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PubMed2005

TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells.

Cystic fibrosis (CF) is a genetic disease characterized by severe neutrophil-dominated airway inflammation. An important cause of inflammation in CF is Pseudomonas aeruginosa infection. We have evaluated the importance of a number of P. aeruginosa components, namely lipopeptides, LPS, and unmethylated CpG DNA, as proinflammatory stimuli in CF by characterizing the expression and functional activity of their cognate receptors, TLR2/6 or TLR2/1, TLR4, and TLR9, respectively, in a human tracheal epithelial line, CFTE29o(-), which is homozygous for the DeltaF508 CF transmembrane conductance regulator mutation. We also characterized TLR expression and function in a non-CF airway epithelial cell line 16HBE14o(-). Using RT-PCR, we demonstrated TLR mRNA expression. TLR cell surface expression was assessed by fluorescence microscopy. Lipopeptides, LPS, and unmethylated CpG DNA induced IL-8 and IL-6 protein production in a time- and dose-dependent manner. The CF and non-CF cell lines were largely similar in their TLR expression and relative TLR responses. ICAM-1 expression was also up-regulated in CFTE29o(-) cells following stimulation with each agonist. CF bronchoalveolar lavage fluid, which contains LPS, bacterial DNA, and neutrophil elastase (a neutrophil-derived protease that can activate TLR4), up-regulated an NF-kappaB-linked reporter gene and increased IL-8 protein production in CFTE29o(-) cells. This effect was abrogated by expression of dominant-negative versions of MyD88 or Mal, key signal transducers for TLRs, thereby implicating them as potential anti-inflammatory agents for CF.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Antimicrobial susceptibility profiles of oropharyngeal viridans group streptococci isolates from cystic fibrosis and non-cystic fibrosis patients.

The antimicrobial susceptibility profile of 77 oropharyngeal viridans streptococci isolates from 34 cystic fibrosis (CF) patients and 58 isolates from 43 healthy non-CF patients were studied by the E-test and the standard disk diffusion methods. Overall penicillin and cefotaxime resistances (intermediate plus resistant isolates) were significantly higher (p < 0.05) among CF isolates (72.7% and 45.5%, respectively) than among non-CF isolates (51.7% and 15.5%, respectively). No significant difference was observed in overall (intermediate plus resistant) erythromycin resistance rates, although high-level erythromycin resistance (> or =32 microg/mL) was more frequently found in CF isolates (24.6%) than in non-CF isolates (12.1%). An unexpected high percentage of isolates showed low level erythromycin resistance (MIC range, 0.5-15 microg/mL): 41.5% in cystic fibrosis and 46.5% in non-CF isolates. No significant differences were observed regarding the percentage of colonized patients with at least one penicillin-resistant isolate. On the contrary, colonization with cefotaxime (p < 0.001) or erythromycin (p = 0.014) resistant isolates were significantly more prevalent in CF patients. Similar tetracycline and chloramphenicol resistance rates were observed for both groups. Viridans isolates resistant to a single antibiotic were more prevalent among non-CF patients and multiple resistance was higher among CF patients. Prior antibiotic exposure could result in differences in beta-lactam resistance and colonization rates with resistant isolates between both groups. None of the non-CF patients was previously treated with antimicrobials for a period of three months before sampling. In contrast, 94.1% of CF patients were treated with antimicrobials within the same period; 65.6% with beta-lactam antibiotics. Patients with CF disease, frequently exposed to antimicrobials, may be a reservoir of viridans streptococci isolates with resistance determinants, particularly to beta-lactam antibiotics.

Adolescent↗
PubMed1995

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

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.

Adult↗
PubMed1992

Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis.

Cystic fibrosis (CF) is an inherited disorder causing pancreatic, pulmonary, and sinus disease in children and young adults. Abnormal viscosity of mucous secretions is a hallmark of the disease, and is believed to be the result of altered electrolyte transport across epithelial cell membranes. The monogenic etiology of this disease has been apparent for more than 40 years, but the defective gene has only recently been identified. This was made possible because of a revolution in genetic technology, called positional cloning, which can pinpoint disease genes without previous knowledge of the abnormal protein product. The protein encoded by the gene defective in CF has been termed the CF transmembrane conductance regulator (CFTR) because of its postulated role in electrolyte transport. Studies investigating the normal function of CFTR and how mutations affect that function, thereby causing CF, have required the combined skills of clinicians, geneticists, molecular biologists, and physiologists. From this collaborative effort a greater understanding of the pathogenesis of this disorder is now emerging. It may soon be possible to introduce novel therapies derived from this new knowledge that will be aimed directly at the basic defect. An ever-increasing number of genes of unknown function will be identified by continuing advances in molecular genetic technology and the advent of the genome sequencing project. The experience in cystic fibrosis research may prove to be a paradigm for investigation of the function of genes isolated by positional cloning methods.

Amino Acid Sequence↗
PubMed1997

Na+/K+ ATPase in lower airway epithelium from cystic fibrosis and non-cystic-fibrosis lung.

The basolateral Na+/K+ ATPase plays a critical role in sodium reabsorption across airway epithelium. Nasal epithelium shows increased Na+/K+ ATPase activity in cystic fibrosis (CF) but Na+/K+ ATPase has not been characterized in human lung epithelium or compared in CF and normal lung. We measured 3[H] ouabain binding and Na+/K+ ATPase activity in human tracheal epithelium and compared Na/K ATPase activity in bronchial epithelium in CF and control subjects. In tracheal epithelium Na+/K+ ATPase pumps were abundant and of high 3[H] ouabain affinity (Kd 4.7 nM, Bmax 38 pmol/mg) and Na+/K+ ATPase activity was 55 +/- 8 nmol/mg protein/min. Bronchial epithelial Na+/K+ ATPase activity was twofold higher in CF patients than in controls. The increased Na+/K+ ATPase activity may contribute to the increased sodium reabsorption seen in cystic fibrosis.

Adolescent↗
PubMed2000

Deoxyribonuclease for cystic fibrosis.

BACKGROUND: Recombinant human deoxyribonuclease is currently used to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. OBJECTIVES: To determine whether the use of recombinant human deoxyribonuclease in cystic fibrosis is associated with improved mortality and morbidity as compared to placebo and to identify any adverse events associated with its use. To compare the efficacy of recombinant human deoxyribonuclease with other mucolytics. SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, hand searching relevant journals and abstracts from conferences. The company producing recombinant human deoxyribonuclease was also contacted. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised and quasi-randomised trials where recombinant human deoxyribonuclease was compared to either placebo, standard therapy or another mucolytic for any duration, dose regimen and age of patient with cystic fibrosis of any disease severity. DATA COLLECTION AND ANALYSIS: Trials were independently assessed for inclusion criteria, methodological quality and data extraction by the two reviewers. Comparisons were between recombinant human deoxyribonuclease and placebo and recombinant human deoxyribonuclease and other mucolytics. The following outcomes were recorded: Mean % change from baseline in forced vital capacity (FVC), forced expiratory voloume at one second (FEV1) and weight, mean number of respiratory tract exacerbations, days intravenous and oral antibiotics used, mean number of days as inpatient, number of deaths, adverse events and the cost of therapy. MAIN RESULTS: Seven primary clinical trials were identified, totalling 1710 patients. Two further studies examined the health care cost of patients from one of the clinical trials. No eligible studies compared recombinant human deoxyribonuclease to another mucolytic. Five trials presented outcomes at up to one month, one at three months and one at six months. No reduction in mortality for treated patients was identified (Relative Risk (RR) at six month 1.01, 95%Confidence Interval (CI) 0.09, 11.11). Lung function improved to a greater extent in the treated groups (at six months Weighted Mean Difference (WMD) FEV1 5.7, 95%CI 4.18, 7.23, at three months 7.3, 95%CI 4.04, 10.65). Pooled data from the five trials of up to one month gave WMD 9.2 95%CI 0.93, 17. 6 although there was significant heterogeneity). Recombinant human deoxyribonuclease was well tolerated with no excess of serious adverse events (RR haemoptysis 0.89, 95%CI 0.54, 1.45, pneumothorax 0.97 95%CI 0.19, 4.96). Voice alteration was, however, reported more frequently in the treated groups (RR 2.33 95%CI 1.38, 3.93). No study analysed our pre-defined outcome measure for respiratory exacerbations and insufficient data was available to analyse differences in antibiotic treatment, inpatient stay and quality of life. REVIEWER'S CONCLUSIONS: Studies are of insufficient duration to identify a reduction in mortality or number of respiratory exacerbations. Further trials are required to answer these important questions. Recombinant human deoxyribonuclease therapy is associated with an improvement in lung function after six months treatment, but it is not possible to assess whether this effect on lung function is sustained in the long-term. No studies were identified that compared recombinant human deoxyribonuclease to another mucolytic.

Cystic Fibrosis↗
PubMed1993

Mutation analysis and haplotype correlation for 139 cystic fibrosis patients from the Nebraska Regional Cystic Fibrosis Center.

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations with an approximate frequency of one in 2,500 live births and a carrier frequency of one in 25. We studied 400 individuals seen at The Nebraska Regional Cystic Fibrosis Center that included 139 CF patients, 206 parents, and 55 unaffected siblings to determine the frequency of the delta F508, R117H, G542X, S549R/N, G551D, R553X, R560T, and W1282X mutations. In addition, we determined haplotypes on each of these individual's chromosomes using four markers that included XV-2c, KM-19, pMP6d.9, and G2. Results from this study showed that the delta F508 mutation was present in 70% of CF chromosomes. Of the 139 CF patients 74 (53%) were homozygous for the delta F508 deletion, 47 (34%) were heterozygous for the delta F508 deletion and an unknown mutation, and 18 (13%) carried two unknown mutations. Four additional mutations were also found in our population and included G542X (6%), G551D (5%), R553X (4%), and R560T (1%). One patient was documented to be a compound heterozygote for G542X/G551D. A polymorphism, F508C, that has previously been reported in several families was also present in our study. The most common haplotype associated with the delta F508 deletion in our CF patients was the E haplotype (CF Consortium B) while other mutations were associated with a variety of haplotypes.

Base Sequence↗
PubMedDate not supplied

Community-based care in cystic fibrosis: role of the cystic fibrosis nurse specialist and implications for patients and families.

Improved survival for cystic fibrosis has rapidly increased over the past four decades, with patients now living well into adult life. With changes in the structure of the National Health Service and the formation of provider units and general practitioner (GP) fund-holding practices, it is important to strengthen links between the hospital and community teams to ensure that the CF patient receives adequate care. Increasingly, treatment is being carried out at home, and this emphasis on home-based therapy demands that parents/carers and patients must acquire the skills and knowledge of complex therapies in order to optimize health. It is the role of the CF nurse specialist (NS) to educate those who will deliver the care, co-ordinate the provision of services at home, liaise with the CF team and community health-care professionals and to support the patient and their carers.

Adolescent↗
PubMed1999

Predicting the risk of cystic fibrosis with echogenic fetal bowel and one cystic fibrosis mutation.

OBJECTIVE: To assess fetal risk for cystic fibrosis when echogenic bowel and one cystic fibrosis mutation are detected. METHODS: A hypothetical cohort of 1000 women with singleton pregnancies and echogenic fetal bowel during the second trimester was used to determine the probability of cystic fibrosis when one cystic fibrosis transmembrane conductance regulator mutation was detected. The risk of cystic fibrosis was calculated using the range of prevalence of cystic fibrosis in fetuses with echogenic bowel reported in the literature. Risk calculations for fetuses of Ashkenazi Jewish, Northern European, African-American, Hispanic, and Asian descent accounted for carrier frequencies and mutation detection rates specific to each ethnic group. RESULTS: As the assumed prevalence of cystic fibrosis increases from 1-25%, the probability that a white fetus with one mutation and echogenic fetal bowel actually has cystic fibrosis increases from 4.8% to 62.5%. Assuming a 2% risk of cystic fibrosis with echogenic fetal bowel, an Ashkenazi Jewish fetus and an Asian fetus with echogenic bowel and one mutation have a 3.1% and 72% risk of cystic fibrosis, respectively. The probability of cystic fibrosis in a nonwhite fetus is between those two extremes. CONCLUSION: The probability of cystic fibrosis after detection of echogenic bowel and one cystic fibrosis mutation varied among ethnic groups. Even at the highest prevalence of cystic fibrosis, most white fetuses will not have cystic fibrosis. In nonwhite populations almost half of these fetuses will have cystic fibrosis, even at the lowest prevalence of cystic fibrosis.

Cystic Fibrosis↗
PubMed1987

Biochemical properties of tracheobronchial mucins from cystic fibrosis and non-cystic fibrosis individuals.

Tracheobronchial mucins from healthy individuals and from patients with bronchial asthma or cystic fibrosis (CF) were isolated from lung mucus, purified, and their chemical and physical properties compared. Normal and asthmatic mucins required both a dissociating and a reducing agent for solubilization and exhibited identical chromatographic behavior on Sepharose 4B, Sepharose 2B, and hydroxylapatite and similar amino acid and carbohydrate compositions. In contrast, 1) CF lung mucins were solubilized in the absence of dissociating and/or reducing agents and 2) the majority of the CF mucins analyzed was eluted in the included volume of Sepharose 4B with Kd values of 0.3 +/- 0.1 rather than in the void volume and thus appeared smaller than normal and asthmatic mucins. The lower molecular weight mucins in CF sputum apparently are produced by bacterial or inflammatory cell proteinases since radiolabelled asthmatic mucin was digested to smaller fragments when incubated with crude CF lung mucosal samples. Furthermore, mucins secreted by tracheal explants from CF and from non-CF individuals eluted in the void volume on Sepharose 4B, suggesting that CF tracheobronchial mucins were not inherently smaller than non-CF mucins.

Adolescent↗
PubMed1998

Bioelectric properties of human cystic fibrosis and non-cystic fibrosis fetal tracheal xenografts in SCID mice.

We measured, the bioelectric properties of 14 cystic fibrosis (CF) and 33 non-CF human fetal tracheal xenografts in severe combined immunodeficiency (SCID) mice. All xenografts exhibited a mature airway-type epithelium irrespective of their gestational age, duration of engraftment, and genotype. The in vivo potential difference and the in vitro baseline short-circuit current (Isc) were significantly higher in non-CF than in CF xenografts. In non-CF xenografts, sequential addition of amiloride, forskolin, and ATP resulted in a 39.4% decrease, a 24.1% increase, and a 43.6% increase in Isc, respectively. In CF xenografts, forskolin had no significant effect on Isc, whereas amiloride- and ATP-induced changes in Isc were proportionally higher than in non-CF xenografts (-60.0 and +68.8%, respectively). These results indicate that the bioelectric properties of non-CF xenografts are similar to those of postnatal airways and that CF xenografts exhibit lower baseline electrogenic activity than non-CF xenografts but similar regulation of ion transport processes to postnatal CF airways. This model of mature human fetal tracheal mucosa may help gain insight into early CF airway pathogenesis.

Animals↗
PubMed1992

Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis.

Cystic fibrosis (CF) is a recessive hereditary disorder, requiring both parental cystic fibrosis conductance transmembrane regulator (CFTR) genes to carry mutations for clinical disease to manifest, i.e., only 50% of normal CFTR gene expression is required to maintain a normal phenotype. To help define the minimum amount of normal CFTR gene expression necessary to maintain normalcy, we have capitalized on our prior observation (Chu, C.-S., B. C. Trapnell, J. J. Murtagh, Jr., J. Moss, W. Dalemans, S. Jallat, A. Mercenier, A. Pavirani, J.-P. Lecocq, G. R. Cutting, et al. 1991. EMBO [Eur. Mol. Biol. Organ] J. 10:1355-1363) that normal individuals can have up to 66% of bronchial CFTR mRNA transcripts that are missing exon 9, a region representing 21% of the sequence coding for the critical nucleotide (ATP)-binding fold 1 (NBF1) of the predicted CFTR protein. The study population included 78 individuals with no prior diagnosis of CF. Evaluation of bronchial epithelial cells (obtained by bronchoscopy) revealed that exon 9 was variably deleted in all individuals. Remarkably, there were four individuals, all greater than or equal to 35 yr, in whom bronchial epithelial cells exhibited 73, 89, 90, and 92% CFTR transcripts with inframe deletion of exon 9, respectively, despite normal sweat Cl- and no clinical manifestation of CF. In the context that only 8% or less of bronchial CFTR transcripts need exon 9 to maintain normal airway function, these observations strongly suggest that either exon 9 is not necessary for CFTR structure and/or function or that only a very small fraction of bronchial epithelial cells need to express normal CFTR mRNA transcripts with exon 9 to perform the function of CFTR sufficient to maintain a normal phenotype in vivo.

Adult↗
PubMed2000

Recommendations for quality improvement in genetic testing for cystic fibrosis. European Concerted Action on Cystic Fibrosis.

These recommendations for quality improvement of cystic fibrosis genetic diagnostic testing provide general guidelines for the molecular genetic testing of cystic fibrosis in patients/individuals. General strategies for testing as well as guidelines for laboratory procedures, internal and external quality assurance, and for reporting the results, including the requirements of minimal services in mutation testing, the nomenclature for describing mutations, procedures to control false-positive amplification reactions and to validate tests, and guidelines to implement a quality system in a molecular diagnostic laboratory are reviewed.

Accreditation↗
PubMed2002

Burkholderia cepacia complex in cystic fibrosis and non-cystic fibrosis patients: identification of a cluster of epidemic lineages.

This study was performed in order to compare Burkholderia cepacia complex strains from cystic fibrosis (CF) and non-CF patients at the genomovar, genetic and epidemiological levels. A total of 92 B. cepacia respiratory tract isolates were obtained from patients attending the following CF centres: Catania and Palermo, Sicily; Gualdo Tadino, Central Italy, and Milan, Northern Italy. A total of 23 B. cepacia isolates were obtained from blood, surgical wound, and intravenous catheter sources of patients without CF, hospitalized in Catania and Varese, Northern Italy. Genomovar status identification, clonality and genetic relatedness determination, antibiotic susceptibility pattern determination and electron microscopy were performed. Transmission of infection was shown in both CF and non-CF patients by identifying clonality of responsible strains. In total 13 clones were involved in cross-transmission episodes. No outbreak was described involving both CF and non-CF patients. The present study indicates the existence of a distinct cluster of strains responsible for epidemics in CF and non-CF patients, based on their genetic relatedness, distinct from strains associated with no or negligible transmissibility. This result suggests that transmissibility is not only associated with a specific genomovar in CF patients, but also with a group of genetically related lineages in CF and non-CF patients. A key role is shown for both segregation measures and careful surveillance of infection, based on selective culture, molecular identification and epidemiological characterization of individual isolates.

Anti-Bacterial Agents↗
PubMed2006

In vitro activity of doripenem against Pseudomonas aeruginosa and Burkholderia cepacia isolates from both cystic fibrosis and non-cystic fibrosis patients.

The in vitro activities of doripenem, imipenem, levofloxacin, piperacillin, ceftazidime, aztreonam, tobramycin, and cefepime were determined for 160 isolates of Pseudomonas aeruginosa (82 from cystic fibrosis [CF] patients) and 34 isolates of Burkholderia cepacia. Doripenem MIC90s were lower than those of all other comparative agents against all isolates combined and against all P. aeruginosa isolates. Doripenem was as active as levofloxacin and 2- to 32-fold more active than the other comparative agents against B. cepacia.

Anti-Bacterial Agents↗
PubMed2004

[Patients with cystic fibrosis managed at the cystic fibrosis units of Madrid: cross-sectional study of 387 subjects].

BACKGROUND AND OBJECTIVE: Our objective was to describe the clinical and genetics features of patients with cystic fibrosis (CF) attended in Madrid. PATIENTS AND METHOD: This was a descriptive, cross-sectional study of CF patients attended during 2001. Demographic, genetic, anthropometric, pancreatic insufficiency, diabetes mellitus, Pseudomonas aeruginosa colonization, lung function and body mass index (BMI) (z score) data were recorded and compared with the American CF Registry. RESULTS: 387 patients were included, most of them living in Madrid (n = 247 [63%]), 209 males (54%), with a mean age (SD) of 15.15 (10.42) years (younger than 18 years, 248, 64.24%). F508del was the most common mutation (52.8% of chromosomes) with 104 homozygous patients. Pancreatic insufficiency was present in 310 subjects (80.1%), diabetes mellitus in 30 (7.8%) and P. aeruginosa colonization in 126 (33.1%). Lung function was measured in 309 patients: mean of FEV1 and FVC predicted values (SD) was 82.5 (27.11) and 89.32 (21.89), respectively. The mean BMI z score was 0.0796 (1.18). CONCLUSIONS: CF patients from Madrid have a good nutritional status, less P. aeruginosa colonization, less pancreatic insufficiency and better lung function than those of the American CF Registry. The lower prevalence of homozygous F508del in our population may explain, at least partly, our findings.

Adolescent↗
PubMed2000

Longitudinal relationship among growth, nutritional status, and pulmonary function in children with cystic fibrosis: analysis of the Cystic Fibrosis Foundation National CF Patient Registry.

OBJECTIVE: To determine prospectively the relationship among growth, nutritional status, and pulmonary function over a 4-year period in a large cohort of children with cystic fibrosis (CF). STUDY DESIGN: CF Foundation National CF Patient Registry data collected from 1991 to 1995 for 968 children (507 male) aged 5 to 8 years with pancreatic insufficiency and forced expiratory volume in 1 second within 60% to 140% of predicted values (FEV(1)%) were analyzed longitudinally. Variables hypothesized to affect FEV(1)% included age, sex, z scores for height, weight, percent of height-appropriate body weight, and annual number of days hospitalized. RESULTS: The significant decline in FEV(1)% was curvilinear and dependent on baseline FEV(1)%; children with initial FEV(1)% > or = 90 declined 2.6 U/y more than those with initial FEV(1)% <90. Boys gained but girls declined in z scores for height. Girls decreased in z scores for weight at a greater rate than boys. The z scores for weight and percent of height-appropriate body weight were significantly associated with longitudinal changes in FEV(1)%, after adjustment was done for hospitalizations. CONCLUSIONS: Growth, nutritional status, and pulmonary function are not stable in prepubertal children with CF and pancreatic insufficiency. Important sex-related differences in growth occur before puberty. Growth and nutritional status are associated with changes in FEV(1)%, suggesting that nutritional intervention may slow the decline in pulmonary function in children with CF.

Body Height↗