La complexité de l’étude des neuropathies héréditaires provient de leur hétérogénéité clinique et génétique et de la diversité des fibres composant les nerfs périphériques. Cette complexité se reflète dans les nombreuses classifications différentes. Les neuropathies héréditaires se classifient entre autres selon leur mode de transmission et leur atteinte sensitive, autonomique et motrice. Les neuropathies héréditaires sensitives et autonomiques (NHSA) se présentent avec une perte de la sensation distale aux membres, accompagnée d’autres manifestations selon le type de NHSA. L’étude des NHSA est facilitée lorsqu’il existe des grappes de familles originaires de régions du Québec où des effets fondateurs pour des maladies récessives ont déjà été identifiés. Nous avons recruté une grande famille canadienne-française originaire de Paspébiac dans la Baie-des-Chaleurs dans laquelle nous avons identifié quatre cas atteints d’une neuropathie héréditaire sensitive avec rétinite pigmentaire et ataxie (NHSRPA). Nous avons émis l’hypothèse que nous étions en présence d’une nouvelle forme de neuropathie héréditaire sensitive récessive à effet fondateur. Afin d’identifier la position chromosomique du gène muté responsable de la NHSRPA, nous avons tout d’abord complété un criblage du génome en génotypant des marqueurs microsatellites «single tandem repeat» (STR) sur des individus clés et nous avons ensuite procédé à une analyse de liaison génétique paramétrique. Ces études nous ont permis de lier cette famille au chromosome 1 et de définir un premier intervalle candidat de 6,7 Mb. Grâce à un génotypage de marqueurs «single nucleotide polymorphism» (SNP), nous avons réduit l’intervalle candidat à 5,3 Mb au locus 1q32,2-q32,3. Cette région contient 44 gènes candidats. Une revue plus fine de la littérature a fait ressortir qu’une famille espagnole et une américaine de souche hollandaise souffrant de la même maladie avaient déjà été liées au même locus. L’origine possiblement basque de notre famille gaspésienne nous a poussé à comparer l’haplotype porteur avec celui de la famille espagnole qui, quoi que gitane, provient du pays basque espagnol. Ces travaux ont démontré le partage d’une région de 203 kb. Afin de rétrécir davantage notre intervalle candidat, nous avons comparé les haplotypes des cas entre les deux familles et nous avons identifié un dernier intervalle candidat de 60 SNP au locus 1q32,3. Cette région ne contient que quatre gènes candidats dont le plus intéressant est le gène «activating transcription factor» (ATF3). À ce jour, aucune mutation n’a été trouvée dans le gène ATF3 et les gènes FAM71A, BATF3 et NSL1. Des expériences supplémentaires sont nécessaires afin d’identifier le gène muté responsable de la NHSRPA. / Hereditary neuropathies study’s complexity comes from their clinical and genetic heterogeneity and the peripheral nerves fibers’ diversity. This complexity leads to numerous different classifications. Hereditary neuropathies are classified based on the transmission mode and the sensitive, autonomic and motor affection. Hereditary sensory and autonomic neuropathies (HSAN) present themselves with members’ distal loss and other manifestations depending on the HSAN type. HSAN study can be facilitated when there are existing family grapes originating from Quebec regions where recessive diseases founder effects have been identified. We have recruited a large French-Canadian family originating from Paspébiac in the Baie-des-Chaleurs in which we have identified four cases affected by a hereditary sensory neuropathy with retinitis pigmentosa and ataxia (HSNRPA). We have hypothesized that we were in presence of a new form of recessive hereditary sensitive neuropathy with founder effect. In order to identify the HSNRPA causing mutated gene chromosomal position, we first completed a genome wide scan by genotyping microsatellite single tandem repeat (STR) markers on informative individuals and we have then proceeded to a parametric genetic linkage analysis. These studies allowed us to link this family to chromosome 1 and define a first candidate interval of 6.7 Mb. Second to the single nucleotide polymorphism (SNP) markers genotyping, we have reduced the candidate interval at 5.3 Mb on locus 1q32.2-q32.3. This region contains 44 genes. A finer literature review made us realize that a Spanish family and an American from Dutch origin suffering from the same disease had already been linked to the same locus. The possible Gaspesian family’s Basque origins brought us to compare their carrier haplotype with the Spanish family’s, although Gypsy but coming from the Spanish Basque country. This work has demonstrated a shared region of 203 kb. In order to further refine our candidate interval, we have compared the haplotypes of the cases between the two families and we have identified a last candidate interval of 60 SNP at locus 1q32.3. This region contains only four candidate genes, the activating transcription factor (ATF3) gene being the most interesting one. Until today, no mutation has been found in the ATF3 gene and in the FAM71A, BATF3 and NSL1 genes. Further experiments will be necessary in order to identify the HSNRPA causing mutated gene.

Paradoxically enhanced cognitive processes in neurological disorders provide vital clues to understanding neural function. However, what determines whether the neurological damage is impairing or enhancing is unclear. Here we use the performance of patients with two disorders of the striatum to dissociate mechanisms underlying cognitive enhancement and impairment resulting from damage to the same system. In a two-choice decision task, Huntington\'s disease patients were faster and less error prone than controls, yet a patient with the rare condition of benign hereditary chorea (BHC) was both slower and more error prone. EEG recordings confirmed significant differences in neural processing between the groups. Analysis of a computational model revealed that the common loss of connectivity between striatal neurons in BHC and Huntington\'s disease impairs response selection, but the increased sensitivity of NMDA receptors in Huntington\'s disease potentially enhances response selection. Crucially the model shows that there is a critical threshold for increased sensitivity: below that threshold, impaired response selection results. Our data and model thus predict that specific striatal malfunctions can contribute to either impaired or enhanced selection, and provide clues to solving the paradox of how Huntington\'s disease can lead to both impaired and enhanced cognitive processes.

Occupational risk management can be a catalyst in generating superior returns for all stakeholders on a sustainable basis. A number of companies in South Africa have implemented Cardinal Rules of Safety adopted from international companies to ensure the safety of their employees. The purpose of this study was to measure the impact of the cardinal rules on employee safety behaviour implemented at power stations in Mpumalanga. The empirical study was done by using a questionnaire as measuring instrument. The questionnaire was developed from a literature review and contains questions and items relevant to the initial research problem. The questionnaire comprised of five–point Likert scale type questions.The convenience sampling method was applied identifying 90 participants at three different power stations in Mpumalanga taking part in the study. Statistical analysis was performed by the Statistical Consulting Service of the North–West University using SPSS. Cronbach’s alpha co–efficients was used to determine the reliability of the factors. Descriptive statistics (Mean, standard, deviation, were used in the compiling of the profile of the results. While Spearman’s rho correlation coefficient was calculated to identify practically significant associations between variables and factors The research findings suggest that there is practical significant correlation between the factors that were measured. The opinion given by respondents suggests that cardinal rules of safety were implemented, given all the necessary support by management and enforced throughout the organisation. / Thesis (Ph.D. (Biochemistry))--North-West University, Potchefstroom Campus, 2012.

Occupational risk management can be a catalyst in generating superior returns for all stakeholders on a sustainable basis. A number of companies in South Africa have implemented Cardinal Rules of Safety adopted from international companies to ensure the safety of their employees. The purpose of this study was to measure the impact of the cardinal rules on employee safety behaviour implemented at power stations in Mpumalanga. The empirical study was done by using a questionnaire as measuring instrument. The questionnaire was developed from a literature review and contains questions and items relevant to the initial research problem. The questionnaire comprised of five–point Likert scale type questions.The convenience sampling method was applied identifying 90 participants at three different power stations in Mpumalanga taking part in the study. Statistical analysis was performed by the Statistical Consulting Service of the North–West University using SPSS. Cronbach’s alpha co–efficients was used to determine the reliability of the factors. Descriptive statistics (Mean, standard, deviation, were used in the compiling of the profile of the results. While Spearman’s rho correlation coefficient was calculated to identify practically significant associations between variables and factors The research findings suggest that there is practical significant correlation between the factors that were measured. The opinion given by respondents suggests that cardinal rules of safety were implemented, given all the necessary support by management and enforced throughout the organisation. / Thesis (Ph.D. (Biochemistry))--North-West University, Potchefstroom Campus, 2012.

My thesis serves two purposes: First, my research addresses what I have come to recognize as colonial misunderstandings of nuu-chah-nulth ha'wiih. My research and writing invoke new ways of thinking about nuu-chah-nulth people, leaders and knowledge. I accomplish this by writing conversationally and by including unedited interviews and poetry. All of which require readers to consider my research outside of their usual perspective. Second, my research responds to a cultural need to archive important family knowledge while providing the opportunity to define, for outsiders, who we are. The interviews archive, in part, the knowledge and teachings of a cha-cha-tsi-us-aht ha'wilth. My analysis of this information shows that while my family’s knowledge comes from a common source. We all interpret that knowledge in our own way. My research is important academically and politically because of its ability to convey knowledge that has not been simplified, appropriated or colonized for public consumption.

DNA damage response pathways are a complicated network of proteins that function to remove and/or reverse DNA damage. Following genetic insult, a signal cascade is generated, which alerts the cell to the presence of damaged DNA. Once recognized, the damage is either removed or the damaged region is excised, and the original genetic sequence is restored. However, when these pathways are defective the cell is unable to effectively mediate the DNA damage response and the damage persists unrepaired. Thus, the proteins that maintain the DNA damage response pathway are critical in preserving genomic stability. One essential DNA repair protein is the Breast Cancer Associated gene, BRCA1. BRCA1 is essential for mediating the DNA damage response, facilitating DNA damage repair, and activating key cell cycle checkpoints. Moreover, mutations in BRCA1 lead to a higher incidence of breast and ovarian cancer, highlighting the importance of BRCA1 as a tumor suppressor. In an effort to better understand how BRCA1 carried out these functions, researchers sought to identify additional BRCA1 interacting proteins. This led to the identification of several proteins including the BRCA1 Associated C-terminal Helicase, BACH1. Due to the direct interaction of BACH1 with a region of BRCA1 essential for DNA repair and tumor suppression, it was speculated that BACH1 may help support these BRCA1 function(s). In fact, initial genetic screenings confirmed that mutations in BACH1 correlated not only with hereditary breast cancer, but also with defects in DNA damage repair processes. The initial correlation between BACH1 and cancer predisposition was further confirmed when mutations in BACH1 were identified in the cancer syndrome Fanconi anemia (FA) (complementation group FA-J), thus giving BACH1 its new name FANCJ. These findings supported a previously established link between the FA and BRCA pathways and between FA and DNA repair. In particular, we demonstrated that similar to other FA/BRCA proteins, suppression of FANCJ lead to a substantial decrease in homologous recombination and enhanced both the cellular sensitivity to DNA interstrand cross-linking agents and chromosomal instability. What remained unknown was specifically how FANCJ functioned and whether these functions were dependent on its interaction with BRCA1 or other associated partners. In fact, we identified that FANCJ interacted directly with the MMR protein MLH1. Moreover, we found that the FANCJ/BRCA1 interaction was not required to correct the cellular defects in FA-J cells, but rather that the FANCJ/MLH1 interaction was required. Although both the FA/BRCA and MMR pathways undoubtedly mediate the DNA damage response, there was no evidence to suggest that these pathways were linked, until recently. Our findings not only indicate a physical link between these pathways by protein-protein interaction, but also demonstrated a functional link.

This diploma thesis summarizes knowledge of significant genetically contitioned deseases occurring in border collies. There is described a total of 14 diseases, some with the location of causal mutation not yet known. Primary focus of this thesis is g.4411956_4411960delGTTT mutation of gene VPS13B causing Trapped Neuthrophil Syndrome (TNS), MDR1 gene's mutation AF045016.1: c.227_230delATAG associated with multidrug resistance (MDR1) and CUBN gene's mutation c.8392delC which causes intestinal malabsorption of cobalamin by another name ImerslundGräsbeck syndrome (IGS). A genotype analysis of 89 border collies with a proof of origin was performed. The DNA was extracted from buccal mucosal swabs, the isolation of DNA was performed by Chelex-100 from the native material. The analysis was proceeded by optimized PCR-RFLP method using restrictive MboI (MDR1) and Msl I (IGS) enzymes. There were detected 4 g.4411956_4411960delGTTT mutation vectors causing TNS. As for the MDR1 and IGS there wasn't detected any affected case.

A Síndrome de von Hippel-Lindau é uma doença hereditária multissistêmica, causada por mutações germinativas no gene VHL que predispõe o portador a manifestações benignas e malignas em diversos órgãos. Entre esses eventos, o carcinoma de células claras renais (CRC) é o de pior prognóstico, com uma penetração média de 25% e sendo a principal causa de morte nestes pacientes. Os CRCs são tumores agressivos, pouco responsivos à quimioterapia e imunoterapia, e muitas vezes são diagnosticados em estágios avançados. Podem estar associados a síndromes hereditárias como o VHL ou apresentar a forma esporádica. Caracteristicamente, o CRC é provocado pela inativação dos dois alelos do gene VHL. Nos casos associados ao VHL, um alelo do gene VHL sofre uma mutação germinativa e um segundo evento mutacional somático nas células do tumor. Por outro lado, na forma esporádica, o CRC é resultado de dois eventos somáticos adquiridos, que incluem uma combinação de metilação do promotor, mutações pontuais que afetam a sequência de leitura aberta (ORF) e rearranjos cromossômicos, principalmente perda de heterozigosidade (LOH). Embora os eventos somáticos nos CRCs esporádicos já tenham sido explorados em outros estudos, os mecanismos de inativação somáticos do gene VHL nos CRCs associados à síndrome ainda não foram bem descritos. Este estudo avaliou os eventos somáticos no gene VHL em CRCs retirados em procedimentos cirúrgicos de pacientes portadores da síndrome. Os eventos somáticos em vários tumores de um mesmo paciente foram comparados a fim de verificarmos se essas mutações são independentes e não clonais. Oito pacientes com amostras CRCs previamente armazenadas no BNT tiveram sua mutação germinativa no gene VHL caracterizada por sequenciamento ou MLPA. Todas as amostras foram submetidas a uma revisão da patologia e macrodissecadas sempre que necessário. Para a análise das manifestações somáticas do gene VHL, o DNA foi extraído de 30 CRCs conservados em RNA latter ou formaldeído (parafina). As amostras foram analisadas quanto à metilação da região promotora do gene pelo método MS-PCR e para mutações pontuais por sequenciamento. Fomos capazes de detectar a mutação somática em 25 dos 30 tumores, incluindo uma mutação pontual e dois tumores diferentes de um mesmo paciente, nenhuma microdeleção e 23 grandes deleções. Em contraste com a literatura, nenhum dos tumores apresentou metilação no promotor do VHL. Devido ao grande número de achados LOH e da resolução limitada da técnica de MLPA para avaliar a extensão dos rearranjos cromossômicos em 3p, não foi possível concluir a análise de clonalidade dos tumores. Um estudo exploratório para caracterizar ganhos e perdas genômicas utilizando a técnica CNV array está em andamento em nosso laboratório. / The von Hippel-Lindau syndrome (VHL) is a multissystemic hereditary disease, caused by germline mutations in the VHL gene that predisposes the carrier to benign and malignant manifestations in different organs. Among these events, the clear cell renal carcinoma (RCC) is the most fearful, with an average penetration of 25% being the leading cause of death in these patients. RCCs are aggressive tumors, poorly responsive to chemo- and immunotherapy that are often diagnosed in advanced stages. They can be associated with hereditary syndromes such as VHL or present in a sporadic form. Characteristically, RCCs carrier the inactivation of the two alleles of VHL gene. In cases associated with VHL, one allele of the VHL gene is mutated in the germline, and the second mutational event occurs in the somatic cells of the tumor. On the other hand, in the sporadic form, RCCs results of two acquired somatic events, which includes a combination of methylation of the promoter, point mutations affecting the ORF, and rearrangements mainly loss of heterozigosity (LOH). Although somatic events in sporadic RCC have been explored before by others, the mechanisms of somatic VHL gene inactivation in VHL-associated RCCs have been poorly characterized. This study evaluated the somatic mutational events in the VHL gene of RCCs removed from VHL patients in therapeutic surgical procedures. The somatic events in multiple tumors from the same patient were compared in order to analyze whether these mutations are independent and not clonal. Eight patients with RCCs samples previously stored at BNT had their germline VHL gene mutation characterized by sequencing or MLPA. All samples were submitted to a pathology review and macrodissected whenever necessary. For the analysis of somatic events of VHL gene, DNA from 30 RCCs were extracted from either RNA later or archival formalin-fixed, paraffin-embedded tissue sections. Samples were analyzed for VHL gene promoter methylation by MS-PCR, and for point mutation in the coding DNA by sequencing. We were able to detect the somatic mutation in 25 of the 30 tumors, including one point mutations in two different tumors of the same patient, no micro-deletions, and 23 large deletions. In contrast to the literature, none of the tumors have shown methylation on the VHL promoter. Because of the large number of LOH findings, and the limited resolution of MLPA to evaluate the extension of 3p chromosomal rearrangements, we could not conclude the analysis of tumor clonality. An exploratory study to characterize genomic gains and losses using CNV-array technique are ongoing in our laboratory.

Osteogenesis imperfecta, innate brittle bone disease, is a very serious disease. It is inheritable disease of connective tissue, which shows by abnormal fragility of bones. The occurrence of this disease is one case in 10 000 30 000 births. The theoretical part of the thesis deals with the disease itself, also the psychical impact on children suffering from Osteogenesis imperfecta and the impact on their families as well. At the beginning of the research, three goals of this thesis were set: map out (on the basis of theoretical and practical backgrounds) the pitfalls of life of children with the disease Osteogenesis imperfecta, find out what are the most common difficulties by children with the disease Osteogenesis imperfecta and also find out the experiences of nurses with the care for children with disease Osteogenesis imperfecta. The empirical part of the thesis was processed by means of qualitative research conducted by the technique of semi-structured interview and narrative biographical interview. The research set were nurses working at the child departments in hospitals, parents of ill children and also an adult woman with the diagnosis of Osteogenesis imperfecta and two doctors. From the research emerged that among the most common difficulties of children is pain, which decreases the quality of their life. Small children can't engage in typical activities of children, such as going to a playground, older children can't attend for example music festivals. Children feel fear from fractures and are therefore limited in sports. Because of injuries and their treatments, the children have more absences at schools and therefore are isolated from peers. Nevertheless, the children with this disease can live a happy life. From the results of the research also emerges, that nurses working at the child departments of the hospitals attended by children with this illness have a good experiences with their treatment. They are able to give parents important information and know the specifics of application of the treatment. The results of the diploma thesis were presented at a national student conference and will be further published.

Made available in DSpace on 2016-06-02T20:12:10Z (GMT). No. of bitstreams: 1 TeseJRBM.pdf: 1767918 bytes, checksum: 200ee529156f1dbfe98eeab387ba9dc6 (MD5) Previous issue date: 2006-12-15 / This doctoral thesis intends to analyze the main concepts of mental disease and the problematic relation between the organicism and the psychodinamism throughout the history of the psychopathologic ideas that came to constitute the scientific clinical psychiatry, from Philippe Pinel, in the beginning of XIX century, until the chaos of the no theoretical pretense descriptive of the official nosography of the end of XX century and beginning of XXI century (I.C.D.-10). The epistemologic conflict between the psychogenic and organogenic doctrines had resulted in many frustrated attempts of solution. The hermeneuticsynthetic psychopathology of Carl Gustav the Jung (1875-1961) and the phenomenonstructural psychopathology of Eugène Minkowski (1885-1972) stand out among the most promising proposals of XX century. The basic concepts of these authors keep an essential similarity, besides belonging to schools have different thoughts. However, their theorization go in parallel thinking about a psychopathologic formularization psychorganodinamic that is similar in its most essential principles. The antimechanist solution, anti-atomicist and antireductionist, of both, remind the current biological psychiatry that the desired and necessary consensual psychiatric theory will not do without a Metapsychopatology of the psychiatry that consider the irreducible biopsychosocial complexity of the normal or pathological human being. And, neither psychiatry will gain a satisfactory nosographic formularization while they don t reveal the mysteries of the complex etiology of mental disorders. / A presente tese de doutorado pretende analisar os principais conceitos de doença mental e a problemática relação entre o organicismo e o psicodinamismo ao longo da história das idéias psicopatológicas que vieram constituir a psiquiatria clínica científica, a partir de Philippe Pinel, no início do século XIX, até o caos da pretensa ateoricidade descritiva da nosografia oficial do final do século XX e início do século XXI (C.I.D.-10). O conflito epistemológico entre as doutrinas psicogênicas e organogênicas resultou em várias tentativas frustradas de solução. Dentre as mais promissoras propostas do século XX, destacam-se as da psicopatologia hermenêutico-sintética de Carl Gustav Jung (1875-1961) e da psicopatologia fenomeno-estrutural de Eugène Minkowski (1885-1972). Os conceitos fundamentais desses autores guardam uma semelhança essencial, apesar de pertencerem a escolas de pensamento diferentes; todavia, suas teorizações caminham paralelamente no sentido de uma formulação psicopatológica psicorganodinâmica muito parecida em seus princípios mais essenciais. A solução antimecanicista, anti-atomicista e anti-reducionista, de ambos, lembram à psiquiatria biológica atual que a tão desejada e necessária teoria psiquiátrica consensual não prescindirá de uma Metapsicopatologia da psiquiatria que considere a complexidade biopsicossocial irredutível do ser humano normal ou patológico. E, tampouco a psiquiatria chegará a uma formulação nosográfica satisfatória enquanto não desvendar os mistérios da etiologia complexa dos transtornos mentais.