Linking existing in vitro dermal absorption data to physicochemical properties: Contribution to the design of a weight-of-evidence approach for the safety evaluation of cosmetic ingredients with low dermal bioavailability.

To characterize the risk of cosmetic ingredients when threshold toxicity is assumed, often the "margin of safety" (MoS) is calculated. This uncertainty factor is based on the systemic no observable (adverse) effect level (NO(A)EL) which can be derived from in vivo repeated dose toxicity studies. As in vivo studies for the purpose of the cosmetic legislation are no longer allowed in Europe and a validated in vitro alternative is not yet available, it is no longer possible to derive a NO(A)EL value for a new cosmetic ingredient. Alternatively, cosmetic ingredients with a low dermal bioavailability might not need repeated dose data, as internal exposure will be minimal and systemic toxicity might not be an issue. This study shows the possibility of identifying compounds suspected to have a low dermal bioavailability based on their physicochemical properties (molecular weight, melting point, topological polar surface area and log P) and their in vitro dermal absorption data. Although performed on a limited number of compounds, the study suggests a strategic opportunity to support the safety assessor's reasoning to omit a MoS calculation and to focus more on local toxicity and mutagenicity/genotoxicity for ingredients for which limited systemic exposure is to be expected

Investigation of Critical Body Residues and Modes of Toxic Action Based on Injection and Aquatic Exposure in Fish

The internal concentration represented by the critical body residue (CBR) is an ideal indicator to reflect the intrinsic toxicity of a chemical. Whilst some studies have been performed on CBR, the effect of exposure route on internal toxicity has not been investigated for fish. In this paper, acute toxicity data to fish comprising LC50 and LD50 values were used to investigate CBR. The results showed that exposure route can significantly affect the internal concentration. LD50 and CBR calculated from LC50 and BCF both vary independently of hydrophobicity as expressed by log Kow; conversely, LC50 is related to log Kow. A poor relationship was observed between LC50 and LD50, but the relationship can be improved significantly by introduction of log Kow because log CBR is positively related to log LD50. The parallel relationship of log CBR-log Kow and log LD50-log Kow indicates that LD50 does not reflect the actual internal concentration. The average LD50 is close to the average CBR for less inert and reactive compounds, but greater than the average CBR for baseline compounds. This difference is due to the lipid fraction being the major storage site for most of the baseline compounds. Investigation on the calculated and observed CBRs shows that calculated CBRs are close to observed CBRs for most of compounds. However, systemic deviations of calculated CBRs have been observed for some compounds. The reasons for these systemic deviations may be attributed to BCF, equilibrium time and experimental error of LC50. These factors are important and should be considered in the calculation of CBRs

Men's Experiences of the UK Criminal Justice System Following Female-Perpetrated Intimate Partner Violence

© 2015 Springer Science+Business Media New York The current study aimed to explore men’s experience of the UK Criminal Justice System (CJS) following female-perpetrated intimate partner violence (IPV). Unstructured face-to-face and Skype interviews were conducted with six men aged between 40–65 years. Interviews were transcribed and analysed using interpretative phenomenological analysis (IPA). Due to the method of analysis and the sensitive nature of the research, the researcher engaged in a process of reflexivity. Four main themes were identified, including ‘Guilty until Proven Innocent: Victim Cast as Perpetrator;’ ‘Masculine Identity;’ ‘Psychological Impact’ and ‘Light at the End of the Tunnel.’ Themes were discussed and illustrated with direct quotes drawn from the transcripts. Directions for future research, criminal justice interventions, and therapeutic interventions were discussed

Penetrating spinal injury with wooden fragments causing cauda equina syndrome: case report and literature review

Study design: Case report Objective: To report an unusual case of cauda equina syndrome following penetrating injury to the lumbar spine by wooden fragments and to stress the importance of early magnetic resonance imaging (MRI) in similar cases. Summary of background data: A 22-year-old girl accidentally landed on wooden bannister and sustained a laceration to her back. She complained of back pain but had fully intact neurological function. The laceration in her back was explored and four large wooden pieces were removed. However 72 h later, she developed cauda equina syndrome. MRI demonstrated the presence of a foreign body between second and third lumbar spinal levels following which she underwent emergency decompressive laminectomy and the removal of the multiple wooden fragments that had penetrated the dura. Results: Post-operatively motor function in her lower limbs returned to normal but she continued to require a catheter for incontinence. At review 6 months later, she was mobilising independently but the incontinence remained unchanged. Conclusion: There are no reported cases in the literature of wooden fragments penetrating the dura from the back with or without the progression to cauda equina syndrome. The need for a high degree of suspicion and an early MRI scan to localise any embedded wooden fragments that may be separate from the site of laceration is emphasized even if initial neurology is intact

Consequences of converting graded to action potentials upon neural information coding and energy efficiency

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ~50% in generator potentials, to ~3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation

Antiepileptic drugs’ tolerability and safety – a systematic review and meta-analysis of adverse effects in dogs

<p>Various anti-epileptic drugs (AEDs) are used for the management of idiopathic epilepsy (IE) in dogs. Their safety profile is an important consideration for regulatory bodies, owners and prescribing clinicians. However, information on their adverse effects still remains limited with most of it derived from non-blinded non-randomized uncontrolled trials and case reports.</p><p><span>This poster won third place, which was presented at the Veterinary Evidence Today conference, Edinburgh November 1-3, 2016. </span></p><br /> <img src="https://www.veterinaryevidence.org/rcvskmod/icons/oa-icon.jpg" alt="Open Access" /

The stellar halo of the Galaxy

Stellar halos may hold some of the best preserved fossils of the formation history of galaxies. They are a natural product of the merging processes that probably take place during the assembly of a galaxy, and hence may well be the most ubiquitous component of galaxies, independently of their Hubble type. This review focuses on our current understanding of the spatial structure, the kinematics and chemistry of halo stars in the Milky Way. In recent years, we have experienced a change in paradigm thanks to the discovery of large amounts of substructure, especially in the outer halo. I discuss the implications of the currently available observational constraints and fold them into several possible formation scenarios. Unraveling the formation of the Galactic halo will be possible in the near future through a combination of large wide field photometric and spectroscopic surveys, and especially in the era of Gaia.Comment: 46 pages, 16 figures. References updated and some minor changes. Full-resolution version available at http://www.astro.rug.nl/~ahelmi/stellar-halo-review.pd

Genetic Architecture of Highly Complex Chemical Resistance Traits across Four Yeast Strains

Many questions about the genetic basis of complex traits remain unanswered. This is in part due to the low statistical power of traditional genetic mapping studies. We used a statistically powerful approach, extreme QTL mapping (X-QTL), to identify the genetic basis of resistance to 13 chemicals in all 6 pairwise crosses of four ecologically and genetically diverse yeast strains, and we detected a total of more than 800 loci. We found that the number of loci detected in each experiment was primarily a function of the trait (explaining 46% of the variance) rather than the cross (11%), suggesting that the level of genetic complexity is a consistent property of a trait across different genetic backgrounds. Further, we observed that most loci had trait-specific effects, although a small number of loci with effects in many conditions were identified. We used the patterns of resistance and susceptibility alleles in the four parent strains to make inferences about the allele frequency spectrum of functional variants. We also observed evidence of more complex allelic series at a number of loci, as well as strain-specific signatures of selection. These results improve our understanding of complex traits in yeast and have implications for study design in other organisms

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

Incompatibilities Involving Yeast Mismatch Repair Genes: A Role for Genetic Modifiers and Implications for Disease Penetrance and Variation in Genomic Mutation Rates

Genetic background effects underlie the penetrance of most genetically determined phenotypes, including human diseases. To explore how such effects can modify a mutant phenotype in a genetically tractable system, we examined an incompatibility involving the MLH1 and PMS1 mismatch repair genes using a large population sample of geographically and ecologically diverse Saccharomyces cerevisiae strains. The mismatch repair incompatibility segregates into naturally occurring yeast strains, with no strain bearing the deleterious combination. In assays measuring the mutator phenotype conferred by different combinations of MLH1 and PMS1 from these strains, we observed a mutator phenotype only in combinations predicted to be incompatible. Surprisingly, intragenic modifiers could be mapped that specifically altered the strength of the incompatibility over a 20-fold range. Together, these observations provide a powerful model in which to understand the basis of disease penetrance and how such genetic variation, created through mating, could result in new mutations that could be the raw material of adaptive evolution in yeast populations