Update on Biological Therapeutics for Asthma

ABSTRACT: Asthma poses a significant burden on patients, families, health care providers, and the medical system. While efforts to standardize care through guidelines have expanded, difficulty in managing severe asthma has encouraged research about its pathobiology and treatment options. Novel biologic therapeutics are being developed for the treatment of asthma and are of potential use for severe refractory asthma, especially where the increased cost of such agents is more likely justified. This review will summarize currently approved (omalizumab) and investigational biologic agents for asthma, such as antibodies, soluble receptors, and other protein-based antagonists, and highlight recent published data on efficacy and safety of these therapies in humans. As these newer agents with highly targeted pharmacology are tested in asthma, we are also poised to learn more about the role of cytokines and other molecules in the pathophysiology of asthma

Potential Targeting of Siglecs, Mast Cell Inhibitory Receptors, in Interstitial Cystitis

Mast cell increases and activation are detected in the chronic inflammatory bladder disease interstitial cystitis (IC), and their proinflammatory mediators are felt to contribute to regional pelvic pain and inflammatory pathophysiology. The immunoreceptor tyrosine-based inhibition motif-containing sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed in mast cells could be evaluated as in vivo signaling regulators capable of inhibiting IC-related mast cell activation

Granulocyte colony-stimulating factor blockade enables dexamethasone to inhibit lipopolysaccharide-induced murine lung neutrophils

Glucocorticoids promote neutrophilic inflammation, the mechanisms of which are poorly characterized. Using a lipopolysaccharide (LPS)-induced acute murine lung injury model, we determined the role of granulocyte colony-stimulating factor (G-CSF) in mouse lung neutrophil numbers in the absence and presence of dexamethasone, a potent glucocorticoid. G-CSF was blocked using a neutralizing antibody. Airway neutrophil numbers, cytokine levels, and lung injury parameters were measured. Glucocorticoid treatment maintained LPS-induced airway G-CSF while suppressing TNF and IL-6. The addition of anti-G-CSF antibodies enabled dexamethasone to decrease airway G-CSF, neutrophils, and lung injury scores. In LPS-challenged murine lungs, structural cells and infiltrating leukocytes produced G-CSF. In vitro using BEAS 2B bronchial epithelial cells, A549 lung epithelial cells, human monocyte-derived macrophages, and human neutrophils, we found that dexamethasone and proinflammatory cytokines synergistically induced G-CSF. Blocking G-CSF production in BEAS 2B cells using shRNAs diminished the ability of BEAS 2B cells to protect neutrophils from undergoing spontaneous apoptosis. These data support that G-CSF plays a role in upregulation of airway neutrophil numbers by dexamethasone in the LPS-induced acute lung injury model

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

Novel targeted therapies for eosinophilic disorders

Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders

Eosinophil Survival and Apoptosis in Health and Disease

Eosinophilia is common feature of many disorders, including allergic diseases. There are many factors that influence the production, migration, survival and death of the eosinophil. Apoptosis is the most common form of physiological cell death and a necessary process to maintain but limit cell numbers in humans and other species. It has been directly demonstrated that eosinophil apoptosis is delayed in allergic inflammatory sites, and that this mechanism contributes to the expansion of eosinophil numbers within tissues. Among the proteins known to influence hematopoiesis and survival, expression of the cytokine interleukin-5 appears to be uniquely important and specific for eosinophils. In contrast, eosinophil death can result from withdrawal of survival factors, but also by activation of pro-apoptotic pathways via death factors. Recent observations suggest a role for cell surface death receptors and mitochondria in facilitating eosinophil apoptosis, although the mechanisms that trigger each of these death pathways remain incompletely delineated. Ultimately, the control of eosinophil apoptosis may someday become another therapeutic strategy for treating allergic diseases and other eosinophil-associated disorders

Experiencing mindfulness meditation—a client narrative perspective

The study was based on the non-participant involvement of the researcher in four six-to-eight weeks' mindfulness meditation training courses led by chartered psychologists. The participants suffered from stress/sleeplessness, depression or agoraphobia in the presented cases. They were selected on the basis of recommendations by the psychologist who was the course instructor, who described them as positive and suitable. The participants wrote diaries on a weekly basis, and they were interviewed at the beginning, middle and end of the course. An in-depth analysis of three individual cases will be presented in the form of narratives constructed from their own words. The narratives demonstrate the unique and embodied changes of the individual participant's experiences during the training course. The purpose was to illustrate richly what happens and how changes happen during these weeks of learning and practicing mindfulness meditation. It is not the intention to give evidence about the effectiveness of mindfulness meditation in general, but to present the whats and hows of cases where mindfulness meditation appears to improve quality of life, health and well-being