RESUMO
Ambroxol, a mucokinetic anti-inflammatory drug, has been used for treatment of cystic fibrosis (CF). The respiratory epithelium is covered by the airway surface liquid (ASL), the thickness and composition of which is determined by Cl(-) efflux via the cystic fibrosis transmembrane conductance regulator (CFTR) and Na(+) influx via the epithelial Na(+) channel (ENaC). In cells expressing wt-CFTR, ambroxol increased the Cl(-) conductance, but not the bicarbonate conductance of the CFTR channels. We investigated whether treatment with ambroxol enhances chloride transport and/or CFTR and ENaC expression in CF airway epithelial cells (CFBE) cells. CFBE cells were treated with 100 µM ambroxol for 2, 4 or 8 h. mRNA expression for CFTR and ENaC subunits was analysed by real-time polymerase chain reaction (RT-PCR); protein expression was measured by Western blot. The effect of ambroxol on Cl(-) transport was measured by Cl(-) efflux measurements with a fluorescent chloride probe. Ambroxol significantly stimulated Cl(-) efflux from CFBE cells (a sixfold increase after 8 h treatment), and enhanced the expression of the mRNA of CFTR and α-ENaC, and of the CFTR protein. No significant difference was observed in ß-ENaC after exposure to ambroxol, whereas mRNA expression of γ-ENaC was reduced. No significant effects of ambroxol on the ENaC subunits were observed by Western blot. Ambroxol did not significantly affect the intracellular Ca(2+) concentration. Upregulation of CFTR and enhanced Cl(-) efflux after ambroxol treatment should promote transepithelial ion and water transport, which may improve hydration of the mucus, and therefore be beneficial to CF-patients.
Assuntos
Ambroxol/farmacologia , Brônquios/patologia , Cloretos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/patologia , Células Epiteliais/metabolismo , Canais Epiteliais de Sódio/metabolismo , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Western Blotting , Cálcio/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células Epiteliais/efeitos dos fármacos , Canais Epiteliais de Sódio/genética , Corantes Fluorescentes/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Since previous studies showed that the endogenous bronchodilator, S-nitrosglutathione (GSNO), caused a marked increase in CFTR-mediated chloride (Cl(-)) efflux and improved the trafficking of CFTR to the plasma membrane, and that also the nitric oxide (NO)-donor GEA3162 had a similar, but smaller, effect on Cl(-) efflux, it was investigated whether the NO-donor properties of GSNO were relevant for its effect on Cl(-) efflux from airway epithelial cells. Hence, the effect of a number of other NO-donors, sodium nitroprusside (SNP), S-nitroso-N-acetyl-DL-penicillamine (SNAP), diethylenetriamine/nitric oxide adduct (DETA-NO), and diethylenetriamine/nitric oxide adduct (DEA-NONOate) on Cl(-) efflux from CFBE (∆F508/∆F508-CFTR) airway epithelial cells was tested. Cl(-) efflux was determined using the fluorescent N-(ethoxycarbonylmethyl)-6-methoxyquinoliniu bromide (MQAE)-technique. Possible changes in the intracellular Ca(2+) concentration were tested by the fluorescent fluo-4 method in a confocal microscope system. Like previously with GSNO, after 4 h incubation with the NO-donor, an increased Cl(-) efflux was found (in the order SNAP>DETA-NO>SNP). The effect of DEA-NONOate on Cl(-) efflux was not significant, and the compound may have (unspecific) deleterious effects on the cells. Again, as with GSNO, after a short (5 min) incubation, SNP had no significant effect on Cl(-) efflux. None of the NO-donors that had a significant effect on Cl(-) efflux caused significant changes in the intracellular Ca(2+) concentration. After 4 h preincubation, SNP caused a significant increase in the mRNA expression of CFTR. SNAP and DEA-NONOate decreased the mRNA expression of all ENaC subunits significantly. DETA-NO caused a significant decrease only in α-ENaC expression. After a short preincubation, none of the NO-donors had a significant effect, neither on the expression of CFTR, nor on that of the ENaC subunits in the presence and absence of L-cysteine. It can be concluded that the effect of GSNO on Cl(-) efflux is, at least in part, due to its properties as an NO-donor, and the effect is likely to be mediated by CFTR, not by Ca(2+)-activated Cl(-) channels.
Assuntos
Cálcio/metabolismo , Cloretos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Células Epiteliais/metabolismo , Canais Epiteliais de Sódio/genética , Doadores de Óxido Nítrico/farmacologia , Brônquios/patologia , Linhagem Celular , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/patologia , Canais Epiteliais de Sódio/metabolismo , Regulação da Expressão Gênica , RNA Mensageiro/metabolismo , Triazóis/farmacologiaRESUMO
Defective chloride transport in epithelial cells increases mucus viscosity and leads to recurrent infections with high oxidative stress in patients with CF (cystic fibrosis). NAC (N-acetylcysteine) is a well known mucolytic and antioxidant drug, and an indirect precursor of glutathione. Since GSNO (S-nitrosoglutathione) previously has been shown to be able to promote Cl- efflux from CF airway epithelial cells, it was investigated whether NAC also could stimulate Cl- efflux from CF and non-CF epithelial cells and through which mechanisms. CFBE (CF bronchial epithelial cells) and normal bronchial epithelial cells (16HBE) were treated with 1 mM, 5 mM, 10 mM or 15 mM NAC for 4 h at 37 degrees C. The effect of NAC on Cl- transport was measured by Cl- efflux measurements and by X-ray microanalysis. Cl- efflux from CFBE cells was stimulated by NAC in a dose-dependent manner, with 10 mM NAC causing a significant increase in Cl- efflux with nearly 80% in CFBE cells. The intracellular Cl- concentration in CFBE cells was significantly decreased up to 60% after 4 h treatment with 10 mM NAC. Moreover immunocytochemistry and Western blot experiments revealed expression of CFTR channel on CFBE cells after treatment with 10 mM NAC. The stimulation of Cl- efflux by NAC in CF airway epithelial cells may improve hydration of the mucus and thereby be beneficial for CF patients.
Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Cloretos/metabolismo , Células Epiteliais/metabolismo , Mucosa Respiratória/metabolismo , Linhagem Celular , Fibrose Cística/metabolismo , Humanos , Imuno-Histoquímica , Estresse Oxidativo , Mucosa Respiratória/citologiaRESUMO
Airway epithelial salt and water transport takes place through paracellular and transcellular pathways. This transport depends critically on the epithelial sodium channel (ENaC) and the cystic fibrosis transmembrane conductance regulator (CFTR), operating in concert with the paracellular pathway through the tight junctions (TJ). Normal (16HBE14o-), cystic fibrosis (CFBE41o-), and corrected CFBE41o- (CFBE41o-pCep4 overexpressing wtCFTR) airway epithelial cell lines were cultured under isotonic conditions. Transepithelial electrical resistance (TEER) was measured as indicator of the tightness of the cultures. Morphology was investigated by immunofluorescence and paracellular permeability by lanthanum nitrate or [14C] mannitol as permeability markers. The CFTR-defective cell line CFBE41o- developed higher TEER than its corrected counterpart CFBE41o-pCep4. Addition of a specific inhibitor of CFTR (CFTR(inh)-172) to 16HBE14o- and CFBE41o-pCep4 cells resulted in a time-dependent increase in TEER, whereas stimulation of CFTR by IBMX and forskolin caused a decrease. Permeability to lanthanum and [14C] mannitol was lower in CFBE41o- and in 16HBE14o- cells exposed to CFTR(inh)-172, compared to untreated 16HBE14o- and CFBE41o-pCep4 cells, respectively. 16HBE14o- cells exposed to IBMX and forskolin showed higher permeability to lanthanum but lower permeability to [14C] mannitol compared to control. Immunofluorescence revealed a disorganization of F-actin and alpha-tubulin in 16HBE14o- cells and CFBE41o- pCep4 exposed to CFTR(inh)-172 and in CFBE41o- cells. Changes in F-actin and alpha-tubulin in 16HBE14o- cells exposed to IBMX and forskolin were also seen. These results suggest the possibility of an interaction between CFTR and the TJ protein complex, probably via the cytoskeleton.
Assuntos
Brônquios/citologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/patologia , Mucosa Respiratória/citologia , Junções Íntimas/fisiologia , 1-Metil-3-Isobutilxantina/farmacologia , Actinas/metabolismo , Brônquios/fisiologia , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/fisiologia , Colforsina/farmacologia , Fibrose Cística/metabolismo , Citoesqueleto/metabolismo , Condutividade Elétrica , Humanos , Lantânio/metabolismo , Manitol/metabolismo , Mucosa Respiratória/fisiologia , Mucosa Respiratória/ultraestrutura , Junções Íntimas/ultraestrutura , Fatores de Tempo , Tubulina (Proteína)/metabolismoRESUMO
Patients with cystic fibrosis (CF) are at increased risk of some cancers. Little is known about the cancer risks among carriers heterozygous for the CF mutation and it is hypothesized this may be associated with reduced cancer risk. Using Swedish general population-based registers, we identified 884 patients with CF from 1968 to 2003 and 3,033 of their first-degree relatives The subjects were followed from birth of index persons or 1958, whichever came later, until death, emigration or 2003, whichever came first. Cancer risks were compared with the general Swedish population using standardized incidence ratios (SIR) with 95% confidence intervals (CI). Patients, followed for an average of 21 years, were at a higher overall risk of cancer. Some 26 cancer diagnoses, after excluding multiple diagnoses of nonmelanoma skin cancer in one man, produced an overall SIR of 3.2 (95% CI 2.1-4.6). We found statistically significantly increased risks for kidney, thyroid, endocrine, lymphoma and nonmelanoma skin cancer. There was no modification of cancer risk among parents and siblings, with an average of 21 years of follow-up. This study did not identify a heterozygote advantage for CF gene mutations in relation to cancer risk.
Assuntos
Fibrose Cística/complicações , Predisposição Genética para Doença/epidemiologia , Neoplasias/epidemiologia , Adulto , Idoso , Estudos de Coortes , Fibrose Cística/genética , Família , Pai , Feminino , Seguimentos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mães , Fatores de Risco , Irmãos , Suécia/epidemiologia , Adulto JovemRESUMO
It was investigated whether azithromycin (AZM) stimulates chloride (Cl-) efflux from cystic fibrosis (CF) and non-CF airway epithelial cells, possibly secondary to up-regulation of the multidrug resistance protein (MDR). CF and non-CF human airway epithelial cell lines (CFBE and 16HBE) were treated with 0.4, 4, and 40 microg/mL AZM for 4 days. Cl- efflux was explored in the presence or absence of specific inhibitors of CFTR and alternative Cl- channels. Six CF patients received AZM (500 mg daily) for 6 months. The percentage of predicted forced vital capacity (FVC%), forced expiratory volume (FEV1%), and the number of acute exacerbations were compared before and after treatment. Nasal biopsies were taken before and after treatment, and mRNA expression of MDR and CFTR was determined by in situ hybridization. A significant dose-dependent increase of Cl- efflux from CFBE cells (but not from 16HBE cells) was observed after AZM treatment. A CFTR inhibitor significantly reduced AZM-stimulated Cl- efflux from CFBE cells. A significant improvement in FEV1%, and fewer exacerbations were observed. AZM treatment did not affect mRNA expression of MDR and CFTR. The stimulation of Cl- efflux could be part of the explanation for the clinical improvement seen among the patients.
Assuntos
Azitromicina/farmacologia , Cloretos/metabolismo , Fibrose Cística/tratamento farmacológico , Células Epiteliais/metabolismo , Azitromicina/administração & dosagem , Azitromicina/uso terapêutico , Estudos de Casos e Controles , Linhagem Celular , Canais de Cloreto/antagonistas & inibidores , Canais de Cloreto/metabolismo , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Transporte de Íons , Masculino , RNA Mensageiro/análise , Testes de Função Respiratória , Sistema Respiratório/patologia , Resultado do Tratamento , Adulto JovemRESUMO
In patients with cystic fibrosis (CF), clinical trials are of paramount importance. Here, the current status of drug development in CF is discussed and future directions highlighted. Methods for pre-clinical testing of drugs with potential activity in CF patients including relevant animal models are described. Study design options for phase II and phase III studies involving CF patients are provided, including required patient numbers, safety issues and surrogate end point parameters for drugs, tested for different disease manifestations. Finally, regulatory issues for licensing new therapies for CF patients are discussed, including new directives of the European Union and the structure of a European clinical trial network for clinical studies involving CF patients is proposed.
Assuntos
Fibrose Cística/terapia , Ensaios Clínicos como Assunto , Humanos , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/normas , Seleção de Pacientes , Projetos de Pesquisa/normas , Avaliação da Tecnologia BiomédicaRESUMO
Immunotherapy with specific antibodies is an alternative to antibiotics for the prevention of infections in humans and animals. We have used orally administered immunoglobulin Y (IgY) preparations, purified from eggs of hens immunized with Pseudomonas aeruginosa bacteria, to prevent pulmonary P. aeruginosa infections in a group of patients with cystic fibrosis (CF). Respiratory infections are major problems for CF patients because of the thick mucus in the airways, and chronic P. aeruginosa lung infections occur in virtually all CF patients and cause morbidity and mortality. The IgY-treated group had only 2.5 P. aeruginosa-positive sputum cultures per 100 months, and none of the IgY-treated patients became chronically colonized with P. aeruginosa. In the control group, 13.7 of the cultures per 100 months were positive for P. aeruginosa, and 24% of patients became chronically colonized with P. aeruginosa. The first enrolled patient in this study has now been treated continuously for more than 10 years. During the first 8 years she only had four P. aeruginosa-positive cultures. After 8 years she became chronically infected, but still after 10 years the bacteria have not turned mucoid. No negative side effects of IgY treatment have been noted during these 10 years. To our knowledge this is the longest treatment with specific yolk antibodies for therapeutic purposes.
Assuntos
Fibrose Cística/microbiologia , Imunização Passiva , Imunoglobulinas/administração & dosagem , Pneumopatias/microbiologia , Infecções por Pseudomonas/prevenção & controle , Adulto , Animais , Galinhas , Gema de Ovo/imunologia , Feminino , Humanos , Pseudomonas aeruginosa/imunologiaRESUMO
The composition of the airway surface liquid, a thin layer of fluid covering the airway wall, has been debated. Two new techniques to determine the ionic composition of the airway surface liquid are presented. In the first technique, pieces of the airway were shock-frozen and analyzed by X-ray microanalysis in the frozen state in the scanning electron microscope. In the second technique, the airway surface liquid was collected with the help of dextran beads that were allowed to absorb the fluid. The beads were collected in silicon oil, cleaned, dried, and analyzed. Airway surface liquid from pig airways was isotonic to lightly hypertonic, whereas airway surface liquid from mouse and rat airways was hypotonic. The ionic composition of airway surface liquid from rodent airways could be changed by pharmacological stimulation of fluid transport. Transgenic mice with cystic fibrosis (CF) had significantly higher Na and C1 concentrations in the airway surface liquid than normal mice. Nasal fluid was also collected from humans. In CF patients, CF heterozygotes, and rhinitis patients, the levels of Na and C1 in the nasal fluid were significantly higher than in healthy controls. In CF patients K levels were also significantly higher than in healthy controls. The ionic concentrations in fluid collected from patients with primary ciliary dyskinesia (PCD) were not different from normal. Females with CF had significantly higher concentrations of Na, Cl and K in their nasal fluid compared to male patients. The dextran bead technique was also used to determine the ionic composition of the apical fluid in cultures of respiratory epithelial cells from healthy controls and CF patients. In the healthy controls, the fluid was hypotonic. In the CF cell cultures, the apical fluid had a higher Na and Cl concentration than in the controls.
Assuntos
Fibrose Cística/diagnóstico , Microanálise por Sonda Eletrônica/métodos , Líquido da Lavagem Nasal/química , Mucosa Respiratória/metabolismo , Animais , Cloro/análise , Fibrose Cística/genética , Células Epiteliais/química , Células Epiteliais/citologia , Feminino , Humanos , Íons/análise , Masculino , Camundongos , Camundongos Endogâmicos CFTR , Líquido da Lavagem Nasal/citologia , Potássio/análise , Radiografia , Ratos , Ratos Sprague-Dawley , Sódio/análise , Suínos , Traqueia/diagnóstico por imagemRESUMO
Primary ciliary dyskinesia (PCD) is an autosomal recessive disease with extensive genetic heterogeneity. Dyskinetic or completely absent motility of cilia predisposes to recurrent pulmonary and upper respiratory tract infections resulting in bronchiectasis. Also infections of the middle ear are common due to lack of ciliary movement in the Eustachian tube. Men have reduced fertility due to spermatozoa with absent motility or abnormalities in the ductuli efferentes. Female subfertility and tendency to ectopic pregnancy has also been suggested. Headache, a common complaint in PCD patients, has been associated with absence of cilia in the brain ventricles, leading to decreased circulation of the cerebrospinal fluid. Finally, half of the patients with PCD has situs inversus, probably due to the absence of ciliary motility in Hensen's node in the embryo, which is responsible for the unidirectional flow of fluid on the back of the embryo, which determines sidedness. PCD, which is an inborn disease, should be distinguished from secondary ciliary dyskinesia (SCD) which is an acquired disease. Transmission electron microscopy is the most commonly used method for diagnosis of PCD, even though alternative methods, such as determination of ciliary motility and measurement of exhaled nitric oxide (NO) may be considered. The best method to distinguish PCD from SCD is the determination of the number of inner and outer dynein arms, which can be carried out reliably on a limited number of ciliary cross-sections. There is also a significant difference in the ciliary orientation (determined by the direction of a line drawn through the central microtubule pair) between PCD and SCD, but there is some overlap in the values, making this parameter less suitable to distinguish PCD from SCD.
Assuntos
Cílios/ultraestrutura , Síndrome de Kartagener/diagnóstico , Microscopia Eletrônica de Transmissão , Humanos , Síndrome de Kartagener/genéticaRESUMO
More women with cystic fibrosis (CF) now reach reproductive age and wish to become pregnant. Although women with CF have reduced fertility, many of them can become mothers. A pregnancy ought to be carefully planned since several studies have shown that pregnancy is well tolerated if good medical care is provided, and the CF woman is in a stable good condition. A short review of the implications of pregnancy for women with CF is presented. A suggested schedule for pregnant women with CF is given.
Assuntos
Fibrose Cística/fisiopatologia , Complicações na Gravidez/fisiopatologia , Fibrose Cística/terapia , Serviços de Planejamento Familiar/métodos , Feminino , Humanos , Gravidez , Complicações na Gravidez/prevenção & controle , Resultado da Gravidez , Cuidado Pré-Natal/métodosRESUMO
While the majority of patients with cystic fibrosis (CF) survive well into adulthood, some do so against the odds. The severity of their illness, their psychosocial environment, or their failure to adhere to treatment are such that survival could not have been predicted. It appears that some patients are more resilient than others. Some specific components of resilience include comprehensibility, manageability and meaningfulness. These are defined and case examples provided to illustrate their significance.
Assuntos
Fibrose Cística/psicologia , Adulto , Feminino , Humanos , MasculinoRESUMO
Respiratory infection is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Chronic Pseudomonas aeruginosa (PA) infections ultimately occur in virtually all patients. It is impossible to eradicate PA when a patient has been chronically colonized. Immunotherapy with specific egg-yolk antibodies (IgY) may be an alternative to antibiotics for the prevention of PA infections. We wanted to determine if treatment with specific IgY can prolong the period between the first and the second PA colonization? And long-term, can the treatment diminish the number of positive PA cultures and postpone the onset of chronic colonization? CF patients gargled daily with an IgY-antibody preparation, purified from eggs of hens immunized with PA bacteria. They were compared to a group of patients who did not gargle with the preparation. Both groups had their first colonization with PA eradicated by antibiotics. The basic treatment was essentially the same in both groups. In the initial study, the period between the first and second colonization with PA was significantly prolonged for the treated vs. the control group (Kaplan-Meier P = 0.015, Breslow test). In the prolonged study, the treated group had only 2.5 sputum cultures positive for PA per 100 months of observation, and none of these patients became chronically colonized with PA. No adverse events were reported. In the control group, 13.7 cultures per 100 months of observation were positive for PA, and 5 (24%) patients became chronically colonized with PA. This feasibility study shows that antipseudomonal IgY has the potential to effectively prevent PA colonization without any severe adverse effects. A phase III study should be initiated.
Assuntos
Fibrose Cística/complicações , Fibrose Cística/microbiologia , Imunoglobulinas/uso terapêutico , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/prevenção & controle , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Viabilidade , Humanos , Escarro/microbiologiaAssuntos
Controle de Medicamentos e Entorpecentes , Pediatria , Preparações Farmacêuticas , Criança , Ensaios Clínicos como Assunto , Aprovação de Drogas , Rotulagem de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , União Europeia , Humanos , Preparações Farmacêuticas/administração & dosagemRESUMO
The lantibiotic duramycin (Moli1901, Lancovutide) has been suggested as a drug of choice in the treatment for cystic fibrosis (CF). It has been proposed that duramycin may stimulate chloride secretion through Ca²(+) -activated Clâ» channels (CaCC). We investigated whether duramycin exhibited any effect on Clâ» efflux and intracellular Ca²(+) concentration ([Ca²(+)](i)) in CF and non-CF epithelial cells. Duramycin did stimulate Clâ» efflux from CF bronchial epithelial cells (CFBE) in a narrow concentration range (around 1 µM). However, 100 and 250 µM of duramycin inhibited Clâ» efflux from CFBE cells. An inhibitor of the CF transmembrane conductance regulator (CFTR(inh)â172) and a blocker of the capacitative Ca²(+) entry, gadolinium chloride, inhibited the duramycin-induced Clâ» efflux. No effect on Clâ» efflux was observed in non-CF human bronchial epithelial cells (16HBE), human airway submucosal gland cell line, human pancreatic epithelial cells, CF airway submucosal gland epithelial cells, and CF pancreatic cells. The [Ca²(+)](i) was increased by 3 µM duramycin in 16HBE cells, but decreased after 1, and 3 µM of duramycin in CFBE cells. The results suggest that the mechanism responsible for the stimulation of Clâ» efflux by duramycin is mainly related to unspecific changes of the cell membrane or its components rather than to effects on CaCC.
Assuntos
Bacteriocinas/farmacologia , Cálcio/metabolismo , Cloretos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Peptídeos/farmacologia , Linhagem Celular , Células Epiteliais , Humanos , Transporte de Íons/fisiologia , Microscopia Confocal , Microscopia de FluorescênciaRESUMO
BACKGROUND: This study examined if CF mutation heterozygosity is associated with diseases of gastrointestinal epithelial barrier function. DESIGN AND METHODS: Swedish registers identified 865 patients with a diagnosis of CF between 1968 and 2003 and matched with 8101 individuals without CF. Gastrointestinal disease risk was examined among 1534 biological parents and 1396 siblings of CF patients, compared with 15,526 parents and 15,542 siblings of individuals without CF. RESULTS: First-degree relatives of CF patients were not at lower risk of the gastrointestinal diseases, in contrast with a raised risk among CF patients. CONCLUSION: Heterozygosity for CF gene mutations does not protect against gastrointestinal diseases where impaired barrier function may be relevant.
Assuntos
Fibrose Cística/genética , Gastroenteropatias/genética , Heterozigoto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pais , Modelos de Riscos Proporcionais , Sistema de Registros , Risco , Irmãos , SuéciaRESUMO
AIMS: To explore whether gender differences in the Scandinavian Cystic Fibrosis (CF) patients exist in the areas of key clinical parameters, complications, and medication. METHODS: Cross-sectional data on 890 (416 female) pancreatic insufficient CF patients were evaluated regarding chronic infection, body mass index, lung function, medication, and diabetes, as well as data of Pseudomonas infection status, antibiotic treatment and hospitalization from 1-year follow-up. RESULTS: We found no differences in lung function, body mass index, or frequency of diabetes. The adult group consisted of more males than females (208:168). We found no significant difference in prevalence of chronic Pseudomonas aeruginosa infection, but during the follow-up the incidence of new chronic infection was higher in adult females (10/33 vs. 4/56). Females had higher prevalence of Burkholderia infection (21/416 vs. 11/474). Adult females had more days on intravenous antibiotics (median 39 vs. 26 days/year), and days in hospital (median 2 vs. 0 days/year). More adult females received inhaled and oral steroids. In the pediatric cohort, females were treated more often with macrolides as an anti-inflammatory agent. CONCLUSION: We found no gender difference in key clinical parameters in our CF population. However, our study showed a higher risk of Pseudomonas and Burkholderia infection among the female patients. Additionally, we found that female patients require more intensified treatment regarding antibiotics, macrolides, steroids and days of hospitalization, indicating a true female disadvantage even with modern aggressive treatment. The finding of more males than females in the adult population suggesting a male advantage, warrants a mortality study.
Assuntos
Fibrose Cística/complicações , Fibrose Cística/epidemiologia , Insuficiência Pancreática Exócrina/epidemiologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos Transversais , Fibrose Cística/diagnóstico , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Países Escandinavos e Nórdicos/epidemiologia , Fatores SexuaisRESUMO
BACKGROUND: Nitrite in exhaled breath condensate (EBC) has been shown to be elevated in cystic fibrosis (CF), while exhaled nitric oxide (FENO) is paradoxically low. This has been argued to reflect increased metabolism of NO while its diffusion is obstructed by mucus. However, we wanted to study the possible influence of salivary nitrite and bacterial nitrate reduction on these parameters in CF patients by the intervention of an anti-bacterial mouthwash. METHODS: EBC and saliva were collected from 15 CF patients (10-43 years) and 15 controls (9-44 years) before and 5 min after a 30s chlorhexidine mouthwash, in parallel with measurements of FENO. Nitrite and nitrate concentrations were measured fluorometrically. RESULTS: EBC nitrite, but not nitrate, was significantly higher in the CF patients (median 3.6 vs 1.3 microM in controls, p<0.05) and decreased after mouthwash in both groups (3.6-1.4 microM, p<0.01; 1.3-0.5 microM, p<0.01). Salivary nitrite correlated significantly to EBC nitrite (r=0.60, p<0.001) and decreased correspondingly after chlorhexidine, whereas salivary nitrate increased. FENO was lower in CF and the difference between patients and controls was accentuated after mouthwash (5.4 vs 8.4 ppb in controls, p<0.05). CONCLUSION: EBC nitrite mainly originates in the pharyngo-oral tract and its increase in CF is possibly explained by a regional change in bacterial activity. The limited lower airway contribution supports the view of a genuinely impaired formation and metabolism of NO in CF, rather than poor diffusion of the molecule.
Assuntos
Bactérias/metabolismo , Fibrose Cística/metabolismo , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Saliva/metabolismo , Adolescente , Adulto , Testes Respiratórios/métodos , Criança , Clorexidina , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Expiração , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Antissépticos Bucais , Adulto JovemRESUMO
BACKGROUND: Chronic Pseudomonas aeruginosa (PA) infection causes increased morbidity and mortality in cystic fibrosis (CF). This study aimed to answer the following questions: Does the prevalence of chronic infection with PA differ between the CF centres in Scandinavia? Which differences exist concerning segregation and treatment of PA? METHODS: 989 patients (86%) from all eight CF-centres in Scandinavia were included. Demographic and clinical data, including PA colonisation status based on cultures and serology, were recorded at inclusion. The patients were followed prospectively for 1 year, recording number of days with anti-PA antibiotic treatment. RESULTS: In all pancreatic insufficient (PI) patients (n=890) the prevalence of chronic PA infection at each centre ranged from 25.8% to 48.9%, but were not significantly different. In PI patients <19 years the prevalence was 14.5% in Copenhagen compared to 30.9% in the Swedish centres pooled (p=0.001). In intermittently colonised PI patients <19 years the median number of days per year on anti-PA antibiotics was almost 6 times higher in Copenhagen (mean 86 (110), median 61 days) compared to the Swedish centres pooled (mean 27 (52), median 11 days) (p=0.037). The pulmonary function was similar. CONCLUSIONS: It is possible to maintain a very low prevalence of chronic PA infection in CF patients <19 years. We speculate that this was most likely due to a very intensive treatment of intermittently colonised patients with inhaled anti-PA antibiotics over prolonged periods of time in some centres. Since lung function was similar in centres with less intensive use of inhaled antibiotics, studies comparing different treatment modalities and other parts of CF care are needed to define the best clinical practice, including how to use antibiotics in the most rational way.
Assuntos
Fibrose Cística/epidemiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/epidemiologia , Pseudomonas aeruginosa/isolamento & purificação , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/epidemiologia , Administração por Inalação , Administração Oral , Adolescente , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Comorbidade , Fibrose Cística/tratamento farmacológico , Fibrose Cística/microbiologia , Dinamarca/epidemiologia , Esquema de Medicação , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Noruega/epidemiologia , Prevalência , Estudos Prospectivos , Infecções por Pseudomonas/microbiologia , Infecções Respiratórias/microbiologia , Escarro/microbiologia , Suécia/epidemiologia , Resultado do Tratamento , Adulto JovemRESUMO
Pseudomonas aeruginosa is the dominant pathogen causing chronic lung infections in patients with cystic fibrosis (CF). After an initial phase characterized by intermittent colonizations, a chronic infection is established upon conversion of P. aeruginosa from the non-mucoid to the mucoid, alginate-overproducing phenotype. During the chronic infection the isolation of both mucoid and non-mucoid isolates in CF sputum samples is very common. The purpose of the present study was to establish, by sequence analysis, the types of mutations present in the algTmucABD operon in a large number of mucoid and non-mucoid P. aeruginosa isolates from Scandinavian CF patients and in in vitro-derived non-mucoid revertants. Mucoid (83) and non-mucoid isolates (103) from 91 Scandinavian patients with chronic P. aeruginosa infection and 24 non-mucoid isolates from intermittently colonized CF patients were investigated. In addition, 88 spontaneous non-mucoid revertants obtained in vitro from nine mucoid CF isolates were also included in the study. Mutations in mucA were found in 92 % of the mucoid and in up to 70 % of the non-mucoid isolates from chronically infected patients, indicating that the majority of non-mucoid isolates are revertants. None of the non-mucoid isolates from intermittently colonized CF patients harboured mucA mutations. Although algT has been considered an important gene for secondary-site mutations responsible for reversion to non-mucoidy, only 30 % of the mucA-mutated non-mucoid CF isolates had mutations in algT. In contrast, 83 % of the in vitro-derived spontaneous non-mucoid revertants had mutations in algT, showing that in the CF lung there is a selection for non-mucoid revertants with secondary-site mutations in genes other than algT. In addition, we report, to our knowledge for the first time, loss-of-function mutations in the negative regulators mucB and mucD in CF clinical isolates. In some of the CF isolates these mutations are associated with moderate alginate production. In conclusion, most non-mucoid isolates from chronically infected CF patients are revertants and the mechanism of revertance is algT-independent in the CF lung.