P-glycoprotein expression in the gastrointestinal tract of male and female rats is influenced differently by food

The aim of this study was to explore the influence of food on P-glycoprotein (P-gp) relative expression in both male and female rats, and its effect on intestinal permeation of P-gp substrates (ranitidine and ganciclovir) and a P-gp non-substrate (metformin). The intestine of 12 male and 12 female Wistar rats were excised and segmented into the duodenum, jejunum, ileum and colon. P-gp extracted from each segment was then determined via Western-blotting. In male rats, the relative P-gp expression decreased significantly after food intake in all segments of the intestine except in the duodenum. The most notable change was demonstrated in the colon where relative expression decreased from 1.75 ± 0.36 in the fasted-state to 0.31 ± 0.15 in the fed-state. In female rats, a fundamentally different result was observed. Food ingestion resulted in a significant increase in relative P-gp expression in all regions of the intestine except in the colon. The largest difference was observed in the jejunum of the fed-state female rat intestine where P-gp expression was 1.76 ± 0.95 which was a six-fold increase from the fasted state at 0.34 ± 0.13. Intestinal permeation studies in an Ussing chamber showed that both ganciclovir and ranitidine exhibited a sex difference in intestinal permeability in the fasted-state. No sex differences and food effects were observed on metformin small intestine permeability. The permeability results of the three drugs highly supported that there was a sex-related food effect on P-gp function in the small intestine. In summary, the current study reports stark differences between male and female rats at a physiological level relating to P-gp expression and the influence of food

Effectiveness of a school-based physical activity-related injury prevention program on risk behavior and neuromotor fitness a cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>To investigate the effects of a school-based physical activity-related injury prevention program, called 'iPlay', on risk behavior and neuromotor fitness.</p> <p>Methods</p> <p>In this cluster randomized controlled trial 40 primary schools throughout the Netherlands were randomly assigned in an intervention (n = 20) or control group (n = 20). The study includes 2,210 children aged 10-12 years.</p> <p>The iPlay-intervention takes one school year and consists of a teacher manual, informative newsletters and posters, a website, and simple exercises to be carried out during physical education classes.</p> <p>Outcomes measures were self-reported injury preventing behavior, self-reported behavioral determinants (knowledge, attitude, social-influence, self-efficacy, and intention), and neuromotor fitness.</p> <p>Results</p> <p>The iPlay-program was not able to significantly improve injury-preventing behavior. The program did significantly improve knowledge and attitude, two determinants of behavior. The effect of the intervention-program on behavior appeared to be significantly mediated by knowledge and attitude. Improved scores on attitude, social norm, self-efficacy and intention were significantly related to changes in injury preventing behavior. Furthermore, iPlay resulted in small non-significant improvements in neuromotor fitness in favor of the intervention group.</p> <p>Conclusion</p> <p>This cluster randomized controlled trial showed that the iPlay-program did significantly improved behavioral determinants. However, this effect on knowledge and attitude was not strong enough to improve injury preventing behavior. Furthermore, the results confirm the hypothetical model that injury preventing behavior is determined by intention, attitude, social norm and self-efficacy.</p> <p>Trial number</p> <p>ISRCTN78846684</p

Effect of Food and an Animal’s Sex on P-Glycoprotein Expression and Luminal Fluids in the Gastrointestinal Tract of Wistar Rats

The rat is one of the most commonly used animal models in pre-clinical studies. Limited information between the sexes and the effect of food consumption on the gastrointestinal (GI) physiology, however, is acknowledged or understood. This study aimed to investigate the potential sex differences and effect of food intake on the intestinal luminal fluid and the efflux membrane transporter P-glycoprotein (P-gp) along the intestinal tract of male and female Wistar rats. To characterise the intestinal luminal fluids, pH, surface tension, buffer capacity and osmolality were measured. Absolute P-gp expression along the intestinal tract was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). In general, the characteristics of the luminal fluids were similar in male and female rats along the GI tract. In fasted male rats, the absolute P-gp expression gradually increased from the duodenum to ileum but decreased in the colon. A significant sex difference (p < 0.05) was identified in the jejunum where P-gp expression in males was 83% higher than in females. Similarly, ileal P-gp expression in male rats was approximately 58% higher than that of their female counterparts. Conversely, following food intake, a significant sex difference (p < 0.05) in P-gp expression was found but in a contrasting trend. Fed female rats expressed much higher P-gp levels than male rats with an increase of 77% and 34% in the jejunum and ileum, respectively. A deeper understanding of the effects of sex and food intake on the absorption of P-gp substrates can lead to an improved translation from pre-clinical animal studies into human pharmacokinetic studies

Prandial state and biological sex modulate clinically relevant efflux transporters to different extents in Wistar and Sprague Dawley rats

P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) are clinically relevant efflux transporters implicated in the oral absorption of many food and drug substrates. Here, we hypothesised that food intake could influence protein and mRNA intestinal expression of P-gp/abcb1a, BCRP/abcg2, and MRP2/abcc2 differently in male and female Wistar and Sprague Dawley rats. To test this hypothesis, we used enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR) to quantify the protein and mRNA intestinal expression of these transporters, respectively. Our study found food and sex differences in P-gp expression, whereby in the fed state P-gp expression decreased in male Wistar rats, but P-gp expression increased in females. In the fed state, BCRP expression increased in both male and female Wistar rats, compared with the fasted state. In contrast, no sex differences or food effect differences were seen in Sprague Dawley rats for P-gp and BCRP expression. On the other hand, in the fed state, MRP2 expression was higher in male and female Wistar and Sprague Dawley rats when compared with the fasted state. Sex differences were also observed in the fasted state. Overall, significant strain differences were reported for P-gp, BCRP and MRP2 expression. Strong to moderate positive linear correlations were found between ELISA and PCR quantification methods. ELISA may be more useful than PCR as it reports protein expression as opposed to transcript expression. Researchers must consider the influence of sex, strain and feeding status in preclinical studies of P-gp, BCRP and MRP2 drug substrates

Quantification of P-Glycoprotein in the Gastrointestinal Tract of Humans and Rodents: Methodology, Gut Region, Sex, and Species Matter

Intestinal efflux transporters affect the gastrointestinal processing of many drugs but further data on their intestinal expression levels are required. Relative mRNA expression and relative and absolute protein expression data of transporters are commonly measured by real-time polymerase chain reaction (RT-PCR), Western blot and mass spectrometry-based targeted proteomics techniques. All of these methods, however, have their own strengths and limitations, and therefore, validation for optimized quantification methods is needed. As such, the identification of the most appropriate technique is necessary to effectively translate preclinical findings to first-in-human trials. In this study, the mRNA expression and protein levels of the efflux transporter P-glycoprotein (P-gp) in jejunal and ileal epithelia of 30 male and female human subjects, and the duodenal, jejunal, ileal and colonic tissues in 48 Wistar rats were quantified using RT-PCR, Western blot and liquid chromatography-tandem mass spectrometry (LC-MS/MS). A similar sex difference was observed in the expression of small intestinal P-gp in humans and Wistar rats where P-gp was higher in males than females with an increasing trend from the proximal to the distal parts in both species. A strong positive linear correlation was determined between the Western blot data and LC-MS/MS data in the small intestine of humans (R^{2} = 0.85). Conflicting results, however, were shown in rat small intestinal and colonic P-gp expression between the techniques (R^{2} = 0.29 and 0.05, respectively). In RT-PCR and Western blot, an internal reference protein is experimentally required; here, beta-actin was used which is innately variable along the intestinal tract. Quantification via LC-MS/MS can provide data on P-gp expression without the need for an internal reference protein and consequently, can give higher confidence on the expression levels of P-gp along the intestinal tract. Overall, these findings highlight similar trends between the species and suggest that the Wistar rat is an appropriate preclinical animal model to predict the oral drug absorption of P-gp substrates in the human small intestine

Sex-Dependence in the Effect of Pharmaceutical Excipients: Polyoxyethylated Solubilising Excipients Increase Oral Drug Bioavailability in Male but not Female Rats

It is known that males and females respond differently to medicines and that differences in drug behaviour are due to inter-individual variability and sex specificity. In this work, we have examined the influence of pharmaceutical excipients on drug bioavailability in males and females. Using a rat model, we report that a portfolio of polyoxyethylated solubilising excipients (polyethylene glycol 2000, Cremophor RH 40, Poloxamer 188 and Tween 80) increase ranitidine bioavailability in males but not in females. The in vivo sex and excipient effects were reflected in vitro in intestinal permeability experiments using an Ussing chamber system. The mechanism of such an effect on drug bioavailability is suggested to be due to the interaction between the excipients and the efflux membrane transporter P-glycoprotein (P-gp), whose expression in terms of gene and protein levels were inhibited by the solubilising agents in male but not in female rats. In contrast, the non-polyoxyethylated excipient, Span 20, significantly increased ranitidine bioavailability in both males and females in a non-sex-dependent manner. These findings have significant implications for the use of polyoxyethylated solubilising excipients in drug formulation in light of their sex-specific modulation on the bioavailability of drugs that are P-gp substrates. As such, pharmaceutical research is required to retract from a ‘one size fits all’ approach and to, instead, evaluate the potential impact of the interplay between excipients and sex on drug effect to ensure effective pharmacotherapy

Multilayer metamaterial absorbers inspired by perfectly matched layers

We derive periodic multilayer absorbers with effective uniaxial properties similar to perfectly matched layers (PML). This approximate representation of PML is based on the effective medium theory and we call it an effective medium PML (EM-PML). We compare the spatial reflection spectrum of the layered absorbers to that of a PML material and demonstrate that after neglecting gain and magnetic properties, the absorber remains functional. This opens a route to create electromagnetic absorbers for real and not only numerical applications and as an example we introduce a layered absorber for the wavelength of $8$~$\mu$m made of SiO$_2$ and NaCl. We also show that similar cylindrical core-shell nanostructures derived from flat multilayers also exhibit very good absorptive and reflective properties despite the different geometry

Process evaluation of a school based physical activity related injury prevention programme using the RE-AIM framework

<p>Abstract</p> <p>Background</p> <p>In general, only information regarding the effectiveness of an intervention programme is ever published. However, in recent years evaluating the translatability and feasibility of an intervention programme has become more important. Therefore, this paper presents the results of the evaluation of the iPlay programme aimed at preventing physical activity related injuries in primary school children.</p> <p>Methods</p> <p>The iPlay programme targeted injuries gained through physical activity, and consisted of a teacher's manual, informative newsletters and posters, a website, and set exercises to be carried out during physical education (PE) classes. In order to evaluate the iPlay programme for translatability and feasibility, teachers, children and parents who participated in the iPlay programme filled out a questionnaire</p> <p>The objective of this study is to describe the results of the process-evaluation of the iPlay programme based on the five dimensions of the RE-AIM framework.</p> <p>Results</p> <p>The results showed that the participation rate of the children was 100% (reach). Nine percent of the schools who were invited to take part were willing to participate in the study (adoption rate). Teachers stated that they implemented the different elements of the programme partly as intended (implementation). The percentage of children and parents who followed the programme was less than expected. In addition, 52% of the teachers indicated that the current iPlay programme could become standard practice in their teaching routine (maintenance).</p> <p>Conclusion</p> <p>The iPlay programme is a first start in the prevention of physical activity related injuries in children, but further improvements need to be made to the programme on the basis of this process evaluation.</p> <p>Trial registration</p> <p>ISRCTN78846684; <url>http://www.controlled-trials.com</url></p

Determining the Veracity of Rumours on Twitter

While social networks can provide an ideal platform for up-to-date information from individuals across the world, it has also proved to be a place where rumours fester and accidental or deliberate mis- information often emerges. In this article, we aim to support the task of making sense from social media data, and specifically, seek to build an autonomous message-classifier that filters relevant and trustworthy information from Twitter. For our work, we collected about 100 million public tweets, including users’ past tweets, from which we identified 72 rumours (41 true, 31 false). We considered over 80 trustworthiness measures including the authors’ profile and past behaviour, the social network connections (graphs), and the content of tweets themselves. We ran modern machine-learning classifiers over those measures to produce trustworthiness scores at various time windows from the outbreak of the rumour. Such time-windows were key as they allowed useful insight into the progression of the rumours. From our findings, we identified that our model was significantly more accurate than similar studies in the literature. We also identified critical attributes of the data that give rise to the trustworthiness scores assigned. Finally we developed a software demonstration that provides a visual user interface to allow the user to examine the analysis

Emotional Fuzzy Sliding-Mode Control for Unknown Nonlinear Systems

[[abstract]]The brain emotional learning model can be implemented with a simple hardware and processor; however, the learning model cannot model the qualitative aspects of human knowledge. To solve this problem, a fuzzy-based emotional learning model (FELM) with structure and parameter learning is proposed. The membership functions and fuzzy rules can be learned through the derived learning scheme. Further, an emotional fuzzy sliding-mode control (EFSMC) system, which does not need the plant model, is proposed for unknown nonlinear systems. The EFSMC system is applied to an inverted pendulum and a chaotic synchronization. The simulation results with the use of EFSMC system demonstrate the feasibility of FELM learning procedure. The main contributions of this paper are (1) the FELM varies its structure dynamically with a simple computation; (2) the parameter learning imitates the role of emotions in mammalians brain; (3) by combining the advantage of nonsingular terminal sliding-mode control, the EFSMC system provides very high precision and finite-time control performance; (4) the system analysis is given in the sense of the gradient descent method.[[notice]]補正完