Made available in DSpace on 2016-04-26T20:26:05Z (GMT). No. of bitstreams: 1 Renato Maia.pdf: 902025 bytes, checksum: 1eb95ac4c51f7dd9353dbbc13a3eee6e (MD5) Previous issue date: 2007-10-17 / Pontifícia Universidade Católica de Minas Gerais / The following paper deal related to the evolution of familial organization and also the format of step family, in order to show that the relationship among relatives is far beyond the blood or the disposition of the law. The legal ties of kinship is praiseworthy in what concerns its changes along the history, focusing on the answers to the anxiety of a Culture of certain time or by establishing the dignity of members from a helpful family, such a way this one could survive in spite of steady social changes. This present writing looks at a probable organization carefully in order to establish relationships among adopted brothers. The presented study analyses the unexpected kinships within a decomposed family. The blood, civil and affinity kinships towards the disposition of the Article 1.595 from Civil Code, and the distinction between kinship and affinity, once it is present in. The analysis is made from the social affection paternity that s going to be performed by the couple according to its previous spouse s son; mainly by the legal or biological absence. This research follows the principle of de lege ferenda such a way the recomposed family s institutional and juridical recognition provides the kinship establishment among real brothers, in obedience to the scientific thesis, considering this writing is useful to obtain the Title of Doctor . It still suggests the study of the recomposed family structure in agreement with compared Civil Law, mainly related to German, Argentinean and Brazilian legislations / O presente trabalho não só aborda a evolução da organização familiar como também o formato da família recomposta ou reconstituída, demonstrando que a parentalidade ultrapassa o sangue ou a disposição de lei. Enaltece que a relação jurídica de parentesco se alterou e se altera no decorrer da história , para atender aos anseios de uma cultura, de uma época, ou do estabelecimento da dignidade dos membros de uma família solidária, fazendo com que esta sobreviva às mudanças sociais constantes. Submete à crítica uma provável organização que venha estabelecer relações de parentesco entre irmãos de criação . O estudo avalia as relações de parentesco que possam surgir no seio de uma família recomposta. O parentesco consangüíneo, civil e por afinidade, até a disposição do artigo 1 .595 do Código Civil, e a distinção entre parentesco e afinidade, se é que existe. A análise é feita a partir da paternidade socioafetiva que o cônjuge ou companheiro vem a desempenhar em relação ao filho anterior do outro, principalmente pelo esvaziamento da paternidade legal ou biológica. Faz a pesquisa à proposição de lege ferenda para que o reconhecimento institucional jurídico da família recomposta leve à fixação de parentalidade na colateralidade entre irmãos de fato, em obediência à característica da tese científica, uma vez que o presente se presta à obtenção do título de doutor. Propõe-se ainda à pesquisa da estrutura da família recomposta à luz do direito civil comparado, principalmente sob o prisma das legislações alemã, argentina e brasileira

Esta pesquisa propõe uma comparação entre contos e romances produzidos por Machado de Assis nas décadas de 1860 e 1870 e produções do teatro realista brasileiro, desenvolvido no país entre as décadas de 1850 e 1860, com o objetivo de capturar suas representações da ordem familiar. Levando-se em conta que Machado de Assis foi entusiasta do realismo teatral, como assinalam alguns dos textos que o autor publicou na imprensa, é possível constatar importantes semelhanças entre a prosa machadiana estudada e obras do teatro realista nacional, no que tange ao tratamento de assuntos concernentes à esfera familiar. De modo geral, esses assuntos têm como eixo o debate sobre a transição de paradigmas familiares por que passava a sociedade brasileira do período, atrelando-se à defesa do casamento eletivo, modelo de união da burguesia então emergente nas cidades, em contraste com o casamento por arranjo familiar, forma de matrimônio típica do universo de relações patriarcais, frequentemente praticada pelas elites locais. Pode-se identificar um complexo estético-ideológico comum às obras de Machado de Assis e às peças mencionadas, marcado pela perspectiva de que a arte teria função didático-moralizante, podendo contribuir para o aprimoramento de instituições sociais como a família e o casamento, sobre as quais esses textos apresentam uma visão positiva. O trabalho separa-se em duas partes. A primeira é dedicada à prosa de Machado de Assis, incluindo os quatro primeiros romances do autor e uma seleção de contos que ele publicou no período correspondente ao recorte cronológico. A segunda parte apresenta a leitura de algumas peças realistas brasileiras, quase todas comentadas por Machado de Assis. Por meio da comparação dessas peças com as obras abarcadas na primeira parte, defende-se a tese de que Machado de Assis incorporou elementos da estética teatral realista para compor a literatura orientada para a vida prática que solicita em alguns de seus contos, e que está sintonizada com os debates sobre a família e as instituições sociais presentes em sua prosa das décadas de 1860 e 1870. / This research establishes a comparison between short stories and novels written by Machado de Assis during the decades of 1860 and 1870, on the one hand, and Brazilian plays pertaining to the theatrical realism, which has been developed in Brazil during the decades of 1850 and 1860, on the other hand. The comparison focuses representations of familial order in those texts. Considering that Machado de Assis was an enthusiast of the theatrical realism, as many of his journalistic texts show, it is possible to identify important similarities between the authors prose and Brazilian realistic plays, in their approach to matters related to familial order. Those texts usually associate these matters with discussions about the changes in the paradigm of family relations in Brazil in the 19th century, standing up for volitional marriage, an ideal of the rising urban bourgeoisie, in contrast to patriarchal arranged marriage, commonly practiced by rural elites. It is possible to recognize an esthetical-ideological structure in both Machado de Assiss prose and realistic plays, characterized by the idea that art had a didactic and moralizing objective, contributing to the development of society institutions such as family and marriage, which these texts present in a positive way. The thesis is divided into two sections. The first one is dedicated to Machado de Assiss prose, including the first four novels written by the author and a selection of the short stories he has published during the selected period. The second one offers an interpretation of some of Brazilian realistic plays, almost all of which were commented by Machado de Assis. From the comparison between these plays and the productions studied at the first section, we argue that Machado de Assis incorporated esthetical elements from theatrical realism, in order to compose a literature directed towards concrete life, which the author stands up for in some of his short stories. This literature, as we shall see, is consistent with the discussions about family and social institutions that are presented in the writers prose in the decades of 1860 and 1870.

Hipercolesterolemia familiar (HF) é uma doença autossômica dominante, caracterizada por elevados níveis plasmáticos da lipoproteína de baixa densidade (LDL), desenvolvimento de xantoma tendíneo e arco corneal, além do aumento do risco de doença coronariana e acidente vascular cerebral prematuros. Frequentemente subdiagnosticada, estima-se que apenas 10% dos 400.000 indivíduos com HF no Brasil têm conhecimento da própria doença; afetando, desta forma, a qualidade e a expetativa de vida dos pacientes. Mutações no gene do receptor da LDL (LDLR) são consideradas as alterações genéticas mais frequentes para o desenvolvimento da hipercolesterolemia familiar, pois comprometem a capacidade de remoção das partículas de LDL circulantes, promovendo seu aumento em níveis plasmáticos. Já foram descritas mais de 1600 mutações diferentes no gene LDLR associadas ao fenótipo da HF; entretanto, ainda é difícil determinar em muitas delas o efeito deletério na atividade do receptor. O objetivo desse estudo foi identificar e caracterizar funcionalmente mutações no gene LDLR não descritas na literatura para determinar sua patogenicidade na hipercolesterolemia familiar. Foi avaliada a atividade residual de LDLR através da captação de LDL marcado com fluoróforo lipofílico em cultura de linfócitos T dos pacientes portadores das mutações analisadas após estimulação dos linfócitos T por mitógenos específicos. As mutações Cys82Ser, Thr404Ser, Gly529Arg e His285Tyr foram consideradas patogênicas por acarretarem diminuição da atividade residual do receptor de LDL. As mutações Glu 602X e His388ProfsX53 confirmaram sua patogenicidade e podem ser considerados como controle positivo para futuros ensaios funcionais. Estudos que esclareçam os mecanismos moleculares da HF e da relação genótipo/fenótipo abrem perspectivas para o desenvolvimento de terapias mais específicas na redução dos níveis de colesterol e, consequentemente, da morbidade e mortalidade associadas às doenças cardiovasculares. / Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated plasma levels of low-density lipoprotein (LDL), and development of corneal arcus tendinous xanthoma, and increased risk of coronary heart disease and premature stroke. Often misdiagnosed, it is estimated that only 10% of the 400.000 patients with FH in Brazil has knowledge of the disease itself, affecting in this way the quality and life expectancy of patients. Mutations in the LDL receptor (LDLR) are considered the most frequent genetic alterations for the development of familial hypercholesterolemia because compromise the ability of removal of circulating LDL particles, promoting its increase in plasma levels. Have been described over 1600 different mutations in the LDLR gene associated with the phenotype of FH, however, it is still difficult to determine in many of the deleterious effects on receptor activity. The aim of this study was to identify mutations in the LDLR gene and functionally characterize mutations not described in the literature to determine its pathogenicity in familial hypercholesterolemia. The residual activity of LDLR was evaluated by raising LDL labeled with lipophilic fluorophore in cultured T lymphocytes of patients with the analyzed mutations after stimulation of T lymphocytes by specific mitogen. The substitution mutations Cys82Ser, Thr404Ser, Gly529Arg e His285Tyr were considered pathogenic because it causes decrease of the residual activity of the LDL receptor in T lymphocytes. The His388ProfsX53 and Glu602X mutations confirmed their pathogenicity and can be considered as positive control for future functional assays. Studies to clarify the molecular mechanisms of HF and genotype/ phenotype open perspectives for the development of more specific therapies for reducing cholesterol levels, and therefore the morbidity and mortality associated with cardiovascular diseases.

Orientador: Lígia Ebner Melchiori / Banca: Maria Auxiliadora Dessen / Banca: Olga Maria Piazentim Rolim Rodrigues / Resumo: No Brasil, estudar família é um desafio devido à grande diversidade cultural existente e a variedade de arranjos familiares. Dentro dessa perspectiva, pode-se falar em "famílias brasileiras" formadas por padrões econômicos, sociais e culturais diversos. Partindo do pressuposto de que o conceito de família deve considerar a subjetividade dos indivíduos, esse estudo teve como objetivo caracterizar e conceituar famílias de zona rural e urbana de uma cidade do interior de São Paulo, segundo a perspectiva de adolescentes. Os participantes foram 48 adolescentes de 13 a 18 anos, sendo 16 da zona rural e 32 da urbana. Para atingir o objetivo proposto buscou-se uma abordagem metodológica capaz de permitir uma ampla coleta de informações, sendo utilizados dois instrumentos, um Questionário de Caracterização do Sistema Familiar e um Roteiro de Entrevista de Conceituação Familiar. Os resultados indicam que, nessa amostra, o percentual de famílias nucleares ainda é alto. O nível de escolaridade dos pais e a renda familiar são maiores na cidade do que no campo. A ocupação dos pais na área rural é mais ligada ao setor agropecuário e na urbana predomina os setores administrativos e gerenciais. Aproximadamente metade das mães rurais não exerce atividade remunerada e na cidade esse índice é de 9%. Nas duas localidades, a maioria tem casa própria (cerca de 77%). Com relação à rede social de apoio, a pessoa da família mais procurada pelos adolescentes é a mãe, seguida do pai que está assumindo várias funções, além do suporte financeiro tradicionalmente esperado; fora da família, os amigos são os mais procurados e, algumas vezes, fornecem mais apoio que os próprios membros familiares. A principal representação de família, para os adolescentes das duas localidades, é a de suporte emocional/afetivo. Quando abordam a concepção da própria família... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: In Brazil, due to the big cultural diversity and the variety of family arrangements, studying family is a challenge. In this perspective, it is possible to talk about "Brazilian families" composed according to different economic, social and cultural standards. Presuming that the concept of family should consider individual subjectivity, this paper sought to characterize and conceptualize families from rural and urban areas of a city in São Paulo state, according to the perspective of teenagers. The participants were 48 teenagers between 13 and 18 years old, 16 from the rural area and 32 from the urban area. To reach this goal, we sought a methodological approach which could permit a broad information collection utilizing two tools, a questionnaire for familial system. Characterization and instructions for family conceptualization interview. The results indicate that the percentage of nuclear families in still high in that pattern. The parents' education level and the family's income are higher in the urban area than in the country side. The parents' jobs are more linked to agro business in the rural area and to the management and administration sectors in the urban area. About half the rural mothers do not have a paid job, while in the city they are 9%. In both places, the majority owns their houses (around 77). When it comes to social support net, mothers are the most wanted by teenagers, followed by fathers, who are taking several functins, besides the tradicional and expected financial support; apart from the family, friends are the most wanted and sometimes give even more support than family members. For the adolescents from both places, the main representation of family is that of emotional/affective support. When approaching the concept of their own families, this category continues to predominate, with inferior percentages... (Complete abstract click electronic access below) / Mestre

A hipercolesterolemia familiar (HF) é uma doença autossômica dominante causada por mutações no gene do receptor de LDL (LDLR) (cromossomo 19p13.1 - p13.3), que alteram parcialmente ou totalmente a função do LDLR. A HF é também uma das doenças genéticas mais comuns com freqüências estimadas de heterozigotos e homozigotos de 1/500 e 1/1.000.000, respectivamente. Manifesta-se com altos níveis de LDL colesterol, arco corneal, xantomas tendíneos e sintomas prematuros de doença coronariana.. A grande heterogeneidade observada na manifestação clínica desta doença pode ser explicada, ao menos parcialmente, pelo amplo espectro de mutações no gene do LDLR. O presente estudo teve por objetivo a caracterização molecular do gene LDLR em pacientes com HF do Rio Grande do Sul (RS), Brasil. Para isso, foram obtidas amostras de DNA de 40 indivíduos provenientes de cinco macrorregiões do Estado, representando seis diferentes populações de ascendência européia, para a realização do seqüenciamento direto do gene do LDLR, com posterior análise por meio das ferramentas de bioinformática. Quinze mutações pontuais foram identificadas no gene do LDLR, a saber: c.408C>T (D115D), c.1616C>T (P518L), c.1773C>T (N570N) e c.2243A>G (D727G) na região codificadora, IVS6+36G>A, IVS6+171G>A, IVS11+56C>T, IVS11- 69G>T, IVS11-55A>C, IVS15-136A>G, IVS16+46C>T e IVS17-42A>G na região intrônica, e *52G>A, *105T>G e *141G>A na região 3\'-UTR. Destas, oito ainda não foram descritas na literatura (três situadas nos exons, quatro nos introns e uma na região 3\'-UTR). A mutação*52G>A foi previamente identificada em pacientes com HF da região Sudeste do Brasil, sugerindo que possa exercer um importante efeito na patogênese da HF em pacientes brasileiros. Em relação às macrorregiões do RS, os portugueses, italianos e espanhóis apresentaram o maior número de mutações dentre os grupos étnicos analisados. Assim, os resultados obtidos confirmam que existe um amplo de espectro de mutações no gene do LDLR. As mutações nas regiões intrônicas precisam ser investigadas sobre seu efeito potencial no desenvolvimento de HF. Considerando que este é o primeiro estudo que teve por objetivo a caracterização molecular de pacientes com HF no RS, novos estudos que visem a elucidação das bases moleculares da HF devem ser realizados, a fim de obter uma melhor caracterização genética desta doença no Brasil. / Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene (chromosome 19p13.1 - p13.3), which alter partially or totally the LDLR function. FH is also one of the most common inherited disorders with frequencies of heterozygotes and homozygotes estimated to be 1/500 and 1/1.000.000, respectively. Affected individuals display high levels of LDL cholesterol, arcus corneae, tendon xanthomas and premature symptomatic coronary heart disease. The extensive heterogeneity observed in the clinical manifestation of this disorder may be explained, at least partially, by the broad spectrum of mutations identified in the LDLR gene. The present study had as the main goal the molecular characterization of the LDLR gene in patients with FH from Rio Grande do Sul (RS) State, Brazil. For this, DNA samples were obtained from 40 individuals living in five macroregions of RS, representing six different isolated populations of European ascendancy. The LDLR gene was subjected to the direct sequencing with further analysis through bioinformatics tools. Fifteen punctual mutations were identified in the LDLR gene, namely: c.408C>T (D115D), c.1616C>T (P518L), c.1773C>T (N570N) and c.2243A>G (D727G) in the coding region, IVS6+36G>A, IVS6+171G>A, IVS11+56C>T, IVS11-69G>T, IVS11-55A>C, IVS15-136A>G, IVS16+46C>T and IVS17-42A>G in the intronic region, and *52G>A, *105T>G and *141G>A in the 3\'-UTR region. Of these, eight were not yet described in the literature (three situated in exons, four in introns and one in 3\'- UTR region). The *52G>A mutation was previously identified in FH patients from Southeast Brazil, suggesting that it can exert an important effect in the pathogenesis of FH in Brazilian patients. In relation to the macroregions of Rio Grande do Sul, Portuguese, Italian and Spanish subjects carried the highest number of mutations among the ethnic groups analyzed. Thus, the results obtained confirm the existence of a broad spectrum of mutations in the LDLR gene. The mutations in intronic regions need to be investigated in relation to its potential effect in the development of FH. Taking into account that this is the first study that had as the goal the molecular characterization of FH patients in RS, further studies aimed at elucidating the molecular bases of FH should be performed, in order to obtain the better characterization of this disease in Brazil.

Familial hypercholesterolemia is a genetic disease affecting about 10 million people around the world. Those who carry the disease have a very high risk of developing cardiovascular diseases and commonly encounter myocardial infarction at the early age of 40. Therefore, a diagnosis and immediate treatment are very important for these patients. Despite many combinations of available drugs, there are many patients who still cannot reach the desired cholesterol levels. Mipomersen is a new lipid-lowering drug which inhibits the synthesis of apolipoprotein B, a common component of lipoproteins such as low-density lipoprotein. Inhibition of this protein leads to reduced production of these lipoproteins and reduces the risk of cardiovascular diseases. The drug is currently only indicated for treating patients with homozygous familial hypercholesterolemia.  Unfortunately, there have been many reports of adverse events in patients using mipomersen which has proven problematic.         The aim of this thesis is to analyze the efficacy and safety of mipomersen when treating patients with familial hypercholesterolemia. This has been done by searching for five clinical trials in the database Web of Science. The studies were required to include patients with familial hypercholesterolemia, use mipomersen as the study drug and analyze its effect and safety.   The studies showed that mipomersen has a very good effect in decreasing low-density lipoproteins as well as other lipoproteins in comparison to placebo. Many of the patients who were treated with mipomersen displayed several adverse events and the most common were injection-site reaction and influenza-like symptoms. Elevated levels of aminotransaminase and increased fat deposit in the liver were also common. Based on the five clinical trials analyzed in this thesis, mipomersen is an effective lipid-lowering drug which reduces low density lipoprotein cholesterol, apolipoprotein B and lipoprotein (a) in patients with familial hypercholesterolemia. Elevations in alanine aminotransferase and aspartate aminotransferase are common in patients treated with mipomersen. This could indicate a negative impact on the liver. To be more certain of its safety profile, more research could be needed. There are however, new treatments that combines statins and a proprotein convertase subtilisin/kexin 9 inhibitor, which could be the future of lipid-lowering treatments and mipomersen would then likely be substituted.

Or Man Wai. / "January 2002." / "glued" in title is superscript. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Orientador: Danilo Moretti-Ferreira / Banca: Henrique Krieguer / Banca: Claudia Regina Furquim de Andrade / Resumo: A gagueira é um distúrbio da comunicação, mais especificamente da fluência, onde há interrupções e alterações na velocidade do fluxo da fala. Acomete de 3 a 4% dos indivíduos do sexo masculino e de 1 a 2% do sexo feminino, em algum momento de suas vidas. A frequencia pode variar de acordo com a idade: entre crianças em idade pré-escolar de 2,4% a 5% e em idade escolar 1%. Em adultos, estima-se que de 1 a 2% sofram com este distúrbio. Em todas as idades, a gagueira parece ser mais comum no sexo masculino do que no feminino, sendo de 4 a 5 M : 1 F em adultos. Em estudos de subgrupos de gagueira persistente familial, a proporção entre os indivíduos foi de apenas 1,5 M : 1 F. A triagem genômica em famílias de gagos provenientes da América do Norte e da Europa demonstrou a existência de um locus de predisposição a gagueira familial no cromossomo 18 envolvendo a região 18p e um segundo locus na região 18q proximal, sugerindo que exista um locus de predisposição a gagueira familial no cromossomo 18 e que genes adicionais possam existir, além dos fatores ambientais. O objetivo deste trabalho foi a análise de associação nas regiões cromossômicas 18p e 18q proximal através de marcadores microssatélites (2 cM) em 31 famílias brasileiras com gagueira persistente, com mais de um indivíduo gago em idade acima de 6 anos. Utilizou-se para a classificação da gagueira, o SSI aplicado por profissionais especializados nesta disfluência. Foram incluídos todos os indivíduos disponíveis do núcleo familial, independente do sexo, etnia, escolaridade e nível social.Todos os participantes tiveram amostras de seu DNA coletados a partir de amostras de sangue periférico. Foram selecionados 14 marcadores microssatélites do cromossomo 18, genotipados após PCR em seqüenciador automático. Na análise dos dados foram utilizados programas SIMWALK 2, FBAT e POINTER... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Stuttering is a communication disorder, or more precisely, a fluency disorder that causes speech interruptions and changes in speech flow rate. It affects 3- 4% of males and 1-2% of females at some point in their lives. Its frequency may vary with age - it has been reported to be 2.4-5% among children of pre-school age and 1% at school age. In adults, it ranges from 1 to 2%. At all ages, stuttering seems to be more frequent in males than in females, being 4-5M:1F among adults. Studies in subsets of familial persistent stuttering showed a sex ratio of only 1.5M:1F. A genome scan in stuttering families from North America and Europe demonstrated the presence of a predisposing locus for family stuttering on chromosome 18 involving the 18p region and a second locus on proximal 18q (Shugart et al.,2004), suggesting that chromosome 18 may harbor a predisposing locus for this disorder, and that additional genes may exist besides environmental factors. The purpose of this study was to perform the association analysis of chromosomal regions 18p and proximal 18q using microsatellite markers (2 cM) in 31 Brazilian families with at least two stuttering members aged more than 6 years. Stuttering was classified by specialized professionals using SSI. All family members available, regardless of gender, ethnicity, educational or social level were assessed provided that they were older than 6 years. DNA samples from peripheral blood of all participants were collected. Fourteen chromosome 18 microsatellites were genotyped after PCR by automated sequencing. Data were analyzed with software SIMWALK 2, FBAT and POINTER. Association analysis revealed no association of stuttering with 13 microsatellites (one was excluded for being noninformative) demonstrating no association between this phenotype and chromosome 18 in the study population / Mestre

Work-life balance is a dominant discourse in contemporary Western society. It has been built on a language of large organizations, hence has not been widely considered in relation to the small-medium enterprise sector. As a consequence, scant research has been conducted on the experiences of immigrant entrepreneurs and work-life balance within the small-medium enterprise sector in New Zealand, a country largely populated with migrants and small businesses which account for 96 per cent of the total enterprises. This study aims to fill this gap by firstly exploring the interpretations of the concept of work-life balance by Chinese immigrant entrepreneurs and, secondly, the main challenges they face in achieving work-life balance. This is done by drawing on literatures including those on work-life balance, small-medium enterprises, and immigrant entrepreneurship theories. Primary research was conducted using a critical interpretive approach where the researcher is an insider to the study. This philosophical and methodological approach makes it possible to give a minority group a voice to effect social change and gain further research attention. Fifteen Chinese business owners, chosen from a variety of industries within the Auckland region, participated in this study. A qualitative methodological technique and semi-structured interviews were used to collect the data for the case study on these entrepreneurs. The results indicate that the majority do not enjoy a sense of work-life balance because they take on filial obligations important for their own culture. They need to work hard to generate financial profit for the benefit of family. About half of them work more than 60 hours per week and three works longer than 70 hours weekly. The motivation for them to work in this way is to provide their family with desirable housing and to enable their children to meet higher education goals. This study challenges the applicability of the work-life balance discourse among the immigrant entrepreneurs who perceive the concept differently based on their cultural values. The results emphasise the need for business case studies from Chinese immigrant entrepreneurs and research attention on contemporary human resource topics to be given to minority groups.

Doctor of Philosophy(PhD) / BCC is the commonest cancer in European-derived populations and Australia has the highest recorded incidence in the world, creating enormous individual and societal cost in management of this disease. The incidence of this cancer has been increasing internationally, with evidence of a 1 to 2% rise in incidence in Australia per year over the last two decades. The main four epidemiological risk factors for the development of BCC are ultraviolet radiation (UVR) exposure, increasing age, male sex, and inability to tan. The pattern and timing of UVR exposure is important to BCC risk, with childhood and intermittent UVR exposure both associated with an increased risk. The complex of inherited characteristics making up an individual’s ‘sun sensitivity’ is also important in determining BCC risk. Very little is known about population genetic susceptibility to BCC outside of the rare genodermatosis Gorlin syndrome. Mutations in the tumour suppressor gene patched (PTCH) are responsible for this BCC predisposition syndrome and the molecular pathway and target genes of this highly conserved pathway are well described. Derangments in this pathway occur in sporadic BCC development, and the PTCH gene is an obvious candidate to contribute to non-syndromic susceptibility to BCC. The melanocortin 1 receptor (MC1R) locus is known to be involved in pigmentary traits and the cutaneous response to UVR, and variants have been associated with skin cancer risk. Many other genes have been considered with respect to population BCC risk and include p53, HPV, GSTs, and HLAs. There is preliminary evidence for specific familial aggregation of BCC, but very little known about the causes. 56 individuals who developed BCC under the age of 40 in the year 2000 were recruited from the Skin and Cancer Foundation of Australia’s database. This represents the youngest 7 – 8% of Australians with BCC from a database that captures approximately 10% of Sydney’s BCCs. 212 of their first degree relatives were also recruited, including 89 parents and 123 siblings of these 56 probands. All subjects were interviewed with respect to their cancer history and all reports of cancer verified with histopathological reports where possible. The oldest unaffected sibling for each proband (where available) was designated as an intra-family control. All cases and control siblings filled out a questionnaire regarding their pigmentary and sun sensitivity factors and underwent a skin examination by a trained examiner. Peripheral blood was collected from these cases and controls for genotyping of PTCH. All the exons of PTCH for which mutations have been documented in Gorlin patients were amplified using PCR. PCR products were screened for mutations using dHPLC, and all detectable variants sequenced. Prevalence of BCC and SCC for the Australian population was estimated from incidence data using a novel statistical approach. Familial aggregation of BCC, SCC and MM occurred within the 56 families studied here. The majority of families with aggregation of skin cancer had a combination of SCC and BCC, however nearly one fifth of families in this study had aggregation of BCC to the exclusion of SCC or MM, suggesting that BCCspecific risk factors are also likely to be at work. Skin cancer risks for first-degree relatives of people with early onset BCC were calculated: sisters and mothers of people with early-onset BCC had a 2-fold increased risk of BCC; brothers had a 5-fold increased risk of BCC; and sisters and fathers of people with early-onset BCC had over four times the prevalence of SCC than that expected. For melanoma, the increased risk was significant for male relatives only, with a 10-fold increased risk for brothers of people with early-onset BCC and 3-fold for fathers. On skin examination of cases and controls, several phenotypic factors were significantly associated with BCC risk. These included increasing risk of BCC with having fair, easyburning skin (ie decreasing skin phototype), and with having signs of cumulative sun damage to the skin in the form of actinic keratoses. Signs reflecting the combination of pigmentary characteristics and sun exposure - in the form of arm freckling and solar lentigines - also gave subjects a significantly increased risk BCC. Constitutive red-green reflectance of the skin was associated with decreased risk of BCC, as measured by spectrophotometery. Other non-significant trends were seen that may become significant in larger studies including associations of BCC with propensity to burn, moderate tanning ability and an inability to tan. No convincing trend for risk of BCC was seen with the pigmentary variables of hair or eye colour, and a non-significant reduced risk of BCC was associated with increasing numbers of seborrhoeic keratoses. Twenty PTCH exons (exons 2, 3, 5 to 18, and 20 to 23) were screened, accounting for 97% of the coding regions with published mutations in PTCH. Nine of these 20 exons were found to harbour single nucleotide polymorphisms (SNPs), seen on dHPLC as variant melting curves and confirmed on direct sequencing. SNPs frequencies were not significantly different to published population frequencies, or to Australian general population frequencies where SNP database population data was unavailable. Assuming a Poisson distribution, and having observed no mutations in a sample of 56, we can be 97.5% confident that if there are any PTCH mutations contributing to early-onset BCC in the Australian population, then their prevalence is less than 5.1%. Overall, this study provides evidence that familial aggregation of BCC is occurring, that first-degree relatives are at increased risk of all three types of skin cancer, and that a combination of environmental and genetic risk factors are likely to be responsible. The PTCH gene is excluded as a major cause of this increased susceptibility to BCC in particular and skin cancer in general. The weaknesses of the study design are explored, the possible clinical relevance of the data is examined, and future directions for research into the genetics of basal cell carcinoma are discussed.