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PubMed1980

Cooperative study comparing three methods of performing sweat tests to diagnose cystic fibrosis.

Directors of cystic fibrosis centers in the United States have noted an increasing number of patients with histories of either false-positive or false-negative sweat tests. These inaccuracies were attributed to the use of rapid test methods which avoided actually weighing the sweat collected. These rapid tests have inherent difficulties which, theoretically at least, could lead to mistaken diagnoses. To evaluate methods of performing the sweat test, the National Cystic Fibrosis Foundation organized a combined study comparing the older Quantitative pilocarpine iontophoretic test (QPIT) method of performing the test with two newer and more rapid methods, the Orion skin electrode, and the Medtherm conductivity apparatus. Five cystic fibrosis centers participated in the study. Although two centers obtained considerably more accurate results with the Orion and the Medtherm than did the other three centers, the combined results of the study indicate that these procedures can be considered to be little more than screening tests.

Child↗
PubMed2005

Cystic fibrosis: an overview.

Cystic fibrosis (CF) is one of the most common inherited disorders of white populations. The isolation and cloning of the gene in CF that encodes the production of a transport protein that acts as an apical membrane chloride channel, termed cystic fibrosis transmembrane conductance regulator (CFTR), have improved our understanding of the disorder's pathophysiology and has aided diagnosis, but has also revealed the disease's complexity. Gene replacement therapy is still far from being used in patients with CF, mostly because of difficulties in targeting the appropriate cells. Life expectancy of patients with this disorder has greatly improved over past decades because of better symptomatic treatment strategies. This article summarizes advances in understanding and treatment of CF.

Cystic Fibrosis↗
PubMed1996

How mutant CFTR may contribute to Pseudomonas aeruginosa infection in cystic fibrosis.

Patients with cystic fibrosis (CF) have a pronounced hypersusceptibility (80 to 90%) to Pseudomonas aeruginosa infection. We hypothesized that airway epithelial cell ingestion of bacteria followed by cellular desquamation may protect the lung from infection, and epithelial cells expressing mutant forms of the cystic fibrosis transmembrane conductance regulator (CFTR) may be defective in this function. We found that transformed human airway epithelial cells homozygous for the delta F508 allele of CFTR were significantly defective in uptake of P. aeruginosa compared with the same cell line complemented with the wild-type allele of CFTR. Partial membrane expression of the delta F508 CFTR protein occurs in cells grown at 26 degrees C, and under these conditions uptake of P. aeruginosa occurred at levels comparable to cells with a wild-type allele of CFTR. Epithelial cell ingestion assays using isogenic bacterial strains differing in lipopolysaccharide (LPS) phenotype, along with inhibition studies, identified the LPS-core oligosaccharide as the bacterial ligand for epithelial cell invasion. Inhibition of epithelial cell ingestion of P. aeruginosa in a neonatal mouse lung infection model led to increased levels of bacteria in the lungs 24 and 48 h after infection. Defective epithelial cell internalization of P. aeruginosa may be a critical factor in hypersusceptibility of CF patients to chronic lung infections.

Animals↗
PubMed1989

Relation between tumor necrosis factor-alpha and granulocyte elastase-alpha 1-proteinase inhibitor complexes in the plasma of patients with cystic fibrosis.

Patients with cystic fibrosis suffer from a chronic, progressively destructive bronchitis characterized by colonization of the airways by Pseudomonas aeruginosa. Cell wall lipopolysaccharides from P. aeruginosa may stimulate secretion of cytokines such as tumor necrosis factor alpha (TNF alpha) by monocytes/macrophages. We found elevated levels of TNF alpha (150 +/- 60 pg/ml), interleukin-1 alpha (144 +/- 205 pg/ml), and interleukin-1 beta (62 +/- 100 pg/ml) in plasma from 25 patients with cystic fibrosis. In patients with less advanced disease, elevated plasma levels of TNF alpha correlated with high levels of complexes between neutrophil elastase and alpha 1-proteinase inhibitor, suggesting that TNF alpha may be a mediator of neutrophil degranulation. TNF alpha, by its chemotactic effect on neutrophils, may also contribute to the massive influx of neutrophils into and around the bronchial tree. Our findings raise the questions whether in patients with cystic fibrosis TNF alpha acts as cachectin and whether it mediates the anorexia that often results in weight loss.

Adolescent↗
PubMedDate not supplied

[Molecular epidemiology of cystic fibrosis in Tunisia].

Cystic fibrosis is the most frequent autosomal recessive genetic disease in North European population. This pathology seems to not be rare in Tunisia. On another hand, development of molecular biology techniques has largely contributed to implement the study of the different mutations in the CFTR gene where over 1,300 mutations were reported. Herein, we describe the strategy used to detect molecular defects responsible of cystic fibrosis on 390 children (383 families) in Tunisian population. Several techniques were performed for genotype diagnosis: DNA extraction was from peripheral blood. Polymerase chain reaction (PCR) and polyacylamide gel electrophoresis, and reverse dot blot procedures were used to detect known point mutations. Denaturant gradient gel electrophoresis (DGGE) were used in a next step searching for the unknown point mutations that are later identified by automated sequencing on ABIprism 310. This strategy allowed us to detect 17 different mutations located on the different exons of the CFTR gene. The most frequent was the F508del (50.74%) followed by three other mutations (G542X, W1282X and N1303K) known to be common in the Mediterranean area. For mutations (T665S, 2766 del8, F1166C, L1043R) were exclusively found, up to now, in the Tunisian population. Our results permitted to establish cystic fibrosis mutations and their distribution in Tunisia and to implement an appropriate prevention program of these diseases through the genetic council and prenatal diagnosis.

Child↗
PubMed2003

Association between serum oncofetal antigens CA 19-9 and CA 125 and clinical status in patients with cystic fibrosis.

UNLABELLED: In cystic fibrosis (CF), mucus plugging in the airways and in the gastrointestinal tract leads to severe morbidity and mortality. The mucin-associated antigens CA 19-9 and CA 125 are markers of gastrointestinal malignancy, and CA 19-9 has also been reported in association with pulmonary function in CF. AIM: To test whether these antigens might serve as markers for the severity of pulmonary and gastrointestinal disease in CF. METHODS: In 99 patients, aged 1 to 48 y, serum levels of CA 19-9 and CA 125 were measured by RIA and ELISA and related to clinical data. RESULTS: Patients with severe mutations had significantly increased serum levels of CA 125, indicating an association with a more severe CF phenotype. This was further supported by the association with lung function, chronic pulmonary colonization of Pseudomonas aeruginosa and pancreatic insufficiency. CA 19-9 was also shown to be associated with lung function and Ps. aeruginosa colonization. No gastrointestinal malignancy was found in our patients despite very high values of CA 19-9 in some patients. During a 5-y follow-up, the very high serum levels of CA 19-9 decreased along with improved general condition of the patients. CONCLUSION: Increased serum levels of CA 125 in CF patients were associated with severe cystic fibrosis transmembrane conductance regulator mutations and a severe phenotype. Both antigens were associated with pseudomonas colonization and lung function and CA 125 also with pancreatic insufficiency. The estimates of CA 19-9 are hampered by the influence of the Lewis histo-blood group system on the synthesis of CA 19-9.

Adolescent↗
PubMed1990

Altered disposition of fleroxacin in patients with cystic fibrosis.

Thirteen patients with cystic fibrosis and 12 healthy control volunteers received a single oral 800 mg dose of fleroxacin and 800 mg every day for 5 days. Interstitial fluid penetration was studied by the suction-induced blister technique. Fleroxacin and its two major metabolites, N-demethyl and N-oxide, were analyzed in plasma and urine by HPLC. Single-dose absorption parameters (absorption rate constant, normalized peak plasma drug concentration, and time to reach peak concentration) and total urinary excretion indicated that fleroxacin was absorbed more slowly and more completely in patients with cystic fibrosis than in control subjects. Fleroxacin volume of distribution tended to be smaller in patients with cystic fibrosis and it reached statistical significance after a single dose when normalization for lean body mass was applied. When normalized for lean body mass, the formation clearance of N-demethyl fleroxacin and N-oxide fleroxacin was significantly greater in patients with cystic fibrosis than in control subjects (p less than 0.05). These data concur with those of others showing an induction of drug-metabolizing enzymes in cystic fibrosis. Renal clearances of fleroxacin and its metabolites were significantly increased in cystic fibrosis (p less than 0.05), and this seems to be explained by a decreased tubular reabsorption of these compounds. The differences seen in the pharmacokinetics of fleroxacin in cystic fibrosis support the theories of generalized induction of drug metabolism and of a defective renal tubular reabsorptive process of drugs in cystic fibrosis.

Administration, Oral↗
PubMed1994

Evaluation of the respiratory epithelium of normals and individuals with cystic fibrosis for the presence of adenovirus E1a sequences relevant to the use of E1a- adenovirus vectors for gene therapy for the respiratory manifestations of cystic fibrosis.

Lung disease associated with disorders such as cystic fibrosis (CF) may be amenable to somatic gene therapy in which there is delivery of the normal gene directly to the respiratory epithelium using E1a- adenovirus (Ad) type 2- or 5-based vectors. For safety reasons, the Ad vectors are rendered replication deficient by deletion of the E1a region. Because there is the theoretical possibility of an E1a- replication-deficient vector replicating as a result of recombination or complementation with Ad 2/5 E1a sequences present in the target cell, this study is directed toward evaluating respiratory epithelium of normals and individuals with CF for the presence of E1a sequences. Using Ad 2/5 E1a-specific primers and the polymerase chain reaction to evaluate DNA recovered from freshly isolated nasal and bronchial epithelium recovered by brushing, E1a sequences were detected in respiratory epithelium of 19 of 91 normals (21%). In the E1a-positive samples, the average of E1a copy number was 55 +/- 18/10(3) recovered cells. In CF individuals, 7 of 52 (13%) had detectable E1a sequences in the respiratory epithelium, with E1a copy number in the positive samples of 80 +/- 21/10(3) recovered cells. These results demonstrate that there are detectable Ad 2/5 E1a sequences in the respiratory epithelium of a small percentage of normals and individuals with CF. Because of the theoretical potential of such sequences supporting replication of E1a- Ad vectors, human gene therapy protocols for CF utilizing such vectors should consider evaluating study individuals for the presence of Ad 2/5 E1a sequences in the respiratory epithelium.

Adenoviridae Infections↗
PubMed2001

Effect of genotype on selected clinical features of Polish cystic fibrosis adults.

UNLABELLED: Cystic fibrosis (CF), the most common autosomal recessive disorder of Caucasians, is caused by the mutations in the gene encoding CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) protein. Until now, approximately 1000 mutations of the CFTR gene have been described. The genotype-phenotype relationships in CF are still not completely understood. This study was undertaken in an attempt to characterise the distribution of CFTR mutations and their effect on selected clinical parameters in a group of Polish CF adults. A total number of 38 adult CF patients (mean age 21.6 +/- 6.8); 18 females & 20 males were enrolled in the study. The CFTR gene identification was conducted with the use of PCR & InnoLipa-CF set. The assessed clinical parameters included: age at diagnosis, age, lung function test, X-ray scored in Brasfield score, weight & height. We found that: (1) the genotypes of the studied population were unevenly distributed (65.8%- genotype deltaF508/M), (2) a high percentage of 3849+10kbC-->T was noted, (3) patients homozygous for the deltaF508 mutation were diagnosed significantly earlier and had a lower body mass index, (4) no differences were observed in the patients' length of life or the progression of lung disease. CONCLUSIONS: 1. In comparison to other populations, Polish adult CF patients display a relatively higher frequency of mild mutations. 2. Late diagnosis of CF in the studied group may be partially caused by a high percentage of CFTR mutations connected with the mild course of the disease that are difficult to identify. 3. Cystic fibrosis should be more commonly taken into consideration in the differential diagnosis in adult patients with milder symptoms.

Journal Article↗
PubMed2006

Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

BACKGROUND: People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. SEARCH STRATEGY: We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: August 2005. SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy and/or toxicity, in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The two authors independently selected the studies to be included in the review and assessed methodological quality of each study. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. MAIN RESULTS: Eleven studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants were included in this review. All studies compared once-daily dosing with thrice-daily dosing. There was no significant difference between treatment groups in: forced expiratory volume at one second, weighted mean difference (WMD) 0.33 (95% confidence interval (CI) -2.81 to 3.48); forced vital capacity, WMD 0.29 (95% CI -6.58 to 7.16); % weight for height, WMD -0.82 (95% CI -3.77 to 2.13); body mass index, WMD 0.00 (95% CI -0.42 to 0.42); or in the incidence of ototoxicity, relative risk 0.56 (95% CI 0.04 to 7.96). The percentage change in creatinine significantly favoured once-daily treatment in children, WMD -8.20 (95% CI -15.32 to -1.08), but showed no difference in adults, WMD 3.25 (95% CI -1.82 to 8.33). AUTHORS' CONCLUSIONS: Once and three times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Adolescent↗
PubMed1996

[Meconium ileus-equivalent in adult patients with cystic fibrosis].

Gastrointestinal complications of cystic fibrosis are becoming more common because patients with cystic fibrosis are living longer. There are 227 cystic fibrosis patients in Norway today, almost half of whom are more than 18 years old. Meconiumileus-equivalent is a complication which increases with age. It is a term used to describe partial or complete intestinal obstruction occurring in patients with cystic fibrosis. It results from abnormally viscid mucofaeculent material in the terminal ileum and right proximal colon. Some patients may experience acute complete obstruction, but most of them suffer from chronic partial obstruction, with recurring colicly abdominal pain and some distension. Of 70 adult cystic fibrosis patients at Aker hospital over a seven year period, 26% had symptoms and signs of this disorder. Conservative treatment is preferable, and surgery should be avoided.

Abdomen, Acute↗
PubMed2000

Once daily versus multiple daily dosing with intravenous aminoglycosides for cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require repeated courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher concentrations less often. OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. SEARCH STRATEGY: We searched the Cystic Fibrosis specialist trials register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search: February 2000. SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy and/or toxicity, in patients with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Both reviewers independently extracted data and assessed trial quality. Authors of one study were contacted to obtain missing information. MAIN RESULTS: Two trials reporting results from a total of 70 patients were included in this review. Both trials compared once-daily dosing with thrice-daily dosing reporting data on Forced Expiratory Volume at one second (FEV1), Forced Vital Capacity (FVC), nutritional status and side effects. There was no significant difference in efficacy or in the incidence of ototoxicity and nephrotoxicity between treatment groups. REVIEWER'S CONCLUSIONS: Despite a lack of difference between the two groups we feel that these results should be viewed with caution as the numbers of patients involved was small and lacks the power to detect a difference between the groups. This systematic review has highlighted the need for a well designed, adequately-powered, multicentre, randomised controlled trial assessing the efficacy of once-daily versus multiple-daily dosing of intravenous aminoglycosides for pulmonary exacerbations in cystic fibrosis.

Adolescent↗
PubMed1994

Regulation of endocytic trafficking and acidification are independent of the cystic fibrosis transmembrane regulator.

Cystic fibrosis is associated with mutations of the cystic fibrosis transmembrane regulator (CFTR), a cAMP-regulated plasma membrane Cl- channel. Mutations in the CFTR have been reported to not only impair Cl-transport at the plasma membrane but also inhibit organelle acidification and disrupt cAMP-regulated plasma membrane recycling. Comparisons of cultured pancreatic adenocarcinoma cells expressing the delta 508 mutant CFTR (CFPAC-1 cells) with genetically matched CFPAC-1 cells transfected with the wild-type CFTR demonstrate that expression of wild-type CFTR restores cAMP-mediated plasma membrane Cl- transport, but has no effect on pH regulation of endosomes labeled with either transferrin or wheat germ agglutinin. Endosome pH was, in all cases, similar in the two cell lines and unaffected by treatment with the cAMP agonist forskolin. Forskolin treatment had no effect on transferrin internalization, but increased recycling by 30-40% in both cell lines. The kinetics of wheat germ agglutinin recycling were negligibly affected by forskolin in either cell line. These results demonstrate that endocytic acidification and cAMP-mediated endocytic protein redistribution are similar in genetically matched CFPAC-1 cells which differ only in the expression of mutant or wild-type CFTR.

Adenocarcinoma↗
PubMed2005

[Cystic fibrosis diabetes in adult].

Cystic fibrosis is an autosomal recessive disorder affecting about 1/3500 case in France. The disease, that affects all epithelia, is responsible for pulmonary tract infections but also pancreas, gut, liver and genital tract abnormalities. It is linked to CFTR gene mutations, inducing unusually high increase of sodium chloride in sweat, used to track down the illness. deltaF508 CFTR mutation, encountered in 70% of cases, is nearly always associated to pancreatic insufficiency with early-onset lung attack. Around 10% of cystic fibrosis cases, whatever the age, are complicated with partially insulinopenic diabetes, favored by pancreatic fibrosis, while one third of patients shows glucose intolerance. After 20 years old, one third of patients suffers from diabetes and one half after 30 years. Diabetes diagnosis is difficult, and requires the fulfillment of oral glucose tolerance test (OGTT). One glycemia greater or equal to 2 g/l, two hours after a 75 g glucose load, established diabetes diagnosis. Indeed, fasting blood glucose and glycated hemoglobin appear as poor diagnosis markers. Despite histological arguments in favor of the mainly mechanical islet disturbances, an increased prevalence of anti-islets auto-antibodies and an increased frequency of HLA DR3/DR4 have been reported in cystic fibrosis population with glucose tolerance troubles. Also, glucose metabolism is influenced by specific factors linked to cystic fibrosis (infection, malnutrition, steroids...). In reason of the silent phase of diabetes, systematic tracking down of diabetes with a yearly OGTT is recommended, all the more so that hyperglycemia appears as a worsening factor of cystic fibrosis. The efficacy of oral anti-diabetic drugs has not been evaluated on large studies. By contrast, some studies argue for insulin therapy as soon as diabetes appears, insulin improving respiratory and nutritional prognosis. In conclusion, the aim of treatment of cystic fibrosis is to prevent the lung function decline by controlling inflammation and infection, to implement endo- and exo-crine pancreas insufficiency, and to improve nutritional status.

Adult↗
PubMed2005

Acupuncture pain management for patients with cystic fibrosis: a pilot study.

Cystic fibrosis is the most commonly occurring genetic disorder among Caucasians. The purpose of this study was to evaluate the effects of acupuncture for pain management in patients with cystic fibrosis; clinical data was obtained regarding the integration of acupuncture into the management of pain in patients with cystic fibrosis. Visual analog scales were used for pain measurement. Acupuncture was found to be effective in decreasing pain complaints in patients with cystic fibrosis. No side effects or complications were reported in relation to the acupuncture treatment. Acupuncture is effective for managing symptoms and illnesses associated with cystic fibrosis. Further randomized controlled trials will be necessary to evaluate additional efficacy in pain management and the improvement of the quality of life of patients with cystic fibrosis.

Acupuncture Analgesia↗
PubMed1996

Gene therapy for cystic fibrosis: a potential cure.

Cystic fibrosis is a lethal autosomal recessive disorder. In 1989, the cystic fibrosis gene was isolated on chromosome 7. Positional cloning, linkage analysis, saturation cloning, and chromosome jumping enabled the isolation and cloning of the gene that encodes the cystic fibrosis transmembrane conductance regulator. Current work focuses on the safe, efficient delivery of a functional cystic fibrosis transmembrane conductance gene to patients who are afflicted with cystic fibrosis and the expression of the gene in somatic cells to correct the genetic defect and restore chloride channel function. It is hoped that successful gene therapy will be a feasible and cost-efficient approach that will lead to a cure.

Cloning, Molecular↗
PubMed2000

Basal nucleotide levels, release, and metabolism in normal and cystic fibrosis airways.

BACKGROUND: Cystic fibrosis (CF) is a syndrome caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Despite advances in our understanding of the molecular pathogenesis of CF, the link between CFTR gene mutations and the pathogenesis of CF lung disease remains poorly defined. CFTR has been assigned a number of putative functions that may contribute to innate airway defense, including the regulation of adenosine 5'-triphosphate (ATP) release into the extracellular environment. Because extracellular ATP and uridine 5'-triphosphate (UTP) may regulate airway mucociliary clearance via interaction with luminal P2Y2 receptors, the loss of CFTR-mediated nucleotide release could explain the defect in CF airway defense. MATERIALS AND METHODS: We tested the physiologic importance of CFTR-mediated nucleotide release in vivo by directly measuring levels of ATP and UTP in nasal airway surface liquid from normal and CF subjects. Because these basal nucleotide levels reflect the net activities of nucleotide release and metabolic pathways, we also measured constitutive rates of nucleotide release and metabolism on well-differentiated normal and CF airway cultures in vitro. The measurement of ATP release rates were paralleled by in vivo studies employing continuous nasal perfusion in normal and CF subjects. Finally, the regulation of ATP release by isoproterenol and methacholine-stimulated submucosal gland secretion was tested. RESULTS: These studies revealed that steady-state ATP and UTP levels were similar in normal (470 +/- 131 nM and 37 +/- 7 nM, respectively) and CF (911 +/- 199 nM and 33 +/- 12 nM, respectively) subjects. The rates of both ATP release and metabolism were also similar in normal and CF airway epithelia both in vitro and in vivo. Airway submucosal glands did not secrete nucleotides, but rather, secreted a soluble nucleotidase in response to cholinergic stimuli. CONCLUSION: The concentration of ATP in airway surface liquid is in a range that is relevant for the activation of airway nucleotide receptors. However, despite this finding that suggests endogenous nucleotides may be important for the regulation of mucociliary clearance, our data do not support a role for CFTR in regulating extracellular nucleotide concentrations on airway surfaces.

Adenosine Triphosphate↗