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PubMed1997

A partnership of care: an approach to the management of adults with cystic fibrosis.

Several factors occurring more or less simultaneously have led to a major change in the management of adults with cystic fibrosis at The Prince Charles Hospital, Brisbane. Less than 50 years ago, 80 per cent of infants born with cystic fibrosis did not survive the first two years of life. In Australia today, the median survival is around 30 years of age, with many surviving into their fourth decade (Landau & Ryan 1991, p 4). Recent developments in the management and treatment of cystic fibrosis provide an exciting and promising foundation for further development and a changing focus in cystic fibrosis management. Increased longevity has significant implications for the management of adults with cystic fibrosis. Until recently, most people with cystic fibrosis were managed within the paediatric setting, with the expectation that life expectancy would not exceed adolescence. In reality, there has been a dramatic increase in the number transferring from children's hospitals to adult facilities, and a subsequent need to provide optimal care to a group of patients coming to terms with their own perceptions of being adolescents with a life-shortening condition. From an organisational perspective, the increased demand for resources has generated the need to consider alternative methods of providing care. Such options include home intravenous therapy, day admission, alternative accommodation and education of staff in remote health centres. Home intravenous therapy has proven to be a popular alternative to hospital treatment and has significant implications for reducing lengths of stay and occupied bed-days. Within the current focus on best practice, developing strategies for providing optimal health care in the hospital setting are paramount. A multidisciplinary team focus based on a 'partnership of care' philosophy underpinned by best practice principles describes the approach adopted by the cystic fibrosis team at The Prince Charles Hospital that has led to successful outcomes in meeting challenges inherent in the care of young adults with cystic fibrosis.

Acute Disease↗

PubMed1992

Localization of cystic fibrosis transmembrane conductance regulator in chloride secretory epithelia.

Cystic fibrosis is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). To further our understanding of CFTR's function and regulation, we used confocal immunofluorescence microscopy to localize CFTR in cells stained with monoclonal antibodies against different regions of the protein: the R (regulatory) domain (M13-1), the COOH terminus (M1-4), and a predicted extracellular domain (M6-4). All three antibodies immunoprecipitated a 155-170-kD polypeptide from cells expressing CFTR. Each antibody stained HeLa and 3T3 cells expressing recombinant CFTR, but not cells lacking endogenous CFTR: HeLa, NIH-3T3, and endothelial cells. For localization studies, we used epithelial cell lines that express endogenous CFTR and have a cAMP-activated apical Cl- permeability: T84, CaCo2, and HT29 clone 19A. Our results demonstrate that CFTR is an apical membrane protein in these epithelial cells because (a) staining for CFTR resembled staining for several apical membrane markers, but differed from staining for basolateral membrane proteins; (b) thin sections of cell monolayers show staining at the apical membrane; and (c) M6-4, an extracellular domain antibody, stained the apical surface of nonpermeabilized cells. Our results do not exclude the possibility that CFTR is also located beneath the apical membrane. Increasing intracellular cAMP levels did not change the apical membrane staining pattern for CFTR. Moreover, insertion of channels by vesicle fusion with the apical membrane was not required for cAMP-mediated increases in apical membrane Cl- conductance. These results indicate that CFTR is located in the apical plasma membrane of Cl(-)-secreting epithelia, a result consistent with the conclusion that Cl TR is an apical membrane chloride channel.

Antibodies, Monoclonal↗

PubMed1990

Gene mapping and cystic fibrosis.

The recent molecular cloning of the gene responsible for cystic fibrosis illustrates the importance of human gene mapping to clinical medicine. Identification of a 3bp detection (delta F508) in the majority of cystic fibrosis patients will result in more accurate DNA-based diagnostic testing in cystic fibrosis families, as well as providing clues to the basic molecular defect and its relationship with alterations of anion transport in cystic fibrosis epithelial cells.

Chloride Channels↗

PubMed2004

[High prevalence of osteoporosis in adult cystic fibrosis patients].

BACKGROUND AND OBJECTIVE: In adult patients with cystic fibrosis bone metabolism may be altered by multiple mechanisms, such as abnormal calcium homeostasis, malnutrition, chronic inflammation or inactivity in the course of respiratory failure. In contrast to the high prevalence of osteoporosis in CF patients before lung transplantation, data from different CF collectives show great variation. It was the purpose of our cross-sectional study to determine changes in bone metabolism by measuring bone mineral density, and assessing calcium metabolism and clinical characteristics in adult patients (mean age 32 years) with cystic fibrosis. PATIENTS AND METHODS: Bone mineral density (quantitative digital radiography), parameters of calcium homeostasis and clinical characteristics were determined in 34 adult patients with cystic fibrosis. RESULTS: The mean age of the study population was 32 years (range 20 to 47; 21m: 13f). 13 patients had normal T-values (mean bone mineral density in young adults), whereas 11 patients (32 %) had osteopenia and 10 (29 %) had osteoporosis. Calcium homeostasis was abnormal in only one case. In contrast T-values were positively correlated with a low body mass index (p = 0.01) and a low one-second forced expiratory volume (FEV1) (p < 0.05). CONCLUSION: Decreased mineral bone density is a frequent complication in adult patients with cystic fibrosis, but does not occur inevitably even in long-standing disease (up to 47 years). In our cohort measurable alterations of calcium homeostasis could be avoided by consistent substitution policy. The main determinants of a low T-value were poor nutritional status, lowered serum calcium or phosphate concentrations and severely impaired lung function as indicator of the progression of the disease. Screening of adult patients with CF can be recommended especially in presence of malnutrition or poor lung function.

Adult↗

PubMed1993

Pharmacokinetics of cefepime in cystic fibrosis patients.

The purposes of this study were to determine and compare the single- and multiple-dose pharmacokinetics of cefepime in patients with and without cystic fibrosis. Twelve patients with cystic fibrosis hospitalized for treatment of acute pulmonary exacerbations were studied. In addition, pharmacokinetic data for seven of the patients with cystic fibrosis were compared with those for seven age-matched control patients. The cefepime dose was 50 mg/kg of body weight (maximum, 2 g) administered as a 30-min intravenous infusion every 8 h for a minimum of 8 days. Serial plasma and urine samples, obtained after the first and last doses, were analyzed for cefepime content by a validated high-pressure liquid chromatographic assay. By standard noncompartmental analysis, the pharmacokinetic parameters ascertained were area under the concentration in plasma-time curve, elimination half-life, total body clearance, renal clearance, and volume of distribution at steady state. In addition, the maximum concentration in plasma was recorded. Mean (+/- standard deviation) results of the first dose analysis in patients with cystic fibrosis were as follows: maximum concentration in plasma, 142.6 (+/- 26.07) micrograms/ml; area under the concentration in plasma-time curve, 265.3 (+/- 114.31) micrograms.h/ml; elimination half-life, 1.8 (+/- 0.53) h; total body clearance, 127.2 (+/- 50.94) ml/min; renal clearance, 91.1 (+/- 38.86) ml/min/kg; volume of distribution at steady state, 14.1 (+/- 4.31) liters. Analysis for the last dose in patients with cystic fibrosis did not vary appreciably from these values, nor did those from the controls. Thus, it appears that the first-dose pharmacokinetics of cefepime are predictive of those at steady state. In order to consistently exceed the MIC for Pseudomonas aeruginosa for the entire dosing interval in patients with cystic fibrosis, a higher dose and/or different dosing interval compared with those used in this study may be necessary.

Adolescent↗

PubMed2005

Update on the evaluation of pancreatic exocrine status in cystic fibrosis.

PURPOSE OF REVIEW: Pancreatic functional status has a very strong effect on outcome in cystic fibrosis and pancreatic insufficiency requires lifelong treatment with pancreatic enzymes. Traditionally, clinical signs and symptoms have been used to decide who should be treated with pancreatic enzyme supplements; however, recent studies show that patients with cystic fibrosis are both undertreated and over-treated using this approach. This paper reviews recent progress in the development of noninvasive, indirect tests of pancreatic function for use as diagnostic tools for patients with cystic fibrosis. RECENT FINDINGS: Breath testing using C-labeled fat and measurement of several pancreatic enzymes in stool, such as chymotrypsin, lipase, and elastase have been explored as ways to define pancreatic functional status. Fecal elastase has good sensitivity, specificity, and positive and negative predictive value for defining severe pancreatic insufficiency in patients with cystic fibrosis and appears to be more useful than measurement of other fecal enzymes. Its role in milder pancreatic insufficiency and in disease states other than cystic fibrosis, such as chronic pancreatitis, is less clear. SUMMARY: Several new noninvasive, indirect tests of pancreatic function have been developed to aid in the definition of pancreatic functional status in patients with cystic fibrosis. An objective measure of pancreatic functional status should be obtained in all patients with cystic fibrosis, and the recent development of new screening tools such as fecal elastase makes this feasible.

Breath Tests↗

PubMed1997

Congenital absence of the vas deferens: incomplete penetrance of cystic fibrosis gene mutations.

PURPOSE: We evaluated the penetrance of cystic fibrosis gene mutations for the clinical phenotype of congenital bilateral absence of the vas deferens. MATERIALS AND METHODS: We retrospectively reviewed the fertility status of 244 brothers of 105 men with congenital bilateral absence of the vas deferens. Testing for the most common cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and for haplotype analysis of the intron 8/polythymidine segment was recommended for all men with congenital bilateral absence of the vas deferens. RESULTS: Of 244 brothers of men with congenital bilateral absence of the vas deferens 131 were eligible for assessment of fertility. Of the 131 evaluable brothers only 7 (5%) were found to have congenital bilateral absence of the vas deferens. This prevalence is 5 times lower than that predicted for congenital bilateral absence of the vas deferens (25%) based on the autosomal recessive inheritance pattern seen in classical cystic fibrosis. For couples in which the man has congenital bilateral absence of the vas deferens and the female partner tests negative for standard CFTR gene mutations including 5T analysis, the maximum risk of having a child with congenital bilateral absence of the vas deferens is less than 1.0%. CONCLUSIONS: Our data are consistent with incomplete penetrance for the congenital bilateral absence of the vas deferens phenotype after inheritance of cystic fibrosis gene mutations, even after adjusting for environmental factors and wolffian anomalies. Incomplete penetrance may account for a low prevalence of congenital bilateral absence of the vas deferens in the population and may lower the risk of having a child with congenital bilateral absence of the vas deferens for couples undergoing sperm retrieval and assisted reproductive techniques.

Congenital Abnormalities↗

PubMed1999

Cytokine expression in bronchial biopsies of cystic fibrosis patients with and without acute exacerbation.

In patients with cystic fibrosis (CF), the progression of pulmonary disease differs considerably, even in identical cystic fibrosis transmembrane conductance regulator-genotypes which could reflect an additional influence of the host's immune response. This study therefore measured cytokine expression patterns in CF patients with different clinical presentation. Expression of interleukin (IL)-8, interferon gamma (IFN-gamma), IL-4, IL-10, and transforming growth factor (TGF)beta(I) was assessed in bronchial mucosal biopsies of eight CF patients with acute exacerbation (age 6.0-14.2 yrs), eight CF patients with chronic stable disease (age 7.3-17.4 yrs), and in five normal control subjects by semiquantitative and quantitative reverse transcriptase polymerase chain reaction combined with histopathological assessment and immunohistochemical staining. All CF patients expressed IL-8. In acute exacerbation, expression of TGF-beta1 and IFN-gamma was either absent or extremely low. In contrast, all patients with stable disease strongly expressed TGF-beta1. The highest expression of TGF-beta1 and IFN-gamma was found in CF patients with mild disease and a history of infrequent exacerbations. No correlation was found between the expression of IL-4 and IL-10 and patient history. In normal control subjects, only a weak expression of TGF-beta1 was observed. These results show a remarkable correlation between cytokine pattern and the clinical course of cystic fibrosis. High expression of transforming growth factor-beta1 and interferon gamma was associated with mild disease, whereas no or very weak expression of these cytokines was typical for patients with acute disease and frequent exacerbations suggesting a contribution of the immune response to the progression of pulmonary disease in cystic fibrosis.

Biopsy↗

PubMed2000

Attitudes to fertility issues among adults with cystic fibrosis in Scotland. The Collaborative Group of Scottish Adult CF Centres.

BACKGROUND: With increasing life expectancy, issues of fertility and pregnancy are pertinent to patients with cystic fibrosis. For this reason, the four Scottish Cystic Fibrosis centres asked men and women with cystic fibrosis about their attitudes to fertility and to information given to them by health professionals. METHODS: A postal questionnaire was sent to 116 men and 79 women aged 16 years and over attending four Scottish Cystic Fibrosis clinics. RESULTS: There was a 70% response rate (82 men, 54 women). All but two men knew that they were likely to be infertile. 37% of respondents lived with a partner; 14 women (26%) and five men (6%) had children. For 85% of men and 72% of women having children was important now or would be in the next 10 years. 43% of men and 26% of women had never had any discussion on fertility issues with cystic fibrosis health professionals. 56% of men thought that first discussion with a health professional about infertility should be before the age of 16 years; 12% remembered having a first discussion at that age. Learning of their infertility was associated with strong negative emotions for most men. Women were more likely than men to have initiated first discussion (17 (32%) versus eight (10%); p<0.01). Twenty five men (31%) and 32 women (59%) were currently using contraception. Ten men (12%) and 15 women (28%) had discussed contraception at the Cystic Fibrosis clinic (p = 0.01). CONCLUSIONS: Parenting and fertility issues are important for men and women with cystic fibrosis but many patients do not find out what they want to know from discussion with health professionals. Patients want discussion to begin in early adolescence. Men in particular are likely to be reluctant to introduce these issues; health professionals should be aware of the need actively to initiate discussion.

Adult↗

PubMedDate not supplied

Immunolocalization and regulation of cystic fibrosis transmembrane conductance regulator in the adult rat epididymis.

Cystic fibrosis is the most common serious autosomal recessive condition in whites, and more than 95% of men with cystic fibrosis are infertile. The cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic adenosine monophosphate (cAMP)-regulated chloride channel, has been localized in the efferent ducts; however, to our knowledge, its expression and regulation in the epididymis by testicular factors have not been examined. In the present study, these parameters were examined immunocytochemically by the light microscope with an anti-CFTR antibody in Bouin-fixed, paraffin-embedded control adult rat epididymides and both orchidectomized adult rats with or without testosterone supplementation and efferent duct-ligated rats sacrificed at different time points. In control animals, a thick dense band of immunoperoxidase reaction product was visualized over the apical plasma membrane of the principal cells but not their microvilli. The apical band was prominent only in the corpus and cauda regions. While there was no CFTR expression in basal cells, clear cells of the corpus and cauda regions showed a weak-to-moderate band of apical plasma membrane staining. An examination of orchidectomized, orchidectomized and testosterone, and efferent duct-ligated rats revealed that CFTR was no longer expressed as an intense band on the apical plasma membrane of the principal cells of the corpus and cauda regions. However, under these conditions, an intense apical/supranuclear reaction was noted in the form of small vesicular structures. Clear cells were unaffected by the different experimental treatments. Together, these data indicate that CFTR is expressed in a cell- and region-specific manner and that, while its synthesis in principal cells is not under the control of testicular factors, targeting to the apical plasma membrane is regulated by a testicular luminal factor.

Animals↗

PubMed1981

Intrapancreatic common bile duct compression causing jaundice in an adult with cystic fibrosis.

A 29-yr-old man with cystic fibrosis had a 4-yr history of recurrent episodes of obstructive jaundice. Endoscopic retrograde cholangiography revealed a common bile duct smoothly narrowed in its intrapancreatic portion, with dilatation above. A choledochojejunostomy was performed, but the patient died of septic complications. At autopsy, extensive pancreatic fibrosis caused compression of the distal bile duct in a manner which is analogous to that seen in chronic pancreatitis. This complication of cystic fibrosis, not previously reported, may become more prevalent as more patients with cystic fibrosis are living into adulthood.

Adult↗

PubMed1996

Burkholderia (Pseudomonas) cepacia epidemiology in a cystic fibrosis population: a genome finger-printing study.

In patients with cystic fibrosis, infection with Pseudomonas cepacia is associated with poor outcomes. However, the epidemiology of Burkholderia cepacia is still unclear. The aim of this study was to investigate the epidemiology of Burkholderia (Pseudomonas) cepacia colonization among cystic fibrosis patients attending the Verona CF Centre, a large specialized unit to which patients from different parts of Italy are admitted. We used a genome finger-printing system to analyse the nucleotidic structure of B. cepacia isolates from 60 colonized cystic fibrosis patients. Forty-two different finger-printing patterns were identified. Thirty-two patients were colonized by individual B. cepacia strains (53.3%). The remaining 28 subjects were divided into 10 different subgroups, each exhibiting a distinct strain of B. cepacia (46.7%). Nevertheless, direct, person-to-person transmission was evident in only 10 cases (16.7%). The stability up to 12 months, of the B. cepacia colonizing strain was documented in 36 individuals. Consistent with other reports, risk of B. cepacia transmission between cystic fibrosis patients through intimacy or nosocomial contact was found in our study. However, besides low contagiousness, our data suggest that the environmental reservoir of B. cepacia outside the hospital seems to play an important role in B. cepacia infection of our cystic fibrosis population.

Burkholderia Infections↗

PubMed1999

Guidelines for the diagnosis and therapy of diabetes mellitus in cystic fibrosis.

Diabetes is a common complication of cystic fibrosis. Because it is associated with increased morbidity and mortality, prompt diagnosis and aggressive management of cystic fibrosis-related diabetes is important. The Cystic Fibrosis Foundation held a consensus conference in 1998 to define the standards of care for patients with this disease [1[symbol: see text]]. In this article, pathophysiology and management of cystic fibrosis-related diabetes are reviewed.

Consensus Statements as Topic↗

PubMed2005

Update on the role of exercise in cystic fibrosis.

PURPOSE OF REVIEW: The role of exercise in patients with cystic fibrosis has been recognized for as long as cystic fibrosis has been identified as a clinical syndrome, as exercise intolerance has always been a hallmark of disease progression. RECENT FINDINGS: Work published in the past year has shed new light on several aspects of this field, including physiologic responses to exercise, responses to exercise programs, and the epidemiologic and prognostic implications of activity and exercise testing. SUMMARY: Barker's work is perhaps the most compelling, as it highlights the overwhelming interest and belief in the utility of exercise testing and prescription among cystic fibrosis physicians and the contrasting paucity of programs that test their patients and prescribe exercise for them. More studies are needed to identify the form of exercise programs and tests that are most likely to be effective and to be used by cystic fibrosis centers and patients.

Adolescent↗

PubMed1998

Molecular pathophysiology of cystic fibrosis based on the rescued knockout mouse model.

Cystic fibrosis transmembrane conductance regulator (cftr) gene mutations are thought to result in cystic fibrosis due to an absence of the protein's chloride channel. Recently, the lethal intestinal blockage in the cftr knockout mouse was reversed by a single in utero dose of a recombinant adenovirus containing the human cftr gene. The rescue of these animals did not require continuous expression of the gene and the cAMP-dependent chloride channel was not permanently restored. These data suggested that cftr was required for normal development of the intestine but not for normal function of the adult organ. Phenotypic changes in the intestines and lungs of in utero cftr-treated knockout and heterozygous mice revealed that altered development was induced. The intestines of the untreated knockout mice were shown to be deficient in both intracellular calcium and UTP receptors. Both of these deficiencies were partially corrected in the rescued knockout mice, whereas treatment of heterozygous animals disrupted the normal pattern of these markers. Examination of the lungs of knockout cftr (-/-) mice with lectins showed an increase in secreted glycoconjugates containing alpha(2,6)-sialic acid and fucose as compared with control heterozygotes. The in utero-treated knockouts showed an increase in this material as well, but it was contained in intracellular vesicles. Electron microscopy of these tissues confirmed the developmental alteration of secretory cell differentiation in the lungs. These data show that cftr is required in both the lung and intestines for normal differentiation of a secretory cell population and that in its absence these cells fail to develop properly.

Animals↗

PubMed1980

Somatic cell genetic studies of the cystic fibrosis mucociliary inhibitor.

A series of cystic fibrosis homozygous fibroblast X mouse cell hybrids were constructed in order to determine the chromosome which carries the gene controlling the cystic fibrosis mucociliary inhibitor (CFMI) phenotype. Several hybrids and their subclones retained the CFMI phenotype for long periods in cell culture. Correlation of the CFMI phenotype with the presence of specific human chromosomes indicated that possible linkage existed between CFMI and human chromosomes 2, 4, 6, 10, and 18. The strongest chance of linkage existed for chromosome 4.

Animals↗

PubMed1996

cAMP- but not Ca(2+)-regulated Cl- conductance is lacking in cystic fibrosis mice epididymides and seminal vesicles.

Cystic fibrosis (CF) reflects the loss of adenosine 3',5'-cyclic monophosphate (cAMP)-regulated Cl- secretion consequent to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In humans, but not mice, with CF, the disease is associated with male infertility. The present study investigated the relative magnitudes of the cAMP pathways and an alternative Ca(2+)-regulated Cl- secretory pathway in primary cultures of the epididymides and the seminal vesicles of normal and CF mice. The basal equivalent short-circuit currents (Ieq) of cultures derived from the epididymides and the seminal vesicles from the CF mice were lower (6.0 +/- 0.6 and 4.0 +/- 1.0 muA/cm2, respectively) than those from normal mice (11.1 +/- 1.0 and 6.6 +/- 0.6 muA/cm2, respectively). Forskolin induced significant Ieq responses in both the epididymis (8.0 +/- 0.7 muA/cm2) and seminal vesicles (4.0 +/- 0.5 muA/cm2) from normal mice, whereas forskolin-induced changes in Ieq in CF mouse epididymis and seminal vesicles were absent, consistent with defective cAMP-CFTR-mediated Cl- secretion in CF mice. Ieq responses to agonists (ionomycin, ATP) that raise intracellular Ca2+ (Ca2+i) were larger than forskolin responses in normal animals (6.6 +/- 0.9 and 13.4 +/- 1.8 muA/cm2, respectively) and were preserved in CF (6.5 +/- 0.9 and 17.1 +/- 1.0 muA/cm2, respectively). We speculate that the fertility of male CF mice is maintained by persistent expression of the predominant alternative Ca(2+)-mediated Cl- transport system in the epididymides and seminal vesicles.

Adenosine Triphosphate↗

PubMed2006

Nonclassical pathway of Pseudomonas aeruginosa DNA-induced interleukin-8 secretion in cystic fibrosis airway epithelial cells.

Pseudomonas aeruginosa is a critical colonizer of the respiratory tract in cystic fibrosis. The chronic infections with this microorganism contribute to excessive inflammation and progressive lung damage in cystic fibrosis patients. The full repertoire of Pseudomonas products that promote inflammation in the cystic fibrosis lung is not known. Here we show that P. aeruginosa DNA released from the bacterium, but not human DNA from epithelial cells or Escherichia coli DNA, displays proinflammatory properties and induces human respiratory epithelial cells to secrete interleukin-8 (IL-8), a key chemokine causing excessive neutrophil infiltration in the cystic fibrosis lung. IL-8 secretion was not due to an increase in NF-kappaB- or activator protein-1-dependent IL-8 promoter transcription, but instead depended on p38 and Erk mitogen-activated protein kinases. No secretion of IL-8 was observed using conventional Toll-like receptor 9 ligands (CpG oligonucleotides), although it could be demonstrated that parts of the Toll-like receptor 9-signaling pathway were functional, since class B and C CpG oligonucleotide ligands stimulated production of RANTES chemokine. The IL-8 secretion in response to P. aeruginosa DNA was decreased by treatments that inhibit acidification of intracellular organelles, using chloroquine, a pH-neutralizing compound, or bafilomycin A1, an inhibitor of vacuolar H+-ATPase. These data indicate that DNA released from P. aeruginosa during chronic infections may significantly contribute to the proinflammatory processes in cystic fibrosis. Our findings also show that treatments with drugs diminishing organellar acidification may reduce the inflammatory response in cystic fibrosis.

Cells, Cultured↗