Clinical and genetic characterization of patients with cystic fibrosis and functional assessment of the chloride channel with the pathogenic variant c.831G>A (p.Trp277*), described for the first time.

The clinical pictures of the disease of two Russian patients with cystic fibrosis with a rare nonsense variant c.831G>A (p.Trp277*) are described. The first case is a patient with the genotype comprising variant c.54-5940_273+10250del21kb (CFTRdele2,3), and the genotype of the second case included variant c.1521_1523delCTT (F508del). Patient 1, whose genotype had two class I genetic variants, revealed severe violations of CFTR synthesis based on the intestinal current measurements (ICM) and results obtained in the intestinal organoids. In both cases of patients with genetic variant c.831G>A, a severe course of cystic fibrosis was observed.

Assessment of Selected Parameters of Liver Fibrosis and Inflammation in Patients with Diagnosed Cystic Fibrosis.

Changes in the liver and bile ducts observed in patients diagnosed with cystic fibrosis result from inflammatory processes as well as fibrosis, remodeling, apoptosis, and cholestasis. As a consequence, portal hypertension, cirrhosis, and hepatic failure may develop. So far, the complexity of these processes has not been elucidated. Study Objectives. The aim of the study was to evaluate the selected parameters of hepatitis and fibrosis (Fibrotest, Actitest, and APRI) in patients diagnosed with cystic fibrosis. Material and Methods. The study included 79 patients with cystic fibrosis, aged 1 to 20 years (mean age 9.8 years), 49 girls (62%) and 30 boys (38%). The analysis involved the following: age, sex, clinical manifestations, laboratory tests evaluating pancreas function, parameters of liver damage, and cholestasis. Fibrotest, Actitest, and APRI were performed in all subjects. Results. Elevated parameters of hepatic cell damage (hypertransaminasemia) were found in 31/79 (39.2%) patients, while abnormal cholestasis parameters in 21/79 (26.6%). The abnormal results of Fibrotest were reported in 15% of patients (12/79), while of Actitest in 10% (8/79). In contrast, elevated APRI values were found in only 7.6% (6/79) of subjects. There was a statistically significant correlation between APRI and age (higher values were observed in younger children) and between Fibrotest and Actitest and pancreatic insufficiency (higher values were found in subjects without this abnormality). Moreover, Fibrotest values were significantly higher in girls. There was no correlation between Fibrotest, Actitest, and APRI values and the type of mutation. Conclusion. It appears that Fibrotest may be used as an early marker of liver fibrosis in patients with cystic fibrosis. Increased APRI values were only found in subjects with advanced hepatic lesions, most often in the form of portal hypertension.

A model-based economic evaluation of four newborn screening strategies for cystic fibrosis in Flanders, Belgium.

Objectives: The most cost-effective newborn screening strategy for cystic fibrosis (CF) for Flanders, Belgium, is unknown. The aim of this study was to assess the cost-effectiveness of four existing newborn screening strategies for CF: IRT-DNA (immunoreactive trypsinogen, cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis), IRT-PAP (pancreatitis-associated protein), IRT-PAP-DNA, and IRT-PAP-DNA-EGA (extended CFTR gene analysis).Methods: Using data from published literature, the cost-effectiveness of the screening strategies was calculated for a hypothetical cohort of 65,606 newborns in Flanders, Belgium. A healthcare payer perspective was used, and the direct medical costs associated with screening were taken into account. The robustness of the model outcomes was assessed in sensitivity analyses.Results: The IRT-PAP strategy was the most cost-effective strategy in terms of costs per CF case detected (€9314 per CF case detected). The IRT-DNA strategy was more costly (€13,966 per CF case detected), but with an expected sensitivity of 93.4% also the most effective strategy, and was expected to detect 2.2 more cases of CF than the IRT-PAP strategy. The incremental cost-effectiveness ratio of IRT-DNA vs. IRT-PAP was €54,180/extra CF case detected. The IRT-PAP-DNA strategy and the IRT-PAP-DNA-EGA strategy were both strongly dominated by the IRT-PAP strategy.Conclusion: The IRT-PAP strategy was the most cost-effective strategy in terms of costs per CF case detected. However, the strategy did not fulfil the European Cystic Fibrosis Society guidelines for sensitivity and positive predictive value. Therefore, the more costly and more effective IRT-DNA strategy may be the most appropriate newborn screening strategy for Flanders.

Cardiopulmonary exercise testing with supramaximal verification produces a safe and valid assessment of V̇o2max in people with cystic fibrosis: a retrospective analysis.

The validity and safety of using supramaximal verification (Smax) to confirm a maximal effort during cardiopulmonary exercise testing (CPET) in people with cystic fibrosis (CF) and/or those with severe disease has been questioned. Therefore, this study aimed to investigate these concerns in children, adolescents, and adults with mild-to-severe CF lung disease. Retrospective analysis of 17 pediatric and 28 adult participants with CF [age range: 9.2-62.9 y; forced expiratory volume in 1 s: 66.7% (range: 29.9%-102.3%); 30 men] who completed a routine ramp-incremental cycling test to determine peak oxygen uptake (V̇o2peak) was studied. Maximal oxygen uptake (V̇o2max) was subsequently confirmed by Smax at 110% of peak power output. All participants satisfied the criteria to verify a maximal effort during CPET. However, Smax-V̇o2peak exceeded ramp-V̇o2peak in 3/14 (21.4%) of pediatric and 6/28 (21.4%) adult exercise tests. A valid measurement of V̇o2max was attained in 85.7% of pediatric and 96.4% of adult exercise tests, as Smax-V̇o2peak did not exceed ramp-V̇o2peak by >9%. Adults ( n = 9) experienced a ≥5% reduction in arterial O2 saturation during CPET, 4 during both the ramp and Smax, 3 during only the ramp, and 2 during only Smax. Smax did not significantly worsen perceived breathing effort, chest tightness, throat narrowing, or exertion compared with ramp-incremental testing. Given the clinical importance of aerobic fitness in people with CF, incorporating Smax is recommended to provide a safe and valid measure of V̇o2max in children, adolescents, and adults who span the spectrum of CF disease severity. NEW & NOTEWORTHY Incorporating supramaximal verification into cardiopulmonary exercise testing protocols did not increase the frequency of adverse events or perceived discomfort versus a single-phase incremental exercise test in people with mild-to-severe cystic fibrosis. Furthermore, a valid measure of maximal oxygen uptake (V̇o2max) was obtained from 85.7% of pediatric and 96.4% of adult exercise tests, whereas peak oxygen uptake underestimated aerobic fitness in comparison with V̇o2max in 21.4% of cases (by up to 24.4%).

Quantitative assessment of cyanide in cystic fibrosis sputum and its oxidative catabolism by hypochlorous acid.

RATIONALE: Cystic fibrosis (CF) patients are known to produce cyanide (CN-) although challenges exist in determinations of total levels, the precise bioactive levels, and specificity of its production by CF microflora, especially P. aeruginosa. Our objective was to measure total CN- levels in CF sputa by a simple and novel technique in P. aeruginosa positive and negative adult patients, to review respiratory tract (RT) mechanisms for the production and degradation of CN-, and to interrogate sputa for post-translational protein modification by CN- metabolites. METHODS: Sputa CN- concentrations were determined by using a commercially available CN- electrode, measuring levels before and after addition of cobinamide, a compound with extremely high affinity for CN-. Detection of protein carbamoylation was measured by Western blot. MEASUREMENTS AND MAIN RESULTS: The commercial CN- electrode was found to overestimate CN- levels in CF sputum in a highly variable manner; cobinamide addition rectified this analytical issue. Although P. aeruginosa positive patients tended to have higher total CN- values, no significant differences in CN- levels were found between positive and negative sputa. The inflammatory oxidant hypochlorous acid (HOCl) was shown to rapidly decompose CN-, forming cyanogen chloride (CNCl) and the carbamoylating species cyanate (NCO-). Carbamoylated proteins were found in CF sputa, analogous to reported findings in asthma. CONCLUSIONS: Our studies indicate that CN- is a transient species in the inflamed CF airway due to multiple biosynthetic and metabolic processes. Stable metabolites of CN-, such as cyanate, or carbamoylated proteins, may be suitable biomarkers of overall CN- production in CF airways.

Assessment of liver disease in cystic fibrosis.

Liver disease in cystic fibrosis has many causes, with biliary fibrosis due to abnormal CFTR protein predominating. Assessment requires aetiology to be defined. Biliary fibrosis may progress to cirrhosis and portal hypertension, which although initially asymptomatic, may cause varices and splenomegaly. Monitoring progression includes clinical and ultrasound assessment with endoscopic assessment of varices for those at risk. Extrapolated primarily from longitudinal assessment of viral hepatitis in adults, non-invasive elastography has a potential role. Evidence is lacking to support intervention strategies, but ursodeoxycholic acid and ligation of varices are widely applied. Indication and timing of liver transplantation are not clearly defined. Multidisciplinary approach is needed to tailor assessment and guide management.

A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators.

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.

Technological advances shed light on left ventricular cardiac disturbances in cystic fibrosis.

Cystic fibrosis (CF), the most common autosomal recessive lethal disease in Caucasians, causes chronic pulmonary disease and can lead to cor pulmonale with right ventricular dysfunction. The presence of the cystic fibrosis transmembrane conductance regulator (CFTR) in cardiac myocardia has prompted debate regarding possible defective ion channel-induced cardiomyopathy. Clinical heart disease in CF is considered rare and is restricted to case reports. It has been unclear if this is due to the lack of physiological importance of CFTR in the heart, the relatively short lifespan of those with CF, or a technical inability to detect subclinical disease. Extensive echocardiographic investigations have yielded contradictory results, leading to the dogma that left ventricular defects in CF occur secondary to lung disease. In this review, we consider why studies examining heart function in CF have not provided clarity on this topic. We then focus on data from new echocardiographic and magnetic resonance imaging technology, which are providing greater insight into cardiac function in CF and demonstrating that, in addition to secondary effects from pulmonary disease, there may be an intrinsic primary defect in the CF heart. With advancing lifespans and activity levels, understanding the risk of cardiac disease is vital to minimizing morbidity in adults with CF.

Prediction Equations Underestimate Resting Energy Expenditure in Patients With End-Stage Cystic Fibrosis.

BACKGROUND: Resting energy expenditure (REE) is increased in patients with cystic fibrosis (CF) with end-stage lung disease due to chronic inflammation and pulmonary infections. After lung transplantation (LTx), energy expenditure is expected to be lower because inflammation will decrease. We assessed the agreement between measured and predicted REE in pre-LTx CF and post-LTx patients with CF and differences in REE in pre-LTx CF and post-LTx patients with CF in a cross-sectional study. METHODS: Included were 12 pre-LTx patients with CF (9 women; median age 31.6 years; interquartile range [IQR], 23.3-40.0) and 12 patients with CF within 2 years after LTx (6 women; median age 33.5 years; IQR, 22.3-40.3). REE was measured in a fasted state using indirect calorimetry. Values were compared with predicted REE calculated by formulas of Harris-Benedict (1919 and 1984), Schofield, and the World Health Organization (1985). A calculated REE between 90% and 110% of REE measured was considered adequate. RESULTS: Prediction equations underestimate REE in at least 75% of pre-LTx and 33% of post-LTx patients with CF. Mean (SD) REE measured by indirect calorimetry was 1735 (251) kcal pre-LTx and 1650 (235) kcal post-LTx ( P = .40). REE expressed per kilogram of fat-free mass (FFM) was 40.5 kcal/kg in pre-LTx patients with CF, which was higher than the 34.3 kcal/kg in post-LTx patients with CF ( P = .01). CONCLUSIONS: Prediction equations underestimate REE in patients with end-stage CF. REE per kg of FFM is lower post-LTx than pre-LTx in patients with CF. Measurement of REE is recommended for patients with CF, especially pre-LTx, to optimize energy requirements for improving nutrition status.

Glucose Fluctuations are Not Modulated by the Proportion of Calories from Macronutrients or Spontaneous Total Energy Expenditure in Adults with Cystic Fibrosis.

OBJECTIVES: To determine the modifiable factors affecting glucose variability in people with cystic fibrosis (CF). CF-related diabetes (CFRD) is the most common complication of CF, and its presence increases morbidity and mortality in patients. Patients with CF (with and without CFRD) have potentially harmful glucose fluctuations and glucose excursions when compared to healthy adults. Carbohydrate intake and exercise have been shown to affect glycemia. Therefore, our hypothesis was that the proportion of energy from carbohydrates and total energy expenditure (TEE) would influence glucose fluctuations in adults with CF. METHODS: A cross-sectional study involved 36 patients with CF, in whom continuous glucose monitoring systems were installed. Glucose fluctuations were then quantified using 3 indexes: mean amplitude of glucose excursions, standard deviation and coefficient of variation. Patients filled out a 3-day food diary to quantify energy intake and the proportions of calories from carbohydrates, fats and proteins, and they wore Sensewear Armbands to estimate spontaneous TEE and footsteps walked. Glucose tolerance status was determined using oral glucose tolerance tests. RESULTS: Patients with CF with normal and impaired glucose tolerance had fewer glucose fluctuations than patients with CFRD (p<0.05). However, linear regression models used to determine whether nutrition or energy expenditure affects glucose fluctuations demonstrated that energy, the proportion of carbohydrates, of fat and of protein, TEE or the number of footsteps walked did not affect glucose fluctuation indexes (p>0.05). CONCLUSIONS: TEE and the proportion of energy from carbohydrates did not affect glucose fluctuations in adults with CF.

Maximal mid-expiratory flow is a surrogate marker of lung clearance index for assessment of adults with bronchiectasis.

Little is known about the comparative diagnostic value of lung clearance index (LCI) and maximal mid-expiratory flow (MMEF) in bronchiectasis. We compared the diagnostic performance, correlation and concordance with clinical variables, and changes of LCI and MMEF% predicted during bronchiectasis exacerbations (BEs). Patients with stable bronchiectasis underwent history inquiry, chest high-resolution computed tomography (HRCT), multiple-breath nitrogen wash-out test, spirometry and sputum culture. Patients who experienced BEs underwent these measurements during onset of BEs and 1 week following antibiotics therapy. Sensitivity analyses were performed in mild, moderate and severe bronchiectasis. We recruited 110 bronchiectasis patients between March 2014 and September 2015. LCI demonstrated similar diagnostic value with MMEF% predicted in discriminating moderate-to-severe from mild bronchiectasis. LCI negatively correlated with MMEF% predicted. Both parameters had similar concordance in reflecting clinical characteristics of bronchiectasis and correlated significantly with forced expiratory flow in one second, age, HRCT score, Pseudomonas aeruginosa colonization, cystic bronchiectasis, ventilation heterogeneity and bilateral bronchiectasis. In exacerbation cohort (n = 22), changes in LCI and MMEF% predicted were equally minimal during BEs and following antibiotics therapy. In sensitivity analyses, both parameters had similar diagnostic value and correlation with clinical variables. MMEF% predicted is a surrogate of LCI for assessing bronchiectasis severity.

Assessment of epithelial sodium channel variants in nonwhite cystic fibrosis patients with non-diagnostic CFTR genotypes.

PURPOSE: Several lines of evidence suggest a role for the epithelial sodium channel (ENaC) in cystic fibrosis (CF). The purpose of our study was to assess the contribution of genetic variants in the ENaC subunits (α, ß, γ) in nonwhite CF patients in whom CFTR molecular testing has been non-diagnostic. METHODS: Samples were obtained from patients who were nonwhite and whose molecular CFTR testing did not identify two mutations. Sequencing of the SCNN1A, B, and G genes was performed and variants assessed for pathogenicity and association with CF using databases, protein and splice site mutation analysis software, and literature review. RESULTS: We identified four nonsynonymous amino acid variants in SCNN1A, three in SCNN1B and one in SCNN1G. There was no convincing evidence of pathogenicity. Whereas all have been reported in the dbSNP database, only p.Ala334Thr, p.Val573Ile, and p.Thr663Ala in SCNN1A, p.Gly442Val in SCNN1B and p.Gly183Ser in SCNN1G were previously reported in ENaC genetic studies of CF or CF-like patients. Synonymous substitutions were also observed but novel synonymous variants were not detected. CONCLUSION: There is no conclusive association of ENaC genetic variants with CF in nonwhite CF patients.

ENaC inhibitors for the treatment of cystic fibrosis.

The epithelial Na(+) channel, ENaC, is a key regulator of the volume of airway surface liquid in the human airway epithelium. In cystic fibrosis (CF), Na(+) hyperabsorption through ENaC in the absence of CFTR-mediated anion secretion results in the dehydration of respiratory secretions and the impairment of mucociliary clearance. The hypothesis of utilizing an ENaC-blocking molecule to facilitate restoration of the airway surface liquid volume sufficiently to allow normal mucociliary clearance is of interest in the management of lung disease in CF patients. This article summarizes the published patent applications from 2010 that claim approaches to inhibit the function of ENaC for utility in the treatment of CF. Patents were located though SciFinder(®), using "ENaC" as the keyword from 2010 onwards; documents not relevant to CF were then manually removed.

Experimental assessment of splicing variants using expression minigenes and comparison with in silico predictions.

Assessment of the functional consequences of variants near splice sites is a major challenge in the diagnostic laboratory. To address this issue, we created expression minigenes (EMGs) to determine the RNA and protein products generated by splice site variants (n = 10) implicated in cystic fibrosis (CF). Experimental results were compared with the splicing predictions of eight in silico tools. EMGs containing the full-length Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) coding sequence and flanking intron sequences generated wild-type transcript and fully processed protein in Human Embryonic Kidney (HEK293) and CF bronchial epithelial (CFBE41o-) cells. Quantification of variant induced aberrant mRNA isoforms was concordant using fragment analysis and pyrosequencing. The splicing patterns of c.1585-1G>A and c.2657+5G>A were comparable to those reported in primary cells from individuals bearing these variants. Bioinformatics predictions were consistent with experimental results for 9/10 variants (MES), 8/10 variants (NNSplice), and 7/10 variants (SSAT and Sroogle). Programs that estimate the consequences of mis-splicing predicted 11/16 (HSF and ASSEDA) and 10/16 (Fsplice and SplicePort) experimentally observed mRNA isoforms. EMGs provide a robust experimental approach for clinical interpretation of splice site variants and refinement of in silico tools.

Non-invasive assessment of upper and lower airway infection and inflammation in CF patients.

BACKGROUND: The upper (UAW) and lower (LAW) airways of patients with cystic fibrosis (CF) have the same ion-channel defects, but little is known about similarities and differences in host immunological responses at the two levels. AIM: Identification and comparison of both levels' pathogen colonization and resulting immunological host responses. METHODS: The UAW and LAW of 40 CF patients were non-invasively assessed by nasal lavage and induced sputum. Pathogen colonization, cytology, and the concentrations of inflammatory mediators (TNF-α, MPO, matrix metalloprotease (MMP)-9, tissue inhibitor of metalloprotease (TIMP)-1, regulated upon activation, normal T-cell expressed and presumably secreted (RANTES), and interleukin (IL)-1ß, -5, -6, -8, and -10) were measured. RESULTS: Inflammatory responses were more pronounced in the LAW than the UAW. Pseudomonas aeruginosa LAW colonization is accompanied by a significantly enhanced neutrophil (PMN)-dominated response (P = 0.041) and IL-8 concentration (P = 0.01) not observed in P. aeruginosa UAW colonization. In contrast, sinonasal P. aeruginosa colonization resulted in elevated RANTES (P = 0.039) and reduced MMP-9 (P = 0.023) and TIMP-1 (P = 0.035) concentrations. Interestingly, LAW P. aeruginosa colonization was associated with reduced sinonasal concentrations of MMP-9 (P = 0.01) and TIMP-1 (P = 0.02), a finding independent of UAW colonization for MMP-9. CONCLUSION: CF UAW and LAW show distinct inflammatory profiles and differentiated responses upon P. aeruginosa colonization. Assessment of UAW colonization and MMP-9 are predictive of chronic pulmonary colonization with P. aeruginosa. Thus, this linkage between CF UAW and LAW can provide new clinical and scientific implications.

Cost effectiveness of newborn screening for cystic fibrosis: a simulation study.

BACKGROUND: Early detection of cystic fibrosis (CF) by newborn screening (NBS) reduces the rate of avoidable complications. NBS protocols vary by jurisdiction and the cost effectiveness of these different protocols is debated. OBJECTIVE: To compare the cost effectiveness of various CF NBS options. METHODS: A Markov model was built to simulate the cost effectiveness of various CF-NBS options for a hypothetical CF-NBS program over a 5-year time horizon assuming its integration into an existing universal NBS program. NBS simulated options were based on a combination of tests between the two commonly used immunoreactive trypsinogen (IRT) cutoffs (96th percentile and 99.5th percentile) as first tier tests, and, as a second tier test, either a second IRT, pancreatic-associated protein (PAP) or CFTR mutation panels. CFTR mutation panels were also considered as an eventual third tier test. Data input parameters used were retrieved from a thorough literature search. Outcomes considered were the direct costs borne by the Quebec public health care system and the number of cases of CF detected through each strategy, including the absence of screening option. RESULTS: IRT-PAP with an IRT cutoff at the 96th percentile is the most favorable option with a ratio of CAD$28,432 per CF case detected. The next most favorable alternative is the IRT1-IRT2 option with an IRT1 cutoff at the 96th percentile. The no-screening option is dominated by all NBS screening protocols considered. Results were robust in sensitivity analyses. CONCLUSION: This study suggests that NBS for cystic fibrosis is a cost-effective strategy compared to the absence of NBS. The IRT-PAP newborn screening algorithm with an IRT cutoff at the 96th percentile is the most cost effective NBS approach for Quebec.

Ventilatory pattern and energy expenditure are altered in cystic fibrosis mice.

BACKGROUND: Altered ventilatory pattern and increased energy expenditure are facets of the complex cystic fibrosis (CF) phenotype. It is not known whether these are inherent attributes of CF, secondary consequences of lung infection or other disease complications. METHODS: Studies were performed in congenic C57BL/6J, F508del (Cftr((tm1kth))) and CF gut-corrected (F508del) mice. Ventilatory patterns were measured using whole-body plethysmography. Indirect calorimetry was used to determine oxygen consumption, carbon dioxide production and resting energy expenditure. RESULTS: CF mice (F508del and F508del gut-corrected) have a significantly faster respiratory rate and increased ventilatory pattern variability as compared to non-CF mice. F508del but not CF gut-corrected mice had significantly increased energy expenditure per gram body weight. CONCLUSIONS: CF mice exhibit a faster, more variable ventilatory pattern. These changes were present in the absence of detectable infection or illness due to gastrointestinal obstruction. Increased resting energy expenditure does not completely account for these differences.

[Assessment of selected bone metabolism marker concentrations in children with cystic fibrosis]. / Analiza stezen wybranych parametrów metabolizmu kostnego u dxieci chorych na mukowiscydoze.

AIM: The aim of this study was to assess bone formation and resorption processes and bone metabolism regulators, such as osteoprotegerin and fetuin-A in children with cystic fibrosis. MATERIAL AND METHODS: We examined 45 children with cystic fibrosis aged 5-13 years treated at the Institute of Mother and Child in Warsaw. The control group consisted of 35 healthy children in the same synage range without any diseases which may influence bone metabolism. We determined serum calcium and phosphate levels by colorimetric methods, vitamin D3 by the chemiluminiscence method and bone metabolism markers (osteocalcin, 5b isoenzyme of tartrate-resistant acid phosphatase, osteoprotegerin, fetuin-A) by immunoenzymatic methods. RESULTS: Mean serum concentrations of calcium and phosphate in the studied children were within the reference ranges. However, the level of 25-hydroxyvitamin D3 was significantly lower in patients with cystic fibrosis compared to the controls (19.3±7.6 vs 25.2±8.9 ng/ml, p<0.01). In cystic fibrosis children we observed a statistically significant lower concentration of osteocalcin (81.9±28.9 vs 97.9±28.6 ng/ ml, p<0.01) and similar activity of 5b isoenzyme of tartrate-resistant acid phosphatase (12.5±2.9 vs 13.4±3.5 U/L) as compared to healthy peers. Mean serum concentration of osteoprotegerin in patients with CF was significantly lower than in the control children (4.1±0.98 vs 4.59±0.86 pmol/l, p<0.05). Serum concentration of fetuin-A was comparable in both groups of children. CONCLUSIONS: In children with cystic fibrosis changes in the profile of bone metabolism markers were observed. Even patients with CF who are clinically stable and supplemented with vitamins are at risk of osteopenia and osteoporosis in their later life. Therefore, they should be under a comprehensive medical and nutritional care in order to achieve their optimal peak bone mass.

Introduction to section III: resources for CFTR research.

This section of Cystic Fibrosis Protocols and Diagnosis focuses on resources available to facilitate the activities of the research community in the field of cystic fibrosis (CF). An overview of the protocols and resources described in subsequent chapters of this book section is provided, as well as how they can accelerate research in this area.