Mary C. Goodchild

Severity of chest disease in cystic fibrosis patients in relation to their genotypes.

A detailed comparison of the severity of chest disease with mutational status was carried out by cross sectional study of 127 cystic fibrosis patients, aged 1 to 31 years, living in Wales. Lung disease was classified according to severity, depending on pulmonary function tests (carried out on 76 patients) and chest radiograph status; information was obtained also on age at diagnosis in relation to severity of chest disease and colonisation with Pseudomonas species. Genotypes were determined by analysis for the mutations delta F508, delta I507, G551D, R553X, G542X, R117H, R560T, 1717--IG > A, and 621 + 1G > T. CF patients homozygous positive and heterozygous for the delta F508 deletion showed a significant decline of lung function with age. Unlike other studies, we did not find patients homozygous positive for the delta F508 deletion to have poorer lung function compared with heterozygous patients. Patients with the genotype 621 + IG > T/delta F508 tended to have more severe chest disease than the delta F508 homozygous patients in the same age group. There was some evidence that four patients heterozygous for R117H have mild chest disease.

Mild pulmonary disease in a cystic fibrosis child homozygous for R553X.

Nonsense mutations frequently cause severe illness because premature termination of messenger RNA translation usually creates un-stable truncated proteins. However, Cutting et al described two patients carrying nonsense mutations in each cystic fibrosis gene (G542X/ S1255X and R553X/W1316X) with severe pancreatic involvement but mild pulmonary disease. Furthermore, Cuppens et al and Bonduelle et al described children homozygous for the G542X stop mutation who were only mildly affected. Recently, Bal et a1 reported a patient homozygous for the R553X nonsense mutation who was moderately severely affected. We present the clinical and molecular findings of a child also homozygous for R553X but with mild pulmonary disease.

Increased phosphoinositide breakdown by phospholipase C in erythrocyte membranes from patients with cystic fibrosis

Phosphoinositide phospholipase C activity has been measured in erythrocyte membranes from age-matched control and CF subjects. Inositol phospholipids were labelled with [3H]myo-inositol and control experiments demonstrated that the [3H]-labelled products released by incubation of membranes with Ca2+ were derived specifically from erythrocytes (a) by purification of erythrocytes on cellulose columns, (b) by demonstration that the phospholipase C activity was inhibited by 10 mmol/l neomycin but not by 1 mmol/l p-methylsulphonylfluoride. The [3H]-labelled products were shown to be inositol phosphates by their elution from anion-exchange columns. Membranes from CF patients showed increased phospholipase C activity compared to controls which did not correlate with the degree of [3H]inositol labelling of the membranes, with pancreatic function as assessed by serum immunoreactive trypsin or with medications taken by the patients.

Altered calmodulin activity in buccal epithelial cells from cystic fribrosis patients

Boiled extracts of buccal epithelial cells from control subjects and cystic fibrosis patients were shown to possess calmodulin like activity, as assessed by their ability to activate calmodulin-deficient cyclic AMP phosphodiesterase. Estimation of calmodulin content, using pure calmodulin as standard revealed that control extracts contained 3.08 +/- 0.71 SEM (n = 7) micrograms calmodulin/mg protein and cystic fibrosis extracts 0.88 +/- 0.30 SEM (n = 12) micrograms calmodulin/mg protein (p less than 0.02 for difference from control). The results indicate that the biological activity of calmodulin is altered in buccal epithelial cells from cystic fibrosis individuals.

Nutritional Management of Cystic Fibrosis

Cystic fibrosis patients have an increased requirement for calories and probably for all the major nutrients. The newer, enteric-coated granular preparations of pancreatic enzyme are more effective than preceding preparations and should permit a normal fat intake. Recent work has emphasized the interdependence of respiratory disease and nutrition.