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PubMed2004

[Expression of the cystic fibrosis gene in the lungs].

Cystic fibrosis (CF) is one of the most common hereditary diseases with a potentially lethal outcome. CF is caused by mutations in a gene on chromosome 7 that encodes for a polypeptide called 'cystic fibrosis transmembrane conductance regulator' (CFTR). Pulmonary complications in CF are a direct consequence of a fault in the production or function of CFTR. The consequences of these faults are a change in the viscosity and volume of the air-surface liquid in the airways and possible malfunctioning of the immunological defence system. The result is stasis of mucus and obstruction of the smaller airways. Secondary to this process, a (chronic) infection with an uncontrolled inflammatory response, leads to destruction of lung tissue and a reduction in lung function. Mutations in CFTR can be classified in five types, which reflect the level of production or the function of CFTR. This classification permits discrimination between mild and severe mutations. The clinical image and the course of CF are often related to the combination of mutations present. This may explain, in part, why some CF patients are diagnosed at a later age with a normal sweat test and a clinical image that is predominantly limited to respiratory symptoms.

Chromosomes, Human, Pair 7↗

PubMed1990

Reverse genetics and cystic fibrosis.

The protein responsible for cystic fibrosis has been identified using an approach called "reverse" genetics. This approach relies on the chromosomal map position to direct the search for a disease gene, several novel cloning strategies to isolate the gene, and the gene's sequence to define the abnormal protein. Reverse genetics, because it does not require prior knowledge of the protein's biochemical function, has wide utility and is being used to define the defects in many single-gene disorders. This update presents the reverse genetics approach and uses cystic fibrosis to illustrate the principles involved.

Chromosome Mapping↗

PubMed1982

The cardiovascular system in cystic fibrosis.

Available evidence indicates that cystic fibrosis causes widespread involvement of the cardiovascular system. Aside from the heart, unusual aberrations have been observed in the bronchial arteries, the aorta, and the systemic capillaries. Of all cardiovascular complications, cor pulmonale is the most serious. Recognition of a significant degree of cor pulmonale is generally possible on the basis of the severity of the underlying disease. Although echocardiography and radionuclide angiography are valuable research tools in the study of cor pulmonale in cystic fibrosis, they add little, from a practical standpoint, to the management of the patient. The basis of cor pulmonale is hypoxemia and unless this is relieved, no enduring effect can be expected from therapy directed toward the heart. Inasmuch as cystic fibrosis is a progressive disease, cor pulmonale is also progressive. At best, cardiac treatment represents a delaying action that may provide more time to combat an intercurrent infection.

Adolescent↗

PubMedDate not supplied

[Tumor necrosis factor in the serum--a useful supplemental parameter in the diagnosis of infection in cystic fibrosis?].

In 15 patients with cystic fibrosis 18 blood samples were investigated for signs of infection including full white blood count, c-reactive protein (CRP) and tumour-necrosis-factor alpha (TNF). Ten patients were hospitalized for pulmonary exacerbation, one for orthostatic collapse and one for equivalent of meconium ileus. The latter two as well as three out-patients with cystic fibrosis on routine-visits served as controls. Blood was taken on admission and at the time of the visit in our out-patient department, respectively. In three cases, blood was taken repeatedly during their stays in hospital. While leucocytosis (17.700 +/- 3.500) and elevated CRP-levels (6.4 +/- 7.3 mg/dl) pointed to an infectious cause of deterioration in the exacerbation-group, TNF-levels without exception were undetectable (less than 15 pg/ml). In the control group, leucocyte counts (10.700 +/- 3.600) and CRP-levels (1.2 +/- 1.1 mg/dl) showed minor pathologic results. TNF-levels were undetectable, too. While elevated TNF-levels measured quantitatively in patients with invasive bacterial infections, e.g. septicaemia due to Neisseria meningitidis, correlate well with prognosis of disease, in patients with cystic fibrosis such a relationship can't be found.

Adolescent↗

PubMed1992

Home intravenous therapy using a silastic long line catheter in cystic fibrosis patients.

Young patients with cystic fibrosis are now accustomed to having regular periods of intravenous therapy to help in the management of their recurring respiratory infections particularly due to pseudomonas organisms. Most patients will eventually experience difficulties in accepting recurring intravenous cannulations and the life span of the conventional intravenous cannula is frequently brief. We have compared percutaneous long line silastic catheters with conventional intravenous cannulas as intravenous access in children with cystic fibrosis being treated for pulmonary exacerbations. We conclude that silastic long lines are superior to conventional cannulas in terms of patient tolerance, reduction in the number of hospital admissions, reduction in the number of repeat venepunctures/cannulations and reduction in local complications. The high degree of patient acceptability has been impressive and has increased with the enthusiasm of children with cystic fibrosis for more frequent intravenous therapy.

Adolescent↗

PubMed1980

Hormonal abnormalities of the pancreas and gut in cystic fibrosis.

We have investigated the effect of cystic fibrosis on alimentary hormones in 10 children by measuring the pancreatic and gut hormone rsponse to a milk drink. Plasma insulin and gastric inhibitory peptide were both significantly reduced (P < 0.05 and P < 0.005, respectively, at 15 min) in the patients with cystic fibrosis, compared with controls, even though the early glucose rise was greater in the former group (P < 0.05 at 15 min). Fasting levels of pancreatic polypeptide were significantly lower in the fibrocystic children (P < 0.01), and the normal response to milk was completely abolished in these patients (P < 0.001). Fasting plasma enteroglucagon concentrations were grossly abolished in the cystic fibrosis patients (P < 0.001) and these remained elevated throughout the test. No significant differences were seen in basal or postmilk responses of plasma glucagon, gastrin, secretin, vasoactive intestinal peptide, or motilin in cystic fibrosis. It would thus appear that the pancreatic polypeptide cell is more susceptible to the effects of the disease process than the beta or alpha cell in cystic fibrosis. Some aspects of the abnormalities in the gastrointestinal endocrine system were similar to those seen in celiac disease and tropical sprue and may, therefore, effect a similar hormonal response in these patients with cystic fibrosis to those with mucosal damage.

Adolescent↗

PubMed1992

Antisense oligonucleotides to CFTR confer a cystic fibrosis phenotype on B lymphocytes.

Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed at low levels in nonepithelial cells. Recently, we demonstrated that CFTR is responsible for cell cycle-dependent adenosine 3',5'-cyclic monophosphate-responsive Cl- permeability in lymphocytes. Agonist responsiveness of cystic fibrosis (CF) lymphocytes was restored by transfection with plasmid containing wild type CFTR cDNA. CFTR mRNA is expressed in the B lymphoid cell line GM03299; however, quantitative reverse transcriptase-polymerase chain reaction indicates that the level of CFTR mRNA is at least 1,000 times lower than in T84 cells. CFTR protein could not be detected by Western blot or by immunoprecipitation of in vitro phosphorylated protein. However, antisense oligonucleotides representing codons 1-12 of CFTR caused a complete inhibition of cell cycle-dependent Cl-permeability [as determined by 6-methoxy-N-(3-sulfopropyl)-quinolinium fluorescence digital-imaging microscopy], thereby inducing normal cells to acquire a "CF phenotype." These studies provide direct evidence that a CFTR-associated Cl- permeability is present and measurable in lymphocytes, even though CFTR mRNA and protein are expressed at low levels.

B-Lymphocytes↗

PubMed1985

Cystic fibrosis and neuroblastoma.

Two cases of coexistent cystic fibrosis and infantile thoracic neuroblastoma are presented. In one patient, neuroblastoma was congenital, and diagnosis of cystic fibrosis was made at 3 months of age; in the other, the diagnosis of cystic fibrosis was made at 7 months of age, preceding that of neuroblastoma by 4 months. In both infants, surgical resection of the tumors have been successful. Recent advances in the genetic aspects of neuroblastoma, including translocation and activation of the oncogene N-myc, are discussed. Current recombinant DNA technology, which can identify translocation of N-myc and allow localization of the cystic fibrosis gene if the translocation occurs near the cystic fibrosis allele, is being applied to these cases.

Cystic Fibrosis↗

PubMed1988

Clinical pharmacology of antibiotics and other drugs in cystic fibrosis.

The disposition of many drugs in cystic fibrosis is abnormal. In general, changes in pharmacokinetics include: increased volume of distribution, decreased plasma concentration, and enhanced renal and sometimes non-renal elimination of drugs. Pathophysiology of the disease important for drug disposition includes: (a) hypersecretion of gastric acid and duodenal secretions which are of small volume, viscous and low in bicarbonate; (b) increased intestinal permeability to some sugars and probe substances; (c) hypergammaglobulinaemia and sometimes hypoalbuminaemia; (d) significant elevation of free fatty palmitoleic acid level and decreased low-density and high-density serum lipoproteins; (e) an average increase by 30 to 45% in plasma volume in patients with cystic fibrosis who have moderately severe pulmonary disease, right ventricle hypertrophy and dilatation, which occurs in 15 to 35% of patients with a Shwachman score of 81 to 100; (f) abnormal bile acid metabolism and enterohepatic recirculation; and (g) enlarged kidneys and glomerulomegaly with increased glomerular filtration rate, tubular clearance and urine flow rate in some patients with cystic fibrosis. Delayed absorption from the gastrointestinal tract has been reported in patients with cystic fibrosis for cloxacillin, epicillin, clindamycin, ciprofloxacin and probably for cephalexin, para-aminobenzoic acid and chloramphenicol. A possible increased absorption was reported for cimetidine. Of 7 drugs studied only theophylline had significantly decreased plasma protein binding. An increased volume of distribution and increased renal clearance reported for several drugs is caused mainly by increases in plasma volume and urine flow rate in many of these patients. Possible increased elimination of some drugs in bile (which probably results from bile acid malabsorption) and in bronchial secretions (which are abundant in some cystic fibrosis patients with acute pulmonary infection) may explain enhanced non-renal elimination of these drugs. The metabolism of cimetidine in cystic fibrosis was reported not to be changed significantly compared to control subjects.

Anti-Bacterial Agents↗

PubMed2000

Sinonasal disease in cystic fibrosis: clinical characteristics, diagnosis, and management.

Cystic fibrosis is an autosomal recessive genetic disorder that causes dysfunction of exocrine glands, and has several clinical manifestations. Among those, sinonasal involvement is almost universal, with or without chronic sinusitis and/or nasal polyposis. This review will detail the pathophysiologic changes of the sinonasal mucosa, and the clinical manifestations, diagnosis, and treatment. Developmental anatomic abnormalities, which are identified radiologically, will also be demonstrated. Medical management is the first treatment for patients with cystic fibrosis, but effective treatment of sinonasal disease in cystic fibrosis relies heavily on surgery. In the past, nasal polyposis was the main indication for surgery, and consisted mostly of polypectomy alone. This procedure was associated with a high recurrence rate. The development of functional endoscopic sinus surgery has contributed to decreasing the morbidity of sinonasal surgery and the recurrence of nasal polyposis in cystic fibrosis. The evolution of the surgical techniques will be discussed and a review of the literature will be provided.

Anti-Bacterial Agents↗

PubMed2002

Cystic fibrosis and renal disease.

Renal disease is relatively rare in cystic fibrosis even though the cystic fibrosis transmembrane regulator (CFTR) protein is expressed in abundance in the kidney. Aberrant CFTR expression probably explains the subtle abnormalities in renal concentrating and diluting ability described in cystic fibrosis and possibly the increased incidence of nephrocalcinosis. It also provides a hypothesis for the important differences in renal handling of some drugs. As the prognosis improves for patients with cystic fibrosis, secondary renal complications, for example glomerulonephritis and amyloidosis, are likely to become more prevalent. There are also a number of potentially nephrotoxic drugs used in the management of cystic fibrosis.

Amyloidosis↗

PubMed1998

What we know and what we do not know about cystic fibrosis transmembrane conductance regulator.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel that resides in the apical membrane of many epithelial cells. Channel opening requires phosophorylation of serine residues in an intracellular regulatory domain by protein kinase A and as the binding and hydrolysis of ATP by intracellular nucleotide binding domains. Besides conducting the chloride ion, CFTR also regulates the function of other membrane proteins, directly or indirectly, notably the outwardly rectifying chloride channel and the epithelial sodium channel. The disease cystic fibrosis is caused by mutations in CFTR, which can result in defective protein production, defective processing and degradation in the endoplasmic reticulum, or defective channel pore properties or gating properties.

Amino Acid Sequence↗

PubMed2005

[New concepts of pathophysiology and therapy in cystic fibrosis].

Today, the majority of cystic fibrosis (CF) patients treated in Germany have reached adulthood. However, with increasing age the morbidity and frequency of severe pulmonary complications continues to rise. Further optimization of conventional therapy alone will be insufficient to compensate for this development. In recent years, there has been impressive progress in our understanding of the molecular basis of the CF gene and its product, the cystic fibrosis transmembrane conductance regulator (CFTR). This knowledge can now be applied to develop new therapeutic strategies. However, important questions remain to be solved, i. e., little is known about the pathways that link the malfunctioning of the CFTR protein with the observed clinical phenotype. This review briefly touches on CF genetics as it applies to lung disease and will focus on the current hypotheses of CFTR (dys)function and its impact on pulmonary fluid homeostasis. New treatment options that target the molecular basis of the disease will be discussed.

Adult↗

PubMed1999

Three common CFTR mutations should be included in a neonatal screening programme for cystic fibrosis in Sweden.

Children with cystic fibrosis (CF) diagnosed by neonatal screening have a better nutritional development and other advantages compared with those in a nonscreened group. The two-tier immunoreactive trypsinogen (IRT)/DNA screening protocol has been found superior to the single-tier IRT approach, improving the positive predictive value and thus reducing the false-positive rate. However, variations of the DNA test are required for different populations. In this study we examined CFTR (cystic fibrosis transmembrane conductance regulator) mutations in 331 CF patients attending the centres in Stockholm, Lund and Uppsala, comprising about 75% of the CF population in Sweden. The frequency of deltaF508 among CF alleles was 68.3%. There were two other mutations, 394delTT and 3659delC, found to be fairly frequent, amounting to 8.5 and 7.9%, respectively. Other mutations were comparatively rare. A simple and effective method of analysing the three mutations from Guthrie cards has been developed. Assuming Hardy-Weinberg equilibrium, 90% of our CF patients will be expected to carry at least one deltaF508 allele and 97.6% to carry at least one deltaF508, 394delTT or 3659delC copy. Including the latter two in a screening programme would thus substantially reduce the risk of a false-negative outcome.

Cystic Fibrosis↗

PubMed1990

Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis.

The gene associated with cystic fibrosis (CF) encodes a membrane-associated, N-linked glycoprotein called CFTR. Mutations were introduced into CFTR at residues known to be altered in CF chromosomes and in residues believed to play a role in its function. Examination of the various mutant proteins in COS-7 cells indicated that mature, fully glycosylated CFTR was absent from cells containing delta F508, delta 1507, K464M, F508R, and S5491 cDNA plasmids. Instead, an incompletely glycosylated version of the protein was detected. We propose that the mutant versions of CFTR are recognized as abnormal and remain incompletely processed in the endoplasmic reticulum where they are subsequently degraded. Since mutations with this phenotype represent at least 70% of known CF chromosomes, we argue that the molecular basis of most cystic fibrosis is the absence of mature CFTR at the correct cellular location.

Animals↗

PubMed1993

An approach for treating the hepatobiliary disease of cystic fibrosis by somatic gene transfer.

Cystic fibrosis (CF) is an inherited disease of epithelial cell ion transport that is associated with pathology in multiple organ systems, including lung, pancreas, and liver. As treatment of the pulmonary manifestations of CF has improved, management of CF liver disease has become increasingly important in adult patients. This report describes an approach for treating CF liver disease by somatic gene transfer. In situ hybridization and immunocytochemistry analysis of rat liver sections indicated that the endogenous CFTR (cystic fibrosis transmembrane conductance regulator) gene is primarily expressed in the intrahepatic biliary epithelial cells. To specifically target recombinant genes to the biliary epithelium in vivo, recombinant adenoviruses expressing lacZ or human CFTR were infused retrograde into the biliary tract through the common bile duct. Conditions were established for achieving recombinant gene expression in virtually all cells of the intrahepatic bile ducts in vivo. Expression persisted in the smaller bile ducts for the duration of the experiment, which was 21 days. These studies suggest that it may be feasible to prevent CF liver disease by genetically reconstituting CFTR expression in the biliary tract, using an approach that is clinically feasible.

Adenoviridae↗

PubMed2000

CFTR regulation of intracellular calcium in normal and cystic fibrosis human airway epithelia.

In cystic fibrosis airway epithelia, mutation of the CFTR protein causes a reduced response of Cl(-) secretion to secretagogues acting via cAMP. Using a Ca(2+) imaging system, the hypothesis that CFTR activation may permit ATP release and regulate [Ca(2+)](i) via a receptor-mediated mechanism, is tested in this study. Application of external nucleotides produced a significant increase in [Ca(2+)](i) in normal (16HBE14o(-) cell line and primary lung culture) and in cystic fibrosis (CFTE29o(-) cell line) human airway epithelia. The potency order of nucleotides on [Ca(2+)](i) variation was UTP >> ATP > UDP > ADP > AMP > adenosine in both cell types. The nucleotide [Ca(2+)](i) response could be mimicked by activation of CFTR with forskolin (20 microm) in a temperature-dependent manner. In 16HBE14o(-) cells, the forskolin-induced [Ca(2+)](i) response increased with increasing temperature. In CFTE29o(-) cells, forskolin had no effect on [Ca(2+)](i) at body temperature-forskolin-induced [Ca(2+)](i) response in CF cells could only be observed at low experimental temperature (14 degrees C) or when cells were cultured at 26 degrees C instead of 37 degrees C. Pretreatment with CFTR channel blockers glibenclamide (100 microm) and DPC (100 microm), with hexokinase (0.5 U/mg), and with the purinoceptor antagonist suramin (100 microm), inhibited the forskolin [Ca(2+)](i) response. Together, these results demonstrate that once activated, CFTR regulates [Ca(2+)](i) by mediating nucleotide release and activating cell surface purinoceptors in normal and CF human airway epithelia.

Adenosine Triphosphate↗

PubMed2000

Pseudomonas aeruginosa cross-infection among patients with cystic fibrosis during a winter camp.

Twenty-seven patients with cystic fibrosis from our Danish Cystic Fibrosis Center went to a winter camp for 1 week in November of 1990. This study is based on 22 of these patients. Prior to attending camp, 17 out of 22 patients harbored Pseudomonas aeruginosa in their sputum, but 5 patients did not. After returning from camp, all 22 patients harbored P. aeruginosa in the sputum, including the 5 patients whose sputum was free of P. aeruginosa before they went. Epidemiological typing used pulsed-field gel electrophoresis of the P. aeruginosa isolates was performed. The typing results showed that the 5 cystic fibrosis patients who were free of P. aeruginosa in their sputum prior to the winter camp had acquired P. aeruginosa isolates identical to the P. aeruginosa strains isolated from the other 17 cystic fibrosis patients. This constitutes a cross-colonization rate of 100%, the highest rate ever detected among patients with cystic fibrosis. We conclude that separate holiday camps based on the infection status of the patients with cystic fibrosis are necessary to avoid cross-infection of patients not infected with P. aeruginosa.

Adolescent↗