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Study of luteinizing hormone's and its receptor's polymorphisms in relation to development of ovarian hyperstimulation syndrome
Chrudimská, Jana ; Macek, Milan (advisor) ; Schierová, Michaela (referee)
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication in an assisted reproduction (ART), which can threaten the life of the patient. It is caused by an increased sensitivity of ovarian receptors to exogenous gonadotrophins during controlled ovarian hyperstimulation (COH) that is necessary for induction more than one oocyte. Treatment for this syndrome is symptomatic hence the emphasis is primarily on the prevention. The purpose of current reproduction genetics is to find risk markers, by which it could be possible to assess the sensitiveness of a hormonal receptor for luteinizing hormone (LH-R) and a receptor for follicle stimulating hormone (FSH-R) just before the start of the therapy. Individualization of the COH would decrease the risk of both, the OHSS, and the risk of canceling the COH through a poor ovarian response. Temporary, only FSH-R genotypes are studied in relation to an increased risk of OHSS and its severity. The aim of further studies is an ascertaining the possible impact of LH-R's and the luteinizing hormone's (LH) genotype on the final ovarian response during COH and other types of hormonal treatment. This bachelor's work summarizes the present knowledge of the possible connection of LH's and LH-R's polymorphisms to OHSS in continuum to findings gained about FSH-R.
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Genetic factors in aetiology and phatogenesisof low gamma-glutamyltransferase cholestasis and hereditary jaundice
Cebecauerová, Dita ; Jirsa, Milan (advisor) ; Brdička, Radim (referee) ; Macek, Milan (referee)
(English) Recent progress in understanding the molecular mechanism of hepatobiliary disorders enabled the improvement of diagnostic accuracy and promoted the study of the regulation of gene expression and its potential modifying factors. Current achievement in the field of genetically determined cholestatic disorders is well illustrated in this thesis, focused on low gamma-glutamyltransferase (γGT) cholestasis and hereditary jaundice. The study describes several distinct defects of hepatocyte transport system, characterises underlying mutations and their phenotypic consequences and, finally, extends these studies for detailed characterisation of ATP8B1 gene regulatory regions. Chapters related to low γGT cholestasis - characterise rare type of mutation associated with benign course of PFIC type I (formerly BRIC1) and explain the putative mechanisms of mutation origin. - provide extensive study of severe forms of ABCB11 deficiency (PFIC2) including genotype-phenotype correlations in 109 affected families, evaluation of the specific ABCB11 genotypes' impact on BSEP immunostaining and risk of hepatobiliary malignancy. - identify and characterise yet unknown regulatory regions of ATP8B1, a gene mutated in Progressive Familial Intrahepatic Cholestasis type I. The studies demonstrate the complex structure...
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Molecular analysis in cases of inherited diseas
Mrázová, Lenka ; Kmoch, Stanislav (advisor) ; Jirsa, Milan (referee) ; Macek, Milan (referee)
Urcení vztahu mezi onemocnením a jeho molekulární podstatou je jedním z hlavních cílu lékarské genetiky. V rámci studie: "Molekulární analýza vybraných dedicne podmínených onemocnení" byly popsány postupy, které vedou k objasnení molekulární podstaty u onemocnení s již známými odpovednými geny i u onemocnení, u kterého byl odpovedný gen teprve identifikován. Studie prispela k rozšírení znalostí zkoumaných dedicných onemocnení. Zavedené postupy molekulárních analýz jsou soucástí diagnostiky na Ústavu dedicných metabolických poruch v Praze. Výsledky techto analýz slouží k prevenci, prognóze i lécbe onemocnení a u postižených rodin byla umožnena prenatální diagnostika. Výsledky byly publikovány v nekolika domácích i zahranicních odborných casopisech a prezentovány na mezinárodních konferencích. Nekteré z publikací byly dále citovány.
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A contribution to analysis of molecular basis of selected lysosomal disorders
Hřebíček, Martin ; Elleder, Milan (advisor) ; Macek, Milan (referee) ; Adam, Tomáš (referee)
4 Conclusion As discussed before, lysosomď disorders can provide clues about the function of a deÍicient protein and about important cellular mechanisms. Because of that it is worthwhile to study patients with these rare disorders and learn from complex disease manifestations at biochemicď, morphologicď and molecular levels. This thesis is accompanied with papers on sphingolipidoses, the most frequent group of lysosomď disorders, and a mucopolysaccharidosis. The core of the thesis is anďysis of the molecular causes of diseases in relation to clinical manifestations. There is a practicď application to that, because enzyrne replacement therapy, an effective, but extremely expensive treatment, is avďlable for severď of lysosomď storage disorders. Prediction of the future severity of the disease can identiý patients, who can benefit most from the treatment. There is a trend to preventive treatment which can stop development of irreversible changes in the patients tissues. Because of excessive costs of the treatment even the richest countries do not treat ďl patients with these diseases. In Fabry disease we have shown for the first time that X-inactivation influences the severity of the disease in heterozygous femďes. Analysis of irractivation has a potentiď to become a predictive test in Fabry femďes - this,...
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A study of aneuploidy in gametes and embryos
Diblík, Jan ; Macek, Milan (advisor) ; Forejt, Julius (referee) ; Rubeš, Jiří (referee)
The thesis deals with improvement and clinical application of molecular cytogenetic methods for reproductive genetics. These methods include both clinical investigations used for improvement of diagnostic and therapeutic care for infertile couples and experimental methods that can become the basis of new diagnostic tools. The thesis concentrates on the study of aneuploidies, because they constitute a major complication of human reproduction especially by means of assisted reproductive technologies. Aims The main practical aim was the introduction of fluorescence in situ hybridization (FISH) for evaluation of chromosomes in sperm, polar bodies and blastomeres for prefertilisation and preimplantation diagnosis of aneuploidies. The main scientific objective was the study of chromosome localization in nuclei of blastomeres, that are removed from human embryos for preimplantation diagnosis. The aim of this study was to find, whether the localization of chromosomes in relation to the nuclear center and periphery is ruled by the same rules as in other cell types in later stages of development and whether the localization is influenced by aneuploidy. Next aim was to search for peripheral localization of chromosome X in embryos with more than one copies of the chromosome X. This could be a manifestation of X...
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Molecular genetic and biochemical studies of selected inherited metabolic disorders, development and applications of new methods
Mušálková, Dita ; Hřebíček, Martin (advisor) ; Adam, Tomáš (referee) ; Macek, Milan (referee)
Inherited metabolic disorders (IMD) form a diverse group of several hundred different diseases with a relatively high cumulative incidence (stated up to 1:600). They are associated with accumulation of the substrates and lack of the products in specific metabolic pathways, which is caused by deficiency of the enzyme or its activator, or dysfunction of the transport protein. However, the underlying cause is at the DNA level. The grounds for different phenotype manifestation in patients with the same genotype are often not known. During my work at the Institute of Inherited Metabolic Disorders, I designed several new methods for the research of IMD and applied them in the patients and their families. I created procedures for the isolation of lysosomal membranes that are used for the research of lysosomal storage disorders and general properties of lysosomes. Next, I introduced several novel assays for determination of the X-inactivation ratio, which led to a significant increase of informative women. Nowadays, we use these methods in heterozygous women with X-linked diseases in order to study the influence of X-inactivation on the manifestation of the diseases. The cases of a girl with mucopolysaccharidosis type II, a girl with OTC deficiency and a family with the mutation in HPRT1 gene are described...
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