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PubMed1995

Pharmacologic modulation of salt and water in the airway epithelium in cystic fibrosis.

Cystic fibrosis (CF) is a recessive genetic disease with thickened airway secretions that result from abnormal airway epithelial ion transport, including defective cyclic AMP-mediated Cl- (liquid) secretion and excessive Na+ (liquid) absorption. These abnormalities reflect mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which normally functions as a cyclic AMP-regulated Cl- channel. Aerosolized pharmacologic agents are being tested as novel treatment for these genetic ion transport defects. Amiloride aerosol inhibits excessive Na+ absorption, and pilot studies in adult patients with CF show improved biorheology and mucociliary clearance of airway secretions, as well as slowing of the decline in lung function. Phase III studies of amiloride in adults and adolescents are underway, and short-term safety studies in children are under way. Aerosolized uridine triphosphate (UTP) induces Cl- secretion in CF airway epithelia via non-CFTR Cl- channels. Initial safety studies suggest that acute aerosolized UTP is well tolerated, and acute studies of the effect on mucociliary clearance are underway. Pharmacotherapy that targets abnormal ion transport holds promise for the treatment of CF airway disease.

Adolescent↗

PubMed2004

[Frequency of delta F508 mutation in Venezuelan patients with cystic fibrosis].

Cystic Fibrosis (CF) is the most common and severe autosomal recessive disease in Caucasian populations, with an incidence of 1 in 2500 live births. It is characterized by a generalized disturbance in exocrine glands and it is caused by over one thousand mutations at the cystic fibrosis conductance regulator gene (CFTR) mapped at 7q31. AF508 is the most frequent mutation worldwide and it consists in a deletion of the codon that encodes fenilalanine at the 508 protein's position. The aim of this study was to determine the frequency of the delta F508 mutation in Venezuelan patients with CF using the Polymerase Chain Reaction (PCR). We studied thirty patients of twenty eight families who were diagnosed with CF based on their clinical features and sweat chloride level > 60 mEq/l in two determinations. Detection of the mutation was performed from the amplification of a 98 pair of bases (pb) CF gene segment which contains the codon that encodes fenilalanine in the 508 position by PCR. This PCR product is absent in those who have the mutation. The delta F508 allelic frequency was 26.79%, distributed in six homozygous and seven compound heterozygote delta F508/X. The reminder mutations (no delta F508) represent 73.21%. The delta F508 frequency in our sample is less than the reported in European countries. On the other hand, a delta F508 frequency highly heterogeneous has been observed in Latin-American countries. This variation results from mixed populations with a different genetic background influenced by external migration and CF molecular alterations, which exists in the analyzed populations. In this study, the delta F508 mutation comes mainly from grandparents (79.41%) who were born in Mediterranean countries and Colombia, while the no delta F508 mutations come from grandparents who were born in Venezuela (79.27%) and Colombia (17.07%).

Cystic Fibrosis↗

PubMed1993

Defective acidification of the biosynthetic pathway in cystic fibrosis.

Cystic fibrosis is associated with defective epithelial sodium chloride and fluid secretion in epithelia. In addition, there is widespread reductions in sialylation of secreted proteins and increases in the sulfation and fucosylation of mucus glycoproteins. The major morbidity in the disease is due to the colonization of respiratory epithelia by Pseudomonas. The cystic fibrosis gene (CFTR) is a cyclic AMP activated Cl channel, which when mutated is retained in the endoplasmic reticulum. We postulate that this Cl channel is responsible for effective acidification of the Golgi. In CF cells, we demonstrate the Golgi pH is higher than in normal cells and suggest that the abnormalities in glycoprotein biosynthesis is due to changes in the kinetics of sialyl transferase, a pH sensitive enzyme. Defects in sialylation also result in decreased sialylation of glycolipids and asialogangliosides are potential Pseudomonas receptors.

Animals↗

PubMed1999

[Gene therapy of cystic fibrosis].

Cystic fibrosis represents a paradigm for gene therapy of hereditary disorders. Because it is a monogenic disease, it was believed that it would be relatively simple to approach by gene therapy. In fact, it turned out that the apical side of the respiratory epithelium is resistant to transduction by various gene vectors, including recombinant adenoviruses. In addition, the relationship between the genetic defect (the mutated CFTR gene) and the pathogenesis of the disease is more complex than was thought at first. So far, the results of gene therapy trials in patients with cystic fibrosis have been disappointing in terms of efficacy. However, they have brought a fair amount of new information about the basic mechanism of this disease.

Cystic Fibrosis↗

PubMed1999

Update on clinical trials in the treatment of pulmonary disease in patients with cystic fibrosis.

Cystic fibrosis is a congenital disease resulting from an abnormality of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A defect in ion transport leads to poor clearance of viscoelastic secretions and a susceptibility to bacterial infection. This initiates a self-perpetuating cycle of infection and inflammation that accounts for the chronic endobronchial sepsis and pulmonary damage observed in patients with cystic fibrosis. Recent studies have attempted to correct the gene defect, enhance the expression and function of the CFTR protein and correct the ion transport defect. Improving the rheological properties of airway secretions, enhancing host defence and controlling inflammation are the other key strategies.

Journal Article↗

PubMed1995

[Molecular diagnosis of cystic fibrosis].

Cystic fibrosis [CF] is the most common autosomal recessively inherited disease in the caucasian population. Based upon the population frequency of approximately 1 in 2000 in Switzerland, the heterozygote frequency can be calculated to be 1 in 22. The genetic basis for CF has been shown to be mutations in the gene coding for an epithelial membrane chloride channel, the Cystic Fibrosis Transmembrane conductance Regulator [CFTR]. To date over 500 mutations have been characterized in this gene. The frequency of specific mutations varies amongst different ethnic groups. In Switzerland 8 mutations have been shown to account for approximately 90% of all CF causing alleles. The cloning and molecular characterization of the CFTR gene has lead to a major breakthrough in the understanding of the biochemical basis of CF pathogenesis. Advances through analysis of cellular and animal model systems have made a genetic based therapy for CF a real possibility.

Adolescent↗

PubMed1990

[Physiopathology of cystic fibrosis].

Cystic Fibrosis (CF) is the most common lethal genetic autosomic disease in Caucasians. The disease expresses itself in airway and other epithelial cells as a defective chloride ion absorption and secretion. At least, an abnormal cAMP-dependent regulation of an apically located chloride channel has been proposed as the underlying molecular defect. The gene responsible for CF has been identified and predicted to encode a membrane protein termed cystic fibrosis transmembrane conductance regulator (CFTR). The functional role of the predicted protein remains unclear, although strong evidence suggest that it is directly or indirectly involved in regulation of the apical chloride permeability in epithelial cells. This review discusses the fundamental issues currently being investigated in CF.

Bucladesine↗

PubMedDate not supplied

Activity levels and the relationship to lung function and nutritional status in children with cystic fibrosis.

Cystic fibrosis is characterized by chronic obstructive lung disease and malnutrition. Previous studies have shown that nutritional status and lung function are limiting factors for exercise capacity. A reduced exercise capacity may in turn diminish activity levels. We evaluated whether the total time spent somewhat active (e.g., walking) or active (e.g., biking), as reported by the Habitual Activity Estimation Scale, was related to lung function, as evaluated by forced expiratory volume in one second (%predicted FEV1), and nutritional status, measured as body mass percentile, in 36 children with cystic fibrosis, aged 6 to 16 years. The Habitual Activity Estimation Scale questionnaires were completed by the parents for children younger than 12 years of age and by both the parent and the child, independently, for those 12 years and older. Patients had a body mass percentile of 99 +/- 15.2% and % predicted FEV1 of 85.7 +/- 20, with no differences between boys (15/36) and girls (21/36). Boys spent 8.1 hours and girls spent 7.5 hours (P > 0.1) being at least somewhat active. These values are similar to those reported for healthy boys and girls. In patients with significant lung disease (%predicted FEV1, < or = 75; n = 11), activity level (the time spent somewhat active or active) was related to nutritional status (r = 0.675; P = 0.02) but not to lung function (r = 0.21; P > 0.1). Activity level reported by patients 12 years of age and older was on average 24.1% higher (P < 0.05) than that reported by their parents, but the two reportings were related (r = 0.758; P = 0.004). These results suggest that activity level may be restricted by nutritional status in those patients with significant air flow limitation. We suggest that improving the nutritional status of cystic fibrosis patients may prevent decreases in activity levels and quality of life of these affected children.

Adolescent↗

PubMed1999

Human neutrophil lipocalin, a highly specific marker for acute exacerbation in cystic fibrosis.

Cystic fibrosis (CF) is characterized by the production of abnormally thick secretions in the airways, chronic bacterial endobronchial infections and a chronic, predominantly neutrophilic inflammatory response. Therefore, myeloperoxidase (MPO) and lactoferrin are frequently used as inflammatory markers. Recently, a new protein in the neutrophil granules, human neutrophil lipocalin (HNL) has been discovered. The aim of the present study was to investigate HNL in sera of patients with CF and its relation to MPO and lactoferrin as well as to acute pulmonary exacerbation. Serum concentrations of HNL, MPO and lactoferrin were determined in 42 patients with CF and in 25 healthy subjects. Patients with CF were divided into groups with and without acute pulmonary exacerbation (APE) and also with and without colonization with Pseudomonas aeruginosa (Pa). Median serum levels of HNL (200.5 microg x L(-1)), MPO (595 microg x L(-1)) and lactoferrin (1,356.5 microg x L(-1)) were significantly increased in patients with CF compared to control subjects (57.7, 178 and 478 microg x L(-1), respectively; p<0.0001). CF patients with APE had significantly increased serum concentrations of HNL (321 versus 97.7 microg x L(-1); p<0.0001), MPO (1,125 versus 300 microg x L(-1); p<0.005) and lactoferrin (4,936 versus 980 microg x L(-1); p<0.001) compared with patients in stable clinical condition. Similarly, patients colonized with Pa had significantly higher concentrations of HNL, MPO and lactoferrin than Pa negative patients. These results indicate that in patients with cystic fibrosis, serum concentrations of human neutrophil lipocalin are markedly increased with a strong relationship to myeloperoxidase and lactoferrin. Thus, determination of serum human neutrophil lipocalin concentrations may be another useful diagnostic tool to monitor neutrophil inflammation in cystic fibrosis. The more marked difference in human neutrophil lipocalin compared with myeloperoxidase concentrations with no overlap between patients with acute pulmonary exacerbation and those in stable condition even suggests that human neutrophil lipocalin may be a more sensitive and specific discriminator.

Acute-Phase Proteins↗

PubMed2006

Mouse as a model of growth retardation in cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disease that results in lung failure and premature death. A long recognized symptom of CF is growth failure, which is clinically relevant because it correlates with the severity of lung disease. We describe growth retardation in a mouse model of CF and discuss its potential for modeling certain aspects of human growth retardation. Mice with a null mutation in Cftr (cystic fibrosis transmembrance conductance regulator) were compared with wild-type (WT) mice at 31, 45, and 84 d of age. CF mice were severely growth retarded in weight and length compared with wild-type controls. Serum insulin like growth factor I (Igf-1) was lower in CF mice by 31-55% (depending on age and sex) and it significantly correlated with the size of mice after controlling for gender, age, and Cftr genotype. There was a marginally significant deficiency of serum growth hormone (Gh) in CF females, but not males. Our findings were consistent with models of an energy deficit in rodents. We, therefore, assessed food intake and found no difference between CF and WT mice, suggesting that CF mice had a malabsorption-mediated energy deficit. We argue that CF mice are suited to study the effects of intestinal disease on growth as well as other proposed growth-modulating processes.

Animals↗

PubMed2000

Multiplex PCR of polymorphic markers flanking the CFTR gene; a general approach for preimplantation genetic diagnosis of cystic fibrosis.

Cystic fibrosis (CF) is the first monogenic disorder for which single cell preimplantation genetic diagnosis (PGD) has been successfully applied. The spectrum of mutations in CF is extremely heterogeneous, and hence, the development of mutation-specific PGD protocols is impracticable. The current study reports the development and evaluation of a general multiplex marker polymerase chain reaction (PCR) protocol for PGD of CF. Four closely linked highly polymorphic (CA)(n) repeat markers D7S523, D7S486, D7S480 and D7S490, flanking the cystic fibrosis transmembrane regulator (CFTR) gene, were used. In 99% of the single cells tested (100 leukocytes and 50 blastomeres), multiplex PCR results were obtained and the overall allelic drop out (ADO) rate varied from 2 to 5%. After validation for the presence of ADO and additional alleles, 95% of the multiplex PCR results were accepted to construct the marker genotypes. Depending on the genotype of the couple, and taking into account the embryos lost for transfer due to validation criteria (5%), ADO (0-2%) and single recombination (1.1-3%), in general >90% of the embryos could be reliably genotyped by PGD using a single blastomere. The risk of misdiagnosis equals the chance of a double recombination between informative flanking markers and is <0.05%. Therefore, this polymorphic and multi-allelic marker system is a reliable and generally applicable alternative for mutation-directed PGD protocols. Furthermore, it provides a test for the origin of the detected genotype and also gives an indication of the chromosomal ploidy status of the blastomere tested.

Blastomeres↗

PubMed1991

[DNA analysis and gene diagnosis of cystic fibrosis].

Cystic fibrosis (CF) is the most common autosomal recessive disorder in the Caucasian population, affecting approximately 1 in 2,000 newborns but the actual estimate varies with the geographic location. The incidence of CF in non-Caucasian populations is low. Intensive efforts using genetic linkage information ultimately led to the cloning of the CF gene prior to the identification of the gene product or its function. The gene encodes what is believed to be a transmembrane protein, which has been named the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR contains two nucleotide-binding folds (NBF) which show homology to numerous transport proteins with the greatest homology to the P-glycoproteins that are encoded by the multiple drug-resistance loci. A three- base deletion resulting in the loss of phenylalanine residue (delta F508) in the tenth exon of the CFTR gene is the mutation occurring on the majority of CF chromosomes. The overall frequency of delta F508 in the present mutant CF gene pool is about 70%, but the study populations are not equally represented: there is marked variation in the population of delta F508 among different geographic populations. Recently, numerous additional, less common mutations have been found. Some mutations occur on 2-5% of the CF chromosomes. Many of these are rare 'private' mutations, occurring in individual families of all racial and ethnic backgrounds. By contrast over 80% of Western European CF mutations have been identified. The highly heterogeneous nature of the remaining CF mutations provides important insights into the structure and function of the protein, but further improvements are needed in DNA-based genetic screening for CF carrier status.

Cystic Fibrosis↗

PubMed1993

Anaesthesia for the parturient with cystic fibrosis.

Cystic fibrosis is an inherited disorder that primarily affects the exocrine glands of the gastrointestinal and respiratory systems. It is commonly diagnosed at birth or shortly thereafter, and until recently few of these patients lived to reproductive age. However, as a result of improved medical care, there are now an increasing number of pregnancies in women with cystic fibrosis. We present the histories of two parturients with cystic fibrosis and discuss the anaesthetic and perinatal implications of this complex disease to their management.

Journal Article↗

PubMed1999

Current developments in the treatment of pulmonary disease in patients with cystic fibrosis.

Cystic fibrosis is a genetic disease that affects one in 2500 live births. A basic defect in chloride transport leads to impaired clearance of airway secretions and a susceptibility to bacterial infection. Once infection is established there is a vicious cycle that leads to progressive inflammation and infection. Although cystic fibrosis is a multisystem disorder, pulmonary disease is the main cause of morbidity and respiratory failure remains the main cause of death. This review discusses the strategies for treating pulmonary disease in patients with cystic fibrosis and focuses on some of the therapeutic developments.

Journal Article↗

PubMed1992

[Assessment of the nephrotoxicity of amikacin in patients with cystic fibrosis].

Cystic fibrosis patients are at risk for nephrotoxic effects of aminoglycosides. Fifteen cystic fibrosis patients were admitted to hospital with 18 acute exacerbations of pulmonary symptoms associated with the isolation of Pseudomonas aeruginosa from sputum. They were treated intravenously with amikacin and ceftazidime for 14 days. Urinary excretion of N-acetyl-beta-D-glucosaminidase and alpha 1-microglobulin, two markers of tubular damage, and of albumin, a marker of glomerular permeability, was studied before and during treatment. Urinary activity of N-acetyl-beta-D-glucosaminidase and excretion of alpha 1-microglobulin was normal before amikacin treatment in approximately two thirds of patients and pathologically increased at the end of the study in 95%. Urinary albumin excretion was always normal before amikacin treatment and failed to increase consistently during treatment. The pattern of urinary protein excretion observed in the study before and during treatment with amikacin indicates a selective tubular toxicity.

Acetylglucosaminidase↗

PubMed2003

Does deficiency of arylsulfatase B have a role in cystic fibrosis?

Cystic fibrosis (CF) is associated with mutation and abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR) that affects cellular chloride transport. Clinically, CF of the lung is associated with excessive accumulation of secretions, including the sulfated glycosaminoglycans, chondroitin sulfate and dermatan sulfate (DS), both of which contain sulfated N-acetylgalactosamine residues. The sulfatase enzymes, which are a highly conserved group of enzymes with high specificity for designated sulfate groups, include arylsulfatase B, a lysosomal enzyme. Arylsulfatase B, also known as N-acetyl galactosamine 4-sulfatase, can degrade DS and chondroitin-4 sulfate. Previously reported data demonstrated diminished activity of arylsulfatase B in lymphoid cell lines of patients with CF compared to normal control subjects. Frequent infections with Pseudomonas, a sulfatase-producing organism, occur in patients with CF, whereas infections with Mycobacterium tuberculosis, which lacks sulfatase activity, are infrequent. Additional investigation to determine if diminished function of arylsulfatase B is a consistent finding in cells of patients with CF may be informative, and may help to correlate the molecular, biochemical, and clinical characteristics of CF.

Bacterial Infections↗

PubMed1995

Protection against bronchial asthma by CFTR delta F508 mutation: a heterozygote advantage in cystic fibrosis.

Cystic fibrosis (CF) is a multisystem autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane regulator (CFTR), a protein that regulates cyclic-AMP-mediated chloride conductance at the apical membrane of secretory epithelia. Mutations in the CFTR gene are common in many populations. In North America, 4-5% of the general population are heterozygous for a CFTR mutation. Although there are over 400 known CFTR mutations, a single mutation, a deletion of the phenylalanine at position 508 (delta F508) in exon 10, accounts for about 70% of all CF chromosomes worldwide. The reasons for the high frequency of the delta F508 CFTR allele--the selective advantage associated with CF heterozygosity--are unknown. Many physiological abnormalities have been observed in CF heterozygotes, although the clinical significance of these observations is unknown. Preliminary unpublished data and anecdotal information from CF families suggested that, remarkably, the delta F508 allele might protect heterozygotes against bronchial asthma prompted us to further investigate this possibility. Here we present evidence that the delta F508 CF allele protects against asthma in childhood and early adult life.

Adult↗

PubMed1989

[Genetic study in 8 families with a child with cystic fibrosis].

Cystic Fibrosis (CF) is the most common genetically determined disease in Caucasians. Major advances in our understanding of the genetics of cystic fibrosis have occurred during the past couple of years. The CF gene has been localized at 7 q31 by the use of linkage analysis with protein and DNA polymorphisms. DNA probes showing close linkage to the CF gene have been discovered and are being used to identify the gene itself and also for purposes of genetic diagnosis. We investigated 35 blood samples from members of 8 CF families with the probes J3.11/MspI, metH/TaqI, metH/MspI, metD/TaqI and 7 c22/EcoRI. In 8 out of 11 siblings of our CF patients we got full information about the carrier status. Since we investigated the siblings as well as the parents of our patients, these results may be of benefit for a later prenatal diagnosis.

Child↗