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PubMed1995

Outcome of pregnancy in women with cystic fibrosis.

BACKGROUND: As women with cystic fibrosis are living longer, pregnancy is becoming increasingly common. The combined experience of pregnancies in women with cystic fibrosis from adult centres in the Midlands and North of England has been examined. METHODS: A retrospective study of the case notes of 22 pregnancies in 20 patients with cystic fibrosis examined changes in lung function, body weight, and microbiological status during the course of pregnancy. Duration of pregnancy, birth weight, and maternal survival were amongst other variables studied. The relation between values before pregnancy and important outcome measures were examined. RESULTS: Eighteen of 22 pregnancies were completed producing healthy, non-cystic fibrosis infants (12 female). Mothers lost 13% of FEV1 and 11% of FVC during pregnancy, most of which was regained. Body weight changes were variable, but most mothers gained weight (mean weight gain 5.7 kg). Microbiological status remained unchanged. Six infants were preterm and two were light for dates. Four mothers died up to 3.2 years following delivery. Of the prepregnancy parameters examined, %FEV1 showed the best correlation with maternal weight gain, gestation, birth weight, and maternal survival. CONCLUSIONS: Pregnancy was well tolerated by most mothers with cystic fibrosis although those with moderate to severe lung disease (%FEV1 < 60%) before pregnancy fared worse, producing preterm infants and suffering increased loss of lung function and mortality compared with mildly affected mothers. Prepregnancy %FEV1 appears to be the most useful predictor of important outcome measures in pregnancies in women with cystic fibrosis.

Adolescent↗

PubMed2002

Maternal and fetal morbidity in pregnancies of Norwegian and Swedish women with cystic fibrosis.

BACKGROUND: The survival of patients with cystic fibrosis has increased. More women with cystic fibrosis reach reproductive age and wish to become pregnant. The aim of this work was to study the outcome of completed pregnancies in women with cystic fibrosis in Norway and Sweden. METHODS: A retrospective audit from medical records was performed for 33 successful pregnancies in 23 women from the cystic fibrosis center in Norway and two cystic fibrosis centers in Sweden. Lung function, body weight and use of antibiotics together with other medical data were related to the complications and outcomes of the pregnancies. RESULTS: The most frequent complication of the pregnancies was preterm delivery, which occurred in 24% of cases. The lung function of the women was significantly lower in the preterm group than in those delivering at term. Those who went on to deliver preterm were more likely to have other cystic fibrosis complications including diabetes, asthma or liver disease. The weight gain of the women with cystic fibrosis delivering preterm was less than in the term group (corrected for gestation), but the frequency of pulmonary infections did not differ. As for the total group, lung function did not deteriorate during pregnancy, even though the need for intravenous antibiotics was doubled compared with the year before and after pregnancy. Weight gain in pregnancy was on average 10.3 kg, and almost half of the women needed supplementary nutrition. Gestational diabetes developed in four of the 23 patients. Caesarean sections were performed in eight of the 33 deliveries (24%), and 26 of the babies (79%) were breast-fed. None of the 33 children suffered from cystic fibrosis. CONCLUSION: Women with cystic fibrosis with mild to moderate disease may safely go through pregnancy. In those with severe disease, preterm delivery is common. A team approach is necessary to provide the best medical care for pregnant women with cystic fibrosis.

Adult↗

PubMed2004

General anesthetic octanol and related compounds activate wild-type and delF508 cystic fibrosis chloride channels.

1. Cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is defective during cystic fibrosis (CF). Activators of the CFTR Cl(-) channel may be useful for therapy of CF. Here, we demonstrate that a range of general anesthetics like normal-alkanols (n-alkanols) and related compounds can stimulate the Cl(-) channel activity of wild-type CFTR and delF508-CFTR mutant. 2. The effects of n-alkanols like octanol on CFTR activity were measured by iodide ((125)I) efflux and patch-clamp techniques on three distinct cellular models: (1). CFTR-expressing Chinese hamster ovary cells, (2). human airway Calu-3 epithelial cells and (3). human airway JME/CF15 epithelial cells which express the delF508-CFTR mutant. 3. Our data show for the first time that n-alkanols activate both wild-type CFTR and delF508-CFTR mutant. Octanol stimulated (125)I efflux in a dose-dependent manner in CFTR-expressing cells (wild-type and delF508) but not in cell lines lacking CFTR. (125)I efflux and Cl(-) currents induced by octanol were blocked by glibenclamide but insensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, as expected for a CFTR Cl(-) current. 4. CFTR activation by octanol was neither due to cell-to-cell uncoupling properties of octanol nor to an intracellular cAMP increase. CFTR activation by octanol requires phosphorylation by protein kinase-A (PKA) since it was prevented by H-89, a PKA inhibitor. 5. n-Alkanols chain length was an important determinant for channel activation, with rank order of potencies: 1-heptanol<1-octanol<2-octanol<1-decanol. Our findings may be of valuable interest for developing novel therapeutic strategies for CF.

Animals↗

PubMed1996

Exocrine pancreatic function in cystic fibrosis.

Pancreatic dysfunction in cystic fibrosis (CF) begins in utero and, at birth, in most cases, cystic fibrosis is characterized by an elevated level of serum immunoreactive trypsin (IRT). If most patients with CF typically present insufficient pancreatic exocrine function, 10-15% of CF patients have pancreatic sufficiency and this status is genetically determined by one or two 'mild' mutations in CF transmembrane conductance regulator (CFTR). However, with age, these patients can develop pancreatic insufficiency.

Cystic Fibrosis↗

PubMed1994

Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). A potential animal model of CF, the CFTR-/- mouse, has had limited utility because most mice die from intestinal obstruction during the first month of life. Human CFTR (hCFTR) was expressed in CFTR-/- mice under the control of the rat intestinal fatty acid-binding protein gene promoter. The mice survived and showed functional correction of ileal goblet cell and crypt cell hyperplasia and cyclic adenosine monophosphate-stimulated chloride secretion. These results support the concept that transfer of the hCFTR gene may be a useful strategy for correcting physiologic defects in patients with CF.

Animals↗

PubMed1991

In vivo cell-specific expression of the cystic fibrosis transmembrane conductance regulator.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The principal manifestations of CF include increased concentration of Cl- in exocrine gland secretions, pancreatic insufficiency, chronic lung disease, intestinal blockage and malabsorption of fat, and male and female infertility. Insight into the function of CFTR can be gained by correlating its cell-specific expression with the physiology of those cells and with CF pathology. Determination of CFTR messenger RNA in rat tissues by in situ hybridization shows that it is specifically expressed in the ductal cells of the pancreas and the salivary glands. In the intestine, decreasing gradients of expression of the CFTR gene are observed on both the crypt-villus and the proximal-distal axes. This expression is consistent with CFTR being responsible for bidirectional Cl- transport, secretion in the intestinal crypts and reabsorption in the silivary gland ducts, and suggests that in these tissues CFTR functions as a regulated Cl- channel. In the lung, a broad band of hybridization includes the mucosa and submucosa of the bronchi and bronchioles. In the testis, CFTR expression is regulated during the cycle of the seminiferous epithelium. Postmeiotic expression is maximal in the round spermatids of stages VII and VIII, suggesting that CFTR plays a critical role in spermatogenesis and that deficiency of this function contributes to CF male infertility.

Animals↗

PubMed1991

Increased plasma cholecystokinin levels and small gall bladders in adult patients with cystic fibrosis.

1. In patients with cystic fibrosis, abnormalities in plasma cholecystokinin level and gall-bladder emptying may contribute to the development of maldigestion and gall-stones. 2. Therefore, we have measured plasma cholecystokinin levels and gall-bladder volumes before and after ingestion of a standard breakfast in eight adult patients with cystic fibrosis and in eight normal control subjects. 3. In the patients with cystic fibrosis basal (2.8 +/- 0.4 pmol/l; P less than 0.05, t-test) and maximum post-prandial (5.7 +/- 0.5 pmol/l; P less than 0.05, t-test) plasma cholecystokinin levels were significantly higher than those in the control subjects (1.9 +/- 0.1 pmol/l, and 4.5 +/- 0.2 pmol/l, respectively). On the other hand, integrated plasma cholecystokinin secretion in response to the meal was similar (t-test, P = 0.4 versus control subjects). The increased plasma cholecystokinin levels in the patients with cystic fibrosis were accompanied by reduced gallbladder volumes in both the basal (7.8 +/- 2.1 cm3 versus 20.9 +/- 2.3 cm3 in control subjects; P less than 0.005, t-test) and the post-prandial state (2.2 +/- 1.0 cm3 versus 4.8 +/- 0.8 cm3 in control subjects; P = 0.06, t-test). Gall-bladder emptying in the patients with cystic fibrosis was well preserved (70 +/- 7% versus 78 +/- 9% in control subjects; P = 0.4, t-test). 4. In comparison with normal control subjects, patients with cystic fibrosis have an increased basal plasma cholecystokinin level and a reduced gall-bladder volume, whereas post-prandial gall-bladder emptying and plasma cholecystokinin secretion are not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2004

Cystic fibrosis: recent structural insights.

Cystic fibrosis (CF) is a debilitating human disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The recently solved crystal structures of the murine CFTR nucleotide binding domain (NBD) provide insight into the molecular basis of several CF-causing mutations. In addition, the NBD structures reveal several unexpected findings that may have implications concerning CFTR function. In this mini-review, we discuss the key structural features of ATP Binding Cassette (ABC) transporter NBDs, as well as highlight how structural information has aided our understanding of the ATP-regulated solute transport cycle.

ATP-Binding Cassette Transporters↗

PubMed1987

[Myocardial fibrosis in 2 children with cystic fibrosis].

We describe the cases of two patients of 9 and 15 months of age who presented episodes of congestive heart failure at the age of 9 and 10 months respectively and who were diagnosed of cystic fibrosis. Death occurred during the first year after diagnosis due to heart failure. Necroscopic study showed pancreatic affectation and heart lesions consisting in areas of myocardial fibrosis and necrosis. We discuss the different hypotheses relating pancreatic affectation to myocardial fibrosis.

Cardiomyopathies↗

PubMed2000

Bronchiolitis obliterans organizing pneumonia: a distinct pulmonary complication in cystic fibrosis.

Organizing pneumonia in cystic fibrosis has hitherto been considered a nonspecific reparative process. We report on an adult patient with cystic fibrosis and histologically proven bronchiolitis obliterans organizing pneumonia, who experienced sustained clinical improvement under corticosteroid therapy. This case suggests that bronchiolitis obliterans organizing pneumonia may be a distinct pulmonary complication in cystic fibrosis and improve with specific therapy.

Adult↗

PubMed1995

Scavenging of neutrophil-derived superoxide anion by 1-hydroxyphenazine, a phenazine derivative associated with chronic Pseudomonas aeruginosa infection: relevance to cystic fibrosis.

The airways of cystic fibrosis patients colonised by Pseudomonas aeruginosa contain the redox active phenazine derivative, 1-hydroxyphenazine (OHP). As the presence of reactive oxygen species is of importance to tissue damage in cystic fibrosis, OHP was investigated for its ability to reduce molecular oxygen to superoxide. In the presence of NADPH, OHP reduced cytochrome c in a dose-dependent manner. This effect was not inhibited by superoxide dismutase and demonstrates an electron transport role for OHP. The OHP/NADPH system was unable to reduce molecular oxygen to superoxide as judged by an inability to oxidase epinephrine to adrenochrome. However, using lucigenin-enhanced chemiluminescence to detect superoxide, it was found that pathophysiologically relevant concentrations of OHP (5-25 microM) effectively scavenged superoxide from a xanthine/xanthine oxidase system. Similarly, in the presence of OHP, superoxide availability from contact-activated neutrophils was substantially reduced. It is concluded that OHP is an efficient scavenger of superoxide and that electron transfer from superoxide to OHP represents a major mechanism for reduction of OHP in vivo. Reduced OHP has the potential to alter cellular function by participating in the reduction of iron-containing proteins and in this manner contribute to the pathogenesis of P. aeruginosa infection in cystic fibrosis.

Acridines↗

PubMed2002

Non-viral approach toward gene therapy of cystic fibrosis lung disease.

Since Cystic Fibrosis (CF) is an autosomal recessive disorder due to mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, studies towards a gene therapy approach to its treatment followed immediately upon the cloning of the gene. It was demonstrated that the insertion of a single copy of the wild-type gene restored the normal phenotype in CF cells in vitro. Encouraging results were obtained in many in vivo model systems (CF transgenic mice) involving viral as well as non-viral vectors, which demonstrated the recovery of CFTR function in the airways. These results constituted the basis for human studies. Of those with a non-viral approach, a total of seven clinical trials using cationic lipids have reported data on efficiency, efficacy and safety. An effective gene transfer approach for the treatment of CF lung disease is not however imminent: low transfection efficiency and poor maintenance of gene expression are so far the main obstacles on this therapeutic path. On the other hand, no important adverse effects have been documented and repeated administration in humans is possible. The understanding of tissue and cellular barriers is a prerequisite for the development of more efficient non-viral gene therapy protocols for CF patients. While cationic lipids have been shown to be blocked by the mucous airway barrier and not be able to transfect differentiated respiratory epithelial cells, a new class of non-viral vectors, cationic polymers, are endowed with chemical and biological properties that make them more efficient in mediating gene transfer than lipids. Cationic polymers, such as polyethylenimine, are promising vectors for CF lung gene therapy.

Animals↗

PubMed1997

Normal vas deferens in fetuses with cystic fibrosis.

PURPOSE: Infertility in patients with cystic fibrosis has been attributed to the congenital bilateral absence of the vas deferens. We studied the vas deferens in cystic fibrosis fetuses to determine whether this condition could be related to primary developmental abnormalities or to secondary obstructions. MATERIALS AND METHODS: Two cystic fibrosis male fetuses, with deltaF508+/+ and deltaF508/G542X genetic mutations, were examined after abortion at 12 and 18 weeks, respectively. The lumens of the vas deferens were measured using histological serial sections in the 2 cystic fibrosis fetuses and in 6 control fetuses. RESULTS: The vas deferens of cystic fibrosis and control fetuses showed a similar development. The diameters of the lumens were smaller at the extremities than in the medial part of the duct in cystic fibrosis and in control fetuses. No epithelial necrosis, focal dilatation or fibrous stenosis could be detected at any age. Secretions were observed in the lumen of the vas deferens of the homozygous fetus, but no obstruction was detected. CONCLUSIONS: The normal organogenesis of the vas deferens, the presence of secretions filling the lumen of the deltaF508 +/+ fetus and the high proportion of normal ducts reported in prepubertal male cystic fibrosis patients suggest a mechanism of luminal obstruction resulting in duct atrophy and infertility in male adults with cystic fibrosis. The term "atresia" or "inspissation" should be used in cases of congenital bilateral absence of the vas deferens associated with cystic fibrosis mutations, whereas the term "agenesis" should be used for cases of congenital bilateral absence of the vas deferens associated with urogenital abnormalities in which regional defects occur during organogenesis.

Cystic Fibrosis↗

PubMedDate not supplied

New perspectives and hope for cure-reflecting recent genetic developments in cystic fibrosis.

The isolation of cystic fibrosis gene at the CF locus assigned to the long arm of chromosome 7 band q31 and definition of its protein product named CFTR (cystic fibrosis transmembrane conductance regulator) permits to understand the basic defect in this inherited disorder known as cystic fibrosis (CF) or mucoviscidosis. A variety of mutations of CF gene was revealed and the most common, a deletion of the 3 nucleotides that encode phenylalanine (Delta F508) with the variable incidence among the different ethnic groups of CF patients was delineated. CF is a variable disease and genetic testing can be useful to explain this variation but to date the phenotype-genotype correlation is not clarified. Polymerase chain reaction (PCR) amplification is used to test CF gene in CF patients and their families but is not sufficiently genetically informative to population screening for carrier detections. Recently identified glycoprotein encoded by CF gene is responsible for the regulation of the membrane chloride channel of epithelial cells and the experiments used retro-virus-mediated gene transfer demonstrated complementation CF defect in vitro. The way for gene therapy in this disease is open. An alternative approach to use the germ line cells to CF gene therapy is prerequisite of the development of the preimplantation preconception genetic CF diagnosis. The researchers managed already to express human CFTR gene in vivo in cotton rats lungs through the viral delivery system. It will be generalized into the airways of CF patients with hope that normal CFTR will reverse the physiological defect in CF cells.

Cystic Fibrosis↗

PubMed1989

Isolation of the "cystic fibrosis protein" from serum.

"Cystic fibrosis protein" (CFP), a minor serum protein marker of the cystic fibrosis allele, was isolated from serum from patients with cystic fibrosis by use of the "FPLC" high-resolution chromatography system and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. CFP currently is characterized by its isoelectric point (8.4) on isoelectric focusing. However, after the first purification steps, we identified the protein, which was present in a very low concentration, by the immunosorbent assay of Hayward et al. (J Immunol Methods 1986;91:117-22), by virtue of its immunological relationship with the "CF antigen," a protein characterized in granulocytes by these same authors [Nature (London) 1985;315:513-5]. CFP, a protein of low molecular mass, about 14 kDa, appears to be strongly associated with IgG in serum. Using the same procedure with control serum permits us to assume that CFP normally is present in serum in trace amounts.

Antibodies, Monoclonal↗

PubMed1999

Pseudomonal pericarditis complicating cystic fibrosis.

Patients with advanced cystic fibrosis typically have chronic bacterial infection of the upper and lower respiratory tracts, but rarely develop extrapulmonary sites of infection. We report a case of purulent pericarditis due to Pseudomonas aeruginosa in a patient with cystic fibrosis and no other risk factors for pericarditis. This is a previously unreported complication in cystic fibrosis prior to lung transplantation.

Adult↗

PubMed1980

Adenylate cyclase in leukocytes from patients with cystic fibrosis.

Lymphocytes from patients with cystic fibrosis produce significantly less cAMP in response to beta-adrenergic stimulation than do cells from healthy persons (p less than 0.0005) or patients with bronchiectasis (p less than 0.005). Adenylate cyclase in the basal state or stimulated by GMPPNP or PGE1 is normal, but isoproterenol-stimulated adenylate cyclase activity is significantly (p less than 0.005) reduced in lymphocyte membrane preparations from patients with cystic fibrosis. Granulocytes from patients with cystic fibrosis also produce significantly less cAMP in response to beta-adrenergic stimulation than do cells from healthy subjects (p less than 0.0005) or subjects with bronchiectasis (p less than 0.05). Adenylate cyclase activity in granulocyte homogenates from patients with cystic fibrosis is normal in the basal state or when stimulated by GMPPNP or PGE1 but is significantly (p less than 0.05) reduced compared to normal when stimulated by isoproterenol. These data suggest that the defect is not related to adenylate cyclase itself or to availability of substrate or cofactor to adenylate cyclase, and they may be indicative of a more generalized membrane defect in cystic fibrosis.

Adenylyl Cyclases↗

PubMed2004

Lentivirus-mediated gene transfer to the respiratory epithelium: a promising approach to gene therapy of cystic fibrosis.

Gene therapy of cystic fibrosis (CF) lung disease needs highly efficient delivery and long-lasting complementation of the CFTR (cystic fibrosis transmembrane conductance regulator) gene into the respiratory epithelium. The development of lentiviral vectors has been a recent advance in the field of gene transfer and therapy. These integrating vectors appear to be promising vehicles for gene delivery into respiratory epithelial cells by virtue of their ability to infect nondividing cells and mediate long-term persistence of transgene expression. Studies in human airway tissues and animal models have highlighted the possibility of achieving gene expression by lentiviral vectors, which outlasted the normal lifespan of the respiratory epithelium, indicating targeting of a 'stem cell' compartment. Modification of the paracellular permeability and pseudotyping with heterologous envelopes are the strategies currently used to overcome the paucity of specific viral receptors on the apical surface of airway epithelial cells and to reach the basolateral surface receptors. Preclinical studies on CF mice, demonstrating complementation of the CF defect, offer hope that lentivirus gene therapy can be translated into an effective treatment of CF lung disease. Besides a direct targeting of the stem/progenitor niche(s) in the CF airways, an alternative approach may envision homing of hematopoietic stem cells engineered to express the CFTR gene by lentiviral vectors. In the context of lentivirus-mediated CFTR gene transfer to the CF airways, biosafety aspects should be of primary concern.

Animals↗