Interplay of drug transporters P-glycoprotein (MDR1), MRP1, OATP1A2 and OATP1B3 in passage of maraviroc across human placenta

Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux. © 2020 The Author

Does peer learning or higher levels of e-learning improve learning abilities? A randomized controlled trial

Background and aims : The fast development of e-learning and social forums demands us to update our understanding of e-learning and peer learning. We aimed to investigate if higher, pre-defined levels of e-learning or social interaction in web forums improved students’ learning ability. Methods : One hundred and twenty Danish medical students were randomized to six groups all with 20 students (eCases level 1, eCases level 2, eCases level 2+, eTextbook level 1, eTextbook level 2, and eTextbook level 2+). All students participated in a pre-test, Group 1 participated in an interactive case-based e-learning program, while Group 2 was presented with textbook material electronically. The 2+ groups were able to discuss the material between themselves in a web forum. The subject was head injury and associated treatment and observation guidelines in the emergency room. Following the e-learning, all students completed a post-test. Pre- and post-tests both consisted of 25 questions randomly chosen from a pool of 50 different questions. Results : All students concluded the study with comparable pre-test results. Students at Level 2 (in both groups) improved statistically significant compared to students at level 1 (p>0.05). There was no statistically significant difference between level 2 and level 2+. However, level 2+ was associated with statistically significant greater student's satisfaction than the rest of the students (p>0.05). Conclusions : This study applies a new way of comparing different types of e-learning using a pre-defined level division and the possibility of peer learning. Our findings show that higher levels of e-learning does in fact provide better results when compared with the same type of e-learning at lower levels. While social interaction in web forums increase student satisfaction, learning ability does not seem to change. Both findings are relevant when designing new e-learning materials

Road users rarely use explicit communication when interacting in today’s traffic: Implications for Automated Vehicles

To be successful, automated vehicles (AVs) need to be able to manoeuvre in mixed traffic in a way that will be accepted by road users, and maximises traffic safety and efficiency. A likely prerequisite for this success is for AVs to be able to communicate effectively with other road users in a complex traffic environment. The current study, conducted as part of the European project interACT, investigates the communication strategies used by drivers and pedestrians while crossing the road at six observed locations, across three European countries. In total, 701 road user interactions were observed and annotated, using an observation protocol developed for this purpose. The observation protocols identified 20 event categories, observed from the approaching vehicles/drivers and pedestrians. These included information about movement, looking behaviour, hand gestures, and signals used, as well as some demographic data. These observations illustrated that explicit communication techniques, such as honking, flashing headlights by drivers, or hand gestures by drivers and pedestrians, rarely occurred. This observation was consistent across sites. In addition, a follow-on questionnaire, administered to a sub-set of the observed pedestrians after crossing the road, found that when contemplating a crossing, pedestrians were more likely to use vehicle-based behaviour, rather than communication cues from the driver. Overall, the findings suggest that vehicle-based movement information such as yielding cues are more likely to be used by pedestrians while crossing the road, compared to explicit communication cues from drivers, although some cultural differences were observed. The implications of these findings are discussed with respect to design of suitable external interfaces and communication of intent by future automated vehicles

Evaluation of atrial septal defects with 4D flow MRI—multilevel and inter-reader reproducibility for quantification of shunt severity

Purpose: With the hypothesis that 4D flow can be used in evaluation of cardiac shunts, we seek to evaluate the multilevel and interreader reproducibility of measurements of the blood flow, shunt fraction and shunt volume in patients with atrial septum defect (ASD) in practice at multiple clinical sites. Materials and methods: Four-dimensional flow MRI examinations were performed at four institutions across Europe and the US. Twenty-nine patients (mean age, 43 years; 11 male) were included in the study. Flow measurements were performed at

β-Catenin Loss in Hepatocytes Promotes Hepatocellular Cancer after Diethylnitrosamine and Phenobarbital Administration to Mice

Hepatocellular Carcinoma (HCC) is the fifth most common cancer worldwide. β-Catenin, the central orchestrator of the canonical Wnt pathway and a known oncogene is paramount in HCC pathogenesis. Administration of phenobarbital (PB) containing water (0.05% w/v) as tumor promoter following initial injected intraperitoneal (IP) diethylnitrosamine (DEN) injection (5 µg/gm body weight) as a tumor inducer is commonly used model to study HCC in mice. Herein, nine fifteen-day male β-catenin knockout mice (KO) and fifteen wild-type littermate controls (WT) underwent DEN/PB treatment and were examined for hepatic tumorigenesis at eight months. Paradoxically, a significantly higher tumor burden was observed in KO (p<0.05). Tumors in KO were β-catenin and glutamine synthetase negative and HGF/Met, EGFR & IGFR signaling was unremarkable. A significant increase in PDGFRα and its ligand PDGF-CC leading to increased phosphotyrosine-720-PDGFRα was observed in tumor-bearing KO mice (p<0.05). Simultaneously, these livers displayed increased cell death, stellate cell activation, hepatic fibrosis and cell proliferation. Further, PDGF-CC significantly induced hepatoma cell proliferation especially following β-catenin suppression. Our studies also demonstrate that the utilized DEN/PB protocol in the WT C57BL/6 mice did not select for β-catenin gene mutations during hepatocarcinogenesis. Thus, DEN/PB enhanced HCC in mice lacking β-catenin in the liver may be due to their ineptness at regulating cell survival, leading to enhanced fibrosis and regeneration through PDGFRα activation. β-Catenin downregulation also made hepatoma cells more sensitive to receptor tyrosine kinases and thus may be exploited for therapeutics

How Do We Study Pedestrian Interaction with Automated Vehicles? Preliminary Findings from the European interACT Project

This paper provides an overview of a set of behavioural studies, conducted as part of the European project interACT, to understand road user behaviour in current urban settings. The paper reports on a number of methodologies used to understand how humans currently interact in urban traffic, in order to establish what information would be useful for the design of future AVs, when interacting with other road users, especially pedestrians. In addition to summarising the results from a number of observation studies, we report on preliminary results from Virtual Reality studies, investigating if, in the absence of a human vehicle controller, externally presented interfaces can be used for communication between AVs and pedestrians. Finally, an overview of the mathematical and computational modelling techniques used to understand how AV and pedestrian behaviour can be both cooperative, and effective is provided. The hope is that future AVs can be designed with an understanding of how humans cooperate and communicate in mixed traffic, promoting good traffic flow, user acceptance and user trust