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PubMed2004

Additional disruption of the ClC-2 Cl(-) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models.

Cystic fibrosis is a fatal inherited disease that is caused by mutations in the gene encoding a cAMP-activated chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). It has been suggested that the cystic fibrosis phenotype might be modulated by the presence of other Cl(-) channels that are coexpressed with CFTR in some epithelial cells. Because the broadly expressed plasma membrane Cl(-) channel, ClC-2, is present in the tissues whose function is compromised in cystic fibrosis, we generated mice with a disruption of both Cl(-) channel genes. No morphological changes in their intestine, lung, or pancreas, tissues affected by cystic fibrosis, were observed in these mice. The mortality was not increased over that observed with a complete lack of functional CFTR. Surprisingly, mice expressing mutant CFTR (deletion of phenylalanine 508), survived longer when ClC-2 was disrupted additionally. Currents across colonic epithelia were investigated in Ussing chamber experiments. The disruption of ClC-2, in addition to CFTR, did not decrease Cl(-) secretion. Colon expressing wild-type CFTR even secreted more Cl(-) when ClC-2 was disrupted, although CFTR transcript levels were unchanged. It is concluded that ClC-2 is unlikely to be a candidate rescue channel in cystic fibrosis. Our data are consistent with a model in which ClC-2 is located in the basolateral membrane.

Animals↗

PubMedDate not supplied

Nasal and paranasal sinus surgery in children with cystic fibrosis.

Cystic fibrosis (mucoviscidosis; fibrocystic disease of the pancreas) is an inherited autosomal recessive disorder that results in generalized dysfunction of exocrine glands. Chronic pansinusitis with nasal polyposis occurs frequently in this disease. Polypectomy and sinus drainage procedures are often required in those cases refractory to medical therapy. Recurrence of nasal polyps following removal is common. Controversy exists regarding the timing and extent of surgery. The management of 40 children with cystic fibrosis who underwent nasal polypectomy, intranasal ethmoidectomy, and Caldwell-Luc procedures to treat extensive sinusitis and nasal polyposis forms the basis for this report. Follow-up data indicate that fewer recurrences and longer symptom-free intervals result when intranasal ethmoidectomy and Caldwell-Luc procedures are combined with polypectomy.

Child↗

PubMed1997

Intestinal physiology and pathology in gene-targeted mouse models of cystic fibrosis.

Cystic fibrosis (CF) is a fatal genetic disorder that affects approximately 1 in 2,500 live Caucasian births. The disease can be described as a generalized exocrine disease affecting a variety of epithelial tissues, with early manifestation as meconium ileus in a significant number of neonates. Cloning of the gene causing CF was accomplished in 1989, and the protein product, cystic fibrosis transmembrane conductance regulator (CFTR), has been conclusively shown to be an adenosine 3',5'-cyclic monophosphate (cAMP)-regulated Cl- channel. Subsequently, several mouse models of CF were generated by gene-targeting approaches in an attempt to further understand this disease. The initial excitement generated by the emergence of these mouse models was somewhat tempered by the finding that none of the models developed airway disease, which is currently responsible for most of the morbidity and mortality in the human CF population. However, the various CF mouse models, of which there are now 10, are remarkably similar to their human counterparts with respect to intestinal pathophysiology. Most importantly, the intestinal tract of the CF mouse models demonstrates the absence of cAMP-mediated Cl- transport, which is a hallmark of CF disease. Furthermore, the murine CF intestinal tract also shows an inability to secrete HCO3-, defective cAMP regulation of electroneutral NaCl absorption, and elevated electrogenic Na+ transport in the distal colon, as well as other ion transport perturbations. Besides the fundamental mechanisms of ion transport studied in the murine CF intestinal tract, these models have also been important in understanding other tissues with regard to CF. Mice heterozygous for the CFTR knockout gene have a reduced ability to secret Cl- and fluid and therefore provide further support for the CF "heterozygote advantage" hypothesis. Some CF mouse models maintain a limited ability to secrete Cl-, which may be due to accessory genes that are hypothesized to ameliorate disease severity in the intestines of these mice. This review describes the CF models generated and compares the murine defects in ion transport with observed abnormalities in the human CF intestine.

Animals↗

PubMed2004

Only when I cough? Adults' disclosure of cystic fibrosis.

Cystic fibrosis has traditionally been conceptualized as a fatal childhood disease. In contrast, survival age has been increasing steadily such that adults now routinely seek to gain employment and form close relationships, situations that might require telling others about the disease. Here, the author examines three situations of disclosure based on interviews with 31 adults with the disease. First, in a low-risk situation, for example a short period of social contact, a low level of intimacy exists between the adult with cystic fibrosis and another. Here the disease may be concealed easily with little risk of discovery. Second, in a medium-risk situation, the perceived reaction of the other begins to influence the decision to disclose, as the level of intimacy becomes higher. Last, in high-risk situations, such as employment, the consequences of disclosing or concealing CF are most severe. However, a multiplicity of factors, including perceived social support and disease progression, are seen to influence adults' decisions to disclose their disease.

Adolescent↗

PubMed1990

Potential for alterations in family process: when a family has a child with cystic fibrosis.

Cystic Fibrosis (CF) is a disease that has profound consequences on a family unit. As a genetically transmitted, chronic illness, it influences every aspect of family life, including time constraints, finances, and relationships among family members. The purpose of this article is to demonstrate the cumulative effect of the nursing diagnoses related to the pathophysiology of CF on the nursing diagnosis, Potential for Alterations in Family Process, when a family has a child with cystic fibrosis. This nursing diagnosis was first recognized by the North American Nursing Diagnosis Association (NANDA) in 1982. It is vital that nurses be able to differentiate between a family having difficulty coping with a child with CF in the home, and one that is coping well on its own. The children of families that are not coping well tend to be hospitalized more than those of families that are coping well. The families use the hospitalizations as rest periods for themselves. By recognizing the cues identified by NANDA of a family having problems, early intervention can be initiated before the family is in a crisis. The family must live with CF on a daily basis for the remainder of the child's life; therefore it must be able to function at its optimum level. It is nursing's responsibility to be able to recognize and assist the family in need. A knowledge of the nursing diagnosis, Alterations in Family Process, will assist nurses in fulfilling this obligation to the family.

Adaptation, Psychological↗

PubMedDate not supplied

Potential for alterations in family process: when a family has a child with cystic fibrosis.

Cystic fibrosis (CF) is a disease that has profound consequences on a family unit. As a genetically transmitted, chronic illness, it influences every aspect of family life, including time constraints, finances, and relationships among family members. The purpose of this article is to demonstrate the cumulative effect of the nursing diagnoses related to the pathophysiology of CF on the nursing diagnosis, Potential for Alterations in Family Process, when a family has a child with cystic fibrosis. This nursing diagnosis was first recognized by the North American Nursing Diagnosis Association (NANDA) in 1982. It is vital that nurses are able to differentiate between a family having difficulty coping with a child with CF in the home, and one that is coping well on its own. The children of families that are not coping well tend to be hospitalized more than those of families that are coping well. The families use the hospitalizations as rest periods for themselves. By recognizing the cues identified by NANDA of a family having problems, early intervention can be initiated before the family is in a crisis. The family must live with CF on a daily basis for the remainder of the child's life; therefore it must be able to function at its optimum level. It is nursing's responsibility to be able to recognize and assist the family in need. A knowledge of the nursing diagnosis, Alterations in Family Process, will assist nurses in fulfilling this obligation to the family.

Adaptation, Psychological↗

PubMed2006

[MRI in mucoviscidosis (cystic fibrosis)].

Cystic fibrosis (CF) is a multi-systemic disease with major impact on the lungs. Pulmonary manifestation is crucial for the prognosis and life expectancy of patients. Imaging modalities and lung function tests reflect the pulmonary status in these patients. The standard imaging modality for diagnosis and follow-up of pulmonary changes is chest x-ray. The gold standard for the detection of parenchymal lung changes remains high resolution computed tomography (HRCT), but this is not used routinely for CF-patients due to radiation exposure. Magnetic resonance imaging (MRI) used to be of no importance in monitoring cystic fibrosis lung disease, as shown in studies from the 1980s and early 1990 s. The continuing improvement of MRI techniques, however, has allowed for an adequate application of this non-radiation method in diagnosing the major pulmonary findings in CF, in addition to the assessment of lung function.

Cystic Fibrosis↗

PubMed1996

[Reduced concentration of insulin-like growth factor I in patients with cystic fibrosis].

Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function and linear growth. Using radioimmunoassay we measured IGF-I once in 235 of our 240 patients (114 males, 121 females, median age 16.2 years, range 0.1-44.0 years). IGF-I was significantly reduced compared with a healthy Scandinavian control population: Mean (-2SD to +2SD) IGF-I-SD score -0.97 (-3.7 to 1.7) in males and -0.67 (-3.2 to 1.9) in females, both values were significantly different from zero (p < 0.001). Height SD score was -0.95 (-3.3 to 1.4) in males and -0.81 (-3.2 to 1.6) in females (p < 0.001). The low IGF-I concentrations may reflect the catabolic state of many patients with cystic fibrosis and play a part in their abnormal growth pattern.

Adolescent↗

PubMed1998

Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis.

Cystic fibrosis (CF) is an inherited disorder associated with severe inflammation and repeated bacterial infection and colonization in the lung. Airway epithelium is involved in defence against bacteria, but this system may be defective in CF. Pro-inflammatory cytokines can stimulate the expression of inducible nitric oxide synthase (iNOS), an enzyme generating nitric oxide, which functions as an important mediator in host defence mechanisms. To understand better the poor resistance to infections in the CF lung, the expression of the iNOS gene was investigated in explanted lungs from patients with cystic fibrosis (n = 13), bronchiectasis (n = 3), emphysema (n = 14), and in normal lungs (n = 8). In addition, bronchial epithelial cell lines were examined to study iNOS gene expression in vitro. Strong immunoreactivity for iNOS was seen in inflammatory cells and bronchial epithelium in all the diseased lungs, except for bronchial epithelium in CF. Quantitative analysis showed a significant reduction in the area of epithelium immunostained in CF [CF 6.8 +/- 1.6 (% +/- SEM); emphysema 18.2 +/- 2.8; normal 9.6 +/- 0.8, P < 0.01], regardless of steroid treatment. These results were supported by in situ hybridization of iNOS mRNA, which showed a pattern of gene expression in CF, emphysema, and normal lung which paralleled that of protein immunoreactivity. Stimulation with cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) increased the expression of iNOS mRNA detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in cultures of normal (16HBE14o-), but not CF (CFBE41o-, with delta F508 CFTR mutation) epithelial cells. Expression of iNOS in inflammatory cells suggests that the gene is normal in CF. Absence of iNOS from bronchial epithelium may be due to low expression of the gene resulting from abnormalities in the signalling system that normally causes induction, such as cytokine receptors, second messengers or transcription factors. The resulting deficiency of the nitric oxide defence system may be relevant to the susceptibility of CF patients to pulmonary bacterial colonization.

Adult↗

PubMed2006

Inhaled heparin in cystic fibrosis.

Cystic fibrosis (CF) is characterised by inspissated airway secretions and chronic endobronchial infection associated with exuberant neutrophilic inflammation. Unfractionated heparin may be mucolytic and has demonstrated a number of anti-inflammatory properties; however, further safety data are needed in these subjects who are at risk of airway bleeding. The current study aimed to assess the medium-term safety and tolerability of moderately high-dose inhaled heparin in CF adults and to explore possible in vivo mucolytic and anti-inflammatory outcomes. A randomised, double-blind, placebo-controlled crossover study of twice daily inhalation of 50,000 IU of heparin for 2 weeks was undertaken in CF adults, with a 1-week washout period. Eighteen subjects were randomised and 14 (mean+/-sd age 23+/-7.8 yrs and percentage-predicted forced expiratory volume in one second 52.1+/-15.56%) completed the study protocol. Heparin neither affected blood coagulation parameters nor resulted in any increase in adverse events. Heparin inhalation had no significant effect upon forced expiratory volume in one second, symptoms of sputum clearance or sputum inflammatory markers. The current pilot study demonstrated no evidence of improved sputum clearance with 50,000 IU of inhaled heparin given twice daily to adult cystic fibrosis subjects. However, inhaled heparin was safe and the future evaluation of larger doses over a longer period may be warranted.

Administration, Inhalation↗

PubMed1999

Effect of elective antibiotic therapy on resting energy expenditure and inflammation in cystic fibrosis.

Cystic fibrosis (CF) patients often present with malnutrition which may partly be due to increased resting energy expenditure (REE) secondary to inflammation. Both REE and tumour necrosis factor-alpha (TNF-alpha), as other markers of inflammation, are elevated during respiratory exacerbations and decrease after antibiotic treatment. However, the effect of antibiotic therapy on REE and inflammation in patients without respiratory exacerbation is not known. The aim of our study was to determine the effect of such an elective antibiotic therapy on REE, TNF-alpha, and other serum markers of inflammation. Twelve CF patients 5F/7M, age 15.9 +/- 6.1 years, weight for height ratio 89 +/- 8% without clinically obvious exacerbation and treated by intravenous antibiotics were studied. Both before (D0) and after (D14) treatment, pulmonary function tests were performed. REE was measured by indirect calorimetry and blood taken to measure inflammation parameters. Body weight increased by 1.1 kg from D0 to D14 (P < 0.001), composed of 0.3 kg fat mass and 0.8 kg fat-free mass (FFM). The forced expiratory volume at 1 s increased from 43 +/- 15% of predicted at D0 to 51 +/- 15% of predicted at D14 (P < 0.01). Mean REE was 41.1 +/- 7.6 kcal/kg FFM per day at D0 and did not change significantly at D14 (40.6 +/- 8.5 kcal/kg FFM per day). Serum markers of inflammation decreased from D0 to D14: C-reactive protein 17 +/- 17 mg/l to 4 +/- 7 mg/l (P < 0.05), elastase 62 +/- 29 microg/l to 45 +/- 18 microg/l (P < 0.02), orosomucoid acid 1.25 +/- 0.11 g/l to 0.80 +/- 0.15 g/l (P < 0.001), and TNF-alpha 37 +/- 14 pg/ml to 29 +/- 6 pg/ml (P = 0.05). Individual values showed a correlation between changes in REE and in TNF-alpha (P < 0.02). The contribution of inflammation to energy expenditure is possible but appears to be minimal in cystic fibrosis patients treated by antibiotics on a regular basis in the absence of clinically obvious exacerbation.

Adolescent↗

PubMed2002

Tidal expiratory flow limitation and chronic dyspnoea in patients with cystic fibrosis.

Cystic fibrosis (CF) eventually leads to hyperinflation linked to tidal expiratory flow limitation (FL) and ventilatory failure. Presence of FL was assessed at rest in 22 seated children and adults with CF (forced expiratory volume in one second (FEV1) range: 16-92% predicted), using both the negative expiratory pressure (NEP) technique and the "conventional" method based on comparison of tidal and maximal expiratory flow/volume curves. In addition, chronic dyspnoea was scored with the modified Medical Research Council (MRC) scale. Measurements were made before and 15 min after inhalation of salbutamol. With NEP, FL was present in only three malnourished patients, who had the lowest FEV1 values (16-27% pred) and claimed very severe dyspnoea (MRC score 5). By contrast, an additional seven patients were classified as FL with the conventional method. Six of these patients had little or no dyspnoea (MRC scores 0-1). Salbutamol administration had no effect on the extent of FL, and the concomitant decrease in functional residual capacity (FRC) was too small to play any clinically significant role. This study concluded that in seated patients with cystic fibrosis, expiratory flow limitation is absent at rest, unless the forced expiratory volume in one second is <30% predicted. If present, expiratory flow limitation is associated with severe chronic dyspnoea. The conventional method for assessing expiratory flow limitation is not reliable and bronchodilator administration has little effect on expiratory flow limitation.

Adolescent↗

PubMed2004

Lung inflammation as a therapeutic target in cystic fibrosis.

Cystic fibrosis (CF) lung disease is characterized by chronic neutrophilic inflammation and infection. Effective management of airway inflammation could complement other therapies for the treatment of CF. Recent progress has been made in understanding the signaling pathways regulating inflammatory cytokines in the lung. Here we examine the mechanisms responsible for inflammation in the CF lung, and discuss potential therapeutic strategies targeting inflammation.

Animals↗

PubMed1993

Spectrum of mutations in cystic fibrosis.

Cystic fibrosis (CF) is a disorder characterized by elevated sweat electrolytes and thick mucous secretions due to abnormal chloride permeability in epithelial tissues. The gene responsible for this disease, the CF transmembrane conductance regulator (CFTR) was identified by a positional cloning approach 3 years ago. Since that time, over two hundred mutations have been found in CFTR genes from affected individuals. Analysis of these disease-associated mutations has provided new insight into the etiology of this disease and into the mechanisms of epithelial electrolyte secretion.

Cystic Fibrosis↗

PubMed1999

Identification of novel mutations of the CFTR gene in a Japanese patient with cystic fibrosis.

Cystic fibrosis (CF) is an inheritable disorder characterized by defective epithelial chloride transport and progressive lung disease, caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The subject of this study was an 8-year old Japanese boy, who developed typical CF symptoms including meconium ileus, pancreatic insufficiency, an elevated sweat chloride concentration and pulmonary disease. Analysis of the CFTR gene of this patient revealed compound heterozygous mutations in exon 11 (1742 delAC) and intron 9 (1525-18 GtoA) of the CFTR gene.

Child↗

PubMed2003

Update on gene therapy for cystic fibrosis.

Cystic fibrosis (CF) is a monogenic autosomal recessive disease. Although several organs are affected, severe lung disease is the cause of most morbidity and mortality in CF individuals. The first clinical trials in CF patients were carried out in 1993, and to date, 29 trial protocols have been published. Although proof-of-principle for gene transfer to the lung has been established, efficiency is generally low. Steady progress has been made over the last two years and key papers, including recent advances in viral and nonviral gene transfer agents, will be reviewed here.

Animals↗

PubMed2000

Failure of local defense mechanisms in cystic fibrosis.

Cystic fibrosis (CF) is an hereditary disease with pancreatic insufficiency and chronic respiratory tract infections leading to irreversible lung damage as its main features. The typical pathogen for the respiratory disease is Pseudomonas aeruginosa. Although the insight into the pathophysiology and genetics of CF have evolved over the past 10 years, there is not yet a full understanding of the increased susceptibility for respiratory infections, specifically with Pseudomonas aeruginosa. In this overview we elucidate the current knowledge and describe the existing hypothesis on the possible links between the pathophysiological defects and the failure of the local defense mechanism in CF airways.

Chronic Disease↗

PubMed1998

Is DNA destiny? A cure for cystic fibrosis.

Cystic fibrosis (CF) remains an attractive target for cure by gene therapy. Results from several trials are reviewed in this article and have shown that mature airway epithelial cells are relatively resistant to gene transfer, that host immune responses determine the duration of transgene expression and define the toxicity, and that the efficiency of transfection remains low. Significant hurdles to the development of gene therapy remain, including the definition of efficacy endpoints, the ability to produce enough material, and the ability to dose the entire lung. Nonetheless, invaluable insights into CF and pulmonary biology have been gained in the gene therapy research effort.

Adenoviruses, Human↗