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PubMed1995

The first nucleotide binding fold of the cystic fibrosis transmembrane conductance regulator can function as an active ATPase.

Cystic fibrosis is caused by mutations in the cell membrane protein called CFTR (cystic fibrosis transmembrane conductance regulator) which functions as a regulated Cl- channel. Although it is known that CFTR contains two nucleotide domains, both of which exhibit the capacity to bind ATP, it has not been demonstrated directly whether one or both domains can function as an active ATPase. To address this question, we have studied the first CFTR nucleotide binding fold (NBF1) in fusion with the maltose-binding protein (MBP), which both stabilizes NBF1 and enhances its solubility. Three different ATPase assays conducted on MBP-NBF1 clearly demonstrate its capacity to catalyze the hydrolysis of ATP. Significantly, the mutations K464H and K464L in the Walker A consensus motif of NBF1 markedly impair its catalytic capacity. MBP alone exhibits no ATPase activity and MBP-NBF1 fails to catalyze the release of phosphate from AMP or ADP. The Vmax of ATP hydrolysis (approximately 30 nmol/min/mg of protein) is significant and is markedly inhibited by azide and by the ATP analogs 2'-(3')-O-(2,4,6-trinitrophenyl)-adenosine-5'-triphosphate and adenosine 5'-(beta, gamma-imido)triphosphate. As inherited mutations within NBF1 account for most cases of cystic fibrosis, results reported here are fundamental to our understanding of the molecular basis of the disease.

Adenosine Triphosphatases↗
PubMed1981

Nasal mucociliary clearance and ciliary beat frequency in cystic fibrosis compared with sinusitis and bronchiectasis.

Nasal ciliary function and mucociliary clearance were studied in patients with cystic fibrosis and in three control groups. Ciliary beat frequency and nasal clearance time were measured in groups of 10 subjects with cystic fibrosis, sinusitis and bronchiectasis and age and sex-matched control subjects. Ciliary beat frequency was also measured in normal subjects matched as bronchiectasis controls. Cystic fibrosis patients and their controls, patients with sinusitis, and the bronchiectasis controls did not differ in ciliary beat frequency, but it was slower in the patients with bronchiectasis (p less than 0.05). Nasal mucociliary clearance in cystic fibrosis and bronchiectasis was slower than in the cystic fibrosis controls (p less than 0.001) and in patients with sinusitis (p less than 0.01). The finding of a normal beat frequency in cystic fibrosis cilia studied in vitro together with abnormal nasal mucociliary clearance measured in vivo in the same patients suggests the existence of an abnormality of mucus in vivo. The innate function of cystic fibrosis cilia, as measured in vitro by beat frequency, is normal.

Adolescent↗
PubMed1989

Cystic fibrosis: prenatal diagnosis and carrier detection by DNA analysis.

The analysis of restriction fragment length polymorphism (RFLP)s was used to detect 11 polymorphisms that are linked to cystic fibrosis in 42 Australian families with at least one child with cystic fibrosis. The data from all the families were fully informative in regard to the gene for cystic fibrosis (CF). Prenatal assessment was performed for 24 of these families: seven fetuses were assessed to be homozygous for cystic fibrosis, 13 fetuses were heterozygous and three fetuses were free of the CF gene. Of the seven pregnancies in which it was predicted that the infant would be affected by cystic fibrosis, two were continued electively; both have come to term and the infants each were shown to have cystic fibrosis at birth. Of the 17 pregnancies in which it was predicted that the infant would not be affected by cystic fibrosis, 13 have come to term and all the infants but one (who has not yet been followed-up) have been shown to be unaffected by cystic fibrosis at birth. The polymerase chain reaction has been used to amplify the CS.7 and KM.19 loci close to the CF gene. This procedure allows a polymorphic site in each locus to be analysed in a much shorter time (one or two days rather than 10 days) and allows the use of very small test-samples, such as dried blood on filter paper ("Guthrie blood spots"). Our observations confirm the results of overseas studies and indicate that these techniques are eminently useful for prenatal diagnosis and the detection of carriers in the vast majority of Australian families with cystic fibrosis.

Alleles↗
PubMed1998

Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease.

The pathogenesis of cystic fibrosis (CF) airways infection is unknown. Two hypotheses, "hypotonic [low salt]/defensin" and "isotonic volume transport/mucus clearance," attempt to link defects in cystic fibrosis transmembrane conductance regulator-mediated ion transport to CF airways disease. We tested these hypotheses with planar and cylindrical culture models and found no evidence that the liquids lining airway surfaces were hypotonic or that salt concentrations differed between CF and normal cultures. In contrast, CF airway epithelia exhibited abnormally high rates of airway surface liquid absorption, which depleted the periciliary liquid layer and abolished mucus transport. The failure to clear thickened mucus from airway surfaces likely initiates CF airways infection. These data indicate that therapy for CF lung disease should not be directed at modulation of ionic composition, but rather at restoring volume (salt and water) on airway surfaces.

Absorption↗
PubMed1985

Intra-abdominal complications of cystic fibrosis.

In recent years patients with cystic fibrosis (CF) have experienced longterm survival and have demonstrated a number of intra-abdominal complications. This report evaluates the intra-abdominal complications seen in 69 of 189 children with cystic fibrosis from 1972 to 1983. Forty-one patients were boys and twenty-eight girls. Complications occurred in 36 neonates, with meconium ileus (MI) noted in 33 and giant cystic meconium peritonitis (GCMP) in 3. Meconium ileus equivalent occurred in seven older children presenting with bowel obstruction. In addition, rectal prolapse occurred in 12, inguinal hernia in 10, intussusception in 3, cholelithiasis in 3, GE reflux in 4, stress ulcer in 1 and appendicitis in 1. Three infants with GCMP survived resection and enterostomy. Infants with MI were divided into simple (15) or complicated (18) cases. Nonoperative therapy using gastrografin enema was successful in three of eight with simple MI. Operative enterotomy and irrigation was successful in three cases while resection and enterostomy was done in nine. MI was complicated by atresia, volvulus and/or perforation in 18 cases requiring resection and anastomosis or enterostomy. Survival for MI was 86% compared to 36% in 25 MI patients treated in the previous two decades. Meconium ileus equivalent was successfully managed using gastrografin enema in five of seven children. Only 3 of 12 children with rectal prolapse required repair. Two cases of intussusception were reduced while one required resection. Three of 10 children had hernia recurrence due to chronic pulmonary problems.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMed1994

Possible nosocomial transmission of Pseudomonas cepacia in patients with cystic fibrosis.

OBJECTIVE: To determine whether nosocomial transmission of Pseudomonas cepacia occurred at a hospital with endemic P cepacia infection of patients with cystic fibrosis. DESIGN: Two retrospective case-control studies. SETTING: A large pediatric cystic fibrosis center. PARTICIPANTS: To assess risk factors for acquisition of P cepacia, 18 cases, defined as any patient with cystic fibrosis with first documented isolation of P cepacia in 1988 or 1989, were compared with 18 matched P cepacia-negative controls with cystic fibrosis. To assess potential modes of nosocomial P cepacia transmission, 14 cases with a hospitalization(s) between their last P cepacia-negative culture and first P cepacia-positive culture were compared with 14 hospitalized P cepacia-negative controls with cystic fibrosis. METHODS: Handwiping cultures (N = 68) and selective environmental cultures were performed. MAIN RESULTS: Cases tended to be more likely than controls to have been hospitalized at the cystic fibrosis center in the 3 months before their first P cepacia-positive culture (P = .08). In addition, cases tended to be more likely than hospitalized controls with cystic fibrosis to have had a P cepacia-positive roommate (P = .06) before becoming colonized with P cepacia organisms. Pseudomonas cepacia was cultured from the hands of two individuals: a P cepacia-colonized patient who had just undergone chest physiotherapy and consequent coughing and the investigator who shook the P cepacia-positive patient's hand after the patient's procedure. CONCLUSIONS: These results suggest that in this cystic fibrosis center, hospitalization is a risk factor for P cepacia acquisition and that person-to-person transmission of P cepacia may occur in the hospital via hand contact.

Adolescent↗
PubMed2004

Prenatal screening for cystic fibrosis: past, present and future.

Prenatal screening for cystic fibrosis is reviewed. The disease, gene involved, molecular basis of disease, genotype/phenotype correlations and pilot trials are discussed, as well as historical perspectives, background and American College of Medical Genetics/American College of Obstetricians and Gynecologists recommendations. A number of complex challenges to the implementation of cystic fibrosis screening exist, including mutation testing of the cystic fibrosis transmembrane conductance regulator gene (CFTR), as well as laboratory and clinical issues. Current technologies for CFTR testing include reverse dot blots, amplification refractory mutation detection systems, oligonucleotide ligation assays, the Invader assay and NanoChip system. Emerging technologies are also considered, as well as quality assurance measures including analytical and clinical validation, reporting, residual risk calculations and prenatal diagnosis. An even greater challenge is clinical implementation, which focuses upon education and communication, choosing models, reporting, counseling and prenatal diagnosis.

Cystic Fibrosis↗
PubMed2003

Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations.

BACKGROUND: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene containing a premature termination signal cause a deficiency or absence of functional chloride-channel activity. Aminoglycoside antibiotics can suppress premature termination codons, thus permitting translation to continue to the normal end of the transcript. We assessed whether topical administration of gentamicin to the nasal epithelium of patients with cystic fibrosis could result in the expression of functional CFTR channels. METHODS: In a double-blind, placebo-controlled, crossover trial, patients with stop mutations in CFTR or patients homozygous for the DeltaF508 mutation received two drops containing gentamicin (0.3 percent, or 3 mg per milliliter) or placebo in each nostril three times daily for two consecutive periods of 14 days. Nasal potential difference was measured at base line and after each treatment period. Nasal epithelial cells were obtained before and after gentamicin treatment from patients carrying stop mutations, and the C-terminal of surface CFTR was stained. RESULTS: Gentamicin treatment caused a significant reduction in basal potential difference in the 19 patients carrying stop mutations (from -45+/-8 to -34+/-11 mV, P=0.005) and a significant response to chloride-free isoproterenol solution (from 0+/-3.6 to -5+/-2.7 mV, P<0.001). This effect of gentamicin on nasal potential difference occurred both in patients who were homozygous for stop mutations and in those who were heterozygous, but not in patients who were homozygous for DeltaF508. After gentamicin treatment, a significant increase in peripheral and surface staining for CFTR was observed in the nasal epithelial cells of patients carrying stop mutations. CONCLUSIONS: In patients with cystic fibrosis who have premature stop codons, gentamicin can cause translational "read through," resulting in the expression of full-length CFTR protein at the apical cell membrane, and thus can correct the typical electrophysiological abnormalities caused by CFTR dysfunction.

Administration, Intranasal↗
PubMed2003

Female sexual health care in cystic fibrosis.

Fifty five teenage girls with cystic fibrosis and their mothers were interviewed to assess the provision of sexual health information. Parents were the most common source of information for adolescents. The cystic fibrosis doctor was identified as the key resource for parents. Yet few parents had spoken to their doctor about these issues, and 96% requested more information. This information was wanted before puberty by mothers, and from puberty onwards by girls.

Adolescent↗
PubMed1995

Ulcerative type of colitis associated with the use of high strength pancreatic enzyme supplements in cystic fibrosis.

A 2 1/2-year-old girl with cystic fibrosis, who presented with hematochezia, developed an inflammatory ulcerative type of colitis with mild interstitial fibrosis and colonic narrowing while being treated with high strength pancreatic enzyme supplements. Findings of contrast enema, endoscopy, and colonic biopsy are described. The spectrum of colonic disease associated with the use of high strength pancreatic enzyme supplements in cystic fibrosis patients is discussed.

Child, Preschool↗
PubMed1998

Towards gene therapy of cystic fibrosis.

Numerous gene mutations associated with hereditary disorders have been identified. In cystic fibrosis the hereditary defect is attributed to mutations in one single gene, the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Conventional therapies of CF have dramatically increased the life expectancy of afflicted individuals. However, the ultimate incurability of this disease calls for novel and better therapeutic strategies. As cystic fibrosis is believed to be caused by mutations in one single gene, it has appeared to be the ideal candidate for one of the most tempting approaches in clinical therapy, namely gene therapy. Laboratory protocols for the introduction of genes into various tissues have been developed and applied over the last 15 years. The ease of gene transfer under laboratory conditions gave rise to the hope that rapid advances in gene transfer protocols under clinical settings could be achieved as well. 20 clinical trials of gene therapy for cystic fibrosis have been initiated using viral and non-viral vectors for gene transfer (Marcel and David Grausz 1997). The outcome of the CF gene therapy studies as well as of those for other diseases have clearly demonstrated that gene transfer and gene therapy in humans is a much more complex and challenging task than originally thought. Still, the encouraging results achieved in animal models and the rapid progress in vector technology justify the hope that the novel genetic therapies will be applied successfully to the benefit of patients suffering from cystic fibrosis.

Cystic Fibrosis↗
PubMed2002

Negative sweat test in hypertrypsinaemic infants with cystic fibrosis carrying rare CFTR mutations.

UNLABELLED: Persistent hypertrypsinaemia in newborn screening for cystic fibrosis (CF) recognises subjects at high risk to be affected. Diagnosis is confirmed by a positive sweat test and/or by the presence of two mutations in the cystic fibrosis transmembrane regulator gene. The aim of the present study was to evaluate the occurrence of a negative sweat test (chloride < 60 mmol/l) during the first months of life, in hypertrypsinaemic infants, which would lead to a delayed diagnosis. We reviewed clinical charts of CF patients born between January 1993 and September 1998, when the neonatal screening programme consisted of an immunoreactive trypsinogen (IRT)/DNA (F508del) + IRT strategy. Laboratory and clinical data were collected for patients diagnosed after 12 months of life. Out of 446,492 newborns, 104 CF patients were diagnosed giving an overall incidence of 1:4293. Of these, six had a blood IRT level above the cut off value (99th percentile) and a negative sweat test in the first trimester of life. At a mean age of 3.5years, the patients were again referred to our CF Centre for re-evaluation in order to confirm or exclude the disorder. Molecular analysis identified the following genotypes: F508del/A309D, F508del/3849 + 10kbC-->T, F508del/R117H (in two patients), R117H/ L997F, and F508del/R117L. CONCLUSION: Infants with cystic fibrosis bearing a spectrum of mild cystic fibrosis transmembrane regulator gene mutations may present as hypertrypsinaemic newborns with a sweat chloride within the normal range. Reference values for normal sweat test during the first months of life should be revised. A wide molecular genetic analysis is recommended for newborns presenting persistent hypertrypsinaemia and a sweat test result > 30 mmol/l in order to diagnose atypical forms of the disease.

Child↗
PubMed1983

Cholelithiasis in adult cystic fibrosis.

The clinical picture of adult cystic fibrosis is usually dominated by respiratory failure. Hepatic dysfunction occurs commonly, but symptomatic cholelithiasis is a rarely reported complication of the disease. This case of common duct obstruction emphasizes the broad spectrum of sequelae that may be expected in this newly emerging population of adults with cystic fibrosis.

Adult↗
PubMed1989

Potassium release in labial glands from controls and patients with cystic fibrosis.

Labial glands from patients with cystic fibrosis (CF) were tested for a disease-related decrease in cholinergically-induced K release. Labial gland slices from normal controls and patients with cystic fibrosis were incubated in vitro in the presence or absence of cholinergic and adrenergic agonists and with or without a phosphodiesterase inhibitor. Both control and CF glands released K in response to cholinergic stimulation only; no K release response was detected to alpha- or beta- adrenergic stimulation. In contrast to previous results reported for parotid glands, no CF-related decrease in cholinergically-induced K release was detected. Both normal and CF glands released significantly less K with carbachol stimulation in the presence of the phosphodiesterase inhibitor. Overall, the results suggest considerable interglandular differences in disease sensitivity and functional regulation of K release.

1-Methyl-3-isobutylxanthine↗
PubMed1993

[Rhinosinusal manifestations of cystic fibrosis].

The generalized disorders which characterize cystic fibrosis often involve the nose and paranasal sinuses and may frequently lead to the development of nasal polyps. A retrospective study of 78 patients with cystic fibrosis, 3 to 28 years old, was undertaken in order to determine the incidence of nasal involvement and to define an approach to the treatment of disabling recurrent nasal polyposis. 65% of these patients presented chronic symptoms such as rhinorrhea, nasal obstruction and disturbances of smell. Nasal polyps were found in 50% of patients and were more frequent in adults than in children. Clinical symptoms were directly related to the extent of polyp development which could be classified according to 3 groups. CT scans showed maxillary sinus involvement in almost all patients. The incidence and extent of ethmoidal sinus involvement on CT scans was correlated to the grade of polyp development. Medical treatment of polyposis failed in all cases. Polypectomy was always followed by recurrence. Intranasal ethmoidectomy seems to be an interesting alternative, since 73% of patients undergoing this procedure had clinical improvement.

Adolescent↗
PubMed1982

Secretin pancreozymin stimulation test and confirmation of the diagnosis of cystic fibrosis.

We have studied the secretin-pancreozymin stimulation test of pancreatic function with particular regard to its usefulness in the diagnosis of cystic fibrosis patients without gastrointestinal symptoms. We have compared the test results in 38 control individuals, 14 patients with cystic fibrosis and five other patients with problems affecting pancreatic function. Of the cystic fibrosis patients tested, six had no gastrointestinal symptoms and were shown to have normal or raised output of pancreatic enzymes measured (lipase, trypsin, chymotrypsin, and amylase). There was a positive correlation between both volume and bicarbonate measurement versus body weight in all subjects, but this relationship was clearly different in the cystic fibrosis patients compared with others regardless of the cystic fibrosis patients' ability to secrete pancreatic enzymes. Among the cystic fibrosis patients, bicarbonate concentration tended to be higher in those able to secrete a significant amount of pancreatic enzymes. However, the actual output of bicarbonate measured in all cystic fibrosis patients (range 0.001-0.037 mmol/kg/45 min post-stimulation) was below that found in all control patients (range 0.104-0.516 mmol/kg/45 min post-stimulation). Therefore the secretin-pancreozymin test of pancreatic function appears to be useful in the diagnosis of cystic fibrosis even in those patients with adequate enzyme production.

Adolescent↗
PubMed2000

Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX.

The cellular basis of cystic fibrosis (CF) is a defect in a cyclic adenosine monophosphate (cAMP)-activated chloride channel (CF transmembrane conductance regulator) in epithelial cells that leads to decreased chloride ion transport and impaired water transport across the cell membrane. This study investigated whether it was possible to activate the defective chloride channel in cystic fibrosis respiratory epithelial cells with 4-phenylbutyrate (4PBA), genistein and 8-cyclopentyl-1,3-dipropylxanthine (CPX). The CF bronchial epithelial cell line CFBE41o-, which expresses the deltaF508 mutation, was treated with these agents and loss of Cl-, indicating Cl- efflux, measured by X-ray microanalysis. 8-bromo-cAMP alone did not induce Cl- efflux in CFBE41o- cells, but after incubation with 4PBA a significant efflux of Cl- occurred. Stimulation of cells with a combination of genistein and cAMP also induced Cl- efflux, whereas a combination of pretreatment with 4PBA and a combined stimulation with genistein and cAMP induced an even larger Cl- efflux. Cl- efflux could also be stimulated by CPX, but this effect was not enhanced by 4PBA pretreatment. The deltaF508 mutation leads to impaired processing of the cystic fibrosis transmembrane conductance regulator. The increased efflux of chloride after 4-phenylbutyrate treatment can be explained by the fact that 4-phenylbutyrate allows the deltaF508 cystic fibrosis transmembrane conductance regulator to escape degradation and to be transported to the cell surface. Genistein and 8-cyclopentyl-1,3-dipropylxanthine act by stimulating chloride ion efflux by increasing the probability of the cystic fibrosis transmembrane conductance regulator being open. The combination of 4-phenylbutyrate and genistein may be useful in a potential pharmacological therapy for cystic fibrosis patients with the deltaF508 mutation.

Cell Line↗