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PubMed1985

Cystic fibrosis in Ontario.

The incidence of cystic fibrosis in Ontario, Canada has been determined from clinical data, from the cystic fibrosis database of the Hospital for Sick Children, Toronto, and from population statistics in the Province of Ontario. The survey included 420 confirmed cases of cystic fibrosis born during the period 1966-1980. The mean incidence during this period was one in 2,927. In the last 5-year period, a decline was noted in incidence that may have reflected in part the effectiveness of early diagnosis and genetic counseling in affected families. During the period of the survey, over 60% of cases were diagnosed within the first year of life, 74% by age 2 years, and 90% by age 5 years. Clinical diagnosis in the first year of life was more common in males (65%) than in females (54%), a consistent finding during the period of the survey. The incidence of meconium ileus was 15.7% of ascertained cases of cystic fibrosis, with similar incidences in males (16.4%) and females (14.4%). Although survival has not been the subject of this survey, mortality in the neonatal period was significantly higher in males than in females with cystic fibrosis.

Age Factors↗

PubMed2000

TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis.

BACKGROUND: Polymorphisms in transforming growth factor (TGF)-beta(1) associated with variations in cytokine levels are linked to fibrosis in a number of tissues. However, the contribution of this cytokine to organ fibrosis in patients with cystic fibrosis is presently unclear. This study was undertaken to examine the association between TGF-beta(1) gene polymorphisms and the development of pulmonary dysfunction in patients with cystic fibrosis. METHODS: Polymorphisms in the TGF-beta(1) gene defining amino acids of codons 10 and 25 were determined by ARMS-PCR using DNA stored on 171 Caucasian patients who were homozygous for the DeltaF508 mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Clinical information on the patients was obtained from medical records. RESULTS: Patients with cystic fibrosis of a TGF-beta(1) high producer genotype for codon 10 had more rapid deterioration in lung function than those with a TGF-beta(1) low producer genotype. The relative risk of accelerated decline in forced expiratory volume in one second (FEV(1)) to 50% predicted and forced vital capacity (FVC) to 70% predicted of patients with a high producer genotype was 1.74 (95% CI 1.11 to 2. 73) compared with 1.95 (95% CI 1.24 to 3.06) for those with a low producer genotype. DISCUSSION: TGF-beta(1) genotypes may have a role in mediating pulmonary dysfunction in patients with cystic fibrosis. Further work is required to determine whether inhibition of TGF-beta(1) activity in these patients may slow disease progression.

Adolescent↗

PubMed2004

Molecular dissection of the butyrate action revealed the involvement of mitogen-activated protein kinase in cystic fibrosis transmembrane conductance regulator biogenesis.

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which belongs to the superfamily of ATP-binding cassette transporters and uniquely possesses an additional large cytoplasmic domain [regulatory (R) domain]. CFTR inefficiently folds by means of co- and post-translational interactions with the cytosolic chaperones as well as luminal chaperones in the endoplasmic reticulum (ER). Aberrant folding and defective trafficking of the CFTR protein, which functions as an apical membrane Cl(-) channel, is the principal cause of cystic fibrosis. Recent data indicated that butyrate improves CFTR trafficking partly by regulating molecular chaperones; however, the precise mechanism of butyrate action remains elusive. In the present study, we examine the molecular aspect underlying the butyrate action in CFTR biogenesis by evaluating the expression and localization of the green fluorescent protein (GFP)-tagged CFTR transgenes in Cos7 cells. Our data show that butyrate significantly promoted stability of the ER-located form of GFP-wild-type (wt)-CFTR, followed by an increase in the amount of plasma membrane GFP-wt-CFTR. In contrast, the expression of the R domain deletion mutant GFP-DeltaR-CFTR was slightly increased by butyrate. The butyrate action on wt-CFTR expression was partially blocked by PD98059 (2'-amino-3'-methoxyflavone), a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK/MEK), which is the upstream activator of extracellular-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). Furthermore, activation of ERK/MAPK by the coexpression of constitutively active MAPKK/MEK predominantly augmented the expression of wt-CFTR, but not of DeltaR-CFTR, induced by butyrate. These data suggest that butyrate may facilitate the biogenesis and trafficking of wt-CFTR by requiring the presence of the R domain and further involving active ERK/MAPK in its biogenesis.

Animals↗

PubMed1973

Hypersecretion of zymogen granules in the pathogenesis of cystic fibrosis.

In the submandibular saliva of 10 cystic fibrosis subjects and 10 controls the turbidity and elevated calcium, protein, and amylase concentrations of the cystic fibrosis secretions, and precipitation of calcium and phosphate in a ratio consistent with hydroxyapatite have been confirmed. By electron microscopy the centrifuged deposits of the cystic fibrosis saliva were seen to be composed predominantly of round or oval subcellular corpuscles. By comparison with submandibular gland, these corpuscles have been identified as inclusion bodies (spherules) from within zymogen granules. Hydroxyapatite crystals formed on standing in the cystic fibrosis saliva. Polyacrylamide gel disc electrophoresis of the cystic fibrosis centrifuged deposits showed five bands, one of which, band 4, was more prominent in the deposit than in the supernatant gels. Comparisons have been made between these results and other studies and have shown (1) elevated calcium and protein in cystic fibrosis exocrine secretions; (2) simultaneous secretion of calcium and enzymes from salivary glands, stomach, and pancreas; and (3) increased salivary secretion of calcium and protein in response to parasympathomimetic and sympathomimetic drugs. Hypersecretion of calcium-containing zymogen granules is postulated as the cause of obstruction in cystic fibrosis.

Adolescent↗

PubMed1995

Paradoxical vocal cord adduction in an adolescent with cystic fibrosis.

Many patients with cystic fibrosis have symptoms of dyspnoea and wheeze which are responsive to treatment with bronchodilators. An adolescent woman with cystic fibrosis is described who presented with inspiratory stridor and in whom the classical features of paradoxical vocal cord adduction were found.

Adolescent↗

PubMedDate not supplied

[Controversies in cystic fibrosis--from pediatrician to specialist].

OBJECTIVE: Cystic fibrosis has become, in the last 70 years, the most important potentially fatal inherited disease that affects white individuals around the world. Although it is considered a genetic disorder, which strikes cells of different organs, not all patients present similar clinical response. Many clinical manifestations, mainly pulmonary and gastrointestinal, may develop in cystic fibrosis patients. The aim of this article is to offer pediatricians an updated review of the controversies and recent advances in the treatment of cystic fibrosis. SOURCES: Systematic review in the Medline database. SUMMARY OF THE FINDINGS: Seventy-nine articles about cystic fibrosis published in international journals were reviewed. This article presents an updated and critical review of the main events related to the incidence, pathophysiology, diagnosis and treatment of cystic fibrosis. CONCLUSIONS: Even though no treatment is available for this disease, new findings about its etiology and pathophysiology have been discovered in the last two decades, improving treatment and survival of cystic fibrosis patients.

English Abstract↗

PubMed1988

Intestinal disease in cystic fibrosis.

Three children with cystic fibrosis developed steatorrhoea unresponsive to changes in pancreatic supplements. The final diagnoses were chronic giardiasis, stagnant loop syndrome, and Crohn's disease. Refractory intestinal symptoms in cystic fibrosis merit further investigation.

Adolescent↗

PubMed2006

Calreticulin negatively regulates the cell surface expression of cystic fibrosis transmembrane conductance regulator.

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent Cl- channel at the plasma membrane, and its malfunction results in cystic fibrosis, the most common lethal genetic disease in Caucasians. Quality control of CFTR is strictly regulated by several molecular chaperones. Here we show that calreticulin (CRT), which is a lectin-like chaperone in the endoplasmic reticulum (ER), negatively regulates the cell surface CFTR. RNA interference-based CRT knockdown induced the increase of CFTR expression. Consistently, this effect was observed in vivo. CRT heterozygous (CRT+/-) mice had a higher endogenous expression of CFTR than the wild-type mice. Moreover, CRT overexpression induced cell surface expression of CRT, and it significantly decreased the cell surface expression and function of CFTR. CRT overexpression destabilized the cell surface CFTR by enhancing endocytosis, leading to proteasomal degradation. Deletion of the carboxyl domain of CRT, which results in its ER export, increased the negative effect and enhanced the interaction with CFTR. Thus, CRT in the post-ER compartments may act as a negative regulator of the cell surface CFTR.

Adenoviridae↗

PubMed1985

Conjugated bile acids in serum and secretions in response to cholecystokinin/secretin stimulation in children with cystic fibrosis.

More than 80% of patients with cystic fibrosis have poor pancreatic function, and have large daily faecal bile acid losses. This has been postulated to lower luminal bile acid concentrations and adversely affect fat absorption. We studied, for the first time, quantitative individual conjugated duodenal bile acid secretion rates into the duodenum during cholecystokinin/secretin infusion in 55 cystic fibrosis patients and six controls, using a quantitative non-absorbable marker technique. We were able to show adequate duodenal total bile acid concentrations and normal secretion rates in these children. The bile acid secretion pattern in cystic fibrosis patients showed a marked increase in bile acid concentration during cholecystokinin/secretin infusion, to levels which were above the critical micellar concentration indicating that the gall bladder is a functional organ in this disease. The subsequent fall in secretion rate was similar to controls. We have documented a significantly raised glycine/taurine bile acid conjugation ration in duodenal juice from cystic fibrosis patients and suggest that the combined effects of lowered ileal pH and increased glycine conjugated proportion of bile acids may cause precipitation of bile acids leading to decreased fat absorption and large faecal bile acid losses. To further investigate bile acid secretion in children with cystic fibrosis, we modified the high performance thin layer chromatography/densitometry method to enable measurement of individual glycine and taurine conjugates in serum. In comparing cystic fibrosis patients and controls, we were able to determine a group of 18 (36%) with bile acid evidence of liver damage who also showed reduced bile acid secretion into the duodenum. We were unable to study changes in serum bile acids during cholecystokinin/secretin infusion because of the high level of bile acid contamination in Boots Secretin. Some patients showed raised fasting serum bile acid concentrations more than two years before changes in conventional liver function tests or clinically evident liver disease. We have shown fasting serum bile acids to be a sensitive measure of liver dysfunction in cystic fibrosis and postulate that raised proportions of glycine conjugated bile acids may be responsible for the high incidence of liver disease in cystic fibrosis.

Adolescent↗

PubMedDate not supplied

The gender gap in cystic fibrosis survival.

Females with cystic fibrosis have significantly higher mortality than males from age 1 to age 20, resulting in an approximate four-year difference in median survival age. Survival is associated with a lack of colonization by pathogenic bacteria, as well as better pulmonary function, weight for height, and fitness. This statistically significant gender gap has been observed for decades and, therefore, is not likely to be the result of differential response to one of the newer treatments for cystic fibrosis.

Animals↗

PubMed1998

Clinical outcome in relation to care in centres specialising in cystic fibrosis: cross sectional study.

OBJECTIVES: To assess the effect on clinical outcome of managing paediatric and adult patients with cystic fibrosis at specialised cystic fibrosis centres. DESIGN: Cross sectional study. SETTING: Two adult cystic fibrosis centres in the United Kingdom. SUBJECTS: Patients from an adult cystic fibrosis centre in Manchester were subdivided into those who had received continuous care from paediatric and adult cystic fibrosis centres (group A), and those who had received paediatric care in a centre not specialising in cystic fibrosis followed by adult care in a cystic fibrosis centre (group B). Group C were referrals to the new adult cystic fibrosis centre in Cambridge who had received neither paediatric nor adult centre care for their cystic fibrosis. MAIN OUTCOME MEASURES: Body mass index (weight (kg)/height (m2)), lung function (forced expiratory volume in one second (FEV1 percentage of predicted)), the Northern chest x ray film score, and age at colonisation with Pseudomonas aeruginosa. RESULTS: A prominent stepwise increase in body mass index was associated with increasing amounts of care at a cystic fibrosis centre; 18.3, 20.2, and 21.3 for groups C, B, and A respectively (P<0.001). Improved nutritional status was correlated with a higher FEV1 and better (lower) chest x ray film scores; r=0. 52 and -0.45 respectively (P<0.001 for both). CONCLUSION: These findings provide the first direct evidence that management of cystic fibrosis in paediatric and adult cystic fibrosis centres results in a better clinical outcome, and strongly supports the provision of these specialist services.

Adult↗

PubMed2004

Update on newborn screening for cystic fibrosis.

PURPOSE OF REVIEW: Cystic fibrosis (CF) is the most common lethal genetic disorder in the United States to be identified in childhood. In November 2003 the US Cystic Fibrosis Foundation and the Centers for Disease Control and Prevention convened an expert panel to review the indications for CF newborn screening. In this review we discuss the information during the year leading up to this meeting as well as publications since the meeting. RECENT FINDINGS: During the past several years an increasing number of CF patients have been diagnosed with newborn screening. These patients have demonstrated several benefits to screening while also uncovering new challenges. Health benefits have included improved nutrition persisting for many years and the avoidance of nutritional complications. Early identification has also meant that these often clinically healthy infants are being followed in CF centers for care. This has added to the need for avoiding infection risks to which these patients might not have otherwise been exposed. Psychosocial benefits include the avoidance of stress due to delayed diagnosis as well as assistance with family planning. Psychosocial challenges include carrier identification and detection of patients with mild disease or without a clear diagnosis. SUMMARY: Although no study has definitively shown reduced lung disease or prolonged survival in CF patients detected by newborn screening, the general consensus is that improved nutrition and cognitive potential, in addition to the reduced costs for hospitalization and intensive therapies, support the benefits of screening.

Cystic Fibrosis↗

PubMed1981

Effect of swimming on forced expiration and sputum clearance in cystic fibrosis.

Ten children with cystic fibrosis participated in swimming training over 7 weeks. Ventilatory status, assessed by spirometry, had improved significantly after the course. 10 weeks after the end of the training most measurements had returned to their preswimming levels. In the majority of the children sputum production on swimming days was higher than on nonswimming days. Regular swimming can assist in mucus clearance and improve ventilatory function in children with cystic fibrosis.

Adolescent↗

PubMed1985

Urticaria in cystic fibrosis.

One hundred patients with cystic fibrosis were screened for urticaria. The prevalence of urticaria in cystic fibrosis was 16 percent. There were eleven patients with urticaria associated with atopy and five without atopy. Acute urticaria was detected more frequently in the atopic group, and chronic urticaria was more common in the nonatopic group. However, there was no statistically significant relationship between the two groups of cystic fibrosis patients with urticaria.

Adolescent↗

PubMed2006

Current prospects for gene therapy of cystic fibrosis.

Conventional therapy for cystic fibrosis has extended the median survival age, but the disease is still fatal. Gene therapy can correct the primary and secondary defects associated with cystic fibrosis, but limited extent and duration of the corrections as well as concerns about the safety of some current delivery systems have prevented gene therapy from being curative. For viral vectors, the main challenges are access to target cells and host immunity, which prevents efficient re-administration. Masking viral particles from the immune system, the use of alternative serotypes, or retargeting have been employed to address these issues. Non-viral vectors have dramatically improved over the past five years but improvements in efficacy are needed. In lung, naked DNA has been inefficient and lipid-based vectors have only achieved efficient gene transfer at doses that elicit limiting inflammatory responses. Molecular conjugates or polymer-based delivery overcomes some limitations, with good ability to transfect non-dividing cells. Improvements of viral and non-viral vectors continue to advance the construction of stable, safe and efficacious vectors that can be re-administered.

Cystic Fibrosis↗

PubMed1998

Cystic fibrosis: present and future.

Cystic fibrosis (CF) is an inherited disorder of epithelial chloride transport affecting primarily pancreas, lungs, gut, liver and exocrine glands. The defect is caused by defects of the cystic fibrosis transmembrane regulation gene on chromosome 7. Genotyping has proved useful in identifying gene carriers, a definitive diagnosis, and in antenetal diagnosis. Genotype/phenotype relationships have shown that the commonest cause of pancreatic insufficiency is the D F508 mutation. Clinical trials are exploring the use of somatic gene therapy but this is not yet a viable treatment option. Liver, lung and intestinal disease result in malnutrition which causes further dysfunction of these organs. Aggressive nutritional and pancreatic enzyme therapy results in improved disease, normal growth and increased survival. However, high-dose enzyme therapy may in some individuals cause a fibrosing colonopathy. For those with end-stage liver and lung disease, transplantation holds out some hope.

Chromosome Aberrations↗

PubMed2005

Autopsy confirmation of severe pulmonary interstitial fibrosis secondary to Munchausen syndrome presenting as cystic fibrosis.

Chronic factitious disorder with physical symptoms, or Munchausen syndrome, is a well-recognized but uncommonly diagnosed psychiatric condition characterized by the deliberate production of signs and symptoms of disease in order to receive medical attention. Clinical suspicion of this disease is rarely confirmed by autopsy, as the patients usually do not die as a consequence of feigning illness. Here we report the autopsy confirmation of a case of a suspected Munchausen syndrome patient who presented with a history of cystic fibrosis. Examination of the lungs demonstrated extensive severe interstitial fibrosis, and polariscopic examination revealed a large quantity of crystalline material throughout the tissue; X-ray diffraction identified the material as talc. Synopses of published cases of Munchausen syndrome presenting as cystic fibrosis, and cases of Munchausen syndrome with pulmonary talcosis are presented as part of the discussion.

Administration, Inhalation↗

PubMed1990

Bronchial artery embolization to control hemoptysis in cystic fibrosis.

Severe hemoptysis in cystic fibrosis can be life-threatening because of acute blood loss or because it interferes with sustaining physical therapy of the chest. Hemoptysis was controlled in 19 of 20 cystic fibrosis patients by means of embolization with a combination of 250-590-microns particles of polyvinyl alcohol foam and absorbable gelatin pledgets. Repeat embolization was needed in eight patients to achieve or maintain effective hemostasis. One or more aberrant bronchial arteries were found in seven patients (35%), and a spinal artery branching from a vessel that also supplied bronchial circulation was present in 11 patients (55%). The data suggest that although embolization has a wider applicability than previously reported, care should be taken during angiography to evaluate the bronchial circulation because aberrant bronchial vessels and spinal arteries arising from bronchial circulation are common.

Adolescent↗