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PubMed1991

Two frameshift mutations in the cystic fibrosis gene.

Cystic fibrosis (CF) is a recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. We have identified in exon 7 two frameshift mutations, one caused by a two-nucleotide insertion and the other caused by a one-nucleotide deletion; these mutations--CF1154insTC and CF1213delT, respectively, are predicted to shift the reading frame of the protein and to introduce UAA(ochre) termination codons at residues 369 and 368.

Adolescent↗

PubMed1998

What is a cystic fibrosis diagnosis?

Cystic fibrosis (CF) should be considered in patients with a wide variety of clinical presentations and of diverse racial and ethnic backgrounds. In most cases the diagnosis is suggested by manifestations of chronic sinopulmonary disease and exocrine pancreatic insufficiency, and then confirmed by a positive sweat test result. Patients may, however, present with pancreatic sufficiency or other atypical clinical features, sometimes in association with normal or borderline sweat test results. In such cases, the ability to detect CF mutations and to measure transepithelial bioelectric properties can be diagnostically useful. Mutation analysis can also be used for carrier screening, prenatal diagnosis, and newborn screening.

Child↗

PubMed1997

Recurrence of allergic bronchopulmonary aspergillosis in the posttransplant lungs of a cystic fibrosis patient.

Cystic fibrosis (CF) is an autosomal recessive disease of exocrine origin. Allergic bronchopulmonary aspergillosis (ABPA) is an immunologic disorder caused by colonization of the airways with Aspergillus fumigatus. A fumigatus has been cultured from posttransplant lungs in CF patients. Colonization of posttransplant lung with Aspergillus is a recognized phenomenon. In this case report, however, we present a patient who developed ABPA both before and after lung transplant. This patient meets the criteria for ABPA based on serologic results. ABPA may be a complication in post-CF lung transplant patients and serologic analysis should be considered when eosinophilia and pulmonary infiltrates or decline in lung function occurs.

Adult↗

PubMed1975

Additional data on hepatic function tests in cystic fibrosis.

Fifty cystic fibrosis (CF) patients, of whom 9 had multilobular cirrhosis, were observed regularly for a period of 3 years and various liver function tests, indicating cytolysis, cholestasis and cellular insufficiency were performed. Immunoglobulin and prothrombin were assayed. In 9 patients with cirrhosis, the tests were generally abnormal. Two distinct biochemical patterns of cirrhosis were distinguished, one clearly cholestatic and the other of a more cellular type. The distinction was made on the basis of the IgA : Transferrin ratio and of gamma-glutamyl-transpeptidase levels. In the non-cirrhotic patients, a temporary increase of cytolysis and cholestasis was observed in 50% of the cases.

Adolescent↗

PubMed1987

Improved exercise tolerance with long-term parenteral nutrition in cystic fibrosis.

Two cystic fibrosis (CF) patients with severe pulmonary disease and malnutrition were followed during a course of long-term home total parenteral nutrition (TPN), which included iv fat emulsion. They gained 7 and 12 kg in body weight, respectively, and their ability to participate in daily activities increased. Progressive exercise testing before and during TPN showed a marked increase in maximal work load: 100% and 30%, respectively. At any given work load, oxygen uptake was increased while the respiratory quotient remained lower after the course of TPN. We believe that the lower respiratory quotient and greater oxygen consumption during exercise were due to a reduction in anaerobic metabolism after TPN.

Adult↗

PubMed1988

Long-term tobramycin aerosol therapy of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis.

Fourteen cystic fibrosis patients (aged 9 to 20 years), chronically infected with Pseudomonas aeruginosa (PA), inhaled 80 mg (2 ml) tobramycin twice daily, because a significant clinical deterioration had occurred. Mean duration of aerosol therapy was 20.3 months (range, 11 to 38 months). There were no toxic side effects and no significant systemic absorption, 50 of 70 tobramycin serum levels being below the minimal detectable value of 0.1 mg/l. After 12 months of therapy there was an improvement of lung function, Po2, and weight. The frequency of intravenous therapy was reduced. Tobramycin resistance occurred in 5.8% of all PA strains after 10 to 29 months and did not represent a clinical problem. In a few patients PA was eradicated from sputum.

Administration, Inhalation↗

PubMed2002

Detecting early structural lung damage in cystic fibrosis.

In cystic fibrosis (CF) patients, both severe lung inflammation and severe lung damage occur early and persist throughout life. High-resolution computed tomography (HRCT), a more sensitive method of detecting structural abnormalities than chest X-ray, shows that airways undergo substantial thickening in early CF lung disease. Lung function tests, which are an indirect measure of structural integrity, are insensitive to localized or early damage. Thickening of the peripheral airways causes a reduction in maximal expiratory flow at 25% of forced vital capacity (MEF(25)) or other measurements of peripheral air flow. Reduced peripheral flows, even in the presence of normal forced expired volume in 1 sec (FEV(1)) and forced vital capacity (FVC), should be considered an early sign of substantial lung damage and should stimulate aggressive treatment to prevent further deterioration.

Cystic Fibrosis↗

PubMed1991

Pitfall in diagnosis of Crohn's disease in a cystic fibrosis patient.

Cystic fibrosis (CF) and Crohn's disease may both present as failure to thrive and recurrent intestinal obstruction. Proper treatment and adequate nutrition may reverse these manifestations and improve the patient's quality of life. We describe a girl with CF who, despite appropriate management, failed to grow and had several episodes of bowel obstruction. After the additional diagnosis of Crohn's disease was reached, the patient improved on antiinflammatory and nutritional therapy. This patient illustrates the pitfall in the diagnosis of Crohn's disease in a CF patient due to the clinical overlap between the two conditions. We suggest that therapeutic failure in a chronic disease justifies additional diagnostic efforts resulting in a completion of diagnosis and significant changes in management.

Child↗

PubMed1999

Removal of multiple arginine-framed trafficking signals overcomes misprocessing of delta F508 CFTR present in most patients with cystic fibrosis.

Many cystic fibrosis transmembrane conductance regulator (CFTR) mutants are recognized as aberrant by the quality control apparatus at the endoplasmic reticulum (ER) and are targeted for degradation. The mechanism whereby nascent chains are distinguished as either competent or incompetent for ER export has not been elucidated. Here we show that export-incompetent chains display multiple arginine-framed tripeptide sequences like the one recently identified in ATP-sensitive K+ channels. Replacement of arginine residues at positions R29, R516, R555, and R766 with lysine residues to inactivate four of these motifs simultaneously causes delta F508 CFTR, present in approximately 90% of CF patients, to escape ER quality control and function at the cell surface. Interference with recognition of these signals may be helpful in the management of CF.

Arginine↗

PubMed1990

Cell cycle dependence of chloride permeability in normal and cystic fibrosis lymphocytes.

Cystic fibrosis (CF) is a genetic disease characterized by abnormal regulation of epithelial cell chloride channels. Nonepithelial cells, including lymphocytes and fibroblasts, may exhibit a similar defect. Two independent techniques were used to assess the macroscopic chloride permeability (PCl) of freshly isolated B lymphocytes and of B and T lymphocyte cell lines. Values for PCl increased specifically during the G1 phase of the cell cycle and could be further enhanced by increasing intracellular adenosine 3',5'-monophosphate (cAMP) or calcium. In lymphocytes from CF patients, regulation of PCl during the cell cycle and by second messengers was absent. Characterization of the cell cycle-dependent expression of the chloride permeability defect in lymphocytes from CF patients increases the utility of these cells in the analysis of the functional consequences of mutations in the CF gene.

B-Lymphocytes↗

PubMed1998

Management of chronic sinusitis in the adult cystic fibrosis patient.

Cystic fibrosis (CF) is an autosomal recessive disorder affecting exocrine gland function. Although CF was formerly a deadly disease of infants and children, recent improvements in antibiotics, nutritional therapy, and supportive care have extended the median survival to adulthood. Patients with CF often present with sinusitis and nasal polyposis in addition to recurrent pulmonary infections. Although the effectiveness of endoscopic sinus surgery in children with CF has been documented, the treatment guidelines and efficacy in the adult CF patient are unknown. We present a series of 16 adult patients with CF and chronic sinusitis. The majority of patients presented with nasal polyposis and concomitant pulmonary complications. Endoscopic findings are reviewed, with an emphasis on improving pulmonary function following endoscopic sinus surgery. Preliminary findings suggest that endoscopic sinus surgery improves symptoms of sinusitis and exercise tolerance and may delay the progressive respiratory failure that often affects the adult CF patient.

Adult↗

PubMed1993

Altered fluid transport across airway epithelium in cystic fibrosis.

In cystic fibrosis (CF), absence or dysfunction of a phosphorylation-regulated chloride channel [CF transmembrane conductance regulator (CFTR)] leads to the loss or reduction of chloride secretion into the airways. Active sodium absorption is also increased in CF, and both of these ion transport changes could alter fluid transport across the airways. Under baseline conditions, cultured human airway epithelia from normal individuals absorbed fluid, and this absorption was increased in epithelia from patients with CF. In normal and CF epithelial cultures fluid absorption was inhibited by amiloride. Adenosine 3',5'-monophosphate stimulated fluid secretion in normal epithelial cultures but not in cultures from individuals with CF. In contrast, fluid secretion induced by nucleotide triphosphates (uridine triphosphate or adenosine triphosphate) was unaltered in cultures of epithelia from patients with CF, suggesting an approach to the treatment of CF.

Absorption↗

PubMed1979

IgA and IgG antibodies against surface antigens of Pseudomonas aeruginosa in sputum and serum from patients with cystic fibrosis.

Eleven cystic fibrosis (CF) patients chronically infected in the lungs with mucoid Pseudomonas aeruginosa and presenting multiple precipitins in serum against this bacterium (CF + P) and 10 CF patients without P. aeruginosa infection (CF-P) had their serum and sputum sol phase specimens examined for antibodies of the IgA and IgG classes against surface antigens of P. aeruginosa by means of an indirect immunofluorescence technique. Both the IgA and IgG antibody titres demonstrated in serum and sputum of the CF + P patients were significantly higher than in those of the CF-P patients (p less than 0.01). The titre of IgA antibodies in the sputum was higher than in serum in 3 cases indicating local pulmonary production of specific IgA antibodies. The role of the demonstrated antibodies in the local pulmonary immune defense mechanisms and the possible patogenesis of the pulmonary tissue damage in CF patients is discussed.

Adolescent↗

PubMed1988

Protein metabolism during treatment of chest infection in patients with cystic fibrosis.

Six cystic fibrosis patients with pulmonary exacerbations were studied to determine the effect of antibiotic treatment on protein nutritional status. Indirect calorimetry, nitrogen balance, protein turnover, urinary 3-methylhistidine, plasma albumin, prealbumin transferrin, and cortisol were measured before and after treatment. N loss averaged 16 and 17% on each balance. N in the sputum was up to 4.5% of absorbed N intake. At the peak of infection, protein synthesis, degradation, and urinary 3-methylhistidine were significantly higher than during recovery (31%, 28%, and 60%, respectively). On recovery a significant fall in blood sugar, albumin, morning cortisol and sputum N and a rise in prealbumin was found. Basal metabolic rate and N balance did not change. For patients in the fed state, active infection is associated with higher rates of protein synthesis and degradation. Antimicrobial treatment alters protein dynamics but does not alter measured N balance or the difference between measured protein synthesis and breakdown.

Adolescent↗

PubMed1997

Recombinant human DNase (rhDNase) influences phospholipid composition, surface activity, rheology and consecutively clearance indices of cystic fibrosis sputum.

Cystic fibrosis (CF) is caused by mutation in the gene for the CF transmembrane conductance regulator which leads to massive, abnormally viscous, purulent sputum, chronic destructive endobronchitis and early death. Purified recombinant human (rh) DNase can digest extracellular DNA and its inhalation in these patients significantly improves lung function. To evaluate the poorly understood mechanisms, saliva protected sputum from patients treated with and without rhDNase were evaluated. Therapy with rhDNase resulted in a soluble sputum fraction that had a higher percentage of phosphatidylethanolamine, a phospholipid present mainly in cellular membranes, a much lower percentage of phosphatidylcholine, but a higher surface activity. The rigidity was significantly lower and the ratio of viscosity in proportion to elasticity increased. All these data are consistent with an increased clearability of the sputum by coughing, but not by mucociliary activity. Thus the interaction of inhaled rhDNase with the purulent mucus and the endobronchial inflammatory processes may induce changes that result in rheological properties favoring clearance of sputum by cough.

Administration, Inhalation↗

PubMed2002

Nitric oxide and protein nitration in the cystic fibrosis airway.

Cystic fibrosis (CF), characterized by chronic airway infection and inflammation, ultimately leads to respiratory failure. Exhaled nitric oxide (NO), elevated in most inflammatory airway diseases, is decreased in CF, suggesting either decreased production or accelerated metabolism of NO. The present studies performed on two groups of CF patients provide further support for a disordered NO airway metabolism in CF respiratory tract disease. Despite confirmation of subnormal NOS2 in the CF airway epithelium, alternative isoforms NOS1 and NOS3 were present, and inflammatory cells in the CF airway expressed abundant NOS2. Increased immunohistochemical staining for nitrotyrosine was demonstrated in lung tissues from patients with CF as compared to control. To our knowledge, this is the first report localizing nitrotyrosine in diseased CF lung tissue. While the relative NOS2 deficiency in CF respiratory tract epithelium may contribute to the lower expired NO levels, these results suggest that increased metabolism of NO is also present in advanced CF lung disease. The significance of altered NO metabolism and protein nitration in CF remains to be fully elucidated.

Adult↗

PubMed2001

Reduced proteolysis of surfactant protein A and changes of the bronchoalveolar lavage fluid proteome by inhaled alpha 1-protease inhibitor in cystic fibrosis.

In cystic fibrosis (CF), the chronic neutrophilic inflammation of the airways results in proteolytic degradation of lung tissue early in the course of the disease. Inhalation of alpha 1-protease inhibitor (alpha 1-PI) may restore the protease-antiprotease imbalance and thus lead to less tissue damage. To monitor its impacts on bronchoalveolar lavage (BAL) fluid protein pattern (proteome) and on surfactant protein A (SP-A), eight young adults with CF inhaled 100 mg of alpha 1-PI twice daily over eight weeks. BAL fluids were obtained before and after inhalation. Total protein, the number and amount of proteins with a molecular mass < 20 kDa were reduced compared to pretreatment values. Degradation products of SP-A were shown by immunoblotting, being reduced after alpha 1-PI treatment. This pilot study demonstrates that inhalation of alpha 1-PI is associated with biochemical changes consistent with reduced proteolysis. The display of the BAL proteome by two-dimensional electrophoresis may be helpful to quantify the overall molecular changes associated with proteolytic or other lung injuries and offers the possibility to monitor directly therapeutic interventions.

Administration, Inhalation↗

PubMed2006

Stem cells and cystic fibrosis.

Although cystic fibrosis at first sight appears to be one of the most obvious human diseases to treat with gene therapy, since it is caused by a single-gene defect and the main affected organ is the lung which is relatively easily accessible, clinical results have thus far been disappointingly limited. At least one cause for this lack of success is the failure to permanently correct the gene defect in addition to the rapid turnover of lung epithelial cells. Alternative approaches therefore involve the search for and use of stem cell populations. This review presents an overview of recent attempts to identify lung- or bone marrow-derived populations of stem cells or progenitor cells and to apply such cells, heterologous or gene-corrected autologous, to colonize the airways while differentiating into functional respiratory columnar epithelial cells. The most successful approaches thus far appear to be obtained with bone marrow-derived cells such as mesenchymal stem cells, although the transdifferentiation rate thus far has been limited to below the 1% level. As an alternative the proven multipotent nature of bronchioalveolar stem cells isolated from lung tissue may provide another promising approach for successful stem cell therapy.

Animals↗