Exhaled nitric oxide is not elevated in the inflammatory airways diseases of cystic fibrosis and bronchiectasis

Airways inflammation has been associated with increased nitric oxide (NO) in the exhaled breath. It was, therefore, questioned whether exhaled NO could act as an indicator of the severity of airways inflammation in the chronic suppurative lung diseases cystic fibrosis (CF) and bronchiectasis. NO levels in a single exhalation were measured using a chemiluminescence analyser. Thirty-six patients with CF and 16 with bronchiectasis were studied and compared with 22 normal subjects and 35 asthmatic patients. All subjects were nonsmokers and all measurements were made when patients were clinically stable. In addition, exhaled NO was measured in 10 CF patients at the time of onset of an acute infective exacerbation and followed for 7 days during the treatment of the exacerbation in eight of the 10 patients. No significant differences were found in NO levels in patients with CF or bronchiectasis compared with normals (median 4.0, 5.5 and 4.4 parts per billion (ppb), respectively), but all were lower than in asthma patients (10.4 ppb). The NO levels in the CF patients at time of exacerbation were not increased and did not change during treatment. These data show that nitric oxide levels in the exhaled breath of patients with chronic suppurative lung diseases, in contrast to asthma, are not elevated, despite the presence of substantial airways inflammation. Possible explanations include poor diffusion of nitric oxide across increased and viscous airway secretions, removal of nitric oxide by reaction with reactive oxygen species in the inflamed environment and failure of upregulation of epithelial inducible nitric oxide synthase in chronic suppurative conditions.     

Severe small airways disease resistant to medical treatment in a child with cystic fibrosis

At the age of 12, a child with cystic fibrosis developed severe small airways obstruction of unknown aetiology, in the absence of significant bronchiectasis. He remained resistant to medical treatment until, following an exacerbation of allergic bronchopulmonary aspergillosis 18 months later, he responded to high dose oral steroids. He now remains steroid-dependent, and suffering from multiple side-effects. Possible aetiology and further therapeutic strategies are discussed.     

Role of heat shock proteins in the pathogenesis of cystic fibrosis arthritis

BACKGROUND: Arthritis is a well recognised complication of cystic fibrosis. The cause of this arthritis is not yet clear but it is likely to be an immunological reaction to one of the many bacterial antigens to which the lungs are exposed. One such group, the heat shock proteins, (hsp), was investigated. These are immunodominant antigens of a wide variety of infectious microorganisms and have varying amino acid chain sequences, some of which are similar to those found in human tissues. METHODS: Antibodies to human hsp 27 and hsp 90 in the serum of patients with cystic fibrosis, with and without arthritis, and in normal age and sex matched healthy controls were measured. The severity of the cystic fibrosis was assessed by lung function tests and chest radiographs. The nature of the organisms colonising the lungs was determined by bacteriological examination of sputum. RESULTS: Higher mean titres of serum IgG anti-human hsp 27 and hsp 90 antibodies were found in 50 patients with cystic fibrosis than in healthy controls (hsp 27, 0.25 (95% CI 0.19 to 0.33) versus 0.05 (95% CI 0.04 to 0.07); hsp 90, 0.27 (95% CI 0.22 to 0.32) versus 0.11 (95% CI 0.08 to 0.14)). These antibodies were higher in patients in whom the lungs were colonised with Pseudomonas aeruginosa than in those without infection (hsp 27, 0.41 (95% CI 0.17 to 0.63) versus 0.18 (95% CI 0.10 to 0.27); hsp 90, 0.37 (95% CI 0.18 to 0.57) versus 0.22 (95% CI 0.16 to 0.29)). The eight patients with cystic fibrosis with arthritis had higher anti-hsp 27 antibodies (0.48 (95% CI 0.13 to 0.92)) than the 42 patients without arthritis (0.22 (95% CI 0.17 to 0.30)). CONCLUSIONS: These findings suggest that the arthritis associated with cystic fibrosis, despite being seronegative for rheumatoid factor, was associated with more severe lung disease and with a greater inflammatory response to heat shock proteins.     

Frontiers in research on cystic fibrosis: understanding its molecular and chemical basis and relationship to the pathogenesis of the disease

In recent years a new family of transport proteins called ABC transporters has emerged. One member of this novel family, called CFTR (cystic fibrosis transmembrane conductance regulator), has received special attention because of its association with the disease cystic fibrosis (CF). This is an inherited disorder affecting about 1 in 2000 Caucasians by impairing epithelial ion transport, particularly that of chloride. Death may occur in severe cases because of chronic lung infections, especially by Pseudomonas aeruginosa, which cause a slow decline in pulmonary function. The prospects of ameliorating the symptoms of CF and even curing the disease were greatly heightened in 1989 following the cloning of the CFTR gene and the discovery that the mutation (deltaF508), which causes most cases of CF, is localized within a putative ATP binding/ATP hydrolysis domain. The purpose of this introductory review in this minireview series is to summarize what we and others have learned during the past eight years about the structure and function of the first nucleotide binding domain (NBF1 or NBD1) of the CFTR protein and the effect thereon of disease-causing mutations. The relationship of these new findings to the pathogenesis of CF is also discussed.     

Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects

To test whether a major contribution of airways epithelial ion transport to lung defense reflects the regulation of airway surface liquid (ASL) ionic composition, we measured ASL composition using the filter paper technique. On nasal surfaces, the Cl- concentration (approximately 125 meq/liter) was similar to plasma, but the Na+ concentration (approximately 110 meq/liter) was below plasma, and K+ concentration (approximately 30 meq/liter) above plasma. The resting ASL osmolarity [2(Na+ + K+); 277 meq/liter] approximated isotonicity. There were no detectable differences between cystic fibrosis (CF) and normal subjects. In the lower airways, the Na+ concentrations were 80-85 meq/liter, K+ levels approximately 15 meq/liter, and Cl- concentrations 75-80 meq/liter. Measurements of Na+ activity with Na(+)-selective electrodes and osmolality with freezing point depression yielded values consistent with the monovalent cation measurements. Like the nasal surfaces, no differences in cations were detected between CF, normal, or chronic bronchitis subjects. The tracheobronchial ASL hypotonicity was hypothesized to reflect collection-induced gland secretion, a speculation consistent with observations in which induction of nasal gland secretion produced hypotonic secretions. We conclude that there are no significant differences in ASL ion concentrations between CF, normal, and chronic bronchitis subjects and, because ASL ion concentrations exceed values consistent with defensin activity, the failure of CF lung defense may reflect predominantly factors other than salt-dependent defensins.     

Evidence for abnormal calcium homeostasis in patients with adynamic bone disease

To investigate whether the derangements in calcium kinetics in patients with renal osteodystrophy are similar in the various histologic forms of this metabolic bone disease, 43 patients on chronic maintenance dialysis underwent calcium kinetic studies using the double isotope technique, iliac crest bone biopsies for mineralized bone histology and histomorphometry and determinations of serum indices of calcium and bone metabolism. Intestinal calcium absorption was not different among the three histologic groups. However, women exhibited lower calcium absorption in each histologic form (P < 0.01). Patients with predominant hyperparathyroid bone disease showed plasma calcium efflux, calcium accretion rate and calcium retention markedly above normal values. Patients with low turnover bone disease exhibited a normal or slightly decreased plasma calcium efflux and calcium accretion rate together with a disproportionately low calcium retention. Patients with mixed uremic osteodystrophy presented with a calcium kinetic profile intermediary to the two other forms. Good relationships existed between plasma calcium efflux, calcium accretion rate, calcium retention and histomorphometric parameters of bone turnover as well as serum levels of parathyroid hormone. However, no serum parameter could indicate with certainty the underlying bone disease. These findings demonstrate that adynamic bone disease does not merely represent an academic finding but is characterized by a very low bone capacity to buffer calcium and inability to handle an extra calcium load. This is particularly relevant for the daily care of end-stage renal failure patients presently receiving higher than ever amounts of vitamin D and calcium salts.     

An approach for treating the hepatobiliary disease of cystic fibrosis by somatic gene transfer

Cystic fibrosis (CF) is an inherited disease of epithelial cell ion transport that is associated with pathology in multiple organ systems, including lung, pancreas, and liver. As treatment of the pulmonary manifestations of CF has improved, management of CF liver disease has become increasingly important in adult patients. This report describes an approach for treating CF liver disease by somatic gene transfer. In situ hybridization and immunocytochemistry analysis of rat liver sections indicated that the endogenous CFTR (cystic fibrosis transmembrane conductance regulator) gene is primarily expressed in the intrahepatic biliary epithelial cells. To specifically target recombinant genes to the biliary epithelium in vivo, recombinant adenoviruses expressing lacZ or human CFTR were infused retrograde into the biliary tract through the common bile duct. Conditions were established for achieving recombinant gene expression in virtually all cells of the intrahepatic bile ducts in vivo. Expression persisted in the smaller bile ducts for the duration of the experiment, which was 21 days. These studies suggest that it may be feasible to prevent CF liver disease by genetically reconstituting CFTR expression in the biliary tract, using an approach that is clinically feasible.     

Community-based care in cystic fibrosis: role of the cystic fibrosis nurse specialist and implications for patients and families

Improved survival for cystic fibrosis has rapidly increased over the past four decades, with patients now living well into adult life. With changes in the structure of the National Health Service and the formation of provider units and general practitioner (GP) fund-holding practices, it is important to strengthen links between the hospital and community teams to ensure that the CF patient receives adequate care. Increasingly, treatment is being carried out at home, and this emphasis on home-based therapy demands that parents/carers and patients must acquire the skills and knowledge of complex therapies in order to optimize health. It is the role of the CF nurse specialist (NS) to educate those who will deliver the care, co-ordinate the provision of services at home, liaise with the CF team and community health-care professionals and to support the patient and their carers.     

Assessment of fitness in patients with cystic fibrosis and mild lung disease

The purpose of this investigation was to examine if exercise-induced arterial oxyhemoglobin desaturation selectively observed in highly trained endurance athletes could be related to differences in the pulmonary diffusing capacity (DL) measured during exercise. The DL of 24 male endurance athletes was measured using a 3-s breath-hold carbon monoxide procedure (to give DLCO) at rest as well as during cycling at 60% and 90% of these previously determined VO2max. Oxyhemoglobin saturation (SaO2%) was monitored throughout both exercise protocols using an Ohmeda Biox II oximeter. Exercise-induced oxyhemoglobin desaturation (DS) (SaO2% < 91% at VO2max) was observed in 13 subjects [88.2 (0.6)%] but not in the other 11 nondesaturation subjects [NDS: 92.9 (0.4)%] (P < or = 0.05), although VO2max was not significantly different between the groups [DS: 4.34 (0.65) l/min vs NDS: 4.1 (0.49) l/min]. At rest, no differences in either DLCO [ml CO.mmHg-1.min-1: 41.7 (1.7) (DS) vs 41.1 (1.8) (NDS)], DLCO/VA [8.2 (0.4) (DS) vs 7.3 (0.9) (NDS)], MVV [l/min: 196.0 (10.4) (DS) vs 182.0 (9.9) (NDS)] or FEV1/FVC [86.3 (2.2) (DS) vs 82.9 (4.7) (NDS)] were found between groups (P > or = 0.05). However, VE/VO2 at VO2max was lower in the DS group [33.0 (1.1)] compared to the NDS group [36.8 (1.5)] (P < or = 0.05). Exercise DLCO (ml CO.mmHg-1.min-1) was not different between groups at either 60% VO2max [DS: 55.1 (1.4) vs NDS: 57.2 (2.1)] or at 90% VO2max [DS: 61.0 (1.8) vs NDS: 61.4 (2.9)]. A significant relationship (r = 0.698) was calculated to occur between SaO2% and VE/VO2 during maximal exercise. The present findings indicate that the exercise-induced oxyhemoglobin desaturation seen during submaximal and near-maximal exercise is not related to differences in DL, although during maximal exercise SaO2 may be limited by a relatively lower exercise ventilation.     

Parent, family, and disease factors as predictors of psychosocial functioning in children with cystic fibrosis.

Examined the relative contribution of disease, parental, and family factors on the psychological and social functioning of children with cystic fibrosis. 33 patients (7–16 yrs old) and 29 mothers completed a battery of tests, including a state-trait anxiety inventory, the Beck Depression Inventory, and a coping health inventory for parents developed by H. I. McCubbin et al (1983). Results show that Ss' self-esteem and occurrence of behavioral problems were associated with maternal trait anxiety, overprotection, and the impact of disease on family functioning. Social competence and athletic self-esteem were associated with nutritional status. Results reflect the need for clinicians to be sensitive to parental and family functioning when dealing with behavioral problems and to consider physical status when providing treatment of social problems. (French abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Membrane trafficking of the cystic fibrosis gene product, cystic fibrosis transmembrane conductance regulator, tagged with green fluorescent protein in madin-darby canine kidney cells

The mechanism by which cAMP stimulates cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride (Cl-) secretion is cell type-specific. By using Madin-Darby canine kidney (MDCK) type I epithelial cells as a model, we tested the hypothesis that cAMP stimulates Cl- secretion by stimulating CFTR Cl- channel trafficking from an intracellular pool to the apical plasma membrane. To this end, we generated a green fluorescent protein (GFP)-CFTR expression vector in which GFP was linked to the N terminus of CFTR. GFP did not alter CFTR function in whole cell patch-clamp or planar lipid bilayer experiments. In stably transfected MDCK type I cells, GFP-CFTR localization was substratum-dependent. In cells grown on glass coverslips, GFP-CFTR was polarized to the basolateral membrane, whereas in cells grown on permeable supports, GFP-CFTR was polarized to the apical membrane. Quantitative confocal fluorescence microscopy and surface biotinylation experiments demonstrated that cAMP did not stimulate detectable GFP-CFTR translocation from an intracellular pool to the apical membrane or regulate GFP-CFTR endocytosis. Disruption of the microtubular cytoskeleton with colchicine did not affect cAMP-stimulated Cl- secretion or GFP-CFTR expression in the apical membrane. We conclude that cAMP stimulates CFTR-mediated Cl- secretion in MDCK type I cells by activating channels resident in the apical plasma membrane.     

Tuberculous pneumopathy in the course of cystic fibrosis

BACKGROUND: Tuberculosis is rarely seen in patients with cystic fibrosis. CASE REPORT: A 14-year old female adolescent, regularly followed for a well-tolerated form of cystic fibrosis, developed an acute respiratory infection with consolidation of the left inferior lobe, and no response to the usual antibiotic treatment of cystic fibrosis. Mycobacterium tuberculosis was found in aspirate by fibroscopy, on Loewenstein medium. No familial or social infection contact were identified. Antituberculous chemotherapy with three drugs brought about a prompt improvement of sytemic signs, weight gain, resolution of pulmonary foci and sedation of biological findings referable to inflammation. CONCLUSION: This case report reminds us that tuberculosis may occur in cystic fibrosis patients. Loewenstein cultures should routinely be made when faced with an unexplainable worsening of the condition.     

Costs, effects, and savings of screening for cystic fibrosis gene carriers

STUDY OBJECTIVE: Evaluating the costs, effects, and savings of several strategies for cystic fibrosis (CF) gene carrier screening. DESIGN: A general model for evaluating prenatal, preconceptional, school, and neonatal carrier screening was constructed. For prenatal and preconceptional screening, two strategies were evaluated: single entry and double entry two step couple screening. Firstly, the Dutch situation was evaluated prospectively; subsequently the results were generalised to other carrier frequencies. SETTING: Prospective simulation model. MAIN RESULTS: Of all screening strategies, neonatal carrier screening gives most carrier couples an informed choice concerning reproduction. If the parents of carrier newborns would not be tested however, prenatal screening detects most carrier couples. Prenatal and single entry preconceptional screening programmes have a favourable cost-savings balance in the Netherlands under a wide range of assumptions. For double entry preconceptional screening and neonatal screening, high enough values of uptake of screening, prenatal diagnosis, and induced abortion are necessary. School carrier screening does not have a favourable cost-savings balance. CONCLUSIONS: If a CF screening programme is judged to be useful on individual and social grounds, costs considerations are no obstacle for prenatal and single entry preconceptional screening.     

Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%

Cystic fibrosis (CF)--an autosomal recessive disorder caused by mutations in CF transmembrane conductance regulator (CFTR) and characterized by abnormal chloride conduction across epithelial membranes, leading to chronic lung and exocrine pancreatic disease--is less common in African-Americans than in Caucasians. No large-scale studies of mutation identification and screening in African-American CF patients have been reported, to date. In this study, the entire coding and flanking intronic sequence of the CFTR gene was analyzed by denaturing gradient-gel electrophoresis and sequencing in an index group of 82 African-American CF chromosomes to identify mutations. One novel mutation, 3120+1G-->A, occurred with a frequency of 12.3% and was also detected in a native African patient. To establish frequencies, an additional group of 66 African-American CF chromosomes were screened for mutations identified in two or more African-American patients. Screening for 16 "common Caucasian" mutations identified 52% of CF alleles in African-Americans, while screening for 8 "common African" mutations accounted for an additional 23%. The combined detection rate of 75% was comparable to the sensitivity of mutation analysis in Caucasian CF patients. These results indicate that African-Americans have their own set of "common" CF mutations that originate from the native African population. Inclusion of these "common" mutations substantially improves CF mutation detection rates in African-Americans.     

Cascade testing for the identification of carriers of cystic fibrosis

Purified preparations of TEM-2, P99, Bacillus cereus I and B. cereus II beta-lactamases were examined by electrospray (ES) mass spectrometry. The ES mass spectra of the B. cereus enzymes revealed the presence of four to five components of different mass, corresponding to the loss of different numbers of N-terminal amino acids (ragged ends). The ES mass spectra of both TEM-2 and P99 consisted of a single component with no evidence of ragged ends. All four beta-lactamase preparations were visualized on isoelectric focusing (IEF) gels stained with nitrocefin to investigate a possible correlation between IEF patterns and ragged ends. Multiple banding patterns were seen with each beta-lactamase preparation. Although these may correlate with the presence of ragged ends in the two B. cereus preparations, the satellite bands seen with P99 and TEM-2 were not associated with differences detected by ES mass spectrometry. In this study we have shown for the first time that beta-lactamase satellite bands seen on IEF are not always associated with ragged ends. Furthermore, we have illustrated the use of ES mass spectrometry to characterize the extent of ragged end formation in protein samples. This is of particular significance if the sample is required for detailed biochemical or crystallography experiments.     

Chloride conduction of nasal fibroblasts in polyposis patients with cystic fibrosis and in patients without cystic fibrosis. Relevance for the ENT physician]

Cystic fibrosis (CF) is a complex systemic disease that has pathological alterations in the upper airways, including the recurrent formation of nasal polyps. Although the fibroblast is the predominant cell type in nasal stroma and nasal polyps, little is known about the electrophysiological properties of nasal fibroblasts. We investigated whether fibroblasts possess a cAMP-regulated chloride conductance which is impaired in patients with CF. Thus far the few studies concerning conductance in fibroblasts have been performed on skin fibroblasts using indirect methods and have yielded conflicting results. Therefore we studied chloride conductance in fused nasal fibroblasts by employing conventional microelectrodes. We have demonstrated that a cAMP-regulated chloride conductance is present in fibroblasts. However, this chloride conductance cannot be activated in fibroblasts from CF-patients. Thus, we present direct evidence that the impairment of the cAMP-regulated chloride conductance in CF is not confined to epithelial cells but also affects the fibroblast. We discuss how this conductance might modulate fibroblast proliferation to produce polyp formation.     

Airway clearance techniques in the treatment of cystic fibrosis

A one-year-old girl with a giant cell fibroblastoma (GCF) of the skin in the left arm is described. The tumor presented as a small, asymptomatic, subcutaneous mass that enlarged relatively slowly. GCF is a rare mesenchymal tumor occurring predominantly in young children. Its unique histopathological feature can lead to a misdiagnosis as sarcoma very easily. We review briefly the clinical and pathological information of 68 documented cases in the literature and discuss the pathogenesis of this peculiar neoplasm.     

The adrenal cortex in cystic fibrosis of the pancreas

The morphologies of the adrenal cortical zones of 25 children with cystic fibrosis and 24 control patients are presented. A technic for objective measurement of these zones is described. Hyperplasia of the zona glomerulosa in the children with cystic fibrosis is significant and may be related to chronic loss of salt in the sweat or demands placed on renal salt-conserving mechanisms.     

Serologic evidence that streptococcal superantigens are not involved in the pathogenesis of Kawasaki disease

We retrospectively reviewed 11 patients with culture-proven Acanthamoeba keratitis who presented at the National Taiwan University Hospital between 1989 and 1996. We assessed predisposing factors, initial diagnosis, clinical presentation, treatment, and outcome. A history of contact lens-wear, poor contact lens hygiene, intractable eye pain, and ring infiltrates in the cornea were the most prominent characteristics and clinical manifestations. Acanthamoeba keratitis was often misdiagnosed, with herpetic keratitis (7/11) being the most common initial diagnosis from referring hospitals. These patients were usually treated on the basis of the inaccurate diagnosis for more than 1 month (range 1-8 mo) before referral. All patients ultimately received penetrating keratoplasty because of poor response to delayed medical treatment. We suggest that inadequate contact lens hygiene may be important in Acanthamoeba keratitis. This condition is often misdiagnosed and, as early diagnosis is a major factor for successful medical treatment in such patients, awareness in clinical practice is critical.     

Carrier screening for cystic fibrosis, Gaucher disease, and Tay-Sachs disease in the Ashkenazi Jewish population: the first 1000 cases at New York University Medical Center, New York, NY

BACKGROUND: Ovarian cancer patients have a poor prognosis. In Norway, however, the prognosis has improved steadily since the 1950s, the age-adjusted 5-year relative survival reaching 37% in 1989 93. The aim of the present study was to explore the prognosis of patients with epithelial ovarian cancer diagnosed during 1975-94 (the prepaclitaxel period) and treated at The Norwegian Radium Hospital. METHOD: Relative risks (RR) of dying and 95% confidence intervals (95% CI) were derived from multivariate Cox proportional hazards regression models. RESULTS: A total of 2,769 patients with epithelial ovarian cancer were included in the present study. Altogether 54% of the patients were diagnosed with advanced stage disease (stages III and IV), whereas 32% were diagnosed with stage I disease. The prognosis of the patients improved from the 1970s to the 1990s, mainly due to increased short-term survival. In multivariate survival analysis, the RR of dying decreased with period of diagnosis. An RR of 0.77 (95% CI=0.66-0.89) was seen in 1990-94 compared with 1975-79. CONCLUSION: The short-term survival of patients with epithelial ovarian cancer improved from the late 1970s to the early 1990s. However, no major improvement in the long-term survival was seen.