My diploma thesis is focused on educational and pedagogical process of students with Rett Syndrome. In its theoretic part, I describe Rett Syndrome as a clinical picture and a diagnostics and a therapy. The practical part of the thesis focuses on three main aims: to determine a certain number of students with Rett Syndrome in the Czech Republic, further to discover these students{\crq} educational and pedagogical process, and finally, to demonstrate a concrete form of this process on two casuistries. All of aims were realized. What follows from my survey is that the students are mostly educated according to the educational Rehabilitation program used for remedial schools; this means that no specific educational and pedagogical program for the children with Rett Syndrome has been created so far. According to my observation, the girls are schooled in autistic classes or in classes of children with combined handicaps, also in special elementary schools and preschool institutions.

Histone lysine methylation is an important epigenetic mark for regulation of gene expression and chromatin organization. Setdb1 (Set domain, bifurcate 1), one of the histone lysine methyltransferases, specifically methylates histone H3 at lysine 9 (H3K9) and participates in transcriptional repression and heterochromatin formation. The major task of my thesis work was to investigate the epigenetic roles of Setdb1 in regulating brain functions. I started my thesis work by examining Setdb1 expression pattern during mouse brain development. The most robust signal of Setdb1 was detected in the fetal brains at embryonic day 12.5, with a ubiquitous distribution in all the proliferative zones, as well as the cortical plate and other regions comprised of postmitotic neurons. The expression of Setdb1 decreased as the brain developed, and this down-regulation profile was correlated to neuronal maturation as examined in a primary culture model of mouse cortical neurons. I then generated CK-Setdb1 transgenic mice, in which a myc-tagged full length mouse Setdb1 was constantly expressed in postmitotic neurons under the control of the CaMK II alpha promoter (CK). The expression of mycSetdb1 was detected in NeuN positive cells throughout most forebrain regions including cerebral cortex, striatum and hippocampus. A sustained increase of Setdb1 in CK-Setdb1 transgenics was verified at both mRNA and protein levels. Furthermore, an increase of H3K9 trimethylation was detected at major satellite DNA repeats in CK-Setdb1forebrains, which indicated that transgene-expressed mycSetdb1 was functionally active in adult brains. The behavioral phenotype of CK-Setdb1 transgenics was examined by using two separate founder lines. Gross neurological functions including body weight, locomotion activity, motor coordination, and breeding behavior were generally normal in CK-Setdb1 mice. CK-Setdb1 mice were further subjected to behavioral paradigms related to mood and cognitive functions. Intriguingly, as compared to the littermate controls, CK-Setdb1 mice represent a lower level of depression as indicated by decreased total immobility in two different behavioral despair tests. Moreover, CK-Setdb1 mice showed an accelerated extinction in the learned helplessness paradigm after a delayed interval (7 days), indicating a faster recovery from an established status of despair. The potential confounding factors, like memory deficits, were ruled out as CK-Setdb1 mice showed normal or even improved performances in different memory-related paradigms. Anxiety scores and stimulant drug response were normal in CK-Setdb1mice. Taken together, these findings suggested that a specific antidepressant-like phenotype was elicited by the over-expression of Setdb1 in adult mice forebrains. To further study the molecular mechanism underlying Setdb1-associated antidepressant-like behavioral changes, I screened for Setdb1-binding sites in a genome-scale by ChIP-on-chip using a tiling microarray from Affymetrix. Unexpectedly, Setdb1 showed a very restricted binding profile with a high specificity towards ionotropic glutamate receptor genes including the NMDA receptor 2B subunit gene Grin2b, which is a new target for the treatment for major depression. An increase of H3K9 dimethylation at Setdb1-binding site on Grin2b locus was detected in CK-Setdb1 hippocampus, which was correlated to a decrease of Grin2b expression as well as an accelerated desensitization of NMDA receptor. Furthermore, Chromosome Conformation Capture (3C) on Grin2b locus revealed a repressive chromatin loop structure, which tethered the distal Setdb1-binding site (~ 32 Kb downstream of transcriptional start site (TSS)) to a proximal intronic region (~12 Kb downstream of TSS) that is enriched for the binding of KAP1, a well-studied Setdb1-interacting transcriptional corepressor. Taken together, our data indicated that Setdb1 repressed Grin2b expression via H3K9 hypermethylation and higher-order chromatin loop formation, which may contribute to the antidepressant-like phenotype we observed in CK-Setdb1mice. The second part of my thesis work was to investigate the role of Setdb1 in the animal model of a neurodevelopmental disorder - Rett syndrome (RTT). Loss-of-function mutations of the gene encoding methyl-CpG binding protein 2 (MECP2) is the primary cause of RTT. There is an overlap between Setdb1- and Mecp2-associated repressive chromatin machineries, which both include histone deacetylase complex, H3K9 methyltransferase, DNA methyltransferase and heterochromatin protein 1 (HP1). Moreover, in contrast to Setdb1, which is downregulated during the cortical neuronal differentiation, Mecp2 is upregulated and the expression level is positively correlated to neuronal maturation. Therefore, we hypothesized that there is a functional redundancy between Setdb1 and Mecp2, and the up-regulation of Setdb1 in mature neurons will compensate for brain deficiency due to the loss of Mecp2. To test this hypothesis, I crossed CK-Setdb1 transgenic mice with nestincre-Mecp2 conditional knockout mice (Mecp2-/y). The behavior changes of CK-Setdb1/Mecp2-/y mice, including body weight, locomotion, motor coordination, and life span, were then compared to Mecp2-/y mice. No significant improvements in behaviors or survival were observed from CK-Setdb1/Mecp2-/y mice. Because the activation of CK promoter is limited to defined population of postmitotic neurons in forebrain, I tested our hypothesis by generating another strain of Setdb1 overexpression mice – tauSetdb1, in which the expression of mycSetdb1 is under the control of an endogenous pan-neuronal active promoter Tau. However, the introduction of tauSetdb1 also failed to rescue Mecp2 deficiency. The life span of tauSetdb1/ Mecp2-/y was even shorter as compared to Mecp2-/y mice (Kaplan-Meier, p=0.07). In conclusion, up-regulation of Setdb1 in adult brain was not sufficient to rescue Mecp2deficiency in the mouse model of RTT. One of the most challenges to study neuronal dysfunctions in brain diseases is the cellular heterogeneity of central nervous system. Current techniques for chromatin studies, including chromatin immunoprecipitation (ChIP) assays, usually lack of single cell resolution and are unable to examine the neurobiological changes in defined cell populations. In the third part of my thesis work, I developed a modified protocol to isolate neuronal nuclei from brain homogenates via Fluorescence-Activated Cell Sorting (FACS). In general, total nuclei was extracted from frozen brains, neuronal nuclei were then immuno-tagged with NeuN and sorted via FACS. Besides the NeuN labeling-FACS protocol, I also generated CK-H2BeGFP transgenic mice, in which a histone H2B-eGFP (enhanced green fluorescent protein) fusion protein was expressed in the nuclei of postmitotic neurons in mouse forebrain. Nuclei extracted from CKH2BeGFP brain were directly applied for FACS sorting. By using this protocol, we routinely got around 6-8 x106neuronal nuclei from one adult mouse forebrain, which was sufficient for ChIP applications followed by single gene PCR and microarray studies. In conclusion, our protocol permits large-scale studies of chromatin modifications or any other nuclei events in defined cell populations from distinct brain regions. Taken together, my dissertation work will lead to a better understanding of the epigenetic roles of histone H3K9 methyltransferase Setdb1 in brain functions, and may provide new targets for the therapeutic treatment of major depression.

Irrespective of the great individual variation, people diagnosed with RTT largely rely on support from others to be able to do and participate in activities throughout their lives. This thesis focuses on which activities are done and liked/disliked by girls and women with RTT in Sweden. The overall aim was to describe the everyday lives of female individuals with Rett syndrome. Two studies are included in this thesis. The first is a descriptive study, using secondary data from three earlier questionnaires, encompassing data from 175 participants (girls/women) described by 365 informants (parents/staff). Content analysis was used to analyse the openended questions. In the second study a Time-geographic diary method and the software VISUAL-TimePAcTs computer program, DAILY LIFE 2011 were used. Ten participants (teenagers/young female adults) with RTT and their 63 informants participated in the diary study. The main findings in the first study (I) were that the girls and women with RTT enjoyed activities that included aspects of ‘contact’, ‘sensory impression’ and ‘motion’. The activities most enjoyed over the years were bathing/swimming, listening to music or being outdoors/walking. The parents and staff also liked to do the same activities that the girls or women enjoyed doing, described as sharing their joy. Of the few activities that were reported as being unenjoyable, most were daily care activities. The diary study (II) showed that the most frequently reported activities were hygiene/toilet, moving around indoors, eating and getting dressed. Most time was spent in sleeping, daily care, medical and health care activities and also for travel/transportation. Little time remained for other kinds of activities especially for the young adults. Most time was spent with staff, thereafter with families, and the least time was spent with friends. The participant response that was reported most often during activities was ‘interested’, while ‘opposed’ was the least reported. Responses of ‘opposition’ were primarily seen during caring activities such as toileting, using the breathing mask, stretching, brushing teeth, being woken up, dressing and putting on orthoses. Responses of ‘engagement’ were noted in contexts of socialising, playing and communicating activities with friends or staff. Engagement responses were also reported during activities of ‘motion’ such as changing body position, moving in the water or gymnastics, eating food and snacks, and even when watching/listening to films, books or music. Thus, increased knowledge concerning the importance of activities for girls and women with RTT is essential for their well-being, participation and continued development. Increased knowledge could facilitate the choice of activities and a more varied use of activities. Regardless of age, severity of symptoms or developed skills, it is important that not only basic needs such as sleep, daily care and medical health care activities are fulfilled for individuals with Rett syndrome. It is also essential for them to spend time with friends, family and staff doing enjoyable activities both at home and in other places. / <p>Funding:</p><p>Linnéa and Josef Carlsson’s Foundation, Helsingborg, Sweden and the Folke Bernadotte Foundation, Stockholm, Sweden.</p>

No description available.

瑞特氏症(Rett syndrome, RTT)為第二型甲基化CPG結合蛋白(2methyl-CpG binding protein 2, MeCP2)基因發生突變所造成的神經發育疾病，其症狀包含了嚴重的運動障礙及自閉傾向等特徵。由於紋狀體(striatum)為運動控制的重要腦區，我們假設RTT的運動障礙主要為紋狀體的功能異常所造成，故利用RTT模式小鼠來研究紋狀體是否為RTT運動障礙的致病原因。利用敞箱試驗(open field test)及加速滾輪測試(accelerating rotarod task)結果發現，Mecp2基因剔除小鼠的活動力明顯下降，並伴隨有運動協調能力的缺失。以免疫組織染色法及西方點墨法分別標定紋狀體中的mu-opioid receptor及calbindin蛋白，發現二者表現量均有明顯下降，然而表現parvalbumin的中間神經元細胞數目卻大量增加。我們發現在紋狀體中多巴胺D2受體的表現量顯著增加，但多巴胺合成酶tyrosine hydroxylase與多巴胺訊號傳遞下游分子DARPP-32蛋白並沒有明顯減少。為了更進一步確認紋狀體的致病角色，我們利用特定在紋狀體中缺少MeCP2的「Mecp2條件缺失小鼠」，觀察其運動行為的改變。結果發現，Mecp2條件缺失小鼠不管是在活動力或是運動學習上都表現出和Mecp2基因剔除小鼠相似的運動障礙，顯示紋狀體所調控的正常活動力及運動學習能力皆需要MeCP2的參與。我們接著進一步探討是否擁有完整MeCP2表現的紋狀體就足以執行正常的運動功能。當Mecp2基因剔除小鼠的紋狀體重新表現MeCP2(即「Mecp2條件回復小鼠」)，MeCP2缺失所造成的運動障礙可被回復到接近野生型小鼠運動能力的正常水準。顯示紋狀體中MeCP2的存在為正常運動控制的充要條件。在以cyclin-dependent kinase-like 5 (Cdkl5)突變小鼠研究MeCP2的磷酸化是否會影響到運動行為，發現Cdkl5突變小鼠在出生早期及成年時期皆存在與Mecp2基因剔除小鼠一致的運動協調能力缺失。免疫組織染色及西方點墨法結果顯示，Cdkl5突變小鼠的紋狀體中mu-opioid receptor表現量有明顯下降，但parvalbumin的中間神經元數目並無改變，而在大腦皮質中多巴胺轉運子DAT1蛋白表現量明顯上升。CDKL5突變造成與RTT相似症狀的原因還須更進一步的探討。綜上所述，本研究為「紋狀體異常可能為RTT運動障礙的主要致病原因」提供動物模式的實驗證據，並提供了一個新的觀點用於未來治療RTT或防止其症狀的惡化。

The aim of this work is to enable a person to perceive and understand the specific features of behaviour of girls having Rett syndrome and to offer effective options for activities and effort in the process of education. The substance of the collection of suggestions and proposals for actions and activities as well as tools and equipment sorted according to equipment and objects used at a special needs education primary school. Practical advice, recommendations and suggestions are based on theoretical grounds and basis, particular examples or photo documentation. The work is founded on study cases of two girls with Rett syndrome where there are not only the girls' results and evaluations in the educational process described but also the personal stories of their families and different way of dealing with the tough life situations. The work results enable to discover a suitable attitude not only towards the girls but as well to their parents, siblings or classmates. KEYWORDS rare disease, Rett syndrome, mental disorder, communication, upbringing, education, general regularities, practical activities and actions, case study

The diploma thesis deals with the care of a girl with Rett syndrome (RTT) in the family. The six main chapters and individual subchapters present the issues of Rett syndrome, the family of a girl with RTT and area of care for a girl with RTT. The first chapter of the diploma thesis presents the fundamental issues related to Rett syndrome with an outline of the history, definition, causes and manifestations. The prevalence and incidence, diagnosis and manifestations of RTT are presented. The following subchapters are devoted to the individual stages of Rett syndrome, their course and the issue of RTT in boys. The second chapter focuses on the issue of the family caring for a child with a disability, presents a definition of the family and the stages of acceptance of a child with a disability. The following subchapters present the complex care for a child with a disability and present an overview of possible forms of support for families of children with disabilities. The third chapter deals with selected areas of care that parents of girls with RTT often have to provide. The individual subchapters include the following areas such as hygiene, sleep, diet, mobility, communication and health care. The fourth chapter is the research survey itself, conducted qualitatively. The research aimed to find out...

Den skadeståndsrättsliga principen om den skadelidandes skyldighet att begränsa sin skada ärväl känd och vedertagen i svensk rätt. Principen åberopas ofta som invändning iskadeståndstvister av alla slag, och har därmed stor praktisk betydelse. Principens köprättsligaoch försäkringsrättsliga motsvarigheter är generöst behandlade i doktrinen. På denskadeståndsrättsliga sidan förhåller det sig annorlunda – det här är första gången som ämnetblir tillägnat ett eget arbete i Sverige. Det finns många rättsfall där skadebegränsningsskyldigheten aktualiseras, men på grund avdomskälens utformning är rättsfallens värde som vägledning begränsat. Jag anser emellertid attuppmärksamheten inte bör överfokuseras på dessa. Intar man ett framåtblickande perspektiv,finns det gott om material och idéer att hämta från den övriga civilrätten, från rättsekonominoch – inte minst – från utlandet. Arbetets strukturella och metodologiska ramverk är utformatså, att största möjliga nytta kan dras av främmande källor utan att en djupgående (och oftastointressant) komparativ utredning av dessa källor behöver göras. Det huvudsakliga syftet med undersökningen var att definiera skadebegränsningsprincipensansvarsgräns. Med hänsyn till framställningen omfattning, hade det inte varit möjligt att göragrundliga utredningar av enskilda delproblem. Istället är arbetet fokuserat på att utrönaallmängiltiga riktlinjer, tankemönster och ledtrådar, dels för skadebegränsningsbedömningen isig, och dels för den tänkbara rättsutvecklingen. Ett flertal sådana riktlinjer har kunnatdefinieras, något utspridda över principens tillämpningsområde, och ibland även i sammanhangdär det inte är uppenbart att det är skadebegränsningshänsyn som styr. Samtidigt har åtskilligasystemiska problem uppdagats såväl i principens tillämpning som i den underliggandenormbildningen. Jag har ödmjukt lagt fram några lösningsförslag, med ändamålet att främja enmer rättssäker tillämpning av principen, dels på grundval av gällande rätt, och dels på grundvalav den tänkbara rättsutvecklingen på området. / The doctrine of avoidable loss is a generally recognized principle in Swedish law. The doctrine is often invoked in damage claim disputes of all kinds, and is therefore important in practice. There is plenty of legal literature where the doctrine is treated in the context of sales law and insurance law. On the tort law side, however, there is nothing – this is the first dedicated work on the subject in Sweden. There are many tort cases where the question of avoidable loss is actualized, but due to the way the courts articulate the grounds for their rulings, the cases provide little guidance for the future, and therefore have little value as precedent. This is not necessarily an obstacle to the study. On the contrary, when looking outwards, I have found a wealth of ideas and study material in other areas of civil law, in law and economics, and in foreign law. The structural and methodological framework of the thesis was designed to allow for extraction of material from foreign sources without needing to conduct a thorough (and often uninteresting) comparative study. The main purpose of the investigation was to define the boundaries of the claimant’s liability as imposed by the doctrine. Considering the limited scope of the thesis, it would not have been possible to deconstruct the subject into details and conduct thorough investigations of those. Instead, the work was focused on determining general guidelines, thought patterns and clues; both de lege lata and de lege ferenda. Multiple such guidelines could be defined in various contexts where the doctrine is applied, but also, interestingly, in certain contexts where it is not obvious that considerations of avoidable loss are decisive. Multiple systemic issues have also been found, both in the application of the doctrine and in the underlying norms. I have humbly put forward several suggestions on how these issues could be alleviated to promote legal certainty in the doctrine’s application, both today and in the future.