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RATIONALE: Although in patients with diffuse bronchiectasis (DB) and a normal sweat test the presence of one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is frequently observed, its pathogenic role in the development of DB remains unclear. OBJECTIVES: To evaluate the association between CFTR heterozygosity and CFTR protein dysfunction in the airways of patients with DB. METHODS: Nasal potential difference was measured in 122 patients with DB of unknown origin and with a normal sweat test (Cl(-) < 60 mmol/L). They were classified according to the presence of CFTR mutations: zero (85 patients), one (22 patients), or two mutations (15 patients). Control groups comprised 26 healthy subjects, 38 obligate heterozygotes for CFTR, and 92 patients with classic cystic fibrosis (CF) with an abnormal sweat test (Cl(-) > or = 60 mmol/L). Patients classified as mild-CF were carrying at least one mild mutation and patients classified as severe-CF were homozygous for the F508del mutation. MEASUREMENTS AND MAIN RESULTS: There was a continuum of airway CFTR dysfunction in the study population as shown by nasal potential difference measurements, ranging from normal values in healthy subjects, to intermediate values in subjects with DB, to highly abnormal values in subjects classified as severe-CF. This continuum of airway CFTR dysfunction was thus strongly associated with defects in the CFTR gene. Moreover, among patients with DB, a similar continuum in intermediate nasal potential difference was identified that was associated with the bearing of zero, one, or two CFTR mutations. These electrophysiological phenotypes and CFTR genotypes were also associated with the clinical phenotype, as shown by the frequency of Staphylococcus aureus and Pseudomonas aeruginosa bronchial colonization. CONCLUSIONS: Our study supports the hypothesis that a unique CFTR mutation may have pathogenic consequences in patients with DB. [ABSTRACT FROM AUTHOR]

We retrospectively studied the outcomes of adult patients with cystic fibrosis (CF) hospitalized for severe pulmonary exacerbations (69 cases) between January 1997 and June 2001. Cases were treated either in the Pulmonary Department (n = 46) or in the intensive care unit (ICU) (n = 23) depending on severity. Noninvasive mechanical ventilation was used in 61% (14 of 23) and 33% (15 of 46) of cases treated in the ICU and the Pulmonary Department groups, respectively. Invasive ventilation was necessary in 4 of 23 cases treated in the ICU. The 1-year survival rate was 52% (12 of 23) and 91% (42 of 46) in the ICU and the Pulmonary Department groups, respectively. Lung transplantation was performed in two patients from the ICU group and in five patients from the Pulmonary Department group after hospital discharge. Factors predictive of death were prior colonization with Burkholderia cepacia and rapid decline in FEV1 before admission and severity of exacerbations (severity of hypoxemia and hypercapnia, simplified acute physiology score II and logistic organ dysfunction (LOD) scores, requirement of noninvasive mechanical ventilation, and hospitalization in the ICU) in the univariate analysis and were prior colonization with B. cepacia, the severity of hypoxemia at admission, and hospitalization in the ICU in the multivariate analysis. In 1-year survivors, pulmonary exacerbation did not affect the progression of the disease. [ABSTRACT FROM AUTHOR]

Study Objectives: In dyspneic patients without left ventricular enlargement, it may be difficult to differentiate between obstructive lung disease and diastolic heart failure. Determination of plasma brain natriuretic peptide (BNP) levels, known to increase with ventricular stretch, may be of clinical relevance in this situation. We compared the discriminant power of BNP blood levels and of echocardiography in patients with either chronic obstructive lung disease or diastolic heart failure.Patients: Twenty-six New York Heart Association class III dyspneic patients with normal left ventricular systolic function were enrolled: 17 patients with chronic obstructive lung disease and 9 patients with unequivocal diastolic heart failure.Results: Echocardiographic data were unable to accurately differentiate between the two groups, whereas BNP levels were significantly and markedly higher in patients with diastolic heart failure when compared to those with obstructive lung disease (224 +/- 240 pg/mL vs 14 +/- 12 pg/mL, p < 0.0001).Conclusions: These preliminary results warrant a prospective, large-scale evaluation of the value of BNP assay for determining diastolic dysfunction, a common cause of dyspnea in elderly patients, and differentiating it from other diagnoses such as obstructive lung disease. [ABSTRACT FROM AUTHOR]

Background: Allergic asthma is a multifactorial and probably multigenic inflammatory disease of the upper airways, and has been associated with the HLA class II alleles DR4 and DR7. Here we investigated possible associations with other polymorphic susceptibility/resistance genes located within the major histocompatibility complex, i.e., the genes coding the major 70‐kDa heat‐shock proteins (HSP; Hsp70) hsp70–1, hsp70–2, and hsp70‐HOM, whose products are overexpressed in the bronchi of asthmatic patients. Methods: Genomic DNA was extracted from peripheral blood lymphocytes or buccal epithelial cells of 48 patients with allergic asthma and 31 selected nonatopic control subjects, in whom we previously reported a strong association of atopy with DR4/DR7 alleles.Results: No evidence was found for an independent role of hsp70 gene polymorphism in susceptibility to allergic asthma. However, hsp70 alleles might be involved in extended haplotypes of HLA markers. Conclusions: Our data suggest that Hsp70 overexpression in asthma results from complex interactions between environmental exposures and genetic background rather than from specific genetic variations in hsp70 genes. [ABSTRACT FROM AUTHOR]

Background Atopy, with or without associated asthma, provides a useful model for evaluating the genetic factors that control human immune responsiveness. HLA class II gene products are involved in the control of immune responses. Objectives We investigated whether susceptibility or resistance to the disease was associated with HLA class II genes. Methods Blood samples were obtained from two groups of unrelated European-born white adults: 56 atopic patients (52 of them with asthma) and 39 healthy controls with no personal or familial history of asthma or atopy. Genomic DNA was extracted from peripheral blood lymphocytes. The exons of DQA1, DQB1, DRB and DPB1 genes were selectively amplified by the polymerase chain reaction (PCR) method. Geno-typing was carried out by digestion of the amplified DNA products with allele-specific endonucleases (PCR-RFLP), which can recognize allelic variations in the polymorphic exon. Results We found no significant differences in the frequency of DPB 1 alleles between patients and controls. HLA class II DR4 and DR7 alleles were present in 39.2% of the patients and in 2.5% of the healthy subjects (Pc*2&les; 3.9 10-3). Conversely, DQA 1*0103 and DQB 1*0502 alleles were more frequent in the control subjects. These results confirm a previous study of an extended pedigree, which showed that DR4 and DR7 alleles were absent in all healthy members of the family and were frequently observed in atopic and/or in asthmatic subjects. Conclusion We observed that HLA-DR 4 and DR7 alleles are significantly implicated in their susceptibility to the disease and suggest that this susceptibility is more related to atopy than to specific responses to allergens. According to previous studies, we could also submit that in atopic patients with asthma, DR4 alleles at the least, could be more closely associated with atopy than with asthma per se. Conversely, we suggest that some allelic DQA 1 and DQB 1 sequences might confer protection against the disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE:: To determine the prevalence and clinical features of malnutrition and its relationship with the CFTR genotype in a cystic fibrosis (CF) adult population. DESIGN:: Cross-sectional study. SETTING:: Department of Pulmonology, Cochin Hospital, Paris, France. SUBJECTS:: 163 CF adults seen between 1997 and 1999. RESULTS:: Mean age was 28.8?y. Mean body mass index (BMI) was 19.1?kg/m2. Malnutrition (BMI<18.5?kg/m2) was seen in 81 patients (49.7%). Its severity was associated with diagnosis of CF before the age of 18?y (P<0.01), FEV1 values below 30%(P<0.01), the yearly decline of FEV1 (P<0.01), pancreatic insufficiency (P<0.01) and gastro-oesophageal reflux (P<0.01). Malnutrition was observed in 58.7%of patients with a severe CFTR genotype but in 28.6%of patients with a mild genotype (P<0.001). CONCLUSION:: Malnutrition remains frequent in adults with CF except in patients presenting with a mild CFTR genotype (leading to a mild phenotype and to later diagnosis). SPONSORSHIP:: None.European Journal of Clinical Nutrition (2005) 59, 152-154. doi:10.1038/sj.ejcn.1602039 Published online 15 September 2004 [ABSTRACT FROM AUTHOR]

Taking account of progress in understanding how cystic fibrosis (CF)-associated mutations cause a loss of CF transmembrane conductance regulator (CFTR) channel function, Michael Welsh and Alan Smith have classified CFTR mutations into five classes. Mutations of class I are mutations throughout the CFTR gene that produce premature termination signals because of splice-site abnormalities, frameshifts owing to insertions or deletions, or nonsense mutations. Class I mutations are expected to have a severe effect on protein function and have been associated with the severe pancreatic-insufficient phenotype. However, J.E. Mickle et al. described a nonsense mutation, S1455X, located in exon 24, which was associated with elevated sweat chloride concentrations in the absence of the CF phenotype in female compound heterozygotes. The 4382delA mutation is a frameshift deletion generating a stop codon - UGA - 15 amino acids downstream, and has been reported by M. Claustres et al. but without any clinical data. The compound heterozygous female for the 4382delA/F508del mutations was diagnosed as having CF at the age of 30 years, on the basis of bronchiectasis and a positive sweat test.