Tom Cattaert

Mepolizumab, a humanized anti–IL-5 mAb, as a treatment option for severe nasal polyposis

BACKGROUND Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. OBJECTIVE We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. METHODS Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. RESULTS Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. CONCLUSION Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis.

Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma.

BACKGROUND The role of IgE in patients with severe asthma is not fully understood. OBJECTIVE We sought to investigate whether IgE to Staphylococcus aureus enterotoxins might be relevant to disease severity in adult asthmatic patients. METHODS Specific IgE antibody concentrations in serum against enterotoxins, grass pollen (GP), and house dust mite allergens and total IgE levels were measured in adult cohorts of 69 control subjects, 152 patients with nonsevere asthma, and 166 patients with severe asthma. Severe asthma was defined as inadequately controlled disease despite high-dose inhaled corticosteroids plus at least 2 other controller therapies, including oral steroids. RESULTS Enterotoxin IgE positivity was significantly greater in patients with severe asthma (59.6%) than in healthy control subjects (13%, P< .001). Twenty-one percent of patients with severe asthma with enterotoxin IgE were considered nonatopic. Logistic regression analyses demonstrated significantly increased risks for enterotoxin IgE-positive subjects to have any asthma (OR, 7.25; 95% CI, 2.7-19.1) or severe asthma (OR, 11.09; 95% CI, 4.1-29.6) versus enterotoxin IgE-negative subjects. The presence of GP or house dust mite IgE antibodies was not associated with either significantly increased risk for asthma or severity. Oral steroid use and hospitalizations were significantly increased in patients with enterotoxin IgE and nonatopic asthma. GP IgE was associated with a higher FEV(1) percent predicted value, and enterotoxin IgE was associated with a lower FEV(1) percent predicted value. CONCLUSIONS Staphylococcal enterotoxin IgE antibodies, but not IgE against inhalant allergens, are risk factors for asthma severity. We hypothesize that the presence of enterotoxin IgE in serum indicates the involvement of staphylococcal superantigens in the pathophysiology of patients with severe asthma.

Envelope solitons associated with electromagnetic waves in a magnetized pair plasma

The amplitude modulation of magnetic field-aligned circularly polarized electromagnetic (CPEM) waves in a magnetized pair plasma is reexamined. The nonlinear frequency shifts include the effects of the radiation pressure driven density and compressional magnetic field perturbations as well as relativistic particle mass variations. The dynamics of the modulated CPEM wave packets is governed by a nonlinear Schrodinger equation, which has attractive and repulsive interaction potentials for fast and slow CPEM waves. The modulational stability of a constant amplitude CPEM wave is studied by deriving a nonlinear dispersion from the cubic Schrodinger equation. The fast (slow) CPEM mode is modulationally unstable (stable). Possible stationary amplitude solutions of the modulated fast (slow) CPEM mode can be represented in the form of bright and dark/gray envelope electromagnetic soliton structures. Localized envelope excitations can be associated with the microstructures in pulsar magnetospheres and in laboratory...

Potential hill electron-acoustic solitons and double layers in plasmas with two electron species

In the description of (high-frequency) electron-acoustic solitons in a plasma consisting of positive ions, cool electrons, and hot electrons, the dynamics of the ions plays no essential role and can be eliminated from the treatment, the ions merely providing a constant positive background. It is widely believed that in such a plasma only potential dip solitary waves can be generated. In a potential dip the cooler electrons are compressed and the hotter electrons rarefied, both being driven towards their sonic points, the cooler ones from above, the hotter ones from below. This transonic feature gives rise to the solitary wave. However, it is shown that the restriction to potential dip solitons is due to the neglect of the inertia of the hot electrons, implicitly or explicitly assumed by most authors. If hot electron inertia is retained, there exists a parameter range where potential hill solitary waves are formed, with both electron species being driven away from their sonic points. This has important consequences for the reinterpretation of several astrophysical phenomena involving two-electron plasmas.

Model-Based Multifactor Dimensionality Reduction for detecting epistasis in case–control data in the presence of noise

Analyzing the combined effects of genes and/or environmental factors on the development of complex diseases is a great challenge from both the statistical and computational perspective, even using a relatively small number of genetic and nongenetic exposures. Several data‐mining methods have been proposed for interaction analysis, among them, the Multifactor Dimensionality Reduction Method (MDR) has proven its utility in a variety of theoretical and practical settings. Model‐Based Multifactor Dimensionality Reduction (MB‐MDR), a relatively new MDR‐based technique that is able to unify the best of both nonparametric and parametric worlds, was developed to address some of the remaining concerns that go along with an MDR analysis. These include the restriction to univariate, dichotomous traits, the absence of flexible ways to adjust for lower order effects and important confounders, and the difficulty in highlighting epistatic effects when too many multilocus genotype cells are pooled into two new genotype groups. We investigate the empirical power of MB‐MDR to detect gene–gene interactions in the absence of any noise and in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Power is generally higher for MB‐MDR than for MDR, in particular in the presence of genetic heterogeneity, phenocopy, or low minor allele frequencies.

Gas-dynamic description of electrostatic solitons

The nonlinear propagation of electrostatic solitary structures in unmagnetized multispecies plasmas is studied in the wave frame, where they are stationary. via the recently developed MeKenzie approach as an alternative to the more usual Saagdeev pseudo-potential method. This way of looking at the problem brings out the gas-dynamic aspects, which then allow a straightforward characterization of the solitary wave possibilities in terms of the species own sonic points and of the global charge neutral points. A qualitative discussion of ion-. dust- and electron-acoustic solitary waves is given in terms of these concepts and the results are contrasted with those obtained by other methods. Ion-acoustic solitons can be shown to always be compressive. without invoking simplifying assumptions such as cold ions or Boltzmann electrons. Beam-plasmas can also be studied, as in the electron-acoustic solitary wave model for the spiky structures of the broadband electrostatic noise observed in the auroral regions of the Earths magnetosphere. Such solitons always show a potential dip.

FAM-MDR: a flexible family-based multifactor dimensionality reduction technique to detect epistasis using related individuals.

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR) with Model-Based MDR (MB-MDR). We focus on continuous traits, although the method is general and can be used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based Generalized MDR (PGMDR), which is a generalization of Multifactor Dimensionality Reduction (MDR) to continuous traits and related individuals, FAM-MDR was found to outperform PGMDR in terms of power, in most of the considered simulated scenarios. Additional simulations revealed that PGMDR does not appropriately deal with multiple testing and consequently gives rise to overly optimistic results. FAM-MDR adequately deals with multiple testing in epistasis screens and is in contrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main) effects is of utmost importance when claiming epistasis. As Type 2 Diabetes Mellitus (T2DM) is a complex phenotype likely influenced by gene-gene interactions, we applied FAM-MDR to examine data on glucose area-under-the-curve (GAUC), an endophenotype of T2DM for which multiple independent genetic associations have been observed, in the Amish Family Diabetes Study (AFDS). This application reveals that FAM-MDR makes more efficient use of the available data than PGMDR and can deal with multi-generational pedigrees more easily. In conclusion, we have validated FAM-MDR and compared it to PGMDR, the current state-of-the-art MDR method for family data, using both simulations and a practical dataset. FAM-MDR is found to outperform PGMDR in that it handles the multiple testing issue more correctly, has increased power, and efficiently uses all available information.

Ion- and dust-acoustic solitons in dusty plasmas: Existence conditions for positive and negative potential solutions

The usual description of dust-modified ion-acoustic and dust-acoustic solitons in plasmas containing negative dust is in terms of Boltzmann distributions for the hotter species. In the dust-modified ion-acoustic regime, besides positive potential solitons, negative structures can also be generated, for electrons with a polytropic index γe≠1, as well as for Boltzmann electrons, subject to conditions that are not too stringent. These general conditions were previously either ignored or given for weakly nonlinear solutions only. In the dust-acoustic domain in plasmas with negatively charged dust, however, only negative potential solitons can occur, even when the lighter species have non-Boltzmann distributions. For Boltzmann electrons only an infinite dust compression limits the soliton amplitudes and corresponding Mach numbers, whereas for γe≠1, the electron density, too, can be a limiting factor for the existence domain of such solitons.

Oblique propagation of electromagnetic waves in a kappa-Maxwellian plasma

Space plasmas are often observed to contain more particles in the high-energy tail than the usual Maxwellian distributions, and are well modeled by kappa distributions. The hybrid kappa-Maxwellian distribution and associated generalized plasma dispersion function ZκM were recently introduced to model magnetized space plasmas. The susceptibility tensor for a kappa-Maxwellian plasma component is derived, making use of ZκM. This enables one to make general studies of obliquely propagating electromagnetic waves in a magnetoplasma. The susceptibility and dielectric tensors reduce to the Maxwellian expressions in the limit κ→∞. As an illustration, the formalism is applied to the lower branch of the R mode and its off-parallel variant. For low κ values, low-wavenumber, low-frequency parallel whistler waves are shown to be stable, unlike the Maxwellian case, which is unstable if the perpendicular temperature exceeds the parallel temperature. A numerical study is made of the effects of the value of kappa, the prop...

On the existence of ion-acoustic double layers in two-electron temperature plasmas

Earlier Sagdeev pseudopotential treatments of ion-acoustic double layers in plasmas with two electron populations were based on a model in which both electron densities were described by isothermal Boltzmann distributions. Using a more recent fluid-dynamical approach, with polytropic equations of state indices γj, one finds analytically that no double layers can be formed for γj⩾3∕2, due to total rarefaction of the cooler electrons or infinite compression of the ions. For γj<3∕2, rarefactive double layers occur, but, just below 3/2, at unrealistically small cool electron densities or large Mach numbers. As γj decreases towards 1, these constraints become less restrictive and go over smoothly to those known from Boltzmann studies. Contrary to what appears in the literature, very weak compressive double layers can also be found for Boltzmann electrons, but only for soliton conditions barely above the existence threshold; i.e., marginally super-ion-acoustic. Any slight increase in the critical Mach number de...