Science.gov

Sample records for cystic fibrosis clinical

  1. Cystic Fibrosis

    MedlinePlus

    ... and Diseases > Lung Disease Lookup > Cystic Fibrosis Cystic Fibrosis Cystic Fibrosis (CF) is an inherited disease that ... quality of life has improved. Learn About Cystic Fibrosis Cystic fibrosis is a genetic (inherited) condition that ...

  2. 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.

  3. Clinical Significance of Microbial Infection and Adaptation in Cystic Fibrosis

    PubMed Central

    Hauser, Alan R.; Jain, Manu; Bar-Meir, Maskit; McColley, Susanna A.

    2011-01-01

    Summary: A select group of microorganisms inhabit the airways of individuals with cystic fibrosis. Once established within the pulmonary environment in these patients, many of these microbes adapt by altering aspects of their structure and physiology. Some of these microbes and adaptations are associated with more rapid deterioration in lung function and overall clinical status, whereas others appear to have little effect. Here we review current evidence supporting or refuting a role for the different microbes and their adaptations in contributing to poor clinical outcomes in cystic fibrosis. PMID:21233507

  4. 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- ...

  5. 75 FR 45646 - Design of Clinical Trials of Aerosolized Antimicrobials for the Treatment of Cystic Fibrosis...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-03

    ... the Treatment of Cystic Fibrosis; Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION... management and/or treatment of patients with cystic fibrosis. Aerosolized antimicrobials are used to treat... design of clinical trials of aerosolized antimicrobials in patients with cystic fibrosis. The input...

  6. Multidisciplinary care in cystic fibrosis: a clinical-nutrition review.

    PubMed

    Haack, A; Carvalho Garbi Novaes, M R

    2012-01-01

    The multidisciplinary care, at different referral centers of cystic fibrosis, is aimed at monitoring and treating cystic fibrosis patients. Mortality attributed to this hereditary disease is high, since it affects the exocrine glands, involving multiple organs, and evolves in a chronic, progressive way. However, systemized care and the improved, shared understanding of gastroenterologists, nutritionists and pulmonologists, contribute to prolonged survival and abated morbimortality. The aim of this study is to describe the main aspects of clinical and nutritional intervention in cystic fibrosis patients so that monitoring by a multidisciplinary team is optimized and performed as early as possible. The review was carried out on articles indexed in the Medline, Lilacs, SciELO, Current Contents and Cochrane databases, finding 189 articles in Portuguese, English and Spanish, with emphasis on articles published between 2000 and 2011. Due to the scientific relevant contribution, some publications before 2000 were included totalized 77 related to the multidisciplinary care. The reviewed studies suggest that multidisciplinary care is essential for knowledge integration in order to impose permanent update of scientific information, thereby contributing to the development of intervention strategies that enhance survival and motivate the development of skills to cope with the complex treatment regimen that is necessary for cystic fibrosis treatment and prevention of related complications.

  7. Multidisciplinary care in cystic fibrosis: a clinical-nutrition review.

    PubMed

    Haack, A; Carvalho Garbi Novaes, M R

    2012-01-01

    The multidisciplinary care, at different referral centers of cystic fibrosis, is aimed at monitoring and treating cystic fibrosis patients. Mortality attributed to this hereditary disease is high, since it affects the exocrine glands, involving multiple organs, and evolves in a chronic, progressive way. However, systemized care and the improved, shared understanding of gastroenterologists, nutritionists and pulmonologists, contribute to prolonged survival and abated morbimortality. The aim of this study is to describe the main aspects of clinical and nutritional intervention in cystic fibrosis patients so that monitoring by a multidisciplinary team is optimized and performed as early as possible. The review was carried out on articles indexed in the Medline, Lilacs, SciELO, Current Contents and Cochrane databases, finding 189 articles in Portuguese, English and Spanish, with emphasis on articles published between 2000 and 2011. Due to the scientific relevant contribution, some publications before 2000 were included totalized 77 related to the multidisciplinary care. The reviewed studies suggest that multidisciplinary care is essential for knowledge integration in order to impose permanent update of scientific information, thereby contributing to the development of intervention strategies that enhance survival and motivate the development of skills to cope with the complex treatment regimen that is necessary for cystic fibrosis treatment and prevention of related complications. PMID:22732957

  8. 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. The mucus clogs the lungs, causing breathing problems and ...

  9. 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.

  10. 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

  11. 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

  12. [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.

  13. [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. PMID:26895996

  14. 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.

  15. 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.

  16. What Causes Cystic Fibrosis?

    MedlinePlus

    ... What Causes Cystic Fibrosis? A defect in the CFTR gene causes cystic fibrosis (CF). This gene makes ... and very salty sweat. Research suggests that the CFTR protein also affects the body in other ways. ...

  17. Living with Cystic Fibrosis

    MedlinePlus

    ... from the NHLBI on Twitter. Living With Cystic Fibrosis If you or your child has cystic fibrosis (CF), you should learn as much as you ... about CF Care Centers, go to the Cystic Fibrosis Foundation's Care Center Network Web page. It's standard ...

  18. Learning about Cystic Fibrosis

    MedlinePlus

    ... order to digest food. Cystic Fibrosis: A Single Gene Disease Mutations in a single gene - the Cystic ... the defective gene, or correcting the defective protein. Gene Therapy Research Offers Promise of a Cure for ...

  19. How Is Cystic Fibrosis Diagnosed?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Cystic Fibrosis Diagnosed? Doctors diagnose cystic fibrosis (CF) based on ... to see whether the baby has CF. Cystic Fibrosis Carrier Testing People who have one normal CFTR ...

  20. 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…

  1. Cystic Fibrosis Therapeutics

    PubMed Central

    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. PMID:23276843

  2. 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.

  3. 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 ...

  4. Using Cystic Fibrosis Therapies for Non-Cystic Fibrosis Bronchiectasis.

    PubMed

    ElMaraachli, Wael; Conrad, Douglas J; Wang, Angela C C

    2016-03-01

    Non-cystic fibrosis bronchiectasis (NCFB) is an increasingly prevalent disease that places a significant burden on patients and health systems globally. Although many of the therapies used to treat NCFB were originally developed as cystic fibrosis (CF) therapies, not all of them have been demonstrated to be efficacious in NCFB and some may even be harmful. This article explores the evidence for which therapeutic strategies used to treat CF have been translated into the care of NCFB. The conclusion is that therapies for adult NCFB cannot be simply extrapolated from CF clinical trials, and in some instances, doing so may actually result in harm.

  5. Cystic fibrosis from the gastroenterologist's perspective.

    PubMed

    Ooi, Chee Y; Durie, Peter R

    2016-03-01

    Cystic fibrosis is a life-limiting, recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Increased survival outcomes and the multisystem nature of the disease, including the involvement of hepatobiliary and gastrointestinal tracts, now require the need for more extensive knowledge and expertise in cystic fibrosis among gastroenterologists. Manifestations are either a direct consequence of the primary defect in cystic fibrosis or a secondary complication of the disease or therapy. Adult patients with cystic fibrosis also have an increased risk of malignancy in the gastrointestinal and pancreatico-biliary tracts compared with the general population. Novel treatments that target the basic defects in the CFTR protein have emerged, but to date not much is known about their effects on the gastrointestinal and hepatobiliary systems. The introduction of such therapies has provided new opportunities for the application of intestinal endpoints in clinical trials and the understanding of underlying disease mechanisms that affect the gut in cystic fibrosis.

  6. 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

  7. 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

  8. 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

  9. Clinical impact of Achromobacter xylosoxidans colonization/infection in patients with cystic fibrosis.

    PubMed

    Firmida, M C; Pereira, R H V; Silva, E A S R; Marques, E A; Lopes, A J

    2016-01-01

    The rate of diagnosis of colonization/infection of the airways with Achromobacter xylosoxidans has increased in cystic fibrosis patients, but its clinical significance is still controversial. This retrospective, case-control study aimed to evaluate the clinical impact of A. xylosoxidans colonization/infection in cystic fibrosis patients. Individuals who were chronically colonized/infected (n=10), intermittently colonized/infected (n=15), and never colonized/infected with A. xylosoxidans (n=18) were retrospectively evaluated during two periods that were 2 years apart. Demographic characteristics, clinical data, lung function, and chronic bacterial co-colonization data were evaluated. Of the total study population, 87% were pediatric patients and 65.1% were female. Individuals chronically colonized/infected with A. xylosoxidans had decreased forced expiratory volume in 1 s (51.7% in the chronic colonization/infection group vs 82.7% in the intermittent colonization/infection group vs 76% in the never colonized/infected group). Compared with the other two groups, the rate of co-colonization with methicillin-resistant Staphylococcus aureus was higher in individuals chronically colonized/infected with A. xylosoxidans (P=0.002). Changes in lung function over 2 years in the three groups were not significant, although a trend toward a greater decrease in lung function was observed in the chronically colonized/infected group. Compared with the other two groups, there was a greater number of annual hospitalizations in patients chronically colonized/infected with A. xylosoxidans (P=0.033). In cystic fibrosis patients, there was an increased frequency of A. xylosoxidans colonization/infection in children, and lung function was reduced in patients who were chronically colonized/infected with A. xylosoxidans. Additionally, there were no differences in clinical outcomes during the 2-year period, except for an increased number of hospitalizations in patients with A. xylosoxidans.

  10. Clinical impact of Achromobacter xylosoxidans colonization/infection in patients with cystic fibrosis

    PubMed Central

    Firmida, M.C.; Pereira, R.H.V.; Silva, E.A.S.R.; Marques, E.A.; Lopes, A.J.

    2016-01-01

    The rate of diagnosis of colonization/infection of the airways with Achromobacter xylosoxidans has increased in cystic fibrosis patients, but its clinical significance is still controversial. This retrospective, case-control study aimed to evaluate the clinical impact of A. xylosoxidans colonization/infection in cystic fibrosis patients. Individuals who were chronically colonized/infected (n=10), intermittently colonized/infected (n=15), and never colonized/infected with A. xylosoxidans (n=18) were retrospectively evaluated during two periods that were 2 years apart. Demographic characteristics, clinical data, lung function, and chronic bacterial co-colonization data were evaluated. Of the total study population, 87% were pediatric patients and 65.1% were female. Individuals chronically colonized/infected with A. xylosoxidans had decreased forced expiratory volume in 1 s (51.7% in the chronic colonization/infection group vs 82.7% in the intermittent colonization/infection group vs 76% in the never colonized/infected group). Compared with the other two groups, the rate of co-colonization with methicillin-resistant Staphylococcus aureus was higher in individuals chronically colonized/infected with A. xylosoxidans (P=0.002). Changes in lung function over 2 years in the three groups were not significant, although a trend toward a greater decrease in lung function was observed in the chronically colonized/infected group. Compared with the other two groups, there was a greater number of annual hospitalizations in patients chronically colonized/infected with A. xylosoxidans (P=0.033). In cystic fibrosis patients, there was an increased frequency of A. xylosoxidans colonization/infection in children, and lung function was reduced in patients who were chronically colonized/infected with A. xylosoxidans. Additionally, there were no differences in clinical outcomes during the 2-year period, except for an increased number of hospitalizations in patients with A. xylosoxidans

  11. 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

  12. 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.

  13. 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. PMID:27578468

  14. 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.

  15. 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. PMID:25929952

  16. 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.

  17. IL8 gene as modifier of cystic fibrosis: unraveling the factors which influence clinical variability.

    PubMed

    Furlan, Larissa Lazzarini; Marson, Fernando Augusto Lima; Ribeiro, José Dirceu; Bertuzzo, Carmen Sílvia; Salomão Junior, João Batista; Souza, Dorotéia Rossi Silva

    2016-08-01

    The severity of cystic fibrosis (CF) is associated with classes of mutations in the CFTR gene (cystic fibrosis transmembrane regulator), physical environment and modifier genes interaction. The IL8 gene (interleukin 8), according to its respective polymorphisms, influences inflammatory responses. This study analyzed IL8 gene polymorphisms (rs4073, rs2227306 and rs2227307), by means of PCR/RFLP, and their association with pulmonary function markers and clinical severity scores in 186 patients with CF, considering the CFTR genotype. There was an association between rs2227307 and precocity of the disease. The severity of lung disease was associated with the following markers: transcutaneous arterial hemoglobin oxygen saturation (SaO2) (regardless of CFTR genotype, for the polymorphisms rs4073, rs2227306 and rs2227307); mucoid Pseudomonas aeruginosa (regardless of CFTR genotype, for the polymorphisms rs2227306 and rs2227307). Pulmonary function markers (SaO2 and spirometric variables) and clinical severity scores were also associated with IL8 gene polymorphisms. This study identified the IL8 gene, represented by rs4073 and rs2227306 polymorphisms, and particularly the rs2227307 polymorphism, as potentiating factors for the degree of variability in the severity of CF, especially in pulmonary clinical manifestation correlated with increased morbidity and mortality. PMID:27209008

  18. Non-cystic fibrosis bronchiectasis.

    PubMed

    McShane, Pamela J; Naureckas, Edward T; Tino, Gregory; Strek, Mary E

    2013-09-15

    There is renewed interest in non-cystic fibrosis bronchiectasis, which is a cause of significant morbidity in adults and can be diagnosed by high-resolution chest computed tomography scan. No longer mainly a complication after pulmonary infection with Mycobacterium tuberculosis, diverse disease processes and mechanisms have been demonstrated to result in the chronic cough, purulent sputum production, and airway dilation that characterize this disease. Improved understanding of the role of mucus stasis in causing bacterial colonization has led to increased emphasis on the use of therapies that enhance airway clearance. Inhalational antibiotics reduce the bacterial burden associated with a worse outcome. Low-dose, chronic macrolide therapy has been shown to decrease exacerbation frequency and airway inflammation. For the first time, a number of therapies for non-cystic fibrosis bronchiectasis are undergoing testing in clinical research trials designed specifically for this population. This concise clinical review focuses on the major etiologies, diagnostic testing, microbiology, and management of patients with adult non-cystic fibrosis bronchiectasis. Systematic evaluation identifies a specific cause in the majority of patients and may affect subsequent treatment. We outline current therapies and review the data that support their use. PMID:23898922

  19. 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.

  20. Clinical Insights into Pulmonary Exacerbations in Cystic Fibrosis from the Microbiome. What Are We Missing?

    PubMed

    Whelan, Fiona J; Surette, Michael G

    2015-11-01

    Pulmonary exacerbations account for much of the decrease in lung function and consequently most of the morbidity and mortality in patients with cystic fibrosis. These events are driven by an acute inflammatory response to infection. Recent technological advancements in molecular profiling techniques have allowed for a proliferation of microbiome studies of the lower airways of patients with cystic fibrosis. But these methods may not provide a comprehensive and unbiased measure of the lung microbiota in these patients and molecular profiles do not always translate to quantitative microbiology. Furthermore, these studies have not yet been able to provide much in the way of mechanistic insights into exacerbations or to guide patient therapy. We propose a model in which pulmonary exacerbations may be driven by an active subpopulation of the lung microbiota, which may represent only a small portion of the microbiota measured in a clinical sample. Methodology should be focused on the ultimate goal, which is to use the best available approaches to provide accurate quantitative measures of the microbiome to inform clinical decisions and provide rapid assessment of treatment efficacy. These strategies would be relevant to other chronic lung diseases such as chronic obstructive pulmonary disease and neutrophilic asthma.

  1. Clinical significance, antimicrobial susceptibility and molecular identification of Nocardia species isolated from children with cystic fibrosis.

    PubMed

    Betrán, Ana; Villuendas, M Cruz; Rezusta, Antonio; Pereira, Javier; Revillo, M José; Rodríguez-Nava, Verónica

    2016-01-01

    Nocardia is an opportunistic pathogen that causes respiratory infections in immunocompromised patients. The aim of this study was to analyze the epidemiology, clinical significance and antimicrobial susceptibility of Nocardia species isolated from eight children with cystic fibrosis. The isolated species were identified as Nocardia farcinica, Nocardia transvalensis, Nocardia pneumoniae, Nocardia veterana and Nocardia wallacei. N. farcinica was isolated in three patients and all of them presented lung affectation with a chronic colonization and pneumonia. N. farcinica showed resistance against gentamicin, tobramycin, cefotaxime, but was susceptible to trimethoprim-sulfamethoxazole and amikacin. N. transvalensis, which was isolated from two patients, showed an association with chronic colonization. N. transvalensis was resistant to tobramycin and amikacin, but susceptible to ciprofloxacin, trimethoprim-sulfamethoxazole and cefotaxime. N. veterana, N. pneumoniae and N. wallacei were isolated from three different patients and appeared in transitory lung colonization. N. veterana and N. pneumoniae were susceptible to imipenem, trimethoprim-sulfamethoxazole, amikacin, tobramycin, and cefotaxime. N. wallacei was resistant to amikacin, tobramycin, imipenem, and trimethoprim-sulfamethoxazole and susceptible to ciprofloxacin and cefotaxime. All the isolates were identified up to species level by 16S rRNA gene sequencing. The presence of Nocardia in the sputum of patients with cystic fibrosis is not always an indication of an active infection; therefore, the need for a treatment should be evaluated on an individual basis. The detection of multidrug-resistant species needs molecular identification and susceptibility testing, and should be performed for all Nocardia infections. PMID:27155949

  2. Clinical significance, antimicrobial susceptibility and molecular identification of Nocardia species isolated from children with cystic fibrosis.

    PubMed

    Betrán, Ana; Villuendas, M Cruz; Rezusta, Antonio; Pereira, Javier; Revillo, M José; Rodríguez-Nava, Verónica

    2016-01-01

    Nocardia is an opportunistic pathogen that causes respiratory infections in immunocompromised patients. The aim of this study was to analyze the epidemiology, clinical significance and antimicrobial susceptibility of Nocardia species isolated from eight children with cystic fibrosis. The isolated species were identified as Nocardia farcinica, Nocardia transvalensis, Nocardia pneumoniae, Nocardia veterana and Nocardia wallacei. N. farcinica was isolated in three patients and all of them presented lung affectation with a chronic colonization and pneumonia. N. farcinica showed resistance against gentamicin, tobramycin, cefotaxime, but was susceptible to trimethoprim-sulfamethoxazole and amikacin. N. transvalensis, which was isolated from two patients, showed an association with chronic colonization. N. transvalensis was resistant to tobramycin and amikacin, but susceptible to ciprofloxacin, trimethoprim-sulfamethoxazole and cefotaxime. N. veterana, N. pneumoniae and N. wallacei were isolated from three different patients and appeared in transitory lung colonization. N. veterana and N. pneumoniae were susceptible to imipenem, trimethoprim-sulfamethoxazole, amikacin, tobramycin, and cefotaxime. N. wallacei was resistant to amikacin, tobramycin, imipenem, and trimethoprim-sulfamethoxazole and susceptible to ciprofloxacin and cefotaxime. All the isolates were identified up to species level by 16S rRNA gene sequencing. The presence of Nocardia in the sputum of patients with cystic fibrosis is not always an indication of an active infection; therefore, the need for a treatment should be evaluated on an individual basis. The detection of multidrug-resistant species needs molecular identification and susceptibility testing, and should be performed for all Nocardia infections.

  3. 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

  4. 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.

  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. PMID:25692532

  6. 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.

  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. Genetics Home Reference: cystic fibrosis

    MedlinePlus

    ... protects the linings of the airways, digestive system, reproductive system, and other organs and tissues. In people with ... experience health problems affecting the respiratory, digestive, and reproductive systems. Most men with cystic fibrosis have congenital bilateral ...

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

    PubMed

    Edmondson, Claire; Davies, Jane C

    2016-05-01

    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. 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

  12. Thinking lean: implementing DMAIC methods to improve efficiency within a cystic fibrosis clinic.

    PubMed

    Smith, Chad; Wood, Suzanne; Beauvais, Bradley

    2011-01-01

    The timely coordination of care in clinics that require frequent assessments by multiple specialists can be challenging for both patients and providers. The cornerstone of care at cystic fibrosis (CF) centers with superior clinical outcomes, as with reduced acuity of episodic disease and incidence of hospitalizations, is frequent clinical encounters coupled with aggressive therapies. However, inefficiencies in the clinical practice structure prevent optimal utilization of resources. To decrease non-value-added time, defined as time a patient spends alone in an examination room, without altering the time providers spend caring for a patient, the application of Lean methods was used to see whether reducing variation could significantly decrease lead time, considered the length of a patient visit, within a CF clinic setting. Baseline capability analyses revealed only 19.3% of patient visits were completed in 60min or less, with mean and median visit times of 84 and 81min, respectively. Final capability analyses demonstrated that 41.5% of patient visits were completed in 60min or less, 23% greater than the baseline capability. Mean and median visit times decreased by 10min per visit. Research efforts increased the available capacity by 500 patient visits per year, representing additional revenue of over US$165,000 annually with no additional administrative costs incurred. PMID:21385279

  13. Clinical Insights from Metagenomic Analysis of Sputum Samples from Patients with Cystic Fibrosis

    PubMed Central

    Evangelista, Jose S.; Schmieder, Robert; Bailey, Barbara; Haynes, Matthew; Furlan, Mike; Maughan, Heather; Edwards, Robert; Rohwer, Forest; Conrad, Douglas

    2014-01-01

    As DNA sequencing becomes faster and cheaper, genomics-based approaches are being explored for their use in personalized diagnoses and treatments. Here, we provide a proof of principle for disease monitoring using personal metagenomic sequencing and traditional clinical microbiology by focusing on three adults with cystic fibrosis (CF). The CF lung is a dynamic environment that hosts a complex ecosystem composed of bacteria, viruses, and fungi that can vary in space and time. Not surprisingly, the microbiome data from the induced sputum samples we collected revealed a significant amount of species diversity not seen in routine clinical laboratory cultures. The relative abundances of several species changed as clinical treatment was altered, enabling the identification of the climax and attack communities that were proposed in an earlier work. All patient microbiomes encoded a diversity of mechanisms to resist antibiotics, consistent with the characteristics of multidrug-resistant microbial communities that are commonly observed in CF patients. The metabolic potentials of these communities differed by the health status and recovery route of each patient. Thus, this pilot study provides an example of how metagenomic data might be used with clinical assessments for the development of treatments tailored to individual patients. PMID:24478471

  14. 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

  15. 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

  16. 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. PMID:6774070

  17. 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.

  18. RISK OF HEMOPTYSIS IN CYSTIC FIBROSIS CLINICAL TRIALS: A RETROSPECTIVE COHORT STUDY

    PubMed Central

    Mayer-Hamblett, N.; Kloster, M.; Bilton, D.; Flume, P. A.

    2015-01-01

    Background Cystic fibrosis (CF) is characterized by airways infection and inflammation resulting in respiratory complications including hemoptysis. The objectives of this study were to characterize risk of hemoptysis attributable to the underlying disease and in the presence of standard of care therapy. Methods This retrospective cohort study estimated hemoptysis rates overall and by relevant risk factors utilizing adverse event data from longitudinal prospective CF clinical trials. Results Of the 1008 participants, 73% were ≤18 years old; of 929 with available spirometry, 27% had an FEV1 < 70% predicted. During the average 8.2 months of follow-up, 8% experienced ≥1 hemoptysis events (95% CI: 6%, 10%). Of the 125 events, 76% were mild in severity and only 9% were serious. Hemoptysis rates were greater among adults than children, those with FEV1 < 70% predicted, and participants infected with P. aeruginosa but not with S. aureus. Conclusions Hemoptysis is a common adverse event among CF clinical trial participants, and particularly in adults with more severe lung disease. These results can be used to predict event occurrence in future clinical trials. PMID:25725985

  19. 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.

  20. Mucolytics in cystic fibrosis.

    PubMed

    Henke, Markus O; Ratjen, Felix

    2007-03-01

    Mucus accumulation in the lower airways is a key feature of cystic fibrosis (CF) lung disease. The major component of mucus in CF is not mucin derived from mucus producing cells but rather pus that includes viscous material such as polymerized DNA derived from degraded neutrophils. This has important implications for mucolytic therapy aiming to improve mucus clearance from the airways, since degradation of mucin may not be a suitable treatment strategy. In addition, thinning of secretions may not always be beneficial, since it may negatively affect certain aspects of mucus transport such as cough clearance. While inhaled N-acetylcysteine has been used as a mucolytic drug in CF for decades, there is little evidence that it has any beneficial effect. Dornase alfa has been shown to reduce pulmonary exacerbations and improve lung function and is currently the only mucolytic agent with proven efficacy in CF. Newer agents targeting other components of CF mucus, such as filamentous actin, are currently in development. Ultimately, drugs that are mucokinetic, which preserve viscoelasticity, rather than mucolytic may prove to be beneficial for CF lung disease in the future. PMID:17419975

  1. Cystic Fibrosis Sinusitis.

    PubMed

    Le, Christopher; McCrary, Hilary C; Chang, Eugene

    2016-01-01

    Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF transmembrane conductance regulator gene(CFTR) resulting in impaired ion transport. Nearly all people with CF will develop chronic rhino-sinusitis (CRS) and present with the characteristic viscous mucus, impaired mucociliary clearance and chronic inflammation/infection of the sinonasal cavity. While some individuals with CF can appear relatively asymptomatic in terms of their sinus disease, commonly reported symptoms include anosmia, headache, facial pain, nasal obstruction, chronic congestion and nasal discharge. Nasal endoscopy typically reveals mucosal edema, purulent discharge and nasal polyposis. Computed tomography (CT) imaging classically demonstrates the distinguishing findings of sinus hypoplasia or aplasia with generalized opacification, medial bulging of the lateral sinonasal sidewall and a demineralized uncinate process. Current treatment for CF sinusitis includes the use of hypertonic saline, topical and systemic steroids, antibiotics and endoscopic surgery. Research investigating novel therapies designed at targeting the primary defect of CF is showing promise for reversal of CF sinus disease, in addition to potential for disease prevention. PMID:27466844

  2. 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

  3. 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. PMID:26903594

  4. Clinical and Genetic Features in Patients with Cystic Fibrosis in Southwestern Iran

    PubMed Central

    Farjadian, Shirin; Moghtaderi, Mozhgan; Kashef, Sara; Alyasin, Soheila; Najib, Khadijehsadat; Saki, Forough

    2013-01-01

    Objective Cystic fibrosis (CF) is a common autosomal recessive genetic disease caused by a mutation in the CF transmembrane conductance regulatory (CFTR) gene. This study attempted to identify the most common CFTR mutations and any correlations between certain mutations and the clinical presentation of the disease in CF patients in southwestern Iran. Methods Twenty nine common CFTR gene mutations were examined in 45 CF patients. Findings Chronic cough, intestinal obstruction, dehydration, heat exhaustion and steatorrhea were the most common early clinical symptoms among our patients. The most common mutation was ΔF508, with an allele frequency of 21%. The homozygous ΔF508 mutation was observed in eight patients (18%), and three patients (7%) were ΔF508 carriers. The 2183AA > G mutation was observed in four patients, one of whom was also a ΔF508 carrier. The R1162X mutation was detected in two patients. The G542X, R334W and N1303K mutations were detected each in one patient, the first of whom was also a ΔF508 carrier. Conclusion Out of 45 patients, 27 (60%) had none of the CFTR gene mutations we tested for. The most frequent mutations in southwestern Iranian patients with CF should be identified by sequencing the entire CFTR gene in order to optimize the design of a diagnostic kit for common regional mutations. PMID:23724185

  5. 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.

  6. 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

  7. 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.

  8. Smell in cystic fibrosis.

    PubMed

    Lindig, J; Steger, C; Beiersdorf, N; Michl, R; Beck, J F; Hummel, T; Mainz, J G

    2013-03-01

    In cystic fibrosis (CF), the most frequent life threatening inherited disease in Caucasians, sinonasal mucosa is regularly affected by defective mucociliary clearance. This facilitates pathogen colonization into CF airways and causes frequent symptoms of rhinosinusitis, including an impaired sense of smell. Despite probable effects on nutrition and overall health, CF-rhinosinusitis is little understood: CF-associated smelling deficiencies reported in literature vary between 12 and 71 %. The aim of this study was to assess olfactory and gustatory function in relation to sinonasal symptoms and sinonasal colonization, and lung function and nutrition. Thirty-five CF patients of different ages were compared to 35 age-matched healthy controls. Olfactory function was assessed by 'Sniffin'Sticks', gustatory qualities by "Taste-strips", and symptoms by sino-nasal outcome test 20 (SNOT-20). Normosmia was found in 62.8 % of healthy controls but only in 28.6 % of CF patients. In contrast the majority of CF patients exhibited a smell loss; almost 62.9 % of them were hyposmic, and 8.6 % functionally anosmic. Importantly, reduced olfactory function only affected odor thresholds, which were significantly increased in CF, not odor identification. This suggests that the olfactory dysfunction in CF results from the olfactory periphery due to either problems in conduction and/or a functional lesion due to the inflammatory process. SNOT-20 scores increased continuously from normosmic to hyposmic and anosmic CF patients (means 7.2/11.1/28.3 points). Neither sinonasal pathogen colonization, gender, pulmonary function, nor allergy or sinonasal surgery appeared to have significant effects on olfactory function and taste. Olfactory disorders are considerably more frequent in CF patients than in age-matched healthy controls. Assessing these parameters within CF-routine care should be considered because of their importance to nutrition and, thus, overall therapy outcome.

  9. [Indoor fungal exposure: What impact on clinical and biological status regarding Aspergillus during cystic fibrosis].

    PubMed

    Pricope, D; Deneuville, E; Frain, S; Chevrier, S; Belaz, S; Roussey, M; Gangneux, J-P

    2015-06-01

    The sources of exposure during diseases due to Aspergillus fungi in cystic fibrosis patients are still poorly explored. We assessed home fungal exposure in patients suffering from cystic fibrosis and analysed its impact on the presence of Aspergillus biological markers, the colonisation of airways, as well as the sensitization and Aspergillus serology. Between March 2012 and August 2012, 34 patients benefited from a visit performed by a home environment medical adviser including sampling for mycological analysis. The number of colonies of Aspergillus was not significantly different in the various sampling sites (P=0.251), but the number of non-Aspergillus colonies was much higher in the kitchen (P=0.0045). Subsequently, home fungal exposure was compared between the groups "absence of Aspergillus-related markers" and "presence of Aspergillus-related markers". Home exposure to Aspergillus (P=0.453) and non-Aspergillus (P=0.972) flora was not significant between the 2 groups. Within this series of 34 patients that should be expanded, we note an absence of clear relationship between home exposure and the Aspergillus-linked markers in patients suffering from cystic fibrosis. This result should be taken into account regarding too restrictive hygiene advices provided to families, given the fact that fungal exposure can also results from activities performed away from home.

  10. 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.

  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. PMID:27086904

  12. Complement Effectors of Inflammation in Cystic Fibrosis Lung Fluid Correlate with Clinical Measures of Disease

    PubMed Central

    Sass, Laura A.; Hair, Pamela S.; Perkins, Amy M.; Shah, Tushar A.; Krishna, Neel K.; Cunnion, Kenji M.

    2015-01-01

    In cystic fibrosis (CF), lung damage is mediated by a cycle of obstruction, infection, and inflammation. Here we explored complement inflammatory effectors in CF lung fluid. In this study soluble fractions (sols) from sputum samples of 15 CF patients were assayed for complement effectors and analyzed with clinical measurements. The pro-inflammatory peptide C5a was increased 4.8-fold (P = 0.04) in CF sols compared with controls. Incubation of CF sols with P. aeruginosa or S. aureus increased C5a concentration 2.3-fold (P = 0.02). A peptide inhibitor of complement C1 (PIC1) completely blocked the increase in C5a concentration from P. aeruginosa in CF sol in vitro (P = 0.001). C5a concentration in CF sol correlated inversely with body mass index (BMI) percentile in children (r = -0.77, P = 0.04). C3a, which has anti-inflammatory effects, correlated positively with FEV1% predicted (rs = 0.63, P = 0.02). These results suggest that complement effectors may significantly impact inflammation in CF lung fluid. PMID:26642048

  13. 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

  14. [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.

  15. [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. PMID:26070393

  16. 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

  17. 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.

  18. Rectal forceps biopsy procedure in cystic fibrosis: technical aspects and patients perspective for clinical trials feasibility

    PubMed Central

    2013-01-01

    Background Measurements of CFTR function in rectal biopsies ex vivo have been used for diagnosis and prognosis of Cystic Fibrosis (CF) disease. Here, we aimed to evaluate this procedure regarding: i) viability of the rectal specimens obtained by biopsy forceps for ex vivo bioelectrical and biochemical laboratory analyses; and ii) overall assessment (comfort, invasiveness, pain, sedation requirement, etc.) of the rectal forceps biopsy procedure from the patients perspective to assess its feasibility as an outcome measure in clinical trials. Methods We compared three bowel preparation solutions (NaCl 0.9%, glycerol 12%, mannitol), and two biopsy forceps (standard and jumbo) in 580 rectal specimens from 132 individuals (CF and non-CF). Assessment of the overall rectal biopsy procedure (obtained by biopsy forceps) by patients was carried out by telephone surveys to 75 individuals who underwent the sigmoidoscopy procedure. Results Integrity and friability of the tissue specimens correlate with their transepithelial resistance (r = −0.438 and −0.305, respectively) and are influenced by the bowel preparation solution and biopsy forceps used, being NaCl and jumbo forceps the most compatible methods with the electrophysiological analysis. The great majority of the individuals (76%) did not report major discomfort due to the short procedure time (max 15 min) and considered it relatively painless (79%). Importantly, most (88%) accept repeating it at least for one more time and 53% for more than 4 times. Conclusions Obtaining rectal biopsies with a flexible endoscope and jumbo forceps after bowel preparation with NaCl solution is a safe procedure that can be adopted for both adults and children of any age, yielding viable specimens for CFTR bioelectrical/biochemical analyses. The procedure is well tolerated by patients, demonstrating its feasibility as an outcome measure in clinical trials. PMID:23688510

  19. [Therapeutic update in cystic fibrosis].

    PubMed

    Durupt, S; Nove Josserand, R; Durieu, I

    2014-06-01

    We present the recent therapeutic advances in the cystic fibrosis care. It concerns improvements in symptomatic treatment with the development of dry powder inhaled antibiotics that improved quality of life, and innovative treatments namely the modulators of the cystic fibrosis transmembrane protein conductance regulator (CFTR), molecules which act specifically at the level of the defective mechanisms implied in the disease. The life expectancy of cystic fibrosis patients born after 2000, is estimated now to be about 50 years. This improvement of survival was obtained with the organization of the care within the specialized centers for cystic fibrosis (Centre de ressource et de compétences de la mucoviscidose) and remains still based on heavy symptomatic treatments. Dry powder inhaled antibiotics constitute a significant time saving for patients to whom all the care can achieve two hours daily. Since 2012, the modulators of CFTR, molecules allowing a pharmacological approach targeted according to the type of the mutations, allows a more specific approach of the disease. Ivacaftor (Kalydeco(®)) which potentialises the function of the CFTR protein expressed on the cellular surface is now available for patients with the G551D mutation. Lumacaftor is going to be tested in association with ivacaftor in patients with the F508del mutation, that is present in at least 75% of the patients. The ataluren which allows the production of a functional protein CFTR in patients with a no sense mutation is the third representing of this new therapeutic class. We presently have numerous symptomatic treatments for the cystic fibrosis care. The development of CFTR modulators, today available to a restricted number of patients treated with ivacaftor represents a very promising therapeutic avenue. It will represent probably the first step to a personalized treatment according to CFTR genotype.

  20. A cystic fibrosis handbook for teachers.

    PubMed

    Ryan, L L; Williams, J K

    1996-01-01

    The purposes of this project were to (1) develop a handbook on cystic fibrosis for elementary school teachers and to (2) pilot this handbook with a group of teachers and school nurses. The project used a descriptive survey design in which parents, teachers, and school nurses of 14 elementary-age children with cystic fibrosis were recruited from one cystic fibrosis clinic. Interest in using the handbook with their child's teachers was elicited from parents; also, interest in using the handbook was obtained by open-ended questions in a mailed survey sent to teachers and school nurses. Levels of teacher and school nurse knowledge were measured with a true/false pretest and posttest instrument. All parents expressed a desire to use the handbook with their child's teachers. Sixty-seven percent of the teachers and 89% of the school nurses returned the survey, and all endorsed the use of the handbook in their classrooms or schools. Comparison of the pretest and posttest scores from the teachers revealed an increase in teachers' knowledge. Scores on pretest and posttest measures from school nurses were high at each testing time. Results support the use of a printed handbook to promote knowledge of cystic fibrosis in teachers and to support communication among nurses, parents, and teachers.

  1. 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. PMID:17724542

  2. The Impact on Genetic Testing of Mutational Patterns of CFTR Gene in Different Clinical Macrocategories of Cystic Fibrosis.

    PubMed

    Lucarelli, Marco; Bruno, Sabina M; Pierandrei, Silvia; Ferraguti, Giampiero; Testino, Giancarlo; Truglio, Gessica; Strom, Roberto; Quattrucci, Serena

    2016-07-01

    More than 2000 sequence variations of the cystic fibrosis transmembrane conductance regulator gene are known. The marked genetic heterogeneity, poor functional characterization of the vast majority of sequence variations, and an uncertain genotype-phenotype relationship complicate the definition of mutational search strategies. We studied the effect of the marked genetic heterogeneity detected in a case series comprising 610 patients of cystic fibrosis (CF), grouped in different clinical macrocategories, on the operative characteristics of the genetic test designed to fully characterize CF patients. The detection rate in each clinical macrocategory and at each mutational step was found to be influenced by genetic heterogeneity. The definition of a single mutational panel that is suitable for all clinical macrocategories proved impossible. Only for classic CF with pancreas insufficiency did a reduced number of mutations yield a detection rate of diagnostic value. All other clinical macrocategories required an extensive genetic search. The search for specific mutational classes appears to be useful only in specific CF clinical forms. A flowchart defining a mutational search that may be adopted for different CF clinical forms, optimized in respect to those already available, is proposed. The findings also have consequences for carrier screening strategies. PMID:27157324

  3. The Impact on Genetic Testing of Mutational Patterns of CFTR Gene in Different Clinical Macrocategories of Cystic Fibrosis.

    PubMed

    Lucarelli, Marco; Bruno, Sabina M; Pierandrei, Silvia; Ferraguti, Giampiero; Testino, Giancarlo; Truglio, Gessica; Strom, Roberto; Quattrucci, Serena

    2016-07-01

    More than 2000 sequence variations of the cystic fibrosis transmembrane conductance regulator gene are known. The marked genetic heterogeneity, poor functional characterization of the vast majority of sequence variations, and an uncertain genotype-phenotype relationship complicate the definition of mutational search strategies. We studied the effect of the marked genetic heterogeneity detected in a case series comprising 610 patients of cystic fibrosis (CF), grouped in different clinical macrocategories, on the operative characteristics of the genetic test designed to fully characterize CF patients. The detection rate in each clinical macrocategory and at each mutational step was found to be influenced by genetic heterogeneity. The definition of a single mutational panel that is suitable for all clinical macrocategories proved impossible. Only for classic CF with pancreas insufficiency did a reduced number of mutations yield a detection rate of diagnostic value. All other clinical macrocategories required an extensive genetic search. The search for specific mutational classes appears to be useful only in specific CF clinical forms. A flowchart defining a mutational search that may be adopted for different CF clinical forms, optimized in respect to those already available, is proposed. The findings also have consequences for carrier screening strategies.

  4. [Azithromycin therapy in cystic fibrosis].

    PubMed

    Máiz Carro, Luis; Cantón Moreno, Rafael

    2004-03-01

    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. PMID:15030744

  5. 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

  6. 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

  7. Pharmacogenetics of cystic fibrosis treatment.

    PubMed

    Carter, Suzanne C; McKone, Edward F

    2016-08-01

    Cystic fibrosis (CF) is genetic autosomal recessive disease caused by reduced or absent function of CFTR protein. Treatments for patients with CF have primarily focused on the downstream end-organ consequences of defective CFTR. Since the discovery of the CFTR gene that causes CF in 1989 there have been tremendous advances in our understanding of the genetics and pathophysiology of CF. This has recently led to the development of new CFTR mutation-specific targeted therapies for select patients with CF. This review will discuss the characteristics of the CFTR gene, the CFTR mutations that cause CF and the new mutation specific pharmacological treatments including gene therapy that are contributing to the dawning of a new era in cystic fibrosis care. PMID:27490265

  8. Non-cystic fibrosis bronchiectasis.

    PubMed

    Al Subie, Haya; Fitzgerald, Dominic A

    2012-05-01

    Non-cystic fibrosis (CF) bronchiectasis is said to be a declining problem in developed countries, although its prevalence in indigenous communities in Australia and New Zealand is among the highest reported in the world. Early childhood pneumonia and underlying conditions such as immunodeficiency and primary ciliary dyskinesia need to be considered in the aetiology. A high-resolution computerised tomography scan is the key investigation in children with a chronic wet cough in whom bronchiectasis is suspected. Regardless of the cause, the treatment of bronchiectasis is centred upon facilitating the clearance of airway secretions and the treatment of pulmonary exacerbations. This review aims to provide general paediatricians with an update on the presenting features, investigation and management of non-cystic fibrosis bronchiectasis. PMID:21040075

  9. 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.

  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. 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. PMID:25395018

  12. Respiratory Conditions Update: Cystic Fibrosis.

    PubMed

    Pritchard, Lyle L

    2016-09-01

    Cystic fibrosis (CF) is an autosomal recessive genetic disease that occurs in approximately 1 in 2,500 white live births. It is less common in nonwhite individuals. A dysfunctional epithelial chloride channel leads to excessively thick mucus affecting multiple organ systems. Common issues include mucous plugging of the airway, lung inflammation, chronic pulmonary infections, intestinal malabsorption, and malnutrition. Universal screening of newborns for CF is recommended in many countries. CF can be diagnosed based on clinical evidence of disease along with genetic testing or other laboratory evidence of chloride channel dysfunction. Pulmonary system dysfunction causes the most morbidity and mortality. Pulmonary function testing is the primary modality used to monitor CF progression. Therapies include chest physiotherapy, mucolytics, antibiotics, anti-inflammatory drugs, targeted therapies, and vaccines. Dysfunction of the exocrine pancreas and gastrointestinal tract leads to malabsorption, malnutrition, and intestinal obstruction. Nutrition should be optimized with adequate calories, pancreatic enzymes, and appropriate dietary supplements. Complications, including acute pulmonary exacerbations, gastrointestinal conditions, chronic rhinosinusitis, CF-related diabetes, osteoporosis, infertility, and psychosocial issues, must be managed. At the appropriate time, lung transplantation and end-of-life issues must be addressed. PMID:27576234

  13. [Swiss registry for patients with cystic fibrosis: design, programming, implementation and first examples of use].

    PubMed

    Schöni-Affolter, F; Oswald, P; Wandt-Baumann, C; Kriemler, S; Schöni, M H

    2000-09-30

    The Swiss Registry for Cystic Fibrosis (SRCF) was designed to collect demographic, clinical and therapeutic data from patients with cystic fibrosis (CF) in Switzerland. It was designed, programmed and implemented for standalone application in Swiss cystic fibrosis centres. It is part of the European Registry for Cystic Fibrosis (ERCF), which has been implemented in Europe to collect data on the use and safety of dornase alpha (Pulmozyme) in the treatment of cystic fibrosis. At the time of first evaluation 245 cystic fibrosis patients are registered, their mean age is 13 years, and 17% are over 18. In larger databases in Germany or North America we observe comparable demographic data, similar degrees of severity and similar therapeutic approaches to those in Swiss cystic fibrosis patients. The aim of the Swiss Registry is to cover the maximum possible number of cystic fibrosis patients from this country.

  14. [Dry powder inhalers in cystic fibrosis].

    PubMed

    Steinkamp, G

    2014-06-01

    Inhaled medications play an important role in the daily treatment of patients with cystic fibrosis (CF). The classic route of administration was nebulisation via jet nebulisers. Respiratory delivery of fluid particles should loosen the viscid respiratory secretions, making airway clearance via cough or physiotherapy more efficient. Until recently, only jet nebulisers allowed to administer high doses of aerosolised antipseudomonal antibiotics. Powder inhalers for the treatment of cystic fibrosis have recently been made available. The newly developed powders and inhalers differ considerably from conventional dry powder inhalers used for the treatment of chronic obstructive airway disease. The present article will review two inhaled antibiotics, i. e. tobramycin and colistin, and the hyperosmotic agent mannitol, which increases the hydration of the airways. Topics are particle engineering, efficacy and tolerability results from clinical trials, as well as functional and practical aspects related to these new drugs. PMID:24664997

  15. Relation between insulin-like growth factor-I, body mass index, and clinical status in cystic fibrosis

    PubMed Central

    Taylor, A; Bush, A; Thomson, A; Oades, P; Marchant, J; Bruce-Morgan, C; Holly, J; Ahmed, L; Dunger, D

    1997-01-01

    Accepted 26 October 1996
 OBJECTIVES—Despite improved nutrition and intensive treatment, subjects with cystic fibrosis have difficulty in maintaining anabolism during intercurrent infections, which can result in reduced body mass index and impaired skeletal growth. Insulin-like growth factor-I (IGF-I) and its binding protein IGFBP3 are sensitive to changes in nutritional status. The aim of this study was to determine the relation between circulating concentrations of these peptides, body mass index, and clinical status in cystic fibrosis.
METHODS—Serum concentrations of IGF-I and IGFBP3 were measured in 197 subjects (108 males, 89 females; mean age 9.69 years, range 0.41-17.9 years) and these data were analysed with respect to body mass index, pubertal stage, and clinical status as assessed by Shwachman score and forced expiratory volume in one second (FEV1 ).
RESULTS—The mean height SD score of the children studied was −0.2 (SD 1.14) and the body mass index SD score −0.26 (1.4). The body mass index SD score declined with increasing age (r=−0.18) and paralleled changes in IGF-I concentrations, which also declined. The IGF-I SD score (calculated from control data) correlated with age (r=−0.53). The abnormalities were most obvious during late puberty, when IGF-I and IGFBP3 concentrations were significantly reduced compared with those in control subjects matched for pubertal stage. The IGF-I SD score correlated with height SD score (r=0.14) and the decline in IGF-I concentrations with the fall in body mass index SD score (r=0.42). IGF-I SD scores also correlated with the Shwachman score (r=0.33) and FEV1 (r=0.17).
CONCLUSIONS—The close relation between declining IGF-I and IGFBP3 concentrations and body mass index in patients with cystic fibrosis may simply reflect poor nutritional status and insulin hyposecretion. Nevertheless, IGF-I deficiency could also contribute towards the catabolism observed in these patients, and IGF-I SD scores

  16. A combination therapy for cystic fibrosis.

    PubMed

    Brodsky, Jeffrey L; Frizzell, Raymond A

    2015-09-24

    The most prevalent form of cystic fibrosis arises from an amino acid deletion in the cystic fibrosis transmembrane conductance regulator, CFTR. A recently approved treatment for individuals homozygous for this mutation combines a chemical corrector, which helps CFTR fold, and a potentiator that increases CFTR channel activity. PMID:26406363

  17. A combination therapy for cystic fibrosis.

    PubMed

    Brodsky, Jeffrey L; Frizzell, Raymond A

    2015-09-24

    The most prevalent form of cystic fibrosis arises from an amino acid deletion in the cystic fibrosis transmembrane conductance regulator, CFTR. A recently approved treatment for individuals homozygous for this mutation combines a chemical corrector, which helps CFTR fold, and a potentiator that increases CFTR channel activity.

  18. Endocrine Disorders in Cystic Fibrosis.

    PubMed

    Blackman, Scott M; Tangpricha, Vin

    2016-08-01

    Cystic fibrosis is frequently complicated by endocrine disorders. Diabetes can be expected to affect most with CF and pancreatic insufficiency and varies widely in age of onset, but early identification and treatment improve morbidity and mortality. Short stature can be exacerbated by relative delay of puberty and by use of inhaled corticosteroids. Bone disease in CF causes fragility fractures and should be assessed by monitoring bone mineral density and optimizing vitamin D status. Detecting and managing endocrine complications in CF can reduce morbidity and mortality in CF. These complications can be expected to become more common as the CF population ages. PMID:27469183

  19. Psychosocial impact of cystic fibrosis in adolescence.

    PubMed

    Harrop, Michele

    2007-12-01

    Over 8,000 children, young people and adults in the UK are affected by cystic fibrosis and although no cure exists, comprehensive therapy started early and administered consistently delays disease progression. This article explores three aspects of the psychosocial effects of cystic fibrosis on the adolescent/young adult: the effect on the family, the effect on relationships and adherence to treatment. Much of the early research on the psychosocial impact of cystic fibrosis on the adolescent and the family presented a dismal picture of dysfunction. More recent studies indicate that cystic fibrosis patients generally lead active, age-appropriate social lives, that good information and support can reduce negative effects on families and that treatment regimes continue to cause difficulties for young people. Further research is needed into the psychosocial impact of cystic fibrosis on the increasing numbers of young people and adults with the disease.

  20. Aspergillus infections in cystic fibrosis.

    PubMed

    King, Jill; Brunel, Shan F; Warris, Adilia

    2016-07-01

    Patients with cystic fibrosis (CF) suffer from chronic lung infection and airway inflammation. Respiratory failure secondary to chronic or recurrent infection remains the commonest cause of death and accounts for over 90% of mortality. Bacteria as Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia complex have been regarded the main CF pathogens and their role in progressive lung decline has been studied extensively. Little attention has been paid to the role of Aspergillus spp. and other filamentous fungi in the pathogenesis of non-ABPA (allergic bronchopulmonary aspergillosis) respiratory disease in CF, despite their frequent recovery in respiratory samples. It has become more apparent however, that Aspergillus spp. may play an important role in chronic lung disease in CF. Research delineating the underlying mechanisms of Aspergillus persistence and infection in the CF lung and its link to lung deterioration is lacking. This review summarizes the Aspergillus disease phenotypes observed in CF, discusses the role of CFTR (cystic fibrosis transmembrane conductance regulator)-protein in innate immune responses and new treatment modalities. PMID:27177733

  1. Hydrator Therapies for Chronic Bronchitis. Lessons from Cystic Fibrosis.

    PubMed

    Bennett, William D; Henderson, Ashley G; Donaldson, Scott H

    2016-04-01

    Patients with the chronic bronchitis form of chronic obstructive pulmonary disease and cystic fibrosis share similar clinical features, including mucus obstruction of airways and the development of chronic/recurrent airways infections that often manifest as disease exacerbations. There is growing evidence that these diseases may have parallels in disease pathogenesis as well, including cystic fibrosis transmembrane conductance regulator dysfunction, mucus dehydration, and defective mucociliary clearance. As progress is made in the development of therapies that target the basic defects that lead to cystic fibrosis lung disease, it is possible that similar approaches could also benefit patients with chronic bronchitis. A deeper understanding of how tobacco smoke and other triggers of chronic bronchitis actually lead to disease, and exploration of the concept that therapies that restore cystic fibrosis transmembrane conductance regulator function, mucus hydration, and/or mucociliary clearance may benefit patients with chronic bronchitis, hold the prospect of significant progress in treating this prevalent disease. PMID:27115955

  2. beta2 adrenoceptor gene polymorphisms in cystic fibrosis lung disease.

    PubMed

    Büscher, Rainer; Eilmes, Katrin Jennifer; Grasemann, Hartmut; Torres, Brian; Knauer, Nicola; Sroka, Karin; Insel, Paul A; Ratjen, Felix

    2002-07-01

    The cystic fibrosis membrane conductance regulator can be activated through beta2-adrenoceptor (beta2AR) stimulation. We tested the hypothesis that coding sequence polymorphisms in the beta2AR gene contribute to the disease state in patients with cystic fibrosis. The Arg16Gly, Gln27Glu, and Thr164Ile beta2AR polymorphisms were studied by specific polymerase chain reaction and restriction fragment length polymorphism analysis in 126 cystic fibrosis patients. Forced expiratory volume in 1 s was significantly (P < 0.05) reduced in cystic fibrosis patients carrying the Gly16 allele in either homozygous or heterozygous form (Gly16Gly + Arg16Gly) compared to patients homozygous for the Arg16 allele (60.3 +/- 3.5% versus 75.7 +/- 4.9% predicted). Similarly, forced vital capacity and flows at lower lung volumes were significantly (P < 0.05 and P < 0.01) lower in cystic fibrosis patients carrying the Gly16 allele. In addition, the Gly16 allele was associated with a greater 5 year decline in pulmonary function (P < 0.01). Bronchodilator responses to albuterol were not significantly different between the groups. The Thr164Ile variant was found in four patients; these patients had markedly reduced pulmonary function. Isoproterenol-stimulated cyclic AMP formation was significantly blunted in cystic fibrosis patients carrying either the Gly16 allele or Thr164Ile genotype compared to cystic fibrosis patients homozygous for the respective Arg16 alleles. These data provide the first evidence suggesting that polymorphisms of the beta2AR gene contribute to clinical severity and disease progression in cystic fibrosis.

  3. Cystic Fibrosis Transmembrane Conductance Regulator. Implications in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

    PubMed

    Cantin, André M

    2016-04-01

    Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) have traditionally been viewed as two distinct entities of unrelated origins. However, molecular, cellular, and clinical studies have revealed that cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction is common to both conditions, one (CF) being defined genetically and the other (COPD) as an acquired CFTR deficiency. Multiple molecular mechanisms of cigarette smoke-induced CFTR dysfunction have been reported. More importantly, considerable evidence of cigarette smoke-induced CFTR dysfunction in several respiratory and nonrespiratory tissues have been confirmed, making CFTR a target that cannot be overlooked in our quest to understand COPD and improve therapies for individuals affected by this disease. This review summarizes the molecular, cellular, and clinical evidence that CFTR dysfunction is induced by cigarette smoke exposure both in vitro and in vivo, and explores how this may contribute to the development of COPD. PMID:27115950

  4. 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

  5. Precision Genomic Medicine in Cystic Fibrosis.

    PubMed

    Chang, Eugene H; Zabner, Joseph

    2015-10-01

    The successful application of precision genomic medicine requires an understanding of how a person's genome can influence his or her 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.

  6. Celiac Disease and Cystic Fibrosis: Challenges to Differential Diagnosis.

    PubMed

    Ramos, Alessandra Teixeira Pessoa; Figueirêdo, Manuella Machado; Aguiar, Ana Paula de B; Almeida, Carolina de Godoy; Mendes, Patrícia S A; Souza, Edna Lucia

    2016-01-01

    Cystic fibrosis and celiac disease were considered a single clinical entity for many years. Differentiation between the diseases occurred some time in the 1930s of the 20th Century. Both diseases may present the intestinal malabsorption syndrome and similar clinical manifestations that contribute to difficulties with clinical distinction. We describe a report of two patients with initial diagnosis of cystic fibrosis, who were subsequently diagnosed with celiac disease. These case reports emphasize the possibility of false positivity being shown in the sweat test in CD, which may result in delayed diagnosis and inadequate management of this disease. PMID:27552792

  7. 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

  8. [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

  9. The clinical benefits of long-term supplementation with omega-3 fatty acids in cystic fibrosis patients - A pilot study.

    PubMed

    Hanssens, L; Thiébaut, I; Lefèvre, N; Malfroot, A; Knoop, C; Duchateau, J; Casimir, G

    2016-05-01

    Effectiveness of omega-3 supplementation in cystic fibrosis (CF) remains controversial. This study sought to evaluate clinical status, exercise tolerance, inflammatory parameters, and erythrocyte fatty acid profile after 1 year of oral omega-3 supplementation in CF patients. Fifteen ΔF508-homozygous patients undergoing chronic azithromycin were randomized to receive omega-3 fish oil supplementation at a dose of 60mg/Kg/day or placebo. In comparison with the previous year, in the supplemented group, the number of pulmonary exacerbations decreased at 12 months (1.7 vs. 3.0, p<0.01), as did the duration of antibiotic therapy (26.5 days vs. 60.0 days, p<0.025). Supplementation significantly increased the levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as early as <3 months of administration, with concomitant decreases in arachidonic acid (AA) levels. This pilot study suggests that long-term omega-3 supplementation offers several clinical benefits as to the number of exacerbations and duration of antibiotic therapy in CF patients.

  10. 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.

  11. 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. PMID:24095197

  12. Lung Transplantation for Cystic Fibrosis

    PubMed Central

    Adler, Frederick R.; Aurora, Paul; Barker, David H.; Barr, Mark L.; Blackwell, Laura S.; Bosma, Otto H.; Brown, Samuel; Cox, D. R.; Jensen, Judy L.; Kurland, Geoffrey; Nossent, George D.; Quittner, Alexandra L.; Robinson, Walter M.; Romero, Sandy L.; Spencer, Helen; Sweet, Stuart C.; van der Bij, Wim; Vermeulen, J.; Verschuuren, Erik A. M.; Vrijlandt, Elianne J. L. E.; Walsh, William; Woo, Marlyn S.; Liou, Theodore G.

    2009-01-01

    Lung transplantation is a complex, high-risk, potentially life-saving therapy for the end-stage lung disease of cystic fibrosis (CF). The decision to pursue transplantation involves comparing the likelihood of survival with and without transplantation as well as assessing the effect of wait-listing and transplantation on the patient's quality of life. Although recent population-based analyses of the US lung allocation system for the CF population have raised controversies about the survival benefits of transplantation, studies from the United Kingdom and Canada have suggested a definite survival advantage for those receiving transplants. In response to these and other controversies, leaders in transplantation and CF met together in Lansdowne, Virginia, to consider the state of the art in lung transplantation for CF in an international context, focusing on advances in surgical technique, measurement of outcomes, use of prognostic criteria, variations in local control over listing, and prioritization among the United States, Canada, the United Kingdom, and The Netherlands, patient adherence before and after transplantation and other issues in the broader context of lung transplantation. Finally, the conference members carefully considered how efforts to improve outcomes for lung transplantation for CF lung disease might best be studied. This Roundtable seeks to communicate the substance of our discussions. PMID:20008865

  13. 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

  14. Detection of methicillin-resistant Staphylococcus aureus in clinical specimens from cystic fibrosis patients by use of chromogenic selective agar.

    PubMed

    Perez, Leandro Reus Rodrigues; Antunes, Ana Lúcia Souza; Bonfanti, Jéssica Weiss; Pinto, Jaqueline Becker; Roesch, Eliane Wurdig; Rodrigues, Diógenes; Dias, Cícero Armídio Gomes

    2012-07-01

    We evaluated the use of a chromogenic selective medium (MRSA ID) as a useful tool for the detection of methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis (CF) patient samples. Fifty-four MRSA isolates were detected by MRSA ID, while only 24/54 (44%) (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.63 to 4.76) were detected by conventional methods. A chromogenic selective medium for MRSA detection may improve its surveillance in CF patients.

  15. Identification of outer membrane Porin D as a vitronectin-binding factor in cystic fibrosis clinical isolates of Pseudomonas aeruginosa

    PubMed Central

    Paulsson, Magnus; Singh, Birendra; Al-Jubair, Tamim; Su, Yu-Ching; Høiby, Niels; Riesbeck, Kristian

    2016-01-01

    Background Pseudomonas aeruginosa is a pathogen that frequently colonizes patients with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Several pathogens are known to bind vitronectin to increase their virulence. Vitronectin has been shown to enhance P. aeruginosa adhesion to host epithelial cells. Methods We screened clinical isolates from the airways of CF patients and from the bloodstream of patients with bacteremia for binding of vitronectin. Two-dimensional SDS-PAGE and a proteomic approach was used to identify vitronectin-receptors in P. aeruginosa. Results P. aeruginosa from the airways of CF patients (n=27) bound more vitronectin than bacteremic isolates (n=15, p=0.025). Porin D (OprD) was identified as a vitronectin-binding protein. A P. aeruginosa oprD transposon insertion mutant had a decreased binding to soluble and immobilized vitronectin (p ≤ 0.001). Conclusions P. aeruginosa isolates obtained from CF patients significantly bound vitronectin. Porin D was defined as a novel P. aeruginosa vitronectin-receptor, and we postulate that the Porin D-dependent interaction with vitronectin may be important for colonization. PMID:26047937

  16. Relationship between CFTR and CTRC variants and the clinical phenotype in late-onset cystic fibrosis disease with chronic pancreatitis.

    PubMed

    Tomaiuolo, Anna C; Sofia, Valentina M; Surace, Cecilia; Majo, Fabio; Genovese, Silvia; Petrocchi, Stefano; Grotta, Simona; Alghisi, Federico; Lucidi, Vincenzina; Angioni, Adriano

    2015-03-01

    Cystic fibrosis (CF), the most common autosomal recessive disease in whites, is caused by mutations in the CF transmembrane conductance regulator (CFTR). So far, >1900 mutations have been described, most of which are nonsense, missense, and frameshift, and can lead to severe phenotypes, reducing the level of function of the CFTR protein. Synonymous variations are usually considered silent without pathogenic effects. However, synonymous mutations exhibiting exon skipping as a consequence of aberrant splicing of pre-mRNA differ. Herein, we describe the effect of the aberrant splicing of the c.273G>C (G91G) synonymous variation found in a 9-year-old white (ΔF508) patient affected by CF and pancreatitis associated with a variant in chymotrypsin C (CTRC). Magnetic resonance imaging showed an atrophic pancreatic gland with substitution of the pancreatic parenchyma with three cysts. Genetic examination revealed compound heterozygosity for the c.1521_1523delCTT (ΔF508) pathogenic variant and the c.273G>C (G91G) variant in CFTR. Sweat test results confirmed the diagnosis of CF. We have thus identified a synonymous variation (G91G) causing the skipping of exon 3 in a CF patient carrying the ΔF508 mutation. However, the clinical phenotype with pancreatic symptoms encouraged us to investigate a panel of pancreas-related genes, which resulted in finding a known sequence variation inside CTRC. We further discuss the role of these variants and their possible interactions in determining the current phenotype.

  17. Influenza vaccination in children with cystic fibrosis.

    PubMed

    Patria, Maria Francesca; Longhi, Benedetta; Esposito, Susanna

    2013-04-01

    Cystic fibrosis (CF) is an inherited autosomal recessive disease characterized by progressive pulmonary damage and respiratory failure. It is known that bacterial infections play a critical role in the development of significant lung damage, whereas the role of respiratory viruses in CF pulmonary exacerbations and the relationship between viral infections and the progression of lung damage are uncertain. Health authorities throughout the world recommend influenza vaccination for CF patients. The aim of this review is to analyze the impact of seasonal and pandemic influenza on CF patients and data concerning influenza vaccination in order to assess the current situation and identify areas for future study. As data are limited, further well-constructed clinical studies of the effectiveness of influenza vaccination on the main clinical outcome measures of pulmonary function and nutritional status in patients with CF are required.

  18. 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)

  19. Meconium ileus equivalent in older patients with cystic fibrosis.

    PubMed

    Hanly, J G; Fitzgerald, M X

    1983-04-30

    Meconium ileus equivalent is one of the lesser known manifestations of cystic fibrosis, and occurs most often in older patients. With the improved overall survival of patients with cystic fibrosis, one would expect to see this condition more often in the future. Of 53 patients attending our cystic fibrosis clinic for adolescents and adults, eight had experienced a total of 25 episodes of meconium ileus equivalent. Recurrent attacks occurred in seven patients, of whom four had at least four separate, well documented episodes: these episodes were associated with obvious recognised precipitating factors in only three patients. All patients responded to appropriate medical treatment with acetylcysteine or sodium diatrizoate, including three who had previously undergone surgery for meconium ileus equivalent elsewhere. Controversies remain, however, concerning the role of prophylactic medical management with acetylcysteine, sodium diatrizoate, and pancreatic supplements. PMID:6404483

  20. 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.

  1. [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. PMID:18361877

  2. 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. PMID:27445556

  3. 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

  4. 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.

  5. Do brine shrimp diagnose cystic fibrosis?

    PubMed

    Hodes, M E; Thomas, J; Morgan, S; Merritt, A D

    1975-11-01

    The nauplii of the brine shrimp Artemia salina are dependent upon the function of their salt gland to maintain osmotic pressure within narrow limits. A number of drugs interfere with this function and are lethal to the nauplii. Saliva and serum from normal persons, patients with cystic fibrosis, and obligate heterozygotes were tested for lethal effect against brine shrimp nauplii. At salt concentrations between 100 mM and 2.5 no difference was found among the phenotypes. At lower concentrations a difference was noted occasionally between some normal subjects and some individuals carrying one or two genes for cystic fibrosis. Data from an independent series of experiments indicate that the naupliar deaths result from distorted ratios of Na+/K+ and not from a specific gene product. No difference was noted in the O2 uptake of nauplii treated with saliva or serum obtained from normal subjects, patients with cystic fibrosis, or obligate heterozygotes. PMID:1187245

  6. 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;…

  7. 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...

  8. 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

  9. Cystic fibrosis: comparison of two mucolytic drugs for inhalation treatment (acetylcysteine and arginine hydrochloride).

    PubMed

    Dietzsch, H J; Gottschalk, B; Heyne, K; Leupoid, W; Wunderlich, P

    1975-01-01

    Clinical, bronchoscopic, spirographic, scintigraphic, and chemical analyses were done in 24 children with cystic fibrosis to assess the mucolytic effects of acetylcysteine inhalations versus L-arginine hydrochloride aerosols. The latter drug is less active than acetylcysteine and should not be used to treat children with cystic fibrosis.

  10. 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...

  11. 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...

  12. Predictive 5-Year Survivorship Model of Cystic Fibrosis

    PubMed Central

    Liou, Theodore G.; Adler, Frederick R.; FitzSimmons, Stacey C.; Cahill, Barbara C.; Hibbs, Jonathan R.; Marshall, Bruce C.

    2007-01-01

    The objective of this study was to create a 5-year survivorship model to identify key clinical features of cystic fibrosis. Such a model could help researchers and clinicians to evaluate therapies, improve the design of prospective studies, monitor practice patterns, counsel individual patients, and determine the best candidates for lung transplantation. The authors used information from the Cystic Fibrosis Foundation Patient Registry (CFFPR), which has collected longitudinal data on approximately 90% of cystic fibrosis patients diagnosed in the United States since 1986. They developed multivariate logistic regression models by using data on 5,820 patients randomly selected from 11,630 in the CFFPR in 1993. Models were tested for goodness of fit and were validated for the remaining 5,810 patients for 1993. The validated 5-year survivorship model included age, forced expiratory volume in 1 second as a percentage of predicted normal, gender, weight-for-age z score, pancreatic sufficiency, diabetes mellitus, Staphylococcus aureus infection, Burkerholderia cepacia infection, and annual number of acute pulmonary exacerbations. The model provides insights into the complex nature of cystic fibrosis and supplies a rigorous tool for clinical practice and research. PMID:11207152

  13. Nutrient Status of Adults with Cystic Fibrosis

    PubMed Central

    GORDON, CATHERINE M.; ANDERSON, ELLEN J.; HERLYN, KAREN; HUBBARD, JANE L.; PIZZO, ANGELA; GELBARD, RONDI; LAPEY, ALLEN; MERKEL, PETER A.

    2011-01-01

    Nutrition is thought to influence disease status in patients with cystic fibrosis (CF). This cross-sectional study sought to evaluate nutrient intake and anthropometric data from 64 adult outpatients with cystic fibrosis. Nutrient intake from food and supplements was compared with the Dietary Reference Intakes for 16 nutrients and outcomes influenced by nutritional status. Attention was given to vitamin D and calcium given potential skeletal implications due to cystic fibrosis. Measurements included weight, height, body composition, pulmonary function, and serum metabolic parameters. Participants were interviewed about dietary intake, supplement use, pulmonary function, sunlight exposure, and pain. The participants’ mean body mass index (±standard deviation) was 21.8±4.9 and pulmonary function tests were normal. Seventy-eight percent used pancreatic enzyme replacement for malabsorption. Vitamin D deficiency [25-hydroxyvitamin D (25OHD)<37.5 nmol/L] was common: 25 (39%) were deficient despite adequate vitamin D intake. Lipid profiles were normal in the majority, even though total and saturated fat consumption represented 33.0% and 16.8% of energy intake, respectively. Reported protein intake represented 16.9% of total energy intake (range 10%–25%). For several nutrients, including vitamin D and calcium, intake from food and supplements in many participants exceeded recommended Tolerable Upper Intake Levels. Among adults with cystic fibrosis, vitamin D deficiency was common despite reported adequate intake, and lipid profiles were normal despite a relatively high fat intake. Mean protein consumption was adequate, but the range of intake was concerning, as both inadequate or excessive intake may have deleterious skeletal effects. These findings call into question the applicability of established nutrient thresholds for patients with cystic fibrosis. PMID:18060897

  14. New and emerging targeted therapies for cystic fibrosis.

    PubMed

    Quon, Bradley S; 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

  15. 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.

  16. 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

  17. Improved sweat test method for the diagnosis of cystic fibrosis.

    PubMed Central

    Carter, E P; Barrett, A D; Heeley, A F; Kuzemko, J A

    1984-01-01

    We describe a new technique of collecting sweat for measurement of osmolality and sodium concentrations. Eighty two subjects were studied--39 controls and 43 patients with cystic fibrosis. Adequate amounts of sweat were obtained in 81 subjects and sweat was analysed for both osmolality and sodium concentrations in 73 subjects. The 34 controls gave sweat osmolality and sodium values ranging from 62 to 196 mmol/kg and 9 to 72 mmol/l respectively. The 39 cystic fibrosis patients gave osmolality values ranging from 220 to 416 mmol/kg and sodium concentrations ranging from 60 to 150 mmol/l. Sweat osmolality alone was determined in eight infants under 50 days of age--four later developed the clinical features of cystic fibrosis and four, in whom cystic fibrosis was suspected, were later excluded. Sweat osmolality values in these two groups ranged from 255 to 345 mmol/kg and 87 to 123 mmol/kg respectively. The simplicity of collecting sweat and the measurement of osmolality offer distinct advantages over techniques previously described. PMID:6497428

  18. Antenatal testing for cystic fibrosis in Cuba, 1988-2011.

    PubMed

    Collazo, Teresa; López, Ixchel; Clark, Yulia; Piloto, Yaixa; González, Laura; Gómez, Manuel; García, Marileivis; Reyes, Lidice; Rodríguez, Fidel

    2014-01-01

    INTRODUCTION Cystic fibrosis is a multisystem autosomal recessive disease with wide variability in clinical severity. It is incurable and characterized by elevated and premature mortality, as well as poor quality of life. Its frequency, lethality and devastating impact on both the physical and psychological wellbeing of patients and their families, make it a serious health problem. Its frequency in Cuba is 1 in 9862 live births, where marked molecular heterogeneity of the CFTR gene makes molecular diagnosis difficult. Six mutations have been identified that together enable molecular characterization of only 55.5% of cystic fibrosis chromosomes. This paper presents national results of antenatal diagnostic testing, using direct and indirect methods, for detection of cystic fibrosis. OBJECTIVE Characterize the Cuban public health system's experience with antenatal molecular testing for cystic fibrosis from 1988 through 2011. METHODS A retrospective descriptive study was conducted with results of antenatal diagnostic testing of amniotic fluid, performed nationwide from 1988 through 2011, for 108 fetuses of couples with some risk of having children affected by cystic fibrosis, who requested testing. Polymerase chain reaction detected mutations p.F508del, p.G542X, p.R1162X, p.R334W, p.R553X and c.3120+1G>A, and markers XV2C and KM19. Data were analyzed using absolute frequencies and percentages, and presented in tables. RESULTS For 93 cases (86.1%), testing for cystic fibrosis was done using direct analysis of mutations p.F508del, p.G542X, p.R1162X, p.R334W, p.R553X and c.3120+1G>A; five cases (4.6%) were tested indirectly using markers XV2C/Taq I and KM19/Pst I; and 10 (9.3%) were tested using a combination of the two methods. A total of 72 diagnoses (66.7% of studies done) were concluded, of which there were 20 healthy fetuses, 16 affected, 27 carrier, and 9 who were either healthy or carriers of an unknown mutation. CONCLUSIONS Direct or indirect molecular study was

  19. Pulmonary Exacerbations in Children with Cystic Fibrosis.

    PubMed

    Waters, Valerie; Ratjen, Felix

    2015-11-01

    Pulmonary exacerbations treated with intravenous antibiotics have significant, well-characterized negative consequences on clinical outcomes in cystic fibrosis (CF). The impact of milder exacerbations in children with CF, commonly treated with oral antibiotics, are less well defined. Pulmonary exacerbations have multiple triggers, but viral infections are particularly common in children. Children with CF and healthy control subjects have similar frequencies of viral respiratory infections, but there is evidence of greater virus-related morbidity in patients with CF, likely due to a combination of increased viral load, more pronounced inflammatory response, and more pronounced impairment in mucociliary clearance. In recent clinical trials in children, definitions have been used that are more symptom based rather than intervention based. These studies have demonstrated differences in the spectrum of symptoms between children and older patients but have also shown that, despite low threshold definitions, a considerable number of patients receive treatment for events not fulfilling the pulmonary exacerbation criteria. Additional research is needed to determine the impact of these milder exacerbations on lung function recovery and time to subsequent exacerbation as well as long-term outcomes such as mortality. PMID:26595740

  20. Choosing a nebulizer for cystic fibrosis applications.

    PubMed

    Geller, D E

    1997-11-01

    As the number of inhaled drugs available for cystic fibrosis grows, there is increasing awareness of delivery device issues. Current jet and ultrasonic nebulizers are inefficient at delivering drugs to the lower respiratory tract. There are large differences in output characteristics between nebulizers and high intersubject variability in lung deposition. The clinical effects of inhaled drugs depend on adequate dosing to the lower airway, so we must choose a nebulizer and patient characteristics that will affect lung deposition positively. Aerosols with particle sizes at the smaller end of the respirable range (2 to 3 microns) may enhance the clinical benefit of some drugs, regardless of patient age or disease severity. Breath-enhanced (Venturi) jet nebulizers are less wasteful than constant-output nebulizers and perform better than conventional nebulizers with many drugs. Patient breathing patterns and degree of airway obstruction are important in determining the site of airway deposition. With increased attention to aerosol delivery issues by clinicians, industry, and regulatory agencies, improved technologies will evolve to target therapies to the lung. PMID:9391760

  1. Anxiety and depression in cystic fibrosis.

    PubMed

    Baiardini, I; Steinhilber, G; DI Marco, F; Braido, F; Solidoro, P

    2015-10-01

    Cystic fibrosis (CF) is the most common genetic disorders in the Caucasian population, with estimated between 70,000 and 100,000 patients worldwide. Even if improved diagnostics and clinical management have led to an increased life expectancy, CF still remains a disease that significantly impacts patients' life in terms of symptoms, daily functioning, psychological morbidity and health related quality of life. Available data suggest that symptoms of anxiety and depression, such as in other chronic conditions, are common features in CF patients and in their caregivers, with a significant impact on disease outcomes. In this review we analyze and discuss the findings of The International Depression and Anxiety Epidemiological Study (TIDES), recently published on Thorax. This study was aimed to determine the prevalence of symptoms of depression and anxiety in a large population of adolescents and adults with CF and in parents of children with CF, across eight European countries and the USA. The TIDES provides useful insights about the psychological/psychiatric comorbidities in CF and its conclusions are absolutely shareable. Nevertheless some doubts remain on the methods and the tools. Further investigation and understanding of anxiety and depression in CF (in terms of prevalence, association with clinical, psychological and socio-cultural factors) is necessary and evidence is crescent that a global and multidisciplinary approach is wanted. PMID:27427260

  2. Choosing a nebulizer for cystic fibrosis applications.

    PubMed

    Geller, D E

    1997-11-01

    As the number of inhaled drugs available for cystic fibrosis grows, there is increasing awareness of delivery device issues. Current jet and ultrasonic nebulizers are inefficient at delivering drugs to the lower respiratory tract. There are large differences in output characteristics between nebulizers and high intersubject variability in lung deposition. The clinical effects of inhaled drugs depend on adequate dosing to the lower airway, so we must choose a nebulizer and patient characteristics that will affect lung deposition positively. Aerosols with particle sizes at the smaller end of the respirable range (2 to 3 microns) may enhance the clinical benefit of some drugs, regardless of patient age or disease severity. Breath-enhanced (Venturi) jet nebulizers are less wasteful than constant-output nebulizers and perform better than conventional nebulizers with many drugs. Patient breathing patterns and degree of airway obstruction are important in determining the site of airway deposition. With increased attention to aerosol delivery issues by clinicians, industry, and regulatory agencies, improved technologies will evolve to target therapies to the lung.

  3. 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.

  4. 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. PMID:18445516

  5. Acquired Cystic Fibrosis Transmembrane Conductance Regulator Deficiency.

    PubMed

    Cho, Do-Yeon; Woodworth, Bradford A

    2016-01-01

    In the genetic airway disease cystic fibrosis (CF), deficiency or dysfunction of the cystic fibrosis membrane conductance regulator (CFTR) alters anion transport in respiratory epithelium and consequently disrupts mucociliary clearance. An enriched understanding of the role of CFTR in the maintenance of normal epithelial function has revealed that mild and variable CFTR mutations play a causative role in a number of diseases not classically associated with CF. Furthermore, recent evidence indicates that acquired defects in wild-type CFTR protein processing, endocytic recycling and function can contribute to the pathogenesis of airway diseases, such as chronic obstructive pulmonary disease. In this chapter, we discuss emerging findings implicating acquired CFTR dysfunction in the pathogenesis of chronic rhinosinusitis and propose a new and leading edge approach to future CRS therapy using CFTR potentiators. PMID:27466849

  6. 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.

  7. Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes.

    PubMed

    Andersson, C; Dragomir, A; Hjelte, L; Roomans, G M

    2002-10-01

    Cystic fibrosis is a heterogenic disease, in which the phenotype can also vary for patients with the same genotype. In the present study the function of the cystic fibrosis transmembrane conductance regulator (CFTR) in nasal epithelial cells from 19 adult patients with cystic fibrosis was investigated. All patients had severe mutations, whereby no or little functional CFTR is expected in the plasma membrane. Of the patients, 15 were homozygous for deltaF508-CFTR (i.e. CTFR lacking residue Phe-508). The others were deltaF508-heterozygous with 3659delC, 394delTT or 2183AA-->G. Nasal epithelial cells, obtained by nasal brushings, were loaded with the fluorescent probe N -(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide to measure Cl(-) efflux. In most of the cystic fibrosis patients, forskolin plus isobutylmethylxanthine was unable to elicit any response. Unexpectedly, cells from three cystic fibrosis patients (two deltaF508/deltaF508 patients and one deltaF508/3659delC patient) responded to stimulation in a wild-type manner. It was investigated whether this residual chloride transport function was associated with a milder phenotype. Clinical parameters studied were lung function, number of antibiotic courses, Shwachman score, Bhalla score, age at chronic colonization with Pseudomonas aeruginosa and the pattern of essential fatty acids in serum phospholipids. Unknown factors may affect the presence of functional CFTR in patients with severe CFTR mutations. However, we could not find a correlation between the response to cAMP and any of the phenotype parameters. It appears that functional cAMP transport in the nasal epithelium is no guarantee of a mild phenotype and, conversely, that a patient lacking cAMP-dependent chloride transport can develop a mild phenotype.

  8. [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. PMID:9280562

  9. Progress in therapies for cystic fibrosis.

    PubMed

    De Boeck, Kris; Amaral, Margarida D

    2016-08-01

    Standard follow-up and symptomatic treatment have allowed most patients with cystic fibrosis to live to young adulthood. However, many patients still die prematurely from respiratory insufficiency. Hence, further investigations to improve these therapies are important and might have relevance for other diseases-eg, exploring how to increase airway hydration, how to safely downscale the increased inflammatory response in the lung, and how to better combat lung infections associated with cystic fibrosis. In parallel, development of modulators that target the underlying dysfunction in the cystic fibrosis transmembrane conductance regulator (CFTR) is fast moving forward. Existing treatments are specific to certain mutations, or mutation class, in CFTR. An effective, although not yet entirely corrective, treatment is available for patients with class III mutations, and a treatment with modest effectiveness is available for patients who are homozygous for Phe508del, albeit at a very high cost. Corrective treatments that are non-specific to mutation class and thus applicable to all patients-eg, gene therapy, cell-based therapies, and activation of alternative ion channels that bypass CFTR-are being explored, but they are still in early stages of development. In view of the large number of patients with very rare mutations, a plan to advance personalised biomarkers to predict treatment effect is also being investigated and validated. PMID:27053340

  10. [Molecular epidemiology of cystic fibrosis in Tunisia].

    PubMed

    Messaoud, T; Bel Haj Fredj, S; Bibi, A; Elion, J; Férec, C; Fattoum, S

    2005-01-01

    Cystic fibrosis is the most frequent autosomal recessive genetic disease in North European population. This pathology seems to not be rare in Tunisia. On another hand, development of molecular biology techniques has largely contributed to implement the study of the different mutations in the CFTR gene where over 1,300 mutations were reported. Herein, we describe the strategy used to detect molecular defects responsible of cystic fibrosis on 390 children (383 families) in Tunisian population. Several techniques were performed for genotype diagnosis: DNA extraction was from peripheral blood. Polymerase chain reaction (PCR) and polyacylamide gel electrophoresis, and reverse dot blot procedures were used to detect known point mutations. Denaturant gradient gel electrophoresis (DGGE) were used in a next step searching for the unknown point mutations that are later identified by automated sequencing on ABIprism 310. This strategy allowed us to detect 17 different mutations located on the different exons of the CFTR gene. The most frequent was the F508del (50.74%) followed by three other mutations (G542X, W1282X and N1303K) known to be common in the Mediterranean area. For mutations (T665S, 2766 del8, F1166C, L1043R) were exclusively found, up to now, in the Tunisian population. Our results permitted to establish cystic fibrosis mutations and their distribution in Tunisia and to implement an appropriate prevention program of these diseases through the genetic council and prenatal diagnosis.

  11. Allergic bronchopulmonary aspergillosis in cystic fibrosis. A European epidemiological study. Epidemiologic Registry of Cystic Fibrosis.

    PubMed

    Mastella, G; Rainisio, M; Harms, H K; Hodson, M E; Koch, C; Navarro, J; Strandvik, B; McKenzie, S G

    2000-09-01

    Allergic bronchopulmonary aspergillosis (ABPA) is a disease resulting from a hypersensitivity response to Aspergillus fumigatus, although the pathogenesis of the disease is unknown and its prevalence in cystic fibrosis (CF) is still poorly defined. Data from the Epidemiologic Registry of Cystic Fibrosis (ERCF) on 12,447 CF patients gathered from 224 CF centres in nine European countries were analysed. The ERCF definition of ABPA diagnosis is a positive skin test and serum precipitins to A. fumigatus, together with serum immunoglobulin (Ig)E levels >1,000 U x mL(-1) and additional clinical or laboratory parameters. The overall prevalence of ABPA in the ERCF population was 7.8% (range: 2.1% in Sweden to 13.6% in Belgium). Prevalence was low <6 yrs of age but was almost constant approximately 10% thereafter. No sex differences were observed. ABPA affected 8.0% of patients with a deltaF508/deltaF508 genotype and 5-6% with deltaF508/G551D, deltaF508/G542X and deltaF508/N1303K genotypes. ABPA patients presented a lower forced expiratory volume in one second (FEV1) than those without ABPA at any age and the prevalence ranged from 6.6% in patients with FEV1 > or =20-12.9% in those with FEV1 <40%. ABPA was associated with higher rates of microbial colonization, pneumothorax and massive haemoptysis, and with higher IgG serum levels and poorer nutritional status. A mixed model regression analysis of lung function showed that FEVI decline during the follow-up period was not substantially different in ABPA patients compared with non-ABPA patients for any subgroups based on age or disease severity at enrollment. To conclude, allergic bronchopulmonary aspergillosis is a frequent complication in cystic fibrosis patients, particularly after the age of 6 yrs, and it is generally associated with a poorer clinical condition. However, any clear independent influence of allergic bronchopulmonary aspergillosis on the rate of lung function decline in the short term was not shown.

  12. 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

  13. Cystic Fibrosis Gene Therapy in the UK and Elsewhere.

    PubMed

    Griesenbach, Uta; Pytel, Kamila M; Alton, Eric W F W

    2015-05-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here.

  14. Cystic Fibrosis Gene Therapy in the UK and Elsewhere

    PubMed Central

    Pytel, Kamila M.; Alton, Eric W.F.W.

    2015-01-01

    Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here. PMID:25838137

  15. 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. PMID:27142487

  16. 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. . PMID:26003065

  17. [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. PMID:21703474

  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. Optimising inhaled mannitol for cystic fibrosis in an adult population

    PubMed Central

    Flume, Patrick A.; Aitken, Moira L.; Agent, Penny; Charlton, Brett; Forster, Emma; Fox, Howard G.; Hebestreit, Helge; Kolbe, John; Zuckerman, Jonathan B; Button, Brenda M.

    2015-01-01

    Abstract There has been remarkable progress in the treatment of cystic fibrosis (CF) patients over the past 20 years. However, limitations of standard therapies have highlighted the need for a convenient alternative treatment to effectively target the pathophysiologic basis of CF-related disease by improving mucociliary clearance of airway secretions and consequently improve lung function and reduce respiratory exacerbations. Mannitol is an osmotic agent available as a dry powder, dispensed in a convenient disposable inhaler device for the treatment of adult patients with CF. Inhalation of mannitol as a dry powder is thought to change the viscoelastic properties of airway secretions, increase the hydration of the airway surface liquid and contribute to increased mucociliary and cough clearance of retained secretions. In two large phase 3 studies [1, 2], long-term use of inhaled mannitol resulted in a significant and clinically meaningful improvement in lung function relative to control in adult CF subjects and had an acceptable safety profile. Clinical experience with inhaled mannitol confirms that it is safe and effective. A minority of patients are unable to tolerate the medication. However, through training in proper inhaler technique and setting clear expectations regarding therapeutic effects, both the tolerance and adherence necessary for long term efficacy can be positively influenced. Educational aims To discuss the importance of airway clearance treatments in the management of cystic fibrosis. To describe the clinical data that supports the use of mannitol in adult patients with cystic fibrosis. To highlight the role of mannitol tolerance testing in screening for hyperresponsiveness. To provide practical considerations for patient education in use of mannitol inhaler. Key points Inhaled mannitol is a safe and effective option in adult patients with cystic fibrosis. Mannitol tolerance testing effectively screens for hyperresponsiveness prior to initiation

  20. Cystic Fibrosis-Related Diabetes in Children: An Update.

    PubMed

    Kim, Roy J

    2016-09-01

    Cystic fibrosis-related diabetes mellitus (CFRD) is the most common endocrine complication of cystic fibrosis (CF), affecting more than 50% of patients by the 4th decade of life. CFRD is often preceded by worsening pulmonary status and nutritional decline. Treatment of CFRD is associated with improvements in body weight and pulmonary function and a reduction in pulmonary exacerbations. Because of the clinical significance of CFRD, diabetes screening with an oral glucose tolerance test (OGTT) is recommended annually for all patients with CF starting at age 10 years. The OGTT detects CFRD with greater sensitivity than random glucose or hemoglobin A1c testing. The first-line treatment for CFRD is insulin. The use of other treatments such as oral medications remains under study. [Pediatr Ann. 2016;45(9):e321-e326.].

  1. Cystic Fibrosis-Related Diabetes in Children: An Update.

    PubMed

    Kim, Roy J

    2016-09-01

    Cystic fibrosis-related diabetes mellitus (CFRD) is the most common endocrine complication of cystic fibrosis (CF), affecting more than 50% of patients by the 4th decade of life. CFRD is often preceded by worsening pulmonary status and nutritional decline. Treatment of CFRD is associated with improvements in body weight and pulmonary function and a reduction in pulmonary exacerbations. Because of the clinical significance of CFRD, diabetes screening with an oral glucose tolerance test (OGTT) is recommended annually for all patients with CF starting at age 10 years. The OGTT detects CFRD with greater sensitivity than random glucose or hemoglobin A1c testing. The first-line treatment for CFRD is insulin. The use of other treatments such as oral medications remains under study. [Pediatr Ann. 2016;45(9):e321-e326.]. PMID:27622916

  2. 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

  3. Cystic Fibrosis of the Pancreas—Diagnosis by Sodium Electrode Sweat Tests

    PubMed Central

    Friedlander, Saul; Gasber, Robert E.; Lieb, Larry M.

    1969-01-01

    One of the most difficult and unreproducible procedures in clinical laboratories has been the measurement of electrolytes in sweat. The iontophoresis techniques for the diagnosis of cystic fibrosis of the pancreas, which are widely used, are fraught with difficulties. Measurement of sweat electrolytes with sodium or chloride electrodes is gradually replacing the iontophoresis methods. A simple modification of the sodium electrode technique was used for diagnosis in 11 cystic fibrosis patients and in 260 normal children. The values obtained with the sodium electrode clearly separated the normal children from those with cystic fibrosis. ImagesChart 1. Case 1.Chart 1. Case 2.Chart 1. Case 3. PMID:5771594

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

    PubMed Central

    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. PMID:22787388

  5. 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.

  6. Rapid Detection and Immune Characterization of Mycobacterium abscessus Infection in Cystic Fibrosis Patients

    PubMed Central

    Mayatepek, Ertan; Mackenzie, Colin R.; Schramm, Dirk; Jacobsen, Marc

    2015-01-01

    Cystic fibrosis patients are highly susceptible to infections with non-tuberculous mycobacteria. Especially Mycobacterium abscessus infections are common but reliable diagnosis is hampered by non-specific clinical symptoms and insensitive mycobacterial culture. In the present study we established novel methods for rapid detection and immune characterization of Mycobacterium abscessus infection in cystic fibrosis patients. We performed Mycobacterium abscessus specific DNA-strip- and quantitative PCR-based analyses of non-cultured sputum samples to detect and characterize Mycobacterium abscessus infections. Concomitantly in vitro T-cell reactivation with purified protein derivatives (PPDs) from different mycobacterial species was used to determine Mycobacterium abscessus specific T-cell cytokine expression of infected cystic fibrosis patients. Four of 35 cystic fibrosis patients (11.4%) were Mycobacterium abscessus culture positive and showed concordant DNA-strip-test results. Quantitative PCR revealed marked differences of mycobacterial burden between cystic fibrosis patients and during disease course. Tandem-repeat analysis classified distinct Mycobacterium abscessus strains of infected cystic fibrosis patients and excluded patient-to-patient transmission. Mycobacterium abscessus specific T-cells were detected in the blood of cystic fibrosis patients with confirmed chronic infection and a subgroup of patients without evidence of Mycobacterium abscessus infection. Comparison of cytokine expression and phenotypic markers revealed increased proportions of CD40L positive T-cells that lack Interleukin-2 expression as a marker for chronic Mycobacterium abscessus infections in cystic fibrosis patients. Direct sputum examination enabled rapid diagnosis and quantification of Mycobacterium abscessus in cystic fibrosis patients. T-cell in vitro reactivation and cytokine expression analyses may contribute to diagnosis of chronic Mycobacterium abscessus infection. PMID:25742660

  7. Rapid detection and immune characterization of Mycobacterium abscessus infection in cystic fibrosis patients.

    PubMed

    Steindor, Mathis; Nkwouano, Vanesa; Mayatepek, Ertan; Mackenzie, Colin R; Schramm, Dirk; Jacobsen, Marc

    2015-01-01

    Cystic fibrosis patients are highly susceptible to infections with non-tuberculous mycobacteria. Especially Mycobacterium abscessus infections are common but reliable diagnosis is hampered by non-specific clinical symptoms and insensitive mycobacterial culture. In the present study we established novel methods for rapid detection and immune characterization of Mycobacterium abscessus infection in cystic fibrosis patients. We performed Mycobacterium abscessus specific DNA-strip- and quantitative PCR-based analyses of non-cultured sputum samples to detect and characterize Mycobacterium abscessus infections. Concomitantly in vitro T-cell reactivation with purified protein derivatives (PPDs) from different mycobacterial species was used to determine Mycobacterium abscessus specific T-cell cytokine expression of infected cystic fibrosis patients. Four of 35 cystic fibrosis patients (11.4%) were Mycobacterium abscessus culture positive and showed concordant DNA-strip-test results. Quantitative PCR revealed marked differences of mycobacterial burden between cystic fibrosis patients and during disease course. Tandem-repeat analysis classified distinct Mycobacterium abscessus strains of infected cystic fibrosis patients and excluded patient-to-patient transmission. Mycobacterium abscessus specific T-cells were detected in the blood of cystic fibrosis patients with confirmed chronic infection and a subgroup of patients without evidence of Mycobacterium abscessus infection. Comparison of cytokine expression and phenotypic markers revealed increased proportions of CD40L positive T-cells that lack Interleukin-2 expression as a marker for chronic Mycobacterium abscessus infections in cystic fibrosis patients. Direct sputum examination enabled rapid diagnosis and quantification of Mycobacterium abscessus in cystic fibrosis patients. T-cell in vitro reactivation and cytokine expression analyses may contribute to diagnosis of chronic Mycobacterium abscessus infection. PMID:25742660

  8. 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

  9. The Dynamics of Disease Progression in Cystic Fibrosis

    PubMed Central

    Adler, Frederick R.; Liou, Theodore G.

    2016-01-01

    In cystic fibrosis, statistical models have been more successful in predicting mortality than the time course of clinical status. We develop a system of partial differential equations that simultaneously track mortality and patient status, with all model parameters estimated from the extensive and carefully maintained database from the Cystic Fibrosis Foundation. Cystic fibrosis is an autosomal recessive disease that leads to loss of lung function, most commonly assessed using the Forced Expiratory Volume in 1 second (FEV1%). This loss results from inflammation secondary to chronic bacterial infections, particularly Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus (MSSA) and members of the virulent Burkholderia complex. The model tracks FEV1% and carriage of these three bacteria over the course of a patient’s life. Analysis of patient state changes from year to year reveals four feedback loops: a damaging positive feedback loop between P. aeruginosa carriage and lower FEV1%, negative feedback loops between P. aeruginosa and MSSA and between P. aeruginosa and Burkholderia, and a protective positive feedback loop between MSSA carriage and higher FEV1%. The partial differential equations built from this data analysis accurately capture the life-long progression of the disease, quantify the key role of high annual FEV1% variability in reducing survivorship, the relative unimportance of short-term bacterial interactions for long-term survival, and the potential benefits of eradicating the most harmful bacteria. PMID:27248696

  10. 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.

  11. [Cystic fibrosis: new treatments targeting the CFTR protein].

    PubMed

    Fajac, I; Sermet-Gaudelus, I

    2013-04-01

    Cystic fibrosis is an autosomal recessive genetic disease due to mutations in the (cystic fibrosis transmembrane conductance regulator) CFTR gene. The CFTR protein is a chloride channel expressed at the surface of several epithelial cells. Defective function of the CFTR protein leads to a severe disease in which lung disease is the leading cause of death. Current treatments are symptomatic. Nevertheless, with specialist and holistic care in dedicated cystic fibrosis centres, the median survival has improved. But the average age of death remains 29 years. Innovative molecules aiming to correct the CFTR protein itself are under development. These will be personalised treatments depending on the genotype or the type of CFTR dysfunction. The first molecule, ivacaftor, has just been approved in Europe and the USA. Adults and children treated with ivacaftor in clinical trials had a 10% improvement in FEV1 that was maintained for more than a year. Although at present ivacaftor is approved for only a small percentage of patients, the therapeutic strategy of correcting CFTR protein has been proved a valid approach. Other molecules targeting other defects in the CFTR protein are under evaluation.

  12. CYSTIC FIBROSIS AND ANTIBIOTIC HYPERSENSITIVITY: PRESENT KNOWLEDGE AND PRACTICAL APPROACH.

    PubMed

    Caimmi, D; Chiron, R; Tremblay, F; Caimmi, S; Ricci, A; Licari, A; Marseglia, G L

    2015-01-01

    Cystic fibrosis is one of the most common fatal genetic diseases (1 in 2500 births). The defect causing the disease is localized on the 7q31 gene, which codifies for the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) transmembrane protein. CFTR is a chloride channel localized on the epithelial cells of the mucosa of the respiratory tract, pancreatic ducts, biliary tree, intestine, vas deferens and sweat glands. More than 2000 different mutations are currently known; some are prominent or relatively frequent, ranging from one population to another. The most frequent complications of cystic fibrosis are those affecting the bronchial tree. Patients suffer from recurrent lung infections, which involve a progressive loss of lung function. The pulmonary infections are frequent or chronic and limit the quality of life of patients. In addition to being enormously exposed to antibiotics, they have many more opportunities to develop hypersensitivity reactions to these molecules. Only a complete allergy work-up with a detailed analysis of the clinical history, skin tests and provocation test can show if the patient has actually experienced an allergic hypersensitivity reaction. Desensitization is to be considered as a treatment that may help patients benefit from antibiotic treatment in those cases in which they have a proven allergy to a certain molecule. PMID:26634585

  13. The Dynamics of Disease Progression in Cystic Fibrosis.

    PubMed

    Adler, Frederick R; Liou, Theodore G

    2016-01-01

    In cystic fibrosis, statistical models have been more successful in predicting mortality than the time course of clinical status. We develop a system of partial differential equations that simultaneously track mortality and patient status, with all model parameters estimated from the extensive and carefully maintained database from the Cystic Fibrosis Foundation. Cystic fibrosis is an autosomal recessive disease that leads to loss of lung function, most commonly assessed using the Forced Expiratory Volume in 1 second (FEV1%). This loss results from inflammation secondary to chronic bacterial infections, particularly Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus (MSSA) and members of the virulent Burkholderia complex. The model tracks FEV1% and carriage of these three bacteria over the course of a patient's life. Analysis of patient state changes from year to year reveals four feedback loops: a damaging positive feedback loop between P. aeruginosa carriage and lower FEV1%, negative feedback loops between P. aeruginosa and MSSA and between P. aeruginosa and Burkholderia, and a protective positive feedback loop between MSSA carriage and higher FEV1%. The partial differential equations built from this data analysis accurately capture the life-long progression of the disease, quantify the key role of high annual FEV1% variability in reducing survivorship, the relative unimportance of short-term bacterial interactions for long-term survival, and the potential benefits of eradicating the most harmful bacteria. PMID:27248696

  14. Evidence for a Cystic Fibrosis Enteropathy

    PubMed Central

    Adriaanse, Marlou P. M.; van der Sande, Linda J. T. M.; van den Neucker, Anita M.; Menheere, Paul P. C. A.; Dompeling, Edward; Buurman, Wim A.; Vreugdenhil, Anita C. E.

    2015-01-01

    Background Previous studies have suggested the existence of enteropathy in cystic fibrosis (CF), which may contribute to intestinal function impairment, a poor nutritional status and decline in lung function. This study evaluated enterocyte damage and intestinal inflammation in CF and studied its associations with nutritional status, CF-related morbidities such as impaired lung function and diabetes, and medication use. Methods Sixty-eight CF patients and 107 controls were studied. Levels of serum intestinal-fatty acid binding protein (I-FABP), a specific marker for enterocyte damage, were retrospectively determined. The faecal intestinal inflammation marker calprotectin was prospectively studied. Nutritional status, lung function (FEV1), exocrine pancreatic insufficiency (EPI), CF-related diabetes (CFRD) and use of proton pump inhibitors (PPI) were obtained from the medical charts. Results Serum I-FABP levels were elevated in CF patients as compared with controls (p<0.001), and correlated negatively with FEV1 predicted value in children (r-.734, p<0.05). Faecal calprotectin level was elevated in 93% of CF patients, and correlated negatively with FEV1 predicted value in adults (r-.484, p<0.05). No correlation was found between calprotectin levels in faeces and sputum. Faecal calprotectin level was significantly associated with the presence of CFRD, EPI, and PPI use. Conclusion This study demonstrated enterocyte damage and intestinal inflammation in CF patients, and provides evidence for an inverse correlation between enteropathy and lung function. The presented associations of enteropathy with important CF-related morbidities further emphasize the clinical relevance. PMID:26484665

  15. Cystic Fibrosis Diagnosis and Newborn Screening.

    PubMed

    Rosenfeld, Margaret; Sontag, Marci K; Ren, Clement L

    2016-08-01

    The diagnosis of cystic fibrosis (CF) has evolved over the past decade as newborn screening has become universal in the United States and elsewhere. The heterogeneity of phenotypes associated with CF transmembrane conductance regulator (CFTR) dysfunction and mutations in the CFTR gene has become clearer, ranging from classic pancreatic-insufficient CF to manifestations in only 1 organ system to indeterminate diagnoses identified by newborn screening. The tools available for diagnosis have also expanded. This article reviews the newest diagnostic criteria for CF, newborn screening, prenatal screening and diagnosis, and indeterminate diagnoses in newborn-screened infants and symptomatic adults. PMID:27469178

  16. 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

  17. Cystic fibrosis diagnosed in an elderly man.

    PubMed

    Gilljam, Marita; Björck, Eva

    2004-01-01

    Although most patients with cystic fibrosis (CF) are diagnosed in early childhood, the diagnosis may be delayed for patients with mild symptoms or single-organ disease. We describe a man with known infertility and a history of productive cough diagnosed with CF at 61 years of age. The patient carries two mutations and one variant in the CF transmembrane conductance regulator gene: 394delTT, P99L and R75Q. During a 15-year follow-up time he has developed significant pulmonary disease.

  18. Nutrition and Growth in Cystic Fibrosis.

    PubMed

    Lusman, Sarah; Sullivan, Jillian

    2016-08-01

    Close attention to nutrition and growth is essential in caring for children with cystic fibrosis (CF). Growth and nutritional status should be monitored as part of routine CF care. Children with CF should achieve growth and nutritional status comparable with that of well-nourished children without CF. Children with CF are at risk for nutritional deficiencies. Optimal nutritional and growth status may be difficult to attain in this population given risk of insufficient caloric intake and likelihood of increased caloric expenditure. Various methods to attain optimal nutritional status may be used, including oral supplementation, behavioral treatment, pharmacotherapy, and enteral nutrition. PMID:27469181

  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. Pseudomonal infection in cystic fibrosis: the battle continues.

    PubMed

    Elkin, Sarah; Geddes, Duncan

    2003-12-01

    Pseudomonas aeruginosa lung infection is the major cause of morbidity and mortality in patients with cystic fibrosis. Infection usually begins in childhood and is responsible for respiratory failure and death in most patients with cystic fibrosis. The organism triggers an exuberant chronic inflammatory reaction which damages the airways and leads to progressive loss of lung function. Over the last decade significant advances have been made in the understanding of the pathophysiology of cystic fibrosis airways disease. These should assist the development of new and better therapies to treat this pathogen. This review provides an overview of pseudomonal infection in cystic fibrosis, including mechanisms by which the bacteria may colonize the cystic fibrosis airway, persistence of pseudomonal infection and the biofilm mode of growth. Available treatments and possible novel approaches to therapy will be discussed. PMID:15482158

  1. New insights into cystic fibrosis-related diabetes in children.

    PubMed

    Ode, Katie L; Moran, Antoinette

    2013-09-01

    Cystic fibrosis-related diabetes (CFRD) is the most common complication of cystic fibrosis. It is associated with significantly increased morbidity and mortality in adults and children. Adolescents with cystic fibrosis have a much higher prevalence of diabetes than any other similar age population. Glucose abnormalities that precede diabetes are even more common, especially in children younger than 10 years. The pathophysiology of glucose metabolic abnormalities is poorly understood, but insulin insufficiency is clearly the main component. Findings from animal studies have provided insight into the pathophysiology of CFRD, and imply that carbohydrate metabolic abnormalities might begin at much younger ages than was previously thought in patients with cystic fibrosis, and might be related to the basic cystic fibrosis chloride channel defect. In this Review we explore present knowledge of CFRD in children and adolescents, and new data that indicate that the pathophysiology of CFRD begins in very young patients.

  2. Moving cystic fibrosis care from rescue to prevention by embedding adherence measurement in routine care.

    PubMed

    Wildman, Martin J; Hoo, Zhe Hui

    2014-06-01

    Cystic fibrosis [CF] is a chronic disease in which preventative treatment with nebulised antibiotics can reduce pulmonary exacerbations that otherwise require rescue therapy. However, adherence is low. Making adherence to maintenance treatment visible is a crucial step towards improving adherence. In this article, we discuss how adherence data can be used to support Quality Improvement in CF through behaviour change in both people with cystic fibrosis and their clinical teams. PMID:24835307

  3. Gene therapy for the treatment of cystic fibrosis.

    PubMed

    Burney, Tabinda J; Davies, Jane C

    2012-01-01

    Gene therapy is being developed as a novel treatment for cystic fibrosis (CF), a condition that has hitherto been widely-researched yet for which no treatment exists that halts the progression of lung disease. Gene therapy involves the transfer of correct copies of cystic fibrosis transmembrane conductance regulator (CFTR) DNA to the epithelial cells in the airways. The cloning of the CFTR gene in 1989 led to proof-of-principle studies of CFTR gene transfer in vitro and in animal models. The earliest clinical trials in CF patients were conducted in 1993 and used viral and non-viral gene transfer agents in both the nasal and bronchial airway epithelium. To date, studies have focused largely on molecular or bioelectric (chloride secretion) outcome measures, many demonstrating evidence of CFTR expression, but few have attempted to achieve clinical efficacy. As CF is a lifelong disease, turnover of the airway epithelium necessitates repeat administration. To date, this has been difficult to achieve with viral gene transfer agents due to host recognition leading to loss of expression. The UK Cystic Fibrosis Gene Therapy Consortium (Imperial College London, University of Edinburgh and University of Oxford) is currently working on a large and ambitious program to establish the clinical benefits of CF gene therapy. Wave 1, which has reached the clinic, uses a non-viral vector. A single-dose safety trial is nearing completion and a multi-dose clinical trial is shortly due to start; this will be powered for clinically-relevant changes. Wave 2, more futuristically, will look at the potential of lentiviruses, which have long-lasting expression. This review will summarize the current status of translational research in CF gene therapy. PMID:23776378

  4. Airway clearance strategies in cystic fibrosis and non-cystic fibrosis bronchiectasis.

    PubMed

    Main, Eleanor; Grillo, Lizzie; Rand, Sarah

    2015-04-01

    Many patients with cystic fibrosis (CF) and non-CF bronchiectasis present with common symptoms in clinical domains that appear to benefit from airway clearance strategies. These symptoms include chronic productive cough, retention of excessive, purulent mucus in dilated airways, impairment of normal mucociliary clearance (MCC), atelectasis, breathlessness, fatigue, respiratory inflammation, fever, infection, and airflow obstruction. Airway clearance strategies may involve singular and focused interventions for the purpose of removing secretions and improving lung recruitment and gas exchange in patients with atelectasis. Strategies may also involve indirect or adjunctive interventions that facilitate or enhance effective airway clearance at different ages or stages of the disease process, for example, inhalation therapy, exercise, oxygen therapy, or noninvasive ventilation. The aim is to optimize care by selecting any one or combination of these in responding intelligently and sensitively to individual and changing patient requirements during their lifetime. Currently, a solid evidence base does not exist for airway clearance strategies in CF and non-CF bronchiectasis, and much of airway clearance clinical practice remains in the domain of clinical expertise. The paucity of evidence is partly explained by the relatively immature research machinery in allied health care internationally but is also partly to do with inadequate or inappropriate research designs. This article aims to provide an overview of the nature of, and physiological basis for, the direct and indirect airway clearance strategies in CF and non-CF bronchiectasis with reference to the best available evidence. PMID:25826592

  5. 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

  6. 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.

  7. [CYSTIC FIBROSIS: CARE OF THE LUNG DISEASE].

    PubMed

    Hubert, Dominique

    2015-10-01

    (Rh-DNase) and/or hydration (hypertonic saline) nebulisations, Moreover, treatment with inhaled antibiotics is indicated (tobramycin, colistine or aztreonam lysine) for chronic lung infection with Pseudomonas aeruginosa (PA). The treatment regimen also includes bronchodilators for bronchospasms and azithromycin. Regular physical activity is recommended. A treatment potentiating the CFTR protein, ivacaftor, is now indicated for patients with a class 3 mutation. Initial bronchial infection with PA must be treated as soon as possible in order to eradicate the pathogen. Pulmonary exacerbations require antibiotic courses, either orally or intravenously for PA infection. Complications require hospitalisation, with thoracic chest tube placement for a pneumothorax or bronchial artery embolisation for massive hemoptysis. Oxygen therapy and non-invasive ventilation with a nasal mask become necessary when respiratory insufficiency progresses, justifying the initiation of the lung transplant process. Lung disease affects the prognosis of cystic fibrosis, therefore its management in cystic fibrosis centres is of utmost importance. Maintenance treatment mainly relies on daily chest physiotherapy, which can be facilitated by mucolytic PMID:26749716

  8. Technology evaluation: cystic fibrosis therapy, Genzyme.

    PubMed

    Cockett, M I

    1999-04-01

    Genzyme is developing therapies to replace the defective forms of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein in CF patients. The company is developing a gene therapy, as well as a recombinant production of CFTR for protein replacement therapy. Both approaches have been granted orphan drug status by the FDA [156348]. The results of several clinical trials were discussed at the first annual meeting of the American Society of Gene Therapy in May 1998. A single dose nasal administration was well tolerated by volunteers, but had disappointing efficacy. In a study completed at the Royal Brompton Hospital, London, a single dose aerosol application of GL-67:DOPE was administered to eight patients, while another eight received GL-67:DOPE plus pCF1-CFTR. In the second group, a moderate increase in the potential difference in the lung was observed, with a slight trend towards bacterial adherence normalization in the airway cells. Seven of the patients in the second group, and three patients who received lipid alone, developed, flu-like symptoms within 24 h. A trial at the University of Alabama, using the same formulation, showed that flu-like symptoms developed in six of eight patients by day two, and in all patients by day seven [290120]. In 1995, the company began a clinical safety trial involving delivery of a normal CF gene to the patient's lungs via an adenovirus vector. The administration involves the inhalation of an aerosol containing the vector or, separately, delivery to one lobe of the patient's lung via a bronchoscope [191678]. To evaluate additional delivery methods for the gene, Genzyme has an exclusive research agreement for the use of Vical's cytofectins as non-viral delivery vectors for CFTR. Also under investigation are delivery systems for the nasal epithelium using liposomes or lipid-DNA complexes. These protocols are being developed in collaboration with the National Heart & Lung Institute, London, and an undisclosed

  9. 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.

  10. 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. PMID:27394157

  11. Blood concentrations of pancreatitis associated protein in neonates: relevance to neonatal screening for cystic fibrosis

    PubMed Central

    Sarles, J.; Barthellemy, S.; Ferec, C.; Iovanna, J.; Roussey, M.; Farriaux, J.; Toutain, A.; Berthelot, J.; Maurin, N.; Codet, J.; Berthezene, P.; Dagorn, J.

    1999-01-01

    AIM—To determine whether pancreatitis associated protein (PAP) is a marker for cystic fibrosis which could be used in neonatal screening for the disease.
METHODS—PAP was assayed on screening cards from 202 807 neonates. Babies with PAP ⩾ 15 ng/ml, or ⩾ 11.5 ng/ml and immunoreactive trypsinogen (IRT) ⩾ 700 ng/ml were recalled for clinical examination, sweat testing, and cystic fibrosis transmembrane regulator (CFTR) gene analysis.
RESULTS—Median PAP value was 2.8 ng/ml. Forty four cases of cystic fibrosis were recorded. Recalled neonates (n=398) included only 11 carriers. A receiver operating characteristic curve analysis showed that PAP above 8.0 ng/ml would select 0.76% of babies, including all those with cystic fibrosis, except for one with meconium ileus and two with mild CFTR mutations. Screening 27146 babies with both PAP and IRT showed that only 0.12% had PAP> 8.0 ng/ml and IRT > 700 ng/ml, including all cases of cystic fibrosis.
CONCLUSION—PAP is increased in most neonates with cystic fibrosis and could be used for CF screening. Its combination with IRT looks promising.

 PMID:10325788

  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. What is the best airway clearance technique in cystic fibrosis?

    PubMed

    Main, Eleanor

    2013-05-01

    The global development of airway clearance techniques (ACTs) for cystic fibrosis (CF) and corresponding research spans over four decades. Five Cochrane reviews synthesising the evidence from a plethora of early short and medium term studies have not uncovered any superior method. Four recent long term RCT studies exposed fundamental shortcomings in the standard RCT trial design and the insensitivity of FEV1 in physiotherapy studies. Strong patient preference, lack of blinding and the requirement for effortful and demanding participation over long intervals will continue to derail efforts to find the best ACT for CF, unless they are addressed in future clinical trials. PMID:23541002

  14. Anabolic agent use in adults with cystic fibrosis.

    PubMed

    Green, Heather D; Barry, Peter J; Jones, Andrew M

    2015-10-01

    The use of non-prescribed anabolic agents amongst non-athletes is increasing with young, adult males with cystic fibrosis (CF) in the highest risk demographic. There is evidence that anabolic agents increase weight and muscle mass in adults with a variety of catabolic conditions but there is no evidence for their use in hormone sufficient adults with CF. We report a case of anabolic agent use in a male adult with CF and review the clinical features of anabolic agent use with a focus on adults with CF.

  15. Anabolic agent use in adults with cystic fibrosis.

    PubMed

    Green, Heather D; Barry, Peter J; Jones, Andrew M

    2015-10-01

    The use of non-prescribed anabolic agents amongst non-athletes is increasing with young, adult males with cystic fibrosis (CF) in the highest risk demographic. There is evidence that anabolic agents increase weight and muscle mass in adults with a variety of catabolic conditions but there is no evidence for their use in hormone sufficient adults with CF. We report a case of anabolic agent use in a male adult with CF and review the clinical features of anabolic agent use with a focus on adults with CF. PMID:26410285

  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. Chronic Rhinosinusitis in Patients with Cystic Fibrosis.

    PubMed

    Hamilos, Daniel L

    2016-01-01

    Chronic rhinosinusitis (CRS) is highly prevalent in patients with cystic fibrosis (CF) and accounts for significant morbidity and contribution to CF lung disease. Mutations of the cystic fibrosis transmembrane regulator gene occur with increased prevalence in patients with CRS without CF, suggesting some contribution to CRS pathophysiology. Nasal polyps (NPs) occur with increased prevalence in patients with CF of all ages and have a more neutrophilic appearance with fewer eosinophils and increased submucosal glandular elements in comparison to NPs from patients without CF. Mainstays of medical treatment include isotonic saline irrigations and topical intranasal glucocorticoids, with some evidence that topical intranasal glucocorticoids reduce NP size. Although inhaled hypertonic saline (7%) has been widely studied as a mucolytic agent for CF lung disease, there are no reports of its use in CF CRS. Mucolytics have also not been studied as a treatment for CRS in CF, and most evidence does not support their use for CF lung disease. Nasally nebulized dornase alfa (recombinant human deoxyribonuclease) following sinus surgery shows promise for treatment. Other unproven therapies include addition of baby shampoo to isotonic saline to potentially thin mucus and help prevent biofilm formation. There are no data to support the use of low-dose oral macrolide antibiotics or the use of prophylactic oral antibiotics for CRS in patients with CF. However, there is some support for the use of topical antibiotics, including colistimethate sodium or tobramycin, administered as a sinus irrigation or antral lavage in patients following sinus surgery when susceptible bacteria are cultured. Key components of CF sinus surgical management include extensive surgery to ensure that the maxillary, frontal, sphenoid, and ethmoid sinuses are all widely opened with smoothing of bony overhangs to prevent mucus retention and bacterial recolonization, postoperative meticulous daily nasal irrigations

  19. Cystic fibrosis mutations in Costa Rica.

    PubMed

    Venegas, Patricia B; Novak, Jessica M; Oscar, Castro A; Sánchez, Félix L; Gutiérrez, Inés G; Rivera, Julio M; Salas, Jorge P; Montero, Jenny F; Grody, Wayne W

    2003-04-01

    Using polymerase chain reaction amplification of DNA in dried blood spots and a nonisotopic reverse dot blot hybridization method, we performed molecular genetic analysis for 6 and for 16 of the most common mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in 24 unrelated Costa Rican individuals with cystic fibrosis (CF). While many countries and ethnic groups have been surveyed for CF mutations since the cloning of CFTR, Costa Rica has not heretofore been studied. Moreover, Costa Rica represents an especially intriguing population because of its mixed European-African-Amerindian origins and the existence of a detailed historical record of the founding Spanish families. Thus, such a study may reveal not only the population frequencies of various mutant alleles in this country, but also something about their geographic migrations and ethnic founder effects. The most common CF mutation in Caucasians, deltaF508, was found in only 11 (23%) of the CF chromosomes studied, while the G542X mutation, relatively rare in the general population but more common in southern Europe, was observed in 12 (25%). None of the other mutations tested was found in any of the subjects. We failed to detect the second mutant allele in 17 subjects and could not detect either allele in 4 subjects. The high prevalence of the G542X mutation in our cohort, which exceeds that of both the general Caucasian population and the American Hispanic population, reflects the strong genetic influence of the original Spanish founding families of Costa Rica. These results highlight important differences in Costa Rican CF genotypes as compared both to other North American and European populations and to American Hispanics, raising important implications about isolated founder effects and strategies for population screening in that country.

  20. Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report.

    PubMed

    Subbarao, Padmaja; Milla, Carlos; Aurora, Paul; Davies, Jane C; Davis, Stephanie D; Hall, Graham L; Heltshe, Sonya; Latzin, Philipp; Lindblad, Anders; Pittman, Jessica E; Robinson, Paul D; Rosenfeld, Margaret; Singer, Florian; Starner, Tim D; Ratjen, Felix; Morgan, Wayne

    2015-06-01

    The lung clearance index (LCI) is a lung function parameter derived from the multiple-breath washout (MBW) test. Although first developed 60 years ago, the technique was not widely used for many years. Recent technological advances in equipment design have produced gains in popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW parameters in the routine clinical management of patients with CF. PMID:26075554

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

    MedlinePlus

    ... from the NHLBI on Twitter. What Are the Signs and Symptoms of Cystic Fibrosis? The signs and ... mucus that contains blood and bacteria. Respiratory System Signs and Symptoms People who have CF have thick, ...

  2. 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. PMID:25151429

  3. Laboratory confirmation of the diagnosis of cystic fibrosis.

    PubMed

    Tocci, P M; McKey, R M

    1976-11-01

    The recent commercial introduction of a method for detecting albumin in meconium makes screening for cystic fibrosis feasible for many hospitals. If the tests is adopted, confirmatory tests should be available. Quantitative analyses of sweat for sodium by flame photometry and for chloride by silver titration and ion-sleective electrodes are now used as confirmatory tests. We compare results of these confirmatory methods applied to presons with cystic fibrosis, respiratory disorders, or digestive disorders, and to control subjects. PMID:975543

  4. Targeted therapies to improve CFTR function in cystic fibrosis.

    PubMed

    Brodlie, Malcolm; Haq, Iram J; Roberts, Katie; Elborn, J Stuart

    2015-01-01

    Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status. In 2012, a new era of precision medicine in cystic fibrosis therapeutics began with the licensing of a small molecule, ivacaftor, which successfully targets the underlying defect and improves CFTR function in a subgroup of patients in a genotype-specific manner. Here, we review the three main targeted approaches that have been adopted to improve CFTR function: potentiators, which recover the function of CFTR at the apical surface of epithelial cells that is disrupted in class III and IV genetic mutations; correctors, which improve intracellular processing of CFTR, increasing surface expression, in class II mutations; and production correctors or read-through agents, which promote transcription of CFTR in class I mutations. The further development of such approaches offers great promise for future therapeutic strategies in cystic fibrosis.

  5. 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

  6. Dornase alfa in the treatment of cystic fibrosis in Europe: a report from the Epidemiologic Registry of Cystic Fibrosis.

    PubMed

    Hodson, M E; McKenzie, S; Harms, H K; Koch, C; Mastella, G; Navarro, J; Strandvik, B

    2003-11-01

    Dornase alfa (Pulmozyme) treatment for patients with cystic fibrosis (CF) has been shown to improve pulmonary function and reduce exacerbations of infection in a number of placebo-controlled double-blind studies. Data in the Epidemiologic Registry of Cystic Fibrosis (ERCF) in November 1998 were used to assess the long-term effectiveness in routine clinical practice of dornase alfa in terms of pulmonary function and frequency of acute pulmonary exacerbations in CF. At that time, the ERCF contained data on 13,684 CF patients, with a mean observation period of 2.3 years. To be included in the analysis, patients had to have 2 years of data in the Registry in appropriate detail. Overall, untreated patients showed a decline in forced expiratory volume in 1 sec over a 2-year period of -2.3% predicted, but treated patients were stable, showing a change of 0.3% predicted, i.e., a treatment benefit of 2.5%. Compared to untreated patients, there were 25 fewer exacerbations per 100 treated patients per year. The analysis suggested that younger patients were likely to benefit more from treatment. The findings of randomized clinical trials were supported by the data collected in routine clinical practice.

  7. 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

  8. 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.

  9. Sepsis Caused by Achromobacter Xylosoxidans in a Child with Cystic Fibrosis and Severe Lung Disease

    PubMed Central

    Stobbelaar, Kim; Van Hoorenbeeck, Kim; Lequesne, Monique; De Dooy, Jozef; Ho, Erwin; Vlieghe, Erika; Ieven, Margaretha; Verhulst, Stijn

    2016-01-01

    Patient: Female, 10 Final Diagnosis: Sepsis Symptoms: Fever • hypotension • not tollerating enteral feeds • respiratory deterioration Medication: — Clinical Procedure: IV antibiotics • lungtransplantion Specialty: Pediatrics and Neonatology Objective: Unusual clinical course Background: Achromobacter xylosoxidans is an aerobic, motile, Gram-negative, opportunistic pathogen that can be responsible for various severe nosocomial and community-acquired infections. It has been found in immunocompromised patients and patients with several other underlying conditions, but the clinical role of this microorganism in cystic fibrosis is unclear. Case Report: We describe a case of septic shock caused by A. xylosoxidans in a 10-year-old child with cystic fibrosis and severe lung disease. Conclusions: As the prevalence of A. xylosoxidans in cystic fibrosis patients is rising and patient-to-patient transmission is highly probable, further studies are warranted to determine its role and to document the appropriate treatment strategy for eradication and long-term treatment of this organism. PMID:27498677

  10. 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

  11. 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

  12. 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.

  13. Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience.

    PubMed

    Sivam, S; Al-Hindawi, Y; Di Michiel, J; Moriarty, C; Spratt, P; Jansz, P; Malouf, M; Plit, M; Pleass, H; Havryk, A; Bowen, D; Haber, P; Glanville, A R; Bye, P T P

    2016-07-01

    Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation. PMID:27405894

  14. The basidiomycetous yeast Trichosporon may cause severe lung exacerbation in cystic fibrosis patients – clinical analysis of Trichosporon positive patients in a Munich cohort

    PubMed Central

    2013-01-01

    Background The relevance of Trichosporon species for cystic fibrosis (CF) patients has not yet been extensively investigated. Methods The clinical course of CF patients with Trichosporon spp. in their respiratory secretions was analysed between 2003 and 2010 in the Munich CF center. All respiratory samples of 360 CF patients (0 – 52.4 years; mean FEV1 2010 81.4% pred) were investigated. Results In 8 patients (2.2%, 3 male, mean age 21.8 years) Trichosporon was detected at least once. One patient carried T. asahii. One patient carried T. mycotoxinivorans and one patient T. inkin as determined by DNA sequencing. As potential risk factors for Trichosporon colonization steroid treatment, allergic bronchopulmonary aspergillosis (ABPA) and CF associated diabetes were identified in 6, 5, and 2 patients respectively. For one patient, the observation period was not long enough to determine the clinical course. One patient had only a single positive specimen and exhibited a stable clinical course determined by change in forced expiratory volume in one second (FEV1), body-mass-index (BMI), C-reactive protein (CRP) and immunoglobulin G (IgG). Of 6 patients with repeatedly positive specimen (mean detection period 4.5 years), 4 patients had a greater decline in FEV1 than expected, 2 of these a decline in BMI and 1 an increase in IgG above the reference range. 2 patients received antimycotic treatment: one patient with a tormenting dry cough subjectively improved under Amphotericin B inhalation; one patient with a severe exacerbation due to T. inkin was treated with i.v. Amphotericin B, oral Voriconazole and Posaconazole which stabilized the clinical condition. Conclusions This study demonstrates the potential association of Trichosporon spp. with severe exacerbations in CF patients. PMID:24180379

  15. Practical Guidelines: Lung Transplantation in Patients with Cystic Fibrosis

    PubMed Central

    Hirche, T. O.; Knoop, C.; Hebestreit, H.; Shimmin, D.; Solé, A.; Elborn, J. S.; Ellemunter, H.; Aurora, P.; Hogardt, M.; Wagner, T. O. F.; ECORN-CF Study Group

    2014-01-01

    There are no European recommendations on issues specifically related to lung transplantation (LTX) in cystic fibrosis (CF). The main goal of this paper is to provide CF care team members with clinically relevant CF-specific information on all aspects of LTX, highlighting areas of consensus and controversy throughout Europe. Bilateral lung transplantation has been shown to be an important therapeutic option for end-stage CF pulmonary disease. Transplant function and patient survival after transplantation are better than in most other indications for this procedure. Attention though has to be paid to pretransplant morbidity, time for referral, evaluation, indication, and contraindication in children and in adults. This review makes extensive use of specific evidence in the field of lung transplantation in CF patients and addresses all issues of practical importance. The requirements of pre-, peri-, and postoperative management are discussed in detail including bridging to transplant and postoperative complications, immune suppression, chronic allograft dysfunction, infection, and malignancies being the most important. Among the contributors to this guiding information are 19 members of the ECORN-CF project and other experts. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Christiane Herzog Foundation. PMID:24800072

  16. Cystic fibrosis transmembrane regulator gene mutations in Bahrain.

    PubMed

    Eskandarani, H A

    2002-12-01

    A genotypic study was undertaken to characterize the cystic fibrosis transmembrane regulator gene mutations (CFTR) in the Bahraini cystic fibrosis (CF) population using a polymerase chain reaction-based direct gene test to search for 15 common CF mutations amongst Arabs. During the period October 2000 to May 2001, 19 patients (12 males and seven females; aged at time of study between 4 months and 14 years with a mean age of 5.4 +/- 4.3 years) from 13 families were recruited in the study. Patients were diagnosed as having CF, based on a typical clinical picture and sweat chloride levels > 60 mmol/l and were screened for CFTR mutations. The rate of consanguinity among the families was 77 per cent. Eight mutations were detected in 21 of the 26 alleles examined. The overall detection rate was approximately 81 per cent. The allele frequency of the eight mutations was estimated to be approximately 73 per cent. There was no specific phenotypic pattern that correlated with a specific genotype. All families except two were of Bahraini origin. Of the eight mutations detected, four were common among Bahrainis (2043delG > 548A --> T > 4041C --> G = deltaF508, in order of decreasing frequency), accounting for 66 per cent of the Bahraini CF alleles. However, we also detected four different heterozygous mutations, namely: 1161delC, 1756G -->T, 3120 + 1G --> A, and 3661A --> T, accounting for 16 per cent of the Bahraini CF alleles.

  17. 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

  18. Improving outcomes in patients with cystic fibrosis.

    PubMed

    Warwick, Geoffrey; Elston, Caroline

    2011-01-01

    Cystic fibrosis (CF) is the most common fatal inherited disease in Caucasian people. Inheritance follows an autosomal recessive pattern. Recent data indicate that there are more than 9,000 patients with CF in the UK. At a cellular level there is an abnormal CF transmembrane conductance regulator (CFTR), a protein essential for chloride and sodium homoeostasis, caused by a mutation in the CF gene. The consequence of this abnormal protein is thick, viscous secretions in the lungs and GI tract, which lead to recurrent lung infections and pancreatic insufficiency with intestinal malabsorption. Most patients present in early childhood with classic CF. They show one or more of the typical CF phenotypic characteristics (chronic pulmonary disease, GI symptoms and malabsorption, nutritional abnormalities and sinus disease). A minority of patients have atypical CF. They tend to present at an older age, often in adulthood, are mainly pancreatic sufficient, have milder disease and a better prognosis. When CF is suspected the diagnosis can be confirmed by measuring sweat chloride concentration and by looking for CFTR mutations. Immunoreactive trypsinogen is measured in blood taken from a heel prick in all neonates, and is a marker of pancreatic injury consistent with (but not specific for) CF. PMID:21932505

  19. Dermatoglyphic Patterns in Cystic Fibrosis Children

    PubMed Central

    Ezzati, Atefeh; Batoei, Fereshteh; Jafari, Seyed-Ali; Kiyani, Mohammad-Ali; Mahdavi-Shahri, Naser; Ahanchian, Hamid; Tehranian, Shahrzad; Kianifar, Hamid-Reza

    2014-01-01

    Objective: It is believed that fingerprints and palm patterns may represent genetically determined congenital abnormalities in Cystic Fibrosis (CF). The main idea of this paper was to determine differences of fingerprints and palm patterns in CF and normal children. Methods: Forty-six CF children (27 males, 19 females) and 341 (113 males, 228 females) healthy individuals were recruited for this study. Fingerprint patterns, Total ridge count (TRC) of each finger, a-b ridge count, and atd angles of all participants were recorded. Asymmetry of the right and left hand for each value was determined and dissimilarity in fingerprint patterns between homologous fingers was compared using Chi-square analysis, Mann-Whitney U test and Fisher's exact test. Findings: There were significant differences in the mean TRC of the right digit IV (P=0.009), left digit III (P=0.02), left digit IV (P=0.03), and left digit V (P=0.03). Furthermore, we found significant differences in right atd angel (P=0.001), left atd angel (P=0.002), right a-b ridge (P=0.007) and left a-b ridge (P=0.001). In contrast, we found no significant differences in atd angle asymmetry, a-b ridge count asymmetry and pattern dissimilarity score between both groups (P>0.05). Conclusion: Dermatoglyphic characteristics could be used as a supplementary diagnostic method in CF children. PMID:25793070

  20. 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

  1. Update on gene modifiers in cystic fibrosis

    PubMed Central

    Collaco, Joseph M.; Cutting, Garry R.

    2009-01-01

    Purpose of review Cystic fibrosis (CF) is a common, life-limiting monogenic disease, which typically manifests as progressive bronchiectasis, exocrine pancreatic dysfunction, and recurrent sinopulmonary infections. Although the gene responsible for CF (CFTR) was described in 1989, it has become increasingly evident that modifier genes and environmental factors play substantial roles in determining the severity of disease, particularly lung disease. Identifying these factors is crucial in devising therapies and other interventions to decrease the morbidity and mortality associated with this disorder. Recent findings Although many genes have been proposed as potential modifiers of CF, only a handful have withstood the test of replication. Several of the replicated findings reveal that genes affecting inflammation and infection response play a key role in modifying CF lung disease severity. Interactions between CFTR genotype, modifier genes, and environmental factors have been documented to influence lung function measures and infection status in CF patients. Summary Several genes have been demonstrated to affect disease severity in CF. Furthermore, it is likely that gene–gene and gene–environment interactions can explain a substantial portion of the variation of lung disease. Ongoing genome-wide studies are likely to identify novel genetic modifiers. Continued exploration of the role of genetic and nongenetic modifiers of CF is likely to yield new options for combating this debilitating disease. PMID:18812833

  2. 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.…

  3. 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

  4. Report of the European Respiratory Society/European Cystic Fibrosis Society task force on the care of adults with cystic fibrosis.

    PubMed

    Elborn, J Stuart; Bell, Scott C; Madge, Susan L; Burgel, Pierre-Regis; Castellani, Carlo; Conway, Steven; De Rijcke, Karleen; Dembski, Birgit; Drevinek, Pavel; Heijerman, Harry G M; Innes, J Alistair; Lindblad, Anders; Marshall, Bruce; Olesen, Hanne V; Reimann, Andreas L; Solé, Ampara; Viviani, Laura; Wagner, Thomas O F; Welte, Tobias; Blasi, Francesco

    2016-02-01

    The improved survival in people with cystic fibrosis has led to an increasing number of patients reaching adulthood. This trend is likely to be maintained over the next decades, suggesting a need to increase the number of centres with expertise in the management of adult patients with cystic fibrosis. These centres should be capable of delivering multidisciplinary care addressing the complexity of the disease, in addition to addressing the psychological burden on patients and their families. Further issues that require attention are organ transplantation and end of life management.Lung disease in adults with cystic fibrosis drives most of the clinical care requirements, and major life-threatening complications, such as respiratory infection, respiratory failure, pneumothorax and haemoptysis, and the management of lung transplantation require expertise from trained respiratory physicians. The taskforce therefore strongly reccommends that medical leadership in multidisciplinary adult teams should be attributed to a respiratory physician adequately trained in cystic fibrosis management.The task force suggests the implementation of a core curriculum for trainees in adult respiratory medicine and the selection and accreditation of training centres that deliver postgraduate training to the standards of the HERMES programme.

  5. Interaction of environmental Burkholderia cenocepacia strains with cystic fibrosis and non-cystic fibrosis bronchial epithelial cells in vitro.

    PubMed

    Bevivino, Annamaria; Pirone, Luisa; Pilkington, Ruth; Cifani, Noemi; Dalmastri, Claudia; Callaghan, Máire; Ascenzioni, Fiorentina; McClean, Siobhán

    2012-05-01

    Burkholderia cenocepacia is an important human pathogen in patients with cystic fibrosis (CF). Non-clinical reservoirs may play a role in the acquisition of infection, so it is important to evaluate the pathogenic potential of environmental B. cenocepacia isolates. In this study, we investigated the interactions of two environmental B. cenocepacia strains (Mex1 and MCII-168) with two bronchial epithelial cell lines, 16HBE14o(-) and CFBE41o(-), which have a non-CF and a CF phenotype, respectively. The environmental strains showed a significantly lower level of invasion into both CF and non-CF cells in comparison with the clinical B. cenocepacia LMG16656(T) strain. Exposure of polarized CFBE41o(-) or 16HBE14o(-) cells to the environmental strains resulted in a significant reduction in transepithelial resistance (TER), comparable with that observed following exposure to the clinical strain. A different mechanism of tight junction disruption in CF versus non-CF epithelia was found. In the 16HBE41o(-) cells, the environmental strains resulted in a drop in TER without any apparent effect on tight junction proteins such as zonula occludens-1 (ZO-1). In contrast, in CF cells, the amount of ZO-1 and its localization were clearly altered by the presence of both the environmental strains, comparable with the effect of LMG16656. This study demonstrates that even if the environmental strains are significantly less invasive than the clinical strain, they have an effect on epithelial integrity comparable with that of the clinical strain. Finally, the tight junction regulatory protein ZO-1 appears to be more susceptible to the presence of environmental strains in CF cells than in cells which express a functional cystic fibrosis transmembrane regulator (CFTR). PMID:22322958

  6. Sepsis Caused by Achromobacter Xylosoxidans in a Child with Cystic Fibrosis and Severe Lung Disease.

    PubMed

    Stobbelaar, Kim; Van Hoorenbeeck, Kim; Lequesne, Monique; De Dooy, Jozef; Ho, Erwin; Vlieghe, Erika; Ieven, Margaretha; Verhulst, Stijn

    2016-01-01

    BACKGROUND Achromobacter xylosoxidans is an aerobic, motile, Gram-negative, opportunistic pathogen that can be responsible for various severe nosocomial and community-acquired infections. It has been found in immunocompromised patients and patients with several other underlying conditions, but the clinical role of this microorganism in cystic fibrosis is unclear. CASE REPORT We describe a case of septic shock caused by A. xylosoxidans in a 10-year-old child with cystic fibrosis and severe lung disease. CONCLUSIONS As the prevalence of A. xylosoxidans in cystic fibrosis patients is rising and patient-to-patient transmission is highly probable, further studies are warranted to determine its role and to document the appropriate treatment strategy for eradication and long-term treatment of this organism. PMID:27498677

  7. New Therapeutic Approaches to Modulate and Correct Cystic Fibrosis Transmembrane Conductance Regulator.

    PubMed

    Ong, Thida; Ramsey, Bonnie W

    2016-08-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are clinically available personalized medicines approved for some individuals with cystic fibrosis (CF) to target the underlying defect of disease. This review summarizes strategies used to develop CFTR modulators as therapies that improve function and availability of CFTR protein. Lessons learned from dissemination of ivacaftor across the CF population responsive to this therapy and future approaches to predict and monitor treatment response of CFTR modulators are discussed. The goal remains to expand patient-centered and personalized therapy to all patients with CF, ultimately improving life expectancy and quality of life for this disease. PMID:27469186

  8. Chloride transport in the cystic fibrosis enterocyte.

    PubMed

    Bijman, J; Veeze, H; Kansen, M; Tilly, B; Scholte, B; Hoogeveen, A; Halley, D; Sinaasappel, M; de Jonge, H

    1991-01-01

    Molecular mechanisms of intestinal chloride channel regulation and potential abnormalities in electrogenic chloride secretion in intestinal epithelium from cystic fibrosis (CF) patients were investigated by a combination of Ussing chamber, vesicle transport and off-cell patch-clamp analysis. Short circuit current (Isc) measurements in normal and CF rectal biopsies provided evidence for i) a defect in the cAMP-provoked activation of chloride secretion and a (hyper)expression of cAMP-dependent potassium secretion in all CF patients examined (n = 11); ii) a defect in the carbachol-provoked chloride secretion and a (hyper)expression of carbachol-induced potassium secretion in 6/11 patients; iii) a residual (but still impaired) carbachol-induced chloride secretion in 5/11 CF patients (including 2 sibs). The latter class of CF patients appeared to consist genetically of compound heterozygotes for the major delta-F508 deletion, suggesting a correlation between the nature of the mutation in the CF gene and the severity of the chloride secretory defect in CF intestine. In our search for a regulatory function of GTP-binding (G-) proteins detected previously in the luminal membrane of rat and human intestinal epithelial cells, evidence was found for the presence of a GTP[S]-activatable- and GDP[S]-inhibitable chloride conductance in the apical membrane of rat enterocytes and human colonocytes. In excised patches of human colonocyt membranes, this G-proteine-sensitive chloride conductance was identified further as a novel type of chloride channel (20pS; inwardly rectifying) that was different from the 33pS outwardly rectifying chloride channel activatable by cAMP-dependent proteinkinase (PK-A) and voltage depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Cystic Fibrosis Therapy: A Community Ecology Perspective

    PubMed Central

    Haynes, Matthew; Salamon, Peter; Rainey, Paul B.; Youle, Merry; Rohwer, Forest

    2013-01-01

    Current therapy for cystic fibrosis (CF) focuses on minimizing the microbial community and the host’s immune response through the aggressive use of airway clearance techniques, broad-spectrum antibiotics, and treatments that break down the pervasive endobronchial biofilm. Antibiotic selection is typically based on the susceptibility of individual microbial strains to specific antibiotics in vitro. Often this approach cannot accurately predict medical outcomes because of factors both technical and biological. Recent culture-independent assessments of the airway microbial and viral communities demonstrated that the CF airway infection is considerably more complex and dynamic than previously appreciated. Understanding the ecological and evolutionary pressures that shape these communities is critically important for the optimal use of current therapies (in both the choice of therapy and timing of administration) and the development of newer strategies. The climax–attack model (CAM) presented here, grounded in basic ecological principles, postulates the existence of two major functional communities. The attack community consists of transient viral and microbial populations that induce strong innate immune responses. The resultant intense immune response creates microenvironments that facilitate the establishment of a climax community that is slower-growing and inherently resistant to antibiotic therapy. Newer methodologies, including sequence-based metagenomic analysis, can track not only the taxonomic composition but also the metabolic capabilities of these changing viral and microbial communities over time. Collecting this information for CF airways will enable the mathematical modeling of microbial community dynamics during disease progression. The resultant understanding of airway communities and their effects on lung physiology will facilitate the optimization of CF therapies. PMID:23103995

  10. Gastroesophageal reflux in patients with cystic fibrosis.

    PubMed

    Scott, R B; O'Loughlin, E V; Gall, D G

    1985-02-01

    Children with cystic fibrosis (CF) and their asymptomatic siblings were surveyed to determine the incidence of symptomatic gastroesophageal reflux. A subgroup of patients with CF with poor nutritional status were studied with esophageal manometry, 24-hour esophageal pH recording, and pulmonary function testing before and after initiation of supplemental continuous nighttime nasogastric feeds. Of 68 patients with CF greater than or equal to 5 years of age, 20.6% experienced regurgitation and 26.5% had heartburn. In the control group of 23 asymptomatic siblings greater than or equal to 5 years of age, none experienced regurgitation and 5.6% had heartburn. Among the patients there was no significant association between symptoms of gastroesophageal reflux and bronchodilator therapy. Eight patients had normal lower esophageal sphincter pressure of 24.8 +/- 8.8 mm Hg and thoracoabdominal pressure gradient of 11.4 +/- 4.6 mm Hg; peristalsis and upper esophageal sphincter pressure were normal. There was a significant increase in reflux episodes, episodes greater than 5 minutes, duration of the longest episode, and percent time esophageal pH was less than 4 in patients, compared with published control data, for the entire 24-hour period and during sleep. During sleep, continuous nasogastric feeding significantly increased episodes of reflux, but did not result in an increase in percent time esophageal pH was less than 4, and was not associated with evidence of aspiration or deterioration in pulmonary function. Our findings indicate that symptoms of gastroesophageal reflux, heartburn, and regurgitation are more frequent in patients with CF than in asymptomatic siblings and that gastroesophageal reflux is significantly more common in patients with CF than in controls. Nighttime nasogastric feedings can safely be used as a means of nutritional rehabilitation in patients with CF.

  11. 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

  12. 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

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Quality control material for cystic fibrosis... 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 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cystic fibrosis transmembrane conductance... DEVICES Immunological Test Systems § 866.5900 Cystic fibrosis transmembrane conductance regulator (CFTR... intended as an aid in confirmatory diagnostic testing of individuals with suspected cystic fibrosis...

  15. [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.

  16. [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. PMID:25116021

  17. Metabolomic analysis of bronchoalveolar lavage fluid from cystic fibrosis patients

    PubMed Central

    Wolak, Justyna E.; Esther, Charles R.; O’Connell, Thomas M.

    2013-01-01

    Metabolite profiles of bronchoalveolar lavage fluid (BALF) from pediatric patients with cystic fibrosis (CF) were correlated to the degree of airway inflammation using nuclear magnetic resonance spectroscopy-based metabolomics. BALF was collected from 11 children with CF during clinically indicated bronchoscopy. The spectra from BALF with high levels of neutrophilic airway inflammation displayed signals from numerous metabolites, whereas the spectra from subjects with low levels of inflammation were very sparse. The metabolites identified in samples taken from subjects with high inflammation include known markers of inflammation such as amino acids and lactate, as well as many novel signals. Statistical analysis highlighted the most important metabolites that distinguished the high- from the low-inflammation groups. This first demonstration of metabolomics of human BALF shows that clear distinctions in the metabolic profiles can be observed between subjects experiencing high versus low inflammation and is a first step toward the goal of discovering novel biomarkers of airway inflammation. PMID:19283525

  18. 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.

  19. Bordetella petrii recovered from chronic pansinusitis in an adult with cystic fibrosis.

    PubMed

    Biederman, Laura; Rosen, Marc R; Bobik, Brent S; Roberts, Amity L

    2015-01-01

    To date Bordetella petrii has infrequently been identified within the clinical setting likely due to the asaccharolytic nature of this organism. We present a case of B. petrii recovered on two separate events in a patient with adult cystic fibrosis experiencing chronic pansinusitis. PMID:26793470

  20. Bordetella petrii recovered from chronic pansinusitis in an adult with cystic fibrosis

    PubMed Central

    Biederman, Laura; Rosen, Marc R.; Bobik, Brent S.; Roberts, Amity L.

    2015-01-01

    To date Bordetella petrii has infrequently been identified within the clinical setting likely due to the asaccharolytic nature of this organism. We present a case of B. petrii recovered on two separate events in a patient with adult cystic fibrosis experiencing chronic pansinusitis. PMID:26793470

  1. 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.

  2. Mutation analysis in 600 French cystic fibrosis patients.

    PubMed Central

    Chevalier-Porst, F; Bonardot, A M; Gilly, R; Chazalette, J P; Mathieu, M; Bozon, D

    1994-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) gene of 600 unrelated cystic fibrosis (CF) patients living in France (excluding Brittany) was screened for 105 different mutations. This analysis resulted in the identification of 86% of the CF alleles and complete genotyping of 76% of the patients. The most frequent mutations in this population after delta F508 (69% of the CF chromosomes) are G542X (3.3%), N1303K (1.8%), W1282X (1.5%), 1717-1G-->A (1.3%), 2184delA + 2183 A-->G (0.9%), and R553X (0.8%). Images PMID:7525963

  3. 394delTT: a Nordic cystic fibrosis mutation.

    PubMed

    Schwartz, M; Anvret, M; Claustres, M; Eiken, H G; Eiklid, K; Schaedel, C; Stolpe, L; Tranebjaerg, L

    1994-02-01

    In a systematic screening for mutations in the gene encoding the cystic fibrosis transmembrane regulator among Danish cystic fibrosis (CF) patients, we identified a mutation in exon 3 (394delTT); this mutation was found to be relatively common in Denmark. We therefore screened for 394delTT in Sweden and Norway, where it turned out to be the second most frequent mutation, accounting for 4% of all CF mutations. It also occurs with a high frequency in Finland, but has not been found in larger surveys of mutations in the CFTR gene. Thus, 394delTT seems to be a specific Nordic CF mutation.

  4. Exercise and Cystic Fibrosis (CF) 2.0.

    PubMed

    Cerny, Frank

    2013-11-01

    In 1989 we knew that exercise, including regular prescribed physical activity, could be safely performed and described some of the physiological responses to exercise in patients with cystic fibrosis (CF). Also in 1989, the genetic defect causing cystic fibrosis (CF) was identified leading to improvements in treatment that greatly extended the life span for these patients. Increased understanding of the factors limiting exercise capacity and of the important role of regular exercise in slowing the progression of CF and in modulating some of the effects of the genetic defect on airway function has led to the consensus that regular exercise should be part of the standard of care for this disease. PMID:24214443

  5. 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

  6. Airway Clearance Devices for Cystic Fibrosis

    PubMed Central

    2009-01-01

    Executive Summary Objective The purpose of this evidence-based analysis is to examine the safety and efficacy of airway clearance devices (ACDs) for cystic fibrosis and attempt to differentiate between devices, where possible, on grounds of clinical efficacy, quality of life, safety and/or patient preference. Background Cystic fibrosis (CF) is a common, inherited, life-limiting disease that affects multiple systems of the human body. Respiratory dysfunction is the primary complication and leading cause of death due to CF. CF causes abnormal mucus secretion in the airways, leading to airway obstruction and mucus plugging, which in turn can lead to bacterial infection and further mucous production. Over time, this almost cyclical process contributes to severe airway damage and loss of respiratory function. Removal of airway secretions, termed airway clearance, is thus an integral component of the management of CF. A variety of methods are available for airway clearance, some requiring mechanical devices, others physical manipulation of the body (e.g. physiotherapy). Conventional chest physiotherapy (CCPT), through the assistance of a caregiver, is the current standard of care for achieving airway clearance, particularly in young patients up to the ages of six or seven. CF patients are, however, living much longer now than in decades past. The median age of survival in Canada has risen to 37.0 years for the period of 1998-2002 (5-year window), up from 22.8 years for the 5-year window ending in 1977. The prevalence has also risen accordingly, last recorded as 3,453 in Canada in 2002, up from 1,630 in 1977. With individuals living longer, there is a greater need for independent methods of airway clearance. Airway Clearance Devices There are at least three classes of airway clearance devices: positive expiratory pressure devices (PEP), airway oscillating devices (AOD; either handheld or stationary) and high frequency chest compression (HFCC)/mechanical percussion (MP

  7. 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.

  8. Unplugging Mucus in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

    PubMed

    Mall, Marcus A

    2016-04-01

    Airway mucus obstruction is a key feature of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The thin layer of mucus that covers healthy airway surfaces has important protective functions in lung defense. However, excess mucus produces airflow obstruction and provides a nidus for bacterial infection and inflammation. Despite its importance in pathogenesis, understanding of the mechanisms underlying airway mucus obstruction, as well as therapeutic options, remain limited. Studies in the rare genetic disease CF identified airway surface dehydration due to cystic fibrosis transmembrane conductance regulator (CFTR) gene dysfunction as an important disease mechanism that may explain mucus stasis and plugging in a spectrum of muco-obstructive lung diseases, including COPD. This concept is supported by the phenotype of the β-epithelial Na(+) channel-transgenic mouse that exhibits airway surface dehydration and develops a spontaneous lung disease that shares key features with CF and COPD, such as airway mucus plugging, chronic neutrophilic inflammation, and structural lung damage. Furthermore, preclinical testing demonstrated that hydration strategies, including osmotically active hypertonic saline and preventive inhibition of the amiloride-sensitive epithelial Na(+) channel are effective in unplugging airways in this mouse model of chronic obstructive lung disease. On the other hand, genetic deletion of neutrophil elastase, a potent stimulus for mucus hypersecretion, reduced goblet cell metaplasia and mucin expression but had no effect on mucus obstruction in vivo. Collectively, these studies demonstrate that airway surface dehydration is sufficient to produce mucus obstruction even in the absence of mucus hypersecretion and support further clinical testing of hydrating agents as a promising therapeutic strategy to unplug mucus in CF and COPD. PMID:27115954

  9. 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.

  10. THE METABOLIC EFFECTS OF PREGNANCY IN CYSTIC FIBROSIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our purpose was to determine glucose tolerance in pregnant women with cystic fibrosis (CF) and to relate glucose tolerance to insulin sensitivity, hepatic glucose production, and protein turnover. We studied 8 CF women during pregnancy (CFPreg). Results were compared with those from 9 pregnant contr...

  11. Pulmonary resection after lung transplantation in cystic fibrosis patients.

    PubMed

    Souilamas, Rédha; Saueressig, Mauricio; Boussaud, Véronique; Amrein, Catherine; Guillemain, Romain; Sonett, Joshua

    2011-06-01

    Pulmonary resection after lung transplantation in end-stage cystic fibrosis presents unique challenges, and scant literature exists to guide physicians. We retrospectively reviewed 78 transplants for cystic fibrosis performed between 2003 and 2008. Fourteen patients underwent posttransplantation pulmonary resection. We analyzed the indications, surgical procedures, outcomes, and survival. Three pneumonectomies, 4 lobectomies, and 11 wedge resections were carried out. We identified 2 groups based on indication: a diagnostic group, and a therapeutic group of patients in whom the indications were septic native lung in 2, allograft infection in 2, lobar torsion in 2, pulmonary infarction in 2, and size mismatch in 4. The mean intensive care unit and hospital stays were 29 and 50 days, respectively. Four (28.57%) patients died during follow-up, including 2 who underwent pneumonectomy; 10 (71.43%) are still alive. Survival was 43.43 ± 8.06 months, and it was not significantly different from that in cystic fibrosis patients who had lung transplantation without pulmonary resection. Pulmonary resection following lung transplantation in cystic fibrosis patients showed acceptable survival and surgical risk, but metachronous pneumonectomy was associated with higher mortality.

  12. 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. PMID:25053610

  13. 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…

  14. 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…

  15. 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…

  16. 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…

  17. 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…

  18. [The respiratory disease of cystic fibrosis, from infancy to childhood].

    PubMed

    Hubert, D; Le Bourgeois, M

    2012-05-01

    The respiratory disease of cystic fibrosis, which is secondary to bronchial inflammation and infection, appears from the youngest age and its evolution is made of exacerbations due to acute respiratory infections. In adulthood, complications such as hemoptysis and pneumothorax are more frequent and respiratory insufficiency is more severe, conditioning prognosis. Care is mainly based on physiotherapy and adapted antibiotics. PMID:22682483

  19. Cepacia Syndrome in a Non-Cystic Fibrosis Patient.

    PubMed

    Hauser, Naomi; Orsini, Jose

    2015-01-01

    Burkholderia (formerly Pseudomonas) cepacia complex is a known serious threat to patients with cystic fibrosis, in whom it has the potential to cause the fatal combination of necrotizing pneumonia, worsening respiratory failure, and bacteremia, known as Cepacia syndrome. The potential for this pathogen to infect non-cystic fibrosis patients is limited and its epidemiology is poorly understood. Previously reported cases of severe Burkholderia cepacia complex lung infection in immunocompetent hosts include pneumonia, bronchiectasis, pyopneumothorax, and cavitary lesions. We present a case of a 64-year-old man with Streptococcus pneumoniae community-acquired pneumonia whose hospital course was complicated by developing cavitary lung lesions, bacteremia, and acute respiratory distress syndrome. Repeated tracheal aspirate and blood cultures grew Burkholderia cepacia. Our case appears to be the first report of Cepacia syndrome in a patient without cystic fibrosis. This report raises concern regarding the potential severity of pulmonary Burkholderia cepacia complex infection and the need to broaden clinicians' suspicion for Cepacia syndrome. A framework to help diagnose and treat infected non-cystic fibrosis individuals may be useful. PMID:26357579

  20. 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

  1. Pulmonary resection after lung transplantation in cystic fibrosis patients.

    PubMed

    Souilamas, Rédha; Saueressig, Mauricio; Boussaud, Véronique; Amrein, Catherine; Guillemain, Romain; Sonett, Joshua

    2011-06-01

    Pulmonary resection after lung transplantation in end-stage cystic fibrosis presents unique challenges, and scant literature exists to guide physicians. We retrospectively reviewed 78 transplants for cystic fibrosis performed between 2003 and 2008. Fourteen patients underwent posttransplantation pulmonary resection. We analyzed the indications, surgical procedures, outcomes, and survival. Three pneumonectomies, 4 lobectomies, and 11 wedge resections were carried out. We identified 2 groups based on indication: a diagnostic group, and a therapeutic group of patients in whom the indications were septic native lung in 2, allograft infection in 2, lobar torsion in 2, pulmonary infarction in 2, and size mismatch in 4. The mean intensive care unit and hospital stays were 29 and 50 days, respectively. Four (28.57%) patients died during follow-up, including 2 who underwent pneumonectomy; 10 (71.43%) are still alive. Survival was 43.43 ± 8.06 months, and it was not significantly different from that in cystic fibrosis patients who had lung transplantation without pulmonary resection. Pulmonary resection following lung transplantation in cystic fibrosis patients showed acceptable survival and surgical risk, but metachronous pneumonectomy was associated with higher mortality. PMID:21885542

  2. 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.

  3. 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

  4. 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.

  5. 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

    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.

  6. 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

  7. miR-17 overexpression in cystic fibrosis airway epithelial cells decreases interleukin-8 production.

    PubMed

    Oglesby, Irene K; Vencken, Sebastian F; Agrawal, Raman; Gaughan, Kevin; Molloy, Kevin; Higgins, Gerard; McNally, Paul; McElvaney, Noel G; Mall, Marcus A; Greene, Catherine M

    2015-11-01

    Interleukin (IL)-8 levels are higher than normal in cystic fibrosis (CF) airways, causing neutrophil infiltration and non-resolving inflammation. Overexpression of microRNAs that target IL-8 expression in airway epithelial cells may represent a therapeutic strategy for cystic fibrosis. IL-8 protein and mRNA were measured in cystic fibrosis and non-cystic fibrosis bronchoalveolar lavage fluid and bronchial brushings (n=20 per group). miRNAs decreased in the cystic fibrosis lung and predicted to target IL-8 mRNA were quantified in βENaC-transgenic, cystic fibrosis transmembrane conductance regulator (Cftr)-/- and wild-type mice, primary cystic fibrosis and non-cystic fibrosis bronchial epithelial cells and a range of cystic fibrosis versus non-cystic fibrosis airway epithelial cell lines or cells stimulated with lipopolysaccharide, Pseudomonas-conditioned medium or cystic fibrosis bronchoalveolar lavage fluid. The effect of miRNA overexpression on IL-8 protein production was measured. miR-17 regulates IL-8 and its expression was decreased in adult cystic fibrosis bronchial brushings, βENaC-transgenic mice and bronchial epithelial cells chronically stimulated with Pseudomonas-conditioned medium. Overexpression of miR-17 inhibited basal and agonist-induced IL-8 protein production in F508del-CFTR homozygous CFTE29o(-) tracheal, CFBE41o(-) and/or IB3 bronchial epithelial cells. These results implicate defective CFTR, inflammation, neutrophilia and mucus overproduction in regulation of miR-17. Modulating miR-17 expression in cystic fibrosis bronchial epithelial cells may be a novel anti-inflammatory strategy for cystic fibrosis and other chronic inflammatory airway diseases.

  8. 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

  9. Lethal course of meconium ileus in preterm twins revealing a novel cystic fibrosis mutation (p.Cys524Tyr)

    PubMed Central

    2014-01-01

    Background In term newborns meconium ileus is frequently associated with cystic fibrosis. Reports on meconium ileus in preterm infants being diagnosed with cystic fibrosis early after birth are very scarce. Associations between genotype and phenotype in cystic fibrosis and its particular comorbidities have been reported. Case presentation Two extremely preterm twin infants (26 weeks of gestation) born from a Malaysian mother and a Caucasian father were presented with typical signs of meconium ileus. Despite immediate surgery both displayed a unique and finally lethal course. Mutation analysis revealed a novel, probably pathogenic cystic fibrosis mutation, p.Cys524Tyr. The novel mutation might explain the severity of disease next to typical sequelae of prematurity. Conclusion Preterm neonates with meconium ileus have to be evaluated for cystic fibrosis beyond ethnical boundaries, but may take devastating clinical courses despite early treatment. The novel, potentially pathogenic CF mutation p.Cys524Tyr might be associated with severe meconium ileus in neonates. Disease-modifying loci are important targets for intestinal comorbidity of cystic fibrosis. PMID:24433235

  10. Targets for cystic fibrosis therapy: proteomic analysis and correction of mutant cystic fibrosis transmembrane conductance regulator

    PubMed Central

    Collawn, James F; Fu, Lianwu; Bebok, Zsuzsa

    2010-01-01

    Proteomic analysis has proved to be an important tool for understanding the complex nature of genetic disorders, such as cystic fibrosis (CF), by defining the cellular protein environment (proteome) associated with wild-type and mutant proteins. Proteomic screens identified the proteome of CF transmembrane conductance regulator (CFTR), and provided fundamental information to studies designed for understanding the crucial components of physiological CFTR function. Simultaneously, high-throughput screens for small-molecular correctors of CFTR mutants provided promising candidates for therapy. The majority of CF cases are caused by nucleotide deletions (ΔF508 CFTR; >75%), resulting in CFTR misfolding, or insertion of premature termination codons (~10%), leading to unstable mRNA and reduced levels of truncated dysfunctional CFTR. In this article, we review recent results of proteomic screens, developments in identifying correctors for the most frequent CFTR mutants, and comment on how integration of the knowledge gained from these studies may aid in finding a cure for CF and a number of other genetic disorders. PMID:20653506

  11. Analysis of Cystic Fibrosis in Federation of Bosnia and Herzegovina

    PubMed Central

    Selimovic, Amina; Mujicic, Ermina; Milisic, Selma; Mesihovic-Dinarevic, Senka; Dzinovic, Amra; Cengic, Selma; Bakalovic, Ganimeta; Moro, Mahir; Djozic, Meliha; Lukic-Bilela, Lada

    2015-01-01

    Aim: The aim of this study is to present the first total number of tested children in the Federation of Bosnia and Herzegovina and the number of children with positive sweat test. During the study we determined the number of ill children, the median age of children with cystic fibrosis, date of initial diagnosis, an average amount of chloride in the sweat. Material and methods: The study was a retrospective, conducted at the Department of Pulmonology Pediatric Clinic of University Clinical Center of Sarajevo. Results: In the period from March 2003 to December 2014, we have tested 625 children. 351 child were from Sarajevo Canton and 272 children from other cantons. Female children were more affected then male children, in the ratio of 1: 1,105. An average age of female children was 4.19±4.26 years, and the male 2.15±3.11 years. The median concentration of chloride in the sweat measured by sweat test was for male children 103.05±21.29 mmol/L, and for the female children 96.05±28.85 mmol/L. Conclusion: Most of children in Federation of Bosnia and Herzegovina have ∆F508 gene mutation. In the post-war period we started to use a sweat test. Male children tend to live longer than female children with CF. PMID:26543305

  12. 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

  13. [Insights into cystic fibrosis-related bone disease].

    PubMed

    Braun, C; Bacchetta, J; Reix, P

    2016-08-01

    With the increasing life expectancy of patients with cystic fibrosis (CF), prevalence of late complications such as CF-related bone disease (CFBD) has increased. It was initially described in 24% of the adult population with CF and has also been reported in the pediatric population. CFBD is multifactorial and progresses in different steps. Both decreased bone formation and increased bone resorption (in different amounts) are observed. CFBD is likely primitive (directly related to the CFTR defect itself), but is also worsened by acquired secondary factors such as lung infections, chronic inflammation, denutrition, vitamin deficiency, and decreased physical activity. CFBD may be clinically apparent (i.e., mainly vertebral and costal fractures), or clinically asymptomatic (therefore corresponding to abnormalities in bone density and architecture). CFBD management mainly aims to prevent the occurrence of fractures. Prevention and regular monitoring of bone disease as early as 8 years of age is of the utmost importance, as is the control of possible secondary deleterious CFBD factors. New radiological tools, such as high-resolution peripheral quantitative computed tomography, allow an accurate evaluation of cortical and trabecular bone micro-architecture in addition to compartmental density; as such, they will likely improve the assessment of the bone fracture threat in CF patients in the near future. PMID:27345551

  14. 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

  15. New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls.

    PubMed

    Bell, Scott C; De Boeck, Kris; Amaral, Margarida D

    2015-01-01

    With the discovery of the CFTR gene in 1989, the search for therapies to improve the basic defects of cystic fibrosis (CF) commenced. Pharmacological manipulation provides the opportunity to enhance CF transmembrane conductance regulator (CFTR) protein synthesis and/or function. CFTR modulators include potentiators to improve channel gating (class III mutations), correctors to improve abnormal CFTR protein folding and trafficking (class II mutations) and stop codon mutation read-through drugs relevant for patients with premature stop codons (most class I mutations). After several successful clinical trials the potentiator, ivacaftor, is now licenced for use in adults and children (>six years), with CF bearing the class III G551D mutation and FDA licence was recently expanded to include 8 additional class III mutations. Alternative approaches for class I and class II mutations are currently being studied. Combination drug treatment with correctors and potentiators appears to be required to restore CFTR function of F508del, the most common CFTR mutation. Alternative therapies such as gene therapy and pharmacological modulation of other ion channels may be advantageous because they are mutation-class independent, however progress is less well advanced. Clinical trials for CFTR modulators have been enthusiastically embraced by patients with CF and health care providers. Whilst novel trial end-points are being evaluated allowing CFTR modulators to be efficiently tested, many challenges related to the complexity of CFTR and the biology of the epithelium still need to be overcome.

  16. 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.

  17. Pandoraea pnomenusa Isolated from an Australian Patient with Cystic Fibrosis

    PubMed Central

    Ambrose, Mark; Malley, Roslyn C.; Warren, Sanchia J. C.; Beggs, Sean A.; Swallow, Oliver F. E.; McEwan, Belinda; Stock, David; Roddam, Louise F.

    2016-01-01

    Pandoraea species are considered as emerging pathogens in people with cystic fibrosis (CF). The contribution of these organisms to disease progression in CF patients is not fully understood owing in large measure to the scant reports in clinical and research literature describing their colonization of CF patients and their associated virulence determinants. In an effort to increase awareness and evidence for Pandoraea spp. infection in people with CF, and to stimulate research aimed at unraveling the pathogenic properties of Pandoraea, we report a case of a 26-year-old Australian (Tasmanian) man with CF who was chronically infected with Pandoraea pnomenusa for at least one year prior to his death from respiratory failure. In addition, we describe for the first time evidence suggesting that this bacterium is a facultative anaerobe and report on the availability of a whole genome sequence for this organism. To the best of our knowledge, this report represents only the second clinical case study of P. pnomenusa infection in the world, and the first in an Australian CF patient. PMID:27242717

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

    PubMed

    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

  19. Bringing new treatments to the bedside in cystic fibrosis.

    PubMed

    Brennan, Amanda L; Geddes, Duncan M

    2004-02-01

    The discovery of the cystic fibrosis transmembrane conductance regulator gene in 1989 led to a dramatic increase in the understanding of the molecular basis of CF. Increased knowledge has provided the opportunity to target drug development at correcting the basic defect either by gene therapy or pharmacological modulation of the abnormal physiological processes. Development of new medications for the CF population poses many challenges. The discovery and development of new medications is always time consuming and expensive. Since CF affects a small population worldwide, the potential for a drug company to profit from a new treatment is limited. In addition, each new therapy must have an additional and proven benefit to be attractive to clinicians and consumers, otherwise it will not be commercially viable. Demonstrating clinical benefit is problematic as a limited number of patients are available to participate in clinical trails and outcome measures, such as length of life, are hard to measure. In this review we will illustrate these challenges by discussing the development of treatments which have successfully reached the bedside and those that were unsuccessful. PMID:14730652

  20. 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.

  1. Is there a role for stool metabolomics in cystic fibrosis?

    PubMed

    Kaakoush, Nadeem O; Pickford, Russell; Jaffe, Adam; Ooi, Chee Y

    2016-08-01

    A number of studies utilizing metabolomics have focused on the pathophysiology of cystic fibrosis (CF) lung disease. Here, we performed fecal metabolomics on pancreatic insufficient (PI) and sufficient (PS) children with CF and compared them with healthy controls (HC). Fecal metabolomics can differentiate between PS-CF and PI-CF. We identified a potential biomarker of disease severity or cystic fibrosis transmembrane conductance regulator function (m/z, 463.247; retention time, 0.570717 min) that discriminates between HC versus PS-CF versus PI-CF. We also identified lipoyl-GMP as a potential novel inflammatory biomarker, and elevation in fecal glycerol 1,2-didodecanoate 3-tetradecanoate may provide clues to the pathogenesis of intestinal inflammation. For the first time, we demonstrate the potential applications of fecal metabolomics in CF. PMID:27553892

  2. Unusual occurrence of cystic fibrosis and alobar holoprosencephaly.

    PubMed

    Cherian, Mathew P; Al-Sanna'a, Nouriya A

    2008-04-01

    Holoprosencephaly (HPE) is a defect of embryonic forebrain resulting from failure of growth and segmentation of the anterior end of the neural tube. It has been classified into 4 types based on the severity of associated brain and facial malformations. The most severe variety called alobar HPE is generally associated with major cranio-facial anomalies such as cyclopia, ethmocephaly, cebocephaly, or cleft-lip/palate. Significant etiological heterogeneity exists in HPE and includes both genetic and environmental causes. Maternal diabetes is a well-established environmental factor with a significant increased risk for HPE. We report on a Saudi Arab girl born to a diabetic mother, with the alobar type of holoprosencephaly, associated with very minimal cranio-facial defects. However, she displayed several other congenital malformations. In addition, she was diagnosed with cystic fibrosis. Simultaneous occurrence of cystic fibrosis and congenital anomalies has been rare. PMID:21063314

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

    PubMed

    Lavelle, Gillian M; White, Michelle M; Browne, Niall; McElvaney, Noel G; Reeves, Emer P

    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

  4. 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.

  5. 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

  6. 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.

  7. Allele frequency for Cystic fibrosis in Indians vis-a/-vis global populations.

    PubMed

    Bepari, Karnajit Kumar; Malakar, Arup Kumar; Paul, Prosenjit; Halder, Binata; Chakraborty, Supriyo

    2015-01-01

    Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. This gene encodes a protein involved in epithelial anion channel. Cystic fibrosis is the most common life-limiting genetic disorder in Caucasians; it also affects other ethnic groups like the Blacks and the Native Americans. Cystic fibrosis is considered to be rare among individuals from the Indian subcontinent. We analyzed a total of 29 world׳s populations for cystic fibrosis on the basis of gene frequency and heterozygosity. Among 29 countries Switzerland revealed the highest gene frequency and heterozygosity for CF (0.022, 0.043) whereas Japan recorded the lowest values (0.002, 0.004) followed by India (0.004, 0.008). Our analysis suggests that the prevalence of cystic fibrosis is very low in India. PMID:26339151

  8. Is deafness mutation screening required in cystic fibrosis patients?

    PubMed

    Abusamra, Rania; McShane, Donna

    2016-08-01

    Aminoglycosides are widely used in cystic fibrosis management. The m.1555A>G mutation predisposes to aminoglycoside ototoxicity. It may cause later onset hearing loss in the absence of aminoglycosides use and gradual hearing loss may be an inevitable consequence of the mutation. Given that aminoglycoside therapy forms the backbone of IV protocols in CF, this article recommends screening for this mutation to allow informed decision-making prior to aminoglycoside administration, to avoid preventable deafness. PMID:27427311

  9. Recent advances in the management of cystic fibrosis.

    PubMed

    Davies, Jane C; Ebdon, Anne-Marie; Orchard, Christopher

    2014-11-01

    Cystic fibrosis is a disease that still causes a reduced life expectancy. The treatment burden remains high for affected individuals with often a combination of multiple oral and inhaled medications, as well as physiotherapy, required on a daily basis. In this article, we look at an overview of the pathogenesis, how this might lead to treatment options and look at some of the available new therapies, all in the aim of increasing life expectancy and reducing treatment burden. PMID:24996790

  10. Partial splenectomy in cystic fibrosis patients with hypersplenism.

    PubMed

    Thalhammer, G H; Eber, E; Uranüs, S; Pfeifer, J; Zach, M S

    2003-02-01

    We report three cystic fibrosis (CF) patients with hypersplenism who underwent partial splenectomy. The postoperative course was uneventful in two patients; one patient developed a complication necessitating resection of the rest of the spleen. Haematological parameters improved and oesophageal varices regressed in all patients. On follow up, one patient showed a normal spleen, the other a normally functioning accessory spleen; the third patient again developed splenomegaly with hypersplenism. Partial splenectomy is a promising therapeutic option for CF patients with hypersplenism. PMID:12538318

  11. 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

  12. Heritability of Respiratory Infection with Pseudomonas aeruginosa in Cystic Fibrosis

    PubMed Central

    Green, Deanna M.; Collaco, J. Michael; McDougal, Kathryn E.; Naughton, Kathleen M.; Blackman, Scott M.; Cutting, Garry R.

    2013-01-01

    Objective To quantify the relative contribution of factors other than cystic fibrosis transmembrane conductance regulator genotype and environment on the acquisition of Pseudomonas aeruginosa (Pa) by patients with cystic fibrosis. Study design Lung infection with Pa and mucoid Pa was assessed using a co-twin study design of 44 monozygous (MZ) and 17 dizygous (DZ) twin pairs. Two definitions were used to establish infection: first positive culture and persistent positive culture. Genetic contribution to infection (ie, heritability) was estimated based on concordance analysis, logistic regression, and age at onset of infection through comparison of intraclass correlation coefficients. Results Concordance for persistent Pa infection was higher in MZ (0.83; 25 of 30 pairs) than DZ twins (0.45; 5 of 11 pairs), generating a heritability of 0.76. Logistic regression adjusted for age corroborated genetic control of persistent Pa infection. The correlation for age at persistent Pa infection was higher in MZ twins (0.589; 95% CI, 0.222-0.704) than in DZ twins (0.162; 95% CI, −0.352 to 0.607), generating a heritability of 0.85. Conclusion Genetic modifiers play a significant role in the establishment and timing of persistent Pa infection in individuals with cystic fibrosis. PMID:22364820

  13. Pseudomonas siderophores in the sputum of patients with cystic fibrosis.

    PubMed

    Martin, Lois W; Reid, David W; Sharples, Katrina J; Lamont, Iain L

    2011-12-01

    The lungs of patients with cystic fibrosis become chronically infected with the bacterium Pseudomonas aeruginosa, which heralds progressive lung damage and a decline in health. Iron is a crucial micronutrient for bacteria and its acquisition is a key factor in infection. P. aeruginosa can acquire this element by secreting pyoverdine and pyochelin, iron-chelating compounds (siderophores) that scavenge iron and deliver it to the bacteria. Siderophore-mediated iron uptake is generally considered a key factor in the ability of P. aeruginosa to cause infection. We have investigated the amounts of pyoverdine in 148 sputum samples from 36 cystic fibrosis patients (30 infected with P. aeruginosa and 6 as negative controls). Pyoverdine was present in 93 samples in concentrations between 0.30 and 51 μM (median 4.6 μM) and there was a strong association between the amount of pyoverdine and the number of P. aeruginosa present. However, pyoverdine was not present, or below the limits of detection (~0.3 μM), in 21 sputum samples that contained P. aeruginosa. Pyochelin was also absent, or below the limits of detection (~1 μM), in samples from P. aeruginosa-infected patients with little or no detectable pyoverdine. Our data show that pyoverdine is an important iron-scavenging molecule for P. aeruginosa in many cystic fibrosis patients, but other P. aeruginosa iron-uptake systems must be active in some patients to satisfy the bacterial need for iron. PMID:21643731

  14. 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

  15. Drug management of noninfective complications of cystic fibrosis.

    PubMed

    Sanchez, I; Guiraldes, E

    1995-10-01

    Cystic fibrosis (CF) is the commonest lethal hereditary disease in Caucasians. The disease involves a gene mutation located at the long arm of chromosome 7, and more than 300 mutations have been identified. CF is a systemic illness affecting the upper respiratory tract and airways, sweat and salivary glands, pancreas, gastrointestinal tract, liver and male reproductive system. The course is highly variable depending on the specific molecular abnormalities in the mutant gene. The current approach to therapy now involves the use of: (i) chest physiotherapy; (ii) bronchodilators when there is evidence of airways hyperreactivity; (iii) oral and intravenous antibiotics for acute pulmonary exacerbations and aerosolised antibiotics for prevention; (iv) recombinant human deoxyribonuclease I (dornase alfa) to promote airways clearance; (v) amiloride to improve sputum viscosity; (vi) pancreatic enzyme replacement therapy along with nutritional support and supplements; (vi) vitamins; and (vii) ursodeoxycholic acid in selected patients. The use of antiprotease and anti-inflammatory agents has been shown to be useful in preventing the damage secondary to chronic lung infection. In patients with severely impaired lung function, lung transplantations have been performed with good results. Finally, it seems probable that lung disease in CF patients will be ameliorated or prevented in the future with early gene therapy, using vectors such as recombinant adenoviruses, adeno-associated virus, lipofection or retrovirus. However, this require extensive basic and clinical research. PMID:8536551

  16. 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

  17. 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

  18. Persistent Bordetella bronchiseptica infection in a child with cystic fibrosis: Relationship to bacterial phenotype.

    PubMed

    El Khatib, Nevine; Ferroni, Agnes; Le Bourgeois, Muriel; Chedevergne, Frederique; Clairicia, Marlene; Avril, Helene; Guiso, Nicole; Sermet-Gaudelus, I

    2015-09-01

    Bordetella bronchiseptica is an opportunistic bacteria infecting the respiratory tract of patients with cystic fibrosis. We present a case of B. bronchiseptica chronic pulmonary infection and documentation of some phenotypic attributes of the clinical isolates allowing the microorganism to induce progressive respiratory degradation and chronic sputum colonization. We recommend implementing adequate treatment aiming eradication from the first isolation of this bacterium. We advise for practices that minimize opportunities for zoonotic transmission of B. bronchiseptica from family pets. PMID:25900817

  19. Persistent Bordetella bronchiseptica infection in a child with cystic fibrosis: Relationship to bacterial phenotype.

    PubMed

    El Khatib, Nevine; Ferroni, Agnes; Le Bourgeois, Muriel; Chedevergne, Frederique; Clairicia, Marlene; Avril, Helene; Guiso, Nicole; Sermet-Gaudelus, I

    2015-09-01

    Bordetella bronchiseptica is an opportunistic bacteria infecting the respiratory tract of patients with cystic fibrosis. We present a case of B. bronchiseptica chronic pulmonary infection and documentation of some phenotypic attributes of the clinical isolates allowing the microorganism to induce progressive respiratory degradation and chronic sputum colonization. We recommend implementing adequate treatment aiming eradication from the first isolation of this bacterium. We advise for practices that minimize opportunities for zoonotic transmission of B. bronchiseptica from family pets.

  20. 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.

  1. 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.

  2. 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. PMID:26526359

  3. 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

  4. 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

  5. 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.

  6. 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. PMID:24920766

  7. Methicillin resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis

    PubMed Central

    Miall, L; McGinley, N; Brownlee, K; Conway, S

    2001-01-01

    BACKGROUND—Methicillin resistant Staphylococcus aureus (MRSA) infection is increasingly found in patients with cystic fibrosis (CF).
AIMS—To determine whether MRSA infection has a deleterious effect on the clinical status of children with CF.
METHODS—Children with MRSA in respiratory cultures during a seven year period were identified and compared with controls matched for age, sex, and respiratory function. Respiratory function tests, anthropometric data, Shwachman-Kulczycki score, Northern chest x ray score, intravenous and nebulised antibiotic therapy, and steroid therapy were compared one year before and one year after MRSA infection.
RESULTS—From a clinic population of 300, 10 children had positive sputum or cough swab cultures for MRSA. Prevalence rose from 0 in 1992-1994 to 7 in 1998. Eighteen controls were identified. Children with MRSA showed significant worsening of height standard deviation scores and required twice as many courses of intravenous antibiotics as controls after one year. They had significantly worse chest x ray scores at the time of the first MRSA isolate and one year later, but showed no increase in the rate of decline in chest x ray appearance. There was a trend towards lower FEV1 and FEF25-75 in children with MRSA. There were no significant differences between the two groups with respect to change in weight, body mass index, or Shwachman score. There was no significant difference in prior use of steroids or nebulised antibiotics.
CONCLUSION—MRSA infection in children with CF does not significantly affect respiratory function, but may have an adverse effect on growth. Children with MRSA require significantly more courses of intravenous antibiotics and have a worse chest x ray appearance than controls.

 PMID:11159295

  8. 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.

  9. 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.

  10. A Randomized Clinical Trial of Behavioral Intervention and Nutrition Education to Improve Caloric Intake and Weight in Children with Cystic Fibrosis

    PubMed Central

    Stark, Lori J.; Quittner, Alexandra L.; Powers, Scott W.; Opipari, Lisa; Bean, Judy; Duggan, Christopher; Stallings, Virginia A.

    2009-01-01

    Objective To evaluate the efficacy of a behavioral plus nutrition education intervention, Be-In-CHARGE!, compared to nutrition education (NE) alone, on calorie intake and weight gain in children with cystic fibrosis (CF) and pancreatic insufficiency. Design Randomized controlled trial Setting CF Centers in the Eastern, Midwestern and Southern United States Participants 79 children ages 4 to12 years, below the 40th percentile weight for age were recruited. 67 completed the intervention and 59 completed a 24 month follow-up assessment. Outcome Measures Primary outcomes were change from pre- to post-treatment in calorie intake and weight gain. Secondary outcomes were change from pre- to post-treatment on % Estimated Energy Requirement (EER), and body mass index z-score (BMIZ). These outcomes were also examined 24 months post-treatment. Results The behavioral plus nutrition education intervention had a statistically greater average increase on the primary and secondary outcomes of calorie intake (872 vs. 489 cal/d), %EER (148% vs. 127%), weight gain (1.47 vs. 0.92kg), and BMIZ (0.38 vs. 0.18) at post-treatment than NE. At 24 month follow-up, children in both conditions maintained an EER around 120% and did not significantly differ on any outcomes. Conclusions Behavioral plus nutrition education intervention is more effective at increasing dietary intake and weight over a brief 9 week period, however across the 24 month follow-up both treatments achieved similar outcomes. Implications for standard nutritional care are discussed. PMID:19805710

  11. Determinants of mild clinical symptoms in cystic fibrosis patients. Residual chloride secretion measured in rectal biopsies in relation to the genotype.

    PubMed

    Veeze, H J; Halley, D J; Bijman, J; de Jongste, J C; de Jonge, H R; Sinaasappel, M

    1994-02-01

    Previous Ussing chamber measurements of secretagogue-provoked changes in short circuit current in rectal suction biopsies of cystic fibrosis (CF) patients showed that in a minority of patients chloride secretion in response to cholinergic agonists is reduced but not completely absent. To assess a possible relationship between this phenomenon and both the genotype and the phenotype, we performed Ussing chamber experiments on rectal suction biopsies of 51 CF patients. The CF mutation was identified in 89 out of 102 CF alleles. No apparent chloride secretion was found in 30 CF patients (group I). Low residual chloride secretion was found in 11 CF patients (group II), while a relatively high residual secretion appeared in 10 CF patients (group III). Pancreatic function was preserved more frequently in CF patients displaying residual secretion: 0% in group I, 27% in group II, and 60% in group III (P < 0.001). The age at diagnosis (mean +/- SEM) in group III (18.4 +/- 6.6) was significantly different from group I (1.2 +/- 0.4, P < 0.01) and group II (3.5 +/- 1.4, P = 0.05). Residual chloride secretion was found in some of the 28 dF508 homozygous patients (three in group II, and one in group III), disclosing that other factors than the CF gene defect itself affect the transepithelial chloride transport. The age at diagnosis correlates significantly with the magnitude of the secretory response, even within the dF508 homozygous patients (r = 0.4, P < 0.05). We conclude that residual chloride secretion in CF is the pathophysiological basis of preserved pancreatic function and delayed presentation of the disease, which is not exclusively determined by the CF genotype.

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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.

  17. 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…

  18. Epidemiological evaluation regarding the role of cystic fibrosis as a risk factor for child malnutrition.

    PubMed

    Florescu, Laura; Paduraru, Dana Teodora Anton; Mîndru, Dana Elena; Temneanu, Oana Raluea; Petrariu, F D; Matei, Mioara Calipsoana

    2014-01-01

    Cystic fibrosis (CF) is the most common monogenic autosomal recessive disorder with progressive chronic evolution which is potentially lethal. Poor growth is a characteristic of children suffering from cystic fibrosis. A poor nutritional status is an independent risk factor for inadequate survival in cystic fibrosis and is associated with disease complications. The appropriate nutritional management is an important part of the treatment so that the patient with cystic fibrosis can achieve normal growth and development and maintain the best possible health status. A balanced diet supplemented with snacks high in fat and calories is necessary to increase the caloric intake in children with cystic fibrosis. Children with cystic fibrosis have higher caloric needs than healthy children of the same age and sex. Malnutrition in CF is multifactorial. Cystic fibrosis is a complex multisystem disorder affecting mainly the gastrointestinal tract and respiratory system. In the past, malnutrition was an inevitable consequence of disease progression, leading to poor growth, impaired respiratory muscle function, decreased exercise tolerance and immunological impairment. A positive association between body weight and height and survival has been widely reported. The energy requirements of patients with CF vary widely and generally increase with age and disease severity. Cystic fibrosis remains a paediatric disorder which is often underdiagnosed but which, if therapeutically managed properly (by means of drug therapy as well as by appropriate physiotherapy techniques), can lead to improved quality of life and, thus, to a bigger life expectancy. PMID:25076714

  19. Physicochemical characterization and biological activity of intrinsic factor in cystic fibrosis.

    PubMed

    Monin, B; Guéant, J L; Gérard, A; Michalski, J C; Vidailhet, M; Grignon, G; Nicolas, J P

    1990-01-01

    Absorption of crystalline labeled cobalamin is strongly decreased in cases of cystic fibrosis. In order to determine if this is due to an alteration or a lack of activation of intrinsic factor by proteases, the physicochemical properties and biological activity of intrinsic factor have been studied. Intrinsic factor was purified 800-fold from stimulated gastric juice of cystic fibrosis patients with a yield of 64.2%. Cystic fibrosis intrinsic factor had an estimated Mr of 57,000 in SDS-polyacrylamide gel electrophoresis. Its carbohydrate content resembled that of normal human intrinsic factor, except that the ratio fucose/sialic acid was higher (6.1 and 1.6, respectively) and that the content in N-acetylgalactosamine was decreased. The same alterations in carbohydrate composition were observed for Hc purified from cystic fibrosis saliva. Purified intrinsic factor from cystic fibrosis gastric juice was biologically active in vitro in the presence of ileal solubilized receptor as well as in vivo (Schilling test). The fate of iodinated cystic fibrosis intrinsic factor in guinea pig ileum studied by high-resolution radioautography was similar to that of normal intrinsic factor. In conclusion, despite modifications of the carbohydrate content of the molecule, the biological activity of intrinsic factor is not altered in cases of cystic fibrosis. The malassimilation of crystalline cobalamin observed in cystic fibrosis is due to a mechanism independent from intrinsic factor secretion. PMID:2324885

  20. Shwachman-Kulczycki score still useful to monitor cystic fibrosis severity

    PubMed Central

    Stollar, Fabíola; Villac Adde, Fabíola; Cunha, Maristela T; Leone, Claudio; Rodrigues, Joaquim C

    2011-01-01

    INTRODUCTION: The Shwachman-Kulczycki score was the first scoring system used in cystic fibrosis to assess disease severity. Despite its subjectivity, it is still widely used. OBJECTIVE: To study correlations among forced expiratory volume in one second (FEV1), chest radiography, chest computed tomography, 6-minute walk test, and Shwachman-Kulczycki score in patients with cystic fibrosis and to test whether the Shwachman-Kulczycki score is still useful in monitoring the severity of the disease. METHODS: A cross-sectional prospective study was performed to analyze the correlations (Spearman). Patients with clinically stable cystic fibrosis, aged 3-21 years, were included. RESULTS: 43 patients, 19F/24M, mean age 10.5 ± 4.7 years, with a median Shwachman-Kulczycki score of 70 were studied. The median Brasfield and Bhalla scores were 17 and 10, respectively. The mean Z score for the 6-minute walk test was −1.1 ± 1.106 and the mean FEV1 was 59 ± 26 (as percentage of predicted values). The following significant correlations versus the Shwachman-Kulczycki score were found: FEV1 (r  =  0.76), 6-minute walk test (r  =  0.71), chest radiography (r  =  0.71) and chest computed tomography (r  =  −0.78). When patients were divided according to FEV1, a statistically significantly correlation with the Shwachman-Kulczycki score was found only in patients with FEV1 <70% (r  =  0.67). CONCLUSIONS: The Shwachman-Kulczycki score remains an useful tool for monitoring the severity of cystic fibrosis, adequately reflecting the functional impairment and chest radiography and tomography changes, especially in patients with greater impairment of lung function. When assessing patients with mild lung disease its limitations should be considered and its usefulness in such patients should be evaluated in larger populations. PMID:21808862

  1. Cystic Fibrosis below the Diaphragm: Abdominal Findings in Adult Patients.

    PubMed

    Lavelle, Lisa P; McEvoy, Sinead H; Ni Mhurchu, Elaine; Gibney, Robert G; McMahon, Colm J; Heffernan, Eric J; Malone, Dermot E

    2015-01-01

    Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in the white population. Mutation of the CF transmembrane conductance regulator gene on chromosome 7 results in production of abnormally viscous mucus and secretions in the lungs of patients with CF. A similar pathologic process occurs in the gastrointestinal tract, pancreas, and hepatobiliary system. Inspissated mucus causes luminal obstruction and resultant clinical and radiologic complications associated with the disease process. Pancreatic involvement can result in exocrine and endocrine insufficiency, pancreatic atrophy, fatty replacement, or lipomatous pseudohypertrophy. Acute and chronic pancreatitis, pancreatic calcification, cysts, and cystosis also occur. Hepatic manifestations include hepatic steatosis, focal biliary and multilobular cirrhosis, and portal hypertension. Biliary complications include cholelithiasis, microgallbladder, and sclerosing cholangitis. The entire digestive tract can be involved. Distal ileal obstruction syndrome, intussusception, appendicitis, chronic constipation, colonic wall thickening, fibrosing colonopathy, pneumatosis intestinalis, gastroesophageal reflux, and peptic ulcer disease have been described. Renal manifestations include nephrolithiasis and secondary amyloidosis. The educational objectives of this review are to reveal the abdominal manifestations of CF to facilitate focused analysis of cross-sectional imaging in adult patients. Life expectancy in patients with CF continues to improve because of a combination of aggressive antibiotic treatment, improved emphasis on nutrition and physiotherapy, and development of promising new CF transmembrane conductance regulator modulators. As lung function and survival improve, extrapulmonary conditions, including hepatic and gastrointestinal malignancy, will be an increasing cause of morbidity and mortality. Awareness of the expected abdominal manifestations of CF may assist radiologists in identifying

  2. Are bioelectric impedance measurements valid in patients with cystic fibrosis?

    PubMed

    Borowitz, D; Conboy, K

    1994-05-01

    This pilot study compared the use of bioelectric impedance analysis (BIA), a rapid, portable, and painless method of measuring body composition, to isotope dilution in patients with and without cystic fibrosis (CF). Many methods exist for measuring body composition but these measures can be difficult to use in the clinical setting. BIA has been validated as a tool for nutritional assessment in healthy adults, but it must be validated in patient populations with specific disease-related nutritional problems, such as CF. Ten ambulatory patients with CF were selected along with ten controls matched for age, sex, and body mass index (BMI; wt/ht2). Total body water (TBW) was determined using isotoperatio mass spectrometry on urine specimens before and after patients consumed 0.2 g/kg deuterium-rich water. BIA was performed using a tetrapolar technique; 500 microA of current at 50 kHz was introduced and the voltage drop measured. Seven men and three women were studied in each group. Median age was 27 (range, 18-39) and median BMI was 19.2 (range, 16.7-30.1) in CF adults. Median age was 27.5 (range, 15-43) and median BMI was 20.7 (range, 19.4-31.6) in controls. The resistance index (RI; ht2/resistance) correlated strongly with TBW in patients with CF (r = 0.88; y = 0.482x + 11.138; p < 0.05) as well as in controls (r = 0.87; y = 0.661x + 1.299; p < 0.05). We conclude that BIA is a rapid, portable, and painless method for measuring body composition that correlates well with the deuterium-dilution method.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Inhaled therapy in cystic fibrosis: agents, devices and regimens

    PubMed Central

    Parrott, Helen

    2015-01-01

    Key points There have been significant advances in both inhalation medicines and delivery devices with “intelligent nebulisers” and “dry-powder inhalers” becoming commonplace in CF care. Inhaled medicines generate high levels of a drug within the airways with limited systemic effects, offering safe and convenient antibiotic and mucolytic therapy for individuals with CF. Variations in adherence are not unique to CF; however, treatment burden is high and therefore fast inhaled drug delivery devices may assist individuals in completing the prescribed treatment regimes. Prescribers of inhaled medicines have a responsibility to consider, in addition to efficacy, the appropriated drug/device combination for each individual in order to promote adherence and achieve the desired clinical benefit. Summary The recognised mainstay daily treatments for cystic fibrosis (CF) focus on inhaled and oral medications, airway clearance and optimised nutrition. This review discusses recent advances in inhaled therapies for the management of CF, including devices such as intelligent nebulisers, drug formulations and supporting evidence for inhaled antibiotics (for the management of chronic Pseudomonas aeruginosa) and muco-active drugs. We include practical advice for clinicians regarding the optimisation of inhalation technique and education. The influence of adherence on the use of inhaled therapies in CF is also reviewed. Educational aims To inform readers about the history and progression of inhaled therapies for people with CF with reference to the literature supporting current practice. To highlight the factors that may impact the success of inhaled therapies, including those which are device specific such as drug deposition and those which influence adherence. PMID:26306111

  4. Developing a handheld record for patients with cystic fibrosis

    PubMed Central

    Narayan, Omendra; Davies, Siobhan; Tibbins, Carly; Rees, JH Martyn; Lenney, Warren; Gilchrist, Francis J

    2015-01-01

    Patient handheld records (PHHRs) promote self-management and empower the holder to take a more active role in the management of their disease. They have been used successfully in improving preventative care for children and have contributed to improved adherence in a number of chronic illnesses. Despite the potential advantages, there are no standard PHHRs for patients with cystic fibrosis (CF). We report the consultation process that led to the development of a CF PHHR, describe the final document, and analyze the feedback from their use at our center. We have made the CF PHHR freely available online. PMID:26316833

  5. Highlights from the 2015 North American Cystic Fibrosis Conference.

    PubMed

    Zemanick, Edith T; Ong, Thida; Daines, Cori L; Dellon, Elisabeth P; Muhlebach, Marianne S; Esther, Charles R

    2016-06-01

    The 29th Annual North American Cystic Fibrosis Conference was held in Phoenix, Arizona on October 8-10, 2015. Abstracts were published in a supplement to Pediatric Pulmonology.(1) In this review, we summarize presentations in several of the topic areas addressed at the conference. Our goal is to provide an overview of presentations with relevance to emerging or changing concepts in several areas rather than a comprehensive review. Citations from the conference are by first author and abstract number or symposium number, as designated in the supplement. Pediatr Pulmonol. 2016;51:650-657. © 2016 Wiley Periodicals, Inc. PMID:27074261

  6. 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.

  7. Burkholderia pyrrocinia in cystic fibrosis lung transplantation: a case report.

    PubMed

    Savi, D; De Biase, R Valerio; Amaddeo, A; Anile, M; Venuta, F; Ruberto, F; Simmonds, N; Cimino, G; Quattrucci, S

    2014-01-01

    Infection with Burkholderia species is typically considered a contraindication leading to transplantation in cystic fibrosis (CF). However, the risks posed by different Burkholderia species on transplantation outcomes are poorly defined. We present the case of a patient with CF who underwent lung transplantation due to a severe respiratory failure from chronic airways infection with Burkholderia pyrrocinia (B. cepacia genomovar IX) and pan-resistant Pseudomonas aeruginosa. The postoperative course was complicated by recurrent B. pyrrocinia infections, ultimately lea ding to uncontrollable sepsis and death. This is the first case report in CF of Burkholderia pyrrocinia infection and lung transplantation, providing further evidence of the high risk nature of the Burkholderia species.

  8. Gastrointestinal, Pancreatic, and Hepatobiliary Manifestations of Cystic Fibrosis.

    PubMed

    Sathe, Meghana Nitin; Freeman, Alvin Jay

    2016-08-01

    Pulmonary disease is the primary cause of morbidity and mortality in people with cystic fibrosis (CF), but significant involvement within gastrointestinal, pancreatic, and hepatobiliary systems occurs as well. As in the airways, defects in CFTR alter epithelial surface fluid, mucus viscosity, and pH, increasing risk of stasis through the various hollow epithelial-lined structures of the gastrointestinal tract. This exerts secondary influences that are responsible for most gastrointestinal, pancreatic, and hepatobiliary manifestations of CF. Understanding these gastrointestinal morbidities of CF is essential in understanding and treating CF as a multisystem disease process and improving overall patient care. PMID:27469182

  9. Exercise as part of a cystic fibrosis therapeutic routine.

    PubMed

    Rand, Sarah; Prasad, S Ammani

    2012-06-01

    The role of exercise in cystic fibrosis (CF) is well established, and over the last three decades it has become an important component in the management of all individuals with CF. The role of exercise as a prognostic indicator or therapeutic tool is an important area of research interest in CF care internationally. This article summarizes the currently available evidence regarding exercise capacity in CF, the potential effects of exercise on health outcomes in CF and the challenges faced when trying to incorporate exercise into a CF therapeutic routine, and highlights some methods to facilitate the incorporation of exercise into CF therapeutic routines. PMID:22788948

  10. Increased Congregational Support for Parents of Children with Cystic Fibrosis

    PubMed Central

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

    2014-01-01

    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. PMID:25119628

  11. Hypertonic saline for cystic fibrosis: worth its salt?

    PubMed

    Goralski, Jennifer L; Donaldson, Scott H

    2014-06-01

    Airway dehydration in cystic fibrosis (CF) leads to chronic inflammation, ongoing infection and progressive lung disease. Restoration of airway hydration by inhalation of an osmotic agent (hypertonic saline) has been shown to be safe, effective and well-tolerated in adults with CF. Although the safety of hypertonic saline in infants and young children with CF has also been established, recent studies have reported inconclusive evidence about its efficacy. In this editorial, we discuss the evidence behind hypertonic saline use for adults, children and infants with CF.

  12. Cystic fibrosis transmembrane conductance regulator (ABCC7) structure.

    PubMed

    Hunt, John F; Wang, Chi; Ford, Robert C

    2013-02-01

    Structural studies of the cystic fibrosis transmembrane conductance regulator (CFTR) are reviewed. Like many membrane proteins, full-length CFTR has proven to be difficult to express and purify, hence much of the structural data available is for the more tractable, independently expressed soluble domains. Therefore, this chapter covers structural data for individual CFTR domains in addition to the sparser data available for the full-length protein. To set the context for these studies, we will start by reviewing structural information on model proteins from the ATP-binding cassette (ABC) transporter superfamily, to which CFTR belongs.

  13. Cystic Fibrosis Transmembrane Conductance Regulator (ABCC7) Structure

    PubMed Central

    Hunt, John F.; Wang, Chi; Ford, Robert C.

    2013-01-01

    Structural studies of the cystic fibrosis transmembrane conductance regulator (CFTR) are reviewed. Like many membrane proteins, full-length CFTR has proven to be difficult to express and purify, hence much of the structural data available is for the more tractable, independently expressed soluble domains. Therefore, this chapter covers structural data for individual CFTR domains in addition to the sparser data available for the full-length protein. To set the context for these studies, we will start by reviewing structural information on model proteins from the ATP-binding cassette (ABC) transporter superfamily, to which CFTR belongs. PMID:23378596

  14. Infections in patients with cystic fibrosis: diagnostic microbiology update.

    PubMed

    Gilligan, Peter H

    2014-06-01

    Survival has improved in patients with cystic fibrosis (CF), in part because of aggressive antimicrobial management. Two multidrug-resistant environmental bacteria, the Burkholderia cepacia group and nontuberculous mycobacteria, have emerged. Improving genomic and proteomic technologies are allowing better identification of bacteria and fungi found in the CF lung and detection of viral agents that may be associated with pulmonary exacerbations. Anaerobic bacteria and Streptococcus angionsus group organisms may play a role in chronic CF lung infections. The diversity of organisms declines perhaps as a result of aggressive antimicrobial therapy, and an apex predator, Pseudomonas aeruginosa, may emerge in many patients with CF.

  15. Proteomics of hosts and pathogens in cystic fibrosis.

    PubMed

    Kamath, Karthik Shantharam; Kumar, Sheemal Shanista; Kaur, Jashanpreet; Venkatakrishnan, Vignesh; Paulsen, Ian T; Nevalainen, Helena; Molloy, Mark P

    2015-02-01

    Cystic fibrosis (CF) is a congenital disease that results in great morbidity and mortality mainly in the Caucasian population. Although CF is a monogenic disease caused by mutation in the CF conductance transmembrane regulator (CFTR) gene, most of the related mortality can be attributed to infection mediated by opportunistic bacterial and fungal pathogens. Over the past decade, advancements in the field of proteomics have helped to gain insight into the repertoire of host and pathogen proteins involved in CF pathophysiology. This review provides an overview of the contributions of proteomic studies in advancing our knowledge of the biology of CF and disease progression associated with pathogen infection and host defense responses. PMID:25418359

  16. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice.

    PubMed

    Mall, Marcus; Grubb, Barbara R; Harkema, Jack R; O'Neal, Wanda K; Boucher, Richard C

    2004-05-01

    Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in defective epithelial cAMP-dependent Cl(-) secretion and increased airway Na(+) absorption. The mechanistic links between these altered ion transport processes and the pathogenesis of cystic fibrosis lung disease, however, are unclear. To test the hypothesis that accelerated Na(+) transport alone can produce cystic fibrosis-like lung disease, we generated mice with airway-specific overexpression of epithelial Na(+) channels (ENaC). Here we show that increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces. Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance. We conclude that increasing airway Na(+) absorption initiates cystic fibrosis-like lung disease and produces a model for the study of the pathogenesis and therapy of this disease. PMID:15077107

  17. Rapid emergence of resistance to linezolid and mutator phenotypes in Staphylococcus aureus isolates from an adult cystic fibrosis patient.

    PubMed

    Tazi, Asmaa; Chapron, Jeanne; Touak, Gerald; Longo, Magalie; Hubert, Dominique; Collobert, Gislène; Dusser, Daniel; Poyart, Claire; Morand, Philippe C

    2013-10-01

    Linezolid has emerged as an important therapeutic option for the treatment of Staphylococcus aureus in patients with cystic fibrosis. We report the rapid emergence, upon treatment with linezolid, of linezolid-resistant S. aureus clinical isolates through the accumulation of resistance-associated 23S rRNA mutations, together with acquisition of an altered mutator phenotype.

  18. Metagenomic analysis of respiratory tract DNA viral communities in cystic fibrosis and non-cystic fibrosis individuals.

    PubMed

    Willner, Dana; Furlan, Mike; Haynes, Matthew; Schmieder, Robert; Angly, Florent E; Silva, Joas; Tammadoni, Sassan; Nosrat, Bahador; Conrad, Douglas; Rohwer, Forest

    2009-01-01

    The human respiratory tract is constantly exposed to a wide variety of viruses, microbes and inorganic particulates from environmental air, water and food. Physical characteristics of inhaled particles and airway mucosal immunity determine which viruses and microbes will persist in the airways. Here we present the first metagenomic study of DNA viral communities in the airways of diseased and non-diseased individuals. We obtained sequences from sputum DNA viral communities in 5 individuals with cystic fibrosis (CF) and 5 individuals without the disease. Overall, diversity of viruses in the airways was low, with an average richness of 175 distinct viral genotypes. The majority of viral diversity was uncharacterized. CF phage communities were highly similar to each other, whereas Non-CF individuals had more distinct phage communities, which may reflect organisms in inhaled air. CF eukaryotic viral communities were dominated by a few viruses, including human herpesviruses and retroviruses. Functional metagenomics showed that all Non-CF viromes were similar, and that CF viromes were enriched in aromatic amino acid metabolism. The CF metagenomes occupied two different metabolic states, probably reflecting different disease states. There was one outlying CF virome which was characterized by an over-representation of Guanosine-5'-triphosphate,3'-diphosphate pyrophosphatase, an enzyme involved in the bacterial stringent response. Unique environments like the CF airway can drive functional adaptations, leading to shifts in metabolic profiles. These results have important clinical implications for CF, indicating that therapeutic measures may be more effective if used to change the respiratory environment, as opposed to shifting the taxonomic composition of resident microbiota.

  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. Future trends in cystic fibrosis demography in 34 European countries.

    PubMed

    Burgel, Pierre-Régis; Bellis, Gil; Olesen, Hanne V; Viviani, Laura; Zolin, Anna; Blasi, Francesco; Elborn, J Stuart

    2015-07-01

    Median survival has increased in people with cystic fibrosis (CF) during the past six decades, which has led to an increased number of adults with CF. The future impact of changes in CF demographics has not been evaluated. The aim of this study was to estimate the number of children and adults with CF in 34 European countries by 2025. Data were obtained from the European Cystic Fibrosis Society Patient Registry. Population forecasts were performed for countries that have extensive CF population coverage and at least 4 years of longitudinal data by modelling future entering and exiting flows in registry cohorts. For the other countries, population projections were performed based on assumptions from knowledge of current CF epidemiology. Western European countries' forecasts indicate that an increase in the overall number of CF patients by 2025, by approximately 50%, corresponds to an increase by 20% and by 75% in children and adults, respectively. In Eastern European countries the projections suggest a predominant increase in the CF child population, although the CF adult population would also increase.It was concluded that a large increase in the adult CF population is expected in the next decade. A significant increase in adult CF services throughout Europe is urgently required.

  2. Hypertonic saline releases the attached small intestinal cystic fibrosis mucus.

    PubMed

    Ermund, Anna; Meiss, Lauren N; Scholte, Bob J; Hansson, Gunnar C

    2015-01-01

    Hypertonic saline inhalation has become a cornerstone in the treatment of cystic fibrosis (CF), but its effect on CF mucus is still not understood. In CF, mucus stagnates in the airways, causing mucus plugging, and forming a substrate for bacterial invasion. Using horizontal Ussing-type chambers to allow easy access to the tissue, we have recently shown that the small intestinal mucus of CF mice is attached to the epithelium and not freely movable as opposed to normal mucus, thus pointing to a similarity between the CF mucus in the ileum and airways. In the same type of system, we investigated how hypertonic saline affects mucus thickness, attachment and penetrability to fluorescent beads the size of bacteria in ileal explants from the cystic fibrosis transmembrane conductance regulator mutant (ΔF508) mouse, in order to characterize how this common therapy affects mucus properties. Hypertonic saline (1.75-5%) detached the mucus from the epithelium, but the mucus remained impenetrable to beads the size of bacteria. This approach might be used to test other mucolytic interventions in CF.

  3. Pathophysiology of gene-targeted mouse models for cystic fibrosis.

    PubMed

    Grubb, B R; Boucher, R C

    1999-01-01

    Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis. Physiol. Rev. 79, Suppl.: S193-S214, 1999. - Mutations in the gene causing the fatal disease cystic fibrosis (CF) result in abnormal transport of several ions across a number of epithelial tissues. In just 3 years after this gene was cloned, the first CF mouse models were generated. The CF mouse models generated to date have provided a wealth of information on the pathophysiology of the disease in a variety of organs. Heterogeneity of disease in the mouse models is due to the variety of gene-targeting strategies used in the generation of the CF mouse models as well as the diversity of the murine genetic background. This paper reviews the pathophysiology in the tissues and organs (gastrointestinal, airway, hepatobiliary, pancreas, reproductive, and salivary tissue) involved in the disease in the various CF mouse models. Marked similarities to and differences from the human disease have been observed in the various murine models. Some of the CF mouse models accurately reflect the ion-transport abnormalities and disease phenotype seen in human CF patients, especially in gastrointestinal tissue. However, alterations in airway ion transport, which lead to the devastating lung disease in CF patients, appear to be largely absent in the CF mouse models. Reasons for these unexpected findings are discussed. This paper also reviews pharmacotherapeutic and gene therapeutic studies in the various mouse models. PMID:9922382

  4. Hypertonic saline releases the attached small intestinal cystic fibrosis mucus

    PubMed Central

    Ermund, Anna; Meiss, Lauren N; Scholte, Bob J; Hansson, Gunnar C

    2015-01-01

    Hypertonic saline inhalation has become a cornerstone in the treatment of cystic fibrosis (CF), but its effect on CF mucus is still not understood. In CF, mucus stagnates in the airways, causing mucus plugging, and forming a substrate for bacterial invasion. Using horizontal Ussing-type chambers to allow easy access to the tissue, we have recently shown that the small intestinal mucus of CF mice is attached to the epithelium and not freely movable as opposed to normal mucus, thus pointing to a similarity between the CF mucus in the ileum and airways. In the same type of system, we investigated how hypertonic saline affects mucus thickness, attachment and penetrability to fluorescent beads the size of bacteria in ileal explants from the cystic fibrosis transmembrane conductance regulator mutant (ΔF508) mouse, in order to characterize how this common therapy affects mucus properties. Hypertonic saline (1.75–5%) detached the mucus from the epithelium, but the mucus remained impenetrable to beads the size of bacteria. This approach might be used to test other mucolytic interventions in CF. PMID:25311799

  5. A comparison of bronchial drainage treatments in cystic fibrosis.

    PubMed

    Kluft, J; Beker, L; Castagnino, M; Gaiser, J; Chaney, H; Fink, R J

    1996-10-01

    We compared standard chest physical therapy and postural drainage (CPT/PD) with a new airway clearance therapy called high-frequency chest wall oscillation (HFCWO) in a group of stable cystic fibrosis (CF) patients. In this crossover trial, 29 CF patients (15 males, 14 females), aged 7-47 years that met the inclusion criteria were randomly assigned to alternate CPT/PD and HFCWO, on a daily basis, over a 4 day period. Each patient received 2 days of each form of therapy; treatment frequency and the length of treatment were the same for both techniques. Expectorated secretions were collected during each 30 minute therapy session and for 15 minutes following treatment. The wet and dry weights of collected secretions were determined gravimetrically, and the therapy methods were compared. Significantly more sputum was expectorated during HFCWO than during CPT/PD as determined by both the wet (P < 0.001) and the dry (P < 0.01) measurements. This study suggests that HFCWO is at least as effective as manual CPT/PD in clearing secretions from the airways in patients with cystic fibrosis.

  6. 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 Central

    Okusanya, Olanrewaju O.; Hammel, Jeffrey P.; Forrest, Alan; Bulik, Catharine C.; Ambrose, Paul G.; Gupta, Renu

    2014-01-01

    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

  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. [Nutritional management of neonates and infants with cystic fibrosis of the pancreas detected at birth].

    PubMed

    Duhamel, J F; Travert, G; Briere, S; Wysocki, E; Laniece, M; Bureau, F; Delmas, P; Venezia, R

    1986-04-01

    From a systematic neonatal screening for cystic fibrosis in the Basse-Normandie area and to prevent disorders of the intestinal transit related to malabsorption, neonates then infants were given a semi-elemental hypercaloric diet, with supplements in nitrogen, MCT, minerals, vitamins and low in LCT. Diets were adjusted every month during a consultation using clinical and biological parameters. Results in the first 14 children showed that clinically as well as biologically, these children may remain within the normal range, avoiding the previously reported growth retardation and mineral or vitamin deficiencies. This procedure should allow an improvement in the quality of life and prognosis of such children, by maintaining adequate nutritional status.

  9. Infections with Pseudomonas aeruginosa in patients with cystic fibrosis.

    PubMed

    Tümmler, B; Bosshammer, J; Breitenstein, S; Brockhausen, I; Gudowius, P; Herrmann, C; Herrmann, S; Heuer, T; Kubesch, P; Mekus, F; Römling, U; Schmidt, K D; Spangenberg, C; Walter, S

    1997-02-01

    The lung infection with Pseudomonas aeruginosa is regarded as one of the major causes of health decline in patients with cystic fibrosis (CF). The CF host response to the persistent bacterial antigen load in the endobronchiolar lumen is characterized by a pronounced humoral response, local production of cytokines, influx of neutrophils into the lung and a protease-protease inhibitor imbalance predominantly sustained by released neutrophil elastase. CF is an autosomal recessive disease, and we could demonstrate for our local patient population that the age-dependent risk to become chronically colonized with P. aeruginosa can be differentiated by the disease-causing CFTR mutation genotype. The age-specific colonisation rates were significantly lower in pancreas sufficient than in pancreas insufficient patients. P. aeruginosa is occasionally detected in throat swabs already in infancy or early childhood in most patients although there is a lapse of several years amenable to preventive measures such as vaccination until onset of persistent colonization. The epidemiology of the infection with P. aeruginosa was investigated by quantitative macrorestriction fragment pattern analysis. The distribution and frequency of clones found in CF patients match that found in other clinical and environmental aquatic habitats, but the over-representation of specific clones at a CF clinic indicates a significant impact of nosocomial transmission for the prevalence of P. aeruginosa-positive patients at a particular center. Most patients remain colonized with the initially acquired P. aeruginosa clone. According to direct sputum analysis the majority of patients is carrying a single clonal variant at a concentration of 10(7)-10(9) CFU. Co-colonization with other species or other clones is infrequent. Independent of the underlying genotype, the CF lung habitat triggers a uniform, genetically fixed conversion of bacterial phenotype. Most CFP, aeruginosa strains become non-motile, mucoid

  10. The presence of quorum-sensing genes in Pseudomonas isolates infecting cystic fibrosis and non-cystic fibrosis patients.

    PubMed

    Perez, Leandro Reus Rodrigues; Machado, Alice Beatriz Mombach Pinheiro; Barth, Afonso Luís

    2013-04-01

    Ninety-one Pseudomonas aeruginosa isolates recovered from cystic fibrosis and non-cystic fibrosis patients were evaluated regarding the ability to form biofilm and acyl-homoserine lactones production and for the presence of five quorum-sensing (QS) regulatory genes (lasI, lasR, rhlI, rhlR, and vfr). Most isolates (90.1 %) presented all five QS genes. Five isolates shown to be lasI/lasR-deficient were not able to produce biofilm in vitro. Moreover, one isolate harboring all five QS genes was also not able to form a biofilm. The function of rhlR gene may be compensated by the las QS system. However, in our study, all isolates which were deficient for the rhlR gene were also deficient for the lasI/lasR system. This may point to some hierarchy in QS regulation which may pose a potential for controlling biofilm infections due to P. aeruginosa.

  11. 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.

  12. Cyanoquinolines with Independent Corrector and Potentiator Activities Restore ΔPhe508-Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Function in Cystic Fibrosis

    PubMed Central

    Phuan, Puay-Wah; Yang, Baoxue; Knapp, John M.; Wood, Alex B.; Lukacs, Gergely L.; Kurth, Mark J.

    2011-01-01

    The ΔPhe508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein impairs its folding, stability, and chloride channel gating. Although small molecules that separately correct defective ΔPhe508-CFTR folding/cellular processing (“correctors”) or chloride channel gating (“potentiators”) have been discovered and are in clinical trials, single compounds with bona fide dual corrector and potentiator activities have not been identified. Here, screening of ∼110,000 small molecules not tested previously revealed a cyanoquinoline class of compounds with independent corrector and potentiator activities (termed CoPo). Analysis of 180 CoPo analogs revealed 6 compounds with dual corrector and potentiator activities and 13 compounds with only potentiator activity. N-(2-((3-Cyano-5,7-dimethylquinolin-2-yl)amino)ethyl)-3-methoxybenzamide (CoPo-22), which was synthesized in six steps in 52% overall yield, had low micromolar EC50 for ΔPhe508-CFTR corrector and potentiator activities by short-circuit current assay. Maximal corrector and potentiator activities were comparable with those conferred by the bithiazole Corr-4a and the flavone genistein, respectively. CoPo-22 also activated wild-type and G551D CFTR chloride conductance within minutes in a forskolin-dependent manner. Compounds with dual corrector and potentiator activities may be useful for single-drug treatment of cystic fibrosis caused by ΔPhe508 mutation. PMID:21730204

  13. 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

  14. Experiences of physical activity: A phenomenological study of individuals with cystic fibrosis.

    PubMed

    Street, Rachael; Mercer, Jenny; Mills-Bennett, Rebekah; O'Leary, Catherine; Thirlaway, Kathryn

    2016-02-01

    Although extensive research has investigated the benefits of physical activity in cystic fibrosis, minimal exploration of the experiences for individuals from a qualitative, phenomenological perspective has been carried out. The aim of this study was to explore the subjective experiences of physical activity for individuals with cystic fibrosis. The health-care team, at an Adult Cystic Fibrosis Unit in the United Kingdom, recruited 12 participants to take part. Interview data were analysed using interpretative phenomenological analysis. A central theme of 'self-monitoring' emerged from the accounts and was embedded in the three super-ordinate themes.

  15. Neutrophil cell death, activation and bacterial infection in cystic fibrosis

    PubMed Central

    Watt, A; Courtney, J; Moore, J; Ennis, M; Elborn, J

    2005-01-01

    Background: Cystic fibrosis (CF) is characterised by chronic endobronchial bacterial infection and neutrophil mediated inflammation. Neutrophil apoptosis is essential for the resolution of inflammation. This study assessed the relationship between levels of neutrophil apoptosis and sputum microbiology in matched clinically stable patients with CF. Methods: Sputum was induced from 34 patients (nine with no Gram negative infection, 10 colonised with Pseudomonas aeruginosa, 10 with Burkholderia cenocepacia, and five with other infections). Apoptotic neutrophils measured by flow cytometric Annexin V/propidium iodide staining and morphology were similar in all groups. Results: Patients infected with P aeruginosa or B cenocepacia had a significantly lower percentage of viable neutrophils in the sputum than those with no Gram negative infection (Kruskal-Wallis p = 0.01, median (interquartile range (IQR)) 14.2% (9.4–21.6), 15.8% (12.3–19.5), and 48.4% (23.0–66.4); p = 0.003 and p = 0.002, respectively). They also had significantly higher levels of secondary necrotic granulocytes in sputum than patients with no Gram negative infection (Kruskal-Wallis p<0.0001, median (IQR) 55.5% (48.4–64.5), 50.4% (44.6–61.9), and 24.8% (14.4–30.5); p<0.0001 and p<0.0001, respectively). Neutrophils (x106/g sputum) in P aeruginosa infected patients (Kruskal-Wallis p = 0.05, median (IQR) 6.3 (3.5–12.7)) and B cenocepacia infected patients (5.7 (1.5–14.5)) were significantly higher than in the group with no Gram negative infection (0.5 (0.5–4.3), p = 0.03 and 0.04, respectively). Conclusion: These results suggest that cell death and clearance may be altered in patients with CF colonised with P aeruginosa and B cenocepacia compared with those with no Gram negative infection. PMID:16061707

  16. Relationship of adherence determinants and parental spirituality in cystic fibrosis.

    PubMed

    Grossoehme, Daniel H; Opipari-Arrigan, Lisa; VanDyke, Rhonda; Thurmond, Sophia; Seid, Michael

    2012-06-01

    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

  17. 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

  18. 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.

  19. International practice patterns by age and severity of lung disease in cystic fibrosis: data from the Epidemiologic Registry of Cystic Fibrosis (ERCF).

    PubMed

    Koch, C; McKenzie, S G; Kaplowitz, H; Hodson, M E; Harms, H K; Navarro, J; Mastella, G

    1997-08-01

    The Epidemiologic Registry of Cystic Fibrosis provides clinical profiles for more than 6,800 patients and descriptions of practice patterns across eight European countries. Preliminary cross-sectional analysis has been performed by age and pulmonary function as an assessment of disease severity. In general, pulmonary treatments including inhaled bronchodilators and rhDNase increased as lung disease became more severe. Use of a number of treatments, including mucolytic agents and inhaled corticosteroids, varied markedly from country to country. Several widely used therapies are not yet supported by controlled clinical trials, particularly in patients under 6 years of age. Nutritional intervention was more common in patients with advanced lung disease regardless of age. Patients with nasal polyps had less severe lung disease at each age than patients without polyps. It is clear that studies of early interventions are needed to determine the optimal types of treatments and the ages at which to begin treatment.

  20. The Pseudomonas aeruginosa generalized transducing phage phiPA3 is a new member of the phiKZ-like group of 'jumbo' phages, and infects model laboratory strains and clinical isolates from cystic fibrosis patients.

    PubMed

    Monson, Rita; Foulds, Ian; Foweraker, Juliet; Welch, Martin; Salmond, George P C

    2011-03-01

    Pseudomonas aeruginosa is an important pathogen in cystic fibrosis patients, and a model organism for the study of nosocomially acquired infections, biofilms and intrinsic multidrug resistance. In this study we characterize ϕPA3, a new generalized transducing bacteriophage for P. aeruginosa. ϕPA3 transduced chromosomal mutations between PAO1 strains, and infected multiple P. aeruginosa clinical isolates as well as the P. aeruginosa model laboratory strains PAK and PA14. Electron microscopy imaging was used to classify ϕPA3 in the order Caudovirales and the family Myoviridae. The genome of ϕPA3 was sequenced and found to contain 309,208 bp, the second-largest bacteriophage currently deposited in GenBank. The genome contains 378 ORFs and five tRNAs. Many ORF products in the ϕPA3 genome are similar to proteins encoded by P. aeruginosa phage ϕKZ and Pseudomonas chlororaphis phage 201ϕ2-1, and so ϕPA3 was classified genetically as a member of the ϕKZ-like group of phages. This is the first report of a member of this group of phages acting as a generalized transducer. Given its wide host range, high transduction efficiency and large genome size, the 'jumbo' phage ϕPA3 could be a powerful tool in functional genomic analysis of diverse P. aeruginosa strains of fundamental and clinical importance.

  1. 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. PMID:25541089

  2. 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

  3. Does NETosis Contribute to the Bacterial Pathoadaptation in Cystic Fibrosis?

    PubMed Central

    Rahman, Samir; Gadjeva, Mihaela

    2014-01-01

    Significant advances in our understanding of neutrophil biology were made in the past several years. The exciting discovery that neutrophils deploy neutrophil extracellular traps (NETs) to catch pathogens paved the way for a series of additional studies to define the molecular mechanisms of NET generation and the biological significance of NETosis in acute and chronic pathologic conditions. This review highlights the latest knowledge regarding NET structures, deployment, and function, with an emphasis on current understanding of NET proteomes, their conservation, and significance in the context of cystic fibrosis (CF), a condition characterized by excessive extracellular DNA/NET presence. We also discuss how our understanding of NETosis yields novel therapeutic approaches and their applicability to CF. PMID:25157250

  4. 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

  5. Lifestyle treatments in cystic fibrosis: The NHS should pay.

    PubMed

    Ketchell, Robert Ian

    2016-08-01

    With the NHS under increasing financial pressure and healthcare costs soaring year on year, it is perhaps not surprising that assessment agencies focus on cost-effectiveness analysis when assessing new therapies. Such an approach does not however, always take sufficient account of treatment burden, lifestyle and patient choice and therefore new equally effective but perhaps "easier to take" formulations and faster delivery systems for current therapies do not always take precedence in current treatment guidelines. In arguing that the NHS should pay for so-called lifestyle treatments in cystic fibrosis the counterintuitive nature of some of the current decision making is discussed and a more holistic approach to improve NHS efficiency is presented.

  6. Implications of carrier identification in newborn screening for cystic fibrosis

    PubMed Central

    Parsons, E; Clarke, A; Bradley, D

    2003-01-01

    Objective: To investigate the psychosocial implications for families whose infant was identified as a cystic fibrosis carrier by newborn screening. Design: Prospective psychosocial assessment. Setting: Primary care. Respondents: Study: (a) families of an affected infant identified by screening (n = 9); (b) families of a carrier infant identified by screening (n = 10). Control: group of mothers from the general population (n = 82). Interventions: Questionnaires and semistructured interviews. Main outcome measures: Attitude to screening, assessments of the mother/baby relationship, anxiety, wellbeing. Results: All families were in favour of screening, with no evidence that the mother/baby relationship, anxiety or wellbeing had been adversely affected. Parents, however, did identify problems in terms of the service delivery protocol and genetic counselling practice. Conclusion: Six months after disclosure, carrier identification was not perceived by parents to be problematic. PMID:14602692

  7. 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

  8. Tuberculosis reinfection in a pregnant cystic fibrosis patient.

    PubMed

    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.

  9. Physiotherapy in cystic fibrosis: optimising techniques to improve outcomes.

    PubMed

    Rand, S; Hill, L; Prasad, S A

    2013-12-01

    Optimisation of physiotherapy techniques to improve outcomes is an area of cystic fibrosis (CF) care, which has developed considerably over the last two decades. With the introduction of newborn screening and an increase in median life expectancy, the management of individuals with CF has needed to adapt to a more dynamic and individualised approach. It is essential that CF physiotherapy management reflects the needs of a changing cohort of paediatric CF patients and it is no longer justifiable to adopt a 'blanket' prescriptive approach to care. The areas of physiotherapy management which are reviewed and discussed in this paper include inhalation therapy, airway clearance techniques, the management of newborn screened infants, physical activity and exercise. PMID:24209461

  10. 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

  11. ENaC inhibitors for the treatment of cystic fibrosis.

    PubMed

    Butler, Rebecca; Hunt, Thomas; Smith, Nichola J

    2015-01-01

    The epithelial Na(+) channel, ENaC, is a key regulator of the volume of airway surface liquid in the human airway epithelium. In cystic fibrosis (CF), Na(+) hyperabsorption through ENaC in the absence of CFTR-mediated anion secretion results in the dehydration of respiratory secretions and the impairment of mucociliary clearance. The hypothesis of utilizing an ENaC-blocking molecule to facilitate restoration of the airway surface liquid volume sufficiently to allow normal mucociliary clearance is of interest in the management of lung disease in CF patients. This article summarizes the published patent applications from 2010 that claim approaches to inhibit the function of ENaC for utility in the treatment of CF. Patents were located though SciFinder(®), using "ENaC" as the keyword from 2010 onwards; documents not relevant to CF were then manually removed. PMID:25565157

  12. Antibiotic and anti-inflammatory therapies for cystic fibrosis.

    PubMed

    Chmiel, James F; Konstan, Michael W; Elborn, J Stuart

    2013-10-01

    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.

  13. Spectrum of viral infections in patients with cystic fibrosis

    PubMed Central

    Frickmann, H.; Jungblut, S.; Hirche, T. O.; Groß, U.; Kuhns, M.; Zautner, A. E.

    2012-01-01

    This review explores the extensive influence of viral infections leading to chronic deterioration of lung function in patients with cystic fibrosis (CF). The mechanisms how viral agents affect the pathogenesis as well as the inflammatory and immune response of CF are discussed. Viral infections of the upper and lower respiratory tract due to viruses in CF patients and methods for diagnosis of respiratory viruses are described in detail. The importance of respiratory and non-respiratory viral agents for the pathogenesis, especially for the exacerbation of bacterial lower respiratory tract infections and course of CF, is stressed, especially emphasizing respiratory syncytial virus, influenza virus, rhinovirus, and human herpes viruses. Possible harmful effects of further viruses like adenovirus, bocavirus, coronavirus, metapneumovirus, parainfluenzavirus on the lung function of CF patients are discussed. The potential use of adenovirus-based vectors for somatic gene therapy is mentioned. PMID:24688762

  14. Isolation of Staphylococcus aureus from sputum in cystic fibrosis.

    PubMed

    Sparham, P D; Lobban, D I; Speller, D C

    1978-10-01

    The success in the isolation of Staphylococcus aureus of different methods of sputum processing was investigated in 60 specimens collected from 14 patients with cystic fibrosis during a seven-month period. Fifty specimens (83%) from 11 patients yielded Staph. aureus by one or more methods. Direct plating of purulent portions of sputum on to media designed for general use in respiratory infections gave unsatisfactory results (35% yield of Staph. aureus). Some increase in isolations was obtained with preliminary liquefaction of sputum; but the best results were given by the addition of a medium selective for staphylococci (mannitol salt agar, BBL) or by initial sonication of sputum (each 83% yield). Seven of the 11 strains of Staph. aureus were thymidine-dependent and otherwise atypical in laboratory characteristics; these were isolated from patients who had received co-trimoxazole. PMID:101553

  15. Recovery of mycobacteria from patients with cystic fibrosis.

    PubMed

    Bange, F C; Kirschner, P; Böttger, E C

    1999-11-01

    Despite decontamination, overgrowth by pseudomonads renders cultural isolation of mycobacteria from respiratory specimens of patients with cystic fibrosis (CF) difficult or impossible. We performed a prospective study by comparing levels of reduction of overgrowth and recovery of mycobacteria using either pretreatment with N-acetyl-L-cysteine (NALC)-NaOH alone or pretreatment with NALC-NaOH and then with oxalic acid. From 406 specimens of 148 CF patients, 11 specimens were positive for mycobacteria, 5 of which grew mycobacteria after decontamination by either procedure. Three specimens grew mycobacteria only after decontamination with NALC-NaOH, whereas three specimens grew mycobacteria only after treatment with NALC-NaOH followed by oxalic acid but were overgrown after decontamination with NALC-NaOH. Thus, inactivation of mycobacteria by the more aggressive oxalic acid treatment offsets its beneficial effect of reducing the proportion of cultures overgrown with microorganisms other than mycobacteria. PMID:10523596

  16. Beta-2-adrenergic receptor polymorphisms in cystic fibrosis

    PubMed Central

    Steagall, Wendy K.; Barrow, Bethany J.; Glasgow, Connie G.; Mendoza, Jennifer Woo; Ehrmantraut, Mary; Lin, Jing-Ping; Insel, Paul A.; Moss, Joel

    2010-01-01

    Objectives Cystic fibrosis (CF), an autosomal recessive disease affecting the lung, pancreas, gut, liver, and reproductive tract, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cyclic adenosine 3′, 5′ monophosphate-regulated chloride channel. The variability of disease progression among patients with CF suggests effects of genetic modifiers of disease. Beta-2 adrenergic receptors (β2AR), which are abundant in airway epithelial cells, accelerate the formation of cyclic adenosine 3′, 5′ monophosphate, which can modulate CFTR activity and affect smooth muscle contractility. We tested the hypothesis that genetic variants of the β2AR gene, which have been shown to influence receptor desensitization, are more frequent in patients than in controls. Methods We genotyped 130 adult CF patients and 1 : 1 age-matched, sex-matched, and ethnicity-matched normal volunteers for Gly16Arg and Gln27Glu β2AR. Results We found that CF patients were more likely than controls to be Gly16 homozygotes (48 and 32%, respectively) (P < 0.01) and Glu27 homozygotes (29 and 10%, respectively) (P < 0.01). Conclusions Our results, showing a higher frequency of Gly16 and Glu27 β2AR alleles in adult CF patients than in the control population, contrast with data from children with CF, who are reported to have lower frequency of Gly16 and similar frequency of G1u27, and with data from young adults with CF, who showed no differences in frequencies of β2AR variants. The Gly16Glu27 variant of β2AR may have properties that lead to enhanced β2AR function, resulting in the upregulation of CFTR activity and the improvement of CF disease. PMID:17502834

  17. 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

  18. 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

  19. 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. PMID:22170922

  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. 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 ...

  3. 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

  4. 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

  5. Sweat testing for cystic fibrosis. Diagnostic screening with a combination chloride ion-selective electrode.

    PubMed Central

    Bray, P T; Clark, G C; Moody, G J; Thomas, G; Thomas, J D

    1978-01-01

    Screening of sweat chloride in newborn infants with the Orion Skin Chloride Measuring System and incorporating some procedural innovations is described. The results indicate that while diagnostic screening for cystic fibrosis can be readily undertaken, the test with the chloride ion-selective electrode is best left at least to the second day of life or later because of insufficient sweating in very young babies. Measurements on 2 babies with cystic fibrosis are also discussed. PMID:686774

  6. Mucoid conversion by phages of Pseudomonas aeruginosa strains from patients with cystic fibrosis.

    PubMed Central

    Miller, R V; Rubero, V J

    1984-01-01

    A total of 21 of 22 independent isolates of cystic fibrosis-associated Pseudomonas aeruginosa were found to be lysogenic for DNA-containing, complex capsid viruses. Several of the phages demonstrated the ability to select mucoid cells from populations of nonmucoid bacteria. Conversion to mucoid growth was more frequently achieved when phages were isolated from mucoid as opposed to nonmucoid cystic fibrosis-associated strains. PMID:6429192

  7. 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.

  8. [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. PMID:10193090

  9. Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation.

    PubMed

    Hsu, Daniel; Taylor, Patricia; Fletcher, Dave; van Heeckeren, Rolf; Eastman, Jean; van Heeckeren, Anna; Davis, Pamela; Chmiel, James F; Pearlman, Eric; Bonfield, Tracey L

    2016-09-01

    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

  10. 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

  11. Chest CT abnormalities and quality of life: relationship in adult cystic fibrosis

    PubMed Central

    Kilcoyne, Aoife; Lavelle, Lisa P.; McCarthy, Colin J.; McEvoy, Sinead H.; Fleming, Hannah; Gallagher, Annika; Loeve, Martine; Tiddens, Harm; McKone, Edward; Gallagher, Charles C.

    2016-01-01

    Background To evaluate the relationship between lung parenchymal abnormalities on chest CT and health-related quality of life in adult cystic fibrosis (CF). Methods The chest CT scans of 101 consecutive CF adults (mean age 27.8±7.9, 64 males) were prospectively scored by two blinded radiologists in consensus using a modified Bhalla score. Health-related quality of life was assessed using the revised Quittner Cystic Fibrosis Questionnaire (CFQ-R). Multiple regressions were performed with each of the CFQ-R domains and all clinical and imaging findings to assess independent correlations. Results There were 18 inpatients and 83 outpatients. For the cohort of inpatients, CT abnormalities were significantly (P<0.005 for all) associated with Respiratory Symptoms (Air Trapping), and also with Social Functioning (Consolidation) and Role Functioning (Consolidation). For outpatients, CT abnormalities were significantly (P<0.005 for all) associated with Respiratory Symptoms (Consolidation) and also with Physical Functioning (Consolidation), Vitality (Consolidation, Severity of Bronchiectasis), Eating Problems (airway wall thickening), Treatment Burden (Total CT Score), Body Image (Severity of Bronchiectasis) and Role Functioning (Tree-in-bud nodules). Consolidation was the commonest independent CT predictor for both inpatients (predictor for 2 domains) and outpatients (predictor in 3 domains). Several chest CT abnormalities excluded traditional measures such as FEV1 and BMI from the majority of CFQ-R domains. Conclusions Chest CT abnormalities are significantly associated with quality of life measures in adult CF, independent of clinical or spirometric measurements. PMID:27047946

  12. 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.

  13. Achromobacter Species Isolated from Cystic Fibrosis Patients Reveal Distinctly Different Biofilm Morphotypes.

    PubMed

    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. 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. PMID:27115953

  15. 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. PMID:27334259

  16. Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry.

    PubMed

    Kerem, Eitan; Viviani, Laura; Zolin, Anna; MacNeill, Stephanie; Hatziagorou, Elpis; Ellemunter, Helmut; Drevinek, Pavel; Gulmans, Vincent; Krivec, Uros; Olesen, Hanne

    2014-01-01

    Pulmonary insufficiency is the main cause of death in cystic fibrosis (CF). We analysed forced expiratory volume in 1 s (FEV1) data of 14,732 patients registered in the European Cystic Fibrosis Society Patient Registry (ECFSPR) database in 2007. We used linear and logistic regressions to investigate associations between FEV1 % predicted and clinical outcomes. Body mass index (BMI), chronic infection by Pseudomonas aeruginosa, pancreatic status and CF-related diabetes (CFRD) showed a statistically significant (all p<0.0001) and clinically relevant effect on FEV1 % pred after adjusting for age. Patients with a lower BMI experience a six-fold increased odds ratio (95% CI 5.0-7.3) of having severe lung disease (FEV1 <40% pred) compared to patients with normal BMI. Being chronically infected with P. aeruginosa increases the odds ratio of severe lung disease by 2.4 (95% CI 2.0-2.7), and patients with pancreatic insufficiency experience a 2.0-fold increased odds ratio (95% CI 1.6-2.5) of severe lung disease compared to pancreatic sufficient patients. Patients with CFRD have a 1.8-fold increased odds ratio (95% CI 1.6-2.2) compared to patients not affected. These potential risk factors for pulmonary disease in patients with CF are to some degree preventable or treatable. We emphasise the importance of their early identification through frequent routine tests, the implementation of infection control measures, and a timely initiation of relevant therapies.

  17. 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.

  18. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.

    PubMed

    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

    2016-02-01

    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.

  19. 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

  20. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.

    PubMed

    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

    2016-02-01

    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

  1. 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. PMID:26627831

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

    PubMed Central

    Wainwright, C.E.; Elborn, J.S.; Ramsey, B.W.; Marigowda, G.; Huang, X.; Cipolli, M.; Colombo, C.; Davies, J.C.; De Boeck, K.; Flume, P.A.; Konstan, M.W.; McColley, S.A.; McCoy, K.; McKone, E.F.; Munck, A.; Ratjen, F.; Rowe, S.M.; Waltz, D.; Boyle, M.P.

    2016-01-01

    . CONCLUSIONS These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.) PMID:25981758

  7. Chronic cough with normal sweat chloride: Phenotypic descriptions of two rare cystic fibrosis genotypes.

    PubMed

    Yadav, Hemang; Lim, Kaiser G

    2016-01-01

    While our understanding of cystic fibrosis genetics has expanded in recent decades, the genetics and clinical manifestations of the disease remains highly heterogeneous. Diagnosis of CF in non-classical mutations remains a clinical challenge. We describe the clinical presentation of two patients with chronic cough found to have normal sweat chlorides. We discuss the subsequent evaluation that lead to the diagnosis of two rare CF mutations. We briefly discuss the use of the expanded 106-panel of CF mutations (homozygous 3849 + 10  kb C > T), and the role of whole CFTR gene sequencing (heterozygous c.2752-26 A > G/5T). PMID:27222777

  8. Chronic cough with normal sweat chloride: Phenotypic descriptions of two rare cystic fibrosis genotypes

    PubMed Central

    Yadav, Hemang; Lim, Kaiser G.

    2015-01-01

    While our understanding of cystic fibrosis genetics has expanded in recent decades, the genetics and clinical manifestations of the disease remains highly heterogeneous. Diagnosis of CF in non-classical mutations remains a clinical challenge. We describe the clinical presentation of two patients with chronic cough found to have normal sweat chlorides. We discuss the subsequent evaluation that lead to the diagnosis of two rare CF mutations. We briefly discuss the use of the expanded 106-panel of CF mutations (homozygous 3849 + 10  kb C > T), and the role of whole CFTR gene sequencing (heterozygous c.2752-26 A > G/5T). PMID:27222777

  9. 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.

  10. 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.

  11. 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

  12. Analysis and Characterization of Staphylococcus aureus Small Colony Variants Isolated From Cystic Fibrosis Patients in Austria.

    PubMed

    Masoud-Landgraf, Lilian; Zarfel, Gernot; Kaschnigg, Tanja; Friedl, Simone; Feierl, Gebhard; Wagner-Eibel, Ute; Eber, Ernst; Grisold, Andrea J; Kittinger, Clemens

    2016-05-01

    Cystic fibrosis (CF) is the most common hereditary lung disease in the Caucasian population, characterized by viscous bronchial secretion, consecutive defective mucociliary clearance, and unavoidable colonization with microorganisms. Besides Pseudomonas aeruginosa, Staphylococcus aureus is the most common bacterial species colonizing the CF respiratory tract. Under antibiotic pressure S. aureus is able to switch to small colony variants (SCV). These small colony variants can invade epithelial cells, overcome antibiotic therapy inside the cells and can be the starting point for extracellular recolonization. The aim of the present study was the isolation and characterization of S. aureus small colony variants from Austrian cystic fibrosis patients. Samples collected from 147 patients were screened for the presence of S. aureus wild-type and small colony variants. Antibiotic susceptibility testing and determination of the small colony variants causing auxotrophism were performed. Wild-type isolates were assigned to corresponding small colony variants with spa typing. In total, 17 different small colony variant isolates and 12 corresponding wild-type isolates were obtained. 13 isolates were determined thymidine auxotroph, 2 isolates were auxotroph for hemin, and none of the tested isolates was auxotroph for both, respectively. The presence of SCVs is directly related to a poor clinical outcome, therefore a monitoring of SCV prevalence is recommended. This study revealed rather low SCV ratios in CF patients compared to other countries. PMID:26821237

  13. Dornase alfa is well tolerated: data from the epidemiologic registry of cystic fibrosis.

    PubMed

    McKenzie, S G; Chowdhury, S; Strandvik, B; Hodson, M E

    2007-10-01

    After closure of the Epidemiologic Registry of Cystic Fibrosis (ERCF), a comprehensive safety analysis of dornase alfa was performed. A planned subanalysis focused on children under 5 years old. Reported serious adverse events (SAEs) were assigned a preferred term and ascribed to a specific organ system. Possible serious adverse reactions to dornase alfa (SADRs) were identified by reporting clinics. Twenty-eight of 15,865 SAEs (0.18%), occurring in 26 of 6,829 patients ever treated with dornase alfa (0.38%), and no deaths were reported as possible SADRs: most were typical complications of cystic fibrosis (CF). There was no evidence of any unrecognized risk of treatment. During 24,586 patient-years of follow-up (FU) of ever-treated patients, SAEs (mostly typical respiratory complications of CF) were more frequent on-treatment (0.4999/patient-year; 95% CI 0.4921-0.5076) than off-treatment (0.3889; 0.3787-0.3992). This was likely caused by within-patient prescription bias. During 655 patient-years of FU in 328 ever-treated patients under 5 years old, SAEs (mostly pulmonary exacerbations of CF) were slightly less frequent during treatment: 0.2911 (0.2367-0.3455) versus 0.3563 (0.3086-0.4040; ns). Results confirm the safety of dornase alfa in CF patients of all ages. Children under 5 years old tolerate dornase alfa at least as well as older patients.

  14. Feasibility and compliance studies of a home measurement monitoring program for cystic fibrosis.

    PubMed

    Finkelstein, S M; Budd, J R; Warwick, W J; Kujawa, S J; Wielinski, C L; Ewing, L B

    1986-01-01

    A home measurement monitoring system has been developed for assessing progress and planning changes in care for patients with cystic fibrosis. Daily diary recording of specified measurements, quantitative symptom data, and free text are to be used for early detection of deteriorating trends before serious complications develop. Daily measurements made at home are lung capacity, body weight, breathing rate, and pulse. The program has been in place for the past two years, and has maintained a 75-80% consistent diary response rate among the 111 patients initially committed to the program. Measurements are easy to perform, equipment design is simple and rugged, and data handling routines designed for the program using the INSIGHT clinical data base system perform satisfactorily. Checking for data entry errors and validity checks of home measurements are a regular part of the data handling activity. Patient acceptance and long-term compliance in this program agrees very favorably with reports of other diary programs in chronic disease. Diary compliance was significantly greater among younger patients and those who lived long distances from the hospital. This study has demonstrated that home monitoring is a feasible program for patients with cystic fibrosis. It presents the possibility of detecting adverse health trends earlier than is now practical, so that patients can be treated before serious complications develop, thereby preventing the large fluctuations in health status that often accompany CF.

  15. 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.

  16. Improved recovery of mycobacteria from respiratory secretions of patients with cystic fibrosis.

    PubMed

    Whittier, S; Hopfer, R L; Knowles, M R; Gilligan, P H

    1993-04-01

    Pulmonary colonization and infection of patients with cystic fibrosis by Mycobacterium spp. has recently been recognized as a potentially important clinical problem. However, frequent contamination of mycobacterial cultures by pseudomonads has hampered efforts to define the extent of this problem. This study was done to evaluate current techniques and to establish a more efficient method of recovering mycobacteria from respiratory secretions of patients with cystic fibrosis. Decontamination of respiratory specimens (n = 121) with 0.25% N-acetyl-L-cysteine and 1% sodium hydroxide (NALC-NaOH) was associated with a high rate of pseudomonas overgrowth for both Lowenstein-Jensen slants (74%) and BacTec vials supplemented with PANTA (polymyxin B [50 U/ml], amphotericin B [5 micrograms/ml], nalidixic acid [20 micrograms/ml], trimethoprim [5 micrograms/ml], azlocillin [10 micrograms/ml]) (36%). This overgrowth limited recovery of mycobacteria to only 64% (9 of 14) of specimens positive by smear for acid-fast bacilli (AFB). Decontamination of specimens (n = 441) with NALC-NaOH, followed by 5% oxalic acid treatment, resulted in contamination of only 5% of Lowenstein-Jensen slants and 3% of BacTec vials. AFB were recovered from all 90 AFB smear-positive specimens following the use of this decontamination technique. We recommend that respiratory secretions be decontaminated with NALC-NaOH and oxalic acid to decrease the incidence of Pseudomonas aeruginosa overgrowth. PMID:8463398

  17. Preliminary study of haplotypes linked to the rare cystic fibrosis E1104X mutation.

    PubMed

    Oueslati, S; Hadj Fredj, S; Belhaj, R; Siala, H; Bibi, A; Messaoud, Taieb

    2015-03-01

    The analysis of some extra- and intragenic markers within or closely linked to the cystic fibrosis transmembrane regulator (CFTR) gene is useful as a molecular method in clinical linkage analysis. Indeed, knowing that the molecular basis of cystic fibrosis (CF) is highly heterogeneous in our population, the study of haplotype association with normal and CF chromosomes could be very helpful in cases where one or both mutations remain unidentified. In this study, we analysed with PCR-RFLP and capillary electrophoresis some extra (pJ3.11, KM19 and XV2C) and intragenic (IVS8CA, IVS17bTA and IVS17bCA) polymorphic markers in 50 normal and 10 Tunisian patients carrying the rare E1104X mutation in order to determine the haplotype associated with this mutation. For the extragenic markers, 8 haplotypes were identified. The most frequent of them are the 221 and 112 accounting for 80% of total haplotypes. For the intragenic markers, five haplotypes were present on the E1104X chromosomes. One of them 16-31-13 accounted for 50%. To our knowledge, this is the first work to be interested to the haplotypes linked to the E1104X mutation. This preliminary study of haplotypes could be a helpful method to determine the molecular lesions responsible of this pathology.

  18. Acute appendicitis mimicking intestinal obstruction in a patient with cystic fibrosis.

    PubMed

    Chen, Chun-Han; Chang, Cheng-Chih; Yang, Bor-Yau; Lin, Paul Y; Wang, Chia-Siu

    2012-10-01

    Cystic fibrosis (CF) is an inherited disease of the secretory glands caused by mutations of the cystic fibrosis transmembrane regulator (CFTR) gene. The clinical manifestations of CF are repetitive lung infections, biliary cirrhosis, pancreatic abnormalities, and gastrointestinal disorders. We report a 21-year-old Taiwanese man with CF who had abdominal pain for 2 days. The diagnosis of CF had been confirmed by peripheral blood analysis of the CFTR gene 5 years before admission. He presented to the emergency department with nausea, vomiting, abdominal distension, and crampy abdominal pain, which is atypical for acute appendicitis. The physical examination and a series of studies revealed intestinal obstruction, but acute appendicitis could not be ruled out. After conservative treatment, together with empiric antibiotics, the refractory abdominal pain and leukocytosis with a left-shift warranted surgical intervention. A diagnostic laparoscopy revealed a swollen, hyperemic appendix, a severely distended small intestine, and serous ascites. The laparoscopic procedure was converted to a laparotomy for open disimpaction and appendectomy. He was discharged on the eighth postoperative day. The histologic examination of the appendix was consistent with early appendicitis. In conclusion, acute abdominal pain in adult CF patients is often associated with intestinal obstruction syndrome. The presentation of concurrent appendicitis may be indolent and lead not only to diagnostic difficulties, but also a number of therapeutic choices.

  19. 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

  20. 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.

  1. 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

  2. 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…

  3. Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth.

    PubMed

    Ghorbani, Peyman; Santhakumar, Prisila; Hu, Qingda; Djiadeu, Pascal; Wolever, Thomas M S; Palaniyar, Nades; Grasemann, Hartmut

    2015-10-01

    The hypoxic environment of cystic fibrosis airways allows the persistence of facultative anaerobic bacteria, which can produce short-chain fatty acids (SCFAs) through fermentation. However, the relevance of SCFAs in cystic fibrosis lung disease is unknown. We show that SCFAs are present in sputum samples from cystic fibrosis patients in millimolar concentrations (mean±sem 1.99±0.36 mM).SCFAs positively correlated with sputum neutrophil count and higher SCFAs were predictive for impaired nitric oxide production. We studied the effects of the SCFAs acetate, propionate and butyrate on airway inflammatory responses using epithelial cell lines and primary cell cultures. SCFAs in concentrations present in cystic fibrosis airways (0.5-2.5 mM) affected the release of granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin (IL)-6. SCFAs also resulted in higher IL-8 release from stimulated cystic fibrosis transmembrane conductance regulator (CFTR) F508del-mutant compared to wild-type CFTR-corrected bronchial epithelial cells. At 25 mM propionate reduced IL-8 release in control but not primary cystic fibrosis epithelial cells. Low (0.5-2.5 mM) SCFA concentrations increased, while high (25-50 mM) concentrations decreased inducible nitric oxide synthase expression. In addition, SCFAs affected the growth of Pseudomonas aeruginosa in a concentration- and pH-dependent manner.Thus, our data suggest that SCFAs contribute to cystic fibrosis-specific alterations of responses to airway infection and inflammation.

  4. 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

  5. Cystic fibrosis heterozygote screening in 5,161 pregnant women.

    PubMed Central

    Witt, D. R.; Schaefer, C.; Hallam, P.; Wi, S.; Blumberg, B.; Fishbach, A.; Holtzman, J.; Kornfeld, S.; Lee, R.; Nemzer, L.; Palmer, R.

    1996-01-01

    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 parents 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. PMID:8644747

  6. Attitudes toward abortion among parents of children with cystic fibrosis.

    PubMed Central

    Wertz, D C; Rosenfield, J M; Janes, S R; Erbe, R W

    1991-01-01

    BACKGROUND: DNA prenatal diagnosis for cystic fibrosis (CF) has been available for parents of affected children since late 1985. METHODS: Using anonymous questionnaires, we surveyed 395 parents of children with CF at 12 New England CF centers with regard to 12 maternal or family situations and 11 fetal characteristics; 271 (68%) responded. RESULTS: The majority supported legal abortion in the first trimester for all 23 situations; 58% would abort for severe mental retardation (MR), 40% would abort for a genetic disorder leading to death before age five years, 41% for a child bedridden for life, 35% for moderate MR, 20% for CF and 17% for a severe incurable disorder starting at age 40 years. Few would abort for a disorder starting at age 60 years, for genetic susceptibility to alcoholism or for sex selection. Variables most strongly related to abortion for CF were attitudes of spouse, respondent's siblings, and CF doctor toward abortion for CF as well as infrequent attendance at religious services. CONCLUSIONS: Prenatal diagnosis may not reduce substantially the number of CF births to parents of CF children because most do not accept abortion for CF. PMID:1854017

  7. 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

  8. Healthcare expenditures for privately insured people with cystic fibrosis.

    PubMed

    Ouyang, Lijing; Grosse, Scott D; Amendah, Djesika D; Schechter, Michael S

    2009-10-01

    With improved survival and new therapies for people with cystic fibrosis (CF), updated information on medical care expenditures for those individuals is needed. We estimated medical care expenditures, including both insurance reimbursements and patient out-of-pocket expenses, for privately insured people with CF and investigated how those expenditures varied with certain complications of CF. From a private insurance claims database of people covered by health plans associated with large corporate employers, we identified people with CF who were currently receiving medical care for the disorder and characterized their medical expenditures during the period 2004-2006. We selected a matching group of people who did not have CF based on age, sex, and geographic area, and calculated incremental expenditures associated with CF. We also examined the effect of age and certain complications of CF on these expenditures. The annual medical care expenditure for a person with actively managed CF averaged $48,098 in 2006 dollars, which was 22 times higher than for a person without CF. This ratio is high relative to other chronic disorders. Outpatient prescription medications made up the largest component of total expenditures for people with CF (39%). Those who were recorded in claims data as having a liver or lung transplant, malnutrition, diabetes, or a chronic Pseudomonas aeruginosa pulmonary infection incurred much higher expenditures than people without these conditions. People with CF will incur high medical expenditures throughout their lifespan. These findings will assist in the development of economic evaluations of future CF screening and management initiatives. PMID:19768806

  9. Ibuprofen regulation of microtubule dynamics in cystic fibrosis epithelial cells.

    PubMed

    Rymut, Sharon M; Kampman, Claire M; Corey, Deborah A; Endres, Tori; Cotton, Calvin U; Kelley, Thomas J

    2016-08-01

    High-dose ibuprofen, an effective anti-inflammatory therapy for the treatment of cystic fibrosis (CF), has been shown to preserve lung function in a pediatric population. Despite its efficacy, few patients receive ibuprofen treatment due to potential renal and gastrointestinal toxicity. The mechanism of ibuprofen efficacy is also unclear. We have previously demonstrated that CF microtubules are slower to reform after depolymerization compared with respective wild-type controls. Slower microtubule dynamics in CF cells are responsible for impaired intracellular transport and are related to inflammatory signaling. Here, it is identified that high-dose ibuprofen treatment in both CF cell models and primary CF nasal epithelial cells restores microtubule reformation rates to wild-type levels, as well as induce extension of microtubules to the cell periphery. Ibuprofen treatment also restores microtubule-dependent intracellular transport monitored by measuring intracellular cholesterol transport. These effects are specific to ibuprofen as other cyclooxygenase inhibitors have no effect on these measures. Effects of ibuprofen are mimicked by stimulation of AMPK and blocked by the AMPK inhibitor compound C. We conclude that high-dose ibuprofen treatment enhances microtubule formation in CF cells likely through an AMPK-related pathway. These findings define a potential mechanism to explain the efficacy of ibuprofen therapy in CF.

  10. Increased expression of senescence markers in cystic fibrosis airways.

    PubMed

    Fischer, Bernard M; Wong, Jessica K; Degan, Simone; Kummarapurugu, Apparao B; Zheng, Shuo; Haridass, Prashamsha; Voynow, Judith A

    2013-03-15

    Cystic Fibrosis (CF) is a chronic lung disease characterized by chronic neutrophilic airway inflammation and increased levels of neutrophil elastase (NE) in the airways. We have previously reported that NE treatment triggers cell cycle arrest. Cell cycle arrest can lead to senescence, a complete loss of replicative capacity. Importantly, senescent cells can be proinflammatory and would perpetuate CF chronic inflammation. By immunohistochemistry, we evaluated whether airway sections from CF and control subjects expressed markers of senescence, including p16(INK4a) (p16), a cyclin-dependent kinase inhibitor, phospho-Histone H2A.X (γH2A.X), and phospho-checkpoint 2 kinase (phospho-Chk2), which are also DNA damage response markers. Compared with airway epithelium from control subjects, CF airway epithelium had increased levels of expression of all three senescence markers. We hypothesized that the high load of NE in the CF airway triggers epithelial senescence by upregulating expression of p16, which inhibits cyclin-dependent kinase 4 (CDK4). Normal human bronchial epithelial (NHBE) cells, cultured in air-liquid interface were treated with NE (0, 200, and 500 nM) to induce visible injury. Total cell lysates were collected and evaluated by Western analysis for p16 protein expression and CDK4 kinase activity. NE significantly increased p16 expression and decreased CDK4 kinase activity in NHBE cells. These results support the concept that NE triggers expression of senescence markers in CF airway epithelial cells. PMID:23316069

  11. 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. PMID:27325484

  12. Proteomic analysis of nasal epithelial cells from cystic fibrosis patients.

    PubMed

    Jeanson, Ludovic; Guerrera, Ida Chiara; 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. Increased Oxidative Stress Induces Apoptosis in Human Cystic Fibrosis Cells

    PubMed Central

    Rottner, Mathilde; Tual-Chalot, Simon; Mostefai, H. Ahmed; Andriantsitohaina, Ramaroson; Freyssinet, Jean-Marie; Martínez, María Carmen

    2011-01-01

    Oxidative stress results in deleterious cell function in pathologies associated with inflammation. Here, we investigated the generation of superoxide anion as well as the anti-oxidant defense systems related to the isoforms of superoxide dismutases (SOD) in cystic fibrosis (CF) cells. Pro-apoptotic agents induced apoptosis in CF but not in control cells that was reduced by treatment with SOD mimetic. These effects were associated with increased superoxide anion production, sensitive to the inhibition of IκB-α phosphorylation, in pancreatic but not tracheal CF cells, and reduced upon inhibition of either mitochondrial complex I or NADPH oxidase. CF cells exhibited reduced expression, but not activity, of both Mn-SOD and Cu/Zn-SOD when compared to control cells. Although, expression of EC-SOD was similar in normal and CF cells, its activity was reduced in CF cells. We provide evidence that high levels of oxidative stress are associated with increased apoptosis in CFTR-mutated cells, the sources being different depending on the cell type. These observations underscore a reduced anti-oxidant defense mechanism, at least in part, via diminished EC-SOD activity and regulation of Cu/Zn-SOD and Mn-SOD expressions. These data point to new therapeutic possibilities in targeting anti-oxidant pathways to reduce oxidative stress and apoptosis in CF cells. PMID:21931865

  18. 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.

  19. 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.

  20. Data Mining of Lung Microbiota in Cystic Fibrosis Patients

    PubMed Central

    Xiao, Yan; Wang, Jianwei; Qin, Xuemei

    2016-01-01

    The major therapeutic strategy used to treat exacerbated cystic fibrosis (CF) is antibiotic treatment. As this approach easily generates antibiotic-resistant strains of opportunistic bacteria, optimized antibiotic therapies are required to effectively control chronic and recurrent bacterial infections in CF patients. A promising future for the proper use of antibiotics is the management of lung microbiota. However, the impact of antibiotic treatments on CF microbiota and vice versa is not fully understood. This study analyzed 718 sputum samples from 18 previous studies to identify differences between CF and uninfected lung microbiota and to evaluate the effects of antibiotic treatments on exacerbated CF microbiota. A reference-based OTU (operational taxonomic unit) picking method was used to combine analyses of data generated using different protocols and platforms. Findings show that CF microbiota had greater richness and lower diversity in the community structure than uninfected control (NIC) microbiota. Specifically, CF microbiota showed higher levels of opportunistic bacteria and dramatically lower levels of commensal bacteria. Antibiotic treatment affected exacerbated CF microbiota notably but only transiently during the treatment period. Limited decrease of the dominant opportunistic bacteria and a dramatic decrease of commensal bacteria were observed during the antibiotic treatment for CF exacerbation. Simultaneously, low abundance opportunistic bacteria were thriving after the antibiotic treatment. The inefficiency of the current antibiotic treatment against major opportunistic bacteria and the detrimental effects on commensal bacteria indicate that the current empiric antibiotic treatment on CF exacerbation should be reevaluated and optimized. PMID:27741283

  1. 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

  2. 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.

  3. Cystic fibrosis in Arabs: a prototype from Jordan.

    PubMed

    Rawashdeh, M; Manal, H

    2000-12-01

    Cystic fibrosis is believed to be rare in Arabs. We report 202 cases (114 boys and 88 girls) diagnosed in Jordan over a period of 9 years. The mean age at diagnosis was 2.9 years. Classical presentation with growth failure, malabsorption and respiratory symptoms occurred in 75.4% of cases. Eighteen (10.8%) presented with hepatomegaly, 12 (7.2%) with meconium ileus and 11 (6.6%) had Pseudo-Bartter syndrome. Thirty-eight (23%) children died, most below the age of 1 year which may reflect a more severe disease in our population. Consanguineous marriage was present in 69% of cases. Genetic screening of 84 children and 66 parents revealed 24 different CFTR mutations with a DF508 mutation accounting for only 7.4%. Among the mutations detected, six were alleles identified for the first time. The fact that boys outnumber girls might reflect more deaths in girls due to the observed gender gap in CF mortality. It is possible that the low incidence of the DF508 mutation is due to a confounding effect and the high mortality in those carrying this mutation. The large number of different mutations reflects the ethnic diversity of the Jordanian population and the complex history of the country.

  4. 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

  5. Physical exercise for patients with cystic fibrosis: a review.

    PubMed

    Stanghelle, J K

    1988-02-01

    Cystic fibrosis (CF) is an inherited, chronic disease which mainly affects the lungs and the nutrition. Intensive treatment has gradually improved the outcome for the patients. Exercise therapy has been increasingly advocated to be included in the CF regimen. Our own studies indicate that both short-term and long-term training ameliorate the physical conditions for CF patients, that there is no danger for well-trained CF patients--both boys and girls--to take part even in vigorous, prolonged exercises, and that CF patients might have a positive attitude toward physical activities. Of course, all physical activities have to be individually designed. A review of the literature is also given: The specific ventilatory factors in CF, the limitations of exercise, the problem with exercise-induced asthma, the training effect on lung drainage, on lung function, on infections, on biochemical and hormonal variables, on nutrition and the gastrointestinal tract, on the musculoskeletal apparatus, and on the mind. Nearly all these reports are favorable for a carefully monitored, high activity in CF patients. Practical considerations for activities are given.

  6. Phylogenetic and metabolic diversity of bacteria associated with cystic fibrosis

    PubMed Central

    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. PMID:20631810

  7. Pharmaceutical intervention in the care of cystic fibrosis patients.

    PubMed

    Ramström, H; Erwander, I; Mared, L; Kornfält, R; Seiving, B

    2000-12-01

    In a prospective, randomised, cross-over study including cystic fibrosis patients with indications for HIVAT (home intravenous antibiotic treatment) the prospect of pharmaceutical intervention was investigated. A comparison between the use of disposable infusion devices with antibiotics from the pharmacy and when the patients prepared the drugs themselves was performed. During a first treatment course the patients received either infusion devices during 5 days or reconstituted the drugs themselves during 5 days, or vice versa. During a second treatment course the order was the reversed. Eight patients were included, out of which six completed the original design as a cross-over study, yielding a total of 550 doses of antibiotics. The patients preferred infusion devices from the pharmacy prepared according to GMP (Good Manufacturing Practice) as opposed to reconstituting the antibiotics themselves. Points of view presented included no anxiety over the correct dosage of drugs and less disruption of family and social life. In a practical sense, portable devices are more expensive than the preparation of the drugs by the patients themselves. However, when comparing with in-hospital treatment the direct costs for a hospital stay exceed that of the devices. Another part of the study evaluated the quality of life using a modified form of SEIQoL-DW (Schedule for the Evaluation of Individual Quality of Life - Direct Weighting). Twenty patients took part in the study and the overall quality of life scores increased significantly when patients received infusion devices compared to reconstituting the drugs themselves.

  8. 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. PMID:22936714

  9. Recent advances and new perspectives in targeting CFTR for therapy of cystic fibrosis and enterotoxin-induced secretory diarrheas

    PubMed Central

    Zhang, Weiqiang; Fujii, Naoaki; Naren, Anjaparavanda P

    2012-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel localized primarily at the apical surfaces of epithelial cells lining airway, gut and exocrine glands, where it is responsible for transepithelial salt and water transport. Several human diseases are associated with an altered channel function of CFTR. Cystic fibrosis (CF) is caused by the loss or dysfunction of CFTR-channel activity resulting from the mutations on the gene; whereas enterotoxin-induced secretory diarrheas are caused by the hyperactivation of CFTR channel function. CFTR is a validated target for drug development to treat these diseases. Significant progress has been made in developing CFTR modulator therapy by means of high-throughput screening followed by hit-to-lead optimization. Several oral administrated investigational drugs are currently being evaluated in clinical trials for CF. Also importantly, new ideas and methodologies are emerging. Targeting CFTR-containing macromolecular complexes is one such novel approach. PMID:22393940

  10. Macrophage activation syndrome induced by A/H1N1 influenza in cystic fibrosis.

    PubMed

    Casciaro, Rosaria; Cresta, Federico; Favilli, Federica; Naselli, Aldo; De Alessandri, Alessandra; Minicucci, Laura

    2014-02-01

    Bacterial respiratory infections have an important impact on the development and progression of pulmonary disease in cystic fibrosis (CF). Viral infections are possible triggers of acute deterioration in the clinical status of CF patients. Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic disease characterized by pancytopenia, hepatitis, hyperferritinemia, coagulopathy, and neurologic symptoms. This syndrome is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction. Here, we report the case of a boy affected by CF who developed MAS triggered by pandemic H1N1 influenza; good clinical response was obtained through high dose prednisone treatment. PMID:23401277

  11. A morphometric study of mucins and small airway plugging in cystic fibrosis

    PubMed Central

    Burgel, Pierre‐Régis; Montani, David; Danel, Claire; Dusser*, Daniel J; Nadel*, Jay A

    2007-01-01

    Rationale Little knowledge exists on structural changes and plugging in small airways in cystic fibrosis. Objective To characterise the extent of plugging and contribution of secreted mucins to the plugs. Methods Small airways in patients with cystic fibrosis at transplantation (n = 18) were compared with control non‐smokers (n = 10). Tissue sections were stained with Alcian blue (AB)/periodic acid‐Schiff (PAS), for mucins MUC5B and MUC5AC, and for neutrophils and its chemoattractant interleukin (IL) 8. Epidermal growth factor receptor (EGFR) and its ligand pro‐transforming growth factor α were also identified using immunohistochemical staining. Epithelial and luminal contents were assessed morphometrically. Results Plugs occupying >50% of total luminal volume were found in 147 of 231 (63.6%) airways in patients with cystic fibrosis, but only in 1 of 39 (2.6%) airways in controls. In the epithelium of patients with cystic fibrosis, AB/PAS, MUC5B, and MUC5AC‐stained volume densities were increased 10‐fold (p<0.01), indicating increased mucin production. In airway lumens, staining for mucins was also increased in cystic fibrosis, indicating increased mucin secretion. In the epithelium of patients with cystic fibrosis, neutrophil numbers were markedly increased and were inversely correlated with volume densities of mucous glycoconjugates (r = −0.66, p<0.005). IL8 staining was increased in the epithelium of patients with cystic fibrosis and colocalised with mucins. Staining for EGFR and for pro‐transforming growth factor α were increased in the epithelium of patients with cystic fibrosis; positive correlations were found between EGFR‐stained volume density and both AB/PAS and IL8‐stained volume densities. Conclusions Most of the small airways are plugged in cystic fibrosis at the time of transplantation. Mucins contribute to airway plugging. Recruited neutrophils may be involved in mucin secretion in the plugs. Increased expression of

  12. 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

  13. Non-pulmonary chronic diseases in adults with cystic fibrosis: analysis of data from the Cystic Fibrosis Registry.

    PubMed

    Somerville, R; Lackson, A; Zhou, S; Fletcher, C; Fitzpatrick, P

    2013-06-01

    The international literature shows that the demography of cystic fibrosis (CF) is changing, with patients increasingly surviving into adulthood. As they age, patients with CF become more susceptible to specific non-pulmonary chronic diseases. In this study, adult data from the CF Registry of Ireland (CFRI) was used to determine the prevalence and associated features of these diseases. 104 (25.7%) adults had diabetes versus 13 (2.9%) children (p < 0.001). Liver disease was present in 47 (11.6%) adults and 26 (5.7%) children (p = 0.002). 173 (42.7%) adults had bone disease versus 25 (5.5%) children (p < 0.001). Adults with one non-pulmonary chronic disease, for example liver disease, were more likely to have another (p = 0.002), those with diabetes and bone disease had a higher number of hospital admissions in the last 12 months (p < 0.001 for both) and higher rates of depression (p = 0.046 and p = 0.049, respectively). These results highlight a number of challenges for the Irish healthcare system. PMID:23909150

  14. Pharmacokinetics of ticarcillin in patients with cystic fibrosis: a controlled prospective study.

    PubMed

    de Groot, R; Hack, B D; Weber, A; Chaffin, D; Ramsey, B; Smith, A L

    1990-01-01

    We compared the pharmacokinetics of ticarcillin at a dose of 120 mg/kg in 11 patients with cystic fibrosis to 11 control subjects matched for age and sex. The mean elimination half-life of ticarcillin in serum was 70.8 minutes in the control subjects and 53.1 minutes in the patients with cystic fibrosis. The total body clearance of ticarcillin was significantly higher in cystic fibrosis patients (65.6 +/- 22.0 versus 46.2 +/- 10.9 ml/min/m2 in control subjects; p = 0.017). The nonrenal clearance of ticarcillin was also significantly higher in patients with cystic fibrosis (24.8 +/- 11.1 versus 13.3 +/- 6.0 ml/min/m2 for the control group; p = 0.006). There was no significant difference in volume of distribution between the two groups. We concluded that the shorter elimination half-life and the higher total body clearance of ticarcillin in patients with cystic fibrosis are a result of an increase in both renal and nonrenal elimination.

  15. ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.

    PubMed

    Pankow, Sandra; Bamberger, Casimir; Calzolari, Diego; Martínez-Bartolomé, Salvador; Lavallée-Adam, Mathieu; Balch, William E; Yates, John R

    2015-12-24

    Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (∆F508 CFTR) is the major cause of cystic fibrosis, one of the most common inherited childhood diseases. The mutated CFTR anion channel is not fully glycosylated and shows minimal activity in bronchial epithelial cells of patients with cystic fibrosis. Low temperature or inhibition of histone deacetylases can partly rescue ∆F508 CFTR cellular processing defects and function. A favourable change of ∆F508 CFTR protein-protein interactions was proposed as a mechanism of rescue; however, CFTR interactome dynamics during temperature shift and inhibition of histone deacetylases are unknown. Here we report the first comprehensive analysis of the CFTR and ∆F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, we identify 638 individual high-confidence CFTR interactors and discover a ∆F508 deletion-specific interactome, which is extensively remodelled upon rescue. Detailed analysis of the interactome remodelling identifies key novel interactors, whose loss promote ∆F508 CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. Our results demonstrate that global remodelling of ∆F508 CFTR interactions is crucial for rescue, and provide comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508.

  16. 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.

  17. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.

    PubMed

    Stallings, Virginia A; Stark, Lori J; Robinson, Karen A; Feranchak, Andrew P; Quinton, Hebe

    2008-05-01

    The Cystic Fibrosis Foundation established a process of systematic review of evidence to inform the development of clinical care guidelines and encourage evidence-based practice. The Subcommittee on Growth and Nutrition reviewed the evidence in two areas: energy intake and dosing for pancreatic enzyme replacement therapy. Evidence-based recommendations are presented here. Also, an ad hoc working group conducted a review of the literature and performed new analyses using the Cystic Fibrosis Foundation Patient Registry to update the recommendations for growth and weight-status monitoring. These Registry data-based recommendations are presented.

  18. 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.

  19. 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.

  20. 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. PMID:26553470

  1. Polysomnographic Markers in Children With Cystic Fibrosis Lung Disease

    PubMed Central

    McGinley, Brian M.; Braun, Andrew T.; Schneider, Hartmut

    2015-01-01

    BACKGROUND AND OBJECTIVES: Children with cystic fibrosis (CF) often report poor sleep, increased daytime sleepiness, and fatigue. The purpose of this study was to identify respiratory patterns over the spectrum of disease severity in children with CF. The overall hypothesis for the current study is that children with CF compared with snoring control subjects demonstrate gas exchange abnormalities and increased respiratory loads during sleep that are not reported or recognized by conventional polysomnography (PSG). METHODS: Analysis of breathing patterns and gas exchange on PSG was performed in children with CF and healthy controls matched by age and BMI. For all CF and control subjects, the indication for PSG was evaluation for obstructive sleep apnea based on a history of snoring. RESULTS: Children with CF, compared with age- and BMI-matched snoring controls, demonstrated lower oxyhemoglobin saturation (95% ± 1.6% vs 98% ± 0.6%, P = .005), higher respiratory rate (19.5 ± 4.9 vs 16.5 ± 1.2 breaths per minute, P = .03), and a higher proportion of inspiratory flow limitation (44.1% ± 24.7% vs 12.1% ± 13.5%, P = .007) during non–rapid eye movement sleep. The respiratory disturbance index did not differ between CF and snoring control groups (1.5 ± 2.7 vs 0.6 ± 0.6 events per hour, P = .11). CONCLUSIONS: Children with CF exhibited abnormalities in gas exchange and increased respiratory load during sleep compared with normal age- and BMI-matched snoring controls. Because these abnormalities were independent of weight and lung function, sleep state may serve as an opportunity for early detection of breathing abnormalities and possibly CF lung disease progression. PMID:26482667

  2. 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. PMID:14695120

  3. 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.

  4. Body Composition and Pulmonary Function in Cystic Fibrosis

    PubMed Central

    Sheikh, Saba; Zemel, Babette S.; Stallings, Virginia A.; Rubenstein, Ronald C.; Kelly, Andrea

    2014-01-01

    Background: Lower body mass index (BMI) is associated with worse pulmonary function in cystic fibrosis (CF). Hypothesis: lean body mass (LBM) is more strongly associated with pulmonary function than BMI is. Methods: Anthropometrics, body composition by dual x-ray absorptiometry, and pulmonary function were determined in pancreatic insufficient CF (PI-CF) youth. Sex and age-adjusted Z-scores (BMI-Z, LBMI-Z, FMI-Z) were generated for CF and controls. (1) Associations of BMI-Z with LBMI-Z and FMI-Z and (2) age-adjusted associations of BMI-Z, LBMI-Z, and FMI-Z with FEV1%-predicted were tested. Results: Two hundred eight PI-CF subjects had lower BMI-Z, LBMI-Z, and FMI-Z compared to 390 controls. BMI-Z was associated with lower LBMI-Z (p < 0.0001) in PI-CF. In females, LBMI-Z and BMI-Z were positively associated with FEV1%-predicted; this relationship did not persist for FMI-Z after adjustment for LBMI-Z. In males, only LBMI-Z and BMI-Z were associated with FEV1%-predicted. Conclusion: In PI-CF youth, deficits in LBM were apparent. At lower BMI percentiles, BMI may not accurately depict LBM in PI-CF. In under-nourished PI-CF youth, this preservation of FM in preference to LBM is relevant since LBMI-Z, but not FMI-Z, is positively associated with FEV1%-predicted. Lean body mass index is more strongly associated with lung function compared to BMI, especially in the under-nourished child and adolescent with PI-CF. PMID:24783186

  5. Emotional health in children and adolescents with cystic fibrosis.

    PubMed

    Pop-Jordanova, Nada; Demerdzieva, Aneta

    2016-01-01

    Although modern therapeutic procedures have considerably improved the survival and the quality of life of children with cystic fibrosis, the relevant psychological aspects have been still insufficiently considered similarly to the other chronic diseases. The aim of this research was to evaluate the emotional health: psychological characteristics and adjustment of CF children and their family coping. The study comprises 25 CF children, mean age 13.13 ± 2.29 years (23 boys and only 2 girls), selected from total 60 actually treated children for CF. Children were examined in the period of improved health conditions (without superinfection, wheezing or gastrointestinal problems). Obtained results are compared with a control group of 25 healthy children of the same age, selected by random from primary schools. The psychometric instruments used were: Kohs Design Test, Child Behavior Checklist, Eysenck Personality Questionnaire, General Anxiety Scale, Emotional Profile Index, MMPI-201 and Human Values Test, together with two projective tests of drawing (Machover and Corman). The unexpected good psychological results obtained from psychometric instruments could be explained by the fact that CF children accept the real situation and express vivacity. However, their deep feelings of fear impose on them high level of self-control and resistance. The results obtained for CBCL presented CF children as immature, with accentuated aggressiveness in interpersonal relations. The most important problem is related to the delay of puberty changes, leading to low self-esteem. Generally, family members cope relatively well with the disease in children, in spite to discrepancies in mother/child reports for child psychopathology. Divorces also occurred in some families. Psychological support for both, children and family members are necessary. The need for a holistic approach in the assessment and treatment, including biofeedback techniques was pointed out. PMID:27442418

  6. 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.

  7. Genome Diversity of Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients and the Hospital Environment

    PubMed Central

    Finnan, Shirley; Morrissey, John P.; O'Gara, Fergal; Boyd, E. Fidelma

    2004-01-01

    Pseudomonas aeruginosa is a gram-negative rod that is ubiquitous in nature. P. aeruginosa is also the quintessential opportunistic pathogen, causing a wide variety of infections in compromised hosts. In cystic fibrosis patients, P. aeruginosa is the leading cause of death. In this study, the evolutionary genetic relationships among 17 P. aeruginosa isolates were examined by comparative sequence analysis of the housekeeping gene encoding malate dehydrogenase and the chaperone groEL. The P. aeruginosa isolates examined included the sequenced strain PAO1, 11 strains recovered from cystic fibrosis patients in Ireland, 4 environmental isolates recovered from a hospital environment, and 1 isolate recovered from a plant rhizosphere. Phylogenetically, clinical and environmental isolates clustered together with one another on the mdh gene tree. At the groEL locus, among the 17 isolates examined, only two polymorphic sites were observed, highlighting the close genetic relationship between isolates from these different environments. Phenotypic analysis of 12 traits among our isolates, however, found that only clinical isolates produced phenazines and elastase. Furthermore, molecular analysis of the distribution of 15 regions associated with virulence showed that two of the environmental isolates examined lacked the majority of regions. Among the clinical isolates examined, the 15 virulence regions were variably present. The distribution of two prophages (Bacto1, Pf1) was also determined, with most isolates encoding both these regions. Of the four genomic islands (the flagellum island and PAGI-1, -2, and -3) examined, only two isolates contained the flagellum island, and PAGI-1, -2, and -3 were absent from all isolates tested. Our data demonstrate the significant role horizontal gene transfer and recombination, together with gene loss, play in the evolution of this important human pathogen. PMID:15583313

  8. [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. PMID:25443661

  9. Disseminated Trichosporon mycotoxinivorans, Aspergillus fumigatus, and Scedosporium apiospermum Coinfection after Lung and Liver Transplantation in a Cystic Fibrosis Patient

    PubMed Central

    Letscher-Bru, Valérie; Pottecher, Julien; Lannes, Béatrice; Jeung, Mi Young; Degot, Tristan; Santelmo, Nicola; Sabou, Alina Marcela; Herbrecht, Raoul; Kessler, Romain

    2012-01-01

    Trichosporon mycotoxinivorans is a novel pathogen recently found in cystic fibrosis patients. We report the first case of a disseminated fatal infection with T. mycotoxinivorans associated with invasive Aspergillus fumigatus and Scedosporium apiospermum infection after lung and liver transplantation in a cystic fibrosis patient. PMID:23035187

  10. Mechanisms of lipid malabsorption in Cystic Fibrosis: the impact of essential fatty acids deficiency

    PubMed Central

    Peretti, N; Marcil, V; Drouin, E; Levy, E

    2005-01-01

    Transport mechanisms, whereby alimentary lipids are digested and packaged into small emulsion particles that enter intestinal cells to be translocated to the plasma in the form of chylomicrons, are impaired in cystic fibrosis. The purpose of this paper is to focus on defects that are related to intraluminal and intracellular events in this life-limiting genetic disorder. Specific evidence is presented to highlight the relationship between fat malabsorption and essential fatty acid deficiency commonly found in patients with cystic fibrosis that are often related to the genotype. Given the interdependency of pulmonary disease, pancreatic insufficiency and nutritional status, greater attention should be paid to the optimal correction of fat malabsorption and essential fatty acid deficiency in order to improve the quality of life and extend the life span of patients with cystic fibrosis. PMID:15869703

  11. 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).

  12. Regulation of Chloride Channels by Protein Kinase C in Normal and Cystic Fibrosis Airway Epithelia

    NASA Astrophysics Data System (ADS)

    Li, Ming; McCann, John D.; Anderson, Matthew P.; Clancy, John P.; Liedtke, Carole M.; Nairn, Angus C.; Greengard, Paul; Welsh, Michael J.

    1989-06-01

    Apical membrane chloride channels control chloride secretion by airway epithelial cells. Defective regulation of these channels is a prominent characteristic of cystic fibrosis. In normal intact cells, activation of protein kinase C (PKC) by phorbol ester either stimulated or inhibited chloride secretion, depending on the physiological status of the cell. In cell-free membrane patches, PKC also had a dual effect: at a high calcium concentration, PKC inactivated chloride channels; at a low calcium concentration, PKC activated chloride channels. In cystic fibrosis cells, PKC-dependent channel inactivation was normal, but activation was defective. Thus it appears that PKC phosphorylates and regulates two different sites on the channel or on an associated membrane protein, one of which is defective in cystic fibrosis.

  13. Failure of the Cystic Fibrosis Transmembrane Conductance Regulator to Conduct ATP

    NASA Astrophysics Data System (ADS)

    Reddy, M. M.; Quinton, P. M.; Haws, C.; Wine, J. J.; Grygorczyk, R.; Tabcharani, J. A.; Hanrahan, J. W.; Gunderson, K. L.; Kopito, R. R.

    1996-03-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is chloride ion channel regulated by protein kinase A and adenosine triphosphate (ATP). Loss of CFTR-mediated chloride ion conductance from the apical plasma membrane of epithelial cells is a primary physiological lesion in cystic fibrosis. CFTR has also been suggested to function as an ATP channel, although the size of the ATP anion is much larger than the estimated size of the CFTR pore. ATP was not conducted through CFTR in intact organs, polarized human lung cell lines, stably transfected mammalian cell lines, or planar lipid bilayers reconstituted with CFTR protein. These findings suggest that ATP permeation through the CFTR is unlikely to contribute to the normal function of CFTR or to the pathogenesis of cystic fibrosis.

  14. 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. PMID:24584798

  15. Population-based carrier screening for cystic fibrosis: a systematic review of 23 years of research.

    PubMed

    Ioannou, Liane; McClaren, Belinda J; Massie, John; Lewis, Sharon; Metcalfe, Sylvia A; Forrest, Laura; Delatycki, Martin B

    2014-03-01

    Cystic fibrosis is the most common severe autosomal recessive disease, with a prevalence of 1 in 2,500-3,500 live births and a carrier frequency of 1 in 25 among Northern Europeans. Population-based carrier screening for cystic fibrosis has been possible since CFTR, the disease-causing gene, was identified in 1989. This review provides a systematic evaluation of the literature from the past 23 years on population-based carrier screening for cystic fibrosis, focusing on the following: uptake of testing; how to offer screening; attitudes, opinions, and knowledge; factors influencing decision making; and follow-up after screening. Recommendations are given for the implementation and evaluation of future carrier-screening programs.

  16. Current issues in the nutritional management of children with cystic fibrosis.

    PubMed

    Daniels, L A; Davidson, G P

    1989-10-01

    Recent evidence suggests that malnutrition has a negative impact on pulmonary function in children with cystic fibrosis. In the past, dietary management has aimed at high energy low fat intake, but this has recently been shown to fall far short of the 120-150% of the recommended daily allowance for energy cystic fibrosis patients require. This paper outlines the current principles of nutritional management for children with cystic fibrosis. These include a high energy, high fat containing diet (within limits of individual tolerance); high carbohydrate intake; high salt intake; replacement of fat-soluble vitamins; appropriate use of pancreatic enzyme preparations; and supplemental feeding when indicated. It is vital that a nutrition education programme be established for each child and his or her family so that the emphasis shifts from treatment of malnutrition to prevention. The long-term aim must be to promote an independent, healthy lifestyle which incorporates good nutrition and other healthy pursuits such as exercise. PMID:2686614

  17. Diagnosis and Treatment of Endocrine Co-Morbidities in Patients with Cystic Fibrosis

    PubMed Central

    Siwamogsatham, Oranan; Alvarez, Jessica

    2015-01-01

    Purpose of review The aim of this review is to provide an update on various relevant endocrine aspects of care in adolescents and adults with cystic fibrosis (CF). Recent findings As life expectancy in CF has continuously improved, endocrine complications have become more apparent. The common endocrine complications include cystic fibrosis related diabetes (CFRD), cystic fibrosis related bone disease, vitamin D deficiency and poor growth and pubertal development. Thyroid and adrenal disorders have also been reported, although the prevalence appears to be less common. Summary Endocrine diseases are an increasingly recognized complication that has a significant impact on the overall health of individuals with CF. This review summarizes the updated screening and management of endocrine diseases in the CF population. PMID:25105995

  18. 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

  19. Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia.

    PubMed Central

    Govan, J R; Deretic, V

    1996-01-01

    Respiratory infections with Pseudomonas aeruginosa and Burkholderia cepacia play a major role in the pathogenesis of cystic fibrosis (CF). This review summarizes the latest advances in understanding host-pathogen interactions in CF with an emphasis on the role and control of conversion to mucoidy in P. aeruginosa, a phenomenon epitomizing the adaptation of this opportunistic pathogen to the chronic chourse of infection in CF, and on the innate resistance to antibiotics of B. cepacia, person-to-person spread, and sometimes rapidly fatal disease caused by this organism. While understanding the mechanism of conversion to mucoidy in P. aeruginosa has progressed to the point where this phenomenon has evolved into a model system for studying bacterial stress response in microbial pathogenesis, the more recent challenge with B. cepacia, which has emerged as a potent bona fide CF pathogen, is discussed in the context of clinical issues, taxonomy, transmission, and potential modes of pathogenicity. PMID:8840786

  20. Determination of right ventricular ejection fraction in children with cystic fibrosis

    SciTech Connect

    Piepsz, A.; Ham, H.R.; Millet, E.; Dab, I.

    1987-01-01

    The radionuclide right ventricular ejection fraction (RVEF) determined by means of Krypton-81m represents a simple, noninvasive, and accurate procedure to quantify the right ventricular contractility. This procedure was applied to 25 young patients with cystic fibrosis. The RVEF tended to decrease with the progression of the lung disease, as assessed by the clinical S-K score, the degree of the defects on lung scintigraphy, the PaO/sub 2/, and the lung function tests. However, the decrease of RVEF in patients with marked lung function tests. However, the decrease of RVEF in patients with marked lung involvement was moderate, and terminal lung disease was sometimes associated with normal right heart contractility.

  1. 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

  2. Development of the First Inhaled Antibiotic for the Treatment of Cystic Fibrosis

    PubMed Central

    Rose, Lynn M.; Neale, Richard

    2011-01-01

    Tobramycin Inhalation Solution USP (TOBI), a therapy developed to treat lung infections associated with cystic fibrosis (CF), was presented as a demonstration case for collaborative pharmaceutical development at a Clinical and Translational Science Awards Industry Forum on “Promoting Efficient and Effective Collaborations Among Academia, Government, and Industry” held in February 2010. TOBI was developed by PathoGenesis Corporation (Seattle, WA) in collaboration with the academic inventors, the National Institutes of Health, the U.S. Food and Drug Administration, and the CF Foundation. The presenters, representing the academic, industry, and foundation partners, each reviewed the program from their perspectives and identified challenges that existed during the discovery, development, and commercialization of TOBI. The attendees were asked to consider other collaborative opportunities that might have further improved TOBI development, including the optimal roles of the academic researchers, foundations, and other agencies when industry drives development and commercialization decisions. PMID:21178134

  3. What is the importance of classifying Aspergillus disease in cystic fibrosis patients?

    PubMed

    Jones, Andrew M; Horsley, Alex; Denning, David W

    2014-08-01

    Aspergillus species are commonly isolated from lower respiratory tract samples of patients with cystic fibrosis (CF) and markers of immunological sensation to Aspergillus are frequently encountered in this group of patients; however, the contribution of Aspergillus to CF lung disease outside of the typical complications of ABPA and aspergilloma formation remains largely unclear. Patients with CF show discretely different responses to Aspergillus, though the underlying reasons for this variation are unknown. Recent work has begun to allow us to categorize patient responses to Aspergillus based upon molecular markers of infection and immune sensitization. Aspergillus sensitization and/or airway infection is associated with worse FEV1, in CF and other patients (asthma, chronic obstructive pulmonary disease, bronchiectasis). Classification of different clinical phenotypes of Aspergillus will enable future studies to determine the natural history of different manifestations of Aspergillus disease and evaluate the effects of intervention with antifungal therapy.

  4. Pseudomonas aeruginosa Evolutionary Adaptation and Diversification in Cystic Fibrosis Chronic Lung Infections

    PubMed Central

    Winstanley, Craig; O’Brien, Siobhan; Brockhurst, Michael A.

    2016-01-01

    Pseudomonas aeruginosa populations undergo a characteristic evolutionary adaptation during chronic infection of the cystic fibrosis (CF) lung, including reduced production of virulence factors, transition to a biofilm-associated lifestyle, and evolution of high-level antibiotic resistance. Populations of P. aeruginosa in chronic CF lung infections typically exhibit high phenotypic diversity, including for clinically important traits such as antibiotic resistance and toxin production, and this diversity is dynamic over time, making accurate diagnosis and treatment challenging. Population genomics studies reveal extensive genetic diversity within patients, including for transmissible strains the coexistence of highly divergent lineages acquired by patient-to-patient transmission. The inherent spatial structure and spatial heterogeneity of selection in the CF lung appears to play a key role in driving P. aeruginosa diversification. PMID:26946977

  5. Pseudomonas aeruginosa in Cystic Fibrosis Patients With G551D-CFTR Treated With Ivacaftor

    PubMed Central

    Heltshe, Sonya L.; Mayer-Hamblett, Nicole; Burns, Jane L.; Khan, Umer; Baines, Arthur; Ramsey, Bonnie W.; Rowe, Steven M.

    2015-01-01

    Background. Ivacaftor improves outcomes in cystic fibrosis (CF) patients with the G551D mutation; however, effects on respiratory microbiology are largely unknown. This study examines changes in CF respiratory pathogens with ivacaftor and correlates them with baseline characteristics and clinical response. Methods. The G551D Observational Study enrolled a longitudinal observational cohort of US patients with CF aged 6 years and older with at least 1 copy of the G551D mutation. Results were linked with retrospective and prospective culture data in the US Cystic Fibrosis Foundation's National Patient Registry. Pseudomonas aeruginosa infection category in the year before and year after ivacaftor was compared and correlated with clinical findings. Results. Among 151 participants prescribed ivacaftor, 29% (26/89) who were culture positive for P. aeruginosa the year prior to ivacaftor use were culture negative the year following treatment; 88% (52/59) of those P. aeruginosa free remained uninfected. The odds of P. aeruginosa positivity in the year after ivacaftor compared with the year prior were reduced by 35% (odds ratio [OR], 0.65; P < .001). Ivacaftor was also associated with reduced odds of mucoid P. aeruginosa (OR, 0.77; P = .013) and Aspergillus (OR, 0.47; P = .039), but not Staphylococcus aureus or other common CF pathogens. Patients with intermittent culture positivity and higher forced expiratory volume in 1 second (FEV1) were most likely to turn culture negative. Reduction in P. aeruginosa was not associated with change in FEV1, body mass index, or hospitalizations. Conclusions. Pseudomonas aeruginosa culture positivity was significantly reduced following ivacaftor treatment. Efficacious CFTR modulation may contribute to lower frequency of culture positivity for P. aeruginosa and other respiratory pathogens, particularly in patients with less established disease. PMID:25425629

  6. A cystic fibrosis patient who is homozygous for the A559T mutation

    SciTech Connect

    McDowell, T.; Shackleton, S.; Dear, S.

    1995-09-01

    We have recently defined a cystic fibrosis (CF) patient who is homozygous for the A559T mutation in exon 11 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This mutation was detected by direct sequence analysis and confirmed to be carried by both parents (of West Indian origin) of the index case. The A559T mutation has not been detected in any Caucasian CF patients. The presence of this mutation in North American black CF patients and a British CF patient of West Indian origin is clearly of interest in designing CF screening tests that are tailored to specific ethnic groups. 1 ref.

  7. Poetry, Music, Writing and Painting; Developing the artistic talents of Adults with Cystic Fibrosis.

    PubMed

    Webb, Anthony Kevin; Fitzjohn, Joan

    2016-01-01

    Art is an expressive outlet for the physical limitations and emotional frustrations of living with a life limiting condition such cystic fibrosis. In the Manchester Adult Cystic Fibrosis Centre we have facilitated the sharing of the inherent artistic talent of our patients with the support of painters, musicians, potters, creative writers, photographers and textile specialists and our own ward staff in our dedicated 22 bed CF inpatient unit. The programme has provided some splendid works that enliven our ward and, more importantly, continue to inspire our patients as they attempt to overcome the socially limiting consequences of hospital admission. PMID:26527357

  8. Cystic Fibrosis Related Liver Disease—Another Black Box in Hepatology

    PubMed Central

    Staufer, Katharina; Halilbasic, Emina; Trauner, Michael; Kazemi-Shirazi, Lili

    2014-01-01

    Due to improved medical care, life expectancy in patients with cystic fibrosis (CF) has veritably improved over the last decades. Importantly, cystic fibrosis related liver disease (CFLD) has become one of the leading causes of morbidity and mortality in CF patients. However, CFLD might be largely underdiagnosed and diagnostic criteria need to be refined. The underlying pathomechanisms are largely unknown, and treatment strategies with proven efficacy are lacking. This review focuses on current invasive and non-invasive diagnostic standards, the current knowledge on the pathophysiology of CFLD, treatment strategies, and possible future developments. PMID:25093717

  9. Deficient Vasoactive Intestinal Peptide Innervation in the Sweat Glands of Cystic Fibrosis Patients

    NASA Astrophysics Data System (ADS)

    Heinz-Erian, Peter; Dey, Richard D.; Flux, Marinus; Said, Sami I.

    1985-09-01

    The innervation of acini and ducts of eccrine sweat glands by immunoreactive, vasoactive intestinal peptide--containing nerve fibers was sharply reduced in seven patients with cystic fibrosis compared to eight normal subjects. The decrease in innervation by this neuropeptide, which has been shown to promote blood flow and the movement of water and chloride across epithelial surfaces in other systems, may be a basic mechanism for the decreased water content and relative impermeability of the epithelium to chloride and other ions that characterize cystic fibrosis.

  10. [Gastroesophageal reflux, pulmonary and gastric function in patients with cystic fibrosis. Results of a randomized trial].

    PubMed

    Escobar Castro, H; Perdomo Giraldi, M; Gimeno Benítez, R; Máiz Carro, L; Suárez Cortina, L

    1996-01-01

    We studied ten patients with Cystic fibrosis. The purposes of this study were to investigate the presence of gastroesophageal reflux and establish the probable association between gastroesophageal reflux and pulmonary and gastric involvement. All 10 patients underwent 24-hour esophageal pH recording, spirometry and gastric function. Abnormal reflux index was found in all these patients. Lung function was pathologic in the 3 older children. There were no relationship between the severity of the gastroesophageal reflux and the degree of pulmonary damage. No patient has gastric acid hypersecretion. Eight of 10 patients had steatorrhea. Our findings confirm the high frequence of gastroesophageal reflux in cystic fibrosis. PMID:9180955

  11. A Synthetic Chloride Channel Restores Chloride Conductance in Human Cystic Fibrosis Epithelial Cells

    PubMed Central

    Wang, Fei; Yao, Xiaoqiang; Yang, Dan

    2012-01-01

    Mutations in the gene-encoding cystic fibrosis transmembrane conductance regulator (CFTR) cause defective transepithelial transport of chloride (Cl−) ions and fluid, thereby becoming responsible for the onset of cystic fibrosis (CF). One strategy to reduce the pathophysiology associated with CF is to increase Cl− transport through alternative pathways. In this paper, we demonstrate that a small synthetic molecule which forms Cl− channels to mediate Cl− transport across lipid bilayer membranes is capable of restoring Cl− permeability in human CF epithelial cells; as a result, it has the potential to become a lead compound for the treatment of human diseases associated with Cl− channel dysfunction. PMID:22514656

  12. Advances in Cell and Gene-based Therapies for Cystic Fibrosis Lung Disease

    PubMed Central

    Oakland, Mayumi; Sinn, Patrick L; McCray Jr, Paul B

    2012-01-01

    Cystic fibrosis (CF) is a disease characterized by airway infection, inflammation, remodeling, and obstruction that gradually destroy the lungs. Direct delivery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to airway epithelia may offer advantages, as the tissue is accessible for topical delivery of vectors. Yet, physical and host immune barriers in the lung present challenges for successful gene transfer to the respiratory tract. Advances in gene transfer approaches, tissue engineering, and novel animal models are generating excitement within the CF research field. This review discusses current challenges and advancements in viral and nonviral vectors, cell-based therapies, and CF animal models. PMID:22371844

  13. Transfer of the Cystic Fibrosis Transmembrane Conductance Regulator to Human Cystic Fibrosis Cells Mediated by Extracellular Vesicles.

    PubMed

    Vituret, Cyrielle; Gallay, Kathy; Confort, Marie-Pierre; Ftaich, Najate; Matei, Constantin I; Archer, Fabienne; Ronfort, Corinne; Mornex, Jean-François; Chanson, Marc; Di Pietro, Attilio; Boulanger, Pierre; Hong, Saw See

    2016-02-01

    Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in a deficiency in chloride channel activity. In this study, extracellular vesicles (EVs), microvesicles, and exosomes were used as vehicles to deliver exogenous CFTR glycoprotein and its encoding mRNA (mRNA(GFP-CFTR)) to CF cells to correct the CFTR chloride channel function. We isolated microvesicles and exosomes from the culture medium of CFTR-positive Calu-3 cells, or from A549 cells transduced with an adenoviral vector overexpressing a GFP-tagged CFTR (GFP-CFTR). Both microvesicles and exosomes had the capacity to package and deliver the GFP-CFTR glycoprotein and mRNA(GFP-CFTR) to target cells in a dose-dependent manner. Homologous versus heterologous EV-to-cell transfer was studied, and it appeared that the cellular uptake of EVs was significantly more efficient in homologous transfer. The incubation of CF15 cells, a nasal epithelial cell line homozygous for the ΔF508 CFTR mutation, with microvesicles or exosomes loaded with GFP-CFTR resulted in the correction of the CFTR function in CF cells in a dose-dependent manner. A time-course analysis of EV-transduced CF cells suggested that CFTR transferred as mature glycoprotein was responsible for the CFTR-associated channel activity detected at early times posttransduction, whereas GFP-CFTR translated from exogenous mRNA(GFP-CFTR) was responsible for the CFTR function at later times. Collectively, this study showed the potential application of microvesicles and exosomes as vectors for CFTR transfer and functional correction of the genetic defect in human CF cells.

  14. Transfer of the Cystic Fibrosis Transmembrane Conductance Regulator to Human Cystic Fibrosis Cells Mediated by Extracellular Vesicles.

    PubMed

    Vituret, Cyrielle; Gallay, Kathy; Confort, Marie-Pierre; Ftaich, Najate; Matei, Constantin I; Archer, Fabienne; Ronfort, Corinne; Mornex, Jean-François; Chanson, Marc; Di Pietro, Attilio; Boulanger, Pierre; Hong, Saw See

    2016-02-01

    Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in a deficiency in chloride channel activity. In this study, extracellular vesicles (EVs), microvesicles, and exosomes were used as vehicles to deliver exogenous CFTR glycoprotein and its encoding mRNA (mRNA(GFP-CFTR)) to CF cells to correct the CFTR chloride channel function. We isolated microvesicles and exosomes from the culture medium of CFTR-positive Calu-3 cells, or from A549 cells transduced with an adenoviral vector overexpressing a GFP-tagged CFTR (GFP-CFTR). Both microvesicles and exosomes had the capacity to package and deliver the GFP-CFTR glycoprotein and mRNA(GFP-CFTR) to target cells in a dose-dependent manner. Homologous versus heterologous EV-to-cell transfer was studied, and it appeared that the cellular uptake of EVs was significantly more efficient in homologous transfer. The incubation of CF15 cells, a nasal epithelial cell line homozygous for the ΔF508 CFTR mutation, with microvesicles or exosomes loaded with GFP-CFTR resulted in the correction of the CFTR function in CF cells in a dose-dependent manner. A time-course analysis of EV-transduced CF cells suggested that CFTR transferred as mature glycoprotein was responsible for the CFTR-associated channel activity detected at early times posttransduction, whereas GFP-CFTR translated from exogenous mRNA(GFP-CFTR) was responsible for the CFTR function at later times. Collectively, this study showed the potential application of microvesicles and exosomes as vectors for CFTR transfer and functional correction of the genetic defect in human CF cells. PMID:26886833

  15. [Respiratory physio-kinesitherapy in cystic fibrosis: the parents' viewpoint].

    PubMed

    Battistini, A; Grzincich, G L; Pisi, G; Bocchi, U; Marvasi, R; Costantini, D; Antonelli, M; Castello, D; Cappelletti, L M; Nantron, M

    1988-01-01

    The aim of this study was to evaluate the problems found in performing chest physiotherapy (PKT) by patients with Cystic Fibrosis (CF) and by their families. The research has been based upon processing 389 questionnaires (46 items) that were compiled by the families. Thirteen CF centers all over the nation have participated in this study. Patients' mean age was 7.4 years (range 2 months to 14 years). Data about the socio-economic status and illness severity were available for every patient. Many graphs (line connects points with a line = n. 8; bar charts = n. 17; pie charts = n. 13) show the results and their statistical processing. Our purpose was to solve the following problems: 1) What is the extent of the compliance? 2) Who perform, or should perform, PKT in the family environment? 3) What is the kind and extent of the help request? 4) What are the mistakes made in executing PKT? 5) What is the usefulness of precursors and aerosol therapy? 6) What is the link between physical activity and PKT? 7) What are the main difficulties in performing PKT? 8) How effective is PKT? 9) What is the extent of the parents' faith in their capabilities? 10) Are there any prejudices against PKT? Three major findings emerge from this study: 1) the compliance appeared good; 2) the average family understood the meaning of PKT correctly and 3) PKT is usually executed properly. As for negative results are concerned, it is to be noted that the burden of performing PKT is usually up to the mother. This finding is linked both to the socio-economics status of the family and to the severity of the illness. On the other hand, a home PKT service is only asked in very extreme situations such as sudden worsening of the patient's illness. The difficulties met in performing PKT range from the patient's refusal to logistical and organization problems, which are correlated with the socio-economic status of the family. The relationship between PKT and sport is understood well and there is a high

  16. Pathogen and autoantigen homologous regions within the cystic fibrosis transmembrane conductance regulator (CFTR) protein suggest an autoimmune treatable component of cystic fibrosis.

    PubMed

    Carter, Chris J

    2011-07-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel provides the glutathione and hypochlorous acid necessary for bactericidal/viricidal actions. CFTR mutations block these effects, diminishing pathogen defence and allowing extracellular pathogen accumulation, where antibody encounter is likely. KEGG pathway analysis of the CFTR interactome shows that CFTR is involved in pathogen entry pathways and immune defence as well as in pathways relevant to comorbid conditions (diabetes, cardiomyopathies and sexual organ development). Pseudomonas aeruginosa and Staphylococcus aureus infections decrease the lifespan of cystic fibrosis patients and Stenotrophomonas maltophilia colonization is increased. Autoantibodies, targeting myeloperoxidase, the bactericidal/permeability-increasing protein and calgranulin may further compromise pathogen defence. Short consensus sequences, within immunogenic extracellular regions of the CFTR protein, are homologous to proteins expressed by P. aeruginosa, S. aureus and S. maltophilia, and to several autoantigens, with a universal overlap between autoantigen/pathogen/CFTR consensi. Antibodies to pathogens are thus likely responsible for the creation of these autoantibodies, which, with pathogen antibodies, may target the CFTR protein acting as antagonists, further compromising its function. This creates a feedforward cycle, diminishing the function of the CFTR protein and increasing the probability of pathogen accumulation and antibody production at every turn. Interruption of this cycle by antibody adsorption or immunosuppressant therapy may be beneficial in cystic fibrosis.

  17. Mechanistic Approaches to Improve Correction of the Most Common Disease-Causing Mutation in Cystic Fibrosis.

    PubMed

    Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham; Matalon, Sadis; Bebok, Zsuzsanna

    2016-01-01

    The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to deletion of the phenylalanine at position 508 (ΔF508) in the CFTR protein and causes multiple folding and functional defects. Contrary to large-scale efforts by industry and academia, no significant therapeutic benefit has been achieved with a single "corrector". Therefore, investigations concentrate on drug combinations. Orkambi (Vertex Pharmaceuticals), the first FDA-approved drug for treatment of cystic fibrosis (CF) caused by this mutation, is a combination of a corrector (VX-809) that facilitates ΔF508 CFTR biogenesis and a potentiator (VX-770), which improves its function. Yet, clinical trials utilizing this combination showed only modest therapeutic benefit. The low efficacy Orkambi has been attributed to VX-770-mediated destabilization of VX-809-rescued ΔF508 CFTR. Here we report that the negative effects of VX-770 can be reversed by increasing the half-life of the endoplasmic reticulum (ER) form (band B) of ΔF508 CFTR with another corrector (Corr-4a.) Although Corr-4a alone has only minimal effects on ΔF508 CFTR rescue, it increases the half-life of ΔF508 CFTR band B when it is present during half-life measurements. Our data shows that stabilization of band B ΔF508 CFTR with Corr-4a and simultaneous rescue with VX-809, leads to a >2-fold increase in cAMP-activated, CFTRinh-172-inhibited currents compared to VX-809 alone, or VX-809+VX-770. The negative effects of VX-770 and the Corr-4a protection are specific to the native I507-ATT ΔF508 CFTR without affecting the inherently more stable, synonymous variant I507-ATC ΔF508 CFTR. Our studies emphasize that stabilization of ΔF508 CFTR band B in the ER might improve its functional rescue by Orkambi. PMID:27214033

  18. Mechanistic Approaches to Improve Correction of the Most Common Disease-Causing Mutation in Cystic Fibrosis

    PubMed Central

    Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham; Matalon, Sadis; Bebok, Zsuzsanna

    2016-01-01

    The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to deletion of the phenylalanine at position 508 (ΔF508) in the CFTR protein and causes multiple folding and functional defects. Contrary to large-scale efforts by industry and academia, no significant therapeutic benefit has been achieved with a single “corrector”. Therefore, investigations concentrate on drug combinations. Orkambi (Vertex Pharmaceuticals), the first FDA-approved drug for treatment of cystic fibrosis (CF) caused by this mutation, is a combination of a corrector (VX-809) that facilitates ΔF508 CFTR biogenesis and a potentiator (VX-770), which improves its function. Yet, clinical trials utilizing this combination showed only modest therapeutic benefit. The low efficacy Orkambi has been attributed to VX-770-mediated destabilization of VX-809-rescued ΔF508 CFTR. Here we report that the negative effects of VX-770 can be reversed by increasing the half-life of the endoplasmic reticulum (ER) form (band B) of ΔF508 CFTR with another corrector (Corr-4a.) Although Corr-4a alone has only minimal effects on ΔF508 CFTR rescue, it increases the half-life of ΔF508 CFTR band B when it is present during half-life measurements. Our data shows that stabilization of band B ΔF508 CFTR with Corr-4a and simultaneous rescue with VX-809, leads to a >2-fold increase in cAMP-activated, CFTRinh-172-inhibited currents compared to VX-809 alone, or VX-809+VX-770. The negative effects of VX-770 and the Corr-4a protection are specific to the native I507-ATT ΔF508 CFTR without affecting the inherently more stable, synonymous variant I507-ATC ΔF508 CFTR. Our studies emphasize that stabilization of ΔF508 CFTR band B in the ER might improve its functional rescue by Orkambi. PMID:27214033

  19. Recombinant human DNase nebulisation in children with cystic fibrosis: before bedtime or after waking up?

    PubMed

    van der Giessen, L J; Gosselink, R; Hop, W C J; Tiddens, H A W M

    2007-10-01

    The present study focused on patients with cystic fibrosis (CF), who were on maintenance therapy with recombinant human deoxyribonuclease (rhDNase), with the aim of comparing efficacy and possible side effects of nebulisation of rhDNase when taken before bedtime with efficacy and side effects when taken after waking up. A randomised, double-blind, double-dummy, crossover study group was used. The inclusion criteria were as follows: 1) CF, 2) stable clinical condition and 3) rhDNase maintenance therapy. Patients in group I inhaled rhDNase before bedtime and a placebo after waking up in weeks 1-2. The protocol was reversed during weeks 3-4. Group II patients performed the reverse of this sequence. Patients continued with their daily routine sputum expectoration. The primary end-point was classified as the maximal instantaneous forced flow when 25% of the forced vital capacity remained to be exhaled (MEF(25%)). Pulmonary functions tests were performed on days 0, 7, 14, 21 and 28. At 1, 2, 3 and 4 weeks arterial oxygen saturation and cough frequency were measured during the night. A total of 24 patients completed the study. The mean (range) age of the patients was 13 (6-19) yrs. MEF(25%), taken to be the primary end-point, did not show a significant difference between nebulisation of rhDNase before bedtime compared with when taken after waking up. Nocturnal cough, oxygen saturation, and other secondary end-points were not significantly different between the two study periods. In conclusion, the present study found that it is equally effective and safe to nebulise recombinant human deoxyribonuclease before bedtime compared with when performed after waking up in children with cystic fibrosis, who are on maintenance treatment with recombinant human deoxyribonuclease.

  20. Cystic fibrosis mouse model-dependent intestinal structure and gut microbiome

    PubMed Central

    Bazett, Mark; Honeyman, Lisa; Stefanov, Anguel N.; Pope, Christopher E.; Hoffman, Lucas R.; Haston, Christina K.

    2015-01-01

    Mice with a null mutation in the cystic fibrosis transmembrane conductance regulator (Cftr) gene show intestinal structure alterations and bacterial overgrowth. To determine whether these changes are model-dependent and whether the intestinal microbiome is altered in cystic fibrosis (CF) mouse models, we characterized the ileal tissue and intestinal microbiome of mice with the clinically common ΔF508 Cftr mutation (FVB/N Cftrtm1Eur) and with Cftr null mutations (BALB/c Cftrtm1UNC and C57BL/6 Cftrtm1UNC). Intestinal disease in 12-week-old CF mice, relative to wild-type strain controls, was measured histologically. The microbiome was characterized by pyrosequencing of the V4–V6 region of the 16S rRNA gene and intestinal load was measured by RT-PCR of the 16S rRNA gene. The CF-associated increases in ileal crypt to villus axis distention, goblet cell hyperplasia, and muscularis externa thickness were more severe in the BALB/c and C57BL/6 Cftrtm1UNC mice than in the FVB/N Cftrtm1Eur mice. Intestinal bacterial load was significantly increased in all CF models, compared to levels in controls, and positively correlated with circular muscle thickness in CF, but not wild-type, mice. Microbiome profiling identified Bifidobacterium and groups of Lactobacillus to be of altered abundance in the CF mice but overall bacterial frequencies were not common to the three CF strains and were not correlative of major histological changes. In conclusion, intestinal structure alterations, bacterial overgrowth, and dysbiosis were each more severe in BALB/c and C57BL/6 Cftrtm1UNC mice than in the FVB/N Cftrtm1Eur mice. The intestinal microbiome differed among the three CF mouse models. PMID:25721416