Achieving Symptom Control in Patients with Moderate Asthma

Disease severity in asthma can be classified as mild, moderate or severe based upon the frequency of symptoms or the severity of airflow obstruction. This review will focus on the treatment of youths greater than 12 years of age and adults with moderate persistent asthma. Moderate asthmatics may have daily symptoms that cause some limitation with normal daily activities and require use of a rescue inhaled short-acting beta2-agonist inhaler or experience nocturnal awakenings secondary to asthma that occur more than once per week. Furthermore, spirometry may reveal airflow obstruction with a reduction in FEV1 to between 60% and 80% of predicted. Although inhaled corticosteroids (ICS) are the primary controller medication used to modify symptoms in moderate asthmatics, additional controller medications, such as inhaled long-acting beta2-agonists (LABA), leukotriene receptor antagonists (LTRA) or theophylline, are often needed to obtain optimal disease control. While the addition of an inhaled LABA to an ICS is very effective at improving disease control in moderate asthma, concerns have arisen over the safety of LABAs, in particular the risk of asthma-related death. Therefore, consideration may be given to initially adding a LTRA, rather than a LABA, to ICS when asthma symptoms are not adequately controlled by ICS alone. Furthermore, individualization of medication regimens, treatment of co-morbid conditions, and patient education are crucial to optimizing compliance with therapy, improving disease control, and reducing the risk of exacerbations. Lastly, the development of new asthma treatments, perhaps based upon personalized medicine, may revolutionize the future treatment of moderate asthma

Achieving Symptom Control in Patients with Moderate Asthma

Disease severity in asthma can be classified as mild, moderate or severe based upon the frequency of symptoms or the severity of airflow obstruction. This review will focus on the treatment of youths greater than 12 years of age and adults with moderate persistent asthma. Moderate asthmatics may have daily symptoms that cause some limitation with normal daily activities and require use of a rescue inhaled short-acting beta(2)-agonist inhaler or experience nocturnal awakenings secondary to asthma that occur more than once per week. Furthermore, spirometry may reveal airflow obstruction with a reduction in FEV(1) to between 60% and 80% of predicted. Although inhaled corticosteroids (ICS) are the primary controller medication used to modify symptoms in moderate asthmatics, additional controller medications, such as inhaled long-acting beta(2)-agonists (LABA), leukotriene receptor antagonists (LTRA) or theophylline, are often needed to obtain optimal disease control. While the addition of an inhaled LABA to an ICS is very effective at improving disease control in moderate asthma, concerns have arisen over the safety of LABAs, in particular the risk of asthma-related death. Therefore, consideration may be given to initially adding a LTRA, rather than a LABA, to ICS when asthma symptoms are not adequately controlled by ICS alone. Furthermore, individualization of medication regimens, treatment of co-morbid conditions, and patient education are crucial to optimizing compliance with therapy, improving disease control, and reducing the risk of exacerbations. Lastly, the development of new asthma treatments, perhaps based upon personalized medicine, may revolutionize the future treatment of moderate asthma

Apolipoprotein Mimetic Peptides: A New Approach for the Treatment of Asthma

New treatments are needed for severe asthmatics to improve disease control and avoid severe toxicities associated with oral corticosteroids. We have used a murine model of house dust mite (HDM)-induced asthma to identify steroid-unresponsive genes that might represent targets for new therapeutic approaches for severe asthma. This strategy identified apolipoprotein E as a steroid-unresponsive gene with increased mRNA expression in the lungs of HDM-challenged mice. Furthermore, apolipoprotein E functioned as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in experimental HDM-induced asthma. The ability of apolipoprotein E, which is expressed by lung macrophages, to attenuate AHR, and goblet cell hyperplasia is mediated by low density lipoprotein (LDL) receptors expressed by airway epithelial cells. Consistent with this, administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130–149 of the LDL receptor-binding domain of the holo-apoE protein, significantly reduced AHR and goblet cell hyperplasia in HDM-challenged apoE−/− mice. These findings identified the apolipoprotein E – LDL receptor pathway as a new druggable target for asthma that can be activated by administration of apoE-mimetic peptides. Similarly, apolipoprotein A-I may have therapeutic potential in asthma based upon its anti-inflammatory, anti-oxidative, and anti-fibrotic properties. Furthermore, administration of apolipoprotein A-I mimetic peptides has attenuated airway inflammation, airway remodeling, and airway hyperreactivity in murine models of experimental asthma. Thus, site-directed delivery of inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides may represent novel treatment approaches that can be developed for asthma, including severe disease

Tidal Imprints of a Dark Sub-Halo on the Outskirts of the Milky Way II. Perturber Azimuth

We extend our analysis of the observed disturbances on the outskirts of the HI disk of the Milky Way. We employ the additional constraints of the phase of the modes of the observed HI image and asymmetry in the radial velocity field to derive the azimuth of the perturber inferred to be responsible for the disturbances in the HI disk. We carry out a modal analysis of the phase of the disturbances in the HI image and in SPH simulations of a Milky Way-like galaxy tidally interacting with dark perturbers, the relative offset of which we utilize to derive the perturber azimuth. To make a direct connection with observations, we express our results in sun-centered coordinates, predicting that the perturber responsible for the observed disturbances is between -50 \la l \la -10. We show explicitly that the phase of the disturbances in the outskirts of simulated galaxies at the time that best fits the Fourier amplitudes, our primary metric for the azimuth determination, is relatively insensitive to the equation of state. Our calculations here represent our continuing efforts to develop the "Tidal Analysis" method of Chakrabarti \& Blitz (2009; CB09). CB09 employed SPH simulations to examine tidal interactions between perturbing dark sub-halos and the Milky Way. They found that the amplitudes of the Fourier modes of the observed planar disturbances are best-fit by a perturbing dark sub-halo with mass one-hundredth that of the Milky Way, and a pericentric approach distance of $\sim 5-10~\rm kpc$. The overarching goal of this work is to attempt to outline an alternate procedure to optical studies for characterizing and potentially discovering dwarf galaxies -- whereby one can approximately infer the azimuthal location of a perturber, its mass and pericentric distance (CB09) from analysis of its tidal gravitational imprints on the HI disk of the primary galaxy.Comment: submitted to ApJ; 12 pages; higher resolution figures can be found at: http://astro.berkeley.edu/~sukanya/perturbersubmit.pd

Effect of tumor necrosis factor antagonism on allergen-mediated asthmatic airway inflammation

SummaryObjectiveTo assess whether tumor necrosis factor (TNF) antagonism can attenuate eosinophilic airway inflammation in patients with mild-to-moderate allergic asthma.DesignRandomized, double-blind, placebo-controlled trial.SettingNational Institutes of Health (NIH) Clinical Center.PatientsTwenty-six patients with mild-to-moderate allergic asthma, receiving only inhaled β-2-agonists, who demonstrated both an early and late phase response to inhalational allergen challenge.InterventionInjection of a soluble TNF receptor (TNFR:Fc, etanercept, Enbrel) or placebo, 25mg subcutaneously, twice weekly for 2 weeks, followed by a bronchoscopic segmental allergen challenge.MeasurementsThe primary outcome measure was whether TNFR:Fc can access the lung and inhibit TNF bioactivity. Secondary outcome measures included pulmonary eosinophilia, Th2-type cytokines, and airway hyperresponsiveness.ResultsAnti-TNF therapy was associated with transient hemiplegia in one patient, which resulted in suspension of the study. Data from the 21 participants who completed the study were analyzed. Following treatment, patients receiving anti-TNF therapy had significantly increased TNFR2 levels in epithelial lining fluid (ELF) (P<0.001), consistent with delivery of TNFR:Fc to the lung. TNF antagonism did not attenuate pulmonary eosinophilia and was associated with an increase in ELF IL-4 levels (P=0.033) at 24h following segmental allergen challenge. TNF antagonism was not associated with a change in airway hyperresponsiveness to methacholine.ConclusionsTNF antagonism may not be effective for preventing allergen-mediated eosinophilic airway inflammation in mild-to-moderate asthmatics. Transient hemiplegia, which may mimic an evolving stroke, may be a potential toxicity of anti-TNF therapy

Scattering and Iron Fluorescence Revealed During Absorption Dips in Circinus X-1

We show that dramatic spectral evolution associated with dips occurring near phase zero in RXTE observations of Cir X-1 is well-fit by variable and at times heavy absorption (N_H > 10^24 cm^-2) of a bright component, plus an underlying faint component which is not attenuated by the variable column and whose flux is ~10% of that of the unabsorbed bright component. A prominent Fe emission line at ~6.5 keV is evident during the dips. The absolute line flux outside the dips is similar to that during the dips, indicating that the line is associated with the faint component. These results are consistent with a model in which the bright component is radiation received directly from a compact source while the faint component may be attributed to scattered radiation. Our results are also generally consistent with those of Brandt et al., who found that a partial- covering model could explain ASCA spectra of a low-to-high transition in Cir X-1. The relative brightness of the two components in our model requires a column density of ~2*10^23 cm^-2 if the faint component is due to Thomson scattering in material that mostly surrounds the source. We find that illumination of such a scattering cloud by the observed direct component would produce an Fe K-alpha fluorescence flux that is in rough agreement with the flux of the observed emission line. We also conclude that if the scattering medium is not highly ionized, our line of sight to the compact source does not pass through it. Finally, we discuss simple pictures of the absorbers responsible for the dips themselves.Comment: Accepted for publication in The Astrophysical Journal (23 pages, including 11 figures

Recovery after nasal surgery vs. tonsillectomy: Discriminant validation of the Postoperative Quality of Recovery Scale

Background Initial validation and feasibility of the Post-Operative Quality of Recovery Scale (PQRS) was published in 2010. Ongoing validation includes studies to determine whether this scale can discriminate differences in recovery in similar patients having different surgery. Methods A prospective observational study included 89 patients undergoing nasal surgery and 46 patients undergoing tonsillectomy as the primary surgical procedure. Patients were assessed using the PQRS. Assessments were performed pre-surgery, at 15 and 40 min, 1 and 3 days, and 3 months after surgery. Results Tonsillectomy patients were younger [25.0 standard deviation (SD) 17.8 vs. 32.1 SD 18.0 years, P = 0.031] and had shorter anaesthesia duration (29.5 SD 12.6 vs. 42.7 SD 15.8 min, P < 0.01). Tonsillectomy patients had worse recovery in the nociceptive (pain and nausea; P < 0.001), activities of daily living (P < 0.001) and overall recovery (P = 0.025) domains, but were not different in the cognitive, emotive (depression and anxiety) or physiological recovery domains. Complete satisfaction was lower for tonsillectomy (P < 0.001). At 3 months, there was equivalence between groups in all assessments. Conclusion The study shows the ability of the PQRS to discriminate recovery in different domains. Tonsillectomy has a worse recovery profile over the first 3 days in nociceptive, activities of daily living and overall recovery, which is associated with poorer satisfaction than nasal surgery

A Thermodynamic Model for Receptor Clustering

Intracellular signaling often arises from ligand-induced oligomerization of cell surface receptors. This oligomerization or clustering process is fundamentally a cooperative behavior between near-neighbor receptor molecules; the properties of this cooperative process clearly affects the signal transduction. Recent investigations have revealed the molecular basis of receptor-receptor interactions, but a simple theoretical framework for using this data to predict cluster formation has been lacking. Here, we propose a simple, coarse-grained, phenomenological model for ligand-modulated receptor interactions and discuss its equilibrium properties via mean-field theory. The existence of a first-order transition for this model has immediate implications regarding the robustness of the cellular signaling response.Comment: Biophysical Journal, to appea

An assessment of the aversive nature of an animal management procedure (clipping) using behavioral and physiological measures

Animal management often involves procedures that, while unlikely to cause physical pain, still cause aversive responses. The domestic horse ( Equus caballus ) regularly has excessive hair clipped off to facilitate its use as a riding/driving animal and this procedure causes adverse behavioral responses in some animals. The aim of this study was to compare behavioral and physiological measures to assess the aversive effect of this procedure. Ten horses were selected on the basis of being either compliant (C: n = 5) or non-compliant (NC: n = 5) during this procedure. The horses were subjected to a sham clipping procedure (SC: where the blades had been removed from the clippers) for a period of ten minutes. Measures were taken pre, during and post SC (−10 min to +30 min) and mean values calculated for ALL horses and for C and NC separately. Behavioral activity was scored (scale 1-5) by twenty students from video footage in (phase/group-blind scoring). Heart rate (HR), salivary cortisol and eye temperature were monitored throughout the procedure. The NC horses were found to be significantly more behaviorally active/less relaxed throughout the trial than C horses(p b 0.05) with the greatest difference occurring during the SC procedure (p b 0.01). NC horses were more active/less relaxed during, compared with pre or post SC (p b 0.05), but showed no behavioral difference pre and post SC. HR of the NC horses was higher than that of the C horses throughout the trial but only significantly so after 10 min of SC (p b 0.01). ALL horses showed significant increase in HR between +5 and +10 min into the procedure (p b 0.05). There was a significant increase in salivary cortisol concentration in ALL horses post procedure (p b 0.01) with levels peaking at 20 minute post SC. No significant differences in salivary cortisol concentration between C and NC were found at any stage of the trial. Eye temperature increased significantly in ALL horses during SC, peaking at +10 min into the procedure (p b 0.05) and then decreased substantially when SC had ceased (p b 0.01). Although no significant differences were found between C and NC per se, there was a significant interaction between group and phase of trial (p b 0.05) with the NC group showing a greater decrease in eye temperature post SC. There was a significant positive correlation between changes in salivary cortisol concentration and eye temperature (p b 0.01) but no correlation between any of the other measures. Although the behavioral response of C and NC to this procedure was significantly different the physiological responses indicated that ALL horses found the procedure aversive. Eye temperature could be used as an objective and immediate measure of how an animal is responding to a specific situation in order to evaluate management procedures and adapt them where appropriate to reduce the negative impact on animal health and welfare