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PubMed2000

[Diagnosis of cystic fibrosis in adults].

Cystic fibrosis is a genetic recessive disorder caused by mutations in the gene that encodes the CFTR protein. The diagnosis of cystic fibrosis is usually established in early childhood but it is now being made in an increasing number of adults. Many of them present with mild or atypical cystic fibrosis clinical features, mostly lung disease. In addition, some adults with congenital bilateral absence of vas deferens or idiopathic chronic pancreatitis may be assigned a diagnosis of cystic fibrosis. The diagnosis of cystic fibrosis in adults should be based on the presence of one or more characteristic clinical features, a history of cystic fibrosis in a sibling, plus evidence of defective CFTR function as documented by elevated sweat chloride concentrations or abnormal ion transport across the nasal epithelium, or identification of mutations on both CFTR genes.

Adolescent↗
PubMed2005

Cystic fibrosis airway epithelial Ca2+ i signaling: the mechanism for the larger agonist-mediated Ca2+ i signals in human cystic fibrosis airway epithelia.

In cystic fibrosis (CF) airways, abnormal epithelial ion transport likely initiates mucus stasis, resulting in persistent airway infections and chronic inflammation. Mucus clearance is regulated, in part, by activation of apical membrane receptors coupled to intracellular calcium (Ca(2+)(i)) mobilization. We have shown that Ca(2+)(i) signals resulting from apical purinoceptor (P2Y(2)-R) activation are increased in CF compared with normal human airway epithelia. The present study addressed the mechanism for the larger apical P2Y(2)-R-dependent Ca(2+)(i) signals in CF human airway epithelia. We show that the increased Ca(2+)(i) mobilization in CF was not specific to P2Y(2)-Rs because it was mimicked by apical bradykinin receptor activation, and it did not result from a greater number of P2Y(2)-R or a more efficient coupling between P2Y(2)-Rs and phospholipase C-generated inositol 1,4,5-trisphosphate. Rather, the larger apical P2Y(2)-R activation-promoted Ca(2+)(i) signals in CF epithelia resulted from an increased density and Ca(2+) storage capacity of apically confined endoplasmic reticulum (ER) Ca(2+) stores. To address whether the ER up-regulation resulted from ER retention of misfolded DeltaF508 CFTR or was an acquired response to chronic luminal airway infection/inflammation, three approaches were used. First, ER density was studied in normal and CF sweat duct human epithelia expressing high levels of DeltaF508 CFTR, and it was found to be the same in normal and CF epithelia. Second, apical ER density was morphometrically analyzed in airway epithelia from normal subjects, DeltaF508 homozygous CF patients, and a disease control, primary ciliary dyskinesia; it was found to be greater in both CF and primary ciliary dyskinesia. Third, apical ER density and P2Y(2)-R activation-mobilized Ca(2+)(i), which were investigated in airway epithelia in a long term culture in the absence of luminal infection, were similar in normal and CF epithelia. To directly test whether luminal infection/inflammation triggers an up-regulation of the apically confined ER Ca(2+) stores, normal airway epithelia were chronically exposed to supernatant from mucopurulent material from CF airways. Supernatant treatment expanded the apically confined ER, resulting in larger apical P2Y(2)-R activation-dependent Ca(2+)(i) responses, which reproduced the increased Ca(2+)(i) signals observed in CF epithelia. In conclusion, the mechanism for the larger Ca(2+)(i) signals elicited by apical P2Y(2)-R activation in CF airway epithelia is an expansion of the apical ER Ca(2+) stores triggered by chronic luminal airway infection/inflammation. Greater ER-derived Ca(2+)(i) signals may provide a compensatory mechanism to restore, at least acutely, mucus clearance in CF airways.

Adult↗
PubMed1992

Cystic fibrosis mutations in French Canadians: three CFTR mutations are relatively frequent in a Quebec population with an elevated incidence of cystic fibrosis.

The French-Canadian population in the Saguenay-Lac St. Jean region of northeastern Quebec has an elevated frequency of cystic fibrosis (CF). The average incidence of cystic fibrosis was 1 in 891 births and the prevalence of CF carriers was estimated to be 1 in 15. We tested for 10 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 133 French-Canadian CF families from Quebec. Ninety-one families were from the Saguenay-Lac St. Jean region and 42 families were referred from other regions of Quebec. We detected the CFTR mutation in 93 and 92% of the CF chromosomes in the Saguenay-Lac St. Jean and the major-urban Quebec families, respectively. The two groups of French-Canadian families were significantly different for the proportions of CFTR mutations. The three most common mutations in the Saguenay-Lac St. Jean families were delta F508 (58%), 621 + 1G----T (23%), and A455E (8%); and in the major-urban Quebec families were delta F508 (71%), 711 + 1G----T (9%), and 621 + 1G----T (5%). These results provide evidence for the role of founder effect in the elevated incidence of cystic fibrosis in the Saguenay-Lac St. Jean population.

Cystic Fibrosis↗
PubMed2000

Effects of cystic fibrosis and congenital bilateral absence of the vas deferens-associated mutations on cystic fibrosis transmembrane conductance regulator-mediated regulation of separate channels.

The protein defective in cystic fibrosis (CF), the CF transmembrane-conductance regulator (CFTR), functions as an epithelial chloride channel and as a regulator of separate ion channels. Although the consequences that disease-causing mutations have on the chloride-channel function have been studied extensively, little is known about the effects that mutations have on the regulatory function. To address this issue, we transiently expressed CFTR-bearing mutations associated with CF or its milder phenotype, congenital bilateral absence of the vas deferens, and determined whether mutant CFTR could regulate outwardly rectifying chloride channels (ORCCs). CFTR bearing a CF-associated mutation in the first nucleotide-binding domain (NBD1), DeltaF508, functioned as a chloride channel but did not regulate ORCCs. However, CFTR bearing disease-associated mutations in other domains retained both functions, regardless of the associated phenotype. Thus, a relationship between loss of CFTR regulatory function and disease severity is evident for NBD1, a region of CFTR that appears important for regulation of separate channels.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1993

Cystic fibrosis mutations in white and black Americans: an approach to identification of unknown mutations with implications for cystic fibrosis screening.

OBJECTIVE: We sought to define the frequency of common cystic fibrosis mutations in white and black American probands from our geographic region. STUDY DESIGN: Mutation analysis was performed for delta F508, G551D, G542X, R553X, S549N, an d N1303K. For probands with undetermined mutations single-stranded conformational polymorphism analysis was performed. RESULTS: Among 40 white subjects with cystic fibrosis 26 (65%) were homozygous for delta F508, 10 (25%) were heterozygous for delta F508 and another unknown mutation, and two were homozygous for unknown mutations. Among 10 black probands one was homozygous for delta F508, seven (70%) were heterozygous for delta F508 and another unknown mutation, and one was homozygous for unknown mutations. Single-stranded conformational polymorphism analysis for selected exons was performed for 11 probands with unknown mutations. One mutation was detected in a white proband. Sequencing of this exon showed the mutation to be Q493X. CONCLUSIONS: Thirty percent of white subjects and 80% of black subjects carried unknown mutations. In one family single-stranded conformational polymorphism was informative in identifying an undetermined cystic fibrosis mutation.

Black People↗
PubMed2002

Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis.

Cystic fibrosis is characterized by an early and sustained influx of inflammatory cells into the airways and by release of proteases. Resolution of inflammation is normally associated with the orderly removal of dying apoptotic inflammatory cells through cell recognition receptors, such as the phosphatidylserine receptor, CD36, and alpha v integrins. Accordingly, removal of apoptotic inflammatory cells may be impaired in persistent inflammatory responses such as that seen in cystic fibrosis airways. Examination of sputa from cystic fibrosis and non-cystic fibrosis bronchiectasis patients demonstrated an abundance of apoptotic cells, in excess of that seen in patients with chronic bronchitis. In vitro, cystic fibrosis and bronchiectasis airway fluid directly inhibited apoptotic cell removal by alveolar macrophages in a neutrophil elastase-dependent manner, suggesting that elastase may impair apoptotic cell clearance in vivo. Flow cytometry demonstrated that neutrophil elastase cleaved the phosphatidylserine receptor, but not CD36 or CD32 (Fc gamma RII). Cleavage of the phosphatidylserine receptor by neutrophil elastase specifically disrupted phagocytosis of apoptotic cells, implying a potential mechanism for delayed apoptotic cell clearance in vivo. Therefore, defective airway clearance of apoptotic cells in cystic fibrosis and bronchiectasis may be due to elastase-mediated cleavage of phosphatidylserine receptor on phagocytes and may contribute to ongoing airway inflammation.

Adolescent↗
PubMed2005

The survival advantage of patients with cystic fibrosis diagnosed through neonatal screening: evidence from the United States Cystic Fibrosis Foundation registry data.

OBJECTIVE: To determine the impact of age and condition at the time of diagnosis on survival of patients with cystic fibrosis (CF). STUDY DESIGN: By mode of diagnosis, 27,692 patients documented in the 1986-2000 CF Foundation Registry were segregated into meconium ileus (MI), prenatal or neonatal screening (SCREEN), positive family history only (FH), and symptoms other than MI (SYMPTOM). Patients in the MI, SCREEN, and SYMPTOM groups were further categorized by initial presenting symptoms into combined respiratory symptoms and malnutrition (RESP + NUTR), RESP, NUTR, other less common symptoms (OTHER), and OTHER + RESP/NUTR. RESULTS: Fifty-five percent of patients in the SCREEN group and 59% of patients in the MI group were diagnosed within age 1 month, as contrasted with 5% in patients in the SYMPTOM group (P < .001). Compared with patients in the SCREEN group, patients in the MI and SYMPTOM groups had significantly greater risks of shortened survival. Patients in the SYMPTOM group presenting with RESP + NUTR had significantly greater risk of shortened survival than the SCREEN group (P < .05). Survival of patients in the SYMPTOM group diagnosed "early," that is, within 1 month of age, did not differ from patients in the SCREEN group but was significantly better than patients in the SYMPTOM group diagnosed beyond age 1 month to 10 years. CONCLUSIONS: Early diagnosis through screening is associated with better survival compared with delayed diagnosis through non-MI symptoms beyond the age of 1 month.

Adolescent↗
PubMed2006

A universal array-based multiplexed test for cystic fibrosis carrier screening.

Cystic fibrosis is a multisystem autosomal recessive disorder with high carrier frequencies in caucasians and significant, but lower, carrier frequencies in other ethnicities. Based on technology that allows high detection of mutations in caucasians and significant detection in other ethnic groups, the American College of Medical Genetics (ACMG) and American College of Obstetricians and Gynecologists (ACOG) have recommended pan-ethnic cystic fibrosis carrier screening for all reproductive couples. This paper discusses carrier screening using the Tag-It multiplex mutation platform and the Cystic Fibrosis Mutation Detection Kit. The Tag-It cystic fibrosis assay is a multiplexed genotyping assay that detects a panel of 40 cystic fibrosis transmembrane conductance regulator mutations including the 23 mutations recommended by the ACMG and ACOG for population screening. A total of 16 additional mutations detected by the Tag-It cystic fibrosis assay may also be common. The assay method is described in detail, and its performance in a genetics reference laboratory performing high-volume cystic fibrosis carrier screening is assessed.

Cell Membrane↗
PubMed1999

Patterns of medical practice in cystic fibrosis: part II. Use of therapies. Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis.

This report describes the prescribing pattern of therapeutic interventions in the management of patients with cystic fibrosis (CF), as observed in the Epidemiologic Study of Cystic Fibrosis (ESCF). Use of 20 therapies by 12,622 patients was recorded from each health care encounter (53,024 outpatient visits and 8,561 hospitalizations) during a 1-year period (1995), and analyzed by gender, age, severity of lung disease, and presence of any Pseudomonas species in the respiratory tract. The percentage of patients using the following pulmonary therapies was observed (in descending order): airway clearance techniques (88.2%); inhaled bronchodilators (82.2%); oral antibiotics (excluding quinolones) (68. 2%); dornase alfa (52.9%); intravenous antibiotics (34.4%); oral quinolones (34.4%); inhaled antibiotics (34.3%); mast cell stabilizers (29.5%); inhaled corticosteroids (25.9%); oral corticosteroids (17.1%); oral bronchodilators (16.2%); oxygen (8. 1%); inhaled mucolytic agent acetyl cysteine (6.5%); and diuretics (1.4%). The percentage of patients using nutritional therapies was: pancreatic enzymes (96%); oral nutritional supplements (31.1%); enteral nutrition (7.3%); and parenteral nutrition (0.7%). The percentage of patients using other therapies was: nonsteroidal anti-inflammatory drugs (7.9%); and insulin or oral hypoglycemic agents (6.1%). The general trend was for therapies to be used more by older patients, those with lower pulmonary function, and by those with Pseudomonas in their respiratory tract. Exceptions to this trend occurred for airway clearance, oral antibiotics, mast cell stabilizers, and pancreatic enzymes. Four therapies (oral nutritional supplements, parenteral nutrition, diuretics, and pancreatic enzymes) were used more by males than females. However, there was no gender difference for this group of therapies on pulmonary or nutritional status.

Adolescent↗
PubMed1997

13Carbon mixed triglyceride breath test and pancreatic enzyme supplementation in cystic fibrosis.

Children with cystic fibrosis have variable degrees of exocrine pancreatic insufficiency which, if untreated, is the main cause of fat malabsorption. The impact of pancreatic enzyme supplementation on fat digestion was measured in 41 children with cystic fibrosis, 11 healthy controls, and five children with mucosal diseases by a non-invasive test of intraluminal lipolysis using 13carbon (13C) labelled mixed triglyceride (1,3-distearyl, 2[13C] octanoyl glycerol). The children with cystic fibrosis without pancreatic supplements had a median (range) 13C cumulative percentage dose recovered over six hours (cPDR) of 3.1% (0-31.7), the controls 31.0% (21.8-41.1), and the subjects with mucosal disease 27.8% (19.7-32.5). In 23 subjects with cystic fibrosis the usual dose of pancreatic enzyme supplements increased the cPDR to a median of 23.9% (0-45.6), and twice the usual dose of enteric coated microspheres increased the cPDR to 31.1% (11.1-47.8). There was no significant difference between the median cPDR of normal controls and children with mucosal disease, but there was a highly significant difference between these groups and children with untreated cystic fibrosis. Thirteen children with cystic fibrosis had no 13C recovery in their breath without enzymes and 10 showed marked increases with regular enzymes. In eight children doubling the dose of enzymes caused no or minimal improvement. The mixed triglyceride breath test offers a simple, non-invasive way of assessing the need for pancreatic enzyme supplementation in children with cystic fibrosis and could be used to optimise treatment.

Breath Tests↗
PubMed1995

Neonatal screening for cystic fibrosis: result of a pilot study using both immunoreactive trypsinogen and cystic fibrosis gene mutation analyses.

We have evaluated a two-tier neonatal cystic fibrosis (CF) screening of immunoreactive trypsinogen (IRT) followed by CFTR gene mutation analysis using a systematic scanning of exons 7, 10, and 11, and, if necessary, by direct DNA sequencing. Over an 18-month period we screened 32,300 neonates born in the western part of Britanny. The first tier, involving IRT screening at 3 days of age, utilizes a low elevation of the trypsinogen level (600 ng/ml), which is highly sensitive. The second tier, which corresponds to the exhaustive screening for mutations in three exons of the gene, is highly specific for this population (Britanny). The false positive rate is very low, and no false negatives have been reported to date. This strategy has allowed the identification of five novel alleles (V322A, V317A, 1806 del A, R553G, G544S).

Base Sequence↗
PubMed1978

Increased intracranial pressure in cystic fibrosis.

Three cystic fibrosis infants with severe respiratory distress had increased intracranial pressure (with bulging fontanels) which cleared parri passu with improvement in the chest condition. It is proposed that the intracranial hypertension is a result of raised venous pressure, itself secondary to the intrathoracic obstruction to venous return, consequent on the bronchial obstructive disease.

Cystic Fibrosis↗
PubMed2000

Protracted neonatal hypertrypsinogenaemia, normal sweat chloride, and cystic fibrosis.

The cystic fibrosis (CF) clinical spectrum has greatly expanded in the past few years, including atypical forms with low sweat chloride concentrations. Two cases are presented which suggest that children detected by neonatal CF screening whose trypsinogen concentrations are still raised by the second month of age could, despite a negative sweat test, be affected by an atypical CF with fully expressed pulmonary involvement.

Adolescent↗
PubMed1995

Amyloid goitre and hypothyroidism secondary to cystic fibrosis.

Although cystic fibrosis (CF) is still the most frequently fatal childhood disease, many adults now survive into their third and fourth decades. Uncommon complications of chronic diseases, such as amyloidosis, while infrequent, may now appear during the course of CF in adulthood. We present a case of a patient with CF who was diagnosed with hypothyroidism due to amyloid deposits in the thyroid.

Adult↗
PubMed2003

[Antibiotic therapy against Pseudomonas aeruginosa and other gram-negative bacteria in cystic fibrosis].

In cystic fibrosis patients, bronchial infection with Pseudomonas aeruginosa (PA) is frequent, occurring often early in life. It becomes chronic because of a particular relationship between bacteria and host. Intensive antibiotic treatment often permits a transient eradication. When infection becomes chronic, antibiotics must be prescribed in a way to afford resistance. Efficacy of nebulized antibiotics is now recognized. Problems persist. Because of the difficulty to eradicate PA, new strategies may consist in diminishing the pathogenicity of PA, by inhibiting adhesion and virulence factors' production.

Anti-Bacterial Agents↗
PubMed1989

Diabetic microangiopathy in patients with cystic fibrosis.

Individuals with cystic fibrosis have a 1% to 7% incidence of insulin-dependent diabetes mellitus. The occurrence of diabetic microangiopathy in patients with cystic fibrosis has been reported recently. From 1978 to 1987, 19 patients with cystic fibrosis and diabetes mellitus were followed up. Four patients (21%) had evidence of diabetic microangiopathy. In one, peripheral neuropathy developed 5 years after the onset of diabetes mellitus, and the other 3 patients each had complications of retinopathy, nephropathy, and neuropathy which developed 10 years after the onset of diabetes mellitus. All were poorly compliant in their medical care. Significant morbidity was seen in the 3 patients with multisystem involvement--blindness, glaucoma, hypertension, and renal failure. The combination of long-standing diabetes mellitus, poor glycemic control, plus pathophysiologic features associated with cystic fibrosis may have contributed to the development of microangiopathy. The use of steroids in 4 other patients and dextrose infusions (as part of hyperalimentation) in another 4 patients precipitated or exacerbated diabetes. The data indicate that diabetic microangiopathy can occur in the individual with cystic fibrosis. Routine screening for diabetes and its complications in the population with cystic fibrosis, as well as optimal control of hyperglycemia, is warranted.

Adolescent↗