The Reliability of Histamine Pharmacodynamic Response Phenotype Classification in Children With Allergic Disease.

We have identified distinct histamine pharmacodynamic response phenotypes in children with allergic disease utilizing histamine iontophoresis with laser Doppler (HILD). These response phenotypes may be relevant in guiding therapeutic decision making for agents targeting the allergic response pathways. However, the reliability of these response phenotypes has not been assessed. Therefore, we performed HILD in children with allergic rhinitis and/or asthma on two to three separate occasions. HILD response-time data were analyzed in NONMEM using a linked effect PKPD model. Examination of observed vs. classified response phenotypes predicted response plots and the sum of residuals. The intraclass correlation coefficient (ICC) was used to determine the reliability of phenotype classification. Eighty-two percent of children exhibited a reliable histamine response phenotype [intraclass correlation coefficient 0.77 (95% CI 0.44–0.93]. These preliminary results suggest moderate reliability of HILD response phenotype in children. Further exploration is needed to determine contributions to phenotype variability

The detection of the imprint of filaments on cosmic microwave background lensing

Galaxy redshift surveys, such as 2dF, SDSS, 6df, GAMA and VIPERS, have shown that the spatial distribution of matter forms a rich web, known as the cosmic web. The majority of galaxy survey analyses measure the amplitude of galaxy clustering as a function of scale, ignoring information beyond a small number of summary statistics. Since the matter density field becomes highly non-Gaussian as structure evolves under gravity, we expect other statistical descriptions of the field to provide us with additional information. One way to study the non-Gaussianity is to study filaments, which evolve non-linearly from the initial density fluctuations produced in the primordial Universe. In our study, we report the first detection of CMB (Cosmic Microwave Background) lensing by filaments and we apply a null test to confirm our detection. Furthermore, we propose a phenomenological model to interpret the detected signal and we measure how filaments trace the matter distribution on large scales through filament bias, which we measure to be around 1.5. Our study provides a new scope to understand the environmental dependence of galaxy formation. In the future, the joint analysis of lensing and Sunyaev-Zel'dovich observations might reveal the properties of `missing baryons', the vast majority of the gas which resides in the intergalactic medium and has so far evaded most observations

Fluids in cosmology

We review the role of fluids in cosmology by first introducing them in General Relativity and then by applying them to a FRW Universe's model. We describe how relativistic and non-relativistic components evolve in the background dynamics. We also introduce scalar fields to show that they are able to yield an inflationary dynamics at very early times (inflation) and late times (quintessence). Then, we proceed to study the thermodynamical properties of the fluids and, lastly, its perturbed kinematics. We make emphasis in the constrictions of parameters by recent cosmological probes.Comment: 34 pages, 4 figures, version accepted as invited review to the book "Computational and Experimental Fluid Mechanics with Applications to Physics, Engineering and the Environment". Version 2: typos corrected and references expande

Individualized dosing of aminoglycosides in neonates: mission accomplished or work in progress?

We have read with great interest the paper of Sherwin et al. on individualized dosing of amikacin based on a population pharmacokinetic and-dynamic (PKPD) study in 80 neonates [1]. To the very best of our knowledge, this is the first PD study (outcome indicator sepsis) of aminoglycosides in neonates. We fully support the clinical need to evaluate both PK and PD of drugs, including aminoglycosides in neonates. The recent review on aminoglycosides in neonates in this journal hereby illustrates that clinical pharmacologists are aware of and interested in the specific needs and characteristics of this patient population [2]. We are, however, intrigued by the dosing suggestions formulated by the authors: 15 mg/kg at 36-h intervals for neonates with a postmenstrual age (PMA)≤28 weeks, 14 mg/kg at 24-h intervals for neonate

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Assessing animal affect: an automated and self-initiated judgement bias task based on natural investigative behaviour

Scientific methods for assessing animal affect, especially affective valence (positivity or negativity), allow us to evaluate animal welfare and the effectiveness of 3Rs Refinements designed to improve wellbeing. Judgement bias tasks measure valence; however, task-training may be lengthy and/or require significant time from researchers. Here we develop an automated and self-initiated judgement bias task for rats which capitalises on their natural investigative behaviour. Rats insert their noses into a food trough to start trials. They then hear a tone and learn either to stay for 2 s to receive a food reward or to withdraw promptly to avoid an air-puff. Which contingency applies is signalled by two different tones. Judgement bias is measured by responses to intermediate ambiguous tones. In two experiments we show that rats learn the task in fewer sessions than other automated variants, generalise responses across ambiguous tones as expected, self-initiate 4-5 trials/min, and can be tested repeatedly. Affect manipulations generate main effect trends in the predicted directions, although not localised to ambiguous tones, so further construct validation is required. We also find that tone-reinforcer pairings and reinforcement or non-reinforcement of ambiguous trials can affect responses to ambiguity. This translatable task should facilitate more widespread uptake of judgement bias testing

Increasing the Depth of Current Understanding: Sensitivity Testing of Deep-Sea Larval Dispersal Models for Ecologists

Larval dispersal is an important ecological process of great interest to conservation and the establishment of marine protected areas. Increasing numbers of studies are turning to biophysical models to simulate dispersal patterns, including in the deep-sea, but for many ecologists unassisted by a physical oceanographer, a model can present as a black box. Sensitivity testing offers a means to test the models' abilities and limitations and is a starting point for all modelling efforts. The aim of this study is to illustrate a sensitivity testing process for the unassisted ecologist, through a deep-sea case study example, and demonstrate how sensitivity testing can be used to determine optimal model settings, assess model adequacy, and inform ecological interpretation of model outputs. Five input parameters are tested (timestep of particle simulator (TS), horizontal (HS) and vertical separation (VS) of release points, release frequency (RF), and temporal range (TR) of simulations) using a commonly employed pairing of models. The procedures used are relevant to all marine larval dispersal models. It is shown how the results of these tests can inform the future set up and interpretation of ecological studies in this area. For example, an optimal arrangement of release locations spanning a release area could be deduced; the increased depth range spanned in deep-sea studies may necessitate the stratification of dispersal simulations with different numbers of release locations at different depths; no fewer than 52 releases per year should be used unless biologically informed; three years of simulations chosen based on climatic extremes may provide results with 90% similarity to five years of simulation; and this model setup is not appropriate for simulating rare dispersal events. A step-by-step process, summarising advice on the sensitivity testing procedure, is provided to inform all future unassisted ecologists looking to run a larval dispersal simulation

Does rearing laying hens in aviaries adversely affect long-term welfare following transfer to furnished cages?

This study tests the hypothesis that hens that are reared in aviaries but produce in furnished cages experience poorer welfare in production than hens reared in caged systems. This hypothesis is based on the suggestion that the spatial restriction associated with the transfer from aviaries to cages results in frustration or stress for the aviary reared birds. To assess the difference in welfare between aviary and cage reared hens in production, non-beak trimmed white leghorn birds from both rearing backgrounds were filmed at a commercial farm that used furnished cage housing. The videos were taken at 19 and 21 weeks of age, following the birds' transition to the production environment at 16 weeks. Videos were analysed in terms of the performance of aversion-related behaviour in undisturbed birds, comfort behaviour in undisturbed birds, and alert behaviour directed to a novel object in the home cage. A decrease in the performance of the former behaviour and increase in the performance of the latter two behaviours indicates improved welfare. The results showed that aviary reared birds performed more alert behaviour near to the object than did cage reared birds at 19 but not at 21 weeks of age (P = 0.03). Blood glucose concentrations did not differ between the treatments (P>0.10). There was a significant difference in mortality between treatments (P = 0.000), with more death in aviary reared birds (5.52%) compared to cage birds (2.48%). The higher mortality of aviary-reared birds indicates a negative effect of aviary rearing on bird welfare, whereas the higher duration of alert behavior suggests a positive effect of aviary rearing

Decreased wheel-running activity in hamsters post myocardial infarction

Reduced exercise capacity is a key symptom and an independent determinant of mortality in patients with heart failure. We analyzed the running activity of hamsters with cardiac dysfunction after myocardial infarction. In 39 male Syrian hamsters aged 10 to 12 weeks, a myocardial infarction (MI) was produced by permanent ligation of the left coronary artery. Spontaneous running activity in a wheel was monitored daily. After four weeks, left ventricular (LV) hemodynamics (catheter tip manometry) were measured at baseline and during inotropic stimulation (isoprenaline 0.03, 0.1 and 0.3 μg/kg/min i.v.). LV infarct size was quantified using planimetry. Four weeks post MI, daily running distance was reduced stepwise in animals with small (4–15 % of LV: 9.8 ± 3.4 km/d) and large (> 15 % of LV: 7.5 ± 3.5 km/d) MI, compared to sham-operated hamsters (11.5 ± 1.5 km/d). Similar reductions were observed in maximum speed and distance of longest running period. MI size influenced daily running distance, maximum speed, and longest running period (linear correlations, all p < 0.05). MI size also impaired LV systolic and diastolic function under isoprenaline stimulation. The results suggest that myocardial infarction reduces running capacity and isoprenaline stimulated LV function in hamsters, mimicking impaired exercise performance in patients with heart failure. Analysis of running activity in hamsters with myocardial infarction offers a unique opportunity for non-invasive and serial functional assessment of heart failure in the experimental setting

Conjunctive Processing of Locomotor Signals by the Ventral Tegmental Area Neuronal Population

The ventral tegmental area (VTA) plays an essential role in reward and motivation. How the dopamine (DA) and non-DA neurons in the VTA engage in motivation-based locomotor behaviors is not well understood. We recorded activity of putative DA and non-DA neurons simultaneously in the VTA of awake mice engaged in motivated voluntary movements such as wheel running. Our results revealed that VTA non-DA neurons exhibited significant rhythmic activity that was correlated with the animal's running rhythms. Activity of putative DA neurons also correlated with the movement behavior, but to a lesser degree. More importantly, putative DA neurons exhibited significant burst activation at both onset and offset of voluntary movements. These findings suggest that VTA DA and non-DA neurons conjunctively process locomotor-related motivational signals that are associated with movement initiation, maintenance and termination