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PubMed2000

Gene therapy for cystic fibrosis.

The gene for cystic fibrosis was identified in 1989 and this together with the emerging technology of gene therapy heralded a new dawn for the treatment of genetic disease. The initial optimism however gave way to the realisation that gene therapy for cystic fibrosis was unlikely to be straightforward. The lung was considered an ideal organ to target due to ease of access, but subsequent research has shown that the airway surface provides an efficient barrier to topically applied gene transfer agents. A number of Phase I clinical safety trials were carried out through the 1990s and provided proof of concept evidence that delivery of DNA by either viral or non-viral means was safe though not clinically efficacious. Current research is now focusing more on the barriers faced by delivery agents, with the aim that more efficient gene delivery will lead to a gene therapeutic for cystic fibrosis.

Cystic Fibrosis↗

PubMed1996

Clinical status, ocular surface changes and tear ferning in patients with cystic fibrosis.

Twenty-three cystic fibrosis patients and 20 controls were examined for ocular surface changes and tear fluid ferning characteristics. The patients were also evaluated systemically and given numerical scores according to Schwachman's scoring system. Frequency of blepharitis, fluorescein staining, and the Schirmer's test values did not differ between patients and controls. Patients with cystic fibrosis had a higher frequency of altered ferning pattern that corresponded to the disease severity as measured by the Schwachman score (r = -0.48, p < 0.05). Although altered ferning pattern was frequent, the rate of type I ferning was also high (30%) in patients with cystic fibrosis. We conclude that the ferning test should not be used as an aid in diagnosis of cystic fibrosis but it may be used as an indicator of clinical status during follow-up.

Adolescent↗

PubMed1971

Opsonic defect in patients with cystic fibrosis of the pancreas.

Cystic fibrosis of the pancreas is one of the most common inborn errors of metabolism. The high incidence of morbidity and mortality in these patients is primarily due to severe and frequent pulmonary infection. To date, no immune deficiency has been found in cystic fibrosis patients. Their sera contain normal quantities of immunoglobulins and hemolytic complement. In an assay of phagocytosis by alveolar macrophage, six out of nine sera from cystic fibrosis patients failed to support normal phagocytosis of Pseudomonas aeruginosa. This deficiency could be corrected by increasing the concentration of serum used in the assay. By contrast, their sera supported normal phagocytosis of Pseudomonas by blood polymorphonuclear leukocytes and continued to support normal phagocytosis when serum dilutions were used. Two patients with severe isolated deficiences of serum immunoglobulin A were found to have a similar defect in the alveolar macrophage assay, but normal phagocytosis by polymorphonuclear leukocytes. It is postulated that cystic fibrosis patients may have a quantitative and (or) functional defect of IgA antibodies, specific for Pseudomonas, and possibly of importance in the pathogenesis of their pulmonary disease.

Adolescent↗

PubMed1997

Inhibition of epithelial Na+ currents by intracellular domains of the cystic fibrosis transmembrane conductance regulator.

Cystic fibrosis is characterized by an impaired cyclic adenosine 3,5-monophosphate (cAMP) activated Cl- conductance in parallel with an enhanced amiloride sensitive Na+ conductance (ENaC) of the respiratory epithelium. Very recently, acute downregulation of ENaC by the cystic fibrosis transmembrane conductance regulator (CFTR) was demonstrated in several studies. The mechanism, however, by which CFTR exerts its inhibitory effect on ENaC remains obscure. We demonstrate that cytosolic domains of human CFTR are sufficient to induce inhibition of rat epithelial Na+ currents (rENaC) when coexpressed in Xenopus oocytes and stimulated with 3-isobutyl-1-methylxanthine (IBMX). Moreover, mutations of CFTR, which occur in cystic fibrosis, abolish CFTR-dependent downregulation of rENaC. Yeast two hybrid analysis of CFTR domains and rENaC subunits suggest direct interaction between the proteins. Enhanced Na+ transport as found in the airways of cystic fibrosis patients is probably due to a lack of CFTR dependent downregulation of ENaC.

1-Methyl-3-isobutylxanthine↗

PubMed1999

[Respiratory disease in cystic fibrosis: from physiopathology to therapy. Kinesitherapy and pulmonary transplantation excluded].

Respiratory disease is the major cause of morbidity and mortality in cystic fibrosis. Cystic fibrosis was long treated in the pediatric setting, but improved survival has led to the implication of adult pneumology in therapeutic management. Since the gene causing cystic fibrosis has been clone, our knowledge of the pathophysiology of the disease has literally exploded, particularly concerning the deleterious consequences of defective expression and distribution of CFTR (cystic fibrosis transmembrane conductance regulator) protein in chronic lung inflammation and infection. This knowledge has led to an optimization of existing therapeutic strategies and to the formulation of hypotheses for the development of new pharmaceutical reagents, allowing an assessment of disease outcome not only in terms of survival but also in terms of quality of life. Early in vivo clinical trials have been encouraging although the efficacy of gene transfer and expression remain modest and the optimal vector remains to be determined. Different potential pharmacological approaches are being studied in order to correct for defective CFTR function at different levels of gene mutation, and to modulate the disorder in transepithelial ionic transfer. One could expect in the near future to see combinations of complementary genotype-specific drugs used for the treatment of cystic fibrosis after patient genotyping to categorize the type of mutation.

Adult↗

PubMed1992

Impact of sinusitis in cystic fibrosis.

The cause of cystic fibrosis has been determined to be faulty ionic transport of chloride across the apical membrane of epithelial cells lining exocrine glands. The subnormal ionic transport leads to dehydration of extra cellular fluids and the development of thickened inspissated mucous secretions. The vast majority of patients with cystic fibrosis develop sinus disease with panopacification of the sinuses present in 90% to 100% of patients older than 8 months of age. Indications for surgical management of sinusitis in children with cystic fibrosis include (1) chronic nasal obstruction with mouth breathing, (2) chronic purulent draining nasal secretions unresponsive to medical treatment, and (3) persistent headaches thought to be related to sinusitis. Operative therapy is based on computerized tomographic scan findings and can be performed endoscopically. Postoperative management is critical for ensuring successful surgical results. Antibiotics, topical steroids, and cleansing of the surgical fields must be performed on a regular basis to ensure adequate healing. The impact of sinusitis on the cystic fibrosis population is significant. Approximately 20% of patients will eventually require surgical treatment of their sinuses. Chronic sinusitis may cause deformities of the external nasal skeleton, a loss of the sense of smell, and headaches.

Cystic Fibrosis↗

PubMed2006

Surgical management of pulmonary and gastrointestinal complications in children with cystic fibrosis.

PURPOSE OF REVIEW: Cystic fibrosis is a common disorder, affecting as many as 1:2500 Caucasian live births. Despite improved medical management, disease-specific complications are common and are responsible for substantial morbidity and ultimately mortality. Both pulmonary and gastrointestinal complications of cystic fibrosis are well known; however, the complications requiring surgical intervention in the pediatric population are infrequent. We provide a detailed review of the cystic fibrosis-associated pulmonary and gastrointestinal complications and potential surgical options for management in children with cystic fibrosis. RECENT FINDINGS: Recent operative approaches are described that include application of minimally invasive surgical techniques primarily for intrathoracic disease. Novel medical therapies are also presented. Finally an attempt is made to put in perspective those surgical care advances that have had a benefit on disease outcomes. SUMMARY: This report will provide the physician caring for the child with cystic fibrosis an understanding of those disease complications that will require surgical consultation and potential operative intervention.

Child↗

PubMed1979

Response to bronchial provocation and exercise in children with cystic fibrosis.

Ten of fifteen cystic fibrosis children with positive skin prick tests to common antigens gave an immediate bronchial reaction to the antigen inhaled, five of them also gave a late reaction; however only one gave a history of asthma. The antigen most commonly eliciting a positive skin reaction in cystic fibrosis patients is Aspergillus fumigatus. In six children tested to this antigen the bronchial response varied, two were negative, one gave an immediate reaction and three gave a dual (immediate and late) reaction. None of the children showed the characteristic pattern of response to exercise seen in asthmatic patients, an initial rise in Peak Expiratory Flow Rate followed by a fall of greater than 14% below the resting level. Two patients showed an abnormal rise in Peak Expiratory Flow Rate during exercise, a pattern described previously in cystic fibrosis. The results suggest that bronchial allergy, immediate or late does completely explain susceptibility to asthma, and that other factors including perhaps the type of bronchial reactivity shown by bronchoconstriction after exercise may be required. However the majority of the children tested had bronchial allergy and anti-allergy therapy such as inhaled sodium cromoglycate may have a place in the management of selected patients with cystic fibrosis.

Adolescent↗

PubMed2004

[Cystic fibrosis of the child].

Cystic fibrosis was regarded a long time as exceptional in the Nord Africaine population and in particular in Tunisia what was at the origin of the ignorance of its various diagnostic and therapeutic aspects in our country. Nevertheless, with the development of the means of the diagnosis, several cases of cystic fibrosis were diagnosed these last years what will pose true problems of assumption of responsibility of these children like illustrates it well our experiment in the pediatric department of Sfax university hospital. In 10 years going of 1991 to 2000 we reported 7 cases of cystic fibrosis in the pediatric department of Sfax university hospital. Our patients are 3 boys and 4 girls. The age of revelation of the disease varied from 3 months to 14 years with 4 years and 10 months an average age. All our patients had a respiratory symptomatology in the foreground. The evolution was marked by the death of 4 patients at an average age of 5 years and half whereas the 3 surviving patients for the moment are more or less balanced on the nutritional level, digestive and respiratory. Cystic fibrosis is not exceptional in our area, its assumption of responsibility therapeutic is difficult, and it requires the collaboration of several experts and a good compliance of the child and of his family.

Child↗

PubMed2005

[Nontuberculous mycobacteria in patients with cystic fibrosis].

OBJECTIVE: Patients with cystic fibrosis are at great risk of infection by nontuberculous mycobacteria from the environment because of certain predisposing factors such as bronchiectasis, malnutrition, and diabetes. The aim of this study was to analyze the mycobacterial content of sputum smears and cultures from adult patients with cystic fibrosis attended at a specialized unit for adults from March 1997 through December 2001. PATIENTS AND METHODS: Sputum samples were collected prospectively according to a protocol applied at each visit, and during most exacerbations staining and culture for mycobacteria were ordered in addition to the usual cultures for bacteria and fungi. A tuberculin test was performed at the end of the study. RESULTS: Twenty-eight patients (16 men) with cystic fibrosis were enrolled. The mean (SD) age was 25.3 (6.7) years. A total of 251 samples were cultured (range in number of samples per patient, 1-31). The mean period of follow up was 40.3 (22.1) months. The sputum smear was positive in 29 cases (4 patients); the culture was positive in 7 patients. More than 3 samples were positive in only 4 patients. Mycobacterium abscessus was isolated in 3 cases, Mycobacterium avium complex in 2 and Mycobacterium simiae in 1 and other an unidentified rapid growth Mycobacterium species. The Mantoux test was positive in 5 patients. Two of the 4 patients in whose samples mycobacteria were isolated repeatedly required treatment. CONCLUSIONS: The prevalence of nontuberculous mycobacterial infection is high in patients with cystic fibrosis. Staining and culture for mycobacteria should be carried out regularly and whenever exacerbation of pulmonary symptoms cannot be attributed to bacteria usually found in such patients. Patients with recurrent isolations of mycobacteria should be monitored closely.

Adult↗

PubMed1992

The cystic fibrosis transmembrane conductance regulator. Effects of the most common cystic fibrosis-causing mutation on the secondary structure and stability of a synthetic peptide.

Deletion of phenylalanine 508 (delta Phe-508) in the cystic fibrosis transmembrane conductance regulator (CFTR) protein causes approximately 70% of all cases of cystic fibrosis. This residue lies in a region of the protein that we have synthesized chemically and shown to bind adenine nucleotides (Thomas, P. J., Shenbagamurthi, P., Ysern, X., and Pedersen, P. L. (1991) Science 251, 555-557). A peptide lacking this critical residue, but otherwise corresponding to this crucial part of the protein, now also has been chemically synthesized and purified. This mutant peptide (P-66) exhibits a significant loss of beta-sheet structure as compared with the wild type peptide (P-67). Furthermore, urea denaturation of peptide structure reveals that P-66 is less stable than P-67. Although under non-denaturing conditions both peptides bind adenine nucleotides with high affinity, the loss of structural stability is reflected in the binding function of the peptides. Thus, P-67, in contrast to P-66, retains a significant capacity for nucleotide binding in 4 M urea. These results suggest a model for impaired delta Phe-508 CFTR function.

Adenosine Triphosphate↗

PubMed2001

Glycoconjugate metabolism in a cystic fibrosis knockout mouse model.

Cystic fibrosis knockout mice (cftr(-/-)) die prematurely of obstruction of the intestine which may result from accumulation of dehydrated glycoconjugate-containing mucus. We noted an increase in the specific activity of [(14)C]glucosamine-labeled high-molecular weight glycoconjugates, probably mucin, in the lumen of the intestine of cftr(-/-) (homozygous) mice compared to cftr(+/+) (wild-type) and cftr(+/-) (heterozygous) mice and a decrease in the turnover of glycoconjugates of several organs of the cftr(-/-) mice. No difference in the anionic composition of secreted intestinal glycoconjugates was detected and no difference in the amount of mucin 1 (Muc1) was found in the small intestine, colon, pancreas, and lungs of the different genotypes. In addition, the spleen of the cftr(-/-) mice was significantly smaller than that of control mice and the small intestine and colon were, respectively, longer and shorter compared to control mice. These results indicate modified glycoconjugate metabolism in cystic fibrosis knockout mice and morphologic changes to the spleen and intestine where the latter modifications are possibly related to the intestinal malabsorption associated with cystic fibrosis.

Animals↗

PubMed2001

Cytological characterization of apatitic calcium phosphate structures in bronchial epithelial tissue cultured from a child with cystic fibrosis (deltaF508).

Patients with cystic fibrosis homozygous for the AF508 mutation have marked disturbances in ion exchanges in a variety of tissues. Alterations in intra- or extracellular levels of Ca2+ and calcifications have been observed in numerous tissues from such patients, although the nature and origin of such calcifications have yet to be elucidated. In this study, we investigated the formation of calcifications in the respiratory tract of a AF508 homozygous child and attempted to establish their origin. Samples of bronchial epithelium from this patient were subjected to cytophysiological analysis ex vivo and in vitro. The defect of targeting of the cystic fibrosis transmembrane conductance regulator (CFTR) to the apical plasma membrane of epithelial cells was verified. Cytochemical and ultrastructural analysis revealed the presence of crystalline aggregates in fine needles in the respiratory tract. Cytochemical analysis, X-ray spectrometry, and electron diffraction showed that these aggregates corresponded to crystals of calcium phosphate in an apatite-like structure. Ultrastructural study of primary cultures of bronchial epithelium showed the presence of calcium phosphate crystals in granules from Golgi apparatus and in mitochondria. These observations indicated that modifications of ionic exchanges due to a defect in targeting of CFTR AF508 to the apical plasma membrane led to the formation of crystals of calcium phosphate in the cytoplasm of pulmonary cells. These crystals could enhance inflammation of the lung in patients with cystic fibrosis.

Apatites↗

PubMed1975

Endogenous and exogenous insulin responses in patients with cystic fibrosis.

Eight male patients with cystic fibrosis, normal nutrition, normal physical activity, relatively mild pulmonary disease, no evidence of liver disease and no family history of diabetes mellitus underwent a series of carbohydrate tolerance tests in comparison with a group of 18 normal male subjects matched for age and body weight. Compared with the normal group, the patients with cystic fibrosis had significantly impaired glucose tolerance and significantly lower serum immunoreactive insulin levels during oral and intravenous glucose tolerance tests; serum insulin levels were also significantly lower after intravenous administration of tolbutamide in the patients with cystic fibrosis, but the reduction in blood glucose concentration in each group was not significantly different. During an intravenous insulin test, the decrease in blood glucose concentration was the same for both groups, in spite of significantly lower serum insulin levels in the patients with cystic fibrosis .The percentage fall in plasma free fatty acids was at least as great in the patients with cystic fibrosis as in normals during the test procedures; while a significant decrease in plasma alpha-amino nitrogen after intravenously administered insulin was seen only in the patients with cystic fibrosis. These studies suggest that the carbohydrate intolerance of cystic fibrosis is consequent upon an impaired insulin response to glucose, but that this insulin deficiency is partly compensated for by increased peripheral tissue sensitivity to insulin.

Administration, Oral↗

PubMed2000

Applicability of different antibodies for immunohistochemical localization of CFTR in sweat glands from healthy controls and from patients with cystic fibrosis.

The hereditary disease cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Understanding of the consequences of CFTR gene mutations is derived chiefly from in vitro studies on heterologous cell cultures and on cells hyperexpressing CFTR. Data from ex vivo studies on human tissue are scarce and contradictory, a fact which is in part explained by secondary tissue destruction in most affected organs. The purpose of this study was to establish conditions under which wild-type and mutated CFTR can be studied in affected human tissue. Sweat glands carry the basic defect underlying CF and are not affected by tissue destruction and inflammation. Therefore, we used this tissue to test a panel of eight different CFTR antibodies under various fixation techniques. The antibodies were tested on skin biopsy sections from healthy controls, from CF patients homozygous for the most common mutation, DeltaF508, and from patients carrying two nonsense mutations. Of the eight CFTR antibodies, only three-M3A7, MATG 1104, and cc24-met the criteria necessary for immunolocalization of CFTR in sweat glands. The labeling pattern in the CF sweat glands was consistent with the postulated processing defect of DeltaF508 CFTR. The antibodies exhibited different sensitivities for detecting DeltaF508 CFTR.

Acetone↗

PubMed2000

[Neonatal cystic fibrosis: report of 2 cases].

Cystic fibrosis is the most common life-limiting recessive genetic disorder in Caucasian. It is caused by mutations of CFTR gene (cystic fibrosis transmembrane conductance regulator); at present over 500 mutations are known. Cystic fibrosis as a cause of respiratory distress in the neonate is quite rare. In neonatal period the most important clinical manifestations are meconium ileum and much rarely cholestatic jaundice. We present two cases of cystic fibrosis in newborns. In the first one, we point out the strict association between meconium ileum and cystic fibrosis. The patient underwent a surgical treatment for meconium ileum and the diagnosis was rapidly confirmed by genetic analysis and sweat test. The second one had intestinal obstruction from birth caused by meconium ileum associated with ileal atresia; besides, he developed cholestatic jaundice, severe and rapidly progressive respiratory disease. He died at 102 degrees day of age for cardiac failure. The diagnosis of cystic fibrosis, supported by typical clinical features and high level of serum trypsin, unfortunately wasn't confirmed by genetic analysis (lambda F508/neg), in addition, the sweat test wasn't reliable because an inadequate quantity of sweat was collected.

Cystic Fibrosis↗

PubMed1999

Cystic fibrosis presenting in adults.

Cystic fibrosis is a common genetic disease occurring in children. Milder forms of cystic fibrosis are increasingly being recognized as presenting in adults as well. This article describes the various ways in which cystic fibrosis can present in adult patients.

Adult↗

PubMed2004

Nodular glomerulosclerosis in cystic fibrosis mimics diabetic nephropathy.

BACKGROUND/AIMS: Despite the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator, being widely expressed throughout the kidney, there is no clearly defined renal phenotype in patients with cystic fibrosis. As patients with cystic fibrosis survive longer progressive pancreatic destruction may lead to abnormal glucose tolerance and diabetes mellitus, which in the kidney may be associated with the characteristic changes of nodular glomerulosclerosis. METHODS: The adult cystic fibrosis service at the Alfred hospital consists of a cohort of 200 patients. We describe 3 cystic fibrosis patients with impaired renal function who had renal biopsies performed as part of their diagnostic work-up. All patients had fasting plasma glucose levels, oral glucose tolerance tests and measurements of HbA1c performed to assess for the presence of cystic fibrosis-related diabetes mellitus. RESULTS: The renal biopsies of all 3 patients showed histological changes characteristic of diabetic nephropathy. In all cases described characteristic Kimmelstiel-Wilson nodules were present. However, in all 3 patients the presence of impaired glucose tolerance and diabetes mellitus was excluded using standard biochemical diagnostic criteria. CONCLUSION: We describe 3 adult CF patients, who on renal biopsy had histological evidence of nodular glomerulosclerosis in the absence of abnormal glucose metabolism. We speculate that the pro-inflammatory cytokine profile, typical of cystic fibrosis, predisposes to the lesions described.

Adult↗