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PubMed1997

8-cyclopentyl-1,3-dipropylxanthine and other xanthines differentially bind to the wild-type and delta F508 first nucleotide binding fold (NBF-1) domains of the cystic fibrosis transmembrane conductance regulator.

Cystic fibrosis is an autosomal recessive disorder affecting chloride transport in pancreas, lung, and other tissues, which is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Certain alkyl xanthines such as CPX (8-cyclopentyl-1,3-dipropylxanthine) stimulate Cl- efflux from cells bearing the delta F508 genotype common to most cases of cystic fibrosis. We have hypothesized that the CFTR molecule itself might be the site for CPX action, perhaps in the region of the first nucleotide binding fold (NBF-1) domain. Therefore, to test this hypothesis directly we have used a rapid membrane filtration assay to measure the kinetics of association and dissociation of [3H]CPX to both recombinant NBF-1 and recombinant NBF-1 bearing the delta F508 mutation. We report that [3H]CPX binds with higher affinity to the delta F508-NBF-1 of CFTR (Kd = 1.0 nM) than to the wild-type NBF-1 of CFTR (Kd = 17.0 nM). These Kd values were calculated from direct measurements of the association and dissociation rate constants. The rate constants for the dissociation reaction of the wild-type NBF-1 and delta F508-NBF-1 of CFTR were not different from each other. However, the corresponding rate constants for the association reaction were k(+1) (NBF-1) = 4.7 +/- 0.9 x 10(4) M(-1) s(-1) and k(+1) (delta F508-NBF-1) = 1.6 +/- 0.3 x 10(5) M(-1) s(-1), respectively. These Kd values were corroborated by equilibrium-binding experiments, which gave very similar values. We have also measured the relative displacement of various xanthines from both wild-type NBF-1 and delta F508-NBF-1, in anticipation that the order of potencies for binding might parallel the action of the different xanthines on CF cells. For wild-type NBF-1, the rank order was DA-CPX > DAX > CPX > caffeine > adenosine >> IBMX > 2-thioCPX. For delta F508-NBF-1, the rank order was DAX > CPX > caffeine > DA-CPX > adenosine >> IBMX > 2-thioCPX. These relative potencies show close parallels with previously observed relative potencies of these drugs on CF cells, and thus lend strong support to the hypothesis that the mechanism of action on CF cells may involve direct interaction with the CFTR molecule itself.

Adenosine↗
PubMed1979

Electrolytes and norepinephrine levels in blood of patients with cystic fibrosis.

Young adults with cystic fibrosis in good to excellent condition have reduced plasma sodium and chloride and elevated plasma potassium compared to a group of healthy young adult control subjects. Blood pressure was also lower in the patients with cystic fibrosis. However, plasma norepinephrine and dopamine-beta-hydroxylase and their response to standing and isometric hand grip were normal in the cystic fibrosis patients.

Adolescent↗
PubMed2002

Hyperacidification of cellubrevin endocytic compartments and defective endosomal recycling in cystic fibrosis respiratory epithelial cells.

The cystic fibrosis transmembrane conductance regulator (CFTR), which is aberrant in patients with cystic fibrosis, normally functions both as a chloride channel and as a pleiotropic regulator of other ion transporters. Here we show, by ratiometric imaging with luminally exposed pH-sensitive green fluorescent protein, that CFTR affects the pH of cellubrevin-labeled endosomal organelles resulting in hyperacidification of these compartments in cystic fibrosis lung epithelial cells. The excessive acidification of intracellular organelles was corrected with low concentrations of weak base. Studies with proton ATPase and sodium channel inhibitors showed that the increased acidification was dependent on proton pump activity and sodium transport. These observations implicate sodium efflux in the pH homeostasis of a subset of endocytic organelles and indicate that a dysfunctional CFTR in cystic fibrosis leads to organellar hyperacidification in lung epithelial cells because of a loss of CFTR inhibitory effects on sodium transport. Furthermore, recycling of transferrin receptor was altered in CFTR mutant cells, suggesting a previously unrecognized cellular defect in cystic fibrosis, which may have functional consequences for the receptors on the plasma membrane or within endosomal compartments.

Acids↗
PubMed1995

The treatment of pulmonary infection in cystic fibrosis.

The survival of cystic fibrosis patients has improved through an aggressive, multidisciplinary approach to the therapy of pulmonary sepsis. Intravenous antibiotics play a major role in the care of cystic fibrosis patients, even though it is not possible to achieve persistent bacterial eradication due to the complex microbiology and pathology of these patients. The most important pathogen in older patients is Pseudomonas aeruginosa. The increasing incidence of Pseudomonas cepacia, strains of which can be highly resistant to many antibiotics, also represents an important challenge to the efficacy of antibiotic therapy. Choice of appropriate antimicrobial therapy is hampered by the fact that a single patient may harbour several different pseudomonas phenotypes with variable resistance patterns. Carbapenem antibiotics possess a wide range of activity against most Gram-negative and Gram-positive bacteria and are therefore a useful addition to the antimicrobial armamentarium available to the clinician. The new carbapenem meropenem is well tolerated at high doses by both children and adults. Results from a comparative trial against ceftazidime suggests that meropenem has a place in the management of cystic fibrosis.

Adult↗
PubMed1976

Cultured cells in cystic fibrosis research: A review.

Cystic fibrosis (CF) is a common inherited disorder which is characterized by the production of exocrine secretions with elevated ion content and abnormally viscous mucus. Over the last few years cells obtained from the peripheral blood or cultured from tissues of cystic fibrosis patients have been used increasingly in the study of the disease. Investigations of the following properties of cystic fibrosis cells are reviewed: morphology, ultrastructure, growth kinetics, cellular metachromasia, the production of ciliary inhibitors, cellular composition, plasma membrane composition, the transport of inorganic ions and small organic molecules, lysosomal enzyme content, and RNA methylation. Studies of the effects on cultured cells and erythrocyte membranes of factors in CF cell culture medium and biological fluids from CF patients are discussed.

Animals↗
PubMed2001

[Paranasal sinuses CT scans analysis of patients with cystic fibrosis].

Thirty patients with cystic fibrosis (CF) were diagnosed of the otolaryngological outpatient clinic, a part of Department of Otorhinolaryngology Medical Academy in Warsaw, in 1996-1998. The control group was formed by thirty patients with chronic rhinosinusitis (CRS). Computed tomography (CT) scans were estimated in all cases. Results showed, that inflammatory changes are more advanced in patients with cystic fibrosis than in patients with chronic rhinosinusitis. The high progression of inflammatory changes in patients with cystic fibrosis, observed in CT scans, caused: disturbed development of a frontal and maxillary sinuses, destruction of bony structures formed the lateral wall of the nasal cavity, medical bulging of the lateral nasal wall.

Adolescent↗
PubMed1992

An animal model for cystic fibrosis made by gene targeting.

Cystic fibrosis results from defects in the gene encoding a cyclic adenosine monophosphate-dependent chloride ion channel known as the cystic fibrosis transmembrane conductance regulator (CFTR). To create an animal model for cystic fibrosis, mice were generated from embryonic stem cells in which the CFTR gene was disrupted by gene targeting. Mice homozygous for the disrupted gene display many features common to young human cystic fibrosis patients, including failure to thrive, meconium ileus, alteration of mucous and serous glands, and obstruction of glandlike structures with inspissated eosinophilic material. Death resulting from intestinal obstruction usually occurs before 40 days of age.

Animals↗
PubMed1996

Abnormal enamel development in a cystic fibrosis transgenic mouse model.

Cystic fibrosis (CF) is a hereditary condition that affects cAMP-regulated chloride channels in epithelial tissues due to a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recently, a transgenic CF mouse model was developed at UNC that exhibits no CFTR expression. Interestingly, the CF mouse demonstrates abnormal incisor enamel. Therefore, the purpose of this investigation was to characterize the enamel in this CF mouse model. Incisors from CF and normal mice were evaluated by light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The enamel proteins were examined by amino acid analysis, SDS-PAGE, and Western blot. Gross examination showed that 100% of CF mice had soft, chalky white incisor enamel, while the enamel of normal mice was hard and yellow-brown. LM indicated that the ameloblasts in the CF mice underwent premature degeneration shortly after completion of the secretory phase. The CF mouse enamel appeared to be of relatively normal thickness and showed a prism structure similar to that of normal mouse enamel. However, the CF mouse enamel crystallites appeared to have a rough granular surface compared with normal enamel. SDS-PAGE indicated that mature CF enamel retained low-molecular-weight material (approximately 20 kDa), whereas normal mature enamel did not. This low-molecular-weight material cross-reacted with anti-amelogenin antibodies in Western blot analysis. This investigation shows that abnormal CFTR expression in the mouse results in developmental abnormalities in the incisor enamel. Although further investigation is required to determine the mechanism leading to abnormal enamel formation, the CF mouse provides a potentially useful animal model for investigating aberrant enamel development.

Amelogenesis↗
PubMed1988

Restricted pulmonary function in cystic fibrosis.

Some patients with cystic fibrosis have reduced pulmonary volumes, indicating a restrictive pattern of pulmonary disease. We identified ten patients with pulmonary functional evidence of restriction among 158 patients with cystic fibrosis followed at the University of California San Diego Medical Center in 1984 and 1985. We characterized the radiographic, pulmonary functional, and clinical characteristics of these restricted patients compared to matched nonrestricted patients. Pulmonary volumes were measured by three different techniques: plethysmography; nitrogen washout; and radiography. Except for plethysmographic pulmonary volumes, there were no significant differences between the matched restricted and nonrestricted patients. Radiographic pulmonary volume tended to overestimate gas volume measured by the other techniques. Differences among these techniques (thought to represent air-space filling) correlated best with radiographic evidence of air trapping and bronchial markings and not with parenchymal lesions. Serial pulmonary function tests demonstrated changes in pulmonary volume in several patients and a trend toward improvement in pulmonary volume in the restricted patients over time. We conclude that restricted pulmonary function does not necessarily indicate more severe disease in patients with cystic fibrosis and may be reversible in some. The mechanism of restriction may be related more to radiographic evidence of airway disease than to parenchymal abnormalities.

Adult↗
PubMed1984

Autonomic and airway reactivity in obligate heterozygotes for cystic fibrosis.

Obligate heterozygotes for cystic fibrosis, like the patients themselves, have significantly increased pupillary alpha-adrenergic and cholinergic sensitivity and significantly decreased lymphocyte beta-adrenergic responses. The parents of patients with cystic fibrosis also have a high prevalence of airway reactivity: one third have a fall in forced expiratory volume in one second (FEV1) of more than 20% (PD20 FEV1) to less than 3 mg/ml methacholine, compared with 4% in control subjects (p = 0.01, chi-square). Airway reactivity (PD20 FEV1) is significantly correlated with the lymphocyte adenosine 3':5' cyclic monophosphate response to isoproterenol (Rs = 0.54, p less than 0.05). Abnormal autonomic and airway reactivity cannot be ascribed to medication usage, preexisting pulmonary disease, or atopy in these subjects. We conclude that the autonomic abnormalities in cystic fibrosis are inherited and may contribute to the development and progression of pulmonary disease by predisposing to increased airway reactivity.

Adult↗
PubMedDate not supplied

Cystic fibrosis and the gastrointestinal tract.

Cystic fibrosis is known to be a serious genetic disease among those of northern European ancestry. Well known to nurses are the pulmonary insults to survival for children with cystic fibrosis. An aspect of health care not often found in the nursing literature is a focus on cystic fibrosis gastrointestinal presentation. Because of the chronic nature of cystic fibrosis, those providing health care to children must have an understanding of the disease in the growing infant and child. An overview of cystic fibrosis and the possible effect on the pancreas, gut, and liver are reviewed. Areas of developmental concern to the pediatric nurse practitioner are listed.

Adolescent↗
PubMed1992

Mineral metabolism in erythrocytes from patients with cystic fibrosis.

In patients with cystic fibrosis plasma concentrations of Zn and Mg were unchanged, plasma Ca concentrations were somewhat decreased, but plasma Fe concentrations were drastically reduced; the ratio Cu/Fe in plasma was increased. The Mg and Zn contents of erythrocytes from patients were unchanged. Therefore, the Mg and Zn content of erythrocytes cannot serve for the detection of patients with cystic fibrosis and their heterozygotes, as has been suggested. Cl(-)-dependent Mg2+ efflux from Mg(2+)-loaded erythrocytes was not affected in cystic fibrosis. Na(+)-dependent Mg2+ efflux was increased only in erythrocytes from patients with the most severe clinical symptoms.

Adolescent↗
PubMed2002

Prenatal screening for cystic fibrosis: an economic analysis.

Cystic fibrosis (CF) is the most common life-shortening genetically transmitted disease in Denmark with a birth prevalence of 1 in 4700, resulting in 12-15 new cases of cystic fibroses annually. The aim of this study is to disclose the societal resource implications of introducing a population wide prenatal screening programme for cystic fibrosis in Denmark. The present analysis is limited to the monetary consequences of introducing a screening programme, where costs of screening are compared to the potential benefits measured in cost savings involved if births of CF patients are avoided. Screening costs in a Danish setting were estimated at DKK 2 771 262 ( pound sterlings 231 438) per aborted affected fetus in the first screening round, stabilising at DKK 1 864 594 ( pound sterlings 155 383) per aborted affected fetus at subsequent screening rounds. Comparing this figure with the estimated benefits of avoiding a CF case (DKK 2.1-4.4 million; pound sterlings 175 000-366 667) suggests that introducing a screening programme for cystic fibrosis will be net cost saving irrespective of the perspective of the analysis, assumptions on replacement children and method of estimating long-term production gains/losses.

Abortion, Legal↗
PubMed1997

Biliary obstruction in infants with cystic fibrosis requiring Kasai portoenterostomy.

Cystic fibrosis is associated with an inspissated bile syndrome producing cholestasis secondary to plugging of macroscopically normal bile ducts. In extreme neonatal forms, with early profound intrahepatic cholestasis, the process can be associated with a marked decrease in ductal diameter, varying from hypoplasia to atresia. From 1990 to 1995 three infants were identified with cystic fibrosis, persistent jaundice, and complete absence of biliary excretion despite expectant and conservative treatment including choleretics and surgical biliary irrigation. Abdominal ultrasounds showed contracted gallbladders and no evidence of dilated ducts. Liver biopsy results in two infants showed portal fibrosis, paucity of bile ducts, and minimal inflammation. The third infant had moderate inflammation, bile duct replication, and plugging. Two infants had undergone intestinal resection followed by hyperalimenation for complications of meconium ileus in the newborn period. Surgical exploration was undertaken at 7 to 12 weeks of age. Gross findings were typical of biliary atresia with microgallbladders and nonpatency of the cystic duct. Cholangiograms failed to document ductal patency in two patients who were then treated with a Kasai portoenterostomy. The third infant had patent hypoplastic ducts and underwent only biliary irrigation. Although bile flow was transiently achieved, jaundice recurred, and at reexploration at 16 weeks of age a Kasai poroenterostomy was performed. Histological review of the biliary specimens showed microscopically patent ducts in two patients and proximal patency and distal atresia in the third. All the ducts had mural fibrosis with cystic changes. Bile drainage was achieved in each instance, although in one patient with hypoplastic ducts scant output of highly concentrated bile proved insufficient to arrest progressive liver failure. The subsequent two patients responded with resolution of hyperbilirubinemia and normalization of liver function. They remain free of biliary complications at 30 and 40 months postoperatively. This manifestation of cystic fibrosis in infants is suggested by prolonged jaundice unresponsive to choleretics, nondilated bile ducts and gallbladder on ultrasound, absent biliary excretion on nuclear scan, and characteristic liver biopsy. Exploration is warranted, and discovery of atrophic bile ducts may be best managed with reconstruction.

Biliary Atresia↗
PubMed1999

Low bone mineral density in adults with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis have several risk factors for the development of low bone mineral density (BMD). To identify the prevalence and clinical correlates of low BMD in adult patients with cystic fibrosis, densitometry was performed in 151 patients (83 men) aged 15-52 years. METHODS: BMD was measured in the lumbar spine (L1-4) using dual energy x ray absorptiometry (DXA) and quantitative computed tomography (QCT). It was also measured in the proximal femur (total hip and femoral neck) using DXA, and in the distal and ultra distal forearm using single energy x ray absorptiometry (SXA). Biochemical markers of bone turnover, vitamin D levels, parathyroid hormone levels, and a variety of anthropometric variables were also assessed. RESULTS: The mean (SD) BMD Z score was -0.73 (0.85) in the distal forearm, -0.31 (0.92) in the ultra distal forearm, -1.21 (1. 18) in the lumbar spine using DXA, -0.56 (1.36) in the lumbar spine using QCT, -1.25 (1.30) in the femoral neck, and -1.01 (1.14) in the total hip. 34% of patients had a BMD Z score of -2 or less at one or more skeletal sites. Body mass index (0.527, p = 0.01), percentage predicted forced expiratory volume in one second (0.388, p = 0.01), and physical activity (0.249, p = 0.05) were positively related to the mean BMD Z score. Levels of C reactive protein (-0.328, p = 0. 01), parathyroid hormone (-0.311, p = 0.01) and biochemical markers of bone turnover (osteocalcin -0.261 and bone specific alkaline phosphatase -0.249, p = 0.05) were negatively related to the mean BMD Z score. Vitamin D insufficiency (25-hydroxyvitamin D <15 ng/ml) was prevalent (53/139 patients, 38%) despite supplementation with 900 IU vitamin D per day. CONCLUSIONS: Low bone density is prevalent in adult patients with cystic fibrosis. Current levels of vitamin D supplementation appear to be inadequate.

Adolescent↗
PubMed1997

Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis are known to have decreased mucociliary clearance. It has previously been shown that inhalation of a 7.0% solution of hypertonic saline significantly improved mucociliary clearance in a group of adult patients with cystic fibrosis. The aim of this study was to measure the response to increasing concentrations of inhaled hypertonic saline. METHODS: Ten patients (seven men) of mean (SE) age 22 (4) years and mean forced expiratory volume in one second (FEV1) 52.0 (6.7)% predicted completed the study. Mucociliary clearance was measured using a radioaerosol technique for 90 minutes after the interventions which comprised 0.9% NaCl + voluntary cough (control), 3.0% NaCl, 7.0% NaCl, and 12% NaCl. RESULTS: There was a significant increase in the amount of activity cleared from the right lung with all concentrations of hypertonic saline (HS) compared with control. The amount cleared at 90 minutes on the control day was 12.7% (95% confidence interval (CI) 9.8 to 17.2) compared with 19.7% (95% CI 13.6 to 29.5) for 3% HS, 23.8% (95% CI 15.9 to 36.7) for 7% HS and 26.0% (95% CI 19.8 to 35.9) for 12% HS. The improvement in mucociliary clearance was not solely due to coughing as the number of coughs recorded on the control day exceeded that recorded on any other day. The hypertonic saline did not induce a clinically significant change in FEV1. CONCLUSIONS: Within the range of concentrations examined in this study, the effect of hypertonic saline appears to be dose dependent. Inhalation of hypertonic saline remains a potentially useful treatment for patients with cystic fibrosis.

Administration, Inhalation↗
PubMed1991

Cloning the mouse homolog of the human cystic fibrosis transmembrane conductance regulator gene.

The cystic fibrosis transmembrane conductance regulator is encoded by the gene known to be mutated in patients with cystic fibrosis. This paper reports the cloning and sequencing of cDNAs for the murine homolog of the human cystic fibrosis transmembrane conductance regulator gene. A clone that, by analogy to the human sequence, extends 3' from exon 9 to the poly(A) tail was isolated from a mouse lung cDNA library. cDNA clones containing exons 4 and 6b were also isolated and sequenced, but the remainder of the mRNA proved difficult to obtain by conventional cDNA library screening. Sequences spanning exons 1-9 were cloned by PCR from mouse RNA. The deduced mouse protein sequence is 78% identical to the human cystic fibrosis transmembrane regulator, with higher conservation in the transmembrane and nucleotide-binding domains. Amino acid sequences in which known cystic fibrosis missense mutations occur are conserved between man and mouse; in particular, the predicted mouse protein has a phenylalanine residue corresponding to that deleted in the most common human cystic fibrosis mutation (delta F508), which should allow the use of transgenic strategies to introduce this mutation in attempts to create a "cystic fibrosis mouse".

Amino Acid Sequence↗