Modifying Factors of Cystic Fibrosis Disease: Residual Chloride Secrefion, Genefic Background and Epigenetics

Cystic fibrosis (CF) is an autosomal recessive disease caused by genetic lesions in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This CFTR gene was cloned in 1989,1-3 and located to the long arm of chromosome 7 (7q3L2). lt encodes the CFTR protein that functions as a adenosine 3',5'-cyclic monophosphate (cAMP)-regulated chloride channe1 in the apical rnembrane of exocrine epithelia, 4,5 like the sweat gland, subrnandibular glands, and the pulmonary, gastrointestinal, hepatobiliaty, and urogenital tracts. In individuals with CF the defective chloride transport leads to abnormal ion and water transport,6 whieh causes dehydration of secretions and malfunctioning of the obstructed exocrine glands, whieh typically results in chronic airway obsttuction, pancreatie insufficiency (PI), and intestinal malabsorption. The sunrival of CF patients has immensely improved throughout the last century: while in 1938, 70% of babies died within the first year of life, 7 the median survival is now reported to be towards 30 years of age,8,9 most probably due to the introduction of new therapeutic regimes, like physiotherapy, aggressive antibiotic treatment, pancreatic enzyme replacement, and proper nutrition. CF is the most common, lethal, inherited disease in the Caucasian population. lO There have been many reports on the incidence in Europe vmying from 1 in 2000 live bitths in Ireland 11 to 1 in 40000 live bit-ths in Finland. 12 In the Netherlands the incidence was estimated around 1 in 3600 life births,13 CF is found to be rare in persons from non-Caucasian origin. The most common CFTR gene mutation in the Caucasian population is the ó.F508 rnutation, a deletion of the amino acid phenylalanine at position 508, which occurs in approximately 70% of CF al1eles and 90% of CF patients. Vet, presently over 870 different CFTR mutations have been identified,14 which give rise to the cystic fibrosis phenotype

Борис Алексеевич Нелепо (к 80-летию со дня рождения)

15 августа 2012 г. исполнилось бы 80 лет со дня рождения известного ученого-океанолога, доктора физико-математических наук, профессора, лауреата Государственной премии УССР (1979 г.) и СССР (1989 г.) в области науки и техники, директора Морского гидрофизического института АН УССР в 1974 – 1985 гг., первого главного редактора «Морского гидрофизического журнала», академика НАН Украины Бориса Алексеевича Нелепо (1932 – 2007)

Is sweat chloride predictive of severity of cystic fibrosis lung disease assessed by chest computed tomography?

BACKGROUND: Cystic Fibrosis (CF) lung disease is characterized by a marked heterogeneity. Sweat chloride-level is a functional marker of the CF Transmembrane Regulator (CFTR) protein and could be an important predictor of later disease severity. METHODS: In this retrospective analysis children from the Rotterdam CF clinic with available sweat chloride level at diagnosis and at least one routine spirometry-controlled volumetric chest CT scan in follow-up were included. CT scans were scored using the CF-CT scoring system (% of maximum). Associations between sweat chloride-levels and CF-CT scores were calculated using linear regression models, adjusting for age at sweat test and age at follow-up. Because structural lung damage develops over the course of many years, effect modification by the age at follow-up CT-scan was tested for by age-stratification. RESULTS: In 59 children (30 male) sweat chloride was measured at diagnosis (median age 0.5 years, range 0-13) and later chest CT performed (median age 14 years, range 6-18). Sweat chloride was associated with significantly higher CT-CT total score, bronchiectasis score, and mucus plugging score. Stratification for age at follow-up in tertiles showed this association remained only in the oldest age group (range 15-18 years). In that subgroup associations were found with all but one of the CF-CT subscores, as well as with all tested lung functions parameters. CONCLUSION: Sweat chloride-level is a significant predictor of CF lung disease severity as determined by chest CT and lung function. This association could only be demonstrated in children with follow-up to age 15 years and above

Treatment with inhaled antibiotics in bronchiectasis, side effects, and evaluation of the tolerance test; analysis from the BATTLE randomized controlled trial

Abstract Introduction Tobramycin inhalation solution (TIS) is a treatment option for patients with frequent exacerbations of bronchiectasis. A possible side effect of TIS is the development of chronic cough and bronchospasm, whereby the guidelines suggest a (in hospital) tolerance test with the first dose of TIS. However, data on respiratory adverse events are not consistent. In the present analysis from the BATTLE study (NCT02657473), we evaluated the added value of the tolerance test and aimed to observe the development of inhaled treatment related bronchial hyperreactivity. Methods Fifty‐seven patients from the BATTLE study were analyzed. Patients were randomized to receive TIS or placebo OD for 1 year. A tolerance test was performed with spirometry measurements before and after the first dose and with a bronchodilator in advance. Adverse events were strictly monitored. Results Fifty‐seven patients (100%) passed the tolerance test with no decrease in spirometry measurements or development of local intolerability. During the study treatment, a total of five TIS‐treated patients (17.8%) withdrew due to airway hyperresponsiveness after a mean of 9.2 (SD13.9) weeks and one placebo‐treated patient (3.5%) after 2 weeks (TIS vs. placebo; p = 0.66). The other TIS‐related adverse events were not clinically significant. Conclusion The use of inhaled medication is well tolerated in the heterogenous bronchiectasis population, without signs of airway hyperresponsiveness after the first dose of inhaled medication. From this observation, it can be concluded that there is no additional value for this advised tolerance test. However, closely monitoring on adverse effects during the first weeks after starting TIS is recommended