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PubMed1996

Psychological impact of population-based carrier testing for cystic fibrosis: 3-year follow-up. UK Cystic Fibrosis Follow-Up Study Group.

BACKGROUND: The objective of this study was to show the long-term psychological effects of population-based screening for cystic fibrosis. METHODS: The sample comprised all carriers (n = 435) and, for each carrier, two matched screen-negative individuals (n = 870) detected during screening programmes for cystic fibrosis in the general population and in antenatal populations carried out a median of 3 years earlier in six UK centres. Questionnaires were sent to all eligible participants, with reminders sent to non-responders. The main endpoints were understanding of test results, degree of anxiety, perceptions of health, and reproductive intentions, and behaviour. FINDINGS: 746 (62%) of 1201 questionnaires were returned. Recall of the meaning of test results was accurate in 225 (80%) of 280 carriers but only 200 (43%) of 466 screen-negative individuals. 46 (16%) of 280 proven carriers believed that their result meant that they were only likely, rather than definitely, to be a carrier; 232 (50%) of 466 of those with a screen-negative result erroneously believed that the result meant that they were definitely not carriers. There was no significant difference between carriers and screen-negative individuals in degree of general anxiety, although 16% of carriers reported feeling worried about their test results. Carriers had a poorer perception of their current health than did non-carriers, even though they had been told that carrier status confers no disadvantages to their own health. There were no differences between carriers and screen-negative individuals in reproductive intentions or behaviour. INTERPRETATION: We have shown that in the long-term, retention of the meaning of test results from cystic fibrosis screening is poor. Further research is needed to improve the performance of test-related counselling programmes to ensure that the main objectives of these programmes, to provide information on carrier status and to allow informed reproductive decisions, are met.

Adult↗

PubMed1988

Ileal pH in cystic fibrosis.

In cystic fibrosis jejunal hyperacidity has an adverse effect on lipid digestion. It is not known whether hyperacidity extends to the ileum. We have studied pH through the whole length of the small bowel in 42 normal and 6 cystic fibrosis subjects by means of pH-sensitive radiotelemetry capsules. In cystic fibrosis subjects the time spent below pH 6.0 was significantly greater during the 1st h in the small bowel than in normal subjects. In the rest of the small bowel the pH remained above 6.0 in both groups. The recordings in the cystic fibrosis group did not show the clear distinction between ileum and colon which is seen in normal subjects. In cystic fibrosis low pH conditions are confined to the proximal small intestine. There is adequate time at optimal pH in the small bowel for dissolution of enzyme supplements and assimilation of nutrients.

Adult↗

PubMed2001

Cystic fibrosis mutations and associated haplotypes in Turkish cystic fibrosis patients.

Identification of mutations causing cystic fibrosis (CF) in the Turkish population is essential for assessment of the molecular basis of CF in Turkey and the development of strategies for prenatal diagnosis and genetic counseling. Here, we present an updated report of mutations found in the Turkish CF population from an extensive screening study of the entire coding region, including exon-intron boundaries and the promoter region. Cases for which mutations could not be identified were also screened for previously defined large alterations and (TG)mTn-M470V loci. This study revealed a total of 27 different mutations accounting for almost 60% of disease genes in the Turkish population. In this study, we also identified the haplotypes associated with 17 mutations and those associated with unknown mutations. The mutation spectrum of CF in Turkey and its associated haplotypes indicated the presence of a major Mediterranean component in the contemporary Turkish population.

Cystic Fibrosis↗

PubMed1999

Restoration of bacterial killing activity of human respiratory cystic fibrosis cells through cationic vector-mediated cystic fibrosis transmembrane conductance regulator gene transfer.

In vitro and in vivo studies have demonstrated that gene transfer of the CFTR (cystic fibrosis transmembrane conductance regulator) cDNA into human respiratory cells through nonviral vectors can occur safely and can be done repeatedly. Although functional evaluation of CFTR in cystic fibrosis (CF) patients enrolled in phase I clinical trials using cationic liposomes has shown a partial correction of nasal potential difference, a biological assay indicating a therapeutic relevance of CFTR gene transfer is still missing. Our aims were to study the induction of killing activity toward Pseudomonas aeruginosa (PA) in CF cells by cationic vector-mediated CFTR gene transfer and to use this assay as a therapeutic end point. Luciferase expression and GFP FACS analysis were used to evaluate the optimal vector and the efficiency of gene transfer into non-CF human respiratory cells growing from nasal polyp explants at the air-liquid interface. To prove that transgenic CFTR was expressed in CF cell cultures under the same experimental conditions, a specific RT-PCR was performed. Challenge of the outgrowths with a known amount of PA showed a bacterial clearance activity by non-CF respiratory cells, while in the case of CF cells it even resulted in bacterial growth. Cationic vector-mediated CFTR cDNA determined the recovery of bacterial clearance activity only under those conditions yielding 5% or more of GFP-positive cells. The results shown in this study might be helpful in considering cationic vectors as therapeutic nonviral vectors for transferring CFTR into human CF respiratory cells, as well as for restoring the bacterial killing activity defective in cystic fibrosis.

Cations↗

PubMed1991

Use of exercise in the management of cystic fibrosis: short communication about a survey of cystic fibrosis referral centers.

A survey of 47 cystic fibrosis referral centers was conducted to study the use of exercise in the management of patients with cystic fibrosis (CF). A questionnaire with 5 brief questions concerning the prescription and application of exercise therapy was sent to the first 47 centers (38.5%) listed in the 1988 CF Foundation Directory, and 46 (97.9%) were returned. While all but one of the respondents recommend exercise at least to selected patients, and while 80.4% of the centers refer patients to summer camp programs, only 43.5% offer exercise stress testing and only 21.7% offer an exercise program for their patients. Most of the respondents who recommend exercise prescribe aerobic exercise, swimming being the most frequently chosen type. Although there is a large discrepancy between those centers that acknowledge the benefits of exercise and those that have arranged for regularly available exercise services, inroads have been made in utilizing this therapeutic tool for patients with CF.

Community Health Centers↗

PubMed1985

Transepithelial potential difference in cystic fibrosis.

In cystic fibrosis the potential difference between interstitial fluid and the surface of respiratory and sweat duct epithelia is abnormally large. This study attempted to confirm this finding and investigate its value for a diagnostic test. With a subcutaneous reference electrode the mean potential difference of the inferior turbinate was -25 mv in 19 patients with cystic fibrosis, which was significantly greater than the difference of -13 mv in 22 normal subjects (p less than 0.02). Of the observations in the patients with cystic fibrosis, 67% were greater than the largest potential difference observed in normal individuals. Potential differences from the lip and forearm were also significantly greater in cystic fibrosis than in normal subjects, but there was considerable overlap. Changes in the electrical properties of nasal epithelium and skin have been confirmed in cystic fibrosis, but these have limited use for diagnosis.

Adult↗

PubMed1992

Cystic fibrosis. Part II. New developments in cystic fibrosis--implications for carrier detection and genetic counselling.

Cystic fibrosis (CF) is an autosomal recessive disorder found predominantly in people of European origin. Prenatal diagnosis for this disorder is now possible using the polymerase chain reaction technique to detect the most common CF-causing mutation, delta F508. Case studies of prenatal diagnosis and carrier detection are presented and some of the genetic counselling issues related to these investigations are discussed.

Cystic Fibrosis↗

PubMed1988

Fibronectin-cleaving activity in bronchial secretions of patients with cystic fibrosis.

In cystic fibrosis, colonization of the airways with Pseudomonas aeruginosa follows colonization with Staphylococcus aureus and is related to accelerated deterioration of pulmonary function. Because P. aeruginosa adheres better to cell surfaces devoid of fibronectin, we searched for fibronectin-cleaving activity in bronchial secretions and saliva from 24 patients with cystic fibrosis who were followed up for 4.5 y and from two control groups. Proteolytic activity against 125I-labeled fibronectin was continuously present in cystic fibrosis bronchial secretions; significantly higher fibronectin-cleaving activity was found in older vs. younger patients, in patients with advanced disease stages determined by a five-stage scoring system, and in those colonized with P. aeruginosa. The fibronectin-cleaving activity was due to neutrophil elastase and cathepsin G. Cystic fibrosis bronchial secretions had proteolytic activity against surface fibronectin of airway mucosal cells. Thus fibronectin-cleaving activity of bronchial secretions rather than of saliva may favor P. aeruginosa colonization of the upper respiratory tract in individuals with cystic fibrosis.

Adolescent↗

PubMed1976

Inflammatory reaction and airway damage in cystic fibrosis.

In cystic fibrosis there is chronic infection and inflammatory reaction in the airways, accompanied by destruction and shedding of airway epithelium. Leukocytes migrate into the airways and some disintegrate, liberating deoxyribonucleoprotein that is incorporated into the gel structure of the bronchial mucus. We compared the status of these processes in cystic fibrosis with that in chronic bronchitis and bronchiectasis, by examining the sputum raised from the lower airways. Measurements also were made on sputum induced in normal subjects. The results indicate that migration of leukocytes into the airways and shedding of damaged airway epithelium were minimal in the normal subjects; they were significant in the patients with chronic bronchitis, higher in those with bronchiectasis, and still higher in those with cystic fibrosis. The large increases found in the total content of DNA and solids in the cystic fibrosis sputum were due to increases in the insoluble fraction containing the whole leukocytes and particulate debris that remained when the sputum mucus gel was solubilized with mercaptoethanol. Despite the large increases in the total content of DNA and solids, the contents of mucus gel components and of deoxyribonucleoprotein from disintegrated leukocytes actually present in the mucus gel structure of the cystic fibrosis sputum were not significantly higher than in the sputum from the patients with chronic bronchitis or brochiectasis.

Bronchi↗

PubMed1997

Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.

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.

Adolescent↗

PubMed2001

[Twin birth after preimplantation diagnosis for cystic fibrosis].

OBJECTIVE: Cystic fibrosis is a common autosomal recessive disease most often caused by a deletion (delta F508) in the CFTR gene. It is the most common indication for preimplantaion genetic diagnosis which allows genetic analysis of embryos obtained after in vitro fertilization and transfer of unaffected embryos into the patient's uterus. PATIENTS AND METHODS: We report the first preimplantation genetic diagnosis performed in Strasbourg for a couple at risk of having a child affected by severe cystic fibrosis due to a homozygous delta F508 mutation. Three days after fertilisation, embryos obtained after intra-cytoplasmic testiculare sperm injection were biopsied and analysed. PCR amplification of the genomic fragment containing the delta F508 locus allowed detection of the delta F508 mutation and transfer only of the unaffected embryos. RESULTS: Three embryos were transferred after this preimplantation genetic diagnosis. A twin pregnancy was obtained and the babies born from this cycle are both exempt from the mutation. CONCLUSIONS: Preimplantation genetic diagnosis for the cystic fibrosis delta F508 mutation is now available in our centre. In this report, we could resolve both the problem of infertility and the risk of transmission of a severe form of cystic fibrosis. Preimplantation genetic diagnosis is also available for other mutations involved in cystic fibrosis and also for other genetic diseases.

Adult↗

PubMed1992

Biochemical characterization of the cystic fibrosis transmembrane conductance regulator in normal and cystic fibrosis epithelial cells.

Affinity-purified polyclonal antibodies, raised against two synthetic peptides corresponding to the R domain and the C terminus of the human cystic fibrosis transmembrane conductance regulator (CFTR), were used to characterize and localize the protein in human epithelial cells. Employing an immunoblotting technique that ensures efficient detection of large hydrophobic proteins, both antibodies recognized and approximately 180-kDa protein in cell lysates and isolated membranes of airway epithelial cells from normal and cystic fibrosis (CF) patients and of T84 colon carcinoma cells. Reactivity with the anti-C terminus antibody, but not with the anti-R domain antibody, was eliminated by limited carboxypeptidase Y digestion. When normal CFTR cDNA was overexpressed via a retroviral vector in CF or normal airway epithelial cells or in mouse fibroblasts, the protein produced had an apparent molecular mass of about 180 kDa. The CFTR expressed in insect (Sf9) cells by a baculovirus vector had a molecular mass of about 140 kDa, probably representing a nonglycosylated form. The CFTR in epithelial cells appears to exist in several forms. N-glycosidase treatment of T84 cell membranes reduces the apparent molecular mass of the major CFTR band from 180 kDa to 140 kDa, but a fraction of the T84 cell CFTR could not be deglycosylated, and the CFTR in airway epithelial cell membranes could not be deglycosylated either. Moreover, wheat germ agglutinin absorbs the majority of the CFTR from detergent-solubilized T84 cell membranes but not from airway cell membranes. The CFTR in all epithelial cell types was found to be an integral membrane protein not solubilized by high salt or lithium diiodosalicylate treatment. Sucrose density gradient fractionation of crude membranes prepared from the airway epithelial cells, previously surface-labeled by enzymatic galactosidation, showed a plasma membrane localization for both the normal CFTR and the CFTR carrying the Phe508 deletion (delta F 508). The CFTR in all cases co-localized with the Na+, K(+)-ATPase and the plasma membrane calcium ATPase, while the endoplasmic reticulum calcium ATPase and mitochondrial membrane markers were enriched at higher sucrose densities. Thus, the CFTR appears to be localized in the plasma membrane both in normal and delta F 508 CF epithelial cells.

3T3 Cells↗

PubMed1977

Studies on cystic fibrosis using isoelectric focusing. III. Correlation between cystic fibrosis protein and ciliary dyskinesia activity in serum shown by a modified rabbit tracheal bioassay.

We have developed a modified rabbit tracheal bioassay for use in investigating a possible correlation between cystic fibrosis protein (CFP) and ciliary dyskinesia factor (CDF) in human serum. The bioassay requires high standards of tissue selection, and all epithelial tissue must be free of underlying connective tissue. When serum samples were collected and processed carefully and warmed to 37 degrees before assay, CDF could be reliably detected in 31 of 31 sera from cystic fibrosis (CF) homozygotes or obligate heterozygotes in 35 min or less without prior fractionation or concentration of sera, whereas 13 of 14 normal control sera were nonreactive. CDF-positive serum reacts in three consecutive phases: (1) initial increase in ciliary beat frequency, (2) ciliary dyskinesia, and (3) tissue destruction with extrusion of single ciliated cells, mucus, and debris. Our results confirm the association of CDF with cystic fibrosis. The bioassay is not specific for CF, however, when whole sera are bioassayed, since serum from several patients with bronchial asthma also caused ciliary dyskinesia. However, this finding need not preclude using rabbit tracheal ciliated epithelial tissue as an assay for following the purification of CDF. Isoelectric focusing showed that the presence or absence of CFP corresponded with that of dyskinesia activity in all sera tested except for the active samples from seven asthma patients, which were negative for CFP. The results indicate that CFP and CDF may be identical or closely related markers for the CF gene, and suggest that the activity detected by the rabbit tracheal bioassay in sera from patients with asthma and other diseases probably is caused by a substance different from a CF-specific CDF.

Animals↗

PubMed1997

Correlation between nasal potential difference measurements, genotype and clinical condition in patients with cystic fibrosis.

In cystic fibrosis (CF), the clinical condition of patients correlates poorly with genotype. One possible explanation is that clinical status is influenced by net preserved chloride secretion rather than the CF mutation. We tested the relationships between residual chloride secretion, as measured by nasal potential difference (PD) and the type of mutation (genotypes expressing apical cystic fibrosis transmembrane conductance regulator (CFTR) protein versus those that do not) and clinical status. Twenty two CF patients (mean age 25.7 yrs, 11 females and 11 males, mean forced expiratory volume in one second (FEV1) 53.1% of predicted) with defined genotypes were recruited. Nasal PD was measured using a standard protocol involving the perfusion of the nasal epithelium with a sodium channel blocker (amiloride), followed by a solution of low chloride and finally with isoprenaline. Patients with apical CFTR protein showed higher residual chloride secretion than those without (amiloride to isoprenaline value of 4.59 and 0.56 mV, respectively, p = 0.01). There was no correlation between mutation type and clinical condition. When these patients were recategorized as "high" (> 10 mV amiloride to isoprenaline response) or "low" (10 mV or less) chloride secretors, we found that the former group had a significantly higher FEV1 (67.7 versus 48.3% pred) and a better pulmonary radiological score (4.14 versus 7.07, by Northern scoring system). These results suggest that some cystic fibrosis patients, regardless of genotype, have an ability to secrete chloride when stimulated with chloride secretatagogues, and this is correlated with a better lung function. These results also have implications for the use of potential difference measurements in novel cystic fibrosis transmembrane conductance regulator replacement trials.

Adult↗

PubMed1993

No added benefit from nebulized amiloride in patients with cystic fibrosis.

In cystic fibrosis (CF) airway epithelial sodium absorption is increased 2-3 fold. Since sodium absorption is inhibited by the sodium channel blocker amiloride, our aim was to assess its therapeutic benefit in cystic fibrosis. A randomized, double-blind, placebo-controlled, cross-over trial of nebulized amiloride was performed in 23 patients with cystic fibrosis. Amiloride or placebo was administered four times daily for two six month periods. Existing treatment was continued, and any infective exacerbations treated in the usual way. Fourteen patients completed the study. No significant changes occurred in forced expiratory volume in one second, forced vital capacity, oxygen saturation, body weight, sputum volume, culture and rheology, serum urea, and electrolytes, white cell count and erythrocyte sedimentation rate during either treatment period. The frequency of infective exacerbations was also not different in either treatment period. We were thus unable to confirm the benefit shown in the only other clinical trial of nebulized amiloride in cystic fibrosis and conclude that, in the presence of established treatment for cystic fibrosis lung disease, nebulized amiloride offers no additional clinical benefit.

Administration, Intranasal↗

PubMed2003

[Towards an improved antenatal screening for cystic fibrosis].

BACKGROUND: Cystic Fibrosis is an autosomal and recessive lethal disease which affects in France one newborn in 3.000. New technologies may afford quite a cheap and efficient screening for a large set of mutations within the same assay in order to test their presence or absence. These procedures are very valuable for prenatal diagnosis for further pregnancies when couples at risk have been identified through a first affected newborn. But, for carriers or couples at risk before the birth of a first child, these antenatal screening methods remain of limited efficacy. However carrier screening would be the only way, on a public health standpoint, to decrease the disease frequency as no therapy seems to emerge till now. Recently hyperechogenic fetal bowel at routine ultrasound in the second trimester has been recognized to be associated with various deleterious conditions, especially cystic fibrosis. These observations lead praticians to investigate for parent CFTRmutations screening and subsequent prenatal diagnosis if the two parents are carriers. METHODS: Through data issued from two prospective investigations, our study aimed at the estimation of both the sensibility and efficiency of the screening for cystic fibrosis using ultrasound foetal bowel examination. RESULTS: Using the frequency of the disease in the population and the number of affected fetuses within the hyperechoic sample (20 in 641 in a recent study), our analysis may lead to the conclusion that fetal echogenic bowel may concern about 0.75% of fetuses. CONCLUSION: Orders of magnitude of the sensibility and efficiency of cystic fibrosis screening through fetal echogenic bowel are calculated and lead to the conclusion that sonographic screening might decrease the number of affected newborn more than two time less.

Cystic Fibrosis↗

PubMed2003

Airway surface pH in subjects with cystic fibrosis.

The cystic fibrosis (CF) transmembrane conductance regulator protein can transport bicarbonate and may therefore regulate airway surface (AS) pH. Disturbances of AS pH could contribute to the pathophysiology of CF lung disease. Five studies were carried out including the following: study 1) nasal pH measurements were made in 25 CF and 10 non-CF adults using an antimony pH probe. Mean nasal pH was significantly lower in the CF group. Nasal potential difference may have been a confounding factor; study 2) in a fresh cohort of CF and non-CF subjects, no significant difference was found between the two groups using a gold pH probe; study 3) simultaneous nasal pH measurements were made in 15 CF and 15 non-CF adults using both probes. In the CF group, there was a trend for the antimony probe to read lower than the gold probe. In the non-CF group, the antimony probe read higher. The pH difference noted in study 1 related to technical factors; study 4) the effect of acute changes in serum acid/base balance on nasal pH was assessed in five non-CF adults. Nasal pH was not altered by either acute respiratory acidosis or alkalosis; study 5) nasal and lower airway pH was measured in five CF and six non-CF children. No difference was found between the groups. There was a correlation between nasal and lower airway pH. The authors conclude that airway surface pH does not differ between cystic fibrosis and noncystic fibrosis subjects and therefore, cystic fibrosis transmembrane conductance regulator may not play a major role in airway surface pH in vivo.

Adolescent↗

PubMedDate not supplied

[Molecular basis of phenotype heterogeneity in cystic fibrosis].

The cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the cystic fibrosis phenotype, was cloned and sequenced in 1989. Since then, more than 650 mutations have been reported. The analysis of the entire coding sequence of the CFTR gene (27 exons) has been able to characterize more than 90% of the mutations in different populations. Moreover, screening of the entire coding and flanking sequences of the CFTR gene in males with congenital bilateral absence of the vas deferens revealed that 80% of these subjects are at least heterozygous for a CF mutation. These results help to improve genetic counselling and prenatal diagnosis of cystic fibrosis. Different studies examining the relation between phenotype and genotype in CF with respect to AF508 or non delta F508 mutations have demonstrated that some "severe" mutations are strongly associated with pancreatic insufficiency or complications. It has been also showed a relationship between the presumed severity of the mutations and the observed phenotype, not only for pancreatic status, but also for the severity of the respiratory involvement. However, some studies found that some individuals do not fit the outcome of their general group of genotype. These findings reinforce the conviction that other factors besides the CFTR mutation are involved in the severity and outcome of the disease.

Cystic Fibrosis↗