Fibroblast growth factor-23 (FGF23) was initially identified as the causative factor of autosomal dominant hypophosphatemic rickets. Further studies confirmed that FGF23 is predominantly expressed in the osteocytes and osteoblasts of bone and that circulating FGF23 acts on the kidney to inhibit renal phosphate reabsorption and 1,25(OH)2D3 hydroxylation. With the progression of chronic kidney disease (CKD), the kidneys become insufficient to maintain a normal systemic mineral homeostasis, resulting in various abnormalities of bone and mineral metabolism, generally referred to as Chronic Kidney Disease – Mineral and Bone Disorders (CKD-MBD). FGF23 increases early in the course of CKD in order to maintain normal serum phosphate levels; long before a significant increase in serum phosphate can be detected. Recent studies suggest that increased FGF23 levels are associated with progression of CKD, mortality, and the development of refractory secondary hyperparathyroidism. Because FGF23 is the very earliest marker of CKD-MBD, it is of particular interest to evaluate the relation between FGF23 and CKD-MBD abnormalities, in the setting of early CKD and also in individuals with normal renal function. In the present work, we show that FGF23 is linked to several dynamic measurements of vascular function, including endothelial dysfunction, arterial stiffness, and atherosclerosis. FGF23 is also positively associated with left ventricular mass index and an increased risk of having left ventricular hypertrophy. All associations were independent of serum phosphate and were strengthened in subjects with diminished renal function. Furthermore, we found significant evidence for an association between higher FGF23 and increased fat mass and dyslipidemia, which could represent a novel pathway linking FGF23 to cardiovascular disease. Finally, we show that FGF23 is a significant predictor of future fracture risk. Although these associations could be reflecting the increased risk associated with hyperphosphatemia and calcitriol deficiency, current evidence points towards FGF23 being more than an innocent bystander. At the very least, FGF23 holds promise of being a bio-marker of cardiovascular status and phosphate-related toxicity both in CKD and in the general population, and might be a therapeutic target that could improve the fatal prognosis in CKD patients.

Kidney failure is frequently associated with the risk factors linked to metabolic syndrome. Lipopolysaccharide (LPS) is a potent inflammatory molecule, which has increased absorption from the gut into blood circulation following a high fat and high-energy diet. We hypothesized that LPS from a high fat diet can amplify inflammation, thereby exacerbating chronic kidney disease and associated disorders. We have found that adding a high fat diet to renal insufficient mice significantly progressed their kidney disease as well as associated disorders, compared to both a high fat diet and renal insufficiency alone. Additionally, we were able to demonstrate in vitro that the combination of LPS and palmitic acid, a marker of high fat diet, induced inflammatory pathways significantly more than either LPS or palmitic acid alone. These results provide insight into connection between a high fat diet and the progression of chronic kidney disease as well as associated disorders.

Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) is a systemic disorder which includes abnormal bone chemistry, vascular or soft tissue calcification, and abnormal bone formation. Many of the parameters of CKD-MBD have been associated with an increased mortality risk in renal patients. There were three main facets to this research project. The first aim of this research was to perform two different studies using the Chronic Renal Insufficiency Standards Implementation Study (CRISIS) data. This prospective epidemiological study is designed to identify factors associated with renal progression and survival in the pre-dialysis CKD population. We have shown that for each 0.323mmol/L (1mg/dL) increase in serum phosphate there was a significant stepwise increased risk of death. (HR1.3 (1.1, 1.5) P=0.01). The association of baseline phenotypic data against vascular stiffness measurements was also investigated. Augmentation index measured at the radial artery was associated with a raised systolic blood pressure but no association with biochemical abnormalities was found.We hypothesised that the phosphate effect on survival was related to the effects within the CKD-MBD spectrum and therefore control of secondary hyperparathyroidism would improve bone and cardiovascular parameters. Therefore for the second part of this research we performed a randomised controlled trial to examine the effects of cinacalcet with standard therapy compared to standard therapy alone on bone and cardiovascular parameters in haemodialysis patients with uncontrolled hyperparathyroidism. The change of biochemical parameters and cardiovascular markers were also further explored in secondary analyses alongside survival data. The primary end point of change in vascular calcification at 52 weeks showed no significant difference between arms. As equivalent control of phosphate and iPTH was achieved in both arms secondary analyses were performed. This showed a significant regression of left ventricular hypertrophy and carotid intima-media thickness associated with phosphate but not iPTH reduction. Patients whose phosphate reduced during the study had a survival advantage when followed for 5 years (HR=10.2 (1.1, 104.5) P=0.049). The third part of this research was to investigate iPTH assay variability. We explored the variation in iPTH assays across the North West and paired this with regional audit data. This study showed that despite there being significant variation among iPTH assays across the region the variation in clinical management was still accounting for some variation in achieving PTH targets.In conclusion, serum phosphate, within the normal laboratory range, is associated with an increased mortality in CKD patients. Haemodialysis patients may have improvement of cardiovascular outcomes with tight control of secondary hyperparathyroidism, by whichever therapeutic means. Intact PTH assays variation may alter our clinical management but variation in practice still affects guideline achievement.

Prague and other cities in the Czech republic are currently struggling with a housing crisis, which causes raising of prices of houses and apartments. For many people it is an unapproachable goal to own a place. Suburb living projects are a slightly cheaper option, although they increase transportation demands and it is not a sustainable option in general. The city government is trying to support transformations of industrial areas - former factories or abandoned buildings – called brownfields. Vysočany district has changed a lot recently. Former industrial areas are demolished and replaced by new residential or administrative buildings. All the development projects have one thing in common – the absence of something that connects them into urban structure. The aim of this project is to desing a new construction instead of former CKD factories, which are not used anymore. Three new urban blocks nearby Kolbenova street are trying to respect other buildings around (if possible) and create a standard for future development. Also, they support the effort of the city council to create a lively boulevard on Kolbenova street. The project is designed as a polyfunctional unit to remain active during the whole day. The concept comprises urban residental blocks, administrative buildings and public spaces.

The Diploma Thesis seeks to evaluate key markets of the SKODA Auto company in terms of purchasing and supply possibilities. It analyzes both Skoda's external and internal environments and assesses current conditions in their key foreign supply market. Furthermore, it describes the purchasing process, methods of localization of suppliers, as well as possible methods of evaluation of Skoda's suppliers. The Thesis should provide the reader with an overview of current trends and opportunities in Skoda's supplier market.

No description available.

L’Insuffisance Rénale Chronique (IRC) résulte de la destruction progressive et irréversible des reins. Elle est associée à une rétention de toxines urémiques à l’origine des nombreuses complications de la maladie rénale chronique (cardiovasculaires, osseuses ou métaboliques). Nos travaux se sont focalisés sur l’impact de la dysfonction rénale et de l’urémie sur la fonction barrière de l’intestin et la motilité intestinale. Deux modèles d’IRC ont été implémentés : un modèle animal, chez la souris, par néphrectomie chimique (régime alimentaire enrichi en adénine) et un modèle cellulaire d’urémie en incubant des cellules coliques Caco-2 avec 10% de plasma de patients hémodialysés (HD). Le transit, la motilité, la perméabilité intestinale et la régulation des protéines des jonctions serrées ont été explorés. Les animaux urémiques présentent un transit gastro-intestinal ralenti et une perméabilité intestinale augmentée associés à une dérégulation de l’expression et de l’abondance des protéines des jonctions serrées dans le côlon (surexpression de la Claudine 1). La perméabilité de la monocouche cellulaire de Caco-2 incubées avec du plasma HD est significativement augmentée et est associée à une augmentation de l’expression et de l’abondance de la Claudine-1. En IRC, la motilité digestive et la fonction barrière de l’intestin sont significativement altérées. Ces dysfonctions pourraient contribuer à la production intestinale et l’absorption des toxines urémiques accélérant ainsi la progression du syndrome urémique et installant un véritable « cercle vicieux ». / Chronic Kidney Disease (CKD) result from a progressive kidney dysfunction. CKD is associated with an increase in the concentration of uremic toxins inducing CKD-associated metabolic alterations. Our work focused on the impact of renal dysfunction on gut permeability and gut motility. In vivo, CKD was induced in mice by chemical nephrectomy (adenine-enriched diet); In vitro, Caco-2 cells were incubated for 24h with 10% (v/v) of uremic plasma to mimic the uremic environment. Gastrointestinal transit time, gut motility, intestinal permeability and expression of tight junction proteins were explored. In vivo, kidney failure was associated with an impaired gastrointestinal transit and an increased intestinal permeability associated with a dysregulation of tight junction proteins (mainly claudine-1 overexpression). The Caco-2 monolayer permeability was significantly increased in cell monolayers incubated with uremic plasma. Claudine-1 expression and abundance was increased. In CKD, gut motility and gut permeability (e.g. « leaky » gut) are significantly impaired. Generally speaking, these gut dysfunctions could promote the production and the absorption of uremic toxins contributing to the uremic syndrom.

Les bicycles imidazo-imidazoles constituent une classe de composés hétérocycliques intéressants tant sur le plan chimique que pharmaceutique. Ils jouent un rôle très important dans la synthèse et la fonctionnalisation des composés à visé thérapeutique. Dans le cadre de la recherche de nouveaux candidats inhibiteurs de kinases, nous avons développé une voie de synthèse des imidazo[1,2-a]imidazoles mono- et bifonctionnalisés. Par la suite, nous avons mis au point une stratégie de synthèse rapide et efficace de bicycles imidazo[1,5-a]imidazolin-2-one et imidazo[1,5-a]imidazole. En outre, nous avons développé deux stratégies de fonctionnalisation via des réactions de couplage pallado-catalysées. Finalement nous avons synthétisé le motif imidazo[1,5-a]imidazole via la réaction de Groebke-Blackburn-Bienaymé (GBB). La potentialité de cette réaction a été exploitée dans des réactions decyclisation intramoléculaire! afin de préparer une nouvelle chimiothèque de composés polyhétérocycliques azotés. / The imidazo-imidazoles bicycles have received special attention among other nitrogen cycles due to their biologically interesting properties exploited in the medicine manufacturing. The imidazo-imidazole scaffold is one of the most representative nitrogen containing heterocycle, as it plays a significant role and possesses a major interest in drug synthesis and functionalization. In this work we report firstly a synthetic pathway to novel imidazo[1,2-a]imidazoles candidates for CKD inhibitors. Secondly we develop two strategies to prepareimidazo[1,5-a]imidazoles and their reactivity via pallado-catalyzed reactions. Finally, we disclose a fast and an efficient access to imidazo[1,5-a]imidazoles by using the Groebke-Blackburn-Bienaymé reaction (GBB), followed by a palladium catalysed intramolecular cyclization, affording thus new tetracyclic products with an elevated degree of molecular diversity.

No description available.

Fibroblast growth factor-23 (FGF23) is a novel, bone-produced hormone that regulates renal phosphate (Pi) reabsorption and calcitriol metabolism. Disorders of mineral and bone metabolism, such as autosomal dominant hypophosphatemic rickets (ADHR) and hyperostosis-hyperphosphatemia syndrome (HHS), witness the importance of well-balanced serum levels of FGF23. Patients with chronic kidney disease (CKD) are highly morbid due to Pi retention/hyperphosphatemia and calcitriol deficiency, which lead to elevated serum levels of parathyroid hormone (PTH) and secondary hyperparathyroidism (sHPT). As a response to hyperphosphatemia, CKD patients have also remarkably high serum FGF23 levels, which are associated with cardiovascular risk factors and increased mortality in CKD. The overall aim of this dissertation was to discern a possible role of FGF23 in parathyroid biology. Our in vitro experiments on isolated bovine parathyroid cells demonstrate that FGF23 directly and dose-dependently suppresses the PTH production and secretion, while increasing the expression of the 25-hydroxyvitamin D3-activating enzyme 1α-hydroxylase. We investigated possible expressional changes in the FGF23 receptor co-factor Klotho in hyperparathyroid disorders and found that Klotho expression is decreased or absent and inversely correlated to serum calcium (Ca) in adenomas of primary HPT (pHPT). In the hyperplastic parathyroid glands of sHPT, Klotho expression declines in parallel with the kidney function and correlates with the glomerular filtration rate. Moreover, Klotho expression is suppressed by Ca and FGF23, increased by calcitriol, but unaffected by Pi and PTH in vitro. Finally, we identified a novel missense mutation in the gene encoding GALNT3, which is normally involved in the post-translational glycosylation of FGF23, as the cause of aberrant FGF23 processing in a patient with HHS. In summary, we provide evidence for a novel bone/parathyroid axis in which FGF23 functions as a direct, negative regulator of the PTH production. High extracellular Ca is a major determinant of the Klotho expression in pHPT, whereas the Klotho levels in sHPT may be attributed to a combination of the high FGF23 and Ca, and low calcitriol levels associated with CKD. Hence, the decreased Klotho expression in sHPT could explain the concomitantly high FGF23 and PTH levels, as well as the failure of FGF23 to prevent or mitigate the development of sHPT in CKD.