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.

Several hundred inherited disorders of the skeleton have been delineated. Individually these conditions are rare, but as a group they cause much crippling and hardship. Several factors, including the rarity and complexity of the manifestations of these conditions, as well as semantic overlap, impede the accurate diagnosis which is essential for effective treatment. In this regard, the adoption of microcomputers warrants evaluation as a high technology aid. Microcomputers have developed tremendous capabilities during recent years. The state of the art has become such that a diagnostic aid facility on such a device has been demonstrated in various disciplines of medicine and may also be feasible in the area of inherited skeletal disorders. The study which forms the basis of this thesis, concerns the investigation of this feasibility and has led to the development of an effective working model which sets the basis for microcomputer-aided diagnosis. The design features followed in this project are similar to those conventionally employed for "Expert systems" on mainframe computers. A comprehensive knowledge base consisting of over 200 skeletal disorders and 700 radiographic and clinical manifestations, has resulted. Furthermore, the application is capable of "learning", although inference as employed by the inference engines of real expert systems, is not employed. In this context learning implies that the knowledge base, with the passage of time, improves considerably when used by experts. Serendipitous findings in this regard are: • 1) Considerable improvement of existing profile descriptions can occur without any increased demands on computer memory and storage space; • 2) Growth of the knowledge base in the form of additional disease profiles can be effected with very modest inroads on memory and storage resources. The computerized diagnostic aid which resulted from this thesis, has been demonstrated to be successful in both the Department of Human Genetics of the University of Cape Town and the Department of Paediatrics of the Johannes Gutenberg University in Mainz. Evaluated both in terms of efficiency and utility, the system provides an enhancement to the specialist genetic diagnostician. These achievements have been effected by means of a unique newly developed application of compressed bit-mapping, attained by writing the applicable programs in Turbo Pascal and 8086- assembler languages. Calculations indicate that much larger data bases may possibly be implemented on present-day microcomputers by means of the methods developed in this project.

This was an exploratory-descriptive study of fifty children afflicted with myelomeningocele, ages one through six, who were known to the Myelomeningocele Clinic of the Crippled Children’s Division. The study identified the degree of multiple physical, emotional, and environmental stress factors that families must be prepared to cope with. The study identified eleven factors felt to play an important role in family dynamics and how they related to the families response to their child with myelomeningocele. The factors were tested and found to be valid by the use of a pre-test on ten case records. Medical records were then obtained from the Crippled Children's Division for chart review purposes and the appropriate material was recorded. Scores were developed that indicated the degree of stress ranging from minimal involvement to maximum involvement. The study found that a majority of the families in the sample live within commuting distance to needed medical services, have transportation available to them and generally utilize the necessary medical care appropriately. The remainder of the study showed, however, that families could be expected to face a variety of other problems that could only serve to increase family stress. Most of the families had limited financial resources. Over one-half of the families needed special education for their children. A majority of families had no medical insurance. Fifty-eight percent of the families were found to have additional stressful problems to cope with e. g., marital stress, sibling rivalry, additional ill members, etc. Added to this was the information that the child with myelomeningocele was found to be greatly involved in a multiplicity of medical problems at many different levels of functioning. e. g., orthopedic, bowel, neurosurgical, etc., that would be expected to add to the already stressful family dynamics. Among the recommendations developed was a plea for the expansion of the satellite clinic concept, development of parent groups on a geographical basis, development of educational programs for educators and community service personnel, brief orientation programs for parents with the goal of helping them understand and integrate the health care system that they find themselves in.

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Prematurity is a worldwide problem. Every year, 15 million babies are born prematurely, and 1 million of those babies die because of related complications. The surviving premature babies are struggling to hold on to their lives, and even when they do live, most of them end up having various complications to survive and get stronger. There are physical complications faced on their journey such as having underdeveloped lungs, pneumonia, obesity, sepsis, retinopathy of prematurity, respiratory distress syndrome, bronchopulmonary dysplasia, asthma, wheezing, bronchiolitis, cerebral palsy, and motor impairment. They can also develop mental and behavioral health complications such as depression, seizures developmental delay, schizophrenia, autism spectrum disorder, psychological development disorders, behavioral problems, attention problems, and ADHD later in life. The purpose of this systemic review is to understand the impact of long-term complications of premature birth on individual life and society. We hypothesized that based on data from primary research, nearly one half of the infants will have either physical and/or cognitive/developmental health complications. We hypothesized that infants born premature have more physical complications than cognitive complications and infants born prematurely have more cognitive complications than physical complications. This research was carried out by finding cohort study design studies through Medline, Academic Search Premier, and APA PsychINFO, where the studies will be compiled from 2003 – 2020.

京都大学 / 新制・課程博士 / 博士(医科学) / 甲第24532号 / 医科博第146号 / 新制||医科||10(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 金子 新, 教授 上杉 志成, 教授 寺田 智祐 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This thesis identifies a claimant narrative tradition in nineteenth-century American literature and examines the role of that tradition in the formation of American national identity. Drawing on Nathaniel Hawthorne’s The American Claimant Manuscripts and Our Old Home (1863) as well as Mark Twain’s The American Claimant (1892), I argue that these writers confronted the paradoxical nature of claimant narratives—what Hawthorne called a “peculiar insanity”—which combined a hereditary sympathy between the United States and Britain with exceptionalist rhetoric about American republican values. Hawthorne’s ambivalence toward the claimant tradition identified the paradox, but his writing merely pointed out inconsistencies, while Twain censured with satire and direct social criticism. America’s British sympathies persisted in later decades, and remained a popular subject of fiction throughout the century, making it ripe for parody by the time Twain wrote his own claimant story. Claimant narratives reinforced class differences in the United States even as they appeared to reject them. The transnational framework of Twain’s novel affords a pointed critical view revealing the latent cruelty of democracy when coupled with attitudes of exceptionalism.

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