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PubMed2006

Quality-of-life in children and adolescents with cystic fibrosis managed in both regional outreach and cystic fibrosis center settings in Queensland.

OBJECTIVES: To assess the health-related quality-of-life (HRQOL) of children/adolescents with cystic fibrosis (CF) and compare HRQOL in children managed by cystic fibrosis outreach service (CFOS) with those treated in a cystic fibrosis center (CFC). To compare HRQOL of children with CF in Queensland with previously published HRQOL data from the United States and examine the relationship between HRQOL scores and pulmonary function. STUDY DESIGN: Participants were children/adolescents with CF and their parents managed by the Royal Children's Hospital Queensland at a CFC or CFOS. Two HRQOL surveys were used: PedsQL and Cystic Fibrosis Questionnaire (CFQ). RESULTS: There were 91 CFC and 71 CFOS participants with similar demographics. PedsQL total summary score was statistically higher in CFOS, P=.05. There was no significant difference in CFQ scores between groups. Queensland parents reported lower HRQOL for their children compared with US parents (P<.01) despite similar pulmonary function. Declining pulmonary function correlated with worse CFQ scores in adolescents, P<.05. CONCLUSIONS: Children living in regional Queensland reported as good as or slightly better HRQOL compared with children attending a CFC. Parent proxy HRQOL scores were generally low suggesting a reduced perception of HRQOL by parents for their children.

Adolescent↗

PubMedDate not supplied

[Dry eye syndrome in children with cystic fibrosis].

BACKGROUND: Cystic fibrosis is a white Caucasian population specific disease, with autosomal recessive mode of inheritance. It is caused by mutations in the protein coding gene of chromosome 7, functioning as the cystic fibrosis transmembrane conductance regulator (CFTR), causing dysfunction of secretory glands in the alimentary tract, respiratory tract and in the eye. PURPOSE: The aim of the study was to evaluate the tear film stability in cystic fibrosis patients. PATIENTS AND METHODS: Fifteen patients with cystic fibrosis aged 8-23, mean age 13.05 +/- 3.45, and fifteen controls aged 8-21, mean age 13.56 +/- 3.45 were examined. The tests included slit-lamp biomacroscopy, tear film break-up time, fluorescein staining and lissamine green staining. RESULTS: 54% Cystic fibrosis patients showed a statistically significant abnormal break-up time results. CONCLUSION: In cystic fibrosis patients we found low tear film stability. Fluorescine break-up time (FBUT) may be useful in the diagnosis of the dry eye in cystic fibrosis.

Adolescent↗

PubMed2002

[Correlation between phenotype and genotype in a group of patients with cystic fibrosis].

BACKGROUND: Cystic fibrosis (CF) is the most common lethal autosomic disease in Caucasians, with a global incidence of 1:3000 newborns. More than 900 mutations have been described, involving the Cystic Fibrosis Transmembrane Regulator (CFTR). The delta F508 mutation is present in 60% of alleles studied worldwide. AIM: To report 25 patients with cystic fibrosis in whom a genetic study was done. MATERIAL AND METHODS: Twenty five patients (14 men, aged between 18 months and 25 years) with a diagnosis of cystic fibrosis based on clinical features plus two abnormal sweat tests are reported. The genetic study considered the 20 most common mutations in cystic fibrosis and was done in genomic DNA of peripheral lymphocytes, by polymerase chain reaction. RESULTS: A mutation was found in 75% of analyzed alleles. delta F508 was present in 50% of cases (delta F508/delta F508 in 8 and delta F508/other in 11). When delta F508 was present, pancreatic insufficiency was always a feature and nutritional status was worse. Respiratory involvement was variable, both for homozygous and heterozygous cases. Other severe mutations such as W128X and G542X were related to clinical manifestations similar to those found in delta F508 mutation. Diagnosis was made before six months of age in 12 patients. The clinical presentation was meconium ileus and there was a family history of the disease in most cases. The majority of cases of early diagnosis presented severe mutations, but milder respiratory symptoms and lesser nutritional compromise at the time of assessment. CONCLUSIONS: Most patients studied had a severe cystic fibrosis mutation, which was associated with more severe respiratory, pancreatic and nutritional involvement. The early diagnosis of the disease, which would allow to improve the prognosis and the quality of life, must be emphasized.

Adolescent↗

PubMed1997

Self-management of cystic fibrosis: short-term outcomes of the Cystic Fibrosis Family Education Program.

This study tested the efficacy of the Cystic Fibrosis Family Education Program, a cystic fibrosis self-management program, on improving participants' knowledge, self-efficacy, self-management behavior, health, and quality of life. A quasi-experimental pretest-posttest nonequivalent comparison group design was employed. Participants made up 104 patient-primary caregiver dyads from the intervention site cystic fibrosis center and 95 from the usual care comparison center. The intervention, a self-paced print curriculum based on social cognitive theory, targeted behavioral capability, self-efficacy, and outcome expectations and was implemented as an integral part of medical care. Parents, early childhood, middle childhood, and adolescents received separate materials on respiratory, nutrition and malabsorption, communication, and coping issues. Significant intervention effects were found on the knowledge scores for caregivers, adolescents, and children; caregiver and adolescent total self-management scores; Child Behavior Checklist total score; one parent coping scale score; the modified NIH score; NIH pulmonary factor 1; and the Brasfield total score. Significant interaction effects were evident in the self-efficacy scores for caregivers and children.

Adolescent↗

PubMed1995

A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis is a monogenic disease that deranges multiple systems of ion transport in the airways, culminating in chronic infection and destruction of the lung. The introduction of a normal copy of the cystic fibrosis transmembrane conductance regulator (CFTR) gene into the airway epithelium through gene transfer is an attractive approach to correcting the underlying defects in patients with cystic fibrosis. We tested the feasibility of gene therapy using adenoviral vectors in the nasal epithelium of such patients. METHODS: An adenoviral vector containing the normal CFTR complementary DNA in four logarithmically increasing doses (estimated multiplicity of infection, 1, 10, 100, and 1000), or vehicle alone, was administered in a randomized, blinded fashion to the nasal epithelium of 12 patients with cystic fibrosis. Gene transfer was quantitated by molecular techniques that detected the expression of CFTR messenger RNA and by functional measurements of transepithelial potential differences (PDs) to assess abnormalities of ion transport specific to cystic fibrosis. The safety of this treatment was monitored by nasal lavage and biopsy to assess inflammation and vector replication. RESULTS: The adenoviral vector was detected in nasal-lavage fluid by culture, the polymerase chain reaction (PCR), or both in a dose-dependent fashion for up to eight days after vector administration. There was molecular evidence of gene transfer by reverse-transcriptase PCR assays or in situ hybridization in five of six patients treated at the two highest doses. However, the percentage of epithelial cells transfected by the vector was very low (< 1 percent), and measurement of PD across the epithelium revealed no significant restoration of chloride transport or normalization of sodium transport. At the lower doses of vector, there were no toxic effects. However, at the highest dose there was mucosal inflammation in two of three patients. CONCLUSIONS: In patients with cystic fibrosis, adenoviral-vector-mediated transfer of the CFTR gene did not correct functional defects in nasal epithelium, and local inflammatory responses limited the dose of adenovirus that could be administered to overcome the inefficiency of gene transfer.

Adenoviruses, Human↗

PubMed1991

Activation by extracellular nucleotides of chloride secretion in the airway epithelia of patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis is characterized by abnormal electrolyte transport across the epithelia of the airways. In particular, there is excessive sodium absorption and deficient chloride secretion. Drugs that block excessive sodium absorption may provide clinical benefit in cystic fibrosis, but there are no available therapeutic agents to improve chloride secretion. In vitro studies in cultured human-airway epithelia indicate that triphosphate nucleotides (ATP and UTP) induce chloride secretion through apical-membrane purinergic receptors. METHODS: We tested the ability of nucleotides to induce chloride secretion in vivo in 9 normal subjects and 12 patients with cystic fibrosis by measuring responses of nasal transepithelial potential difference (PD) to superfusion of nucleotides. Changes in transepithelial bioelectric properties and the permeability of the apical membrane to chloride in response to extracellular (apical) UTP were determined with ion-selective microelectrodes in cultured nasal epithelia. RESULTS: ATP and UTP induced chloride secretion in vivo in both groups. At their maximal effective concentrations of 10(-4) M, ATP and UTP were more effective chloride secretagogues in the patients with cystic fibrosis (mean [+/- SE] change in PD, -19.8 +/- 1.4 mV and -15.0 +/- 1.7 mV, respectively) than in the normal subjects (-6.9 +/- 0.6 mV and -8.1 +/- 0.9 mV, respectively). Microelectrode studies established that extracellular UTP stimulated a larger increase in PD and chloride secretory current in epithelial cells from patients with cystic fibrosis than in cells from normal subjects, by actions localized to the apical membrane. CONCLUSIONS: Extracellular nucleotides are effective in vivo chloride secretagogues in the nasal epithelia of patients with cystic fibrosis. The equipotency of ATP and UTP suggests that the effect is mediated by P2 nucleotide receptors. Selected nucleotides, such as UTP or nucleotide analogues, should be investigated as therapeutic agents for lung disease in cystic fibrosis.

Adenosine↗

PubMed2003

Effects of C-terminal deletions on cystic fibrosis transmembrane conductance regulator function in cystic fibrosis airway epithelia.

To better understand the function of the conserved C terminus of the cystic fibrosis (CF) transmembrane conductance regulator, we studied constructs containing deletions in the C-terminal tail. When expressed in well differentiated CF airway epithelia, each construct localized predominantly to the apical membrane and generated transepithelial Cl(-) current. The results suggested that neither the C-terminal PSD-95/Discs-large/ZO-1 (PDZ)-interacting motif nor other C-terminal sequences were absolutely required for apical expression in airway epithelia. Surprisingly, deleting an acidic cluster near the C terminus reduced both channel opening rate and transepithelial Cl(-) transport, indicating that it influences channel gating. These results may help explain the relative paucity of CF-associated mutations in the C terminus.

Amino Acid Sequence↗

PubMed2002

Metabolic risk factors for stone formation in patients with cystic fibrosis.

PURPOSE: Cystic fibrosis is characterized by chronic pulmonary disease, insufficient pancreatic and digestive function, and abnormal sweat concentrations. Patients with cystic fibrosis also have an increased incidence of nephrolithiasis. We compared the results of metabolic evaluation in patients with cystic fibrosis with and without nephrolithiasis. MATERIALS AND METHODS: A total of 496 patients were evaluated at our center, including 98 with a mean age of 25 years who had cystic fibrosis and complete metabolic evaluation available between 1996 and 2000. Of these patients 13 (13%) had a history of nephrolithiasis. The records were reviewed for clinical characteristics and all patients underwent metabolic evaluation, including serum electrolyte measurement and 24-hour urine collection. Statistical analysis was done to compare the stone versus nonstone groups. RESULTS: The incidence of nephrolithiasis in our study was 3%. We identified 13 patients 16 to 41 years old (mean age 27) with nephrolithiasis, of whom 62% had had multiple episodes. Flank pain was the presenting symptom in 9 of the 13 cases (69%). Renal ultrasound and computerized tomography were the most common imaging modalities. In 9 cases stones were passed without intervention, extracorporeal shock wave lithotripsy was required in 2 and ureteroscopy with stone extraction was done in 2. Calcium oxalate was the dominant stone composition in the 9 patients in whom stone analysis was performed. Metabolic evaluation of the stone versus no stone groups showed elevated urinary oxalate (45.5 versus 42.5 mg./24 hours), relative calcium oxalate supersaturation (5.3 versus 7.2) and decreased urinary citrate in the 2 groups. There was a statistical difference in citrate excretion with lower levels in stone formers (102 versus 218 mg./24 hours, p = 0.0007). CONCLUSIONS: Patients with cystic fibrosis have an increased incidence of nephrolithiasis and are at high risk for recurrence. Metabolic evaluation is indicated in all patients with cystic fibrosis and urolithiasis since most have hyperoxaluria, urinary calcium oxalate supersaturation and decreased urinary citrate. Correcting detected stone risk factors in these cases may decrease stone recurrence.

Adolescent↗

PubMed1988

Temporal bone pneumatization in cystic fibrosis patients.

Cystic fibrosis patients commonly have nasal polyps and sinusitis, but surprisingly are spared from an increased occurrence of otitis media. Twenty cystic fibrosis patients whose ages ranged from 13 to 26 years were studied. Only one of these patients had a history of otitis. Minimal temporal bone pneumatization, as determined by computed tomography, was used as an indicator of childhood otitis. The computed tomography had been done as part of the medical evaluation of their symptomatic paranasal sinusitis. On the average, pneumatization volume was larger for the cystic fibrosis patients than for the normal population (p = 0.033, Student's t-test). That is, these data indicate that cystic fibrosis patients had significantly less otitis than the normal population. Assuming that these cystic fibrosis patients are representative, the data may imply that the gene for good musculoskeletal eustachian differentiation is linked with the gene for cystic fibrosis. The data also imply that poor mucociliary transport does not necessarily induce otitis media.

Adolescent↗

PubMed1999

Pharmacogenomics of the cystic fibrosis transmembrane conductance regulator (CFTR) and the cystic fibrosis drug CPX using genome microarray analysis.

BACKGROUND: Cystic fibrosis (CF) is the most common lethal recessive disease affecting children in the U.S. and Europe. For this reason, a number of ongoing attempts are being made to treat the disease either by gene therapy or pharmacotherapy. Several phase 1 gene therapy trials have been completed, and a phase 2 clinical trial with the xanthine drug CPX is in progress. The protein coded by the principal CFTR mutation, DeltaF508-CFTR, fails to traffic efficiently from the endoplasmic reticulum to the plasma membrane, and is the pathogenic basis for the missing cAMP-activated plasma membrane chloride channel. CPX acts by binding to the mutant DeltaF508-CFTR and correcting the trafficking deficit. CPX also activates mutant CFTR channels. The comparative genomics of wild-type and mutant CFTR has not previously been studied. However, we have hypothesized that the gene expression patterns of human cells expressing mutant or wild-type CFTR might differ, and that a drug such as CPX might convert the mutant gene expression pattern into one more characteristic of wild-type CFTR. To the extent that this is true, a pharmacogenomic profile for such corrective drugs might be deduced that could simplify the process of drug discovery for CF. MATERIALS AND METHODS: To test this hypothesis we used cDNA microarrays to study global gene expression in human cells permanently transfected with either wild-type or mutant CFTR. We also tested the effects of CPX on global gene expression when incubated with cells expressing either mutant or wild-type CFTR. RESULTS: Wild-type and mutant DeltaF508-CFTR induce distinct and differential changes in cDNA microarrays, significantly affecting up to 5% of the total genes in the array. CPX also induces substantial mutation-dependent and -independent changes in gene expression. Some of these changes involve movement of gene expression in mutant cells in a direction resembling expression in wild-type cells. CONCLUSIONS: These data clearly demonstrate that cDNA array analysis of cystic fibrosis cells can yield useful pharmacogenomic information with significant relevance to both gene and pharmacological therapy. We suggest that this approach may provide a paradigm for genome-based surrogate endpoint testing of CF therapeutics prior to human administration.

Cell Line↗

PubMed1996

Quality of life in adults with cystic fibrosis.

BACKGROUND: Cystic fibrosis is an inherited condition with a high mortality and morbidity. The aims of this study were to assess quality of life in a population of adults with cystic fibrosis, to compare quality of life with published scores from a healthy population and other patient groups, and to examine the relation between quality of life and other measured clinical variables. METHODS: Patients over 16 years of age attending an adult cystic fibrosis outpatient clinic were surveyed at a time when they were clinically stable. A self-complete questionnaire was administered which comprised the Nottingham Health Profile (NHP) together with six additional questions related to cystic fibrosis. RESULTS: Completed questionnaires were obtained from 240 subjects (100 women) of median age 26 years (range 16-56). Mean (SD) forced expiratory volume in one second (FEV1) was 49 (26)% predicted, forced vital capacity (FVC) was 68 (26)% predicted, and the FEV1:FVC ratio was 59 (16)%. In this cross sectional study different patterns of perceived quality of life were seen in men and women. In part 1 of the NHP there was an age related trend compared with norms in men, with more distress/disability in the dimensions of emotion, sleep, and social isolation in the older age groups. In women there was no age related trend in the degree of distress/disability compared with norms. The mean score was different from norms in the dimensions of pain, emotion and sleep. For the patients with cystic fibrosis as a whole the scores in part 1 were comparable with published scores of patients with minor non-acute conditions. Scores in part 2 of the NHP for men were different from norms in six of the seven areas of daily living (all except home life). For women the scores were different from norms in the areas of looking after the home, social life, hobbies, and holidays. There were correlations between several of the quality of life dimensions and other measured variables such as FEV1, breathlessness score, and the time spent on home treatment. CONCLUSIONS: Men and women with cystic fibrosis have different patterns of perceived quality of life, and there is an age related trend of perceived quality of life in men in some dimensions. Quality of life scores in this group, as assessed by the NHP, are similar to those reported in subjects with minor non-acute conditions.

Activities of Daily Living↗

PubMed1992

Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis.

BACKGROUND: Cystic fibrosis is a common, severe autosomal recessive disease caused in a majority of cases by a three-nucleotide deletion (delta F508) in the cystic fibrosis transmembrane regulator gene. Current methods of prenatal diagnosis involve chorionic-villus sampling or amniocentesis. In vitro fertilization and diagnosis during embryonic development before implantation would allow only unaffected embryos to be selected for transfer to the uterus, thereby avoiding the need to terminate a pregnancy. METHODS: Preimplantation diagnosis of cystic fibrosis was attempted in the cases of three couples, both members of which carried the delta F508 deletion. In vitro fertilization techniques were used to recover oocytes from each woman and fertilize them with her husband's sperm. Three days after insemination, embryos in the cleavage stage underwent biopsy and removal of one or two cells for DNA amplification and analysis. RESULTS: Only two oocytes from one woman were fertilized normally; DNA analysis of one of the embryos failed and cystic fibrosis was diagnosed in the other (i.e., it was homozygous for delta F508), so neither was transferred. The oocytes of each of the other two women produced noncarrier, carrier, and affected embryos. Both couples chose to have one noncarrier embryo and one carrier embryo transferred. One woman became pregnant and gave birth to a girl free of the deletion in both chromosomes. CONCLUSIONS: Preimplantation diagnosis of the delta F508 deletion causing cystic fibrosis is possible through in vitro fertilization, biopsy of a cleavage-stage embryo, and amplification of DNA from single embryonic cells. This approach should be equally applicable to other single-gene diseases in which the defect has been identified. Analysis of a series of pregnancies, however, will be required to assess the method adequately.

Base Sequence↗

PubMed2003

[A case report of cystic fibrosis and review of 16 cases of cystic fibrosis in Chinese patients].

OBJECTIVE: To report a case of cystic fibrosis (CF) in a Chinese and to review the clinical features, gene mutations, diagnosis and outcome of CF in Chinese patients. METHODS: A 14-year-old Chinese girl presenting with recurrent productive cough since birth with parasinusitis and otitis media was confirmed to have CF in Peking University First Hospital. Chest CT scan showed bronchiectasis, more severe in the right upper lobe. Sweat tests were taken three times, and the values of Na(+) and Cl(-) were (126.6 +/- 5.4) mmol/L and (108.9 +/- 3.3) mmol/L, respectively. The examination of the pancreas showed no remarkable cystic changes on CT scan and there was no pancreatic insufficiency. Sixteen patients with CF in Chinese reported from 1974 to 1999 were reviewed. RESULTS: Sixteen of the 17 patients (7 males and 9 females, aged from 6 months to 25 years) had clinical data available for analysis. Eleven of them had died, nine before the age of 13. They all suffered from frequent episodes of pneumonia, while 14 had malnutrition and 4 had jaundice. The diagnostic procedures included clinical features, sweat test and autopsy. Four of them had DNA screened and four kinds of novel mutations in the cystic fibrosis transmembrane conductance regulator gene were found. CONCLUSIONS: Chinese patients with CF show similar clinical manifestations to patients in the European and North American populations, but the CFTR mutation was different.

Adolescent↗

PubMed2000

Nasal and exhaled nitric oxide is reduced in adult patients with cystic fibrosis and does not correlate with cystic fibrosis genotype.

STUDY OBJECTIVES: Inducible nitric oxide synthase (iNOS) is upregulated in a number of inflammatory lung conditions, and exhaled nitric oxide (NO) concentration is increased. However, previous studies in children with cystic fibrosis (CF) have shown that exhaled NO is reduced. The purpose of this investigation was to study exhaled NO concentration in adults with CF, and to investigate the effect of CF genotype and respiratory tract infection on this measurement. DESIGN: Exhaled and nasal NO levels were measured in 54 adult CF subjects and 37 healthy nonsmoking age-matched subjects using a chemiluminesence analyzer. Spirometry (FEV(1) and FVC), CF genotype, and bacterial colonization were also recorded. SETTING: This study was conducted at a national CF center. RESULTS: The mean age of patients was 26.9 years, and the mean FEV(1) was 50.5% predicted (range, 17 to 104%). Nasal NO in the CF patients (mean, 520 parts per billion [ppb]; confidence interval [CI], 452 to 588) was significantly lower (p < 0.001) than in control subjects (987 ppb; CI, 959 to 1,015). Exhaled NO was significantly lower (p < 0. 001) in CF patients (5.0 ppb; CI, 4.1 to 6.1) than in control subjects (7.3 ppb; CI, 6.8 to 7.8). FEV(1) did not correlate with nasal or exhaled NO. No association was observed between genotype and NO values or colonization with Pseudomonas aeruginosa. CONCLUSIONS: Despite the airway inflammation that is characteristic of CF, both nasal and exhaled NO were reduced. There was no association with genotype or infection status. As NO has bacteriostatic effects and may augment mucociliary clearance, this observation may be of clinical importance.

Adolescent↗

PubMed1992

Differential localization of the cystic fibrosis transmembrane conductance regulator in normal and cystic fibrosis airway epithelium.

Deletion of the amino acid residue Phe 508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein represents the most common mutation identified in cystic fibrosis (CF) patients. A monoclonal and a polyclonal antibody directed against different regions of CFTR were used to localize the CFTR protein in normal and CF airway epithelium derived from polyps of non-CF and CF subjects homozygous for the delta Phe 508 CFTR mutation. To identify the cellular and subcellular localization of CFTR, immunofluorescent light microscopy, confocal scanning microscopy, and immunogold transmission electron microscopy were performed on cryofixed tissue. A markedly different subcellular distribution was identified between normal and CF airway epithelial cells. In normal epithelium, labeling was restricted to the surface apical compartment of the ciliated cells. In contrast, in the epithelium from homozygous delta Phe 508 CF patients, CFTR markedly accumulated in the cytosol of all the epithelial cells. These findings are consistent with the concept that the CFTR delta Phe 508 mutation modifies the intracellular maturation and trafficking of the protein, leading to an altered subcellular distribution of the delta Phe 508 mutant CFTR.

Cystic Fibrosis↗

PubMed2006

CFTR chloride channel drug discovery--inhibitors as antidiarrheals and activators for therapy of cystic fibrosis.

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a cAMP-activated chloride channel expressed in epithelia in the lung, intestine, pancreas, testis and other tissues, where it facilitates transepithelial fluid transport. In the intestine CFTR provides the major route for chloride secretion in certain diarrheas. Mutations in CFTR cause the hereditary disease cystic fibrosis, where chronic lung infection and deterioration in lung function cause early death. CFTR is a well-validated targeted for development of inhibitors for therapy of secretory diarrheas and activators for therapy in cystic fibrosis. Our lab has identified and optimized small molecule inhibitors of CFTR, as well as activators of DeltaF508-CFTR, the most common mutant CFTR causing cystic fibrosis. High-throughput screening of small molecule collections utilizing a cell-based fluorescence assay of halide transport yielded thiazolidinone and glycine hydrazide CFTR inhibitors that block enterotoxin-mediated secretory diarrhea in rodent models, including a class of non-absorbable inhibitors that target the CFTR pore at its external entrance. Benzothiophene, phenylglycine and sulfonamide potentiators were identified that correct the defective gating of DeltaF508-CFTR chloride channels, and other small molecules that correct its defective cellular processing. Small molecule modulators of CFTR function may be useful in the treatment of cystic fibrosis, secretory diarrhea and polycystic kidney disease.

Animals↗

PubMed2000

Exhaled 8-isoprostane as a new non-invasive biomarker of oxidative stress in cystic fibrosis.

BACKGROUND: Cystic fibrosis is characterised by oxidative stress in the airways. Isoprostanes are prostaglandin isomers formed by free radical catalysed peroxidation of arachidonic acid. 8-Isoprostane is increased in interstitial lung diseases, asthma, chronic obstructive pulmonary disease, and adult respiratory distress syndrome. Exhaled nitric oxide (NO) and carbon monoxide (CO) are biomarkers of inflammation and oxidative stress in the airways, respectively. METHODS: Concentrations of 8-isoprostane in the breath condensate of 10 normal subjects and 19 patients with stable cystic fibrosis were measured using an enzyme immunoassay (EIA). Breath condensate is a non-invasive method of collecting airway secretions. Exhaled nitric oxide (NO) and carbon monoxide (CO) levels were measured by a chemiluminescence analyser. RESULTS: Concentrations of 8-isoprostane in the breath condensate of patients with stable cystic fibrosis were increased about threefold compared with normal subjects (42.7 (4.5) pg/ml vs 15.2 (1.7) pg/ml; p<0.005, 95% CI 14.6 to 40.9). 8-Isoprostane concentrations were negatively correlated with forced expiratory volume in one second in patients with cystic fibrosis (r = -0.61; p<0.005). Exhaled CO was also increased in patients with cystic fibrosis compared with normal subjects (6.7 (1.2) ppm vs 2.9 (0.3) ppm; p<0.05, 95% CI 0.2 to 7.4). 8-Isoprostane concentrations were significantly correlated with CO levels (r = 0.66; p<0.002). CONCLUSIONS: The results of this study show that oxidative stress is increased in cystic fibrosis and may be quantified by measuring 8-isoprostane concentrations in breath condensate.

Adult↗

PubMed1999

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

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

Alleles↗