Background: We aimed to increase the knowledge regarding the familial arrhythmogenic disorder Long QT Syndrome (LQTS) and its recessive variant Jervell and Lange-Nielsen Syndrome (JLNS) in Sweden, including prevalences and clinical phenotypes. A specific focus was directed towards two KCNQ1 mutations –p.Y111C and p.R518X- commonly identified in Swedish LQTS index cases. Methods: Cases and families with LQTS (p.Y111C or p.R518X) and JLNS were recruited via regional clinical practices, national referrals to the Clinical Genetics laboratory, Umeå University Hospital, and a national inventory. Molecular genetics methods were used for case ascertainment. Clinical data was obtained via medical records, a questionnaire, and/or an interview. Electrocardiograms were manually assessed. In p.R518X heterozygotes intra-familial phenotypic variability (QTc and cardiac events) was assessed by analysis of sequence variants (modifier genes). The origins of the mutations p.Y111C and p.R518X were investigated using genealogical and haplotype analysis (microsatellite markers). In families sharing a common haplotype mutation age and associated prevalence was analyzed using ESTIAGE and DMLE computer software. Results: We identified p.Y111C (170 mutation-carriers) and p.R518X (101 mutation-carriers) as two major causes of LQTS/JLNS in Sweden. LQTS phenotype was revealed to be relatively benign in p.Y111C and p.R518X (annual incidence of life-threatening cardiac events, before therapy 0.05% and 0.04%, respectively). Gender-specific effects of genetic modifiers on phenotypic expression were seen. A founder origin, approximately 600-700 years ago in two northern river valleys was established for p.Y111C and p.R518X, and a high prevalence of LQTS founder descendants suggested. A minimum JLNS prevalence of 1:200 000 in preadolescent Swedish children was revealed. JLNS phenotype was mainly severe, with a cumulative incidence of life-threatening cardiac events of 53% (annual incidence rate before therapy 5%) and four sudden deaths. Possible founder effects regarding four KCNQ1 mutations; p.Y111C (8%), p.R518X (50%), c.572_576del (17%) and p.Q530X (8%) together explained 83% of the JLNS mutation-spectrum in Sweden, consisting of 8 KCNQ1 mutations. Conclusion: The high prevalence of p.Y111C- and p.R518X-related LQTS as well as JLNS revealed in Sweden could be explained by the combination of mild clinical phenotypes in heterozygotes and strong founder effects present during the population development of northern Sweden. Increased knowledge regarding the occurrence of LQTS and JLNS as well as mutation- and/or genotype-specific data constitute prerequisites for possible improvement of patient management.

Final work - Abstract Surname and Name: Bc. Trčková Dagmar Title of the thesis: Comparison of the requirements for the professional competence and job description of directors of kindergartens in the Czech Republic and the Slovak Republic Type of thesis: Diploma thesis Name of faculty: Pedagogická fakulta Univerzity Karlovy v Praze Name of university department: School Management Centre Supervisor: PhDr. Václav Trojan, PhD. Level of professional qualification: Management of education Year of submission of the thesis: 2014 Number of pages: 72 Keywords: Comparison, Kindergarten, Professional Competence, Job Description, Director, Founder

TITLE: Specifics of the Church grammar schools in the Czech Republic AUTHOR: Bc. Jan Pech DEPARTMENT: School Management Center SUPERVISOR: Mgr. et. Bc. Jiří Trunda ABSTRACT: The Churches and religious denominations can become school and school facility founders according to the law no. 561/2004 of the Statute book, Education law. What are the specifics of the Church schools from the management of education point of view, which this work deals with? And do these specifics actually exist? Do the tangible differences that clearly specify the Church school against the school founded by the municipality, region or the union of municipalities exist? We will focus on the Church grammar schools. There are 18 such grammar schools in the Czech Republic and all of them, were founded by the Roman Catholic Church. These institutions create a specific, not large group of schools that provide high-quality education and also pass religious values on with emphasis on respecting the uniqueness and value of each human being. In the beginning, this work shortly looks into the historical development of the Church schools and their actual legal status. Then, using the qualitative research method - the analysis of the materials, it deals with the questions of the Church schools management and noticing their potential specifics....

Mutações inativadoras do receptor de GnRH (GNRHR) são a causa genética mais frequente de hipogonadismo hipogonadotrófico isolado (HHI) normósmico. Os genes envolvidos da patogênese do HHI, incluindo o GNRHR, estão associados a um amplo espectro fenotípico, variando de HHI parcial a completo. O atraso constitucional do crescimento e desenvovimento (ACCD) poderia constituir uma variante fenotípica leve do HHI. Neste estudo avaliamos a frequência de mutações no gene GNRHR em pacientes com HHI normósmico e ACCD, bem como correlacionamos o genótipo/fenótipo nesses pacientes. Além disso, avaliamos o efeito fundador de uma mutação do GNRHR (p.R139H) frequente na população brasileira com HHI normósmico. Para esse estudo, selecionamos 116 pacientes com HHI normósmico e 51 com ACCD. Um grupo de 130 indivíduos com desenvolvimento puberal normal foi utilizado como controle. A região codificadora do gene GNRHR foi amplificada por PCR e sequenciada. Análises in silico e in vitro foram realizadas nas duas novas variantes (p.V134G e p.Y283H). Três marcadores de microssatélites (D4S409, D4S2387, D4S3018) foram amplificados e analisados nos pacientes portadores da mutação p.R139H, familiares e controles. No grupo de HHI normósmico, nove mutações (p.N10K,p.Q11K, p.Q106R, p.R139H, p.C200Y, p.R262Q, p.Y284C, p.Y283H, p.V134G) foram identificadas em onze pacientes (9,5%). Entre as mutações identificadas no GNRHR, duas foram descritas pela primeira vez no estudo atual: p.Y283H e p.V134G, cuja análise in vitro demonstrou inativação completa do receptor. Em geral, uma boa correlação genótipo-fenótipo foi observada. Pacientes portadores de mutações inativadoras apresentavam HHI completo e mutações com perda parcial de função causavam HHI parcial, incluindo dois pacientes que evoluíram com reversão do hipogonadismo após reposição androgênica. Por outro lado, não houve diferença fenotípica entre os casos com e sem mutação do GNRHR. Análise de ancestralidade genética da mutação p.R139H demonstrou que todos os casos brasileiros apresentaram o mesmo haplótipo, sugerindo que a mutação p.R139H possui um ancestral comum na população brasileira. Por outro lado o caso familial proveniente da Polônia apresentou apenas um marcador em comum com as famílias brasileiras e estudos mais abrangentes seriam necessários para determinar a origem da mutação p.R139H em indivíduos não Brasileiros. Na casuística de ACCD apenas a mutação p.Q106R foi identificada no gene GNRHR em heterozigose em um paciente. Em conclusão, o GNRHR foi o gene mais comumente afetado, apresentando uma boa correlação genótipo-fenótipo, e deve ser o primeiro candidato para análise genética em HHI normósmico. Os resultados sugerem que a mutação p.R139H possui um ancestral comum na população brasileira. Mutações no GNRHR parecem não estar envolvidas na patogênese do ACCD / GnRH receptor (GNRHR) inactivating mutations are the most common genetic cause of normosmic IHH. The genes involved in the IHH, including GNRHR, have been associated with a large phenotypic spectrum, varying from partial to complete IHH. Constitutional delay of growth and puberty (CDGP) might represent a mild phenotypic variant of IHH. In this study we investigated novel variants and characterized the frequency and phenotype-genotype correlation of GNRHR mutations in normosmic IHH and CDGP patients. Additionally, we determined de cause of the recurrence of GNRHR p.R139H mutation in patients with normosmic IHH. We studied 116 patients with normosmic IHH and 51 with CDGP. The control group was composed by 130 adults with normal pubertal development. The coding region of GNRHR was amplified and automatically sequenced. The two novel variants identified (p.Y283H, p.V134G) were submitted to in silico and in vitro analysis. Three microsatellite markers (D4S409, D4S2387, D4S3018) were amplified by PCR and analyzed in the patients with the p.R139H mutation. In the CDGP group, the previously described mutation p.Q106R was identified in the heterozygous state in one boy. The p.Q106R mutation has been identified in heterozygous state in individuals with normal pubertal development and does not appear be involved on the CDGP phenotype in this patient. In the normosmic IHH group, nine variants were identified (p.N10K, p.Q11K, p.Q106R, p.R139H, p.C200Y, p.R262Q, p.Y284C, p.Y283H, p.V134G) in eleven patients (9.5%). In vitro analysis of the novel variants p.Y283H and the p.V134G demonstrated that both of them cause complete loss of function of the receptor. The founder effect study revealed that all the p.R139H affected Brazilian patients presented the same haplotype, suggesting that the this mutation has a common ancestor in the Brazilian population. Nevertheless the affected Polish family presented a different haplotype, with only one marker in common with the Brazilian families and further studies would be necessary to determine the origin of the p.R139H mutation in the European population. In conclusion this study demonstrated that GNRHR was the most commonly affected gene in normosmic IHH, with a good genotype-phenotype correlation, and should be the first candidate gene for genetic screening in this condition. The results of the founder effect study suggested that the p.R139H mutation has a common ancestor in the Brazilian population. Finally, mutations in the GNRHR do not appear to be involved in the pathogenesis of CDGP

The aim of this dissertation is to describe current state of evaluation of leisure time centres' directors, approaching the topic from the point of view of a superior institution that adjusts reward amounts. Firstly, the paper classifies leisure time centres in the Czech education system. Then, it goes on to describe current state of these centres in the Czech Republic, including funding, youth workers and laws that influence activities of particular directors and superior institutions. After that, the work focuses on the topic of directors' evaluation from various aspects. It describes evaluation methods that can be used in the process, including the procedure of adjusting reward amounts. Then, the work analyses particular kriteria that are published in certain cases by superior institutions at their web pages. It describes the most common evaluation criteria and procedures, seen both from the position of leisure time centres' directors and from their superior institutions. At the end, there are recommendations for superior institutions that can be used in the process of adjusting reward amounts for leisure time centres' directors.

Spinocerebellar ataxia type 7 (SCA7) is a hereditary neurodegenerative disorder affecting the cerebellum, pons and retina. SCA7 patients present with gait ataxia and visual impairment as the main symptoms. Anticipation, commonly observed in SCA7 families, is a phenomenon where an earlier age at onset and a more severe progression of disease is seen in successive generations. In order to identify the gene responsible for SCA7, we performed linkage analysis on a Swedish SCA7 kindred. Evidence for linkage of the SCA7 disease locus to a 32 cM region on chromosome 3p12-21.1, between markers D3S1547 and D3S1274, was established. A number of neurodegenerative disorders associated with anticipation are caused by expanded (CAG)n repeats in their respective disease genes. In order to isolate the SCA7 disease gene we, therefore, screened a human infant brain stem cDNA library for CAG repeat containing clones, mapping to chromosome 3. Four candidate clones were isolated and analysed, but could all be excluded as the SCA7 disease gene. In 1997, the SCA7 disease gene was identified and, as expected, shown to harbour a CAG repeat, expanded in SCA7 patients. Analysis of the SCA7 CAG repeat region in Swedish SCA7 patients demonstrated that CAG repeat size was negatively correlated to age at onset of disease. Furthermore, patients with larger repeats presented with visual impairment, whereas patients with smaller repeats presented with ataxia as the initial symptom. SCA7 is the most common autosomal dominant cerebellar ataxia in Sweden and Finland, but rare in other populations. In order to investigate if the relatively high frequency of SCA7 in these countries is the result of a founder effect in the region, a haplotype analysis was performed on all SCA7 families available. All 7 families shared a common haplotype of at least 1.9 cM surrounding the SCA7 locus. In addition, strong linkage disequilibrium was demonstrated for marker D3S1287 closely linked to the SCA7 gene, suggesting a founder effect for the SCA7 mutation in Sweden and Finland. The function of the SCA7 protein, ataxin-7, is not known and it does not show significant homologies to any previously known proteins. In order to gain insight into the function of ataxin-7 we analysed the expression of ataxin-7 in brain and peripheral tissue from SCA7 patients and controls. In brain, expression was found to be mainly neuronal with a nuclear subcellular localisation. Ataxin-7 expression was found throughout the CNS, not restricted to sites of pathology. We also confirmed previously reported findings of neuronal intranuclear inclusions (NIls) in the brains of SCA7 patients. Based on our findings, we conclude that the cell type specific neurodegeneration in SCA7 is not due to differences in expression pattern in affected and non-affected tissue or the distribution pattern of aggregated protein.

Reintroduction of Anatolian mouflon population at Bozdag Protection &amp / Breeding Station to its former habitats(Emremsultan Wildlife Development Area in Ankara-Nallihan, and Karadag in Karaman) started in 2004. The magnitude of genetic change among Bozdag and reintroduced populations was evaluated by 11 microsatellite loci. Study populations revealed close results (&plusmn / st.dev.) &ndash / Bozdag population: nk = 2.9091 (&plusmn / 1.1362), AE = 2.0250 (&plusmn / 0.9537), Ho = 0.3830 (&plusmn / 0.2717), He = 0.3956 (&plusmn / 0.2746) / Nallihan population: nk = 2.9091 (&plusmn / 1.1362), AE = 2.0592 (&plusmn / 0.9451), Ho = 0.4086 (&plusmn / 0.2977), He = 0.4052 (&plusmn / 0.2767) / and Karadag population: nk = 2.5455 (&plusmn / 1.1282), AE = 1.8809 (&plusmn / 0.8758), Ho = 0.3388 (&plusmn / 0.2775), He = 0.3607 (&plusmn / 0.2716). Population differences for major genetic parameters were not significant (p &gt / 0.05) by comparisons with paired t-test. Also, temporal change in genetic diversity for Bozdag population was investigated by comparison with temporal data. Temporal changes in genetic parameters were found to be not significant and possible causes for differences were argued. Additionally, genetic diversity and PI computations for different traps were verified and compared to uncover any potential bias due to the catching method. Comparisons did not reveal significant differences illustrating the homogeneity among traps. On the other hand, simulations detected the higher sensitivity of allelic diversity (A) to founder events than P and heterozygosity (Ho &amp / He) levels which supports heterozygosity excess method for bottleneck analysis. With the same simulation analysis, observed genetic diversity within reintroduced samples were found to be in the ranges of expectation (99% CI) indicating that translocated individuals were chosen randomly. Bottleneck analysis based on heterozygosity excess method (one-tailed test for heterozygosity excess: pSMM = 0.28515, pTPM = 0.06445, pIAM = 0.02441) and allele frequency distributions method (normal L-shaped) could not detect a recent genetic bottleneck for Bozdag population. However, simulations determined that these two methods are prone to type II error. Bottleneck detection failure for the study population is probably due to type II error instead of other sources of error like violations of model assumptions.

No description available.

Background: Hereditary transthyretin amyloidosis is an autosomal dominant disease with a reduced penetrance. The most common mutation in Sweden is the V30M mutation in the transthyretin gene. Clustering areas of the disease can be found in Northern Sweden, Portugal, Brazil and Japan, although sporadic cases exist worldwide. Despite being caused by the same mutation, there are large differences in onset, penetrance and symptoms of the disease. Swedish V30M patients typically have a later onset with a lower penetrance compared to those from the clustering Portuguese V30M areas. The reasons for these differences have not been fully understood. The aim of this thesis is to study mechanisms that may influence onset and symptoms and investigate why patients carrying the same mutation have different phenotypes. Methods: Genealogy studies were performed on all known V30M carriers in Sweden using standard genealogy methods. DNA samples from patients, asymptomatic carriers and controls from different countries were collected and the transthyretin gene was sequenced. Liver biopsies from patients were used for allele specific expression analysis and a cell assay was used for miRNA analysis with the mutated allele. Gene expression analysis was performed on biopsies from liver and fat from patients and controls. Results and conclusions: Genealogic analysis of all known Swedish V30M carriers managed to link together 73% of the Swedish ATTR V30M population to six different ancestors from the 17th and 18th century, thus dating the Swedish V30M mutation to be more than 400 years old. A founder effect was also visible in descendants to one of the ancestors, producing a later age at onset. Sequencing of the transthyretin gene revealed a SNP in the 3’ UTR of all Swedish V30M carriers that was not found in any of the Japanese or French V30M carriers. The SNP was present on the Swedish transthyretin haplotype and defined the Swedish V30M population as separate from others. However, the SNP itself had no effect upon phenotype or onset of disease. Gene expression analysis of liver and fat tissue revealed a change in genetic profile of the patients’ livers, in contrast to the unchanged profile of the fat tissue. A changed genetic profile of the liver could explain why domino liver recipients develop the disease much earlier than expected.

The thesis deals with F. František Xaver Paleček´s work and his historical legacy to the Czech society. The author depicts František Xaver Paleček´s life, but separated and fundamental work lies finally in the elaboration of his pastoral activity in the region. His numerous sermons, his confessional, club,pedagogical and charitable activities, which made F. Paleček famous during his life already, mainly during his 24-year-work in a Central Bohemian village Kovářov, are analysed there. The thesis also tries to find out his political opinions and his material background as well. It follows his everyday steps in the region. At the end of the thesis it is pointed to F. Paleček´s life after death in memories of many contemporaries, and to his authority in social-spiritual events in the region for decades ahead. This thesis has been worked out on the base of up to now non-published archival sources. Formaly published literature, once secretly printed articles and memories helped to create the frame of the work in the second line, mainly there, where the primary sources did not offer the continuity.