Mutagenicity testing with transgenic mice. Part II: Comparison with the mouse spot test

The mouse spot test, an in vivo mutation assay, has been used to assess a number of chemicals. It is at present the only in vivo mammalian test system capable of detecting somatic gene mutations according to OECD guidelines (OECD guideline 484). It is however rather insensitive, animal consuming and expensive type of test. More recently several assays using transgenic animals have been developed. From data in the literature, the present study compares the results of in vivo testing of over twenty chemicals using the mouse spot test and compares them with results from the two transgenic mouse models with the best data base available, the lacI model (commercially available as the Big Blue(® )mouse), and the lacZ model (commercially available as the Muta™ Mouse). There was agreement in the results from the majority of substances. No differences were found in the predictability of the transgenic animal assays and the mouse spot test for carcinogenicity. However, from the limited data available, it seems that the transgenic mouse assay has several advantages over the mouse spot test and may be a suitable test system replacing the mouse spot test for detection of gene but not chromosome mutations in vivo

Dose Response for the Stimulation of Cell Division by Caffeic Acid in Forestomach and Kidney of the Male F344 Rat

Caffeic acid (CA, 3,4-dihydroxycinnainic acid), at 2% in the diet, had been shown to be carcinogenic in forestomach and kidney of F344 rats and B6C3F1 mice. Based on its occurrence in coffee and numerous foods and using a linear interpolation for cancer incidence between dose 0 and 2%, the cancer risk in humans would be considerable. In both target organs, tumor formation was preceded by hyperplasia, which could represent the main mechanism of carcinogenic action. The dose-response relationship for this effect was investigated in male F344 rats after 4-week feeding with CA at different dietary concentrations (0, 0.05, 0.14, 0.40, and 1.64%). Cells in S-phase of DNA replication were visualized by iminunohistochemical analysis of incorporated 5-bromo-2′-deoxyuridine (BrdU), 2 hr after intraperitoneal injection. In the forestomach, both the total number of epithelial cells per millimeter section length and the unit length labeling index of BrdU-positive cells (ULLI) were increased, about 2.5-fold, at 0.44) and 1.64%. The lowest concentration (0.05%) had no effect. At 0.14%, both variables were decreased by about one-third. In the kidney, the labeling index in proximal tubular cells also indicated a J-shaped (or U-shaped) dose response with a 1.8-fold increase at 1.64%. In the glandular stomach and in the liver, which are not target organs, no dose-related effect was seen. The data show a good correlation between the organ specificity for cancer induction and stimulation of cell division. With respect to the dose-response relationship and the corresponding extrapolation of the animal tumor data to a human cancer risk, a linear extrapolation appears not to be appropriat

Refugium i Nordre Kapel: Et evidensbaseret grønt landskab til mennesker i sorg

Intet resumé

Substantiate a read-across hypothesis by using transcriptome data—A case study on volatile diketones

This case study explores the applicability of transcriptome data to characterize a common mechanism of action within groups of short-chain aliphatic α-, β-, and γ-diketones. Human reference in vivo data indicate that the α-diketone diacetyl induces bronchiolitis obliterans in workers involved in the preparation of microwave popcorn. The other three α-diketones induced inflammatory responses in preclinical in vivo animal studies, whereas beta and gamma diketones in addition caused neuronal effects. We investigated early transcriptional responses in primary human bronchiolar (PBEC) cell cultures after 24 h and 72 h of air-liquid exposure. Differentially expressed genes (DEGs) were assessed based on transcriptome data generated with the EUToxRisk gene panel of Temp-O-Seq®. For each individual substance, genes were identified displaying a consistent differential expression across dose and exposure duration. The log fold change values of the DEG profiles indicate that α- and β-diketones are more active compared to γ-diketones. α-diketones in particular showed a highly concordant expression pattern, which may serve as a first indication of the shared mode of action. In order to gain a better mechanistic understanding, the resultant DEGs were submitted to a pathway analysis using ConsensusPathDB. The four α-diketones showed very similar results with regard to the number of activated and shared pathways. Overall, the number of signaling pathways decreased from α-to β-to γ-diketones. Additionally, we reconstructed networks of genes that interact with one another and are associated with different adverse outcomes such as fibrosis, inflammation or apoptosis using the TRANSPATH-database. Transcription factor enrichment and upstream analyses with the geneXplain platform revealed highly interacting gene products (called master regulators, MRs) per case study compound. The mapping of the resultant MRs on the reconstructed networks, visualized similar gene regulation with regard to fibrosis, inflammation and apoptosis. This analysis showed that transcriptome data can strengthen the similarity assessment of compounds, which is of particular importance, e.g., in read-across approaches. It is one important step towards grouping of compounds based on biological profiles

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

"always crashing in the same car": Jacques Lacans Mathematik des Unbewußten

Etre parlant nennt Lacan seine mathematisch erzeugte Vision, die nicht aufhört, auf den Wegen eines unendlichen und unmöglichen Begehrens zu prozessieren und Visionen, Träume, Kontingenzen, die mille fleurs verkürzter Räusche zu erzeugen - être parlant, unbewußtes Ereignis der Psychoanalyse nach Freud, lichtscheues Kind der kybernetischen Wissenschaft und der reellen Mathematik des zwanzigsten Jahrhunderts. Das vorliegende Buch unternimmt den Versuch, den Schicksalslinien und Fieberkurven des être parlant zu folgen, sich auf die Wanderung des Begehrens Lacans zu begeben, von der mathematischen Wissenschaft formatiertes und instruiertes Begehren mit einem Ende, das im Ungewissen und Unausdenkbaren sich verläuft - letzter Blick aufs Schützenfest des Szientismus, letzter Steppunkt, schon solipsistisch und sehr fern, bevor das Reelle alles überfegt

Analyzing dermal absorption data of chemicals

Knowledge about the exposure to chemical substances forms an inevitable part of risk assessments and is as such required for many regulatory authorization processes. In the past, the focus was on inhalation and oral uptake; the dermal route was often disregarded. This might have been guided by the general assumption that skin provides a robust barrier to the external environment. However, the skin forms a large surface for chemical exposure and thus, dermal absorption could be a crucial dimension that contributes to internal exposure. Penetration through skin is a complex process depending on very different factors such as 1) physicochemical properties of the test compound, 2) solvent/vehicle, 3) skin condition, 4) interactions between chemical and skin or metabolism in skin 5) test conditions (dose, area, duration, etc.). Thus, a general prediction on the basis of one single test might be misleading. In addition, measured endpoints differ with the used test system (in-vitro: steady-state flux and permeability coefficient, in-vivo: absorption rate in % of applied dose). Theoretical equations and models have been developed to describe transport of chemicals through the skin but so far they have limited acceptance. Within the new EU legislations (e.g. BPD/BPR, PPP) the dermal exposure got enhanced attention and dermal exposure including absorption data has to be considered. If there is a lack of absorption data for biocides a skin absorption rate of 100% has to be used as default. This prediction assumes complete absorption of the total amount of the substance getting in contact to the skin surface independent of the load and duration which seems to be rather implausible. Therefore, we gathered publicly available information e.g. from the EDETOX Database (1) and the eChemPortal (2) and built-up a separate database. This database should allow to match chemicals to certain absorption ranges and to identify common structural features which might trigger higher skin absorption. In addition information about concentration effects and other influencing factors can be extracted from this data pool. As dermal absorption depends not only on substance inherent property, but also on the exposure situation, a reasonable prediction of dermal absorption requires consistent and comparable data from various exposure situations and can consequently be achieved by a comprehensive database

Evaluation of the toxicity and data gaps of e-cigarette aerosol

The electronic cigarette (e-cigarette) is a device for inhaling vaporized liquid that is mostly consumed by smokers and has emerged in recent years as a supposedly less harmful alternative to conventional cigarettes. As no combustion is associated with the "smoking" of an e-cigarette it is often tolerated in confined areas. A harmonized regulation does not exist currently. At the moment e-cigarettes and refills are covered by the EU Directive 2014/40 / EU if it is not declared as a medical product. The increase in the consumption of e-cigarettes in recent years suggests that consumption of e-cigarettes has already attained a general social significance. In commercial products excipients typical used are propylene glycol (PG) and glycerin that classification relates exclusively are classified as GRAS (GeneRally Assumed to be Safe). However, to oral this ingestion. In addition to the uncertainty of possible long-term effects of excipients due to inhalation exposure, uncertainties arise regarding the uniformity of nicotine release, and on the exact chemical composition of the aerosol phase compared to the original liquid. It is intended that the EU Commission reports potential risks from the use of refillable electronic cigarettes until May 20, 2016. In this point uniform quality standards and test methods are required. The aim of this presentation is to address data gaps for the toxicological evaluation of e-cigarettes to identify further study requirements, and the need for standardization of product testing and assessment