Airway resistance at maximum inhalation as a marker of asthma and airway hyperresponsiveness

<p>Abstract</p> <p>Background</p> <p>Asthmatics exhibit reduced airway dilation at maximal inspiration, likely due to structural differences in airway walls and/or functional differences in airway smooth muscle, factors that may also increase airway responsiveness to bronchoconstricting stimuli. The goal of this study was to test the hypothesis that the minimal airway resistance achievable during a maximal inspiration (R_min) is abnormally elevated in subjects with airway hyperresponsiveness.</p> <p>Methods</p> <p>The R_minwas measured in 34 nonasthmatic and 35 asthmatic subjects using forced oscillations at 8 Hz. R_minand spirometric indices were measured before and after bronchodilation (albuterol) and bronchoconstriction (methacholine). A preliminary study of 84 healthy subjects first established height dependence of baseline R_minvalues.</p> <p>Results</p> <p>Asthmatics had a higher baseline R_min% predicted than nonasthmatic subjects (134 ± 33 vs. 109 ± 19 % predicted, p = 0.0004). Sensitivity-specificity analysis using receiver operating characteristic curves indicated that baseline R_minwas able to identify subjects with airway hyperresponsiveness (PC₂₀< 16 mg/mL) better than most spirometric indices (Area under curve = 0.85, 0.78, and 0.87 for R_min% predicted, FEV₁% predicted, and FEF_25-75% predicted, respectively). Also, 80% of the subjects with baseline R_min< 100% predicted did not have airway hyperresponsiveness while 100% of subjects with R_min> 145% predicted had hyperresponsive airways, regardless of clinical classification as asthmatic or nonasthmatic.</p> <p>Conclusions</p> <p>These findings suggest that baseline R_min, a measurement that is easier to perform than spirometry, performs as well as or better than standard spirometric indices in distinguishing subjects with airway hyperresponsiveness from those without hyperresponsive airways. The relationship of baseline R_minto asthma and airway hyperresponsiveness likely reflects a causal relation between conditions that stiffen airway walls and hyperresponsiveness. In conjunction with symptom history, R_mincould provide a clinically useful tool for assessing asthma and monitoring response to treatment.</p

Major Neutrophil-Derived Soluble Mediators Associate With Baseline Lung Pathology and Post-Treatment Recovery in Tuberculosis Patients

Background: The inflammatory response to Mycobacterium tuberculosis results in variable degrees of lung pathology during active TB (ATB) with central involvement of neutrophils. Little is known about neutrophil-derived mediators and their role in disease severity at baseline and recovery upon TB treatment initiation. Methods: 107 adults with confirmed pulmonary TB were categorised based on lung pathology at baseline and following successful therapy using chest X-ray scores (Ralph scores) and GeneXpert bacterial load (Ct values). Plasma, sputum, and antigen-stimulated levels of MMP1, MMP3, MMP8, MMP9, MPO, S100A8/9, IL8, IL10, IL12/23(p40), GM-CSF, IFNγ, and TNF were analysed using multiplex cytokine arrays. Results: At baseline, neutrophil counts correlated with plasma levels of MMP8 (rho = 0.45, p = 2.80E-06), S100A8 (rho = 0.52, p = 3.00E-08) and GM-CSF (rho = 0.43, p = 7.90E-06). Levels of MMP8 (p = 3.00E-03), MMP1 (p = 1.40E-02), S100A8 (p = 1.80E-02) and IL12/23(p40) (p = 1.00E-02) were associated with severe lung damage, while sputum MPO levels were directly linked to lung damage (p = 1.80E-03), Mtb load (p = 2.10E-02) and lung recovery (p = 2.40E-02). Six months of TB therapy significantly decreased levels of major neutrophil-derived pro-inflammatory mediators: MMP1 (p = 4.90E-12 and p = 2.20E-07), MMP8 (p = 3.40E-14 and p = 1.30E-05) and MMP9 (p = 1.60E-04 and p = 1.50E-03) in plasma and sputum, respectively. Interestingly, following H37Rv whole cell lysate stimulation, S100A8 (p = 2.80E-02), MMP9 (p = 3.60E-02) and MPO (p = 9.10E-03) levels at month 6 were significantly higher compared to baseline. Sputum MMP1 (p = 1.50E-03), MMP3 (p = 7.58E-04), MMP9 (p = 2.60E-02) and TNF (p = 3.80E-02) levels were lower at month 6 compared to baseline in patients with good lung recovery. Conclusion: In this study, patients with severe lung pathology at baseline and persistent lung damage after treatment were associated with higher plasma and sputum levels of major pro-inflammatory neutrophil-derived mediators. Interestingly, low sputum MPO levels were associated with severe lung damage, higher Mtb burden and low recovery. Our data suggest that therapeutic agents which target these mediators should be considered for future studies on biomarkers and host-directed therapeutic approaches against TB-related lung pathology and/or lung recovery

Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma

<p>Abstract</p> <p>Background</p> <p>Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.</p> <p>Methods</p> <p>509 people (6–50 yr) were enrolled, 78% were atopic, median FEV₁92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV₁on at least one of two tests, to methacholine a PC₂₀≤ 16 mg/ml and to mannitol a 15% fall in FEV₁at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.</p> <p>Results</p> <p>Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV₁in subjects positive to exercise was 19%, (SD 9.2), mannitol PD₁₅158 (CI:129,193) mg, and methacholine PC₂₀2.1(CI:1.7, 2.6)mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.</p> <p>Conclusion</p> <p>In this group with normal FEV₁, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.</p> <p>Trial registration</p> <p>This was a multi-center trial comprising 25 sites across the United States of America. (NCT0025229).</p

Underweight and overweight men have greater exercise-induced dyspnoea than normal weight men.

INTRODUCTION: Persons with high or low body mass index (BMI), involved in clinical or mechanistic trials involving exercise testing, might estimate dyspnoea differently from persons with a normal BMI. AIMS: Our objective was to investigate the relationship between BMI and dyspnoea during exercise in normal subjects with varying BMI. MATERIAL AND METHODS: A total of 37 subjects undertook progressive exercise testing. Subjects were divided into three groups: underweight (UW), normal weight (NW), and overweight (OW). Dyspnoea was estimated using the visual analogue scale (VAS). Spirometry, maximum voluntary ventilation (MVV), and respiratory muscle strength (RMS) were measured. RESULTS AND DISCUSSION: The intercept of the VAS/ventilation relationship was significantly higher in NW subjects compared to UW (P = 0.029) and OW subjects (P = 0.040). Relative to the OW group, FVC (P = 0.020), FEV(1) (P = 0.024), MVV (P = 0.019), and RMS (P = 0.003) were significantly decreased in the UW group. The greater levels of dyspnoea in UW subjects could possibly be due to decreased RMS. Healthy persons should aim to achieve an optimum BMI range to have the lowest exercise-induced dyspnoea

Major-Effect Alleles at Relatively Few Loci Underlie Distinct Vernalization and Flowering Variation in Arabidopsis Accessions

We have explored the genetic basis of variation in vernalization requirement and response in Arabidopsis accessions, selected on the basis of their phenotypic distinctiveness. Phenotyping of F2 populations in different environments, plus fine mapping, indicated possible causative genes. Our data support the identification of FRI and FLC as candidates for the major-effect QTL underlying variation in vernalization response, and identify a weak FLC allele, caused by a Mutator-like transposon, contributing to flowering time variation in two N. American accessions. They also reveal a number of additional QTL that contribute to flowering time variation after saturating vernalization. One of these was the result of expression variation at the FT locus. Overall, our data suggest that distinct phenotypic variation in the vernalization and flowering response of Arabidopsis accessions is accounted for by variation that has arisen independently at relatively few major-effect loci

Serotonergic, brain volume and attentional correlates of trait anxiety in primates.

Trait anxiety is a risk factor for the development and maintenance of affective disorders, and insights into the underlying brain mechanisms are vital for improving treatment and prevention strategies. Translational studies in non-human primates, where targeted neurochemical and genetic manipulations can be made, are critical in view of their close neuroanatomical similarity to humans in brain regions implicated in trait anxiety. Thus, we characterised the serotonergic and regional brain volume correlates of trait-like anxiety in the marmoset monkey. Low- and high-anxious animals were identified by behavioral responses to a human intruder (HI) that are known to be sensitive to anxiolytic drug treatment. Extracellular serotonin levels within the amygdala were measured with in vivo microdialysis, at baseline and in response to challenge with the selective serotonin reuptake inhibitor, citalopram. Regional brain volume was assessed by structural magnetic resonance imaging. Anxious individuals showed persistent, long-term fearful responses to both a HI and a model snake, alongside sustained attention (vigilance) to novel cues in a context associated with unpredictable threat. Neurally, high-anxious marmosets showed reduced amygdala serotonin levels, and smaller volumes in a closely connected prefrontal region, the dorsal anterior cingulate cortex. These findings highlight behavioral and neural similarities between trait-like anxiety in marmosets and humans, and set the stage for further investigation of the processes contributing to vulnerability and resilience to affective disorders.This research was supported by a Medical Research Programme Grant (G0901884) from the Medical Research Council UK (MRC) to Angela Roberts, and a PhD studentship from MRC and final-term funding from Trinity College, Cambridge, UK to Yevheniia Mikheenko.This is the author accepted manuscript. The final version is available from NPG at http://www.nature.com/npp/journal/v40/n6/full/npp2014324a.htm

Bronchial Responsiveness Is Related to Increased Exhaled NO (FENO) in Non-Smokers and Decreased FENO in Smokers

Rationale Both atopy and smoking are known to be associated with increased bronchial responsiveness. Fraction of nitric oxide (NO) in the exhaled air (FENO), a marker of airways inflammation, is decreased by smoking and increased by atopy. NO has also a physiological bronchodilating and bronchoprotective role. Objectives To investigate how the relation between FENO and bronchial responsiveness is modulated by atopy and smoking habits. Methods Exhaled NO measurements and methacholine challenge were performed in 468 subjects from the random sample of three European Community Respiratory Health Survey II centers: Turin (Italy), Gothenburg and Uppsala (both Sweden). Atopy status was defined by using specific IgE measurements while smoking status was questionnaire-assessed. Main Results Increased bronchial responsiveness was associated with increased FENO levels in non-smokers (p = 0.02) and decreased FENO levels in current smokers (p = 0.03). The negative association between bronchial responsiveness and FENO was seen only in the group smoking less &lt;10 cigarettes/day (p = 0.008). Increased bronchial responsiveness was associated with increased FENO in atopic subjects (p = 0.04) while no significant association was found in non-atopic participants. The reported interaction between FENO and smoking and atopy, respectively were maintained after adjusting for possible confounders (p-values&lt;0.05). Conclusions The present study highlights the interactions of the relationship between FENO and bronchial responsiveness with smoking and atopy, suggesting different mechanisms behind atopy- and smoking-related increases of bronchial responsiveness

Adrenal suppression: A practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy

Inhaled corticosteroids (ICSs) are the most effective anti-inflammatory agents available for the treatment of asthma and represent the mainstay of therapy for most patients with the disease. Although these medications are considered safe at low-to-moderate doses, safety concerns with prolonged use of high ICS doses remain; among these concerns is the risk of adrenal suppression (AS). AS is a condition characterized by the inability to produce adequate amounts of the glucocorticoid, cortisol, which is critical during periods of physiological stress. It is a proven, yet under-recognized, complication of most forms of glucocorticoid therapy that can persist for up to 1 year after cessation of corticosteroid treatment. If left unnoticed, AS can lead to significant morbidity and even mortality. More than 60 recent cases of AS have been described in the literature and almost all cases have involved children being treated with ≥500 μg/day of fluticasone