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Sample records for cystic fibrosis clinical

  1. Genetics of Cystic Fibrosis: Clinical Implications.

    PubMed

    Egan, Marie E

    2016-03-01

    Cystic fibrosis (CF) is a common life-shortening autosomal recessive genetic disorder caused by mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator protein (CFTR). Almost 2000 variants in the CFTR gene have been identified. The mutational classes are based on the functional consequences on CFTR. New therapies are being developed to target mutant CFTR and restore CFTR function. Understanding specific CF genotypes is essential for providing state-of-the art care to patients. In addition to the variation in CFTR genotype, there are several modifier genes that contribute to the respiratory phenotype.

  2. Cystic Fibrosis

    MedlinePlus

    Cystic fibrosis (CF) is an inherited disease of the mucus and sweat glands. It affects mostly your lungs, pancreas, liver, intestines, sinuses, and sex organs. CF causes your mucus to be thick and sticky. ...

  3. Cystic fibrosis - resources

    MedlinePlus

    Resources - cystic fibrosis ... The following organizations are good resources for information on cystic fibrosis : Cystic Fibrosis Foundation -- www.cff.org March of Dimes -- www.marchofdimes.org/baby/cystic-fibrosis-and- ...

  4. Clinical features of cystic fibrosis patients with rare genotypes.

    PubMed Central

    Castaldo, G; Rippa, E; Raia, V; Salvatore, D; Massa, C; de Ritis, G; Salvatore, F

    1996-01-01

    We describe the clinical features of seven cystic fibrosis patients from southern Italy who bear rare genotypes: (1) a patient homozygous for the 2183 AA-->G mutation who was affected by a very early pulmonary form of cystic fibrosis, and five patients who were compound heterozygotes either for the 2183 AA-->G mutation or for the I148T mutation, in both instances with the delta F508 mutation; and (2) a patient homozygous for the early nonsense R553X mutation who showed only a moderately severe form of cystic fibrosis. Our results confirm that environmental or genetic factors unrelated to the CF disease contribute significantly to the development of the phenotype. Images PMID:8825054

  5. Diabetes in cystic fibrosis.

    PubMed

    Bridges, Nicola

    2013-05-01

    Cystic fibrosis related diabetes (CFRD) is a common complication of cystic fibrosis, caused by a fall in insulin secretion with age in individuals with pancreatic insufficiency. CFRD is associated with worse clinical status and increased mortality. Treatment of CFRD with insulin results in sustained improvements in lung function and nutrition. While clinical experience with insulin treatment in CF has increased, the selection of who to treat and glycaemic targets remain unclear.

  6. What Causes Cystic Fibrosis?

    MedlinePlus

    ... page from the NHLBI on Twitter. What Causes Cystic Fibrosis? A defect in the CFTR gene causes cystic ... in the severity of the disease. How Is Cystic Fibrosis Inherited? Every person inherits two CFTR genes—one ...

  7. Cystic Fibrosis

    PubMed Central

    Asay, Lyal D.

    1965-01-01

    Cystic fibrosis, a disease thought to be transmitted as a recessive genetic trait, is found as a disease in about one in 1,000 to one in 10,000 births. It involves all of the exocrine glands with presenting symptoms dependent upon the extent of involvement of any group of glands. Many aspects of the disease can be corrected by substitution therapy. This applies particularly to the use of animal pancreas for the steatorrhea and salt for prevention of heat prostration. Unfortunately, the obstructive pulmonary disease with secondary bronchial infections can only be treated symptomatically by the use of mucus thinning agents, postural drainage, and antibiotics. Nevertheless, longevity can be increased and a great deal of hope offered to the families of these unfortunate children by careful supervision of their medical care. ImagesFigure 1.Figure 2.Figure 3.Figure 4.Figure 5.Figure 6.Figure 7.Figure 8.Figure 9.Figure 10.Figure 11. PMID:14288148

  8. Multidimensional Clinical Phenotyping of an Adult Cystic Fibrosis Patient Population

    PubMed Central

    Conrad, Douglas J.; Bailey, Barbara A.

    2015-01-01

    Background Cystic Fibrosis (CF) is a multi-systemic disease resulting from mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene and has major manifestations in the sino-pulmonary, and gastro-intestinal tracts. Clinical phenotypes were generated using 26 common clinical variables to generate classes that overlapped quantiles of lung function and were based on multiple aspects of CF systemic disease. Methods The variables included age, gender, CFTR mutations, FEV1% predicted, FVC% predicted, height, weight, Brasfield chest xray score, pancreatic sufficiency status and clinical microbiology results. Complete datasets were compiled on 211 subjects. Phenotypes were identified using a proximity matrix generated by the unsupervised Random Forests algorithm and subsequent clustering by the Partitioning around Medoids (PAM) algorithm. The final phenotypic classes were then characterized and compared to a similar dataset obtained three years earlier. Findings Clinical phenotypes were identified using a clustering strategy that generated four and five phenotypes. Each strategy identified 1) a low lung health scores phenotype, 2) a younger, well-nourished, male-dominated class, 3) various high lung health score phenotypes that varied in terms of age, gender and nutritional status. This multidimensional clinical phenotyping strategy identified classes with expected microbiology results and low risk clinical phenotypes with pancreatic sufficiency. Interpretation This study demonstrated regional adult CF clinical phenotypes using non-parametric, continuous, ordinal and categorical data with a minimal amount of subjective data to identify clinically relevant phenotypes. These studies identified the relative stability of the phenotypes, demonstrated specific phenotypes consistent with published findings and identified others needing further study. PMID:25822311

  9. Novel Outcome Measures for Clinical Trials in Cystic Fibrosis

    PubMed Central

    Tiddens, Harm AWM; Puderbach, Michael; Venegas, Jose G; Ratjen, Felix; Donaldson, Scott H; Davis, Stephanie D; Rowe, Steven M; Sagel, Scott D; Higgins, Mark; Waltz, David A

    2015-01-01

    Cystic fibrosis (CF) is a common inherited condition caused by mutations in the gene encoding the CF transmembrane regulator protein. With increased understanding of the molecular mechanisms underlying CF and the development of new therapies there comes the need to develop new outcome measures to assess the disease, its progression and response to treatment. As there are limitations to the current endpoints accepted for regulatory purposes, a workshop to discuss novel endpoints for clinical trials in CF was held in Anaheim, California in November 2011. The pros and cons of novel outcome measures with potential utility for evaluation of novel treatments in CF were critically evaluated. The highlights of the 2011 workshop and subsequent advances in technologies and techniques that could be used to inform the development of clinical trial endpoints are summarized in this review. Pediatr Pulmonol. © 2014 The Authors. Pediatric Pulmonology published by Wiley Periodicals, Inc. PMID:25641878

  10. Molecular Diagnosis of Cystic Fibrosis.

    PubMed

    Deignan, Joshua L; Grody, Wayne W

    2016-01-01

    This unit describes a recommended approach to identifying causal genetic variants in an individual suspected of having cystic fibrosis. An introduction to the genetics and clinical presentation of cystic fibrosis is initially presented, followed by a description of the two main strategies used in the molecular diagnosis of cystic fibrosis: (1) an initial targeted variant panel used to detect only the most common cystic fibrosis-causing variants in the CFTR gene, and (2) sequencing of the entire coding region of the CFTR gene to detect additional rare causal CFTR variants. Finally, the unit concludes with a discussion regarding the analytic and clinical validity of these approaches.

  11. [Cystic Fibrosis Cloud database: An information system for storage and management of clinical and microbiological data of cystic fibrosis patients].

    PubMed

    Prieto, Claudia I; Palau, María J; Martina, Pablo; Achiary, Carlos; Achiary, Andrés; Bettiol, Marisa; Montanaro, Patricia; Cazzola, María L; Leguizamón, Mariana; Massillo, Cintia; Figoli, Cecilia; Valeiras, Brenda; Perez, Silvia; Rentería, Fernando; Diez, Graciela; Yantorno, Osvaldo M; Bosch, Alejandra

    2016-01-01

    The epidemiological and clinical management of cystic fibrosis (CF) patients suffering from acute pulmonary exacerbations or chronic lung infections demands continuous updating of medical and microbiological processes associated with the constant evolution of pathogens during host colonization. In order to monitor the dynamics of these processes, it is essential to have expert systems capable of storing and subsequently extracting the information generated from different studies of the patients and microorganisms isolated from them. In this work we have designed and developed an on-line database based on an information system that allows to store, manage and visualize data from clinical studies and microbiological analysis of bacteria obtained from the respiratory tract of patients suffering from cystic fibrosis. The information system, named Cystic Fibrosis Cloud database is available on the http://servoy.infocomsa.com/cfc_database site and is composed of a main database and a web-based interface, which uses Servoy's product architecture based on Java technology. Although the CFC database system can be implemented as a local program for private use in CF centers, it can also be used, updated and shared by different users who can access the stored information in a systematic, practical and safe manner. The implementation of the CFC database could have a significant impact on the monitoring of respiratory infections, the prevention of exacerbations, the detection of emerging organisms, and the adequacy of control strategies for lung infections in CF patients.

  12. Cystic fibrosis genetics: from molecular understanding to clinical application

    PubMed Central

    Cutting, Garry R.

    2015-01-01

    The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to apply genetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate how genetics can provide insights into disease. Cystic fibrosis, one of the more common lethalautosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the d iscove1y of the disease-causing gene. PMID:25404111

  13. Considerations for the Conduct of Clinical Trials with Antiinflammatory Agents in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report.

    PubMed

    Torphy, Theodore J; Allen, Janet; Cantin, André M; Konstan, Michael W; Accurso, Frank J; Joseloff, Elizabeth; Ratjen, Felix A; Chmiel, James F

    2015-09-01

    Inflammation leads to lung destruction and loss of pulmonary function in patients with cystic fibrosis (CF). Drugs that modulate the cystic fibrosis transmembrane conductance regulator (CFTR) have recently been approved. Although the impact of CFTR modulators on sweat chloride and lung function are exciting, they have not yet demonstrated an effect on inflammation. Therefore, CF antiinflammatory drug development must continue. Unfortunately, the lack of clarity with this process has left investigators and industry sponsors frustrated. The Cystic Fibrosis Foundation established a working group in early 2014 to address this issue. There are many inflammatory processes disrupted in CF, and, therefore, there are many potential targets amenable to antiinflammatory therapy. Regardless of a drug's specific mechanism of action, it must ultimately affect the neutrophil or its products to impact CF. The working group concluded that before bringing new antiinflammatory drugs to clinical trial, preclinical safety studies must be conducted in disease-relevant models to assuage safety concerns. Furthermore, although studies of antiinflammatory therapies must first establish safety in adults, subsequent studies must involve children, as they are most likely to reap the most benefit. The working group also recommended that pharmacokinetic-pharmacodynamic studies and early-phase safety studies be performed before proceeding to larger studies of longer duration. In addition, innovative study designs may improve the likelihood of adequately assessing treatment response and mitigating risk before conducting multiyear studies. Learning from past experiences and incorporating this knowledge into new drug development programs will be instrumental in bringing new antiinflammatory therapies to patients.

  14. Haemophilus infection in cystic fibrosis.

    PubMed Central

    Rayner, R J; Hiller, E J; Ispahani, P; Baker, M

    1990-01-01

    Twenty seven patients with cystic fibrosis under the age of 12 years and 27 matched patients with asthma were followed up in a prospective study for one year. The isolation rate of non-capsulated strains of Haemophilus influenzae from cough swabs and sputum specimens taken at routine clinic visits every two months was significantly greater in cystic fibrosis than in asthma. Haemophilus para-influenzae was equally common in both groups. During exacerbations the isolation rate of H influenzae in cystic fibrosis was significantly greater than at other times, whereas in asthma there was no significant difference. The distribution of biotypes of H influenzae and H parainfluenzae was similar in the two groups. In cystic fibrosis, biotype I was associated with exacerbations. Biotype V was more common than in previous studies, but was not associated with exacerbations. PMID:2185699

  15. Caring for Children with Cystic Fibrosis: A Collaborative Clinical and School Approach

    ERIC Educational Resources Information Center

    Strawhacker, MaryAnn Tapper; Wellendorf, Joyce

    2004-01-01

    Earlier diagnosis and more effective treatments have improved both morbidity and mortality associated with cystic fibrosis, making regular school attendance a reality. School nurses have a unique opportunity to assist students with cystic fibrosis successfully manage their disease. Medical treatment for cystic fibrosis can be complex, leaving…

  16. Cystic fibrosis related diabetes.

    PubMed

    O'Shea, Donal; O'Connell, Jean

    2014-08-01

    Improved life expectancy in cystic fibrosis (CF) has led to an expanding population of adults with CF, now representing almost 50 % of the total CF population. This creates new challenges from long-term complications such as diabetes mellitus (DM), a condition that is present in 40 %-50 % of adults with CF. Cystic fibrosis-related diabetes (CFRD) results from a primary defect of insulin deficiency and although sharing features with type 1 (DM1) and type 2 diabetes (DM2), it is a clinically distinct condition. Progression to diabetes is associated with poorer CF clinical outcomes and increased mortality. CFRD is not associated with an increased risk of cardiovascular disease and the prevalence of microvascular complications is lower than DM1 or DM2. Rather, the primary goal of insulin therapy is the preservation of lung function and optimization of nutritional status. There is increasing evidence that appropriate screening and early intervention with insulin can reverse weight loss and improve pulmonary function. This approach may include targeting postprandial hyperglycemia not detected by standard diagnostic tests such as the oral glucose tolerance test. Further clinical research is required to guide when and how much to intervene in patients who are already dealing with the burden of one chronic illness.

  17. Cystic Fibrosis (CF) Respiratory Screen: Sputum

    MedlinePlus

    ... Cystic Fibrosis (CF) Chloride Sweat Test Lungs and Respiratory System Cystic Fibrosis: Diet and Nutrition Cystic Fibrosis Cystic Fibrosis: Diet and Nutrition Lungs and Respiratory System Contact Us Print Resources Send to a Friend ...

  18. Cystic Fibrosis (CF) Respiratory Screen: Sputum

    MedlinePlus

    ... Cystic Fibrosis (CF) Chloride Sweat Test Lungs and Respiratory System Cystic Fibrosis: Diet and Nutrition Cystic Fibrosis Cystic Fibrosis: Diet and Nutrition Lungs and Respiratory System Contact Us Print Resources Send to a friend ...

  19. A new method to improve the clinical evaluation of cystic fibrosis patients by mucus viscoelastic properties.

    PubMed

    Tomaiuolo, Giovanna; Rusciano, Giulia; Caserta, Sergio; Carciati, Antonio; Carnovale, Vincenzo; Abete, Pasquale; Sasso, Antonio; Guido, Stefano

    2014-01-01

    In cystic fibrosis (CF) patients airways mucus shows an increased viscoelasticity due to the concentration of high molecular weight components. Such mucus thickening eventually leads to bacterial overgrowth and prevents mucus clearance. The altered rheological behavior of mucus results in chronic lung infection and inflammation, which causes most of the cases of morbidity and mortality, although the cystic fibrosis complications affect other organs as well. Here, we present a quantitative study on the correlation between cystic fibrosis mucus viscoelasticity and patients clinical status. In particular, a new diagnostic parameter based on the correlation between CF sputum viscoelastic properties and the severity of the disease, expressed in terms of FEV1 and bacterial colonization, was developed. By using principal component analysis, we show that the types of colonization and FEV1 classes are significantly correlated to the elastic modulus, and that the latter can be used for CF severity classification with a high predictive efficiency (88%). The data presented here show that the elastic modulus of airways mucus, given the high predictive efficiency, could be used as a new clinical parameter in the prognostic evaluation of cystic fibrosis.

  20. Cystic fibrosis in Uruguay.

    PubMed

    Luzardo, Gerardo; Aznarez, Isabel; Crispino, Beatriz; Mimbacas, Adriana; Martínez, Liria; Poggio, Rossana; Zielenski, Julian; Tsui, Lap-Chee; Cardoso, Horacio

    2002-03-31

    We conducted clinical and genetic analyses of 52 cystic fibrosis (CF) patients in Uruguay, which is about half of the known affected individuals in the country. A relatively high proportion had a mild presentation, characterized by pancreatic sufficiency (28%), a strong pulmonary component (97%), and borderline sweat electrolyte measurements (25%). Mutational analysis of CF chromosomes demonstrated a relatively low incidence of the DeltaF508 allele (40%) and a large number of other cystic fibrosis conductance regulator mutations, with an overall detection rate of about 71%. Fifteen different mutations were detected in our patients: DeltaF508, G542X, R1162X, G85E, N1303K, R334W, R75Q, R74W, D1270N, W1282X, DeltaI507, 2789+5G-->A, R1066C, -816C/T, R553X, as well as RNA splicing variant IVS8-5T. This group of Uruguayan CF patients has some characteristics in common with other populations of similar origin (Hispanics), as well as some unique characteristics.

  1. Genetics Home Reference: cystic fibrosis

    MedlinePlus

    ... signs and symptoms include progressive damage to the respiratory system and chronic digestive system problems. The features of ... with cystic fibrosis experience health problems affecting the respiratory, digestive, and reproductive systems. Most men with cystic fibrosis have congenital bilateral ...

  2. Nutritional management of cystic fibrosis.

    PubMed Central

    MacDonald, A

    1996-01-01

    Nutritional support is an integral part of the management of cystic fibrosis patients. It is arguably best provided by a qualified dietitian and nutritional care sister working in conjunction with the rest of the cystic fibrosis team. The patient's nutritional needs should be assessed, regularly reviewed, and nutritional treatment tailored to meet the changing clinical and psychosocial needs of the patient. Nutritional intervention is not without complications, and in particular attention to normal feeding behaviour and vigilance when instituting supplementary nutrition may prevent many feeding difficulties. PMID:8660059

  3. Pneumothorax in cystic fibrosis

    PubMed Central

    Kioumis, Ioannis P.; Zarogoulidis, Konstantinos; Huang, Haidong; Li, Qiang; Dryllis, Georgios; Pitsiou, Georgia; Machairiotis, Nikolaos; Katsikogiannis, Nikolaos; Papaiwannou, Antonis; Lampaki, Sofia; Porpodis, Konstantinos; Zaric, Bojan; Branislav, Perin; Mpoukovinas, Ioannis; Lazaridis, George

    2014-01-01

    Pneumothorax is recognized as a common and life-threatening complication in cystic fibrosis (CF) patients, especially in those who are infected with P. aeruginosa, B. cepacia or Aspergillus, need enteral feeding, are diagnosed as suffering from allergic bronchopulmonary aspergillosis (ABPA), developed massive hemoptysis, and their respiratory function is seriously compromised. Structural impairment and altered airflow dynamics in the lungs of CF patients are considered as the main predisposing factors, but also inhaled medications and non-invasive positive pressure ventilation (NIPPV) could increase the risk of pneumothorax. Clinical presentation could range from dramatic to very mild. Management of spontaneous pneumothorax occurring to patients with CF is essentially similar to that for non-CF patients. Therapeutic options include intercostal tube drainage, video-assisted thoracoscopic surgery (VATS), and medical or surgical pleurodesis. Pneumothorax increases both short- and long-term morbidity and mortality in CF patients and causes significant deterioration of their quality of life. PMID:25337406

  4. Antibiotic Tolerance Induced by Lactoferrin in Clinical Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients

    PubMed Central

    Andrés, María T.; Viejo-Diaz, Mónica; Pérez, Francisco; Fierro, José F.

    2005-01-01

    Lactoferrin-induced cell depolarization and a delayed tobramycin-killing effect on Pseudomonas aeruginosa cells were correlated. This antibiotic tolerance effect (ATE) reflects the ability of a defense protein to modify the activity of an antibiotic as a result of its modulatory effect on bacterial physiology. P. aeruginosa isolates from cystic fibrosis patients showed higher ATE values (≤6-fold) than other clinical strains. PMID:15793153

  5. Baseline ultrasound and clinical correlates in children with cystic fibrosis

    PubMed Central

    Leung, Daniel H.; Ye, Wen; Molleston, Jean P.; Weymann, Alexander; Ling, Simon; Paranjape, Shruti M.; Romero, Rene; Schwarzenberg, Sara Jane; Palermo, Joseph; Alonso, Estella M.; Murray, Karen F.; Marshall, Bruce C.; Sherker, Averell H.; Siegel, Marilyn J.; Krishnamurthy, Rajesh; Harned, Roger; Karmazyn, Boaz; Magee, John C.; Narkewicz, Michael R

    2015-01-01

    Objective To investigate the relationship between abdominal ultrasound (US) findings and demographic, historical and clinical features in children with CF. Study design Children age 3-12 years with CF without known cirrhosis, were enrolled in a prospective, multi-center study of US to predict hepatic fibrosis. Consensus US patterns were assigned by 3 radiologists as normal, heterogeneous, homogeneous, or cirrhosis. Data were derived from direct collection and U.S. or Toronto CF registries. Chi-square or ANOVA were used to compare variables among US groups and between normal and abnormal. Logistic regression was used to study risk factors for having abnormal US. Results Findings in 719 subjects were normal (n=590, 82.1%), heterogeneous (64, 8.9%), homogeneous (41, 5.7%), and cirrhosis (24, 3.3%). Cirrhosis (p=0.0004), homogeneous (p<0.0001) and heterogeneous (p=0.03) were older than normal. More males were heterogeneous (p=0.001). More heterogeneous (15.0%, p=0.009) and cirrhosis (25.0%, p=0.005) had CF-related diabetes or impaired glucose tolerance versus normal (5.4%). Early infection with Pseudomonas aeruginosa (<2 years old) was associated with a lower risk (OR 0.42, p=0.0007) of abnormal. Ursodeoxycholic acid use (OR 3.69, p <0.0001) and CF-related diabetes (OR 2.21, p=0.019) were associated with increased risk of abnormal. Conclusions Unsuspected cirrhosis is seen in 3.3% of young patients with CF, heterogeneous in 8.9%. abnormal US is associated with CF-related diabetes, and early P aeruginosa is associated with normal US. Prospective assessment of these risk factors may identify potential interventional targets. PMID:26254836

  6. Detection of Cystic Fibrosis Transmembrane Conductance Regulator Activity in Early-Phase Clinical Trials

    PubMed Central

    Rowe, Steven M.; Accurso, Frank; Clancy, John P.

    2007-01-01

    Advances in our understanding of cystic fibrosis pathogenesis have led to strategies directed toward treatment of underlying causes of the disease rather than treatments of disease-related symptoms. To expedite evaluation of these emerging therapies, early-phase clinical trials require extension of in vivo cystic fibrosis transmembrane conductance regulator (CFTR)–detecting assays to multicenter trial formats, including nasal potential difference and sweat chloride measurements. Both of these techniques can be used to fulfill diagnostic criteria for the disease, and can discriminate various levels of CFTR function. Full realization of these assays in multicenter clinical trials requires identification of sources of nonbiological intra- and intersite variability, and careful attention to study design and statistical analysis of study-generated data. In this review, we discuss several issues important to the performance of these assays, including efforts to identify and address aspects that can contribute to inconsistent and/or potentially erroneous results. Adjunctive means of detecting CFTR including mRNA expression, immunocytochemical localization, and other methods are also discussed. Recommendations are presented to advance our understanding of these biomarkers and to improve their capacity to predict cystic fibrosis outcomes. PMID:17652506

  7. Clinical impact of a highly prevalent Pseudomonas aeruginosa clone in Dutch cystic fibrosis patients.

    PubMed

    de Vrankrijker, A M M; Brimicombe, R W; Wolfs, T F W; Heijerman, H G M; van Mansfeld, R; van Berkhout, F T; Willems, R J L; Bonten, M J M; van der Ent, C K

    2011-03-01

    Studies suggest that infection with highly prevalent Pseudomonas aeruginosa clones in cystic fibrosis (CF) is associated with an unfavourable clinical outcome. We studied the clinical characteristics of patients infected with a recently described, highly prevalent P. aeruginosa clone (ST406) in two CF centres in The Netherlands. Multilocus sequence typing data were available for 219 patients, of whom 40 (18.3%) were infected with ST406 and 179 with other sequence types. ST406 infection was independently associated with age, having a sibling with ST406 infection and use of inhaled antibiotics, but not with unfavourable clinical outcome, suggesting that high transmissibility is not necessarily associated with high virulence.

  8. Heart involvement in cystic fibrosis: A specific cystic fibrosis-related myocardial changes?

    PubMed

    Labombarda, Fabien; Saloux, Eric; Brouard, Jacques; Bergot, Emmanuel; Milliez, Paul

    2016-09-01

    Cystic fibrosis is a complex multi-systemic chronic disease characterized by progressive organ dysfunction with development of fibrosis, possibly affecting the heart. Over the last four decades pathological, experimental, and clinical evidence points towards the existence of a specific myocardial involvement in cystic fibrosis. Multi-modality cardiac imaging, especially recent echocardiographic techniques, evidenced diastolic and/or systolic ventricular dysfunction in cystic fibrosis leading to the concept of a cystic fibrosis-related cardiomyopathy. Hypoxemia and inflammation are among the most important factors for heart involvement in cystic fibrosis. Cystic Fibrosis Transmembrane Regulator was found to be involved in the regulation of cardiomyocyte contraction and may also account for cystic fibrosis-related myocardial dysfunction. This review, mainly focused on echocardiographic studies, seeks to synthesize the existing literature for and against the existence of heart involvement in cystic fibrosis, its mechanisms and prognostic implications. Careful investigation of the heart function may be helpful for risk stratification and therapeutic decisions in patients with cystic fibrosis.

  9. Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders

    PubMed Central

    Moskowitz, Samuel M.; Chmiel, James F.; Sternen, Darci L.; Cheng, Edith; Gibson, Ronald L; Marshall, Susan G.; Cutting, Garry R.

    2009-01-01

    Cystic fibrosis transmembrane conductance regulator-related disorders encompass a disease spectrum from focal male reproductive tract involvement in congenital absence of the vas deferens to multiorgan involvement in classic cystic fibrosis. The reproductive, gastrointestinal, and exocrine manifestations of cystic fibrosis transmembrane conductance regulator deficiency are correlated with CFTR genotype, whereas the respiratory manifestations that are the main cause of morbidity and mortality in cystic fibrosis are less predictable. Molecular genetic testing of CFTR has led to new diagnostic strategies and will enable targeting of molecular therapies now in development. Older diagnostic methods that measure sweat chloride and nasal potential difference nonetheless remain important because of their sensitivity and specificity. In addition, the measurement of immunoreactive trypsinogen and the genotyping of CFTR alleles are key to newborn screening programs because of low cost. The multiorgan nature of cystic fibrosis leads to a heavy burden of care, thus therapeutic regimens are tailored to the specific manifestations present in each patient. The variability of cystic fibrosis lung disease and the variable expressivity of mild CFTR alleles complicate genetic counseling for this autosomal recessive disorder. Widespread implementation of newborn screening programs among populations with significant cystic fibrosis mutation carrier frequencies is expected to result in increasing demands on genetic counseling resources. PMID:19092437

  10. Neonatal cystic fibrosis screening test

    MedlinePlus

    Cystic fibrosis screening - neonatal; Immunoreactive trypsinogen; IRT test; CF - screening ... better nutrition, growth, and lung function. This screening test helps doctors identify children with CF before they ...

  11. CXCR4+ granulocytes reflect fungal cystic fibrosis lung disease.

    PubMed

    Carevic, Melanie; Singh, Anurag; Rieber, Nikolaus; Eickmeier, Olaf; Griese, Matthias; Hector, Andreas; Hartl, Dominik

    2015-08-01

    Cystic fibrosis airways are frequently colonised with fungi. However, the interaction of these fungi with immune cells and the clinical relevance in cystic fibrosis lung disease are incompletely understood.We characterised granulocytes in airway fluids and peripheral blood from cystic fibrosis patients with and without fungal colonisation, non-cystic fibrosis disease controls and healthy control subjects cross-sectionally and longitudinally and correlated these findings with lung function parameters.Cystic fibrosis patients with chronic fungal colonisation by Aspergillus fumigatus were characterised by an accumulation of a distinct granulocyte subset, expressing the HIV coreceptor CXCR4. Percentages of airway CXCR4(+) granulocytes correlated with lung disease severity in patients with cystic fibrosis.These studies demonstrate that chronic fungal colonisation with A. fumigatus in cystic fibrosis patients is associated with CXCR4(+) airway granulocytes, which may serve as a potential biomarker and therapeutic target in fungal cystic fibrosis lung disease.

  12. A randomised, double-blind, placebo-controlled phase IIB clinical trial of repeated application of gene therapy in patients with cystic fibrosis.

    PubMed

    Alton, Eric W F W; Boyd, A Christopher; Cheng, Seng H; Cunningham, Steve; Davies, Jane C; Gill, Deborah R; Griesenbach, Uta; Higgins, Tracy; Hyde, Stephen C; Innes, J Alastair; Murray, Gordon D; Porteous, David J

    2013-11-01

    The UK Cystic Fibrosis Gene Therapy Consortium has been working towards clinical gene therapy for patients with cystic fibrosis for several years. We have recently embarked on a large, multi-dose clinical trial of a non-viral, liposome-based formulation powered for the first time to detect clinical benefit. The article describes the details of the protocol.

  13. Pseudomonas aeruginosa quorum sensing molecules correlate with clinical status in cystic fibrosis.

    PubMed

    Barr, Helen L; Halliday, Nigel; Cámara, Miguel; Barrett, David A; Williams, Paul; Forrester, Douglas L; Simms, Rebecca; Smyth, Alan R; Honeybourne, David; Whitehouse, Joanna L; Nash, Edward F; Dewar, Jane; Clayton, Andrew; Knox, Alan J; Fogarty, Andrew W

    2015-10-01

    Pseudomonas aeruginosa produces quorum sensing signal molecules that are potential biomarkers for infection.A prospective study of 60 cystic fibrosis patients with chronic P. aeruginosa, who required intravenous antibiotics for pulmonary exacerbations, was undertaken. Clinical measurements and biological samples were obtained at the start and end of the treatment period. Additional data were available for 29 of these patients when they were clinically stable.Cross-sectionally, quorum sensing signal molecules were detectable in the sputum, plasma and urine of 86%, 75% and 83% patients, respectively. They were positively correlated between the three biofluids. Positive correlations were observed for most quorum sensing signal molecules in sputum, plasma and urine, with quantitative measures of pulmonary P. aeruginosa load at the start of a pulmonary exacerbation. Plasma concentrations of 2-nonyl-4-hydroxy-quinoline (NHQ) were significantly higher at the start of a pulmonary exacerbation compared to clinical stability (p<0.01). Following the administration of systemic antibiotics, plasma 2-heptyl-4-hydroxyquinoline (p=0.02) and NHQ concentrations (p<0.01) decreased significantly.In conclusion, quorum sensing signal molecules are detectable in cystic fibrosis patients with pulmonary P. aeruginosa infection and are positively correlated with quantitative measures of P. aeruginosa. NHQ correlates with clinical status and has potential as a novel biomarker for P. aeruginosa infection.

  14. Pseudomonas aeruginosa quorum sensing molecules correlate with clinical status in cystic fibrosis

    PubMed Central

    Halliday, Nigel; Cámara, Miguel; Barrett, David A.; Williams, Paul; Forrester, Douglas L.; Simms, Rebecca; Smyth, Alan R.; Honeybourne, David; Whitehouse, Joanna L.; Nash, Edward F.; Dewar, Jane; Clayton, Andrew; Knox, Alan J.; Fogarty, Andrew W.

    2015-01-01

    Pseudomonas aeruginosa produces quorum sensing signal molecules that are potential biomarkers for infection. A prospective study of 60 cystic fibrosis patients with chronic P. aeruginosa, who required intravenous antibiotics for pulmonary exacerbations, was undertaken. Clinical measurements and biological samples were obtained at the start and end of the treatment period. Additional data were available for 29 of these patients when they were clinically stable. Cross-sectionally, quorum sensing signal molecules were detectable in the sputum, plasma and urine of 86%, 75% and 83% patients, respectively. They were positively correlated between the three biofluids. Positive correlations were observed for most quorum sensing signal molecules in sputum, plasma and urine, with quantitative measures of pulmonary P. aeruginosa load at the start of a pulmonary exacerbation. Plasma concentrations of 2-nonyl-4-hydroxy-quinoline (NHQ) were significantly higher at the start of a pulmonary exacerbation compared to clinical stability (p<0.01). Following the administration of systemic antibiotics, plasma 2-heptyl-4-hydroxyquinoline (p=0.02) and NHQ concentrations (p<0.01) decreased significantly. In conclusion, quorum sensing signal molecules are detectable in cystic fibrosis patients with pulmonary P. aeruginosa infection and are positively correlated with quantitative measures of P. aeruginosa. NHQ correlates with clinical status and has potential as a novel biomarker for P. aeruginosa infection. PMID:26022946

  15. Cystic Fibrosis: Diet and Nutrition

    MedlinePlus

    ... in the Operating Room? Cystic Fibrosis: Diet and Nutrition KidsHealth > For Kids > Cystic Fibrosis: Diet and Nutrition A A A What's in this article? CF ... is someone who knows all about food and nutrition. Each kid is different, but most kids with ...

  16. Cystic Fibrosis: Diet and Nutrition

    MedlinePlus

    ... Getting an X-ray Cystic Fibrosis: Diet and Nutrition KidsHealth > For Kids > Cystic Fibrosis: Diet and Nutrition Print A A A What's in this article? ... is someone who knows all about food and nutrition. Each kid is different, but most kids with ...

  17. Key findings of the US Cystic Fibrosis Foundation's clinical practice benchmarking project.

    PubMed

    Boyle, Michael P; Sabadosa, Kathryn A; Quinton, Hebe B; Marshall, Bruce C; Schechter, Michael S

    2014-04-01

    Benchmarking is the process of using outcome data to identify high-performing centres and determine practices associated with their outstanding performance. The US Cystic Fibrosis Foundation (CFF) Patient Registry contains centre-specific outcomes data for all CFF-certified paediatric and adult cystic fibrosis (CF) care programmes in the USA. The CFF benchmarking project analysed these registry data, adjusting for differences in patient case mix known to influence outcomes, and identified the top-performing US paediatric and adult CF care programmes for pulmonary and nutritional outcomes. Separate multidisciplinary paediatric and adult benchmarking teams each visited 10 CF care programmes, five in the top quintile for pulmonary outcomes and five in the top quintile for nutritional outcomes. Key practice patterns and approaches present in both paediatric and adult programmes with outstanding clinical outcomes were identified and could be summarised as systems, attitudes, practices, patient/family empowerment and projects. These included: (1) the presence of strong leadership and a well-functioning care team working with a systematic approach to providing consistent care; (2) high expectations for outcomes among providers and families; (3) early and aggressive management of clinical declines, avoiding reliance on 'rescues'; and (4) patients/families that were engaged, empowered and well informed on disease management and its rationale. In summary, assessment of practice patterns at CF care centres with top-quintile pulmonary and nutritional outcomes provides insight into characteristic practices that may aid in optimising patient outcomes.

  18. Clinical Impact of Blood Culture Results in Acutely Ill Hospitalized Adult Patients With Cystic Fibrosis

    PubMed Central

    Vender, Robert J.; Vender, Robert L.

    2016-01-01

    Background Blood cultures are obtained clinically to confirm site and source of acute infection as well as to guide effective antibiotic therapies. Patients with cystic fibrosis (CF) are at risk for blood stream infection (BSI) as identified from positive blood culture results. Methods A retrospective chart review was performed of 190 adult CF patients from January 1, 2001 through December 1, 2015. All positive blood culture results were identified as to clinical relevance and source of BSI. Results There were a total of 3,053 blood cultures. One hundred fifty-one positive blood cultures were considered pathogenic and clinically significant. Venous access device-related BSI was identified in 31 evaluable patients and 106 blood cultures. Nineteen patients and 45 positive blood cultures were attributable to organ-specific sources. Conclusion Two patterns of BSI were identified: 1) venous access device infections without causal mortality and 2) organ-specific site infections with associated 26% mortality. PMID:27829951

  19. Immunoglobulin and IgG subclass levels in a regional pediatric cystic fibrosis clinic.

    PubMed

    Garside, J P; Kerrin, D P; Brownlee, K G; Gooi, H C; Taylor, J M; Conway, S P

    2005-02-01

    The aim of this study was to report serum immunoglobulin (Ig) and IgG subclass levels in a large pediatric population with cystic fibrosis, and relate these to measures of disease severity. Total immunoglobulin levels were measured in 154 patients, and IgG subclass levels were measured in 136 patients and compared to age-related normal population data and to levels reported in previously published studies of children with cystic fibrosis. Clinical data were also collected: genotype; height, weight, and BMI standard deviation scores; FEV(1) (as percent predicted); Shwachmann-Kulczycki (S-K) and Northern chest X-ray scores; and Pseudomonas aeruginosa infection status. The clinical well-being of patients with hypo- or hyper-gammaglobulinemia was compared with age- and sex-matched control patients who had normal levels of gammaglobulin. IgG subclass levels were measured, and the results were compared with previous studies. Eleven patients had hypergammaglobulinemia (7.8% compared with 0-69% in the published literature). Patients with hypergammaglobulinemia had lower FEV(1) percent-predicted values, and worse S-K and Northern chest X-ray scores than controls. Three patients had hypogammaglobulinemia (1.9% compared with 0-10.8% in the published literature). There was no difference in any clinical parameter between controls and those with hypogammaglobulinemia. Nineteen patients (14%) had low levels of IgG1, and 40 patients (29%) had low levels of IgG2. The low percentage of patients with abnormally high immunoglobulin levels probably reflects the improved respiratory status of today's children with CF. The low percentage of those with low IgG probably reflects better nutritional status. The finding of worse lung function and clinical scores in patients with hypergammaglobulinemia agrees with the published literature. The high percentage of patients with low IgG2 was unexpected and was not previously reported. The clinical significance of this in patients with CF is

  20. Nutritional Issues in Cystic Fibrosis.

    PubMed

    Solomon, Missale; Bozic, Molly; Mascarenhas, Maria R

    2016-03-01

    The importance of maintaining adequate nutrition in patients with cystic fibrosis has been well known for the past 3 decades. Achieving normal growth and maintaining optimal nutrition is associated with improved lung function. Comprehensive and consistent nutritional assessments at regular intervals can identify those at risk of nutritional failure and uncover micronutrient deficiencies contributing to malnutrition. Management of malnutrition in cystic fibrosis should follow a stepwise approach to determine the causes and comorbidities and to develop a nutritional plan. Nutritional management is crucial at every stage in a person's life with cystic fibrosis and remains a cornerstone of management.

  1. Gastrointestinal Manifestations of Cystic Fibrosis

    PubMed Central

    2016-01-01

    Cystic fibrosis has historically been considered a pulmonary disease, but with the increasing life expectancy of these patients, gastrointestinal manifestations are becoming more important. Furthermore, nutritional status is closely linked to pulmonary function and, thus, overall mortality. This article discusses gastrointestinal manifestations (which involve nutritional, pancreatic, hepatobiliary, and, in particular, gastrointestinal tract issues) of cystic fibrosis as well as management of the disease. In addition, the article discusses studies that have been critical to our understanding of gastrointestinal manifestations of cystic fibrosis. PMID:27330503

  2. Outcome measures for clinical trials assessing treatment of cystic fibrosis lung disease

    PubMed Central

    VanDevanter, Donald R; Konstan, Michael W

    2015-01-01

    Cystic fibrosis (CF) is a complex genetic disease characterized by death from loss of lung function. Therapies target pathophysiologic changes associated with pulmonary disease progression. Although therapeutic mechanisms differ, efficacy demonstration is limited to a few accepted outcome measures, each with shortcomings that are becoming more pronounced as CF population health improves. Pulmonary function improvement (as forced expiratory volume in 1 s [FEV1]) and reduction of pulmonary exacerbation risk are commonly used outcomes. Changes in FEV1 decline rate, quality of life, linear growth and/or weight gain are less utilized outcomes. Validated outcomes tend to work best in subjects with more aggressive or advanced lung disease and less so in healthier subjects. Assays of effects on primary therapeutic targets have yet to be validated as surrogate measures of clinical efficacy. As CF population health improves, it will become increasingly difficult to employ current clinical outcome measures to demonstrate efficacy. PMID:26146539

  3. Cystic fibrosis in pregnancy.

    PubMed Central

    Kent, N E; Farquharson, D F

    1993-01-01

    OBJECTIVE: To review the outcomes of pregnancies in women with cystic fibrosis (CF) and to address issues pertinent to the obstetric care of such women. DATA SOURCES: English-language case reports and case series published from 1960 to 1991 identified through a search of MEDLINE and Index Medicus. The terms of reference were "cystic fibrosis" and "pregnancy". Not all the reports reviewed addressed all the outcomes under consideration. STUDY SELECTION: A total of 20 reports citing cases of pregnancy in women with CF. DATA EXTRACTION: Outcomes included the number of spontaneous abortions, pregnancies continued beyond 20 weeks, preterm deliveries, maternal deaths at 6 months and 2 years after delivery and perinatal deaths. Breast-feeding was addressed. Measures to assess the severity of maternal disease included the mean age at diagnosis of CF, weight gain during pregnancy, pulmonary function studies if available and the need for pancreatic enzyme replacement therapy. DATA SYNTHESIS: Of 217 pregnancies in 162 women spontaneous abortion occurred in 10 (4.6%). Pregnancy progressed beyond 20 weeks in 81.6% of cases; 24.3% of the deliveries were preterm. The maternal death rate did not exceed that among age-related women with CF who were not pregnant. The rate of perinatal death was 7.9%. Breast milk was not hypernatremic. Poor outcomes were associated with a weight gain of less than 4.5 kg and a forced vital capacity of less than 50% of the predicted value. CONCLUSIONS: Premature labour and delivery remain a significant risk for pregnant women with CF, contributing to a high rate of perinatal death. Maternal illness and death result from deteriorating pulmonary function. Breast-feeding is not contraindicated. Attention to energy intake and pulmonary function is important. PMID:8374843

  4. Assessment of Correlation between Sweat Chloride Levels and Clinical Features of Cystic Fibrosis Patients

    PubMed Central

    Raina, Manzoor A.; Khan, Mosin S.; Malik, Showkat A.; Raina, AB Hameed; Makhdoomi, Mudassir J.; Bhat, Javed I.

    2016-01-01

    Introduction Cystic Fibrosis (CF) is an autosomal recessive disorder and the incidence of this disease is undermined in Northern India. The distinguishable salty character of the sweat belonging to individuals suffering from CF makes sweat chloride estimation essential for diagnosis of CF disease. Aim The aim of this prospective study was to elucidate the relationship of sweat chloride levels with clinical features and pattern of CF. Materials and Methods A total of 182 patients, with clinical features of CF were included in this study for quantitative measurement of sweat chloride. Sweat stimulation and collection involved pilocarpine iontophoresis based on the Gibson and Cooks methodology. The quantitative estimation of chloride was done by Schales and Schales method with some modifications. Cystic Fibrosis Trans Membrane Conductance Regulator (CFTR) mutation status was recorded in case of patients with borderline sweat chloride levels to correlate the results and for follow-up. Results Out of 182 patients having clinical features consistent with CF, borderline and elevated sweat chloride levels were present in 9 (5%) and 41 (22.5%) subjects respectively. Elevated sweat chloride levels were significantly associated with wheeze, Failure To Thrive (FTT), history of CF in Siblings, product of Consanguineous Marriage (CM), digital clubbing and steatorrhoea on univariate analysis. On multivariate analysis only wheeze, FTT and steatorrhoea were found to be significantly associated with elevated sweat chloride levels (p<0.05). Among the nine borderline cases six cases were positive for at least two CFTR mutations and rest of the three cases were not having any mutation in CFTR gene. Conclusion The diagnosis is often delayed and the disease is advanced in most patients at the time of diagnosis. Sweat testing is a gold standard for diagnosis of CF patients as genetic mutation profile being heterozygous and unlikely to become diagnostic test. PMID:28208841

  5. Management of pulmonary exacerbations in cystic fibrosis: still an unmet medical need in clinical practice.

    PubMed

    Justicia, José Luis; Solé, Amparo; Quintana-Gallego, Esther; Gartner, Silvia; de Gracia, Javier; Prados, Concepción; Máiz, Luis

    2015-04-01

    Pulmonary exacerbation (PEx) is a hallmark of cystic fibrosis. Although several criteria have been proposed for the definition of PEx, no consensus has yet been reached. Very often, many PEx cases go unreported. A standardized and validated definition is needed to reduce variability in clinical practice. The pathophysiology of recurrent episodes remains unclear, and both onset and risk are multifactorial. PEx leads to increased healthcare costs, impaired quality of life and a cycle in which PEx causes loss of lung function, which predisposes to further episodes. The number of episodes affects survival. Although early diagnosis and aggressive treatment are highly recommended, measures to prevent the emergence of new PEx are even more important. In particular, inhaled antibiotics administered under new treatment schedules could play a key role in preventing exacerbations and thus delay decline in lung function and reduce mortality. The primary objective is zero exacerbations.

  6. The differential clinical impact of human coronavirus species in children with cystic fibrosis.

    PubMed

    da Silva Filho, Luiz Vicente Ribeiro Ferreira; Zerbinati, Rodrigo Melim; Tateno, Adriana Fumie; Boas, Lucy Vilas; de Almeida, Marina Buarque; Levi, José Eduardo; Drexler, Jan Felix; Drosten, Christian; Pannuti, Cláudio Sérgio

    2012-08-01

    We investigated the clinical impact of human coronaviruses (HCoV) OC43, 229E, HKU1 and NL63 in pediatric patients with cystic fibrosis (CF) during routine and exacerbation visits. A total of 408 nasopharyngeal aspirate samples were obtained from 103 patients over a 1-year period. Samples positive for HCoV were submitted for nucleotide sequencing to determine the species. Nineteen samples (4.65%) were positive for HCoV, of which 8 were positive for NL63, 6 for OC43, 4 for HKU1, and 1 for 229E. Identification of HCoV was not associated with an increased rate of respiratory exacerbations, but NL63-positive patients had higher exacerbation rates than patients who were positive for other HCoV species.

  7. Association between clinical antibiotic resistance and susceptibility of Pseudomonas in the cystic fibrosis lung

    PubMed Central

    Jansen, Gunther; Mahrt, Niels; Tueffers, Leif; Barbosa, Camilo; Harjes, Malte; Adolph, Gernot; Friedrichs, Anette; Krenz-Weinreich, Annegret; Rosenstiel, Philip; Schulenburg, Hinrich

    2016-01-01

    Background and objectives: Cystic fibrosis patients suffer from chronic lung infections that require long-term antibiotic therapy. Pseudomonas readily evolve resistance, rendering antibiotics ineffective. In vitro experiments suggest that resistant bacteria may be treated by exploiting their collateral sensitivity to other antibiotics. Here, we investigate correlations of sensitivity and resistance profiles of Pseudomonas aeruginosa that naturally adapted to antibiotics in the cystic fibrosis lung. Methodology: Resistance profiles for 13 antibiotics were obtained using broth dilution, E-test and VITEK mass spectroscopy. Genetic variants were determined from whole-genome sequences and interrelationships among isolates were analyzed using 13 MLST loci. Result: Our study focused on 45 isolates from 13 patients under documented treatment with antibiotics. Forty percent of these were clinically resistant and 15% multi-drug resistant. Colistin resistance was found once, despite continuous colistin treatment and even though colistin resistance can readily evolve experimentally in the laboratory. Patients typically harbored multiple genetically and phenotypically distinct clones. However, genetically similar clones often had dissimilar resistance profiles. Isolates showed mutations in genes encoding cell wall synthesis, alginate production, efflux pumps and antibiotic modifying enzymes. Cross-resistance was commonly observed within antibiotic classes and between aminoglycosides and β-lactam antibiotics. No evidence was found for consistent phenotypic resistance to one antibiotic and sensitivity to another within one genotype. Conclusions and implications: Evidence supporting potential collateral sensitivity in clinical P. aeruginosa isolates remains equivocal. However, cross-resistance within antibiotic classes is common. Colistin therapy is promising since resistance to it was rare despite its intensive use in the studied patients. PMID:27193199

  8. What Are the Signs and Symptoms of Cystic Fibrosis?

    MedlinePlus

    ... Twitter. What Are the Signs and Symptoms of Cystic Fibrosis? The signs and symptoms of cystic fibrosis (CF) ... respiratory, digestive, or reproductive systems of the body. Cystic Fibrosis Figure A shows the organs that cystic fibrosis ...

  9. Current and future treatment options for cystic fibrosis lung disease: latest evidence and clinical implications

    PubMed Central

    Edmondson, Claire; Davies, Jane C.

    2016-01-01

    Treatment for cystic fibrosis (CF) has conventionally targeted downstream consequences of the defect such as mucus plugging and infection. More recently, significant advances have been made in treating the root cause of the disease, namely a defective CF transmembrane conductance regulator (CFTR) gene. This review summarizes current pulmonary treatment options and highlights advances in research and development of new therapies. PMID:27347364

  10. Concomitant cystic fibrosis and coeliac disease: reminder of an important clinical lesson

    PubMed Central

    Cohen-Cymberknoh, Malena; Wilschanski, Michael

    2009-01-01

    A 3½-year-old apparently healthy girl with normal development presented with steatorrhoea. Both positive serum anti-tissue transglutaminase antibody levels and an intestinal biopsy were consistent with coeliac disease. A positive sweat test and genetic analysis confirmed cystic fibrosis. PMID:21686738

  11. Cystic Fibrosis: Brazilian ENT Experience

    PubMed Central

    Sih, Tania; Godinho, Ricardo; Franco, Leticia Paiva; Piltcher, Otávio

    2012-01-01

    Most published studies about Cystic Fibrosis (CF) are European or North American. There are still few publications about the characteristics of fibrocystic populations in developing countries. The incidence of cystic fibrosis (CF) in Brazil varies among different regions (1 : 10,000 in Minas Gerais, 1 : 9,500 in Paraná, 1 : 8,700 in Santa Catarina, and 1 : 1600 in Rio Grande do Sul). The prevalence of the DF508 mutation also varies according to population: 33% in Sao Paulo, 49% in Rio Grande do Sul, 27% in Santa Catarina, and 52% in Minas Gerais. Cough and nasal obstruction are the most common symptoms. The variation in nasal polyposis prevalence may be explained by population genotypic characteristics in a country that spans a continent. Findings on nasal endoscopy and computed tomography (CT) have better correlation than do this information compared with surgical and clinical history. Microbiologic studies suggest a high level of early contamination of the airways. Sensorineural hearing loss (SNHL) occurs in these patients as a result of ototoxic antibiotics. The data compiled in this paper is useful, but also lead to the general agreement that more research would be welcome due to the unique characteristics of this country. PMID:22611403

  12. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice

    PubMed Central

    Castellani, C.; Cuppens, H.; Macek, M.; Cassiman, J.J.; Kerem, E.; Durie, P.; Tullis, E.; Assael, B.M.; Bombieri, C.; Brown, A.; Casals, T.; Claustres, M.; Cutting, G.R.; Dequeker, E.; Dodge, J.; Doull, I.; Farrell, P.; Ferec, C.; Girodon, E.; Johannesson, M.; Kerem, B.; Knowles, M.; Munck, A.; Pignatti, P.F.; Radojkovic, D.; Rizzotti, P.; Schwarz, M.; Stuhrmann, M.; Tzetis, M.; Zielenski, J.; Elborn, J.S.

    2009-01-01

    It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients. PMID:18456578

  13. Diabetes mellitus and bone disease in cystic fibrosis.

    PubMed

    Curran, David R; McArdle, John R; Talwalkar, Jaideep S

    2009-10-01

    Patients with cystic fibrosis are frequently affected with pancreatic insufficiency and are predisposed to the development of diabetes mellitus (DM) and bone demineralization. Cystic fibrosis-related diabetes mellitus is a clinical entity distinct from type 1 and type 2 diabetes, with important implications for the nutritional and pulmonary health of cystic fibrosis patients. This form of diabetes owes largely to insulin deficiency, but alterations in insulin sensitivity and hepatic glucose production have also been described. Therapy for cystic fibrosis-related diabetes differs substantially from type 2 DM, with careful attention to prandial glycemic excursions crucial to controlling its metabolic effects. Bone disease, including osteopenia and osteoporosis, also occurs with increased frequency in cystic fibrosis, owing to defects in intestinal absorption, chronic inflammation, lung disease, low body weight, and gonadal dysfunction. The pathogenesis, implications, diagnosis, and therapy of cystic fibrosis-related bone demineralization are discussed, with attention to recommended approaches to prevention of and treatment of established bone disease.

  14. Alcaligenes infection in cystic fibrosis.

    PubMed

    Tan, Kenneth; Conway, Steven P; Brownlee, Keith G; Etherington, Christine; Peckham, Daniel G

    2002-08-01

    The aim of this study was to investigate the effect of chronic Alcaligenes species infection of the respiratory tract on the clinical status of patients with cystic fibrosis. We conducted a retrospective case-controlled study. The microbiological records of all patients attending the Leeds Regional Pediatric and Adult Cystic Fibrosis Units from 1992-1999 were examined. Chronic Alcaligenes infection was defined as a positive sputum culture on at least three occasions over a 6-month period. These patients were compared with controls matched for age, gender, respiratory function, and Pseudomonas aeruginosa infection status. Respiratory function tests, anthropometric data, Shwachman-Kulczycki score, Northern chest x-ray score, intravenous and nebulized antibiotic treatment, and corticosteroid treatment were compared from 2 years before to 2 years after Alcaligenes infection. From a clinic population of 557, 13 (2.3%) fulfilled the criteria for chronic infection. The median age at acquisition of infection was 17.2 years (range, 6.5-33.6). There was no significant difference in the changes of percentage predicted values for FEV(1), FVC, FEF(25-75), or Shwachman-Kulczycki and Northern chest x-ray scores, or in weight, height, and body mass index z-scores between Alcaligenes-infected cases and controls. There was also no significant difference in the use of antibiotics (intravenous and nebulized) or corticosteroids (inhaled and oral). We conclude that in our clinic, chronic infection with Alcaligenes species was uncommon. Chronically infected patients showed no excess deterioration in clinical or pulmonary function status from 2 years before to 2 years after primary acquisition.

  15. Clinical Sensitivity of Cystic Fibrosis Mutation Panels in a Diverse Population.

    PubMed

    Hughes, Erin E; Stevens, Colleen F; Saavedra-Matiz, Carlos A; Tavakoli, Norma P; Krein, Lea M; Parker, April; Zhang, Zhen; Maloney, Breanne; Vogel, Beth; DeCelie-Germana, Joan; Kier, Catherine; Anbar, Ran D; Berdella, Maria N; Comber, Paul G; Dozor, Allen J; Goetz, Danielle M; Guida, Louis; Kattan, Meyer; Ting, Andrew; Voter, Karen Z; van Roey, Patrick; Caggana, Michele; Kay, Denise M

    2016-02-01

    Infants are screened for cystic fibrosis (CF) in New York State (NYS) using an IRT-DNA algorithm. The purpose of this study was to validate and assess clinical validity of the US FDA-cleared Illumina MiSeqDx CF 139-Variant Assay (139-VA) in the diverse NYS CF population. The study included 439 infants with CF identified via newborn screening (NBS) from 2002 to 2012. All had been screened using the Abbott Molecular CF Genotyping Assay or the Hologic InPlex CF Molecular Test. All with CF and zero or one mutation were tested using the 139-VA. DNA extracted from dried blood spots was reliably and accurately genotyped using the 139-VA. Sixty-three additional mutations were identified. Clinical sensitivity of three panels ranged from 76.2% (23 mutations recommended for screening by ACMG/ACOG) to 79.7% (current NYS 39-mutation InPlex panel), up to 86.0% for the 139-VA. For all, sensitivity was highest in Whites and lowest in the Black population. Although the sample size was small, there was a nearly 20% increase in sensitivity for the Black CF population using the 139-VA (68.2%) over the ACMG/ACOG and InPlex panels (both 50.0%). Overall, the 139-VA is more sensitive than other commercially available panels, and could be considered for NBS, clinical, or research laboratories conducting CF screening.

  16. CLINICAL PRACTICES FOR INTERMEDIATE/EQUIVICAL SWEAT TESTS FOLLOWING ABNORMAL CYSTIC FIBROSIS NEWBORN SCREENS

    PubMed Central

    Nelson, Megan R.; Adamski, Craig R.; Tluczek, Audrey

    2013-01-01

    Background Newborn screening (NBS) for cystic fibrosis (CF) has become standard practice in many countries. Consequently, the prevalence of infants with intermediate/equivalent sweat test results has increased. This study examined clinical practices in the United States (US) related to intermediate sweat test results subsequent to NBS. Methods Telephone surveys were conducted with staff from 77 (47% response rate) US CF centers documenting clinical practices related to intermediate/equivalent sweat chloride levels (30–59 mmol/L) following abnormal NBS. Results Thirty percent of centers followed CF Foundation guidelines for classifying intermediate/equivalent results. There was much variability in sweat testing procedures, diagnostic labels, additional diagnostics, addressing prognosis, and services offered to parents. CF center staff identified a need for resources to better address the uncertainty associated with intermediate/equivalent results. Conclusion Findings warrant evaluation of barriers to adherence with existing guidelines and establishment of internationally accepted, evidenced-based, clinical standards for infants with intermediate/equivalent CF NBS results. PMID:21855423

  17. Improved growth and clinical, nutritional, and respiratory changes in response to nutritional therapy in cystic fibrosis.

    PubMed

    Shepherd, R; Cooksley, W G; Cooke, W D

    1980-09-01

    To investigate the role of nutritional factors in growth and in the clinical, nurtitional, and respiratory status in cystic fibrosis, we studied 12 problem CF patients from six months before to six months after a period of supplemental parenteral nutrition. During the initial six months' observation period on appropriate conventional therapy, the patients (aged 0.5 to 11 years) had inadequate growth and weight gain, a total of 21 active pulmonary infections, and, despite dietary supplements, inadequate ad libitum nutrient intakes. After nutritional therapy, providing a balanced consistent hypercaloric intake for 21 days, catch-up weight gain occurred by one month and continued at six months; catch-up in linear growth was observed by three months and continued at six months. In addition, significantly fewer pulmonary infections were observed in the six months' post-therapy (n = 3), sustained and significant improvements were noted in clinical score and plumonary function, and there was a marked improvement in well-being and ad libitum nutrient intake. We conclude that adequate nutritional support can favorably affect growth, clinical status, and the course of chronic pulmonary disease in problem cases of CF.

  18. Airway Microbiota in Bronchoalveolar Lavage Fluid from Clinically Well Infants with Cystic Fibrosis

    PubMed Central

    Wagner, Brandie D.; Williams, Cynthia B.; Stevens, Mark J.; Robertson, Charles E.; Welchlin, Cole W.; Moen, Catherine E.; Zemanick, Edith T.; Harris, Jonathan K.

    2016-01-01

    Background Upper airway cultures guide the identification and treatment of lung pathogens in infants with cystic fibrosis (CF); however, this may not fully reflect the spectrum of bacteria present in the lower airway. Our objectives were to characterize the airway microbiota using bronchoalveolar lavage fluid (BALF) from asymptomatic CF infants during the first year of life and to investigate the relationship between BALF microbiota, standard culture and clinical characteristics. Methods BALF, nasopharyngeal (NP) culture and infant pulmonary function testing data were collected at 6 months and one year of age during periods of clinical stability from infants diagnosed with CF by newborn screening. BALF was analyzed for total bacterial load by qPCR and for bacterial community composition by 16S ribosomal RNA sequencing. Clinical characteristics and standard BALF and NP culture results were recorded over five years of longitudinal follow-up. Results 12 BALF samples were collected from 8 infants with CF. Streptococcus, Burkholderia, Prevotella, Haemophilus, Porphyromonas, and Veillonella had the highest median relative abundance in infant CF BALF. Two of the 3 infants with repeat BALF had changes in their microbial communities over six months (Morisita-Horn diversity index 0.36, 0.38). Although there was excellent percent agreement between standard NP and BALF cultures, these techniques did not routinely detect all bacteria identified by sequencing. Conclusions BALF in asymptomatic CF infants contains complex microbiota, often missed by traditional culture of airway secretions. Anaerobic bacteria are commonly found in the lower airways of CF infants. PMID:27930727

  19. Diagnosis of Adult Patients with Cystic Fibrosis.

    PubMed

    Nick, Jerry A; Nichols, David P

    2016-03-01

    The diagnosis of cystic fibrosis (CF) is being made with increasing frequency in adults. Patients with CF diagnosed in adulthood typically present with respiratory complaints, and often have recurrent or chronic airway infection. At the time of initial presentation individuals may appear to have clinical manifestation limited to a single organ, but with subclinical involvement of the respiratory tract. Adult-diagnosed patients have a good response to CF center care, and newly available cystic fibrosis transmembrane receptor-modulating therapies are promising for the treatment of residual function mutation, thus increasing the importance of the diagnosis in adults with unexplained bronchiectasis.

  20. Cystic Fibrosis (CF): Chloride Sweat Test

    MedlinePlus

    ... to 2-Year-Old Cystic Fibrosis (CF) Chloride Sweat Test KidsHealth > For Parents > Cystic Fibrosis (CF) Chloride Sweat Test Print A A A What's in this ... en el sudor What It Is A chloride sweat test helps diagnose cystic fibrosis (CF) , an inherited ...

  1. What's it Like to Have Cystic Fibrosis?

    MedlinePlus

    ... de los dientes Video: Getting an X-ray Cystic Fibrosis KidsHealth > For Kids > Cystic Fibrosis Print A A A What's in this article? ... with a condition she's known all her life — cystic fibrosis (say: SIS-tik fi-BRO-sus). Her parents ...

  2. Cystic Fibrosis (CF): Chloride Sweat Test

    MedlinePlus

    ... 1- to 2-Year-Old Cystic Fibrosis (CF) Chloride Sweat Test KidsHealth > For Parents > Cystic Fibrosis (CF) Chloride Sweat Test A A A What's in this ... cloruro en el sudor What It Is A chloride sweat test helps diagnose cystic fibrosis (CF) , an ...

  3. What's it Like to Have Cystic Fibrosis?

    MedlinePlus

    ... Room? What Happens in the Operating Room? Cystic Fibrosis KidsHealth > For Kids > Cystic Fibrosis A A A What's in this article? What ... a condition she's known all her life — cystic fibrosis (say: SIS-tik fi-BRO-sus). Her parents ...

  4. Advancing clinical development pathways for new CFTR modulators in cystic fibrosis.

    PubMed

    Mayer-Hamblett, Nicole; Boyle, Michael; VanDevanter, Donald

    2016-05-01

    Cystic fibrosis (CF) is a life-shortening genetic disease affecting approximately 70,000 individuals worldwide. Until recently, drug development efforts have emphasised therapies treating downstream signs and symptoms resulting from the underlying CF biological defect: reduced function of the CF transmembrane conductance regulator (CFTR) protein. The current CF drug development landscape has expanded to include therapies that enhance CFTR function by either restoring wild-type CFTR protein expression or increasing (modulating) the function of mutant CFTR proteins in cells. To date, two systemic small-molecule CFTR modulators have been evaluated in pivotal clinical trials in individuals with CF and specific mutant CFTR genotypes that have led to regulatory review and/or approval. Advances in the discovery of CFTR modulators as a promising new class of therapies have been impressive, yet work remains to develop highly effective, disease-modifying modulators for individuals of all CF genotypes. The objectives of this review are to outline the challenges and opportunities in drug development created by systemic genotype-specific CFTR modulators, highlight the advantages of sweat chloride as an established biomarker of CFTR activity to streamline early-phase development and summarise options for later phase clinical trial designs that respond to the adoption of approved genotype-specific modulators into standard of care. An optimal development framework will be needed to move the most promising therapies efficiently through the drug development pipeline and ultimately deliver efficacious and safe therapies to all individuals with CF.

  5. Pseudomonas aeruginosa infection in patients with cystic fibrosis: scientific evidence regarding clinical impact, diagnosis, and treatment*

    PubMed Central

    da Silva, Luiz Vicente Ribeiro Ferreira; Ferreira, Flavia de Aguiar; Reis, Francisco José Caldeira; de Britto, Murilo Carlos Amorim; Levy, Carlos Emilio; Clark, Otavio; Ribeiro, José Dirceu

    2013-01-01

    Evidence-based techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. The use of levels of evidence allows the reader to identify the quality of scientific information that supports the recommendations made by experts. The objective of this review was to address current concepts related to the clinical impact, diagnosis, and treatment of Pseudomonas aeruginosa infections in patients with cystic fibrosis. For the preparation of this review, the authors defined a group of questions that would be answered in accordance with the principles of PICO–an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. For each question, a structured review of the literature was performed using the Medline database in order to identify the studies with the methodological design most appropriate to answering the question. The questions were designed so that each of the authors could write a response. A first draft was prepared and discussed by the group. Recommendations were then made on the basis of the level of scientific evidence, in accordance with the classification system devised by the Oxford Centre for Evidence-Based Medicine, as well as the level of agreement among the members of the group. PMID:24068273

  6. Advancing clinical development pathways for new CFTR modulators in cystic fibrosis

    PubMed Central

    Mayer-Hamblett, Nicole; Boyle, Michael; VanDevanter, Donald

    2016-01-01

    Cystic fibrosis (CF) is a life-shortening genetic disease affecting approximately 70 000 individuals worldwide. Until recently, drug development efforts have emphasised therapies treating downstream signs and symptoms resulting from the underlying CF biological defect: reduced function of the CF transmembrane conductance regulator (CFTR) protein. The current CF drug development landscape has expanded to include therapies that enhance CFTR function by either restoring wild-type CFTR protein expression or increasing (modulating) the function of mutant CFTR proteins in cells. To date, two systemic small-molecule CFTR modulators have been evaluated in pivotal clinical trials in individuals with CF and specific mutant CFTR genotypes that have led to regulatory review and/or approval. Advances in the discovery of CFTR modulators as a promising new class of therapies have been impressive, yet work remains to develop highly effective, disease-modifying modulators for individuals of all CF genotypes. The objectives of this review are to outline the challenges and opportunities in drug development created by systemic genotype-specific CFTR modulators, highlight the advantages of sweat chloride as an established biomarker of CFTR activity to streamline early-phase development and summarise options for later phase clinical trial designs that respond to the adoption of approved genotype-specific modulators into standard of care. An optimal development framework will be needed to move the most promising therapies efficiently through the drug development pipeline and ultimately deliver efficacious and safe therapies to all individuals with CF. PMID:26903594

  7. Laboratory diagnosis of cystic fibrosis.

    PubMed

    Webster, H L

    1983-01-01

    The demonstration of abnormally high concentrations of electrolytes in eccrine sweat is still the only practical laboratory procedure available for diagnosis of cystic fibrosis. Properly performed, the sweat test is very reliable, but there are many published reports that all of the methods in current use frequently generate incorrect diagnoses. Analysis of potential for error in sweat test methods shows that of the three essential phases involved, stimulation, collection, and analysis, the major cause of intrinsic inaccuracy occurs in the collection process. In this case the problem is due to condensate formation, which leads to the subsequent analysis of nonrepresentative sweat. Human error is also an important cause of false results and is a direct function of the number of critical manual operations involved in the technic. This review provides a critical examination of sweat test methods, identifying problem areas and suggesting ways to improve procedures in the interests of clinically reliable laboratory data in support of diagnosis.

  8. [Historical compilation of cystic fibrosis].

    PubMed

    Navarro, Salvador

    2016-01-01

    Cystic fibrosis is the most common life-shortening recessively inherited disorder in the Caucasian population. The genetic mutation that most frequently provokes cystic fibrosis (ΔF508) appeared at least 53,000years ago. For many centuries, the disease was thought to be related to witchcraft and the "evil eye" and it was only in 1938 that Dorothy H. Andersen characterized this disorder and suspected its genetic origin. The present article reviews the pathological discoveries and diagnostic and therapeutic advances made in the last 75 years. The review ends with some considerations for the future.

  9. Gastrointestinal manifestations in cystic fibrosis.

    PubMed

    Eggermont, E

    1996-08-01

    CFTR, or cystic fibrosis transmembrane conductance regulator, the gene product that is defective in cystic fibrosis, is present in the apical membrane of the epithelial cells from the stomach to the colon. In the foregut, the clinical manifestations are not directly related to the primary defect of the CFTR chloride channel. The most troublesome complaints and symptoms originate from the oesophagus as peptic oesophagitis or oesophageal varices. In the small intestinal wall, the clinical expression of CF depends largely on the decreased secretion of fluid and chloride ions, the increased permeability of the paracellular space between adjacent enterocytes and the sticky mucous cover over the enterocytes. As a rule, the brush border enzyme activities are normal and there is some enhanced active transport as shown for glucose and alanine. The results of continuous enteral feeding of CF patients clearly show that the small intestinal mucosa, in the daily situation, is not functioning at maximal capacity. Although CFTR expression in the colon is lower, the large intestine may be the site of several serious complications such as rectal prolapse, meconium ileus equivalent, intussusception, volvulus and silent appendicitis. In recent years colonic strictures, after the use of high-dose pancreatic enzymes, are being increasingly reported; the condition has recently been called CF fibrosing colonopathy. The CF gastrointestinal content itself differs mainly from the normal condition by the lower acidity in the foregut and the accretion of mucins and proteins, eventually resulting in intestinal obstruction, in the ileum and colon. Better understanding of the CF gastrointestinal phenotype may contribute to improvement of the overall wellbeing of these patients.

  10. Clinical features of cystic fibrosis patients with rare genotypes in Saguenay Lac-Saint-Jean (Quebec, Canada).

    PubMed

    de Braekeleer, M; Mari, G; Verlingue, C; Allard, C; Leblanc, J P; Simard, F; Aubin, G; Férec, C

    1997-01-01

    We describe the clinical features of six cystic fibrosis (CF) patients from Saguenay Lac-Saint-Jean who bear rare genotypes. Two patients with a delta F508/I148T genotype had pancreatic insufficiency, as did two patients compound heterozygous for the 621 + 1G-->T mutation who also had a major growth retardation. One CF adult who carried a delta F508/Q890X genotype had meconium ileus and bronchiectasis. The sixth patient (A455E/R117C) had borderline sweat chloride concentrations; the diagnosis of cystic fibrosis had remained doubtful until the molecular analysis showed the presence of two CF mutations. The seventh patient with a delta F508/R1158X genotype experienced several complications and is now 43 years old.

  11. Physiotherapy for cystic fibrosis in Australia and New Zealand: A clinical practice guideline.

    PubMed

    Button, Brenda M; Wilson, Christine; Dentice, Ruth; Cox, Narelle S; Middleton, Anna; Tannenbaum, Esta; Bishop, Jennifer; Cobb, Robyn; Burton, Kate; Wood, Michelle; Moran, Fiona; Black, Ryan; Bowen, Summar; Day, Rosemary; Depiazzi, Julie; Doiron, Katherine; Doumit, Michael; Dwyer, Tiffany; Elliot, Alison; Fuller, Louise; Hall, Kathleen; Hutchins, Matthew; Kerr, Melinda; Lee, Annemarie L; Mans, Christina; O'Connor, Lauren; Steward, Ranjana; Potter, Angela; Rasekaba, Tshepo; Scoones, Rebecca; Tarrant, Ben; Ward, Nathan; West, Samantha; White, Dianne; Wilson, Lisa; Wood, Jamie; Holland, Anne E

    2016-05-01

    Physiotherapy management is a key element of care for people with cystic fibrosis (CF) throughout the lifespan. Although considerable evidence exists to support physiotherapy management of CF, there is documented variation in practice. The aim of this guideline is to optimize the physiotherapy management of people with CF in Australia and New Zealand. A systematic review of the literature in key areas of physiotherapy practice for CF was undertaken. Recommendations were formulated based on National Health and Medical Research Council (Australia) guidelines and considered the quality, quantity and level of the evidence; the consistency of the body of evidence; the likely clinical impact; and applicability to physiotherapy practice in Australia and New Zealand. A total of 30 recommendations were made for airway clearance therapy, inhalation therapy, exercise assessment and training, musculoskeletal management, management of urinary incontinence, managing the newly diagnosed patient with CF, delivery of non-invasive ventilation, and physiotherapy management before and after lung transplantation. These recommendations can be used to underpin the provision of evidence-based physiotherapy care to people with CF in Australia and New Zealand.

  12. GH improves growth and clinical status in children with cystic fibrosis -- a review of published studies.

    PubMed

    Hardin, Dana S

    2004-08-01

    Children with cystic fibrosis (CF) have problems with poor linear growth and inadequate weight gain. Nutritional augmentation has been the mainstay of therapy for improving both weight and height in CF; however, inadequate growth continues to be a problem. Furthermore, protein catabolism has been documented even in non-acutely ill adults and children with CF, and could adversely affect longitudinal growth. Human recombinant GH has positive effects on nitrogen balance, and multiple studies have demonstrated improved height and weight in children treated with GH. The purpose of this article is to summarize studies evaluating GH use in children with CF. All published studies of GH use in children with CF have demonstrated significant improvement in height velocity and height Z score. All studies but one, in which subjects were treated only three times per week with GH, have demonstrated improvement in weight as reported by weight velocity and/or weight Z score, and one trial has demonstrated a substantial improvement when GH was used to augment nutritional therapy. Several reports suggest that GH treatment results in improved forced vital capacity, and multiple studies have found improved clinical status as measured by decreased hospitalizations and courses of intravenous antibiotics. Furthermore studies to date also suggest that GH results in improvement in exercise tolerance and bone accumulation. To date significant side effects, including glucose intolerance, have not been reported. Thus mounting evidence suggests that human recombinant GH provides safe and effective therapy in children with CF.

  13. Evaluation of colistin susceptibility in multidrug-resistant clinical isolates from cystic fibrosis, France.

    PubMed

    Biswas, S; Dubus, J-C; Reynaud-Gaubert, M; Stremler, N; Rolain, J-M

    2013-11-01

    The emergence of multidrug-resistant (MDR) bacteria in cystic fibrosis (CF) patients has led to the use of colistin drug and the emergence of colistin-resistant Gram-negative bacteria. The aim of this study was to compare the disk diffusion and Etest methods for colistin susceptibility testing on MDR bacteria associated with CF from Marseille, France. Forty-nine MDR clinical isolates (27 Stenotrophomonas maltophilia, 22 Achromobacter xylosoxidans) were used in this study. Disk diffusion and Etest assays were used to assess the reliability of these two techniques. For S. maltophilia, 25 out of 27 isolates had low minimum inhibitory concentrations (MICs, 0.125-0.75 mg/L), whereas two isolates displayed high MICs (32 mg/L). Similarly, 19 out of 22 A. xylosoxidans isolates had low MICs (0.75-3.0 mg/L), whereas three isolates had high MICs (32-256 mg/L). The diameters of zone inhibition with a 50-μg colistin disk displayed a good correlation with the MICs obtained by the Etest. Susceptible and resistant strains were eventually separated using a disk diffusion assay at a cut-off of ≤ 12 mm for a 50-μg disk. Colistin displayed excellent activity against S. maltophilia and A. xylosoxidans and the disk diffusion assay could be confidently used to determine the susceptibility to colistin for MDR Gram-negative bacteria in the context of CF.

  14. Association of Lung Function, Chest Radiographs and Clinical Features in Infants with Cystic Fibrosis

    PubMed Central

    Rosenfeld, Margaret; Farrell, Philip M.; Kloster, Margaret; Swanson, Jonathan O.; Vu, Thuy; Brumback, Lyndia; Acton, James D.; Castile, Robert G.; Colin, Andrew A.; Conrad, Carol K.; Hart, Meeghan A.; Kerby, Gwendolyn S.; Hiatt, Peter W.; Mogayzel, Peter J.; Johnson, Robin C.; Davis, Stephanie D.

    2013-01-01

    Background The optimal strategy for monitoring cystic fibrosis (CF) lung disease in infancy remains unclear. Objective To describe longitudinal associations between infant pulmonary function tests (iPFTs), chest radiograph (CXR) scores and other characteristics. Methods CF patients ≤ 24 months old were enrolled in a 10-center study evaluating iPFTs 4 times over a year. CXRs ~1 year apart were scored with the Wisconsin and Brasfield systems. Associations of iPFT parameters with clinical characteristics were evaluated with mixed effects models. Results The 100 participants contributed 246 acceptable flow/volume (FEV0.5, FEF75) and 303 acceptable functional residual capacity (FRC) measurements and 171 CXRs. Both Brasfield and Wisconsin CXR scores worsened significantly over the 1 year interval. Worse Wisconsin CXR scores and S. aureus were both associated with hyperinflation (significantly increased FRC) but not with diminished FEV0.5 or FEF75. Parent-reported cough was associated with significantly diminished FEF75 but not with hyperinflation. Conclusions In this infant cohort in whom we previously reported worsening in average lung function, CXR scores also worsened over a year. The significant associations detected between both Wisconsin CXR score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of iPFTs and CXRs to detect early CF lung disease. PMID:23722613

  15. Development, clinical utility, and place of ivacaftor in the treatment of cystic fibrosis.

    PubMed

    O'Reilly, Ruth; Elphick, Heather E

    2013-01-01

    Cystic fibrosis (CF) is a life-limiting, multisystem disease characterized by thick viscous secretions leading to recurrent lung infections, bronchiectasis, and progressive deterioration in lung function. CF is caused by loss or dysfunction of the CF transmembrane conductance regulator (CFTR) protein which is responsible for transepithelial chloride and water transport. Improved understanding of CFTR protein dysfunction has allowed the development of mutation-specific small-molecule compounds which directly target the underlying CFTR defect. Ivacaftor is the first licensed small-molecule compound for CF patients which targets the CFTR gating mutation Gly551Asp (previously termed G551D) and has the potential to be truly disease-modifying. Ivacaftor is an oral medication given twice daily and has shown benefit in terms of an increase in lung function, decreased sweat chloride, weight gain, improvement in patient-reported quality of life, and reduction in number of respiratory exacerbations in clinical trials. Although ivacaftor is currently only licensed for use in approximately 5% of the CF population (those who have at least one Gly551Asp mutation), the developmental pathway established by ivacaftor paves the way for other CFTR modulators that may benefit many more patients. In particular, a CFTR modulator for those with the Phe508del deletion (previously ∆F508) would allow 90% of the CF population to benefit from disease-modifying treatment.

  16. The clinical significance of the gut microbiota in cystic fibrosis and the potential for dietary therapies.

    PubMed

    Li, Li; Somerset, Shawn

    2014-08-01

    Cystic fibrosis (CF) is characterised by many comorbidities related to aberrant mucosa and chronic inflammation in the respiratory and digestive systems. The intestinal mucosa serves as the primary interface between the gut microbiota and endocrine, neural and immune systems. There is emerging evidence that aberrant intestinal mucosa in CF may associate with an altered gut microbiota. Compared to healthy subjects, the overall bacterial abundance and species richness seems to be reduced in CF, accompanied by a trend in suppression of Firmicutes and Bacteroidetes spp. and an augmentation of potentially pathogenic species. There is also some concordance of gut and respiratory microbiotas in CF infants over time. The clinical significance of these observations awaits investigation. The gut microbiota have some potential in CF management by affecting inflammatory and immune responses, and influencing aberrant mucosa. As an important modifiable factor, diet therapies such as probiotics and prebiotics have shown initial promise in improving CF related conditions associated with chronic inflammation. More studies are needed to confirm this, as well as the efficacy of other dietary strategies such as modulating dietary fat and indigestible carbohydrate. Similarly, dietary modification of gut microbiota to optimise nutritional status in CF may be feasible, although more CF-specific studies are warranted.

  17. Physiotherapy for cystic fibrosis in Australia and New Zealand: A clinical practice guideline*

    PubMed Central

    Wilson, Christine; Dentice, Ruth; Cox, Narelle S.; Middleton, Anna; Tannenbaum, Esta; Bishop, Jennifer; Cobb, Robyn; Burton, Kate; Wood, Michelle; Moran, Fiona; Black, Ryan; Bowen, Summar; Day, Rosemary; Depiazzi, Julie; Doiron, Katherine; Doumit, Michael; Dwyer, Tiffany; Elliot, Alison; Fuller, Louise; Hall, Kathleen; Hutchins, Matthew; Kerr, Melinda; Lee, Annemarie L.; Mans, Christina; O'Connor, Lauren; Steward, Ranjana; Potter, Angela; Rasekaba, Tshepo; Scoones, Rebecca; Tarrant, Ben; Ward, Nathan; West, Samantha; White, Dianne; Wilson, Lisa; Wood, Jamie; Holland, Anne E.

    2016-01-01

    Abstract Physiotherapy management is a key element of care for people with cystic fibrosis (CF) throughout the lifespan. Although considerable evidence exists to support physiotherapy management of CF, there is documented variation in practice. The aim of this guideline is to optimize the physiotherapy management of people with CF in Australia and New Zealand. A systematic review of the literature in key areas of physiotherapy practice for CF was undertaken. Recommendations were formulated based on National Health and Medical Research Council (Australia) guidelines and considered the quality, quantity and level of the evidence; the consistency of the body of evidence; the likely clinical impact; and applicability to physiotherapy practice in Australia and New Zealand. A total of 30 recommendations were made for airway clearance therapy, inhalation therapy, exercise assessment and training, musculoskeletal management, management of urinary incontinence, managing the newly diagnosed patient with CF, delivery of non‐invasive ventilation, and physiotherapy management before and after lung transplantation. These recommendations can be used to underpin the provision of evidence‐based physiotherapy care to people with CF in Australia and New Zealand. PMID:27086904

  18. Ivacaftor for patients with cystic fibrosis.

    PubMed

    Wainwright, Claire E

    2014-10-01

    Ivacaftor is an oral bioavailable potentiator of the cystic fibrosis transmembrane conductance regulator protein. It is the first therapeutic agent that has been registered for clinical use which targets the basic defect in people with cystic fibrosis who carry a G551D mutation or other rarer specific gating mutations. Clinical trials have shown consistent and impressive clinical benefit that appears to be sustained over time in people with cystic fibrosis who carry a G551D mutation and similar benefits have been seen in those who carry rarer gating mutations. Ivacaftor is orally administered twice daily with a dose that does not vary between children aged 6 years through to adult life in patients with G551D. It appears to be well tolerated although there are potential interactions with drugs that are metabolised through CYPP450 CYP3A. Ivacaftor is also currently being trialled in combination with correctors for patients with the most common mutation of cystic fibrosis transmembrane conductance regulator the F508del mutation.

  19. Emerging treatments in cystic fibrosis.

    PubMed

    Jones, Andrew M; Helm, Jennifer M

    2009-10-01

    There are a number of potential drugs for the treatment of cystic fibrosis (CF) currently undergoing clinical studies. A number of antibacterials formulated for delivery by inhalation are at various stages of study; these include dry-powder inhaler versions of colistin, tobramycin and ciprofloxacin, and formulations of azteonam, amikacin, levofloxacin, ciprofloxacin and fosfomycin/tobramycin for nebulization. Clinical trials of anti-inflammatory agents, including glutathione, phosphodiesterase-5 inhibitors such as sildenafil, oral acetylcysteine, simvastatin, methotrexate, docosahexaenoic acid, hydroxychloroquine, pioglitazone and alpha1-antitrypsin, are ongoing. Ion channel modulating agents, such as lancovutide (Moli1901, duramycin) and denufosol, which activate alternate (non-CF transmembrane regulator [CFTR]) chloride channels, and GS 9411, a sodium channel antagonist, are now at the stages of clinical study and if successful, will offer a new category of therapeutic agent for the treatment of CF. Correction of the underlying gene effect, either by agents that help to correct the dysfunctional CFTR, such as ataluren, VX-770 and VX-809, or by gene transfer (gene therapy), is a particularly exciting prospect as a new therapy for CF and clinical studies are ongoing. This article reviews the exciting potential drug treatments for CF currently being evaluated in clinical studies, and also highlights some of the challenges faced by research and clinical teams in assessing the efficacy of potential new therapies for CF.

  20. Survival rates in cystic fibrosis.

    PubMed Central

    Wilmott, R W; Tyson, S L; Dinwiddie, R; Matthew, D J

    1983-01-01

    Life tables were calculated for 273 British children with cystic fibrosis for the period 1974-9. There was a marked improvement in survival rates in the meconium ileus group compared with the 1969-73 data, but there was little improvement in patients presenting later with other symptoms. PMID:6639137

  1. Nutritional management of cystic fibrosis.

    PubMed

    Goodchild, M C

    1987-01-01

    Cystic fibrosis patients have an increased requirement for calories and probably for all the major nutrients. The newer, enteric-coated granular preparations of pancreatic enzyme are more effective than preceding preparations and should permit a normal fat intake. Recent work has emphasized the interdependence of respiratory disease and nutrition.

  2. Gender Differences in Clinical Presentations of Cystic Fibrosis Patients in Azeri Turkish Population

    PubMed Central

    Vahedi, Leila; Jabarpoor-Bonyadi, Morteza; Ghojazadeh, Morteza; Vahedi, Amir

    2016-01-01

    Background Cystic fibrosis (CF) is an autosomal recessive disorder with several clinical presentations. This study was undertaken in the Azeri Turkish population in Iran, to investigate gender differences in the age at onset and diagnosis, age of death, and duration of illness of CF. Methods The data of 331 CF patients from 2001 to 2015 was surveyed. Parameters including age, sex, ΔF508 mutation, age at onset, age at diagnosis, age of death and clinical presentations were evaluated for both sexes, using descriptive analysis. The association of gender with these variables was studied using logistic regression, chi-square test and Mann-Whitney U test by SPSS version 18. Odds ratio with a confidence interval of 95% and p≤0.05 was considered statistically significant. Results The study included 191 males (57.7%) and 140 females (42.3%), all showing statistically significant difference (p<0.001). Age duration differed between genders. Male and female patients were further under 9 and 4 years, respectively. The occurrence of ΔF508 mutation was 0.51 times more in females than in males. Age, diagnosis and sex were closely associated: males were diagnosed at a significantly later age than females (p=0.05). While this compression performed based on clinical presentations, males with respiratory disease had a later median age at diagnosis than females at lifespan (p=0.001). The risk of infertility in males was approximately two times greater than in females (p=0.02). Conclusion These findings indicate gender differences in CF patients. Future studies are needed to establish other differences and evaluate the causes for the gender variations. PMID:27790278

  3. Variation in lung function is associated with worse clinical outcomes in cystic fibrosis

    PubMed Central

    Heinzmann-Filho, João Paulo; Pinto, Leonardo Araujo; Marostica, Paulo José Cauduro; Donadio, Márcio Vinícius Fagundes

    2015-01-01

    ABSTRACT OBJECTIVE: To determine whether the variation in lung function over one year is associated with worse clinical outcomes, as well as with a decline in lung function in the following years, in patients with cystic fibrosis (CF). METHODS: This was a retrospective study involving CF patients (4-19 years of age), evaluated over a three-year period. We evaluated demographic characteristics, chronic Pseudomonas aeruginosa infection, antibiotic use, hospitalization, six-minute walk distance (6MWD), and lung function. The inclusion criterion was having undergone pulmonary function testing at least three times in the first year and at least once in each of the next two years. RESULTS: We evaluated 35 CF patients. The variation in FEV1 in the first year (ΔFEV1) was greater among those who, in the third year, showed reduced FEV1, had a below-average 6MWD, or were hospitalized than among those with normal FEV1, normal 6MWD, or no hospital admissions, in that same year (p < 0.05), although no such difference was found for antibiotic use in the third year. Subjects showing a ΔFEV1 ≥ 10% also showed a greater decline in FEV1 over the two subsequent years (p = 0.04). The ΔFEV1 also showed an inverse correlation with absolute FEV1 in the third year (r = −0.340, p = 0.04) and with the rate of FEV1 decline (r = −0.52, p = 0.001). Linear regression identified ΔFEV1 as a predictor of FEV1 decline (coefficient of determination, 0.27). CONCLUSIONS: Significant variation in lung function over one year seems to be associated with a higher subsequent rate of FEV1 decline and worse clinical outcomes in CF patients. Short-term ΔFEV1 might prove useful as a predictor of CF progression in clinical practice. PMID:26785959

  4. Diabetes mellitus in patients with cystic fibrosis.

    PubMed

    Alves, Crésio de Aragão Dantas; Aguiar, Renata Arruti; Alves, Ana Cláudia S; Santana, Maria Angélica

    2007-01-01

    Cystic fibrosis-related diabetes (CFRD) is the principal extra-pulmonary complication of cystic fibrosis, occurring in 15-30% of adult cystic fibrosis patients. The number of cystic fibrosis patients who develop diabetes is increasing in parallel with increases in life expectancy. The aim of this study was to review the physiopathology, clinical presentation, diagnosis and treatment of CFRD. A bibliographic search of the Medline and Latin American and Caribbean Health Sciences Literature databases was made. Articles were selected from among those published in the last twenty years. Insulin deficiency, caused by reduced beta-cell mass, is the main etiologic mechanism, although insulin resistance also plays a role. Presenting features of type 1 and type 2 diabetes, CFRD typically affects individuals of approximately 20 years of age. It can also be accompanied by fasting, non-fasting or intermittent hyperglycemia. Glucose intolerance is associated with worsening of nutritional status, increased morbidity, decreased survival and reduced pulmonary function. Microvascular complications are always present, although macrovascular complications are rarely seen. An oral glucose tolerance test is recommended annually for patients > or = 10 years of age and for any patients presenting unexplained weight loss or symptoms of diabetes. Patients hospitalized with severe diseases should also be screened. If fasting hyperglycemia persists for more than 48 h, insulin therapy is recommended. Insulin administration remains the treatment of choice for diabetes and fasting hyperglycemia. Calories should not be restricted, and patients with CFRD should be managed by a multidisciplinary team.

  5. Craniofacial morphology in children with cystic fibrosis.

    PubMed

    Hellsing, E; Brattström, V; Strandvik, B

    1992-04-01

    Cystic fibrosis (CF) is a hereditary metabolic disorder with clinical symptoms of abnormal mucus production. This blocks the airways, gives pancreatic insufficiency, and increases sweat electrolytes. The progressive respiratory disease often leads to respiratory insufficiency and cor pulmonale. The aim of the present investigation was to examine the facial morphology in children with cystic fibrosis. The sample comprised 11 children with cystic fibrosis, who were divided in two groups, one with gastrointestinal disorders and the other with predominantly respiratory insufficiency. Eleven healthy children with normal occlusions were selected as controls. Lateral skull radiographs obtained in natural head posture were digitized, and linear and angular variables for the different groups calculated and compared statistically. The cystic fibrosis group showed open bite, decreased posterior facial height, increased mandibular and craniocervical inclination. Additionally, within the CF-group, the children with respiratory insufficiency differed more from the controls than the children with gastrointestinal disorders. Despite the small number of subjects, the facial morphology of the CF children showed a similar pattern to that of children with nasal respiratory obstruction due to enlarged adenoids or tonsils.

  6. [Azithromycin therapy in cystic fibrosis].

    PubMed

    Máiz Carro, Luis; Cantón Moreno, Rafael

    2004-03-06

    Progressive lung disease, caused by chronic endobronchial colonization, is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Several pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa are responsible for this effect. The steadily improving prognosis of CF has been attributed to the use of antibiotics with activity against these organisms. Despite a significant increase in the amount of published material demonstrating the potential role of macrolide antibiotics as antiinflammatory agents and their effects on bacterial virulence, their mechanism of action in CF patients is still unknown. Although there is a limited number of clinical trials assessing the efficacy and safety of azithromycin (AZM) in CF, increasing evidence suggests that 3 to 6-month AZM treatment in CF patients is safe and well tolerated. This treatment results in clinical improvement, decreasing the number of pulmonary exacerbations and increasing pulmonary function. Therefore, chronic treatment with AZM should be considered in CF patients added to conventional therapy. Clinical experience with macrolides other than AZM in CF patients is very limited.

  7. A first-year dornase alfa treatment impact on clinical parameters of patients with cystic fibrosis: the Brazilian cystic fibrosis multicenter study

    PubMed Central

    Rozov, Tatiana; Silva, Fernando Antônio A. e; Santana, Maria Angélica; Adde, Fabíola Villac; Mendes, Rita Heloisa

    2013-01-01

    OBJECTIVE: To describe the clinical impact of the first year treatment with dornase alfa, according to age groups, in a cohort of Brazilian Cystic Fibrosis (CF) patients. METHODS: The data on 152 eligible patients, from 16 CF reference centers, that answered the medical questionnaires and performed laboratory tests at baseline (T0), and at six (T2) and 12 (T4) months after dornase alfa initiation, were analyzed. Three age groups were assessed: six to 11, 12 to 13, and >14 years. Pulmonary tests, airway microbiology, emergency room visits, hospitalizations, emergency and routine treatments were evaluated. Student's t-test, chi-square test and analysis of variance were used when appropriated. RESULTS: Routine treatments were based on respiratory physical therapy, regular exercises, pancreatic enzymes, vitamins, bronchodilators, corticosteroids, and antibiotics. In the six months prior the study (T0 phase), hospitalizations for pulmonary exacerbations occurred in 38.0, 10.0 and 61.4% in the three age groups, respectively. After one year of intervention, there was a significant reduction in the number of emergency room visits in the six to 11 years group. There were no significant changes in forced expiratory volume in one second (VEF1), in forced vital capacity (FVC), in oxygen saturation (SpO2), and in Tiffenau index for all age groups. A significant improvement in Shwachman-Kulczychi score was observed in the older group. In the last six months of therapy, chronic or intermittent colonization by P. aeruginosa was detected in 75.0, 71.4 and 62.5% of the studied groups, respectively, while S. aureus colonization was identified in 68.6, 66.6 and 41.9% of the cases. CONCLUSIONS: The treatment with dornase alfa promoted the maintenance of pulmonary function parameters and was associated with a significant reduction of emergency room visits due to pulmonary exacerbations in the six to 11 years age group, with better clinical scores in the >14 age group, one year after the

  8. Biomarkers in Paediatric Cystic Fibrosis Lung Disease.

    PubMed

    Ramsey, Kathryn A; Schultz, André; Stick, Stephen M

    2015-09-01

    Biomarkers in cystic fibrosis are used i. for the measurement of cystic fibrosis transmembrane regulator function in order to diagnose cystic fibrosis, and ii. to assess aspects of lung disease severity (e.g. inflammation, infection). Effective biomarkers can aid disease monitoring and contribute to the development of new therapies. The tests of cystic fibrosis transmembrane regulator function each have unique strengths and weaknesses, and biomarkers of inflammation, infection and tissue destruction have the potential to enhance the management of cystic fibrosis through the early detection of disease processes. The development of biomarkers of cystic fibrosis lung disease, in particular airway inflammation and infection, is influenced by the challenges of obtaining relevant samples from infants and children for whom early detection and treatment of disease might have the greatest long term benefits.

  9. Cystic Fibrosis Research | NIH MedlinePlus the Magazine

    MedlinePlus

    ... please turn Javascript on. Feature: Steady Advances Against Cystic Fibrosis Cystic Fibrosis Research Past Issues / Fall 2012 Table of Contents "Remarkable strides in cystic fibrosis research over the past two decades have culminated ...

  10. Cystic fibrosis and physiological responses to exercise.

    PubMed

    Williams, Craig A; Saynor, Zoe L; Tomlinson, Owen W; Barker, Alan R

    2014-12-01

    Cardiopulmonary exercise testing is underutilized within the clinical management of patients with cystic fibrosis. But within the last 5 years, there has been considerable interest in its implementation, which has included deliberations by the European Cystic Fibrosis Society about incorporating this method within the clinical assessment of patients. This review examines the current use of cardiopulmonary exercise testing in assessing the extent and cause(s) of exercise limitation from a pediatric perspective. Examples of the measured parameters and their interpretation are provided. Critical synthesis of recent work in the oxygen uptake (VO2) kinetics response to and following exercise is also discussed, and although identified more as a research tool, its utilization advances researchers understanding of the cardiovascular, respiratory and muscular limitations to exercise tolerance. Finally, exercise and its application in therapeutic interventions are highlighted and a number of recommendations made about the utility of exercise prescription.

  11. A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

    PubMed Central

    Lucarelli, Marco; Bruno, Sabina Maria; Pierandrei, Silvia; Ferraguti, Giampiero; Stamato, Antonella; Narzi, Fabiana; Amato, Annalisa; Cimino, Giuseppe; Bertasi, Serenella; Quattrucci, Serena; Strom, Roberto

    2015-01-01

    Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype–phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype–phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype–phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway. PMID:25910067

  12. Relationship between the chest radiograph, regional lung function studies, exercise tolerance, and clinical condition in cystic fibrosis.

    PubMed Central

    Coates, A L; Boyce, P; Shaw, D G; Godfrey, S; Mearns, M

    1981-01-01

    This study evaluated the accuracy of the interpretation of the chest film in delineating localised abnormalities of ventilation and perfusion, as well as the overall severity of airways obstruction, exercise tolerance, and clinical condition in children with cystic fibrosis. Radiographic findings in various regions of the chest film were compared with the functional values obtained with regional lung function tests which evaluated the arrival and disappearance of boluses of radioactive nitrogen given by inhalation and infusion. While the more severely affected areas on the chest radiograph were found to correlate with similar regions on the lung function tests, as did overall scores, errors occurred in some cases if the x-ray film alone was used as a judge of regional physiological derangement. In addition the degree of airways obstruction, the exercise tolerance on a cycle ergometer, and clinical grading, each correlated significantly with the radiographic score. We conclude that the chest radiograph is a good indicator of the overall severity of the lung disease and that it correlates well with exercise tolerance and clinical condition in cystic fibrosis. PMID:7469460

  13. Clinical utility of C-reactive protein to predict treatment response during cystic fibrosis pulmonary exacerbations

    PubMed Central

    Sharma, Ashutosh; Kirkpatrick, Gordon; Chen, Virginia; Skolnik, Kate; Hollander, Zsuzsanna; Wilcox, Pearce; Quon, Bradley S.

    2017-01-01

    Rationale C-reactive protein (CRP) is a systemic marker of inflammation that correlates with disease status in cystic fibrosis (CF). The clinical utility of CRP measurement to guide pulmonary exacerbation (PEx) treatment decisions remains uncertain. Objectives To determine whether monitoring CRP during PEx treatment can be used to predict treatment response. We hypothesized that early changes in CRP can be used to predict treatment response. Methods We reviewed all PEx events requiring hospitalization for intravenous (IV) antibiotics over 2 years at our institution. 83 PEx events met our eligibility criteria. CRP levels from admission to day 5 were evaluated to predict treatment non-response, using a modified version of a prior published composite definition. CRP was also evaluated to predict time until next exacerbation (TUNE). Measurements and main results 53% of 83 PEx events were classified as treatment non-response. Paradoxically, 24% of PEx events were characterized by a ≥ 50% increase in CRP levels within the first five days of treatment. Absolute change in CRP from admission to day 5 was not associated with treatment non-response (p = 0.58). Adjusted for FEV1% predicted, admission log10 CRP was associated with treatment non-response (OR: 2.39; 95% CI: 1.14 to 5.91; p = 0.03) and shorter TUNE (HR: 1.60; 95% CI: 1.13 to 2.27; p = 0.008). The area under the receiver operating characteristics (ROC) curve of admission CRP to predict treatment non-response was 0.72 (95% CI 0.61–0.83; p<0.001). 23% of PEx events were characterized by an admission CRP of > 75 mg/L with a specificity of 90% for treatment non-response. Conclusions Admission CRP predicts treatment non-response and time until next exacerbation. A very elevated admission CRP (>75mg/L) is highly specific for treatment non-response and might be used to target high-risk patients for future interventional studies aimed at improving exacerbation outcomes. PMID:28178305

  14. Human Genome Project and cystic fibrosis--a symbiotic relationship.

    PubMed

    Tolstoi, L G; Smith, C L

    1999-11-01

    When Watson and Crick determined the structure of DNA in 1953, a biological revolution began. One result of this revolution is the Human Genome Project. The primary goal of this international project is to obtain the complete nucleotide sequence of the human genome by the year 2005. Although molecular biologists and geneticists are most enthusiastic about the Human Genome Project, all areas of clinical medicine and fields of biology will be affected. Cystic fibrosis is the most common, inherited, lethal disease of white persons. In 1989, researchers located the cystic fibrosis gene on the long arm of chromosome 7 by a technique known as positional cloning. The most common mutation (a 3-base pair deletion) of the cystic fibrosis gene occurs in 70% of patients with cystic fibrosis. The knowledge gained from genetic research on cystic fibrosis will help researchers develop new therapies (e.g., gene) and improve standard therapies (e.g., pharmacologic) so that a patient's life span is increased and quality of life is improved. The purpose of this review is twofold. First, the article provides an overview of the Human Genome Project and its clinical significance in advancing interdisciplinary care for patients with cystic fibrosis. Second, the article includes a discussion of the genetic basis, pathophysiology, and management of cystic fibrosis.

  15. What is Cystic Fibrosis?

    MedlinePlus

    ... Intramural Research Research Resources Research Meeting Summaries Technology Transfer Clinical Trials What Are Clinical Trials? Children & Clinical ... heart rate, fatigue (tiredness), weakness, decreased blood pressure, heat stroke, and, rarely, death. If you or your ...

  16. Cystic fibrosis lung disease in adult patients.

    PubMed

    Vender, Robert L

    2008-04-01

    As the longevity of all patients with cystic fibrosis (CF) continues to increase (median 2005 survival=36.8 years), more adult patients will be receiving their medical care from nonpediatric adult-care providers. Cystic fibrosis remains a fatal disease, with more than 80% of patients dying after the age of 18 years, and most deaths resulting from pulmonary disease. The changing epidemiology requires adult-care providers to become knowledgeable and competent in the clinical management of adults with CF. Physicians must understand the influence of specific genotype on phenotypic disease presentation and severity, the pathogenic factors determining lung disease onset and progression, the impact of comorbid disease factors such as CF-related diabetes and malnutrition upon lung disease severity, and the currently approved or standard accepted therapies used for chronic management of CF lung disease. This knowledge is critical to help alleviate morbidity and improve mortality for the rapidly expanding population of adults with CF.

  17. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations.

    PubMed

    Flume, Patrick A; Mogayzel, Peter J; Robinson, Karen A; Goss, Christopher H; Rosenblatt, Randall L; Kuhn, Robert J; Marshall, Bruce C

    2009-11-01

    The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis.

  18. [Treatment of Cystic Fibrosis with CFTR Modulators].

    PubMed

    Tümmler, B

    2016-05-01

    Personalized medicine promises that medical decisions, practices and products are tailored to the individual patient. Cystic fibrosis, an inherited disorder of chloride and bicarbonate transport in exocrine glands, is the first successful example of customized drug development for mutation-specific therapy. There are two classes of CFTR modulators: potentiators that increase the activity of CFTR at the cell surface, and correctors that either promote the read-through of nonsense mutations or facilitate the translation, folding, maturation and trafficking of mutant CFTR to the cell surface. The potentiator ivacaftor and the corrector lumacaftor are approved in Germany for the treatment of people with cystic fibrosis who carry a gating mutation such as p.Gly551Asp or who are homozygous for the most common mutation p.Phe508del, respectively. This report provides an overview of the basic defect in cystic fibrosis, the population genetics of CFTR mutations in Germany and the bioassays to assess CFTR function in humans together with the major achievements of preclinical research and clinical trials to bring CFTR modulators to the clinic. Some practical information on the use of ivacaftor and lumacaftor in daily practice and an update on pitfalls, challenges and novel strategies of bench-to-bedside development of CFTR modulators are also provided.

  19. Negative sweat tests and cystic fibrosis.

    PubMed Central

    Sarsfield, J K; Davies, J M

    1975-01-01

    Two brothers are described with chronic suppurative pulmonary disease. One has classical cystic fibrosis with complete pancreatic involvement and abnormal sweat test. The other had incomplete pancreatic disease with repeatedly normal sweat tests. The implications of a negative sweat test in patients with cystic fibrosis are discussed. Images FIG. PMID:1147688

  20. [Bronchopulmonary infection in cystic fibrosis].

    PubMed

    Munck, Anne; Bingen, Edouard

    2003-01-15

    Bronchopulmonary infection determines the vital prognosis of the patients with cystic fibrosis. Following Staphylococcus aureus infection, patients are colonized or cocolonized by Pseudomonas aeruginosa, greatly involved in the pulmonary deterioration; intensive antibiotic treatment of primocolonisation helps to prevent or delay chronic colonisation. Chronic colonization needs a rational long term antibiotic strategy to prevent the occurrence of multiresistant germs; antibiotic cures are performed every 3 or 4 months before pulmonary exacerbation symptoms. Antibiotherapy, physiotherapy and nutritional management helps to increase the survival and quality of life.

  1. Cystic fibrosis: a mucosal immunodeficiency syndrome

    PubMed Central

    Cohen, Taylor Sitarik; Prince, Alice

    2013-01-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a channel that regulates the transport of ions and the movement of water across the epithelial barrier. Mutations in CFTR, which form the basis for the clinical manifestations of cystic fibrosis, affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pulmonary pathogens. Compounding the effects of excessive neutrophil recruitment, the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Whereas mutant CFTR expression in leukocytes outside of the lung does not markedly impair their function, the expected regulation of inflammation in the airways is clearly deficient in cystic fibrosis. The resulting bacterial infections, which are caused by organisms that have substantial genetic and metabolic flexibility, can resist multiple classes of antibiotics and evade phagocytic clearance. The development of animal models that approximate the human pulmonary phenotypes—airway inflammation and spontaneous infection—may provide the much-needed tools to establish how CFTR regulates mucosal immunity and to test directly the effect of pharmacologic potentiation and correction of mutant CFTR function on bacterial clearance. PMID:22481418

  2. Staphylococcus aureus and Pseudomonas aeruginosa co-infection is associated with cystic fibrosis-related diabetes and poor clinical outcomes.

    PubMed

    Limoli, D H; Yang, J; Khansaheb, M K; Helfman, B; Peng, L; Stecenko, A A; Goldberg, J B

    2016-06-01

    Cystic fibrosis-related diabetes (CFRD) patients suffer from accelerated rates of pulmonary decline compared to cystic fibrosis (CF) patients with normal glucose tolerance (NGT). However, the mechanisms underlying this difference are unknown. While CFRD is associated with increased respiratory infections, a link between infection and enhanced pulmonary dysfunction remains unclear. The development of glucose intolerance is spectral, resulting in impaired glucose tolerance (IGT) prior to the diagnosis of CFRD. Inclusion of IGT patients within the NGT group may diminish the ability to identify correlations with CFRD. With this in mind, this study aimed to determine if the association between CFRD and respiratory infections is correlated with pulmonary decline. Respiratory cultures from 234 CF patients with confirmed diagnosis of NGT or CFRD were analyzed to measure rates of infection, focusing on the two most prevalent bacteria in CF, Staphylococcus aureus and Pseudomonas aeruginosa. Infection status was correlated with pulmonary function and confounding clinical variables including age, gender, blood glucose levels, and CF transmembrane conductance regulator (CFTR) phenotype were considered in multivariate analyses. CFRD patients, particularly those with extremely high blood glucose levels, were more likely than NGT patients to be co-infected with S. aureus and P. aeruginosa, compared to infection with only one pathogen. Co-infection was associated with decreased lung function and increased frequency of pulmonary exacerbations, even after adjustment for confounding variables. Alterations in the microbial community composition, as opposed to the presence of a single pathogen, may account for greater pulmonary decline in CFRD patients.

  3. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience.

    PubMed

    Durmowicz, Anthony G; Witzmann, Kimberly A; Rosebraugh, Curtis J; Chowdhury, Badrul A

    2013-01-01

    Cystic fibrosis (CF) is a life-shortening inherited disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR), which encodes for the CF transmembrane conductance regulator (CFTR) ion channel that regulates chloride and water transport across the surface of epithelial cells. Ivacaftor, a drug recently approved by the US Food and Drug Administration, represents the first mutation-specific therapy for CF. It is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV(1) and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV(1) and sweat chloride would facilitate development of new drugs that target the defective CFTR. Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV(1) (10%-12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV(1), nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV(1) was apparent. The lack of correlation of sweat chloride with improvement in FEV(1) speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points.

  4. Cystic fibrosis in adults. From researcher to practitioner.

    PubMed Central

    Marelich, G P; Cross, C E

    1996-01-01

    The Cystic Fibrosis Foundation currently tracks about 20,000 Americans with cystic fibrosis, an autosomal recessive genetic disease that leads to multisystem complications. With the institution of better therapeutic regimens over the past 2 decades, more patients with this disease are surviving to adulthood. Within the past decade, both clinical and basic science research in the field of cystic fibrosis has progressed at a rapid rate. The intent of this review is to introduce readers to the molecular, cellular, and systemic disorders of this disease. We discuss treatment strategies involving antibiotics, nutrition, immune-response mediators, chest physiotherapy, and sputum-active agents with respect to the airway dysfunction of cystic fibrosis. Other common complications, recent developments, transplantation, and gene therapy are also reviewed. PMID:8732732

  5. Fungi in cystic fibrosis and non-cystic fibrosis bronchiectasis.

    PubMed

    Moss, Richard B

    2015-04-01

    Bronchiectasis is a pathologic bronchial dilatation with loss of function that can result from multiple inflammatory and infectious injuries to the conducting airways of the lung. Molds, particularly the filamentous fungus Aspergillus fumigatus, have been implicated as a common cause of both cystic fibrosis (CF) and non-CF bronchiectasis, the latter primarily in patients with severe asthma. The pathogenesis of mold-associated bronchiectasis is usually due to atopic sensitization to mold allergens in the presence of active chronic endobronchial fungal infection with host innate and adaptive immune deviation to a Th2-dominated inflammation, a condition known as allergic bronchopulmonary aspergillosis (ABPA) (or allergic bronchopulmonary mycosis if a non-Aspergillus mold is implicated). Diagnostic criteria of ABPA continue to evolve, while treatment relies upon downregulation of the allergic inflammatory response with immunomodulatory agents and antifungal pharmacotherapy.

  6. Swimming Motility in a Longitudinal Collection of Clinical Isolates of Burkholderia cepacia Complex Bacteria from People with Cystic Fibrosis

    PubMed Central

    Zlosnik, James E. A.; Mori, Paul Y.; To, Derek; Leung, James; Hird, Trevor J.; Speert, David P.

    2014-01-01

    Chronic bacterial lung infections in cystic fibrosis (CF) are the leading cause of morbidity and mortality. While a range of bacteria are known to be capable of establishing residence in the CF lung, only a small number have a clearly established link to deteriorating clinical status. The two bacteria with the clearest roles in CF lung disease are Pseudomonas aeruginosa and bacteria belonging to the Burkholderia cepacia complex (BCC). A number of common adaptations by P. aeruginosa strains to chronic lung infection in CF have been well described. Typically, initial isolates of P. aeruginosa are nonmucoid and display a range of putative virulence determinants. Upon establishment of chronic infection, subsequent isolates ultimately show a reduction in putative virulence determinants, including swimming motility, along with an acquisition of the mucoid phenotype and increased levels of antimicrobial resistance. Infections by BCC are marked by an unpredictable, but typically worse, clinical outcome. However, in contrast to P. aeruginosa infections in CF, studies describing adaptive changes in BCC bacterial phenotype during chronic lung infections are far more limited. To further enhance our understanding of chronic lung infections by BCC bacteria in CF, we assessed the swimming motility phenotype in 551 isolates of BCC bacteria from cystic fibrosis (CF) lung infections between 1981 and 2007. These data suggest that swimming motility is not typically lost by BCC during chronic infection, unlike as seen in P. aeruginosa infections. Furthermore, while we observed a statistically significant link between mucoidy and motility, we did not detect any link between motility phenotype and clinical outcome. These studies highlight the need for further work to understand the adaptive changes of BCC bacteria during chronic infection in the CF lung. PMID:25203161

  7. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up.

    PubMed

    Narzi, L; Ferraguti, G; Stamato, A; Narzi, F; Valentini, S B; Lelli, A; Delaroche, I; Lucarelli, M; Strom, R; Quattrucci, S

    2007-07-01

    The neonatal screening protocol for cystic fibrosis (CF) is based on a first determination of blood immunoreactive trypsin (IRT1), followed by a first level genetic test that includes the 31 worldwide most common mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (DNA31), and a second determination of blood immunoreactive trypsin (IRT2). This approach identifies, in addition to affected subjects, a high proportion of newborns with hypertrypsinaemia at birth, in whom only one mutation is identified and who have a negative or borderline sweat test and pancreatic sufficiency. Although it has been suggested that hypertrypsinaemia may be caused by a single CFTR mutation, whether such neonates should be merely considered as healthy carriers remains a matter of debate as hypertrypsinaemia at birth may be a biochemical marker of a CFTR malfunction because of a second mild mutation. We analyzed, by means of an extended sequencing protocol, 32 newborns who tested positive at an IRT1/DNA31/IRT2 screening protocol and in whom only one CFTR mutation was found. The results obtained demonstrate that 62.5% of these newborns were also carrying a second mild CFTR mutation. The high proportion of compound heterozygous subjects, combined with the results of a 4-year follow-up in nine of these subjects all of whom displaying initial CF clinical symptoms, suggest that it may be possible to use the IRT1/DNA31/IRT2 protocol of neonatal screening to identify newborns with atypical forms of CF. In view of these findings, an extended genetic search for subjects with compound heterozygosity and a periodic clinical assessment should be considered.

  8. [New tools in cystic fibrosis].

    PubMed

    Dournes, G; De Boeck, K; Bui, S; Vermeulen, F; Ramalho, A; Chateil, J-F; Laurent, F; Fayon, M

    2016-12-01

    The use of 3 novel tools available for the diagnosis and treatment in cystic fibrosis are described here. 1) The lung clearance index is a sensitive method which can detect functional impairment in the first months after birth. 2) Detailed morphological analyses of the lung can be performed with the new MRI sequences, without any contrast medium or risk of radiation. The analysis of functional MRI data (perfusion, diffusion, ventilation, inflammation) will be possible, and these data will be correlated to morphological data. The exploration of other organs such as the sinuses, liver and abdomen during the same examination represents another definite advantage. 3) Organoïds are a good example of personalized medicine. This tool explores CFTR function and treatment response in each of the 2000 or so known CFTR mutations. These tests are limited to specialized centers, mostly within a research context. However, their generalization after standardization is expected in the near future.

  9. Chronic pancreatitis and cystic fibrosis

    PubMed Central

    Witt, H

    2003-01-01

    Recent discoveries of trypsinogen and trypsin inhibitor mutations in patients with chronic pancreatitis (CP) support the hypothesis that an inappropriate activation of pancreatic zymogens to active enzymes within the pancreatic parenchyma starts the inflammatory process. Current data suggest that CP may be inherited dominant, recessive, or complex as a result of mutations in the above mentioned or yet unidentified genes. Evaluation of patients with CP should include genetic testing. Cystic fibrosis (CF) is an autosomal recessive inherited disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterised by pancreatic insufficiency and chronic bronchopulmonary infection. The progression and severity of pulmonary disease differs considerably between people with identical CFTR mutations and does not seem to correlate with the type or class of the CFTR mutation. The identification of further disease modifying genetic factors will increase the pathophysiological understanding and may help to identify new therapeutic targets. PMID:12651880

  10. Vaccine strategies against cystic fibrosis pathogens

    PubMed Central

    Le Moigne, Vincent; Gaillard, Jean-Louis; Herrmann, Jean-Louis

    2016-01-01

    ABSTRACT A great number of cystic fibrosis (CF) pathogens such as Pseudomonas aeruginosa, the Burkholderia cepacia and the Mycobacterium abscessus complex raised difficult therapeutic problems due to their intrinsic multi-resistance to numerous antibiotics. Vaccine strategies represent one of the key weapons against these multi-resistant bacteria in a number of clinical settings like CF. Different strategies are considered in order to develop such vaccines, linked either to priming the host response, or by exploiting genomic data derived from the bacterium. Interestingly, virulence factors synthesized by various pathogens might serve as targets for vaccine development and have been, for example, evaluated in the context of CF. PMID:26618824

  11. Cystic fibrosis-associated liver disease.

    PubMed

    Herrmann, Ulrike; Dockter, Gerd; Lammert, Frank

    2010-10-01

    Liver disease is increasingly common in cystic fibrosis (CF). As new therapeutic options emerge, life expectancy increases and common hepatobiliary manifestations impact on quality of life and survival of CF patients. Hepatobiliary abnormalities in CF vary in nature and range from defects attributable to the underlying CFTR gene defect to those related to systemic disease and malnutrition. Today complications of liver disease represent the third most frequent cause of disease-related death in patients with CF. Here we review molecular and clinical genetics of CF, including genetic modifiers of CF-associated liver disease, and provide practical recommendations for genetic testing, diagnosis and treatment of hepatobiliary manifestations in CF.

  12. Eating disorders in patients with cystic fibrosis.

    PubMed

    Raymond, N C; Chang, P N; Crow, S J; Mitchell, J E; Dieperink, B S; Beck, M M; Crosby, R D; Clawson, C C; Warwick, W J

    2000-06-01

    This study was designed to examine rates of eating disorders and psychopathology in patients with cystic fibrosis (CF). Fifty-eight CF patients and 43 healthy control participants were evaluated using structured psychiatric interviews and rating scales. Two control participants and no CF patients were diagnosed with an eating disorder. Additionally, 11 CF patients were diagnosed with one or more psychiatric disorders. Group means on the rating scales did not show clinically meaningful elevations in either group. These data indicate no evidence for elevated rates of eating disorders in CF patients. Similarly, rates of other psychiatric disorders in the CF group were not greater than the prevalence reported in the general population.

  13. [Cystic fibrosis in a woman aged seventy].

    PubMed

    Ras, Janneke E; van Velzen, Edwin; van Berkhout, Ferdinand Teding; van den Brand, Joop J G

    2010-01-01

    A seventy-year-old woman was admitted to hospital with a Staphylococcus aureus respiratory tract infection. She had a history of extensive bronchiectasis and allergic bronchopulmonary aspergillosis (ABPA). Cystic fibrosis (CF) was suspected and cystic fibrosis transmembrane conductance regulator (CFTR) gene analysis showed F508del and R117H-7T mutations. In these mutations there is residual activity in the chloride channel in the cell membrane coded by the CFTR gene. This results in a much milder disease pattern varying from no disease at all to isolated organ disease. This type of disease is known as non-classical cystic fibrosis. In our patient the diagnosis of cystic fibrosis was made exceptionally late in life.

  14. [Vitamin E deficiency in cystic fibrosis].

    PubMed

    Muñoz, C; Polanco, I; Hernanz, A; Carrasco, S; Barea, I; Murga, M L; Arroba, M L; Codoceo, R

    1987-12-01

    Plasma vitamin E levels were measured by high performance liquid chromatography in 42 children with cystic fibrosis and were correlated with the following parameters: sex, age, time of follow-up, clinical evolution (Schwachman score), vitamin E/cholesterol and faecal fat excretion. All children in this study received oral alfa-tocoferol (50-100 mg daily) from the diagnosis. According to the vitamin E level patients were distributed in two groups. Group I: 27 patients (64.3%) with normal concentrations. Group II: 15 patients (35.7%) with decreases plasma levels but without clinical manifestations. Steatorrhea was present in all children except 4 patients from group I and one patient from group II. On the other hand, vitamin E/cholesterol was normal in 80% of patients with vitamin E deficiency (group II). We did not find any correlation between plasma vitamin E levels and the different clinical and biological parameters studied. Further studies should be carried out to throw more light on the mechanism underlying the pathogenesis of vitamin E deficiency in patients with cystic fibrosis.

  15. Cystic fibrosis therapeutics: the road ahead.

    PubMed

    Hoffman, Lucas R; Ramsey, Bonnie W

    2013-01-01

    A great deal of excitement and hope has followed the successful trials and US Food and Drug Administration approval of the drug ivacaftor (Kalydeco), the first therapy available that targets the underlying defect that causes cystic fibrosis (CF). Although this drug has currently demonstrated a clinical benefit for a small minority of the CF population, the developmental pathway established by ivacaftor paves the way for other CF transmembrane conductance regulator (CFTR) modulators that may benefit many more patients. In addition to investigating CFTR modulators, researchers are actively developing numerous other innovative CF therapies. In this review, we use the catalog of treatments currently under evaluation with the support of the Cystic Fibrosis Foundation, known as the Cystic Fibrosis Foundation Therapeutics Pipeline, as a platform to discuss the variety of candidate treatments for CF lung disease that promise to improve CF care. Many of these approaches target the individual components of the relentless cycle of airway obstruction, inflammation, and infection characteristic of lung disease in CF, whereas others are aimed directly at the gene defect, or the resulting dysfunctional protein, that instigates this cycle. We discuss how new findings from the laboratory have informed not only the development of novel therapeutics, but also the rationales for their use and the outcomes used to measure their effects. By reviewing the breadth of candidate treatments currently in development, as well as the recent progress in CF therapies reflected by the evolution of the therapeutics pipeline over the past few years, we hope to build upon the optimism and anticipation generated by the recent success of Kalydeco.

  16. Cystic fibrosis chronic rhinosinusitis: A comprehensive review

    PubMed Central

    Chaaban, Mohamad R.; Kejner, Alexandra; Rowe, Steven M.

    2013-01-01

    Background: Advances in the care of patients with cystic fibrosis (CF) have improved pulmonary outcomes and survival. In addition, rapid developments regarding the underlying genetic and molecular basis of the disease have led to numerous novel targets for treatment. However, clinical and basic scientific research focusing on therapeutic strategies for CF-associated chronic rhinosinusitis (CRS) lags behind the evidence-based approaches currently used for pulmonary disease. Methods: This review evaluates the available literature and provides an update concerning the pathophysiology, current treatment approaches, and future pharmaceutical tactics in the management of CRS in patients with CF. Results: Optimal medical and surgical strategies for CF CRS are lacking because of a dearth of well-performed clinical trials. Medical and surgical interventions are supported primarily by level 2 or 3 evidence and are aimed at improving clearance of mucus, infection, and inflammation. A number of novel therapeutics that target the basic defect in the cystic fibrosis transmembrane conductance regulator channel are currently under investigation. Ivacaftor, a corrector of the G551D mutation, was recently approved by the Food and Drug Administration. However, sinonasal outcomes using this and other novel drugs are pending. Conclusion: CRS is a lifelong disease in CF patients that can lead to substantial morbidity and decreased quality of life. A multidisciplinary approach will be necessary to develop consistent and evidence-based treatment paradigms. PMID:24119602

  17. [Nutrition, cystic fibrosis and the digestive tract].

    PubMed

    Olveira, Gabriel; Olveira, Casilda

    2008-05-01

    The prevalence of hyponutrition in cystic fibrosis is high although it may vary according to the different studies. Detection of hyponutrition should be done by combining different methods, depending on their availability. However, the simplest and most validated criterion is to measure at each visit the weight (and height in children) in order to calculate the body mass index and categorizing hyponutrition according to absolute criteria: in adults < 18.5 kg/m(2), and in children as percentiles of the body mass index. Worsening of the nutritional status is directly related with the decrease in lung function parameters and it has been proposed as a morbidity (and even mortality) predictive factor in people with cystic fibrosis, independently of the level of pulmonary dysfunction. Exocrine pancreatic insufficiency is present is approximately 70-90% of the patients with cystic fibrosis and the genotype-phenotype correlation is high. Most of the patients with exocrine pancreatic insufficiency tolerate a high-fat diet provided that they are treated with pancreatic enzymes at appropriate doses. The prevalence of diabetes increases with age, reaching up 40% of the cases in patients older than 30 years. Clinical liver involvement is less prevalent (it approximately affects 1/3 of the patients). Other intestinal complications such as meconial ileus, gastroesophageal reflux, obstruction of the distal intestine, or fibrosing colon disease may also condition malnourishment. In patients with cystic fibrosis, a usual high-fat diet providing 120%-150% of the recommended calories is advised. If the nutritional goals are not achieved or maintained with diet modifications, artificial supplements may be added, although the recommendation for their use has not been endorsed by solid scientific evidences. The most frequently used preparations usually are polymeric or hypercaloric. The indications for enteral (through a tube, especially gastrostomy) or parenteral nutritional support are

  18. Other mucoactive agents for cystic fibrosis.

    PubMed

    Bye, Peter T P; Elkins, Mark R

    2007-03-01

    This review examines specific mucoactive agents from three classes: expectorants, which add water to the airway; ion-transport modifiers, which promote ion and water transport across the epithelium of the airway; and mucokinetics, which improve cough-mediated clearance by increasing airflow or reducing sputum adhesivity. The agents are isotonic and hypertonic saline, mannitol, denufosol and beta-agonists. Our understanding of these agents has recently improved through pre-clinical research, clinical trials and, in particular, extensive research into the nature of the liquid lining the surface of the airway, both in health and in cystic fibrosis (CF). For each agent, recent research is reviewed, highlighting the evidence for possible mechanisms of action and for clinical efficacy in CF, as well as the implications for the optimal clinical application of the agent.

  19. Abnormal Ion Permeation through Cystic Fibrosis Respiratory Epithelium

    NASA Astrophysics Data System (ADS)

    Knowles, M. R.; Stutts, M. J.; Spock, A.; Fischer, N.; Gatzy, J. T.; Boucher, R. C.

    1983-09-01

    The epithelium of nasal tissue excised from subjects with cystic fibrosis exhibited higher voltage and lower conductance than tissue from control subjects. Basal sodium ion absorption by cystic fibrosis and normal nasal epithelia equaled the short-circuit current and was amiloride-sensitive. Amiloride induced chloride ion secretion in normal but not cystic fibrosis tissue and consequently was more effective in inhibiting the short-circuit current in cystic fibrosis epithelia. Chloride ion-free solution induced a smaller hyperpolarization of cystic fibrosis tissue. The increased voltage and amiloride efficacy in cystic fibrosis reflect absorption of sodium ions across an epithelium that is relatively impermeable to chloride ions.

  20. Lessons learned from metabolomics in cystic fibrosis.

    PubMed

    Muhlebach, Marianne S; Sha, Wei

    2015-12-01

    Cystic fibrosis is a mono-genetic multi-system disease; however, respiratory manifestations cause the main morbidity and mortality where chronic bacterial infections lead to bronchiectasis and ultimately respiratory failure. Metabolomics allows a relatively complete snapshot of metabolic processes in a sample using different mass spectrometry methods. Sample types used for discovery of biomarkers or pathomechanisms in cystic fibrosis (CF) have included blood, respiratory secretions, and exhaled breath to date. Metabolomics has shown distinction of CF vs. non-CF for matrices of blood, exhaled breath, and respiratory epithelial cultures, each showing different pathways. Severity of lung disease has been addressed by studies in bronchoalveolar lavage and exhaled breath condensate showing separation by metabolites that the authors of each study related to inflammation; e.g., ethanol, acetone, purines. Lipidomics has been applied to blood and sputum samples showing associations with lung function and Pseudomonas aeruginosa infection status. Finally, studies of bacteria grown in vitro showed differences of bacterial metabolites to be associated with clinical parameters. Metabolomics, in the sense of global metabolomic profiling, is a powerful technique that has allowed discovery of pathways that had not previously been implicated in CF. These may include purines, mitochondrial pathways, and different aspects of glucose metabolism besides the known differences in lipid metabolism in CF. However, targeted studies to validate such potential metabolites and pathways of interest are necessary. Studies evaluating metabolites of bacterial origin are in their early stages. Thus further well-designed studies could be envisioned.

  1. CFTR protein repair therapy in cystic fibrosis.

    PubMed

    Quintana-Gallego, Esther; Delgado-Pecellín, Isabel; Calero Acuña, Carmen

    2014-04-01

    Cystic fibrosis is a single gene, autosomal recessive disorder, in which more than 1,900 mutations grouped into 6 classes have been described. It is an example a disease that could be well placed to benefit from personalised medicine. There are currently 2 very different approaches that aim to correct the basic defect: gene therapy, aimed at correcting the genetic alteration, and therapy aimed at correcting the defect in the CFTR protein. The latter is beginning to show promising results, with several molecules under development. Ataluren (PTC124) is a molecule designed to make the ribosomes become less sensitive to the premature stop codons responsible for class i mutations. Lumacaftor (VX-809) is a CFTR corrector directed at class ii mutations, among which Phe508del is the most frequent, with encouraging results. Ivacaftor (VX-770) is a potentiator, the only one marketed to date, which has shown good efficacy for the class iii mutation Gly551Asp in children over the age of 6 and adults. These drugs, or a combination of them, are currently undergoing various clinical trials for other less common genetic mutations. In the last 5 years, CFTR has been designated as a therapeutic target. Ivacaftor is the first drug to treat the basic defect in cystic fibrosis, but only provides a response in a small number of patients. New drugs capable of restoring the CFTR protein damaged by the most common mutations are required.

  2. Rehabilitation with Cystic Fibrosis: From Utopia to Reality.

    ERIC Educational Resources Information Center

    Goldberg, Richard T.; And Others

    1980-01-01

    The paper dispels some of the myths regarding cystic fibrosis (a genetic metabolism disorder), provides information on the latest developments in rehabilitation, summarizes research in the field, and projects future needs of the patient with cystic fibrosis. (SBH)

  3. Whole-Genome Sequencing of Three Clonal Clinical Isolates of B. cenocepacia from a Patient with Cystic Fibrosis

    PubMed Central

    Miller, Ruth R.; Hird, Trevor J.; Tang, Patrick; Zlosnik, James E. A.

    2015-01-01

    Burkholderia cepacia complex bacteria are amongst the most feared of pathogens in cystic fibrosis (CF). The BCC comprises at least 20 distinct species that can cause chronic and unpredictable lung infections in CF. Historically the species B. cenocepacia has been the most prevalent in CF infections and has been associated in some centers with high rates of mortality. Modeling chronic infection by B. cenocepacia in the laboratory is challenging and no models exist which effectively recapitulate CF disease caused by BCC bacteria. Therefore our understanding of factors that contribute towards the morbidity and mortality caused by this organism is limited. In this study we used whole-genome sequencing to examine the evolution of 3 clonal clinical isolates of B. cenocepacia from a patient with cystic fibrosis. The first isolate was from the beginning of infection, and the second two almost 10 years later during the final year of the patients’ life. These isolates also demonstrated phenotypic heterogeneity, with the first isolate displaying the mucoid phenotype (conferred by the overproduction of exopolysaccharide), while one of the later two was nonmucoid. In addition we also sequenced a nonmucoid derivative of the initial mucoid isolate, acquired in the laboratory by antibiotic pressure. Examination of sequence data revealed that the two late stage isolates shared 20 variant nucleotides in common compared to the early isolate. However, despite their isolation within 10 months of one another, there was also considerable variation between the late stage isolates, including 42 single nucleotide variants and three deletions. Additionally, no sequence differences were identified between the initial mucoid isolate and its laboratory acquired nonmucoid derivative, however transcript analysis indicated at least partial down regulation of genes involved in exopolysaccharide production. Our study examines the progression of B. cenocepacia throughout chronic infection

  4. Breakthrough therapies: Cystic fibrosis (CF) potentiators and correctors.

    PubMed

    Solomon, George M; Marshall, Susan G; Ramsey, Bonnie W; Rowe, Steven M

    2015-10-01

    Cystic Fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene resulting in abnormal protein function. Recent advances of targeted molecular therapies and high throughput screening have resulted in multiple drug therapies that target many important mutations in the CFTR protein. In this review, we provide the latest results and current progress of CFTR modulators for the treatment of cystic fibrosis, focusing on potentiators of CFTR channel gating and Phe508del processing correctors for the Phe508del CFTR mutation. Special emphasis is placed on the molecular basis underlying these new therapies and emerging results from the latest clinical trials. The future directions for augmenting the rescue of Phe508del with CFTR modulators are also emphasized.

  5. Cystic fibrosis and pregnancy: counseling, obstetrical management and perinatal outcome.

    PubMed

    Grigoriadis, Charalampos; Tympa, Aliki; Theodoraki, Kassiani

    2015-03-01

    The progress in research of in vitro fertilization and fetal-maternal medicine allows more women and men, with fertility problems due to cystic fibrosis, to have a baby. In the majority of cases, pregnancy in women with cystic fibrosis results in favorable maternal and fetal outcomes. However, the incidence of preterm delivery, intrauterine growth restriction, caesarean section and deterioration of the maternal health are increased. Pre-pregnancy counseling is a crucial component of overall obstetric care, especially in women with poor pulmonary function. Additionally, closer monitoring during pregnancy with a multidisciplinary approach is required. The value of serial ultrasound scans and fetal Doppler assessment is important for the control of maternal and fetal wellbeing, as well as for the definition of the appropriate timing of delivery. In this article, clinical issues of pregnant women with cystic fibrosis are reviewed; counseling, obstetrical management and perinatal outcomes are being discussed.

  6. [Isolation of Nocardia species in patients with cystic fibrosis].

    PubMed

    Barrio, M Isabel; Martínez, M Carmen; Prados, Concepción; Girón, Rosa M; Maiz, Luis; Martínez, M Teresa

    2008-02-01

    The isolation of Nocardia species from the respiratory secretions of patients with cystic fibrosis presents problems with important clinical implications. From the sputum culture of a total of 387 patients with cystic fibrosis, Nocardia species was isolated in 9 cases (2%; 8 females and 1 male) with a mean (SD) age of 17 (7) years. Sixty-seven percent of the patients were asymptomatic and no relevant radiographic or analytical changes were detected. In only 3 patients was of Nocardia species isolated again in successive samples. Two patients were not treated, 7 were treated with cotrimoxazole and 3 with minocycline; in 2 cases therapy was intravenous. After a mean follow-up of 48 (33) months, all patients had improved. Isolation of Nocardia species from the secretions of patients with cystic fibrosis does not necessarily imply infection and the need for treatment should be assessed on an individual basis.

  7. Venous thromboembolism in cystic fibrosis.

    PubMed

    Takemoto, Clifford M

    2012-02-01

    The incidence of venous thromboembolism (VTE) is increasing in the pediatric population. Individuals with cystic fibrosis (CF) have an increased risk of thrombosis due to central venous catheters (CVCs), as well as acquired thrombophilia secondary to inflammation, or deficiencies of anticoagulant proteins due to vitamin K deficiency and/or liver dysfunction. CVC-associated thrombosis commonly results in line occlusion, but may develop into serious life-threatening conditions such as deep venous thrombosis (DVT), superior vena cava syndrome or pulmonary embolism (PE). Post-thrombotic syndrome (PTS) may be a long complication. Local occlusion of the catheter tip may be managed with instillation of thrombolytics (such as tPA) within the lumen of the catheter; however, CVC-associated thrombosis involving the proximal veins is most often is treated with systemic anticoagulation. Initial treatment with heparin is a standard approach, but thrombolytic therapy, which may carry higher bleeding risks, should be considered for life and limb threatening episodes of VTE. Recommended duration of anticoagulation with low molecular weight heparin (LMWH) or warfarin ranges from 3 to 6 months for major removable thrombotic risks; longer anticoagulation is considered for recurrent thrombosis, major persistent thrombophilia, or the continued presence of a major risk factor such as a CVC. While CVCs are the most common risk for development of VTE in children, studies have not demonstrated a clear benefit with routine use of systemic thromboprophylaxis. The incidence and risk factors of VTE in CF patients will be reviewed and principles of diagnosis and management will be summarized.

  8. [Cystic fibrosis in a 70-year-old woman].

    PubMed

    Bruun, Lene Søndberg; Jensen, Michael Skov

    2002-05-06

    Cystic fibrosis is usually diagnosed in early childhood, and patients rarely live beyond the age of 40. We present a case of a 70-year-old woman, in whom cystic fibrosis was diagnosed with the rare mutation, R117C. Cystic fibrosis should therefore also be considered in older patients.

  9. 78 FR 26681 - Medical Criteria for Evaluating Cystic Fibrosis

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-07

    ... ADMINISTRATION RIN 0960-AF58 Medical Criteria for Evaluating Cystic Fibrosis AGENCY: Social Security....04 to evaluate claims involving cystic fibrosis in adults and children under titles II and XVI of the... information on the disability program. 2. Information for individuals with cystic fibrosis who apply...

  10. Living with Cystic Fibrosis: A Guide for the Young Adult.

    ERIC Educational Resources Information Center

    Cystic Fibrosis Foundation, Atlanta, GA.

    Intended for the young adult with cystic fibrosis, the booklet provides information on dealing with problems and on advances in treatment and detection related to the disease. Addressed are the following topics: description of cystic fibrosis; inheritance of cystic fibrosis; early diagnosis; friends, careers, and other matters; treatment;…

  11. Health Human Resources Guidelines: Minimum Staffing Standards and Role Descriptions for Canadian Cystic Fibrosis Healthcare Teams

    PubMed Central

    2016-01-01

    In cystic fibrosis clinics across Canada, the most common barrier that healthcare workers face when providing care to their patients is having too little time. The Health Human Resources Guidelines were developed to define specifically what amounts of time should be allocated for each discipline of cystic fibrosis clinical care and to provide a description of all the roles involved, reinforcing how these work together to provide comprehensive multidisciplinary care. With involvement from all cystic fibrosis clinics in Canada, through the use of a tailored survey, the Health Human Resources Guidelines are an exclusively Canadian document that has been developed for implementation across the country. The guidelines have been incorporated into a national Accreditation Site Visit program for use in evaluating and improving care across the country and have been distributed to all Canadian cystic fibrosis clinics. The guidelines provide hospital administrators with clear benchmarks for allocating personnel resources to the cystic fibrosis clinics hosted within their institutions. PMID:27445556

  12. Health Human Resources Guidelines: Minimum Staffing Standards and Role Descriptions for Canadian Cystic Fibrosis Healthcare Teams.

    PubMed

    McIntosh, Ian D

    2016-01-01

    In cystic fibrosis clinics across Canada, the most common barrier that healthcare workers face when providing care to their patients is having too little time. The Health Human Resources Guidelines were developed to define specifically what amounts of time should be allocated for each discipline of cystic fibrosis clinical care and to provide a description of all the roles involved, reinforcing how these work together to provide comprehensive multidisciplinary care. With involvement from all cystic fibrosis clinics in Canada, through the use of a tailored survey, the Health Human Resources Guidelines are an exclusively Canadian document that has been developed for implementation across the country. The guidelines have been incorporated into a national Accreditation Site Visit program for use in evaluating and improving care across the country and have been distributed to all Canadian cystic fibrosis clinics. The guidelines provide hospital administrators with clear benchmarks for allocating personnel resources to the cystic fibrosis clinics hosted within their institutions.

  13. Management Issues for Adolescents with Cystic Fibrosis

    PubMed Central

    Withers, Adelaide Lindsay

    2012-01-01

    The healthy adolescent will encounter major changes in biological and psychosocial domains. The adolescent period can be greatly affected by a chronic illness. Cystic fibrosis is a terminal illness that can significantly affect an adolescent's biological, mental and psychosocial health. This paper discusses general issues to consider when managing an adolescent with a chronic medical condition, and specifically how cystic fibrosis may impact upon puberty, body image, risk-taking behaviours, mental health, independence, nonadherence, reproductive health, transition, lung transplantation, and end of life care. PMID:22991662

  14. The Cystic Fibrosis of Exocrine Pancreas

    PubMed Central

    Wilschanski, Michael

    2013-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in the pancreatic duct epithelia, and permits anions and water to enter the ductal lumen. This results in an increased volume of alkaline fluid allowing the highly concentrated proteins secreted by the acinar cells to remain in a soluble state. This work will expound on the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. We will also discuss the relationship between cystic fibrosis (CF) and pancreatitis, and outline present and potential therapeutic approaches in CF treatment relevant to the pancreas. PMID:23637307

  15. Precision genomic medicine in cystic fibrosis

    PubMed Central

    Chang, Eugene H.; Zabner, Joseph

    2015-01-01

    The successful application of precision genomic medicine requires an understanding of how a person’s genome can influence their disease phenotype and how medical therapies can provide personalized therapy to one’s genotype. In this review, we highlight advances in precision genomic medicine in cystic fibrosis (CF), a classic autosomal recessive genetic disorder. We discuss genotype-phenotype correlations in CF, genetic and environmental modifiers of disease, and pharmacogenetic therapies that target specific genetic mutations thereby addressing the primary defect of cystic fibrosis. PMID:26073768

  16. Global impact of bronchiectasis and cystic fibrosis

    PubMed Central

    Redondo, Margarida; Keyt, Holly; Dhar, Raja

    2016-01-01

    Educational aims To recognise the clinical and radiological presentation of the spectrum of diseases associated with bronchiectasis. To understand variation in the aetiology, microbiology and burden of bronchiectasis and cystic fibrosis across different global healthcare systems. Bronchiectasis is the term used to refer to dilatation of the bronchi that is usually permanent and is associated with a clinical syndrome of cough, sputum production and recurrent respiratory infections. It can be caused by a range of inherited and acquired disorders, or may be idiopathic in nature. The most well recognised inherited disorder in Western countries is cystic fibrosis (CF), an autosomal recessive condition that leads to progressive bronchiectasis, bacterial infection and premature mortality. Both bronchiectasis due to CF and bronchiectasis due to other conditions are placing an increasing burden on healthcare systems internationally. Treatments for CF are becoming more effective leading to more adult patients with complex healthcare needs. Bronchiectasis not due to CF is becoming increasingly recognised, particularly in the elderly population. Recognition is important and can lead to identification of the underlying cause, appropriate treatment and improved quality of life. The disease is highly diverse in its presentation, requiring all respiratory physicians to have knowledge of the different “bronchiectasis syndromes”. The most common aetiologies and presenting syndromes vary depending on geography, with nontuberculous mycobacterial disease predominating in some parts of North America, post-infectious and idiopathic disease predominating in Western Europe, and post-tuberculosis bronchiectasis dominating in South Asia and Eastern Europe. Ongoing global collaborative studies will greatly advance our understanding of the international impact of bronchiectasis and CF. PMID:28210295

  17. Novel molecular approaches to cystic fibrosis gene therapy

    PubMed Central

    Lee, Tim W. R.; Matthews, David A.; Blair, G. Eric

    2005-01-01

    Gene therapy holds promise for the treatment of a range of inherited diseases, such as cystic fibrosis. However, efficient delivery and expression of the therapeutic transgene at levels sufficient to result in phenotypic correction of cystic fibrosis pulmonary disease has proved elusive. There are many reasons for this lack of progress, both macroscopically in terms of airway defence mechanisms and at the molecular level with regard to effective cDNA delivery. This review of approaches to cystic fibrosis gene therapy covers these areas in detail and highlights recent progress in the field. For gene therapy to be effective in patients with cystic fibrosis, the cDNA encoding the cystic fibrosis transmembrane conductance regulator protein must be delivered effectively to the nucleus of the epithelial cells lining the bronchial tree within the lungs. Expression of the transgene must be maintained at adequate levels for the lifetime of the patient, either by repeat dosage of the vector or by targeting airway stem cells. Clinical trials of gene therapy for cystic fibrosis have demonstrated proof of principle, but gene expression has been limited to 30 days at best. Results suggest that viral vectors such as adenovirus and adeno-associated virus are unsuited to repeat dosing, as the immune response reduces the effectiveness of each subsequent dose. Nonviral approaches, such as cationic liposomes, appear more suited to repeat dosing, but have been less effective. Current work regarding non-viral gene delivery is now focused on understanding the mechanisms involved in cell entry, endosomal escape and nuclear import of the transgene. There is now increasing evidence to suggest that additional ligands that facilitate endosomal escape or contain a nuclear localization signal may enhance liposome-mediated gene delivery. Much progress in this area has been informed by advances in our understanding of the mechanisms by which viruses deliver their genomes to the nuclei of host

  18. Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis Foundation Consensus Report

    PubMed Central

    Farrell, Philip M.; Rosenstein, Beryl J.; White, Terry B.; Accurso, Frank J.; Castellani, Carlo; Cutting, Garry R.; Durie, Peter R.; Legrys, Vicky A.; Massie, John; Parad, Richard B.; Rock, Michael J.; Campbell, Preston W.

    2009-01-01

    Newborn screening (NBS) for cystic fibrosis (CF) is increasingly being implemented and is soon likely to be in use throughout the United States, because early detection permits access to specialized medical care and improves outcomes. The diagnosis of CF is not always straightforward, however. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a clear answer. Genotype analysis also does not always provide clarity; more than 1500 mutations have been identified in the CF transmembrane conductance regulator (CFTR) gene, not all of which result in CF. Harmful mutations in the gene can present as a spectrum of pathology ranging from sinusitis in adulthood to severe lung, pancreatic, or liver disease in infancy. Thus, CF identified postnatally must remain a clinical diagnosis. To provide guidance for the diagnosis of both infants with positive NBS results and older patients presenting with an indistinct clinical picture, the Cystic Fibrosis Foundation convened a meeting of experts in the field of CF diagnosis. Their recommendations, presented herein, involve a combination of clinical presentation, laboratory testing, and genetics to confirm a diagnosis of CF. PMID:18639722

  19. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.

    PubMed

    Farrell, Philip M; Rosenstein, Beryl J; White, Terry B; Accurso, Frank J; Castellani, Carlo; Cutting, Garry R; Durie, Peter R; Legrys, Vicky A; Massie, John; Parad, Richard B; Rock, Michael J; Campbell, Preston W

    2008-08-01

    Newborn screening (NBS) for cystic fibrosis (CF) is increasingly being implemented and is soon likely to be in use throughout the United States, because early detection permits access to specialized medical care and improves outcomes. The diagnosis of CF is not always straightforward, however. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a clear answer. Genotype analysis also does not always provide clarity; more than 1500 mutations have been identified in the CF transmembrane conductance regulator (CFTR) gene, not all of which result in CF. Harmful mutations in the gene can present as a spectrum of pathology ranging from sinusitis in adulthood to severe lung, pancreatic, or liver disease in infancy. Thus, CF identified postnatally must remain a clinical diagnosis. To provide guidance for the diagnosis of both infants with positive NBS results and older patients presenting with an indistinct clinical picture, the Cystic Fibrosis Foundation convened a meeting of experts in the field of CF diagnosis. Their recommendations, presented herein, involve a combination of clinical presentation, laboratory testing, and genetics to confirm a diagnosis of CF.

  20. Nutritional assessment in children with cystic fibrosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Optimal nutrition, including consuming 35–40% of calories (kcal) as fat, is a vital part of the management of cystic fibrosis (CF), and involves accurate assessment of dietary intake. We compared 3 methods of nutritional assessment in 8– to 14-year-old children (n=20) with CF: 1) a 24-h Dietary Reca...

  1. Zinc supplementation in children with cystic fibrosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cystic fibrosis (CF) leads to malabsorption of macro- and micronutrients. Symptomatic zinc deficiency has been reported in CF but little is known about zinc homeostasis in children with CF. Zinc supplementation (Zn suppl) is increasingly common in children with CF but it is not without theoretcial r...

  2. Exercise is medicine in cystic fibrosis.

    PubMed

    Wheatley, Courtney M; Wilkins, Brad W; Snyder, Eric M

    2011-07-01

    Exercise activates adrenergic and purinergic pathways that regulate activity of ion channels on airway epithelia cells and sweat glands. Therefore, we hypothesize that exercise is not only an important therapy for cystic fibrosis (CF) patients by facilitating systemic improvements but, more importantly, that exercise can improve the pathophysiological ion dysregulation at a cellular level, thereby enhancing quality of life in CF.

  3. [New prospects in cystic fibrosis treatment].

    PubMed

    Prados, C; Serrano, S; Alvarez-Sala, R; Villamor, J

    1997-04-01

    Only a few years ago, cystic fibrosis (CF) was considered the most frequent genetic disease in childhood, although survival has increased considerably in recent years owing to improved treatment. We discuss treatments that are still relevant as well as others that are under investigation now, aiming for better understanding of the disease and the therapies that have improved quality of life for CF patients.

  4. New and emerging targeted therapies for cystic fibrosis.

    PubMed

    Quon, Bradley S; Rowe, Steven M

    2016-03-30

    Cystic fibrosis (CF) is a monogenic autosomal recessive disorder that affects about 70,000 people worldwide. The clinical manifestations of the disease are caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The discovery of the CFTR gene in 1989 has led to a sophisticated understanding of how thousands of mutations in the CFTR gene affect the structure and function of the CFTR protein. Much progress has been made over the past decade with the development of orally bioavailable small molecule drugs that target defective CFTR proteins caused by specific mutations. Furthermore, there is considerable optimism about the prospect of gene replacement or editing therapies to correct all mutations in cystic fibrosis. The recent approvals of ivacaftor and lumacaftor represent the genesis of a new era of precision medicine in the treatment of this condition. These drugs are having a positive impact on the lives of people with cystic fibrosis and are potentially disease modifying. This review provides an update on advances in our understanding of the structure and function of the CFTR, with a focus on state of the art targeted drugs that are in development.

  5. New and emerging targeted therapies for cystic fibrosis

    PubMed Central

    Rowe, Steven M

    2016-01-01

    Cystic fibrosis (CF) is a monogenic autosomal recessive disorder that affects about 70 000 people worldwide. The clinical manifestations of the disease are caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The discovery of the CFTR gene in 1989 has led to a sophisticated understanding of how thousands of mutations in the CFTR gene affect the structure and function of the CFTR protein. Much progress has been made over the past decade with the development of orally bioavailable small molecule drugs that target defective CFTR proteins caused by specific mutations. Furthermore, there is considerable optimism about the prospect of gene replacement or editing therapies to correct all mutations in cystic fibrosis. The recent approvals of ivacaftor and lumacaftor represent the genesis of a new era of precision medicine in the treatment of this condition. These drugs are having a positive impact on the lives of people with cystic fibrosis and are potentially disease modifying. This review provides an update on advances in our understanding of the structure and function of the CFTR, with a focus on state of the art targeted drugs that are in development. PMID:27030675

  6. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis.

    PubMed

    Derichs, Nico

    2013-03-01

    Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

  7. Relationships between cystic fibrosis transmembrane conductance regulator, extracellular nucleotides and cystic fibrosis.

    PubMed

    Marcet, Brice; Boeynaems, Jean-Marie

    2006-12-01

    Cystic fibrosis (CF) is one of the most common lethal autosomal recessive genetic diseases in the Caucasian population, with a frequency of about 1 in 3000 livebirths. CF is due to a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding the CFTR protein, a cyclic adenosine 5'-monophosphate (cAMP)-regulated chloride channel localized in the apical membrane of epithelial cells. CFTR is a multifunctional protein which, in addition to be a Cl-channel, is also a regulator of multiple ion channels and other proteins. In particular CFTR has been reported to play a role in the outflow of adenosine 5'-triphosphate (ATP) from cells, but this remains controversial. Extracellular nucleotides are signaling molecules that regulate ion transport and mucociliary clearance by acting on P2 nucleotide receptors, in particular the P2Y(2) receptor. Nucleotides activating the P2Y(2) receptor represent thus one pharmacotherapeutic strategy to treat CF disease, via improvement of mucus hydration and mucociliary clearance in airways. Phase II clinical trials have recently shown that aerosolized denufosol (INS37217, Inspire(R)) improves pulmonary function in CF patients: denufosol was granted orphan drug status and phase III trials are planned. Here, we review what is known about the relationship between extracellular nucleotides and CFTR, the role of extracellular nucleotides in epithelial pathophysiology and their putative role as therapeutic agents.

  8. Lung disease in mice with cystic fibrosis.

    PubMed Central

    Kent, G; Iles, R; Bear, C E; Huan, L J; Griesenbach, U; McKerlie, C; Frndova, H; Ackerley, C; Gosselin, D; Radzioch, D; O'Brodovich, H; Tsui, L C; Buchwald, M; Tanswell, A K

    1997-01-01

    The leading cause of mortality and morbidity in humans with cystic fibrosis is lung disease. Advances in our understanding of the pathogenesis of the lung disease of cystic fibrosis, as well as development of innovative therapeutic interventions, have been compromised by the lack of a natural animal model. The utility of the CFTR-knockout mouse in studying the pathogenesis of cystic fibrosis has been limited because of their failure, despite the presence of severe intestinal disease, to develop lung disease. Herein, we describe the phenotype of an inbred congenic strain of CFTR-knockout mouse that develops spontaneous and progressive lung disease of early onset. The major features of the lung disease include failure of effective mucociliary transport, postbronchiolar over inflation of alveoli and parenchymal interstitial thickening, with evidence of fibrosis and inflammatory cell recruitment. We speculate that the basis for development of lung disease in the congenic CFTR-knockout mice is their observed lack of a non-CFTR chloride channel normally found in CFTR-knockout mice of mixed genetic background. PMID:9399953

  9. Inflammation and its genesis in cystic fibrosis.

    PubMed

    Nichols, David P; Chmiel, James F

    2015-10-01

    The host inflammatory response in cystic fibrosis (CF) lung disease has long been recognized as a central pathological feature and an important therapeutic target. Indeed, many believe that bronchiectasis results largely from the oxidative and proteolytic damage comprised within an exuberant airway inflammatory response that is dominated by neutrophils. In this review, we address the longstanding argument of whether or not the inflammatory response is directly attributable to impairment of the cystic fibrosis transmembrane conductance regulator or only secondary to airway obstruction and chronic bacterial infection and challenge the importance of this distinction in the context of therapy. We also review the centrality of neutrophils in CF lung pathophysiology and highlight more recent data that suggest the importance of other cell types and signaling beyond NF-κB activation. We discuss how protease and redox imbalance are critical factors in CF airway inflammation and end by reviewing some of the more promising therapeutic approaches now under development.

  10. Mycobacterium abscessus and Children with Cystic Fibrosis

    PubMed Central

    Sermet-Gaudelus, Isabelle; Le Bourgeois, Muriel; Pierre-Audigier, Catherine; Offredo, Catherine; Guillemot, Didier; Halley, Sophie; Akoua-Koffi, Chantal; Vincent, Véronique; Sivadon-Tardy, Valérie; Ferroni, Agnès; Berche, Patrick; Scheinmann, Pierre; Lenoir, Gérard

    2003-01-01

    We prospectively studied 298 patients with cystic fibrosis (mean age 11.3 years; range 2 months to 32 years; sex ratio, 0.47) for nontuberculous mycobacteria in respiratory samples from January 1, 1996, to December 31, 1999. Mycobacterium abscessus was by far the most prevalent nontuberculous mycobacterium: 15 patients (6 male, 9 female; mean age 11.9 years; range 2.5–22 years) had at least one positive sample for this microorganism (versus 6 patients positive for M. avium complex), including 10 with >3 positive samples (versus 3 patients for M. avium complex). The M. abscessus isolates from 14 patients were typed by pulsed-field gel electrophoresis: each of the 14 patients harbored a unique strain, ruling out a common environmental reservoir or person-to-person transmission. Water samples collected in the cystic fibrosis center were negative for M. abscessus. This major mycobacterial pathogen in children and teenagers with cystic fibrosis does not appear to be acquired nosocomially. PMID:14720400

  11. Large-insert genome analysis technology detects structural variation in Pseudomonas aeruginosa clinical strains from cystic fibrosis patients.

    PubMed

    Hayden, Hillary S; Gillett, Will; Saenphimmachak, Channakhone; Lim, Regina; Zhou, Yang; Jacobs, Michael A; Chang, Jean; Rohmer, Laurence; D'Argenio, David A; Palmieri, Anthony; Levy, Ruth; Haugen, Eric; Wong, Gane K S; Brittnacher, Mitch J; Burns, Jane L; Miller, Samuel I; Olson, Maynard V; Kaul, Rajinder

    2008-06-01

    Large-insert genome analysis (LIGAN) is a broadly applicable, high-throughput technology designed to characterize genome-scale structural variation. Fosmid paired-end sequences and DNA fingerprints from a query genome are compared to a reference sequence using the Genomic Variation Analysis (GenVal) suite of software tools to pinpoint locations of insertions, deletions, and rearrangements. Fosmids spanning regions that contain new structural variants can then be sequenced. Clonal pairs of Pseudomonas aeruginosa isolates from four cystic fibrosis patients were used to validate the LIGAN technology. Approximately 1.5 Mb of inserted sequences were identified, including 743 kb containing 615 ORFs that are absent from published P. aeruginosa genomes. Six rearrangement breakpoints and 220 kb of deleted sequences were also identified. Our study expands the "genome universe" of P. aeruginosa and validates a technology that complements emerging, short-read sequencing methods that are better suited to characterizing single-nucleotide polymorphisms than structural variation.

  12. Lessons learned from the cystic fibrosis pig.

    PubMed

    Meyerholz, David K

    2016-07-01

    Deficient function in the anion channel cystic fibrosis (CF) transmembrane conductance regulator is the fundamental cause for CF. This is a monogenic condition that causes lesions in several organs including the respiratory tract, pancreas, liver, intestines, and reproductive tract. Lung disease is most notable, given it is the leading cause of morbidity and mortality in people with CF. Shortly after the identification of CF transmembrane conductance regulator, CF mouse models were developed that did not show spontaneous lung disease as seen in humans, and this spurred development of additional CF animal models. Pig models were considered a leading choice for several reasons including their similarity to humans in respiratory anatomy, physiology, and in size for translational imaging. The first CF pig models were reported in 2008 and have been extremely valuable to help clarify persistent questions in the field and advance understanding of disease pathogenesis. Because CF pigs are susceptible to lung disease like humans, they have direct utility in translational research. In addition, CF pig models are useful to compare and contrast with current CF mouse models, human clinical studies, and even newer CF animal models being characterized. This "triangulation" strategy could help identify genetic differences that underlie phenotypic variations, so as to focus and accelerate translational research.

  13. A millennial view of cystic fibrosis.

    PubMed

    Dodge, John A

    2015-01-01

    Although only identified as a distinct disease in the 1930s, it was soon apparent that Cystic Fibrosis (CF) had been present, but unrecognised, in European populations for many years - perhaps even centuries [1] . Within a decade of the early descriptions, the autosomal recessive nature of this genetic disease had been clarified, and its clinical features had been expanded. Secondary nutritional deficiencies complicated the underlying condition: the first clear description of CF as "a new disease", which included a speculation about its genetic basis (because there were 2 pairs of sibs in the case series) was published as Vitamin A deficiency in children [2]. The diagnosis was most often made at autopsy. When it was suspected in life, the diagnostic tests used included duodenal intubation to obtain fluid which would show impaired tryptic digestion of the coating of X-Ray film in CF children, and measurement of vitamin A in the blood. Some nutritional improvement could be expected with simple, rather inefficient pancreatic enzyme preparations, but it was not until mid-century that antibiotics began to treat pulmonary infections effectively. As a young doctor in the 1950s I soon became aware that the median age at death for affected children was about one year, and most died before reaching school age. .

  14. Is cystic fibrosis genetic medicine's canary?

    PubMed

    Lindee, Susan; Mueller, Rebecca

    2011-01-01

    In 1989 the gene that causes cystic fibrosis (CF) was identified in a search accompanied by intense anticipation that the gene, once discovered, would lead rapidly to gene therapy. Many hoped that the disease would effectively disappear. Those affected were going to inhale vectors packed with functioning genes, which would go immediately to work in the lungs. It was a bewitching image, repeatedly invoked in both scientific and popular texts. Gene therapy clinical trials were carried out with a range of strategies and occasionally success seemed close, but by 1996 the idea that gene therapy for CF would quickly provide a cure was being abandoned by the communities engaged with treatment and research. While conventional wisdom holds that the death of Jesse Gelsinger in an unrelated gene therapy trial in 1999 produced new skepticism about gene therapy, the CF story suggests a different trajectory, and some different lessons. This article considers the rise and fall of gene therapy for CF and suggests that CF may provide a particularly compelling case study of a failed genomic technology, perhaps even of a medical "canary." The story of CF might be a kind of warning to us that genetic medicine may create as many problems as it solves, and that moving forward constructively with these techniques and practices requires many kinds of right information, not just about biology, but also about values, priorities, market forces, uncertainty, and consumer choice.

  15. [Inhaled antibiotic therapy in cystic fibrosis].

    PubMed

    Girón Moreno, Rosa M; Salcedo Posadas, Antonio; Mar Gómez-Punter, Rosa

    2011-06-01

    Cystic fibrosis is the most frequent fatal genetically-transmitted disease among Caucasians. Chronic bronchial infection, especially by Pseudomonas aeruginosa, is the main cause of morbidity and mortality in this disease. Aerosolized antibiotic therapy achieves high drug concentrations in the airway with low toxicity, allowing chronic use. Currently, two antibiotics have been approved for inhalation therapy, tobramycin inhalation solution and colistimethate sodium aerosol. There is less evidence from clinical trials for the latter. The main indication for these drugs is chronic bronchial colonization by P. aeruginosa, although there is increasing evidence of the importance of the primary infection by this bacterium, whether treated by oral or intravenous antibiotics or not. More controversial is the use of aerosolized antibiotic therapy in bacterial prophylaxis or respiratory exacerbations. For many years, intravenous formulations of distinct antibiotics for aerosolized use have been employed, which are in distinct phases of research for use in nebulizer therapy. In addition to being used to treat P. aeruginosa infection, aerosolized antibiotics have been used to treat other pathogens such as methicillin-resistant Staphylococus aureus, Mycobacterium abscessus and Aspergillus fumigatus.

  16. Progress in cystic fibrosis and the CF Therapeutics Development Network

    PubMed Central

    Rowe, Steven M; Borowitz, Drucy S; Burns, Jane L; Clancy, John P; Donaldson, Scott H; Retsch-Bogart, George; Sagel, Scott D; Ramsey, Bonnie W

    2013-01-01

    Cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians, affects approximately 70 000 individuals worldwide. In 1998, the Cystic Fibrosis Foundation (CFF) launched the CF Therapeutics Development Network (CF-TDN) as a central element of its Therapeutics Development Programme. Designed to accelerate the clinical evaluation of new therapies needed to fulfil the CFF mission to control and cure CF, the CF-TDN has conducted 75 clinical trials since its inception, and has contributed to studies as varied as initial safety and proof of concept trials to pivotal programmes required for regulatory approval. This review highlights recent and significant research efforts of the CF-TDN, including a summary of contributions to studies involving CF transmembrane conductance regulator (CFTR) modulators, airway surface liquid hydrators and mucus modifiers, anti-infectives, anti-inflammatories, and nutritional therapies. Efforts to advance CF biomarkers, necessary to accelerate the therapeutic goals of the network, are also summarised. PMID:22960984

  17. Use of the Cystic Fibrosis Foundation's extensive sputum-culturing protocol for patients without cystic fibrosis: implications for infection control and antimicrobial resistance.

    PubMed

    Brown, Jennifer

    2014-05-01

    The US Cystic Fibrosis Foundation has guidelines for culturing respiratory tract specimens from patients with cystic fibrosis. Pulmonary physicians were surveyed regarding their use of these extensive cystic fibrosis culture protocols for patients without cystic fibrosis. The survey results and a discussion of the implications of these practices are reported.

  18. Chloride and potassium channels in cystic fibrosis airway epithelia

    NASA Astrophysics Data System (ADS)

    Welsh, Michael J.; Liedtke, Carole M.

    1986-07-01

    Cystic fibrosis, the most common lethal genetic disease in Caucasians, is characterized by a decreased permeability in sweat gland duct and airway epithelia. In sweat duct epithelium, a decreased Cl- permeability accounts for the abnormally increased salt content of sweat1. In airway epithelia a decreased Cl- permeability, and possibly increased sodium absorption, may account for the abnormal respiratory tract fluid2,3. The Cl- impermeability has been localized to the apical membrane of cystic fibrosis airway epithelial cells4. The finding that hormonally regulated Cl- channels make the apical membrane Cl- permeable in normal airway epithelial cells5 suggested abnormal Cl- channel function in cystic fibrosis. Here we report that excised, cell-free patches of membrane from cystic fibrosis epithelial cells contain Cl- channels that have the same conductive properties as Cl- channels from normal cells. However, Cl- channels from cystic fibrosis cells did not open when they were attached to the cell. These findings suggest defective regulation of Cl- channels in cystic fibrosis epithelia; to begin to address this issue, we performed two studies. First, we found that isoprenaline, which stimulates Cl- secretion, increases cellular levels of cyclic AMP in a similar manner in cystic fibrosis and non-cystic fibrosis epithelial cells. Second, we show that adrenergic agonists open calcium-activated potassium channels, indirectly suggesting that calcium-dependent stimulus-response coupling is intact in cystic fibrosis. These data suggest defective regulation of Cl- channels at a site distal to cAMP accumulation.

  19. Lumacaftor/Ivacaftor: A Review in Cystic Fibrosis.

    PubMed

    Deeks, Emma D

    2016-08-01

    Lumacaftor/ivacaftor (Orkambi™) is a fixed-dose tablet containing a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel's open probability and transport of chloride. In two 24-week trials in the approved patient population (TRAFFIC and TRANSPORT), lumacaftor 400 mg plus ivacaftor 250 mg, administered every 12 h in combination with standard therapy, was associated with an ≈3 % statistically significant improvement in lung function relative to placebo (as measured by the percent predicted forced expiratory volume in 1 s). Lumacaftor plus ivacaftor did not significantly improve respiratory symptoms, although reduced pulmonary exacerbations to a clinically meaningful extent and, in one trial (TRANSPORT), significantly improved body mass index (BMI). In an ongoing extension of these studies (PROGRESS), lumacaftor plus ivacaftor provided clinical benefit over a further 72 weeks of treatment. Lumacaftor plus ivacaftor had an acceptable tolerability profile, with the most common adverse events being respiratory or gastrointestinal in nature. Thus, lumacaftor/ivacaftor expands the treatment options available for patients with cystic fibrosis homozygous for the F508del-CFTR mutation, although its precise place in clinical practice remains to be determined.

  20. Natural Compounds as Therapeutic Agents in the Treatment Cystic Fibrosis

    PubMed Central

    Dey, Isha; Shah, Kalpit; Bradbury, Neil A

    2016-01-01

    The recent FDA approval of two drugs to treat the basic defect in cystic fibrosis has given hope to patients and their families battling this devastating disease. Over many years, with heavy financial investment from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation, pre-clinical evaluation of thousands of synthetic drugs resulted in the production of Kalydeco and Orkambi. Yet, despite the success of this endeavor, many other compounds have been proposed as therapeutic agents in the treatment of CF. Of note, several of these compounds are naturally occurring, and are present in spices from the grocery store and over the counter preparations in health food stores. In this short review, we look at three such compounds, genistein, curcumin, and resveratrol, and evaluate the scientific support for their use as therapeutic agents in the treatment of patients with CF. PMID:27081574

  1. Autopsy confirmation of severe pulmonary interstitial fibrosis secondary to Munchausen syndrome presenting as cystic fibrosis.

    PubMed

    Croft, Philip R; Racz, Mark I; Bloch, John D; Palmer, Charles H

    2005-09-01

    Chronic factitious disorder with physical symptoms, or Munchausen syndrome, is a well-recognized but uncommonly diagnosed psychiatric condition characterized by the deliberate production of signs and symptoms of disease in order to receive medical attention. Clinical suspicion of this disease is rarely confirmed by autopsy, as the patients usually do not die as a consequence of feigning illness. Here we report the autopsy confirmation of a case of a suspected Munchausen syndrome patient who presented with a history of cystic fibrosis. Examination of the lungs demonstrated extensive severe interstitial fibrosis, and polariscopic examination revealed a large quantity of crystalline material throughout the tissue; X-ray diffraction identified the material as talc. Synopses of published cases of Munchausen syndrome presenting as cystic fibrosis, and cases of Munchausen syndrome with pulmonary talcosis are presented as part of the discussion.

  2. How Is Cystic Fibrosis Treated?

    MedlinePlus

    ... of Intramural Research Research Resources Research Meeting Summaries Technology Transfer Clinical Trials What Are Clinical Trials? Children & ... high-frequency airwaves to force the mucus that's deep in your lungs toward your upper airways so ...

  3. In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.

    PubMed

    Trouvé, Pascal; Génin, Emmanuelle; Férec, Claude

    2017-01-01

    Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

  4. In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

    PubMed Central

    Génin, Emmanuelle; Férec, Claude

    2017-01-01

    Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance. PMID:28339466

  5. Normalization of sweat chloride concentration and clinical improvement with ivacaftor in a patient with cystic fibrosis with mutation S549N.

    PubMed

    McGarry, Meghan E; Nielson, Dennis W

    2013-10-01

    The cystic fibrosis (CF) protein forms an anion channel in epithelial cells, and the absence or defective function of this channel results in the clinical manifestations of CF. CF is an autosomal recessive disorder, and its many disease-causing mutations divide into five or six classes. There are 10 known class 3 gating mutations, the most common of which is G551D. Ivacaftor is a drug that in vitro increases open time and transepithelial chloride transport in all 10 gating mutations, but it is approved for use only in patients with the G551D mutation. We report complete normalization of sweat chloride concentration and rapid clinical improvement over 6 weeks of treatment with ivacaftor in a patient with CF with the gating mutation S549N. The findings suggest that ivacaftor should be considered for use in patients with any of the known gating mutations.

  6. [New therapeutic developments in cystic fibrosis].

    PubMed

    Bui, S; Macey, J; Fayon, M; Bihouée, T; Burgel, P-R; Colomb, V; Corvol, H; Durieu, I; Hubert, D; Marguet, C; Mas, E; Munck, A; Murris-Espin, M; Reix, P; Sermet-Gaudelus, I

    2016-12-01

    Since the discovery of chloride secretion by the Cystic Fibrosis Transport regulator CFTR in 1983, and CFTR gene in 1989, knowledge about CFTR synthesis, maturation, intracellular transfer and function has dramatically expanded. These discoveries have led to the distribution of CF mutations into 6 classes with different pathophysiological mechanisms. In this article we will explore the state of art on CFTR synthesis and its chloride secretion function. We will then explore the consequences of the 6 classes of mutations on CFTR protein function and we will describe the new therapeutic developments aiming at correcting these defects.

  7. Genetic therapies for cystic fibrosis lung disease.

    PubMed

    Sinn, Patrick L; Anthony, Reshma M; McCray, Paul B

    2011-04-15

    The aim of gene therapy for cystic fibrosis (CF) lung disease is to efficiently and safely express the CF transmembrane conductance regulator (CFTR) in the appropriate pulmonary cell types. Although CF patients experience multi-organ disease, the chronic bacterial lung infections and associated inflammation are the primary cause of shortened life expectancy. Gene transfer-based therapeutic approaches are feasible, in part, because the airway epithelium is directly accessible by aerosol delivery or instillation. Improvements in standard delivery vectors and the development of novel vectors, as well as emerging technologies and new animal models, are propelling exciting new research forward. Here, we review recent developments that are advancing this field of investigation.

  8. Influenza immunization in children with cystic fibrosis.

    PubMed

    Adlard, P; Bryett, K

    1987-01-01

    Nineteen children with cystic fibrosis and aged between 5 and 13 years were randomized to receive two doses at monthly intervals of either a split-virion influenza vaccine (MFV-Ject, Institut Merieux) or a sub-unit vaccine (Fluvirin, Evans). In those completing the study, there was a satisfactory serological response. There was no statistically significant difference between the immunogenicity of the two vaccines as evaluated by haemagglutination inhibition or single radial haemolysis tests. The incidence of local side-effects was similar in the two groups.

  9. Vitamin D Deficiency in Cystic Fibrosis

    PubMed Central

    Hall, William B.; Sparks, Amy A.; Aris, Robert M.

    2010-01-01

    Cystic Fibrosis is the most common inherited genetic respiratory disorder in the Western World. Hypovitaminosis D is almost universal in CF patients, likely due to a combination of inadequate absorption, impaired metabolism, and lack of sun exposure. Inadequate levels are associated with the high prevalence of bone disease or osteoporosis in CF patients, which is associated with increased morbidity including fractures, kyphosis, and worsening pulmonary status. Treatment goals include regular monitoring 25 hydroxyvitamin D (25OHD) levels with aggressive treatment for those with levels <75 nmol/L (<30 ng/mL). More research is needed to determine optimal supplementation goals and strategies. PMID:20148079

  10. The Changing Microbial Epidemiology in Cystic Fibrosis

    PubMed Central

    LiPuma, John J.

    2010-01-01

    Summary: Infection of the airways remains the primary cause of morbidity and mortality in persons with cystic fibrosis (CF). This review describes salient features of the epidemiologies of microbial species that are involved in respiratory tract infection in CF. The apparently expanding spectrum of species causing infection in CF and recent changes in the incidences and prevalences of infection due to specific bacterial, fungal, and viral species are described. The challenges inherent in tracking and interpreting rates of infection in this patient population are discussed. PMID:20375354

  11. Cystic Fibrosis in the African Diaspora.

    PubMed

    Stewart, Cheryl; Pepper, Michael S

    2017-01-01

    Identifying mutations that cause cystic fibrosis (CF) is important for making an early, unambiguous diagnosis, which, in turn, is linked to better health and a greater life expectancy. In patients of African descent, a molecular diagnosis is often confounded by the fact that the majority of investigations undertaken to identify causative mutations have been conducted on European populations, and CF-causing mutations tend to be population specific. We undertook a survey of published data with the aim of identifying causative CF mutations in patients of African descent in the Americas. We found that 1,584 chromosomes had been tested in only 6 countries, of which 876 alleles (55.3%) still remained unidentified. There were 59 mutations identified. Of those, 41 have been shown to cause CF, 17 have no associated functional studies, and one (R117H) is of varying clinical consequence. The most common mutations identified in the patients of African descent were: ΔF508 (29.4% identified in the United States, Colombia, Brazil, and Venezuela); 3120 + 1G>A (8.4% identified in Brazil, the United States, and Colombia); G85E (3.8% identified in Brazil); 1811 + 1.6kbA>G (3.7% identified in Colombia); and 1342 - 1G>C (3.1% identified in the United States). The majority of the mutations identified (81.4%) have been described in just one country. Our findings indicate that there is a need to fully characterize the spectrum of CF mutations in the diaspora to improve diagnostic accuracy for these patients and facilitate treatment.

  12. Personalized medicine for cystic fibrosis: establishing human model systems.

    PubMed

    Mou, Hongmei; Brazauskas, Karissa; Rajagopal, Jayaraj

    2015-10-01

    With over 1,500 identifiable mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that result in distinct functional and phenotypical abnormalities, it is virtually impossible to perform randomized clinical trials to identify the best therapeutics for all patients. Therefore, a personalized medicine approach is essential. The only way to realistically accomplish this is through the development of improved in vitro human model systems. The lack of a readily available and infinite supply of human CFTR-expressing airway epithelial cells is a key bottleneck. We propose that a concerted two-pronged approach is necessary for patient-specific cystic fibrosis research to continue to prosper and realize its potential: (1) more effective culture and differentiation conditions for growing primary human airway and nasal epithelial cells and (2) the development of collective protocols for efficiently differentiating disease- and patient-specific induced pluripotent stem cells (iPSC) into pure populations of adult epithelial cells. Ultimately, we need a personalized human model system for cystic fibrosis with the capacity for uncomplicated bankability, widespread availability, and universal applicability for patient-specific disease modeling, novel pharmacotherapy investigation and screening, and readily executable genetic modification.

  13. Blunted perception of neural respiratory drive and breathlessness in patients with cystic fibrosis

    PubMed Central

    Jolley, Caroline J.; Elston, Caroline; Moxham, John; Rafferty, Gerrard F.

    2016-01-01

    The electromyogram recorded from the diaphragm (EMGdi) and parasternal intercostal muscle using surface electrodes (sEMGpara) provides a measure of neural respiratory drive (NRD), the magnitude of which reflects lung disease severity in stable cystic fibrosis. The aim of this study was to explore perception of NRD and breathlessness in both healthy individuals and patients with cystic fibrosis. Given chronic respiratory loading and increased NRD in cystic fibrosis, often in the absence of breathlessness at rest, we hypothesised that patients with cystic fibrosis would be able to tolerate higher levels of NRD for a given level of breathlessness compared to healthy individuals during exercise. 15 cystic fibrosis patients (mean forced expiratory volume in 1 s (FEV1) 53.5% predicted) and 15 age-matched, healthy controls were studied. Spirometry was measured in all subjects and lung volumes measured in the cystic fibrosis patients. EMGdi and sEMGpara were recorded at rest and during incremental cycle exercise to exhaustion and expressed as a percentage of maximum (% max) obtained from maximum respiratory manoeuvres. Borg breathlessness scores were recorded at rest and during each minute of exercise. EMGdi % max and sEMGpara % max and associated Borg breathlessness scores differed significantly between healthy subjects and cystic fibrosis patients at rest and during exercise. The relationship between EMGdi % max and sEMGpara % max and Borg score was shifted to the right in the cystic fibrosis patients, such that at comparable levels of EMGdi % max and sEMGpara % max the cystic fibrosis patients reported significantly lower Borg breathlessness scores compared to the healthy individuals. At Borg score 1 (clinically significant increase in breathlessness from baseline) corresponding levels of EMGdi % max (20.2±12% versus 32.15±15%, p=0.02) and sEMGpara % max (18.9±8% versus 29.2±15%, p=0.04) were lower in the healthy individuals compared to the cystic fibrosis

  14. Blunted perception of neural respiratory drive and breathlessness in patients with cystic fibrosis.

    PubMed

    Reilly, Charles C; Jolley, Caroline J; Elston, Caroline; Moxham, John; Rafferty, Gerrard F

    2016-01-01

    The electromyogram recorded from the diaphragm (EMGdi) and parasternal intercostal muscle using surface electrodes (sEMGpara) provides a measure of neural respiratory drive (NRD), the magnitude of which reflects lung disease severity in stable cystic fibrosis. The aim of this study was to explore perception of NRD and breathlessness in both healthy individuals and patients with cystic fibrosis. Given chronic respiratory loading and increased NRD in cystic fibrosis, often in the absence of breathlessness at rest, we hypothesised that patients with cystic fibrosis would be able to tolerate higher levels of NRD for a given level of breathlessness compared to healthy individuals during exercise. 15 cystic fibrosis patients (mean forced expiratory volume in 1 s (FEV1) 53.5% predicted) and 15 age-matched, healthy controls were studied. Spirometry was measured in all subjects and lung volumes measured in the cystic fibrosis patients. EMGdi and sEMGpara were recorded at rest and during incremental cycle exercise to exhaustion and expressed as a percentage of maximum (% max) obtained from maximum respiratory manoeuvres. Borg breathlessness scores were recorded at rest and during each minute of exercise. EMGdi % max and sEMGpara % max and associated Borg breathlessness scores differed significantly between healthy subjects and cystic fibrosis patients at rest and during exercise. The relationship between EMGdi % max and sEMGpara % max and Borg score was shifted to the right in the cystic fibrosis patients, such that at comparable levels of EMGdi % max and sEMGpara % max the cystic fibrosis patients reported significantly lower Borg breathlessness scores compared to the healthy individuals. At Borg score 1 (clinically significant increase in breathlessness from baseline) corresponding levels of EMGdi % max (20.2±12% versus 32.15±15%, p=0.02) and sEMGpara % max (18.9±8% versus 29.2±15%, p=0.04) were lower in the healthy individuals compared to the cystic fibrosis

  15. Maintenance of nutritional status in patients with cystic fibrosis: new and emerging therapies.

    PubMed

    Kalnins, Daina; Wilschanski, Michael

    2012-01-01

    Poor clinical outcomes in cystic fibrosis are often associated with undernutrition. Normal growth and development should be achieved in cystic fibrosis, and nutritional counseling is paramount at all ages. Prevention and early detection of growth failure is the key to successful nutritional intervention. The advance in nutritional management is certainly one factor that has contributed to the improved survival in recent decades. This review outlines the major nutritional parameters in the management of the patient with cystic fibrosis, including recent advances in pancreatic enzyme replacement therapy and fat-soluble vitamin therapy. There are sections on complicated clinical situations which directly affect nutrition, for example, before and after lung transplantation, cystic fibrosis-related diabetes, and bone health.

  16. Cystic fibrosis: need for mass deployable screening methods.

    PubMed

    Sengar, Aditya Singh; Agarwal, Anirudh; Singh, Manish K

    2014-10-01

    Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is a member of the adenosine triphosphate (ATP)-binding cassette superfamily of proteins and it functions as a chloride channel. CFTR largely controls the working of epithelial cells of the airways, the gastrointestinal tract, exocrine glands, and genitourinary system. Cystic fibrosis is responsible for severe chronic pulmonary disorders in children. Other maladies in the spectrum of this life-limiting disorder include nasal polyposis, pansinusitis, rectal prolapse, pancreatitis, cholelithiasis, insulin-dependent hyperglycemia, and cirrhosis. This review summarizes the recent state of art in the field of cystic fibrosis diagnostic methods with the help of CF literature published so far and proposes new research domains in the field of cystic fibrosis diagnosis.

  17. [Technical aspects and relevance of energy expenditure and physical activity assessment in clinical research for cystic fibrosis patients].

    PubMed

    Béghin, L; Michaud, L; Turck, D; Gottrand, F

    2005-07-01

    Cystic fibrosis (CF) is characterized by deteriorating lung function and mal-digestion, which result in growth failure and/or under-nutrition. Several factors, alone or combined, contribute to malnutrition in CF: poor energy intake, elevation of energy loss as a result of malabsorption, increasing resting energy expenditure due to genetic mutation and/or pulmonary exacerbation. Several techniques have been used to assess energy expenditure and physical activity in order to better understand mechanisms of malnutrition in CF and follow therapeutic interventions. Indirect calorimetry (IC) studies have shown that resting energy expenditure (REE) was 10-22% higher than predictive values. This increase could be attributed to chronic inflammation as a result of Pseudomonas aeruginosa (PA) infection. Indeed, intravenous antibiotic therapy decreases REE. Doubly labelled water technique and heart rate monitoring calibrated against IC techniques shows that total energy expenditure (TEE) was not different than in healthy children. Physical activity level assessed by the ratio TEE-REE is also not different between CF of healthy children. Recently, new accelerometry technics, easier to use and less invasive have been successfully used in order to assess physical activity level in CF. Precise and ambulatory assessment of energy expenditure and physical activity permit to check and adapt dietary allowances in CF. These techniques could be simultaneously used and be helpful to assess efficacy of intervention studies.

  18. Chest CT Features of Cystic Fibrosis in Korea: Comparison with Non-Cystic Fibrosis Diseases

    PubMed Central

    Yang, So Yeon; Cha, Min Jae; Kim, Tae Jung; Kim, Tae Sung; Yoon, Hyun Jung

    2017-01-01

    Objective Cystic fibrosis (CF) is a rare congenital disease in Korea, and its clinical and imaging findings are unclear. The objective of our study was to describe the clinical and CT features of CF in Korea and compare its features with those of other diseases mimicking CF. Materials and Methods From November 1994 to December 2014, a presumptive diagnosis of CF was made in 23 patients based on clinical or radiological examination. After the exclusion of 10 patients without diagnostic confirmation, 13 patients were included in the study. A diagnosis of CF was made with the CF gene study. CT findings were evaluated for the presence and distribution of parenchymal abnormalities including bronchiectasis, tree-in-bud (TIB) pattern, mucus plugging, consolidation, and mosaic attenuation. Results Of the 13 patients, 7 (median age, 15 years) were confirmed as CF, 4 (median age, 19 years) had primary ciliary dyskinesia, 1 had bronchiectasis of unknown cause, and 1 had chronic asthma. CT of patients with CF showed bilateral bronchiectasis, TIB pattern, mosaic attenuation, and mucus plugging in all patients, with upper lung predominance (57%). In CT of the non-CF patients, bilateral bronchiectasis, TIB pattern, mosaic attenuation, and mucus plugging were also predominant features, with lower lung predominance (50%). Conclusion Korean patients with CF showed bilateral bronchiectasis, cellular bronchiolitis, mucus plugging, and mosaic attenuation, which overlapped with those of non-CF patients. CF gene study is recommended for the definitive diagnosis of CF in patients with these clinical and imaging features. PMID:28096734

  19. Clinical spectrum in homozygotes and compound heterozygotes inheriting cystic fibrosis mutation 3849+10kbC>T: Significance for geneticists

    SciTech Connect

    Gilbert, F.; Li, Zhen; Arzimanoglou, I.

    1995-09-25

    We describe patients inheriting cystic fibrosis (CF) mutation 3849+10kbC>T as homozygotes or compound heterozygotes. Three unrelated homozygotes for this mutation were all pancreatic-sufficient and sweat test-negative or inconclusive. Among the compound heterozygotes, both pancreatic sufficiency and insufficiency, as well as positive and negative/inconclusive sweat test results are reported, expanding the range of clinical expression associated with inheritance of this mutation. 3849+10kbC>T is one of several CF mutations that can result in atypical or variant forms of CF. For geneticists, the diagnosis of variant CF has implications for recurrence risk and prognosis counseling of the families of affected individuals, and possibly for CF carrier screening in the general population. 19 refs., 1 tab.

  20. Improved clinical and radiographic outcomes after treatment with ivacaftor in a young adult with cystic fibrosis with the P67L CFTR mutation.

    PubMed

    Yousef, Shatha; Solomon, George M; Brody, Alan; Rowe, Steven M; Colin, Andrew A

    2015-03-01

    The underlying cause of cystic fibrosis (CF) is the loss of epithelial chloride and bicarbonate transport due to mutations in the CF transmembrane conductance regulator (CFTR) gene encoding the CFTR protein. Ivacaftor is a gene-specific CFTR potentiator that augments in vivo chloride transport in CFTR mutations affecting channel gating. Originally approved for the G511D CFTR mutation, ivacaftor is now approved for eight additional alleles exhibiting gating defects and has also been tested in R117H, a CFTR mutation with residual function that exhibits abnormal gating. P67L is a class 4 conductance (nongating) mutation exhibiting residual CFTR function. We report marked clinical improvement, normalization of spirometry, and dramatic reduction in radiographic structural airway changes after > 1 year of treatment with ivacaftor in a young adult with the compound heterozygous genotype P67L/F508del CFTR. The case suggests that ivacaftor may have a potential benefit for patients with CF with nongating mutations.

  1. Imaging the Abdominal Manifestations of Cystic Fibrosis

    PubMed Central

    McDermott, S.; Chan, V. O.; Ridge, C. A.

    2017-01-01

    Cystic fibrosis (CF) is a multisystem disease with a range of abdominal manifestations including those involving the liver, pancreas, and kidneys. Recent advances in management of the respiratory complications of the disease has led to a greater life expectancy in patients with CF. Subsequently, there is increasing focus on the impact of abdominal disease on quality of life and survival. Liver cirrhosis is the most important extrapulmonary cause of death in CF, yet significant challenges remain in the diagnosis of CF related liver disease. The capacity to predict those patients at risk of developing cirrhosis remains a significant challenge. We review representative abdominal imaging findings in patients with CF selected from the records of two academic health centres, with a view to increasing familiarity with the abdominal manifestations of the disease. We review their presentation and expected imaging findings, with a focus on the challenges facing diagnosis of the hepatic manifestations of the disease. An increased familiarity with these abdominal manifestations will facilitate timely diagnosis and management, which is paramount to further improving outcomes for patients with cystic fibrosis. PMID:28250993

  2. Targeting ion channels in cystic fibrosis.

    PubMed

    Mall, Marcus A; Galietta, Luis J V

    2015-09-01

    Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause a characteristic defect in epithelial ion transport that plays a central role in the pathogenesis of cystic fibrosis (CF). Hence, pharmacological correction of this ion transport defect by targeting of mutant CFTR, or alternative ion channels that may compensate for CFTR dysfunction, has long been considered as an attractive approach to a causal therapy of this life-limiting disease. The recent introduction of the CFTR potentiator ivacaftor into the therapy of a subgroup of patients with specific CFTR mutations was a major milestone and enormous stimulus for seeking effective ion transport modulators for all patients with CF. In this review, we discuss recent breakthroughs and setbacks with CFTR modulators designed to rescue mutant CFTR including the common mutation F508del. Further, we examine the alternative chloride channels TMEM16A and SLC26A9, as well as the epithelial sodium channel ENaC as alternative targets in CF lung disease, which remains the major cause of morbidity and mortality in patients with CF. Finally, we will focus on the hurdles that still need to be overcome to make effective ion transport modulation therapies available for all patients with CF irrespective of their CFTR genotype.

  3. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

    PubMed Central

    Corradi, Valentina; Vergani, Paola; Tieleman, D. Peter

    2015-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter superfamily. CFTR controls the flow of anions through the apical membrane of epithelia. Dysfunctional CFTR causes the common lethal genetic disease cystic fibrosis. Transitions between open and closed states of CFTR are regulated by ATP binding and hydrolysis on the cytosolic nucleotide binding domains, which are coupled with the transmembrane (TM) domains forming the pathway for anion permeation. Lack of structural data hampers a global understanding of CFTR and thus the development of “rational” approaches directly targeting defective CFTR. In this work, we explored possible conformational states of the CFTR gating cycle by means of homology modeling. As templates, we used structures of homologous ABC transporters, namely TM(287–288), ABC-B10, McjD, and Sav1866. In the light of published experimental results, structural analysis of the transmembrane cavity suggests that the TM(287–288)-based CFTR model could correspond to a commonly occupied closed state, whereas the McjD-based model could represent an open state. The models capture the important role played by Phe-337 as a filter/gating residue and provide structural information on the conformational transition from closed to open channel. PMID:26229102

  4. Comparative biology of cystic fibrosis animal models.

    PubMed

    Fisher, John T; Zhang, Yulong; Engelhardt, John F

    2011-01-01

    Animal models of human diseases are critical for dissecting mechanisms of pathophysiology and developing therapies. In the context of cystic fibrosis (CF), mouse models have been the dominant species by which to study CF disease processes in vivo for the past two decades. Although much has been learned through these CF mouse models, limitations in the ability of this species to recapitulate spontaneous lung disease and several other organ abnormalities seen in CF humans have created a need for additional species on which to study CF. To this end, pig and ferret CF models have been generated by somatic cell nuclear transfer and are currently being characterized. These new larger animal models have phenotypes that appear to closely resemble human CF disease seen in newborns, and efforts to characterize their adult phenotypes are ongoing. This chapter will review current knowledge about comparative lung cell biology and cystic fibrosis transmembrane conductance regulator (CFTR) biology among mice, pigs, and ferrets that has implications for CF disease modeling in these species. We will focus on methods used to compare the biology and function of CFTR between these species and their relevance to phenotypes seen in the animal models. These cross-species comparisons and the development of both the pig and the ferret CF models may help elucidate pathophysiologic mechanisms of CF lung disease and lead to new therapeutic approaches.

  5. European Cystic Fibrosis Society Standards of Care: Framework for the Cystic Fibrosis Centre.

    PubMed

    Conway, Steven; Balfour-Lynn, Ian M; De Rijcke, Karleen; Drevinek, Pavel; Foweraker, Juliet; Havermans, Trudy; Heijerman, Harry; Lannefors, Louise; Lindblad, Anders; Macek, Milan; Madge, Sue; Moran, Maeve; Morrison, Lisa; Morton, Alison; Noordhoek, Jacquelien; Sands, Dorota; Vertommen, Anneke; Peckham, Daniel

    2014-05-01

    A significant increase in life expectancy in successive birth cohorts of people with cystic fibrosis (CF) is a result of more effective treatment for the disease. It is also now widely recognized that outcomes for patients cared for in specialist CF Centres are better than for those who are not. Key to the effectiveness of the specialist CF Centre is the multidisciplinary team (MDT), which should include consultants, clinical nurse specialist, microbiologist, physiotherapist, dietitian, pharmacist, clinical psychologist, social worker, clinical geneticist and allied healthcare professionals, all of whom should be experienced in CF care. Members of the MDT are also expected to keep up to date with developments in CF through continued professional development, attendance at conferences, auditing and involvement in research. Specialists CF Centres should also network with other Centres both nationally and internationally, and feed Centre data to registries in order to further the understanding of the disease. This paper provides a framework for the specialist CF Centre, including the organisation of the Centre and the individual roles of MDT members, as well as highlighting the value of CF organisations and disease registries.

  6. Recombinant Human DNase I Reduces the Viscosity of Cystic Fibrosis Sputum

    NASA Astrophysics Data System (ADS)

    Shak, Steven; Capon, Daniel J.; Hellmiss, Renate; Marsters, Scot A.; Baker, Carrie L.

    1990-12-01

    Respiratory distress and progressive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in the airways. More than 30 yr ago it was suggested that the large amounts of DNA in purulent secretions contribute to its viscosity and that bovine pancreatic DNase I could reduce the viscosity. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase) in the treatment of cystic fibrosis, we have cloned, sequenced, and expressed rhDNase. Catalytic amounts of rhDNase greatly reduce the viscosity of purulent cystic fibrosis sputum, transforming it within minutes from a nonflowing viscous gel to a flowing liquid. The reduction in viscosity is associated with a decrease in size of DNA in the sputum. Inhalation of a rhDNase aerosol may be a simple direct approach that will help individuals with cystic fibrosis and other patients with pneumonia or bronchitis to clear their airways of purulent secretions.

  7. Genotypes and phenotypes in cystic fibrosis and cystic fibrosis transmembrane regulator-related disorders.

    PubMed

    Bombieri, Cristina; Seia, Manuela; Castellani, Carlo

    2015-04-01

    Cystic fibrosis (CF) is characterized by remarkable variability in severity, rate of disease progression, and organ involvement. In spite of the considerable amount of data collected on the relationship between genotype and phenotype in CF, this is still a challenging matter of debate. Barriers to the interpretation of this connection are the large number of mutations in the CF transmembrane regulator (CFTR) gene, the difficulties in attributing several of them to a specific mode of dysfunction, and a limited number of the almost 2,000 mutations so far detected, which have been clinically annotated. In addition to that, the heterogeneity of clinical manifestations in individuals with the same CFTR genotypes indicates that disease severity is modulated by other genes and by environmental factors, of which the most relevant is possibly treatment in its aspects of appropriateness, early start in life, and adherence. The phenotype variability extends to conditions, named CFTR-related disorders, which are connected with CFTR dysfunction, but do not satisfy diagnostic criteria for CF. The current level of knowledge does not allow use of the CFTR genotype to predict individual outcome and cannot be used as an indicator of CF prognosis. This might change with the development of treatments targeting specific mutations and possibly capable of changing the natural history of the disease.

  8. Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.

    PubMed

    Schwarzenberg, Sarah Jane; Hempstead, Sarah E; McDonald, Catherine M; Powers, Scott W; Wooldridge, Jamie; Blair, Shaina; Freedman, Steven; Harrington, Elaine; Murphy, Peter J; Palmer, Lena; Schrader, Amy E; Shiel, Kyle; Sullivan, Jillian; Wallentine, Melissa; Marshall, Bruce C; Leonard, Amanda Radmer

    2016-11-01

    Nutrition is integral to the care of individuals with cystic fibrosis (CF). Better nutritional status is associated with improved pulmonary function. In some individuals with CF, enteral tube feeding can be useful in achieving optimal nutritional status. Current nutrition guidelines do not include detailed recommendations for enteral tube feeding. The Cystic Fibrosis Foundation convened an expert panel to develop enteral tube feeding recommendations based on a systematic review of the evidence and expert opinion. These guidelines address when to consider enteral tube feeding, assessment of confounding causes of poor nutrition in CF, preparation of the patient for placement of the enteral feeding tube, management of the tube after placement and education about enteral feeding. These recommendations are intended to guide the CF care team, individuals with CF, and their families through the enteral tube feeding process.

  9. Air Trapping and Airflow Obstruction in Newborn Cystic Fibrosis Piglets

    PubMed Central

    Adam, Ryan J.; Michalski, Andrew S.; Bauer, Christian; Abou Alaiwa, Mahmoud H.; Gross, Thomas J.; Awadalla, Maged S.; Bouzek, Drake C.; Gansemer, Nicholas D.; Taft, Peter J.; Hoegger, Mark J.; Diwakar, Amit; Ochs, Matthias; Reinhardt, Joseph M.; Hoffman, Eric A.; Beichel, Reinhard R.; Meyerholz, David K.

    2013-01-01

    Rationale: Air trapping and airflow obstruction are being increasingly identified in infants with cystic fibrosis. These findings are commonly attributed to airway infection, inflammation, and mucus buildup. Objectives: To learn if air trapping and airflow obstruction are present before the onset of airway infection and inflammation in cystic fibrosis. Methods: On the day they are born, piglets with cystic fibrosis lack airway infection and inflammation. Therefore, we used newborn wild-type piglets and piglets with cystic fibrosis to assess air trapping, airway size, and lung volume with inspiratory and expiratory X-ray computed tomography scans. Micro–computed tomography scanning was used to assess more distal airway sizes. Airway resistance was determined with a mechanical ventilator. Mean linear intercept and alveolar surface area were determined using stereologic methods. Measurements and Main Results: On the day they were born, piglets with cystic fibrosis exhibited air trapping more frequently than wild-type piglets (75% vs. 12.5%, respectively). Moreover, newborn piglets with cystic fibrosis had increased airway resistance that was accompanied by luminal size reduction in the trachea, mainstem bronchi, and proximal airways. In contrast, mean linear intercept length, alveolar surface area, and lung volume were similar between both genotypes. Conclusions: The presence of air trapping, airflow obstruction, and airway size reduction in newborn piglets with cystic fibrosis before the onset of airway infection, inflammation, and mucus accumulation indicates that cystic fibrosis impacts airway development. Our findings suggest that early airflow obstruction and air trapping in infants with cystic fibrosis might, in part, be caused by congenital airway abnormalities. PMID:24168209

  10. Cystic Fibrosis Patents: A Case Study of Successful Licensing.

    PubMed

    Minear, Mollie A; Kapustij, Cristina; Boden, Kaeleen; Chandrasekharan, Subhashini; Cook-Deegan, Robert

    2013-03-01

    From 2006-2010, Duke University's Center for Public Genomics prepared eight case studies examining the effects of gene patent licensing practices on clinical access to genetic testing for ten clinical conditions. One of these case studies focused on the successful licensing practices employed by the University of Michigan and the Hospital for Sick Children in Toronto for patents covering the CFTR gene and its ΔF508 mutation that causes a majority of cystic fibrosis cases. Since the licensing of these patents has not impeded clinical access to genetic testing, we sought to understand how this successful licensing model was developed and whether it might be applicable to other gene patents. We interviewed four key players who either were involved in the initial discussions regarding the structure of licensing or who have recently managed the licenses and collected related documents. Important features of the licensing planning process included thoughtful consideration of potential uses of the patent; anticipation of future scientific discoveries and technological advances; engagement of relevant stakeholders, including the Cystic Fibrosis Foundation; and using separate licenses for in-house diagnostics versus kit manufacture. These features led to the development of a licensing model that has not only allowed the patent holders to avoid the controversy that has plagued other gene patents, but has also allowed research, development of new therapeutics, and wide-spread dissemination of genetic testing for cystic fibrosis. Although this licensing model may not be applicable to all gene patents, it serves as a model in which gene patent licensing can successfully enable innovation, investment in therapeutics research, and protect intellectual property while respecting the needs of patients, scientists, and public health.

  11. Cystic Fibrosis Patents: A Case Study of Successful Licensing

    PubMed Central

    Minear, Mollie A.; Kapustij, Cristina; Boden, Kaeleen; Chandrasekharan, Subhashini; Cook-Deegan, Robert

    2013-01-01

    From 2006–2010, Duke University’s Center for Public Genomics prepared eight case studies examining the effects of gene patent licensing practices on clinical access to genetic testing for ten clinical conditions. One of these case studies focused on the successful licensing practices employed by the University of Michigan and the Hospital for Sick Children in Toronto for patents covering the CFTR gene and its ΔF508 mutation that causes a majority of cystic fibrosis cases. Since the licensing of these patents has not impeded clinical access to genetic testing, we sought to understand how this successful licensing model was developed and whether it might be applicable to other gene patents. We interviewed four key players who either were involved in the initial discussions regarding the structure of licensing or who have recently managed the licenses and collected related documents. Important features of the licensing planning process included thoughtful consideration of potential uses of the patent; anticipation of future scientific discoveries and technological advances; engagement of relevant stakeholders, including the Cystic Fibrosis Foundation; and using separate licenses for in-house diagnostics versus kit manufacture. These features led to the development of a licensing model that has not only allowed the patent holders to avoid the controversy that has plagued other gene patents, but has also allowed research, development of new therapeutics, and wide-spread dissemination of genetic testing for cystic fibrosis. Although this licensing model may not be applicable to all gene patents, it serves as a model in which gene patent licensing can successfully enable innovation, investment in therapeutics research, and protect intellectual property while respecting the needs of patients, scientists, and public health. PMID:24231943

  12. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives

    PubMed Central

    Schmidt, Béla Z; Haaf, Jérémy B; Leal, Teresinha; Noel, Sabrina

    2016-01-01

    Mutations of the CFTR gene cause cystic fibrosis (CF), the most common recessive monogenic disease worldwide. These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction. In spite of great advances in early and multidisciplinary medical care, and in our understanding of the pathophysiology, CF is still considerably reducing the life expectancy of patients. This review highlights the current development in pharmacological modulators of CFTR, which aim at rescuing the expression and/or function of mutated CFTR. While only Kalydeco® and Orkambi® are currently available to patients, many other families of CFTR modulators are undergoing preclinical and clinical investigations. Drug repositioning and personalized medicine are particularly detailed in this review as they represent the most promising strategies for restoring CFTR function in CF. PMID:27703398

  13. Nutrition and growth in cystic fibrosis.

    PubMed

    Hankard, Régis; Munck, Anne; Navarro, Jean

    2002-01-01

    Malnutrition is a common complication of chronic diseases in children and may lead to growth impairment (stunting). Malnutrition in cystic fibrosis (CF) results from increased energy expenditure, decreased energy intakes, malabsorption of ingested nutrients because of pancreatic insufficiency and chronic inflammation. Malnutrition and high levels of inflammatory cytokines affect IGF-1 production through interrelated mechanisms. Nutritional support was shown to improve both nutritional status and outcome in CF. However, some nutrients have a direct effect on the disease. n-3 fatty acids supplementation is able to correct lipid abnormalities resulting from a primary mechanism. Moreover, n-3 fatty acids have a direct effect on the inflammatory response, decreasing eicosanoid synthesis and modulating nuclear transcriptional factors nuclear factor kappaB and peroxisome proliferator-activated receptors gamma. Nutritional support may be considered part of the care of the CF patient together with antibiotics, pancreatic enzymes and physiotherapy, influencing significantly the evolution of the disease.

  14. High dose Nutrizym 22 in cystic fibrosis.

    PubMed

    Shah, A; Dinwiddie, R; Madge, S; Prescott, P; Hudson, G

    1993-09-01

    New high dose pancreatic enzyme preparations could be potentially helpful to cystic fibrosis (CF) patients. The purpose of this study was to compare the efficacy of the new high dose pancreatic enzyme preparation, Nutrizym 22 with the standard preparation Nutrizym GR. Twenty-five CF children (aged 7-16 years) entered the study and 22 completed it; 3 did not, due to non-compliance. All were taking Nutrizym GR for at least 2 weeks before entering the study. A randomised double blind, crossover method using standard Nutrizym GR or double strength Nutrizym 22 capsules was carried out over two consecutive 14-day periods. Crossover analyses of variance showed no statistically significant differences in actual weight gain, appetite, abdominal pain, stool consistency or faecal fat during the prestudy and study periods. It is concluded that half the capsule numbers of the high strength preparation are just as effective as the standard capsule dosage.

  15. Genetic therapies for cystic fibrosis lung disease

    PubMed Central

    Sinn, Patrick L.; Anthony, Reshma M.; McCray, Paul B.

    2011-01-01

    The aim of gene therapy for cystic fibrosis (CF) lung disease is to efficiently and safely express the CF transmembrane conductance regulator (CFTR) in the appropriate pulmonary cell types. Although CF patients experience multi-organ disease, the chronic bacterial lung infections and associated inflammation are the primary cause of shortened life expectancy. Gene transfer-based therapeutic approaches are feasible, in part, because the airway epithelium is directly accessible by aerosol delivery or instillation. Improvements in standard delivery vectors and the development of novel vectors, as well as emerging technologies and new animal models, are propelling exciting new research forward. Here, we review recent developments that are advancing this field of investigation. PMID:21422098

  16. Scoliosis in cystic fibrosis - an appraisal

    SciTech Connect

    Paling, M.R.; Spasovsky-Chernick, M.

    1982-03-01

    An unusually high prevalence (10%) of scoliosis is described in a series of 151 patients aged four years and older with cystic fibrosis. The scolioses were of the late onset (juvenile and adolescent) type, being typically thoracic with the curve convex to the right, although there was no significant preference for either sex. No direct relationship was found between the spinal curvature and the severity or distribution of the lung disease, although the worse scolioses tended to occur in patients with relatively severe pulmonary involvement. There was no evidence of metabolic bone disease as a predisposing cause. Some indication of a familial tendency towards scoliosis was apparent, and a genetic or constitutional basis is postulated with an unknown precipitating factor.

  17. Fungi in the cystic fibrosis lung: bystanders or pathogens?

    PubMed

    Chotirmall, Sanjay H; McElvaney, Noel G

    2014-07-01

    Improvement to the life expectancy of people with cystic fibrosis (PWCF) brings about novel challenges including the need for evaluation of the role of fungi in the cystic fibrosis (CF) lung. To determine if such organisms represent bystanders or pathogens affecting clinical outcomes we review the existing knowledge from a clinical, biochemical, inflammatory and immunological perspective. The prevalence and importance of fungi in the CF airway has likely been underestimated with the most frequently isolated filamentous fungi being Aspergillus fumigatus and Scedosporium apiospermum and the major yeast Candida albicans. Developing non-culture based microbiological methods for fungal detection has improved both our classification and understanding of their clinical consequences including localized, allergic and systemic infections. Cross-kingdom interaction between bacteria and fungi are discussed as is the role of biofilms further affecting clinical outcome. A combination of host and pathogen-derived factors determines if a particular fungus represents a commensal, colonizer or pathogen in the setting of CF. The underlying immune state, disease severity and treatment burden represent key host variables whilst fungal type, form, chronicity and virulence including the ability to evade immune recognition determines the pathogenic potential of a specific fungus at a particular point in time. Further research in this emerging field is warranted to fully elucidate the spectrum of disease conferred by the presence of fungi in the CF airway and the indications for therapeutic interventions.

  18. Modular microfluidic system as a model of cystic fibrosis airways

    PubMed Central

    Skolimowski, M.; Weiss Nielsen, M.; Abeille, F.; Skafte-Pedersen, P.; Sabourin, D.; Fercher, A.; Papkovsky, D.; Molin, S.; Taboryski, R.; Sternberg, C.; Dufva, M.; Geschke, O.; Emnéus, J.

    2012-01-01

    A modular microfluidic airways model system that can simulate the changes in oxygen tension in different compartments of the cystic fibrosis (CF) airways was designed, developed, and tested. The fully reconfigurable system composed of modules with different functionalities: multichannel peristaltic pumps, bubble traps, gas exchange chip, and cell culture chambers. We have successfully applied this system for studying the antibiotic therapy of Pseudomonas aeruginosa, the bacteria mainly responsible for morbidity and mortality in cystic fibrosis, in different oxygen environments. Furthermore, we have mimicked the bacterial reinoculation of the aerobic compartments (lower respiratory tract) from the anaerobic compartments (cystic fibrosis sinuses) following an antibiotic treatment. This effect is hypothesised as the one on the main reasons for recurrent lung infections in cystic fibrosis patients. PMID:23908680

  19. Cystic fibrosis-related diabetes: a distinct condition.

    PubMed

    Cano Megías, Marta; González Albarrán, Olga

    2015-01-01

    Cystic fibrosis is the most common fatal inherited autosomal recessive disease in Caucasians, affecting approximately one out of every 2,000 births. Survival of patients with cystic fibrosis has significantly improved due to advances in respiratory and nutritional care, and their current average life expectancy is 30-40 years. Development of cystic fibrosis-related diabetes is a comorbidity that increases with age and may reach a prevalence up to 50% in adults. Its development is associated to impaired lung function and nutritional status, and early diagnosis and treatment are therefore essential to improve quality of life and performance status. Insulin therapy for diabetes and other early carbohydrate metabolism disorders may improve lung function and nutritional status of patients with cystic fibrosis.

  20. Treatment and prognosis of rectal prolapse in cystic fibrosis.

    PubMed

    Stern, R C; Izant, R J; Boat, T F; Wood, R E; Matthews, L W; Doershuk, C F

    1982-04-01

    Rectal prolapse occurred in 112 (18.5%) of 605 cystic fibrosis patients. In 48 patients prolapse preceded diagnosis of cystic fibrosis, but physicians (pediatricians, pediatric and general surgeons, and proctologists) rarely appreciated its importance as a symptom of this disease. Prolapses frequently cease with institution of pancreatic enzyme replacement therapy following diagnosis of cystic fibrosis. However, even when the disease remains undiagnosed, the symptom is often transient and frequently resolves at 3-5 yr of age. Prolapse occurring initially after cystic fibrosis is diagnosed rarely responds to manipulation of diet or enzyme doses. Many patients develop a method of reduction which involves voluntary abdominal, perineal, and gluteal muscles and does not require manual pressure on the prolapsed segment. Most patients do not need specific treatment for the prolapse. Surgery is rarely necessary. A sweat test should be obtained on any child who has had even a single episode of rectal prolapse.

  1. Reduced upper airway nitric oxide in cystic fibrosis.

    PubMed Central

    Balfour-Lynn, I M; Laverty, A; Dinwiddie, R

    1996-01-01

    Nitric oxide (NO) produced within the respiratory tract is detectable in exhaled and nasal air. Its synthesis may be induced by inflammatory cytokines and reduced by glucocorticoids. Increased concentrations have been found in asthma and bronchiectasis. In this study, NO concentrations were determined in 63 children with cystic fibrosis, of whom 13 were on inhaled steroids (mean age 13.3 years) and 50 were not (mean age 12.3 years); 57 normal children (mean age 12.2 years) were also studied. NO was measured by chemiluminescence analyser, exhaled NO following a relaxed vital capacity manoeuvre, and nasal NO with the breath held following a full inspiration. Mean concentration of exhaled NO in cystic fibrosis patients (no steroids) was 4.7 parts per billion (ppb) (95% confidence interval (CI) 4.0 to 5.3); this did not differ from values in normal children (mean 4.8 ppb, 95% CI 3.8 to 5.8) or in cystic fibrosis patients on inhaled steroids (mean 3.6 ppb, 95% CI 2.5 to 4.8). Nasal concentrations were significantly lower in cystic fibrosis patients, with or without inhaled steroids, than in normal children (cystic fibrosis, no inhaled steroids: 460 ppb, 95% CI 399 to 520; cystic fibrosis, inhaled steroids: 522 ppb, 95% CI 313 to 730, v normal children: 1024 ppb, 95% CI 896 to 1152, p < 0.0001). Considering the inflammatory nature of cystic fibrosis, it is surprising exhaled NO levels were not increased, but this may have been due to alteration in NO diffusion through thick mucus. The low nasal NO concentrations, which are probably the result of impaired flow from the paranasal sinuses, may contribute to the recurrent respiratory infections typical of cystic fibrosis. PMID:8984918

  2. The novel complex allele [A238V;F508del] of the CFTR gene: clinical phenotype and possible implications for cystic fibrosis etiological therapies.

    PubMed

    Diana, Anna; Polizzi, Angela Maria; Santostasi, Teresa; Ratclif, Luigi; Pantaleo, Maria Giuseppina; Leonetti, Giuseppina; Iusco, Danila Rosa; Gallo, Crescenzio; Conese, Massimo; Manca, Antonio

    2016-06-01

    Few mutations in cis have been annotated for F508del homozygous patients. Southern Italy patients who at a first analysis appeared homozygous for the F508del mutation (n=63) or compound heterozygous for the F508del and another mutation in the cystic fibrosis transmembrane conductance regulator gene (n=155) were searched for the A238V mutation in exon 6. The allelic frequency of the complex allele [A238V;F508del] was 0.04. When the whole data set was used (comprised also of 56 F508del/F508del and 34 F508del/other mutation controls), no differences reached the statistical significance in the clinical parameters, except chloride concentrations which were lower in [A238V;F508del]/other mutation compared with F508del/other mutation (P=0.03). The two study groups presented less complications than the control groups. Within the minimal data set (34 F508del/F508del, 27 F508del/other mutation, 4 [A238V;F508del]/F508del cases and 5 [A238V;F508del]/other mutation cases); that is, presenting all the variables in each patient, forced expiratory volume in 1 s and forced vital capacity presented a trend to lower levels in the study groups in comparison with the F508del/F508del group, and C-reactive protein approximated statistically significant higher levels in the [A238V;F508del]/other mutation as compared with F508del/F508del patients (P=0.09). The analysis of statistical dependence among the variables showed a significant anticorrelation between chloride and body mass index in the [A238V;F508del]/other mutation group. In conclusion, the complex allele [A238V;F508del] seems to be associated with less general complications than in the control groups, on the other hand possibly giving a worse pulmonary phenotype and higher systemic/local inflammatory response. These findings have implications for the correct recruitment and clinical response of F508del patients in the clinical trials testing the new etiological drugs for cystic fibrosis.

  3. Reduced Arylsulfatase B Activity in Leukocytes from Cystic Fibrosis Patients

    PubMed Central

    Sharma, Girish; Burke, Jenifer; Bhattacharyya, Sumit; Sharma, Neha; Katyal, Shivani; Park, R. Lucy; Tobacman, Joanne

    2013-01-01

    Summary The enzyme Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) removes 4-sulfate groups from chondroitin-4-sulfate and dermatan sulfate and is required for the degradation of these sulfated glycosaminoglycans (GAGs). Since these GAGs accumulate in patients with Cystic Fibrosis (CF), we investigated the activity of ARSB in leukocytes of patients with CF, to consider if reduced activity of ARSB might contribute to the pathophysiology of CF. Previous cell-based experiments had demonstrated that when the deficiency of the cystic fibrosis transmembrane regulator (CFTR) was corrected in bronchial epithelial cells, the ARSB activity increased significantly. De-identified, citrated blood samples were collected from 16 children with cystic fibrosis and 31 control subjects, seen in the Pediatric Clinic at Rush University Medical Center. Polymorphonuclear (PMN) and mononuclear cell (MC) populations were separated by density gradient, and blinded determinations of ARSB activity were performed using the exogenous substrate 4-methylumbilliferyl sulfate. Interleukin-6 was measured in the plasma samples by ELISA. ARSB activity was significantly less in the PMN and MC from the CF patients than controls (p<0.0001, unpaired t-test, two-tailed). Interleukin-6 levels in plasma were significantly greater in the CF population (p<0.001). Mean age, age range, and male:female ratio of CF patients and controls were similar, and no association of ARSB activity with age, gender, or CFTR genotype was evident. Since recombinant human ARSB is used successfully for replacement therapy in Mucopolysaccharidosis VI, it may be useful to restore ARSB activity to normal levels and increase degradation of sulfated GAGs in CF patients. PMID:22550062

  4. Changes of CFTR functional measurements and clinical improvements in cystic fibrosis patients with non p.Gly551Asp gating mutations treated with ivacaftor.

    PubMed

    Mesbahi, Myriam; Shteinberg, Michal; Wilschanski, Michael; Hatton, Aurelie; Nguyen-Khoa, Thao; Friedman, Hannah; Cohen, Michael; Escabasse, Virginie; Le Bourgeois, Muriel; Lucidi, Vicenzina; Sermet-Gaudelus, Isabelle; Bassinet, Laurence; Livnat, Galit

    2017-01-01

    Ivacaftor, a CFTR potentiator, has been found to improve CFTR function and clinical outcomes in patients with cystic fibrosis (CF) gating mutations. We investigated the effects of ivacaftor on CFTR functional measurement in CF patients carrying gating mutations other than p.Gly551Asp. Two siblings aged 13 and 12 carrying the p.Ser549Asn mutation, two sisters (45 and 43years old) compound heterozygotes for p.Asp1152His and p.Gly1244Glu, a 37year old man homozygous for the p.Gly1244Glu mutation, and a 7year old girl with p.Arg352Gln and p.Gly1244Glu mutations commenced treatment with ivacaftor. NPD was performed in all the patients and approached normal for four patients who had also clinical improvement (p.Ser549Asn compound heterozygotes, and p.Asp1152His/p.Gly1244Glu siblings). Beta-adrenergic sweat chloride secretion performed in thep.Asp1152His/p.Gly1244Glu patients improved significantly. The p.Gly1244Glu mutation homozygous patient, who had undergone an ileal resection with ileostomy and enterocutaneous fistula, did not respond clinically to ivacaftor and did not modify his sweat test. These results highlight the importance of different CFTR activity measurements to explore CFTR modulator efficacy.

  5. Hormonal abnormalities of the pancreas and gut in cystic fibrosis.

    PubMed

    Adrian, T E; McKiernan, J; Johnstone, D I; Hiller, E J; Vyas, H; Sarson, D L; Bloom, S R

    1980-09-01

    We have investigated the effect of cystic fibrosis on alimentary hormones in 10 children by measuring the pancreatic and gut hormone rsponse to a milk drink. Plasma insulin and gastric inhibitory peptide were both significantly reduced (P < 0.05 and P < 0.005, respectively, at 15 min) in the patients with cystic fibrosis, compared with controls, even though the early glucose rise was greater in the former group (P < 0.05 at 15 min). Fasting levels of pancreatic polypeptide were significantly lower in the fibrocystic children (P < 0.01), and the normal response to milk was completely abolished in these patients (P < 0.001). Fasting plasma enteroglucagon concentrations were grossly abolished in the cystic fibrosis patients (P < 0.001) and these remained elevated throughout the test. No significant differences were seen in basal or postmilk responses of plasma glucagon, gastrin, secretin, vasoactive intestinal peptide, or motilin in cystic fibrosis. It would thus appear that the pancreatic polypeptide cell is more susceptible to the effects of the disease process than the beta or alpha cell in cystic fibrosis. Some aspects of the abnormalities in the gastrointestinal endocrine system were similar to those seen in celiac disease and tropical sprue and may, therefore, effect a similar hormonal response in these patients with cystic fibrosis to those with mucosal damage.

  6. Mechanisms of gastro-oesophageal reflux in cystic fibrosis.

    PubMed Central

    Cucchiara, S; Santamaria, F; Andreotti, M R; Minella, R; Ercolini, P; Oggero, V; de Ritis, G

    1991-01-01

    Abnormal degrees of gastro-oesophageal reflux (GOR) were detected by 24 hour intraoesophageal pH measurement in 12 of 14 children (mean age 7.9 years; range 5 months-16 years) affected by cystic fibrosis and complaining of symptoms suggesting GOR. These patients underwent combined recording of distal oesophageal motility and intraluminal pH in order to investigate mechanisms of GOR. Inappropriate lower oesophageal sphincter relaxation was the most common mechanism of reflux in all patients. Other mechanisms (appropriate relaxation or lowered pressure of the lower oesophageal sphincter, increased intragastric pressure) were detected less frequently. Frequency of inappropriate lower oesophageal sphincter relaxations was significantly higher in patients with cystic fibrosis than in other study groups (symptomatic GOR, GOR disease complicated by respiratory complaints). Inappropriate lower oesophageal sphincter relaxations occurred with the same frequency in patients with cystic fibrosis and in a group of children with GOR disease complicated by oesophagitis. Abnormalities of distal oesophageal contractions such as decreased amplitude or uncoordinated waves were also recorded in cystic fibrosis patients. Seven patients with cystic fibrosis completed a therapeutic trial for eight weeks consisting of postural treatment and oral cisapride, a new prokinetic drug. The oesophageal acid exposure improved in only three patients. We conclude that pathologic GOR is commonly associated with cystic fibrosis. The predominant reflux mechanism in these patients is a transient inappropriate lower oesophageal sphincter relaxation rather than a low steady state basal lower oesophageal sphincter pressure. PMID:2039253

  7. Respiratory infections in patients with cystic fibrosis undergoing lung transplantation.

    PubMed

    Lobo, Leonard J; Noone, Peadar G

    2014-01-01

    Cystic fibrosis is an inherited disease characterised by chronic respiratory infections associated with bronchiectasis. Lung transplantation has helped to extend the lives of patients with cystic fibrosis who have advanced lung disease. However, persistent, recurrent, and newly acquired infections can be problematic. Classic cystic fibrosis-associated organisms, such as Staphylococcus aureus and Pseudomonas aeruginosa, are generally manageable post-transplantation, and are associated with favourable outcomes. Burkholderia cenocepacia poses particular challenges, although other Burkholderia species are less problematic. Despite concerns about non-tuberculous mycobacteria, especially Mycobacterium abscessus, post-transplantation survival has not been definitively shown to be less than average in patients with these infections. Fungal species can be prevalent before and after transplantation and are associated with high morbidity, so should be treated aggressively. Appropriate viral screening and antiviral prophylaxis are necessary to prevent infection with and reactivation of Epstein-Barr virus and cytomegalovirus and their associated complications. Awareness of drug pharmacokinetics and interactions in cystic fibrosis is crucial to prevent toxic effects and subtherapeutic or supratherapeutic drug dosing. With the large range of potential infectious organisms in patients with cystic fibrosis, infection control in hospital and outpatient settings is important. Despite its complexity, lung transplantation in the cystic fibrosis population is safe, with good outcomes if the clinician is aware of all the potential pathogens and remains vigilant by means of surveillance and proactive treatment.

  8. Increased oral bioavailability of ciprofloxacin in cystic fibrosis patients.

    PubMed Central

    Christensson, B A; Nilsson-Ehle, I; Ljungberg, B; Lindblad, A; Malmborg, A S; Hjelte, L; Strandvik, B

    1992-01-01

    The altered pharmacokinetic properties of, e.g., aminoglycosides in cystic fibrosis patients have to be considered when pulmonary exacerbations are treated. Since reported data on ciprofloxacin, a fluorinated quinolone, are conflicting, we compared intravenous and oral administration in cystic fibrosis patients when treating them for mild symptoms of pulmonary infection. All of the patients were colonized with Pseudomonas species. Ciprofloxacin was administered orally (15 mg/kg of body weight) or intravenously (6 mg/kg) twice a day for at least 10 days during separate treatment periods. Five healthy volunteers received single intravenous and oral doses. Pharmacokinetic evaluations were performed at first dose and at steady state. The results showed that cystic fibrosis patients have increased oral bioavailability of ciprofloxacin (80% in cystic fibrosis patients versus 57% in volunteers) and increased total clearance (688 ml/min in CF patients versus 528 ml/min in volunteers). Our data indicate that the pharmacokinetic properties of ciprofloxacin are altered in cystic fibrosis patients with mild symptoms of pulmonary exacerbations and that the changes most probably are due to cystic fibrosis per se or to the impact of chronic infection. PMID:1489195

  9. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary.

    PubMed

    Floto, R Andres; Olivier, Kenneth N; Saiman, Lisa; Daley, Charles L; Herrmann, Jean-Louis; Nick, Jerry A; Noone, Peadar G; Bilton, Diana; Corris, Paul; Gibson, Ronald L; Hempstead, Sarah E; Koetz, Karsten; Sabadosa, Kathryn A; Sermet-Gaudelus, Isabelle; Smyth, Alan R; van Ingen, Jakko; Wallace, Richard J; Winthrop, Kevin L; Marshall, Bruce C; Haworth, Charles S

    2016-01-01

    Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease, such as cystic fibrosis (CF). Pulmonary disease (PD) caused by NTM has emerged as a major threat to the health of individuals with CF, but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened a panel of 19 experts to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM-PD in individuals with CF. PICO (population, intervention, comparison, outcome) methodology and systematic literature reviews were employed to inform draft recommendations, which were then modified to achieve consensus and subsequently circulated for public consultation within the USA and European CF communities. We have thus generated a series of pragmatic, evidence-based recommendations as an initial step in optimising management for this challenging condition.

  10. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary

    PubMed Central

    Olivier, Kenneth N; Saiman, Lisa; Daley, Charles L; Herrmann, Jean-Louis; Nick, Jerry A; Noone, Peadar G; Bilton, Diana; Corris, Paul; Gibson, Ronald L; Hempstead, Sarah E; Koetz, Karsten; Sabadosa, Kathryn A; Sermet-Gaudelus, Isabelle; Smyth, Alan R; van Ingen, Jakko; Wallace, Richard J; Winthrop, Kevin L; Marshall, Bruce C; Haworth, Charles S

    2016-01-01

    Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease, such as cystic fibrosis (CF). Pulmonary disease (PD) caused by NTM has emerged as a major threat to the health of individuals with CF, but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened a panel of 19 experts to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM-PD in individuals with CF. PICO (population, intervention, comparison, outcome) methodology and systematic literature reviews were employed to inform draft recommendations, which were then modified to achieve consensus and subsequently circulated for public consultation within the USA and European CF communities. We have thus generated a series of pragmatic, evidence-based recommendations as an initial step in optimising management for this challenging condition. PMID:26678435

  11. Cystic fibrosis sputum: a barrier to the transport of nanospheres.

    PubMed

    Sanders, N N; De Smedt, S C; Van Rompaey, E; Simoens, P; De Baets, F; Demeester, J

    2000-11-01

    Cystic fibrosis (CF) is characterized by the presence of a viscoelastic mucus layer in the upper airways and bronchi. The underlying problem is a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator protein. Clinical studies of gene transfer for CF are ongoing. For gene delivery to the airways of CF patients to be effective, the mucus covering the target cells must be overcome. We therefore examined the extent to which CF sputum presents a physical barrier to the transport of nanospheres of a size comparable to that of lipoplexes and other transfection systems currently being clinically evaluated for CF gene therapy. We observed that an extremely low percentage of nanospheres (< 0.3%) moved through a 220-microm-thick CF sputum layer after 150 min. The largest nanospheres studied (560 nm) were almost completely blocked by the sputum, whereas the smaller nanospheres (124 nm) were retarded only by a factor of 1.3 as compared with buffer. Surprisingly, the nanospheres diffused significantly more easily through the more viscoelastic sputum samples. We hypothesize that the structure of the network in sputum becomes more macroporous when the sputum becomes more viscoelastic. Sputum from a patient with chronic obstructive pulmonary disease retarded the transport of nanospheres to the same extent as did CF sputum. When directly mixed with CF sputum, recombinant human deoxyribonuclease I moderately facilitated the transport of nanospheres through CF sputum.

  12. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells

    NASA Astrophysics Data System (ADS)

    Rich, Devra P.; Anderson, Matthew P.; Gregory, Richard J.; Cheng, Seng H.; Paul, Sucharita; Jefferson, Douglas M.; McCann, John D.; Klinger, Katherine W.; Smith, Alan E.; Welsh, Michael J.

    1990-09-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in cultured cystic fibrosis airway epithelial cells and Cl- channel activation assessed in single cells using a fluorescence microscopic assay and the patch-clamp technique. Expression of CFTR, but not of a mutant form of CFTR (ΔF508), corrected the Cl- channel defect. Correction of the phenotypic defect demonstrates a causal relationship between mutations in the CFTR gene and defective Cl- transport which is the hallmark of the disease.

  13. Lung Transplantation and Survival in Children with Cystic Fibrosis

    PubMed Central

    Liou, Theodore G.; Adler, Frederick R.; Cox, David R.; Cahill, Barbara C.

    2008-01-01

    BACKGROUND The effects of lung transplantation on the survival and quality of life in children with cystic fibrosis are uncertain. METHODS We used data from the U.S. Cystic Fibrosis Foundation Patient Registry and from the Organ Procurement and Transplantation Network to identify children with cystic fibrosis who were on the waiting list for lung transplantation during the period from 1992 through 2002. We performed proportional-hazards survival modeling, using multiple clinically relevant covariates that were available before the children were on the waiting list and the interactions of these covariates with lung transplantation as a time-dependent covariate. The data were insufficient in quality and quantity for a retrospective quality-of-life analysis. RESULTS A total of 248 of the 514 children on the waiting list underwent lung transplantation in the United States during the period from 1992 through 2002. Proportional-hazards modeling identified four variables besides transplantation that were associated with changes in survival. Burkholderia cepacia infection decreased survival, regardless of whether the patient underwent transplantation. A diagnosis of diabetes before the patient was placed on the waiting list decreased survival while the patient was on the waiting list but did not decrease survival after transplantation, whereas older age did not affect waiting-list survival but decreased post-transplantation survival. Staphylococcus aureus infection increased waiting-list survival but decreased post-transplantation survival. Using age, diabetes status, and S. aureus infection status as covariates, we estimated the effect of transplantation on survival for each patient group, expressed as a hazard factor of less than 1 for a benefit and more than 1 for a risk of harm. Five patients had a significant estimated benefit, 315 patients had a significant risk of harm, 76 patients had an insignificant benefit, and 118 patients had an insignificant risk of harm

  14. Lung Transplantation and Survival in Children with Cystic Fibrosis

    PubMed Central

    Liou, Theodore G.; Adler, Frederick R.; Cox, David R.; Cahill, Barbara C.

    2016-01-01

    BACKGROUND The effects of lung transplantation on the survival and quality of life in children with cystic fibrosis are uncertain. METHODS We used data from the U.S. Cystic Fibrosis Foundation Patient Registry and from the Organ Procurement and Transplantation Network to identify children with cystic fibrosis who were on the waiting list for lung transplantation during the period from 1992 through 2002. We performed proportional-hazards survival modeling, using multiple clinically relevant covariates that were available before the children were on the waiting list and the interactions of these covariates with lung transplantation as a time-dependent covariate. The data were insufficient in quality and quantity for a retrospective quality-of-life analysis. RESULTS A total of 248 of the 514 children on the waiting list underwent lung transplantation in the United States during the period from 1992 through 2002. Proportional-hazards modeling identified four variables besides transplantation that were associated with changes in survival. Burkholderia cepacia infection was associated with a trend toward decreased survival, regardless of whether the patient underwent transplantation. A diagnosis of diabetes before the patient was placed on the waiting list decreased survival while the patient was on the waiting list but did not decrease survival after transplantation, whereas older age did not affect waiting-list survival but decreased post-transplantation survival. Staphylococcus aureus infection increased waiting-list survival but decreased post-transplantation survival. Using age, diabetes status, and S. aureus infection status as covariates, we estimated the effect of transplantation on survival for each patient group, expressed as a hazard factor of less than 1 for a benefit and more than 1 for a risk of harm. Five patients had a significant estimated benefit, 283 patients had a significant risk of harm, 102 patients had an insignificant benefit, and 124 patients

  15. Achromobacter xylosoxidans genomic characterization and correlation of randomly amplified polymorphic DNA profiles with relevant clinical features [corrected] of cystic fibrosis patients.

    PubMed

    Magni, Annarita; Trancassini, Maria; Varesi, Paola; Iebba, Valerio; Curci, Anna; Pecoraro, Claudia; Cimino, Giuseppe; Schippa, Serena; Quattrucci, Serena

    2010-04-01

    Achromobacter xylosoxidans is an emerging pathogen increasingly being isolated from respiratory samples of cystic fibrosis (CF) patients. Its role and clinical significance in lung pathogenesis have not yet been clarified. The aim of the present study was to genetically characterize A. xylosoxidans strains isolated from CF patients by use of randomly amplified polymorphic DNA (RAPD) profiles and to look for a possible correlation between RAPD profiles and the patients' clinical features, such as their spirometry values, the presence of concomitant chronic bacterial flora at the time of isolation, and the persistent or intermittent presence of A. xylosoxidans strains. A set of 106 strains of A. xylosoxidans were typed by RAPD analysis, and their profiles were analyzed by agglomerative hierarchical classification (AHC) and associated with the patient characteristics mentioned above by factorial discriminant analysis (FDA). The overall results obtained in this study showed that (i) there is a marked genetic relationship between strains isolated from the same patients at different times, (ii) characteristic RAPD profiles are associated with different predicted classes for forced expiratory volume in 1 s (FEV1%), (iii) some characteristic RAPD profiles are associated with different concomitant chronic flora (CCF) profiles, and (iv) there is a significant division of RAPD profiles into "persistent strains" and "intermittent strains" of A. xylosoxidans. These findings seem to imply that the lung habitats found in CF patients are capable of shaping and selecting the colonizing bacterial flora, as seems to be the case for the A. xylosoxidans strains studied.

  16. Cystic Fibrosis Heterozygote Resistance to Cholera Toxin in the Cystic Fibrosis Mouse Model

    NASA Astrophysics Data System (ADS)

    Gabriel, Sherif E.; Brigman, Kristen N.; Koller, Beverly H.; Boucher, Richard C.; Stutts, M. Jackson

    1994-10-01

    The effect of the number of cystic fibrosis (CF) alleles on cholera toxin (CT)-induced intestinal secretion was examined in the CF mouse model. CF mice that expressed no CF transmembrane conductance regulator (CFTR) protein did not secrete fluid in response to CT. Heterozygotes expressed 50 percent of the normal amount of CFTR protein in the intestinal epithelium and secreted 50 percent of the normal fluid and chloride ion in response to CT. This correlation between CFTR protein and CT-induced chloride ion and fluid secretion suggests that CF heterozygotes might possess a selective advantage of resistance to cholera.

  17. Cystic fibrosis transmembrane conductance regulator mutations at a referral center for cystic fibrosis*

    PubMed Central

    Coutinho, Cyntia Arivabeni de Araújo Correia; Marson, Fernando Augusto de Lima; Ribeiro, Antônio Fernando; Ribeiro, José Dirceu; Bertuzzo, Carmen Silvia

    2013-01-01

    OBJECTIVE: To determine the frequency of six mutations (F508del, G542X, G551D, R553X, R1162X, and N1303K) in patients with cystic fibrosis (CF) diagnosed, at a referral center, on the basis of abnormal results in two determinations of sweat sodium and chloride concentrations. METHODS: This was a cross-sectional study involving 70 patients with CF. The mean age of the patients was 12.38 ± 9.00 years, 51.43% were female, and 94.29% were White. Mutation screening was performed with polymerase chain reaction (for F508del), followed by enzymatic digestion (for other mutations). Clinical analysis was performed on the basis of gender, age, ethnicity, pulmonary/gastrointestinal symptoms, and Shwachman-Kulczycki (SK) score. RESULTS: All of the patients showed pulmonary symptoms, and 8 had no gastrointestinal symptoms. On the basis of the SK scores, CF was determined to be mild, moderate, and severe in 22 (42.3%), 17 (32.7%), and 13 (25.0%) of the patients, respectively. There was no association between F508del mutation and disease severity by SK score. Of the 140 alleles analyzed, F508del mutation was identified in 70 (50%). Other mutations (G542X, G551D, R553X, R1162X, and N1303K) were identified in 12 (7.93%) of the alleles studied. In F508del homozygous patients with severe disease, the OR was 0.124 (95% CI: 0.005-0.826). CONCLUSIONS: In 50% of the alleles studied, the molecular diagnosis of CF was confirmed by identifying a single mutation (F508del). If we consider the analysis of the six most common mutations in the Brazilian population (including F508del), the molecular diagnosis was confirmed in 58.57% of the alleles studied. PMID:24310628

  18. A metagenomic approach to characterize temperate bacteriophage populations from Cystic Fibrosis and non-Cystic Fibrosis bronchiectasis patients

    PubMed Central

    Tariq, Mohammad A.; Everest, Francesca L. C.; Cowley, Lauren A.; De Soyza, Anthony; Holt, Giles S.; Bridge, Simon H.; Perry, Audrey; Perry, John D.; Bourke, Stephen J.; Cummings, Stephen P.; Lanyon, Clare V.; Barr, Jeremy J.; Smith, Darren L.

    2015-01-01

    Pseudomonas aeruginosa (Pa), normally a soil commensal, is an important opportunistic pathogen in Cystic Fibrosis (CF) and non-Cystic Fibrosis Bronchiectasis (nCFBR). Persistent infection correlates with accelerated decline in lung function and early mortality. The horizontal transfer of DNA by temperate bacteriophages can add gene function and selective advantages to their bacterial host within the constrained environment of the lower lung. In this study, we chemically induce temperate bacteriophages from clonal cultures of Pa and identify their mixed viral communities employing metagenomic approaches. We compared 92 temperate phage metagenomes stratified from these clinical backgrounds (47 CF and 45 nCFBR Pa isolates) using MG-RAST and GeneWise2. KEGG analysis shows the complexity of temperate phage accessory gene carriage increases with duration and severity of the disease. Furthermore, we identify the presence of Ig-like motifs within phage structural genes linked to bacterial adhesion and carbohydrate binding including Big_2, He_Pig, and Fn3. This study provides the first clinical support to the proposed bacteriophage adherence to mucus (BAM) model and the evolution of phages interacting at these mucosal surfaces over time. PMID:25741327

  19. Genotype-phenotype correlation for pulmonary function in cystic fibrosis

    PubMed Central

    de Gracia, J; Mata, F; Alvarez, A; Casals, T; Gatner, S; Vendrell, M; de la Rosa, D; Guarner, L; Hermosilla, E

    2005-01-01

    Background: Since the CFTR gene was cloned, more than 1000 mutations have been identified. To date, a clear relationship has not been established between genotype and the progression of lung damage. A study was undertaken of the relationship between genotype, progression of lung disease, and survival in adult patients with cystic fibrosis (CF). Methods: A prospective cohort of adult patients with CF and two CFTR mutations followed up in an adult cystic fibrosis unit was analysed. Patients were classified according to functional effects of classes of CFTR mutations and were grouped based on the CFTR molecular position on the epithelial cell surface (I–II/I–II, I–II/III–V). Spirometric values, progression of lung disease, probability of survival, and clinical characteristics were analysed between groups. Results: Seventy four patients were included in the study. Patients with genotype I–II/I–II had significantly lower current spirometric values (p<0.001), greater loss of pulmonary function (p<0.04), a higher proportion of end-stage lung disease (p<0.001), a higher risk of suffering from moderate to severe lung disease (odds ratio 7.12 (95% CI 1.3 to 40.5)) and a lower probability of survival than patients with genotype I–II/III, I–II/IV and I–II/V (p<0.001). Conclusions: The presence of class I or II mutations on both chromosomes is associated with worse respiratory disease and a lower probability of survival. PMID:15994263

  20. IRON HOMEOSTASIS DURING CYSTIC FIBROSIS PULMONARY EXACERBATION

    PubMed Central

    Gifford, Alex H.; Moulton, Lisa A.; Dorman, Dana B.; Olbina, Gordana; Westerman, Mark; Parker, H. Worth; Stanton, Bruce A.; O’Toole, George A.

    2012-01-01

    Hypoferremia is a marker of disease severity in cystic fibrosis (CF). The effect of systemic antibiotics on iron homeostasis during CF pulmonary exacerbation (CFPE) is unknown. Our central hypotheses were that, by the completion of treatment, serum iron would increase, serum concentrations of interleukin-6 (IL-6) and hepcidin-25, two mediators of hypoferremia, would decrease, and sputum iron would decrease. Methods: Blood and sputum samples were collected from 12 subjects with moderate-to-severe CF (median percent-predicted forced expiratory volume in one second (FEV1%) = 29%; median weight = 56 kg) within 24 hours of starting and completing a course of systemic antibiotics. Results: After treatment, subjects showed median FEV1% and body weight improvements of 4.5% and 2.0 kg, respectively (p <0.05). Median serum iron rose by 2.4 μmol/l (p <0.05), but 75% of patients remained hypoferremic. Median serum IL-6 and hepcidin-25 levels fell by 12.1 pg/ml and 37.5 ng/ml, respectively (p <0.05). Median serum erythropoietin (EPO) and hemoglobin levels were unaffected by treatment. We observed a trend toward lower sputum iron content after treatment. Conclusions: Hypoferremia is a salient characteristic of CFPE that improves with waning inflammation. Despite antibiotic treatment, many patients remain hypoferremic and anemic due to ineffective erythropoiesis. PMID:22883617

  1. Sodium chloride deficiency in cystic fibrosis patients.

    PubMed

    Ozçelik, U; Göçmen, A; Kiper, N; Coşkun, T; Yilmaz, E; Ozgüç, M

    1994-11-01

    Sodium chloride deficiency (SCD) was observed within the 1st year of life in 12 of 46 cystic fibrosis (CF) patients between July 1989 and September 1992. All patients showed sweating, loss of appetite, fever, vomiting, irritation, dehydration, weakness, and cyanosis during an attack. Mean plasma sodium, potassium and chloride levels were 122.9 (range 106-135), 2.5 (range 1.6-3.5), and 73.3 (range 60-90) mEq/l respectively. Alkalosis and elevated plasma renin activity were detected in all patients. Of the patients, 50% showed microscopic haematuria, and hypercalciuria was detected in two out of four patients. Low urinary sodium and high urinary potassium were observed in the four examined patients. Increased creatinine, BUN and uric acid values returned to normal with treatment. All the patients were treated initially with intravenous fluids and electrolyte solutions. All patients were less than 7 months of age during the first attack, five received only breast milk and the others breast milk with formula milk. Their oral salt supplement was 2-4 mEq/kg per day, which is recommended for CF patients, but could be deficient in excessively sweating infants. The genotype of these patients might be cause of high salt losses. F508 is the most common mutation with the frequency of 38% in our CF patients with SCD, but the frequency of unknown mutations is high (54%).

  2. Appetite stimulants use in cystic fibrosis.

    PubMed

    Nasr, Samya Z; Drury, Donna

    2008-03-01

    Cystic fibrosis (CF) is an autosomal recessive disease. It affects multiple body organs. The lungs and pancreas are the most affected which results in progressive lung damage and pancreatic insufficiency. Due to the disease process, CF patients require significantly higher caloric intake than recommended for other individuals. The nutritional goal for CF patients is to achieve normal growth and development and, once genetic potential is reached, to maintain good nutritional status throughout life. Evidence has shown that lung function is closely associated with nutritional status in CF and that nutritional status is an independent predictor of survival. Most CF patients are on a high calorie diet to help achieve normal growth and development and maintain good lung function. Inadequate caloric intake in CF can lead to malnutrition. Malnutrition in CF requires careful, multidisciplinary history taking, physical exam, and overall patient/family assessment. Only by determining the actual cause of the malnutrition can appropriate and safe therapies be used to treat it. Appetite stimulants, although efficacious in treating malnutrition in CF, should only be prescribed if decreased food intake secondary to inadequate appetite is the principal cause of the malnutrition and all other contributing factors have been assessed, ruled-out or treated. In this review, we attempted to summarize the use of several appetite stimulants used in CF and other diseases to improve appetite and maximize caloric intake.

  3. Tracheal microaspiration in adult cystic fibrosis.

    PubMed

    Ledson, M J; Wilson, G E; Tran, J; Walshaw, M J

    1998-01-01

    Gastro-oesophageal reflux (GOR) has been implicated in the aetiology of lung disease. Cystic fibrosis (CF) patients have a high incidence of GOR symptoms with demonstrable episodes of oesophageal acidification. We studied 24-hour ambulatory tracheal and oesophageal pH in 11 CF patients with GOR symptoms to identify any episodes of tracheal acidification and define their temporal relation to oesophageal reflux and respiratory symptoms. 8 patients had evidence of significant GOR (DeMeester score mean 58; range 17-107) and in 6 it was gross (DeMeester score > 30). 4 patients had tracheal acidification (defined as tracheal pH < 5.5): all had greatly raised DeMeester scores. Two patterns of lowered tracheal pH were seen: a gradual drift downwards of tracheal pH to < 5.5 which recovered slowly, and an acute fall in tracheal pH to < 5.5 with rapid recovery. Only one patient had a fall in peak expiratory flow in conjunction with a decline in tracheal pH, and no association was found between the presence of tracheal microaspiration and pulmonary function. We conclude that tracheal acidification occurs in adult CF patients with GOR.

  4. The cystic fibrosis lower airways microbial metagenome

    PubMed Central

    Moran Losada, Patricia; Chouvarine, Philippe; Dorda, Marie; Hedtfeld, Silke; Mielke, Samira; Schulz, Angela; Wiehlmann, Lutz

    2016-01-01

    Chronic airway infections determine most morbidity in people with cystic fibrosis (CF). Herein, we present unbiased quantitative data about the frequency and abundance of DNA viruses, archaea, bacteria, moulds and fungi in CF lower airways. Induced sputa were collected on several occasions from children, adolescents and adults with CF. Deep sputum metagenome sequencing identified, on average, approximately 10 DNA viruses or fungi and several hundred bacterial taxa. The metagenome of a CF patient was typically found to be made up of an individual signature of multiple, lowly abundant species superimposed by few disease-associated pathogens, such as Pseudomonas aeruginosa and Staphylococcus aureus, as major components. The host-associated signatures ranged from inconspicuous polymicrobial communities in healthy subjects to low-complexity microbiomes dominated by the typical CF pathogens in patients with advanced lung disease. The DNA virus community in CF lungs mainly consisted of phages and occasionally of human pathogens, such as adeno- and herpesviruses. The S. aureus and P. aeruginosa populations were composed of one major and numerous minor clone types. The rare clones constitute a low copy genetic resource that could rapidly expand as a response to habitat alterations, such as antimicrobial chemotherapy or invasion of novel microbes. PMID:27730195

  5. The cystic fibrosis lower airways microbial metagenome.

    PubMed

    Moran Losada, Patricia; Chouvarine, Philippe; Dorda, Marie; Hedtfeld, Silke; Mielke, Samira; Schulz, Angela; Wiehlmann, Lutz; Tümmler, Burkhard

    2016-04-01

    Chronic airway infections determine most morbidity in people with cystic fibrosis (CF). Herein, we present unbiased quantitative data about the frequency and abundance of DNA viruses, archaea, bacteria, moulds and fungi in CF lower airways. Induced sputa were collected on several occasions from children, adolescents and adults with CF. Deep sputum metagenome sequencing identified, on average, approximately 10 DNA viruses or fungi and several hundred bacterial taxa. The metagenome of a CF patient was typically found to be made up of an individual signature of multiple, lowly abundant species superimposed by few disease-associated pathogens, such as Pseudomonas aeruginosa and Staphylococcus aureus, as major components. The host-associated signatures ranged from inconspicuous polymicrobial communities in healthy subjects to low-complexity microbiomes dominated by the typical CF pathogens in patients with advanced lung disease. The DNA virus community in CF lungs mainly consisted of phages and occasionally of human pathogens, such as adeno- and herpesviruses. The S. aureus and P. aeruginosa populations were composed of one major and numerous minor clone types. The rare clones constitute a low copy genetic resource that could rapidly expand as a response to habitat alterations, such as antimicrobial chemotherapy or invasion of novel microbes.

  6. The Evolution of Cystic Fibrosis Care

    PubMed Central

    Ferkol, Thomas W.

    2015-01-01

    Cystic fibrosis (CF) is the most common life-limiting inherited illness of whites. Most of the morbidity and mortality in CF stems from impaired mucociliary clearance leading to chronic, progressive airways obstruction and damage. Significant progress has been made in the care of patients with CF, with advances focused on improving mucociliary clearance, minimizing inflammatory damage, and managing infections; these advances include new antimicrobial therapies, mucolytic and osmotic agents, and antiinflammatory treatments. More recently, researchers have targeted disease-causing mutations using therapies to promote gene transcription and improve channel function, which has led to impressive physiologic changes in some patients. As we develop more advanced, allele-directed therapies for the management of CF, it will become increasingly important to understand the specific genetic and environmental interactions that cause the significant heterogeneity of lung disease seen in the CF population. This understanding of CF endotypes will allow for more targeted, personalized therapies for future patients. This article reviews the genetic and molecular basis of CF lung disease, the treatments currently available, and novel therapies that are in development. PMID:25764168

  7. Cystic fibrosis and estrogens: a perfect storm

    PubMed Central

    Zeitlin, Pamela L.

    2008-01-01

    Irreversible destruction and widening of the airways due to acquired infections or genetic mutations as well as those of unknown cause are more severe in females. Differences between male and female anatomy, behavior, and hormonal state have been proposed to explain the increased incidence and severity in females with airway disease such as cystic fibrosis (CF); however, a mechanism to explain a sex-related difference has remained elusive. In this issue of the JCI, Coakley et al. report that elevations in the major estrogen hormone in humans — 17β-estradiol — reduce Ca2+-activated Cl– secretion by airway epithelial cells in culture, thereby disrupting ion and water balance (see the related article beginning on page 4025). They measure a similar diminution of nasal epithelial Ca2+-activated Cl– secretion in women with CF during the menstrual cycle phase at which 17β-estradiol level is at its highest. These data suggest that for about one week of a four-week menstrual cycle, women with CF will have a reduced ability to efficiently clear airway secretions, the buildup of which is a hallmark of CF. The authors suggest that these data warrant the testing of antiestrogen therapy in females with CF and propose an alternative avenue for CF therapeutic development. PMID:19033654

  8. Lentiviral Vectors and Cystic Fibrosis Gene Therapy

    PubMed Central

    Castellani, Stefano; Conese, Massimo

    2010-01-01

    Cystic fibrosis (CF) is a chronic autosomic recessive syndrome, caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, a chloride channel expressed on the apical side of the airway epithelial cells. The lack of CFTR activity brings a dysregulated exchange of ions and water through the airway epithelium, one of the main aspects of CF lung disease pathophysiology. Lentiviral (LV) vectors, of the Retroviridae family, show interesting properties for CF gene therapy, since they integrate into the host genome and allow long-lasting gene expression. Proof-of-principle that LV vectors can transduce the airway epithelium and correct the basic electrophysiological defect in CF mice has been given. Initial data also demonstrate that LV vectors can be repeatedly administered to the lung and do not give rise to a gross inflammatory process, although they can elicit a T cell-mediated response to the transgene. Future studies will clarify the efficacy and safety profile of LV vectors in new complex animal models with CF, such as ferrets and pigs. PMID:21994643

  9. IgG antibodies to Aspergillus fumigatus in cystic fibrosis: a laboratory correlate of disease activity.

    PubMed Central

    Forsyth, K D; Hohmann, A W; Martin, A J; Bradley, J

    1988-01-01

    Serum was collected from 50 patients with cystic fibrosis, and IgG antibodies to Aspergillus fumigatus were measured by enzyme linked immunosorbent assay (ELISA). In addition, total IgE and Aspergillus specific IgE antibodies were measured in 41 of the 50. A close association was found between pulmonary function and clinical state, and IgG antibodies to Aspergillus. There was no association between pulmonary function or clinical state and IgE antibodies. It is postulated that in patients with cystic fibrosis, Aspergillus fumigatus may contribute to deterioration in pulmonary function by local pathogenicity, or by hypersensitivity mechanisms mediated by IgG. PMID:3046514

  10. Family Stress with Chronic Childhood Illness: Cystic Fibrosis, Neuromuscular Disease, and Renal Disease.

    ERIC Educational Resources Information Center

    Holroyd, Jean; Guthrie, Donald

    1986-01-01

    Parents of children with neuromuscular disease, cystic fibrosis, and renal disease were compared with parents of control subjects matched by age to the clinical cases. The three clinical groups exhibited different patterns of stressful response, consistent with the nature of their illnesses and the requirements for care imposed on the families.…

  11. Antimicrobial resistance in the respiratory microbiota of people with cystic fibrosis.

    PubMed

    Sherrard, Laura J; Tunney, Michael M; Elborn, J Stuart

    2014-08-23

    Cystic fibrosis is characterised by chronic polymicrobial infection and inflammation in the airways of patients. Antibiotic treatment regimens, targeting recognised pathogens, have substantially contributed to increased life expectancy of patients with this disease. Although the emergence of antimicrobial resistance and selection of highly antibiotic-resistant bacterial strains is of major concern, the clinical relevance in cystic fibrosis is yet to be defined. Resistance has been identified in recognised cystic fibrosis pathogens and in other bacteria (eg, Prevotella and Streptococcus spp) detected in the airway microbiota, but their role in the pathophysiology of infection and inflammation in chronic lung disease is unclear. Increased antibiotic resistance in cystic fibrosis might be attributed to a range of complex factors including horizontal gene transfer, hypoxia, and biofilm formation. Strategies to manage antimicrobial resistance consist of new antibiotics or localised delivery of antimicrobial agents, iron sequestration, inhibition of quorum-sensing, and resistome analysis. Determination of the contributions of every bacterial species to lung health or disease in cystic fibrosis might also have an important role in the management of antibiotic resistance.

  12. Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion.

    PubMed

    Knauf, Felix; Thomson, Robert B; Heneghan, John F; Jiang, Zhirong; Adebamiro, Adedotun; Thomson, Claire L; Barone, Christina; Asplin, John R; Egan, Marie E; Alper, Seth L; Aronson, Peter S

    2017-01-01

    Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal absorption of dietary oxalate results from passive paracellular oxalate absorption as modified by oxalate back secretion mediated by the SLC26A6 oxalate transporter. We used mice deficient in the cystic fibrosis transmembrane conductance regulator gene (Cftr) to test the hypothesis that SLC26A6-mediated oxalate secretion is defective in cystic fibrosis. We mounted isolated intestinal tissue from C57BL/6 (wild-type) and Cftr(-/-) mice in Ussing chambers and measured transcellular secretion of [(14)C]oxalate. Intestinal tissue isolated from Cftr(-/-) mice exhibited significantly less transcellular oxalate secretion than intestinal tissue of wild-type mice. However, glucose absorption, another representative intestinal transport process, did not differ in Cftr(-/-) tissue. Compared with wild-type mice, Cftr(-/-) mice showed reduced expression of SLC26A6 in duodenum by immunofluorescence and Western blot analysis. Furthermore, coexpression of CFTR stimulated SLC26A6-mediated Cl(-)-oxalate exchange in Xenopus oocytes. In association with the profound defect in intestinal oxalate secretion, Cftr(-/-) mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice. We conclude that defective intestinal oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis. Future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone formation observed in patients with cystic fibrosis.

  13. A functional CFTR assay using primary cystic fibrosis intestinal organoids.

    PubMed

    Dekkers, Johanna F; Wiegerinck, Caroline L; de Jonge, Hugo R; Bronsveld, Inez; Janssens, Hettie M; de Winter-de Groot, Karin M; Brandsma, Arianne M; de Jong, Nienke W M; Bijvelds, Marcel J C; Scholte, Bob J; Nieuwenhuis, Edward E S; van den Brink, Stieneke; Clevers, Hans; van der Ent, Cornelis K; Middendorp, Sabine; Beekman, Jeffrey M

    2013-07-01

    We recently established conditions allowing for long-term expansion of epithelial organoids from intestine, recapitulating essential features of the in vivo tissue architecture. Here we apply this technology to study primary intestinal organoids of people suffering from cystic fibrosis, a disease caused by mutations in CFTR, encoding cystic fibrosis transmembrane conductance regulator. Forskolin induces rapid swelling of organoids derived from healthy controls or wild-type mice, but this effect is strongly reduced in organoids of subjects with cystic fibrosis or in mice carrying the Cftr F508del mutation and is absent in Cftr-deficient organoids. This pattern is phenocopied by CFTR-specific inhibitors. Forskolin-induced swelling of in vitro-expanded human control and cystic fibrosis organoids corresponds quantitatively with forskolin-induced anion currents in freshly excised ex vivo rectal biopsies. Function of the CFTR F508del mutant protein is restored by incubation at low temperature, as well as by CFTR-restoring compounds. This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis.

  14. Early Anti-Pseudomonal Acquisition in Young Patients with Cystic Fibrosis: Rationale and Design of the EPIC Clinical Trial and Observational Study

    PubMed Central

    Treggiari, Miriam M; Rosenfeld, Margaret; Mayer-Hamblett, Nicole; Retsch-Bogart, George; Gibson, Ronald L.; Williams, Judy; Emerson, Julia; Kronmal, Richard A; Ramsey, Bonnie W

    2009-01-01

    Background The primary cause of morbidity and mortality in patients with cystic fibrosis (CF) is progressive obstructive pulmonary disease due to chronic endobronchial infection, particularly with Pseudomonas aeruginosa (Pa). Risk factors for and clinical impact of early Pa infection in young CF patients are less well understood. Purpose The present studies are designed to evaluate risk factors and outcomes associated with early Pa acquisition, and the benefits and harms of four anti-pseudomonal treatment regimens in young CF patients initiated after the first Pa positive respiratory culture. Methods The Early Pseudomonas Infection Control (EPIC) program consists of two studies, a randomized multicenter trial in CF patients ages 1–12 years at first isolation of Pa from a respiratory culture, and a longitudinal cohort study enrolling Pa-negative patients. Using a factorial design, trial participants are assigned for 18 months to either anti-pseudomonal treatment on a scheduled quarterly basis (cycled therapy) or based on recovery of Pa from quarterly respiratory cultures (culture-based therapy). The study drugs include inhaled tobramycin (300 mg BID) for 28 days, combined with either oral ciprofloxacin (15–20 mg/kg BID) or oral placebo for 14 days. The primary endpoints of the trial are the time to pulmonary exacerbation requiring IV antibiotics or hospitalization for respiratory symptoms, and the proportion of patients with new Pa-positive respiratory cultures during the study. The broad goals of the observational study are to describe the risk factors and outcomes associated with early acquisition of Pa. 306 patients were randomized in the clinical trial and 1,787 were enrolled in the cohort study. Conclusions These companion studies will provide valuable epidemiological and microbiological information on early CF lung disease and Pa acquisition, and safety and clinical efficacy data on anti-pseudomonal treatment strategies for early Pa infections in the

  15. A novel case of diabetic muscle necrosis in a patient with cystic fibrosis-related diabetes.

    PubMed

    Chalasani, Sreelatha; Bettadahalli, Shankar S; Bhupathi, Satya V; Aswani, Vijay H

    2013-09-01

    Cystic fibrosis is a recessive autosomal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. Cystic fibrosis-related diabetes (CFRD) is a common comorbidity of cystic fibrosis. Diabetic myonecrosis is a rare self-limited complication of poorly controlled diabetes mellitus that commonly presents with acute, intense pain and swelling of lower extremities and responds well to conservative management. We report the first case of diabetic myonecrosis in a patient with CFRD.

  16. Draft genome sequences of four Achromobacter ruhlandii strains isolated from cystic fibrosis patients

    PubMed Central

    Rodrigues, Elenice RA; Rocha, Géssica A; Ferreira, Alex G; Leão, Robson S; Albano, Rodolpho M; Marques, Elizabeth A

    2016-01-01

    Achromobacter species are being increasingly isolated from the respiratory tract of cystic fibrosis patients. Recent reports indicate that Achromobacter ruhlandii is a potential human pathogen in cystic fibrosis-related infections. Here we report the draft genome of four A. ruhlandii strains isolated from cystic fibrosis patients in Brazil. This report describes A. ruhlandii as a potential opportunistic pathogen in cystic fibrosis and provides a framework to for additional enquires into potential virulence factors and resistance mechanisms within this species. PMID:27812598

  17. C-Reactive Protein in Stable Cystic Fibrosis: An Additional Indicator of Clinical Disease Activity and Risk of Future Pulmonary Exacerbations

    PubMed Central

    Matouk, Elias; Nguyen, Dao; Benedetti, Andrea; Bernier, Joanie; Gruber, James; Landry, Jennifer; Rousseau, Simon; Ahlgren, Heather G; Lands, Larry C; Wojewodka, Gabriella; Radzioch, Danuta

    2016-01-01

    Introduction In stable adult cystic fibrosis (CF) patients, we assessed the role of baseline high sensitivity C-reactive protein (hs-CRP) on CF clinical variables and frequency of intravenous (IV) treated pulmonary exacerbations (PExs) 1-year post-baseline. Methods We recruited 51 clinically stable CF patients from our Adult CF Center. We incorporated collected parameters into Matouk CF clinical score and CF questionnaire-revised quality of life score (QOL). We used the clinical minus complications subscores as a clinical disease activity score (CDAS). We dichotomized our patients according to the cohort median baseline hs-CRP of 5.2 mg/L. Results Patients in the high hs-CRP group (≥ 5.2 mg/L) demonstrated worse CDAS (r=0.67, p=0.0001) and QOL scores (r=0.57, p=0.0017) at a given FEV1% predicted. In both hs-CRP groups, prior-year IV-treated PExs and baseline CDASs were significant predictors of future IV-treated PExs. Interestingly, the association between baseline CDAS and future PExs frequency was more robust in the high compared to the low hs-CRP group (r=−0.88, p<0.0001, r=−0.48, p=0.017, respectively) with a steeper regression slope (p=0.001). In addition, a significant interaction was demonstrated between elevated baseline hs-CRP levels and CDASs for the prediction of increased risk of future PExs (p=0.02). This interaction provided an additional indicator of clinical disease activity and added another dimension to the prior year PExs frequency phenotype to identify patients at increased risk for future PExs. Conclusion Stable CF patients with elevated baseline hs-CRP (≥ 5.2 mg/L) demonstrated worse clinical disease activity and QOL scores at a given level of disease severity (FEV1% predicted). Elevated baseline hs-CRP values combined with clinical disease activity scores are associated with increased risk for future IV-treated PExs even in those with mild clinical disease activity scores. PMID:28066689

  18. Can Cystic Fibrosis Patients Finally Catch a Breath With Lumacaftor/Ivacaftor?

    PubMed

    Schneider, E K; Reyes-Ortega, F; Li, J; Velkov, T

    2017-01-01

    Cystic fibrosis (CF) is a life-limiting disease caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) activity. The recent US Food and Drug Administration (FDA) approval of lumacaftor combined with ivacaftor (Orkambi) targets patients with the F508del-CFTR. The question remains: Is this breakthrough combination therapy the "magic-bullet" cure for the vast majority of patients with CF? This review covers the contemporary clinical and scientific knowledge-base for lumacaftor/ivacaftor and highlights the emerging issues from recent conflicting literature reports.

  19. Antiinflammatory therapies for cystic fibrosis: past, present, and future.

    PubMed

    Prescott, William A; Johnson, Cary E

    2005-04-01

    Inflammation is a major component of the vicious cycle characterizing cystic fibrosis pulmonary disease. If untreated, this inflammatory process irreversibly damages the airways, leading to bronchiectasis and ultimately respiratory failure. Antiinflammatory drugs for cystic fibrosis lung disease appear to have beneficial effects on disease parameters. These agents include oral corticosteroids and ibuprofen, as well as azithromycin, which, in addition to its antimicrobial effects, also possesses antiinflammatory properties. Inhaled corticosteroids, colchicine, methotrexate, montelukast, pentoxifylline, nutritional supplements, and protease replacement have not had a significant impact on the disease. Therapy with oral corticosteroids, ibuprofen, and fish oil is limited by adverse effects. Azithromycin appears to be safe and effective, and is thus the most promising antiinflammatory therapy available for patients with cystic fibrosis. Pharmacologic therapy with antiinflammatory agents should be started early in the disease course, before extensive irreversible lung damage has occurred.

  20. Preimplantation genetic diagnosis for cystic fibrosis: a case report

    PubMed Central

    Biazotti, Maria Cristina Santoro; Pinto, Walter; de Albuquerque, Maria Cecília Romano Maciel; Fujihara, Litsuko Shimabukuro; Suganuma, Cláudia Haru; Reigota, Renata Bednar; Bertuzzo, Carmen Sílvia

    2015-01-01

    Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. This disorder produces a variable phenotype including lung disease, pancreatic insufficiency, and meconium ileus plus bilateral agenesis of the vas deferens causing obstructive azoospermia and male infertility. Preimplantation genetic diagnosis is an alternative that allows identification of embryos affected by this or other genetic diseases. We report a case of couple with cystic fibrosis; the woman had the I148 T mutation and the man had the Delta F508 gene mutation. The couple underwent in vitro fertilization, associated with preimplantation genetic diagnosis, and with subsequent selection of healthy embryos for uterine transfer. The result was an uneventful pregnancy and delivery of a healthy male baby. PMID:25993078

  1. Atomic Structure of the Cystic Fibrosis Transmembrane Conductance Regulator.

    PubMed

    Zhang, Zhe; Chen, Jue

    2016-12-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel evolved from the ATP-binding cassette (ABC) transporter family. In this study, we determined the structure of zebrafish CFTR in the absence of ATP by electron cryo-microscopy to 3.7 Å resolution. Human and zebrafish CFTR share 55% sequence identity, and 42 of the 46 cystic-fibrosis-causing missense mutational sites are identical. In CFTR, we observe a large anion conduction pathway lined by numerous positively charged residues. A single gate near the extracellular surface closes the channel. The regulatory domain, dephosphorylated, is located in the intracellular opening between the two nucleotide-binding domains (NBDs), preventing NBD dimerization and channel opening. The structure also reveals why many cystic-fibrosis-causing mutations would lead to defects either in folding, ion conduction, or gating and suggests new avenues for therapeutic intervention.

  2. Disrupted Intestinal Microbiota and Intestinal Inflammation in Children with Cystic Fibrosis and Its Restoration with Lactobacillus GG: A Randomised Clinical Trial

    PubMed Central

    Bruzzese, Eugenia; Callegari, Maria Luisa; Raia, Valeria; Viscovo, Sara; Scotto, Riccardo; Ferrari, Susanna; Morelli, Lorenzo; Buccigrossi, Vittoria; Lo Vecchio, Andrea; Ruberto, Eliana; Guarino, Alfredo

    2014-01-01

    Background & Aims Intestinal inflammation is a hallmark of cystic fibrosis (CF). Administration of probiotics can reduce intestinal inflammation and the incidence of pulmonary exacerbations. We investigated the composition of intestinal microbiota in children with CF and analyzed its relationship with intestinal inflammation. We also investigated the microflora structure before and after Lactobacillus GG (LGG) administration in children with CF with and without antibiotic treatment. Methods The intestinal microbiota were analyzed by denaturing gradient gel electrophoresis (DGGE), real-time polymerase chain reaction (RT-PCR), and fluorescence in situ hybridization (FISH). Intestinal inflammation was assessed by measuring fecal calprotectin (CLP) and rectal nitric oxide (rNO) production in children with CF as compared with healthy controls. We then carried out a small double-blind randomized clinical trial with LGG. Results Twenty-two children with CF children were enrolled in the study (median age, 7 years; range, 2–9 years). Fecal CLP and rNO levels were higher in children with CF than in healthy controls (184±146 µg/g vs. 52±46 µg/g; 18±15 vs. 2.6±1.2 µmol/L NO2−, respectively; P<0.01). Compared with healthy controls, children with CF had significantly different intestinal microbial core structures. The levels of Eubacterium rectale, Bacteroides uniformis, Bacteroides vulgatus, Bifidobacterium adolescentis, Bifidobacterium catenulatum, and Faecalibacterium prausnitzii were reduced in children with CF. A similar but more extreme pattern was observed in children with CF who were taking antibiotics. LGG administration reduced fecal CLP and partially restored intestinal microbiota. There was a significant correlation between reduced microbial richness and intestinal inflammation. Conclusions CF causes qualitative and quantitative changes in intestinal microbiota, which may represent a novel therapeutic target in the treatment of CF. Administration of

  3. Sputum glucose and glycemic control in cystic fibrosis-related diabetes: a cross-sectional study.

    PubMed

    Van Sambeek, Lindsey; Cowley, Elise S; Newman, Dianne K; Kato, Roberta

    2015-01-01

    Cystic fibrosis-related diabetes affects up to half of cystic fibrosis patients and is associated with increased mortality and more frequent pulmonary exacerbations. However, it is unclear to what degree good glycemic control might mitigate these risks and clinical outcomes have not previously been studied in relation to glucose from the lower airways, the site of infection and CF disease progression. We initially hypothesized that diabetic cystic fibrosis patients with glycosylated hemoglobin (HbA(1c)) > 6.5% have worse pulmonary function, longer and more frequent exacerbations and also higher sputum glucose levels than patients with HbA(1c) ≤ 6.5% or cystic fibrosis patients without diabetes. To test this, we analyzed spontaneously expectorated sputum samples from 88 cystic fibrosis patients. The median sputum glucose concentration was 0.70 mM (mean, 4.75 mM; range, 0-64.6 mM). Sputum glucose was not correlated with age, sex, body mass index, diabetes diagnosis, glycemic control, exacerbation frequency or length, or pulmonary function. Surprisingly, sputum glucose was highest in subjects with normal glucose tolerance, suggesting the dynamics of glycemic control, sputum glucose and pulmonary infections are more complex than previously thought. Two-year mean HbA(1c) was positively correlated with the length of exacerbation admission (p < 0.01), and negatively correlated with measures of pulmonary function (p < 0.01). While total number of hospitalizations for exacerbations were not significantly different, subjects with an HbA(1c) > 6.5% were hospitalized on average 6 days longer than those with HbA(1c) ≤ 6.5% (p < 0.01). Current clinical care guidelines for cystic fibrosis-related diabetes target HbA(1c) ≤ 7% to limit long-term microvascular damage, but more stringent glycemic control (HbA(1c) ≤ 6.5%) may further reduce the short-term pulmonary complications.

  4. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

    PubMed Central

    Sosnay, Patrick R; Siklosi, Karen R; Van Goor, Fredrick; Kaniecki, Kyle; Yu, Haihui; Sharma, Neeraj; Ramalho, Anabela S; Amaral, Margarida D; Dorfman, Ruslan; Zielenski, Julian; Masica, David L; Karchin, Rachel; Millen, Linda; Thomas, Philip J; Patrinos, George P; Corey, Mary; Lewis, Michelle H; Rommens, Johanna M; Castellani, Carlo; Penland, Christopher M; Cutting, Garry R

    2013-01-01

    Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation to clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 cystic fibrosis patients in registries and clinics in North America and Europe. Among these patients, 159 CFTR variants had an allele frequency of ≥0.01%. These variants were evaluated for both clinical severity and functional consequence with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of cystic fibrosis patients enabled assignment of 12 of the remaining 32 variants as neutral while the other 20 variants remained indeterminate. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically-relevant genomic variation. PMID:23974870

  5. Gastroesophageal Reflux Disease in Children with Cystic Fibrosis.

    PubMed

    Dziekiewicz, Marcin A; Banaszkiewicz, Aleksandra; Urzykowska, Agnieszka; Lisowska, Aleksandra; Rachel, Marta; Sands, Dorota; Walkowiak, Jaroslaw; Radzikowski, Andrzej; Albrecht, Piotr

    2015-01-01

    Previously published studies have indicated that gastroesophageal reflux (GER) disease is common in pediatric patients with cystic fibrosis. The aim of the present study was to get insight into the incidence of GER and to characterize the nature of reflux episodes in children with cystic fibrosis. This was a multicenter, prospective study of children with cystic fibrosis older than 18 months. Forty four consecutive patients (22 boys, mean age 10.4 ± 3.6, range 3.0-17.8 years) were enrolled into the study. All patients underwent 24 h pH-impedance monitoring. GER were classified according to the widely recognized criteria as an acid, weakly acid, weakly alkaline, or proximal. The pH-impedance trace was considered abnormal when acid exposure was >6 %. GER was diagnosed in 24/44 (54.5 %) children. A total of 1585 (median 35, range 7-128) reflux episodes were detected; 1199 (75.6 %) were acidic, 382 (24.1 %) weakly acidic, and 4 (0.3 %) weakly alkaline. Six hundred and ninety-one (43.6 %) reflux episodes reached the proximal esophagus. In 14/44 patients typical GER symptoms were present. We conclude that the incidence of GER in children with cystic fibrosis is very high. In the majority of patients typical GER symptoms are absent. Therefore, diagnostic procedures should be considered, regardless of lacking symptoms. Although acid reflux episodes predominate in children with cystic fibrosis, classical pH-metry may not constitute a sufficient diagnostic method in this population because of a relatively high number of proximal reflux episodes. Such episodes also indicate an increased risk for aspiration. The pH-impedance diagnostic measurement is advocated when suspecting GER in children with cystic fibrosis.

  6. Outbreak of Corynebacterium pseudodiphtheriticum Infection in Cystic Fibrosis Patients, France

    PubMed Central

    Bittar, Fadi; Cassagne, Carole; Bosdure, Emmanuelle; Stremler, Nathalie; Dubus, Jean-Christophe; Sarles, Jacques; Reynaud-Gaubert, Martine; Raoult, Didier

    2010-01-01

    An increasing body of evidence indicates that nondiphtheria corynebacteria may be responsible for respiratory tract infections. We report an outbreak of Corynebacterium pseudodiphtheriticum infection in children with cystic fibrosis (CF). To identify 18 C. pseudodiphtheriticum strains isolated from 13 French children with CF, we used molecular methods (partial rpoB gene sequencing) and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. Clinical symptoms were exhibited by 10 children (76.9%), including cough, rhinitis, and lung exacerbations. The results of MALDI-TOF identification matched perfectly with those obtained from molecular identification. Retrospective analysis of sputum specimens by using specific real-time PCR showed that ≈20% of children with CF were colonized with these bacteria, whereas children who did not have CF had negative test results. Our study reemphasizes the conclusion that correctly identifying bacteria at the species level facilitates detection of an outbreak of new or emerging infections in humans. PMID:20678316

  7. Outbreak of Corynebacterium pseudodiphtheriticum infection in cystic fibrosis patients, France.

    PubMed

    Bittar, Fadi; Cassagne, Carole; Bosdure, Emmanuelle; Stremler, Nathalie; Dubus, Jean Christophe; Sarles, Jacques; Reynaud-Gaubert, Martine; Raoult, Didier; Rolain, Jean-Marc

    2010-08-01

    An increasing body of evidence indicates that nondiphtheria corynebacteria may be responsible for respiratory tract infections. We report an outbreak of Corynebacterium pseudodiphtheriticum infection in children with cystic fibrosis (CF). To identify 18 C. pseudodiphtheriticum strains isolated from 13 French children with CF, we used molecular methods (partial rpoB gene sequencing) and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. Clinical symptoms were exhibited by 10 children (76.9%), including cough, rhinitis, and lung exacerbations. The results of MALDI-TOF identification matched perfectly with those obtained from molecular identification. Retrospective analysis of sputum specimens by using specific real-time PCR showed that approximately 20% of children with CF were colonized with these bacteria, whereas children who did not have CF had negative test results. Our study reemphasizes the conclusion that correctly identifying bacteria at the species level facilitates detection of an outbreak of new or emerging infections in humans.

  8. Body image and cystic fibrosis: a critical review.

    PubMed

    Tierney, Stephanie

    2012-01-01

    A slight frame and poor appetite are common among patients with cystic fibrosis (CF) yet healthy body weight has been related to a better prognosis. A review of studies exploring body image (BI) among adults and adolescents with CF was conducted. Seven electronic databases were searched for potential papers. They located 128 references, of which 24 were read in full and 12 included in the review. Accepted papers suggested females with CF had a better BI compared to males, but this could compromise survival, given their preference for a low body weight. Males may be more motivated to adhere to nutritional advice because they favor a larger form. Practitioners should broach the topic of BI at clinic appointments to ensure this does not have a detrimental impact on self-management, although more research is required to guide professionals in this task.

  9. [NUTRITIONAL STATUS ASSESSMENT IN PATIENTS WITH CYSTIC FIBROSIS].

    PubMed

    Lambe, Cécile; Mallet, Pascale; Bailly, Céline; Sermet-Gaudelus, Isabelle

    2015-10-01

    Prognosis of cystic fibrosis has been largely modified over the past 30 years. Optimization of nutrition is one of the most important contributing factors of this improvement. Nutritional defect result from the conjunction of loss of calories, maldigestion, hypercatabolism and insufficient intake. Pancreatic opotherapy and ADEK vitamin administration is mandatory in pancreatic insufficient patients. Nutritional status must be evaluated at each clinics to detect nutritional defect as early as possible. Nutritional intake must be hypercaloric, normalipidic and adapted to the tastes of the patient. The clinician must be aware of at risk nutritional period: first year of life, puberty, infectious exacerbation, respiratory worsening and diabetes, In neonatal screened babies, recovery of birth weight percentile must be targeted at 6 months, and for the height must be in accordance to genetic height at 2 years. In all cases it is mandatory to treat denutrition by oral supplementation and if necessay enteral nutrition.

  10. Ethnic intermarriage and its consequences for cystic fibrosis carrier screening.

    PubMed

    Gilbert, F; Schoelkopf, J; Li, Z; Arzimanoglou, I I; Shaham, M; Udey, J; Arzimanoglou, I

    1995-01-01

    Cystic fibrosis gene mutations can vary in frequency between different ethnic populations. However, there is a rising trend of ethnic intermarriage in the United States, a situation suggesting that differences in specific mutation frequencies currently apparent in Europe may not persist for long in this country. Therefore, limited mutation screens targeted at specific ethnic groups and risk calculations based on data from more homogeneous European populations may not be appropriate in the United States. The genetic consequences of ethnic admixture are also likely to extend to other recessive diseases (e.g., Tay-Sachs, thalassemia), which, in the past, have been limited largely to particular ethnic, racial, or religious subgroups, with implications for public health agencies overseeing newborn screening programs for genetic diseases and for clinical genetics programs offering population-based carrier-detection programs, carrier risk assessment, and counseling.

  11. [Non-cystic fibrosis bronchiectasis: diagnosis and treatment].

    PubMed

    Huber, L C; Bürgi, U; Schuurmans, M M; Benden, C

    2014-08-01

    Bronchiectasis is the term used for irreversibly dilated airways. Exact epidemiological information on the frequency of bronchiectasis is not available, but the morphological findings are increasingly detected and the associated syndrome is more frequently diagnosed due to improved imaging techniques and increased awareness among chest physicians. The workup of these patients includes a wide panel of investigations guided by patient history and clinical presentation. Despite thorough evaluation the aetiology frequently remains unclear. Chronic infection with Pseudomonas aeruginosa is associated with a severe course of the disease and its detection has impacts on the therapeutic management. Chest physiotherapy, mucoactive substances and antibiotics are the mainstay of therapy. In this review the evaluation of bronchiectasis and the recent therapeutic insights for non-cystic fibrosis bronchiectasis are discussed.

  12. Cystic fibrosis in Latin America-Improving the awareness.

    PubMed

    Silva Filho, Luiz Vicente Ribeiro F; Castaños, Claudio; Ruíz, Héctor Hernán

    2016-11-01

    The burden of cystic fibrosis (CF) in Latin America is being increasingly recognized and is significant compared with other regions of the world. In this short communication, we assess the current situation in some Latin American countries and make suggestions for possible directions for future focus. We discuss the work that remains in deciphering how the various genetic, environmental and medical factors interact and influence outcomes in different ethnic groups. We also consider the need for consistency in both research and access to services across Latin America, including CF registries, neonatal screening programs, access to specialized CF healthcare practitioners, transition to adult clinics and treatment regimens. Progress in these areas is likely to build on the advances to date, and improve the lives of patients in Latin America who are affected by this debilitating and life-limiting disorder.

  13. Fluoroquinolones in the treatment of bronchopulmonary disease in cystic fibrosis

    PubMed Central

    2012-01-01

    Fluoroquinolones are commonly used to treat lung infections in those with cystic fibrosis. Patients with cystic fibrosis are susceptible to lung infection with common bacteria such as Staphylococcus aureus and Haemophilus influenzae, but also are prone to infection by opportunistic bacteria, including Pseudomonas aeruginosa. The good oral bioavailability and broad antimicrobial spectrum of activity, including anti-pseudomonal properties make this class of antimicrobial attractive. We review the evidence assessing the use of fluoroquinolones in the context of preventing and eradicating early lung infection and in managing chronic lung infection and pulmonary exacerbations. The safety of fluoroquinolones and the use of newer agents in the class is also discussed. PMID:22968160

  14. The Approach to Pseudomonas aeruginosa in Cystic Fibrosis.

    PubMed

    Talwalkar, Jaideep S; Murray, Thomas S

    2016-03-01

    There is a high prevalence of Pseudomonas aeruginosa in patients with cystic fibrosis and clear epidemiologic links between chronic infection and morbidity and mortality exist. Prevention and early identification of infection are critical, and stand to improve with the advent of new vaccines and laboratory methods. Once the organism is identified, a variety of treatment options are available. Aggressive use of antipseudomonal antibiotics is the standard of care for acute pulmonary exacerbations in cystic fibrosis, and providers must take into account specific patient characteristics when making treatment decisions related to antibiotic selection, route and duration of administration, and site of care.

  15. Australian standards of care for cystic fibrosis-related diabetes.

    PubMed

    Middleton, Peter G; Wagenaar, Monica; Matson, Angela G; Craig, Maria E; Holmes-Walker, Deborah Jane; Katz, Tamarah; Hameed, Shihab

    2014-02-01

    Multiple guidelines have been published over the last few years for the diagnosis and management of cystic fibrosis (CF) and cystic fibrosis related diabetes (CFRD), although some of the recommendations are based on extrapolation from other forms of diabetes and/or expert opinions. This document seeks to combine the guidelines to provide an Australian approach to the management of CFRD and establish the guidelines within the Australian CF Standards of Care. It is intended that this document will provide assistance to doctors, nurses, dietitians, physiotherapists, diabetes educators and CF patients concerning the issues surrounding CFRD, and will be reviewed and updated in 2016.

  16. Dual core quantum dots for highly quantitative ratiometric detection of trypsin activity in cystic fibrosis patients

    NASA Astrophysics Data System (ADS)

    Castelló Serrano, Iván; Stoica, Georgiana; Matas Adams, Alba; Palomares, Emilio

    2014-10-01

    We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. Current detection methods for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a highly sensitive, fast (minutes), and single-step approach nanosensor for the screening and diagnosis of cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range relevant for clinical applications (25-350 μg L-1). Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human genotypes, i.e. CF homozygotic, CF heterozygotic, and unaffected, respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescent biomarkers for recessive genetic diseases like human cystic fibrosis. In a screening program in which the goal is to detect disease and also the carrier status, early diagnosis could be of great help.We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. Current detection methods for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a highly sensitive, fast (minutes), and single-step approach nanosensor for the screening and diagnosis of cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range relevant for clinical applications (25-350 μg L-1). Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human genotypes, i.e. CF homozygotic, CF heterozygotic, and unaffected, respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescent biomarkers for

  17. Pancreatic changes in cystic fibrosis: CT and sonographic appearances

    SciTech Connect

    Daneman, A.; Gaskin, K.; Martin, D.J.; Cutz, E.

    1983-10-01

    The computed tomographic (CT) and sonographic appearances of the late stages of pancreatic damage in three patients with cystic fibrosis are illustrated. All three had severe exocrine pancreatic insufficiency with steatorrhea. In two patients CT revealed complete fatty replacement of the entire pancreas. In the third, increased echogenicity of the pancreas on sonography and the inhomogeneous attenuation on CT were interpreted as being the result of a combination of fibrosis, fatty replacement, calcification, and probable cyst formation.

  18. Structure-function analysis of a double-mutant cystic fibrosis transmembrane conductance regulator protein occurring in disorders related to cystic fibrosis.

    PubMed

    Fanen, P; Clain, J; Labarthe, R; Hulin, P; Girodon, E; Pagesy, P; Goossens, M; Edelman, A

    1999-06-11

    A number of disorders related to cystic fibrosis have been described since the cloning of the cystic fibrosis gene, including infertility due to the congenital bilateral absence of the vas deferens. We have identified, in several patients, complex cystic fibrosis transmembrane conductance regulator genotypes like double-mutant alleles. We have now analyzed the structure-function relationships of one of these mutants, R74W-D1270N cystic fibrosis transmembrane conductance regulator, expressed in HeLa cells, to evaluate the contribution of each mutation in the phenotype. We found that R74W cystic fibrosis transmembrane conductance regulator appears to be a polymorphism, while D1270N cystic fibrosis transmembrane conductance regulator could be responsible for the congenital bilateral absence of the vas deferens phenotype. The combination of the two produced a more severe effect on the chloride conductance pathway as well as on the phenotype.

  19. L206W mutation of the cystic fibrosis gene, relatively frequent in French Canadians, is associated with atypical presentations of cystic fibrosis

    SciTech Connect

    Rozen, R.; Ferreira-Rajabi, L.; Robb, L.

    1995-07-03

    Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Over 400 mutations have been reported at this locus. Although severe forms of cystic fibrosis are usually associated with pancreatic insufficiency, pulmonary dysfunction, and elevated sweat chloride, there is a wide range of phenotypes, including congenital absence of the vas deferens, observed with some of the milder mutations. The L206W mutation, which was first identified in patients from South France, is relatively frequent in French Canadians from Quebec. In this report, we document the atypical form of cystic fibrosis associated with this mutation in a cohort of 7 French Canadian probands. 20 refs.

  20. Mycobacterium chimaera pulmonary infection complicating cystic fibrosis: a case report

    PubMed Central

    2011-01-01

    Background Mycobacterium chimaera is a recently described species within the Mycobacterium avium complex. Its pathogenicity in respiratory tract infection remains disputed. It has never been isolated during cystic fibrosis respiratory tract infection. Case presentation An 11-year-old boy of Asian ethnicity who was born on Réunion Island presented to our hospital with cystic fibrosis after a decline in his respiratory function over the course of seven years. We found that the decline in his respiratory function was correlated with the persistent presence of a Mycobacterium avium complex organism further identified as M. chimaera. Conclusion Using sequencing-based methods of identification, we observed that M. chimaera organisms contributed equally to respiratory tract infections in patients with cystic fibrosis when compared with M. avium subsp. hominissuis isolates. We believe that M. chimaera should be regarded as an emerging opportunistic respiratory pathogen in patients with cystic fibrosis, including young children, and that its detection warrants long-lasting appropriate anti-mycobacterial treatment to eradicate it. PMID:21939536

  1. Strength and Conditioning for the Person with Cystic Fibrosis.

    ERIC Educational Resources Information Center

    Waller, Mike

    2001-01-01

    Discusses how a strength and conditioning program can be safety incorporated into the daily life of people with cystic fibrosis as a complementary therapy to medications, regular checkups, bronchial drainage, and respiratory therapy, examining physical restrictions and guidelines, exercise prescriptions, and exercise applications, and explaining…

  2. The Cystic Fibrosis Database: Content and Research Opportunities.

    ERIC Educational Resources Information Center

    Shaw, William M., Jr.; And Others

    1991-01-01

    Describes the files contained in the Cystic Fibrosis (CF) database and discusses educational and research opportunities using this database. Topics discussed include queries, evaluating the relevance of items retrieved, and use of the database in an online searching course in the School of Information and Library Science at the University of North…

  3. Vocational Rehabilitation of the Person with Cystic Fibrosis.

    ERIC Educational Resources Information Center

    Isralsky, Marc; And Others

    1979-01-01

    Explored vocational development, self-concept, and vocational adjustment of persons with cystic fibrosis. The following measures of vocational development correlated with work adjustment: vocational plans, educational plans, initiative, occupational information, and average vocational development score. Vocational development did not correlate…

  4. Psychological Concomitants of Cystic Fibrosis in Children and Adolescents.

    ERIC Educational Resources Information Center

    Kashani, Javad H.; And Others

    1988-01-01

    Administered several psychiatric inventories to 30 cystic fibrosis and 30 matched control children and their parents. Data analysis revealed few differences in either psychopathological symptoms or psychiatric diagnoses between groups. Differences were either physical in nature or did not depart enough from normal scores to merit label of high…

  5. Chronic rhinovirus infection in an adult with cystic fibrosis.

    PubMed

    Flight, William G; Bright-Thomas, Rowland J; Tilston, Peter; Mutton, Kenneth J; Guiver, Malcolm; Webb, A Kevin; Jones, Andrew M

    2013-11-01

    Rhinovirus is a common cause of exacerbations of cystic fibrosis (CF) and is usually considered a self-limiting infection. We report a case of chronic infection with rhinovirus A type 33 in a 43-year-old male with CF which has persisted for over 2 years.

  6. [CFTR and ENaC functions in cystic fibrosis].

    PubMed

    Palma, Alejandra G; Kotsias, Basilio A; Marino, Gabriela I

    2014-01-01

    Cystic fibrosis is caused by dysfunction or lack of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that has a key role in maintaining ion and water homoeostasis in different tissues. CFTR is a cyclic AMP-activated Cl- channel found in the apical and basal plasma membrane of airway, intestinal, and exocrine epithelial cells. One of CFTR's primary roles in the lungs is to maintain homoeostasis of the airway surface liquid layer through its function as a chloride channel and its regulation of the epithelial sodium channel ENaC. More than 1900 CFTR mutations have been identified in the cftr gene. The disease is characterized by viscous secretions of the exocrine glands in multiple organs and elevated levels of sweat sodium chloride. In cystic fibrosis, salt and fluid absorption is prevented by the loss of CFTR and ENaC is not appropriately regulated, resulting in increased fluid and sodium resorption from the airways and formation of a contracted viscous surface liquid layer. In the sweat glands both Na+ and Cl- ions are retained in the lumen, causing significant loss of electrolytes during sweating. Thus, elevated sweat NaCl concentration is the basis of the classic pilocarpine-induced sweat test as a diagnostic feature of the disease. Here we discuss the ion movement of Cl- and Na+ ions in two tissues, sweat glands and in the air surface as well as the role of ENaC in the pathogenesis of cystic fibrosis.

  7. Digestive system dysfunction in cystic fibrosis: challenges for nutrition therapy.

    PubMed

    Li, Li; Somerset, Shawn

    2014-10-01

    Cystic fibrosis can affect food digestion and nutrient absorption. The underlying mutation of the cystic fibrosis trans-membrane regulator gene depletes functional cystic fibrosis trans-membrane regulator on the surface of epithelial cells lining the digestive tract and associated organs, where Cl(-) secretion and subsequently secretion of water and other ions are impaired. This alters pH and dehydrates secretions that precipitate and obstruct the lumen, causing inflammation and the eventual degradation of the pancreas, liver, gallbladder and intestine. Associated conditions include exocrine pancreatic insufficiency, impaired bicarbonate and bile acid secretion and aberrant mucus formation, commonly leading to maldigestion and malabsorption, particularly of fat and fat-soluble vitamins. Pancreatic enzyme replacement therapy is used to address this insufficiency. The susceptibility of pancreatic lipase to acidic and enzymatic inactivation and decreased bile availability often impedes its efficacy. Brush border digestive enzyme activity and intestinal uptake of certain disaccharides and amino acids await clarification. Other complications that may contribute to maldigestion/malabsorption include small intestine bacterial overgrowth, enteric circular muscle dysfunction, abnormal intestinal mucus, and intestinal inflammation. However, there is some evidence that gastric digestive enzymes, colonic microflora, correction of fatty acid abnormalities using dietary n-3 polyunsaturated fatty acid supplementation and emerging intestinal biomarkers can complement nutrition management in cystic fibrosis.

  8. Students as Technicians: Screening Newborns for Cystic Fibrosis

    ERIC Educational Resources Information Center

    Gusky, Sharon

    2014-01-01

    In this activity, freshman college students learn biotechnology techniques while playing the role of a laboratory technician. They perform simulations of three diagnostic tests used to screen newborns for cystic fibrosis. By performing an ELISA, a PCR analysis, and a conductivity test, students learn how biotechnology techniques can be used to…

  9. Microbiology of airway disease in patients with cystic fibrosis.

    PubMed Central

    Gilligan, P H

    1991-01-01

    Individuals with cystic fibrosis have abbreviated life spans primarily due to chronic airway infection. A limited number of types of organisms are responsible for these infections, with Staphylococcus aureus and Pseudomonas aeruginosa being of primary importance. In the pre-antibiotic era, greater than 90% of deaths due to infection were caused by S. aureus and death usually occurred in the first 2 years of life. With the advent of effective antistaphylococcal therapy, life spans increased and P. aeruginosa became the pathogen of primary importance. P. aeruginosa isolates recovered from patients with cystic fibrosis have a unique phenotypic characteristic referred to as "mucoid." The mucoid phenotype is due to the production of a mucoid exopolysaccharide. A mucoid exopolysaccharide is believed to play a central role in the establishment of chronic pseudomonal lung infection in these patients. A third organism, Pseudomonas cepacia, has recently been detected in the airways of older patients with cystic fibrosis and is associated with increased mortality. The virulence of P. cepacia is not understood, but the organism is extremely refractory to antimicrobial therapy. Other bacteria, including Haemophilus influenzae and members of the family Enterobacteriaceae, appear to play a secondary role in airway infection. Aspergillus fumigatus is the most important fungal agent causing allergic bronchopulmonary disease. The role of viruses has only recently been examined. At least in some patients with cystic fibrosis, respiratory syncytial virus may be important in predisposing to subsequent bacterial infections. PMID:1900735

  10. Non-cystic fibrosis bronchiectasis: review and recent advances

    PubMed Central

    Livnat, Galit

    2009-01-01

    Bronchiectasis is an abnormal dilatation of bronchi and bronchioles associated with repeated cycles of airway infection and inflammation. This review will focus on non-cystic fibrosis bronchiectasis in children, with regard to etiology, diagnosis, treatment options, and recent advances. PMID:20948713

  11. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.

    PubMed

    Floto, R Andres; Olivier, Kenneth N; Saiman, Lisa; Daley, Charles L; Herrmann, Jean-Louis; Nick, Jerry A; Noone, Peadar G; Bilton, Diana; Corris, Paul; Gibson, Ronald L; Hempstead, Sarah E; Koetz, Karsten; Sabadosa, Kathryn A; Sermet-Gaudelus, Isabelle; Smyth, Alan R; van Ingen, Jakko; Wallace, Richard J; Winthrop, Kevin L; Marshall, Bruce C; Haworth, Charles S

    2016-01-01

    Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered 'good' agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition.

  12. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis

    PubMed Central

    Olivier, Kenneth N; Saiman, Lisa; Daley, Charles L; Herrmann, Jean-Louis; Nick, Jerry A; Noone, Peadar G; Bilton, Diana; Corris, Paul; Gibson, Ronald L; Hempstead, Sarah E; Koetz, Karsten; Sabadosa, Kathryn A; Sermet-Gaudelus, Isabelle; Smyth, Alan R; van Ingen, Jakko; Wallace, Richard J; Winthrop, Kevin L; Marshall, Bruce C; Haworth, Charles S

    2016-01-01

    Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered ‘good’ agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition. PMID:26666259

  13. International Committee on Mental Health in Cystic Fibrosis: Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus statements for screening and treating depression and anxiety

    PubMed Central

    Quittner, Alexandra L; Abbott, Janice; Georgiopoulos, Anna M; Goldbeck, Lutz; Smith, Beth; Hempstead, Sarah E; Marshall, Bruce; Sabadosa, Kathryn A; Elborn, Stuart

    2016-01-01

    Studies measuring psychological distress in individuals with cystic fibrosis (CF) have found high rates of both depression and anxiety. Psychological symptoms in both individuals with CF and parent caregivers have been associated with decreased lung function, lower body mass index, worse adherence, worse health-related quality of life, more frequent hospitalisations and increased healthcare costs. To identify and treat depression and anxiety in CF, the CF Foundation and the European CF Society invited a panel of experts, including physicians, psychologists, psychiatrists, nurses, social workers, a pharmacist, parents and an individual with CF, to develop consensus recommendations for clinical care. Over 18 months, this 22-member committee was divided into four workgroups: Screening; Psychological Interventions; Pharmacological Treatments and Implementation and Future Research, and used the Population, Intervention, Comparison, Outcome methodology to develop questions for literature search and review. Searches were conducted in PubMed, PsychINFO, ScienceDirect, Google Scholar, Psychiatry online and ABDATA by a methodologist at Dartmouth. The committee reviewed 344 articles, drafted statements and set an 80% acceptance for each recommendation statement as a consensus threshold prior to an anonymous voting process. Fifteen guideline recommendation statements for screening and treatment of depression and anxiety in individuals with CF and parent caregivers were finalised by vote. As these recommendations are implemented in CF centres internationally, the process of dissemination, implementation and resource provision should be closely monitored to assess barriers and concerns, validity and use. PMID:26452630

  14. Synthesis of sulfated oligosaccharides by cystic fibrosis trachea epithelial cells.

    PubMed

    Mendicino, J; Sangadala, S

    1999-11-01

    The mucin glycoproteins in tracheal mucus of patients with cystic fibrosis is more highly sulfated than the corresponding secretions from healthy individuals [16]. In order to further characterize these differences in sulfation and possibly also glycosylation patterns, we compared the structures of sulfated mucin oligosaccharides synthesized by continuously cultured human tracheal cells transformed by simian virus 40. The synthesis of highly sulfated oligosaccharide chains in mucins secreted by normal human epithelial and submucosal cell lines were compared with mucins formed by cystic fibrosis tracheal epithelial and submucosal cell lines. The epithelial cell lines from cystic fibrosis trachea showed a higher rate of sulfate uptake and a significantly higher rate of synthesis and sulfation of high molecular weight chains. Mucins synthesized by each cell line in the presence of 35SO4 were isolated and oligosaccharide chains were released by beta-elimination and separated by ion exchange chromatography and gel filtration. The sulfated high molecular weight chains synthesized by the cystic fibrosis cell lines were characterized by methylation analysis and sequential glycosidase digestion before and after desulfation. Carbohydrate analysis yielded Fuc, Gal and GlcNAc in a ratio of 1:2:2.2 and only one galactosaminitol residue for about every 150-200 sugar residues present. The average molecular size of oligosaccharide chains in these fractions was between 30,000-40,000 daltons. These studies show that increased sulfation of oligosaccharides in mucins synthesized by cells from cystic fibrosis trachea is accompanied by a significant increase in the extension of a basic branched structure present in many of the lower molecular weight oligosaccharides.

  15. Treatment and prognosis of nasal polyps in cystic fibrosis.

    PubMed

    Stern, R C; Boat, T F; Wood, R E; Matthews, L W; Doershuk, C F

    1982-12-01

    Nasal polyposis complicated the course of fibrosis in 157 (26%) of 605 patients. Onset before age 5 years or after age 20 years was rare. Polyposis was the initial symptom of cystic fibrosis in 13 patients. Common symptoms included obstruction to nasal air flow, mouth breathing, epistaxis, and rhinorrhea. Intranasal and oral corticosteroids and antihistamines were ineffective in preventing recurrences but did occasionally afford symptomatic relief of obstruction. Nineteen (31%) of 62 patients who never had surgery had spontaneous and permanent disappearance of polyps. Simple polypectomy was an adequate procedure for patients with substantial nasal symptoms. There were no visual complications. Other surgical complications were rare. Children and adolescents with nasal polyps should have sweat tests by pilocarpine iontophoresis to rule out cystic fibrosis.

  16. Changing susceptibility of Pseudomonas aeruginosa isolates from cystic fibrosis patients with the clinical use of newer antibiotics.

    PubMed Central

    Bosso, J A; Allen, J E; Matsen, J M

    1989-01-01

    To detect a change in antibiotic susceptibility patterns in Pseudomonas aeruginosa isolates upon the introduction and clinical use of ciprofloxacin, aztreonam, and ceftazidime, MICs for clinical isolates collected before introduction of the antibiotics, during early clinical use, and later were determined for these and seven other antipseudomonal antibiotics. Concomitant resistance to two or more antibiotics was also studied. Over the three study periods, rates of susceptibility to 9 of the 10 antibiotics decreased. The largest decrease occurred with ceftazidime. Analysis of subsets of isolates from patients treated with ciprofloxacin or aztreonam also showed declining susceptibility to the latter but a stabilization of susceptibility to the former after an initial decline. Concomitant resistance within and among antibiotic classes was common. PMID:2499252

  17. Molecular Characterization of Achromobacter Isolates from Cystic Fibrosis and Non-Cystic Fibrosis Patients in Madrid, Spain

    PubMed Central

    Barrado, Laura; Brañas, Patricia; Orellana, M. Ángeles; Martínez, M. Teresa; García, Gloria; Otero, Joaquín R.

    2013-01-01

    Multilocus sequence typing and nrdA sequence analysis identified 6 different species or genogroups and 13 sequence types (STs) among 15 Achromobacter isolates from cystic fibrosis (CF) patients and 7 species or genogroups and 11 STs among 11 isolates from non-CF patients. Achromobacter xylosoxidans was the most frequently isolated species among CF patients. PMID:23536401

  18. Personalized Drug Therapy in Cystic Fibrosis: From Fiction to Reality.

    PubMed

    de Lima Marson, Fernando Augusto; Bertuzzo, Carmen Silvia; Ribeiro, Jose Dirceu

    2015-01-01

    Personalized drug therapy for cystic fibrosis (CF) is a long-term dream for CF patients, caregivers, physicians and researchers. After years of study, the fiction of personalized treatment has turned to hope. Basic information about CFTR mutations classes and new treatments is needed if we are to deal properly with the new CF era. The problems involved in this issue, however, should be evaluated with greater care and attention. VX-770 is a new drug available to treat CF patients with some class III CFTR mutations and other drugs are being studied regarding other classes. The scientific literature has constantly given information about each therapy, both in vitro and in vivo. The hope is increasing. Nevertheless the "scientific world" still lacks information about patients' reality and daily health related practical needs. Clinical trials have showed good evaluation of some drugs so far, but clinical response is a wide spectrum yet to be analyzed: CFTR mutations spectrum, costs related to the treatment with new drugs (for VX-770 therapy), variability of CF clinical expression, limitations to test in vitro drugs, absence of good clinical markers to evaluate drug response, absence of long-term studies and with patients below six years old, multidrug treatment used to improve the expression response, and finally, the most important problem, who will benefit from the new drugs therapy, are issues that constitute a barrier that should be overcome. Personalized drug therapy may not be a fiction anymore, but it is not yet a reality for all CF patients.

  19. Current strategies for the long-term assessment, monitoring, and management of cystic fibrosis patients treated with CFTR modulator therapy.

    PubMed

    Elborn, J Stuart; Davies, Jane; Mall, Marcus A; Flume, Patrick A; Plant, Barry

    2017-01-01

    The content for this activity is based on the satellite symposium, "Current Strategies for the Long-term Assessment, Monitoring, and Management for Cystic Fibrosis Patients Treated with CFTR Modulator Therapy" that was presented at the 39th European Cystic Fibrosis Society Conference on June 10, 2016 (Online access: http://courses.elseviercme.com/ecfs2016e/619e). The emergence of novel targeted agents, that directly correct CFTR loss function alleles, has created new treatment opportunities for patients with cystic fibrosis with advanced disease. Knowledge of the role of these agents in the clinical setting is quickly evolving and will require physicians to stay acquainted with the latest data as well as evidence-based treatment guidelines in order to achieve optimized cystic fibrosis patient care. Ideally, after diagnosis, a personalized approach would be adapted and tailored to the patient through genome-informed medicine. However, due to the relative recentness of genomic-based therapeutics, physicians may have a limited knowledge base regarding these new treatment options and how to best incorporate these agents into patient management plans. Although cystic fibrosis is still largely regarded as a pediatric disease, the median survival for patients is 35years of age. Consequently, pediatric-to-adult cystic fibrosis care programs would allow suitable preparation time for this transition and develop a standardized group of self-care and management skills.

  20. Environmental Pseudomonads Inhibit Cystic Fibrosis Patient-Derived Pseudomonas aeruginosa.

    PubMed

    Chatterjee, Payel; Davis, Elizabeth; Yu, Fengan; James, Sarah; Wildschutte, Julia H; Wiegmann, Daniel D; Sherman, David H; McKay, Robert M; LiPuma, John J; Wildschutte, Hans

    2017-01-15

    Pseudomonas aeruginosa is an opportunistic pathogen which is evolving resistance to many currently used antibiotics. While much research has been devoted to the roles of pathogenic P. aeruginosa in cystic fibrosis (CF) patients, less is known of its ecological properties. P. aeruginosa dominates the lungs during chronic infection in CF patients, yet its abundance in some environments is less than that of other diverse groups of pseudomonads. Here, we sought to determine if clinical isolates of P. aeruginosa are vulnerable to environmental pseudomonads that dominate soil and water habitats in one-to-one competitions which may provide a source of inhibitory factors. We isolated a total of 330 pseudomonads from diverse habitats of soil and freshwater ecosystems and competed these strains against one another to determine their capacity for antagonistic activity. Over 900 individual inhibitory events were observed. Extending the analysis to P. aeruginosa isolates revealed that clinical isolates, including ones with increased alginate production, were susceptible to competition by multiple environmental strains. We performed transposon mutagenesis on one isolate and identified an ∼14.8-kb locus involved in antagonistic activity. Only two other environmental isolates were observed to carry the locus, suggesting the presence of additional unique compounds or interactions among other isolates involved in outcompeting P. aeruginosa This collection of strains represents a source of compounds that are active against multiple pathogenic strains. With the evolution of resistance of P. aeruginosa to currently used antibiotics, these environmental strains provide opportunities for novel compound discovery against drug-resistant clinical strains.

  1. Ivacaftor: a review of its use in patients with cystic fibrosis.

    PubMed

    Deeks, Emma D

    2013-09-01

    Ivacaftor (Kalydeco™) is a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first drug that treats an underlying cause of cystic fibrosis to be licensed for use. Ivacaftor increases the open probability (i.e. gating) of CFTR channels with the G551D mutation, thus enhancing chloride transport, and is indicated in a number of countries for the treatment of cystic fibrosis in patients aged ≥6 years who carry this mutation. This review focuses on pharmacological, clinical efficacy and tolerability data relevant to the use of ivacaftor in this indication. In two 48-week, double-blind, phase III trials in patients aged ≥12 (STRIVE) or 6-11 (ENVISION) years with cystic fibrosis and the G551D mutation, oral ivacaftor 150 mg every 12 h significantly improved lung function relative to placebo, when used in combination with standard care. Significant improvements in pulmonary exacerbation risk (in STRIVE) as well as bodyweight and some aspects of health-related quality of life (both studies) were also seen with the drug versus placebo. Moreover, the beneficial effects of ivacaftor on parameters such as lung function and bodyweight were maintained over up to 96 weeks of treatment in an ongoing open-label extension of these studies. Ivacaftor was generally well tolerated, with headache, oropharyngeal pain, upper respiratory tract infection and nasal congestion being among the most common adverse events. Thus, ivacaftor expands the current treatment options for patients with cystic fibrosis who have the G551D mutation. Its potential for use in patients with other CFTR mutations is also of interest.

  2. Genetic Influences on Cystic Fibrosis Lung Disease Severity

    PubMed Central

    Weiler, Colleen A.; Drumm, Mitchell L.

    2013-01-01

    Understanding the causes of variation in clinical manifestations of disease should allow for design of new or improved therapeutic strategies to treat the disease. If variation is caused by genetic differences between individuals, identifying the genes involved should present therapeutic targets, either in the proteins encoded by those genes or the pathways in which they function. The technology to identify and genotype the millions of variants present in the human genome has evolved rapidly over the past two decades. Originally only a small number of polymorphisms in a small number of subjects could be studied realistically, but speed and scope have increased nearly as dramatically as cost has decreased, making it feasible to determine genotypes of hundreds of thousands of polymorphisms in thousands of subjects. The use of such genetic technology has been applied to cystic fibrosis (CF) to identify genetic variation that alters the outcome of this single gene disorder. Candidate gene strategies to identify these variants, referred to as “modifier genes,” has yielded several genes that act in pathways known to be important in CF and for these the clinical implications are relatively clear. More recently, whole-genome surveys that probe hundreds of thousands of variants have been carried out and have identified genes and chromosomal regions for which a role in CF is not at all clear. Identification of these genes is exciting, as it provides the possibility for new areas of therapeutic development. PMID:23630497

  3. Sleep-disordered breathing in patients with cystic fibrosis *

    PubMed Central

    Veronezi, Jefferson; Carvalho, Ana Paula; Ricachinewsky, Claudio; Hoffmann, Anneliese; Kobayashi, Danielle Yuka; Piltcher, Otavio Bejzman; Silva, Fernando Antonio Abreu e; Martinez, Denis

    2015-01-01

    Abstract Objective: To test the hypothesis that disease severity in patients with cystic fibrosis (CF) is correlated with an increased risk of sleep apnea. Methods: A total of 34 CF patients underwent clinical and functional evaluation, as well as portable polysomnography, spirometry, and determination of IL-1β levels. Results: Mean apnea-hypopnea index (AHI), SpO2 on room air, and Epworth Sleepiness Scale score were 4.8 ± 2.6, 95.9 ± 1.9%, and 7.6 ± 3.8 points, respectively. Of the 34 patients, 19 were well-nourished, 6 were at nutritional risk, and 9 were malnourished. In the multivariate model to predict the AHI, the following variables remained significant: nutritional status (β = −0.386; p = 0.014); SpO2 (β = −0.453; p = 0.005), and the Epworth Sleepiness Scale score (β = 0.429; p = 0.006). The model explained 51% of the variation in the AHI. Conclusions: The major determinants of sleep apnea were nutritional status, SpO2, and daytime sleepiness. This knowledge not only provides an opportunity to define the clinical risk of having sleep apnea but also creates an avenue for the treatment and prevention of the disease. PMID:26398755

  4. CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

    PubMed Central

    Lopes-Pacheco, Miquéias

    2016-01-01

    Cystic fibrosis (CF) is the most common life-threatening monogenic disease afflicting Caucasian people. It affects the respiratory, gastrointestinal, glandular and reproductive systems. The major cause of morbidity and mortality in CF is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue remodeling and end-stage lung disease. Over the past decades, life expectancy of CF patients has increased due to early diagnosis and improved treatments; however, these patients still present limited quality of life. Many attempts have been made to rescue CF transmembrane conductance regulator (CFTR) expression, function and stability, thereby overcoming the molecular basis of CF. Gene and protein variances caused by CFTR mutants lead to different CF phenotypes, which then require different treatments to quell the patients’ debilitating symptoms. In order to seek better approaches to treat CF patients and maximize therapeutic effects, CFTR mutants have been stratified into six groups (although several of these mutations present pleiotropic defects). The research with CFTR modulators (read-through agents, correctors, potentiators, stabilizers and amplifiers) has achieved remarkable progress, and these drugs are translating into pharmaceuticals and personalized treatments for CF patients. This review summarizes the main molecular and clinical features of CF, emphasizes the latest clinical trials using CFTR modulators, sheds light on the molecular mechanisms underlying these new and emerging treatments, and discusses the major breakthroughs and challenges to treating all CF patients. PMID:27656143

  5. Cystic fibrosis transmembrane conductance regulator expression in human hypothalamus.

    PubMed

    Mulberg, A E; Weyler, R T; Altschuler, S M; Hyde, T M

    1998-01-05

    We have previously characterized the expression of the cystic fibrosis transmembrane conductance regulator protein (CFTR) gene, mRNA and protein in rat brain with reverse transcriptase (RT)-PCR amplification, in situ hybridization and immunocytochemistry. We now report that the CFTR mRNA is expressed in the human anterior hypothalamus, an area involved in regulation of appetite, resting energy expenditure and sexual differentiation. Expression of CFTR in neurons localized to this region may elucidate the pathogenesis of other non-pulmonary manifestations of cystic fibrosis which commonly are observed in children with CF, including congenital absence of the vas deferens. Neuron-specific expression of CFTR in brain may be involved in the regulation of homeostatic functions including reproductive function and fertility through effects on neurosecretion, i.e. GnRH release. Dysregulation of normal neuropeptide vesicle trafficking by mutant CFTR in brain my lead to alteration in physiological function.

  6. Analysis of 16 cystic fibrosis mutations in Mexican patients

    SciTech Connect

    Villalobos-Torres, C.; Rojas-Martinez, A.; Barrera-Saldana, H.A.

    1997-04-14

    We carried out molecular analysis of 80 chromosomes from 40 unrelated Mexican patients with a diagnosis of cystic fibrosis. The study was performed in two PCR steps: a preliminary one to identify mutation AF508, the most frequent cause of cystic fibrosis worldwide, and the second a reverse dot-blot with allele-specific oligonucleotide probes to detect 15 additional common mutations in the Caucasian population. A frequency of 45% for AF508 was found, making it the most common in our sample of Mexican patients. Another five mutations (G542X, 3849 + 10 kb C{r_arrow}T, N1303K, S549N, and 621 + 1 G{r_arrow}T) were detected, and these accounted for 11.25%. The remaining mutations (43.75%) were undetectable with the methodology used. 20 refs., 2 tabs.

  7. Multifunctional superparamagnetic nanoparticles for enhanced drug transport in cystic fibrosis

    NASA Astrophysics Data System (ADS)

    Armijo, Leisha M.; Brandt, Yekaterina I.; Rivera, Antonio C.; Cook, Nathaniel C.; Plumley, John B.; Withers, Nathan J.; Kopciuch, Michael; Smolyakov, Gennady A.; Huber, Dale L.; Smyth, Hugh D.; Osinski, Marek

    2012-10-01

    Iron oxide colloidal nanoparticles (ferrofluids) are investigated for application in the treatment of cystic fibrosis lung infections, the leading cause of mortality in cystic fibrosis patients. We investigate the use of iron oxide nanoparticles to increase the effectiveness of administering antibiotics through aerosol inhalation using two mechanisms: directed particle movement in the presence of an inhomogeneous static external magnetic field and magnetic hyperthermia. Magnetic hyperthermia is an effective method for decreasing the viscosity of the mucus and biofilm, thereby enhancing drug, immune cell, and antibody penetration to the affected area. Iron oxide nanoparticles of various sizes and morphologies were synthesized and tested for specific losses (heating power). Nanoparticles in the superparamagnetic to ferromagnetic size range exhibited excellent heating power. Additionally, iron oxide / zinc selenide core/shell nanoparticles were prepared, in order to enable imaging of the iron oxide nanoparticles. We also report on synthesis and characterization of MnSe/ZnSeS alloyed quantum dots.

  8. Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences

    PubMed Central

    McElvaney, Noel G.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic neutrophil-dominated inflammation. Much knowledge surrounding the pathophysiology of the disease has been gained through the generation of animal models, despite inherent limitations in each. The failure of certain mouse models to recapitulate the phenotypic manifestations of human disease has initiated the generation of larger animals in which to study CF, including the pig and the ferret. This review will summarise the basic phenotypes of three animal models and describe the contributions of such animal studies to our current understanding of CF. PMID:27340661

  9. Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

    PubMed Central

    Campόdonico, Victoria L; Gadjeva, Mihaela; Paradis-Bleau, Catherine; Uluer, Ahmet; Pier, Gerald B

    2013-01-01

    Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism. PMID:18262467

  10. ATPase activity of the cystic fibrosis transmembrane conductance regulator.

    PubMed

    Li, C; Ramjeesingh, M; Wang, W; Garami, E; Hewryk, M; Lee, D; Rommens, J M; Galley, K; Bear, C E

    1996-11-08

    The gene mutated in cystic fibrosis codes for the cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP-activated chloride channel thought to be critical for salt and water transport by epithelial cells. Plausible models exist to describe a role for ATP hydrolysis in CFTR channel activity; however, biochemical evidence that CFTR possesses intrinsic ATPase activity is lacking. In this study, we report the first measurements of the rate of ATP hydrolysis by purified, reconstituted CFTR. The mutation CFTRG551D resides within a motif conserved in many nucleotidases and is known to cause severe human disease. Following reconstitution the mutant protein exhibited both defective ATP hydrolysis and channel gating, providing direct evidence that CFTR utilizes ATP to gate its channel activity.

  11. Family structure and mothers' caregiving of children with cystic fibrosis.

    PubMed

    Gayer, Debra; Ganong, Lawrence

    2006-11-01

    The purpose of this investigation is to examine differences in the experiences of mothers of children with cystic fibrosis who are in diverse family structures (first-marriage families, stepfamily households, single-parent households). In particular, mothers' perceptions of children's health, adherence to prescribed treatments, and help received from others were compared and predictors of treatment adherence were examined. Children's health and adherence to treatment regimens were not related to family structure. Mothers had the major responsibility for seeing that cystic fibrosis treatments were followed, regardless of family structure. Single mothers received less help than married and repartnered mothers. Married fathers helped with treatments more than nonresidential divorced fathers and stepfathers. Implications for nursing practice and suggestions for future research are offered.

  12. Intermediate-range sweat chloride concentration and Pseudomonas bronchitis. A cystic fibrosis variant with preservation of exocrine pancreatic function.

    PubMed

    Stern, R C; Boat, T F; Abramowsky, C R; Matthews, L W; Wood, R E; Doershuk, C F

    1978-06-23

    We studied the clinical and laboratory characteristics of seven patients with sweat chloride concentration consistently between 40 and 60 mEq/liter. Each has chronic Pseudomonas bronchitis, and all lack digestive symptoms. Laboratory findings indicate the preservation of exocrine pancreatic function. The patients include two of five children in one family and two of four in another. In a third family, one of five siblings has an intermediate sweat chloride concentration, but another has a typical fibrosis value (105 mEq/liter). One patient died of respiratory failure; results of an autopsy showed bronchiolectasis typical of cystic fibrosis, but minimal pancreatic changes. The data suggest a genetic basis for this variant of cystic fibrosis. These patients may be homozygous for a portion of a closely linked multigene cystic fibrosis locus or may have modifier genes that ameliorate the pancreatic and sweat lesions.

  13. Improvement of hepatic steatosis in cystic fibrosis with ivacaftor therapy.

    PubMed

    Hayes, Don; Warren, Patrick S; McCoy, Karen S; Sheikh, Shahid I

    2015-05-01

    Treatment of liver disease, including hepatic steatosis, in patients with cystic fibrosis (CF) is limited. With the development of ivacaftor, which corrects the gating defect of the CF transmembrane regulator channel, there is a potential new therapy available for this subgroup of the CF patient population. We present an adolescent with CF who had significant improvement in hepatic steatosis with ivacaftor treatment while hypothesizing on a mechanism of why it occurred.

  14. Cystic fibrosis compatible with a full term army engagement.

    PubMed

    Jackson, S M J S; Cooper, N K

    2011-09-01

    A case of a specialist senior non-commissioned officer with cystic fibrosis (CF) is described. Partial expression of the CF trait is well known and sporadic cases are detected from time to time at recruitment, during recruit training and service. Respiratory symptoms may be mis-diagnosed as self-limiting asthma until a sweat chloride or other specific test for CF is performed.

  15. Model of mucociliary clearance in cystic fibrosis lungs.

    PubMed

    Kurbatova, P; Bessonov, N; Volpert, V; Tiddens, H A W M; Cornu, C; Nony, P; Caudri, D

    2015-05-07

    Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways.

  16. Validity of a modified shuttle test in adult cystic fibrosis

    PubMed Central

    Bradley, J.; Howard, J.; Wallace, E.; Elborn, S.

    1999-01-01

    BACKGROUND—The purpose of this study was to provide some evidence of the validity of a modified shuttle test (MST) by comparing performance on the MST with peak oxygen consumption (V̇O2peak) measured during a treadmill test in a group of adult patients with cystic fibrosis.
METHOD—Twenty patients with stable cystic fibrosis performed a ramped maximal treadmill test (STEEP protocol) and the MST using a randomised balanced design.
RESULTS—The relationship between the distance achieved on the MST and V̇O2peak was strong (r = 0.95, p<0.01) with 90% of the variance in V̇O2peak explained by the variance in MST distance. The relationship was represented by the regression equation (with 95% confidence intervals) V̇O2peak = 6.83 (2.85 to 10.80) + 0.028 (0.019 to 0.024)× MST distance.
CONCLUSION—This study provides evidence of the construct validity of the MST as an objective measure of exercise capacity in adults with cystic fibrosis.

 PMID:10212110

  17. A Haplotype Framework for Cystic Fibrosis Mutations in Iran

    PubMed Central

    Elahi, Elahe; Khodadad, Ahmad; Kupershmidt, Ilya; Ghasemi, Fereshteh; Alinasab, Babak; Naghizadeh, Ramin; Eason, Robert G.; Amini, Mahshid; Esmaili, Mehran; Esmaeili Dooki, Mohammad R.; Sanati, Mohammad H.; Davis, Ronald W.; Ronaghi, Mostafa; Thorstenson, Yvonne R.

    2006-01-01

    This is the first comprehensive profile of cystic fibrosis transmembrane conductance regulator (CFTR) mutations and their corresponding haplotypes in the Iranian population. All of the 27 CFTR exons of 60 unrelated Iranian CF patients were sequenced to identify disease-causing mutations. Eleven core haplotypes of CFTR were identified by genotyping six high-frequency simple nucleotide polymorphisms. The carrier frequency of 2.5 in 100 (1 in 40) was estimated from the frequency of heterozygous patients and suggests that contrary to popular belief, cystic fibrosis may be a common, under-diagnosed disease in Iran. A heterogeneous mutation spectrum was observed at the CFTR locus in 60 cystic fibrosis (CF) patients from Iran. Twenty putative disease-causing mutations were identified on 64 (53%) of the 120 chromosomes. The five most common Iranian mutations together represented 37% of the expected mutated alleles. The most frequent mutation, ΔF508 (p.F508del), represented only 16% of the expected mutated alleles. The next most frequent mutations were c.1677del2 (p.515fs) at 7.5%, c.4041C>G (p.N1303K) at 5.6%, c.2183AA>G (p.684fs) at 5%, and c.3661A>T (p.K1177X) at 2.5%. Three of the five most frequent Iranian mutations are not included in a commonly used panel of CF mutations, underscoring the importance of identifying geographic-specific mutations in this population. PMID:16436643

  18. A haplotype framework for cystic fibrosis mutations in Iran.

    PubMed

    Elahi, Elahe; Khodadad, Ahmad; Kupershmidt, Ilya; Ghasemi, Fereshteh; Alinasab, Babak; Naghizadeh, Ramin; Eason, Robert G; Amini, Mahshid; Esmaili, Mehran; Esmaeili Dooki, Mohammad R; Sanati, Mohammad H; Davis, Ronald W; Ronaghi, Mostafa; Thorstenson, Yvonne R

    2006-02-01

    This is the first comprehensive profile of cystic fibrosis transmembrane conductance regulator (CFTR) mutations and their corresponding haplotypes in the Iranian population. All of the 27 CFTR exons of 60 unrelated Iranian CF patients were sequenced to identify disease-causing mutations. Eleven core haplotypes of CFTR were identified by genotyping six high-frequency simple nucleotide polymorphisms. The carrier frequency of 2.5 in 100 (1 in 40) was estimated from the frequency of heterozygous patients and suggests that contrary to popular belief, cystic fibrosis may be a common, under-diagnosed disease in Iran. A heterogeneous mutation spectrum was observed at the CFTR locus in 60 cystic fibrosis (CF) patients from Iran. Twenty putative disease-causing mutations were identified on 64 (53%) of the 120 chromosomes. The five most common Iranian mutations together represented 37% of the expected mutated alleles. The most frequent mutation, DeltaF508 (p.F508del), represented only 16% of the expected mutated alleles. The next most frequent mutations were c.1677del2 (p.515fs) at 7.5%, c.4041C>G (p.N1303K) at 5.6%, c.2183AA>G (p.684fs) at 5%, and c.3661A>T (p.K1177X) at 2.5%. Three of the five most frequent Iranian mutations are not included in a commonly used panel of CF mutations, underscoring the importance of identifying geographic-specific mutations in this population.

  19. Highlights of the 28(th) North American Cystic Fibrosis Conference 2014.

    PubMed

    Nwokoro, Chinedu E C

    2015-10-01

    This is a selection of papers presented at the 28(th) North American Cystic Fibrosis Conference held in Atlanta in October 2014. The papers discussed are thought to be of particular interest to CF caregivers in the UK. Topics discussed include recent progress in the modification of the cystic fibrosis transmembrane regulator (CFTR), the potential of OligoG, a novel inhaled alginate mucolytic, and the changing approach to cystic fibrosis-related diabetes screening.

  20. Recent advances in understanding and managing cystic fibrosis transmembrane conductance regulator dysfunction

    PubMed Central

    Alton, Eric W.F.W.

    2015-01-01

    Cystic fibrosis is the most common autosomal recessive genetic disease in Caucasians and has been extensively studied for many decades. The cystic fibrosis transmembrane conductance regulator gene was identified in 1989. It encodes a complex protein which has numerous cellular functions. Our understanding of cystic fibrosis pathophysiology and genetics is constantly expanding and being refined, leading to improved management of the disease and increased life expectancy in affected individuals. PMID:26097737

  1. Early airway infection, inflammation, and lung function in cystic fibrosis

    PubMed Central

    Nixon, G; Armstrong, D; Carzino, R; Carlin, J; Olinsky, A; Robertson, C; Grimwood, K

    2002-01-01

    Aims: To determine the relation between lower airway infection and inflammation, respiratory symptoms, and lung function in infants and young children with cystic fibrosis (CF). Methods: A prospective study of children with CF aged younger than 3 years, diagnosed by a newborn screening programme. All were clinically stable and had testing as outpatients. Subjects underwent bronchial lavage (BL) and lung function testing by the raised volume rapid thoracoabdominal compression technique under general anaesthesia. BL fluid was cultured and analysed for neutrophil count, interleukin 8, and neutrophil elastase. Lung function was assessed by forced expiratory volume in 0.5, 0.75, and 1 second. Results: Thirty six children with CF were tested on 54 occasions. Lower airway infection shown by BL was associated with a 10% reduction in FEV0.5 compared with subjects without infection. No relation was identified between airway inflammation and lung function. Daily moist cough within the week before testing was reported on 20/54 occasions, but in only seven (35%) was infection detected. Independent of either infection status or airway inflammation, those with daily cough had lower lung function than those without respiratory symptoms at the time of BL (mean adjusted FEV0.5 195 ml and 236 ml respectively). Conclusions: In young children with CF, both respiratory symptoms and airway infection have independent, additive effects on lung function, unrelated to airway inflammation. Further studies are needed to understand the mechanisms of airway obstruction in these young patients. PMID:12244003

  2. Nocturnal hypoxemia in children and adolescents with cystic fibrosis*

    PubMed Central

    Ramos, Regina Terse Trindade; Santana, Maria Angélica Pinheiro; Almeida, Priscila de Carvalho; Machado, Almério de Souza; Araújo-Filho, José Bouzas; Salles, Cristina

    2013-01-01

    OBJECTIVE: To determine the prevalence of nocturnal hypoxemia and its association with pulmonary function, nutritional status, sleep macrostructure, and obstructive respiratory events during sleep in a population of clinically stable children and adolescents with cystic fibrosis (CF). METHODS: This was a cross-sectional study involving 67 children and adolescents with CF between 2 and 14 years of age. All of the participants underwent polysomnography, and SpO2 was measured by pulse oximetry. We also evaluated the Shwachman-Kulczycki (S-K) scores, spirometry findings, and nutritional status of the patients. RESULTS: The study involved 67 patients. The mean age of the patients was 8 years. The S-K scores differed significantly between the patients with and without nocturnal hypoxemia, which was defined as an SpO2 < 90% for more than 5% of the total sleep time (73.75 ± 6.29 vs. 86.38 ± 8.70; p < 0.01). Nocturnal hypoxemia correlated with the severity of lung disease, FEV1 (rs = −0.42; p = 0.01), FVC (rs = −0.46; p = 0.01), microarousal index (rs = 0.32; p = 0.01), and apnea-hypopnea index (rs = 0.56; p = 0.01). CONCLUSIONS: In this sample of patients with CF and mild-to-moderate lung disease, nocturnal oxygenation correlated with the S-K score, spirometry variables, sleep macrostructure variables, and the apnea-hypopnea index. PMID:24473760

  3. Bacteriophages as vehicles of the resistome in cystic fibrosis.

    PubMed

    Rolain, Jean Marc; Fancello, Laura; Desnues, Christelle; Raoult, Didier

    2011-11-01

    Environmental microbial communities and human microbiota represent a huge reservoir of mobilizable genes, the 'mobilome', including a pool of genes encoding antimicrobial resistance, the 'resistome'. Whole-genome sequencing of bacterial genomes from cystic fibrosis (CF) patients has demonstrated that bacteriophages contribute significantly to bacterial genome alterations, and metagenomic analysis of respiratory tract DNA viral communities has revealed the presence of genes encoding antimicrobial resistance in bacteriophages of CF patients. CF airways should now be considered as the site of complex microbiota, where bacteriophages are vehicles for the adaptation of bacteria to this specific environment and for the emergence and selection of multidrug-resistant bacteria with chimeric repertoires. As phages are already known to be mobilized during chronic infection of the lungs of patients with CF, it seems particularly important to improve the understanding of the mechanisms of phage induction to prevent the spread of virulence and/or antimicrobial resistance determinants within the CF population as well as in the community. Such a modern point of view may be a seminal reflection for clinical practice in the future since current antimicrobial therapy guidelines in the context of CF may lead to the emergence of genes encoding antimicrobial resistance.

  4. Orphan Missense Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator

    PubMed Central

    Fresquet, Fleur; Clement, Romain; Norez, Caroline; Sterlin, Adélaïde; Melin, Patricia; Becq, Frédéric; Kitzis, Alain; Thoreau, Vincent; Bilan, Frédéric

    2011-01-01

    More than 1860 mutations have been found within the human cystic fibrosis transmembrane conductance regulator (CFTR) gene sequence. These mutations can be classified according to their degree of severity in CF disease. Although the most common mutations are well characterized, few data are available for rare mutations. Thus, genetic counseling is particularly difficult when fetuses or patients with CF present these orphan variations. We describe a three-step in vitro assay that can evaluate rare missense CFTR mutation consequences to establish a correlation between genotype and phenotype. By using a green fluorescent protein–tagged CFTR construct, we expressed mutated proteins in COS-7 cells. CFTR trafficking was visualized by confocal microscopy, and the cellular localization of CFTR was determined using intracellular markers. We studied the CFTR maturation process using Western blot analysis and evaluated CFTR channel activity by automated iodide efflux assays. Of six rare mutations that we studied, five have been isolated in our laboratory. The cellular and functional impact that we observed in each case was compared with the clinical data concerning the patients in whom we encountered these mutations. In conclusion, we propose that performing this type of analysis for orphan CFTR missense mutations can improve CF genetic counseling. PMID:21708286

  5. Neonatal screening for cystic fibrosis: present and future.

    PubMed

    Wilcken, B; Travert, G

    1999-12-01

    Despite there being effective tests for detecting cystic fibrosis (CF) using newborn screening blood samples, screening in neonates has not had universal approval because of uncertainty about its benefits. After up to 18 y experience, at a recent conference in Caen several aspects attracted universal agreement. There is still major delay in clinical diagnosis after the onset of symptoms. There is short-term benefit in early diagnosis by screening, with reduced morbidity in the first 2 y, evidence of significant nutritional benefits up to the age of 10 y, and probable respiratory benefit over this time frame. There is great potential for research into treatment modalities and no evidence of significant psychological harm to CF babies from early diagnosis. With a screening protocol that includes a DNA test there is some unwanted carrier detection and careful genetic counselling is needed. There is no evidence yet that screening will extend the life of CF patients, so some doubts remain as to its overall effectiveness, and there have been no good studies on comparative costs in screened and unscreened cohorts. Even so, the weight of evidence suggests very worthwhile advantages for screened babies and their families. Because of this, it is unlikely that further trials will take place. It may be that the onus now is on those who do not support screening to justify this stance to parents who may favour it.

  6. Cystic fibrosis transmembrane conductance regulator protein expression in the male excretory duct system during development.

    PubMed

    Marcorelles, Pascale; Gillet, Danièle; Friocourt, Gaëlle; Ledé, Françoise; Samaison, Laura; Huguen, Geneviève; Ferec, Claude

    2012-03-01

    Sterility due to bilateral destruction in utero or in early infancy resulting in congenital absence of the vas deferens is the rule in male patients with cystic fibrosis. To understand the developmental pattern of this anomaly, the microscopic morphology of the male excretory system was analyzed during development and the expression of the cystic fibrosis transmembrane conductance regulator protein was explored by immunohistochemistry. We observed that cystic fibrosis fetuses had no excretory ducts agenesis or obstruction until 22 weeks of gestation. However, a focal inflammatory pattern and mucinous plugs in the oldest cystic fibrosis case suggested a disruptive mechanism. Immunolabeling of cytoplasmic epithelial cystic fibrosis transmembrane conductance regulator protein was demonstrated in all cystic fibrosis and control cases with a similar pattern of expression of the protein between age-matched controls and cystic fibrosis cases. At midgestation, an apical intensification appeared in both cystic fibrosis and control cases and was stable during the remainder of fetal life. No gradient of intensity could be detected between the different segments of the excretory tract. These findings are different from those reported in adults. The absence of any morphologic anomaly until 22 weeks of gestation, the focal destruction of the epithelial structures during the second trimester, and the chronological pattern of expression of cystic fibrosis transmembrane conductance regulator are of interest for a better understanding of the pathophysiology of this disease.

  7. Flow rate and inorganic components of submandibular saliva in cystic fibrosis

    PubMed Central

    Blomfield, Jeanette; Warton, Kathryn L.; Brown, J. M.

    1973-01-01

    The inorganic components of submandibular saliva were determined in 35 patients with cystic fibrosis and in 28 controls. No differences due to flow rate were apparent between the two groups. At comparable flow rates, cystic fibrosis submandibular saliva had higher concentrations of calcium, sodium, and chloride, and similar concentrations of magnesium, inorganic phosphate, potassium, copper, and zinc. The insoluble, turbid fraction of the cystic fibrosis submandibular saliva contained both calcium and phosphate, and these were precipitated in a ratio which was consistent with hydroxyapatite. The secretory granules are postulated as the source of the excess calcium in cystic fibrosis submandibular saliva. PMID:4705932

  8. Effect of sinus surgery on pulmonary function in patients with cystic fibrosis.

    PubMed

    Madonna, D; Isaacson, G; Rosenfeld, R M; Panitch, H

    1997-03-01

    The impact of sinus surgery on the pulmonary status of cystic fibrosis patients is unknown. This retrospective study reviewed the charts of the cystic fibrosis patients presenting to our institution's cystic fibrosis center with nasal obstruction, recurrent sinusitis, and nasal polyposis. This group subsequently underwent endoscopic ethmoidectomy and antrostomy. Fourteen of the 15 patients, ages 5-24 years, received preoperative and postoperative pulmonary function testing obtained by spirometry. The data were compiled and analyzed statistically. Our results suggested no significant improvement in the pulmonary function of cystic fibrosis patients after sinus surgery.

  9. Restoration of Chloride Efflux by Azithromycin in Airway Epithelial Cells of Cystic Fibrosis Patients▿

    PubMed Central

    Saint-Criq, Vinciane; Rebeyrol, Carine; Ruffin, Manon; Roque, Telma; Guillot, Loïc; Jacquot, Jacky; Clement, Annick; Tabary, Olivier

    2011-01-01

    Azithromycin (AZM) has shown promising anti-inflammatory properties in chronic obstructive pulmonary diseases, and clinical studies have presented an improvement in the respiratory condition of cystic fibrosis (CF) patients. The aim of this study was to investigate, in human airway cells, the mechanism by which AZM has beneficial effects in CF. We demonstrated that AZM did not have any anti-inflammatory effect on CF airway cells but restored Cl− efflux. PMID:21220528

  10. Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants.

    PubMed

    Sánchez, Karen; de Mendonca, Elizabeth; Matute, Xiorama; Chaustre, Ismenia; Villalón, Marlene; Takiff, Howard

    2016-01-01

    The mutations in the CFTR gene found in patients with cystic fibrosis (CF) have geographic differences, but there are scant data on their prevalence in Venezuelan patients. This study determined the frequency of common CFTR gene mutations in a group of Venezuelan patients with CF. The 27 exons of the CFTR gene from 110 Venezuelan patients in the National CF Program were amplified and sequenced. A total of 36 different mutations were identified, seven with frequencies greater than 1%: p.Phe508del (27.27%), p.Gly542* (3.18%), c.2988+1G>A (3.18%), p.Arg334Trp (1.36%), p.Arg1162* (1.36%), c.1-8G>C (1.36%), and p.[Gly628Arg;Ser1235Arg](1.36). In 40% of patients, all with a clinical diagnosis of CF, no mutations were found. This report represents the largest cohort of Venezuelan patients with CF ever examined, and includes a wider mutation panel than has been previously studied in this population. Mutations common in Southern European populations predominate, and several new mutations were discovered, but no mutations were found in 40% of the cohort.

  11. Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants

    PubMed Central

    Sánchez, Karen; de Mendonca, Elizabeth; Matute, Xiorama; Chaustre, Ismenia; Villalón, Marlene; Takiff, Howard

    2016-01-01

    The mutations in the CFTR gene found in patients with cystic fibrosis (CF) have geographic differences, but there are scant data on their prevalence in Venezuelan patients. This study determined the frequency of common CFTR gene mutations in a group of Venezuelan patients with CF. The 27 exons of the CFTR gene from 110 Venezuelan patients in the National CF Program were amplified and sequenced. A total of 36 different mutations were identified, seven with frequencies greater than 1%: p.Phe508del (27.27%), p.Gly542* (3.18%), c.2988+1G>A (3.18%), p.Arg334Trp (1.36%), p.Arg1162* (1.36%), c.1-8G>C (1.36%), and p.[Gly628Arg;Ser1235Arg](1.36). In 40% of patients, all with a clinical diagnosis of CF, no mutations were found. This report represents the largest cohort of Venezuelan patients with CF ever examined, and includes a wider mutation panel than has been previously studied in this population. Mutations common in Southern European populations predominate, and several new mutations were discovered, but no mutations were found in 40% of the cohort. PMID:27022295

  12. Hallmarks of therapeutic management of the cystic fibrosis functional landscape.

    PubMed

    Amaral, Margarida D; Balch, William E

    2015-11-01

    The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein does not operate in isolation, rather in a dynamic network of interacting components that impact its synthesis, folding, stability, intracellular location and function, referred to herein as the 'CFTR Functional Landscape (CFFL)'. For the prominent F508del mutation, many of these interactors are deeply connected to a protein fold management system, the proteostasis network (PN). However, CF encompasses an additional 2000 CFTR variants distributed along its entire coding sequence (referred to as CFTR2), and each variant contributes a differential liability to PN management of CFTR and to a protein 'social network' (SN) that directs the probability of the (patho)physiologic events that impact ion transport in each cell, tissue and patient in health and disease. Recognition of the importance of the PN and SN in driving the unique patient CFFL leading to disease highlights the importance of precision medicine in therapeutic management of disease progression. We take the view herein that it is not CFTR, rather the PN/SN, and their impact on the CFFL, that are the key physiologic forces driving onset and clinical progression of CF. We posit that a deep understanding of each patients PN/SN gained by merging genomic, proteomic (mass spectrometry (MS)), and high-content microscopy (HCM) technologies in the context of novel network learning algorithms will lead to a paradigm shift in CF clinical management. This should allow for generation of new classes of patient specific PN/SN directed therapeutics for personalized management of the CFFL in the clinic.

  13. Hallmarks of Therapeutic Management of the Cystic Fibrosis Functional Landscape

    PubMed Central

    Amaral, Margarida D.; Balch, William E.

    2015-01-01

    The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein does not operate in isolation, rather in a dynamic network of interacting components that impact its synthesis, folding, stability, intracellular location and function, referred to herein as the ‘CFTR Functional Landscape (CFFL)’. For the prominent F508del mutation, many of these interactors are deeply connected to a protein fold management system, the proteostasis network (PN). However, CF encompasses an additional 2000 CFTR variants distributed along its entire coding sequence (referred to as CFTR2), and each variant contributes a differential liability to PN management of CFTR and to a protein ‘Social Network’ (SN) that directs the probability of the (patho)physiologic events that impact ion transport in each cell, tissue and patient in health and disease. Recognition of the importance of the PN and SN in driving the unique patient CFFL leading to disease highlights the importance of precision medicine in therapeutic management of disease progression. We take the view herein that it is not CFTR, rather the PN/SN, and their impact on the CFFL, that are the key physiologic forces driving onset and clinical progression of CF. We posit that a deep understanding of each patients PN/SN gained by merging genomic, proteomic (mass spectrometry (MS)), and high-content microscopy (HCM) technologies in the context of novel network learning algorithms will lead to a paradigm shift in CF clinical management. This should allow for generation of new classes of patient specific PN/SN directed therapeutics for personalized management of the CFFL in the clinic. PMID:26526359

  14. BPI-ANCA Provides Additional Clinical Information to Anti-Pseudomonas Serology: Results from a Cohort of 117 Swedish Cystic Fibrosis Patients.

    PubMed

    Lindberg, Ulrika; Carlsson, Malin; Hellmark, Thomas; Segelmark, Mårten

    2015-01-01

    Patients with cystic fibrosis (CF) colonized with Pseudomonas aeruginosa (P. aeruginosa) have worse prognosis compared with patients who are not. BPI-ANCA is an anti-neutrophil cytoplasmic antibody against BPI (bactericidal/permeability increasing protein) correlating with P. aeruginosa colonization and adverse long time prognosis. Whether it provides additional information as compared to standard anti-P. aeruginosa serology tests is not known. 117 nontransplanted CF patients at the CF centre in Lund, Sweden, were followed prospectively for ten years. Bacterial colonisation was classified according to the Leeds criteria. IgA BPI-ANCA was compared with assays for antibodies against alkaline protease (AP), Elastase (ELA), and Exotoxin A (ExoA). Lung function and patient outcome, alive, lung transplanted, or dead, were registered. BPI-ANCA showed the highest correlation with lung function impairment with an r-value of 0.44. Forty-eight of the 117 patients were chronically colonized with P. aeruginosa. Twenty of these patients experienced an adverse outcome. Receiver operator curve (ROC) analysis revealed that this could be predicted by BPI-ANCA (AUC = 0.77), (p = 0.002) to a better degree compared with serology tests. BPI-ANCA correlates better with lung function impairment and long time prognosis than anti-P. aeruginosa serology and has similar ability to identify patients with chronic P. aeruginosa.

  15. Parents' religious coping styles in the first year after their child's cystic fibrosis diagnosis.

    PubMed

    Grossoehme, Daniel H; Ragsdale, Judy; Cotton, Sian; Wooldridge, Jamie L; Grimes, Lisa; Seid, Michael

    2010-01-01

    Parents of children diagnosed with cystic fibrosis described it as "devastating." Given religion's importance to many Americans, parents may utilize religious coping. Relatively little is known about parents' use of religious coping to handle their child's illness. Interviews with 15 parents about their use of religion in the year following their child's cystic fibrosis diagnosis were coded for religious coping styles. Sixteen styles were identified. Positive religious coping styles were more frequent than negative styles (previously associated with poorer health outcomes), and occurred more frequently than in other studies. Religious coping styles used to make meaning, gain control, or seek comfort/intimacy with God were equally prevalent. The most common styles were: Pleading, Collaboration, Benevolent Religious Reappraisals, and Seeking Spiritual Support. Parents described active rather than passive coping styles. Religious coping involving religious others was rare. Clinical attention to negative religious coping may prevent it becoming chronic and negatively affecting health.

  16. Epidemiology and genetics of cystic fibrosis in Asia: In preparation for the next-generation treatments.

    PubMed

    Singh, Meenu; Rebordosa, Cristina; Bernholz, Juliane; Sharma, Neeraj

    2015-11-01

    Cystic fibrosis (CF) in the Asian population is less frequently reported due to under-diagnosis and lack of centralized CF patient registries. Clinical studies on CF cases from Asia have documented a severe course of the disease. The spectrum of the cystic fibrosis transmembrane conductance regulator (CFTR) variants in this population is quite heterogeneous. In total, 166 variants have been reported on approximately 3700 Asian CF chromosomes. The frequency of F508del among Asians is low compared with Caucasians. Recent in vitro studies have shown promise of small molecule correction and potentiation of 45 different CFTR variants. Of these variants, 16 (including G551D and F508del) have also been observed among Asian CF individuals. We suggest undertaking molecular studies extensively to annotate CFTR variants that will help Asian CF individuals to benefit from the precision medicine gaining momentum in the Western countries.

  17. Acute Muscle Trauma due to Overexercise in an Otherwise Healthy Patient with Cystic Fibrosis

    PubMed Central

    Neubauer, Henning; Wirth, Clemens; Ruf, Katharina; Hebestreit, Helge; Beer, Meinrad

    2012-01-01

    Cystic fibrosis (CF) is one of the most common inherited diseases and is caused by mutations in the CFTR gene. Although the pulmonary and gastrointestinal manifestations of the disease remain in the focus of treatment, recent studies have shown expression of the CFTR gene product in skeletal muscle cells and observed altered intramuscular Ca2+ release dynamics in CFTR-deficient animal models. Physical exercise is beneficial for maintaining fitness and well-being in CF patients and constitutes one aspect of modern multimodal treatment, which has considerably increased life span and reduced morbidity. We report on a case of acute muscle trauma resulting from excessive dumbbell exercise in a young adult with cystic fibrosis and describe clinical, laboratory and imaging characteristics of acute exercise-induced muscle injury. PMID:22606534

  18. Edema, anemia, hypoproteinemia, and acrodermatitis enteropathica: an uncommon initial presentation of cystic fibrosis.

    PubMed

    Muñiz, Antonio E; Bartle, Sam; Foster, Robin

    2004-02-01

    Cystic fibrosis is a genetic disorder characterized by chronic obstructive pulmonary disease, pancreatic exocrine deficiency, and abnormally high sweat electrolyte concentrations. Less frequently, the presenting features in infants may include edema, anemia, hypoproteinemia, and acrodermatitis enteropathica. Liver involvement may produce hepatomegaly and mild elevation of transaminases. This clinical symptom usually presents within the first 6 months of life and is associated with a high morbidity and mortality. Early recognition and institution of appropriate nutritional supplementation and pancreatic enzymes is essential to improve outcome. Since the sweat test may be falsely negative, emergency physicians must maintain a high index of suspicion to make the diagnosis of cystic fibrosis in an infant who presents with edema, anemia, hypoproteinemia, and acrodermatitis enteropathica.

  19. Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models.

    PubMed

    Wang, Yiting; Wrennall, Joe A; Cai, Zhiwei; Li, Hongyu; Sheppard, David N

    2014-07-01

    Defective epithelial ion transport is the hallmark of the life-limiting genetic disease cystic fibrosis (CF). This abnormality is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), the ATP-binding cassette transporter that functions as a ligand-gated anion channel. Since the identification of the CFTR gene, almost 2000 disease-causing mutations associated with a spectrum of clinical phenotypes have been reported, but the majority remain poorly characterised. Studies of a small number of mutations including the most common, F508del-CFTR, have identified six general mechanisms of CFTR dysfunction. Here, we review selectively progress to understand how CF mutations disrupt CFTR processing, stability and function. We explore CFTR structure and function to explain the molecular mechanisms of CFTR dysfunction and highlight new knowledge of disease pathophysiology emerging from large animal models of CF. Understanding CFTR dysfunction is crucial to the development of transformational therapies for CF patients.

  20. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies

    PubMed Central

    Kreindler, James L.

    2009-01-01

    Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in epithelial cells throughout the body. In the lungs, absence or dysfunction of CFTR results in altered epithelial salt and water transport eventuating in impaired mucociliary clearance, chronic infection and inflammation, and tissue damage. CF lung disease is the major cause of morbidity and mortality in CF despite the many therapies aimed at reducing it. However, recent technological advances combined with two decades of research driven by the discovery of the CFTR gene have resulted in the development and clinical testing of novel therapies aimed at the principal underlying defect in CF, thereby ushering in a new age of therapy for CF. PMID:19903491

  1. [Pulmonary metabolism of nitric oxide (NO) in patients with cystic fibrosis].

    PubMed

    Grasemann, H; Ratjen, F

    2002-06-01

    Airway nitric oxide (NO) and its metabolites are involved in a number of physiological and pathophysiological processes. For instance, NO relaxes airway smooth muscle, improves airway ciliary motility, has antimicrobial effects, and increases expression of the CFTR (cystic fibrosis transmembrane regulator) protein in airway epithelial cells. Of interest, concentrations of NO and of bioactive S-nitrosothiols (SNOs) are decreased in the airways of patients with cystic fibrosis (CF). When compared to patients with relatively normal pulmonary NO formation, CF patients with low NO-concentrations have a significantly reduced pulmonary function and a higher frequency of bacterial colonisation of the airways with pathogens such as P. aeruginosa. As a consequence of these observations clinical trails have now been initiated to study possible effects of an augmented bronchial NO-concentration in CF-patients.

  2. The concentration of calprotectin in the stools of children with diagnosed cystic fibrosis

    PubMed Central

    Woś, Halina; Kordys-Darmolińska, Bożena; Sankiewicz-Szkółka, Magda; Grzybowska-Chlebowczyk, Urszula

    2016-01-01

    Introduction Calprotectin is a protein that plays a regulatory role in inflammatory reactions as an antibacterial and antiproliferative factor. Aim To assess the concentration of calprotectin in the stools of patients with diagnosed cystic fibrosis. Material and methods Forty-one patients were included in the study, 24 boys and 17 girls, aged from 7 weeks to 18 years. The concentration of calprotectin in stools was assessed with the ELISA method. The analysis included clinical symptoms and the results of laboratory tests and the type of mutation. Results An elevated level of calprotectin in the stool was observed in 4/41 (9.7%) patients, mainly in older children, and mainly delta F508/deltaF508 mutation. The correlation between the concentration of calprotectin and clinical symptoms, age, increased indicators of an inflammatory process, levels of protein and aminotransferases in blood serum and the values of acid steatocrit of the stool was not proven. Conclusions High concentrations of calprotectin in the stools of children with diagnosed cystic fibrosis do not correlate with the level of advancement of lesions within the gastrointestinal tract. Elevated concentrations of calprotectin in the stools of patients with cystic fibrosis may indicate inflammation of intestine and should be further scrutinised.

  3. Prevalence of streptococci and increased polymicrobial diversity associated with cystic fibrosis patient stability.

    PubMed

    Filkins, L M; Hampton, T H; Gifford, A H; Gross, M J; Hogan, D A; Sogin, M L; Morrison, H G; Paster, B J; O'Toole, G A

    2012-09-01

    Diverse microbial communities chronically colonize the lungs of cystic fibrosis patients. Pyrosequencing of amplicons for hypervariable regions in the 16S rRNA gene generated taxonomic profiles of bacterial communities for sputum genomic DNA samples from 22 patients during a state of clinical stability (outpatients) and 13 patients during acute exacerbation (inpatients). We employed quantitative PCR (qPCR) to confirm the detection of Pseudomonas aeruginosa and Streptococcus by the pyrosequencing data and human oral microbe identification microarray (HOMIM) analysis to determine the species of the streptococci identified by pyrosequencing. We show that outpatient sputum samples have significantly higher bacterial diversity than inpatients, but maintenance treatment with tobramycin did not impact overall diversity. Contrary to the current dogma in the field that Pseudomonas aeruginosa is the dominant organism in the majority of cystic fibrosis patients, Pseudomonas constituted the predominant genera in only half the patient samples analyzed and reported here. The increased fractional representation of Streptococcus in the outpatient cohort relative to the inpatient cohort was the strongest predictor of clinically stable lung disease. The most prevalent streptococci included species typically associated with the oral cavity (Streptococcus salivarius and Streptococcus parasanguis) and the Streptococcus milleri group species. These species of Streptococcus may play an important role in increasing the diversity of the cystic fibrosis lung environment and promoting patient stability.

  4. Multidrug-resistant nontuberculous mycobacteria isolated from cystic fibrosis patients.

    PubMed

    Cândido, Pedro Henrique Campanini; Nunes, Luciana de Souza; Marques, Elizabeth Andrade; Folescu, Tânia Wrobel; Coelho, Fábrice Santana; de Moura, Vinicius Calado Nogueira; da Silva, Marlei Gomes; Gomes, Karen Machado; Lourenço, Maria Cristina da Silva; Aguiar, Fábio Silva; Chitolina, Fernanda; Armstrong, Derek T; Leão, Sylvia Cardoso; Neves, Felipe Piedade Gonçalves; Mello, Fernanda Carvalho de Queiroz; Duarte, Rafael Silva

    2014-08-01

    Worldwide, nontuberculous mycobacteria (NTM) have become emergent pathogens of pulmonary infections in cystic fibrosis (CF) patients, with an estimated prevalence ranging from 5 to 20%. This work investigated the presence of NTM in sputum samples of 129 CF patients (2 to 18 years old) submitted to longitudinal clinical supervision at a regional reference center in Rio de Janeiro, Brazil. From June 2009 to March 2012, 36 NTM isolates recovered from 10 (7.75%) out of 129 children were obtained. Molecular identification of NTM was performed by using PCR restriction analysis targeting the hsp65 gene (PRA-hsp65) and sequencing of the rpoB gene, and susceptibility tests were performed that followed Clinical and Laboratory Standards Institute recommendations. For evaluating the genotypic diversity, pulsed-field gel electrophoresis (PFGE) and/or enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR) was performed. The species identified were Mycobacterium abscessus subsp. bolletii (n = 24), M. abscessus subsp. abscessus (n = 6), Mycobacterium fortuitum (n = 3), Mycobacterium marseillense (n = 2), and Mycobacterium timonense (n = 1). Most of the isolates presented resistance to five or more of the antimicrobials tested. Typing profiles were mainly patient specific. The PFGE profiles indicated the presence of two clonal groups for M. abscessus subsp. abscessus and five clonal groups for M. abscesssus subsp. bolletii, with just one clone detected in two patients. Given the observed multidrug resistance patterns and the possibility of transmission between patients, we suggest the implementation of continuous and routine investigation of NTM infection or colonization in CF patients, including countries with a high burden of tuberculosis disease.

  5. Quantitative deposition of aerosolized gentamicin in cystic fibrosis

    SciTech Connect

    Ilowite, J.S.; Gorvoy, J.D.; Smaldone, G.C.

    1987-12-01

    In cystic fibrosis (CF), the clinical effectiveness of aerosolized antibiotics is controversial. Previous investigators have not considered the type of nebulizer, droplet size, and dose to the lung in assessing the results of aerosol therapy. The present study tests the importance of these factors by standardizing an aerosol system for delivery of antibiotics and other agents to patients with CF. Particle size, distribution, and output from a commercially available nebulizer were measured. Thirteen patients with CF inhaled aerosol (MMAD = 1.1 micron) containing gentamicin (160 mg in nebulizer) and /sup 99m/Tc-labeled human serum albumin. Patients' sputum and serum were analyzed for gentamicin levels by immunoenzymatic assay. Using a gamma camera and suitable filters, central versus peripheral deposition (C/P ratio) and whole lung deposition were measured and related to sputum gentamicin levels. Gentamicin deposit averaged 12.3 mg +/- 5.9 (SD) or 7.69% of the original amount placed in the nebulizer. Peak sputum levels averaged 376.6 micrograms/ml +/- 275, whereas serum levels were undetectable in all patients. When peak sputum levels were normalized for the amount deposited, a close correlation with C/P ratio was obtained (r = 0.88, p less than 0.05). Furthermore, an inverse relationship was found between the C/P ratio and the %FEV1 (r = 0.76, p less than 0.05). Finally, a bell-shaped relationship between deposited dose and minute ventilation was seen in the patients (r = 0.88, p less than 0.05), i.e., an optimal minute ventilation was shown. These relationships may be important when designing future clinical studies.

  6. Cystic fibrosis research in allied health and nursing professions.

    PubMed

    Bradley, Judy M; Madge, Susan; Morton, Alison M; Quittner, Alexandra L; Elborn, J Stuart

    2012-09-01

    This report is the result of the "Allied Health and Nursing Professions Working Group" meeting which took place in Verona, Italy, November 2009, which was organised by the European Cystic Fibrosis Society, and involved 32 experts. The meeting was designed to provide a "roadmap" of high priority research questions that can be addressed by Allied Health Professionals (AHP) and nursing. The other goal was to identify research skills that would be beneficial to AHP and nursing researchers and would ultimately improve the research capacity and capability of these professions. The following tasks were accomplished: 1) a Delphi survey was used to identify high priority research areas and themes, 2) common research designs used in AHP and nursing research were evaluated in terms of their strengths and weaknesses, 3) methods for assessing the clinimetric and psychometric properties, as well as feasibility, of relevant outcome measures were reviewed, and 4) a common skill set for AHPs and nurses undertaking clinical research was agreed on and will guide the planning of future research opportunities. This report has identified important areas and themes for future research which include: adherence; physical activity/exercise; nutritional interventions; interventions for the newborn with CF and evaluation of outcome measures for use in AHP and nursing research. It has highlighted the significant challenges AHPs and nurses experience in conducting clinical research, and proposes strategies to overcome these challenges. It is hoped that this report will encourage research initiatives that assess the efficacy/effectiveness of AHP and nursing interventions in order to improve the evidence base. This should increase the quality of research conducted by these professions, justify services they currently provide, and expand their skills in new areas, with the ultimate goal of improving care for patients with CF.

  7. Subepithelial fibrosis and degradation of the bronchial extracellular matrix in cystic fibrosis.

    PubMed

    Durieu, I; Peyrol, S; Gindre, D; Bellon, G; Durand, D V; Pacheco, Y

    1998-08-01

    Cystic fibrosis is a genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator gene. Chronic inflammation and proteolysis lead to progressive damage of the bronchial wall. Extracellular matrix determines the structural organization and the mechanical properties of lung airways. It was thus examined in nine patients with cystic fibrosis (six bronchial biopsies and three lobectomies) in order to assess its level of alteration. The submucosal changes in matrix protein distribution were analyzed by immunochemistry and electron microscopy: the subepithelial basal lamina was thinned; an acellular collagen fiber layer composed of interstitial collagens (types I and III) subtended by tenascin and devoid of elastin-associated microfibrils was deposited beneath the basal lamina; this dense fibrous deposit generally formed a thick layer and could extend into the bronchial wall; the bronchial elastic framework lost arborescent distribution and appeared slender, packed, or lacunar; ultrastructural observation gave evidence for elastic and collagenic fiber lysis. Proteolytic activity is probably the major cause of matrix degradation. Fibrosis appears as a repair process rather than as an active fibrogenesis. The reversibility of extracellular matrix alterations is an important challenge and various interventions such as anti-inflammatory treatments can be targeted to halt or reverse this degradation process.

  8. New horizons in the treatment of cystic fibrosis

    PubMed Central

    Cuthbert, AW

    2011-01-01

    Cystic fibrosis (CF) is a lethal, recessive, genetic disease affecting approximately 1 in 2500 live births among Caucasians. The CF gene codes for a cAMP/PKA-dependent, ATP-requiring, membrane chloride ion channel, generally found in the apical membranes of many secreting epithelia and known as CFTR (cystic fibrosis transmembrane conductance regulator). There are currently over 1700 known mutations affecting CFTR, many of which give rise to a disease phenotype. Around 75% of CF alleles contain the ΔF508 mutation in which a triplet codon has been lost, leading to a missing phenylalanine at position 508 in the protein. This altered protein fails to be trafficked to the correct location in the cell and is generally destroyed by the proteasome. The small amount that does reach the correct location functions poorly. Clearly the cohort of patients with at least one ΔF508 allele are a major target for therapeutic intervention. It is now over two decades since the CF gene was discovered and during this time the properties of CFTR have been intensely investigated. At long last there appears to be progress with the pharmaco-therapeutic approach. Ongoing clinical trials have produced fascinating results in which clinical benefit appears to have been achieved. To arrive at this point ingenious ways have been devised to screen very large chemical libraries for one of two properties: (i) agents promoting trafficking of mutant CFTR to, and insertion into the membrane, and known as correctors or (ii) agents which activate appropriately located mutant CFTR, known as potentiators. The best compounds emerging from these programmes are then used as chemical scaffolds to synthesize other compounds with appropriate pharmaceutical properties, hopefully with their pharmacological activity maintained or even enhanced. In summary, this approach attempts to make the mutant CFTR function in place of the real CFTR. A major function of CFTR in healthy airways is to maintain an adequate airway

  9. Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis.

    PubMed

    Castellani, Carlo; Tridello, Gloria; Tamanini, Anna; Assael, Baroukh M

    2016-01-11

    Newborns with raised immunotrypsinogen levels who have non-pathological sweat chloride values and carry two cystic fibrosis transmembrane regulator (CFTR) mutations of which at least one is not acknowledged to be cystic fibrosis (CF)-causing are at risk of developing clinical manifestations consistent with CFTR-related disorders or even CF. It is not known whether newborns with similar genotypes and normal immunoreactive trypsinogen (IRT) may share the same risk. This study found that newborns with these characteristics and normal IRT have lower sweat chloride values than those with raised IRT (p=0.007).

  10. 21 CFR 866.5910 - Quality control material for cystic fibrosis nucleic acid assays.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... nucleic acid assays. 866.5910 Section 866.5910 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Test Systems § 866.5910 Quality control material for cystic fibrosis nucleic acid assays. (a) Identification. Quality control material for cystic fibrosis nucleic acid assays. A quality control material...

  11. 21 CFR 866.5910 - Quality control material for cystic fibrosis nucleic acid assays.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... nucleic acid assays. 866.5910 Section 866.5910 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Test Systems § 866.5910 Quality control material for cystic fibrosis nucleic acid assays. (a) Identification. Quality control material for cystic fibrosis nucleic acid assays. A quality control material...

  12. 21 CFR 866.5910 - Quality control material for cystic fibrosis nucleic acid assays.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... nucleic acid assays. 866.5910 Section 866.5910 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Test Systems § 866.5910 Quality control material for cystic fibrosis nucleic acid assays. (a) Identification. Quality control material for cystic fibrosis nucleic acid assays. A quality control material...

  13. 21 CFR 866.5910 - Quality control material for cystic fibrosis nucleic acid assays.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... nucleic acid assays. 866.5910 Section 866.5910 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Test Systems § 866.5910 Quality control material for cystic fibrosis nucleic acid assays. (a) Identification. Quality control material for cystic fibrosis nucleic acid assays. A quality control material...

  14. 21 CFR 866.5910 - Quality control material for cystic fibrosis nucleic acid assays.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... nucleic acid assays. 866.5910 Section 866.5910 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Test Systems § 866.5910 Quality control material for cystic fibrosis nucleic acid assays. (a) Identification. Quality control material for cystic fibrosis nucleic acid assays. A quality control material...

  15. Self-Efficacy, Pulmonary Function, Perceived Health and Global Quality of Life of Cystic Fibrosis Patients

    ERIC Educational Resources Information Center

    Wahl, Astrid K.; Rustoen ,Tone; Hanestad, Berit R.; Gjengedal, Eva; Moum, Torbjorn

    2005-01-01

    This study examined the extent that pulmonary function is related to perceived health status and global quality of life in adults suffering from cystic fibrosis, and the extent that self-efficacy modifies these relationships. Our sample comprised 86 adults (48% female; mean age, 29 years; age range, 18-54 years) with cystic fibrosis, recruited…

  16. Cystic Fibrosis Survival Better in Canada Than in U.S.

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_164055.html Cystic Fibrosis Survival Better in Canada Than in U.S. Canadians ... MONDAY, March 13, 2017 (HealthDay News) -- People with cystic fibrosis are living longer than ever, but those in ...

  17. Pseudomonas infection and mucociliary and absorptive clearance in the cystic fibrosis lung.

    PubMed

    Locke, Landon W; Myerburg, Michael M; Weiner, Daniel J; Markovetz, Matthew R; Parker, Robert S; Muthukrishnan, Ashok; Weber, Lawrence; Czachowski, Michael R; Lacy, Ryan T; Pilewski, Joseph M; Corcoran, Timothy E

    2016-05-01

    Airway surface liquid hyperabsorption and mucus accumulation are key elements of cystic fibrosis lung disease that can be assessed in vivo using functional imaging methods. In this study we evaluated experimental factors affecting measurements of mucociliary clearance (MCC) and small-molecule absorption (ABS) and patient factors associated with abnormal absorption and mucus clearance.Our imaging technique utilises two radiopharmaceutical probes delivered by inhalation. Measurement repeatability was assessed in 10 adult cystic fibrosis subjects. Experimental factors were assessed in 29 adult and paediatric cystic fibrosis subjects (51 scans). Patient factors were assessed in a subgroup with optimal aerosol deposition (37 scans; 24 subjects). Paediatric subjects (n=9) underwent initial and 2-year follow-up scans. Control subjects from a previously reported study are included for comparison.High rates of central aerosol deposition influenced measurements of ABS and, to a lesser extent, MCC. Depressed MCC in cystic fibrosis was only detectable in subjects with previous Pseudomonas aeruginosa infection. Cystic fibrosis subjects without P. aeruginosa had similar MCC to control subjects. Cystic fibrosis subjects had consistently higher ABS rates.We conclude that the primary experimental factor affecting MCC/ABS measurements is central deposition percentage. Depressed MCC in cystic fibrosis is associated with P. aeruginosa infection. ABS is consistently increased in cystic fibrosis.

  18. Cystic Fibrosis in a Female Infant with Cardiac, Ocular, and Musculoskeletal Anomalies

    PubMed Central

    Farooqui, Azhar; Eldin, Susan Gamal; Ali, Muna Dawood; AlTalhi, Ali; AlDigheari, Ahmad

    2015-01-01

    Cystic fibrosis (CF) remains the most common hereditary disease in the western population. Its concomitant presence with other congenital abnormalities is a rare phenomenon with very little documentation. In this case report we describe a case of cystic fibrosis in a female infant with cardiac, ocular, and musculoskeletal abnormalities. A brief literature review is also provided. PMID:26693372

  19. Ceftazidime in cystic fibrosis: pharmacokinetics and therapeutic response.

    PubMed

    Kercsmar, C M; Stern, R C; Reed, M D; Myers, C M; Murdell, D; Blumer, J L

    1983-07-01

    The pharmacokinetics of ceftazidime were assessed following a single-dose in 20 patients (8 to 30 years) with cystic fibrosis. All patients received 50 mg/kg (0.9 to 3.5 g) bolus over 30 to 60 sec. Multiple timed samples were obtained over 8 h and analysed by a sensitive HPLC technique. Two-compartment pharmacokinetic analysis revealed means (+/- S.D.) T 1/2 alpha, 0.45 (0.20) h; T 1/2 beta, 1.74 (0.63) h; Vd, 270.0 (50.0) ml/kg; Vc, 190.0 (50.0) ml/kg and Cl beta, 133.7 (22.8) ml/min/1.73 m2. Probenecid pretreatment in six patients was without effect on T 1/2 beta and Cl beta. Urinary excretion was (% of dose) 0 to 2 h, 65.4 (11.1); 2 to 4 h, 14.9 (3.4) and 4 to 8 h, 9.8 (5.8). Ceftazidime was used to treat pulmonary exacerbations in 12 adult cystic fibrosis patients with multiply-resistant Pseudomonas species. Each patient received 2 g iv 8-hourly for 14 to 35 days. Ten of 12 patients showed dramatic improvement as determined by increased appetite and weight gain and arterial pCO2. No hepatic, renal or bone-marrow toxicity was noted. Ceftazidime is an effective antipseudomonal agent possessing favourable pharmacokinetic characteristics with potential use in the treatment of pulmonary exacerbations in cystic fibrosis.

  20. Transepithelial nasal potential difference (NPD) measurements in cystic fibrosis (CF).

    PubMed

    Sands, Dorota

    2013-01-01

    The main underlying physiologic abnormality in cystic fibrosis (CF) is dysfunction of the CF transmembrane conductance regulator (CFTR), which results in abnormal transport of sodium and chloride across epithelial surfaces. CFTR function could be tested in vivo using measurements of nasal transepithelial potential difference (PD). Nasal measurements show characteristic features of CF epithelia, including hyperpolarized baseline readings (basal PD), excessive depolarization in response to sodium channel inhibitors, such as amiloride (ΔAmiloride), and little or no chloride (Cl-) secretion in response to isoproterenol in a chloride-free solution (ΔCl- free-isoproterenol). PD test is applied for CF diagnosis and monitoring of new therapeutic modulations and corrections.

  1. Complications of gastroesophageal reflux in patients with cystic fibrosis.

    PubMed

    Bendig, D W; Seilheimer, D K; Wagner, M L; Ferry, G D; Barrison, G M

    1982-04-01

    Seven patients with cystic fibrosis who had complications of gastroesophageal reflux including abdominal pain, peptic esophagitis, upper gastrointestinal hemorrhage, and esophageal stricture are described. We believe that these are gastrointestinal complications of CF and that they may be responsible for significant morbidity. The mechanical influence of a depressed diaphragm caused by hyperinflation, along with increased abdominal pressure with chronic coughing, may contribute to GER in CF. Early detection and treatment are important not only to prevent esophageal complications but also to increase the quality of life by relief of pain and by avoiding the resultant decrease in appetite, which can contribute to malnutrition.

  2. Energy intake and nutrition counseling in cystic fibrosis.

    PubMed

    Hubbard, V S; Mangrum, P J

    1982-02-01

    Historically, it has been thought that the patient with cystic fibrosis (CF) has a voracious appetite. It is now becoming apparent that many patients do not have caloric intakes which meet their full energy requirements. Our study of CF patient, utilizing, a five-day written record of food consumptions and direct observation, supports this finding and points out the need for further nutritional counseling in providing optimal care for these patients. The cause of increased nutrient requirements and considerations for individualization of counseling are briefly discussed.

  3. Fluoroquinolones in the treatment of bronchopulmonary disease in cystic fibrosis.

    PubMed

    Hurley, Matthew; Smyth, Alan

    2012-12-01

    Fluoroquinolones are commonly used to treat lung infections in patients with cystic fibrosis. These patients are susceptible to lung infection with common bacteria such as Staphylococcus aureus and Haemophilus influenzae, but are also prone to infection by opportunistic bacteria, including Pseudomonas aeruginosa. The good oral bioavailability and broad antimicrobial spectrum of activity, including antipseudomonal properties, make this class of antimicrobial attractive. We review the evidence assessing the use of fluoroquinolones in the context of preventing and eradicating early lung infection and in managing chronic lung infection and pulmonary exacerbations. The safety of fluoroquinolones and the use of newer agents in the class are also discussed.

  4. Molecular modelling approaches for cystic fibrosis transmembrane conductance regulator studies.

    PubMed

    Odolczyk, Norbert; Zielenkiewicz, Piotr

    2014-07-01

    Cystic fibrosis (CF) is one of the most common genetic disorders, caused by loss of function mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. CFTR is a member of ATP-binding cassette (ABC) transporters superfamily and functions as an ATP-gated anion channel. This review summarises the vast majority of the efforts which utilised molecular modelling approaches to gain insight into the various aspects of CFTR protein, related to its structure, dynamic properties, function and interactions with other protein partners, or drug-like compounds, with emphasis to its relation to CF disease.

  5. Genetics and epithelial cell dysfunction in cystic fibrosis

    SciTech Connect

    Riordan, J.R.; Buchwald, M.

    1987-01-01

    This book examines the advances being made in the study of the physiology, cell biology, and molecular genetics of cystic fibrosis. Emphasis is placed on various areas of research that involve epithelial cells (e.g., the CF-specific phenotypes exhibited by epithelial cells, abnormalities in epithelium ion transport, chloride channel regulation in CF epithelial.) Coverage is presented on the current status of CF, including data on the incidence of the disease, its mode of inheritance, chromosomal localization, genetic heterogeneity, and screening and management.

  6. State of progress in treating cystic fibrosis respiratory disease

    PubMed Central

    2012-01-01

    Since the discovery of the gene associated with cystic fibrosis (CF), there has been tremendous progress in the care of patients with this disease. New therapies have entered the market and are part of the standard treatment of patients with CF, and have been associated with marked improvement in survival. Now there are even more promising therapies directed at different components of the pathophysiology of this disease. In this review, our current knowledge of the pathophysiology of lung disease in patients with CF is described, along with the current treatment of CF lung disease, and the therapies in development that offer great promise to our patients. PMID:22883684

  7. Increased congregational support for parents of children with cystic fibrosis.

    PubMed

    Szczesniak, Rhonda D; Zou, Yuanshu; Wetzel, J Denise; Krause, Neal; Grossoehme, Daniel H

    2015-04-01

    Positive health outcomes are related to adults' religious congregational participation. For parents of children with chronic disease, structured daily care routines and/or strict infection control precautions may limit participation. For this exploratory study, we examined the relationship between congregational support and religious coping by parents of children with cystic fibrosis (CF) compared to parents for whom child health issues were not significant stressors. CF parents reported higher levels of emotional support from congregation members and use of religious coping. Within-group differences were found for CF parents by denominational affiliation. Congregational support for parents dealing with child chronic disease is important.

  8. Bone mineral density in cystic fibrosis: benefit of exercise capacity.

    PubMed

    Dodd, Jonathan D; Barry, Sinead C; Barry, Rupert B M; Cawood, Tom J; McKenna, Malachi J; Gallagher, Charles G

    2008-01-01

    The aim of this study was to evaluate the association between bone mineral density (BMD) and objective maximal exercise measurements in adults with cystic fibrosis (CF). Twenty-five CF patients (19 males, 6 females, mean age 25.5 yr, range: 17-52) underwent BMD assessment and maximal-cycle ergometer exercise testing. We examined the relationship between gas exchange (% peak-predicted O(2) uptake, CO(2) output, O(2) saturation), exercise performance (maximum power, exercise duration), and respiratory mechanics (tidal volume, rate) with lumbar spine and total proximal femur BMD. The strongest clinical correlate with BMD was forced expiratory volume at 1s (lumbar spine Z-score, r=0.36; total proximal femur Z-score, r=0.68, p<0.01). The strongest exercise correlate was % peak-predicted O(2) uptake (lumbar spine Z-score, r=0.44, p<0.01; total proximal femur Z-score, r=0.59, p<0.01). There was a closer association between exercise parameters and total proximal femur BMD (r=0.43-0.60) than with lumbar spine BMD (r=0.04-0.45). Multiple regression analysis revealed VO(2) to be the strongest independent predictor of BMD (R(2)=0.86, p<0.001) followed by petCO(2) and body mass index (R(2)=0.7 and 0.5, respectively, p<0.01). Exercise appears to influence total proximal femur BMD more than lumbar spine BMD in CF. Exercise rehabilitation programs focusing on peripheral strength training may benefit those CF patients with low total proximal femur BMD.

  9. Determinants of Serum Glycerophospholipid Fatty Acids in Cystic Fibrosis

    PubMed Central

    Drzymała-Czyż, Sławomira; Krzyżanowska, Patrycja; Koletzko, Berthold; Nowak, Jan; Miśkiewicz-Chotnicka, Anna; Moczko, Jerzy A.; Lisowska, Aleksandra; Walkowiak, Jarosław

    2017-01-01

    The etiology of altered blood fatty acid (FA) composition in cystic fibrosis (CF) is understood only partially. We aimed to investigate the determinants of serum glycerophospholipids’ FAs in CF with regard to the highest number of FAs and in the largest cohort to date. The study comprised 172 CF patients and 30 healthy subjects (HS). We assessed Fas’ profile (gas chromatography/mass spectrometry), CF transmembrane conductance regulator (CFTR) genotype, spirometry, fecal elastase-1, body height and weight Z-scores, liver disease, diabetes and colonization by Pseudomonas aeruginosa. The amounts of saturated FAs (C14:0, C16:0) and monounsaturated FAs (C16:1n-7, C18:1n-9, C20:1n-9, C20:3n-9) were significantly higher in CF patients than in HS. C18:3n-6, C20:3n-6 and C22:4n-6 levels were also higher in CF, but C18:2n-6, C20:2n-6 and C20:4n-6, as well as C22:6n-3, were lower. In a multiple regression analysis, levels of seven FAs were predicted by various sets of factors that included age, genotype, forced expiratory volume in one second, pancreatic status and diabetes. FA composition abnormalities are highly prevalent in CF patients. They seem to be caused by both metabolic disturbances and independent clinical risk factors. Further research into the influence of CFTR mutations on fat metabolism and desaturases’ activity is warranted. PMID:28106773

  10. Aspergillus fumigatus colonization in cystic fibrosis: implications for lung function?

    PubMed

    de Vrankrijker, A M M; van der Ent, C K; van Berkhout, F T; Stellato, R K; Willems, R J L; Bonten, M J M; Wolfs, T F W

    2011-09-01

    Aspergillus fumigatus is commonly found in the respiratory secretions of patients with cystic fibrosis (CF). Although allergic bronchopulmonary aspergillosis (ABPA) is associated with deterioration of lung function, the effects of A. fumigatus colonization on lung function in the absence of ABPA are not clear. This study was performed in 259 adults and children with CF, without ABPA. A. fumigatus colonization was defined as positivity of >50% of respiratory cultures in a given year. A cross-sectional analysis was performed to study clinical characteristics associated with A. fumigatus colonization. A retrospective cohort analysis was performed to study the effect of A. fumigatus colonization on lung function observed between 2002 and 2007. Longitudinal data were analysed with a linear mixed model. Sixty-one of 259 patients were at least intermittently colonized with A. fumigatus. An association was found between A. fumigatus colonization and increased age and use of inhaled antibiotics. In the longitudinal analysis, 163 patients were grouped according to duration of colonization. After adjustment for confounders, there was no significant difference in lung function between patients colonized for 0 or 1 year and patients with 2-3 or more than 3 years of colonization (p 0.40 and p 0.64) throughout the study. There was no significant difference in lung function decline between groups. Although colonization with A. fumigatus is more commonly found in patients with more severe lung disease and increased treatment burden, it is not independently associated with lower lung function or more severe lung function decline over a 5-year period.

  11. EXERCISE OXIDATIVE SKELETAL MUSCLE METABOLISM IN ADOLESCENTS WITH CYSTIC FIBROSIS

    PubMed Central

    Werkman, Maarten; Jeneson, Jeroen; Helders, Paul; Arets, Bert; van der Ent, Kors; Velthuis, Birgitta; Nievelstein, Rutger; Takken, Tim; Hulzebos, Erik

    2015-01-01

    Introduction Patients with Cystic Fibrosis (CF) are reported to have limited exercise capacity. There is no consensus about a possible abnormality in skeletal muscle oxidative metabolism in CF. Our aim is to test the hypothesis that abnormalities in oxygenation and/or muscle oxidative metabolism contribute to exercise intolerance in adolescents with mild CF. Methods Ten adolescents with CF (12–18 years of age, FEV1>80%pred, resting oxygen saturation > 94%) and ten healthy age-matched controls (HC) were tested with supine cycle ergometry using near-infrared spectroscopy (NIRS) and 31Phosphorus magnetic resonance spectroscopy (31P MRS) to study skeletal muscle oxygenation and oxidative metabolism during rest, exercise and recovery. Results No statistically significant (p>0.1) differences in peak workload and peak oxygen uptake per kilogram lean body mass were found between CF and HC. No differences were found between CF and HC in bulk changes of quadriceps phosphocreatine (PCr) (p = .550) and inorganic phosphate (Pi) (p = .896) content and pH (p = .512) during symptom limited exercise. Furthermore, we found statistically identical kinetics for PCr resynthesis during recovery for CF and HC (p = .53). No statistically significant difference in peak exercise arbitrary unit for total haemoglobin content (tHb_AU) was found between CF and HC (p = .66). Discussion The results of this study provide evidence that in patients with mild CF and a stable clinical status (without signs of systemic inflammation and/or chronic PA colonisation), no intrinsic metabolic constraints and/or abnormalities in oxygenation and/or muscle oxidative metabolism contribute to exercise intolerance. PMID:26707538

  12. Novel Approaches for Potential Therapy of Cystic Fibrosis.

    PubMed

    Sawczak, Victoria; Getsy, Paulina; Zaidi, Aliya; Sun, Fei; Zaman, Khalequz; Gaston, Benjamin

    2015-01-01

    Cystic fibrosis (CF) is a lethal autosomal recessive disease that causes severe damage to the respiratory and digestive systems. It results from a dysfunctional CF Transmembrane Conductance Regulator (CFTR) protein, which is a cAMP- regulated epithelial chloride channel. CFTR is also a subtype of the ABC-transporter superfamily, and is expressed primarily in the apical membrane of epithelial cells in the airways, pancreas, and intestines. A single amino acid deletion of phenylalanine (Phe) is the most common mutation in CF patients known as F508del-CFTR. Normally, wild-type CFTR is largely degraded before reaching the cell membrane and F508del-CFTR virtually never reaches the cell surface. Ultimately, our goal is to correct dysfunctional CFTR proteins in CF patients. Via high-throughput screening techniques, several novel compounds for potential drugs effective in reversing the molecular CF defect and prohibiting further progression of CF have recently been discovered. S-nitrosothiols (SNOs) are small, naturally occurring endogenous cell signaling compounds, which have potential relevance to human lung diseases, including CF. Remarkably, researchers have found that the level of SNOs are reduced in the CF airway. It was previously reported that different types of SNOs, such as GSNO and S-nitrosoglutathione diethyl ester will increase CFTR maturation and function at the plasma membrane in human airway epithelial cells. The mechanisms by which SNOs improve CFTR maturation remain elusive. Currently, clinical trials are still investigating the effectiveness and safety of novel corrector and potentiator drugs for F508del- CFTR. This review article offers a summary of our knowledge on the most up-to-date CF therapies.

  13. Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis.

    PubMed

    Farrell, Philip M; Li, Zhanhai; Kosorok, Michael R; Laxova, Anita; Green, Christopher G; Collins, Jannette; Lai, Hui-Chuan; Makholm, Linda M; Rock, Michael J; Splaingard, Mark L

    2003-09-01

    Children with cystic fibrosis (CF) develop bronchopulmonary disease at variable ages. Determining the epidemiology of chronic lung disease and quantifying its severity, however, have been difficult in infants and young children. As part of the Wisconsin CF Neonatal Screening Project, we were presented with an ideal opportunity to assess longitudinally the evolution of symptoms, signs, and quantitative measures of CF respiratory disease. After newborn screening test results led to early recognition, 64 patients diagnosed at a median age of 6.71 weeks were enrolled and studied systematically at a median age of 11.3 years to obtain clinical information, chest radiographs, and pulmonary function tests. Our observations revealed that a frequent cough by history is evident by 10.5 months of age in half the patients. Quantitative chest radiology (CXR scoring) demonstrated that potentially irreversible abnormalities are present in half the children by 2 years. The severity of Wisconsin and Brasfield CXR scores increased in association with respiratory infections. Longitudinal progression of Wisconsin CXR scores was related to age (P < 0.001), pancreatic insufficiency (P = 0.005), and respiratory secretion cultures positive for Staphylococus aureas (P = 0.039). In contrast, serial spirometry showed limited sensitivity, as did lung volume determinations; neither was satisfactory as repeated measures with acceptable quality control until after 7 years of age. Time to event analyses revealed that half the patients had % predicted FEF(25-75) and FEV(1)/FVC values greater than 80% until 10.7 and 9.9 years, respectively. We conclude that of the methods evaluated, quantitative chest radiology is currently the best procedure for frequent assessment of bronchopulmonary disease in CF, and that radiographic progression is evident in approximately 85% of patients by 5 years of age. Our results also suggest that bronchiectasis and other radiographic evidence of chronic infection are

  14. Application of mass spectrometry to study proteomics and interactomics in cystic fibrosis.

    PubMed

    Balch, William E; Yates, John R

    2011-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) does not function in isolation, but rather in a complex network of protein-protein interactions that dictate the physiology of a healthy cell and tissue and, when defective, the pathophysiology characteristic of cystic fibrosis (CF) disease. To begin to address the organization and operation of the extensive cystic fibrosis protein network dictated by simultaneous and sequential interactions, it will be necessary to understand the global protein environment (the proteome) in which CFTR functions in the cell and the local network that dictates CFTR folding, trafficking, and function at the cell surface. Emerging mass spectrometry (MS) technologies and methodologies offer an unprecedented opportunity to fully characterize both the proteome and the protein interactions directing normal CFTR function and to define what goes wrong in disease. Below we provide the CF investigator with a general introduction to the capabilities of modern mass spectrometry technologies and methodologies with the goal of inspiring further application of these technologies for development of a basic understanding of the disease and for the identification of novel pathways that may be amenable to therapeutic intervention in the clinic.

  15. Biliary liver cirrhosis secondary to cystic fibrosis: a rare indication for liver transplantation.

    PubMed

    Sańko-Resmer, J; Paczek, L; Wyzgał, J; Ziółkowski, J; Ciszek, M; Alsharabi, A; Grzelak, I; Paluszkiewicz, R; Patkowski, W; Krawczyk, M

    2006-01-01

    As more effective therapies prolong the lives of patients with cystic fibrosis, there are now more patients in this population diagnosed with liver diseases. Secondary biliary cirrhosis is not a rare complication of mucoviscidosis. It is diagnosed in 20% of patients with mucoviscidosis; in 2% it is accompanied by portal hypertension. On average patients with portal hypertension and its complications are 12 years old. Liver transplantation is an accepted method of treatment for children with cystic fibrosis and portal hypertension. It eliminates the cause of the portal hypertension, decreases life-threatening medical conditions, and improves their nutritional status and quality of life. Despite immunosuppressive treatment they do not seem to beat increased risk of upper respiratory tract infections. On the contrary improved respiratory function and status are generally observed. We present our first case of orthotopic liver transplantation performed in a 29-year-old man with cystic fibrosis. The donor was a 42-year-old woman who died of a ruptured cerebral aneurysm. The surgery was performed in September 2004. The patient received immunosuppression based on steroids, basiliximab, tacrolimus, and mycophenolic acid due to renal insufficiency. Antibiotic (meropenem) and antiviral prophylaxis (gancyclovir) were used. A 6-month period of observation confirmed the clinical data from the pediatric population-a good prognosis with improved nutritional status, respiratory function, and quality of life.

  16. Cystic fibrosis-related liver disease: a single-center experience.

    PubMed

    Costa, Paula Catarino; Barreto, Celeste Canha; Pereira, Luisa; Lobo, Maria Luisa; Costa, Maria Adília; Lopes, Ana Isabel Gouveia

    2011-06-30

    Prospective studies concerning liver disease in pediatric cystic fibrosis patients are scarce. The present study aimed to describe the prevalence and clinical expression of cystic fibrosis - related liver disease, in a cohort of 62 pediatric patients. Descriptive study, resulting from the prospective evaluation, between 1994 and 2009, of 62 pediatric patients (age <18 years) with cystic fibrosis. The follow-up protocol included a clinical assessment every 2 months, liver function tests every 6 months and annual liver ultrasonography. The cumulative prevalence of liver disease was 11.2% (7/62 cases). All patients had ΔF508 mutation and pancreatic insufficiency, none had meconium ileus. The liver involvement became clinically evident at a mean age of 8 years (3-15 years), revealed by hepatomegaly or hepatosplenomegaly (3 cases) and/ or abnormalities of liver function tests (3 cases) changes of liver ultrasound (7 cases) with evidence of portal hypertension (2 cases). Four patients were submitted to liver biopsy; biliary fibrosis was documented in one case, focal biliary cirrhosis in 2 cases and multilobular cirrhosis in another case. Within a median 11.6 years follow-up period (all patients under UDCA therapy after liver disease diagnosis), progression of liver disease was observed in 2 patients; one patient developed refractory variceal bleeding and progressive hepatic failure, requiring liver transplant. The results of the present study agree with those of previous pediatric studies, further documenting clinical expression of liver disease in CF patients, which is usually detected in the first decade of life and emphasize the contribution of ultrasound to early diagnosis of liver involvement. Moreover, although advanced liver disease is a relatively rare event, early isolated liver transplantation may have to be considered at this age group.

  17. Environmental Pseudomonads Inhibit Cystic Fibrosis Patient-Derived Pseudomonas aeruginosa

    PubMed Central

    Chatterjee, Payel; Davis, Elizabeth; Yu, Fengan; James, Sarah; Wildschutte, Julia H.; Wiegmann, Daniel D.; Sherman, David H.; McKay, Robert M.; LiPuma, John J.

    2016-01-01

    ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen which is evolving resistance to many currently used antibiotics. While much research has been devoted to the roles of pathogenic P. aeruginosa in cystic fibrosis (CF) patients, less is known of its ecological properties. P. aeruginosa dominates the lungs during chronic infection in CF patients, yet its abundance in some environments is less than that of other diverse groups of pseudomonads. Here, we sought to determine if clinical isolates of P. aeruginosa are vulnerable to environmental pseudomonads that dominate soil and water habitats in one-to-one competitions which may provide a source of inhibitory factors. We isolated a total of 330 pseudomonads from diverse habitats of soil and freshwater ecosystems and competed these strains against one another to determine their capacity for antagonistic activity. Over 900 individual inhibitory events were observed. Extending the analysis to P. aeruginosa isolates revealed that clinical isolates, including ones with increased alginate production, were susceptible to competition by multiple environmental strains. We performed transposon mutagenesis on one isolate and identified an ∼14.8-kb locus involved in antagonistic activity. Only two other environmental isolates were observed to carry the locus, suggesting the presence of additional unique compounds or interactions among other isolates involved in outcompeting P. aeruginosa. This collection of strains represents a source of compounds that are active against multiple pathogenic strains. With the evolution of resistance of P. aeruginosa to currently used antibiotics, these environmental strains provide opportunities for novel compound discovery against drug-resistant clinical strains. IMPORTANCE We demonstrate that clinical CF-derived isolates of P. aeruginosa are susceptible to competition in the presence of environmental pseudomonads. We observed that many diverse environmental strains exhibited varied

  18. Effects of sildenafil on pulmonary hypertension and exercise tolerance in severe cystic fibrosis-related lung disease.

    PubMed

    Montgomery, Gregory S; Sagel, Scott D; Taylor, Amy L; Abman, Steven H

    2006-04-01

    Cystic fibrosis (CF) patients with advanced lung disease are at risk for developing pulmonary vascular disease and pulmonary hypertension, characterized by progressive exercise intolerance beyond the exercise-limiting effects of airways disease in CF. We report on a patient with severe CF lung disease who experienced clinically significant improvements in exercise tolerance and pulmonary hypertension without changing lung function during sildenafil therapy.

  19. Improving performance in the detection and management of cystic fibrosis-related diabetes in the Mountain West Cystic Fibrosis Consortium

    PubMed Central

    Liou, Theodore G; Jensen, Judith L; Allen, Sarah E; Brayshaw, Sara J; Brown, Mark A; Chatfield, Barbara; Koenig, Joni; McDonald, Catherine; Packer, Kristyn A; Peet, Kimberly; Radford, Peggy; Reineke, Linda M; Otsuka, Kim; Wagener, Jeffrey S; Young, David; Marshall, Bruce C

    2016-01-01

    Objective Cystic fibrosis (CF)-related diabetes (CFRD) is associated with increased morbidity and mortality. Improved detection and management may improve outcomes; however, actual practice falls short of published guidelines. We studied efforts to improve CFRD screening and management in the Mountain West CF Consortium (MWCFC). Research design and methods This is a prospective observational cohort study evaluating quality improvement by accredited CF centers in Arizona, Colorado, New Mexico, and Utah performed between 2002 and 2008. After Institutional Review Board (IRB) approval, centers evaluated adherence with CF Foundation guidelines for CFRD. Each center developed and implemented quality improvement plans to improve both screening and management. Centers were reassessed 1 year later. Results Initially, each CF center had low adherence with screening recommendations (26.5% of eligible patients) that did not improve during the study. However, patients with confirmed CFRD markedly increased (141 (12% of MWCFC patients) to 224 (17%), p<0.001), and with improved adherence to management guidelines, patients with CFRD had increased weight (56.8–58.9 kg, p<0.001), body mass index (21.1–21.4, p=0.003), and weight-for-age z-score (−1.42 to –0.84, p<0.001). Quality improvement methods were specific to the practice settings of each center but shared the common goal of adhering to CFRD care guidelines. 1 year after implementation, no center significantly differed from any other in level of adherence to guidelines. Conclusions Improving adherence with CFRD care guidelines requires substantial effort and may be incompletely successful, particularly for CFRD screening, but the effort may significantly improve patient monitoring and clinically relevant outcomes such as weight. PMID:27158517

  20. Airway acidification initiates host defense abnormalities in cystic fibrosis mice

    PubMed Central

    Shah, Viral S.; Meyerholz, David K.; Tang, Xiao Xiao; Reznikov, Leah; Alaiwa, Mahmoud Abou; Ernst, Sarah E.; Karp, Philip H.; Wohlford-Lenane, Christine L.; Heilmann, Kristopher P.; Leidinger, Mariah R.; Allen, Patrick D.; Zabner, Joseph; McCray, Paul B.; Ostedgaard, Lynda S.; Stoltz, David A.; Randak, Christoph O.; Welsh, Michael J.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H+ secretion by the nongastric H+/K+ adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H+; consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF. PMID:26823428

  1. Molecular basis of cystic fibrosis in the Republic of Macedonia.

    PubMed

    Petreska, L; Koceva, S; Plaseska, D; Chernick, M; Gordova-Muratovska, A; Fustic, S; Nestorov, R; Efremov, G D

    1998-09-01

    Eighty-three cystic fibrosis (CF) patients and their families, belonging to various ethnic groups living in the Republic of Macedonia were studied for molecular defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and for the associated extragenic marker loci XV-2c and KM19. The DNA methodology used included characterization of CFTR mutations in 19 exons (and flanking sequences) of the gene and analysis of distribution of the XV-2c/KM19 haplotypes among normal (N) and CF chromosomes by polymerase chain reaction (PCR) amplification followed by dot blot hybridization, restriction digestion, single-strand conformational polymorphism, constant denaturing gel electrophoresis, denaturing gradient gel electrophoresis, and sequencing. We identified 58.4% (97/166) of the CF chromosomes. Nine different CFTR gene mutations, including three novel ones, were found. Eight known and one new CFTR intragene polymorphisms were also characterized. The haplotype analysis of the XV-2c/TaqI and KM19/PstI polymorphic loci have shown that haplotype C is the most frequently found haplotype among the non-deltaF508 CF chromosomes from Macedonia (36.5%). The results demonstrate the broad heterogeneity of CF origin in this part of the Balkan Peninsula.

  2. The Cystic Fibrosis Gene: A Molecular Genetic Perspective

    PubMed Central

    Tsui, Lap-Chee; Dorfman, Ruslan

    2013-01-01

    The positional cloning of the gene responsible for cystic fibrosis (CF) was the important first step in understanding the basic defect and pathophysiology of the disease. This study aims to provide a historical account of key developments as well as factors that contributed to the cystic fibrosis transmembrane conductance regulator (CFTR) gene identification work. A redefined gene structure based on the full sequence of the gene derived from the Human Genome Project is presented, along with brief reviews of the transcription regulatory sequences for the CFTR gene, the role of mRNA splicing in gene regulation and CF disease, and, various related sequences in the human genome and other species. Because CF mutations and genotype-phenotype correlations are covered by our colleagues (Ferec C, Cutting GR. 2012. Assessing the disease-liability of mutations in CFTR. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a009480), we only attempt to provide an introduction of the CF mutation database here for reference purposes. PMID:23378595

  3. Impact of exacerbations of cystic fibrosis on muscle strength

    PubMed Central

    2013-01-01

    Background Adult patients with cystic fibrosis have peripheral muscle weakness, which is related to exercise intolerance and poor prognosis. The influence of acute exacerbations on muscle strength has been poorly studied. This study aimed to investigate whether quadriceps force (QF), as assessed with an involuntary technique, changes during intravenous antibiotics therapy (IVAT) for an exacerbation. Methods QF was measured in 20 patients using twitch stimulation of the femoral nerve at the day of hospitalization (day 1) and at termination (day 14) of the IVAT. Physical activity was monitored during IVAT using a SenseWear armband. Ten stable patients served as control subjects. Results QF did not change during exacerbation (potentiated twitch force at day 1: 140 ± 42 N, at day 14: 140 ± 47 N), but a decrease was observed in individual patients. Changes in twitch force during exacerbation were correlated with time spent in activities of at least moderate intensity (r = 0.61, p = 0.007). Conclusions QF does not systematically decrease during exacerbations of cystic fibrosis. Individual changes in QF are well correlated with daily time spent in activities of at least moderate intensity. PMID:23601143

  4. Too much salt, too little soda: cystic fibrosis.

    PubMed

    Quinton, Paul M

    2007-08-25

    Cystic fibrosis (CF) of the pancreas is the most widely accepted name of the most common fatal inherited single gene defect disease among Caucasians. Its incidence among other races is thought to be significantly less, but mutations in the gene have been reported in most, if not all, major populations. This review is intended to give general concepts of the molecular as well as physiological basis of the pathology that develops in the disease. First, an overview of the organ pathology and genetics is presented, followed by the molecular structure of the gene product (cystic fibrosis transmembrane conductance regulator, CFTR), its properties, functions, and controls as currently understood. Second, since mutations appear to be expressed primarily as a defect in electrolyte transport, effects and mechanisms of pathology are presented for two characteristically affected organs where the etiology is best described: the sweat gland, which excretes far too much NaCl ("salt") and the pancreas, which excretes far too little HCO3(- )("soda"). Unfortunately, morbidity and mortality in CF develop principally from refractory airway infections, the basis of which remains controversial. Consequently, we conclude by considering possible mechanisms by which defects in anion transport might predispose the CF lung to chronic infections.

  5. Interactions between Neutrophils and Pseudomonas aeruginosa in Cystic Fibrosis

    PubMed Central

    Rada, Balázs

    2017-01-01

    Cystic fibrosis (CF) affects 70,000 patients worldwide. Morbidity and mortality in CF is largely caused by lung complications due to the triad of impaired mucociliary clearance, microbial infections and chronic inflammation. Cystic fibrosis airway inflammation is mediated by robust infiltration of polymorphonuclear neutrophil granulocytes (PMNs, neutrophils). Neutrophils are not capable of clearing lung infections and contribute to tissue damage by releasing their dangerous cargo. Pseudomonas aeruginosa is an opportunistic pathogen causing infections in immunocompromised individuals. P. aeruginosa is a main respiratory pathogen in CF infecting most patients. Although PMNs are key to attack and clear P. aeruginosa in immunocompetent individuals, PMNs fail to do so in CF. Understanding why neutrophils cannot clear P. aeruginosa in CF is essential to design novel therapies. This review provides an overview of the antimicrobial mechanisms by which PMNs attack and eliminate P. aeruginosa. It also summarizes current advances in our understanding of why PMNs are incapable of clearing P. aeruginosa and how this bacterium adapts to and resists PMN-mediated killing in the airways of CF patients chronically infected with P. aeruginosa. PMID:28282951

  6. DHPLC screening of cystic fibrosis gene mutations.

    PubMed

    Ravnik-Glavac, Metka; Atkinson, Andrew; Glavac, Damjan; Dean, Michael

    2002-04-01

    Denaturing high performance liquid chromatography (DHPLC) using ion-pairing reverse phase chromatography (IPRPC) columns is a technique for the screening of gene mutations. In order to evaluate the potential utility of this assay method in a clinical laboratory setting, we subjected the PCR products of 73 CF patients known to bear CFTR mutations to this analytic technique. We used thermal denaturation profile parameters specified by the MELT program tool, made available by Stanford University. Using this strategy, we determined an initial analytic sensitivity of 90.4% for any of 73 known CFTR mutations. Most of the mutations not detected by DHPLC under these conditions are alpha-substitutions. This information may eventually help to improve the MELT algorithm. Increasing column denaturation temperatures for one or two degrees above those recommended by the MELT program allowed 100% detection of CFTR mutations tested. By comparing DHPLC methodology used in this study with the recently reported study based on Wavemaker 3.4.4 software (Transgenomic, Omaha, NE) [Le Marechal et al., 2001) and with previous SSCP analysis of CFTR mutations [Ravnik-Glavac et al., 1994] we emphasized differences and similarities in order to refine the DHPLC system and discuss the relationship to the alternative approaches. We conclude that the DHPLC method, under optimized conditions, is highly accurate, rapid, and efficient in detecting mutations in the CFTR gene and may find high utility in screening individuals for CFTR mutations. Hum Mutat 19:374-383, 2002. Published 2002 Wiley-Liss, Inc.

  7. Evaluation of the pharmacokinetics and pharmacodynamics of liposomal amikacin for inhalation in cystic fibrosis patients with chronic pseudomonal infections using data from two phase 2 clinical studies.

    PubMed

    Okusanya, Olanrewaju O; Bhavnani, Sujata M; Hammel, Jeffrey P; Forrest, Alan; Bulik, Catharine C; Ambrose, Paul G; Gupta, Renu

    2014-09-01

    The pharmacokinetic-pharmacodynamic (PK-PD) relationships between serum exposure measures of liposomal amikacin for inhalation (LAI) and the change in pulmonary function test (PFT) measures and number of CFU from baseline were evaluated in cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. A dose of 70, 140, 280, or 560 mg of LAI or placebo was administered to CF patients once daily for 28 days. PFTs and sputum samples for microbiology were assessed on days 7, 14, 21, 28, 35 (for log10 CFU), and 56 (for PFTs). Serum, urine, and sputum samples were collected for PK evaluation. The relationships between efficacy endpoints (relative change in forced expiratory volume in 1 s [FEV1 {expressed in liters}] and FEV1% predicted and the absolute change in log10 CFU of P. aeruginosa from baseline) and exposure measures (dose, day 1 area under the curve [AUC], dose/MIC ratio, and day 1 AUC/MIC ratio) and baseline MIC value were assessed. The serum and urine PK data were best fit by a 3-compartment model (lung, serum, and urine) with linear clearance and interoccasional variation on total and renal clearance. Significant univariable relationships between dose or day 1 AUC and the relative change in PFT measures (P≤0.017) or the absolute change in log10 CFU from baseline (P≤0.037) on the study days were identified. Repeated-measures mixed-effects models, which showed dose- and AUC-related improvements for each efficacy endpoint (P≤0.041), predicted the observed data well. The increases in the relative change in FEV1 and FEV1% predicted of 11% and 9.9%, respectively, and a 1.23-log10 CFU reduction per 560 mg of LAI estimated on day 7 were comparable to the observed increases of 10.7% and 10.3%, respectively, and a 1.24-log10 CFU reduction on the same day. The model-estimated PFT effects were predicted to be sustained to day 28. An additional 0.451-log10 CFU reduction (P=0.022) was estimated on day 14 relative to day 7, with a persistence of

  8. Nasal mucociliary clearance and ciliary beat frequency in cystic fibrosis compared with sinusitis and bronchiectasis.

    PubMed Central

    Rutland, J; Cole, P J

    1981-01-01

    Nasal ciliary function and mucociliary clearance were studied in patients with cystic fibrosis and in three control groups. Ciliary beat frequency and nasal clearance time were measured in groups of 10 subjects with cystic fibrosis, sinusitis and bronchiectasis and age and sex-matched control subjects. Ciliary beat frequency was also measured in normal subjects matched as bronchiectasis controls. Cystic fibrosis patients and their controls, patients with sinusitis, and the bronchiectasis controls did not differ in ciliary beat frequency, but it was slower in the patients with bronchiectasis (p less than 0.05). Nasal mucociliary clearance in cystic fibrosis and bronchiectasis was slower than in the cystic fibrosis controls (p less than 0.001) and in patients with sinusitis (p less than 0.01). The finding of a normal beat frequency in cystic fibrosis cilia studied in vitro together with abnormal nasal mucociliary clearance measured in vivo in the same patients suggests the existence of an abnormality of mucus in vivo. The innate function of cystic fibrosis cilia, as measured in vitro by beat frequency, is normal. PMID:7314040

  9. Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis

    SciTech Connect

    Trapnell, B.C.; Chinshyan Chu; Paakko, P.K.; Banks, T.C.; Yoshimura, Kunihiko; Ferrans, V.J.; Chernick, M.S.; Crystal, R.G. )

    1991-08-01

    The most common mutation of the cystic fibrosis transmembrane conductance regulator gene, CFTR, associated with the clinical disorder cystic fibrosis (CF) is called {Delta}Phe{sup 508}, a triple-base deletion resulting in loss of phenylalanine at residue 508 of the predicted 1480-amino acid CFTR protein. In the context that the lung is the major site of morbidity and mortality in CF, the authors evaluated airway epithelial cells for CFTR mRNA transcripts in normal individuals, normal-{Delta}Phe{sup 508} heterozygotes, and {Delta}Phe{sup 508} homozygotes to determine if the normal and {Delta}Phe{sup 508} CFTR alleles are expressed in the respiratory epithelium, to what extent they are expressed, and whether there are relative differences in the expression of the normal and abnormal alleles at the mRNA level. Respiratory tract epithelial cells recovered by fiberoptic bronchoscopy with a cytology brush demonstrated CFTR mRNA transcripts with sequences appropriately reflecting the normal and {Delta}Phe{sup 508} CFTR alleles of the various study groups. CFTR gene expression quantified by limited polymerase chain reaction amplification showed that in normal individuals, CFTR mRNA transcripts are expressed in nasal, tracheal, and bronchial epithelial cells.

  10. Comparison of Microbiomes from Different Niches of Upper and Lower Airways in Children and Adolescents with Cystic Fibrosis

    PubMed Central

    Boutin, Sébastien; Graeber, Simon Y.; Weitnauer, Michael; Panitz, Jessica; Stahl, Mirjam; Clausznitzer, Diana; Kaderali, Lars; Einarsson, Gisli; Tunney, Michael M.; Elborn, J. Stuart

    2015-01-01

    Changes in the airway microbiome may be important in the pathophysiology of chronic lung disease in patients with cystic fibrosis. However, little is known about the microbiome in early cystic fibrosis lung disease and the relationship between the microbiomes from different niches in the upper and lower airways. Therefore, in this cross-sectional study, we examined the relationship between the microbiome in the upper (nose and throat) and lower (sputum) airways from children with cystic fibrosis using next generation sequencing. Our results demonstrate a significant difference in both α and β-diversity between the nose and the two other sampling sites. The nasal microbiome was characterized by a polymicrobial community while the throat and sputum communities were less diverse and dominated by a few operational taxonomic units. Moreover, sputum and throat microbiomes were closely related especially in patients with clinically stable lung disease. There was a high inter-individual variability in sputum samples primarily due to a decrease in evenness linked to increased abundance of potential respiratory pathogens such as Pseudomonas aeruginosa. Patients with chronic Pseudomonas aeruginosa infection exhibited a less diverse sputum microbiome. A high concordance was found between pediatric and adult sputum microbiomes except that Burkholderia was only observed in the adult cohort. These results indicate that an adult-like lower airways microbiome is established early in life and that throat swabs may be a good surrogate in clinically stable children with cystic fibrosis without chronic Pseudomonas aeruginosa infection in whom sputum sampling is often not feasible. PMID:25629612

  11. Desensitisation of neutrophil responses by systemic interleukin 8 in cystic fibrosis.

    PubMed Central

    Dai, Y.; Dean, T. P.; Church, M. K.; Warner, J. O.; Shute, J. K.

    1994-01-01

    BACKGROUND--Inflammation associated with neutrophil infiltration is a commonly observed feature of children with cystic fibrosis. Production of the major neutrophil chemotactic cytokine interleukin 8 (IL-8) is potentially of great importance in the pathology of cystic fibrosis. Concentrations of IL-8 in both sputum and bronchoalveolar lavage fluid have been found to be higher in children with cystic fibrosis than in controls. The IL-8 induced chemotactic response and numbers of IL-8 receptors on peripheral neutrophils obtained from children with cystic fibrosis have been compared with a control group of children. METHODS--Cells were isolated from 18 patients with cystic fibrosis (aged 4-20 years) and 13 controls (aged 5-12 years) by dextran centrifugation followed by separation on Lymphoprep. Chemotaxis was assayed using multiwell microchemotaxis chambers and 5 microns polycarbonate filters. Filters were fixed and stained with Haema-Gurr for counting. Results were expressed as numbers of neutrophils per high power field (HPF). RESULTS--At the optimum concentration (1 x 10(-8) mol/l) the number of cells migrating were similar for controls (150 (12)/HPF) and for the cystic fibrosis group (140 (14)/HPF)). At lower concentrations the numbers of neutrophils migrating were lower for the cystic fibrosis group. Scatchard analysis of 125I-labelled IL-8 binding revealed lower numbers of receptors on neutrophils from patients with cystic fibrosis (22,000 per cell) than from controls (75,000 per cell). CONCLUSIONS--Reduced responsiveness to IL-8 of neutrophils from patients with cystic fibrosis is associated with receptor desensitisation as a result of exposure to high systemic levels of IL-8. PMID:7940424

  12. Cystic fibrosis: current survival and population estimates to the year 2000.

    PubMed Central

    Elborn, J S; Shale, D J; Britton, J R

    1991-01-01

    BACKGROUND: Survival from cystic fibrosis is increasing rapidly. Estimates of the extent of this improvement should allow health care facilities to be planned to deal with the expanding population of patients with cystic fibrosis. Estimates of life expectancy are also essential if accurate information on current prognosis is to be given to parents of an affected child, or to prospective parents deciding whether to proceed with a pregnancy where the fetus may be affected. METHODS: Survival trends in the national data on cystic fibrosis have been analysed to produce estimates of the likely size of the cystic fibrosis population over the next decade and to predict the life expectancy of children born with cystic fibrosis in the years up to 1990. RESULTS: In England and Wales the estimated number of patients with cystic fibrosis is at present about 5200, of whom 3300 (63%) are aged under 16 years. By the year 2000 the total population will increase to 6000, with 3400 (57%) aged under 16. Thus the number of children with cystic fibrosis will remain fairly constant over the next 10 years, whereas adult numbers will increase by about 36% (from 1901 to 2577). The median life expectancy of children with cystic fibrosis born in 1990 is estimated to be 40 years, double that of 20 years ago. CONCLUSION: This study suggests that health service provision for children will not need to change substantially over the next 10 years whereas services for adults will need to increase by about a third. Parents can be counselled that the median life expectancy of a newborn child with cystic fibrosis is currently likely to be of the order of 40 years. PMID:1792634

  13. Relationship of Adherence Determinants and Parental Spirituality in Cystic Fibrosis

    PubMed Central

    Grossoehme, Daniel H.; Opipari-Arrigan, Lisa; VanDyke, Rhonda; Thurmond, Sophia; Seid, Michael

    2015-01-01

    Summary The course of cystic fibrosis (CF) progression in children is affected by parent adherence to treatment plans. The Theory of Reasoned Action (TRA) posits that intentions are the best behavioral predictors and that intentions reasonably follow from beliefs (“determinants”). Determinants are affected by multiple “background factors,” including spirituality. This study’s purpose was to understand whether two parental adherence determinants (attitude towards treatment and self-efficacy) were associated with spirituality (religious coping and sanctification of the body). We hypothesized that parents’ attitudes toward treatment adherence are associated with these spiritual constructs. A convenience sample of parents of children with CF aged 3–12 years (n = 28) participated by completing surveys of adherence and spirituality during a regular outpatient clinic visit. Type and degree of religious coping was examined using principal component analysis. Adherence measures were compared based on religious coping styles and sanctification of the body using unpaired t-tests. Collaborative religious coping was associated with higher self-efficacy for completing airway clearance (M = 1070.8; SD = 35.8; P = 0.012), for completing aerosolized medication administration (M = 1077.1; SD = 37.4; P = 0.018), and for attitude towards treatment utility (M = 38.8; SD = 2.36; P = 0.038). Parents who attributed sacred qualities to their child’s body (e.g., “blessed” or “miraculous”) had higher mean scores for self-efficacy (airway clearance, M = 1058.6; SD = 37.7; P = 0.023; aerosols M = 1070.8; SD = 41.6; P = 0.020). Parents for whom God was manifested in their child’s body (e.g., “My child’s body is created in God’s image”) had higher mean scores for self-efficacy for airway clearance (M = 1056.4; SD = 59.0; P = 0.039), aerosolized medications (M = 1068.8; SD = 42.6; P = 0.033) and treatment utility (M = 38.8; SD = 2.4; P = 0.025). Spiritual

  14. Parent routines for managing cystic fibrosis in children

    PubMed Central

    Grossoehme, Daniel H.; Filigno, Stephanie Spear; Bishop, Meredith

    2014-01-01

    Management of cystic fibrosis (CF) is burdensome and adherence is often suboptimal. Family routines are associated with adherence and health outcomes in other disease populations. Few studies have examined routines in CF. The study's aim was to describe parent experiences developing and utilizing CF care routines. Semi-structured interviews with a convenience sample of 25 parents of children under 13 years of age with CF were analyzed using phenomenological analysis. Three domains emerged: parent experiences developing a routine, support systems facilitating maintenance of routines, and challenges with maintaining care routines. Parents found routines difficult to establish, used trial and error, encountered barriers, and found support helpful to manage care demands. Some parents chose to deviate from their routine. Providing anticipatory guidance to promote the use of care routines and strategies to manage potential challenges may facilitate use of routines and improve CF management. PMID:24838648

  15. [Recommendations for the management of bone demineralization in cystic fibrosis].

    PubMed

    Sermet-Gaudelus, I; Nove-Josserand, R; Loeille, G-A; Dacremont, G; Souberbielle, J-C; Fritsch, J; Laurans, M; Moulin, P; Cortet, B; Salles, J-P; Ginies, J-L; Guillot, M; Perez-Martin, S; Ruiz, J-C; Montagne, V; Cohen-Solal, M; Cormier, C; Garabédian, M; Mallet, E

    2008-03-01

    A high prevalence of low bone mineralization is documented in adult patients with cystic fibrosis (CF). Osteopenia is present in as much as 85% of adult patients and osteoporosis in 13 to 57% of them. In children, studies are discordant probably because of different control database. Denutrition, inflammation, vitamin D and vitamin K deficiency, altered sex hormone production, glucocorticoid therapy, and physical inactivity are well known risk factors for poor bone health. Puberty is a critical period and requires a careful follow-up for an optimal bone peak mass. This review is a consensus statement established by the national working group of the French Federation of CF Centers to develop practice guidelines for optimizing bone health in patients with CF. Recommendations for screening and for calcium, vitamin D and K supplementation are given. Further work is needed to define indications for treatment with biphosphonates and anabolic agents.

  16. Prenatal screening of Cystic Fibrosis: a single centre experience

    PubMed Central

    Bizzoco, Domenico; Mesoraca, Alvaro; Cima, Antonella; Sarti, Monica; Di Giacomo, Gianluca; Scerra, Giovanna; Barone, Maria Antonietta; Di Natale, Manuela; Gabrielli, Ivan; Tamburino, Caterina; Scargiali, Claudia; Ernandez, Cristina; D’Aleo, Maria Pia; Todini, Michele; Pompili, Rita; Mobili, Luisa; Mangiafico, Lucia; Carcioppolo, Ornella; Coco, Claudio; Cignini, Pietro; D’Emidio, Laura; Girgenti, Alessandra; Brizzi, Cristiana; Cavaliere, Alessandro; Giorlandino, Claudio

    2008-01-01

    Objective: The gene responsible for the pathogenesis of cystic fibrosis has been known for over 15 years and represent the most common autosomal recessive disease in the european population. We aimed to investigate the incidence of this condition during fetal life. Methods: In the past 10 years we examined in our centre 25393 fetuses of women underwent to amniocentesis. We carried out the examination of the most frequent mutations which enable, according to the literature data, the identification of almost 80% of the affected alleles. Result: We identified 922 heterozygous and 9 homozygous for the mutation. The frequency of heterozygousin the examined sample was 1/27,5 while that of the affected was 1/2821. Conclusion: We encourage new thoughts regarding the diagnostic validity of the most frequent panel of mutations among the italian population in order to exclude never encountered mutations and the insertion of other more significant mutations. PMID:22439019

  17. Liver transplantation for hepatic cirrhosis in cystic fibrosis.

    PubMed Central

    Noble-Jamieson, G; Valente, J; Barnes, N D; Friend, P J; Jamieson, N V; Rasmussen, A; Calne, R Y

    1994-01-01

    Five children with cystic fibrosis complicated by hepatic cirrhosis received liver grafts. They all had portal hypertension with varices and three had variceal bleeding; respiratory function was only moderately impaired, but four were colonised with pseudomonas and one with aspergillus. Liver transplantation was well tolerated and there was no increase in respiratory or other early postoperative complications. Four of the children were fully well from 14 to 35 months after transplantation; the most recently transplanted had problems from a biliary stricture. In spite of the need for immunosuppression there was no increase in infection and respiratory function improved or remained stable. Once the children were stabilised after transplantation their nutrition and general health were greatly improved. PMID:7979532

  18. Infection in cystic fibrosis: impact of the environment and climate.

    PubMed

    Ramsay, K A; Stockwell, R E; Bell, S C; Kidd, T J

    2016-01-01

    In many countries numbers of adults with cystic fibrosis (CF) exceed that of children, with median survival predicted to surpass 50 years. Increasing longevity is, in part, due to intensive therapies including eradication of early infection and suppressive therapies and pulmonary exacerbations. Initial infections with common CF pathogens are thought to arise from the natural environment. We review the impact of climate and environment on infection in CF. Specifically, several studies indicate that higher ambient temperatures, proximity to the equator and the summer season may be linked to the increased prevalence of Pseudomonas aeruginosa in people with CF. The environment may also play an important role in the acquisition of Gram negative organisms other than P. aeruginosa. There is emerging data suggesting that climatic and environmental factors are likely to impact on the risk of infection with NTM and fungi in people which are found extensively throughout the natural environment.

  19. Cystic fibrosis presenting as diabetes insipidus unresponsive to desmopressin.

    PubMed

    Vande Velde, S; Van Biervliet, S; Robberecht, E

    2007-01-01

    The diagnosis of cystic fibrosis (CF) can be confusing when only a part of the typical symptoms is present. In children, CF is usually suspected when dealing with chronic pulmonary symptoms (chronic productive cough, recurrent pneumonia or bronchiolitis). The pediatric gastroenterologist will exclude CF in all children with a meconium ileus, rectal prolaps or a poor weight gain. Atypical CF symptoms are hypochloremic alkalosis, recurrent pancreatitis and increased appetite to compensate for the pancreatic insufficiency. This case report shows how a diagnosis can be delayed when you are mislead by atypical symptoms. It shows the importance of looking in napkins and argues for the inclusion of CF in the differential diagnosis of polyuria in infants.

  20. Computed tomography dose optimisation in cystic fibrosis: A review

    PubMed Central

    Ferris, Helena; Twomey, Maria; Moloney, Fiachra; O’Neill, Siobhan B; Murphy, Kevin; O’Connor, Owen J; Maher, Michael

    2016-01-01

    Cystic fibrosis (CF) is the most common autosomal recessive disease of the Caucasian population worldwide, with respiratory disease remaining the most relevant source of morbidity and mortality. Computed tomography (CT) is frequently used for monitoring disease complications and progression. Over the last fifteen years there has been a six-fold increase in the use of CT, which has lead to a growing concern in relation to cumulative radiation exposure. The challenge to the medical profession is to identify dose reduction strategies that meet acceptable image quality, but fulfil the requirements of a diagnostic quality CT. Dose-optimisation, particularly in CT, is essential as it reduces the chances of patients receiving cumulative radiation doses in excess of 100 mSv, a dose deemed significant by the United Nations Scientific Committee on the Effects of Atomic Radiation. This review article explores the current trends in imaging in CF with particular emphasis on new developments in dose optimisation. PMID:27158420

  1. The Use of Home Spirometry in Pediatric Cystic Fibrosis Patients

    PubMed Central

    Shakkottai, Aarti; Nasr, Samya Z.

    2017-01-01

    Medication adherence is poor among pediatric cystic fibrosis (CF) patients, with adolescents having one of the lowest adherence rates. We wanted to identify an adherence intervention that would be acceptable to CF adolescents and assess its feasibility. We surveyed 40 adolescents with CF and asked about barriers to and motivators for their own adherence and to generate ideas for potential adherence interventions. Since most of the respondents chose frequent spirometry at home and medication reminders for interventions, we selected 5 subjects, 10 to 14 years of age, with CF to test the feasibility of home spirometry and medication reminders in pediatric CF patients. This article summarizes the results of both the survey and the feasibility pilot study. PMID:28229102

  2. Tuberculosis reinfection in a pregnant cystic fibrosis patient

    PubMed Central

    Marco, Asween; Montales, Maria Theresa; Mittadodla, Penchala; Mukasa, Leonard; Bhaskar, Nutan; Bates, Joseph; Patil, Naveen

    2015-01-01

    Cystic Fibrosis (CF) is a multisystem disease predominantly affecting the airways and predisposing patients to recurrent infections with various multidrug resistant organisms. Mycobacterium tuberculosis (MTB) infection is rarely seen, but considered a potential pathogen in CF patients. We report a 26 year old pregnant CF patient on Ivacaftor who was admitted with symptoms suggestive of tuberculosis. Three years prior to the current admission, she had completed four drug anti- MTB therapy for pulmonary tuberculosis and was considered cured as her sputum cultures after six months of treatment were negative. Genotype analysis revealed the current MTB strain to be different from the strain causing the previous infection. After receiving first line anti-tuberculous regimen for nine months, the patient's condition markedly improved culminating in an uneventful pregnancy and delivery. To our knowledge, this is the only reported case of reinfection tuberculosis in a CF patient. PMID:26744656

  3. Cystic fibrosis – a multiorgan protein misfolding disease

    PubMed Central

    Fraser-Pitt, Douglas; O’Neil, Deborah

    2015-01-01

    Cystic fibrosis (CF) is a heterogeneous multiorgan disease caused by mutations in the CFTR gene leading to misfolding (and other defects) and consequent dysfunction of CFTR protein. The majority of mutations cause a severe CF phenotype, and people with this condition will require a wide variety of medical interventions and therapies throughout their lives to address the symptoms of their condition. CF affects many different organ systems, but the most serious consequence of the disease is degeneration of lung function due to chronic respiratory infection and colonization of the airways with opportunistic microbial pathogens. Improvements in therapeutics, particularly the effective use of antibiotics, have led to significant gradual increases in life expectancy. There remains, however, a continuing need for newer, safer and more effective antimicrobials and mucolytic agents to maintain and improve our ability to combat CF lung infections before other curative approaches which target the root cause of the disease become available. PMID:28031875

  4. Antibiotic and Anti-Inflammatory Therapies for Cystic Fibrosis

    PubMed Central

    Chmiel, James F.; Konstan, Michael W.; Elborn, J. Stuart

    2013-01-01

    Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and an unremitting inflammatory response, which are responsible for most of CF morbidity and mortality. The median expected survival has increased from <6 mo in 1940 to >38 yr now. This dramatic improvement, although not great enough, is due to the development of therapies directed at secondary disease pathologies, especially antibiotics. The importance of developing treatments directed against the vigorous inflammatory response was realized in the 1990s. New therapies directed toward the basic defect are now visible on the horizon. However, the impact of these drugs on downstream pathological consequences is unknown. It is likely that antibiotics and anti-inflammatory drugs will remain an important part of the maintenance regimen for CF in the foreseeable future. Current and future antibiotic and anti-inflammatory therapies for CF are reviewed. PMID:23880054

  5. The problems of antibiotic resistance in cystic fibrosis and solutions.

    PubMed

    López-Causapé, Carla; Rojo-Molinero, Estrella; Macià, María D; Oliver, Antonio

    2015-02-01

    Chronic respiratory infection is the main cause of morbidity and mortality in cystic fibrosis (CF) patients. One of the hallmarks of these infections, led by the opportunistic pathogen Pseudomonas aeruginosa, is their long-term (lifelong) persistence despite intensive antimicrobial therapy. Antimicrobial resistance in CF is indeed a multifactorial problem, which includes physiological changes, represented by the transition from the planktonic to the biofilm mode of growth and the acquisition of multiple (antibiotic resistance) adaptive mutations catalyzed by frequent mutator phenotypes. Emerging multidrug-resistant CF pathogens, transmissible epidemic strains and transferable genetic elements (such as those encoding class B carbapenemases) also significantly contribute to this concerning scenario. Strategies directed to combat biofilm growth, prevent the emergence of mutational resistance, promote the development of novel antimicrobial agents against multidrug-resistant strains and implement strict infection control measures are thus needed.

  6. Sinonasal characteristics and quality of life by SNOT-22 in adult patients with cystic fibrosis.

    PubMed

    Kang, Suzie Hyeona; Meotti, Camila Degen; Bombardelli, Karine; Piltcher, Otávio Bejzman; de Tarso Roth Dalcin, Paulo

    2017-04-01

    The prevalence of chronic sinus disease in cystic fibrosis (CF) has gradually increased. Sinonasal involvement may have influence on pulmonary exacerbations and can have a negative impact on the quality of life. To evaluate nasal characteristics and quality of life in adult patients with CF; to establish an association and determine the predictors in SNOT-22 questionnaire. Cross- sectional study with prospective data collection was performed to evaluate adult CF patients. Patients underwent clinical evaluation, lung function tests, nasal endoscopy, and paranasal sinuses CT scan. All the patients answered the SNOT-22 questionnaire.

  7. Critical evaluation of lung scintigraphy in cystic fibrosis: study of 113 patients

    SciTech Connect

    Piepsz, A.; Wetzburger, C.; Spehl, M.; Machin, D.; Dab, I.; Ham, H.R.; Vandevivere, J.; Baran, D.

    1980-10-01

    A long-term study has been performed on 285 lung perfusion scintigrams obtained from 113 patients with cystic fibrosis. Transverse and longitudinal comparisons with clinical and radiological scores, as well as retrospective analysis of the deceased patients, were the methods used in order to evaluate the importance of the scintigraphic images. It appears that lung scintigraphy is the best index of the regional lung impairment, and contributes, as does a chest radiograph, to the early detection of lung lesions, the two methods being complementary.

  8. CFTR, Mucins, and Mucus Obstruction in Cystic Fibrosis

    PubMed Central

    Kreda, Silvia M.; Davis, C. William; Rose, Mary Callaghan

    2012-01-01

    Mucus pathology in cystic fibrosis (CF) has been known for as long as the disease has been recognized and is sometimes called mucoviscidosis. The disease is marked by mucus hyperproduction and plugging in many organs, which are usually most fatal in the airways of CF patients, once the problem of meconium ileus at birth is resolved. After the CF gene, CFTR, was cloned and its protein product identified as a cAMP-regulated Cl− channel, causal mechanisms underlying the strong mucus phenotype of the disease became obscure. Here we focus on mucin genes and polymeric mucin glycoproteins, examining their regulation and potential relationships to a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR). Detailed examination of CFTR expression in organs and different cell types indicates that changes in CFTR expression do not always correlate with the severity of CF disease or mucus accumulation. Thus, the mucus hyperproduction that typifies CF does not appear to be a direct cause of a defective CFTR but, rather, to be a downstream consequence. In organs like the lung, up-regulation of mucin gene expression by inflammation results from chronic infection; however, in other instances and organs, the inflammation may have a non-infectious origin. The mucus plugging phenotype of the β-subunit of the epithelial Na+ channel (βENaC)-overexpressing mouse is proving to be an archetypal example of this kind of inflammation, with a dehydrated airway surface/concentrated mucus gel apparently providing the inflammatory stimulus. Data indicate that the luminal HCO3 − deficiency recently described for CF epithelia may also provide such a stimulus, perhaps by causing a mal-maturation of mucins as they are released onto luminal surfaces. In any event, the path between CFTR dysfunction and mucus hyperproduction has proven tortuous, and its unraveling continues to offer its own twists and turns, along with fascinating glimpses into biology. PMID:22951447

  9. Cystic Fibrosis-Related Oxidative Stress and Intestinal Lipid Disorders

    PubMed Central

    Kleme, Marie-Laure

    2015-01-01

    Abstract Significance: Cystic fibrosis (CF) is the most common lethal genetic disorder in the Caucasian people. It is due to the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) gene located on the long arm of the chromosome 7, which encodes for CFTR protein. The latter, an adenosine triphosphate binding cassette, is a transmembrane chloride channel that is also involved in glutathione transport. As glutathione/glutathione disulfide constitutes the most important pool of cellular redox systems, CFTR defects could thus disrupt the intracellular redox balance. Resulting multisystemic diseases are essentially characterized by a chronic respiratory failure, a pancreatic insufficiency, an essential fatty acid deficiency (EFAD), and inadequate levels of antioxidant vitamins. Recent Advances: The pathophysiology of CF is complex; however, several mechanisms are proposed, including oxidative stress (OxS) whose implication is recognized and has been clearly demonstrated in CF airways. Critical Issues: Little is known about OxS intrinsic triggers and its own involvement in intestinal lipid disorders. Despite the regular administration of pancreatic supplements, high-fat high-calorie diets, and antioxidant fat-soluble vitamins, there is a persistence of steatorrhea, EFAD, and harmful OxS. Intriguingly, several trials with elevated doses of antioxidant vitamins have not yielded significant improvements. Future Directions: The main sources and self-maintenance of OxS in CF should be clarified to improve treatment of patients. Therefore, this review will discuss the potential sources and study the mechanisms of OxS in the intestine, known to develop various complications, and its involvement in intestinal lipid disorders in CF patients. Antioxid. Redox Signal. 22, 614–631. PMID:25611180

  10. Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Cystic Fibrosis

    PubMed Central

    Chandrasekharan, Subhashini; Heaney, Christopher; James, Tamara; Conover, Chris; Cook-Deegan, Robert

    2010-01-01

    Cystic fibrosis (CF) is one of the most commonly tested autosomal recessive disorders in the US. Clinical CF is associated with mutations in the CFTR gene, of which the most common mutation among Caucasians, ΔF508, was identified in 1989. The University of Michigan, Johns Hopkins University, and the Hospital for Sick Children, where much of the initial research occurred, hold key patents for CF genetic sequences, mutations and methods for detecting them. Several patents including the one that covers detection of the ΔF508 mutation are jointly held by the University of Michigan and the Hospital for Sick Children in Toronto, with Michigan administering patent licensing in the US. The University of Michigan broadly licenses the ΔF508 patent for genetic testing with over 60 providers of genetic testing to date. Genetic testing is now used in newborn screening, diagnosis, and reproductive decisions. Interviews with key researchers and intellectual property managers, a survey of laboratories’ prices for CF genetic testing, a review of literature on CF tests’ cost effectiveness, and a review of the developing market for CF testing provide no evidence that patents have significantly hindered access to genetic tests for CF or prevented financially cost-effective screening. Current licensing practices for cystic fibrosis (CF) genetic testing appear to facilitate both academic research and commercial testing. More than one thousand different CFTR mutations have been identified, and research continues to determine their clinical significance. Patents have been nonexclusively licensed for diagnostic use, and have been variably licensed for gene transfer and other therapeutic applications. The Cystic Fibrosis Foundation has been engaged in licensing decisions, making CF a model of collaborative and cooperative patenting and licensing practice. PMID:20393308

  11. Nocardia farcinica lung infection in a patient with cystic fibrosis: a case report

    PubMed Central

    2010-01-01

    Introduction Respiratory tract infections are the major causes of morbidity and mortality in patients with cystic fibrosis. Nocardia are rarely implicated in these infections and few reports of the involvement of this species are found in the literature. Case presentation We describe a case of lung infection followed by chronic colonization of trimethoprim and sulfamethoxazole resistant Nocardia farcinica in a patient with cystic fibrosis. The chronic colonization of this uncommon bacterium in patients with cystic fibrosis was proved using a newly developed real-time polymerase chain reaction assay, which indicates that this bacterium, despite treatment, is difficult to eradicate. Conclusion Our case report confirms that this organism can be recovered in persons with cystic fibrosis. Its eradication is necessary especially if the patient is to undergo lung transplantation. PMID:20211000

  12. The Molecular Genetics of Cystic Fibrosis: The Work of Francis Collins

    PubMed Central

    Kresge, Nicole; Simoni, Robert D.; Hill, Robert L.

    2011-01-01

    When Francis Collins enrolled at Yale University to earn a doctorate in physical chemistry, he considered the field of biology to be “chaotic and unpredictable.” However, a biochemistry course unexpectedly sparked his interest and led him to develop the positional cloning technique that he subsequently used to identify the disease-causing mutations for cystic fibrosis, neurofibromatosis, and Huntington disease. The JBC Classic reprinted here follows up on some of Collins' initial cystic fibrosis research, investigating the regulation of the cystic fibrosis transmembrane conductance regulator. Characterization of the Cystic Fibrosis Transmembrane Conductance Regulator Promoter Region (Koh, J. , Sferra, T. J., and Collins, F. S. (1993) J. Biol. Chem. 268, 15912–15921)

  13. Iron accumulates in the lavage and explanted lungs of cystic fibrosis patients.

    EPA Science Inventory

    Abstract Oxidative stress participates in the pathophysiology of cystic fibrosis (CF). An underlying disruption in iron homeostasis can frequently be demonstrated in injuries and diseases associated with an oxidative stress. We tested the hypothesis that iron accumulation and ...

  14. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Allelic Variants Relate to Shifts in Faecal Microbiota of Cystic Fibrosis Patients

    PubMed Central

    Santangelo, Floriana; Gagliardi, Antonella; De Biase, Riccardo Valerio; Stamato, Antonella; Bertasi, Serenella; Lucarelli, Marco

    2013-01-01

    Introduction In this study we investigated the effects of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene variants on the composition of faecal microbiota, in patients affected by Cystic Fibrosis (CF). CFTR mutations (F508del is the most common) lead to a decreased secretion of chloride/water, and to mucus sticky secretions, in pancreas, respiratory and gastrointestinal tracts. Intestinal manifestations are underestimated in CF, leading to ileum meconium at birth, or small bowel bacterial overgrowth in adult age. Methods Thirty-six CF patients, fasting and under no-antibiotic treatment, were CFTR genotyped on both alleles. Faecal samples were subjected to molecular microbial profiling through Temporal Temperature Gradient Electrophoresis and species-specific PCR. Ecological parameters and multivariate algorithms were employed to find out if CFTR variants could be related to the microbiota structure. Results Patients were classified by two different criteria: 1) presence/absence of F508del mutation; 2) disease severity in heterozygous and homozygous F508del patients. We found that homozygous-F508del and severe CF patients exhibited an enhanced dysbiotic faecal microbiota composition, even within the CF cohort itself, with higher biodiversity and evenness. We also found, by species-specific PCR, that potentially harmful species (Escherichia coli and Eubacterium biforme) were abundant in homozygous-F508del and severe CF patients, while beneficial species (Faecalibacterium prausnitzii, Bifidobacterium spp., and Eubacterium limosum) were reduced. Conclusions This is the first report that establishes a link among CFTR variants and shifts in faecal microbiota, opening the way to studies that perceive CF as a ‘systemic disease’, linking the lung and the gut in a joined axis. PMID:23613805

  15. Mutant cystic fibrosis transmembrane conductance regulator inhibits acidification and apoptosis in C127 cells: possible relevance to cystic fibrosis.

    PubMed Central

    Gottlieb, R A; Dosanjh, A

    1996-01-01

    We have shown elsewhere that acidification is an early event in apoptosis, preceding DNA cleavage. Cells expressing the most common mutation (delF508) of the cystic fibrosis transmembrane regulator (CFTR) exhibit a higher resting intracellular pH and are unable to secrete chloride and bicarbonate in response to cAMP. We hypothesized that defective acidification in cells expressing delF508 CFTR would interfere with the acidification that accompanies apoptosis, which in turn, would prevent endonuclease activation and cleavage of DNA. We therefore determined whether the function of the CFTR would affect the process of apoptosis in mouse mammary epithelial C127 cells stably transfected with the wild-type CFTR (C127/wt) or the delF508 mutation of the CFTR (C127/508). C127 cells possessed an acid endonuclease capable of DNA degradation at low pH. Sixteen hours after treatment with cycloheximide, C127/wt cells underwent cytoplasmic acidification. In contrast, C127/508 cells failed to demonstrate acidification. Furthermore, the C127/508 cells did not show nuclear condensation or DNA fragmentation detected by in situ nick-end labeling after treatment with cycloheximide or etoposide, in contrast to the characteristic features of apoptosis demonstrated by the C127/wt cells. Measurement of cell viability indicated a preservation of cell viability in C127/508 cells but not in C127/wt cells. That this resistance to the induction of apoptosis depended upon the loss of CFTR activity is shown by the finding that inhibition of the CFTR with diphenylamine carboxylate in C127/wt cells conferred similar protection. These findings suggest a role for the CFTR in acidification during the initiation of apoptosis in epithelial cells and imply that a failure to undergo programmed cell death could contribute to the pathogenesis of cystic fibrosis. Images Fig. 1 Fig. 2 Fig. 3 PMID:8622979

  16. Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities.

    PubMed

    Li, Weili; Soave, David; Miller, Melissa R; Keenan, Katherine; Lin, Fan; Gong, Jiafen; Chiang, Theodore; Stephenson, Anne L; Durie, Peter; Rommens, Johanna; Sun, Lei; Strug, Lisa J

    2014-02-01

    The existence of pleiotropy in disorders with multi-organ involvement can suggest therapeutic targets that could ameliorate overall disease severity. Here we assessed pleiotropy of modifier genes in cystic fibrosis (CF). CF, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects the lungs, liver, pancreas and intestines. However, modifier genes contribute to variable disease severity across affected organs, even in individuals with the same CFTR genotype. We sought to determine whether SLC26A9, SLC9A3 and SLC6A14, that contribute to meconium ileus in CF, are pleiotropic for other early-affecting CF co-morbidities. In the Canadian CF population, we assessed evidence for pleiotropic effects on (1) pediatric lung disease severity (n = 815), (2) age at first acquisition of Pseudomonas aeruginosa (P. aeruginosa) (n = 730), and (3) prenatal pancreatic damage measured by immunoreactive trypsinogen (n = 126). A multiple-phenotype analytic strategy assessed evidence for pleiotropy in the presence of phenotypic correlation. We required the same alleles to be associated with detrimental effects. SLC26A9 was pleiotropic for meconium ileus and pancreatic damage (p = 0.002 at rs7512462), SLC9A3 for meconium ileus and lung disease (p = 1.5 × 10(-6) at rs17563161), and SLC6A14 for meconium ileus and both lung disease and age at first P. aeruginosa infection (p = 0.0002 and p = 0.006 at rs3788766, respectively). The meconium ileus risk alleles in SLC26A9, SLC9A3 and SLC6A14 are pleiotropic, increasing risk for other early CF co-morbidities. Furthermore, co-morbidities affecting the same organ tended to associate with the same genes. The existence of pleiotropy within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues.

  17. Phenotype-optimized sequence ensembles substantially improve prediction of disease-causing mutation in cystic fibrosis.

    PubMed

    Masica, David L; Sosnay, Patrick R; Cutting, Garry R; Karchin, Rachel

    2012-08-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) mutation is associated with a phenotypic spectrum that includes cystic fibrosis (CF). The disease liability of some common CFTR mutations is known, but rare mutations are seen in too few patients to categorize unequivocally, making genetic diagnosis difficult. Computational methods can predict the impact of mutation, but prediction specificity is often below that required for clinical utility. Here, we present a novel supervised learning approach for predicting CF from CFTR missense mutation. The algorithm begins by constructing custom multiple sequence alignments called phenotype-optimized sequence ensembles (POSEs). POSEs are constructed iteratively, by selecting sequences that optimize predictive performance on a training set of CFTR mutations of known clinical significance. Next, we predict CF disease liability from a different set of CFTR mutations (test-set mutations). This approach achieves improved prediction performance relative to popular methods recently assessed using the same test-set mutations. Of clinical significance, our method achieves 94% prediction specificity. Because databases such as HGMD and locus-specific mutation databases are growing rapidly, methods that automatically tailor their predictions for a specific phenotype may be of immediate utility. If the performance achieved here generalizes to other systems, the approach could be an excellent tool to help establish genetic diagnoses.

  18. [Nocardia farcinica lung infection in a patient with cystic fibrosis and a lung transplant].

    PubMed

    Chacón, C F; Vicente, R; Ramos, F; Porta, J; Lopez Maldonado, A; Ansotegui, E

    2015-03-01

    Patients with cystic fibrosis have a higher risk of developing chronic respiratory infectious diseases. The Nocardia farcinica lung infection is rare in this group of patients, and there are limited publications about this topic. Its diagnosis is complex, due to the clinical and the radiology signs being non-specific. Identification of the agent responsible in the sputum culture is occasionally negative. It is a slow growing organism and for this reason treatment is delayed, which can lead to an increase in complications, hospitable stays, and mortality. A case is reported on a 26 year-old woman with cystic fibrosis and chronic lung colonization by Nocardia farcinica and Aspergillus fumigatus, on long-term treatment with ciprofloxacin, trimethoprim-sulfamethoxazole, and posaconazole, who was admitted to ICU after bilateral lung transplantation. The initial post-operative progress was satisfactory. After discharge, the patient showed a gradual respiratory insufficiency with new chest X-ray showing diffuse infiltrates. Initially, the agent was not seen in the sputum culture. Prompt and aggressive measures were taken, due to the high clinical suspicion of a Nocardia farcinica lung infection. Treatment with a combination of amikacin and meropenem, and later combined with linezolid, led to the disappearance of the lung infiltrates and a clinical improvement. In our case, we confirm the rapid introduction of Nocardia farcinica in the new lungs. The complex identification and the delay in treatment increased the morbimortality. There is a special need for its eradication in patients with lung transplant, due to the strong immunosuppressive treatment.

  19. Ceftaroline Fosamil for Methicillin-Resistant Staphylococcus aureus Pulmonary Exacerbation in a Pediatric Cystic Fibrosis Patient

    PubMed Central

    Snyder, Ashley Hall; Srivastava, Ruma; Rybak, Michael J.; McGrath, Eric

    2014-01-01

    Ceftaroline, an advanced generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA), may present a new therapeutic alternative for treating lung infections among patients with cystic fibrosis. We report a case of ceftaroline therapy in a pediatric patient with cystic fibrosis, whose dose was increased from 9.7 mg/kg/dose every 12 hours to 10.8 mg/kg/dose every 8 hours by using pharmacokinetic analyses. PMID:25024675

  20. Clinical and microbiological features of a cystic fibrosis patient chronically colonized with Pandoraea sputorum identified by combining 16S rRNA sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry.

    PubMed

    Fernández-Olmos, A; Morosini, M I; Lamas, A; García-Castillo, M; García-García, L; Cantón, R; Máiz, L

    2012-03-01

    Clonal isolates identified as various nonfermentative Gram-negative bacilli over a 5-year period from sputum cultures of a 30-year-old cystic fibrosis patient were successfully reidentified as Pandoraea sputorum by combining 16S rRNA sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Decreased lung function improved after 1 year of azithromycin and inhaled 7%-hypertonic saline treatment.

  1. Clinical and Microbiological Features of a Cystic Fibrosis Patient Chronically Colonized with Pandoraea sputorum Identified by Combining 16S rRNA Sequencing and Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry

    PubMed Central

    Fernández-Olmos, A.; Morosini, M. I.; Lamas, A.; García-Castillo, M.; García-García, L.; Máiz, L.

    2012-01-01

    Clonal isolates identified as various nonfermentative Gram-negative bacilli over a 5-year period from sputum cultures of a 30-year-old cystic fibrosis patient were successfully reidentified as Pandoraea sputorum by combining 16S rRNA sequencing and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Decreased lung function improved after 1 year of azithromycin and inhaled 7%-hypertonic saline treatment. PMID:22170922

  2. Repairing the basic defect in cystic fibrosis - one approach is not enough.

    PubMed

    Farinha, Carlos M; Matos, Paulo

    2016-01-01

    Cystic fibrosis has attracted much attention in recent years due to significant advances in the pharmacological targeting of the basic defect underlying this recessive disorder: the deficient functional expression of mutant cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels at the apical membrane of epithelial cells. However, increasing evidence points to the reduced efficacy of single treatments, thus reinforcing the need to combine several therapeutic strategies to effectively target the multiple basic defect(s). Protein-repair therapies that use potentiators (activating membrane-located CFTR) or correctors (promoting the relocation of intracellular-retained trafficking mutants of CFTR) in frequent mutations such as F508del and G551D have been put forward and made their way to the clinic with moderate to good efficiency. However, alternative (or additional) approaches targeting the membrane stability of mutant proteins, or correcting the cellular phenotype through a direct effect upon other ion channels (affecting the overall electrolyte transport or simply promoting alternative chloride transport) or targeting less frequent mutations (splicing variants, for example), have been proposed and tested in the field of cystic fibrosis (CF). Here, we cover the different strategies that rely on novel findings concerning the CFTR interactome and signalosome through which it might be possible to further influence the cellular trafficking and post-translational modification machinery (to increase rescued CFTR abundance and membrane stability). We also highlight the new data on strategies aiming at the regulation of sodium absorption or to increase chloride transport through alternative channels. The development and implementation of these complementary approaches will pave the way to combinatorial therapeutic strategies with increased benefit to CF patients.

  3. Oral health and related factors in cystic fibrosis and other chronic respiratory disorders

    PubMed Central

    Narang, A; Maguire, A; Nunn, J; Bush, A

    2003-01-01

    Aim: To compare the prevalence of dental caries, dental calculus, and enamel defects in children with cystic fibrosis (CF) and children with other chronic respiratory disorders. Methods: A cross sectional observational survey. One examiner (AN) undertook oral examinations to assess dental caries, periodontal health, and enamel defects in children attending respiratory outpatient clinics. Results: A total of 74 patients with CF (35 male; mean age 10.7 years, range 2.5–16.5) were compared with a control group of 106 patients with other chronic respiratory disorders (52 male; mean age 9.1 years, range 3.0–16.5). There were significantly more defects of enamel in the permanent teeth of CF patients, compared with the teeth of those children with other chronic respiratory disorders. In addition, non-significant trends towards a lower caries prevalence in both dentitions, increased numbers of sextants with calculus deposits, and a reduced number of healthy gingival sextants were observed in the patients with cystic fibrosis. Conclusions: Enamel defects, particularly enamel opacities, which can be disfiguring, are more common in CF patients. Early, regular dental visits may prevent such defects becoming dentally disabling and would also permit the removal of dental calculus deposits. The use of long term antibiotics and pancreatic enzymes may confer some protection against the development and progression of dental caries in patients with cystic fibrosis. The inclusion of a specialist paediatric dentist, as part of the multiprofessional team managing the care of these children, would be an advantage. PMID:12876168

  4. [Digestive alterations in cystic fibrosis. Retrospective study of a series of 46 adult patients].

    PubMed

    Pérez-Aguilar, F; Ferrer-Calvete, J; Nicolás, D; Berenguer, J; Ponce, J

    1999-02-01

    The clinical histories of 46 adult patients (24 men and 22 women, mean age 20.6 +/- 5.1 years) diagnosed of cystic fibrosis were reviewed evaluating the digestive alterations. The age at diagnosis of cystic fibrosis was 5.63 +/- 5.3 years (range: newborns-19 years). The initial diagnosis was established by ileus meconium, in four, lung disease in 15, steatorrhea in 12, lung disease and steatorrhea in 13 and following the diagnosis of cystic fibrosis in siblings in two. Four patients presented ileus meconium, nine occlusive syndrome of the distal intestine, 42 steatorrhea (20 severe, 12 moderate and 10 mild), with the severity of the steatorrhea not being associated with the severity of the respiratory insufficiency. Two patients presents rectal prolapse, five gastroesophageal reflux syndrome (four with hiatal hernia), six cholelithiasis, one recurrent pancreatitis without detection of biliary lithiasis, one neonatal cholestasis and 10 malnutrition (five severe and five moderate) fundamentally in relation to the severity of the lung disease and, to a lesser degree, liver disease. In 10 patients chronic liver disease was diagnosed corresponding to established cirrhosis in seven, indicating liver transplantation in two. In most cases, the liver disease was already manifest in adolescence even in the cirrhotic stage. Cholangiography by magnetic resonance was useful in the study of liver disease showing abnormalities which imitated primary sclerosing cholangitis. Treatment with ursodesoxicholic acid at a dosis of 20 mg/kg/day led to a significant decrease in the transaminase values and overall of gammaglutamyltranspeptidase but did not avoid complications in the cirrhotic stages. Genetic studies performed in 36 patients detected the delta F508 mutation in 69.4%, being found in almost all of the patients with ileus meconium, occlusive syndrome of the distal intestine, liver disease, cholelithiasis and malnutrition.

  5. Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

    PubMed Central

    Hsu, Daniel; Taylor, Patricia; Fletcher, Dave; van Heeckeren, Rolf; Eastman, Jean; van Heeckeren, Anna; Davis, Pamela; Chmiel, James F.; Pearlman, Eric

    2016-01-01

    Cystic fibrosis (CF) is characterized by an excessive neutrophilic inflammatory response within the airway as a result of defective cystic fibrosis transmembrane receptor (CFTR) expression and function. Interleukin-17A induces airway neutrophilia and mucin production associated with Pseudomonas aeruginosa colonization, which is associated with the pathophysiology of cystic fibrosis. The objectives of this study were to use the preclinical murine model of cystic fibrosis lung infection and inflammation to investigate the role of IL-17 in CF lung pathophysiology and explore therapeutic intervention with a focus on IL-17. Cftr-deficient mice (CF mice) and wild-type mice (WT mice) infected with P. aeruginosa had robust IL-17 production early in the infection associated with a persistent elevated inflammatory response. Intratracheal administration of IL-17 provoked a neutrophilic response in the airways of WT and CF animals which was similar to that observed with P. aeruginosa infection. The neutralization of IL-17 prior to infection significantly improved the outcomes in the CF mice, suggesting that IL-17 may be a therapeutic target. We demonstrate in this report that the pathophysiological contribution of IL-17 may be due to the induction of chemokines from the epithelium which is augmented by a deficiency of Cftr and ongoing inflammation. These studies demonstrate the in vivo contribution of IL-17 in cystic fibrosis lung disease and the therapeutic validity of attenuating IL-17 activity in cystic fibrosis. PMID:27271746

  6. Impact of cystic fibrosis disease on archaea and bacteria composition of gut microbiota.

    PubMed

    Miragoli, Francesco; Federici, Sara; Ferrari, Susanna; Minuti, Andrea; Rebecchi, Annalisa; Bruzzese, Eugenia; Buccigrossi, Vittoria; Guarino, Alfredo; Callegari, Maria Luisa

    2017-02-01

    Cystic fibrosis is often associated with intestinal inflammation due to several factors, including altered gut microbiota composition. In this study, we analyzed the fecal microbiota among patients with cystic fibrosis of 10-22 years of age, and compared the findings with age-matched healthy subjects. The participating patients included 14 homozygotes and 14 heterozygotes with the delF508 mutation, and 2 heterozygotes presenting non-delF508 mutations. We used PCR-DGGE and qPCR to analyze the presence of bacteria, archaea and sulfate-reducing bacteria. Overall, our findings confirmed disruption of the cystic fibrosis gut microbiota. Principal component analysis of the qPCR data revealed no differences between homozygotes and heterozygotes, while both groups were distinct from healthy subjects who showed higher biodiversity. Archaea were under the detection limit in all homozygotes subjects, whereas methanogens were detected in 62% of both cystic fibrosis heterozygotes and healthy subjects. Our qPCR results revealed a low frequency of sulfate-reducing bacteria in the homozygote (13%) and heterozygote (13%) patients with cystic fibrosis compared with healthy subjects (87.5%). This is a pioneer study showing that patients with cystic fibrosis exhibit significant reduction of H2-consuming microorganisms, which could increase hydrogen accumulation in the colon and the expulsion of this gas through non-microbial routes.

  7. Impact of cystic fibrosis disease on archaea and bacteria composition of gut microbiota

    PubMed Central

    Miragoli, Francesco; Federici, Sara; Ferrari, Susanna; Minuti, Andrea; Rebecchi, Annalisa; Bruzzese, Eugenia; Buccigrossi, Vittoria; Guarino, Alfredo; Callegari, Maria Luisa

    2016-01-01

    Cystic fibrosis is often associated with intestinal inflammation due to several factors, including altered gut microbiota composition. In this study, we analyzed the fecal microbiota among patients with cystic fibrosis of 10–22 years of age, and compared the findings with age-matched healthy subjects. The participating patients included 14 homozygotes and 14 heterozygotes with the delF508 mutation, and 2 heterozygotes presenting non-delF508 mutations. We used PCR-DGGE and qPCR to analyze the presence of bacteria, archaea and sulfate-reducing bacteria. Overall, our findings confirmed disruption of the cystic fibrosis gut microbiota. Principal component analysis of the qPCR data revealed no differences between homozygotes and heterozygotes, while both groups were distinct from healthy subjects who showed higher biodiversity. Archaea were under the detection limit in all homozygotes subjects, whereas methanogens were detected in 62% of both cystic fibrosis heterozygotes and healthy subjects. Our qPCR results revealed a low frequency of sulfate-reducing bacteria in the homozygote (13%) and heterozygote (13%) patients with cystic fibrosis compared with healthy subjects (87.5%). This is a pioneer study showing that patients with cystic fibrosis exhibit significant reduction of H2-consuming microorganisms, which could increase hydrogen accumulation in the colon and the expulsion of this gas through non-microbial routes. PMID:27810876

  8. Association of growth and nutritional parameters with pulmonary function in cystic fibrosis: a literature review

    PubMed Central

    Mauch, Renan Marrichi; Kmit, Arthur Henrique Pezzo; Marson, Fernando Augusto de Lima; Levy, Carlos Emilio; Barros-Filho, Antonio de Azevedo; Ribeiro, José Dirceu

    2016-01-01

    Abstract Objective: To review the literature addressing the relationship of growth and nutritional parameters with pulmonary function in pediatric patients with cystic fibrosis. Data source: A collection of articles published in the last 15 years in English, Portuguese and Spanish was made by research in electronic databases - PubMed, Cochrane, Medline, Lilacs and Scielo - using the keywords cystic fibrosis, growth, nutrition, pulmonary function in varied combinations. Articles that addressed the long term association of growth and nutritional parameters, with an emphasis on growth, with pulmonary disease in cystic fibrosis, were included, and we excluded those that addressing only the relationship between nutritional parameters and cystic fibrosis and those in which the aim was to describe the disease. Data synthesis: Seven studies were included, with a total of 12,455 patients. Six studies reported relationship between growth parameters and lung function, including one study addressing the association of growth parameters, solely, with lung function, and all the seven studies reported relationship between nutritional parameters and lung function. Conclusions: The review suggests that the severity of the lung disease, determined by spirometry, is associated with body growth and nutritional status in cystic fibrosis. Thus, the intervention in these parameters can lead to the better prognosis and life expectancy for cystic fibrosis patients. PMID:27181343

  9. The Relevance of Sweat Testing for the Diagnosis of Cystic Fibrosis in the Genomic Era

    PubMed Central

    2005-01-01

    Cystic fibrosis (CF) is the most common inherited disorder of childhood. The diagnosis of CF has traditionally been based on clinical features with confirmatory evidence by sweat electrolyte analysis. Since 1989 it has been possible to also use gene mutation analysis to aid the diagnosis. Cloning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has advanced our understanding of CF, in particular the molecular basis of an expanded CF phenotype. However, because there are over 1000 mutations and 200 polymorphisms, many without recognised effects on CFTR, the molecular diagnosis can be troublesome. This has necessitated measurement of CFTR function with renewed interest in the sweat test. This review provides an overview of the clinical features of CF, the diagnosis and complex genetics. We provide a detailed discussion of the structure and function of CFTR and the classification of CFTR mutations. Sweat electrolyte analysis is discussed, from the physiology of sweating to the rigours of a properly performed sweat test and its interpretation. With this information it is possible to understand the relevance of the sweat test in the genomic era. PMID:16648884

  10. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations

    PubMed Central

    Veit, Gudio; Avramescu, Radu G.; Chiang, Annette N.; Houck, Scott A.; Cai, Zhiwei; Peters, Kathryn W.; Hong, Jeong S.; Pollard, Harvey B.; Guggino, William B.; Balch, William E.; Skach, William R.; Cutting, Garry R.; Frizzell, Raymond A.; Sheppard, David N.; Cyr, Douglas M.; Sorscher, Eric J.; Brodsky, Jeffrey L.; Lukacs, Gergely L.

    2016-01-01

    More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients. PMID:26823392

  11. Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop.

    PubMed

    Ehrhardt, Annette; Chung, W Joon; Pyle, Louise C; Wang, Wei; Nowotarski, Krzysztof; Mulvihill, Cory M; Ramjeesingh, Mohabir; Hong, Jeong; Velu, Sadanandan E; Lewis, Hal A; Atwell, Shane; Aller, Steve; Bear, Christine E; Lukacs, Gergely L; Kirk, Kevin L; Sorscher, Eric J

    2016-01-22

    In this study, we present data indicating a robust and specific domain interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed that binding kinetics were not altered by the common clinical mutation F508del. Both intrinsic ATPase activity and CFTR channel gating were inhibited severely by CL1 peptide, suggesting that NBD1/CL1 binding is a crucial requirement for ATP hydrolysis and channel function. In addition to cystic fibrosis, CFTR dysregulation has been implicated in the pathogenesis of prevalent diseases such as chronic obstructive pulmonary disease, acquired rhinosinusitis, pancreatitis, and lethal secretory diarrhea (e.g. cholera). On the basis of clinical relevance of the CFTR as a therapeutic target, a cell-free drug screen was established to identify modulators of NBD1/CL1 channel activity independent of F508del CFTR and pharmacologic rescue. Our findings support a targetable mechanism of CFTR regulation in which conformational changes in the NBDs cause reorientation of transmembrane domains via interactions with CL1 and result in channel gating.

  12. Therapeutic Approaches to Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in Chronic Bronchitis.

    PubMed

    Solomon, George M; Raju, S Vamsee; Dransfield, Mark T; Rowe, Steven M

    2016-04-01

    Chronic obstructive pulmonary disease is a common cause of morbidity and a rising cause of mortality worldwide. Its rising impact indicates the ongoing unmet need for novel and effective therapies. Previous work has established a pathophysiological link between the chronic bronchitis phenotype of chronic obstructive pulmonary disease and cystic fibrosis as well as phenotypic similarities between these two airways diseases. An extensive body of evidence has established that cigarette smoke and its constituents contribute to acquired dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways, pointing to a mechanistic link with smoking-related and chronic bronchitis. Recent interest surrounding new drugs that target both mutant and wild-type CFTR channels has paved the way for a new treatment opportunity addressing the mucus defect in chronic bronchitis. We review the clinical and pathologic evidence for modulating CFTR to address acquired CFTR dysfunction and pragmatic issues surrounding clinical trials as well as a discussion of other ion channels that may represent alternative therapeutic targets.

  13. Achromobacter Species Isolated from Cystic Fibrosis Patients Reveal Distinctly Different Biofilm Morphotypes

    PubMed Central

    Nielsen, Signe M.; Nørskov-Lauritsen, Niels; Bjarnsholt, Thomas; Meyer, Rikke L.

    2016-01-01

    Achromobacter species have attracted attention as emerging pathogens in cystic fibrosis. The clinical significance of Achromobacter infection is not yet fully elucidated; however, their intrinsic resistance to antimicrobials and ability to form biofilms renders them capable of establishing long-term chronic infections. Still, many aspects of Achromobacter biofilm formation remain uncharacterized. In this study, we characterized biofilm formation in clinical isolates of Achromobacter and investigated the effect of challenging the biofilm with antimicrobials and/or enzymes targeting the extracellular matrix. In vitro biofilm growth and subsequent visualization by confocal microscopy revealed distinctly different biofilm morphotypes: a surface-attached biofilm morphotype of small aggregates and an unattached biofilm morphotype of large suspended aggregates. Aggregates consistent with our in vitro findings were visualized in sputum samples from cystic fibrosis patients using an Achromobacter specific peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) probe, confirming the presence of Achromobacter biofilms in the CF lung. High antibiotic tolerance was associated with the biofilm phenotype, and biocidal antibiotic concentrations were up to 1000 fold higher than for planktonic cultures. Treatment with DNase or subtilisin partially dispersed the biofilm and reduced the tolerance to specific antimicrobials, paving the way for further research into using dispersal mechanisms to improve treatment strategies. PMID:27681927

  14. Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation.

    PubMed

    Sermet-Gaudelus, Isabelle

    2013-03-01

    Cystic fibrosis (CF) is an autosomal recessive lethal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for CFTR, an epithelial cell-surface expressed protein responsible for the transport of chloride (Cl(-)). Gating mutations associated with defective conductance can be modulated by CFTR potentiators. Ivacaftor is a CFTR potentiator approved for the treatment of CF patients >6 yrs of age with at least one copy of the G551D-CFTR mutation. Herein, the clinical trial development programme for ivacaftor will be reviewed, including two pivotal studies in adolescents/adults and in children. These studies report sustained improvements in lung function and sweat chloride concentrations, and a reduction in pulmonary exacerbations over a 48-week treatment period. In the era of personalised medicine, ivacaftor offers an effective and well-tolerated treatment for the clinical management of CF patients with the G551D mutation. A long-term, open-label study will report the effects of ivacaftor over a further 48 weeks.

  15. Ivacaftor: the first therapy acting on the primary cause of cystic fibrosis.

    PubMed

    McPhail, G L; Clancy, J P

    2013-04-01

    Cystic fibrosis (CF) is a life-shortening disorder that affects over 30,000 people in the U.S. and 70,000 worldwide. CF is caused by mutations in the CFTR gene, which codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is a chloride and bicarbonate channel and regulates several ion transporters at the epithelial cell membrane, controlling hydration or ionic composition of epithelial secretions. Management of CF is currently supportive, but recent advances in drug development have focused on therapies that assist mutant CFTR function. In the current review, we summarize the development and clinical experience with VX-770 (ivacaftor), a small molecule that increases CFTR chloride conductance in vitro and in vivo, including wild-type and G551D CFTR. The G551D CFTR mutation is the third most common CF disease-causing mutation, in which the CFTR protein localizes to the epithelial cell membrane but has defective gating. With restoration of adequate CFTR function through pharmacotherapy, it is possible that the clinical course of patients with CF could be markedly improved, including longevity, quality of life and treatment burden.

  16. Determination of right ventricular ejection fraction in children with cystic fibrosis, using krypton-81m

    SciTech Connect

    Piepsz, A.; Ham, H.R.; Millet, E.; Dab, I.

    1984-01-01

    The diagnosis of cor pulmonale and incipient heart failure remains difficult to assess in cystic fibrosis (CF) on the basis of the clinical as well as the biological parameters. The measurement of the right ventricular ejection fraction has been facilitated these last years by the introduction of the radionuclide methods. Methodological difficulties are however encountered when Tc-99m RBC are used, and are mainly related to heart chambers superposition (equilibrium method) or the low count density (first pass method). Few papers have been published on RVEF in cystic fibrosis and the results are somewhat contradictory. The authors have recently introduced a new method for the determination of RVEF, using equilibrium study during continuous injection of Kr-81m in glucose solution. This method offers several advantages related to an increased accuracy and a favorable dosimetry. In 25 patients aged 2 to 23 years with CF, one or more RVEF studies were performed. The severity of the disease was evaluated on the basis of the clinical Schwachman score, the lung function tests, the ventilation scan and the pa02. RVEF tended to decrease with the progression of the lung disease, although, owing to the spread of the results, no RVEF could be predicted on the basis of the other parameters. The decrease of RVEF in patients with advanced lung disease was moderate and terminal lung disease was sometimes associated with normal right heart contractility.

  17. Pathophysiology of cystic fibrosis and drugs used in associated digestive tract diseases

    PubMed Central

    Haack, Adriana; Aragão, Giselle Gonçalves; Novaes, Maria Rita Carvalho Garbi

    2013-01-01

    Cystic fibrosis (CF) causes chronic infections in the respiratory tract and alters the digestive tract. This paper reviews the most important aspects of drug treatment and changes in the digestive tract of patients with CF. This is a review of the literature, emphasizing the discoveries made within the last 15 years by analyzing scientific papers published in journals indexed in the Scientific Electronic Library Online, Sciences Information, United States National Library of Medicine and Medical Literature Analysis and Retrieval System Online databases, both in English and Portuguese, using the key words: cystic fibrosis, medication, therapeutic, absorption, digestion. Randomized, observational, experimental, and epidemiological clinical studies were selected, among others, with statistical significance of 5%. This review evaluates the changes found in the digestive tract of CF patients including pancreatic insufficiency, constipation and liver diseases. Changes in nutritional status are also described. Clinical treatment, nutritional supplementation and drug management were classified in this review as essential to the quality of life of CF patients, and became available through public policies for monitoring and treating CF. The information gathered on CF and a multi professional approach to the disease is essential in the treatment of these patients. PMID:24379572

  18. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.

    PubMed

    Dekkers, Johanna F; Berkers, Gitte; Kruisselbrink, Evelien; Vonk, Annelotte; de Jonge, Hugo R; Janssens, Hettie M; Bronsveld, Inez; van de Graaf, Eduard A; Nieuwenhuis, Edward E S; Houwen, Roderick H J; Vleggaar, Frank P; Escher, Johanna C; de Rijke, Yolanda B; Majoor, Christof J; Heijerman, Harry G M; de Winter-de Groot, Karin M; Clevers, Hans; van der Ent, Cornelis K; Beekman, Jeffrey M

    2016-06-22

    Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.

  19. Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop*

    PubMed Central

    Ehrhardt, Annette; Chung, W. Joon; Pyle, Louise C.; Wang, Wei; Nowotarski, Krzysztof; Mulvihill, Cory M.; Ramjeesingh, Mohabir; Hong, Jeong; Velu, Sadanandan E.; Lewis, Hal A.; Atwell, Shane; Aller, Steve; Bear, Christine E.; Lukacs, Gergely L.; Kirk, Kevin L.; Sorscher, Eric J.

    2016-01-01

    In this study, we present data indicating a robust and specific domain interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed that binding kinetics were not altered by the common clinical mutation F508del. Both intrinsic ATPase activity and CFTR channel gating were inhibited severely by CL1 peptide, suggesting that NBD1/CL1 binding is a crucial requirement for ATP hydrolysis and channel function. In addition to cystic fibrosis, CFTR dysregulation has been implicated in the pathogenesis of prevalent diseases such as chronic obstructive pulmonary disease, acquired rhinosinusitis, pancreatitis, and lethal secretory diarrhea (e.g. cholera). On the basis of clinical relevance of the CFTR as a therapeutic target, a cell-free drug screen was established to identify modulators of NBD1/CL1 channel activity independent of F508del CFTR and pharmacologic rescue. Our findings support a targetable mechanism of CFTR regulation in which conformational changes in the NBDs cause reorientation of transmembrane domains via interactions with CL1 and result in channel gating. PMID:26627831

  20. Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients.

    PubMed Central

    Schaefer, H G; Stass, H; Wedgwood, J; Hampel, B; Fischer, C; Kuhlmann, J; Schaad, U B

    1996-01-01

    The pharmacokinetic characteristics of ciprofloxacin were studied in 10 children with cystic fibrosis, aged from 6 to 16 years, who had completed the standard regimen of intravenous ceftazidime and amikacin. The aim of the investigation was to derive dosing guidelines for young cystic fibrosis patients to be treated with ciprofloxacin. Each child received ciprofloxacin given as two 30-min infusions (10 mg/kg of body weight each) 12 h apart; this was followed by the administration of oral ciprofloxacin (15 mg/kg every 12 h). Blood samples were taken after both infusions and after the first oral dose. A total of 232 ciprofloxacin concentrations (203 concentrations in plasma and 29 concentrations in urine) were analyzed by use of NONMEM and a two-compartment body model with seven parameters: total body clearance (CL), volume of the central compartment (V2), volume of the peripheral compartment (V3), intercompartmental clearance, renal clearance, absorption rate constant, and bioavailability. The influences of weight (range, 18 to 42 kg) and age (range, 6 to 16 years) were investigated. CL (in liters per hour) was found to be linearly correlated with weight (typical value of CL = 8.8 + 0.396. WT, where WT is weight; (interindividual coefficient of variation, 7.8%). V2 and V3 were directly proportional to weight, with slopes of 0.7 and 1.3 liters/kg, respectively. Interindividual variabilities were calculated to be 22.6 and 14.9% for V2 and V3, respectively. No dependency of the other pharmacokinetic parameters on age or weight was seen. Because of the high correlations between age and weight, only one covariable was necessary. Weight had the strongest effect. Bioavailability (population mean) was estimated to be 61.8%, and renal clearance (population mean) was estimated to be 11.4 liters/h. The residual (intraindividual) variability was 31.9%. The protein binding was about 34%, which is similar to the results obtained for adults. In order to define the appropriate

  1. Intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells

    SciTech Connect

    Verhaeghe, Catherine; Tabruyn, Sebastien P.; Oury, Cecile; Bours, Vincent . E-mail: vbours@ulg.ac.be; Griffioen, Arjan W.

    2007-05-11

    Cystic fibrosis is a common genetic disorder characterized by a severe lung inflammation and fibrosis leading to the patient's death. Enhanced angiogenesis in cystic fibrosis (CF) tissue has been suggested, probably caused by the process of inflammation, as similarly described in asthma and chronic bronchitis. The present study demonstrates an intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells. Microarray experiments showed that CF airway epithelial cells expressed several angiogenic factors such as VEGF-A, VEGF-C, bFGF, and PLGF at higher levels than control cells. These data were confirmed by real-time quantitative PCR and, at the protein level, by ELISA. Conditioned media of these cystic fibrosis cells were able to induce proliferation, migration and sprouting of cultured primary endothelial cells. This report describes for the first time that cystic fibrosis epithelial cells have an intrinsic angiogenic activity. Since excess of angiogenesis is correlated with more severe pulmonary disease, our results could lead to the development of new therapeutic applications.

  2. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis

    SciTech Connect

    Miller, P.W.; Hamosh, A.; Macek, M. Jr.

    1996-07-01

    The etiology of allergic bronchopulmonary aspergillosis (ABPA) is not well understood. A clinical phenotype resembling the pulmonary disease seen in cystic fibrosis (CF) patients can occur in some individuals with ABPA. Reports of familial occurrence of ABPA and increased incidence in CF patients suggest a possible genetic basis for the disease. To test this possibility, the entire coding region of the cystic fibrosis transmembrane regulator (CFTR) gene was analyzed in 11 individuals who met strict criteria for the diagnosis of ABPA and had normal sweat electrolytes ({le}40 mmol/liter). One patient carried two CF mutations ({Delta}F508/R347H), and five were found to carry one CF mutation (four {Delta}F508; one R117H). The frequency of the {Delta}F508 mutation in patients with ABPA was significantly higher than in 53 Caucasian patients with chronic bronchitis (P < .0003) and the general population (P < .003). These results suggest that CFTR plays an etiologic role in a subset of ABPA patients. 54 refs., 2 tabs.

  3. A Novel Lung Disease Phenotype Adjusted for Mortality Attrition for Cystic Fibrosis Genetic Modifier Studies

    PubMed Central

    Taylor, Chelsea; Commander, Clayton W.; Collaco, Joseph M.; Strug, Lisa J.; Li, Weili; Wright, Fred A.; Webel, Aaron D.; Pace, Rhonda G.; Stonebraker, Jaclyn R.; Naughton, Kathleen; Dorfman, Ruslan; Sandford, Andrew; Blackman, Scott M.; Berthiaume, Yves; Paré, Peter; Drumm, Mitchell L.; Zielenski, Julian; Durie, Peter; Cutting, Garry R.; Knowles, Michael R.; Corey, Mary

    2011-01-01

    SUMMARY Genetic studies of lung disease in Cystic Fibrosis are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. Using data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies, Johns Hopkins University CF Twin and Sibling Study, and University of North Carolina/Case Western Reserve University Gene Modifier Study), the authors calculated age-specific CF percentile values of FEV1 which were adjusted for CF age-specific mortality data. The phenotype was computed for 2061 patients representing the Canadian CF population, 1137 extreme phenotype patients in the UNC/Case Western study, and 1323 patients from multiple CF sib families in the CF Twin and Sibling Study. Despite differences in ascertainment and median age, our phenotype score was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype score was highly correlated with the previously recommended complex phenotype, but the new phenotype is more robust for shorter follow-up and for extreme ages. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible distortions. This approach will facilitate large scale genetic and environmental epidemiological studies which will provide targeted therapeutic pathways for the clinical benefit of patients with CF. PMID:21462361

  4. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis.

    PubMed Central

    Miller, P. W.; Hamosh, A.; Macek, M.; Greenberger, P. A.; MacLean, J.; Walden, S. M.; Slavin, R. G.; Cutting, G. R.

    1996-01-01

    The etiology of allergic bronchopulmonary aspergillosis (ABPA) is not well understood. A clinical phenotype resembling the pulmonary disease seen in cystic fibrosis (CF) patients can occur in some individuals with ABPA. Reports of familial occurrence of ABPA and increased incidence in CF patients suggest a possible genetic basis for the disease. To test this possibility, the entire coding region of the cystic fibrosis transmembrane regulator (CFTR) gene was analyzed in 11 individuals who met strict criteria for the diagnosis of ABPA and had normal sweat electrolytes (< or = 40 mmol/liter). One patient carried two CF mutations (deltaF508/R347H), and five were found to carry one CF mutation (four deltaF508; one R117H). The frequency of the deltaF508 mutation in patients with ABPA was significantly higher than in 53 Caucasian patients with chronic bronchitis (P < .0003) and the general population (P < .003). These results suggest that CFTR plays an etiologic role in a subset of ABPA patients. PMID:8659542

  5. Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies.

    PubMed

    Jacquot, J; Delion, M; Gangloff, S; Braux, J; Velard, F

    2016-04-01

    Mutations within the gene encoding for the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) results in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease that causes a number of long-term health problems, as the bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The etiology of low bone density is multifactorial, most probably a combination of inadequate peak bone mass during puberty and increased bone losses in adults. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease (CFBD). Consistently, recent evidence has confirmed that CFTR plays a major role in the osteoprotegerin (OPG) and COX-2 metabolite prostaglandin E2 (PGE2) production, two key regulators in the bone formation and regeneration. Several others mechanisms were also recognized from animal and cell models contributing to malfunctions of osteoblast (cell that form bone) and indirectly of bone-resorpting osteoclasts. Understanding such mechanisms is crucial for the development of therapies in CFBD. Innovative therapeutic approaches using CFTR modulators such as C18 have recently shown in vitro capacity to enhance PGE2 production and normalized the RANKL-to-OPG ratio in human osteoblasts bearing the mutation F508del-CFTR and therefore potential clinical utility in CFBD. This review focuses on the recently identified pathogenic mechanisms leading to CFBD and potential future therapies for treating CFBD.

  6. Colistin susceptibility testing: evaluation of reliability for cystic fibrosis isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia

    PubMed Central

    Moskowitz, Samuel M.; Garber, Elizabeth; Chen, Yunhua; Clock, Sarah A.; Tabibi, Setareh; Miller, Amanda K.; Doctor, Michael; Saiman, Lisa

    2010-01-01

    Objectives Antibiotic susceptibility methods that are commonly used to test bacterial isolates from patients with cystic fibrosis are of uncertain reliability for the polymyxins. To assess the reliability of four standard testing methods, this pilot study used a challenge set that included polymyxin-resistant isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia. Methods Twenty-five P. aeruginosa and 12 S. maltophilia isolates were tested for susceptibility to colistin (polymyxin E). Repeatability (concordance of replicates performed concurrently), reproducibility (concordance of replicates performed over time) and comparability (concordance of different methods) of agar dilution, broth microdilution, Etest and disc diffusion were assessed through the use of descriptive statistics and scatterplot analyses. Results All four methods displayed excellent repeatability (overall concordance rate of 99%). However, analysis of reproducibility revealed substantially lower rates of concordance (74% for agar dilution, 84% for broth microdilution and Etest, and 91% for disc diffusion). In addition, comparability to agar dilution of the three other methods was generally poor, with overall rates of very major error ranging from 12% for broth microdilution to 18% for Etest and disc diffusion. Conclusions Compared with agar dilution, other susceptibility testing methods give high rates of apparent false polymyxin susceptibility for cystic fibrosis isolates of P. aeruginosa and S. maltophilia. Prospective study of the correlation between in vitro susceptibility and clinical response is needed to clarify whether these discrepancies reflect oversensitivity of the agar dilution method or insensitivity of the other methods. PMID:20430789

  7. Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa.

    PubMed Central

    Heeckeren, A; Walenga, R; Konstan, M W; Bonfield, T; Davis, P B; Ferkol, T

    1997-01-01

    In cystic fibrosis (CF), defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelial cells and submucosal glands results in chronic pulmonary infection with Pseudomonas aeruginosa. The pulmonary infection incites an intense host inflammatory response, causing progressive suppurative pulmonary disease. Mouse models of CF, however, fail to develop pulmonary disease spontaneously. We examined the effects of bronchopulmonary infection on mice homozygous for the S489X mutation of the CFTR gene using an animal model of chronic Pseudomonas endobronchial infection. Slurries of sterile agarose beads or beads containing a clinical isolate of mucoid P. aeruginosa were instilled in the right lung of normal or CF mice. The mortality of CF mice inoculated with Pseudomonas-laden beads was significantly higher than that of normal animals: 82% of infected CF mice, but only 23% of normal mice, died within 10 d of infection (P = 0.023). The concentration of inflammatory mediators, including TNF-alpha, murine macrophage inflammatory protein-2, and KC/N51, in bronchoalveolar lavage fluid in CF mice 3 d after infection and before any mortality, was markedly elevated compared with normal mice. This inflammatory response also correlated with weight loss observed in both CF and normal littermates after inoculation. Thus, this model may permit examination of the relationship of bacterial infections, inflammation, and the cellular and genetic defects in CF. PMID:9389746

  8. An Approach for Treating the Hepatobiliary Disease of Cystic Fibrosis by Somatic Gene Transfer

    NASA Astrophysics Data System (ADS)

    Yang, Yiping; Raper, Steven E.; Cohn, Jonathan A.; Engelhardt, John F.; Wilson, James M.

    1993-05-01

    Cystic fibrosis (CF) is an inherited disease of epithelial cell ion transport that is associated with pathology in multiple organ systems, including lung, pancreas, and liver. As treatment of the pulmonary manifestations of CF has improved, management of CF liver disease has become increasingly important in adult patients. This report describes an approach for treating CF liver disease by somatic gene transfer. In situ hybridization and immunocytochemistry analysis of rat liver sections indicated that the endogenous CFTR (cystic fibrosis transmembrane conductance regulator) gene is primarily expressed in the intrahepatic biliary epithelial cells. To specifically target recombinant genes to the biliary epithelium in vivo, recombinant adenoviruses expressing lacZ or human CFTR were infused retrograde into the biliary tract through the common bile duct. Conditions were established for achieving recombinant gene expression in virtually all cells of the intrahepatic bile ducts in vivo. Expression persisted in the smaller bile ducts for the duration of the experiment, which was 21 days. These studies suggest that it may be feasible to prevent CF liver disease by genetically reconstituting CFTR expression in the biliary tract, using an approach that is clinically feasible.

  9. Novel short chain fatty acids restore chloride secretion in cystic fibrosis

    SciTech Connect

    Nguyen, Toan D. . E-mail: T1Nguyen@u.washington.edu; Kim, Ug-Sung; Perrine, Susan P.

    2006-03-31

    Phenylalanine deletion at position 508 of the cystic fibrosis transmembrane conductance regulator ({delta}F508-CFTR), the most common mutation in cystic fibrosis (CF), causes a misfolded protein exhibiting partial chloride conductance and impaired trafficking to the plasma membrane. 4-Phenylbutyrate corrects defective {delta}F508-CFTR trafficking in vitro, but is not clinically efficacious. From a panel of short chain fatty acid derivatives, we showed that 2,2-dimethyl-butyrate (ST20) and {alpha}-methylhydrocinnamic acid (ST7), exhibiting high oral bioavailability and sustained plasma levels, correct the {delta}F508-CFTR defect. Pre-incubation ({>=}6 h) of CF IB3-1 airway cells with {>=}1 mM ST7 or ST20 restored the ability of 100 {mu}M forskolin to stimulate an {sup 125}I{sup -} efflux. This efflux was fully inhibited by NPPB, DPC, or glibenclamide, suggesting mediation through CFTR. Partial inhibition by DIDS suggests possible contribution from an additional Cl{sup -} channel regulated by CFTR. Thus, ST7 and ST20 offer treatment potential for CF caused by the {delta}F508 mutation.

  10. Airway microbiota and pathogen abundance in age-stratified cystic fibrosis patients.

    PubMed

    Cox, Michael J; Allgaier, Martin; Taylor, Byron; Baek, Marshall S; Huang, Yvonne J; Daly, Rebecca A; Karaoz, Ulas; Andersen, Gary L; Brown, Ronald; Fujimura, Kei E; Wu, Brian; Tran, Diem; Koff, Jonathan; Kleinhenz, Mary Ellen; Nielson, Dennis; Brodie, Eoin L; Lynch, Susan V

    2010-06-23

    Bacterial communities in the airways of cystic fibrosis (CF) patients are, as in other ecological niches, influenced by autogenic and allogenic factors. However, our understanding of microbial colonization in younger versus older CF airways and the association with pulmonary function is rudimentary at best. Using a phylogenetic microarray, we examine the airway microbiota in age stratified CF patients ranging from neonates (9 months) to adults (72 years). From a cohort of clinically stable patients, we demonstrate that older CF patients who exhibit poorer pulmonary function possess more uneven, phylogenetically-clustered airway communities, compared to younger patients. Using longitudinal samples collected form a subset of these patients a pattern of initial bacterial community diversification was observed in younger patients compared with a progressive loss of diversity over time in older patients. We describe in detail the distinct bacterial community profiles associated with young and old CF patients with a particular focus on the differences between respective "early" and "late" colonizing organisms. Finally we assess the influence of Cystic Fibrosis Transmembrane Regulator (CFTR) mutation on bacterial abundance and identify genotype-specific communities involving members of the Pseudomonadaceae, Xanthomonadaceae, Moraxellaceae and Enterobacteriaceae amongst others. Data presented here provides insights into the CF airway microbiota, including initial diversification events in younger patients and establishment of specialized communities of pathogens associated with poor pulmonary function in older patient populations.

  11. Facilitating Positive Psychosocial Adaptation in Children with Cystic Fibrosis by Increasing Family Communication and Problem-Solving Skills. A Research Report to the Cystic Fibrosis Foundation.

    ERIC Educational Resources Information Center

    Stabler, Brian; And Others

    This study tested the effects of two group-oriented supportive and educational approaches on the parents of children with cystic fibrosis (CF). Thirteen families were randomly assigned either to a group which received information on medical and technical aspects of CF or to a group which received instruction in communication skills in addition to…

  12. Analysis of cystic fibrosis gene mutations in children with cystic fibrosis and in 964 infertile couples within the region of Basilicata, Italy: a research study

    PubMed Central

    2014-01-01

    Introduction Cystic fibrosis is the most common autosomal recessive genetic disease in the Caucasian population. Extending knowledge about the molecular pathology on the one hand allows better delineation of the mutations in the CFTR gene and the other to dramatically increase the predictive power of molecular testing. Methods This study reports the results of a molecular screening of cystic fibrosis using DNA samples of patients enrolled from January 2009 to December 2013. Patients were referred to our laboratory for cystic fibrosis screening for infertile couples. In addition, we identified the gene mutations present in 76 patients affected by cystic fibrosis in the pediatric population of Basilicata. Results In the 964 infertile couples examined, 132 subjects (69 women and 63 men) resulted heterozygous for one of the CFTR mutations, with a recurrence of carriers of 6.85%. The recurrence of carriers in infertile couples is significantly higher from the hypothetical value of the general population (4%). Conclusions This study shows that in the Basilicata region of Italy the CFTR phenotype is caused by a small number of mutations. Our aim is to develop a kit able to detect not less than 96% of CTFR gene mutations so that the relative risk for screened couples is superimposable with respect to the general population. PMID:25304080

  13. Impact of gene editing on the study of cystic fibrosis.

    PubMed

    Harrison, Patrick T; Sanz, David J; Hollywood, Jennifer A

    2016-09-01

    Cystic fibrosis (CF) is a chronic and progressive autosomal recessive disorder of secretory epithelial cells, which causes obstructions in the lung airways and pancreatic ducts of 70,000 people worldwide (for recent review see Cutting Nat Rev Genet 16(1):45-56, 2015). The finding that mutations in the CFTR gene cause CF (Kerem et al. Science 245(4922):1073-1080, 1989; Riordan et al. Science 245(4922):1066-1073, 1989; Rommens et al. Science 245(4922):1059-1065, 1989), was hailed as the very happy middle of a story whose end is a cure for a fatal disease (Koshland Science 245(4922):1029, 1989). However, despite two licensed drugs (Ramsey et al. N Engl J Med 365(18):1663-1672, 2011; Wainwright et al. N Engl J Med 373(3):220-231, 2015), and a formal demonstration that repeated administration of CFTR cDNA to patients is safe and effects a modest but significant stabilisation of disease (Alton et al. Lancet Respir Med 3(9):684-691, 2015), we are still a long way from a cure, with many patients taking over 100 tablets per day, and a mean age at death of 28 years. The aim of this review is to discuss the impact on the study of CF of gene-editing techniques as they have developed over the last 30 years, up to and including the possibility of editing as a therapeutic approach.

  14. Heterogeneity of Pseudomonas aeruginosa in Brazilian Cystic Fibrosis Patients

    PubMed Central

    Silbert, Suzane; Barth, Afonso Luis; Sader, Hélio S.

    2001-01-01

    The aim of this study was to assess the diversity and genomic variability of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients being treated at a university hospital in Brazil. Ninety-seven isolates of P. aeruginosa from 43 CF patients were characterized by macrorestriction analysis of chromosomal DNA by pulsed-field gel electrophoresis (PFGE) and tested for susceptibility to 20 antimicrobial agents by broth microdilution. It was possible to evaluate single isolates from 20 patients and multiple isolates (two to seven) from 23 patients collected during a 22-month period. Among all of the unrelated patients, we detected only one pair of patients sharing a common strain. Among the 77 isolates from 23 patients who had multiple isolates analyzed, we identified 37 major types by PFGE, and five different colonization patterns were recognized. The isolates were susceptible to several antimicrobial agents, although consecutive isolates from the same patient may display differences in their susceptibilities. Mucoid isolates were more resistant (P < 0.001) than nonmucoid isolates to five antibiotics. Our results indicate that CF patients remain colonized by more than one strain of P. aeruginosa for long periods of time. In addition, the finding of several different genotypes in the same patient suggests that the colonizing strain may occasionally be replaced. PMID:11682517

  15. Phylogenetic and metabolic diversity of bacteria associated with cystic fibrosis.

    PubMed

    Guss, Adam M; Roeselers, Guus; Newton, Irene L G; Young, C Robert; Klepac-Ceraj, Vanja; Lory, Stephen; Cavanaugh, Colleen M

    2011-01-01

    In patients afflicted with cystic fibrosis (CF), morbidity and mortality are primarily associated with the adverse consequences of chronic microbial bronchial infections, which are thought to be caused by a few opportunistic pathogens. However, recent evidence suggests the presence of other microorganisms, which may significantly affect the course and outcome of the infection. Using a combination of 16S rRNA gene clone libraries, bacterial culturing and pyrosequencing of barcoded 16S rRNA amplicons, the microbial communities present in CF patient sputum samples were examined. In addition to previously recognized CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus, >60 phylogenetically diverse bacterial genera that are not typically associated with CF pathogenesis were also detected. A surprisingly large number of fermenting facultative and obligate anaerobes from multiple bacterial phyla was present in each sample. Many of the bacteria and sequences found were normal residents of the oropharyngeal microflora and with many containing opportunistic pathogens. Our data suggest that these undersampled organisms within the CF lung are part of a much more complex microbial ecosystem than is normally presumed. Characterization of these communities is the first step in elucidating potential roles of diverse bacteria in disease progression and to ultimately facilitate advances in CF therapy.

  16. CFTR and Ca2+ Signaling in Cystic Fibrosis

    PubMed Central

    Antigny, Fabrice; Norez, Caroline; Becq, Frédéric; Vandebrouck, Clarisse

    2011-01-01

    Among the diverse physiological functions exerted by calcium signaling in living cells, its role in the regulation of protein biogenesis and trafficking remains incompletely understood. In cystic fibrosis (CF) disease the most common CF transmembrane conductance regulator (CFTR) mutation, F508del-CFTR generates a misprocessed protein that is abnormally retained in the endoplasmic reticulum (ER) compartment, rapidly degraded by the ubiquitin/proteasome pathway and hence absent at the plasma membrane of CF epithelial cells. Recent studies have demonstrated that intracellular calcium signals consequent to activation of apical G-protein-coupled receptors by different agonists are increased in CF airway epithelia. Moreover, the regulation of various intracellular calcium storage compartments, such as ER is also abnormal in CF cells. Although the molecular mechanism at the origin of this increase remains puzzling in epithelial cells, the F508del-CFTR mutation is proposed to be the onset of abnormal Ca2+ influx linking the calcium signaling to CFTR pathobiology. This article reviews the relationships between CFTR and calcium signaling in the context of the genetic disease CF. PMID:22046162

  17. Nasal Potential Difference in Cystic Fibrosis considering Severe CFTR Mutations

    PubMed Central

    Ng, Ronny Tah Yen; Marson, Fernando Augusto de Lima; Ribeiro, Jose Dirceu; Ribeiro, Antonio Fernando; Bertuzzo, Carmen Silvia; Ribeiro, Maria Angela Gonçalves de Oliveira; Severino, Silvana Dalge; Sakano, Eulalia

    2015-01-01

    The gold standard for diagnosing cystic fibrosis (CF) is a sweat chloride value above 60 mEq/L. However, this historical and important tool has limitations; other techniques should be studied, including the nasal potential difference (NPD) test. CFTR gene sequencing can identify CFTR mutations, but this method is time-consuming and too expensive to be used in all CF centers. The present study compared CF patients with two classes I-III CFTR mutations (10 patients) (G1), CF patients with classes IV-VI CFTR mutations (five patients) (G2), and 21 healthy subjects (G3). The CF patients and healthy subjects also underwent the NPD test. A statistical analysis was performed using the Mann-Whitney, Kruskal-Wallis, χ2, and Fisher's exact tests, α = 0.05. No differences were observed between the CF patients and healthy controls for the PDMax, Δamiloride, and Δchloride + free + amiloride markers from the NPD test. For the finger value, a difference between G2 and G3 was described. The Wilschanski index values were different between G1 and G3. In conclusion, our data showed that NPD is useful for CF diagnosis when classes I-III CFTR mutations are screened. However, if classes IV-VI are considered, the NPD test showed an overlap in values with healthy subjects. PMID:25667564

  18. Fatty acyltranferases in serum in cystic fibrosis (CF) patients

    SciTech Connect

    Zielenski, J.; Newman, L.J.; Slomiany, B.L.; Slomiany, A.

    1987-05-01

    Studies on serum and gastrointestinal secretion from CF patient is suggest that defective accumulation of mucus in gastrointestinal tract and excessive amount of a protease resistant peptides in serum are related to the abnormal activity of enzymes responsible for fatty acylation of proteins. Here, the authors investigated the fatty acyltransferase activities in serum of normal and CF patients. A 15 l of serum was mixed with 0.85 nmol ( UC)palmitoyl CoA, 200 g of serine and threonine and incubated at 37C for 30 min. The incubates were immediately frozen, dried extracted with C/M and chromatographed in chloroform/methanol/water. The incorporation of ( UC)palmitate was determined using linear radioscanner and authoradiography. The results of HPTLC revealed that CF serum in addition of ACAT and LCAT contained enzymes responsible for the transfer of ( UC)palmitate to monoacylphosphoglycerides, and serine and threonine. In normal serum the formation of a small amount of palmitoyl serine and palmitoyl threonine was also observed but the acylation of monoacylphosphoglycerides was not detectable. The authors conclude that in cystic fibrosis the abnormal fatty acyltransferases are responsible for the occurrence of protease resistant glycoprotein, unusual peptides in serum and possibly for the modification of membrane proteins and lipids.

  19. Opportunities for Quality Improvement in Cystic Fibrosis Newborn Screening

    PubMed Central

    Groose, Molly K.; Reynolds, Richard; Li, Zhanhai; M.Farrell, Philip

    2010-01-01

    Background With the rapid implementation of cystic fibrosis (CF) newborn screening (NBS), quality improvement (QI) has become essential to identify and prevent errors. Using Process Failure Modes and Effects Analysis (PFMEA), we adapted this method to determine if it could be applied to discover and rank high priority QI opportunities. Methods Site visits to three programmes were conducted, and PFMEA exercises were accomplished in Colorado, Massachusetts and Wisconsin with 23 experienced professionals. During each of these comprehensive sessions, participants identified and ranked potential failures based on severity, occurrence and detection to calculate risk priority number (RPN) values. Results A total of 96 failure modes were generated and ranked in a list of the 20 riskiest problems that show no significant discordances by site, although there were differences by profession of the rater, particularly nurses. Conclusions Our results illustrate that the PFMEA method applies well to CF NBS and that steps requiring communication and information transfer are perceived to be the highest risks. The number of identified failure makes and their potential impact demonstrate considerable overall risk and a need for ongoing QI. PMID:20471332

  20. Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs

    PubMed Central

    Stoltz, David A.; Rokhlina, Tatiana; Ernst, Sarah E.; Pezzulo, Alejandro A.; Ostedgaard, Lynda S.; Karp, Philip H.; Samuel, Melissa S.; Reznikov, Leah R.; Rector, Michael V.; Gansemer, Nicholas D.; Bouzek, Drake C.; Alaiwa, Mahmoud H. Abou; Hoegger, Mark J.; Ludwig, Paula S.; Taft, Peter J.; Wallen, Tanner J.; Wohlford-Lenane, Christine; McMenimen, James D.; Chen, Jeng-Haur; Bogan, Katrina L.; Adam, Ryan J.; Hornick, Emma E.; Nelson, George A.; Hoffman, Eric A.; Chang, Eugene H.; Zabner, Joseph; McCray, Paul B.; Prather, Randall S.; Meyerholz, David K.; Welsh, Michael J.

    2013-01-01

    Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid–binding protein (iFABP) promoter would alleviate the meconium ileus. We produced 5 CFTR–/–;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time. These data indicate that expressing CFTR in intestine without pancreatic or hepatic correction is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies. PMID:23676501

  1. Quantitative imaging of airway liquid absorption in cystic fibrosis.

    PubMed

    Locke, Landon W; Myerburg, Michael M; Markovetz, Matthew R; Parker, Robert S; Weber, Lawrence; Czachowski, Michael R; Harding, Thomas J; Brown, Stefanie L; Nero, Joseph A; Pilewski, Joseph M; Corcoran, Timothy E

    2014-09-01

    New measures are needed to rapidly assess emerging treatments for cystic fibrosis (CF) lung disease. Using an imaging approach, we evaluated the absorptive clearance of the radiolabeled small molecule probe diethylene triamine penta-acetic acid (DTPA) as an in vivo indicator of changes in airway liquid absorption. DTPA absorption and mucociliary clearance rates were measured in 21 patients with CF (12 adults and nine children) and nine adult controls using nuclear imaging. The effect of hypertonic saline on DTPA absorption was also studied. In addition, in vitro studies were conducted to identify the determinants of transepithelial DTPA absorption. CF patients had significantly increased rates of DTPA absorption compared with control subjects but had similar mucociliary clearance rates. Treatment with hypertonic saline resulted in a decrease in DTPA absorption and an increase in mucociliary clearance in 11 out of 11 adult CF patients compared with treatment with isotonic saline. In vitro studies revealed that ∼ 50% of DTPA absorption can be attributed to transepithelial fluid transport. Apically applied mucus impedes liquid and DTPA absorption. However, mucus effects become negligible in the presence of an osmotic stimulus. Functional imaging of DTPA absorption provides a quantifiable marker of immediate response to treatments that promote airway surface liquid hydration.

  2. Expression of cystic fibrosis transmembrane conductance regulator in rat ovary.

    PubMed

    Jin, Lei; Tang, Ruiling

    2008-10-01

    The protein expression of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl(-) channel, in ovarian stimulated premature female rat ovary during a cycle of follicle development and corpus luteum formation was investigated. Animals were injected with 10 U pregnant Mare's serum gonadotropin (PMSG) and subsequently 10 U hCG 48 h later. Time-dependent immunohistochemistry and Western blotting experiments were performed before and 24, 48, 72 h after hCG treatment. The immunohistochemistry revealed that administration of PMSG stimulated the CFTR expression in thecal cell layer and granulosa cell layer of mature follicles 48 h post injection, coincident with the PMSG-induced peak in follicular estradiol. However, the expression of CFTR in the granulose lutein cell layer and thecal lutein cell layer was time-dependently reduced following hCG injection, in accordance with the gradually increased progestogen level during luteum corpus formation. Western blotting analysis demonstrated that rat ovarian tissue expressed the special CFTR band at 170 kD. It is concluded that cAMP-dependent Cl(-) channels are involved in regulation of follicle development and luteum formation.

  3. Rationale for hypertonic saline therapy for cystic fibrosis lung disease.

    PubMed

    Tarran, Robert; Donaldson, Scott; Boucher, Richard C

    2007-06-01

    Cystic fibrosis (CF) is caused by alterations in the CF transmembrane conductance regulator ( CFTCR) gene. More than 1400 mutations in the CFTCR gene have been described, but the most common mutation (noted in 70% of CF chromosomes) is DeltaF508. Alterations in the CFTCR gene result in deranged sodium and chloride ion transport channels. This leads to failure of airway epithelia to hydrate their surfaces normally, particularly in response to infectious or toxic insults. Additional effects include mucus adhesion to airway surface, chronic inflammation, and infections. The concept that airway surface dehydration can cause CF-like lung disease is supported by in vitro data and in vivo animal models. Rehydrating airway surfaces may reduce or prevent lung injury and damage. Short- and longer term studies have shown that inhalation of hypertonic saline is well tolerated and improves lung function, reduces exacerbations, and improves quality of life in CF patients. This review discusses the importance of airway epithelial sodium and chloride channels in the pathogenesis of CF, and strategies (particularly the use of inhaled hypertonic saline) to reverse or minimize lung inflammation and injury in this disease.

  4. Screening for cystic fibrosis in the newborn by meconium analysis.

    PubMed Central

    Ryley, H C; Neale, L M; Brogan, T D; Bray, P T

    1979-01-01

    During a 4-year routine screening programme for cystic fibrosis (CF) 15 464 specimens were examined for raised meconium albumin levels by a test strip method and by electroimmunoassay. The incidence of false-positive results was about 5 per 1000 specimens in either test. This could be reduced by 90% by determining the ratio of albumin : alpha-1-trypsin inhibitor (a ratio below 2.0 being considered as a negative result), and it could be reduced to zero by determining the ratio in subsequent faecal specimens. Three of 12 meconium specimens from infants with proved CF gave false-negative results in all 3 tests. The other 9 specimens had greater than 100 mg albumin/g dry weight and albumin: alpha-1-trypsin inhibitor ratios of greater than 3.0; in subsequent faecal specimens the ratios were over 4.0. 176 meconium specimens from elsewhere in the UK were examined and these included 23 from infants who were subsequently proved to have CF. Six of these 23 CF specimens gave false-negative results, the other 17 being strongly positive. The origins of meconium serum protein suggest that infants with CF in whom meconium gives false-negative results have normal pancreatic functions at birth. The specificity of current meconium tests therefore cannot be improved as they depend on pancreatic dysfunction. PMID:312055

  5. Lung Transplantation for Cystic Fibrosis: Results, Indications, Complications, and Controversies

    PubMed Central

    Lynch, Joseph P.; Sayah, David M.; Belperio, John A.; Weigt, S. Sam

    2016-01-01

    Survival in patients with cystic fibrosis (CF) has improved dramatically over the past 30 to 40 years, with mean survival now approximately 40 years. Nonetheless, progressive respiratory insufficiency remains the major cause of mortality in CF patients, and lung transplantation (LT) is eventually required. Timing of listing for LT is critical, because up to 25 to 41% of CF patients have died while awaiting LT. Globally, approximately 16.4% of lung transplants are performed in adults with CF. Survival rates for LT recipients with CF are superior to other indications, yet LT is associated with substantial morbidity and mortality (~50% at 5-year survival rates). Myriad complications of LT include allograft failure (acute or chronic), opportunistic infections, and complications of chronic immunosuppressive medications (including malignancy). Determining which patients are candidates for LT is difficult, and survival benefit remains uncertain. In this review, we discuss when LT should be considered, criteria for identifying candidates, contraindications to LT, results post-LT, and specific complications that may be associated with LT. Infectious complications that may complicate CF (particularly Burkholderia cepacia spp., opportunistic fungi, and nontuberculous mycobacteria) are discussed. PMID:25826595

  6. Cyproheptadine is an effective appetite stimulant in cystic fibrosis.

    PubMed

    Homnick, Douglas N; Homnick, Benjamin D; Reeves, Andrew J; Marks, John H; Pimentel, Ronald S; Bonnema, Sally K

    2004-08-01

    Chronic pulmonary infection and intestinal malabsorption often lead to malnutrition in children and adults with cystic fibrosis (CF). Appetite stimulants, along with provision of adequate calories, may aid in overcoming nutritional deficits, allowing a better prognosis. We undertook a trial of cyproheptadine hydrochloride (CH) to determine its effectiveness as an appetite stimulant in 18 adults and children with CF. This was a 12-week, randomized, double-blind, controlled trial of CH vs. placebo. Eighteen subjects with documented CF (sweat or genetics positive), minimum age of 5 years, and ideal body weight for height <100% were entered, and 16 completed the study. Subjects were seen at baseline and every 4 weeks. Measures included baseline demographics, Shwachman score, anthropometrics (weight, height, body mass index, skin folds, and body composition by bioelectric impedance analysis), spirometry, caloric intake, days of oral (PO) and intravenous (IV) antibiotics, and a symptom and satisfaction survey. Subjects in the CH group showed significant increases in weight (mean 3.45 kg vs. 1.1 kg in the placebo group), height, BMI percentiles, ideal body weight/height, weight for age z-scores, and fat and fat-free mass. There were no changes or differences in PO or IV antibiotic use or spirometric changes. No significant side effects except transient mild sedation occurred in the CH group. Patient acceptance was good. In conclusion, CH appears to be an effective appetite stimulant with minimal side effects in children and adults with CF.

  7. Bacteriocin-mediated competition in cystic fibrosis lung infections

    PubMed Central

    Ghoul, Melanie; West, Stuart A.; Johansen, Helle Krogh; Molin, Søren; Harrison, Odile B.; Maiden, Martin C. J.; Jelsbak, Lars; Bruce, John B.; Griffin, Ashleigh S.

    2015-01-01

    Bacteriocins are toxins produced by bacteria to kill competitors of the same species. Theory and laboratory experiments suggest that bacteriocin production and immunity play a key role in the competitive dynamics of bacterial strains. The extent to which this is the case in natural populations, especially human pathogens, remains to be tested. We examined the role of bacteriocins in competition using Pseudomonas aeruginosa strains infecting lungs of humans with cystic fibrosis (CF). We assessed the ability of different strains to kill each other using phenotypic assays, and sequenced their genomes to determine what bacteriocins (pyocins) they carry. We found that (i) isolates from later infection stages inhibited earlier infecting strains less, but were more inhibited by pyocins produced by earlier infecting strains and carried fewer pyocin types; (ii) this difference between early and late infections appears to be caused by a difference in pyocin diversity between competing genotypes and not by loss of pyocin genes within a lineage over time; (iii) pyocin inhibition does not explain why certain strains outcompete others within lung infections; (iv) strains frequently carry the pyocin-killing gene, but not the immunity gene, suggesting resistance occurs via other unknown mechanisms. Our results show that, in contrast to patterns observed in experimental studies, pyocin production does not appear to have a major influence on strain competition during CF lung infections. PMID:26311664

  8. The role for neutrophil extracellular traps in cystic fibrosis autoimmunity

    PubMed Central

    Skopelja, Sladjana; Hamilton, B. JoNell; Jones, Jonathan D.; Yang, Mei-Ling; Mamula, Mark; Ashare, Alix; Gifford, Alex H.; Rigby, William F.C.

    2016-01-01

    While respiratory failure in cystic fibrosis (CF) frequently associates with chronic infection by Pseudomonas aeruginosa, no single factor predicts the extent of lung damage in CF. To elucidate other causes, we studied the autoantibody profile in CF and rheumatoid arthritis (RA) patients, given the similar association of airway inflammation and autoimmunity in RA. Even though we observed that bactericidal permeability-increasing protein (BPI), carbamylated proteins, and citrullinated proteins all localized to the neutrophil extracellular traps (NETs), which are implicated in the development of autoimmunity, our study demonstrates striking autoantibody specificity in CF. Particularly, CF patients developed anti-BPI autoantibodies but hardly any anti-citrullinated protein autoantibodies (ACPA). In contrast, ACPA-positive RA patients exhibited no reactivity with BPI. Interestingly, anti-carbamylated protein autoantibodies (ACarPA) were found in both cohorts but did not cross-react with BPI. Contrary to ACPA and ACarPA, anti-BPI autoantibodies recognized the BPI C-terminus in the absence of posttranslational modifications. In fact, we discovered that P. aeruginosa–mediated NET formation results in BPI cleavage by P. aeruginosa elastase, which suggests a novel mechanism in the development of autoimmunity to BPI. In accordance with this model, autoantibodies associated with presence of P. aeruginosa on sputum culture. Finally, our results provide a role for autoimmunity in CF disease severity, as autoantibody levels associate with diminished lung function. PMID:27777975

  9. Inhaled therapies, azithromycin and Mycobacterium abscessus in cystic fibrosis patients.

    PubMed

    Catherinot, Emilie; Roux, Anne-Laure; Vibet, Marie-Anne; Bellis, Gil; Lemonnier, Lydie; Le Roux, Evelyne; Bernède-Bauduin, Claire; Le Bourgeois, Muriel; Herrmann, Jean-Louis; Guillemot, Didier; Gaillard, Jean-Louis

    2013-05-01

    Cystic fibrosis (CF) patients are at particularly high risk of developing lung disease caused by Mycobacterium abscessus complex (MABSC). Over the last 10 years, changes in CF treatment, with increasing use of inhaled therapies and low-dose azithromycin, have been accompanied by an increase in the prevalence of MABSC infections in CF patients. There is therefore some concern about the role of new CF treatments in the emergence of MABSC infections. We addressed this issue by means of a case-control study including 30 MABSC-positive cases and 60 nontuberculous mycobacteria-negative CF controls matched for age, sex and centre. We also compared practices at the CF centres with the highest prevalence of MABSC with those at the other centres. No positive association was found between MABSC lung disease and the use of inhaled therapies or low-dose azithromycin in the 4 years preceding MABSC isolation. These treatments were not significantly more frequently used at the CF centres with the highest MABSC prevalence rates. In conclusion, there is no evidence for a link between M. abscessus complex lung disease and inhaled therapies or low-dose azithromycin in patients with CF.

  10. Altered chloride metabolism in cultured cystic fibrosis skin fibroblasts

    SciTech Connect

    Mattes, P.M.; Maloney, P.C.; Littlefield, J.W.

    1987-05-01

    An abnormal regulation of chloride permeability has been described for epithelial cells from patients with cystic fibrosis (CF). To learn more about the biochemical basis of this inherited disease, the authors have studied chloride metabolism in cultured CF fibroblasts by comparing the efflux of /sup 36/Cl/sup -/ from matched pairs of CF and normal fibroblasts. The rate constants describing /sup 36/Cl/sup -/ efflux did not differ between the two cell types, but in each of the four pairs tested the amount of /sup 36/Cl/sup -/ contained within CF cells was consistently reduced, by 25-30%, relative to normal cells. Comparisons of cell water content and /sup 22/Na/sup +/ efflux showed no differences between the two cell types, suggesting that overall intracellular chloride concentration is lower than normal in CF fibroblasts. Such data suggest that the CF gene defect is expressed in skin fibroblasts and that this defect may alter the regulation of intracellular Cl/sup -/ concentration, perhaps through changes in Cl/sup -/ permeability.

  11. Microstructural alterations of sputum in cystic fibrosis lung disease

    PubMed Central

    Duncan, Gregg A.; Jung, James; Joseph, Andrea; Thaxton, Abigail L.; West, Natalie E.; Boyle, Michael P.; Hanes, Justin

    2016-01-01

    The stasis of mucus secretions in the lungs of cystic fibrosis (CF) patients leads to recurrent infections and pulmonary exacerbations, resulting in decreased survival. Prior studies have assessed the biochemical and biophysical features of airway mucus in individuals with CF. However, these measurements are unable to probe mucus structure on microscopic length scales relevant to key players in the progression of CF-related lung disease, namely, viruses, bacteria, and neutrophils. In this study, we quantitatively determined sputum microstructure based on the diffusion of muco-inert nanoparticle probes in CF sputum and found that a reduction in sputum mesh pore size is characteristic of CF patients with reduced lung function, as indicated by measured FEV1. We also discovered that the effect of ex vivo treatment of CF sputum with rhDNase I (Pulmozyme) on microstructure is dependent upon the time interval between the most recent inhaled rhDNase I treatment and the sample collection. Microstructure of mucus may serve as a marker for the extent of CF lung disease and as a parameter for assessing the effectiveness of mucus-altering agents. PMID:27812540

  12. Prenatal screening for cystic fibrosis carriers: an economic evaluation.

    PubMed Central

    Rowley, P T; Loader, S; Kaplan, R M

    1998-01-01

    The cloning of the CFTR gene has made it technically possible to avert the unwanted birth of a child with cystic fibrosis (CF). Several large trials offering prenatal CF carrier screening suggest that such screening is practical and that identified carriers generally use the information obtained. Therefore, a critical question is whether the cost of such screening is justified. Decision analysis was performed that used information about choices that pregnant women were observed to make at each stage in the Rochester prenatal carrier-screening trial. The cost of screening per CF birth voluntarily averted was estimated to be $1,320,000-$1,400,000. However, the lifetime medical cost of the care of a CF child in today's dollars was estimated to be slightly>$1,000,000. Therefore, despite both the high cost of carrier testing and the relative infrequency of CF conceptions in the general population, the averted medical-care cost resulting from choices freely made are estimated to offset approximately 74%-78% of the costs of a screening program. At present, if it is assumed that a pregnancy terminated because of CF is replaced, the marginal cost for prenatal CF carrier screening is estimated to be $8,290 per quality-adjusted life-year. This value compares favorably with that of many accepted medical services. The cost of prenatal CF carrier screening could fall to equal the averted costs of CF patient care if the cost of carrier testing were to fall to $100. PMID:9758600

  13. Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs.

    PubMed

    Stoltz, David A; Rokhlina, Tatiana; Ernst, Sarah E; Pezzulo, Alejandro A; Ostedgaard, Lynda S; Karp, Philip H; Samuel, Melissa S; Reznikov, Leah R; Rector, Michael V; Gansemer, Nicholas D; Bouzek, Drake C; Abou Alaiwa, Mahmoud H; Hoegger, Mark J; Ludwig, Paula S; Taft, Peter J; Wallen, Tanner J; Wohlford-Lenane, Christine; McMenimen, James D; Chen, Jeng-Haur; Bogan, Katrina L; Adam, Ryan J; Hornick, Emma E; Nelson, George A; Hoffman, Eric A; Chang, Eugene H; Zabner, Joseph; McCray, Paul B; Prather, Randall S; Meyerholz, David K; Welsh, Michael J

    2013-06-01

    Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus. We produced 5 CFTR-/-;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time. These data indicate that expressing CFTR in intestine without pancreatic or hepatic correction is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies.

  14. Lentiviral-mediated phenotypic correction of cystic fibrosis pigs

    PubMed Central

    Cooney, Ashley L.; Abou Alaiwa, Mahmoud H.; Shah, Viral S.; Bouzek, Drake C.; Stroik, Mallory R.; Powers, Linda S.; Gansemer, Nick D.; Meyerholz, David K.; Welsh, Michael J.; Stoltz, David A.; Sinn, Patrick L.; McCray, Paul B.

    2016-01-01

    Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in CF transmembrane conductance regulator (CFTR), resulting in defective anion transport. Regardless of the disease-causing mutation, gene therapy is a strategy to restore anion transport to airway epithelia. Indeed, viral vector–delivered CFTR can complement the anion channel defect. In this proof-of-principle study, functional in vivo CFTR channel activity was restored in the airways of CF pigs using a feline immunodeficiency virus–based (FIV-based) lentiviral vector pseudotyped with the GP64 envelope. Three newborn CF pigs received aerosolized FIV-CFTR to the nose and lung. Two weeks after viral vector delivery, epithelial tissues were analyzed for functional correction. In freshly excised tracheal and bronchus tissues and cultured ethmoid sinus cells, we observed a significant increase in transepithelial cAMP-stimulated current, evidence of functional CFTR. In addition, we observed increases in tracheal airway surface liquid pH and bacterial killing in CFTR vector–treated animals. Together, these data provide the first evidence to our knowledge that lentiviral delivery of CFTR can partially correct the anion channel defect in a large-animal CF model and validate a translational strategy to treat or prevent CF lung disease. PMID:27656681

  15. Inhaled corticosteroids and Aspergillus fumigatus isolation in cystic fibrosis.

    PubMed

    Noni, Maria; Katelari, Anna; Dimopoulos, George; Kourlaba, Georgia; Spoulou, Vana; Alexandrou-Athanassoulis, Helen; Doudounakis, Stavros-Eleftherios; Tzoumaka-Bakoula, Chryssa

    2014-10-01

    Aspergillus fumigatus isolation in cultures from respiratory specimens of patients with cystic fibrosis (CF) is quite common; however, the role of A. fumigatus as a pathogen and whether its presence is associated with progression of pulmonary disease remain unclear. We investigated the association between inhaled corticosteroids and the recovery of A. fumigatus by performing a retrospective cohort study of CF patients born between 1988 and 1996. The patients' medical records from their first visit to the CF Center until December 2010 were reviewed. Outcomes were the occurrence of A. fumigatus first isolation, chronic colonization, or the last visit at the CF Center. A number of possible confounders were included in the multivariate logistic regression analysis in order to identify an independent association between inhaled corticosteroids and colonization status. A total of 121 patients were included in the study. Thirty-nine patients (32.2%) had at least one positive culture and 14 (11.6%) developed chronic colonization. Multivariate logistic regression analysis was used to determine the independent effect of inhaled corticosteroids on the odds of first isolation (odds ratio [OR], 1.165; 95% confidence interval [CI], 1.015-1.337; P = 0.029) and chronic colonization (OR, 1.180; 95% CI, 1.029-1.353; P = 0.018). In conclusion, A. fumigatus first isolation and chronic colonization are associated with the duration of inhaled corticosteroid treatment.

  16. Cystic fibrosis heterozygote screening in 5,161 pregnant women

    SciTech Connect

    Witt, D.R.; Hallam, P.; Blumberg, B.; Fishbach, A.

    1996-04-01

    A screening program for cystic fibrosis (CF) heterozygotes was conducted in a large HMO prenatal population, to evaluate the level of interest among eligible patients, the effectiveness of prescreening education, attitudes toward the screening process, psychological effects, and utilization of prenatal diagnosis and its outcomes. The heterozygote identification rate and frequency of specific CFTR mutations were also assessed. Identified carriers were offered genetic counseling and testing of male partners. Prenatal diagnosis was offered if both partners were identified as carriers. A total of 5,161 women underwent carrier testing; 947 others completed survey instruments only. The acceptance rate of screening was high (78%), and pretest education by videotape was generally effective. Adverse psychological effects were not reported. Participants generally found screening to be desirable and useful. Screening identified 142 female heterozygotes, 109 couples in which the male partner was not a carrier, and 7 high-risk couples. The incidence of R117H mutations was much higher than expected. The number of identified carriers was much lower in Hispanics than in Caucasians. We conclude that large-scale prenatal screening for CF heterozygotes in the absence of a family history of CF is an acceptable method for identifying couples at risk for affected fetuses. Sufficient pretest education can be accomplished efficiently, test insensitivity is well accepted, adverse psychological events are not observed, and general patient satisfaction is high. 66 refs., 1 fig., 8 tabs.

  17. Siderophore Production by Cystic Fibrosis Isolates of Burkholderia cepacia

    PubMed Central

    Darling, Patricia; Chan, Maria; Cox, Andrew D.; Sokol, Pamela A.

    1998-01-01

    Sixty-one Burkholderia cepacia isolates from patients with cystic fibrosis (CF) and four plant isolates were screened for production of the siderophores salicylic acid (SA), pyochelin, cepabactin, and ornibactins and fingerprinted by a PCR-based randomly amplified polymorphic DNA (RAPD) method. Of the 24 RAPD types determined, 22 (92%) were associated with isolates that produced SA, 21 (87%) were associated with isolates that produced ornibactins, 15 (60%) were associated with isolates that produced pyochelin, and 3 (12%) were associated with isolates that produced cepabactin. Of the 24 RAPD types plus 2 phenotypic variants of types 1 and 9, 3 were associated with isolates that produced all four siderophores, 8 were associated with isolates that produced three siderophores, 12 were associated with isolates that produced two siderophores, and 3 were associated with isolates that produced only one siderophore. These results suggest that the numbers and types of siderophores produced by CF isolates of B. cepacia correlate with RAPD type and that SA and ornibactins are the most prevalent siderophores produced. PMID:9453660

  18. Proteomic Analysis of Nasal Epithelial Cells from Cystic Fibrosis Patients

    PubMed Central

    Papon, Jean-François; Chhuon, Cerina; Zadigue, Patricia; Prulière-Escabasse, Virginie; Amselem, Serge; Escudier, Estelle; Coste, André; Edelman, Aleksander

    2014-01-01

    The pathophysiology of cystic fibrosis (CF) lung disease remains incompletely understood. New explanations for the pathogenesis of CF lung disease may be discovered by studying the patterns of protein expression in cultured human nasal epithelial cells (HNEC). To that aim, we compared the level of protein expressions in primary cultures of HNEC from nasal polyps secondary to CF (CFNP, n = 4), primary nasal polyps (NP, n = 8) and control mucosa (CTRL, n = 4) using isobaric tag for relative and absolute quantification (iTRAQ) labeling coupled with liquid chromatography (LC)-MS-MS. The analysis of the data revealed 42 deregulated protein expressions in CFNP compared to NP and CTRL, suggesting that these alterations are related to CF. Overall, AmiGo analysis highlighted six major pathways important for cell functions that seem to be impaired: metabolism, G protein process, inflammation and oxidative stress response, protein folding, proteolysis and structural proteins. Among them, glucose and fatty acid metabolic pathways could be impaired in CF with nine deregulated proteins. Our proteomic study provides a reproducible set of differentially expressed proteins in airway epithelial cells from CF patients and reveals many novel deregulated proteins that could lead to further studies aiming to clarify the involvement of such proteins in CF pathophysiology. PMID:25268127

  19. Cystic fibrosis in Finland: a molecular and genealogical study.

    PubMed

    Kere, J; Norio, R; Savilahti, E; Estivill, X; de la Chapelle, A

    1989-08-01

    The incidence of cystic fibrosis (CF) in Finland is one tenth that in other Caucasian populations. To study the genetics of CF in Finland, we used a combined molecular and genealogical approach. Out of the 20 Finnish families with a living CF patient, 19 were typed for eight closely linked restriction fragment length polymorphisms (RFLP) at the MET, D7S8, and D7S23 loci. The birthplaces of the parents and grandparents were traced using population registries. Allele and haplotype frequencies in Finland are similar to those of other European and North American populations, but are modified by sampling: two regional CF gene clusters, evidently the results of a founder effect, were identified. Generally, the gene was evenly distributed over the population, carrier frequency being estimated at approximately 1.3%. We conclude that CF in Finland is caused by the common Caucasian mutation(s), and that the low frequency of the gene can be explained by a negative sampling effect and genetic drift.

  20. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis

    PubMed Central

    Alton, Eric W F W; Beekman, Jeffery M; Boyd, A Christopher; Brand, June; Carlon, Marianne S; Connolly, Mary M; Chan, Mario; Conlon, Sinead; Davidson, Heather E; Davies, Jane C; Davies, Lee A; Dekkers, Johanna F; Doherty, Ann; Gea-Sorli, Sabrina; Gill, Deborah R; Griesenbach, Uta; Hasegawa, Mamoru; Higgins, Tracy E; Hironaka, Takashi; Hyndman, Laura; McLachlan, Gerry; Inoue, Makoto; Hyde, Stephen C; Innes, J Alastair; Maher, Toby M; Moran, Caroline; Meng, Cuixiang; Paul-Smith, Michael C; Pringle, Ian A; Pytel, Kamila M; Rodriguez-Martinez, Andrea; Schmidt, Alexander C; Stevenson, Barbara J; Sumner-Jones, Stephanie G; Toshner, Richard; Tsugumine, Shu; Wasowicz, Marguerite W; Zhu, Jie

    2017-01-01

    We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air–liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and ‘benchmarked’ against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90–100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F

  1. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis.

    PubMed

    Alton, Eric W F W; Beekman, Jeffery M; Boyd, A Christopher; Brand, June; Carlon, Marianne S; Connolly, Mary M; Chan, Mario; Conlon, Sinead; Davidson, Heather E; Davies, Jane C; Davies, Lee A; Dekkers, Johanna F; Doherty, Ann; Gea-Sorli, Sabrina; Gill, Deborah R; Griesenbach, Uta; Hasegawa, Mamoru; Higgins, Tracy E; Hironaka, Takashi; Hyndman, Laura; McLachlan, Gerry; Inoue, Makoto; Hyde, Stephen C; Innes, J Alastair; Maher, Toby M; Moran, Caroline; Meng, Cuixiang; Paul-Smith, Michael C; Pringle, Ian A; Pytel, Kamila M; Rodriguez-Martinez, Andrea; Schmidt, Alexander C; Stevenson, Barbara J; Sumner-Jones, Stephanie G; Toshner, Richard; Tsugumine, Shu; Wasowicz, Marguerite W; Zhu, Jie

    2017-02-01

    We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air-liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and 'benchmarked' against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90-100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F

  2. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.

    PubMed Central

    Macek, M; Mackova, A; Hamosh, A; Hilman, B C; Selden, R F; Lucotte, G; Friedman, K J; Knowles, M R; Rosenstein, B J; Cutting, G R

    1997-01-01

    Cystic fibrosis (CF)--an autosomal recessive disorder caused by mutations in CF transmembrane conductance regulator (CFTR) and characterized by abnormal chloride conduction across epithelial membranes, leading to chronic lung and exocrine pancreatic disease--is less common in African-Americans than in Caucasians. No large-scale studies of mutation identification and screening in African-American CF patients have been reported, to date. In this study, the entire coding and flanking intronic sequence of the CFTR gene was analyzed by denaturing gradient-gel electrophoresis and sequencing in an index group of 82 African-American CF chromosomes to identify mutations. One novel mutation, 3120+1G-->A, occurred with a frequency of 12.3% and was also detected in a native African patient. To establish frequencies, an additional group of 66 African-American CF chromosomes were screened for mutations identified in two or more African-American patients. Screening for 16 "common Caucasian" mutations identified 52% of CF alleles in African-Americans, while screening for 8 "common African" mutations accounted for an additional 23%. The combined detection rate of 75% was comparable to the sensitivity of mutation analysis in Caucasian CF patients. These results indicate that African-Americans have their own set of "common" CF mutations that originate from the native African population. Inclusion of these "common" mutations substantially improves CF mutation detection rates in African-Americans. PMID:9150159

  3. Late vitamin K deficiency bleeding leading to a diagnosis of cystic fibrosis: a case report.

    PubMed

    Ngo, B; Van Pelt, K; Labarque, V; Van De Casseye, W; Penders, J

    2011-01-01

    Vitamin K deficiency bleeding (VKDB) in infants still occurs despite worldwide use of prophylaxis. Clinical manifestations can be dramatic with over 50% of patients presenting with intracranial haemorrhage and a mortality rate of 20% in late vitamin K deficiency bleeding. Special attention should be given to infants with a high risk profile (preterm, breast feeding, cholestasis, malabsorption). A tentative diagnosis can be made observing quick normalisation of some easy-to-perform haemostatic parameters (PT, aPTT) after administration of vitamin K. Nowadays, VKDB can still be the first clinical sign of diseases causing malabsorption of fat-soluble vitamins. In this case report, VKDB led to the diagnosis of cystic fibrosis, the most common fatal autosomal recessive disease among Caucasian people.

  4. eSensor®: A Microarray Technology Based on Electrochemical Detection of Nucleic Acids and Its Application to Cystic Fibrosis Carrier Screening

    NASA Astrophysics Data System (ADS)

    Reed, Michael R.; Coty, William A.

    We have developed a test for identification of carriers for cystic fibrosis using the eSensor® DNA detection technology. Oligonucleotide probes are deposited within self-assembled monolayers on gold electrodes arrayed upon printed circuit boards. These probes allow sequence-specific capture of amplicons containing a panel of mutation sites associated with cystic fibrosis. DNA targets are detected and mutations genotyped using a “sandwich” assay methodology employing electrochemical detection of ferrocene-labeled oligonucleotides for discrimination of carrier and non-carrier alleles. Performance of the cystic fibrosis application demonstrates sufficient accuracy and reliability for clinical diagnostic use, and the procedure can be performed by trained medical technologists available in the hospital laboratory.

  5. Antibiotic therapy and fat digestion and absorption in cystic fibrosis.

    PubMed

    Lisowska, Aleksandra; Pogorzelski, Andrzej; Oracz, Grzegorz; Skorupa, Wojciech; Cofta, Szczepan; Szydłowski, Jarosław; Socha, Jerzy; Walkowiak, Jarosław

    2011-01-01

    Antibiotic therapy in the cystic fibrosis (CF) mouse model has been shown to result in reduced bacterial load of the intestine and significant body mass gain. The effect was suggested to be linked to the improvement of intestinal digestion and absorption. Therefore, we aimed to assess the influence of routinely applied antibiotic therapy in CF patients on fat assimilation. Twenty-four CF patients aged 6 to 30 years entered the study. Inclusion criteria comprised confirmed exocrine pancreatic insufficiency and bronchopulmonary exacerbation demanding antibiotic therapy. Exclusion criteria comprised: antibiotic therapy six weeks prior to the test, liver cirrhosis, diabetes mellitus, oxygen dependency, the use of systemic corticosteroids. In all enrolled CF subjects, (13)C-labelled mixed triglyceride breath test ((13)C MTG-BT) was performed to assess lipid digestion and absorption, before and after antibiotic therapy. Sixteen subjects were treated intravenously with ceftazidime and amikacin, eight patients orally with ciprofloxacin. Cumulative percentage dose recovery (CPDR) was considered to reflect digestion and absorption of lipids. The values are expressed as means (medians). The values of CPDR before and after antibiotic therapy did not differ in the whole studied group [4.6(3.3) % vs. 5.7(5.3) %, p = 0.100] as well as in the subgroup receiving them intravenously [4.6(3.2) % vs. 5.7(5.3) %, p = 0.327] or in that with oral drug administration [4.6(3.4) % vs. 5.7(5.4) %, p = 0.167]. In conclusion, antibiotic therapy applied routinely in the course of pulmonary exacerbation in CF patients does not seem to result in an improvement of fat digestion and absorption.

  6. Correction of a Cystic Fibrosis Splicing Mutation by Antisense Oligonucleotides.

    PubMed

    Igreja, Susana; Clarke, Luka A; Botelho, Hugo M; Marques, Luís; Amaral, Margarida D

    2016-02-01

    Cystic fibrosis (CF), the most common life-threatening genetic disease in Caucasians, is caused by ∼2,000 different mutations in the CF transmembrane conductance regulator (CFTR) gene. A significant fraction of these (∼13%) affect pre-mRNA splicing for which novel therapies have been somewhat neglected. We have previously described the effect of the CFTR splicing mutation c.2657+5G>A in IVS16, showing that it originates transcripts lacking exon 16 as well as wild-type transcripts. Here, we tested an RNA-based antisense oligonucleotide (AON) strategy to correct the aberrant splicing caused by this mutation. Two AONs (AON1/2) complementary to the pre-mRNA IVS16 mutant region were designed and their effect on splicing was assessed at the RNA and protein levels, on intracellular protein localization and function. To this end, we used the 2657+5G>A mutant CFTR minigene stably expressed in HEK293 Flp-In cells that express a single copy of the transgene. RNA data from AON1-treated mutant cells show that exon 16 inclusion was almost completely restored (to 95%), also resulting in increased levels of correctly localized CFTR protein at the plasma membrane (PM) and with increased function. A novel two-color CFTR splicing reporter minigene developed here allowed the quantitative monitoring of splicing by automated microscopy localization of CFTR at the PM. The AON strategy is thus a promising therapeutic approach for the specific correction of alternative splicing.

  7. Improvement of cystic fibrosis during treatment with isotretinoin.

    PubMed

    Buckley, Jennifer L; Chastain, Mark A; Rietschel, Robert L

    2006-01-01

    A 15-year-old boy with a history significant for multiple respiratory infections since birth presented for evaluation of acne vulgaris. He was initially prescribed doxycycline, topical tretinoin, and topical clindamycin solution, with the later addition of a benzoyl peroxide preparation to his regimen. The patient returned 6 months later after having been diagnosed with CF (cystic fibrosis) by sweat testing and genetic testing. His skin condition had not responded adequately to prior therapy, so all acne medications were discontinued. The 84-kg patient was started on 80 mg (0.95 mg/kg/d) of isotretinoin (13-cis-retinoic acid) daily. The patient's dose was decreased to 40 mg/d 2 weeks later following an episode of blood in his stool and epistaxis. At the 1- and 2-month follow-up visits, the patient reported improvement in his acne and mentioned that his lung secretions seemed reduced. His acne cleared after 4 months of therapy, so the isotretinoin was discontinued. The patient and his mother noted that no respiratory infections had occurred during the course of therapy. The patient's acne relapsed nearly 2 years later, so isotretinoin was restarted at 60 mg/d. During the next 7 months while on the drug, he experienced no further episodes of epistaxis or bloody stools and his acne had resolved by the end of therapy. The patient and his mother again reported fewer bronchopulmonary secretions and no infections requiring antibiotics during treatment with isotretinoin. This was unusual because he had experienced numerous respiratory infections requiring antibiotics during the prior 2 years. Since discontinuing the drug, the patient has had intermittent pulmonary infections and exacerbations in the symptomatology of his CF.

  8. Porcine Nasal Epithelial Cultures for Studies of Cystic Fibrosis Sinusitis

    PubMed Central

    Dean, Nichole; Ranganath, Neel K.; Jones, Brandon; Zhang, Shaoyan; Skinner, Daniel; Rowe, Steven M.; Sorscher, Eric J.; Woodworth, Bradford A.

    2014-01-01

    Background Transgenic cystic fibrosis (CF) murine models do not develop spontaneous lung or sinus disease, two major causes of morbidity in human CF patients. Because of these limitations, transgenic CFTR−/− pigs have been developed and are currently being characterized. These CF animal models have phenotypes closely resembling that of human CF subjects. The objectives of the current study were to develop primary porcine nasal epithelial (PNE) cultures and evaluate their usefulness as a means to investigate sinonasal transepithelial transport and CFTR function. Methods PNE derived from the septum or turbinates of CFTR+/+ and CFTR−/− pigs were cultured at an air-liquid interface to confluence and full differentiation. Epithelial monolayers were mounted in Ussing chambers to investigate pharmacologic manipulation of ion transport. Ciliary beat frequency (CBF) and scanning electron microscopy of monolayers were used to indicate degree of ciliation and cell differentiation. Results Stimulation of CFTR-mediated anion transport(ΔIsc in μA/cm2) was significantly greater in epithelia derived from the septum when compared to turbinates(33.04+/−1.17 vs. 18.9+/−0.73;p<0.05). cAMP-activated Cl− secretion was absent in CFTR−/− and present in CFTR+/+ epithelia. Calcium-activated Cl− (CaCC) secretion was increased in CF, however, overall Cl− transport through CaCCs was very low. Degree of ciliation (90%) and CBF were similar between groups. Discussion Septal PNE exhibit a robust ion transport phenotype and indicate CFTR−/− sinus disease could be attributable to diminished alternative pathways for Cl− transport. Overall, PNE have similarities to human respiratory epithelia not demonstrated in murine cells and represent useful in vitro models for studying CF sinus disease. PMID:24733748

  9. Thioredoxin liquefies and decreases the viscoelasticity of cystic fibrosis sputum.

    PubMed

    Rancourt, Raymond C; Tai, Shusheng; King, Malcolm; Heltshe, Sonya L; Penvari, Churee; Accurso, Frank J; White, Carl W

    2004-05-01

    The persistent and viscous nature of airway secretions in cystic fibrosis (CF) disease leads to airway obstruction, opportunistic infection, and deterioration of lung function. Thioredoxin (Trx) is a protein disulfide reductase that catalyzes numerous thiol-dependent cellular reductive processes. To determine whether Trx can alter the rheological properties of mucus, sputum obtained from CF patients was treated with TRX and its reducing system (0.1 microM thioredoxin reductase + 2 mM NADPH), and liquid phase-gel phase ratio (percent liquid phase) was assessed by compaction assay. Exposure to low Trx concentrations (1 microM) caused significant increases in the percentage of liquid phase of sputum. Maximal increases in percent liquid phase occurred with 30 microM Trx. Additional measurements revealed that sputum liquefaction by the Trx reducing system is dependent on NADPH concentration. The relative potency of the Trx reducing system also was compared with other disulfide-reducing agents. In contrast with Trx, glutathione and N-acetylcysteine were ineffective in liquefying sputum when used at concentrations <1 mM. Sputum viscoelasticity, measured by magnetic microrheometry, also was diminished significantly following 20-min treatment with 3, 10, or 30 microM Trx. Similarly, this reduction in viscoelasticty also was dependent on NADPH concentration. Further investigation has indicated that Trx treatment increases the solubility of high-molecular-weight glycoproteins and causes redistribution of extracellular DNA into the liquid phase of sputum. Recognizing that mucins are the major gel-forming glycoproteins in mucus, we suggest that Trx alters sputum rheology by enzymatic reduction of glycoprotein polymers present in sputum.

  10. Cystic fibrosis carrier population screening in the primary care setting.

    PubMed Central

    Loader, S.; Caldwell, P.; Kozyra, A.; Levenkron, J. C.; Boehm, C. D.; Kazazian, H. H.; Rowley, P. T.

    1996-01-01

    To determine the receptivity of prenatal care providers and their patients to carrier testing for cystic fibrosis (CF), we offered free carrier screening, followed by genetic counseling of carriers, to all prenatal care providers in Rochester, NY, for all their female patients of reproductive age, pregnant or not. Of 124 prenatal care providers, only 37 elected to participate, but many of these offered screening only to pregnant women. The acceptance rate among pregnant women was approximately 57%. The most common reasons for accepting screening were to obtain reassurance (50.7%) and to avoid having a child with CF (27.8 %). The most common reasons for declining screening were not intending to terminate a pregnancy for CF (32.4%) and believing that the chance of having a CF child was very low (32.2%). Compared with decliners, acceptors were more likely to have no children, regarded having a child with CF as more serious, believed themselves more susceptible to having such a child, knew more about CF, would be more likely to terminate a pregnancy if the fetus were shown to have CF, and more strongly supported offering CF screening to women of reproductive age. Of 4,879 women on whom results were obtained, 124 were found to be carriers. Of these 124 carriers, the partners of 106 were tested. Of the five at-risk couples, four requested prenatal diagnosis and one requested neonatal diagnosis. No woman found to be a carrier whose partner tested negative requested prenatal diagnosis. Except for the imperfect knowledge of those testing negative, none of the adverse outcomes predicted for CF carrier testing in the general population were observed in this study. Images p236-a p236-b p236-c PMID:8659530

  11. Culture Enriched Molecular Profiling of the Cystic Fibrosis Airway Microbiome

    PubMed Central

    Sibley, Christopher D.; Grinwis, Margot E.; Field, Tyler R.; Eshaghurshan, Christina S.; Faria, Monica M.; Dowd, Scot E.; Parkins, Michael D.; Rabin, Harvey R.; Surette, Michael G.

    2011-01-01

    The microbiome of the respiratory tract, including the nasopharyngeal and oropharyngeal microbiota, is a dynamic community of microorganisms that is highly diverse. The cystic fibrosis (CF) airway microbiome refers to the polymicrobial communities present in the lower airways of CF patients. It is comprised of chronic opportunistic pathogens (such as Pseudomonas aeruginosa) and a variety of organisms derived mostly from the normal microbiota of the upper respiratory tract. The complexity of these communities has been inferred primarily from culture independent molecular profiling. As with most microbial communities it is generally assumed that most of the organisms present are not readily cultured. Our culture collection generated using more extensive cultivation approaches, reveals a more complex microbial community than that obtained by conventional CF culture methods. To directly evaluate the cultivability of the airway microbiome, we examined six samples in depth using culture-enriched molecular profiling which combines culture-based methods with the molecular profiling methods of terminal restriction fragment length polymorphisms and 16S rRNA gene sequencing. We demonstrate that combining culture-dependent and culture-independent approaches enhances the sensitivity of either approach alone. Our techniques were able to cultivate 43 of the 48 families detected by deep sequencing; the five families recovered solely by culture-independent approaches were all present at very low abundance (<0.002% total reads). 46% of the molecular signatures detected by culture from the six patients were only identified in an anaerobic environment, suggesting that a large proportion of the cultured airway community is composed of obligate anaerobes. Most significantly, using 20 growth conditions per specimen, half of which included anaerobic cultivation and extended incubation times we demonstrate that the majority of bacteria present can be cultured. PMID:21829484

  12. Genetic analysis of hispanic individuals with cystic fibrosis

    SciTech Connect

    Grebe, T.A.; Doane, W.W.; Norman, R.A.; Rhodes, S.N. ); Seltzer, W.K. ); DeMarchi, J.; Silva, D.K.; Gozal, D.; Bowman, C.M.; Accurso, F.J.; Jain, K.D. )

    1994-03-01

    The authors have performed molecular genetic analysis of Hispanic individuals with cystic fibrosis (CF) in the southwestern United States. Of 129 CF chromosomes analyzed, oly 46% (59/129) carry [Delta]F508. The G542X mutation was found on 5% (7/129) of CF chromosomes. The 3849+10kbC[yields]T mutation, detected primarily in Ashkenazi Jews, was present on 2% (3/129). R1162X and R334W, mutations identified in Spain and Italy, each occurred on 1.6% (2/129) of CF chromosomes. W1282X and R553X were each detected once. G551D and N1303K were not found. Overall, screening for 22 or more mutations resulted in detection of only 58% of CF transmembrane conductance regulator gene mutations among Hispanic individuals. Analysis of KM19/XV2c haplotypes revealed an unusual distribution. Although the majority of [Delta]508 mutations are on chromosomes of B haplotypes, the other CF mutations are on A and C haplotypes at higher-than-expected frequencies. These genetic analysis demonstrate significant differences between Hispanic individuals with CF and those of the general North American population. Assessment of carrier/affected risk in Hispanic CF individuals cannot, therefore, be based on the mutation frequencies found through studies of the general population but must be adjusted to better reflect the genetic makeup of this ethnic group. Further studies are necessary to identify the causative mutation(s) in this population and to better delineate genotype/phenotype correlations. These will enable counselors to provide more accurate genetic counseling. 22 refs., 2 tabs.

  13. CFTR expression and organ damage in cystic fibrosis

    SciTech Connect

    Tizzano, E.; Chitayat, D.; Buchwald, M.

    1994-09-01

    To assist our understanding of the origin of organ damage caused by cystic fibrosis (CF) disease, we have analyzed the pattern of expression of the CF gene (CFTR). mRNA in situ hybridization analysis was carried out in human fetal, newborn, infant and adult tissues and the abundance of the mRNA was correlated with the known pathology at the various stages of human development. Analysis of the pattern of expression indicates a constitutive level of mRNA in gastrointestinal tissues starting during early development and maintained throughout life. Prenatal respiratory tissues show qualitative and quantitative major differences in comparison to postnatal lung samples. Male reproductive tissues show high levels of expression in the head of the epididymis compared with the rest of the male ducts. Female reproductive tissues show a variable pattern of expression at different stages during fetal development and during puberty probably due to changes in hormonal levels. Gastrointestinal and male reproductive tissues have a consistent pathology at birth, whereas no lung abnormalities have been described in newborns affected by CF. Our results show that there is no exact correlations between organ damage present at birth and the degree of CFTR expression. To explain these observations, we hypothesize that the pathogenesis of organ damage in CF depend on at least three factors: the rate of CFTR-mediated fluid secretion, differences in genotype and environmental factors, such as the amount of macromolecules in the lumen of the ducts. This last element predicts that damage will occur in tissues with high protein loads and low flow rates (e.g. pancreas, epididymis), where the absence of CFTR function leads to obstruction and pathology. Organs that express CFTR but with no significant damage (e.g. prenatal lung, female reproductive tissues), will have a low protein load and a high flow rates.

  14. Heritability of Lung Disease Severity in Cystic Fibrosis

    PubMed Central

    Vanscoy, Lori L.; Blackman, Scott M.; Collaco, Joseph M.; Bowers, Amanda; Lai, Teresa; Naughton, Kathleen; Algire, Marilyn; McWilliams, Rita; Beck, Suzanne; Hoover-Fong, Julie; Hamosh, Ada; Cutler, Dave; Cutting, Garry R.

    2007-01-01

    Rationale: Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the disease-causing gene, indicating that other factors determine severity of lung disease. Objectives: To quantify the contribution of modifier genes to variation in CF lung disease severity. Methods: Pulmonary function data from patients with CF living with their affected twin or sibling were converted into reference values based on both healthy and CF populations. The best measure of FEV1 within the last year was used for cross-sectional analysis. FEV1 measures collected over at least 4 years were used for longitudinal analysis. Genetic contribution to disease variation (i.e., heritability) was estimated in two ways: by comparing similarity of lung function in monozygous (MZ) twins (∼ 100% gene sharing) with that of dizygous (DZ) twins/siblings (∼ 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects. Measurements and Main Results: Forty-seven MZ twin pairs, 10 DZ twin pairs, and 231 sibling pairs (of a total of 526 patients) with CF were studied. Correlations for all measures of lung function for MZ twins (0.82–0.91, p < 0.0001) were higher than for DZ twins and siblings (0.50–0.64, p < 0.001). Heritability estimates from both methods were consistent for each measure of lung function and ranged from 0.54 to 1.0. Heritability estimates generally increased after adjustment for differences in nutritional status (measured as body mass index z-score). Conclusions: Our heritability estimates indicate substantial genetic control of variation in CF lung disease severity, independent of CFTR genotype. PMID:17332481

  15. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers.

    PubMed

    Cohn, Jonathan A; Neoptolemos, John P; Feng, Jinong; Yan, Jin; Jiang, Zefei; Greenhalf, William; McFaul, Christopher; Mountford, Roger; Sommer, Steve S

    2005-10-01

    Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF-causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF-causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF-causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR-related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk.

  16. Comparison of immunoreactive serum trypsinogen and lipase in Cystic Fibrosis

    SciTech Connect

    Lloyd-Still, J.D.; Weiss, S.; Wessel, H.; Fong, L.; Conway, J.J.

    1984-01-01

    The incidence of Cystic Fibrosis (CF) is 1 in 2,000. Early detection and treatment of CF may necessitate newborn screening with a reliable and cost-effective test. Serum immunoreactive trypsinogen (IRT) an enzyme produced by the pancreas, is detectable by radioimmunoassay (RIA) techniques. Recently, it has been shown that IRT is elevated in CF infants for the first few months of life and levels become subnormal as pancreatic insufficiency progresses. Other enzymes produced by the pancreas, such as lipase, are also elevated during this time. The author's earlier work confirmed previous reports of elevated IRT levels in CF infants. The development of a new RIA for lipase (nuclipase) has enabled comparison of these 2 pancreatic enzymes in C.F. Serum IRT and lipase determinations were performed on 2 groups of CF patients; infants under 1 year of age, and children between 1 and 18 years of age. Control populations of the same age groups were included. The results showed that both trypsin (161 +- 92 ng/ml, range 20 to 400) and lipase (167 +- 151 ng/ml, range 29 to 500) are elevated in CF in the majority of infants. Control infants had values of IRT ranging from 20 to 29.5 ng/ml and lipase values ranging from 23 to 34 ng/ml. IRT becomes subnormal in most CF patients by 8 years of age as pancreatic function insufficiency increases. Lipase levels and IRT levels correlate well in infancy, but IRT is a more sensitive indicator of pancreatic insufficiency in older patients with CF.

  17. Relative ion permeability of normal and cystic fibrosis nasal epithelium.

    PubMed Central

    Knowles, M; Gatzy, J; Boucher, R

    1983-01-01

    The raised transepithelial electric potential difference (PD) across respiratory epithelia in cystic fibrosis (CF) has suggested an abnormality in ion permeation. We characterized this abnormality further by measuring in the nasal epithelia of CF and normal subjects the concentration-PD relationship for amiloride, an inhibitor of cell Na+ permeability, and PD responses to superfusion with solutions of different composition. Amiloride was more efficacious in the CF subjects but the ED50 was not different from that of normals (approximately 2 X 10(-6) M). Na+ replacement by choline induced effects similar to those of amiloride, i.e. a greater depolarization in CF subjects. A 10-fold increase in the K+ concentration of the perfusate induced a small (less than 10 mV) depolarization in both subject populations. When Cl- in the perfusate was replaced by gluconate or SO2-(4) the nasal PD of normal subjects hyperpolarized (lumen became more negative) by approximately 35 mV. A significantly smaller response (less than 17 mV) was induced in CF homozygotes but not in heterozygotes (38 mV). The smaller response of CF subjects appears to reflect an absolute decrease in luminal surface Cl- permeability because pretreatment with amiloride did not increase the response to Cl- free solution (7 mV). Accordingly, three abnormalities (decreased Cl- permeability, raised PD, greater amiloride efficacy) have been identified in CF respiratory epithelia. Whereas "excessive" active Na+ transport can account for these abnormalities and the dessication of airway surface liquid, it is possible that a lower lumenal cell membrane Cl- permeability and inhibition of a potential path of Cl- secretion can also explain the observations. PMID:6853720

  18. Respiratory and peripheral muscle function in cystic fibrosis.

    PubMed

    Lands, L C; Heigenhauser, G J; Jones, N L

    1993-04-01

    Respiratory muscle strength (RMS) and endurance are often preserved in cystic fibrosis (CF) despite malnutrition, chronic airflow limitation, and hyperinflation. Inspiratory muscle function may be relatively preserved due to a selective "training stimulus" from chronic lung disease. Respiratory and peripheral muscle function were evaluated in 14 stable CF patients and 16 healthy control subjects. RMS was measured using static maximal pressures performed at FRC. Respiratory fatigue (RF) was assessed using 18 repeated static efforts (10 s on/5 s off) over 4.5 min. Peripheral function was evaluated by leg strength (LS) and leg fatigue (LF) measured during sprint efforts on an isokinetic cycle ergometer. Despite a lower weight (mean +/- SD, 94 +/- 9.6% ideal wt for CF patients versus 107 +/- 14.6% for controls) and elevated residual volume (RV)/TLC ratio (38 +/- 13.0 versus 22 +/- 5.3), the CF group maintained RMS (inspiratory 96 +/- 23.2 versus 114 +/- 33.2; expiratory 105 +/- 28.3 versus 123 +/- 40.9 cm H2O) but had decreased LS (590 +/- 201.7 versus 813 +/- 167.1 W). There were no differences between the groups with respect to RF or LF. For the control group, inspiratory and expiratory RMS correlated with LS (p < 0.01) and lean body mass (p < 0.01). For the CF group, while expiratory RMS (p < 0.05) and LS (p < 0.01) correlated with lean body mass and each other (p < 0.01), inspiratory RMS was independent of lean body mass and LS (p > 0.1). Female CF patients appeared to have a better preservation of inspiratory RMS than males with CF.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Draft Genome Sequences of Burkholderia contaminans, a Burkholderia cepacia Complex Species That Is Increasingly Recovered from Cystic Fibrosis Patients

    PubMed Central

    Bloodworth, Ruhi A. M.; Selin, Carrie; López De Volder, Maria Agustina; Drevinek, Pavel; Galanternik, Laura; Degrossi, José

    2015-01-01

    Burkholderia contaminans belongs to the Burkholderia cepacia complex (BCC), a group of bacteria that are ubiquitous in the environment and capable of infecting the immunocompromised and people with cystic fibrosis. We report here draft genome sequences for the B. contaminans type strain LMG 23361 and an Argentinian cystic fibrosis sputum isolate. PMID:26251482

  20. Draft Genome Sequences of Burkholderia contaminans, a Burkholderia cepacia Complex Species That Is Increasingly Recovered from Cystic Fibrosis Patients.

    PubMed

    Bloodworth, Ruhi A M; Selin, Carrie; López De Volder, Maria Agustina; Drevinek, Pavel; Galanternik, Laura; Degrossi, José; Cardona, Silvia T

    2015-08-06

    Burkholderia contaminans belongs to the Burkholderia cepacia complex (BCC), a group of bacteria that are ubiquitous in the environment and capable of infecting the immunocompromised and people with cystic fibrosis. We report here draft genome sequences for the B. contaminans type strain LMG 23361 and an Argentinian cystic fibrosis sputum isolate.

  1. Polymorphisms in the glutathione pathway modulate cystic fibrosis severity: a cross-sectional study

    PubMed Central

    2014-01-01

    Background Cystic fibrosis (CF) clinically manifests with various levels of severity, which are thought to be modulated by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), modifier genes, and the environment. This study verified whether polymorphisms in modifier genes associated with glutathione (GSH) metabolism influence CF severity. Methods A cross-sectional study of 180 CF patients was carried out from 2011 to 2012. We analyzed CFTR mutations, polymorphisms (GSTM1 and GSTT1 deletions, GSTP1 + 313A > G, GCLC-129C > T, and GCLC-3506A > G) in modifier genes and CF clinical severity as assessed by 28 clinical and laboratory variables. Results Significant associations were found between modifier gene polymorphisms and particular phenotypes or genotype changes. These included GCLC-129C > T with a higher frequency of the Pseudomonas aeruginosa mucoid to CC genotype (p = 0.044), and GCLC-3506A > G with a higher frequency of the no-mucoid P. aeruginosa (NMPA) to AA genotype (p = 0.012). The GSTT1 deletion was associated with a higher frequency of the NMPA to homozygous deletion (p = 0.008), GSTP1 + 313A > G with a minor risk of osteoporosis (p = 0.036), and patient age ≤ 154 months (p = 0.044) with the AA genotype. The Bhalla score was associated with GCLC-3506A > G (p = 0.044) and GSTM1/GSTT1 deletion polymorphisms (p = 0.02), while transcutaneous hemoglobin oxygen saturation levels were associated with GSTT1 deletions (p = 0.048). Conclusion CF severity is associated with polymorphisms in GSH pathways and CFTR mutations. PMID:24593045

  2. Limited premature termination codon suppression by read-through agents in cystic fibrosis intestinal organoids.

    PubMed

    Zomer-van Ommen, D D; Vijftigschild, L A W; Kruisselbrink, E; Vonk, A M; Dekkers, J F; Janssens, H M; de Winter-de Groot, K M; van der Ent, C K; Beekman, J M

    2016-03-01

    Premature termination codon read-through drugs offer opportunities for treatment of multiple rare genetic diseases including cystic fibrosis. We here analyzed the read-through efficacy of PTC124 and G418 using human cystic fibrosis intestinal organoids (E60X/4015delATTT, E60X/F508del, G542X/F508del, R1162X/F508del, W1282X/F508del and F508del/F508del). G418-mediated read-through induced only limited CFTR function, but functional restoration of CFTR by PTC124 could not be confirmed. These studies suggest that better read-through agents are needed for robust treatment of nonsense mutations in cystic fibrosis.

  3. Lumbar disc herniation in a child with cystic fibrosis: case report.

    PubMed

    Alexiou, George A; Stefanaki, Kalliopi; Sfakianos, George; Prodromou, Neofytos

    2014-04-01

    We report a case of child with cystic fibrosis and lumbar disc herniation. An 8-year-old boy presented with low back pain that exacerbated on coughing, sitting, walking, or bending and diminished when lying down. The straight leg raising test was positive when the right leg was lifted at 60 degrees. Crossed leg raising test was negative. Lumbar MRI revealed a L5-S1central disc protrusion. Conservative treatment was not effective and the patient underwent surgery. Postoperatively the patient experienced regression of the pain. To the best of our knowledge this is the first reported case of lumbar disc herniation in a child with cystic fibrosis. Although this case might be coincidental, thorough investigation of back pain, which is frequent in patients with cystic fibrosis, should be performed.

  4. Lung transplantation in patients with cystic fibrosis: special focus to infection and comorbidities.

    PubMed

    Dorgan, Daniel J; Hadjiliadis, Denis

    2014-06-01

    Despite advances in medical care, patients with cystic fibrosis still face limited life expectancy. The most common cause of death remains respiratory failure. End-stage cystic fibrosis can be treated with lung transplantation and is the third most common reason for which the procedure is performed. Outcomes for cystic fibrosis are better than most other lung diseases, but remain limited (5-year survival 60%). For patients with advanced disease lung transplantation appears to improve survival. Outcomes for patients with Burkholderia cepacia remain poor, although they are better for patients with certain genomovars. Controversy exists about Mycobacterium abscessus infection and appropriateness for transplant. More information is also becoming available for comorbidities, including diabetes and pulmonary hypertension among others. Extra-corporeal membrane oxygenation is used more frequently for end-stage disease as a bridge to lung transplantation and will likely be used more in the future.

  5. Intestinal permeability to (/sup 51/Cr)EDTA in children with cystic fibrosis

    SciTech Connect

    Leclercq-Foucart, J.; Forget, P.; Sodoyez-Goffaux, F.; Zappitelli, A.

    1986-05-01

    Intestinal permeability was investigated in 14 children with cystic fibrosis making use of (/sup 51/Cr)EDTA as probe molecule. Ten normal young adults and 11 children served as controls. After oral administration of (/sup 51/Cr)EDTA, 24 h urine was collected. Urinary radioactivity was calculated and results expressed as percentage of oral dose excreted in 24 h urine. Mean and SEM were as follows: 2.51 +/- 0.21, 2.35 +/- 0.24, and 13.19 +/- 1.72 for control children, normal adults, and cystic fibrosis patients, respectively. The permeability differences between cystic fibrosis patients and either control children or control adults are significant (p less than 0.001).

  6. Cystic fibrosis mice carrying the missense mutation G551D replicate human genotype-phenotype correlations.

    PubMed Central

    Delaney, S J; Alton, E W; Smith, S N; Lunn, D P; Farley, R; Lovelock, P K; Thomson, S A; Hume, D A; Lamb, D; Porteous, D J; Dorin, J R; Wainwright, B J

    1996-01-01

    We have generated a mouse carrying the human G551D mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR) by a one-step gene targeting procedure. These mutant mice show cystic fibrosis pathology but have a reduced risk of fatal intestinal blockage compared with 'null' mutants, in keeping with the reduced incidence of meconium ileus in G551D patients. The G551D mutant mice show greatly reduced CFTR-related chloride transport, displaying activity intermediate between that of cftr(mlUNC) replacement ('null') and cftr(mlHGU) insertional (residual activity) mutants and equivalent to approximately 4% of wild-type CFTR activity. The long-term survival of these animals should provide an excellent model with which to study cystic fibrosis, and they illustrate the value of mouse models carrying relevant mutations for examining genotype-phenotype correlations. Images PMID:8605891

  7. Front-Runners for pharmacotherapeutic correction of the airway ion transport defect in cystic fibrosis

    PubMed Central

    Clunes, Mark T.; Boucher, Richard C.

    2008-01-01

    Summary Although cystic fibrosis patients display multi organ dysfunction (e.g. pancreas, gut, lung) it is lung disease that is the leading cause of premature death in these patients. Cystic fibrosis lung disease is characterized by persistent pulmonary infection and mucus plugging of the airways initiated by failure of solute transport across the airway epithelium. Many drug therapies aim to alleviate the secondary characteristics of CF lung disease, however, new therapies in development are targeted at correcting the ion transport deficiency of CF. The goal is to hydrate airway surfaces by stimulating secretion (through activation of the cystic fibrosis transmembrane conductance regulator and calcium activated chloride channels), and/or inhibiting absorption (through the epithelial sodium channel) thereby stimulating healthy mucociliary clearance. If mucociliary clearance can be stimulated sufficiently from an early age then there is the possibility that secondary lung infection may be eradicated from the syndrome of CF disease. PMID:18468487

  8. Association of body mass index with disease severity and prognosis in patients with non-cystic fibrosis bronchiectasis.

    PubMed

    Qi, Q; Li, T; Li, J C; Li, Y

    2015-08-01

    The objective of this observational, multicenter study was to evaluate the association of body mass index (BMI) with disease severity and prognosis in patients with non-cystic fibrosis bronchiectasis. A total of 339 patients (197 females, 142 males) diagnosed with non-cystic fibrosis bronchiectasis by high-resolution computed tomography were classified into four groups: underweight (BMI<18.5 kg/m2), normal weight (18.5≤BMI<25.0 kg/m2), overweight (25.0≤BMI<30.0 kg/m2), and obese (BMI≥30.0 kg/m2). Clinical variables expressing disease severity were recorded, and acute exacerbations, hospitalizations, and survival rates were estimated during the follow-up period. The mean BMI was 21.90 kg/m2. The underweight group comprised 28.61% of all patients. BMI was negatively correlated with acute exacerbations, C-reactive protein, erythrocyte sedimentation rate, radiographic extent of bronchiectasis, and chronic colonization by P. aeruginosa and positively correlated with pulmonary function indices. BMI was a significant predictor of hospitalization risk independent of relevant covariates. The 1-, 2-, 3-, and 4-year cumulative survival rates were 94%, 86%, 81%, and 73%, respectively. Survival rates decreased with decreasing BMI (χ2=35.16, P<0.001). The arterial carbon dioxide partial pressure, inspiratory capacity, age, BMI, and predicted percentage of forced expiratory volume in 1 s independently predicted survival in the Cox proportional hazard model. In conclusion, an underweight status was highly prevalent among patients with non-cystic fibrosis bronchiectasis. Patients with a lower BMI were prone to developing more acute exacerbations, worse pulmonary function, amplified systemic inflammation, and chronic colonization by P. aeruginosa. BMI was a major determinant of hospitalization and death risks. BMI should be considered in the routine assessment of patients with non-cystic fibrosis bronchiectasis.

  9. [Autosomal-recessive renal cystic disease and congenital hepatic fibrosis: clinico-anatomic case].

    PubMed

    Rostol'tsev, K V; Burenkov, R A; Kuz'micheva, I A

    2012-01-01

    Clinico-anatomic observation of autosomal-recessive renal cystic disease and congenital hepatic fibrosis at two fetuses from the same family was done. Mutation of His3124Tyr in 58 exon of PKHD1 gene in heterozygous state was found out. The same pathomorphological changes in the epithelium of cystic renal tubules and bile ducts of the liver were noted. We suggest that the autopsy research of fetuses with congenital abnormalities, detected after prenatal ultrasonic screening, has high diagnostic importance.

  10. Modified Uncertainty Theory and Parents’ Perspectives about Equivocal Diagnostic Results for Cystic Fibrosis

    PubMed Central

    Tluczek, Audrey; McKechnie, Anne Chevalier; Lynam, Patrice A.

    2010-01-01

    A grounded, dimensional analysis described the experiences of five couples whose infants had equivocal diagnostic test results following positive genetic newborn screens for cystic fibrosis. We analyzed interview data collected at two times during each infant’s first year. Uncertainty emerged as the central thematic dimension. Results showed that parents passed through a series of stages similar to the process described by Mishel’s Uncertainty in Illness Theory (UIT), thus extending the application of the theory to circumstances in which the very presence of an illness is uncertain. Findings informed a modified version of the UIT comprised of five domains: stimuli frame, degree of uncertainty, opportunity-danger continuum, affective responses, and coping. This model incorporated Morse’s conception of suffering. Three contextual domains influenced parents’ experiences at various junctures along the uncertainty trajectory: individual characteristics, structure providers, and time. We discussed implications of the model for future research and clinical practice relative to genetic testing. PMID:20065305