Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive respiratory disorder resulting from defects of motile cilia. Various axonemal ultrastructural phenotypes have been observed, including one with so-called central-complex (CC) defects, whose molecular basis remains unexplained in most cases. To identify genes involved in this phenotype, whose diagnosis can be particularly difficult to establish, we combined homozygosity mapping and whole-exome sequencing in a consanguineous individual with CC defects. This identified a nonsense mutation in RSPH1, a gene whose ortholog in Chlamydomonas reinhardtii encodes a radial-spoke (RS)-head protein and is mainly expressed in respiratory and testis cells. Subsequent analyses of RSPH1 identified biallelic mutations in 10 of 48 independent families affected by CC defects. These mutations include splicing defects, as demonstrated by the study of RSPH1 transcripts obtained from airway cells of affected individuals. Wild-type RSPH1 localizes within cilia of airway cells, but we were unable to detect it in an individual with RSPH1 loss-of-function mutations. High-speed-videomicroscopy analyses revealed the coexistence of different ciliary beating patterns-cilia with a normal beat frequency but abnormal motion alongside immotile cilia or cilia with a slowed beat frequency-in each individual. This study shows that this gene is mutated in 20.8% of individuals with CC defects, whose diagnosis could now be improved by molecular screening. RSPH1 mutations thus appear as a major etiology for this PCD phenotype, which in fact includes RS defects, thereby unveiling the importance of RSPH1 in the proper building of CCs and RSs in humans.

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The present multicenter, randomized crossover study compared the safety and efficacy of continuous infusion with those of short infusions of ceftazidime in patients with cystic fibrosis. Patients with chronic Pseudomonas aeruginosa colonization received two successive courses of intravenous tobramycin and ceftazidime (200 mg/kg of body weight/day) for pulmonary exacerbation administered as thrice-daily short infusions or as a continuous infusion. The primary endpoint was the variation in the forced expiratory volume in 1 s (FEV 1 ) during the course of antibiotic treatment. Sixty-nine of the 70 patients enrolled in the study received at least one course of antibiotic treatment. The improvement in FEV 1 at the end of therapy was not statistically different between the two treatment procedures (؉7.6% after continuous infusion and ؉5.5% after short infusions) but was better after continuous ceftazidime treatment in patients harboring resistant isolates (P < 0.05). The interval between the course of antibiotic treatments was longer after the continuous infusion than after the short infusion of ceftazidime (P ‫؍‬ 0.04). The mean serum ceftazidime concentration during the continuous infusion was 56.2 ؎ 23.2 g/ml; the mean peak and trough concentrations during the short infusions were 216.3 ؎ 71.5 and 12.1 ؎ 8.7 g/ml, respectively. The susceptibility profiles of the P. aeruginosa isolates remained unchanged and were similar for both regimens. Quality-of-life scores were similar whatever the treatment procedure, but 82% of the patients preferred the continuous-infusion regimen. Adverse events were not significantly different between the two regimens. In conclusion, the continuous infusion of ceftazidime did not increase its toxicity and appeared to be as efficient as short infusions in patients with cystic fibrosis as a whole, but it gave better results in patients harboring resistant isolates of P. aeruginosa.

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