"July, 2003" / "Amendments of the thesis" and "abbreviations (additional)" inside back cover. / Includes bibliographical references (leaves 195-231) / x, 231, [20] leaves : ill., plates ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2003

This thesis is an integrated study that links several disciplines-archaeology, anthropology, geography, atmospheric sciences, and microbiology. It attempts to generate an argument that central to climate change is disequilibrium in human ecologies- in my case, disease ecologies in Iceland during the 15th century. This thesis investigates the environment's effect on human adaptability. The effect of the environment on Icelanders as they moved from settlement to later periods was disquieting. The climate of the world was changing- moving from the Medieval Warm Period to the colder Little Ice Age. I analyze the disease ecology of the 15th century and also conduct an archeological and cultural analysis of the Icelandic people, to show the deficiencies in their adaptation, and submit that certain shortcomings in their physical environment, as well as the inadequate adaptive synthesis to the environment, led to a marginal adaptation. This was augmented by political unrest and problems with outside trade, which left them vulnerable and susceptible to disease pathogenesis. I discuss the climate change during the Little Ice Age, and assert that this event is the crucible that crushed Iceland after 400 years of reasonably good fortune. Hundreds of epidemics, natural disasters, and hardships befall the Icelanders. One of them is the plague, which comes twice in the 15th century. The important observation here is that the epidemiological and archeological evidence does not always match up. The principal problem is that the traditional vector for the disease cannot have survived the climate as it was in the winters during the LIA. I offer an analysis that pontificates this issue and I examine the ongoing debate concerning The Black Death in Europe. I introduce another possible explanation: the introduction of disease through environmental vectors. The creation of disease ecologies through climate change is important, in light of problems that we face today. I discuss the phenomenon of the dust storm and its connection to disease pathogenesis. By showing several key examples of dust from Africa to disease pathogenesis in the Caribbean, I make the connection a good one. In addition to this connection is the atmospheric analysis that shows incontrovertibly that the dust found in Greenland ice cores is only from Asia. Finally, there is the fact that the inveterate loci of the plague bacterium is located in the same areas that Asian Dust Events occur and travel from. I create a methodology for investigating this disease ecology and am able to show that the pathogen can be identified in situ- meaning that it can be found in geological deposits that can be properly dated. My pilot study creates a methodology for the examination of ice cores- the principal reservoir for atmospheric deposits made during the LIA. Finally, I look at the aftermath. I introduce the idea of disease ecology, as opposed to that of a healthy ecology, and suggest by the end of the thesis that within the disease ecology are created many of the platforms for emergent biological changes that translate through evolution over time. Like the bacterium in the ice core, I suggest that evidence for disease states in the history of a people can be found through laboratory techniques. The presence of the CCR5 gene mutation is indicative of such a presence. I believe that the presence of the delta 32 gene mutation found in Icelandic people is the result of being exposed to the plague in the 15th century. This thesis is a platform for future synoptic scale disease studies. / Graduation date: 2005

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Juvenile violence is a phenomenon that consistently garners great attention in the media, the public, and across a multitude of academic disciplines. A growing body of literature in developmental and lifecourse criminology has called for innovative research to further investigate the causes and correlates of serious juvenile offenders. Toward this end, the present study uses prospective, longitudinal data from the Pittsburgh Youth Study (PYS) to gauge the temporal impact of childhood and adolescent mental health problems on the development of serious offending behaviors in boys. Borrowing largely from the work of Achenbach and colleagues (2001), data from parent and teacher reports of psychopathological problems were used to create DSM-oriented scales for Oppositional Defiant, Attention-Deficit/Hyperactivity, Anxiety, and Affective Problems. These scales offer a more continuous form of measurement than DSM diagnoses and allowed for distinctions between normal, borderline, and clinical levels of mental health problems. Forward-step logistic regression analyses indicated that three different teacher-reported DSM-oriented mental health problems emerged at three different stages of development as significant predictors of serious violence over the lifecourse. The significant substantive, methodological, and public policy implications of the study are discussed.

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, a methyl donor for conversion of homocysteine to methionine. A common thermolabile variant causes mild MTHFR deficiency, induces mild hyperhomocysteinemia when plasma folate levels are low and increases risk for neural tube defects (NTD) and pregnancy loss. To increase our understanding of Mthfr regulation, the 5' and 3' regions of the mouse cDNA and gene were characterized. These studies revealed two major promoters, an internal coding exon in the 5'UTR, alternative transcriptional and translational start sites and alternative splicing and polyadenylation. These data suggest that Mthfr regulation is likely to be complex. To investigate the role of Mthfr in NTD, several approaches were taken. First, folate and MTHFR co-factor, flavin adenine dinucleotide, were shown to stabilize normal and thermolabile MTHFR during heat inactivation, suggesting that folate might prevent hyperhomocysteinemia in individuals with thermolabile enzyme through protein stabilization. Next, in situ hybridization of neurulating mouse embryos showed that Mthfr is expressed in the forebrain, hindbrain, branchial arches, blood vessels, gut, and importantly, in the ventral part of the neural tube. Mthfr+/- mice were then used as a model of mild deficiency to address the effects of maternal and embryonic Mthfr deficiency on development. When combined with inadequate dietary folate, Mthfr +/- pregnant females showed a two-fold higher rate of pregnancy loss than Mthfr+/+ pregnant females. As well, a percentage of day 10.5 embryos from only the Mthfr+/- pregnant females were underdeveloped by 2 days. These effects were not apparent when dietary folate was sufficient, consistent with a genetic-nutritional interactive effect. Finally, folate metabolism was investigated in an NTD model, the curly-tail (ct) mouse, since the ct defect and Mthfr were mapped in close proximity. However, Mthfr sequence in ct mice was simila

No description available.

The liver is a vital organ, playing numerous critical roles in the body. The liver's ability to perform essential functions is disturbed by injuries that are often associated with many complications such as calcification. Although many reports in the literature document observations of liver calcification, the mechanisms regulating this phenomenon remain unclear. Herein, we aim to investigate the cellular and molecular events that occur during pathological calcification of the liver. / To study the mechanisms of calcification, assessments included histological-staining, immunolabeling, and biochemical and electron microscopy analyses. The findings suggest that calcification may result from hydroxyapatite precipitation in necrotic or apoptotic hepatocytes. Similarly, calcification may be associated with differentiated myofibroblasts expressing bone matrix proteins downstream of TGFbeta signalling. / To identify specific protein regulators linked to the various stages in calcification, and to assess the protein composition of the tissue, a proteomic analysis was used. This analysis identified IQGAP1, an effector of the Rho-GTPases and a master regulator of cell adhesion and migration. IQGAP1 is strongly expressed in myofibroblasts, suggesting that IQGAP1 may be implicated in myofibroblasts migrating towards calcification. Studies on IQGAP1 interactions with its binding partners reveal that it is part of a protein complex that includes beta-catenin, an adhesion protein, and Rac1, a cytoskeletal regulator. These results suggest that IQGAP1 may play an important role in myofibroblast migration upon liver injury. / Having identified that activin and TGFbeta signalling are activated in myofibroblasts, we hypothesised that they may stimulate myofibroblast differentiation and proliferation. Studies using a C3H/10T1/2 cell model reveal that both activin and TGFbeta stimulate differentiation, but only activin induces cell proliferation in a Smad-independent fashion, which requires activation of the ERK/MAPK pathway. / In summary, this work provides new mechanistic insights on the global regulation of liver calcification. The various phases of this work collectively cover the central role of myofibroblasts in liver injury: association with calcification, rapid proliferation, differentiation to an activated form, and migration toward the injured area. The findings allow us to better understand the mechanisms by which liver myofibroblasts are regulated in a specific pathological context.

Cyclic guanosine 3', 5'-monophosphate (cGMP) has recently emerged as an endogenous regulator for controlling or reversing cardiac hypertrophy. Increased protein accumulation is a key feature of cardiac hypertrophy; thus, our study investigates the effects of a cGMP analog on protein accumulation in primary culture of adult rat cardiomyocytes and dissects out the mechanisms involved. We confirmed that a cGMP analog, 8-bromo-cGMP, inhibits phenylephrine (PE)-increased accumulation of newly synthesized proteins in cultured adult rat ventricular cardiomyocytes. Firstly, we have obtained data showing that 8-bromo-cGMP does not inhibit phosphorylation of S6K1 by PE during short time treatment (10 min to 2 h), but blocks phosphorylation of S6K1 by PE at 6 h; moreover this blocking effect is completely abolished by phosphatase inhibitor Tautomycin. Then, we have demonstrated that PE and cGMP induce sustained and transient increased phosphorylation of ERK, respectively. Moreover, cGMP inhibits PE-induced phosphorylation of ERK during long term treatment (3 and 6h). We have also shown that 8-bromo-cGMP inhibits ROS generation induced by PE. Other effects of PE that could be related to hypertrophy (i.e. increased concentration of upstream binding factor mRNA and decreased concentration of the mRNAs of Atrogin and muscle specific RING finger) were not abolished by 8-bromo-cGMP. We conclude that cGMP analog blocks protein accumulation by inhibiting the sustained phosphorylation of S6K1 via the activation of phosphatases.

Repeated exposure to amphetamine (AMPH) induces sensitization to its behavioral-activating effects. The development of sensitization depends on (1) the direct actions of AMPH in the ventral tegmental area (VTA), the cell body region of the mesocorticolimbic DA system, and (2) AMPH-induced glutamatergic neurotransmission in this region. Moreover, sensitization is accompanied by morphological changes in mesocorticolimbic DA circuitry. During development, the DA system is organized, at least in part, by the netrin-1 family of guidance cues. Both netrin-1 and its DCC and UNC-5 receptors continue to be expressed in the mesocorticolimbic DA system of the adult brain. Importantly, netrin-1 receptor deficient mice do not develop sensitization to AMPH, implicating an involvement of netrin-1 signaling in AMPH-induced plasticity of the DA system. To explore this possibility, adult rats were pretreated with repeated AMPH or saline, and DCC and UNC-5 receptor expression was examined in DA cell body and terminal regions using western blot. Striking AMPH-induced increases in the expression of DCC and UNC-5 were observed in the VTA only. Remarkably, these changes depended on NMDA-mediated glutamatergic neurotransmission. This is the first demonstration that repeated AMPH pretreatment regulates netrin-1 receptor expression in the adult brain and suggests that netrin-1 receptor regulation may be involved in the development of AMPH-induced sensitization.