Gene expression can be regulated at multiple steps once transcription is initiated. I have studied two different gene models, the α-Fetoprotein (AFP) and the immunoglobulin heavy chain (IgM) genes, to better understand post-transcriptional gene regulation mechanisms. The AFP gene is highly expressed during fetal liver development and dramatically repressed after birth. There is a mouse strain-specific difference between adult levels of AFP, with BALB/cJ mice expressing 10 to 20-fold higher levels compared to other mouse strains. BALB/cJ mice express low levels of Zhx2 and thus incompletely repress AFP. Despite differences in steady state AFP mRNA levels in the adult liver between Balb/cJ and wild-type mice, transcription rates across this gene were similar, indicating a post-transcriptional regulatory mechanism. I found accumulated unspliced RNA across multiple AFP introns in wild-type mice where mature AFP mRNA levels are low, suggesting overall AFP splicing is inefficient in the presence of Zhx2. The IgM gene is alternative processed to produce two mRNA isoforms through a competition between cleavage/polyadenylation (μspA) and splicing reactions and the pA/splice RNA expression ratio increases during B cell maturation. Cotranscriptional cleavage (CoTC) events, driven by specific cis-acting elements, are required downstream of some poly(A) signals to terminate transcription. In some cases, a pause site can produce similar effect. I explored whether there is a CoTC-like element within the IgM gene that may contribute to developmental changes in the mRNA ratio. In both a B cell and plasma cell line there was a gradual decrease in transcripts downstream from the μspA signal, suggesting that there is not evidence for a CoTC element within the IgM gene. To examine the effect a CoTC element would have on the competition between the splice and μspA reactions, we inserted the CoTC sequence of the β-globin gene into different locations downstream of the μspA signal. While the β-globin CoTC element caused cotranscriptional cleavage in all locations, it only affected the μspA/splice ratio when located close to the μspA site. This suggests there is a position effect of the inserted CoTC element on the competing polyadenylation and splicing reactions within the IgM transcripts.

Preimplantation genetic diagnosis is a technique used in the field of assisted reproduction. The technique is applied to embryos that have been created in vitro, in order to facilitate the selection of embryos according to particular genetic parameters. The use of preimplantation genetic diagnosis by prospective parents at high risk for having a child affected by a genetic disorder has facilitated the birth of unaffected children. Preimplantation genetic diagnosis has already been used for other purposes, such as screening for gender, and could in principle be used to screen for a wide range of genetic traits. The aim of this thesis is to provide good answers to the ethical questions provoked by the advent and continuing development of preimplantation genetic diagnosis. The thesis is divided into four parts. Part One provides a brief overview of the science of genetic selection. Part Two is centred on a discussion of two ethical principles. The principle of procreative liberty is based upon the idea that acts of interference in the reproductive lives of others should be avoided unless there is good justification for such acts. The principle of procreative beneficence is based upon the idea that prospective parents should select the child, of the possible children they could have, who is expected to have the best life. I will argue that the principle of procreative liberty should be applied to acts of interference in individuals� freedom to use preimplantation genetic diagnosis, while the principle of procreative beneficence should be applied to acts of selecting children. In Part Three, I will endorse a position that accords embryos a relatively low moral status, reject the arguments of the disability rights critique, argue that the eugenic aspects of preimplantation genetic diagnosis do not warrant much concern, and develop a framework for critically evaluating slippery slope arguments. Finally, in Part Four, specific applications of preimplantation genetic diagnosis will be examined in detail. Although each application raises unique ethical questions, this thesis aims to demonstrate that the consistent application of the principles and preliminary conclusions developed in Parts Two and Three provides the best means for determining how PGD should be used and which uses should be restricted.

Offprints of several author's journal articles inserted / Includes bibliography / xx, 285 leaves : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 1985

Thesis (Ph. D.)--University of Wisconsin--Madison, 1968. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M.S.)--Brandeis University, 2009. / Title from PDF title page (viewed on August 9, 2009). Includes bibliographical references.

Orientadores: Antonia Paula Marques de Faria, Luis Alberto Magna / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T13:15:47Z (GMT). No. of bitstreams: 1 Moraes_AnaMariaSilveiraMachadode_D.pdf: 41612973 bytes, checksum: 8855a4185126a5a57c25db1786b2d7b9 (MD5) Previous issue date: 2006 / Resumo: Foi realizado um estudo de levantamento, para averiguar o perfil do atendimento preventivo para retardo mental (RM) na rede de atenção primária do município de Maringá, Paraná. Aplicou-se um questionário a 90 médicos, compreendendo pediatras, ginecologistas-obstetras, clínicos gerais e médicos do Programa de Saúde da Família, e a 66 enfermeiros que trabalham na rede municipal de saúde, e uma entrevista estruturada a 100 mães residentes no município, escolhidas aleatoriamente, a partir do cadastro de nascidos-vivos do ano de 2003. A coleta de dados entre os profissionais de saúde foi realizada no período de agosto a dezembro de 2003 e a entrevista com as mães, entre junho e outubro do mesmo ano. Os dados dos profissionais de saúde foram analisados pela comparação das respostas entre médicos e enfermeiros e entre as especialidades dos médicos. Para o grupo das mães, os dados foram analisados pela comparação do grupo que fez o pré-natal na rede pública com o atendido na rede privada. As variáveis qualitativas foram comparadas pelo teste do qui-quadrado e as quantitativas pelo teste t de Student. Os resultados demonstraram que 69,7% dos médicos e 78,8% dos enfermeiros desconhecem a prevalência do RM (p= 0,011); 63,3% dos médicos e 65,2% dos enfermeiros não sabem qual é a fração de RM evitável (p= 0,764); 16,5% dos médicos e 45,6% dos enfermeiros não têm segurança para orientar sobre o efeito teratogênico do etanol (p= 0,001); 45,7% e 80,3% dos médicos, 77,2% e 96,4% dos enfermeiros não se sentem seguros para orientar sobre a translucência nucal e sobre o teste triplo, respectivamente (p= 0,001 e p= 0,053). Comparando as respostas dos médicos, os pediatras (71,4%) e os clínicos gerais (54,8%) demonstraram maior insegurança para orientar quanto aos efeitos teratogênicos do misoprostol do que os ginecologistas obstetras (11,8%) e sobre as técnicas de diagnóstico pré-natal. Entre as mães, 65% não planejaram a gravidez; a maioria não foi questionada sobre história familial de retardo mental (70%) ou sobre consangüinidade (84%); a maioria desconhece diagnóstico pré-natal (83%) e aconselhamento genético (92%), e 46% desconhecem a associação entre idade materna e risco aumentado de filho com síndrome de Down. Conclui-se que a busca de situações de risco, no que se refere à exposição a fatores deletérios do ambiente e a antecedentes familiais relevantes, não está sendo feita na prática e que a maior parte das mães desconhece informações básicas sobre fatores de risco comuns para RM. Portanto, é necessário que sejam adotadas medidas de educação em genética para que os profissionais de saúde passem a reconhecer a importância dos fatores de risco e da história familial na identificação e prevenção do RM, incluindo a busca desse tipo de informação à sua prática rotineira; sejam desenvolvidos programas educacionais sobre fatores de risco e meios de prevenção dessa condição, no âmbito da saúde pública, de fácil compreensão e incorporação pela população geral, bem como a disponibilização de material de orientação para o manejo dos pacientes com problemas genéticos, incluindo RM e/ou defeitos congênitos / Abstract: This is a survey to verify the preventive attendance profile for mental retardation (MR) in the primary health service in the town of Maringá, Paraná. A questionnaire was applied to 90 physicians, involving pediatricians, gynecologist obstetricians, general practitioners and family physicians, as well as to 66 nurses and a structural interview was also applied to 100 mothers who live in the city. The health professionals work for the health municipal service and the mothers were selected at random based on the official register of born-alive individuals in 2003. Data collection related to the health professionals was carried out from August to December, 2003, and the interviews with the mothers from June to October of the same year. The data of the health professionals had been analyzed by the comparison of the answers between physicians and nurses and among the physicians' specialties. Dates related to mothers were analyzed through the comparison between the group assisted at the health public system and the ones assisted at the private system. The qualitative variables had been compared by the test of the Chi-square and the quantitative variables by the Student's / test. The findings showed that 69.7% of the physicians and 78.8% of the nurses do not know MR prevalence (p= 0.011); 63.3% of the physicians and 65.2% of the nurses do not know the fraction can be avoided (p- 0.764); 16.5% of the physicians and 45.6% of the nurses are not self-confident in order to inform the patients on ethanol teratogenic effect (p= 0.001); 45.7% and 80.3% of the physicians and 77.2% and 96.4% of the nurses are not self-confident in the sense of giving information on the nuchal translucence and about the triple test, respectively (p- 0.001 and p= 0.053). Comparing the physicians, pediatricians (71.4%) and the general practitioners (54.8%) showed higher unsteady behavior to guide on the teratogenic effects of misoprostol instead of the gynecologists obstetricians (11.8%) and about the prenatal diagnostic techniques. Considering the mothers, 65% had not planned pregnancy. Most of them had not been questioned on either the familial MR (70%) or consanguinity (84%) and are not aware of the prenatal diagnosis (83%) and genetic counseling (92%); 46% do not know the association between the maternal age and the increased risk to have a child with Down syndrome. It was concluded that the search for risk situations, regarding the exposure to environmental deleterious factors and the relevant / Doutorado / Genetica Medica / Doutor em Ciências Médicas

Orientador: Vera Lúcia Gil da Silva Lopes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-18T17:55:29Z (GMT). No. of bitstreams: 1 Fontes_MarshallItaloBarros_M.pdf: 3724290 bytes, checksum: a718bf4ec25c48712d910bdb7b259ad5 (MD5) Previous issue date: 2011 / Resumo: As fendas orofaciais (FOF) têm prevalência mundial em torno de 1:600 nascidos-vivos. Trata-se de um grupo heterogêneo, com significativa associação a comorbidades e que demanda assistência multiprofissional, integral e especializada. No Brasil, embora exista a Rede de Referência no Tratamento de Deformidades Craniofaciais (RRTDCF), com atuação na esfera de alta complexidade, não existem propostas para os demais níveis de atenção no Sistema Único de Saúde (SUS). O presente estudo representa uma abordagem pioneira em Alagoas, com o objetivo de contribuir para a atenção em genética de portadores de fendas orofaciais no estado, por meio do reconhecimento das características clínicas e genéticas de seus portadores. Os dados foram coletados entre setembro de 2009 e fevereiro de 2011, por meio de protocolo validado. A casuística foi composta por 104 indivíduos (M1,1:F1). Apenas 11,5% dos pacientes tinham idade inferior a um ano. Do total da amostra, 38/104 (36,5%) ainda necessitam de cirurgia primária para correção da FOF e, destes, 15/38 (39,5%) apresentam idade superior a 2 anos. Quanto ao tipo de FOF, 61,5% apresentavam fenda labiopalatal, 23,1%, fenda labial e 15,4%, fenda palatal. Setenta e cinco por cento dos casos eram de FOF isolada e 25,0%, de FOF sindrômicas. Os defeitos major acometiam os sistemas nervoso central, cardiovascular e esquelético. A taxa de consanguinidade parental foi 9,7% e de recorrência familial, 28,7%. Houve associação preferencial entre deficiência mental e FOF sindrômica (p=0,003). Os resultados retratam a realidade local, relativos ao diagnóstico e ao tratamento de FOF. As características clínicas apresentadas foram similares às descritas na literatura. Detectou-se acesso tardio à cirurgia e avaliação genético-clínica de parte significativa da amostra. Esses resultados poderão ser aplicados na estruturação da atenção à saúde de pessoas com FOF no SUS, de acordo com as necessidades de saúde específicas da população de Alagoas / Abstract: Introduction: Orofacial clefts (OC) occur in approximately 1/600 newborns babies worldwide and are among the most common birth defects. Multidisciplinary, team-based, coordinated and family-centered healthcare is accepted as the state of the art in this field. Public healthcare for patients with orofacial clefts was structured in 1998 in Brazil through 21 units arranged as a network unevenly distributed. Alagoas is a poor state located in the Northeast region of the country in which there is not specialized center for care of patients with OC. Aim: to describe demographic and clinical-genetic characteristics as a subside to structure healthcare for patients with OC in Alagoas. Methods: All patients were systematically seen by two clinical geneticists using a pretested protocol from September 2009 to February 2011. Conventional and molecular cytogenetic analyses were performed in selected patients. Fisher Test was used for statistics with p-value<0.05. Results: majority of patients were males, country side residents, with isolated cleft lip with cleft palate. Ages ranged between 0-37 years. Thirty six percent had never undergone surgery while 100% had never attended to genetic evaluation. Isolated cleft was diagnosed in 75%, syndromes in 14.4%, multiple congenital defects in 9.6% cases and additive randomic defects in 1.0%. Organs systems most affected by major defects were central nervous, cardiovascular and skeletal systems. Recurrence and parental consanguinity were, respectively, 28.7% and 9.7%. Twenty-three individuals without cleft surgery were registered for multidisciplinary treatment. Conclusions: Clinical-genetic characteristics corroborate the literature. Findings revealed high levels of unmet medical needs and provided an evidence base for health care planning / Mestrado / Genetica Medica / Mestre em Ciências Médicas

Inledning: När en äldre människa har ett stort omvårdnadsbehov finns möjligheten att flytta till ett särskilt boende. Då äldres vardag ser olika ut är det av yttersta vikt att omvårdnadspersonalen kan ge stöd och hjälp så att den äldre skall kunna anpassa sig till den nya situationen. Syfte: Syftet med denna studie är att belysa hur anhöriga upplever att deras närstående i särskilt boende får en god omvårdnad. Metod: En kvalitativ ansats med empiriskt inslag användes där anhörigas upplevelser av omvårdnad, delaktighet och bemötande insamlades med hjälp av intervjuer. Resultat: Tre olika kategorier Omvårdnad, Delaktighet och Bemötande med nio underkategorier. En betydelsefull del i omvårdnaden är att det skapas en god kontakt mellan anhöriga och omvårdnadspersonalen för att finna ett bra sätt att kommunicera på. Det framkom hur viktigt det är att som vårdtagare känna att de blir sedda för den de är och att de får vara delaktiga i de omvårdnadsåtgärder som beslutas av omvårdnadspersonalen. Diskussion: Resultatet kan bidra till en ökad förståelse för anhörigas upplevelser av hur omvårdnaden bedrivs i särskilt boende. När anhöriga göras mer delaktiga i omvårdnaden, kan det leda till en bättre omvårdnad för vårdtagaren i särskilt boende. Slutsats: Resultatet som författarna kom fram till skulle kunna användas i utbildningssyfte då omsorgen av äldre människor kräver att omvårdnadspersonalen ständigt förnyar sina kunskaper. Detta kan vara till gagn för sjuksköterskan, de anhöriga och de äldre som bor i särskilt boende. / Introduction: When a senior person has a large need for special care there is an option to relocate to a nursing home. The seniors every day varies there for it is of outmost importance the nursing care staff can support the senior that he maybe adapt to the new situation. Purpose: The purpose with this study is to enlighten how relatives experience their close ones in special nursing home receive good care treatment. Method: A quality approach with empirical elements is used where relatives experiences of care, being part of and recievment was collected with the help of interviews. Results: Three categories Care, Involvment and Recievment with nine sub categories. An important part in care is to create good contact between relatives and nursing care staff to evolve good ways for communication. It was revealed how important it is as a health care patient to feel they’re being looked upon for who they are and they be part of treatment measures and decisions made by nursing care staff. Discussion: The results can contribute to an increased understanding to how relatives experience care is being conducted in a special accommodation. When relatives are made more involved in care, may lead to a better care for care patient in a nursing home. Conclusion: The results which have been concluded could be used in educational purposes when the care of senior people demands that nursing care staff continuously renews their knowledges. This could be of use for the nurse, the relatives and the seniors living in a nursing home.

Malt lymphoma is a malignant disease that can arise in a variety of extra nodal sites. Previous studies indicate that tumour arise from more mature B-cells. Our purpose was to examine the presence of clonality and somatic hypermutation of immunoglobulin (IgVн) of MALT lymphomas. Paraffin-embedded tumour samples from13 MALT lymphoma were subjected to rearrangement analysis, by using PCR, heteroduplex gels and sequence analysis. Successful amplification was seen in 10/13 cases and sequences of IgVн genes were obtained in 6/13, all of them were mutated. The percentage of mutation compared to germline sequences was 1,1% to 8,6% monoclonal rearrangemang. It was demonstrated that 5 of 7 clones were derived from the Vн3 family, 2 from Vн1 and 1 from the Vн 4 family.

Identifying disease risk genes is a central topic of human genetics. Cost-effective exome and whole genome sequencing enabled large-scale discovery of genetic variations. However, the statistical power of finding new risk genes through rare genetic variation is fundamentally limited by sample sizes. As a result, we have an incomplete understanding of genetic architecture and molecular etiology of most of human conditions and diseases. In this thesis, I developed new computational methods that integrate functional genomics data sets, such as epigenomic profiles and single-cell transcriptomics, to improve power for identifying genetic risks and gain more insights on etiology of developmental disorders. The overall hypothesis that disease risk genes contributing to developmental disorders are bottleneck genes under normal development and subject to precise transcriptional regulations to maintain spatiotemporal specific expression during development. In this thesis I describe two major research projects. The first project, Episcore, predicts haploinsufficient genes based on a large integrated epigenomic profiles from multiple tissues and cell lines by supervised machine learning methods. The second one, A-risk, predicts plausibility of being risk genes of autism spectrum disorder based on single-cell RNA-seq data collected in human fetal midbrain and prefrontal cortex. Both methods were shown to be able to improve gene discovery in analysis of de novo mutations in developmental disorders. Overall, my thesis represents an effort to integrate functional genomics data by machine learning to facilitate both discovery and interpretation of genetic studies of human diseases. We believe that such integrative analysis can help us better understand genetic variants and disease etiology.