Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis (M.S.)--Brandeis University, 2009. / Title from PDF title page (viewed on May 29, 2009). Includes bibliographical references.

Edited by Samuel S. Epstein, with associate editors: Joshua Lederberg [and others] / "Based on a symposium cosponsored by the Center for Studies of Narcotic and Drug Abuse, NIMH, and by the Environmental Mutagen Society, San Francisco, October 29 and 30, 1969." / Includes bibliographies.

Made available in DSpace on 2015-12-10T14:23:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-25. Added 1 bitstream(s) on 2015-12-10T14:29:22Z : No. of bitstreams: 1 000847907.pdf: 435955 bytes, checksum: 28562835fdb8912e96dfb94f7a160314 (MD5) / Introdução: A infertilidade é definida como a incapacidade de um casal obter uma gravidez ou parto de um bebê vivo. Ela não é exclusiva da mulher, mas sim do casal, e os fatores mais comuns associados são de origem genética, como alterações dos cromossomos, incluindo também causas hormonais, anatômicas, infecciosas, imunológicas, entre outras. A definição dos tipos de alterações cromossômicas presentes em um casal com dificuldades reprodutivas é de fundamental importância para sua vida reprodutiva. Objetivo: Verificar a importância das diferentes alterações cromossômicas na etiologia da infertilidade e discutir a indicação do cariótipo nos casos de dificuldades reprodutivas. Metodologia: Estudo retrospectivo de dados de 832 indivíduos, atendidos na Faculdade de Ciências/ UNESP, Bauru, no período de Janeiro de 2005 a Dezembro de 2012, referentes a estudos cromossômicos (cariótipo de sangue periférico e abortos espontâneos) e anamnese. Resultados: Dos 832 casos, 431 foram avaliados através dos cariótipos de sangue periférico e 514 através de seus cariótipos de abortos espontâneos; 113 foram avaliados tanto pelos cariótipos de sangue como pelos cariótipos de seus abortos. A frequência das alterações cromossômicas em sangue periférico foi de 5,6%, e de 32,5 % em abortos espontâneos. Não houve correlação estatística entre ocorrência das alterações cromossômicas, sexo, idade e número de abortos. Conclusões: Na população estudada observou-se que as alterações cromossômicas são importantes na etiologia da infertilidade. As alterações cromossômicas numéricas nos abortos são as mais frequentes; contudo, sua ocorrência pode ser maior devido a possível superestimação dos cariótipos normais pela contaminação de material materno. Para prevenção de malformações congênitas, ambos os membros do casal relacionados a problemas reprodutivos devem realizar o estudo cromossômico / Introduction: Infertility is defined as the inability of a couple of getting pregnant or give birth to a live baby. It is not only related to women, but also to the couple, and the most common factors associated are genetic, such as chromosome abnormalities as well as hormonal, anatomical, infectious and immunological causes, among others. The definition of the types of chromosomal abnormalities present in a couple with reproductive difficulties is of fundamental importance to their reproductive life. Objective: To assess the importance of different chromosomal abnormalities in the etiology of infertility and discuss the indication of the karyotype in cases of reproductive difficulties. Methodology: Karyotypes of peripheral blood and miscarriages (Chromosomal studies) and anamnesis of 832 individuals attended at the Faculdade de Ciências/ UNESP, Bauru, from January 2005 to December 2012 were assessed retrospectively. Results: Of the 832 cases, 431 were evaluated by peripheral blood karyotypes and 514 through their karyotypes of miscarriages; 113 were evaluated both by karyotypes of both blood and abortions. The frequency of chromosomal abnormalities in peripheral blood was 5.6%, and 32.5% in spontaneous abortions. There was no statistical correlation between occurrence of chromosomal abnormalities, sex, age and number of abortions. Conclusions: Chromosomal abnormalities are important in the etiology of infertility within the population studied. The numerical chromosomal abnormalities in abortions were the most common; however, its occurrence may be higher due to possible overestimation of normal karyotypes by contamination of maternal material. Aiming the prevention of congenital malformations, both couple members presenting reproductive problems should perform a chromosome study

Made available in DSpace on 2014-06-11T19:32:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-03-21Bitstream added on 2014-06-13T21:03:45Z : No. of bitstreams: 1 domingues_cef_dr_botib.pdf: 8383595 bytes, checksum: 12825237e7433888847a69be2e9616ba (MD5) / A gagueira é uma doença comum que afeta a fluência da fala, caracterizada por repetições ou prolongamentos frequentes de sons, sílaba, palavras, ou por hesitações, ou interrupções no fluxo normal da fala. Trata-se de uma doença que tipicamente surge na infância em crianças com idade entre dois e quatro anos, com taxa de incidência estimada em torno de 5% da população. No entanto devido à elevada taxa de recuperação espontânea, estima-se uma prevalência de 1% na população em geral. Apesar do envolvimento de fatores ambientais, o fator genético é determinante para o desenvolvimento da doença. Algumas evidências que sustentam essa relação são: agregação familial, estudos com gêmeos e envolvendo adoções e, relações de consanguinidade em famílias com diversos afetados. Entretanto, trata-se de uma doença complexa na qual a identificação exata do tipo de herança é difícil de ser determinada uma vez que não seguem as leis de Mendel. Este estudo teve como principal finalidade realizar análises de ligação em 43 famílias brasileiras do Estado de São Paulo, não relacionadas, portadoras de gagueira desenvolvimental persistente a fim de identificar regiões cromossômicas com possíveis genes candidatos; Para as análises de ligação, inicialmente foi realizada a genotipagem de todas as famílias através de chips específicos para essa finalidade contendo 6056 marcadores SNP. Posteriormente, para o refinamento do mapa de ligação foram utilizados marcadores microssatélites polimórficos marcados com fluoróforos e analisados em sequenciador automático capilar. Para as estimativas das frequências alélicas destes marcadores na população brasileira foram utilizados amostras do grupo controle, não relacionadas, previamente selecionadas. Apenas duas famílias (BRPD_47 e BRPD_50) sob o padrão de herança dominante... / Stuttering is a common disease that affects the fluency of speech, and is characterized by frequent repetitions or prolongations of sounds, syllables, or words, or by interruptions in the normal flow of speech. The disorder typically begins in children aged two to four years, and has an estimated incidence rate of around 5% of the population. Due to the high rate of spontaneous recovery, the estimated prevalence of the disorder is 1% in the general population. Despite the involvement of environmental factors, genetic factors have been shown to be critical to the development of the disease. Evidence supporting genetic factors include twin studies, adoption studies, family clusters of stuttering, and consanguineous relations in families with many cases of the disorder. However stuttering is a complex disorder in which the identification of the exact type of inheritance is difficult to determine because it does not follow Mendelian laws. The main goal of this study was to perform a genome-wide linkage analysis in 43 unrelated families from the Brazilian state of São Paulo, which had multiple cases of persistent developmental stuttering, in an effort to identify chromosomal regions containing possible causal genes, Linkage analysis was initially performed by genotyping of all families with chip-based methods that assayed 6056 sNP markers. Subsequent refinement of linkage locations used polymorphic microsatellite markers analyzed by capillary electrophoresis unsing an automated DNA sequencer. Unrelated normal Brazilian samples were used as a control group to estimate the allele frequencies of these markers in this population. Two families (BRPD_47 and BRPD_50) showed significant evidence for linkage in the region of chromosome 10q21 under a dominant inheritance model. Combining these two families produced... (Complete abstract click electronic access below)

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

A form of familial sex-linked mental retardation has been associated with the expression of a fragile site near the terminal end of the long arm of the X chromosome. Previous reports on the fragile X chromosome showed expression of the fragile site to be limited to chromosome preparations from peripheral blood lymphocytes of mentally retarded males and their female relatives in families in which the disorder was segregating. Fragile site expression has also been shown to be a function of the medium employed in cell culture. The fragile X chromosome could only be demonstrated in lymphocytes cultured in medium 199 or media deprived of folic acid. This study was undertaken to develop a method for demonstrating the fragile X chromosome in cultured skin fibroblasts. Fibroblast cell lines from five patients (two mentally retarded males, two obligate carrier females, and a potential carrier female) from a family in which familial sex-linked mental retardation was known to be segregating were established and routinely maintained in a complete culture medium. Forty-three hours prior to chromosome harvest, cells from each patient were transferred to media deficient in folic acid. Under conditions of folic acid deprivation, it was possible to elicit expression of the fragile X chromosome in skin fibroblasts from all five patients studied. No fragile X chromosomes were detected in fibroblasts from three normal control subjects. In a preliminary assessment of the reliability of the fibroblast method, three patients (two mentally retarded males and a potential carrier female) from a second unrelated family in which the disorder is known to be segregating were studied with this method. The fragile X chromosome could be demonstrated in fibroblasts from both of the retarded male patients but could not be. demonstrated in fibroblast chromosome preparations from the potential carrier female. Lymphocytes for all patients studied were grown under similar folate deprived conditions for the purpose of comparing the effectiveness of fibroblast culture with lymphocyte culture in demonstrating the expression of the fragile X chromosome. Neither tissue was shown to consistently provide a higher frequency of expression of the fragile X chromosome. In addition to folate deprivation, it was shown that two other features of the fibroblast method influenced the frequency of expression of the fragile X chromosome. The fragile site was expressed at a significantly higher frequency in chromosome preparations in which the chromosomes were not severely contracted. The frequency of expression in fibroblasts was also shown to be significantly higher with a hypotonic treatment at chromosome harvest using 1% NaCitrate rather than 0.075M KC1. Because fragile site expression was shown to be a function of the degree of chromosome condensation, two agents, 5-BrdU and actinomycin-D, were studied to examine their decondensation effects on the frequency of expression. Neither BrdU nor actinomycin D proved effective in accentuating the frequency of expression. Since fibroblasts behave much like amniocytes in terms of cell culture and chromosome harvest, the development of a method for demonstrating the fragile X chromosome in cultured skin fibroblasts is a step toward the prospect of reliable antenatal diagnosis of familial sex-linked mental retardation associated with a fragile X chromosome. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

No description available.

M.Comm. / A revolution in genetic research, known as the Human Genome Project (HGP), is taking place. This project, initiated in 1984, is a twenty-year, six billion-dollar science project designed to map the entire genetic structure (Genome) of the human species (Brockett and Tankersley, 1995). In 1998, the HGP leaders expected to complete the project by 2003 (Lowden, J. A., 1999:33). The Human Genome Project is designed to sequence the human genome (the blue print of genetic information) and to identify the estimated 100000 genesherein. This has added a new dimension to the technology available to underwriters in the life and health insurance industry for the selection of medical risks. Genetic testing can identify inherited diseases and predict illnesses that might not manifest for decades (Brackenridge & Elder, 1998:89). Genome research has opened up new opportunities for diagnosis and in some cases, early treatment of medical conditions. This new basis of knowledge is referred to as the advent of the molecular age in medicine. Medical journals, the mass media and genetic interest groups are treating human genetics and the opportunities it presents as a high-profile issue, with great attention being paid to the complex and emotive topics of life insurance and genetic testing (Regenauer & Schmidtke, 1998:5). The Insurance Industry can use genetic testing to identify high-risk applicants more accurately and price products accordingly, thereby improving risk assessment and profitability. These potential advantages, however, are counter-balanced by ethical considerations that are much more difficult to address (Lowden, J. A., 1999:33). Many consumers, ethicists and geneticists fear that insurers will use this data for unfair discriminatory purposes, identifying a genetic underclass of people who, although clinically well, will be uninsurable. Genetic testing could invade the privacy of applicants and their families. There are concerns about the confidential handling of genetic information as well as the accurate interpretation of genetic tests. The uncertainty about the predictive value of genetic tests, the shortage of trained geneticists and counsellors and the psychological impact of that knowledge of a predictable serious disease might have, have lead to much opposition to the use of genetic information by third parties. In the United States most Americans receive health insurance through their place of employment. There are fears that genetic testing will be used to discriminate against prospective employees and render many people unemployable and uninsurable (Council for responsible Genetics, 1997: http://www.gene-watch.org/genclisc htuil Consumer groups have lobbied effectively for the prohibition of testing or the use of testing by insurers in the United States and Europe and legislators aim to ban the use of genetic information on a broad basis. Insurers, on the other hand, are assuming that the new laws will cause untold damage to the fiscal stability of their companies (Lowden, J. A., 1999:33). However, it seems inevitable that genetic testing will affect risk classification sooner rather than later and to a greater extent than most believe (Chambers, 1997: http://www.Inrc.com/epirr/issues/143/143-4.htm).

目前廣泛應用于胎兒醫學的唐氏綜合症篩查法，即結合早孕期胎兒頸項透明層的超聲檢查，及母體血清生化指標的綜合篩查法。頸項透明層是指在早孕期利用超聲檢測到的胎兒頸后的皮下積水，其作為預測胎兒異常的一項重要“軟指標，其臨床意義，尤其是與胎兒染色體異常及器官結構異常之間的關係，逐漸得到深入的認識，但其形成機制尚未明確。現在已知有一百餘種畸形及遺傳綜合征與胎兒頸項透明層增厚相關，但其染色體異常譜系，尤其是亞顯微的染色體異常仍有待明確。大部分頸項透明層增厚但核型正常的胎兒預後良好，但約3-10%的這部分胎兒會伴有畸形或出生后的神經智力發育缺陷。而傳統核型分析無法檢測到亞顯微的染色體異常，從而無法判斷這部分核型正常卻伴有缺陷的胎兒是否因為這類染色體異常而致病。 / 微陣列比較基因組雜交芯片作為檢測兒童發育遲緩者及器官結構異常原因的重要手段已廣泛應用于臨床。在染色體核型正常的胎兒中，若伴有器官結構異常的胎兒，5-12%被檢出與該畸形相關的微缺失及微重複；若僅伴有孕婦高齡或唐氏篩查高危，則微缺失及微重複檢出率約1%。 / 該課題旨在研究頸項透明層增厚但核型正常的胎兒中，染色體拷貝數變異發生的頻率及頻譜；評估微陣列比較基因組雜交芯片在協助臨床判斷胎兒預後中的作用。因此，我們開展該多中心隊列研究，通過納入449例頸項透明層厚度≧3.5 mm但正常核型胎兒的，檢測其染色體拷貝數變異，監測并記錄其圍產、產後及新生兒期情況。微陣列比較基因組雜交芯片總共檢出2.8%的異常拷貝數變異，其大小範圍為0.1 kb至18Mb。在伴有器官結構異常的胎兒組中，異常拷貝數變異檢出率達7.8%。對於頸項透明層厚度≧4.0 mm的胎兒，異常拷貝數變異檢出率可達7.3%。 / 對於頸項透明層增厚的胎兒，致病拷貝數變異暫未發現特定的頻譜。但，該研究中發現重複的致病拷貝數變異，如22號染色體長臂1區1帶的微重複或微缺失，2號染色體長臂2區2帶的微缺失。未在3號、7號、12號、13號、18號、20號、21號或Y染色體上發現與胎兒頸項透明層增厚相關的致病拷貝數變異。 / 頸項透明層增厚的胎兒79.3%預後良好；若經微陣列比較基因組雜交芯片未檢出致病拷貝數變異，則81.2%預後良好。如果僅頸項透明層增厚不伴有結構異常的胎兒，經微陣列比較基因組雜交芯片未檢出致病拷貝數變異，則93.5%預後良好。 / 綜上所述，微陣列比較基因組雜交芯片顯著提高了致病拷貝數變異的檢出率。可考慮將微陣列比較基因組雜交芯片作為頸項透明層厚度≧4.0 mm的胎兒染色體異常檢查的首要方法。對於僅頸項透明層增厚不伴有結構異常的胎兒，且經微陣列比較基因組雜交芯片未檢出致病拷貝數變異，絶大部分預後良好。對於頸項透明層增厚的胎兒，致病拷貝數變異暫未發現特定的頻譜，但發現重複出現的致病拷貝數變異。通過初步的基因本體分析及基因通路分析，神經嵴細胞的分化遷徙功能異常可作為今後研究頸項透明層增厚的病理生理機制的方向。 / Measurement of nuchal translucency (NT) has been recognized as a sensitive marker for fetal chromosomal disorders for more than a decade, and is presently used as a routine first-trimester screening test. Although over 100 abnormalities and genetic syndromes have been reported to be associated with increased NT, these associations have not been fully explored and the relevant spectrum of associated submicroscopic chromosomal abnormalities has not been sufficiently investigated. The majority of euploid fetuses with increased NT have a good outcome, but around 3-10% of fetuses present with structural or neurodevelopmental abnormalities postnatally. A range of genetic syndromes has been reported, many of which are linked to submicroscopic chromosomal abnormalities that are typically missed by conventional karyotyping. / Microarray-based comparative genomic hybridization (arrayCGH) has been applied as the first-tier diagnostic tool for the evaluation of developmental delay and structural malformations in children. In fetuses with a normal karyotype, microarray analysis revealed clinically relevant deletions or duplications in 5-12% with a structural anomaly and in about 1% of those whose indications were advanced maternal age or positive screening results. / The objectives of this study were to delineate the frequency and spectrum of pathogenic chromosome copy number variants (CNVs) among fetuses with increased NT and normal karyotype; to evaluate the role of arrayCGH to predict the prognosis of the high NT fetuses; to explore the genotype-phenotype correlations of increased NT. Therefore, a multi-centre cohort of 449 fetuses with NT ≧3.5 mm and normal karyotype were further investigated by arrayCGH. Antenatal surveillance, pregnancy outcome and paediatric follow up were documented. ArrayCGH detected abnormal CNVs in 2.8% (14 of 449) of the fetuses with high NT; the size of CNVs ranged from 0.1 kb to 18Mb. Among fetuses with major congenital abnormalities the incidence of abnormal CNV reached 7.8% (4 of 51). By adjusting the NT to ≧4.0 mm as the referral indication, 7.3% (14 of 192) of the fetuses would have abnormal arrayCGH results. The spectrum of pathogenic CNVs found associated with increased NT was diverse. However, there were recurrent ones such as the deletions or duplications at chromosomal region 22q11, and deletions in ZEB2. There was no pathogenic CNV related with increased NT found in chromosomes 3, 7, 12, 13, 18, 20, 21, or Y. The total normal outcome rate of euploid fetuses with an increased NT was 79.3%; for fetuses with normal arrayCGH results 81.2% had a normal outcome. In fetuses with isolated increased NT, normal arrayCGH results predict a favorable prognosis of 93.5%. / In conclusion, arrayCGH significantly increased the diagnostic yield of pathogenic CNVs. In clinical practice arrayCGH may be considered as the first tier investigation in fetuses with an increased NT more than 4.0 mm. In cases with an isolated increased NT with normal arrayCGH results the pregnancy outcome is likely to be favorable. The spectrum of abnormal CNVs found by arrayCGH is diverse but there are recurrent cases such as del/dup 22q11 and del ZEB2. Our preliminary gene ontology and pathway analysis showed that gene pathways related to neural crest cells may be considered as a future study for physiopathologic mechanisms of NT. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Huang, Jin. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 106-120). / Abstracts also in Chinese.