Down Syndrome (DS), the most common aneuploidy seen in live-borns, is caused by trisomy for chromosome 21. DS imposes high risks for multiple health issues involving various systems of the body. The genetic complexity of trisomy 21 and natural variation between all individuals has impeded understanding of the specific cell pathologies and pathways involved. In addition, chromosomal disorders have been considered outside the hopeful progress in gene therapies for single-gene disorders. Here we test the feasibility of correcting imbalanced expression of genes across an extra chromosome by expression of a single gene, XIST, the key player in X chromosome inactivation. We targeted a large XIST transgene into one chromosome 21 in DS iPS cells, and demonstrated XIST RNA spreads and induces heterochromatin and gene silencing across that autosome in cis. By making XIST inducible, this allows direct comparison of effects of trisomy 21 expression on cell function and phenotypes. Importantly, XIST-induction during in vitro hematopoiesis normalized excess production of differentiated blood cell types (megakaryocytes and erythrocytes), known to confer high risk for myeloproliferative disorder and leukemia. In contrast, trisomy silencing enhances production of iPS and neural stem cells, consistent with DS clinical features. Further analysis revealed that trisomy 21 initially impacts the endothelial hematopoietic transition (EHT) to generate excess CD43+ progenitors, and also increases their colony forming potential. Furthermore, results provide evidence for a key role for enhanced IGF signaling, involving over-expression of non-chromosome 21 genes controlled by trisomy 21. Finally, experiments to examine trisomy effects on angiogenesis showed no effect on production of endothelial cells, but it remains unclear whether trisomic cells may differ in ability to form vessels. Collectively, this thesis demonstrates proof-of-principle for XIST-mediated “trisomy silencing”. Phenotypic improvement of hematopoietic and neural stem cells demonstrates the value for research into DS pathogenesis, but also provides a foundation of potential for future development of “chromosome therapy” for DS patients.

No description available.

<p>  </p> <p>Down syndrome (DS) is caused by the partial or complete trisomy of human chromosome 21 (Hsa21) and can result in skeletal deficits, including lower bone mineral density (BMD) and increased risk of fracture and osteoporosis or osteopenia earlier than the general population. Mouse models of DS have been developed to understand the genetic mechanisms resulting in these phenotypes, but models differ due to the complex genetic nature of DS and differing genome structures between humans and mice. Ts65Dn mice have been a popular model of DS as they contain ~50% of Hsa21 orthologous genes on a freely segregating minichromosome, but there is speculation that the phenotypes are exaggerated by non-Hsa21 orthologous trisomic genes also present. To address this issue, the Ts66Yah mouse model was developed to remove the non-Hsa21 orthologous trisomic genes. In this study, male and female Ts66Yah mouse femurs were evaluated during bone accrual and peak bone mass to investigate structural differences using micro-computed tomography. Additionally, the role of trisomic <em>Dyrk1a</em>, a Hsa21 gene previously linked to bone deficits in Ts65Dn mice, was evaluated through genetic and pharmacological means in Ts66Yah femurs at postnatal day 36. Ts66Yah mice were found to have little or no trabecular deficits at any age evaluated, but sex-dependent cortical deficits were present at all ages investigated. Reducing <em>Dyrk1a</em> copy number in Ts66Yah mice significantly improved cortical deficits but did not return cortical bone to euploid levels. Pharmacological treatment with DYRK1A inhibitor L21 was confounded by multiple variables, making it difficult to draw conclusions about DYRK1A inhibition in this manner. Overall, these results indicate trabecular deficits associated with Ts65Dn mice may be due to the non-Hsa21 orthologous trisomic genes, and more Hsa21 orthologous trisomic genes are necessary to produce trabecular deficits in DS model mice. As more mouse models of DS are developed, multiple models need to be assessed to accurately define DS-associated phenotypes and test potential treatments.</p>

The intent of this thesis is to discover teaching strategies for students who have exceptionalities with a focus on students who have Autism, Down syndrome, or Visual Impairment and how these teaching strategies can be used to teach students in a mainstreamed secondary art classroom. Since the mainstreaming of the public school system has increased, students with exceptionalities have caused uncertainty among teachers about which teaching strategies to use in the classroom to meet all of their students needs. New teaching strategies need to be brought into the classroom to change the way students are learning. This thesis will include: the general facts, characteristics, accommodations, and modifications of Autism, Down syndrome, and Visual Impairment. An understanding of how students with Autism, Down syndrome, or Visual Impairment learn and what teaching strategies can be used in a secondary art classroom to provide the least restrictive learning environment to the students will be addressed. Suggested teaching strategies for students with Autism include the use of visualizations, change in pace, adaptive tools, and choosing materials wisely. For students with Down syndrome include simplification, repetition, breaking the lesson down into parts, and pacing. Students with Visual Impairment will need tactile materials, clear wording, descriptive visuals, and labeling, light, and intense color.

Syfte: Syftet med denna studie var att utvärdera effekten av stimulerande gomplattor på den orala motoriken hos barn med Downs syndrom. Studien syftar också till att undersöka om behandlingen är kostnadseffektiv.Material och Metod: Studien är en systematisk litteraturstudie enligt PRISMAs kriterier och artiklarna kvalitetsgranskades med hjälp SBU: s handbok. De databaser som användes för litteratursökningen var PubMed, Cochrane Library, Scopus och CINAHL.Resultat: Screeningen av 107 unika artiklar resulterade i 14 relevanta publikationer. Kvaliteten på artiklarna var överlag låg och 9 artiklar bedömdes måttlig risk för bias och 5 artiklar bedömdes ha hög risk för bias. Alla 14 inkluderade artiklar visade en positiv effekt på minst en orofacial variabel men det finns ingen konsensus gällande utvärderingsmetoder för behandling med gomplattor, behandlingstider eller vilka orofaciala variabler som bör undersökas.Slutsats: I denna litteraturgenomgång identifierades ett antal studier, som undersökte effekten av behandling med stimulerande gomplattor. På grund av att artiklarna använde icke standardiserade metoder, hade olika behandlingstider och använde olika variabler för att mäta effekten, kan ingen slutsats dras från dessa studier. Fler RCT studier med större grupper av barn och standardiserade metoder för utvärdering behövs. / Aim: The aim of this study was to evaluate the effect of treatment with stimulating palatal plates on the oral motor function in children with Down syndrome. The study also aims to investigate if the treatment is cost-effective.Material and Method: The study is a systematic review made according to the PRISMA criteria. The articles were quality reviewed using Swedish Agency for Health Technology Assessment and Assessment of Social Services - SBU’s manual. The databases used for the literature search were PubMed, Cochrane Library, Scopus and CINAHL.Result: Screening of 107 unique papers resulted in 14 eligible publications. The quality of the articles was overall low. Nine articles were rated moderate risk of bias and 5 articles were rated high risk of bias. All 14 included articles showed a positive effect in one or more aspects on oral motor function but there is no consensus regarding evaluation methods for treatment with palatal plates, treatment times or which orofacial variables that should be investigated. No meta-analysis was made due to the lack of consensus.Conclusion: This literature review identified a number of studies, which investigated the effect of treatment with stimulating palatal plates. Due to the unstandardized methods, different treatment times, and different orofacial measuring variables, no consensus can be drawn from these studies. More RCT studies with larger groups of children and standardized methods for evaluation are required.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in an array of phenotypes including intellectual disability. Ts65Dn mice, the most extensively studied DS model, have three copies of ~50% of the genes on Hsa21 and display many phenotypes associated with DS, including cognitive deficits. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including CNS development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have shown that a three-week EGCG treatment (~10mg/kg/day) during adolescence normalizes skeletal abnormalities in Ts65Dn mice, yet the same dose did not rescue deficits in the Morris water maze spatial learning task (MWM) or novel object recognition (NOR). Others have reported that An EGCG dose of 2-3 mg per day (90mg/ml) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated deficits in a radial arm maze pattern separation task in Ts65Dn mice. Pattern separation requires differentiation between similar memories acquired during learning episodes; distinguishing between these similar memories is thought to depend on distinctive encoding in the hippocampus. Pattern separation has been linked to functional activity of newly generated granule cells in the dentate gyrus. Recent studies in Ts65Dn mice have reported significant reductions in adult hippocampal neurogenesis, and after EGCG treatment, enhanced hippocampal neurogenesis. Thus, it was hypothesized that Ts65Dn mice would be impaired in the pattern separation task, and that EGCG would alleviate the pattern separation deficits seen in trisomic mice, in association with increased adult hippocampal neurogenesis. At weaning, Ts65Dn mice and euploid littermates were randomly assigned to the water control, or EGCG [0.4 mg/mL], with both treatments yielding average daily intakes of ~50 mg/kg/day. Beginning on postnatal day 75, all mice were trained on a radial arm maze-delayed non-matching-to-place pattern separation task. Euploid mice performed significantly better over training than Ts65Dn mice, including better performance at each of the three separations. EGCG did not significantly alleviate the pattern separation deficits in Ts65Dn mice. After the behavioral testing commenced, animals were given ad libitum food access for five days, received a 100mg/kg injection of BrdU, and were perfused two hours later. Coronal sections through the dorsal hippocampus were processed for BrdU labeling, and cells were manually counted throughout the subgranular zone of the dentate gyrus. The euploid controls had significantly more BrdU labeled cells than Ts65Dn mice, however, EGCG does not appear to increase proliferation of the hippocampal neuroprogenitor cells. This is the first report of deficits in Ts65Dn mice on a pattern separation task. To the extent that pattern separation depends on the functional involvement of newly generated neurons in an adult dentate gyrus, this approach in Ts65Dn mice may help identify more targeted pharmacotherapies for cognitive deficits in individuals with DS.

Indiana University-Purdue University Indianapolis (IUPUI) / Little is known regarding the psychosocial outcomes of adult siblings of adults with autism. Accordingly, the current study sought to: (1) illuminate factors that predict health-related quality of life, caregiver burden, and reported benefits in adult siblings of adults with autism, using a stress and coping framework and (2) compare outcomes of siblings of adults with autism (n = 31) to siblings of adults with Down syndrome (DS) (n = 54). For the within subject hypotheses, analyses were repeated within the DS group and an overall Disability group (n = 97). The Disability group consisted of participants in the Autism and Down syndrome groups plus twelve individuals in a mixed group of adult siblings of adults with DS who presented with co-morbid symptoms of autism. Variables were organized using The Adult Sibling Caregiver Conceptual Model (ASCCM) into three categories: antecedents (e.g., sibling relationship quality, problem behaviors of the disabled sibling), mediators (e.g., coping strategies, cognitive appraisal types), and psychosocial outcome variables (i.e., mental and physical health-related quality of life, caregiver burden, and reported benefits). For the within subject primary hypotheses, I posited a series of relationships between the antecedents and outcomes based on prior literature on demographic and individual difference predictors (e.g., siblings of adults with autism with fewer problem behaviors would have increased health-related quality of life [HRQOL], decreased caregiver burden, and increased reported benefits) and on stress and coping factors related to the burden of providing care for an individual with autism (e.g., greater use of avoidant coping strategies would be related to lower HRQOL, increased caregiver burden, and decreased reports of benefits). Exploratory hypotheses also were examined (e.g., being married would be associated with increased HRQOL, decreased burden, and increased reported benefits). The within-subject results indicated support for eight of the ten primary hypotheses and five of the six exploratory hypotheses when examined within at least one of the study groups: Autism, DS, or Disability. Overall, sibling caregivers, regardless of their sibling’s disability, reported more favorable psychosocial outcomes when demands were lower (e.g., less severe levels of problem behaviors, fewer autism symptoms exhibited by their disabled sibling, decreased additional pile-up stress), when resources were available to cope with stress (e.g., social support, respite care), and when healthy responses to stress were reported (e.g., use of emotion focused vs. avoidant coping strategies, use of challenge vs. threat appraisal types). Of note, reported benefits, which have rarely been examined in the autism literature, were strongly related to the quality of a sibling relationship across all study groups, and with the helpfulness of received services and perceived social support within the Autism group. The between subject hypotheses also were largely supported. As expected, compared to siblings of those with Down syndrome, siblings of those with autism demonstrated greater levels of caregiver burden and lower mental HRQOL. Moreover, there was a rank ordering in levels of caregiver burden across disability groups; siblings of adults with DS reported the lowest burden, siblings of adults with DS with symptoms of autism reported significantly higher levels of burden, and siblings of those with autism reported the most burden. The results imply that autism, either alone or co-morbid with another diagnosis, presents an increased risk of stress and caregiver burden, not only in parent caregivers, but also in sibling caregivers. Interestingly, there was also evidence for higher levels of stress related growth within the Autism group compared to the DS group. Future research will be needed to generalize the results of this study to broader samples of adult siblings while taking a life course perspective to assess changes in non-disabled siblings’ outcomes over time.

Thesis (MEd)--University of Stellenbosch, 2005. / ENGLISH ABSTRACT: This study was undertaken to identify key aspects related to the promotion of the effective inclusion of a learner with Down Syndrome in a mainstream school and at the same time to give close attention to the implementation of the principles of inclusive education. The study was done over a period of four years in an Afrikaans medium primary school in a large rural town. The Educational Management and Development Centre (EMDC) in the region in which the school is situated is currently promoting and implementing inclusive education and the proposals set out in the Education White Paper 6. The findings of this study will be used to support and encourage this process (also at grassroots level) as well as the inclusion of learners with Down Syndrome. The study takes the form of a single case study and falls within an interprevistlconstructivist paradigm. Qualitative research methods were used to develop an understanding and an insight into the key aspects in order to promote the successful inclusion of learners with Down Syndrome. The primary methods of investigation were four individual interviews and one focus group interview with educators. The data generated in this manner was verified by means of recent literature, observations and available documents. During the process of data analysis the data were reduced to four themes relating to the inclusion of learners with Down Syndrome: attitudes and views with regard to inclusion, the address of specific challenges with which mainstream education is presented, specific strategies for promoting inclusion and the value that inclusion holds for mainstream education. The findings show that the principles of inclusive education and the educational practice associated with it do take into account the barriers to learning and development that learners with Down Syndrome experience: these barriers can be addressed within mainstream education. The key aspects attached to this depend mainly on the attitudes and views of the school and parent community, the address of the challenges such a learner presents, the use of specific educational and teaching strategies to promote inclusion and the acknowledgment of the value that inclusion holds for mainstream education. / AFRIKAANSE OPSOMMING: Hierdie studie is onderneem om die kernaspekte ter bevordering van effektiewe insluiting van 'n leerder met Downsindroom in 'n hoofstroomskool te identifiseer en terselfdertyd die implementering van die beginsels van inklusiewe onderwys onder die loep te neem. Die studie is oor 'n tydperk van vier jaar in 'n Afrikaansmedium laerskool op 'n groot plattelandse dorp onderneem. Die Onderwysbestuur- en Ontwikkelingsentrum (OBOS) van die streek waarbinne die betrokke skool geleë is, is besig om inklusiewe onderwys en die voorstelle soos in Onderwys Witskrif 6 uiteengesit aktief te bevorder en te implementeer. Die bevindinge van die studie sal aangewend word ter ondersteuning en bevordering van hierdie proses (ook op voetsoolvlak), sowel as die insluiting van ander leerders met Downsindroom. Die studie het die vorm van 'n indiwiduele gevallestudie aangeneem en is vanuit 'n interpretatiewe/konstruktiwistiese paradigma benader. Kwalitatiewe navorsingsmetodes is aangewend ten einde begrip en insig te ontwikkelomtrent die kernaspekte ter bevordering van effektiewe insluiting van leerders met Downsindroom. Die primêre metode van ondersoek was vier indiwiduele onderhoude en een fokusgroep onderhoud met opvoeders. Die data wat op hierdie wyse gegenereer is, is aan die hand van resente literatuur, observasies en beskikbare dokumente geverifieer. Die proses van data-analise het die data tot vier temas met betrekking tot die insluiting van 'n leerder met Downsindroom gereduseer, naamlik houdings en sieninge ten opsigte van sodanige insluiting, die aanspreek van spesifieke uitdagings wat aan hoofstroomonderwys gestel word, spesifieke strategieë om insluiting te bevorder en die waarde wat insluiting tot hoofstroomonderwys toevoeg. Die bevindinge dui daarop dat die beginsels van inklusiewe onderwys en onderwyspraktyk daaraan verbonde, voorsiening maak dat die algemene hindernisse tot leer en onwikkeling wat leerders met Downsindroom ondervind effektief binne hoofstroomonderwys aangespreek kan word. Die kernaspekte hieraan verbonde berus hoofsaaklik op die houdings en sieninge van die skool- en ouergemeenskap, die aanspreek van die uitdagings wat so In leerder stel, die benutting van spesifieke onderwys- en onderrigstrategieë ter bevordering van insluiting en die erkenning van die waarde wat die insluiting van In leerder met Downsindroom tot hoofstroomonderwys toevoeg.

La trisomie 21 (t21) est l'anomalie génétique la plus fréquente à l'origine d'une déficience intellectuelle. Bien que la recherche concernant le stéréotype social de la t21 soit limitée, les personnes porteuses de t21, et particulièrement les enfants, semblent être associées à des traits de personnalité tels que « affectueux » et « heureux », les caractéristiques positives l'emportant sur les négatives comme « retardé ». Cependant, ce stéréotype positif coexiste avec des attitudes ambivalentes notamment à propos de l'intégration scolaire de ces enfants. L'objectif principal de cette thèse est d'étudier ce stéréotype au niveau implicite ainsi que l'impact des caractéristiques faciales sur le stéréotype au niveau explicite et implicite. Nos résultats confirment d'une part, un stéréotype social positif explicite dans des échantillons d'étudiants, d'adultes non étudiant et de professionnels du handicap intellectuel. Les visages d'enfants présentant plus de traits faciaux associés à la t21 sont associés à un stéréotype moins positif que ceux en présentant moins. D'autre part, nous mettons en évidence un stéréotype négatif au niveau implicite, même chez les professionnels du handicap. Nous étudions l'influence des variables individuelles sexe, familiarité avec la t21 et théories implicites de l'intelligence sur le stéréotype explicite et implicite. Puis, nous montrons une relation négative entre la typicalité des visages et le jugement sur l'intelligence alors que nous n'observons pas de relation significative entre la typicalité des visages et le niveau cognitif. Nous discutons l'implication de ces résultats sur l'étude du stéréotype et sur les personnes stigmatisées. / Trisomy 21 (t21) or Down syndrome is the most frequent genetic disorder associated with intellectual disability. Although research on the social stereotype toward t21 is very limited, it seems that persons with t21 are typically viewed as “affectionate” and “happy”; with positive personality traits prevailing over the negative ones (e.g., “mentally retarded”). However, this positive stereotype coexists with ambivalent attitudes. The main objective of this study was to investigate the stereotype at the implicit level and the impact of t21 facial features on the stereotype of t21 at the both explicit and implicit levels. Our results confirm, on one hand, a positive social stereotype explicit in samples of young adult students, non-student adults and professional caregivers working with intellectually disabled persons. The positive bias typically found in explicit judgments of children with t21 is smaller for those whose facial features are highly characteristic of this disorder, compared to their counterparts with less distinctive features and to typically developing children. On the other hand, we also show that this bias can coexist with negative evaluations at the implicit level, even among professional caregivers but to a lesser extent. We study the influence of individual variables sex, familiarity with the t21 and implicit theories of intelligence on explicit and implicit stereotypes. Finally, we show a negative relationship between t21 typicality of faces and the judgment of the intelligence as we do not observe a significant relationship between typicality and the cognitive level. We discuss the implications of these results.