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PubMed1992

Newborn screening for cystic fibrosis. The Cystic Fibrosis Neonatal Screening Study Group.

Many questions remain regarding the efficacy, risks, and costs of CF neonatal screening. The major gap in knowledge that must be closed before CF neonatal screening can be recommended generally in the United States concerns the potential long-term medical benefits of initiating treatment in early infancy. It would be premature, in our opinion, to implement mass population screening of newborns for CF until the benefits and risks have been fully defined, and an adequate and logistically feasible testing system developed and/or highly effective therapy for CF lung disease becomes available. It is for this reason we designed a randomized, controlled investigation of CF neonatal screening and implemented this project in Wisconsin during 1985. The fact that 5 years of randomized screening and systematic evaluation of outcome measures have not yet revealed any pulmonary benefits underscores the importance of rigorous investigation to resolve the efficacy issue. In addition to the medical uncertainties, we believe that the ethical issues described herein need to be resolved; this concern pertains not only to the CF patient but also the heterozygote carrier. On the other hand, financial factors and uncertainty about the cost effectiveness of CF neonatal screening do not appear to be dominant issues according to our assessment of current data. Despite the reservations related to the benefit/risk relationship, we expect that the discovery of the CF gene should have a favorable impact on neonatal screening for the disease, as well as for management.

Cost-Benefit Analysis↗

PubMed1992

Craniofacial morphology in children with cystic fibrosis.

Cystic fibrosis (CF) is a hereditary metabolic disorder with clinical symptoms of abnormal mucus production. This blocks the airways, gives pancreatic insufficiency, and increases sweat electrolytes. The progressive respiratory disease often leads to respiratory insufficiency and cor pulmonale. The aim of the present investigation was to examine the facial morphology in children with cystic fibrosis. The sample comprised 11 children with cystic fibrosis, who were divided in two groups, one with gastrointestinal disorders and the other with predominantly respiratory insufficiency. Eleven healthy children with normal occlusions were selected as controls. Lateral skull radiographs obtained in natural head posture were digitized, and linear and angular variables for the different groups calculated and compared statistically. The cystic fibrosis group showed open bite, decreased posterior facial height, increased mandibular and craniocervical inclination. Additionally, within the CF-group, the children with respiratory insufficiency differed more from the controls than the children with gastrointestinal disorders. Despite the small number of subjects, the facial morphology of the CF children showed a similar pattern to that of children with nasal respiratory obstruction due to enlarged adenoids or tonsils.

Adolescent↗

PubMed1987

Molecular genetic approaches to cystic fibrosis.

Cystic fibrosis (CF) is the most common lethal genetic disease of white populations. The underlying biochemical defect remains unknown, but recently polymorphic DNA markers linked to the cystic fibrosis gene have been discovered. These markers provide useful tools both for antenatal diagnosis and carrier detection, and for isolating the cystic fibrosis gene. In this paper we present data summarizing the results of retrospective and prospective antenatal series as well as a report on molecular approaches to isolation of the cystic fibrosis gene.

Cystic Fibrosis↗

PubMed1999

Chronic sinusitis in patients with cystic fibrosis.

Cystic fibrosis is a lethal genetic disorder whose victims currently have a median life span of approximately 30 years. With this increased life span, new aspects of the disease are identified in patients with cystic fibrosis, including chronic sinusitis. Sinusitis severely affects the quality of life of patients with sinusitis. This article discusses several aspects of sinusitis in patients with cystic fibrosis, including clinical presentation, radiologic findings, and treatment options. By recognizing and treating sinusitis in patients with cystic fibrosis, physicians may improve the quality of life of these patients.

Chronic Disease↗

PubMedDate not supplied

Inspissation of pancreatic zymogen material in cystic fibrosis.

Cystic fibrosis is characterized by the elaboration of abnormal, thick, tenacious mucus resulting in obstructive disease in sites such as the lung and pancreas. In the pancreas, acinar plugs of mucus have been reported as the earliest recognizable morphologic lesion in cystic fibrosis. Since mucus is not normally elaborated within the pancreatic lobular tissue, the mechanism of accumulation of mucus in acini is enigmatic. To investigate this phenomenon, well-preserved autopsy pancreatic tissue was studied ultrastructurally. This study demonstrated very prominent mucous metaplasia in these diseased organs. Acinar plugs, though, developed before mucous metaplasia. Subsequent histochemical study was performed, which demonstrated that the early acinar plugs exhibited the same staining properties as zymogen granules and were distinct from the staining pattern of mucus in pancreatic tissue of cystic fibrosis patients. These findings, then, indicate that zymogen material, not mucus, becomes inspissated in the acini of the pancreas in early cystic fibrosis, and that subsequent mucous metaplasia occurs as the obstruction and exocrine atrophy progress.

Child↗

PubMed1993

Cystic fibrosis.

Cystic fibrosis, an autosomal recessive disorder, is the most common genetic disease of Caucasians. One in 25 Caucasians are carriers of the gene. The gene is found far less commonly in other races. There are over 230 different alleles of the gene, located on the 7th chromosome. The gene encodes for a membrane protein that functions as an ion channel. The survival of cystic fibrosis patients has been gradually increasing, with a mean survival in 1990 of 28 years. If the current trend of improved survival continues, it is estimated that half of cystic fibrosis patients will be over 18 years old by 1996. Disease is found in many organs including the lungs, sinuses, pancreas, gastrointestinal tract, hepatobiliary system, sweat glands and reproductive tract. The majority of patients die of pulmonary disease. The airways become chronically colonized with bacteria that cannot be eradicated, leading to bronchitis, bronchiectasis, and finally, pulmonary fibrosis with respiratory failure. The pulmonary disease may be complicated by massive hemoptysis and pneumothorax. Patient survival rates have increased because of antibiotic therapy and improved nutrition with pancreatic enzyme replacements. New treatments for the pulmonary disease are under clinical trial and include antiproteases, amiloride, a sodium channel blocker, and DNase. The insertion of the normal cystic fibrosis allele into an animal model using a modified adenovirus with effective transcription suggests that gene therapy may be possible in the future, but safety and technical problems have to be addressed.

Cystic Fibrosis↗

PubMed2006

[Nasal potential difference test to diagnose cystic fibrosis].

Cystic fibrosis is usually diagnosed based on suspicion arising from a typical clinical picture and must be confirmed by either a finding of high chloride concentrations in sweat tests on 2 separate days or detection of 2 gene mutations. The nasal potential difference (NPD) test has been proposed to provide evidence of abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR), a receptor that forms a chloride ion channel. The test is especially useful for patients who have normal chloride concentrations in sweat tests and in whom 2 gene mutations related to cystic fibrosis have not been detected. The NPD test requires 2 electrodes connected to a voltmeter (a Tholy-Medicap device). One is placed on the nasal mucosa of the inferior turbinate and the other is placed subcutaneously on the forearm. A reading less than -40 mV is considered abnormal, as values under that cut point are never found in healthy individuals. Two abnormal NPD findings on separate days are required for a diagnosis of CFTR dysfunction. False negatives arise when the integrity of the epithelium is altered. After application of amiloride, NPD decreases more markedly in cystic fibrosis patients than in healthy individuals and applying isoproterenol or fenoterol after amiloride provokes no response in patients with the genetic defect that prevents chloride ion channel activation.

Action Potentials↗

PubMed1993

Feeding practices and nutrition recommendations for infants with cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disease characterized clinically by recurrent respiratory tract infections and malabsorption caused by pancreatic insufficiency. Typically diagnosed during infancy or childhood, CF impairs weight gain and growth, increases susceptibility to infection, and decreases longevity. Until recently, no guidelines for infant feedings were available. A consensus report prepared through the Cystic Fibrosis Foundation summarizes guidelines for the optimal nutrition management of patients with CF. This study identified current feeding practices and nutrition recommendations of dietitians who treat infants with CF and compared them with the recommendations of the consensus report. A survey was developed and sent to dietitians (n = 130) who work in accredited cystic fibrosis centers. Eighty-six dietitians (66%) responded after two mailings, and 75 usable surveys were analyzed. The survey investigated practitioners' recommendations for infant formulas, energy intake, nutritional supplements, and pancreatic enzyme supplementation. Protein hydrolysate infant formulas were recommended by most respondents (69%). Energy intake greater than 130% of the Recommended Dietary Allowances (RDAs) was recommended for well-nourished infants with CF and greater than 140% of the RDAs for malnourished infants with CF at 1 year of age. Formula additives, including fat and carbohydrate modules, were used by all respondents and were frequently added to infant foods to increase caloric density. Enteric coated pancreatic enzymes were used by the majority (76%) of dietitians. These findings indicate that most dietitians follow the nutrition guidelines established by the Cystic Fibrosis Foundation consensus report for goals for energy and protein intake, use of nutritional supplements, and replacement of pancreatic enzymes in infants with CF.

Cystic Fibrosis↗

PubMedDate not supplied

[Relation between gene mutations and pancreatic exocrine function in patients with cystic fibrosis].

Cystic fibrosis (CF), is the most common autosomal-recessive disease in Caucasians, with an incidence of approximately 1:2500 live births and a carrier frequency of approximately 4-5%. Causes of the disease are mutations in the CF gene which is located on chromosome 7 (region 7q31). Although a single mutation, a deletion of phenylalanine at position 508 (DF508) in exon 10, accounts for almost 70% of all CF chromosomes, over 900 other mutations have been identified in this large gene. CF gene encodes a membrane protein, which functions as aion channel- CFTR (cystic fibrosis transmembrane regulator protein). The exocrine pancreas is a gland that secretes water, enzymes and electrolytes into the intestinal lumen. These enzymes are needed for the normal digestion of food, and their reduced secretion in cystic fibrosis will cause malabsortion and malnutrition in CF patients. Pancreatic dysfunction in CF begins in uteri. Most patients with CF typically present insufficient pancreatic exocrine function (PI phenotype) and 10-15% of CF patients are pancreatic sufficient (PS phenotype). It has been shown elsewhere that the pancreatic function status in CF could be correlated to mutations in the CFTR gene. To determine the relation between genotype and pancreatic status, we analyzed 32 CF patients in whom both CF gene mutant alleles were identified (Table 1). Patients included in this study attended the Paediatric Department of Mother and Child Health Institute in Belgrade. The diagnosis was based on typical clinical manifestations and high levels of sweat chloride concentration (higher than 60 mmol/L). Of the 32 patients studied, only one (3.12%) was PS and the rest (96.88%) had PI phenotype. For each CF genotype the number of patients who were PI or PS is given in Table 1. The most striking observation was that all given genotypes correlated with either PI or PS, but not with both. On the basis of both preceding hypotheses and our present data (Table 2 and Table 3), it was possible to classify mutations as "severe" or "mild" with respect to pancreatic function (Table 4). This study strengthens the hypothesis that pancreatic function status in CF is genetically determined by specific mutations at the CF locus. Our data also strongly support the hypothesis that, with respect to pancreatic function, "mild" mutant alleles confer a higher residual CFTR activity than do "severe" mutant alleles. Although PS occurs in patients who have one or two "mild" mutations, PI occurs in patients who are homozygous or who are genetic compounds of two "severe" mutant alleles.

Adult↗

PubMed2003

Cor pulmonale in cystic fibrosis.

Cystic fibrosis is a common autosomal recessive disorder that is associated with a defective chloride transport channel in epithelial cells. The discovery of the cystic fibrosis gene in 1989 has led to a better understanding of the pathophysiology of the disease and the development of more effective therapeutic interventions. Chronic recurrent lung infections, pancreatic exocrine insufficiency, and elevated sweat chloride levels are hallmarks of the disease. Survival of patients with cystic fibrosis is steadily improving and most patients survive into adulthood. As lung disease progresses, secondary pulmonary hypertension and cor pulmonale are likely to develop. Pulmonary hypertension is correlated with the degree of hypoxemia and may be associated with increased mortality. The goal of therapy of cor pulmonale in cystic fibrosis is to correct hypoxemia and lower the elevated pulmonary artery pressures. This is best achieved by supplemental oxygen and aggressive treatment of the pulmonary disease with antibiotics and airway clearance techniques. It is also important to assess oxygenation during sleep and exercise. Bilateral lung transplantation is a treatment option for patients with end-stage lung disease, even in the presence of cor pulmonale.

Journal Article↗

PubMed1995

Gene therapy for the respiratory manifestations of cystic fibrosis.

Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The major manifestations are on the airway epithelial surface, with purulent mucus, recurrent infections, chronic inflammation, and loss of lung function. Consequent to mutations in both parental genes, airway epithelial cells have insufficient CFTR function. Because this can be corrected in vitro by transfer of the normal CFTR gene into airway epithelial cells, it is reasonable to hypothesize that the respiratory manifestations of CF could be prevented by transfer of the normal human CFTR cDNA to the airway epithelium in vivo. Over the past 6 years, our laboratory has developed a strategy to accomplish this goal using a replication deficient E1-E3- recombinant adenovirus (Ad) serotype 5 vector containing the normal human CFTR cDNA (AdCFTR). Studies with experimental animals demonstrate that with administration of such a vector to the airways, the human CFTR cDNA could be transferred to the airway epithelium, with expression of the human CFTR cDNA for at least 6 weeks. Extensive preclinical studies in vitro and in vivo demonstrated that the risks to humans were sufficiently low to initiate a Phase I trial using the AdCFTR vector to treat the respiratory manifestations of CF in humans. Following approval by the National Heart, Lung, and Blood Institute Institutional Review Board, the National Institutes of Health Biosafety Committee, the National Institutes of Health Recombinant DNA Advisory Committee, and the Food and Drug Administration, we initiated the first human trial of gene therapy for CF on April 17, 1993. The clinical study is still ongoing, with safety and efficacy data being evaluated, but there is clear evidence that it is feasible to transfer and express the normal CFTR cDNA to the airway epithelium in vivo in individuals with CF.

Adenoviridae↗

PubMed2006

Light and alcohol evoked electro-oculograms in cystic fibrosis.

Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) which is a chloride channel. CFTR is expressed in the retinal pigment epithelium (RPE) where it is believed to be important in generating the fast oscillations (FOs) and potentially contributing to the light-electro-oculogram (EOG). The role of CFTR in the alcohol-EOG is unknown. We recruited six individuals with CF (three homozygotes for Delta508 and three heterozygous for Delta508) and recorded the light- and alcohol-EOGs as well as the FOs and compared them to a control group. The results showed that in the CF group the amplitude of the alcohol- and light-EOGs were normal. However, the time to peak of the light- and alcohol-rises were significantly faster than in the control group. We conclude that CFTR is not primarily responsible for the alcohol- or light-rises but is involved in altering the timing of these responses. The FOs showed differences between the homozygotes, heterozygotes and the controls. The amplitudes were significantly higher and the time to the dark troughs were significantly slower in the heterozygote group compared to both controls and the homozygotes. In contrast, the homozygotes did not differ in either amplitude or the timing of the FOs compared to the controls.

Adaptation, Ocular↗

PubMed2006

[Pathogenesis and novel possibilities of diagnosis of cystic fibrosis].

Bacterial Infections↗

PubMed2001

Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis.

Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Initially, Cl- conductance in the sweat duct was discovered to be impaired in CF, a finding that has been extended to all CFTR-expressing cells. Subsequent cloning of the gene showed that CFTR functions as a cyclic-AMP-regulated Cl- channel; and some CF-causing mutations inhibit CFTR Cl- channel activity. The identification of additional CF-causing mutants with normal Cl- channel activity indicates, however, that other CFTR-dependent processes contribute to the disease. Indeed, CFTR regulates other transporters, including Cl(-)-coupled HCO3- transport. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues, indicating the importance of this activity. HCO3- and pH affect mucin viscosity and bacterial binding. We have examined Cl(-)-coupled HCO3- transport by CFTR mutants that retain substantial or normal Cl- channel activity. Here we show that mutants reported to be associated with CF with pancreatic insufficiency do not support HCO3- transport, and those associated with pancreatic sufficiency show reduced HCO3- transport. Our findings demonstrate the importance of HCO3- transport in the function of secretory epithelia and in CF.

Bicarbonates↗

PubMed2006

[Novel therapeutic possibilities in cystic fibrosis].

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in cystic fibrosis transport regulator (CFTR) gene. The clinical picture is characterized mainly by: bronchopulmonary disease (BPD), exocrine pancreatic insufficiency, hepatobiliary disease, meconium ileus, malnutrition and congenital bilateral absence of vas deferens. Life-span is closely related to respiratory system status, thus the treatment of the BPD is the key element of the management of CF. BPD is characterized by progressive destruction of bronchopulmonary tissues. It is due to chronic inflammation which, in turn, is caused by chronic colonization/infection by typical pathogens, such as Pseudomonas aeruginosa, Staphylococcus aureus and Burkholderia cepacia. The end stage of the BPD is the respiratory insufficiency and death. Management of BPD is complex, but two main aspects can be distinguished: treatment of exacerbations and chronic therapy. The first one is based on aggressive antibiotic treatment. The second one includes: chronic antibiotic administration, mucolytic therapy, control of bronchial hyperreactivity, anti-inflammatory treatment, oxygen supplementation and physiotherapy. The huge progress in management of cystic fibrosis achieved in last years can be proved by the fact that the mean life-span of patients increased from about 20 years in early seventies to nearly 50 years nowadays.

Anti-Bacterial Agents↗

PubMed1995

Quality of life in cystic fibrosis.

Cystic fibrosis is a chronic, multisystem genetic disease with a wide variability in clinical severity. In recent years, advances in therapy have led to improved patient survival into adulthood. New treatments are rapidly being developed and require evaluation to determine their efficacy. The measurement of health-related quality of life in cystic fibrosis provides additional information about the impact of this disease that cannot be obtained by physiological tests such as pulmonary function. An instrument to measure health-related quality of life is especially useful as an outcome measure for clinical trials. To date, only a few general quality-of-life (QOL) measures have been used in people with cystic fibrosis. There has been some demonstration of validity in 2 measures (the Quality of Well-Being Scale and the Functional Status Index) but the responsiveness of these instruments in this population has not been established. A cystic fibrosis-specific QOL instrument would be valuable as an outcome measure because of its potential for increased responsiveness, but no published measures exist as yet.

Cystic Fibrosis↗

PubMed2004

Establishing a diagnosis of cystic fibrosis.

Cystic fibrosis (CF) is a recessively inherited condition caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Characterization of the genetic defect has improved understanding of the condition and, in the majority of cases, diagnosis is straightforward. However, in a significant number, diagnosis remains a challenge. This paper will discuss the management of these issues and reflect on atypical presentations. In addition we will discuss situations in which genetic variations of the CFTR gene are not associated with a classical CF phenotype and the implications for practice in both paediatric and adult clinics.

Cystic Fibrosis↗

PubMed1995

Altered antioxidant status and increased lipid peroxidation in children with cystic fibrosis.

Cystic fibrosis often combines an infectious pathology with a syndrome of malabsorption, both potentially capable of favoring the deleterious effects of reactive oxygen species. This study was a simultaneous evaluation of the main antioxidant systems dependent on micronutrients and of lipid peroxidation products in 27 children with cystic fibrosis and 17 healthy children. Plasma of cystic fibrosis patients showed very low concentrations of beta-carotene (0.30 +/- 0.2 vs 1.63 +/- 0.5 mumol/g cholesterol, P < 0.0001) and a lower activity of selenium-dependent glutathione peroxidase (263.6 +/- 42 vs 296.9 +/- 57 U/L, P = 0.028). In parallel, the higher plasma concentrations of organic hydroperoxides (171.5 +/- 54.4 vs 122.6 +/- 23.3 mumol/L, P = 0.001) and of thiobarbituric acid reactants (2.9 +/- 0.6 vs 2.4 +/- 0.3 mumol/L, P = 0.004) reflected oxidative stress in this pathology. In addition, in these patients the major substrates of lipoperoxidation were significantly lower, whether they be linoleic acid (2.26 +/- 0.8 vs 3.60 +/- 0.9 mmol/L, P < 0.0001) or arachidonic acid (0.55 +/- 0.2 vs 0.74 +/- 0.2 mmol/L, P = 0.006). These results suggested that nutritional deficiencies resulting from malabsorption could considerably amplify disorders related to toxicity of reactive oxygen species. These nutritional deficits could also be aggravated by the destruction of antioxidant compounds by the inflammatory process.

Adolescent↗