A genome-wide search was conducted in 107 nuclear families with at least two siblings with asthma, as part of the French EGEA study. A two-stage analysis strategy was applied to the 107 families divided into two independent subsets of 46 and 61 families, where all regions detected in the first set of families were tested for replication in the second set. In addition, all regions reported by published genome scans in different populations were examined in the total sample. A total of 254 markers were typed in the first set of families and 70% of them in the second set. Linkage was investigated by model-free methods for asthma and four asthma-related phenotypes: bronchial responsiveness (BR), skin test response, total immunoglobulin E (IgE) levels, and eosinophil count. The two-stage analysis led to the detection of three regions: 11p13 for IgE, 12q24 for eosinophils, and 17q12-21 for asthma and skin tests. Among the regions reported by published genome screens, seven were found in the 107 French EGEA families: three being already detected by the two-stage analysis, 11p13 (p = 0.005), 12q24 (p = 0.0008), and 17q12-21 (p = 0.001), and four additional ones, 1p31 (p = 0.005) for asthma, 11q13 (p = 0.006) for IgE, 13q31 (p = 0.001) for eosinophils, and 19q13 (p = 0.02) for BR.

To elucidate the pathogenesis of bronchospasm in congestive heart failure, we studied 23 patients with chronic impairment of left ventricular function due to coronary artery disease or dilated cardiomyopathy. In 21 of them we found marked bronchial hyperresponsiveness to methacholine. The mean dose (+/- SD) of methacholine that elicited a 20 percent decrease in the forced expiratory volume in one second (FEV1) was 421 +/- 298 micrograms, nearly the same as in patients with symptomatic asthma. In contrast, there was no bronchial response to methacholine in 9 of 10 patients who had coronary artery disease but normal left ventricular function. Administration of the bronchodilator albuterol led to a partial (43 percent) reversal of the methacholine-induced bronchial obstruction. In 12 patients, pretreatment with the alpha-adrenergic agonist methoxamine (10 mg by inhalation), a potent vasoconstrictor, fully prevented the methacholine-induced decrease in FEV1. The protective effect of methoxamine was blocked by the alpha-adrenergic antagonist phentolamine in all six patients who received this agent. We conclude that bronchial hyperresponsiveness to cholinergic agonists is frequent in patients with impaired left ventricular function and may contribute to the wheezy dyspnea commonly observed in such patients. The bronchoconstriction may be mediated at least in part by dilatation of the bronchial vessels.

Exercise termination was not associated with evidence of failure in any physiological system during prolonged exercise performed at MLSS. Thus the biological mechanisms of exercise termination at MLSS were compatible with an integrative homoeostatic control of peripheral physiological systems during exercise.

PurposeThe aim of this study was to evaluate whether oxidative stress markers and biomarkers of muscle injury would be affected by aging at rest and in response to an incremental exhaustive exercise.MethodsFifteen young (20.3±2.8 years) and fifteen older adults (65.1±3.5 years) performed an incremental cycle ergometer test to exhaustion. Before and after exercise, oxidative stress [superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GR), ascorbic acid, α-Tocopherol, malondialdehyde (MDA)] and muscle injury [creatine kinase (CK), lactate deshydrogenase (LDH)] biomarkers were assessed.ResultsAt rest, there was no difference in oxidative stress markers and LDH level between the groups, however CK was significantly higher in the young group than the elderly group (p<0.05). During recovery, in comparison with resting values, a significant increase in SOD (1092±145.9 vs. 1243±98 U/g Hb), GPX (67.4±12.7 vs. 79.2±15.6 U/g Hb) and GR (6.5±0.9 vs. 7.7±0.5 U/g Hb) activities were observed only in the young group (p<0.05). MDA has increased only in the older group (0.54±0.2 vs. 0.79±0.2 µmol/l) (p<0.01). CK increased in both groups (young group: 122.5±22.2 vs. 161.9±18.7 UI/l; older group: 88.8±34.1 vs. 111.1±25.9 UI/l) (p<0.01), however LDH has increased only in the young group (400.5±22.2 vs. 485±18.7 UI/l) (p<0.01) without alteration in the older group (382.8±34.1 vs. 418.5±25.9 UI/l).ConclusionsThese findings indicate that aging is associated with a decrease in antioxidant efficiency and an increase in oxidative stress damage. Furthermore, older adults would not more susceptible to exercise-induced muscle injury than young people.

A major challenge of drug delivery using colloids via the airway is to understand the mechanism implied in their interactions with epithelial cells. The purpose of this work was to characterize the process of endocytosis and exocytosis of cationic nanoparticles (NPs) made of maltodextrin which were developed as a delivery system for antigens in vaccine applications. Confocal microscopy demonstrated that these NP are rapidly endocytosed after as little as 3 min incubation, and that the endocytosis was also faster than NP binding since most of the NPs were found in the middle of the cells around the nuclei. A saturation limit was observed after a 40 min incubation, probably due to an equilibrium becoming established between endocytosis and exocytosis. Endocytosis was dramatically reduced at 4 degrees C compared with 37 degrees C, or by NaN(3) treatment, both results suggesting an energy dependent process. Protamine pretreatment of the cells inhibited NPs uptake and we found that clathrin pathway is implied in their endocytosis. Cholesterol depletion increased NP uptake by 300% and this phenomenon was explained by the fact that cholesterol depletion totally blocked NP exocytosis. These results suggest that these cationic NPs interact with anionic sites, are quickly endocytosed via the clathrin pathway and that their exocytosis is cholesterol dependent, and are similar to those obtained in other studies with viruses such as influenza.

These results demonstrate that when two Wingate tests are performed almost successively but with a short recovery between the two, passive recovery is more appropriate than active recovery to restore the performance level.

Rationale: Targeted lung denervation (TLD) is a bronchoscopic radiofrequency ablation therapy for chronic obstructive pulmonary disease (COPD), which durably disrupts parasympathetic pulmonary nerves to decrease airway resistance and mucus hypersecretion.Objectives: To determine the safety and impact of TLD on respiratory adverse events.Methods: We conducted a multicenter, randomized, sham bronchoscopy–controlled, double-blind trial in patients with symptomatic (modified Medical Research Council dyspnea scale score, ≥2; or COPD Assessment Test score, ≥10) COPD (FEV1, 30–60% predicted). The primary endpoint was the rate of respiratory adverse events between 3 and 6.5 months after randomization (defined as COPD exacerbation, tachypnea, wheezing, worsening bronchitis, worsening dyspnea, influenza, pneumonia, other respiratory infections, respiratory failure, or airway effects requiring therapeutic intervention). Blinding was maintained through 12.5 months.Measurements and Main Results: Eighty-two patients (50% female; mean ± SD: age, 63.7 ± 6.8 yr; FEV1, 41.6 ± 7.3% predicted; modified Medical Research Council dyspnea scale score, 2.2 ± 0.7; COPD Assessment Test score, 18.4 ± 6.1) were randomized 1:1. During the predefined 3- to 6.5-month window, patients in the TLD group experienced significantly fewer respiratory adverse events than those in the sham group (32% vs. 71%, P = 0.008; odds ratio, 0.19; 95% confidence interval, 0.0750–0.4923, P = 0.0006). Between 0 and 12.5 months, these findings were not different (83% vs. 90%; P = 0.52). The risk of COPD exacerbation requiring hospitalization in the 0- to 12.5-month window was significantly lower in the TLD group than in the sham group (hazard ratio, 0.35; 95% confidence interval, 0.13–0.99; P = 0.039). There was no statistical difference in the time to first moderate or severe COPD exacerbation, patient-reported symptoms, or other physiologic measures over the 12.5 months of follow-up.Conclusions: Patients with symptomatic COPD treated with TLD combined with optimal pharmacotherapy had fewer study-defined respiratory adverse events, including hospitalizations for COPD exacerbation.Clinical trial registered with www.clinicaltrials.gov (NCT02058459).

Pulmonary function tests are seldom performed in preschool children with asthma. The aim of this multicenter study was to compare pulmonary function in 74 preschool children with asthma (height of 90-130 cm) and 84 healthy control subjects. Functional residual capacity (helium dilution technique) and expiratory interrupter resistance (interrupter technique) were measured. As compared with control children, children with asthma had a significantly higher resistance (0.77 +/- 0.20 vs. 0.92 +/- 0.22 kPa. L-1. second, p < 0.001) and significantly lower specific expiratory interrupter conductance (p < 0.005) values. Resistance values were significantly higher in children with asthma with than without symptoms on exertion (p < 0.05). The effect of bronchodilator administration, expressed as the percentage of baseline and predicted resistance values, was significantly greater in children with asthma than in control subjects (-18.6 +/- 13.6% vs. -11.2 +/- 15.2%, p