Release of Mast Cell Tryptase into Saliva: A Tool to Diagnose Food Allergy by a Mucosal Challenge Test?

Background: Our aim was to examine whether measurement of the saliva mast cell tryptase (MCT) concentrations before and after a mucosal challenge test with the offending food would be helpful in diagnosing food allergy. Methods: We performed a retrospective analysis of 44 food challenge tests performed in 38 patients between 2006 and 2009. Patients with a suspected history of food allergy chewed the food until they developed symptoms or until the amount of time known from the patients' history to usually be required for the provocation of symptoms had passed. In 5 patients, saliva samples for the measurement of MCT were collected at minutes 0, 1, 4, 8, 11, and 16 after the first onset of symptoms. The remainder of the patients only had samples taken before chewing and 4 min after the end of the test period. Results: During repeated measurements, MCT peaked about 4 min after the onset of symptoms (p = 0.028). During 33 of the 44 tests (75.0%), we observed oral symptoms during testing; after 25 of the 33 (75.8%) tests evoking symptoms, the saliva MCT concentration increased. The MCT increase was negative in all other tests where no oral symptoms could be provoked. Conclusions: The measurement of saliva MCT 4 min after the onset of symptoms may be helpful to diagnose food allergy. Because of numerous confounding variables, however, a negative saliva MCT increase does not exclude food allergy. Copyright (C) 2011 S. Karger AG, Base

Variability-Specific Abstraction Refinement for Family-Based Model Checking

Variational systems are ubiquitous in many application areas today. They use features to control presence and absence of system functionality. One challenge in the development of variational systems is their formal analysis and verification. Researchers have addressed this problem by designing aggregate so-called family-based verification algorithms. Family-based model checking allows simultaneous verification of all variants of a system family (variational system) in a single run by exploiting the commonalities between the variants. Yet, the computational cost of family-based model checking still greatly depends on the number of variants. In order to make it computationally cheaper, we can use variability abstractions for deriving abstract family-based model checking, where the variational model of a system family is replaced with an abstract (smaller) version of it which preserves the satisfaction of LTL properties. The variability abstractions can be combined with different partitionings of the set of variants to infer various verification scenarios for the variational model. However, manually finding an optimal verification scenario is hard since it requires a good knowledge of the family and property, while the number of possible scenarios is very large.In this work, we present an automatic iterative abstraction refinement procedure for family-based model checking. We use Craig interpolation to refine abstract variational models based on the obtained spurious counterexamples (traces). The refinement procedure works until a genuine counterexample is found or the property satisfaction is shown for all variants in the family. We illustrate the practicality of this approach for several variational benchmark models

Spreading, Nonergodicity, and Selftrapping: a puzzle of interacting disordered lattice waves

Localization of waves by disorder is a fundamental physical problem encompassing a diverse spectrum of theoretical, experimental and numerical studies in the context of metal-insulator transitions, the quantum Hall effect, light propagation in photonic crystals, and dynamics of ultra-cold atoms in optical arrays, to name just a few examples. Large intensity light can induce nonlinear response, ultracold atomic gases can be tuned into an interacting regime, which leads again to nonlinear wave equations on a mean field level. The interplay between disorder and nonlinearity, their localizing and delocalizing effects is currently an intriguing and challenging issue in the field of lattice waves. In particular it leads to the prediction and observation of two different regimes of destruction of Anderson localization - asymptotic weak chaos, and intermediate strong chaos, separated by a crossover condition on densities. On the other side approximate full quantum interacting many body treatments were recently used to predict and obtain a novel many body localization transition, and two distinct phases - a localization phase, and a delocalization phase, both again separated by some typical density scale. We will discuss selftrapping, nonergodicity and nonGibbsean phases which are typical for such discrete models with particle number conservation and their relation to the above crossover and transition physics. We will also discuss potential connections to quantum many body theories.Comment: 13 pages in Springer International Publishing Switzerland 2016 1 M. Tlidi and M. G. Clerc (eds.), Nonlinear Dynamics: Materials, Theory and Experiment, Springer Proceedings in Physics 173. arXiv admin note: text overlap with arXiv:1405.112

Incentivizing research into the effectiveness of medical devices

Introduction Medical devices (MDs) often obtain market authorization with much less clinical evidence than other health technologies, especially pharmaceuticals. This is due to a number of reasons. First, in contrast to pharmaceuticals, there is no legal requirement to conduct adequately controlled clinical studies, other than for ‘high-risk’ devices in some jurisdictions. In the US for example, high-risk devices and innovative lower-risk devices are required to demonstrate ‘reasonable assurance of safety and effectiveness’, which may imply clinical evidence based on randomized studies in many instances. In contrast, in the EU the requirement is to demonstrate adequate performance and safety, which can often be achieved by conducting observational studies such as registries [1, 2]. Secondly, the devices industry comprises many small and medium-size enterprises (SMEs), which would find the cost of conducting clinical studies, especially randomized controlled trials, prohibitive. However, although some larger manufacturers do undertake clinical studies of some of their products, manufacturers with similar products (called ‘fast-followers’) can often claim ‘substantial equivalence’ to a product that already has market authorization, thus avoiding the need to conduct costly and timeconsuming clinical studies. Since regulatory agencies often accept these claims of equivalence, for example under the 510(k) process in the US [3], this further reduces the incentives for manufacturers to conduct expensive clinical studies. Therefore, although device manufacturers have patent protection, they are often not granted data exclusivity in the same way as pharmaceutical manufacturers. Finally, unlike pharmaceuticals, devices are often modified once on the market, meaning that even if clinical evidence was available for the original version of the product, it may not necessarily be available for the version currently being marketed. For example in the US, one analysis showed that for 77 original market authorization applications for cardiac implantable electronic devices (e.g., pacemakers, implantable cardioverter-defibrillators) since 1979, the FDA approved 5829 ‘supplements’ reflecting product modifications in the period up until 2012. Of course, many of these product modifications were minor and unlikely to affect the performance of the device, but 37 % involved a change to the device’s design. In the vast majority of these cases the FDA deemed that new clinical data were not necessary for approval [4]. The lack of clinical evidence prior to product launch, especially evidence of comparative effectiveness, limits the possibilities for health technology assessment [2]. However, it should be remembered that clinical evidence can be gathered both pre-market (i.e., through conducting controlled clinical trials in an experimental setting), and postmarket, through clinical studies undertaken in regular clinical practice. Post-market effectiveness research may be more important for MDs than pharmaceuticals, as the performance of the device often depends on the interaction with the user (the so-called learning curve) [5]. This suggests that solutions to the problem of inadequate clinical evidence should address the issue of conducting clinical research in both the pre- and post-market phase. In this editorial we consider ways in which MD manufacturers could be incentivized to produce more clinical evidence to facilitate health technology assessments, including economic evaluations

Relativistic versus Nonrelativistic Optical Potentials in A(e,e'p)B Reactions

We investigate the role of relativistic and nonrelativistic optical potentials used in the analysis of ($e,e'p$) data. We find that the relativistic calculations produce smaller ($e,e'p$) cross sections even in the case in which both relativistic and nonrelativistic optical potentials fit equally well the elastic proton--nucleus scattering data. Compared to the nonrelativistic impulse approximation, this effect is due to a depletion in the nuclear interior of the relativistic nucleon current, which should be taken into account in the nonrelativistic treatment by a proper redefinition of the effective current operator.Comment: Added one new figure, the formalism section has been enlarged and the list of references updated. Added one appendix. This version will appear in Phys. Rev. C. Revtex 3.0, 6 figures (not included). Full postscript version of the file and figures available at http://www.nikhefk.nikhef.nl/projects/Theory/preprints

Borrelia recurrentis employs a novel multifunctional surface protein with anti-complement, anti-opsonic and invasive potential to escape innate immunity

Borrelia recurrentis, the etiologic agent of louse-borne relapsing fever in humans, has evolved strategies, including antigenic variation, to evade immune defence, thereby causing severe diseases with high mortality rates. Here we identify for the first time a multifunctional surface lipoprotein of B. recurrentis, termed HcpA, and demonstrate that it binds human complement regulators, Factor H, CFHR-1, and simultaneously, the host protease plasminogen. Cell surface bound factor H was found to retain its activity and to confer resistance to complement attack. Moreover, ectopic expression of HcpA in a B. burgdorferi B313 strain, deficient in Factor H binding proteins, protected the transformed spirochetes from complement-mediated killing. Furthermore, HcpA-bound plasminogen/plasmin endows B. recurrentis with the potential to resist opsonization and to degrade extracellular matrix components. Together, the present study underscores the high virulence potential of B. recurrentis. The elucidation of the molecular basis underlying the versatile strategies of B. recurrentis to escape innate immunity and to persist in human tissues, including the brain, may help to understand the pathological processes underlying louse-borne relapsing fever

Off-Diagonal Deformations of Kerr Metrics and Black Ellipsoids in Heterotic Supergravity

Geometric methods for constructing exact solutions of motion equations with first order $\alpha ^{\prime}$ corrections to the heterotic supergravity action implying a non-trivial Yang-Mills sector and six dimensional, 6-d, almost-K\"ahler internal spaces are studied. In 10-d spacetimes, general parametrizations for generic off-diagonal metrics, nonlinear and linear connections and matter sources, when the equations of motion decouple in very general forms are considered. This allows us to construct a variety of exact solutions when the coefficients of fundamental geometric/physical objects depend on all higher dimensional spacetime coordinates via corresponding classes of generating and integration functions, generalized effective sources and integration constants. Such generalized solutions are determined by generic off-diagonal metrics and nonlinear and/or linear connections. In particular, as configurations which are warped/compactified to lower dimensions and for Levi-Civita connections. The corresponding metrics can have (non) Killing and/or Lie algebra symmetries and/or describe (1+2)-d and/or (1+3)-d domain wall configurations, with possible warping nearly almost-K\"ahler manifolds, with gravitational and gauge instantons for nonlinear vacuum configurations and effective polarizations of cosmological and interaction constants encoding string gravity effects. A series of examples of exact solutions describing generic off-diagonal supergravity modifications to black hole/ ellipsoid and solitonic configurations are provided and analyzed. We prove that it is possible to reproduce the Kerr and other type black solutions in general relativity (with certain types of string corrections) in 4-d and to generalize the solutions to non-vacuum configurations in (super) gravity/ string theories.Comment: latex2e, 44 pages with table of content, v2 accepted to EJPC with minor typos modifications requested by editor and referee and up-dated reference

End-to-End Joint Antenna Selection Strategy and Distributed Compress and Forward Strategy for Relay Channels

Multi-hop relay channels use multiple relay stages, each with multiple relay nodes, to facilitate communication between a source and destination. Previously, distributed space-time codes were proposed to maximize the achievable diversity-multiplexing tradeoff, however, they fail to achieve all the points of the optimal diversity-multiplexing tradeoff. In the presence of a low-rate feedback link from the destination to each relay stage and the source, this paper proposes an end-to-end antenna selection (EEAS) strategy as an alternative to distributed space-time codes. The EEAS strategy uses a subset of antennas of each relay stage for transmission of the source signal to the destination with amplify and forwarding at each relay stage. The subsets are chosen such that they maximize the end-to-end mutual information at the destination. The EEAS strategy achieves the corner points of the optimal diversity-multiplexing tradeoff (corresponding to maximum diversity gain and maximum multiplexing gain) and achieves better diversity gain at intermediate values of multiplexing gain, versus the best known distributed space-time coding strategies. A distributed compress and forward (CF) strategy is also proposed to achieve all points of the optimal diversity-multiplexing tradeoff for a two-hop relay channel with multiple relay nodes.Comment: Accepted for publication in the special issue on cooperative communication in the Eurasip Journal on Wireless Communication and Networkin

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Binary and Millisecond Pulsars at the New Millennium

We review the properties and applications of binary and millisecond pulsars. Our knowledge of these exciting objects has greatly increased in recent years, mainly due to successful surveys which have brought the known pulsar population to over 1300. There are now 56 binary and millisecond pulsars in the Galactic disk and a further 47 in globular clusters. This review is concerned primarily with the results and spin-offs from these surveys which are of particular interest to the relativity community.Comment: 59 pages, 26 figures, 5 tables. Accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org