs, under both fasted and fed state conditions in a cross-over study design. Overall, this study found that small intestinal transit in landrace pigs ranged from 2.3 – 4.0 h, and was broadly similar to reported human estimates and was not affected by the intake conditions. Gastric emptying was highly variable and prolonged in landrace pigs ranging from 20 – 233 h and up to 264 h in one specific case. Under dynamic conditions pigs have a low gastric pH comparable to humans, however a high variability under fasted conditions could be observed. The comparison of the data from this study with a recent similar study in beagle dogs revealed major differences between gastric maximum pressures observed in landrace pigs and dogs. In the porcine stomach maximum pressures of up to 402 mbar were observed, which are comparable to reported human data. Intestinal maximum pressures in landrace pigs were in the same range as in humans. Overall, the study provides new insights of gastrointestinal conditions in landrace pigs, which can lead to more accurate interpretation of in vivo results obtained of pharmacokinetic studies in preclinical models. While small intestinal transit conditions, GI pH and pressures were similar to humans, the prolonged gastric emptying observed in pigs need to be considered in assessing the suitability of the pig model for assessing in vivo performance of large non-disintegrated oral drug products.

Improving exercise capacity and quality of life using non-invasive heart failure treatments: evidence from clinical trials

Endpoints of large-scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and – with less certainty – testosterone in highly selected patients. Erythropoiesis-stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co-morbidities such as sleep-disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state-of-the-art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co-morbidities may be important for these patient-related outcomes. Additional studies on functional capacity and quality of life in heart failure are required