New approaches to determination pathophysiological changes in patients with cystic fibrosis

Nové přístupy vedoucí ke stanovení patofyziologických změn u pacientů s cystickou fibrózou Cystická fibróza (CF) je život limitující onemocnění způsobené mutací genu pro transmembránový regulátor vodivosti (CFTR, cystic fibrosis transmembrane regulator). Do dnešního dne bylo popsáno více než 2000 mutací CFTR genu, z toho pouze 360 v přímé souvislosti se vznikem onemocnění CF. U pacientů nesoucích mutace s nejasným či variabilním klinickým významem může být obtížná nejen diagnostika CF, ale pro nemožnost uspořádání standardních klinických studií je také výzvou zjišťování účinnosti nových léků, které cílí na narušený CFTR protein. Tyto tzv. modulátory CFTR proteinu otevřely novou etapu kauzální léčby CF. Zásadní pro maximalizaci efektu terapie je nejen genotyp, ale také skutečná míra odpovědi jednotlivého pacienta na léčbu. Intestinální organoidy představují v posledních letech ex vivo model využitelný ke stanovení míry funkce CFTR proteinu a současně k predikci léčebné odpovědi na dostupné léčebné molekuly. V rámci našeho projektu jsme s využitím nativní tkáně pacienta a z ní odvozených kultur intestinálních organoidů prokázali různou míru reziduální funkce CFTR proteinu u celkem 14 pacientů s CF (0-39,7 % funkce zdravé kontroly). Charakterizovali jsme doposud nepopsanou mutaci CFTR genu u pacienta, jehož...New approaches to determination pathophysiological changes in patients with cystic fibrosis Cystic fibrosis (CF) is a life-limiting disease caused by mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. To date, more than 2,000 mutations in the CFTR gene have been described, of which only 360 are directly related to CF. In a group of patients carrying mutations of unknown or variable clinical significance, it may be difficult not only to diagnose CF but also to facilitate clinical studies to determine the efficacy of new low - molecular weight compounds targeting disrupted CFTR protein. These so-called CFTR modulators have opened a new era in causal treatment of CF. To maximize the effect of these new therapies, not only the patient's genotype, but also the individual rate of response is crucial. In recent years, intestinal organoids have been used as an ex vivo model to determine the degree of CFTR function and at the same time to predict the therapeutic response to available therapeutic molecules. In our project, using the patient's native tissue and cultures of intestinal organoids derived from this tissue, we demonstrated varying degrees of CFTR residual function in a total of 14 patients with CF (0-39.7% of healthy control function). We characterized de novo mutation of the CFTR gene in...Department of Medical MicrobiologyÚstav lékařské mikrobiologie2. lékařská fakultaSecond Faculty of Medicin

THE CHANGE OF THE CHARACTERISTICS OF KNITTED FABRICS AFTER REPEATED WASHING

katedra: KHT; rozsah: 45 s., 7 s. obr. příloh.Cílem této bakalářské práce je zjistit zda dochází vlivem opakovaného praní ke změnám vlastností pletenin. V teoretické části jsou obsaženy poznatky o pleteninách. Co to pleteniny jsou, jak se mohou rozdělovat, jakými vlastnostmi se vyznačují. Dále v této části byly zjištěny poznatky o měření a údržbě pletenin a dle jakých norem se měří. V praktické části byly nejprve porovnány parametry vybraných vzorků. Poté bylo provedeno praní vzorků, spolu s vytvářením obrazové dokumentace vzhledu pletenin pomocí mikroskopu po několika cyklech praní. Na závěr je uvedeno vyhodnocení změn a nejvhodnější způsob použití pro danou pleteninu.The aim of this bachelor work is to find out whether repeated washing has any effects at characteristics changes of knitted fabrics. In the theoretical part there is included theoretical knowledge about knitted fabrics. What the knitted fabrics are, how they can be divide and by which features are knitted fabrics characterized. Further in this part was knowledge about measuring and maintaining knitted fabrics found out, what standards are used for measurement. In the practical part were firstly compared parameters of selected samples and then washing the samples together with creation of visual documentation of appearance by using microscope, after several cycles of washing. In the end there is stated evaluation of changes and most suitable use for particular kind of knitted fabrics

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

The inflammatory airway disease cystic fibrosis (CF) is characterized by airway obstruction due to mucus hypersecretion, airway plugging, and bronchoconstriction. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is dysfunctional in CF, leading to defects in epithelial transport. Although CF pathogenesis is still disputed, activation of alternative Cl− channels is assumed to improve lung function in CF. Two suitable non-CFTR Cl− channels are present in the airway epithelium, the Ca2+ activated channel TMEM16A and SLC26A9. Activation of these channels is thought to be feasible to improve hydration of the airway mucus and to increase mucociliary clearance. Interestingly, both channels are upregulated during inflammatory lung disease. They are assumed to support fluid secretion, necessary to hydrate excess mucus and to maintain mucus clearance. During inflammation, however, TMEM16A is upregulated particularly in mucus producing cells, with only little expression in ciliated cells. Recently it was shown that knockout of TMEM16A in ciliated cells strongly compromises Cl− conductance and attenuated mucus secretion, but does not lead to a CF-like lung disease and airway plugging. Along this line, activation of TMEM16A by denufosol, a stable purinergic ligand, failed to demonstrate any benefit to CF patients in earlier studies. It rather induced adverse effects such as cough. A number of studies suggest that TMEM16A is essential for mucus secretion and possibly also for mucus production. Evidence is now provided for a crucial role of TMEM16A in fusion of mucus-filled granules with the apical plasma membrane and cellular exocytosis. This is probably due to local Ca2+ signals facilitated by TMEM16A. Taken together, TMEM16A supports fluid secretion by ciliated airway epithelial cells, but also maintains excessive mucus secretion during inflammatory airway disease. Because TMEM16A also supports airway smooth muscle contraction, inhibition rather than activation of TMEM16A might be the appropriate treatment for CF lung disease, asthma and COPD. As a number of FDA-approved and well-tolerated drugs have been shown to inhibit TMEM16A, evaluation in clinical trials appears timely

Mucus Release and Airway Constriction by TMEM16A May Worsen Pathology in Inflammatory Lung Disease

Activation of the Ca2+ activated Cl− channel TMEM16A is proposed as a treatment in inflammatory airway disease. It is assumed that activation of TMEM16A will induce electrolyte secretion, and thus reduce airway mucus plugging and improve mucociliary clearance. A benefit of activation of TMEM16A was shown in vitro and in studies in sheep, but others reported an increase in mucus production and airway contraction by activation of TMEM16A. We analyzed expression of TMEM16A in healthy and inflamed human and mouse airways and examined the consequences of activation or inhibition of TMEM16A in asthmatic mice. TMEM16A was found to be upregulated in the lungs of patients with asthma or cystic fibrosis, as well as in the airways of asthmatic mice. Activation or potentiation of TMEM16A by the compounds Eact or brevenal, respectively, induced acute mucus release from airway goblet cells and induced bronchoconstriction in mice in vivo. In contrast, niclosamide, an inhibitor of TMEM16A, blocked mucus production and mucus secretion in vivo and in vitro. Treatment of airway epithelial cells with niclosamide strongly inhibited expression of the essential transcription factor of Th2-dependent inflammation and goblet cell differentiation, SAM pointed domain-containing ETS-like factor (SPDEF). Activation of TMEM16A in people with inflammatory airway diseases is likely to induce mucus secretion along with airway constriction. In contrast, inhibitors of TMEM16A may suppress pulmonary Th2 inflammation, goblet cell metaplasia, mucus production, and bronchoconstriction, partially by inhibiting expression of SPDEF

Development of methodology for measuring elemental composition of hair using LIBS analyses

77 s., 14 s. příl. :il., tab., grafy +CD ROMCílem diplomové práce je vývoj metodiky měření prvkového složení lidských vlasů pomocí metody LIBS. V teoretické části jsou obsaženy poznatky o prvkové analýze vlasů a popsána charakteristika lidských vlasů. Dále se tato část zabývá metodou LIBS, jejím využitím a principem laserového analyzátoru LEA S500, který je využíván pro měření. Experimentální část je zaměřena na popis testovaných vlasů a vytvoření vhodných způsobů pro jejich uchycení. Dále se zabývá mapováním stopových prvků v lidských vlasech

New approaches to determination pathophysiological changes in patients with cystic fibrosis

New approaches to determination pathophysiological changes in patients with cystic fibrosis Cystic fibrosis (CF) is a life-limiting disease caused by mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. To date, more than 2,000 mutations in the CFTR gene have been described, of which only 360 are directly related to CF. In a group of patients carrying mutations of unknown or variable clinical significance, it may be difficult not only to diagnose CF but also to facilitate clinical studies to determine the efficacy of new low - molecular weight compounds targeting disrupted CFTR protein. These so-called CFTR modulators have opened a new era in causal treatment of CF. To maximize the effect of these new therapies, not only the patient's genotype, but also the individual rate of response is crucial. In recent years, intestinal organoids have been used as an ex vivo model to determine the degree of CFTR function and at the same time to predict the therapeutic response to available therapeutic molecules. In our project, using the patient's native tissue and cultures of intestinal organoids derived from this tissue, we demonstrated varying degrees of CFTR residual function in a total of 14 patients with CF (0-39.7% of healthy control function). We characterized de novo mutation of the CFTR gene in..

Analysis of Financial Management of Allowance Organization

This bachelor thesis focuses on Allowance Organization and their management. The elementary school J. A. Komenského in Lysá nad Labem and primary school Letců R. A. F. in Nymburk are compared in this thesis. The first part is theoretical, and it includes basic information about the Allowance Organization and also description of the different indicators used for their assessment. The second part informs about the basic characteristic of the chosen Allowance Organizations, and contains information about their management and financial analysis. The indicators of financial analysis have mostly positive results. The biggest amount of the revenues is provided by state in the form of subsidies and the biggest amount of the expenses is used as a salary of the employees. The number of pupils was increasing during the monitored period, therefore it led to the increasing in amount of the state subsidies for paying salaries to a bigger number of teachers. In the conclusion of the thesis, the extracted results are being compared on the basis of the calculated indicators