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PubMed2004

Depression in children and adolescents with cystic fibrosis: case studies.

OBJECTIVE: Cystic fibrosis is an autosomal recessively inherited multi-system disorder of children and adults characterized by the obstruction and infection of airways presenting as a wide variety of symptoms. It has varying degrees of psychological impact on patients and their families, requiring numerous adjustments in their life styles. Newer sophisticated medical treatments of cystic fibrosis has led to an increase in life expectancy; however, the same kind of progress has not been made in the psychological interventions available to treat emotional disturbances. METHOD: We report three cases of children and adolescents with cystic fibrosis who were diagnosed with depression and treated with a combination of antidepressant medications and other psychosocial interventions. RESULTS AND CONCLUSIONS: Two of the three cases suggest that treatment with antidepressant medications has a positive influence on psychological outcomes. We further propose clinical studies to test efficacy, safety, and long-term effects of these medications in patients with cystic fibrosis.

Adolescent↗
PubMed2001

[Cystic fibrosis in adulthood].

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations of the CFTR gene. The number of adult CF patients increased dramatically, since life expectancy is now around thirty years. CF is usually a pediatric disease. In adult patients the disease associate a diffuse bronchectasia with chronic colonisation of sputum with Pseudomonas aeruginosa, and pancreatic insufficiency. Mortality is usually related to respiratory insufficiency. One third of adult patients develop diabetes mellitus. A diagnosis of CF can be made in adult patients particularly when it exists male infertility with congenital absence of vas deferens, chronic sinusitis or diffuse bronchectasia or chronic pancreatitis, acute and recurrent pancreatitis, allergic bronchopulmonary aspergillosis. The diagnosis is established with positive sweat chloride concentration, or double CFTR mutations and/or other suggestive organ involvement.

Adult↗
PubMed2001

Cystic fibrosis and CFTR.

Cystic fibrosis (CF) is a complex disease affecting epithelial ion transport. There are not many diseases like CF that have triggered such intense research activities. The complexity of the disease is due to mutations in the CFTR protein, now known to be a Cl(-) channel and a regulator of other transport proteins. The various interactions and the large number of disease-causing CFTR mutations is the reason for a variable genotype-phenotype correlation and sometimes unpredictable clinical manifestation. Nevertheless, the research of the past 10 years has resulted in a tremendous increase in knowledge, not only in regard to CFTR but also in regard to molecular interactions and completely new means of ion channel and gene therapy.

Cystic Fibrosis↗
PubMed2003

Pubertal development in cystic fibrosis: an overview.

Cystic fibrosis (CF) is an autosomal recessive disease characterized by respiratory and intestinal insufficiencies. It has been reported in the literature that patients with CF show delayed growth and puberty and girls with CF achieve menarche at older age than normal females. Infertility, in both sexes, and menstrual dysfunction, in girls, are common in patients with CF. Previous data suggest that the degree of failure of growth and development is correlated with malnutrition and severity of progressing pulmonary disease. Despite improved nutrition and intensive treatment, patients with CF have delayed puberty and growth pubertal spurt. This maturational lag is accompanied by a significant delay in attaining pubertal levels of insulin-like growth factor-I (IGF-I), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex steroid hormones.

Cystic Fibrosis↗
PubMed1997

Toward cystic fibrosis gene therapy.

Cystic fibrosis (CF) is a common genetic disorder characterized by defective epithelial chloride transport and progressive lung disease. Although great strides have been made in the treatment of CF, it remains lethal, often by early adulthood. CF is one of the most extensively researched genetic diseases as a target for gene therapy development. It may also serve as an important model for gene therapy of other diseases. Preclinical and clinical research has lead to the rapid development of a variety of vectors designed to correct the basic defect in CF, including adenovirus, adeno-associated virus, and liposomes. Clinical studies have identified the host immune response and low vector efficiency as key impediments to effective CF gene therapy. Further research promises to refine vector technology and bring CF gene therapy to the bedside.

Adolescent↗
PubMed2006

Immunopathophysiologic mechanisms of cystic fibrosis lung disease.

Cystic fibrosis is a life-threatening autosomal recessive disorder with a highly variable clinical presentation. The pathophysiology is related to the mutant transmembrane conductance regulator (CFTR), a chloride channel that is encoded by the CF single gene located on chromosome 7. The variability of the clinical presentations, even among patients carrying the same mutation, is extensive enough to justify the hypothesis that other pathophysiologic mechanisms participate in the evolution of the disease phenotype. Presented here are recent lines of research on the contributing factors to respiratory tract morbidity, as well as the innate defense mechanisms in the CF lungs, the cytokines and chemokines that influence the inflammatory processes, the antioxidative system, and the composition of the airways surface fluid. These studies concluded that the clinical presentation is determined by pathology of the CFTR as well as by other mechanisms, some of which are related to the CFTR functions and others to the products of modifier genes as well as the influence of the environment.

Cystic Fibrosis↗
PubMed2003

Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein, an epithelial chloride channel expressed in the airways, pancreas, testis, and other tissues. A central question is how defective CFTR function in CF leads to chronic lung infection and deterioration of lung function. Several mechanisms have been proposed to explain lung disease in CF, including abnormal airway surface liquid (ASL) properties, defective airway submucosal gland function, altered inflammatory response, defective organellar acidification, loss of CFTR regulation of plasma membrane ion transporters, and others. This review focuses on the physiology of the ASL and submucosal glands with regard to their proposed role in CF lung disease. Experimental evidence for defective ASL properties and gland function in CF is reviewed, and deficiencies in understanding ASL/gland physiology are identified as areas for further investigation. New model systems and measurement technologies are being developed to make progress in establishing lung disease mechanisms in CF, which should facilitate mechanism-based design of therapies for CF.

Animals↗
PubMed2003

Modifier genes in cystic fibrosis lung disease.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterized by progressive bronchiectatic lung disease and pancreatic exocrine insufficiency. A broad spectrum of disease severity exists; some individuals with CF die early in childhood, whereas others live well into adulthood with only mild lung disease. It is now clear that CFTR genotype alone does not account for the wide diversity in CF pulmonary phenotype. Evidence is accumulating that secondary genetic factors separate from the CFTR locus significantly influence the severity of CF lung disease. The general classes of these potential modifier genes include inflammatory and antiinflammatory mediators, antioxidants, mediators of airway reactivity, molecules involved in CFTR trafficking, and alternative ion channels. The best-studied CF candidate modifiers include mannose-binding lectin, glutathione-S-transferase, transforming growth factor-beta1, tumor necrosis factor-alpha, beta2-adrenegic receptor, and HLA class II antigens. Ongoing studies designed to identify genetic modifiers of CF pulmonary phenotype may offer new insights into the pathophysiology of CF lung disease and provide leads for new CF therapeutic interventions.

Cystic Fibrosis↗
PubMed2001

Recombinant adeno-associated virus vectors for cystic fibrosis gene therapy.

Cystic fibrosis (CF) is an autosomal recessive inherited disorder that affects approximately 30,000 North Americans. Defects in the CF transmembrane conductance regulator (CFTR) gene lead to altered secretions from exocrine glands and the pulmonary airways, to a heightened susceptibility to airway infections with Pseudomonas aeruginosa, and to severe airway inflammation. Early attempts to develop a genetic therapy for CF have not met with great clinical success, but these efforts have driven the development of viral gene transfer technology for in vivo gene delivery. The recombinant adeno-associated virus (rAAV) system has proven to be safe for in vivo gene delivery in the airways of experimental animals and CF patients, although potential barriers to delivery have been identified. These barriers may limit the transduction efficiency of this vector, especially in the context of the inflamed airways of adolescent and adult CF patients. We anticipate that the use of alternative rAAV serotype capsids and other vector alterations, along with targeting the lungs of CF patients in the earlier stages of their disease, might eventually allow for these potential limitations to be overcome.

Animals↗
PubMed2000

[Correlation of results of immunocytochemical, electrophysiologic, and molecular studies in patients with cystic fibrosis].

In 13 cystic fibrosis (CF) patients of 5 to 23 years of age with a known mutation spectrum of gene CFTR, sweat chloride values and nasal-potential differences (NPD) were measured and localization characteristics of the protein product of gene CFTR in the cells of nasal epithelium were studied. Sweat Chloride values were normal or boundary (24 to 62 mM/l) in six CF patients. In seven CF patients, these values were significantly above the estimates for the control group. On average, the NPD values were -44.7 +/- 2.2 mV (from -32.5 to -68.9 mV) and -17.2 +/- 1.8 mV (from -6.8 to -30.2 mV) in CF patients and the control group, respectively. Histochemical studies clearly revealed the localization of the CFTR protein on the apical membrane of the nasal epithelium. Depending on the type of mutation, the protein product of gene CFTR was either absent or regularly distributed in the cytoplasm in CF patients; it was not detected in the apical membrane. Thus, NPD measurements and the analysis of the localization of the protein product of gene CFTR in scrapes of nasal epithelium were shown to be additional, highly informative methods of CF diagnostics.

Adolescent↗
PubMed2003

Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium.

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-dependent airway epithelial bicarbonate transport is hypothesized to participate in airway surface liquid pH regulation and contribute to lung defense. We measured pH and ionic composition in apical surface liquid (ASL) on polarized normal (NL) and CF primary bronchial epithelial cell cultures under basal conditions, after cAMP stimulation, and after challenge with luminal acid loads. Under basal conditions, CF epithelia acidified ASL more rapidly than NL epithelia. Two ASL pH regulatory paths that contributed to basal pH were identified in the apical membrane of airway epithelia, and their activities were measured. We detected a ouabain-sensitive (nongastric) H+,K+-ATPase that acidified ASL, but its activity was not different in NL and CF cultures. We also detected the following evidence for a CFTR-dependent HCO3- secretory pathway that was defective in CF: (i). ASL [HCO3-] was higher in NL than CF ASL; (ii). activating CFTR with forskolin/3-isobutyl-1-methylxanthine alkalinized NL ASL but acidified CF ASL; and (iii). NL airway epithelia more rapidly and effectively alkalinized ASL in response to a luminal acid challenge than CF epithelia. We conclude that cultured human CF bronchial epithelial pHASL is abnormally regulated under basal conditions because of absent CFTR-dependent HCO3- secretion and that this defect can lead to an impaired capacity to respond to airway conditions associated with acidification of ASL.

Bicarbonates↗
PubMed2001

Reduced Smad3 protein expression and altered transforming growth factor-beta1-mediated signaling in cystic fibrosis epithelial cells.

Cystic fibrosis (CF) is a disease characterized by an aggressive inflammatory response in the airways. Given the antiinflammatory properties of transforming growth factor (TGF)-beta1, it was our goal to examine components of TGF-beta1-mediated signaling in both a cultured cell model and a mouse model of CF. A CF-related reduction of protein levels of the TGF-beta1 signaling molecule Smad3 was found in both of these model systems, whereas Smad4 levels were unchanged. Functional effects of reduced Smad3 expression are manifest in our cultured cell model, as reduced basal and TGF-beta1-stimulated levels of luciferase expression using the TGF-beta1-responsive reporter construct 3TP-Lux in the CF-phenotype cells compared with control cells. However, TGF-beta1-stimulated responses using the A3-Luc reporter construct were normal in both cell lines. These results suggest that select TGF-beta1-mediated signaling pathways are impaired in CF epithelial cells. This selective loss of Smad3 protein expression in CF epithelium may also influence inflammatory responses. Our data demonstrate that both CF-phenotype cells lacking Smad3 expression, and A549 cells expressing a dominant-negative Smad3, are unable to support TGF-beta1-mediated inhibition of either the interleukin (IL)-8 or the NOS2 promoter. We conclude that a CF-related reduction in Smad3 protein expression selectively alters TGF- beta1-mediated signaling in CF epithelium, potentially contributing to aggressive inflammatory responses.

Animals↗
PubMed2001

Height and weight fail to detect early signs of malnutrition in children with cystic fibrosis.

BACKGROUND: Many children with cystic fibrosis grow poorly and are malnourished. This study was undertaken to determine whether extensive anthropometry could detect early signs of malnutrition in prepubertal children with cystic fibrosis to prevent deficits in height and weight. METHODS: Height, weight, six skin folds (triceps, subscapular, supraspinale, abdominal, front thigh, and medial calf) and five girths (arm relaxed, forearm, chest, thigh, and calf) were measured in a cross-sectional study of children aged 6 to 11 years with cystic fibrosis. RESULTS: The children with cystic fibrosis were shorter and lighter for their age and gender than those in the reference groups. The mean weight and height z scores for the girls with cystic fibrosis were lower than those for the boys, significantly so for z weight ( P < 0.05). Although, the mean percent ideal body weight value of 98.6% suggested that the children with cystic fibrosis were adequately nourished, most of the measures of muscularity and adiposity of the children with cystic fibrosis were significantly lower than those of the reference group ( P < 0.05). The z scores of the anthropometric measures revealed that the deficit in muscularity of the children with cystic fibrosis was relatively much greater than the deficit in adiposity. CONCLUSIONS: The percent ideal body weight index does not seem to be an adequate measure of nutritional status in children with cystic fibrosis. Anthropometric assessments should include skin-fold and circumference measurements of numerous sites on the upper and lower body, the trunk, and the limbs to detect deterioration in nutritional status early. Early detection of deficits in nutritional status may result in the adverse effects of malnutrition on height and weight, and possibly clinical status, being prevented.

Anthropometry↗
PubMed2004

Towards preimplantation diagnosis of cystic fibrosis using microarrays.

Cystic fibrosis (CF) is a common indication for preimplantation genetic diagnosis (PGD). A 3-bp deletion (DeltaF508) in the cftr gene, which accounts for approximately 80% of all CF mutations in the Caucasian population, is normally diagnosed in IVF embryos using fluorescent PCR (FL-PCR) and allelic sizing. In PGD, the possibility of using microarrays for genetic diagnosis is largely unexplored. Therefore, the aim of this study was to prove the diagnostic capability of microarrays for PGD, using DeltaF508 as a model mutation. To this end, oligonucleotide probes representing both the normal and DeltaF508 disease alleles were used to construct a single microarray platform. Target DNA, which was generated by PCR and labelled with the fluorescent dye Cy3, was hybridized to the array and the DeltaF508 genotypes assigned from the fluorescence bound to each allelic probe. The performance of the array was evaluated by its ability to detect DeltaF508 mutations in target DNA. Strong binding of the target to the probes was observed, allowing the expected DeltaF508 genotypes to be assigned. The reliability and accuracy of the microarray diagnosis for DeltaF508 was blindly assessed on 10 samples with either a homozygous normal, homozygous affected or heterozygous genotype. All samples were correctly genotyped. In addition, PCR products from a previous PGD case involving DeltaF508 were re-evaluated on the array, with results in complete concordance with allelic sizing methods used to make the original diagnosis. Together, these findings prove the concept that the DeltaF508 mutation of CF can be reliably and accurately diagnosed at the single cell level using microarray analysis. The availability of more cost-effective array platforms comprising mutation probes for common single-gene disorders and a reliable method of whole genome amplification (WGA) would allow PGD to be offered to the majority of PGD patients with minimal or no change to methodology.

Adenine↗
PubMed1992

Pancreatitis in young children with cystic fibrosis.

Five young children with cystic fibrosis and abdominal pain were found to have pancreatitis. Diagnosis was delayed in four patients because of the belief that pancreatitis occurs only in older patients with cystic fibrosis. In one patient pancreatitis was diagnosed before cystic fibrosis and diagnosis of cystic fibrosis was delayed. Pancreatitis should be considered as a possible cause of abdominal pain in pancreatic-sufficient children with cystic fibrosis and cystic fibrosis should be considered as a possible cause of pancreatitis, even in the young child.

Abdominal Pain↗
PubMed1992

Nasal and paranasal disease in adult cystic fibrosis patients.

Children with cystic fibrosis frequently have nasal polyps and sinusitis. This study addresses (para-) nasal disease in 39 adult cystic fibrosis patients. Fifteen patients (39%) had recently had serious nasal symptoms and 26% sinusitis. Seventeen (44%) had nasal polyposis. Almost all sinus radiographs taken showed opacification, which was unrelated to symptoms. Polypectomies and antral irrigations were usually ineffective, whilst more extensive surgery generally gave better results. It is concluded that a substantial number of adult cystic fibrosis patients frequently have upper airway symptoms. Sinus radiographs have little or no diagnostic value. Treatment of (para-) nasal disease in cystic fibrosis patients can be difficult; a guideline for treatment is suggested, calling for simple interventions coupled with intranasal steroids and nasal irrigation in early disease and for endoscopic to radical sinus surgery in recurrent advanced disease.

Adolescent↗
PubMed1997

Enhanced drug metabolism in young children with cystic fibrosis.

The effect of cystic fibrosis on caffeine metabolism was studied in young children using the caffeine breath test. Eight children with cystic fibrosis aged 2-6 years and nine age matched controls were studied on a single occasion, and the cumulative percentage of labelled caffeine exhaled as carbon dioxide measured over two hours. This was significantly higher in the patients with cystic fibrosis than in controls, suggesting an increase in the CYP1A2 metabolic pathway in the former. The fact that these were young children with minimal lung and liver disease suggests that enhanced drug metabolism in children with cystic fibrosis is hereditary rather than secondary to lung and liver damage.

Breath Tests↗