Cystic fibrosis modifier genes related to Pseudomonas aeruginosa infection

Cystic fibrosis (CF) is one of the most common life-shortening genetic disorders, and the CF transmembrane conductance regulator (CFTR) is the major causal gene. However, a substantial clinical variability among patients with identical CFTR genotypes suggests the presence of modifier genes. We tested the effect of four genes involved in Pseudomonas aeruginosa infection. Analysis of a primary cohort detected eight candidate polymorphisms that were genotyped in the secondary cohort of 1579 patients; lung function and age at first infection with P. aeruginosa were considered as the phenotypes. Both additive and codominant models were considered, adjusting for confounding variables but not for multiple comparisons. In the secondary cohort, heme oxygenase-1 (HMOX1) rs2071749 had the most significant effect on lung function in the pediatric group (P=0.01; P(corrected)=0.03), and complement factor 3 (C3) rs11569393 and HMOX1 rs2071746 in the adult groups (P=0.03 for both variants; P(corrected)=0.16, 0.09). No polymorphism of complement factor B (CFB) or toll-like receptor 4 (TLR4) had a significant modifying effect on lung function in either group. We have identified two genes that showed nominal association with disease severity among CF patients. However, because of the multiple comparisons made, further studies are required to confirm the interaction between these modifying genes and CFTR.     

Cystic fibrosis and CFTR

Cystic fibrosis (CF) is a complex disease affecting epithelial ion transport. There are not many diseases like CF that have triggered such intense research activities. The complexity of the disease is due to mutations in the CFTR protein, now known to be a Cl(-) channel and a regulator of other transport proteins. The various interactions and the large number of disease-causing CFTR mutations is the reason for a variable genotype-phenotype correlation and sometimes unpredictable clinical manifestation. Nevertheless, the research of the past 10 years has resulted in a tremendous increase in knowledge, not only in regard to CFTR but also in regard to molecular interactions and completely new means of ion channel and gene therapy.     

Cystic fibrosis patient with Burkholderia pseudomallei infection acquired in Brazil

Burkholderia pseudomallei is rarely isolated from cystic fibrosis patients outside known areas of endemicity. We report the recovery of B. pseudomallei from the sputum of a cystic fibrosis patient who lives in Brazil. We highlight the importance of careful attention to unusual nonfermentative gram-negative rods in cystic fibrosis patients.     

Cystic fibrosis: a casualty of "detoxification"?

It is proposed that excessive and/or aberrant function of cytochromes P450, due to a combination of genetic and environmental influences, is the basic defect in cystic fibrosis. Organs that are involved in oxidative detoxification reactions in foetal life are thus at risk: tissue damage is initiated by excessive production of oxygen free radicals which deplete cellular antioxidants and provoke the secretion of mucus.     

Cystic fibrosis: Cell culture classes in a Danish population

The cystic fibrosis (CF) culture phenotype of dermal fibroblasts (metachromasia, metabolic cooperation) of a group of 131 Danish CF patients and their families were studied to determine the distribution of the two CF culture classes and their prognostic significance. Of these, 62.6% (82) were Class I, 31.3% (41) Class II and 61.1% (8) were proposed to be genetic compounds. The occurrence of Class II was twice that found in a group of patients from New York (13%) and Minnesota (18%). The prognosis for Class II CF patients was considered to be poorer as: (1) The initial diagnosis was made earlier in Class II than in Class I or the compounds (63% of Class II were diagnosed in the first year of life, as compared to 35% in Class I and 13% of the compounds). (2) Only 5% of the Class II patients survived over the age of 15 years, both being deceased at the end of the study in 1976, whereas 24% of Class I and 63% of the compounds were over 15 years at the end of the study. This research added further evidence for genetic heterogeneity within the clinical syndrome, cystic fibrosis.     

Influenza and schizophrenia: a possible connection with the substantia nigra

The neurovirulent influenza virus of the 1918 pandemic induced clinical schizophrenia. The biochemistry, the neurovascular anatomy, the afferent connections, and the efferent connections of the substantia nigra suggest that a (Na+K)-ATPase injury could be a cause of some positive schizophrenias. The genetic trait in schizophrenia may be an inheritable susceptibility to an infectious agent.     

Cystic fibrosis heterozygote detection: A study on a normal population

Detection of the cystic fibrosis (CF) heterozygote by testing for cystic fibrosis factor activity (CFFA) in serum samples using bioassays has been reported to give unreliable results. The present study was undertaken to find whether the use of medium from short term white blood cell or skin fibroblast cultures, rather than serum, as the test sample would eliminate such inconsistencies. Short term white blood cell cultures were established from 107 normal, healthy individuals. Cultures from 97 had no CFFA, six (No. 1–6) showed variable results and four (No. 7–10) had activity in all four tests done on a single sample. When the assays were repeated 3 months later on new cultures from these four positive CFFA individuals, two showed activity (Nos. 7 & 9) and two did not (Nos. 8 & 10). All 10 individuals whose cultures showed CFFA had histories of allergies. The association of CFFA in the culture medium derived from individuals having allergies with the intermittent presence of this activity suggested that environmental factors induced a CFF-like activity in such white blood cell cultures. The oyster ciliary assay, using medium from white blood cell cultures, cannot be used for screening for the CF heterozygote since the substitution of culture medium for serum did not eliminate inconsistent results and CFFA was not specific by this assay for the CF gene.
Of the fibroblast lines established from the four persons whose initial white blood cell cultures consistently showed CFFA, only one (No. 7) showed the CF culture phenotype (CFFA positive and metachromasia).     

Cystic fibrosis in adolescents and adults

A cystic fibrosis (CF) clinic for adults was established in 1977. We have reviewed the data on 164 patients who attended between 1977 and 1989. Twenty four patients had died, 11 being over 20 years after time of death. Of the 140 patients still alive, 61% were male and 53% were aged over 20 years. Only 55% were diagnosed by 1 year and 88% by 10 years. Almost all patients had respiratory symptoms and sputum culture yielded Pseudomonas species in 69%. Other respiratory problems included major haemoptysis and pneumothorax, each in 10%. We found a wide range of respiratory impairment among older patients. Among 3 patients aged over 23 years the mean (+/- S.D.) percent predicted FEV1 and FVC were 53.3% (+/- 18%) and 71.4% (+/- 20%) respectively. Mean weight in this group was 92.5% (+/- 14) of predicted. Malabsorption occurred in most patients and meconium ileus equivalent occurred in most patients and meconium ileus equivalent occurred in 34%. Other complications were clinical hepatomegaly (16%), diabetes mellitus (9%) and arthropathy (20%). Most patients were taking continuous antibiotics by mouth (89%) and by nebuliser (48%), beta-2 agonists by inhaler (57%) and oral steroids (29%). Almost all were taking multivitamins, pancreatic replacement therapy and multiple nutritional supplements. The number of CF "bed days" grew 12 fold since 1979 and the mean stay in hospital was double the hospital mean. The economic impact was such that over 1/4 of the annual hospital antibiotic budget was expended on CF patients.