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Selected aspects of methotrexate treatment in patients with rheumatoid arthritis
Hloch, Karel ; Pávek, Petr (advisor) ; Souček, Miroslav (referee) ; Tomčík, Michal (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Social and Clinical Pharmacy Doctoral Degree Program Clinical and Social Pharmacy Candidate MSc. Karel Hloch Supervisor prof. PharmD. Petr Pávek, Ph.D. Advisor assoc. prof. MUDr. Tomáš Soukup, Ph.D.; PharmD. Martin Doseděl, Ph.D. Title of Doctoral Thesis: Selected aspects of methotrexate treatment in patients with rheumatoid arthritis Introduction and objectives Rheumatoid arthritis (RA) is an autoimmune disease typically connected with chronic inflammation of the joints, causing their swelling and pain. The prevalence of RA is about 1% in the general population. A crucial role in higher morbidity and mortality in RA patients has been associated with increased inflammatory activity. Methotrexate (MTX), a drug with immunosuppressive activity, is the most frequent drug of choice used in RA therapy. It seems that main anti-inflammatory effect is mediated via release of purine nucleoside adenosine. The status of patients with inflammatory diseases is influenced by activation of A2a and A3 adenosine receptors. High caffeine (adenosine receptor antagonist) consumption may therefore lead to alteration of MTX treatment efficacy. 1) The aim of first study was to determine whether RA patients who had discontinued...
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Genetic and molecular mechanisms of arterial hypertension in relation to chronic inflammation, oxidative stress, and chronic kidney disease
Krajčoviechová, Alena ; Cífková, Renata (advisor) ; Widimský, Jiří (referee) ; Vaněčková, Ivana (referee)
This thesis provides an appraisal of the structure of clustering of metabolic phenotypes and evaluates the pathophysiological mechanisms underlying the relationship between urinary uric acid and albumin excretion. Two population-based studies were involved. In the first part, we used data obtained in a large representative cross-sectional survey in the Czech Republic (Czech post-MONICA study). We showed that the urinary albumin/creatinine ratio (uACR) was an independent factor for an increase in serum uric acid (SUA) levels in adults without manifest metabolic syndrome (MetS), but with 1-2 MetS component(s). Furthermore, SUA levels increased by the synergistic interaction of uACR with visceral adiposity and blood pressure, which may suggest obesity-related hypertension with altered renal hemodynamics as the primary mechanism. In the second part, we analyzed data captured in a representative population sample of French Canadians (CARTaGENE study) with more detailed urine biochemical analyses available. This study yielded two novel observations. First, we showed that the rs13129697 major T allele, which has been associated with increased SUA levels in our analysis as well as in prior publications, was associated with a paradoxical decrease in uACR. The reason for this discrepant finding is the...
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Local metabolism of glucocorticoids in female Prague hereditary hypertriglyceridemic rats
Klusoňová, Petra ; Pácha, Jiří (advisor) ; Kopecký, Jan (referee) ; Haluzík, Martin (referee)
11-hydroxysteroid dehydrogenase (11HSD1) is an oxidoreductase which catalyzes conversion of inactive 11-oxo steroid derivatives into active 11-hydroxy forms. 11HSD1 elevates intracellular level of active glucocorticoid (GC) hormones: cortisol in human tissues and corticosterone in rodents, therefore local level of active GCs can be set independently from systemic secretion driven by hypothalamo-pituitary-adrenal axis (HPA axis). Chronic systemic excess of GCs results in development of Cushing's syndrome which is characterised by central obesity and other metabolic disturbances. Despite normal serum levels of GCs, the patients with idiopathic obesity also develop metabolic syndrome. It was suggested that GCs could be elevated locally in target tissues due to enhanced 11HSD1 activity. This hypothesis was confirmed in transgenic rodent models. Prague hereditary hypertriglyceridemic (HHTg) rats represent a non-obese model of metabolic syndrome without genetic manipulations or specific mutations. The strain was bred by cross-mating of Wistar rat individuals with elevated serum levels of triglycerides (TGs). The strain exhibit hypertriglyceridemia and hypertension. When kept on high carbohydrate diet HHTg rats exhibit alterations in glucose homeostasis. Since there are no data that would describe...
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Evaluation of Selected Biochemical Markers of Metabolic Syndrome and Adipose Tissue After Bariatric Surgery
Horká, Veronika ; Bužga, Marek (advisor) ; Holéczy, Pavol (referee)
The diploma thesis deals the problematics of weight reduction with the using of bariatric- metabolic surgery and focuses on the changing risk components of the metabolic syndrome during one year long observation of 45 probands who have undergone Partial Jejuno-Ileal Diversion, Laparoscopic Sleeve Gastrectomy or Laparoscopic Gastric Plication. The main aim of the diploma thesis is to evaluate the changing risk components of the metabolic syndrome during weight reduction after undergoing bariatric surgery. The thesis shows that in the studied sample of bariatric patients it is an effective method of weight reduction (in PJID the success rate was 48 % EWL, in LGCP 51 % EWL and the most successful was LSG with 76 % EWL) with metabolic effect such as for example observed positive changes in risk components of the metabolic syndrome - reduction of morning glucose levels, increase of HDL cholesterol and decrease of triacylglycerols in the blood, decrease of waist circumferences and decrease of blood pressure or elimination of metabolic syndrome. Up to 68.9 % of the monitored probands showed signs of metabolic syndrome when evaluating the initial measurement before bariatric surgery, the remaining 22.2 % of the probands showed the signs after the year's observation. As part of the risk assessment for the...
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Surgical models of the study of the pro-inflammatory effect of adipose tissue in the development of atherosclerosis
Thieme, Filip ; Froněk, Jiří (advisor) ; Vrablík, Michal (referee) ; Broďák, Miloš (referee)
Univerzita Karlova v Praze 1. lékařská fakulta Doktorský studijní program Studijní obor: Experimentální chirurgie MUDr. Filip Thieme Název závěrečné práce Chirurgické modely studia proinflamačního vlivu tukové tkáně v rozvoji aterosklerózy Title Surgical models of the study of the pro-inflammatory effect of adipose tissue in the development of atherosclerosis Typ závěrečné práce Disertační Školitel: doc. MUDr. Jiří Froněk, Ph.D., FRSC Konzultant doc. MUDr. Libor Janoušek, Ph.D. Klinika transplantační chirurgie, IKEM Praha, 2021 Abstract Background: Atherosclerosis is a serious inflammatory systemic disease. Surgery mainly addresses its vascular complications. Conversely, surgery may also lead to the development and acceleration of atherosclerosis, e.g., in a living kidney donor. This would especially be the case in a donor who meets internationally recognized donation criteria but suffers from metabolic syndrome. The effort to refine assessments of living kidney donors in terms of eliminating the risk of developing atherosclerosis is a long-term project. Our aim is to determine risk factors for living kidney donors and to prevent long-term complications after donation. Collecting tissue from a living donor involves not oly subcutaneous tissue (SCAT) but also visceral (VAT) and perivascular tissue (PVAT),...
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Activity of antioxidant enzymes in different pathophysilogical states.
Vávrová, Lucie
Background: Oxidative stress is supposed to be implicated in the pathogenesis of several diseases which are connected with increased formation of reactive oxygen and nitrogen species (RONS). Oxidative stress could play an important role in the pathogenesis of inflammation and sepsis, acute and chronic pancreatitis or in the development of cancer. Organisms are protected against RONS from antioxidant system that is composed of antioxidant enzymes and non-enzymatic antioxidants. To the most important antioxidant enzymes belong superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase, glutathione reductase and paraoxonase (PON). The aim of this Doctoral Thesis was to investigate the behaviour of three of these antioxidant enzymes - CuZnSOD, CAT and PON1 in different pathophysiological states. Materials and methods: The activities of CuZnSOD, CAT and PON1 were measured in six different pathophysiological states. Forty patients with metabolic syndrome (MetS), 35 women with depressive disorder (DD), 30 septic patients (SP), 50 patients with pancreatic cancer (PC), 50 patients with chronic pancreatitis (CP) and 13 patients with acute pancreatitis (AP) were included in different studies together with sex- and age-matched healthy controls (CON). Patients with AP and SP were observed in the course...
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Effects of n-3 polyunsaturated fatty acids on development of non-alcoholic fatty liver disease in experiment, prevalence in patients with type 2 diabetes mellitus and metabolic syndrome, non-invasive diagnostics
Dvořák, Karel ; Brůha, Radan (advisor) ; Ehrmann, Jiří (referee) ; Lotková, Halka (referee)
This thesis focuses on the effects of n-3 polyunsaturated fatty acids (n-3 PUFA) on development of non-alcoholic fatty liver disease (NAFLD) in experiment, on prevalence of this condition in patients with type 2 diabetes mellitus and metabolic syndrome and also on non-invasive diagnostics. The aim was to study the effect of n-3 PUFA on NAFLD development in an experimental model and based on analysis of a group of patients with type 2 diabetes and metabolic syndrome to assess the prevalence of this condition. Lastly we aimed to evaluate non-invasive diagnostic methods of liver fibrosis and NASH. We demonstrated beneficial effects of n-3 PUFA administration on NAFLD development in a C57/Bl6 mice high fat methionin-cholin defficient dietary model of NAFLD. n-3 PUFA administration led to biochemical improvement, decrease of lipid accumulation in the liver as well as improvement of histology. These effects are determined by complex modulation of lipid metabolism, mainly due to decrease in availability of fatty acids for triglyceride synthesis in the liver, changes of adipokine levels and amelioration of proinflammatory status in the liver. In a group of type 2 diabetics we found NAFLD prevalence of almost 80%, 14% of these patients had also signs of liver fibrosis or cirrhosis. Non-invasive methods...
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Functional genomic and pharmacogenomic analysis of metabolic syndrome aspects
Krupková, Michaela ; Šeda, Ondřej (advisor) ; Haluzík, Martin (referee) ; Polák, Jan (referee)
Metabolic syndrome is a prevalent disease characterized by concurrent manifestation of insulin resistance, obesity, dyslipidemia, hypertension and other hemodynamic and metabolic disorders. It has multifactorial type of inheritance and its resultant phenotype is determined by both environmental and genetic factors as well as their interactions. That is the main reason why comprehensive analysis of the genetic component of this syndrome is complicated in human population. Genetically designed experimental animal models are significant tools for analysis of genetic architecture of human complex conditions including the metabolic syndrome. The aim of this Thesis is utilization of functional and comparative genomic tools to uncover pathogenesis of metabolic syndrome aspects and their genetic determinants. We also studied pharmacogenetic interactions of these genetic determinants with drugs affecting particular components of the metabolic syndrome. Establishing and utilizing several genetically designed congenic rat strains, we undertook four different research projects focusing on pharmacogenetic interaction of all-trans retinoic acid and ondansetron with differential segment of rat chromosome 8, pharmacogenetic interaction of differential segment of rat chromosome 4 and dexamethasone, determining Plzf...
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