Semiclassical quantization with bifurcating orbits

Bifurcations of classical orbits introduce divergences into semiclassical spectra which have to be smoothed with the help of uniform approximations. We develop a technique to extract individual energy levels from semiclassical spectra involving uniform approximations. As a prototype example, the method is shown to yield excellent results for photo-absorption spectra for the hydrogen atom in an electric field in a spectral range where the abundance of bifurcations would render the standard closed-orbit formula without uniform approximations useless. Our method immediately applies to semiclassical trace formulae as well as closed-orbit theory and offers a general technique for the semiclassical quantization of arbitrary systems

Photoabsorption spectra of the diamagnetic hydrogen atom in the transition regime to chaos: Closed orbit theory with bifurcating orbits

With increasing energy the diamagnetic hydrogen atom undergoes a transition from regular to chaotic classical dynamics, and the closed orbits pass through various cascades of bifurcations. Closed orbit theory allows for the semiclassical calculation of photoabsorption spectra of the diamagnetic hydrogen atom. However, at the bifurcations the closed orbit contributions diverge. The singularities can be removed with the help of uniform semiclassical approximations which are constructed over a wide energy range for different types of codimension one and two catastrophes. Using the uniform approximations and applying the high-resolution harmonic inversion method we calculate fully resolved semiclassical photoabsorption spectra, i.e., individual eigenenergies and transition matrix elements at laboratory magnetic field strengths, and compare them with the results of exact quantum calculations.Comment: 26 pages, 9 figures, submitted to J. Phys.

Serum methylarginines and spirometry-measured lung function in older adults

Rationale: Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in animal models of lung disease but have not previously been examined for their association with spirometric measures of lung function in humans. Objectives: This study measured serum concentrations of asymmetric and symmetric dimethylarginine in a representative sample of older community-dwelling adults and determined their association with spirometric lung function measures. Methods: Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and L-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. The five key lung function measures included as outcomes were Forced Expiratory Volume in 1 second, Forced Vital Capacity, Forced Expiratory Volume in 1 second to Forced Vital Capacity ratio, Percent Predicted Forced Expiratory Volume in 1 second, and Percent Predicted Forced Vital Capacity. Measurements and Main Results: In adjusted analyses there were statistically significant independent associations between a) higher asymmetric dimethylarginine, lower Forced Expiratory Volume in 1 second and lower Forced Vital Capacity; and b) lower L-arginine/asymmetric dimethylarginine ratio, lower Forced Expiratory Volume in 1 second, lower Percent Predicted Forced Expiratory Volume in 1 second and lower Percent Predicted Forced Vital Capacity. By contrast, no significant associations were observed between symmetric dimethylarginine and lung function. Conclusions: After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum asymmetric dimethylarginine was independently associated with a reduction in key measures of lung function. Further research is needed to determine if methylarginines predict the decline in lung function

Multi analyte profiling and variability of inflammatory markers in blood and induced sputum in patients with stable COPD

<p>Abstract</p> <p>Background</p> <p>We analyzed serial concentrations of multiple inflammatory mediators from serum and induced sputum obtained from patients with stable COPD and controls. The objective was to determine which proteins could be used as reliable biomarkers to assess COPD disease state and severity.</p> <p>Methods</p> <p>Forty-two subjects; 21 with stable COPD and 21 controls, were studied every 2 weeks over a 6-week period. Serum and induced sputum were obtained at each of 3 visits and concentrations of 19 serum and 22 sputum proteins were serially assessed using multiplex immunoassays. We used linear mixed effects models to test the distribution of proteins for an association with COPD and disease severity. Measures of within- and between-subject coefficients of variation were calculated for each of the proteins to assess reliability of measurement.</p> <p>Results</p> <p>There was significant variability in concentrations of all inflammatory proteins over time, and variability was greater for sputum proteins (median intra-subject coefficient of variation 0.58) compared to proteins measured in serum (median intra-subject coefficient of variation 0.32, P = 0.03). Of 19 serum proteins and 22 sputum proteins tested, only serum CRP, myeloperoxidase and VEGF and sputum IL-6, IL-8, TIMP-1, and VEGF showed acceptable intra and inter-patient reliability and were significantly associated with COPD, the severity of lung function impairment, and dyspnea.</p> <p>Conclusions</p> <p>Levels of many serum and sputum biomarkers cannot be reliably ascertained based on single measurements. Multiple measurements over time can give a more reliable and precise estimate of the inflammatory burden in clinically stable COPD patients.</p

Cigarette smoke exposure facilitates allergic sensitization in mice

BACKGROUND: Active and passive smoking are considered as risk factors for asthma development. The mechanisms involved are currently unexplained. OBJECTIVE: The aim of this study was to determine if cigarette smoke exposure could facilitate primary allergic sensitization. METHODS: BALB/c mice were exposed to aerosolized ovalbumin (OVA) combined with air or tobacco smoke (4 exposures/day) daily for three weeks. Serology, lung cytopathology, cytokine profiles in bronchoalveolar lavage fluid (BALF) and on mediastinal lymph node cultures as well as lung function tests were performed after the last exposure. The natural history and the immune memory of allergic sensitization were studied with in vivo recall experiments. RESULTS: Exposure to OVA induced a small increase in OVA-specific serum IgE as compared with exposure to PBS (P < 0.05), while no inflammatory reaction was observed in the airways. Exposure to cigarette smoke did not induce IgE, but was characterized by a small but significant neutrophilic inflammatory reaction. Combining OVA with cigarette smoke not only induced a significant increase in OVA-specific IgE but also a distinct eosinophil and goblet cell enriched airway inflammation albeit that airway hyperresponsiveness was not evidenced. FACS analysis showed in these mice increases in dendritic cells (DC) and CD4(+ )T-lymphocytes along with a marked increase in IL-5 measured in the supernatant of lymph node cell cultures. Immune memory experiments evidenced the transient nature of these phenomena. CONCLUSION: In this study we show that mainstream cigarette smoke temporary disrupts the normal lung homeostatic tolerance to innocuous inhaled allergens, thereby inducing primary allergic sensitization. This is characterized not only by the development of persistent IgE, but also by the emergence of an eosinophil rich pulmonary inflammatory reaction

Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways

BACKGROUND: The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR. METHODS: The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01–3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR. RESULTS: Dexamethasone reduced BAL and lung tissue eosinophilia (ED(50 )values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED(50 )of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia. CONCLUSION: This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma

Serum interleukin-5 levels are elevated in mild and moderate persistent asthma irrespective of regular inhaled glucocorticoid therapy

BACKGROUND: Interleukin-5 (IL-5) is thought to play a pivotal role in the pathogenesis of asthma. High levels of circulating IL-5 have been documented in acute asthma. However, serum IL-5 levels in mild to moderate asthmatics and the influence of regular use of inhaled glucocorticoids, is not known. METHODS: Fifty-six asthmatics and 56 age and sex matched controls were recruited prospectively from an outpatient department. Information on asthma severity and treatment was gathered by a questionnaire. Serum IL-5, total IgE and specific IgE levels were measured in a blinded fashion. RESULTS: There were 32 atopic and 24 non-atopic mild-to-moderate asthmatics. The median serum IL-5 levels in atopic asthmatics (9.5 pg/ml) and in non-atopic asthmatics (8.1 pg/ml) were significantly higher than in normal controls (4.4 pg/ml, both p < 0.003). However, median serum IL-5 levels in atopic and non-atopic asthmatics were not significantly different. The median serum IL-5 level was insignificantly higher in fourteen moderate persistent asthmatics (10.6 pg/ml) compared to forty-two mild persistent asthmatics (7.3 pg/ml) (p = 0.13). The median serum IL-5 levels in asthmatics using regular inhaled steroids (7.8 pg/ml) was not significantly different from those not using inhaled steroids (10.2 pg/ml). Furthermore, serum total IgE levels and eosinophil counts were not significantly different in those using versus those not using inhaled glucocorticoids. CONCLUSION: Serum IL-5 levels are elevated in mild and moderate persistent atopic and non-atopic asthmatics. Regular use of inhaled glucocorticoids may not abrogate the systemic Th2 type of inflammatory response in mild-moderate persistent asthma

Prolonged ozone exposure in an allergic airway disease model: Adaptation of airway responsiveness and airway remodeling

BACKGROUND: Short-term exposure to high concentrations of ozone has been shown to increase airway hyper-responsiveness (AHR). Because the changes in AHR and airway inflammation and structure after chronic ozone exposure need to be determined, the goal of this study was to investigate these effects in a murine model of allergic airway disease. METHODS: We exposed BALB/c mice to 2 ppm ozone for 4, 8, and 12 weeks. We measured the enhanced pause (Penh) to methacholine and performed cell differentials in bronchoalveolar lavage fluid. We quantified the levels of IL-4 and IFN-γ in the supernatants of the bronchoalveolar lavage fluids using enzyme immunoassays, and examined the airway architecture under light and electron microscopy. RESULTS: The groups exposed to ozone for 4, 8, and 12 weeks demonstrated decreased Penh at methacholine concentrations of 12.5, 25, and 50 mg/ml, with a dose-response curve to the right of that for the filtered-air group. Neutrophils and eosinophils increased in the group exposed to ozone for 4 weeks compared to those in the filtered-air group. The ratio of IL-4 to INF-γ increased significantly after exposure to ozone for 8 and 12 weeks compared to the ratio for the filtered-air group. The numbers of goblet cells, myofibroblasts, and smooth muscle cells showed time-dependent increases in lung tissue sections from the groups exposed to ozone for 4, 8, and 12 weeks. CONCLUSION: These findings demonstrate that the increase in AHR associated with the allergic airway does not persist during chronic ozone exposure, indicating that airway remodeling and adaptation following repeated exposure to air pollutants can provide protection against AHR