Development of Eosinophilic Airway Inflammation and Airway Hyperresponsiveness in Mast Cell–deficient Mice

Mast cells are the main effector cells of immediate hypersensitivity and anaphylaxis. Their role in the development of allergen-induced airway hyperresponsiveness (AHR) is controversial and based on indirect evidence. To address these issues, mast cell–deficient mice (W/W  v) and their congenic littermates were sensitized to ovalbumin (OVA) by intraperitoneal injection and subsequently challenged with OVA via the airways. Comparison of OVA-specific immunoglobulin E (IgE) levels in the serum and numbers of eosinophils in bronchoalveolar lavage fluid or lung digests showed no differences between the two groups of mice. Further, measurements of airway resistance and dynamic compliance at baseline and after inhalation of methacholine were similar. These data indicate that mast cells or IgE–mast cell activation is not required for the development of eosinophilic inflammation and AHR in mice sensitized to allergen via the intraperitoneal route and challenged via the airways

Optimal prediction for moment models: Crescendo diffusion and reordered equations

A direct numerical solution of the radiative transfer equation or any kinetic equation is typically expensive, since the radiative intensity depends on time, space and direction. An expansion in the direction variables yields an equivalent system of infinitely many moments. A fundamental problem is how to truncate the system. Various closures have been presented in the literature. We want to study moment closure generally within the framework of optimal prediction, a strategy to approximate the mean solution of a large system by a smaller system, for radiation moment systems. We apply this strategy to radiative transfer and show that several closures can be re-derived within this framework, e.g. $P_N$, diffusion, and diffusion correction closures. In addition, the formalism gives rise to new parabolic systems, the reordered $P_N$ equations, that are similar to the simplified $P_N$ equations. Furthermore, we propose a modification to existing closures. Although simple and with no extra cost, this newly derived crescendo diffusion yields better approximations in numerical tests.Comment: Revised version: 17 pages, 6 figures, presented at Workshop on Moment Methods in Kinetic Gas Theory, ETH Zurich, 2008 2 figures added, minor correction

Inflation: flow, fixed points and observables to arbitrary order in slow roll

I generalize the inflationary flow equations of Hoffman and Turner to arbitrary order in slow roll. This makes it possible to study the predictions of slow roll inflation in the full observable parameter space of tensor/scalar ratio $r$, spectral index $n$, and running $d n / d \ln k$. It also becomes possible to identify exact fixed points in the parameter flow. I numerically evaluate the flow equations to fifth order in slow roll for a set of randomly chosen initial conditions and find that the models cluster strongly in the observable parameter space, indicating a ``generic'' set of predictions for slow roll inflation. I comment briefly on the the interesting proposed correspondence between flow in inflationary parameter space and renormalization group flow in a boundary conformal field theory.Comment: 16 pages, 7 figures. LaTeX. V4: Fixed important error in numerical constant in the second-order slow roll expressions for the observables r, n, and dn/dlog(k). See footnote after Eq. (48). New figures, minor changes to conclusions. Supersedes version published in Phys. Rev.

Globular cluster luminosity function as distance indicator

Globular clusters are among the first objects used to establish the distance scale of the Universe. In the 1970-ies it has been recognized that the differential magnitude distribution of old globular clusters is very similar in different galaxies presenting a peak at M_V ~ -7.5. This peak magnitude of the so-called Globular Cluster Luminosity Function has been then established as a secondary distance indicator. The intrinsic accuracy of the method has been estimated to be of the order of ~0.2 mag, competitive with other distance determination methods. Lately the study of the Globular Cluster Systems has been used more as a tool for galaxy formation and evolution, and less so for distance determinations. Nevertheless, the collection of homogeneous and large datasets with the ACS on board HST presented new insights on the usefulness of the Globular Cluster Luminosity Function as distance indicator. I discuss here recent results based on observational and theoretical studies, which show that this distance indicator depends on complex physics of the cluster formation and dynamical evolution, and thus can have dependencies on Hubble type, environment and dynamical history of the host galaxy. While the corrections are often relatively small, they can amount to important systematic differences that make the Globular Cluster Luminosity Function a less accurate distance indicator with respect to some other standard candles.Comment: Accepted for publication in Astrophysics and Space Science. Review paper based on the invited talk at the conference "The Fundamental Cosmic Distance Scale: State of the Art and Gaia Perspective", Naples, May 2011. (13 pages, 8 figures

Systematic Review of Medicine-Related Problems in Adult Patients with Atrial Fibrillation on Direct Oral Anticoagulants

New oral anticoagulant agents continue to emerge on the market and their safety requires assessment to provide evidence of their suitability for clinical use. There-fore, we searched standard databases to summarize the English language literature on medicine-related problems (MRPs) of direct oral anticoagulants DOACs (dabigtran, rivaroxban, apixban, and edoxban) in the treatment of adults with atri-al fibrillation. Electronic databases including Medline, Embase, International Pharmaceutical Abstract (IPA), Scopus, CINAHL, the Web of Science and Cochrane were searched from 2008 through 2016 for original articles. Studies pub-lished in English reporting MRPs of DOACs in adult patients with AF were in-cluded. Seventeen studies were identified using standardized protocols, and two reviewers serially abstracted data from each article. Most articles were inconclusive on major safety end points including major bleeding. Data on major safety end points were combined with efficacy. Most studies inconsistently reported adverse drug reactions and not adverse events or medication error, and no definitions were consistent across studies. Some harmful drug effects were not assessed in studies and may have been overlooked. Little evidence is provided on MRPs of DOACs in patients with AF and, therefore, further studies are needed to establish the safety of DOACs in real-life clinical practice

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD.'' All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.Genetics of disease, diagnosis and treatmen