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Seven patients with cystic fibrosis taking high doses of pancreatin supplements were assessed to determine whether this dose was necessary to achieve adequate fat absorption. Patients reduced their intake from a group mean of 45 to 21 capsules a day. Five patients did not have any significant alteration in fat malabsorption while taking the reduced enzyme dose.
An electrophoretically fast transferrin (Tf) variant, TfB, was found in a cystic fibrosis homozygote. Since neither cystic fibrosis nor the transferrin structural gene has been mapped on human chromosomes, a study was made of this kindred. Genetic markers including ABO, MN, Rh, Fy blood groups and Tf, group-specific component, and haptoglobin serum protein polymorphisms were determined in available members of the kindred. The genes for cystic fibrosis and Tf appear to segregate independently in the kindred, although crossing-over between linked genes in the homozygous cystic fibrosis brother of the propositus could account for the genotypes observed.
This study evaluated adherence to current dietary recommendations of children with cystic fibrosis and mild lung disease and their siblings by comparing energy intake. Fifty children (25 with cystic fibrosis) aged between 7 and 12 years completed the study. Energy intake was assessed by weighed dietary intake, resting energy expenditure was used to calculate recommended daily intakes. The children with cystic fibrosis had significant deficits in Z scores for both height and weight compared with their siblings, but there was no difference in percentage of ideal weight for height. The cystic fibrosis group had a significantly higher energy intake per kilogram body weight per day but there was no difference in the percentage of energy derived from fat, protein or carbohydrate. Energy intake (per kg/day) and fat intake (g/kg) were both significant predictors of weight for height in the cystic fibrosis group. Targets for dietary management in cystic fibrosis should perhaps be related to fat intake per kilogram body weight.
Twelve patients with skin vasculitis complicating cystic fibrosis are described. Seven of these were proven histologically and of these two had systemic vascultitis. Staining of vasculitic tissue by the avidin-biotin immunoperoxidase technique using both monoclonal and polyclonal antisera directed against Haemophilus influenzae, staphylococcus aureus and Pseudomonas aeruginosa did not consistently reveal any bacterial antigens in these tissues. In one patient the vasculitis appeared secondary to ranitidine. There was no evidence of autoimmune disease in any of the patients. Antineutrophil cytoplasmic antibodies were detected in the serum of 40 per cent of the patients with vasculitis complicating cystic fibrosis but in none of 61 controls with cystic fibrosis (but without vasculitis) matched for age and sex and with similar bacteriological flora of sputum.
The presence of cystic fibrosis (CF)-related diabetes was evaluated in 19 adolescents with CF by continuous glucose monitoring system (CGMS) and oral glucose tolerance testing. CGMS confirmed diabetic glucose excursions in 7/19 subjects deemed diabetic on oral glucose tolerance testing. CGMS is a useful tool for detecting hyperglycemia in CF.
Eight patients with cystic fibrosis had chronic abdominal pain and the other features of distal intestinal obstruction syndrome. Coexistent abdominal pathology was shown in six patients. Two had a small bowel volvulus, and the others had Crohn's disease, a small bowel fistula, appendix abscess, and an ovarian dermoid. Opiate abuse exacerbated symptoms in two other patients.
Sixteen adults with cystic fibrosis and chronic bronchopulmonary infection with Pseudomonas aeruginosa, admitted to hospital for chemotherapy, were randomized to treatment with either carbenicillin or ticarcillin. In addition all patients received gentamicin. Both antibiotic treatments produced clinical improvement and significant improvement in respiratory function, but there was no difference between them. Pseudomonas aeruginosa was not eradicated from sputum with either treatment regimen.
Six children with cystic fibrosis who had persistently had Pseudomonas aeruginosa isolated from their respiratory tract, completed a double-blind cross-over comparison of oral flucloxacillin and nebulized aminoglycoside versus double placebo. The patients had higher FEV1 results at the end of the month of active treatment than after the month of placebo.
Sixteen patients with cystic fibrosis experienced vasculitic rashes of the lower extremities that resembled hypergammaglobulinemic purpura. The rashes were associated with increased serum gammaglobulin G levels and rather severe lung disease. The rashes are probably the expression of chronic lung infection and high antigenic load in these patients. Their appearance was associated, in most cases, with poor long-term survival.
The aim of this hypothesis is to provide new insights into the still unclear mechanisms governing airway inflammation in cystic fibrosis. Although the genetic basis of cystic fibrosis as well as the molecular structure of cystic fibrosis transmembrane regulator (CFTR), the mutated protein which causes the disease, have been well defined, a clear relationship between the genetic defect and the pulmonary pathophysiology, especially chronic infections and neutrophil-dominated airway inflammation has not been established. Cystic fibrosis is thus a unique pathological situation in that neutrophils can be depicted as both an antiinfectious and a proinflammatory cell. In cystic fibrosis there is an emerging picture of an imbalance between these two roles with both a reduction in the antiinfectious efficacy and an augmentation of the proinflammatory functions. Better knowledge of fundamental defects in neutrophil function in cystic fibrosis as well as a novel cellular function of CFTR, which will be reviewed, will allow identification of potentially new clinical targets and aid selective therapeutic action aimed at counteracting the lethal neutrophil-induced airway inflammation. The rationale for colchicine therapy is a significant example of a drug which might act both at the molecular levels on CFTR expression in epithelial cells and on neutrophils to mediate antiinflammatory effects. Preliminary results are presented in this issue (Med Inflamm 1999; 8: 13-15).
Five children with cystic fibrosis (CF) and chronic suppurative lung disease had eicosapentaenoic acid (EPA) supplementation for 12 months. Outcome was measured by the change in frequency of admissions/bed days while taking EPA compared to the previous 2 years. Although no significant changes occurred, there is an indication that this treatment may benefit children who don't have end-stage disease. Further studies are indicated in the use of this neglected mode of treatment.
Cystic fibrosis (mucoviscidosis) is a genetic disorder characterized by dysfunction of the exocrine glands. Ninety percent of the morbidity and mortality is due to repeated pulmonary infections and respiratory impairment. Pancreatic disease and intestinal complications result from thick, tenacious mucous secretions. Aggressive medical therapy has improved the prognosis. The family physician plays an important role in dealing with the psychologic and social aspects of the disease, as well as the medical management.
Methane production was studied in 28 cystic fibrosis patients aged 3-16 years and in 290 healthy children. The percentages of methane producers in the cystic fibrosis and control groups were 60.7 and 20.6%, respectively. In the patient group there was no difference between methane producers and nonproducers with respect to the degree of malabsorption or the administration of pancreatic supplements or antibiotics. We hypothesize that the high proportion of methane producers in cystic fibrosis patients may be associated with the presence of specific substrate(s) (glycoprotein?) in their intestinal contents. Changes of the intestinal microenvironment may favor the development of a methanogenic flora.
Diabetes mellitus in cystic fibrosis (CF-DM) is increasingly prevalent with age, develops insidiously and is characterized by insulinopenia, normal insulin sensitivity, increased insulin clearance rate and concomitant exocrine pancreatic insufficiency. Since CF-DM impairs overall CF clinical status, including lung function, and may result in late diabetic complications, the condition should be screened for by annual oral glucose tolerance tests (OGTTs) from the age of 10 years, and be treated with insulin from the time of diagnosis of CF-DM.
PURPOSE OF REVIEW: The first cystic fibrosis gene therapy trials were carried out in 1993, and although proof-of-principle for gene transfer to the lungs was established, efficiency was generally low. The authors review the most recent advances in preclinical airway gene transfer and summarize the results from the latest clinical trials. RECENT FINDINGS: Recent clinical trials report encouraging results. Repeat administration of adeno-associated virus to the lung was safe. Nonviral nanoparticles used, for the first time, in the nose of cystic fibrosis patients were also safe and led to partial correction of the chloride transport defect in nasal epithelium. Important advances have been made in preclinical research, including the development of new viral and nonviral gene transfer agents and improved plasmid DNA. In addition, physical delivery methods, such a magnetofection and electroporation, are being assessed to improve nonviral gene transfer. SUMMARY: Considerable progress has been made in understanding and overcoming the problems associated with gene transfer to airway epithelial cells, the target cells for cystic fibrosis gene therapy. It has also been recognized that novel preclinical and clinical assays are crucial for the success of cystic fibrosis gene therapy, and considerable effort is currently being put into assay development and trial designs.
More women with cystic fibrosis (CF) now reach reproductive age and wish to become pregnant. Although women with CF have reduced fertility, many of them can become mothers. A pregnancy ought to be carefully planned since several studies have shown that pregnancy is well tolerated if good medical care is provided, and the CF woman is in a stable good condition. A short review of the implications of pregnancy for women with CF is presented. A suggested schedule for pregnant women with CF is given.
In 38 children and adolescents with cystic fibrosis, in 19 normal children and 62 healthy adults the serum alpha1-fetoprotein concentrations were measured by radioimmunoassay. In cystic fibrosis patients 97.5% and in normal children 95% of the alpha1-fetoprotein values were within the normal range for healthy adults (1--9 ng/ml). Critical judgement of the reported findings in literature and our own results demonstrate that the investigation of alpha1-fetoprotein in the serum cannot serve for detecting homozygotes of cystic fibrosis genes or heterozygote carriers.
Pseudomonas aeruginosa is a common opportunistic pathogen that causes chronic lung infections in individuals with cystic fibrosis. Despite advances in therapies that restore cystic fibrosis transmembrane conductance regulator function, persistent colonization of the airway remains a major clinical challenge. Reduced clearance of P. aeruginosa from the cystic fibrosis airway has been associated with the increased activity of histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase that decreases microtubule acetylation and stability. In this study, we investigated the role of HDAC6 in modulating interactions between P. aeruginosa and cystic fibrosis airway epithelial cells. Pharmacologic inhibition of HDAC6 significantly reduced bacterial adherence in both mouse and human cystic fibrosis epithelial cells. Genetic deletion of HDAC6 produced similar effects, while knockout of a microtubule-stabilizing protein increased bacterial adherence, mimicking the cystic fibrosis phenotype. HDAC6 inhibition also reduced bacterial internalization, although to a lesser extent compared to adherence. These results suggest that microtubule destabilization contributes to the enhanced colonization of cystic fibrosis airways by P. aeruginosa. Targeting host microtubule regulatory pathways, particularly by inhibiting HDAC6, may represent a promising host-directed strategy to limit early bacterial attachment and reduce the risk of chronic infection in cystic fibrosis.