Diabetic pregnancy is associated with increased risk of congenital malformations. Previous studies have shown that maternal diabetes can interact with the vitamin A metabolite, all-trans retinoic acid (RA), in increasing embryonic susceptibility to caudal regression and neural tube defects. The aim of this thesis is to investigate the cellular and molecular mechanisms that underlie this interaction. / First hypothesis. RA concentration in the embryo is tightly regulated by the synthesizing enzyme retinaldehyde dehydrogenase type II (RALDH2), and the degrading enzyme CYP26. Alteration in expression levels of these enzymes under maternal diabetes may affect the availability of RA and thus its teratogenicity. / In conclusion, results of this thesis provide insight into the mechanism of how maternal diabetes interacts with RA in enhancing embryonic susceptibility to congenital malformations. This is also the first report to show that maternal diabetes alters RA homeostasis. (Abstract shortened by UMI.) / Second hypothesis. The transfer of RA to the nucleus for molecular action is regulated by cytoplasmic cellular retinoic acid binding proteins CRABP-I and CRABP-II. Alteration in expression levels of these binding proteins under maternal diabetes may affect the amount of RA reaching the nucleus and thus its teratogenicity. / Third hypothesis. The action of RA is mediated via different nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR). Alteration in expression levels of these receptors under maternal diabetes may affect the efficacy of RA signal transduction and thus its teratogenicity. / Three hypotheses are proposed to explain the underlying mechanism of increased embryonic susceptibility to RA teratogenicity under maternal diabetes: / To investigate these hypotheses, expression levels of various genes in different groups were compared. Result show that there are no significant differences in mRNA expression levels of CRABP-I, CRABP-II, RARgamma, RARgamma and RXRalpha between embryos of diabetic and non-diabetic mice with or without RA treatment. In contrast, expression levels of Raldh2 and CYP26 are significantly reduced in embryos of diabetic mothers, and in embryos of non-diabetic mice cultured in vitro in hyperglycemic conditions. Moreover, embryos of diabetic mice show significantly reduced response to RA-induced up-regulation of CYP26. These findings suggest that the rate of degradation of RA is slower in embryos of diabetic mice and thus the teratogenic effect of RA is enhanced. / Leung Bo Wah. / "July 2005." / Adviser: Alisa S. W. Shum. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3779. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 158-198). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Tong, Yan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 66-78). / Abstracts in English and Chinese; includes Chinese. / Acknowledgements --- p.i / Conferences & Academic Awards --- p.ii / Table of contents --- p.iii / List of figures --- p.vii / List of tables --- p.viii / List of abbreviations --- p.ix / Abstract --- p.x / Abstract (Chinese) / Chapter Chapter I --- Background of diabetes mellitus and DM complicating pregnancy …… --- p.1 / Chapter 1.1 --- Definitions and clinical manifestations of Diabetes Mellitus --- p.1 / Chapter 1.2 --- Diagnostic criteria of DM --- p.1 / Chapter 1.3 --- Classification of DM --- p.1 / Chapter 1.4 --- Prevalence of DM --- p.2 / Chapter 1.5 --- Aetiology and Pathogenesis of DM --- p.3 / Chapter 1.6 --- Treatment of DM --- p.3 / Chapter 1.7 --- Complications of DM --- p.4 / Chapter 1.8 --- DM complicating pregnancy --- p.4 / Chapter 1.8.1 --- Implications of DM complicating pregnancy --- p.4 / Chapter 1.8.2 --- Diabetic Embryopathy --- p.5 / Chapter 1.8.3 --- Incidences of the major congenital anomalies --- p.5 / Chapter 1.8.4 --- Possible pathogenesis of congenital anomalies in DM complicating pregnancy --- p.6 / Chapter 1.8.4.1 --- Apoptosis --- p.6 / Chapter 1.8.4.2 --- Oxidative stress --- p.7 / Chapter 1.8.4.3 --- Arachidonic acid and PGE2 --- p.7 / Chapter 1.8.5 --- Clinical management of DM complicating pregnancy --- p.8 / Chapter 1.8.5.1 --- Pre-pregnancy care --- p.8 / Chapter 1.8.5.2 --- Antenatal management of DM complicating pregnancy --- p.9 / Chapter Chapter II --- Background of Traditional Chinese Medicine in treatment of DM --- p.10 / Chapter 2.1 --- Definition and manifestations of DM in TCM theory --- p.10 / Chapter 2.2 --- Historical context of DM in TCM --- p.10 / Chapter 2.2.1 --- "Spring and Autumn Period and Warring States Period (770 B.C.一8 A.D.): The first nomenclature of ""Wasting Thirst""" --- p.10 / Chapter 2.2.2 --- "Han Dynasty (9 A.D.-280 A.D.)： monograph on ""Wasting Thirst""" --- p.11 / Chapter 2.2.3 --- "Sui and Tang Dynasty (581 A.D.-960 A.D.)： the diagnosing marker of ""Wasting Thirst""" --- p.11 / Chapter 2.2.4 --- Song Dynasty (960 A.D.-1270 A.D.): the Golden Time of developing the treatment on DM --- p.12 / Chapter 2.2.5 --- Ming and Qing Dynasty (1270 A.D. - 1911 A.D.): the integration period of TCM theory on DM --- p.15 / Chapter 2.3 --- Aetiology of DM in TCM theory --- p.15 / Chapter 2.3.1 --- Congenital weakness --- p.16 / Chapter 2.3.2 --- Improper diet --- p.16 / Chapter 2.3.3 --- Emotional disorders and overstrain --- p.17 / Chapter 2.3.4 --- Excessive sexual activities --- p.17 / Chapter 2.4 --- Pathogenesis of DM in TCM theory --- p.17 / Chapter 2.5 --- Prognosis of DM in TCM theory --- p.19 / Chapter 2.5.1 --- """Dual Qi-Yin Deficiency"" and ""Dual Yin-Yang Deficiency""" --- p.19 / Chapter 2.5.2 --- "Multi-systemic malfunction of ""Zang Fu""" --- p.19 / Chapter 2.6 --- Principle of treatment --- p.20 / Chapter 2.7 --- Commonly used herbal remedies and recent experimental studies --- p.20 / Chapter 2.8 --- TCM on relieving DM complications --- p.21 / Chapter 2.9 --- "Dwarf Lilyturf Tuber (Ophiopogonis Radix, Mai Dong,麥冬）" --- p.21 / Chapter 2.10 --- Objectives and hypothesis --- p.22 / Chapter 2.10.1 --- Objectives --- p.22 / Chapter 2.10.2 --- Hypotheses --- p.23 / Chapter Chapter III --- Methodology and Results --- p.24 / Chapter 3.1 --- Set up of mouse embryos --- p.24 / Chapter 3.1.1 --- Mouse strain --- p.24 / Chapter 3.1.2 --- Research animal ethnics and care guidelines --- p.24 / Chapter 3.1.3 --- Mouse sacrifice and embryo dissection --- p.24 / Chapter 3.1.4 --- Grouping of embryos --- p.25 / Chapter 3.2 --- Preparations of D-glucose --- p.25 / Chapter 3.3 --- Chinese medicine quality controls and preparations --- p.25 / Chapter 3.4 --- Whole mouse embryo culture --- p.26 / Chapter 3.5 --- Morphological scoring on mouse embryos and statistical analysis --- p.27 / Chapter 3.6 --- Establishment of cranial NTD by D-glucose --- p.28 / Chapter 3.6.1 --- Dosage of D-glucose to induce cranial NTD --- p.29 / Chapter 3.6.2 --- Result --- p.30 / Chapter 3.7 --- Experimental designs --- p.31 / Chapter 3.8 --- Part I: Efficacy and dose-response effects of Maidong extract --- p.32 / Chapter 3.8.1 --- Safety dose of Maidong extract on non-diabetic mouse embryos --- p.32 / Chapter 3.8.1.1 --- Dosage --- p.32 / Chapter 3.8.1.2 --- Result --- p.35 / Chapter 3.8.2 --- Efficacy and dose-effect response of Maidong extract on non-diabetic mouse embryos --- p.36 / Chapter 3.8.2.1 --- Dosage and grouping --- p.37 / Chapter 3.8.2.2 --- Result --- p.38 / Chapter 3.9 --- Part II: Efficacy and dose-response effects of serum from Maidong extract-treated rat serum --- p.40 / Chapter 3.9.1 --- Preparation of Maidong treated non-diabetic full rat serum --- p.41 / Chapter 3.9.1.1 --- Rats --- p.41 / Chapter 3.9.1.2 --- Dosage for feeding --- p.41 / Chapter 3.9.1.3 --- Administration --- p.42 / Chapter 3.9.1.4 --- Termination of rats and preparation of rat serum --- p.42 / Chapter 3.9.2 --- Safety dose of Maidong treated non-diabetic full rat serum non-diabetic mouse embryos --- p.43 / Chapter 3.9.2.1 --- Dosage --- p.43 / Chapter 3.9.2.2 --- Result --- p.44 / Chapter 3.9.3 --- Protective Effect of Maidong extract-treated full rat serum --- p.46 / Chapter 3.9.3.1 --- Dosage and grouping --- p.46 / Chapter 3.9.3.2 --- Result --- p.47 / Chapter 3.10 --- "Part III: Efficacy and dose-response effects of Ophiopogonin D, a major chemical component of Maidong in preventing hyperglycemia-induced cranial neural tube defect" --- p.49 / Chapter 3.10.1 --- Safety dose of Ophiopogonin D --- p.50 / Chapter 3.10.1.1 --- Preparation of Ophiopogonin D --- p.50 / Chapter 3.10.1.2 --- Dosage --- p.50 / Chapter 3.10.1.3 --- Results --- p.52 / Chapter 3.10.2 --- Efficacy and dose-response effects of Ophiopogonin D --- p.53 / Chapter 3.10.2.1 --- Dosage and grouping --- p.53 / Chapter 3.10.2.2 --- Results --- p.55 / Chapter Chapter IV --- Discussion --- p.58 / Chapter 4.1 --- Whole embryo culture system --- p.58 / Chapter 4.2 --- Quality control of Maidong extract --- p.58 / Chapter 4.3 --- "Therapeutic effect of single herb, formula and chemical components" --- p.59 / Chapter 4.4 --- Dosage of D-glucose to induce cranial NTD --- p.60 / Chapter 4.5 --- Dosage and efficacy of Maidong extract and Ophiopogonin D --- p.60 / Chapter 4.6 --- Administration of Maidong extract to non-diabetic female rats --- p.61 / Chapter Chapter V --- Conclusions --- p.63 / Chapter Chapter VI --- Future Study --- p.64 / References --- p.66

Thesis (Ph. D.)--University of Texas Health Science Center at Houston, School of Public Health, 2006. / Includes bibliographical references (leaves 100-107).

Thesis (M. A.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 118-130). Also available via the World Wide Web

Orientador: Vera Lucia Gil da Silva Lopes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-03T22:55:58Z (GMT). No. of bitstreams: 1 Monlleo_IsabellaLopes_M.pdf: 586069 bytes, checksum: 706db2a35c57b9e799229264653c4708 (MD5) Previous issue date: 2004 / Resumo: As anomalias craniofaciais estão entre os defeitos congênitos humanos mais freqüentes e demandam assistência multiprofissional, integral e especializada, cujo custo é elevado. O médico geneticista destaca-se na equipe por ter habilidades para a caracterização etiológica e nosológica dessas condições, fundamentais para o aconselhamento genético e a correta obtenção de dados epidemiológicos. Todavia, o acesso ao tratamento ainda é precário em muitas nações, motivo pelo qual a Organização Mundial de Saúde vem estimulando pesquisas sobre oferta de serviços e qualidade da assistência prestada. Além disso, é reconhecido que a ampla variação da qualidade e dos custos da assistência estão relacionados às características estruturais e funcionais dos serviços. A primeira iniciativa para atenção a portadores de Anomalias Craniofaciais no Sistema Único de Saúde do Brasil ocorreu em 1993. Com a criação da Rede de Referência no Tratamento de Deformidades Craniofaciais, o atendimento foi ampliado, contando atualmente com 29 centros credenciados. Até o momento, esses centros não foram caracterizados. Os objetivos deste trabalho foram avaliar a organização dessa Rede, descrever a estrutura e funcionamento dos centros que a integram e verificar a oferta e o acesso à genética clínica nesses locais. Para coleta dos dados, foi utilizado um questionário semi-estruturado, remetido por correio. Os resultados demonstram agregação de centros no Sudeste, em universidades e na área de fissuras labiopalatais, com atendimento de rotina em cerca de 90% deles. A denominação da rede de assistência não parece corresponder à sua atual abrangência. As equipes estão constituídas de acordo com critérios americanos em 14 e, com europeus, em cinco centros participantes do estudo. Há geneticistas clínicos em 13 centros. Dentre esses, 61,8% contam com apenas um especialista dessa área. Apesar da baixa inserção do geneticista, em 22 centros, pais e pacientes solicitam informações sobre etiologia e prevenção que são fornecidas em 80,0% dos centros; todavia em 55% deles essa atividade é realizada por médicos não geneticistas e outros integrantes da equipe. Em conclusão, os dados sugerem a necessidade de revisão da definição, objetivos, abrangência e critérios de credenciamento dos centros de atendimento e caracterizam a precariedade da oferta e do acesso à genética clínica na Rede de Referência no Tratamento de Deformidades Craniofaciais / Abstract: Craniofacial anomalies are one of the most common birth defects in man, which have considerable medical costs in view of the long, specialized and complex treatment. The presence of the Clinical Geneticist on the team is important for clinical and etiologic characterization of these anomalies, genetic counseling and epidemiologic register. As the access for treatment is not easy in many countries, the World Health Organization launched a project for research availability and quality of the specialized services. Previous research demonstrates that variation of costs and quality of the services were related with theirs structural and functional characteristics, as well. The first initiative for public craniofacial anomalies health care in Brazil was in 1993. An important improvement occurred with the creation of the Net for Craniofacial Deformities Treatment, which is composed by 29 centers. Until now, these centers had not been studied before. The aims of this study were to evaluate the Net for Craniofacial Deformities Treatment, to describe the structural and functional characteristics of these centers and the access for genetic evaluation and genetic counseling for individuals and families in them. Data were collected by a questionnaire mailed for all these centers. The results showed an increased of centers in Southeast and in universities. Cleft lip and palate is the main clinical condition treated. Routine attendance occurred in 90% of the centers. Teams¿ composition is similar to American criteria in 14 of the centers and to European, in 5. The denomination of this assistance net does not seem in accordance to its actual activities. Clinical geneticist was present in 13 centers and 61,8% had one professional. In spite of few Clinical Geneticists in the composition of the teams, in 22 centers of attendance patients and parents asked for etiology and prevention, which have been done in 80% of them. These informations are transmitted by a non-specialized physicians and others members of the team in 55% of the centers. These data suggested that it would be necessary the revision of definition, goals, activities and standards for inclusion of the craniofacial centers. They also demonstrated that the availability and the access for clinical geneticist is not enough in the Net for Craniofacial Deformities Treatment of Brazil / Mestrado / Genetica Medica / Mestre em Ciências Médicas

Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Indiana University-Purdue University Indianapolis (IUPUI) / Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21) and occurs in ~1 of every 700 live births. Individuals with DS present craniofacial abnormalities, specifically an undersized, dysmorphic mandible which may lead to difficulty with eating, breathing, and speech. Using the Ts65Dn DS mouse model, which mirrors these phenotypes and contains three copies of ~50% Hsa21 homologues, our lab has traced the mandibular deficit to a neural crest cell (NCC) deficiency in the first pharyngeal arch (PA1 or mandibular precursor) at embryonic day 9.5 (E9.5). At E9.5, the PA1 is reduced in size and contains fewer cells due to fewer NCC populating the PA1 from the neural tube (NT) as well as reduced cellular proliferation in the PA1. We hypothesize that both the deficits in NCC migration and proliferation may cause the reduction in size of the PA1. To identify potential genetic mechanisms responsible for trisomic PA1 deficits, we generated RNA-sequence (RNA-seq) data from euploid and trisomic E9.25 NT and E9.5 PA1 (time points occurring before and after observed deficits) using a next-generation sequencing platform. Analysis of RNA-seq data revealed differential trisomic expression of 53 genes from E9.25 NT and 364 genes from E9.5 PA1, five of which are present in three copies in Ts65Dn. We also further analyzed the data to find that fewer alternative splicing events occur in trisomic tissues compared to euploid tissues and in PA1 tissue compared to NT tissue. In a subsequent study, to test gene-specific treatments to rescue PA1 deficits, we targeted Dyrk1A, an overexpressed DS candidate gene implicated in many DS phenotypes and predicted to cause the NCC and PA1 deficiencies. We hypothesize that treatment of pregnant Ts65Dn mothers with Epigallocatechin gallate (EGCG), a known Dyrk1A inhibitor, will correct NCC deficits and rescue the undersized PA1 in trisomic E9.5 embryos. To test our hypothesis, we treated pregnant Ts65Dn mothers with EGCG from either gestational day 7 (G7) to G8 or G0 to G9.5. Our study found an increase in PA1 volume and NCC number in trisomic E9.5 embryos after treatment on G7 and G8, but observed no significant improvements in NCC deficits following G0-G9.5 treatment. We also observed a developmental delay of embryos from trisomic mothers treated with EGCG from G0-G9.5. Together, these data show that timing and sufficient dosage of EGCG treatment is most effective during the developmental window the few days before NCC deficits arise, during G7 and G8, and may be ineffective or harmful when administered at earlier developmental time points. Together, the findings of both studies offer a better understanding of potential mechanisms altered by trisomy as well as preclinical evidence for EGCG as a potential prenatal therapy for craniofacial disorders linked to DS.

Indiana University-Purdue University Indianapolis (IUPUI) / Ciliopathies with multiorgan pathology include renal cysts and eye pathology. Previous studies showed meckelin (MKS3 protein product) are crucial to cilia function and its absence in Wpk rats (with mutated rMks3 gene) causes Leber's congenital amaurosis. Retinal photoreceptors have connecting cilium that joins the inner to the outer segment and plays a role in the transport of molecules necessary for morphological and molecular development and maintenance of the outer segment process. The present study evaluated meckelin expression during normal postnatal retinal development and the consequences of mutant meckelin on photoreceptor development and survival in Wistar-Wpk/Wpk rat. Meckelin was co-expressed in photoreceptors, amacrine, Muller glia and ganglion cells in postnatal day 10 (P10) and P21 wild type retinae. Meckelin was detected in both inner and outer segments of photoreceptors. By P10, both wild type and homozygous Wpk mutant retina had all retinal cell types. In contrast, by P21, cells expressing photoreceptor-specific markers in the Wpk mutant were fewer in number with abnormal expression patterns. Cell death assays confirmed a significant amount of cells undergoing apoptosis in the outer nuclear layer of the mutant rat retina. By electron microscopy, mutant photoreceptors did not develop an outer segment process beyond a connecting cilium and rudimentary outer segment. We conclude that MKS3 is not important for formation of connecting cilium and rudimentary outer segments, but is critical for the elongation and/or maintenance of mature outer segment processes.

The works of Vladimir Nabokov have traditionally functioned in a way that challenges its reader to question existing notions of normality. In his works, Nabokov has frequently utilized representations of disability as a means to comment or critique the human condition. Throughout this project I intend to demonstrate how the narratives in both Lolita and Laughter in the Dark function as a normative force which embodies the cultural attitudes regarding disability. This is accomplished through the enforcement of a normative reading by the narrative. It is clear then that Nabakov is attempting to subvert literary conventions by using nontraditional narrators to demonstrate the relativity of normality. Throughout this project, I will be focusing on Nabakov’s use of narrator to distort the cultural line between disability and ability. Ultimately, the goal of this project is to demonstrate that current societal notions of normality and disability are outdated and arbitrary. / Includes bibliography. / Thesis (M.A.)--Florida Atlantic University, 2013.

The dramatic improvement of neonatal intensive care has produced vexing ethical and legal questions. One of the most striking issues is to determine whether the most defective neonates should be provided with intensive care and to what extent they should be treated. This thesis demonstrates that an attempt to answer this question and an analysis of the demands and limitations of a duty to treat defective neonates cannot properly occur without first considering the legal concerns and ethical issues surrounding the notion of "person". The author examines germane ethical theories and North-American jurisprudence to see what approaches and standards commentators and courts have adopted in this respect. This thesis demonstrates that in the context of the cessation or non-initiation of intensive care, the legal and moral status of very defective neonates remain ambiguous. In particular, the author suggests that a legal best interests analysis that includes quality of life considerations may actually involve the use of criteria similar to those supported by the authors of the controversial moral theories that negate the personhood of seriously handicapped newborns. The author ultimately concludes that a clear divide between the legal definition of the "person" and the moral and social perceptions of that term is misleading.