Introduction: The wide-ranging prognostic implications of a breast cancer diagnosis highlight the need to better enable women to make informed decisions regarding screening and treatment options. As several cancer susceptibility syndromes have been linked to germline mutations resulting in defective DNA repair, including the predisposition to breast cancer due to BRCA1 and BRCA2 mutations, more subtle defects in DNA repair capacity may contribute to the components driving differential susceptibility within the general population. Hence, understanding the role of DNA repair capacity in breast cancer onset may aid in the development of a more comprehensive risk profile, thereby furthering the effort to target relevant populations for early screening. In the studies undertaken for this dissertation, we employed various methodologies capturing endpoints across different repair pathways detectable in blood to both further elucidate the etiologic basis of breast cancer development and leverage the information into the potential development of a screening biomarker. Methods: For the phenotypic assessment of nucleotide excision repair (NER) capacity, we developed an ELISA-based method to determine benzo(a)pyrene diolepoxide (BPDE)-DNA adduct capacity in lymphoblastoid cell lines. Gene expression levels were assessed with pre-designed Taqman kits in RNA-derived cDNAs from mononuclear cells using a real-time PCR-based platform. Methylation analysis was conducted with in-house designed assays on bisulfite-converted DNA from mononuclear cells using a pyrosequencing platform. Finally, single nucleotide polymorphisms (SNP) genotyping was assessed in DNA derived from white blood cells with pre-designed Taqman SNP genotyping assays using a real-time PCR-based platform. All studies were conducted in sister-sets enrolled in the New York site within the Breast Cancer Family Registry and all statistical analysis was conducted using the R Foundation for Statistical Computing (2011). Results: We did not detect an association between the ELISA-based phenotypic assessment of NER capacity in the lymphoblastoid cells lines of the sister-sets (n=246, 114 sister-sets) and breast cancer risk (OR = 1.0, 95%CI=0.95, 1.04). Furthermore, we did not observe a correlation with previously determined NER capacity in the same population using an immunohistochemical-based method (r= -0.01, p=0.86). In our gene expression study (n=569, 218 sister-sets), women in the lowest tertile of ATM expression had a heightened risk of breast cancer compared to women in the highest tertile of expression, adjusted for age at blood draw and smoking status (OR=2.12, 95%CI=1.09, 4.12). This association was largely restricted to women with an extended family history of breast cancer (pinteraction = 0.06). Additionally, women in the lowest tertile of MSH2 expression also had a heightened risk of breast cancer compared to women in the highest tertile of expression, adjusted for age at blood draw and smoking status (OR=2.75, 95%CI=1.31, 5.79). The association observed between reductions in ATM expression level and breast cancer risk was lost upon incorporating previously determined end-joining capacity of EcoRI-generated sticky end substrates (OR=1.28, 95%CI=0.15, 11.2) and HincII-generated blunt end substrates (OR=1.55, 95%CI=0.15, 15.5) into the model, suggesting that the impact on risk due to reductions in ATM expression maybe partially driven by the reduction in double strand break repair capacity. In our study investigating breast cancer risk due to the impact of epigenetic modulation on DNA repair gene activity (n=569, 218 sister-sets), no association with risk was observed due to differential promoter methylation levels of BRCA1 (OR=1.09, 95%CI=0.98, 1.20), MLH1 (OR=1.19, 95%CI=0.91, 1.55) or MSH2 (OR=0.89, 95%CI=0.48, 1.64). Furthermore, no correlation between BRCA1 and expression (r=-0.05, p=0.39) or MSH2 methylation and expression (r=-0.04, p=0.39) was observed. Finally, our mismatch repair genotyping study (n=714, 313 sister-sets) indicated an association between the variant MutY_rs3219489 (OR=2.23, 95%CI=1.10, 4.52) and breast cancer risk, as well as a borderline association with risk due to the variant MSH2_rs2303428 (OR=1.71, 95%CI=0.99, 2.95). Furthermore, a protective effect was observed due to the variant MLH3_rs175080, restricted to women without an extended family history of breast cancer (pinteraction = 0.03). Conclusion: These studies suggest that the deregulation of targets spanning various DNA repair pathways contribute to the risk of familial breast cancer.

ZAMPRONIO, C. D. P. A deficiência auditiva nas cidades abrangidas pela DRS-6: caracterização da população atendida na Divisão de Saúde Auditiva do HRAC- USP Bauru. 2009. 86 f. Dissertação (Mestrado em Saúde na Comunidade). Faculdade de Medicina de Ribeirão Preto-USP. A deficiência auditiva presente ao nascimento ou estabelecida na mais tenra idade interfere significativamente no processo de desenvolvimento da criança. Quando ocorre em uma pessoa adulta pode levar a um quadro de isolamento, podendo torná-la dissociada da sua comunidade, limitando sua capacidade de atuar com independência e autonomia perante a sociedade. Assim, qualquer distúrbio no processo de audição normal, seja qual for sua causa, tipo ou severidade, constitui uma alteração auditiva que pode e deve ser evitada, em benefício da saúde do indivíduo e da sociedade como um todo. Objetivo: Caracterização da deficiência auditiva nos pacientes atendidos na Divisão de Saúde Auditiva (DSA), do Hospital de Reabilitação de Anomalias Craniofaciais (HRAC), Universidade de São Paulo (USP), residentes nas 68 cidades do estado de São Paulo abrangidas pelo Departamento Regional de Saúde (DRS)-6, segundo algumas variáveis como: faixa etária, gênero, nível socioeconômico, escolaridade, etiologia, grau e tipo da deficiência auditiva. Métodos: Levantamento dos pacientes que iniciaram tratamento na DSA do HRAC/USP, no período 1998 a 2007, residentes nas cidades abrangidas pelo DRS-6 e que tiveram diagnóstico audiológico concluído em deficiência auditiva em pelo menos uma orelha. Para melhor visualização das características da amostra estudada, os 692 sujeitos foram separados em dois grupos, sendo um grupo da cidade de Bauru e outro das demais cidades da DRS-6. Resultados: Não houve predomínio entre os gêneros; a população idosa representou um número significativo de sujeitos quando comparada às demais faixas etárias; a maioria dos sujeitos pertence à classe socioeconômica baixa. Constatou-se que as principais etiologias encontradas em ambos os grupos foram: otite, otosclerose e presbiacusia. Conclusão: Conhecendo as características de uma população, outras pesquisas poderão ser feitas e mudanças realizadas para melhoria na qualidade do atendimento ao deficiente auditivo, principalmente quanto à precisão do diagnóstico diferencial. / ZAMPRONIO, C. D. P. Hearing deficiency in DRS - 6 cities: characterization of people attended at Hearing Health Division of HRAC-USP Bauru. 2009. 86 f. Dissertation (Master Degree). Faculdade de Medicina de Ribeirão Preto-USP. Hearing loss, present at birth time or established at an early age, presents a significant influence upon child development process. When it occurs in an adult individual it may lead to some isolation, separating him or her from its community, limiting his ability to act independently and autonomously toward society. Thus, any disturbance in normal hearing process, whatever the cause, severity or type might be, means a hearing change that may and can be avoided for the benefit of the health of the individual and the whole society. Objective: Characterization of hearing loss in patients attended at Hearing Health Division (HHD) of the Hospital for Craniofacial Anomalies Rehabilitation (HRAC), living in the 68 cities of the State of Sao Paulo comprising the Regional Health Department (DRS-6), according to some variables like age range, gender, socioeconomic level, school range, etiology, grade and kind of hearing loss. Methods: Survey of patients that started a treatment at the HHD of HRAC/USP, during the period from 1998 to 2007, living in the cities comprising the DRS-6 and that received an audiologic diagnosis of hearing loss at least in one of the ears. For a better visualization of the studied sample, the 692 subjects were divided in two groups, one living in Bauru and one living in the other cities of DRS-6. Results: There has not been any predominance between genders; elderly population represented a significant number of subjects compared to the other age ranges and most subjects belonged to low socioeconomic class. It was observed that the main etiologies found for both groups were: otitis, otosclerosis, and presbyacusis. Conclusion: Knowing the characteristics of a population, other surveys may be performed and changes made to make better the attendance quality for hearing loss people and, especially, the accuracy of differential diagnosis.

Among those subjects admitted with AECOPD and concomitant pneumonia, a total of 118 patients (91 males) with 150 episodes were identified. Haemophilus influenzae was the commonest organism found in sputum (26.0%), followed by Pseudomonas aeruginosa (5.5%), Streptococcus pneumoniae (3.4%), and Moraxella catarrhalis (3.4%). In contrast to most studies from other countries reporting Streptococcus pneumoniae as the most likely bacterial pathogen, Haemophilus influenzae was the commonest bacterium isolated in sputum in this cohort of patients with AECOPD and concomitant pneumonia. / Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. / Exhaled breath condensate (EBC) analysis is a novel tool which has been developed in recent years and the technique is believed to reflect the lower airway lining fluid. My previous work has demonstrated the repeatability of certain inflammatory markers in the EBC of stable asthma and COPD patients. / Hypothesis 1: Bacterial pathogens are the major cause of AECOPD with and without concomitant pneumonia in patients requiring hospitalization. In the one-year retrospective bacteriology study, there were 329 patients with 418 episodes of AECOPD without concomitant pneumonia. These result noted that H. influenzae was the commonest bacterium isolated in sputum in patients with AECOPD without concomitant pneumonia. In areas endemic of tuberculosis, it is advisable to use fluoroquinolones for AECOPD with caution in view of the positive sputum culture of mycobacterium tuberculosis in some patients. / Hypothesis 2: Viral pathogens are an important cause of AECOPD in patients hospitalized with AECOPD. For the prospective infectious aetiology study, there were 643 episodes of AECOPD among 373 patients (307 males). Severe airflow obstruction (stable state spirometry) was associated with a higher chance of positive sputum culture (28.2% for FEV1 ≥30% vs. 40.4% for FEV1 <30% predicted normal, p=0.006). In this study, Haemophilus influenzae and influenza A were the commonest aetiological agents in patients hospitalized with AECOPD. More severe airflow obstruction was associated with a higher chance of positive sputum culture. / Hypothesis 3: The rates of hospital admissions due to AECOPD are associated with indices of air pollution in Hong Kong. Concerning the effect of air pollutants on AECOPD, significant associations were found between hospital admissions for COPD with all 5 air pollutants. Adverse effects of ambient concentrations of air pollutants on hospitalization rates for COPD are evident, especially during the winter season in Hong Kong. / Hypothesis 4: During the course of AECOPD, it is possible to assess inflammation in the airway by measuring biomarkers non-invasively using the method of EBC collection. To explore the course of inflammation in the airway during AECOPD, 26 patients (22 male) with AECOPD (mean percentage predicted FEV1, 44.8 +/- 14.3), 11 stable COPD and 14 age and sex-matched healthy controls were studied. Repeatability measurements of TNFalpha and LTB4 in 6 stable COPD patients were satisfactory. EBC TNFalpha level was low in patients receiving systemic steroid and antibiotic therapy for AECOPD whereas EBC TNFalpha level was also lower in stable patients receiving ICS post AECOPD than those who were not. These findings suggest a potential role for serial EBC TNFalpha for non-invasive monitoring of disease activity. / Summary. The above studies have shown that bacterial pathogens are the major cause of AECOPD with and without concomitant pneumonia in patients requiring hospitalization and the commonest bacterium found in the sputum of the patients was Haemophilus influenzae. Viral pathogens are also an important cause of AECOPD in patients hospitalized with AECOPD in Hong Kong and the commonest virus identified in the NPA of the patients was influenza A. Concerning the effect of air pollutants on AECOPD, significant associations were found between hospital admissions for AECOPD with the air pollutants of SO2, NO3, O3, PM10 and PM2.5. Finally, TNFalpha could be measured in the EBC of patients during the course of AECOPD and its level was low in patients receiving systemic steroid and antibiotic therapy for AECOPD. The results suggest that it is possible to assess inflammation in the airway by measuring biomarkers non-invasively using the method of EBC collection. (Abstract shortened by UMI.) / Ko, Wai-san Fanny. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0926. / Thesis (M.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 207-250). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

A fissura labiopalatina (FL/P) é uma das malformações craniofaciais mais comuns em humanos, com variação epidemiológica nas diferentes populações. Possui diferentes apresentações clínicas, divergindo de acordo com a extensão e estruturas acometidas, podendo acometer somente o lábio ou lábio e palato em conjunto, uni ou bilateralmente, de maneira completa ou incompleta ou apenas o palato (FP) tanto completa como incompletamente. Podem fazer parte de um quadro sindrômico, recebendo a denominação de FL/P sindrômica ou acontecer como um fenótipo isolado, sendo chamada de FL/P isolada ou não sindrômica. Em relação a etiologia da FL/P não sindrômica, a literatura afirma ser multifatorial com a predisposição genética associada a fatores ambientais. Apesar de se apresentarem frequentemente associadas, a FL/P e FP não sindrômicas são consideradas etiologicamente e embriologicamente distintas. Objetivo: Aprofundar e ampliar o conhecimento das FP isoladas não sindrômicas, descrevendo o fenótipo principal (FP isolada) e seus subfenótipos clínicos, investigando o fator genético relacionado à recorrência por meio do histórico familial e buscando elucidar possível fatores ambientais envolvidos por meio do histórico gestacional. Material e métodos: Foram coletados dados de 165 prontuários médicos de pacientes com FP isolada não sindrômica matriculados no Hospital de Reabilitação de Anomalias Craniofaciais da Universidade de São Paulo (HRAC-USP). Para a coleta desses dados foram analisados segmentos do prontuário referentes a atendimentos realizados no HRACUSP em diferentes setores. Resultados: Em 165 pacientes estudados, o sexo feminino foi o mais acometido com 106 casos (64,24%) encontrados. O tipo de FP predominante foi a incompleta correspondendo a 88,48% da amostra total, sendo dentre elas a fissura de palato duro parcial a mais prevalente. Em cinco casos não foi possível realizar a classificação nos grupos referentes ao tipo de fissura adotados, sendo necessária a criação de um grupo de classificação adicional. Recorrência familial positiva foi relatada em 28,47% de 144 casos em que havia informação, e na maioria das vezes havia apenas 1 outro familiar acometido. A média da idade das mães e dos pais no momento da concepção foi de 26,9 e 31,4 anos, respectivamente. A porcentagem de abortos anteriores foi de 11,95% dos 92 casos informados e a consanguinidade foi de 3,29% dos 91 casos informados. A intercorrência mais frequentemente relatada (25 em 154 casos informados) foi o uso de medicamentos, tais como, antibióticos, anti-hipertensivos e medicamentos que auxiliam na prevenção do parto prematuro. Conclusão: O fenótipo FP isolada possui variações quanto à extensão de cometimento, sendo que as fissuras incompletas foram as mais frequentes e o sexo feminino predominantemente acometido. Em relação ao histórico familial e gestacional os dados que mais chamaram atenção estão relacionados ao percentual de recorrência familial (28,47%) e o uso de medicação durante a gestação. / Cleft lip and palate (CL/P) is one of the most common craniofacial malformations in humans, with epidemiological variation in different populations. It has different clinical presentations that diverge according to the extension and affected structures, and may either affect the lip or lip and palate together, unilaterally or bilaterally, in a complete or incomplete way or just affect the palate (CP) completely or incompletely. CL/P can either be related to a syndrome, classified as syndromic CL/P or unrelated to a syndrome, occurring as an isolated phenotype, designated as isolated or nonsyndromic CL/P. Regarding the etiology of nonsyndromic CL/P, research indicates multifactorial causes with a genetic predisposition associated with environmental factors. Although it is often present in association, nonsyndromic CL/P and CP are considered embryologically and etiologically distinct. Objective: To deepen and broaden the knowledge of individual nonsyndromic CP, describing the main phenotype (isolated CP) and its clinical subphenotypes, investigating the genetic factors related to recurrence through family history and to elucidate possible environmental factors involving gestational history. Material and Methods: Data were collected from 165 medical patients records with isolated nonsyndromic CP enrolled at the Hospital de Reabilitação de Anomalias Craniofaciais da Universidade de São Paulo (HRAC-USP). For data collection, segments of the records pertaining to care provided by HRAC-USP in different sectors were analyzed. Results: In the 165 patients studied, females were the most affected with 106 cases (64.24%) found. The predominant type of CP was incomplete corresponding to 88.48% of the total sample, and among these incomplete CP, the clefts involving partial hard palate were the most prevalent. In five cases it was impossible to classify the type of cleft, and the creation of an additional classification group was required. Positive familial recurrence was reported in 28.47% of 144 cases where information was available and in most cases there was only one other affected family member. The average age of mothers and fathers at conception was 26.9 and 31.4 years respectively. The percentage of previous miscarriages was 11.95% of the 92 reported cases and consanguineous marriage was found in 3.29% of the 91 reported cases. The most frequently reported complication (25 in 154 reported cases) was the use of drugs such as antibiotics, antihypertensives drugs, and drugs used to prevent premature birth. Conclusion: The phenotype Isolated CP presents variations in the extent of involvement, and incomplete clefts were the most frequent, with females predominantly affected. Regarding family history and gestational data what calls more attention were the percentage of familial recurrence (28.47%) and the use of medication during pregnancy.

Abstract not available

The thoracolumbar transversospinal muscles are vital in normal function and are implicated in the pathogenesis of different forms of spinal pathology and pain. They are the target for specific forms of clinical intervention such as exercise regimens and the release of �trigger points�, and are often analysed through imaging studies and electromyographic recordings. Despite the importance of these muscles, there is a paucity of knowledge in regard to aspects of their functional morphology. The aim of this thesis was to examine the thoracolumbar transversospinal muscles between the mid-thoracic spine and sacrum, examining their gross morphology, fibre arrangement, fibre types, and an animal model in order to provide a better understanding of their functional morphology. The gross morphology of these muscles was studied by micro-dissection of cadaveric material. Their form was found to differ from that published in either text book or peer reviewed articles, clearly indicating the existence of a �semispinalis� muscle in the lumbar spine. In addition, the arrangement of these muscles was found to be homologous between the thoracic and lumbar regions, which is contrary to published descriptions. Arrangement of the muscle fibres was examined by identifying motor endplates with acetylcholinesterase histochemistry in all muscles throughout the area of interest. Only one endplate per fibre was observed, and no in-series fibres were found. All muscles showed a complex multipinnate form with large areas of muscle tendon intruding into each muscle. Fibre type proportions in each muscle were investigated by immunohistochemistry. Results indicate the percentage of total muscle area occupied by type I fibres decreased the more caudad the vertebral level of origin, for all muscles. There were significant differences in the area percentage of type I fibres between many different vertebral levels. These differences were mostly found between the most cranial and most caudal levels examined. The percentage of type I fibres recorded suggest all muscles are likely postural in function, and the gradual decrease in type I fibres and the lack of a distinct thoracic / lumbar boundary in the data suggests the thoracic and lumbar transversospinal muscles are homologous. The thoracolumbar transversospinal muscles of the MLC3F nlacZ transgenic mouse were micro-dissected to determine their morphology, and their fibre arrangement subsequently determined using acetylcholinesterase histochemistry. These muscles showed a homogeneous form throughout the thoracolumbar spine, and no in-series muscle fibres were observed with all muscles having one motor endplate per fibre. Results indicated similarities between the morphology of mouse and human transversospinal muscles, perhaps indicative of an adaptation to an upright posture. This thesis provides information that facilitates a more complete understanding of the morphology and function of the thoracolumbar transversospinal muscles. In addition, results indicate that these muscles are homologous through the thoracic and lumbar spine, and therefore the classification and nomenclature used to describe these muscles should be re-examined. Furthermore, the morphological evidence, combined with recent embryological studies, supports the use of the term �spinotransverse� to more accurately describe this muscle group.

The pituitary hormone prolactin (Prl) is essential for alveolar morphogenesis and plays a role in breast carcinogenesis, however the mechanism that underlies these actions remains to be defined. Alterations in serum Prl provide the primary endocrine signal regulating developmental events in the mammary gland in sexually mature mammals. Prl production and post-translational phosphorylation by the pituitary is regulated by the neuropeptide Galanin (Gal) in response to hypothalamic signals integrating neuronal and endocrine inputs. Prl exerts its effects on the mammary epithelium in two ways, indirectly by modulation of the systemic hormonal environment, for example the release of progesterone from the corpus luteum, and directly by binding to Prl receptors (Prlr) within the mammary epithelium. Prl binding to Prlr initiates signalling predominantly via activation of the Jak2/Stat5 pathway, leading to altered patterns of gene transcription. One of these target genes is the ets transcription factor Elf5, which is required by the epithelium for alveolar morphogenesis. This thesis aims to further our understanding of the mechanisms by which prolactin exerts its influence on the mammary gland during alveolar morphogenesis and carcinogenesis. Transcript profiling revealed a lactation signature of 35 genes in Prlr+/- mice, Gal-/- mice and mice treated with a Prl mutant (S179D) that mimics phosphorylated Prl. We discovered that the majority of changes in gene expression were produced by prolactin rather than by Gal. The action of Gal was predominantly via modulation of Prl phosphorylation and release, as its effects were very similar to that of S179D. Knockout of Elf5 phenocopied knockout of Prlr, resulting in failure of alveolar morphogenesis and reduced expression of milk and lipid synthesis genes. Forced Elf5 expression at puberty resulted in aberrant differentiation of the terminal end buds and milk protein synthesis during ductal morphogenesis. Re-expression of Elf5 in Prlr-/- mammary epithelial cells completely rescued alveolar morphogenesis. These observations indicate that Elf5 is a master regulator of alveolar morphogenesis downstream of the Prlr. Loss of mammary epithelial Prlr resulted in reduced proliferation of low-grade neoplastic lesions resulting in increased tumour latency in the C3(1)/SV40T model of mammary carcinogenesis. There was no change in the growth rate, proliferation nor the morphology of tumours in Prlr-/-/C3(1)/SV40T transplants, thus Prl acts early in carcinogenesis to drive the proliferation of pre-invasive lesions resulting in faster progression to cancer.

Cardiovascular pathology is seen in both animals and humans after domoic acid intoxication. Whether this damage is direct (i.e., cardiotoxic) or indirect (i.e., CNS/autonomic seizures) is not known. We have previously shown that acute in vitro domoic acid (0.05-0.25[mu]M; 10 min) treatment of isolated cardiac mitochondria compromises mitochondrial FADH and NAD⁺-linked respiratory control and mitochondrial energetics. Domoic acid was shown to traverse and bind the cellular membrane of H9c2 cardiac myoblasts. However it did not compromise cellular viability as assessed using cell quantification or lactate dehydrogenase leakage assays. Exposure of intact H9c2 cells to domoic acid only resulted in complex II-III activity impairment and assessment of reactive oxygen species (superoxide and hydrogen peroxide) production in both isolated cardiac mitochondria and H9c2 cardiomyocytes failed to show any significant differences following exposure to domoic acid. Acute ex vivo domoic acid treatment of an isolated myocardium in Langendorff perfusion mode failed to result in cardiac haemodynamic dysfunction, however there appeared to be small but significant decrease in mitochondrial oxygen utilization. The absence of any substantial damage to intact cardiomyocytes and isolated myocardium suggested that domoic acid does not have a direct toxicological effect on cardiac energetics. We therefore investigated the possibility that cardiovascular pathology is an indirect consequence of autonomic seizure activity. Domoic acid was administered intraperitoneally or intrahippocampally and the development of cardiac pathologies was assessed and compared. Sprague-Dawley rats receiving either i.p. or i.h. domoic acid were assessed behaviourally and shown to reach similar levels in their cumulative seizure scores. Assessment of the cardiac haemodynamics (LVDP, dP/dt, heart rate and coronary flow) revealed a significant time-dependent decrease in function at 1, 3, 7 & 14-days post-i.p. and 7 & 14-days post-i.h. domoic acid administration. Measurement of ventricular mitochondrial oxygen utilization revealed a similar time-dependent decrease in respiratory control, which appeared to be associated with increased proton leakage, shown by an increase in state-4 respiration rate (P<0.01). Assessment of the mitochondrial electron transport chain (complexes I-V) and the mitochondrial marker of integrity, citrate synthase, showed marked time-dependent impairment in both models of domoic acid -induced seizures. Oxidative stress did play a small role in the myocardial damage as indicated by the small decrease in aconitase activity (P<0.05). Plasma IL-1α, IL-1β and TNF-α levels were significantly increased from 3-days post seizures. Haematoxylin & Eosin staining of ventricular sections revealed the formation of contraction bands, inflammation and oedema, confirming a structural pathology. Cardiac damage did not differ between i.p. and i.h. animals, suggesting cardiac damage following domoic acid results from CNS autonomic seizures and resultant sympathetic storm. This thesis has demonstrated, for the first time, that the cardiac pathology seen following domoic acid exposure is most likely to be a result of CNS activation and resultant seizure episodes, and is not a consequence of the direct interaction between domoic acid and the myocardium. We have also demonstrated for the first time, that seizure episodes result in chronic cardiac dysfunction and a structural pathology which is similar, but not identical to that seen following isoprotenerol administration in vivo.

Includes copies of author's previously published works. / Bibliography: leaves 106-122. / xiii, 123 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the relationship between circulating adrenaline (AD) and blood pressure. Results suggest that the elevation of circulating AD in hypertensive rats is a consequence rather than a cause of their hypertension. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1995

Includes bibliographical references (leaves 219-236) / v, 236 leaves : ill. (some col.), plates, photos ; 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, School of Earth and Environmental Sciences, Discipline of Environmental Biology, 2004