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Energy metabolism control, selected genetic and hormonal factor
Vejražková, Daniela ; Bendlová, Běla (advisor) ; Rossmeisl, Martin (referee) ; Pelikánová, Terezie (referee)
I I I I I I I 4, CONCLUSIONS r) The postulatedaim of thework was fulfilled: Quite a large cohorts of DM2 patients,direct offspring of DM2 patients,and obese subjectsas well as a group of women suffering from PCOS, and sufficiently large groupof controlsubjectswerecompleted a. All the probands underwenta detailed anthropometricand biochemical characeterization b. The DNA bank was establishedandcompleted An electronicdatabasewas established Molecular geneticmethodsPCR, RFLP, andSSCP wereestablishedandoptimized Specific polymorphismsin the selectedcandidategenes were genotypedand unique data regarding genotypic frequenciesof these polymorphisms in Czech population wereobtained Genetic, biochemical and anthropometric data underwent statistical analysis. Especially associationsbetweengeneticpolymorphisms/adipocytokineconcentrations andanthropometric/biochemicalparametersweretested Final resultswere evaluatedand possibleeffectof the studiedgeneticpolymorphisms and/oradipocytokineson body compositionanďor biochemical statuswas assessed. Also an eventual involvement of the studied genetic and hormonal factors in aethiopathogenesisof obesity,DMZ, metabolicsyndrome,and PCOS was considered Main resultsand conclusionsof theresearchwerepublishedin scientificjournals.The publicationsrepresentthepivotal partof...
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Pathobiochemistry of diabetes mellitus and its complications - oxidative stress, microinflammation and genetic predisposition.
Škrha, Jan ; Kalousová, Marta (advisor) ; Rybka, Jaroslav (referee) ; Bendlová, Běla (referee)
Diabetes is a chronic disease with high prevalence and significant morbidity. Chronic changes in the wall of small and large vessels lead to main diabetes complications. Apart from long- term hyperglycemia, several factors are involved in the development of diabetes vasculopathy. The aim of this work was to describe new early biomarkers of these vascular changes, to identify risky patients. Alongside, gene polymorphisms involved in protective pathways of glucose metabolism were studied. In three human studies with Type 1 (T1D) and Type 2 (T2D) diabetes patients special biochemical parameters of receptor for advanced glycation endproducts (RAGE) and its ligands, deglycation enzyme glyoxalase 1 (GLO1) and fructosamine 3-kinase (FN3K) gene polymorphisms were analyzed. Non-invasive measurement of glycation by skin autofluorescence (SAF) was assessed in all subjects. Soluble RAGE, HMGB1 and endothelial dysfunction markers were increased in patients with diabetes as compared with controls, however the differences between T1D and T2D were not significant. For the first time, an association between FN3K (rs1056534) and (rs3848403) polymorphism and sRAGE concentration in diabetes was shown. GLO1 (rs4746) polymorphism was associated with changes in endothelial dysfunction. Patients with diabetes had higher...
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Genetic causes of MODY (Maturity-Onset Diabetes of the Young)- prevalence of mutations in the MODY genes in the Czech diabetic and nondiabetic populations
Lukášová, Petra ; Bendlová, Běla (advisor) ; Gašperíková, Daniela (referee) ; Mazura, Ivan (referee)
I I a I I I I I I I I I I I I I I I I I 6. CONCLUSTONS Theaimsof ourstudywereperformed. Twelvefamilieswithunrecognizedtypeof MODYwerecotlected. Quite largecohortsof DM2patients,direct offspringof DM2patients,gestational diabeticsandsufficienttylargegroupof controlsubjectswerecompleted.Attthe probands underwenta detaitedanthropometricand biochemicalcharacterisation.Datawere filled in anelectronicdatabase. TheDNAbankwasestablishedandcompleted. For GCK gene we adopted screeningmethodsSSCP for all exons specific for B-celts(1a-10)andTGGEfor exons1a-7andwe confirmedtheirhighsensitivityandthe 100%concordanceof both methods.Resultswere consequentlyconfirmedby direct sequencingin bothdirections. We founda novelheterozygousmissensemutationV33Aand a previoustypubtished mutationE40Kin exon2 of GCK genein two differnentCzechMODYfamilies.However, ourstudydid not providethe evidenceof GCK geneas a risk genein the pathogenesis of diabetesmellitustype2 or of the gestationaldiabetesin Czechpopulationbecausewe identifiedontyone intronicmutationin a gestationaldiabeticand no differencesin the frequenciesof GCKpolymorphismsbetweenCzechdiabeticandnondiabeticpopulations. We assessedthe frequencyof commonvariant-30G>Ain B-promoterof GCK gene. Atthoughwe did not detect the higherfrequencyof minor attele A in diabetic in...
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The genetic background of obesity and its treatment with bariatric surgery
Lischková, Olga ; Bendlová, Běla (advisor) ; Šeda, Ondřej (referee) ; Mráz, Miloš (referee)
Obesity is a frequent metabolic disease that causes many other health and socioeconomic complications. Obesity arises due to excessive energy intake and decrease in energy expenditure, which is a conseqence of contemporary lifestyle. Moreover, obesity has a strong genetic component. Common obesity is polygenic, multifactorial disease, in which individual genes interact with each other and with environmental factors. Genome-wide association studies, conducted between 2006-09, led to the discovery of dozens of gene loci that predispose individuals to obesity. The strongest signals were registered for polymorphisms in FTO (fat mass and obesity-associated) and near a gene MC4R (melanocortin 4 receptor). However, the contributions of these variations on the phenotype of obesity are very small, therefore, it is necessary to validate the results of such robust studies. It is very important to uncover the effects of genetic variants for understanding the molecular mechanisms of energy metabolism. The studies presented in this thesis refer about the impact of polymorphisms in selected genes on anthropometric and metabolic parameters of the patients of the Institute of Endocrinology and of healthy volunteers who underwent functional tests. Our cohort includes a representative sample of Czech children (COPAT...
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Genetic causes of medullary thyroid carcinoma and Hirschsprung's disease
Václavíková, Eliška ; Bendlová, Běla (advisor) ; Dvořáková, Lenka (referee) ; Stárka, Luboslav (referee)
Genetic causes of medullary thyroid carcinoma and Hirschsprung's disease Abstract Medullary thyroid carcinoma (MTC) and Hirschsprung's disease (HSCR) are classified as simple neurocristopathies, i.e. diseases linked to neural crest-derived cells. MTC is derived from parafollicular cells of the thyroid and HSCR is characterized by absence of enteric ganglia in the gastrointestinal tract. The RET proto-oncogene is only expressed in neural crest-derived cells, including parafollicular cells and enteric neurons. The RET encodes a transmembrane tyrosinekinase receptor that plays an important role during proliferation, differentiation and cell survival, and activates many signaling pathways. If the strictly regulated activation fails, e.g. due to mutations in the specific gene locations, the RET becomes a highly effective oncogene. Activating germline mutations in the RET proto- oncogene lead to hereditary forms of MTC, whereas sporadic forms of MTC are caused by somatic mutations in the tumor tissue. On the contrary, inactivating mutations induce migration failure of ganglion cell precursors during the development of enteric nervous system and result in the development of HSCR. In rare cases, the coexistence of both diseases is caused by mutations with a dual gain-of-function and loss-of-function character....
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An estimation of the development trends of the selected biomarkers for monitored population groups using data from the human biomonitoring in the Czech Republic
Grafnetterová, Anna ; Černá, Milena (advisor) ; Bendlová, Běla (referee)
The human biomonitoring is today an important tool for monitoring of people exposition to environmental pollutants. Mercury and cadmium are long-term monitored biomarkers in the Czech population. A developmental trend of mercury concentration level in urine and hair of children population as well as in urine and blood of adult population is investigated. These biomarkers were monitored in the years 1996 - 2011. Data originate from the NIPH (National Institute of Public Health) databases and from the international project COPHES/DEMOCOPHES. Adult blood donors at age of 18 to 64 were the first monitored group, the second one were children at age of 6 to 12, which were selected based on an agreement with elementary schools or with the paediatricians' cooperation. Available data were statistically processed; trends are presented in graphs as a dependence of geometric means on the time (the year of the biological samples collection). Results show an unstable development of biomarkers levels in different matrixes. A moderate decreasing trend of cadmium level in urine of adults was observed. GM values for adults decreased from 0.43 μg/g creatinine in 2009 to 0.24 μg/g creatinine in 2009. For year 2011, data are available only for women (GM = 0.21 μg/g creatinine). The downward trend was also found in the...
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Molecular- genetic analysis of the Thyroid carcinomas
Sýkorová, Vlasta ; Bendlová, Běla (advisor) ; Zamrazil, Václav (referee) ; Peterka, Miroslav (referee)
Introduction: Thyroid cancer represents more than 90% of endocrine tumors and its incidence, predominantly of papillary thyroid carcinoma (PTC), is still increasing in the Czech Republic. Several genetic changes are known, but thein impact to phenotype is still controversial. Aims: To study of the genetic causes (RET/PTC, BRAF and RAS alterations) and the role of RET polymorphisms in thyroid cancer (predominantly PTC), and to correlate genotype with phenotype. Subjects and Methods: Overall 234 PTC tissues, 8 poorly differentiated carcinomas, 3 anaplastic carcinomas, 23 medullary carcinomas, 6 follicular carcinomas and one follicular adenoma were analyzed. Samples of fresh frozen thyroid tissues, fine-needle aspiration biopsies and paraffin-embedded formalin-fixed tissue sections of patients with thyroid cancer and blood samples of healthy controls were used for analysis. The expression of RET/PTC rearrangements was detected on agarose gel. Five RET polymorphisms were analyzed using specific TaqMan probes. Detection of mutations in the BRAF gene and three RAS genes was performed by direct sequencing. Presence of alteration was correlated with clinicopathological parameters. Results: We found out that some RET polymophisms are associated with development of RET/PTC rearrangements in PTC and proved,...
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