Cystic fibrosis: current concepts

Cystic fibrosis (CF), a common fatal genetic disease, is a multisystem disorder whose pathogenesis has recently been linked to defects in CFTR, a newly discovered protein. CFTR is a molecular channel which controls chloride concentration in secretions of the sweat glands and the respiratory, GI, and reproductive tracts. Defective forms of CFTR, arising from various mutations in its gene, are responsible for the inadequate hydration of mucus, pancreatic juice, and other exocrine secretions. The result is dysfunction of the lungs, pancreas, and other involved organs. This article describes the diagnosis, clinical features, and approach to management of CF.     

Cystic fibrosis: present and future

Cystic fibrosis (CF) is an inherited disorder of epithelial chloride transport affecting primarily pancreas, lungs, gut, liver and exocrine glands. The defect is caused by defects of the cystic fibrosis transmembrane regulation gene on chromosome 7. Genotyping has proved useful in identifying gene carriers, a definitive diagnosis, and in antenetal diagnosis. Genotype/phenotype relationships have shown that the commonest cause of pancreatic insufficiency is the D F508 mutation. Clinical trials are exploring the use of somatic gene therapy but this is not yet a viable treatment option. Liver, lung and intestinal disease result in malnutrition which causes further dysfunction of these organs. Aggressive nutritional and pancreatic enzyme therapy results in improved disease, normal growth and increased survival. However, high-dose enzyme therapy may in some individuals cause a fibrosing colonopathy. For those with end-stage liver and lung disease, transplantation holds out some hope.     

Cystic fibrosis: a disease of altered protein folding

Patch clamp technique was employed to record single Na channel currents in isolated guinea-pig ventricular myocytes. Burst mode could be elicited by step depolarization and terminates immediately after repolarization. The unitary current of burst mode was not only dependent on Na concentration in the pipettes but also on the test voltage. The open time constant increased as testing voltage becomes more positive. The results from stepwise-depolarization and ramp depolarization experiments showed that the more steps or the faster the upstroke velocity of depolarization used, the more the burst mode would occure.     

Cystic fibrosis: a system for assessing and predicting progression

Renal lymphoma has a broad spectrum of imaging manifestations. Typical patterns of renal lymphoma include multiple renal masses, solitary masses, diffuse infiltration, and invasion from contiguous retroperitoneal disease. Isolated perirenal disease is probably the most atypical form of renal lymphoma and has a variety of appearances, including small curvilinear densities and soft-tissue nodules or plaques. In general, the CT diagnosis of renal lymphoma is not difficult because most patients already have a known diagnosis of lymphoma. Nevertheless, it is important to be familiar with both the typical and the atypical manifestations of renal lymphoma because numerous disease processes, normal variants, and artifacts may potentially mimic renal lymphoma.     

Effect of caffeine on mucus secretion and agonist-dependent Ca2+ mobilization in human gastric mucus secreting cells

Caffeine is known to stimulate gastric acid secretion, but, the effects of caffeine on gastric mucus secretion have not been clarified. To elucidate the action of caffeine on gastric mucin-producing cells and its underlying mechanism, the effects of caffeine on mucus glycoprotein secretion and agonist-induced [Ca2+]i mobilization were examined in human gastric mucin secreting cells (JR-I cells). The measurement of [Ca2+]i using Indo-1 and the whole cell voltage clamp technique were applied. Mucus glycoprotein secretion was assessed by release of [3H]glucosamine. Caffeine by itself failed to increase [Ca2+]i and affect membrane currents, while it dose-dependently inhibited agonist (acetylcholine (ACh) or histamine)-induced [Ca2+]i rise, resulting in inhibiting activation of Ca2+-dependent K+ current (I(K.Ca)) evoked by agonists. The effect of caffeine was reversible, and the half maximal inhibitory concentration was about 0.5 mM. But, caffeine did not suppress [Ca2+]i rise and activation of I(K.Ca) induced by A23187 or inositol trisphosphate (IP3). Theophylline or 3-isobutyl-1-methyl-xanthine (IBMX) did not mimic the effect of caffeine. Caffeine failed to stimulate mucus secretion, while it significantly decreased ACh-induced mucus secretion. These results indicate that caffeine selectively inhibits agonist-mediated [Ca2+]i rise in human gastric epithelial cells, probably through the blockade of receptor-IP3 signaling pathway, which may affect the mucin secretion.     

The effects of irritation at various levels of the airway upon tracheal mucus secretion in the cat

1. Sulphated glycoprotein output from the trachea, isolated in situ, has been measured in anaesthetized cats by a radio-isotopic method. The effects of irritation of various parts of the airway on this mucus output were studied. 2. Mechanical stimulation of the nose and nasopharynx increased tracheal mucus output by reflexes which involved parasympathetic and probably also sympathetic motor pathways. 3. Laryngeal stimulation had a similar through the same motor pathways. 4. Inhalation of ammonia vapour into the lower airways reflexly increased mucus output from the isolated trachea. The efferent pathway for this reflex was mainly or entirely parasympathetic. It is argued that the afferent pathway involved cough receptors. 5. Lung inflation, inhalation of histamine aerosol and intravenous injection of phenyl diguanide (which excite mainly lung stretch receptors, lung 'irritant' receptors and alveolar 'J-receptors' respectively) had no consistent effect on tracheal mucus secretion. 6. The afferent and efferent pathways of these reflexes are discussed.     

Cystic fibrosis screening by sweat analysis: a critical review of techniques

Currently employed methods for the assay of electrolytes in sweat, relevant to the diagnosis of cystic fibrosis, are critically evaluated with particular reference to the measurement of electrical conductivity. Attention is drawn to the factors responsible for potentially large errors. On the basis of experimentation, supported by laboratory practice, recommendations are made for the reduction of these errors to clinically acceptable levels. Data concerning sodium and potassium content, electrical conductivity and osmolality of undiluted sweat collections are compared. The feasibility and comparative advantages of measuring sweat osmolality with a vapour pressure osmometer are discussed.     

Cystic fibrosis in Malay children--a report of three cases

A staining device for sectioned material supported on grids for viewing at the Transmission Electron Microscope is described. The method based in a double side sticky tape is inexpensive, rapid and clean. By using only pipettes and a double side sticky tape the best solution to the tedious problems of sections staining is obtained. The tape is discarded and the staining solution too. Precipitates have not been observed.     

Self-management of cystic fibrosis: short-term outcomes of the Cystic Fibrosis Family Education Program

This study tested the efficacy of the Cystic Fibrosis Family Education Program, a cystic fibrosis self-management program, on improving participants' knowledge, self-efficacy, self-management behavior, health, and quality of life. A quasi-experimental pretest-posttest nonequivalent comparison group design was employed. Participants made up 104 patient-primary caregiver dyads from the intervention site cystic fibrosis center and 95 from the usual care comparison center. The intervention, a self-paced print curriculum based on social cognitive theory, targeted behavioral capability, self-efficacy, and outcome expectations and was implemented as an integral part of medical care. Parents, early childhood, middle childhood, and adolescents received separate materials on respiratory, nutrition and malabsorption, communication, and coping issues. Significant intervention effects were found on the knowledge scores for caregivers, adolescents, and children; caregiver and adolescent total self-management scores; Child Behavior Checklist total score; one parent coping scale score; the modified NIH score; NIH pulmonary factor 1; and the Brasfield total score. Significant interaction effects were evident in the self-efficacy scores for caregivers and children.     

Cystic fibrosis transmembrane conductance regulator mediates the cyclic adenosine monophosphate-induced fluid secretion but not the inhibition of resorption in mouse gallbladder epithelium

The haemostatic system and the use of heparin during cardiopulmonary bypass (CPB) have been studied extensively in adults but not in children. Results from adult trials cannot be extrapolated to children because of age-dependent physiologic differences in haemostasis. We studied 22 consecutive paediatric patients who underwent CPB at The Hospital for Sick Children, Toronto. Fibrinogen, factors II, V, VII, VIII, IX, XII, prekallikrein, protein C, protein S, antithrombin (AT), heparin cofactor II, alpha 2-macroglobulin, plasminogen, alpha 2-antiplasmin, tissue plasminogen activator (tPA), plasminogen activator inhibitor, thrombin-AT complexes (TAT), D-dimer, heparin (by both anti-factor Xa assay and protamine titration) and activated clotting time (ACT) were assayed perioperatively. The timing of the sampling was: pre heparin, post heparin, after initiation of CPB, during hypothermia, post hypothermia, post protamine reversal and 24 h post CPB. Plasma concentrations of all haemostatic proteins decreased by an average of 56% immediately following the initiation of CPB due to haemodilution. During CPB, the majority of procoagulants, inhibitors and some components of the fibrinolytic system (plasminogen, alpha 2 AP) remained stable. However, plasma concentrations of TAT and D-dimers increased during CPB showing that significant activation of the coagulation and fibrinolytic systems occurred. Mechanisms responsible for the activation of haemostasis are likely complex. However, low plasma concentrations of heparin (< 2.0 units/ml in 45% of patients) during CPB were likely a major contributing etiology. ACT values showed a poor correlation (r = 0.38) with heparin concentrations likely due to concurrent haemodilution of haemostatic factors, activation of haemostatic system, hypothermia and activation of platelets. In conclusion, CPB in paediatric patients causes global decreases of components of the coagulation and fibrinolytic systems, primarily by haemodilution and secondarily by consumption.     

Cystic fibrosis screening: a fetus with hyperechogenic bowel may be the index case

BACKGROUND: The potential of hyperechogenic fetal bowel to act as a hallmark for prenatal cystic fibrosis screening in the general population is controversial. METHODS: Our goal was to evaluate the incidence of cystic fibrosis in 209 fetuses with hyperechogenic bowel diagnosed at routine ultrasonography and with no family history of cystic fibrosis. The diagnosis of cystic fibrosis was based on prenatal screening for the eight mutations most frequently observed in France (deltaF508, deltaI507, 1717-1G-->A, G542X, G551D, R553X, W1282X, N1303K) and at postnatal follow up. RESULTS: The overall incidence of cystic fibrosis was 7/209 (3.3%) which is 84 times the estimated risk of CF in the general population (112500). Of these seven cases, six were diagnosed prenatally based on DNA analysis (deltaF508/deltaF508, n=5; deltaF508/G542X, n=1). One case in which only one mutation had been recognised was diagnosed clinically after birth (deltaF508/unidentified mutation). Of the seven cases, none was diagnosed at 16-19 weeks, four at 16-24 weeks, and three after this. The incidence of heterozygous fetuses (15/209, 7%) was not significantly higher than the 5% expected in the general population. The mutations involved in these heterozygous cases were deltaF508 (n=13), G542X (n=1), and G551D (n=1). CONCLUSIONS: Screening for cystic fibrosis should be offered to families in which fetal hyperechogenic bowel is diagnosed at routine ultrasonography. This underlines the need to review genetic counselling in this situation where the fetus is the index case for a genetic disease.     

Effects of gravity on tracheal mucus transport rates in normal subjects and in patients with cystic fibrosis

A noninvasive, radionuclide imaging technique for measuring the rate of mucus clearance in the trachea (RT), was used to study gravitational effects on mucus clearance in 13 patients with cystic fibrosis (CF), average age 17 years; 7 normal, nonsmoking adults, average age 26 years; and a normal subject who was recovering from an acute upper respiratory tract infection (URTI). In the upright position, nine of the CF patients and the subject with URTI demonstrated abnormal tracheal mucus clearance which approached normal when they were placed in 25 degrees headdown position. The normal subjects and two of the CF patients showed no significant difference in the RT measured in the two positions. The results of the study indicate that the force of gravity can be a major influence on tracheal mucus clearance in CF and URTI subjects. This conclusion supports the use of postural drainage as an effective form of therapy in patients with cystic fibrosis.     

Composition of nasal secretion in patients with cystic fibrosis

Quantitative examination of nasal secretion in patients with cystic fibrosis revealed a significantly greater than normal concentration of calcium, a finding in keeping with the hypothesized importance of this ion in the pathophysiology of the disease.     

Effect of polyamines and cystic fibrosis serum on glucose transport

The effect of plasma or serum from homozygotes and heterozygotes for the cystic fibrosis (CF) gene on the active uptake of 3-0-14C-methyl-D-glucose (3-0-14C-MDG) by rat jejunal epithelium was studied. Furthermore, the role of the polyamine, spermidine, and its products of metabolic degradation on glucose transport were investigated, and a relationship to the pathogenesis of membrane dysfunction in cystic fibrosis was postulated. Glucose transport in everted rat jejunal rings was used in the study. Results were expressed as 3-0-14C-MDG concentration ratio between the intracellular (ICF) and the extracellular fluid spaces (ECF) of the jejunal rings at the end of a 60 min incubation period. The mean ratio obtained from incubations of the rat jejunal rings in medium consisting of Krebs-Ringer-bicarbonate buffer and the labeled sugar was considered as 100% uptake. When plasma or serum, with or without spermidine, was mixed with the medium in a volume ratio of 1:3, a decrease in the active uptake of 3-0-14C-MDG was observed, expressed as percent inhibition. Percent inhibition of 3-0-14C-MDG uptake obtained when the rat jejunal rings were incubated in normal plasma was compared to that obtained with plasma from cystic fibrosis genotypes. It was found that: 1) plasma from 25 homozygous children had greater inhibitory effect on glucose uptake than plasma from 26 normal children; 2) plasma from 9 heterozygous women had greater inhibitory effect than that from 6 normal women; 3) the inhibitory effect of plasma from 3 homozygous children was not influenced by dialysis; 4) the inhibitory effects of paired plasma and serum samples from 9 homozygotes were comparable; 5) spermidine added to the incubating electrolyte solution did not affect glucose transport; 6) the addition of spermidine to reaction mixtures containing normal plasma potentiated the inhibitory effect; and 7) mixing and incubation of fresh bovine serum with reaction mixtures containing plasma from homozygotes decreased the inhibitory effect. The predominant inhibitory effect of plasma or serum from homozygotes and heterozygotes for the CF gene appears to be related to a nondialyzeable molecule(s). It does not seem to reflect the presence of high plasma glucose levels in cystic fibrosis nor to be the result of competitive inhibition between sugars. It does not seem to be the result of sodium or other electrolyte differences. A similar inhibitory effect is acquired by normal plasma after the addition of spermidine. On the other hand, plasma from CF homozygotes loses its inhibitory effect after incubation with fresh bovine serum. These findings may indicate that products of metabolic degradation of spermidine are responsible for the inhibitory effect of glucose transport and suggest the possibility of a role in abnormal polyamine metabolism in the pathogenesis of cystic fibrosis.     

Fatty acids modulate lecithin:cholesterol acyltransferase secretion independently of effects on triglyceride secretion in primary rat hepatocytes

The regulation of plasma lecithin:cholesterol acyltransferase (LCAT) expression is not well understood. Although oleic acid increases both the secretion of triglycerides and LCAT by primary rat hepatocytes, the effect of other fatty acids (FA) on LCAT secretion is not known. This study was designed to examine the effect of FA on the hepatic secretion of LCAT, triglyceride and apolipoprotein A-1 (apoA-1). Primary rat hepatocytes were incubated with serum-free medium, supplemented with individual FA (0-1 mmol/L) for 22-24 h. Preliminary studies indicated a linear secretion of LCAT up to 24 h in both control and FA-treated cells. When hepatocytes were incubated with 1 mmol/L FA, the LCAT secretion increased 50-100% (P < 0.01) in the presence of the 18-carbon FA (stearic, oleic, elaidic and linoleic acids), whereas the presence of butyric, lauric and palmitic acids had no significant effect. LCAT secretion decreased (P < 0.01) in the presence of docosahexaenoic acid (DHA). All FA (except DHA) significantly enhanced triglyceride secretion; however, only the 18 carbon FA significantly stimulated the synthesis and secretion of apoA-1 and secretion of LCAT. The secretion of LCAT correlated with apoA-1 secretion (r = 0.88, P = 0.004) but not with triglyceride secretion (r = 0.55, P = 0.12). Treatment with oleic acid resulted in a 1.5-fold increase in hepatocyte LCAT mRNA accumulation, whereas butyrate and palmitate had no effect. These data indicate that FA that promote the apparent synthesis and secretion of apoA-1 also stimulate the secretion of LCAT in vitro, suggesting a coordinate regulatory mechanism for apoA-1 and LCAT expression.     

Constitutive and regulated prolactin secretion: effects of estradiol

Dysfunction of dopamine neural systems is hypothesized to underlie neuropsychiatric disorders and psychostimulant drug abuse. At least three dopamine systems have been characterized in the brain-nigrostriatal, mesolimbic, and mesocortical. Abnormalities of nigrostriatal dopamine neurons cause motor impairment leading to Parkinson's disease, whereas dysfunction of mesolimbic and mesocortical dopamine neurons are most implicated in psychotic disorders such as schizophrenia and in drug addition. One of the primary neural sites of action of potent antipsychotic agents and psychostimulant drugs of abuse are dopamine receptors and dopamine transporters which, respectively, mediate the induction and termination of dopamine's actions. Very limited information is, however, available about which particular set of dopaminergic cells in the human brain actually express the genes for these dopamine-specific proteins. In this study, we observed that the dopamine transporter and D2 receptor messenger RNAs are differentially expressed within the human mesencephalon: highest expression in ventral subpopulations of the substantia nigra pars compacta neurons with lowest expression in the mesolimbic/mesocortical ventral tegmental area and retrorubral cell groups. These findings suggest that motor- and limbic-related mesencephalic neurons in the human brain differ in the degree of dopamine transporter and D2 receptor gene expression.