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At least 433 records · Page 24Linked to original sources
PubMed1999

Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus.

OBJECTIVE: The host immune response and low vector efficiency have been key impediments to effective cystic fibrosis transmembrane regulator (CFTR) gene transfer for cystic fibrosis (CF). An adeno-associated virus vector (AAV-CFTR) was used in a phase I dose-escalation study to transfer CFTR cDNA into respiratory epithelial cells of the maxillary sinus of 10 CF patients. STUDY DESIGN: A prospective, randomized, unblinded, dose-escalation, within-subjects, phase I clinical trial of AAV-CFTR was conducted. PATIENTS: Ten patients with previous bilateral maxillary antrostomies were treated. MAIN OUTCOME MEASURES: Safety, gene transfer as measured by semiquantitative polymerase chain reaction (PCR), and sinus transepithelial potential difference (TEPD) were measured. RESULTS: The highest level of gene transfer was observed in the range of 0.1-1 AAV-CFTR vector copy per cell in biopsy specimens obtained 2 weeks after treatment. When tested, persistence was observed in one patient for 41 days and in another for 10 weeks. Dose-dependent changes in TEPD responses to pharmacologic intervention were observed following treatments. Little or no inflammatory or immune responses were observed. CONCLUSION: AAV-CFTR administration to the maxillary sinus results in successful, dose-dependent gene transfer to the maxillary sinus and alterations in sinus TEPD suggestive of a functional effect, with little or no cytopathic or host immune response. Further study is warranted for AAV vectors as they may prove useful for CFTR gene transfer and other in vivo gene transfer therapies. A prospective, randomized, double-blind, placebo-controlled, within-subjects, phase II clinical trial of the effect AAV-CFTR on clinical recurrence of sinusitis will determine the clinical efficacy of AAV gene therapy for CF.

Adult↗
PubMed1997

Proficiency testing of clinical microbiology laboratories using modified decontamination procedures for detection of nontuberculous mycobacteria in sputum samples from cystic fibrosis patients. The Nontuberculous Mycobacteria in Cystic Fibrosis Study Group.

An improved decontamination method has been demonstrated to reduce overgrowth of mycobacterial media by Pseudomonas aeruginosa and allow the successful recovery of nontuberculous mycobacteria (NTM) from cystic fibrosis (CF) patients. Twenty microbiology laboratories participating in a multicenter investigation designed to determine the significance of NTM in CF patients were required to demonstrate proficiency in the incorporation of this improved method; this was accomplished by successful decontamination and culture workup of a panel of simulated sputum samples seeded with P. aeruginosa and various NTM. All laboratories successfully recovered NTM from samples with acid-fast bacillus (AFB) smear scores of 3+/4+ (i.e., 2 to 18 or > 18 organisms/field). Low-inoculum samples (1+/2+ AFB smears [2 to 18 organisms in 100 or 10 fields]) were problematic in that processed specimens were often smear and/or culture negative.

Bacteriological Techniques↗
PubMed1992

Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium.

Cystic fibrosis is the most common autosomal disorder in the Caucasian population. Since the description of the major mutation of this disease in 1989, over 150 of additional mutations have been identified in the CFTR gene. This update summarizes the different mutations identified and reported before March 15 by members of the international Cystic Fibrosis Genetic Analysis Consortium. The report includes information on DNA sequence variations found in the gene.

Amino Acid Sequence↗
PubMed1977

The biologic activities of cystic fibrosis serum. I. The effects of cystic fibrosis sera and calcium ionophore A 23187 on rabbit tracheal explants.

An ionophore A23187-induced increase in membrane permeability to calcium ions in culture medium produced a rabbit tracheal mucociliary response indistinguishable from that caused by cystic fibrosis (CF) sera on three different occasions. Specific chelation of calcium ions with EGTA in the basal medium Eagle (BME) media with no additive or in native CF sera abolished the mucociliary disturbances in all cases. Increased membrane permeability to calcium may be important in the production of the mucociliary response by CF serum factor(s) in the tracheal assay system.

Animals↗
PubMed2001

Liver expression in cystic fibrosis could be modulated by genetic factors different from the cystic fibrosis transmembrane regulator genotype.

During a multicentric study conducted in Southern Italy, we studied five sets of cystic fibrosis siblings bearing a strongly discordant liver phenotype, three with genotype DeltaF508/R553X, one with genotype DeltaF508/unknown, and one with genotype unknown/unknown. The siblings of each set were raised in the same family environment, and there were no interpair differences in nutritional state or in therapy compliance. All siblings had pancreatic insufficiency and moderate respiratory expression. One sibling of each of the five sets was free of liver involvement, and the other had severe liver expression. Other causes of liver disease (viral, metabolic, and genetic other than cystic fibrosis) were ruled out. Therefore, environmental factors, nutritional state, and therapy compliance are not involved in the liver expression of cystic fibrosis in the five unrelated sibships. This suggests that modifier genes, inherited independently of the cystic fibrosis transmembrane regulator gene, could modulate the liver expression in cystic fibrosis patients.

Adolescent↗
PubMed2000

Allergic bronchopulmonary aspergillosis in cystic fibrosis. A European epidemiological study. Epidemiologic Registry of Cystic Fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a disease resulting from a hypersensitivity response to Aspergillus fumigatus, although the pathogenesis of the disease is unknown and its prevalence in cystic fibrosis (CF) is still poorly defined. Data from the Epidemiologic Registry of Cystic Fibrosis (ERCF) on 12,447 CF patients gathered from 224 CF centres in nine European countries were analysed. The ERCF definition of ABPA diagnosis is a positive skin test and serum precipitins to A. fumigatus, together with serum immunoglobulin (Ig)E levels >1,000 U x mL(-1) and additional clinical or laboratory parameters. The overall prevalence of ABPA in the ERCF population was 7.8% (range: 2.1% in Sweden to 13.6% in Belgium). Prevalence was low <6 yrs of age but was almost constant approximately 10% thereafter. No sex differences were observed. ABPA affected 8.0% of patients with a deltaF508/deltaF508 genotype and 5-6% with deltaF508/G551D, deltaF508/G542X and deltaF508/N1303K genotypes. ABPA patients presented a lower forced expiratory volume in one second (FEV1) than those without ABPA at any age and the prevalence ranged from 6.6% in patients with FEV1 > or =20-12.9% in those with FEV1 <40%. ABPA was associated with higher rates of microbial colonization, pneumothorax and massive haemoptysis, and with higher IgG serum levels and poorer nutritional status. A mixed model regression analysis of lung function showed that FEVI decline during the follow-up period was not substantially different in ABPA patients compared with non-ABPA patients for any subgroups based on age or disease severity at enrollment. To conclude, allergic bronchopulmonary aspergillosis is a frequent complication in cystic fibrosis patients, particularly after the age of 6 yrs, and it is generally associated with a poorer clinical condition. However, any clear independent influence of allergic bronchopulmonary aspergillosis on the rate of lung function decline in the short term was not shown.

Adolescent↗
PubMed1990

Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells.

The cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in cultured cystic fibrosis airway epithelial cells and Cl- channel activation assessed in single cells using a fluorescence microscopic assay and the patch-clamp technique. Expression of CFTR, but not of a mutant form of CFTR (delta F508), corrected the Cl- channel defect. Correction of the phenotypic defect demonstrates a causal relationship between mutations in the CFTR gene and defective Cl- transport which is the hallmark of the disease.

Cell Membrane Permeability↗
PubMed1999

High-efficiency transfer of cystic fibrosis transmembrane conductance regulator cDNA into cystic fibrosis airway cells in culture using lactosylated polylysine as a vector.

To find more efficient vectors for the transfer of CFTR cDNA, lactosylated polylysine was explored for transfer into airway epithelial cells in primary culture. The efficacy and high efficiency of transfection were shown by several criteria: expression of both mRNA and protein for CFTR and the functional correction of the Cl- channel activity. Using specific combinations of agents to enhance the transfection, an efficiency of 90% was obtained as detected by in situ hybridization with digoxigenin-labeled probes generated against exon 14 of CFTR. The highest efficiency was observed by adding E5CA peptide (10 microg) and 5% glycerol to the transfection mixture. The degree of transfection could be controlled by the enhancing agents, thus modulating the efficiency of transfection. The highest level of transfection efficiency is equivalent to that reported for viral vectors. None of the agents or their combinations in the concentrations used were cytotoxic to the primary cells. Antibody pAb3145 was used to detect the expression of the CFTR protein in the cells. When an N-terminal GFP-CFTR fusion gene was used to transfect the CF cells a functional correction of the CFTR Cl- channel was detected by patch-clamp electrophysiology. The high efficiency of CFTR gene transfer with lactosylated polylysine leads to the conclusion that lactosylated polylysine is a promising vector to transfer the CFTR gene into human airway cells in culture.

Base Sequence↗
PubMed1997

International practice patterns by age and severity of lung disease in cystic fibrosis: data from the Epidemiologic Registry of Cystic Fibrosis (ERCF).

The Epidemiologic Registry of Cystic Fibrosis provides clinical profiles for more than 6,800 patients and descriptions of practice patterns across eight European countries. Preliminary cross-sectional analysis has been performed by age and pulmonary function as an assessment of disease severity. In general, pulmonary treatments including inhaled bronchodilators and rhDNase increased as lung disease became more severe. Use of a number of treatments, including mucolytic agents and inhaled corticosteroids, varied markedly from country to country. Several widely used therapies are not yet supported by controlled clinical trials, particularly in patients under 6 years of age. Nutritional intervention was more common in patients with advanced lung disease regardless of age. Patients with nasal polyps had less severe lung disease at each age than patients without polyps. It is clear that studies of early interventions are needed to determine the optimal types of treatments and the ages at which to begin treatment.

Adolescent↗
PubMed2004

Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects.

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, DeltaF508, results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation. Curcumin is a nontoxic Ca-adenosine triphosphatase pump inhibitor that can be administered to humans safely. Oral administration of curcumin to homozygous DeltaF508 CFTR mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans corrected these animals' characteristic nasal potential difference defect. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of DeltaF508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Thus, curcumin treatment may be able to correct defects associated with the homozygous expression of DeltaF508 CFTR.

Animals↗
PubMed1999

Calculating posterior cystic fibrosis risk with echogenic bowel and one characterized cystic fibrosis mutation: avoiding pitfalls in the risk calculations.

We describe a general approach to derive fetal risk following two separate test results that each raise the likelihood of the same fetal abnormality without clearly determining whether the abnormality exists. Echogenic bowel observed on fetal ultrasonography may have multiple causes, including an a priori risk of approximately 1% of cystic fibrosis (CF). On numerous occasions our laboratory tests have detected only normal cystic fibrosis transmembrane regulator (CFTR) alleles in fetuses with echogenic bowel. This result indicates that another cause most likely explains the abnormal ultrasound finding. One of our tested fetuses was heterozygous for the deltaF508 CFTR mutation and had a normal karyotype. Over 770 CFTR mutations have been described, and a significant proportion of parental mutant alleles could not be detected by our 25-mutation test. Further mutation analysis demonstrated that the fetus' mother carried the deltaF508 mutation but the father (of different ethnic background than the mother) did not carry a detectable mutation. Thus, this test result substantially increased the risk of the fetus having CF, while still not giving a definitive answer to whether the fetus was affected. A rigorous mathematical analysis determined that the 1% risk of CF following ultrasound study was increased to slightly under 12% following DNA analysis. The case is described, and the mathematical formulas are explained and illustrated with examples, along with a review of conditional probability (Appendix 2).

Bayes Theorem↗
PubMed2003

Contemporary management of rhinosinusitis and cystic fibrosis.

Historically, cystic fibrosis has been a devastating disease, with patients rarely living beyond childhood. Recent advances during the last two decades, however, have led to an improved understanding of the disease on a molecular level. Such understanding has in turn led to new treatments, longer life expectancy, as well as new challenges in the management of both pulmonary and extrapulmonary manifestations of cystic fibrosis. The otolaryngologist caring for patients with cystic fibrosis is thus challenged with the medical and surgical management of chronic sinusitis and sinonasal polyposis in these challenging circumstances.

Chronic Disease↗
PubMed1992

The occurrence of various non-delta F508 CFTR gene mutations among Hungarian cystic fibrosis patients.

Cystic fibrosis (CF) is an autosomal recessive disease caused by different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The frequency of the major mutation (delta F508) in the Hungarian population is 64%. To identify other common mutations in CF families from Hungary, 30 non-delta F508 CF chromosomes were analyzed for selected mutations in exon 11 (G551D, R553X, G542X), intron 4 (621 + 1G----T), intron 10 (1717-1G----A), exon 20 (W1282X), and in exon 21 (N1303K) of the CFTR gene. In 6 of the 30 non-delta F508 CF chromosomes the following mutations were detected: R553X, G542X, 1717-1G----A, W1282X, and N1303K. After analysis of the above eight mutations, 30% of CF chromosomes are as yet undefined and further analysis is planned.

Base Sequence↗
PubMed1997

Early pulmonary disease in cystic fibrosis.

In cystic fibrosis, airway infection and inflammation lead to chronic progressive lung disease. The pathogenesis of cystic fibrosis is still not completely understood, but increasing evidence indicates that the disease process occurs in young patients. Treatment of respiratory symptoms in young patients, although not well studied, is commonly accepted and includes the full range of treatments used in older patients-secretion clearance techniques, bronchodilators, anti-inflammatory agents, and antibiotics by oral, inhaled, and systemic routes. It is not clear, however, whether early treatment can delay or prevent progressive lung disease in these patients. Outcome measures, including determination of infant lung function, imaging techniques, and direct lower airway sampling through bronchoalveolar lavage are under development and will allow large, multicenter interventional trials in young children. These studies will be aimed at delaying the initiation of lung disease and slowing disease progression.

Bronchoalveolar Lavage↗
PubMed2006

A novel CFTR mutation found in a Chinese patient with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is rare in Chinese. We investigated the mutations in the gene of cystic fibrosis transmembrane conductance regulator (CFTR) in a Chinese CF patient and reviewed the clinical features, gene mutations in Chinese CF cases. METHODS: Blood samples were collected from a previously reported CF girl and her parents. The 24 coding exons of CFTR of the proband were amplified and sequenced. RESULTS: A Chinese girl of 16 years old was diagnosed as CF at the age of 14. She had recurrent productive cough with bronchiectasis in bilateral upper lobes, parasinusitis and otitis media, but without pancreatic involvement. Her sweat chloride was (108.9 +/- 3.3) mmol/L. A heterozygous novel missense mutation of 699 C --> A which results in the amino acid change of N189K was identified in exon 5. In addition, a heterozygous 3821 - 3823 delT mutation in exon 19 was found in CFTR. The mutation 699C --> A was inherited from her father, and the 3821 - 3823 delT mutation was from her mother. Twenty patients with CF in Chinese reported from 1974 to 2004 were also reviewed. DelF508 mutation was not found in the nine cases whose CFTR mutations were analyzed. CONCLUSIONS: The CF proband carries two heterozygous mutations (699C --> A and 3821 - 3823 delT) in CFTR. 699C --> A mutation is a novel mutation which is not reported previously. Review of reported Chinese cases suggests that the genotype of Chinese CF may be different from those of white cases. More studies are needed to understand the spectra of CFTR and clinical CF features in Chinese.

Adolescent↗
PubMed2004

Small intestinal glucose absorption in cystic fibrosis: a study in human and transgenic DeltaF508 cystic fibrosis mouse tissues.

Intestinal transport is disturbed in cystic fibrosis (CF), with both defective Cl- secretion and changes in absorption being reported. We have examined the effects of the disease on Na(+)-dependent glucose absorption by the small intestine. Active glucose absorption was monitored as changes in short-circuit current (SCC) in intact and stripped intestinal sheets from normal (Swiss) and transgenic CF (Cftr(tm1Eur) and Cftr(tm2Cam)) mice with the DeltaF508 mutation, and in jejunal biopsies from children with CF and normal controls. Na(+)-dependent glucose uptake at the luminal membrane was measured in brush-border membrane vesicles (BBMVs). Intact and stripped sheets of jejunum and midintestine from Swiss mice exhibited a concentration-dependent increase in SCC with glucose. Apparent Km values were similar in the two preparations, but the apparent Vmax was greater in stripped sheets. This difference was not due to a loss of neural activity in stripped sheets as tetrodotoxin did not influence the glucose-induced SCC in intact sheets. Similar results were observed in stripped sheets of jejunum and mid-intestine from wild-type Cftr(tm1Eur) mice, but in tissues from CF mice the apparent Vmax value was reduced significantly. A lower Vmax was also obtained in intact sheets of mid-intestine from CF (Cftr(tm2Cam)) mice. Jejunal biopsies from CF patients however, exhibited an enhanced glucose-dependent rise in SCC. Na(+)-dependent uptake by BBMVs from CF (Cftr(tm1Eur)) mice was not reduced compared with wild-type and Swiss BBMVs. It was concluded that, in contrast to human intestine, intestinal glucose absorption was reduced in transgenic mouse models of CF with the DeltaF508 mutation, but that this could not be detected in an isolated preparation of brush-border membranes. Transgenic mouse models of CF may not accurately reflect all aspects of intestinal dysfunction in the human disease.

Animals↗