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PubMed1983

Effect of short-term cimetidine administration on fecal bile acid losses in cystic fibrosis.

Eight children with cystic fibrosis and exocrine pancreatic insufficiency were voluntarily hospitalized in a clinical research setting so that diet and enzyme supplements could be well controlled for consecutive 72-h balance studies. We previously reported on these patients, as part of a larger study group, because they showed significantly reduced fecal losses of fat and nitrogen at the highest dose of cimetidine added to the otherwise constant regimen. Analysis of specimens from this same study shows a cimetidine-related reduction in fecal bile acid loss. Numerous variables thought to influence fecal bile acid loss were closely controlled and/or measured in this clinical study setting. In order to potentially learn more about this complex phenomenon, we carried out a stepwise regression analysis of the data which indicated that half of the variance in fecal bile acid loss is still unaccounted for by the five "independent" variables tested in the regression. However, in this variance analysis system cimetidine assumes a larger relative role in modulating bile acid loss than it does in fecal losses of fat and nitrogen.

Adolescent↗

PubMed2006

Aspergillus fumigatus generates an enhanced Th2-biased immune response in mice with defective cystic fibrosis transmembrane conductance regulator.

Cystic fibrosis (CF) lung disease is characterized by persistent airway inflammation and airway infection that ultimately leads to respiratory failure. Aspergillus sp. are present in the airways of 20-40% of CF patients and are of unclear clinical significance. In this study, we demonstrate that CF transmembrane conductance regulator (CFTR)-deficient (CFTR knockout, Cftr(tm1Unc-)TgN(fatty acid-binding protein)CFTR) and mutant (DeltaF508) mice develop profound lung inflammation in response to Aspergillus fumigatus hyphal Ag exposure. CFTR-deficient mice also develop an enhanced Th2 inflammatory response to A. fumigatus, characterized by elevated IL-4 in the lung and IgE and IgG1 in serum. In contrast, CFTR deficiency does not promote a Th1 immune response. Furthermore, we demonstrate that CD4+ T cells from naive CFTR-deficient mice produce higher levels of IL-4 in response to TCR ligation than wild-type CD4+ T cells. The Th2 bias of CD4+ T cells in the absence of functional CFTR correlates with elevated nuclear levels of NFAT. Thus, CFTR is important to maintain the Th1/Th2 balance in CD4+ T cells.

Animals↗

PubMed2004

Decreased interleukin-18 expression in BAL cells and peripheral blood mononuclear cells in adult cystic fibrosis patients.

Lymphocytes from cystic fibrosis (CF) patients secrete less interferon-gamma (IFN-gamma) upon stimulation compared to controls. Expression of interleukin (IL)-18 as an IFN-gamma inducing factor and of IL-10 as an IL-18 inhibiting factor were determined in bronchoalveolar lavage (BAL) cells from CF patients (n=5) and from normal control subjects (n=9) as well as in peripheral blood mononuclear cells (PBMC) from patients (n=12) and from control subjects (n=9) with RT-PCR. IL-18 and IL-10 serum protein levels were measured using ELISA. BAL cells and PBMC of CF patients expressed significantly less IL-18 compared to controls (p<0.05). There was no significant difference for IL-10 in BAL cells. However, PBMC from patients expressed significantly more IL-10 mRNA (p<0.05). IL-18 serum protein levels were decreased in the patient group, whereas IL-10 serum concentrations were elevated. Stimulation with rhIL-10 reduced IL-18 expression in PBMC from CF patients. Decreased IL-18 expression in CF patients may contribute to decreased IFN-gamma production. IL-10 may contribute to inhibit IL-18 expression in PBMC in CF.

Adult↗

PubMed1979

Inflammatory middle ear diseases in patients with cystic fibrosis.

111 patients with cystic fibrosis (CF), aged 7 months to 29 years, were examined to detect inflammatory middle ear diseases. 35% had a history of one or more attacks of acute otitis media, an incidence at the same level as in non-CF patients. None had chronic suppurative otitis. Only 4 out of the 88 patients able to cooperate in audiometry had a hearing impairment. In 2, the hearing loss was perceptive, in 3 very mild, and in the fourth case, moderately severe. The middle ear pressure was measured in 108 patients, in 86 of whom it proved normal. In 15 patients the middle ear pressure was lower than--100 mmH2O, indicating tubal occlusion, and in 7 patients the impedance minimum was lacking, indicating an accumulation of mucus. These 7 patients (6%) had secretory otitis media. Nasal polyps were or had been present in 32%. There was no correlation between nasal polyps and tubal occlusion or secretory otitis. The incidence of inflammatory middle ear diseases in CF patients was in the same range as in non-CF patients, a finding at variance with some previous investigations showing middle ear pathology in 25--48%.

Acoustic Impedance Tests↗

PubMed1987

Combined imipenem/cilastatin and tobramycin therapy of multiresistant Pseudomonas aeruginosa in cystic fibrosis.

Ten patients with cystic fibrosis (CF) and chronic broncho-pulmonary Pseudomonas aeruginosa infection were given imipenem/cilastatin (100 mg/kg/day) in combination with tobramycin (15 mg/kg/day). Forced vital capacity and forced expiratory volume in the first second improved significantly in nine out of ten patients, and most of the patients improved clinically. P. aeruginosa was not eradicated in any patient and resistance against imipenem developed in all patients during treatment. A concomitant increase in MIC of piperacillin and ceftazidime occurred during treatment. In-vitro bactericidal synergy of imipenem and tobramycin was noted in 57% of pretreatment isolates. Seven patients complained of adverse reactions, mainly gastrointestinal, and treatment of three patients was discontinued after 5, 8, and 12 days of therapy, because of rash or nausea and vomiting. The side effects were considered to be due to imipenem/cilastatin. Because of the rapid development of imipenem resistance despite combination therapy, the high proportion of side effects, and the risk of induction of beta-lactam resistance, imipenem/cilastatin cannot be recommended for routine treatment of CF-patients with P. aeruginosa infection.

Adolescent↗

PubMed1998

Effects of a proton-pump inhibitor in cystic fibrosis.

Most children with cystic fibrosis (CF) show persisting steatorrhoea even when treated with pancreatic enzyme. As a low duodenal pH could be responsible for this persisting fat loss, we evaluated the effects of a proton-pump inhibitor (lansoprazole) on both steatorrhoea and growth parameters in 15 CF patients, aged 3.1-22.6 y. Acid steatocrit, anthropometry and dual-energy X-ray absorptiometry were used to evaluate steatorrhoea and the nutritional status before, during and 3 months after stopping lansoprazole treatment (15 mg/d for 3 months). Mean +/- SD acid steatocrit values decreased from 37.1 +/- 8.8% to 28.5 +/- 10.6% (p = 0.02). Significant mean Z-score improvements were found for weight (+0.14; p = 0.02), height (+0.15; p = 0.03), subscapular (+0.61; p = 0.003), supra-iliac (+0.8; p = 0.002) and the sum of the four measured skinfolds (+0.61; p = 0.002). Z-scores deteriorated again after stopping lansoprazole. Fat mass and bone mineral content increased significantly on lansoprazole (p = 0.008 and p = 0.005, respectively). We conclude that lansoprazole as adjuvant therapy significantly improves both steatorrhoea and the nutritional status in CF children who maintain steatorrhoea while on pancreatic enzymes.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2006

Bafilomycin A1-sensitive pathway is required for the maturation of cystic fibrosis transmembrane conductance regulator.

Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasians caused by the trafficking defects of CF transmembrane conductance regulator (CFTR), which is a cAMP-dependent Cl- channel at the plasma membrane. The trafficking pathway of CFTR is thought to be non-conventional because CFTR maturation is inhibited by the dysfunction of syntaxin 13, which is involved in protein recycling via endosomal pathway. In this study, to clarify whether the endosomal trafficking is required for CFTR maturation, we utilized a specific vacuolar H+-ATPase inhibitor, bafilomycin A1 (BafA1), which inhibits the protein trafficking from early endosome. Our data showed that low concentration of BafA1 (50 nM) decreased the expression of mature CFTR but induced the accumulation of immature CFTR in the juxta-nuclear region containing an early endosome marker. Pulse-chase analysis showed that BafA1 inhibited the maturation of CFTR, but it slightly stabilized immature CFTR. These results indicate that BafA1-sensitive pathway is required for CFTR maturation and emphasize that endosomal trafficking pathway might be involved in the maturation of CFTR.

Animals↗

PubMedDate not supplied

Tracheal potential difference in the reserpine and isoproterenol rat models of cystic fibrosis.

Basic research into cystic fibrosis (CF) has been hampered by the lack of a suitable animal model. Reserpinized or isoproterenol-treated rats have been proposed as models because they exhibit certain morphological and physiological features characteristic of CF. Recent evidence suggests that abnormal epithelial transport of Na+ [corrected] and Cl- may underlie pathogenesis, defects that may contribute to the markedly more negative transepithelial electrical potential differences (PD) recorded in CF airways compared with controls. To test the models further, we measured tracheal PD in vivo in treated rats (reserpinized - 6.9 mV, SEM 0.7 mV, n = 7; isoproterenol-treated -10.2 mV, SEM 1.5 mV, n = 12) and found it to be no different from that of controls (-8.7 mV, SEM 0.6 mV, n = 25). The animals did, however, demonstrate a reduced gain in body weight as well as increased submaxillary gland weight, which reflected an increased mucus content in the acini. These observations suggest that although the reserpinized or isoproterenol-treated rat may be useful in the study of the pathogenesis of exocrine disturbances in disease, their use as models for the effect of the basic defect of CF in the airways may be limited.

Animals↗

PubMed1980

Gentamicin and tobramycin compared in the treatment of mucoid pseudomonas lung infections in cystic fibrosis.

18 children with cystic fibrosis and mucoid pseudomonas lung infection were treated with courses either of gentamicin plus carbenicillin, or tobramycin plus carbenicillin, with 2 children each receiving two courses. 10 courses of gentamicin at a dose of 9 mg/kg per day plus carbenicillin at 800 mg/kg per day, and 10 courses of tobramycin at 9 mg/kg per day plus carbenicillin at 800 mg/kg per day were given. There was clinical and x-ray improvement in both groups of children, but there was no difference between the therapeutic benefit of either regimen. Pseudomonas aeruginosa was not cultured at the end of treatment after 15 of the 20 courses, but it returned in all but one patient within 3 months. Neither ototoxicity nor renal damage with these high doses of aminoglycoside was detected. P. aeruginosa had not been eliminated when 9 of these patients earlier had received courses of gentamicin in a dose of 6 mg/kg per day plus carbenicillin at 800 mg/kg per day. The results show that P. aeruginosa can successfully be eliminated or suppressed with high-dose aminoglycoside plus carbenicillin, but such elimination is usually short lived.

Adolescent↗

PubMed2006

Proton MRI appearance of cystic fibrosis: comparison to CT.

Cystic fibrosis (CF) is the most frequent inherited disorder leading to premature death in the Caucasian population. As life expectancy is limited by pulmonary complications, repeated imaging [chest X-ray, multislice high-resolution computed tomography (MS-HRCT)] is required in the follow-up. Magnetic resonance imaging (MRI) of the lung parenchyma is a promising new diagnostic tool. Its value for imaging lung changes caused by CF compared with CT is demonstrated. MRI performs well when compared with CT, which serves as the gold standard. Its lack in spatial resolution is obvious, but advantages in contrast and functional assessment compensate for this limitation. Thus, MRI is a reasonable alternative for imaging the CF lung and should be introduced as a radiation-free modality for follow-up studies in CF patients. For further evaluation of the impact of MRI, systematic studies comparing MRI and conventional imaging modalities are necessary. Furthermore, the value of the additional functional MRI (fMRI) information has to be studied, and a scoring system for the morphological and functional aspect of MRI has to be established.

Adolescent↗

PubMed2004

Reproductive attitudes of couples having a child with cystic fibrosis in Brittany (France).

Cystic fibrosis (CF) has an incidence of one in 2,636 livebirths and a carrier rate of one in 26 inhabitants in Brittany. One objective of a major enquiry among parents having a CF child as well as CF adolescents and adults was to evaluate the reproductive behavior of 124 couples attending a CF care center. Knowledge of recurrence risk resulted in deciding against further progeny or in reducing the number of children (average number of children: 1.96; ideal mean number of children: 3.7). Thirty-five percent adopted or changed their method of contraception after the birth of their affected child, but the change was due to the birth of the CF child in only 14.3% of the couples. Prenatal diagnosis (PD) was favored by 95.1%, and 41.2% had used it; 68.6% were in favor of pregnancy interruption for CF and 76.2% would interrupt the pregnancy should PD reveal that their fetus had CF. All 123 respondents thought that genetic counseling was useful, but only 87.1% knew of its availability. Our results are quite different from those previously published. Although results could be population-specific, one cannot exclude the fact that they reflect a change of attitudes among parents, the other studies being much older.

Attitude↗

PubMed2006

Osteoclastogenesis during infective exacerbations in patients with cystic fibrosis.

RATIONALE: Adults with cystic fibrosis (CF) are at increased risk of developing osteoporosis. During infective exacerbations, increased production of proinflammatory cytokines and markers of bone resorption have been reported. OBJECTIVE: The aim of this study is to investigate the growth and proliferation of potential osteoclast precursor cells before, during, and after intravenous antibiotic treatment of infective exacerbations in patients with CF. METHODS: Hematopoietic precursor cell growth was examined using colony formation assays using Methocult culture medium. Circulating potential osteoclast precursors were identified using four-color flow cytometry by CD14, CD33, CD34, and CD45 expression. RESULTS: At the start of an infective exacerbation increases in hematopoietic precursor colony formation (15.42 colonies/10(5) cells plated, p = 0.025), proliferation (28.5%, p < 0.001), and the numbers of circulating potential osteoclast precursors (6.5%, p < 0.001) were seen in comparison with baseline levels. These increases declined after treatment with intravenous antibiotics to a level close to baseline. CONCLUSIONS: The results demonstrate an increase in the production of potential osteoclast precursors in the peripheral blood during CF infective exacerbations. This may result in increased bone resorption and contribute to bone loss in patients with CF.

Anti-Bacterial Agents↗

PubMed2003

Liver and intestinal transplantation in a child with cystic fibrosis: a case report.

Cystic fibrosis (CF) is an inherited disorder that presents as a multisystem disease with meconium ileus being the presenting symptom in 20% of patients. Approximately half of these patients present with complicated meconium ileus mandating early surgical intervention, potentially resulting in short gut syndrome. Although liver transplantation in children with CF has been described, this is the first report of a combined liver and small bowel transplant in a recipient with CF. A 7-month-old boy with CF presented with short bowel syndrome following extensive small bowel resection for meconium ileus and progressive cholestatic liver failure from intravenous hyperalimentation. He underwent combined liver and small intestinal transplant. He was discharged home three weeks post-transplant on enteral feeds with supplemental intravenous fluid. He has had routine protocol small bowel allograft biopsies with no documented rejection episodes. He has been treated for minor respiratory infections without major sequelae. Improvements in pulmonary therapy have impacted on the survival in the CF population to the point where the need for multiorgan transplantation will be increased in the future. Extrapolating from the excellent experience of liver transplantation in children with CF, early liver and small intestinal multivisceral transplantation, if indicated, can be performed safely in children with CF.

Cystic Fibrosis↗

PubMed1982

The effect of cimetidine on meal-stimulated gastric function and exogenous pancreatic enzymes in cystic fibrosis.

Some patients with cystic fibrosis (CF) have malabsorption of fat and protein in spite of large amounts of supplemental pancreatic enzymes. This is partly due to acid inactivation of exogenous pancreatic enzymes in the stomach. The effect of cimetidine on gastric function and exogenous pancreatic enzymes was assessed by a marker perfusion technique in 4 CF children in a double-blind controlled fashion. Gastric acid secretion was higher in CF patients than in controls (P less than 0.005) and was reduced significantly by oral cimetidine (P less than 0.02). Rapid inactivation of exogenous trypsin and lipase occurred when gastric pH fell to less than 4.5. There was no loss of enzyme activity during treatment with cimetidine when gastric pH remained above 5.5. Activity of lipase and trypsin in the jejunum improved in all subjects. Fat and nitrogen absorption assessed by a balance technique during the study period showed a small improvement in fat absorption while on cimetidine. We conclude that some CF patients have a high meal-stimulated gastric acid output which causes inactivation of trypsin and lipase. Cimetidine was effective in reducing acid secretion in such patients and led to small improvements in fat absorption.

Adolescent↗

PubMedDate not supplied

Detection of mycobacterial DNA from sputum of patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) are at high risk from atypical mycobacterial infections. There have been few attempts to delineate the intensity of mycobacterial infection in CF patients in Ireland. AIMS: To examine the incidence of mycobacterial DNA in an archived collection of genomic DNA extracted from the sputa of CF patients within the Northern Ireland population. METHODS: One hundred and eighty-two CF patients (66 adults and 116 children) were examined for the presence of mycobacterial DNA in their sputum by a genus specific PCR assay based on 16S rRNA, followed by direct automated sequencing of the PCR amplicons. RESULTS: One of 116 (0.9%) children and 2 of 66 adults were positive. Sequence identity revealed Mycobacterium xenopi in the paediatric patient and M. xenopi and M. chelonei in the two adult patients. False-positive results occurred in 11 patients (four adults), mainly due to Corynebacterium spp. CONCLUSIONS: There was a low prevalence of Mycobacterium spp in the CF patient population. All PCR positive results should be confirmed by direct automated sequencing and an alternative specific assay employed. Enhanced molecular screening will contribute in understanding their role as opportunistic pathogens in patients with worsening lung function.

Adult↗

PubMed1992

Nontuberculous mycobacteria in adult patients with cystic fibrosis.

Because patients with cystic fibrosis (CF) may be predisposed to airway infections with unusual microorganisms, we screened the sputum of adult CF patients for mycobacterial organisms. Acid-fast bacilli (AFB) smears and mycobacterial culture were performed on 297 sputum specimens from 87 patients. Cultures for mycobacteria were frequently overgrown with other bacteria; 22.6 percent of cultures were contaminated. Despite this limitation of mycobacterial culture, 17 patients had at least one positive culture for a Mycobacterium other than tuberculosis (MOTT). Eleven patients were positive for Mycobacterium avium-intracellulare (MAI), two for MAI and M chelonei, three for M chelonei, and one for M fortuitum. None was positive for M tuberculosis. Patients with CF with MOTT were similar to patients with CF without MOTT; only a slightly different (older) age distribution was recognized. The clinical significance of MOTT was difficult to determine in any individual patient, but patients with positive AFB smears appeared more likely to suffer pathogenic effects. We conclude that MOTT is frequently recovered from adult CF patients in the southeastern United States. A specific risk factor for colonization and/or pathogenic infection in this patient group was not evident. The general prevalence and clinical pathogenesis in CF patients in the United States remains to be determined.

Adolescent↗

PubMed2003

Airway surface liquid calcium modulates chloride permeability in the cystic fibrosis airway.

Patients with cystic fibrosis (CF) demonstrate a characteristic defect in epithelial chloride movement, which can be demonstrated in vivo by the nasal potential difference technique. After amiloride pretreatment, the CF airway exhibits only a transient response to perfusion with low-chloride solution, contrasting with the sustained hyperpolarization seen in control subjects. This study further investigated the response to low-chloride solution in the CF airway, examining the interaction between surface divalent ions and the low-chloride response. Sequential perfusion with amiloride, low chloride, and isoproterenol was tested in groups of subjects with CF, with the diluent containing different concentrations of calcium and magnesium, on different days. When the low-chloride response was measured with the nominally calcium-free diluents, the subjects with CF had mean (SEM) responses of 8.0 (0.7), 8.6 (2.4), and 9.6 (1.6) mV in the presence of 0, 1, and 3 mM Mg2+, respectively, significantly different from the response in the presence of divalent ions. However, the subsequent response to isoproterenol was not different in the presence or absence of divalent ions. We hypothesize that perfusion of the CF airway with nominally calcium-free solutions reduces tonic inhibition of chloride secretion.

Adolescent↗

PubMed2001

Assessing the quality of life in children with cystic fibrosis.

Although patients with cystic fibrosis (CF) are experiencing increased longevity, it is unclear that improved quality of life (QoL) accompanies the greater quantity of life. This is especially true of children with CF where the burdens of treatment are substantial. Assessing QoL in such children is difficult, and only one instrument--the Quality of Well-Being (QWB) scale--seems to have been used extensively to assess QoL in children with CF. After thoroughly reviewing the literature, we surveyed the 113 certified CF centers in the United States about QoL assessment. With 84% responding, it was found that only 7 centers are assessing QoL--4 have been using the QWB instrument. Concurrently, we pilot tested the QWB instrument in children being followed longitudinally in the Wisconsin CF Neonatal Screening Project. Our results indicated that QWB scores reflecting QoL decreased as the number of respiratory infections increased, as the number of concurrent medical conditions increased, and as the number of different medications increased. However, we recognized problems with the assessed domains and data interpretation. In fact, the QWB instrument has limited sensitivity and responds more to the extent of physician-determined treatment than to QoL. There is a need for more QoL assessment and better instruments, particularly in young children with CF.

Child↗