No abstract

In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional CF transmembrane conductance regulator (CFTR). Ataluren (PTC124) allows ribosomal readthrough of premature stop codons in mRNA.We evaluated drug activity and safety in patients with nonsense mutation CF who took ataluren three times daily (morning, midday and evening) for 12 weeks at either a lower dose (4, 4 and 8 mg?kg -1 ) or higher dose (10, 10 and 20 mg?kg -1). The study enrolled 19 patients (10 males and nine females aged 19-57 yrs; dose: lower 12, higher seven) with a classic CF phenotype, at least one CFTR nonsense mutation allele, and an abnormal nasal total chloride transport. Both ataluren doses were similarly active, improving total chloride transport with a combined mean change of -5.4 mV (p,0.001), and on-treatment responses (at least -5 mV improvement) and hyperpolarisations (values more electrically negative than -5 mV) in 61% (p,0.001) and 56% (p50.002) of patients. CFTR function was greater with time and was accompanied by trends toward improvements in pulmonary function and CF-related coughing. Adverse clinical and laboratory findings were uncommon and usually mild.Chronic ataluren administration produced time-dependent improvements in CFTR activity and clinical parameters with generally good tolerability.

BackgroundPrimary ciliary dyskinesia (PCD) is a genetic disorder characterized by impaired ciliary function, leading to chronic sinopulmonary disease. The genetic causes of PCD are still evolving, while the diagnosis is often dependent on finding a ciliary ultrastructural abnormality and immotile cilia. Here we report a novel gene associated with PCD but without ciliary ultrastructural abnormalities evident by transmission electron microscopy, but with dyskinetic cilia beating.MethodsGenetic linkage analysis was performed in a family with a PCD subject. Gene expression was studied in Chlamydomonas reinhardtii and human airway epithelial cells, using RNA assays and immunostaining. The phenotypic effects of candidate gene mutations were determined in primary culture human tracheobronchial epithelial cells transduced with gene targeted shRNA sequences. Video-microscopy was used to evaluate cilia motion.ResultsA single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD. CCDC65, an orthologue of the Chlamydomonas nexin-dynein regulatory complex protein DRC2, was localized to the cilia of normal nasal epithelial cells but was absent in those from the proband. CCDC65 expression was up-regulated during ciliogenesis in cultured airway epithelial cells, as was DRC2 in C. reinhardtii following deflagellation. Nasal epithelial cells from the affected individual and CCDC65-specific shRNA transduced normal airway epithelial cells had stiff and dyskinetic cilia beating patterns compared to control cells. Moreover, Gas8, a nexin-dynein regulatory complex component previously identified to associate with CCDC65, was absent in airway cells from the PCD subject and CCDC65-silenced cells.ConclusionMutation in CCDC65, a nexin-dynein regulatory complex member, resulted in a frameshift mutation and PCD. The affected individual had altered cilia beating patterns, and no detectable ultrastructural defects of the ciliary axoneme, emphasizing the role of the nexin-dynein regulatory complex and the limitations of certain methods for PCD diagnosis.

The survival of patients with cystic fibrosis (CF) continues to improve. The discovery and cloning of the CFTR gene more than 21 years ago led to the identification of the structure and function of the CFTR chloride channel. New therapies based on the understanding of the function of CFTR are currently under development. The better clinical status and improved survival of patients with CF is not only a result of understanding of the molecular mechanisms of CF but also a result of the development of therapeutic strategies that are based on insights into the natural course of the disease. Current CF treatments that target respiratory infections, inflammation, mucociliary clearance, and nutritional status are associated with improved pulmonary function and reduced exacerbations. Patients benefit from treatment at a specialized CF center by a multidisciplinary dedicated team with emphasis being placed on frequent visits, periodic testing, and monitoring adherence to therapy. The purpose of this review is to survey recent developments in CF care that are responsible for the improved survival and quality of life of patients with CF.

The coronavirus disease 2019 (COVID-19) pandemic has dominated nearly everyone's life since its initial outbreak in the Hubei province of China in December 2019. The disease had spread quickly throughout the world causing extensive, widespread morbidity, over two million deaths, and economical and social devastation over the entire world. Researchers and pharmaceutical companies around the globe have been racing to develop potent and safe vaccines for the disease. Pfizer-BioNTech COVID-19 vaccine followed by Moderna COVID-19 mRNA-1273 vaccine were the first to receive FDA approval. These vaccines are based on messenger RNA novel technology and considered efficient in preventing contagion ensuring safety. Known side effects for this vaccine have been reported as very similar to those known for other vaccines. Specifically, lymphadenopathy has not been considered a common manifestation of COVID-19 vaccination. Israel has been cited as leading in the introduction of these vaccines, which are available for every citizen older than 16 years. Here, we present the cases of three patients who developed lymphadenopathy after the first dose of Pfizer-BioNTech COVID-19 vaccine. Time elapsed from the injection until the appearance of the enlarged nodes, clinical symptoms, and sonographic features differed between the patients, but in all cases gradual regression was noted in the enlarged nodes until complete resolution. Accordingly, to our knowledge, this is the first report describing post-COVID-19 vaccine lymphadenopathy detailing the clinical aspects, sonographic features, and outcomes.