In vivo imaging of hepatic neutrophil migration in severe alcoholic hepatitis with 111In-radiolabelled leucocytes.

The study's aim was to image severe alcoholic hepatitis (SAH) using 111In-labelled leucocytes with two objectives in mind: firstly for non-invasive diagnosis and secondly to provide a platform for experimental therapies aiming to inhibit intrahepatic neutrophil migration. 111In-leucocyte scintigraphy was performed 30 min and 24 h post-injection in 19 patients with SAH, 14 abstinent patients with alcohol-related cirrhosis and 11 normal controls. Eleven with SAH and seven with cirrhosis also had 99mTc-nanocolloid scintigraphy. Change in hepatic 111In radioactivity was expressed as decay-corrected 24 h:30 min count ratio and, in SAH, compared with histological grading of steatohepatitis and expression of granulocyte marker, CD15. Hepatic microautoradiography on biopsy specimens obtained 24 h post-injection of 111In-leucocytes was performed in one patient. Median 24 h:30 min hepatic 111In activity ratio was higher in SAH (2.5 (interquartile range (IQR): 1.7-4.0) compared with cirrhotics and normal controls (1.0 (0.8-1.1) and 0.8 (0.7-0.9) respectively, P<0.0001). In SAH, it correlated with CD15 expression (r = 0.62, P=0.023) and was higher in marked compared with mild/moderate steatohepatitis (4.0 (3.0-4.6) compared with 1.8 (1.5-2.6), P=0.006). Hepatic-to-splenic 99mTc count rate ratio was reduced in SAH (0.5 (0.4-1.4)) compared with cirrhotics (2.3( 0.6-3.0)) and three historic normal controls (4.2 (3.8-5.0); P=0.003), consistent with impaired hepatic reticuloendothelial function. Scintigraphic findings in SAH included prominent lung radioactivity at 30 min, likely the result of neutrophil primimg. Microautoradiography demonstrated cell-associated 111In in areas of parenchymal neutrophil infiltration. In conclusion, 111In-leucocyte scintigraphy can non-invasively diagnose SAH and could provide a platform for evaluation of novel treatments aiming to inhibit intrahepatic neutrophil migration.The study was funded by a project grant from Brighton and Sussex Medical Schoo

EvoFIT composite face construction via practitioner interviewing and a witness-administered protocol

Police require reliable facial-composite systems to help identify, arrest and convict criminals. Recent developments, however, have allowed newer versions of the EvoFIT composite system to be made available for policing. The outcome is an online (cloud-based) version and a new system called Witness At Home, both using a simpler interface. Here, we formally compare these two versions to establish potential benefits to policing. Two experiments were conducted. In Experiment 1, participants observed a target identity for 1 minute and returned 4 hours (Witness At Home) or 24 hours (EvoFIT Online) to construct a composite from memory. No significant difference in composite accuracy was found. In Experiment 2, participants constructed a composite, 24-hours after seeing a target identity, using either EvoFIT Online or Witness At Home. A significant increase in accurate identification was found for EvoFIT Online, with some utility for the self-administered procedure, together indicating benefit for these newer systems plus some areas for development

Adiabatic and Isocurvature Perturbations for Multifield Generalized Einstein Models

Low energy effective field theories motivated by string theory will likely contain several scalar moduli fields which will be relevant to early Universe cosmology. Some of these fields are expected to couple with non-standard kinetic terms to gravity. In this paper, we study the splitting into adiabatic and isocurvature perturbations for a model with two scalar fields, one of which has a non-standard kinetic term in the Einstein-frame action. Such actions can arise, e.g., in the Pre-Big-Bang and Ekpyrotic scenarios. The presence of a non-standard kinetic term induces a new coupling between adiabatic and isocurvature perturbations which is non-vanishing when the potential for the matter fields is nonzero. This coupling is un-suppressed in the long wavelength limit and thus can lead to an important transfer of power from the entropy to the adiabatic mode on super-Hubble scales. We apply the formalism to the case of a previously found exact solution with an exponential potential and study the resulting mixing of adiabatic and isocurvature fluctuations in this example. We also discuss the possible relevance of the extra coupling in the perturbation equations for the process of generating an adiabatic component of the fluctuations spectrum from isocurvature perturbations without considering a later decay of the isocurvature component.Comment: 11 pages, 3 figures, one equation corrected, typos fixed, conclusions unchange

Comparative toxicity of pesticides and environmental contaminants in bees: are honey bees a useful proxy for wild bee species?

Threats to wild and managed insect pollinators in Europe are cause for both ecological and socio-economic concern. Multiple anthropogenic pressures may be exacerbating pollinator declines. One key pressure is exposure to chemicals including pesticides and other contaminants. Historically the honey bee (Apis mellifera spp.) has been used as an ‘indicator’ species for ‘standard’ ecotoxicological testing but it has been suggested that it is not always a good proxy for other types of eusocial and solitary bees because of species differences in autecology and sensitivity to various stressors. We developed a common toxicity test system to conduct acute and chronic exposures of up to 240 h of similar doses of seven chemicals, targeting different metabolic pathways, on three bee species (Apis mellifera spp., Bombus terrestris and Osmia bicornis). We compared the relative sensitivity between species in terms of potency between the chemicals and the influence of exposure time on toxicity. While there were significant interspecific differences that varied through time, overall the magnitude of these differences (in terms of treatment effect ratios) was generally comparable ( 25 fold within test). These are rarely considered in standard regulatory testing but may have severe environmental consequences, especially when coupled with the likelihood of differential species exposures in the wild. These insights indicate that further work is required to understand how differences in toxicokinetics vary between species and mixtures of chemicals

A Chromosomal Memory Triggered by Xist Regulates Histone Methylation in X Inactivation

We have elucidated the kinetics of histone methylation during X inactivation using an inducible Xist expression system in mouse embryonic stem (ES) cells. Previous reports showed that the ability of Xist to trigger silencing is restricted to an early window in ES cell differentiation. Here we show that this window is also important for establishing methylation patterns on the potential inactive X chromosome. By immunofluorescence and chromatin immunoprecipitation experiments we show that histone H3 lysine 27 trimethylation (H3K27m3) and H4 lysine 20 monomethylation (H4K20m1) are associated with Xist expression in undifferentiated ES cells and mark the initiation of X inactivation. Both marks depend on Xist RNA localisation but are independent of silencing. Induction of Xist expression after the initiation window leads to a markedly reduced ability to induce H3K27m3, whereas expression before the restrictive time point allows efficient H3K27m3 establishment. Our data show that Xist expression early in ES cell differentiation establishes a chromosomal memory, which is maintained in the absence of silencing. One consequence of this memory is the ability to introduce H3K27m3 efficiently after the restrictive time point on the chromosome that has expressed Xist early. Our results suggest that this silencing-independent chromosomal memory has important implications for the maintenance of X inactivation, where previously self-perpetuating heterochromatin structures were viewed as the principal form of memory

Comparing bee species responses to chemical mixtures: common response patterns?

Pollinators in agricultural landscapes can be exposed to mixtures of pesticides and environmental pollutants. Existing mixture toxicity modelling approaches, such as the models of concentration addition and independent action and the mechanistic DEBtox framework have been previously shown as valuable tools for understanding and ultimately predicting joint toxicity. Here we apply these mixture models to investigate the potential to interpret the effects of semi-chronic binary mixture exposure for three bee species: Apis mellifera, Bombus terrestris and Osmia bicornis within potentiation and mixture toxicity experiments. In the potentiation studies, the effect of the insecticide dimethoate with added propiconazole fungicide and neonicotinoid insecticide clothianidin with added tau-fluvalinate pyrethroid acaricide showed no difference in toxicity compared to the single chemical alone. Clothianidin toxicity showed a small scale, but temporally conserved increase in exposure conducted in the presence of propiconazole, particularly for B. terrestris and O. bicornis, the latter showing a near three-fold increase in clothianidin toxicity in the presence of propiconazole. In the mixture toxicity studies, the dominant response patterns were of additivity, however, binary mixtures of clothianidin and dimethoate in A. mellifera, B. terrestris and male O. bicornis there was evidence of a predominant antagonistic interaction. Given the ubiquitous nature of exposures to multiple chemicals, there is an urgent need to consider mixture effects in pollinator risk assessments. Our analyses suggest that current models, particularly those that utilise time-series data, such as DEBtox, can be used to identify additivity as the dominant response pattern and also those examples of interactions, even when small-scale, that may need to be taken into account during risk assessment

X Chromosomes Alternate between Two States prior to Random X-Inactivation

Early in the development of female mammals, one of the two X chromosomes is silenced in half of cells and the other X chromosome is silenced in the remaining half. The basis of this apparent randomness is not understood. We show that before X-inactivation, the two X chromosomes appear to exist in distinct states that correspond to their fates as the active and inactive X chromosomes. Xist and Tsix, noncoding RNAs that control X chromosome fates upon X-inactivation, also determine the states of the X chromosomes prior to X-inactivation. In wild-type ES cells, X chromosomes switch between states; among the progeny of a single cell, a given X chromosome exhibits each state with equal frequency. We propose a model in which the concerted switching of homologous X chromosomes between mutually exclusive future active and future inactive states provides the basis for the apparently random silencing of one X chromosome in female cells