Úvod: Polycystická autozomálne recesívna choroba obličiek (ARPCHO) je raritná, značne fenotypovo variabilná primárna cíliopatia. Poškodenie obličiek a pečene sú typickými prejavmi a prognóza ochorenia závisí od ich progresie v čase. Hlavným extrarenálnym prejavom je fibrocystická prestavba pečene, ktorá sa prejavuje intrahepatálnou portálnouhypertenziou a cholangitídou. Metódy: Retrospektívne zhodnotenie výskytu a vývoja hepatobiliárnych prejavov ochorenia. Výsledky: Do súboru bolo zaradených 8 detí s polycystickou autozomálne recesívnou chorobou obličiek. Poškodenie obličiek a hypertenzia boli prítomné u všetkých detí v súbore. Hepatobiliárne prejavy boli popísané u 5 detí (62,5 %). Trombocytopénia predchádzala splenomegáliu v časovom období jeden rok. Súčasťou výsledkov sú aj tri kazuistiky. Záver: Pacienti s ARPCHO by mali byť cielene vyšetrení so zameraním na posúdenie hepatálnych prejavov ochorenia. #938486
Introduction: Autosomal recessive polycystic kidney disease (ARPKD) is a rare, phenotypically variable primary ciliopathy. Kidney and liver damage are typical manifestations, and the prognosis of the disease depends on their progression over time. The main extrarenal manifestation is fibrocystic rebuilding of the liver, which is manifested by intrahepatic portal hypertension and cholangitis. Methods: The aim of the retrospective study was to evaluate the incidence and development hepatobiliary manifestations. Results: Eight children with polycystic autosomal recessive kidney disease were included in the group. Renal damage and hypertension were present in all children. Hepatobiliary manifestations were described in five children (62.5%). Thrombocytopenia preceded splenomegaly by one year. The results also include three case reports. Conclusion: Patients with ARPKD should be examined with a focus on the presence of hepatic manifestations of the disease.
- MeSH
- cystická fibróza * ekonomika farmakoterapie komplikace patofyziologie patologie prevence a kontrola MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- protein CFTR agonisté MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
There are concerns about altered vascular functions that could play an important role in the pathogenesis and influence the severity of chronic disease, however, increased cardiovascular risk in paediatric cystic fibrosis (CF) has not been yet fully understood. Aim was to analyse vascular disease risk and investigate changes over times in CF and controls. We prospectively enrolled 22 CF subjects (a median age of 16.07 years), and 22 healthy demographically matched controls (a median age of 17.28 years) and determined endothelial function. We utilised a combined diagnostic approach by measuring the plethysmographic Reactive Hyperemia Index (RHI) as the post-to preocclusive endothelium-dependent changes of vascular tone, and biomarkers that are known to be related to endothelial dysfunction (ED): asymmetric dimethyl arginine (ADMA), high-sensitive CRP (hsCRP), VCAM-1 and E-selectin. RHI values were significantly lower in CF young adults (p<0.005). HsCRP (p<0.005), E-selectin (p<0.001) and VCAM-1 (p<0.001) were significantly increased in CF patients since childhood. The findings have provided a detailed account of the ongoing process of microvascular dysfunction with gradual progression with the age of CF patients, making them further at risk of advanced vascular disease. Elevations of biomarkers in CF children with not yet demonstrated RHI changes but with significantly reduced RHI in adulthood and lipid profile changes indicate the possible occurrence of ED with CF-related specific risk factors over time and will enable us to provide the best possible support.
- MeSH
- biologické markery krev MeSH
- cévní endotel patofyziologie MeSH
- cystická fibróza krev diagnóza patofyziologie MeSH
- dítě MeSH
- dospělí MeSH
- hyperemie * MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- progrese nemoci MeSH
- prospektivní studie MeSH
- studie případů a kontrol MeSH
- věkové faktory MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- MeSH
- bronchiektazie diagnóza etiologie klasifikace MeSH
- cystická fibróza * diagnóza farmakoterapie patofyziologie terapie MeSH
- lidé MeSH
- progrese nemoci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Bronchial epithelial reticular basement membrane (RBM) thickening occurs in diseases with both eosinophilic (allergic bronchial asthma [BA]) and neutrophilic (cystic fibrosis [CF] and primary ciliary dyskinesia [PCD]) chronic airway inflammation; however, the lung function and airway remodeling relation remains unclear. The aim of this study was to test whether ventilation inhomogeneity is related to RBM thickening. METHODS: Multiple breath washout test, endobronchial biopsy, and BAL were performed in 24 children with CF, 11 with PCD, 15 with BA, and in 19 control subjects. Lung clearance index at 2.5% (1/40th) of starting nitrogen concentration (LCI2.5), RBM thickness, and lavage fluid cytology were quantified; their mutual associations were studied by using Spearman rank correlations (r). RESULTS: In asthma, ventilation inhomogeneity (mean ± SD) was mild (LCI2.5, 9.3 ± 1.4 vs 7.9 ± 0.9 in control subjects; P = .0391), and the RBM thickened (5.26 ± 0.98 μm vs 3.12 ± 0.62 μm in control subjects; P < .0001). No relation between RBM thickness and ventilation inhomogeneity or lavage cytology was found. In CF and PCD, RBM thickness was similar to that in asthma (4.54 ± 0.66 μm and 5.27 ± 1.11 μm, respectively), but ventilation inhomogeneity was significantly higher (LCI2.5, 12.5 ± 2.4 and 11.8 ± 2.5). Both in CF and PCD, RBM thickness correlated with LCI2.5 (r = 0.594, P = .015; r = 0.821, P = .023). In PCD only, RBM thickness was also related to the number of neutrophils in lavage fluid (r = 0.821; P = .023). CONCLUSIONS: Lung function impairment in relation to RBM thickness was milder in BA than in CF and PCD. In asthma, ventilation inhomogeneity did not correlate with RBM thickness, whereas it did in CF and PCD. This outcome suggests a different structure-function relation in these diseases.
- MeSH
- bazální membrána patologie MeSH
- biopsie metody MeSH
- bronchiální astma * patologie patofyziologie MeSH
- bronchoalveolární lavážní tekutina MeSH
- bronchoskopie MeSH
- bronchy * patologie patofyziologie MeSH
- cystická fibróza * patologie patofyziologie MeSH
- dítě MeSH
- korelace dat MeSH
- lidé MeSH
- mukociliární clearance MeSH
- neutrofily patologie MeSH
- plicní ventilace fyziologie MeSH
- poruchy ciliární motility * patologie patofyziologie MeSH
- remodelace dýchacích cest MeSH
- respirační funkční testy metody MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Monitoring changes in the epidemiology of cystic fibrosis (CF) pathogens is essential for clinical research, quality improvement, and clinical management. METHODS: We analyzed data reported to the European Cystic Fibrosis Society Patient Registry (ECFSPR) from 2011 to 2016 to determine the overall and the age-specific annual prevalence and incidence of selected CF pathogens and their trends during these years. The ECFSPR collects data on three chronic infections: Pseudomonas aeruginosa (PsA), Burkholderia cepacia complex Species (BCC) and Staphylococcus aureus (SA), as well as on the occurrence of non-tuberculous mycobacteria (NTM) and Stenotrophomonas maltophilia (SM). The same analyses were performed for different country groups, according to their gross national income (GNI). RESULTS: The pathogens with the highest prevalence were SA and PsA, with prevalence, in 2016, equal to 38.3% and 29.8% respectively, followed by SM (8.1%). The pathogens with the lowest prevalence were NTM (3.3%) and BCC (3.1%). The overall prevalence and incidence significantly decreased for PsA; they also decreased for BCC, while they increased significantly for SA. The overall prevalence of NTM and SM increased significantly. The most considerable prevalence changes were observed for PsA, which decreased across all income country groups and all age strata (with the exception of 0-1 years) The prevalence and incidence of pathogens differed significantly according to GNI. CONCLUSIONS: The epidemiology of CF pathogens in Europe has changed; epidemiologic data differ significantly among countries with different socio-economic status. The causes of these observations are multifactorial and include improvements in clinical care and infection control.
- MeSH
- Burkholderia cepacia komplex izolace a purifikace MeSH
- cystická fibróza * epidemiologie mikrobiologie patofyziologie MeSH
- dítě MeSH
- dospělí MeSH
- epidemiologické monitorování MeSH
- infekce dýchací soustavy * epidemiologie mikrobiologie patofyziologie MeSH
- lidé MeSH
- netuberkulózní mykobakterie izolace a purifikace MeSH
- prevalence MeSH
- Pseudomonas aeruginosa izolace a purifikace MeSH
- registrace statistika a číselné údaje MeSH
- socioekonomické faktory MeSH
- Staphylococcus aureus izolace a purifikace MeSH
- Stenotrophomonas maltophilia izolace a purifikace MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
BACKGROUND: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation. METHODS: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV1 > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS). RESULTS: Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment. CONCLUSIONS: Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients.
- MeSH
- antisense oligonukleotidy aplikace a dávkování škodlivé účinky MeSH
- aplikace inhalační MeSH
- cystická fibróza * farmakoterapie genetika patofyziologie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- klinické křížové studie MeSH
- lidé MeSH
- monitorování léčiv metody MeSH
- mutace MeSH
- oligonukleotidy * aplikace a dávkování škodlivé účinky MeSH
- protein CFTR genetika MeSH
- respirační funkční testy metody MeSH
- určení symptomu metody MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
PURPOSE: Cystic fibrosis (CF) is a progressive disease which causes a continuous decline in lung capacity with age. Our study aimed to investigate the age-dependent deterioration in lung function and the effects of treatment with Fenretinide formulation (LAU-7b) in Cftr knockout (KO) mice. METHODS: Non-invasive whole-body plethysmography (WBP) was done to measure the baseline lung functions of KO and wild-type (WT) mice at the ages of 2 and 4 months. Mice were then treated for 21 days with PBS or 10 mg/kg/day LAU-7b initiated at 4 and 7 months. Standard airway resistance measurements, haematoxylin and eosin staining, and analysis of lipids, and markers of oxidation were performed. RESULTS: The 4- and 7-month-old KO mice had significantly higher lung enhanced pause (Penh) and resistance values than age-matched WT mice and 2-month-old KO mice. Likewise, analysis of ceramides showed that PBS-treated mice had higher levels of long-chain ceramides (LCCs; C14-C18) and lower levels of very-long-chain ceramides (VLCCs; C24-C26) compared to LAU-7b-treated mice. Cftr KO mice displayed markedly greater inflammatory cell infiltration and epithelial hyperplasia at the ages of 2, 4, and 7 months compared to WT. LAU-7b treatment significantly diminished this cellular infiltration and epithelial hyperplasia compared to PBS-treated mice. CONCLUSION: Our results demonstrate a progressive age-dependent decline in lung function in Cftr KO mice. Treatment with LAU-7b corrects the lipid imbalance observed in the aging KO and WT mice and, more importantly, inhibits the age-dependent deterioration in lung physiology and histopathology.
- MeSH
- ceramidy metabolismus MeSH
- cystická fibróza metabolismus patofyziologie MeSH
- mastné kyseliny metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši knockoutované MeSH
- myši MeSH
- pletysmografie MeSH
- plíce patofyziologie MeSH
- progrese nemoci MeSH
- rezistence dýchacích cest fyziologie MeSH
- stárnutí * MeSH
- věkové faktory MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).
- MeSH
- aktivátory chloridových kanálů aplikace a dávkování škodlivé účinky MeSH
- aminofenoly aplikace a dávkování škodlivé účinky MeSH
- benzodioxoly aplikace a dávkování škodlivé účinky MeSH
- chinolony aplikace a dávkování škodlivé účinky MeSH
- chloridy analýza MeSH
- cystická fibróza farmakoterapie genetika patofyziologie MeSH
- dítě MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- fixní kombinace léků MeSH
- genotyp MeSH
- indoly aplikace a dávkování škodlivé účinky MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace * MeSH
- pot chemie MeSH
- protein CFTR genetika MeSH
- pyrazoly aplikace a dávkování škodlivé účinky MeSH
- pyridiny aplikace a dávkování škodlivé účinky MeSH
- pyrrolidiny aplikace a dávkování škodlivé účinky MeSH
- usilovný výdechový objem MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy. METHODS: In this retrospective clinical study, 3 independent CF patient cohorts (US-American: 29, Australian: 12 and Irish: 19 cases) were enrolled carrying at least one Class III CFTR CF-causing mutation (p.Gly551Asp) and being treated with CFTR potentiator ivacaftor. Plasma HE4 was measured by immunoassay before treatment (baseline) and 1-6 months after commencement of ivacaftor, and were correlated with FEV1 (% predicted), sweat chloride, C-reactive protein (CRP) and body mass index (BMI). RESULTS: After 1 month of therapy, HE4 levels were significantly lower than at baseline and remained decreased up to 6 months. A significant inverse correlation between absolute and delta values of HE4 and FEV1 (r = -0.5376; P < .001 and r = -0.3285; P < .001), was retrospectively observed in pooled groups, including an independent association of HE4 with FEV1 by multiple regression analysis (β = -0.57, P = .019). Substantial area under the receiver operating characteristic curve (ROC-AUC) value was determined for HE4 when 7% mean change of FEV1 (0.722 [95% CI 0.581-0.863]; P = .029) were used as classifier, especially in the first 2 months of treatment (0.806 [95% CI 0.665-0.947]; P < .001). CONCLUSIONS: This study shows that plasma HE4 levels inversely correlate with lung function improvement in CF patients receiving ivacaftor. Overall, this potential biomarker may be of value for routine clinical and laboratory follow-up of CFTR modulating therapy.
- MeSH
- aktivátory chloridových kanálů terapeutické užití MeSH
- aminofenoly terapeutické užití MeSH
- biologické markery analýza MeSH
- chinolony terapeutické užití MeSH
- cystická fibróza * genetika patofyziologie terapie MeSH
- dítě MeSH
- dospělí MeSH
- index tělesné hmotnosti MeSH
- lidé MeSH
- monitorování léčiv metody MeSH
- mutace MeSH
- pot chemie MeSH
- protein CFTR genetika MeSH
- protein WFDC2 analýza MeSH
- respirační funkční testy metody MeSH
- retrospektivní studie MeSH
- usilovný výdechový objem účinky léků MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinická studie MeSH
- práce podpořená grantem MeSH
