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Acute respiratory effects of low-level ozone exposure are not well defined in older adults.MOSES (The Multicenter Ozone Study in Older Subjects), although primarily focused on acute cardiovascular effects, provided an opportunity to assess respiratory responses to low concentrations of ozone in older healthy adults.We performed a randomized crossover, controlled exposure study of 87 healthy adults (59.9 ± 4.5 yr old; 60% female) to 0, 70, and 120 ppb ozone for 3 hours with intermittent exercise. Outcome measures included spirometry, sputum markers of airway inflammation, and plasma club cell protein-16 (CC16), a marker of airway epithelial injury. The effects of ozone exposure on these outcomes were evaluated with mixed-effect linear models. A P value less than 0.01 was chosen a priori to define statistical significance.The mean (95% confidence interval) FEVExposure to ozone at near ambient levels induced lung function effects, airway injury, and airway inflammation in older healthy adults. Clinical trial registered with www.clinicaltrials.gov (NCT01487005).

Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD. Objectives: To identify disease-causingmutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD. Methods: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis. Measurements and Main Results: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P , 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 % predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.16Hz at 258C), but an abnormal, circular beat pattern. Conclusions: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function. We hypothesized that the major clinical and biologic phenotypic markers of the disease could be evaluated by studying a cohort of subjects suspected of having PCD. Of 110 subjects evaluated, PCD was diagnosed in 78 subjects using a combination of compatible clinical features coupled with tests of ciliary ultrastructure and function. Chronic rhinitis/sinusitis (n = 78; 100%), recurrent otitis media (n = 74; 95%), neonatal respiratory symptoms (n = 57; 73%), and situs inversus (n = 43; 55%) are strong phenotypic markers of the disease. Mucoid Pseudomonas aeruginosa (n = 12; 15%) and nontuberculous mycobacteria (n = 8; 10%) were present in older (> 30 years) patients with PCD. All subjects had defects in ciliary structure, 66% in the outer dynein arm. Nasal nitric oxide production was very low in PCD (nl/minute; 19 +/- 17 vs. 376 +/- 124 in normal control subjects). Rigorous clinical and ciliary phenotyping and measures of nasal nitric oxide are useful for the diagnosis of PCD. An increased awareness of the clinical presentation and diagnostic criteria for PCD will help lead to better diagnosis and care for this orphan disease.

Since NOx emissions bear a precursor-product relation with ambient ozone (O3) levels, the sequence of peak ambient concentrations is first nitrogen dioxide (NO2) followed later in the day by ozone (O3). We ascertained whether preliminary exposure to 0.6 parts per million (ppm) NO2 would affect the lung function response to subsequent exposure to 0.3 ppm O3. Twenty-one healthy young nonsmoking women (18 to 35 yr of age) underwent two sets of exposures on two different days separated by a minimum of 2 wk. On one day, subjects were exposed to air for 2 h followed 3 h later by a 2-h exposure to O3. On the other day, the first exposure was to NO2; order of the days was randomized. During each exposure subjects intermittently exercised, alternating 15 min of rest with 15 min of exercise (Ve approximately 40 L/min). Spirometry was performed before the first exposure and at 1-h intervals until the end of the 2-h (O3) exposure. Plethysmography measurements were made before and after NO2 and O3 exposures. Nonspecific airway reactivity (AR) was determined at least 1 wk prior to the first exposure and following each O3 exposure. AR to methacholine (MCh) was expressed as dose required to decrease FEV1 by 10% (PD10FEV1). Nitrogen dioxide exposure alone did not reduce FEV1 but did significantly enhance O3-induced spirometric changes. No significant effects were observed in plethysmography. On both exposure days, the median PD10FEV1 was significantly reduced (p0.05) from control PD10FEV1 (14.3 mg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Measurements of ambient ozone (O2) concentration during daylight hours have shown a spectrum of concentration profiles, from a relatively stable to a variable pattern usually reaching a peak level in the early afternoon. Several recent studies have suggested that in estimating exposure dose (O3 concentration [C] x exposure time [T] x ventilation [V]), O3 concentration needs to be weighted more heavily than either ventilation or duration of exposure in the estimates. In this study we tested the hypothesis that regardless of concentration pattern and exposure rate the same exposure dose of O3 will induce the same spirometric response. We exposed 23 healthy male volunteers (20 to 35 yr of age) for 8 h to air, 0.12 ppm O3 (steady-state), and a triangular exposure pattern (concentration increased steadily from zero to 0.24 ppm over the first 4 h and decreased back to zero by 8 h). During the first 30 min of each hour, subjects exercised for 30 min at minute ventilation (VE) approximately 40 L/min. The order of the exposures was randomized, and the exposures were separated by at least 7 days. The response patterns over the 8-h periods for spirometric variables in both O3 exposures were statistically different from air exposure changes and from each other. For FEV1 the p values were 0.017 between air and steady-state profile, 0.002 between air and triangular profile, and 0.037 between steady-state and triangular profiles. Although in the triangular pattern of exposure the maximal O3 concentration was reached at 4 h, the maximum FEV1 decrement (10.2%) was observed at 6 h of exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Rationale: Nasal nitric oxide (nNO) is a promising non−invasive screening test for Primary Ciliary Dyskinesia (PCD) in people over 6 years of age. Little is known about how nNO production changes between birth and 6 years. Methods: Using an IRB approved protocol, a chemiluminescence analyzer was used to measure nNO in 162 children less than 6 years (101 healthy controls, 22 with PCD, 24 with asthma, and 15 with cystic fibrosis (CF)). In addition, nNO was measured in 19 healthy normal newborn infants. All patients were tested during tidal breathing with mouth open. Results: Normal newborn infants have very low nNO production at 9.2 ± 3.3 nl/min (mean ± SD) which overlaps with previously reported values for PCD. There is an age−associated increase in nNO in healthy controls (solid circles) and in PCD (open circles) under 6 years of age. After 1 year of age, nNO in PCD children (19.7 ± 13.8 nl/min, range 4.5 − 45) is significantly different from healthy controls (121.1 ± 61.1 nl/min, range 49 − 488.7) (p