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Bilirubin secretory pathway and its disorders.
Sticová, Eva ; Jirsa, Milan (advisor) ; Bronský, Jiří (referee) ; Jirásek, Tomáš (referee)
Identification and functional characterization of numerous transport systems at the sinusoidal and canalicular membrane of hepatocytes have significantly expanded our understanding of bilirubin metabolism and contributed to elucidation of molecular basis of hereditary jaundice. Moreover, dysregulation of hepatobiliary transport systems could explain jaundice in many acquired liver disorders. This thesis is focused on the new aspects of bilirubin handling in hepatocytes based on elucidation of the molecular basis of Rotor syndrome. The first study is focused on the antioxidative properties of bilirubin in liver tissue in a model of obstructive cholestasis. In the second part of the thesis we present several novel mutations in ABCC2, the gene associated with Dubin-Johnson syndrome, identified in patients selected for the Rotor locus mapping study. In the key third study concerned with Rotor syndrome we demonstrated that biallelic inactivating mutations causing complete absence of transport proteins OATP1B1 and OATP1B3 result in disruption of hepatic reuptake of bilirubin, which is the molecular basis of Rotor-type jaundice. These results indicate that apart from secretion of conjugated bilirubin into bile, a significant fraction of bilirubin glucuronide is secreted via MRP3 into sinusoidal blood and...
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Inherited Disorders of Bilirubin Metabolism
Šlachtová, Lenka ; Martásek, Pavel (advisor) ; Baxová, Alice (referee)
Inherited disorders of bilirubin metabolism - hereditary hyperbilirubinemias - are metabolic disorders manifested in early childhood. Unconjugated hyperbilirubinemias result from the defect of the enzyme uridine diphosphoglucuronosyltransferase (UGT1A1). UGT1A1 mediates the conjugation of bilirubin with glucuronid acid in hepatocytes and its elimination to water soluble compound. In the next step of bilirubin degradation the transport of conjugated bilirubin from hepatocyte into the bile occure. It is caused by the ATP dependent transporters ABCC2, ATP1B1 and OATP1B3. Mutations in the genes coding the bilirubin transporters results in conjugated hyperbilirubinemia Dubin-Johnson or Rotor syndrome. This study is focused on unconjugated hyperbilirubinemia in adolescents including the non-typical manifestations and the defects of ABCC2 transporter and their phenotype in humans.
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Gilbert Syndrome.
Šimáková, Eva ; Kuklík, Miloslav (advisor) ; Kovář, Jan (referee)
This thesis focuses on finding a possible link between genotype typical for Gilberts syndrome and specific diseases. It nvestigates a possible protective effect of the 7TA allele. It explains the origin, symptoms, pathology of this syndrome and its consequences for clinical medicine. Possible protective effect of this polymorphic mutation including reduced incidence of vascular diseases (myocardial infarction, stroke, atherosclerosis, etc.). is discussed. Reduced oxidative stress in hyperbilirubinaemia can be the mechanism behind. The work was carried out in the co-operation with the GENVIA laborator.
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Study of thiol addition to biliverdine, the synthesis of labelled bilirubine
Felklová, Veronika ; Lešetický, Ladislav (advisor) ; Smrček, Stanislav (referee)
Biliverdin and bilirubin are bile pigments which are degradation products of heme. Biliverdin (BV) is greenish-blue pigment and is reduction product of tetrapyrrolic core of heme by influence of the hemoxygenase (HO). The final product of this degradation is yellowish-brown pigment bilirubin (BR) which forms from BV thanks to the biliverdinreduktase (BVR). Normal and slightly raised level of bilirubin in plasma has cytoprotective effects whereas high levels are cytotoxic often. In severe unconjugated hyperbilirubinemia cases (newborn children) unconjugated bilirubin (UCB) accumulates in central nervous system (CNS) and causes bilirubin-induced neurologic dysfunction (BIND). Unfortunately there is a limitation for finding UCB pathophysiology caused by difficult determination of UCB content and distribution in tissues and biological fluids. So the main purpose of this thesis is to find and integrate isolated methods which will serve as the basis of finding bilirubin distribution. This progress would have a significant effect on studies of bilirubin neurotoxicity on newborn children. This method is based on radioactive labeling of UCB. Preferentially atom C 10 used for binding suitable functional group (thiols) because conformation of indicated bilirubin shouldn't change in this position. And then the...
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Gilbetr syndrome
Šimáková, Eva ; Kuklík, Miloslav (advisor) ; Kučerová, Mária (referee)
The mail focus of this thesis is to assess a genealogical frequency of homo- and heterozygotes for a mutation in a promotor region of UGT 1A1 gene. This mutation is typical for Gilbert's syndrome. It explains a genesis, symptoms, pathology and also a therapy of this syndrome. It discusses a possibly protective effect of this polymorphic mutation that might result in a lower incidence of vascular diseases (myocardial infarction, stroke, atherosclerosis, pulmonary embolism). An important contribution is also an attenuation of stress due to hyperbilirubinaemia. This thesis was worked out in a cooperation with GENVIA Ltd.
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The aspects of laboratory diagnostics of neonatal jaundice, the comparison of two laboratory methods and POCT method of determination of bilirubin.
SLÁMOVÁ, Martina
The topic of my Bachelor Thesis was laboratory diagnostics of newborn jaundice. It consists in determining full blood or plasma bilirubin concentration. I assessed the cross-correlation and the possible interchangeability of two laboratory methods based on different principles of determination, in different types of biological material, by means of statistical evaluation of lab results. I treated the topic of bilirubin determination in newborns from a complex perspective, and I included a comparison of POCT bilirubin level measurements with lab-determined blood bilirubin concentrations in the assessment. The theoretical part contains general facts about types of icterus and about bilirubin metabolism in the organism. It also contains information pertaining of newborns jaundice as such. I have described the causes, the health risks for the newborn implied by their hyperbilirubinemia, and I have also specified the possible therapy. I have collected the backgrounds for the assessment of the methods of bilirubin determination experimentally. The population consisted of normal term and pre-term babies, 37 of whom were treated with phototherapy during the experiment. I determined the bilirubin concentration in a full blood sample by means of direct photometry on a Cobas b221 analyzer. I centrifuged the remaining material in the collecton tube, and I determined the bilirubin concentration in the separated plasma by chemical azo coupling method on the Integra 400 plus analyzer. The POCT measurements were carried out by the pediatric nurses on the department before every blood sampling. They were non-invasive bilirubin measurements in newborns by means of the transcutaneous bilirubinometer JM-103 Konica Minolta Hill-Room Air-Shields. In order to assess the correlation of results, I used the linear regression (Passing-Bablok) statistical method, and the difference chart (Bland-Altman) method. The statistical evaluation implies that the lab methods show very good mutual correlation, which can be expressed with a correlation coefficient of r = 1,025 and a mean difference of -1,41 umol/l. I used direct photometry method as a comparison method to assess the bilirubin measurements done by the POCT method. While the correlation coefficient reached the value 0,803, the average difference between both methods amounted to -45,6 umol/l. This data clearly shows that newborn bilirubin levels measured by transcutaneous bilirubinometer are lower compared to the bilirubin concentration determined by the lab method. Many studies imply that bilirubin measurements in the POCT mode using transcutaneous bilirubinometer often yield rather underestimated results. Measurement results from the discrimination range must be re-checked in the lab. Transcutaneous measurement of newborn bilirubin is a reliable screening method eliminating the numerous blood takings in newborns. Making transcutaneous measurements during phototherapy conditions is not generally recommended, which was confirmed by my experimental results. The only way of how to monitor the effect of this therapy while the therapy is going on, is by means of lab determination of bilirubin concentration. The results of my study imply that full blood bilirubin concentration determination by direct photometry method in newborns correlates excellently with the plasma determination by the chemical method. This method is fully capable to be used as a substitute for the chemical method. I prefer full-blood determination method. The examination requires only a small quantity of the sample, the sample does not require separation before analysis, the result is available quickly, and analyzer operation and maintenance are simple. Analyzers of this type, equipped with modules for direct bilirubin measurement in newborns are often used as POCT instruments near the patient?s bed.
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Nursing process in newborn with hyperbilirubinemia
SEKALOVÁ, Monika
The thesis deals with Nursing process with neonates diagnosed with hyperbilirubinemia. The theoretical part focuses on the physiological and premature new-born babies, anatomy and physiology of blood, neonatal hyperbilirubinemia problems, nursing process and NANDA and NIC classification systems. The practical part contains research results. Qualitative method was used for the research and it was carried out at the neonatal department in Nemocnice Ceske Budejovice, a.s. (Ceske Budejovice Hospital). The first objective was to determine the specifics of nursing care for full-term new-borns and premature new-borns diagnosed with hyperbilirubinemia. It was found that the specifics were mainly in monitoring of the physiological functions, measurement frequency of transcutaneous bilirubinometry, in positioning the new-born during phototherapy, in the prescribed temperature inside the incubator and in children's diets. All information necessary was collected through interviews with nurses, from documentation content analysis and by observation. Based on the information, case studies were developed. The research sample consisted of two new-born babies diagnosed with hyperbilirubinemia. The second objective of the thesis was to determine nurses´ position when using NANDA classification systems to diagnose Neonatal jaundice and NIC Phototherapy: new-born. It was found that nurses would change some defining characteristics and related factors to diagnose Neonatal jaundice (00194) as well asinterventions from NIC Phototherapy: new-born (6924). Most of them agreed that they would not like to use these classifications during care of the new-borns. Information was collected using structured interviews with three neonatal nurses and two midwives. The results could be used to improve nursing care for neonates diagnosed with hyperbilirubinemia.
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