BACKGROUND & AIMS: Oral supplementation with vitamin D is recommended for older adults to maintain a sufficient 25-hydroxyvitamin D (25(OH)D) status throughout the year. While supplementation with vitamin D2 or D3 is most common, alternative treatment regimens exist which require further investigation with respect to increasing 25(OH)D concentration. We investigated the dose-response effects of supplementation with calcifediol compared to vitamin D3 and assessed the dose which results in mean serum 25(OH)D3 concentrations between 75 and 100 nmol/L.METHODS: This randomized, double-blind intervention study included men and women aged ≥65 years (n = 59). Participants received either 5, 10 or 15 μg calcifediol or 20 μg vitamin D3 per day, for a period of 24 weeks. Blood samples were collected every four weeks to assess response profiles of vitamin D related metabolites; serum vitamin D3, 25(OH)D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3). Further, serum calcium, plasma parathyroid hormone, and urinary calcium were evaluated.RESULTS: Supplementation with 20 μg vitamin D3 increased 25(OH)D3 concentrations towards 70 nmol/L within 16 weeks. Supplementation with 10 or 15 μg calcifediol increased 25(OH)D3 levels >75 nmol/L in 8 and 4 weeks, respectively. Steady state was achieved from week 12 onwards with serum 25(OH)D3 levels stabilizing between 84 and 89 nmol/L in the 10 μg calcifediol group. A significant association was observed between the changes in 25(OH)D3 and 24,25(OH)2D3 (R2 = 0.83, P < 0.01), but not between 25(OH)D3 and 1,25(OH)2D3 (R2 = 0.04, P = 0.18). No cases of hypercalcemia occurred in any treatment during the study period.CONCLUSIONS: Calcifediol supplementation rapidly and safely elevates serum 25(OH)D3 concentrations to improve vitamin D status in older adults. A daily dose of 10 μg calcifediol allows serum 25(OH)D3 concentrations to be maintained between 75 and 100 nmol/L.TRIAL REGISTRATION NUMBER: NCT01868945.
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Although stressors are frequently linked to several negative health outcomes, experiencing stressors may be necessary for enhancing performance. At present, the literature is lacking a unified, comprehensive framework that accounts for both positive and negative outcomes following stressors. Therefore, we introduce the framework of hormesis, which has been applied in biological research for decades. According to hormesis, small-to-medium doses of a stressor can stimulate an organism's response, while large doses cause detrimental effects. In this article, we argue that these dose-response dynamics can be found in various domains of performance psychology (i.e., eustress and distress, psychological momentum, emotions, motivation, confidence, cognitive performance, training, skill acquisition, adversity, and trauma). Furthermore, hormesis also accounts for the inter- and intra-individual variability commonly found in responses to stressors. Finally, from an applied perspective, leveraging hormesis may stimulate new psychological interventions that mimic the well-known effects of (toxic) vaccinations at the level of behavior.
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Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.
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New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose–response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals.
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Abstract gepubliceerd in Elsevier: Introduction: Recent research has identified the issue of ‘dose creep’ in diagnostic radiography and claims it is due to the introduction of CR and DR technology. More recently radiographers have reported that they do not regularly manipulate exposure factors for different sized patients and rely on pre-set exposures. The aim of the study was to identify any variation in knowledge and radiographic practice across Europe when imaging the chest, abdomen and pelvis using digital imaging. Methods: A random selection of 50% of educational institutes (n ¼ 17) which were affiliated members of the European Federation of Radiographer Societies (EFRS) were contacted via their contact details supplied on the EFRS website. Each of these institutes identified appropriate radiographic staff in their clinical network to complete an online survey via SurveyMonkey. Data was collected on exposures used for 3 common x-ray examinations using CR/DR, range of equipment in use, staff educational training and awareness of DRL. Descriptive statistics were performed with the aid of Excel and SPSS version 21. Results: A response rate of 70% was achieved from the affiliated educational members of EFRS and a rate of 55% from the individual hospitals in 12 countries across Europe. Variation was identified in practice when imaging the chest, abdomen and pelvis using both CR and DR digital systems. There is wide variation in radiographer training/education across countries.
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Journal of Physics: Conference Series Paper • The following article is Open access Exploring the relationship between light and subjective alertness using personal lighting conditions J. van Duijnhoven1, M.P.J. Aarts1, E.R. van den Heuvel2 and H.S.M. Kort3,4 Published under licence by IOP Publishing Ltd Journal of Physics: Conference Series, Volume 2042, CISBAT 2021 Carbon-neutral cities - energy efficiency and renewables in the digital era 8-10 September 2021, EPFL Lausanne, Switzerland Citation J. van Duijnhoven et al 2021 J. Phys.: Conf. Ser. 2042 012119 Download Article PDF References Download PDF 29 Total downloads Turn on MathJax Share this article Share this content via email Share on Facebook (opens new window) Share on Twitter (opens new window) Share on Mendeley (opens new window) Hide article information Author e-mails j.v.duijnhoven1@tue.nl Author affiliations 1 Building Lighting Group, Department of the Built Environment, Eindhoven University of Technology, Eindhoven, The Netherlands 2 Stochastics, Department of Mathematics and Computer Science, Eindhoven University of Technology, Eindhoven, The Netherlands 3 Research Centre Healthy and Sustainable Living, University of Applied Sciences Utrecht, Utrecht, The Netherlands 4 Building Healthy Environments for Future Users Group, Department of the Built Environment, Eindhoven University of Technology, Eindhoven, The Netherlands DOI https://doi.org/10.1088/1742-6596/2042/1/012119 Buy this article in print Journal RSS Sign up for new issue notifications Create citation alert Abstract The discovery of the ipRGCs was thought to fully explain the mechanism behind the relationship between light and effects beyond vision such as alertness. However, this relationship turned out to be more complicated. The current paper describes, by using personal lighting conditions in a field study, further exploration of the relationship between light and subjective alertness during daytime. Findings show that this relationship is highly dependent on the individual. Although nearly all dose-response curves between personal lighting conditions and subjective alertness determined in this study turned out to be not significant, the results may be of high importance in the exploration of the exact relationship.
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Een fles rode wijn per dag drinken is ongezond, maar een glas per dag reduceert mogelijk de kans op hartkwalen. Dit is een voorbeeld van ‘hormese’: het verschijnsel dat een agens dat in grote hoeveelheden schadelijk is, bij lage doses juist gezond is. Iets vergelijkbaars geldt voor zonlicht: lage doses worden geassocieerd met positieve gezondseffecten, hoge doses met verbranden en een hogere kans op huidkanker. Er zijn onderzoekers die zich op het omstreden standpunt stellen dat ook ioniserende straling hormetische eigenschappen heeft. In dit artikel gaan we nader in op de verschillende standpunten omtrent lage-dosiseffecten, de argumenten voor en tegen hormese en de consequenties van recente inzichten.
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From Pubmed: " BACKGROUND: Antigen-specific immunotherapy (AIT) is a promising therapeutic approach for both cow's milk allergy (CMA) and peanut allergy (PNA), but needs optimization in terms of efficacy and safety. AIM: Compare oral immunotherapy (OIT) and subcutaneous immunotherapy (SCIT) in murine models for CMA and PNA and determine the dose of allergen needed to effectively modify parameters of allergy. METHODS: Female C3H/HeOuJ mice were sensitized intragastrically (i.g.) to whey or peanut extract with cholera toxin. Mice were treated orally (5 times/week) or subcutaneously (3 times/week) for three consecutive weeks. Hereafter, the acute allergic skin response, anaphylactic shock symptoms and body temperature were measured upon intradermal (i.d.) and intraperitoneal (i.p.) challenge, and mast cell degranulation was measured upon i.g. challenge. Allergen-specific IgE, IgG1 and IgG2a were measured in serum at different time points. Single cell suspensions derived from lymph organs were stimulated with allergen to induce cytokine production and T cell phenotypes were assessed using flow cytometry. RESULTS: Both OIT and SCIT decreased clinically related signs upon challenge in the CMA and PNA model. Interestingly, a rise in allergen-specific IgE was observed during immunotherapy, hereafter, treated mice were protected against the increase in IgE caused by allergen challenge. Allergen-specific IgG1 and IgG2a increased due to both types of AIT. In the CMA model, SCIT and OIT reduced the percentage of activated Th2 cells and increased the percentage of activated Th1 cells in the spleen. OIT increased the percentage of regulatory T cells (Tregs) and activated Th2 cells in the MLN. Th2 cytokines IL-5, IL-13 and IL-10 were reduced after OIT, but not after SCIT. In the PNA model, no differences were observed in percentages of T cell subsets. SCIT induced Th2 cytokines IL-5 and IL-10, whereas OIT had no effect. CONCLUSION: We have shown clinical protection against allergic manifestations after OIT and SCIT in a CMA and PNA model. Although similar allergen-specific antibody patterns were observed, differences in T cell and cytokine responses were shown. Whether these findings are related to a different mechanism of AIT in CMA and PNA needs to be elucidated."
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Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) known to cause liver toxicity. The aim of this study was to predict the inter-species and inter-ethnic human differences in acute liver toxicity of lasiocarpine and riddelliine using physiologically based kinetic (PBK) modelling based reverse dosimetry of in vitro toxicity data. The concentration–response curves of in vitro cytotoxicity of lasiocarpine and riddelliine defined in pooled human hepatocytes were translated to in vivo dose–response curves by PBK models developed using kinetic data obtained from incubations with pooled tissue fractions from Chinese and Caucasian individuals, providing PBK models for the average Chinese and average Caucasian, respectively. From the predicted in vivo dose–response curves, the benchmark dose lower and upper confidence limits for 5% effect (BMDL5 and BMDU5) were derived and subsequently compared to those previously obtained in rat to evaluate inter-species differences. The inter-species differences amounted to 2.0-fold for lasiocarpine and 8.2-fold for riddelliine with humans being more sensitive than rats. The inter-ethnic human differences varied 2.0-fold for lasiocarpine and 5.0-fold for riddelliine with the average Caucasian being more sensitive than the average Chinese. In conclusion, the present study provides the proof-of-principle to predict inter-species and inter-ethnic differences in in vivo liver toxicity for PAs by an alternative testing strategy integrating in vitro cytotoxicity data with PBK modelling-based reverse dosimetry.
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Het doel van het onderzoek is om te bepalen welke voordelen de fusie van PET-CT en MRI-CT hebben in het voorbereidingstraject van de behandeling van de gynaecologische patiënt met radiotherapie ten opzichte van CT alleen. Hierbij is gekeken naar voordelen met betrekking tot intekenen van doelvolumina en risico organen, effecten op intekenvariaties en ook de effecten op het bestralingsplan. Vooral MRI blijkt nuttig te zijn voor de intekening van lymfeklieren, het gebruik van PET in combinatie met CT laat een afname van het doelvolume zien van de primaire tumor. Bij het maken van het bestralingsplan wordt het gebruik van één van beide modaliteiten daarom aanbevolen.
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