A Case of Internal Carotid Artery Thrombosis associated with Thalidomide Administration in Multiple Myeloma

Thalidomide is an effective chemotherapeutic agent used to achieve remission in multiple myeloma. However, its administration is associated with several adverse effects including venous thromboembolism, while arterial thrombosis has also, although rarely, been described in the literature. We report a case of internal carotid artery occlusion within 1 week of starting thalidomide with prophylactic low molecular weight heparin in a patient who had no other prothrombotic risk factors. It is not known why this complication occurs despite the administration of anticoagulant prophylaxis. The role of factor VIII, von Willebrand factor antigen levels and fibrinogen in multiple myeloma patients should be studied in order to determine if these factors should be targeted in future prophylactic treatment.

Multiple Imputation of missing values in exploratory factor analysis of multidimensional scales: estimating latent trait scores

ABSTRACT Researchers frequently have to analyze scales in which some participants have failed to respond to some items. In this paper we focus on the exploratory factor analysis of multidimensional scales (i.e., scales that consist of a number of subscales) where each subscale is made up of a number of Likert-type items, and the aim of the analysis is to estimate participants' scores on the corresponding latent traits. We propose a new approach to deal with missing responses in such a situation that is based on (1) multiple imputation of non-responses and (2) simultaneous rotation of the imputed datasets. We applied the approach in a real dataset where missing responses were artificially introduced following a real pattern of non-responses, and a simulation study based on artificial datasets. The results show that our approach (specifically, Hot-Deck multiple imputation followed of Consensus Promin rotation) was able to successfully compute factor score estimates even for participants that have missing data.

Role of Serum Levels of Vascular Endothelial Growth Factor and Its Receptor in Retinopathy of Prematurity

Background: Retinopathy of prematurity (ROP) is a disorder of developing retina of low birth weight preterm infants which can lead to blindness. One theory attributes the fibrosis seen in ROP to deregulation of vascularization in the retina. Vascular endothelial growth factor (VEGF) is one of the important mediators involved in vascularization. Objectives: This study was carried out to assess the role of VEGF and its receptor in retinopathy of prematurity. Patients and Methods: Around 200 preterm infants born in SSK hospital were screened at 33 - 34 weeks. These babies were followed up according to the international classification of retinopathy of prematurity (ICROP) criteria. Those infants who developed ROP at 38 - 40 weeks were enrolled in group A while an equal number of infants who did not develop ROP were included in group B. Each group comprised of 30 subjects each. Venous sampling was carried out twice, once at 33 - 34 weeks and then again at 38 - 40 weeks. VEGF and VEGF-R2 were estimated by commercially available ELISA kits. Results: There was no statistically significant difference between the levels of VEGF and VEGF-R2 in both groups at first visit as well as the follow up visit. However, the intra-group difference was significant between the first and the final visit in VEGF and VEGF-R2 levels in the cases with ROP. In the control population, the VEGF levels were significantly lower in the follow up visit as compared to the initial visit. Conclusions: Our study demonstrates that a significant difference is seen in the serum VEGF and VRGF-R2 in the second visit of the infants with ROP demonstrating that VEGF might be responsible for the initiation and aggravation of ROP.

The Role of the Transcription Factor Ets1 in Melanocyte Development

Melanocytes, pigment-producing cells, derive from the neural crest (NC), a population of pluripotent cells that arise from the dorsal aspect of the neural tube during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The deletion of the transcription factor Ets1 in mice results in hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The goal of the present study was to establish the temporal requirement and role of Ets1 in murine melanocyte development. In the mouse, Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick cranial NC, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of melanocytes, enteric ganglia, and other NC derivatives. Using a combination of immunofluorescence and cell survival assays Ets1 was found to be required between embryonic days 10 and 11, when it regulates NC cell and melanocyte precursor (melanoblast) survival. Given the requirement of Ets1 for Sox10 expression in the chick cranial NC, a potential interaction between these genes was investigated. Using genetic crosses, a synergistic genetic interaction between Ets1 and Sox10 in melanocyte development was found. Since Sox10 is essential for enteric ganglia formation, the importance of Ets1 on gut innervation was also examined. In mice, Ets1 deletion led to decreased gut innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate a Sox10 enhancer critical for Sox10 expression in melanoblasts. Furthermore, mutating Ets1 at a site I characterized in the spontaneous variable spotting mouse pigmentation mutant, led to a 2-fold decrease in enhancer activation. Overexpression and knockdown of Ets1 did not affect Sox10 expression; nonetheless, Ets1 knockdown led to a 6-fold upregulation of the transcription factor Sox9, a gene required for melanocyte and chondrocyte development, but which impairs melanocyte development when its expression is prolonged. Together, these results suggest that Ets1 is required early during melanocyte development for NC cell and melanoblast survival, possibly acting upstream of Sox10. The transcription factor Ets1 may also act indirectly in melanocyte fate specification by repressing Sox9 expression, and consequently cartilage fate.

Microglia as therapeutic targets in retinal degeneration: role of translocator protein (18 κDa) (TSPO) and minocycline.

Microglia are the resident immune cells of the central nervous system (CNS) and play an important role in innate immune defense as well as tissue homeostasis. Chronic microglial reactivity, microgliosis, is a general hallmark of inflammatory and degenerative diseases that affect the CNS, including the retina. There is increasing evidence that chronic microgliosis is more than just a bystander effect, but rather actively contributes to progression of degeneration through processes such as toxic nitric oxide (NO) production and even phagocytosis of stressed but viable photoreceptors. Therefore immunmodulation of microglia presents a possible therapeutic strategy for retinal degenerations. Notably, the expression of the mitochondrial translocator protein 18 (κDa) (TSPO) is highly elevated in reactive microglia as seen in several neuroinflammatory diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Therefore it is used as a gliosis biomarker in the brain. Moreover TSPO ligands show potent effects in resolving neuroinflammatory brain disorders. However, TSPO expression in the eye had not been investigated before. Further, it was unknown whether TSPO ligands’ potent immunomodulatory effects could be used to treat retinal degenerations. To fill this gap, the study aimed to analyze whether TSPO is also a potential biomarker for degenerative processes in the retina. Moreover the thesis attempted to determine whether a specific TSPO ligand, XBD173, might modulate microglial reactivity and is a potent therapeutic, to treat retinal degenerative diseases. The findings revealed that TSPO is strongly upregulated in microglial cells of retinoschisin-deficient (RS1-/y) mice, a model of inherited retinal degeneration and in a murine light damage model. A co-localization of TSPO and microglia was furthermore detectable in human retinal sections, indicating a potential role for TSPO as a biomarker for retinal degenerations. In vitro assays showed that the TSPO ligand XBD173 effectively inhibited features of microglial activation such as morphological transformation into reactive phagocytes and enhanced expression of pro-inflammatory cytokines. XBD173 also reduced microglial migration and proliferation and reduced their neurotoxic potential on photoreceptor cells. In two independent mouse models of light-induced retinal degeneration, the treatment with XBD173 reduced accumulation of amoeboid, reactive microglia in the outer retina and attenuated degenerative processes, indicated by a nearly preserved photoreceptor layer. A further question addressed in this thesis was whether minocycline, an antibiotic with additional anti-inflammatory properties is able to reduce microglial neurotoxicity and to protect the retina from degeneration. Minocycline administration dampened microglial pro-inflammatory gene expression, NO production and neurotoxicity on photoreceptors. Interestingly, in addition to its immunomodulatory effect, minocycline also increased the viability of photoreceptors in a direct manner. In the light damage model, minocycline administration counter-acted microglial activation and blocked retinal degeneration. Taken together these results identified TSPO as a biomarker for microglial reactivity and as therapeutic target in the retina. Targeting TSPO with XBD173 was able to reverse microglial reactivity and could prevent degenerative processes in the retina. In addition, the study showed that the antibiotic minocycline effectively counter-regulates microgliosis and light-induced retinal degeneration. Considering that microgliosis is a major contributing factor for retinal degenerative disorders, this thesis supports the concept of a microglia-directed therapy to treat retinal degeneration.

The role of microcomputer-based laboratory display in supporting the construction of new understanding in kinematics

Teachers' failure to utilise MBL activities more widely may be due to not recognising their capacity to transform the nature of laboratory activities to be more consistent with contemporary constructivist theories of learning. This research aimed to increase understanding of how MBL activities specifically designed to be consistent with a constructivist theory of learning support or constrain student construction of understanding. The first author conducted the research with his Year 11 physics class of 29 students. Dyads completed nine tasks relating to kinematics using a Predict-Observe-Explain format. Data sources included video and audio recordings of students and teacher during four 70-minute sessions, students' display graphs and written notes, semi-structured student interviews, and the teacher's journal. The study identifies the actors and describes the patterns of interactions in the MBL. Analysis of students' discourse and actions identified many instances where students' initial understanding of kinematics were mediated in multiple ways. Students invented numerous techniques for manipulating data in the service of their emerging understanding. The findings are presented as eight assertions. Recommendations are made for developing pedagogical strategies incorporating MBL activities which will likely catalyse student construction of understanding.

Combination strategies for a factor analysis phone-conditioned speaker verification system

This work aims to take advantage of recent developments in joint factor analysis (JFA) in the context of a phonetically conditioned GMM speaker verification system. Previous work has shown performance advantages through phonetic conditioning, but this has not been shown to date with the JFA framework. Our focus is particularly on strategies for combining the phone-conditioned systems. We show that the classic fusion of the scores is suboptimal when using multiple GMM systems. We investigate several combination strategies in the model space, and demonstrate improvement over score-level combination as well as over a non-phonetic baseline system. This work was conducted during the 2008 CLSP Workshop at Johns Hopkins University.

Predicting behaviour to reduce stroke risk in at-risk populations : the role of beliefs

Aims: Changing behaviour to reduce stroke risk is a difficult prospect made particularly complex because of psychological factors. This study examined predictors of intentions and behaviours to reduce stroke risk in a sample of at-risk individuals, seeking to find how knowledge and health beliefs influenced both intention and actual behaviour to reduce stroke risk. Methods: A repeated measures design was used to assess behavioural intentions at time 1 (T1) and subsequent behaviour (T2). One hundred and twenty six respondents completed an online survey at T1, and behavioural follow-up data were collected from approximately 70 participants 1 month later. Predictors were stroke knowledge, demographic variables, and beliefs about stroke that were derived from an expanded health belief model. Dependent measures were: exercise and weight loss, and intention to engage in these behaviours to reduce stroke risk. Findings: Multiple hierarchical regression analyses showed that, for exercise and weight loss respectively, different health beliefs predicted intention to control stroke risk. The most important exercise-related health beliefs were benefits, susceptibility, and self-efficacy; for weight loss, the most important beliefs were barriers, and to a lesser degree, susceptibility and subjective norm. Conclusions: Health beliefs may play an important role in stroke prevention, particularly beliefs about susceptibility because these emerged for both behaviours. Stroke education and prevention programmes that selectively target the health beliefs relevant to specific behaviours may prove most efficacious.

The role of periosteum : a neglected aspect of osteoporosis

Most current studies on the pathogenesis of osteoporosis emphasize the bone metabolic activities occurring on endosteal surfaces, whereas the periosteal aspect is somewhat neglected. In terms of bone physiology, periosteum plays a determining role in de novo cortical bone formation and cortical bone expansion through periosteum is the most efficient way of increasing bone strength against fractures. Despite the important role of periosteum in the pathogenesis and treatment of osteoporosis, little is known about the structural and cellular features of periosteum in osteoporosis. This chapter will focus on the major changes occurring in the periosteum of osteoporosis and possible implications of these changes in the pathogenesis of osteoporosis. The changes identified in the periosteum of osteoporosis are mainly located in the metaphyseal compartment, which include: (a) much thicker and more cellular cambial layer; (b) increased number of TRAP (tartrate resistant acid phosphatase), VEGF (vascular endothelial growth factor) cells and the degree of vascularization; and (c) enhanced expression of sympathetic nerve fibers. The structural and cellular changes of osteoporotic periosteum indicate that periosteum plays an important role in the cortical bone resorption in metaphyseal areas and this pathological process may be regulated by the sympathetic nervous system.

Development of the benefit finding in multiple sclerosis (MS) caregiving scale: A longitudinal study of relations between benefit finding and adjustment

Benefit finding is a meaning making construct that has been shown to be related to adjustment in people with MS and their carers. This study investigated the dimensions, stability and potency of benefit finding in predicting adjustment over a 12 month interval using a newly developed Benefit Finding in Multiple Sclerosis Scale (BFiMSS). Usable data from 388 persons with MS and 232 carers was obtained from questionnaires completed at Time 1 and 12 months later (Time 2). Factor analysis of the BFiMSS revealed seven psychometrically sound factors: Compassion/Empathy, Spiritual Growth, Mindfulness, Family Relations Growth, Life Style Gains, Personal Growth, New Opportunities. BFiMSS total and factors showed satisfactory internal and retest reliability coefficients, and convergent, criterion and external validity. Results of regression analyses indicated that the Time 1 BFiMSS factors accounted for significant amounts of variance in each of the Time 2 adjustment outcomes (positive states of mind, positive affect, anxiety, depression) after controlling for Time 1 adjustment, and relevant demographic and illness variables. Findings delineate the dimensional structure of benefit finding in MS, the differential links between benefit finding dimensions and adjustment and the temporal unfolding of benefit finding in chronic illness.

The genetic basis of human height : the role of estrogen

Height is a complex physical trait that displays strong heritability. Adult height is related to length of the long bones, which is determined by growth at the epiphyseal growth plate. Longitudinal bone growth occurs via the process of endochondral ossification, where bone forms over the differentiating cartilage template at the growth plate. Estrogen plays a major role in regulating longitudinal bone growth and is responsible for inducing the pubertal growth spurt and fusion of the epiphyseal growth plate. However, the mechanism by which estrogen promotes epiphyseal fusion is poorly understood. It has been hypothesised that estrogen functions to regulate growth plate fusion by stimulating chondrocyte apoptosis, angiogenesis and bone cell invasion in the growth plate. Another theory has suggested that estrogen exposure exhausts the proliferative capacity of growth plate chondrocytes, which accelerates the process of chondrocyte senescence, leading to growth plate fusion. The overall objective of this study was to gain a greater understanding of the molecular mechanisms behind estrogen-mediated growth and height attainment by examining gene regulation in chondrocytes and the role of some of these genes in normal height inheritance. With the heritability of height so well established, the initial hypothesis was that genetic variation in candidate genes associated with longitudinal bone growth would be involved in normal adult height variation. The height-related genes FGFR3, CBFA1, ER and CBFA1 were screened for novel polymorphisms using denaturing HPLC and RFLP analysis. In total, 24 polymorphisms were identified. Two SNPs in ER (rs3757323 C>T and rs1801132 G>C) were strongly associated with adult male height and displayed an 8 cm and 9 cm height difference between homozygous genotypes, respectively. The TC haplotype of these SNPs was associated with a 6 cm decrease in height and remarkably, no homozygous carriers of the TC haplotype were identified in tall subjects. No significant associations with height were found for polymorphisms in the FGFR3, CBFA1 or VDR genes. In the epiphyseal growth plate, chondrocyte proliferation, matrix synthesis and chondrocyte hypertrophy are all major contributors to long bone growth. As estrogen plays such a significant role in both growth and final height attainment, another hypothesis of this study was that estrogen exerted its effects in the growth plate by influencing chondrocyte proliferation and mediating the expression of chondrocyte marker genes. The examination of genes regulated by estrogen in chondrocyte-like cells aimed to identify potential regulators of growth plate fusion, which may further elucidate mechanisms involved in the cessation of linear growth. While estrogen did not dramatically alter the proliferation of the SW1353 cell line, gene expression experiments identified several estrogen regulated genes. Sixteen chondrocyte marker genes were examined in response to estrogen concentrations ranging from 10-12 M to 10-8 M over varying time points. Of the genes analysed, IHH, FGFR3, collagen II and collagen X were not readily detectable and PTHrP, GHR, ER, BMP6, SOX9 and TGF1 mRNAs showed no significant response to estrogen treatments. However, the expression of MMP13, CBFA1, BCL-2 and BAX genes were significantly decreased. Interestingly, the majority of estrogen regulated genes in SW1353 cells are expressed in the hypertrophic zone of the growth plate. Estrogen is also known to regulate systemic GH secretion and local GH action. At the molecular level, estrogen functions to inhibit GH action by negatively regulating GH signalling. GH treated SW1353 cells displayed increases in MMP9 mRNA expression (4.4-fold) and MMP13 mRNA expression (64-fold) in SW1353 cells. Increases were also detected in their respective proteins. Treatment with AG490, an established JAK2 inhibitor, blocked the GH mediated stimulation of both MMP9 and MMP13 mRNA expression. The application of estrogen and GH to SW1353 cells attenuated GH-stimulated MMP13 levels, but did not affect MMP9 levels. Investigation of GH signalling revealed that SW1353 cells have high levels of activated JAK2 and exposure to GH, estrogen, AG490 and other signalling inhibitors did not affect JAK2 phosphorylation. Interestingly, AG490 treatment dramatically decreased ERK2 signalling, although GH did stimulate ERK2 phosphorylation above control levels. AG490 also decreased CBFA1 expression, a transcription factor known to activate MMP9 and MMP13. Finally, GH and estrogen treatment increased expression of SOCS3 mRNA, suggesting that SOCS3 may regulate JAK/STAT signalling in SW1353 cells. The modulation of GH-mediated MMP expression by estrogen in SW1353 cells represents a potentially novel mechanism by which estrogen may regulate longitudinal bone growth. However, further investigation is required in order to elucidate the precise mechanisms behind estrogen and GH regulation of MMP13 expression in SW1353 cells. This study has provided additional evidence that estrogen and the ER gene are major factors in the regulation of growth and the determination of adult height. Newly identified polymorphisms in the ER gene not only contribute to our understanding of the genetic basis of human height, but may also be useful in association studies examining other complex traits. This study also identified several estrogen regulated genes and indicated that estrogen modifies the expression of genes which are primarily expressed in the hypertrophic region of the epiphyseal growth plate. Furthermore, synergistic studies incorporating GH and estrogen have revealed the ability of estrogen to attenuate the effects of GH on MMP13 expression, revealing potential pathways by which estrogen may modulate growth plate fusion, longitudinal bone growth and even arthritis.

Theory and its role in mathematics education

The increased recognition of the theory in mathematics education is evident in numerous handbooks, journal articles, and other publications. For example, Silver and Herbst (2007) examined ―Theory in Mathematics Education Scholarship‖ in the Second Handbook of Research on Mathematics Teaching and Learning (Lester, 2007) while Cobb (2007) addressed ―Putting Philosophy to Work: Coping with Multiple Theoretical Perspectives‖ in the same handbook. And a central component of both the first and second editions of the Handbook of International Research in Mathematics Education (English, 2002; 2008) was ―advances in theory development.‖ Needless to say, the comprehensive second edition of the Handbook of Educational Psychology (Alexander & Winne, 2006) abounds with analyses of theoretical developments across a variety of disciplines and contexts. Numerous definitions of ―theory‖ appear in the literature (e.g., see Silver & Herbst, in Lester, 2007). It is not our intention to provide a ―one-size-fits-all‖ definition of theory per se as applied to our discipline; rather we consider multiple perspectives on theory and its many roles in improving the teaching and learning of mathematics in varied contexts.

Biochemical characterization of Aprataxin, the protein deficient in Ataxia with Oculomotor Apraxia type 1

Neurodegenerative disorders are heterogenous in nature and include a range of ataxias with oculomotor apraxia, which are characterised by a wide variety of neurological and ophthalmological features. This family includes recessive and dominant disorders. A subfamily of autosomal recessive cerebellar ataxias are characterised by defects in the cellular response to DNA damage. These include the well characterised disorders Ataxia-Telangiectasia (A-T) and Ataxia-Telangiectasia Like Disorder (A-TLD) as well as the recently identified diseases Spinocerebellar ataxia with axonal neuropathy Type 1 (SCAN1), Ataxia with Oculomotor Apraxia Type 2 (AOA2), as well as the subject of this thesis, Ataxia with Oculomotor Apraxia Type 1 (AOA1). AOA1 is caused by mutations in the APTX gene, which is located at chromosomal locus 9p13. This gene codes for the 342 amino acid protein Aprataxin. Mutations in APTX cause destabilization of Aprataxin, thus AOA1 is a result of Aprataxin deficiency. Aprataxin has three functional domains, an N-terminal Forkhead Associated (FHA) phosphoprotein interaction domain, a central Histidine Triad (HIT) nucleotide hydrolase domain and a C-terminal C2H2 zinc finger. Aprataxins FHA domain has homology to FHA domain of the DNA repair protein 5’ polynucleotide kinase 3’ phosphatase (PNKP). PNKP interacts with a range of DNA repair proteins via its FHA domain and plays a critical role in processing damaged DNA termini. The presence of this domain with a nucleotide hydrolase domain and a DNA binding motif implicated that Aprataxin may be involved in DNA repair and that AOA1 may be caused by a DNA repair deficit. This was substantiated by the interaction of Aprataxin with proteins involved in the repair of both single and double strand DNA breaks (XRay Cross-Complementing 1, XRCC4 and Poly-ADP Ribose Polymerase-1) and the hypersensitivity of AOA1 patient cell lines to single and double strand break inducing agents. At the commencement of this study little was known about the in vitro and in vivo properties of Aprataxin. Initially this study focused on generation of recombinant Aprataxin proteins to facilitate examination of the in vitro properties of Aprataxin. Using recombinant Aprataxin proteins I found that Aprataxin binds to double stranded DNA. Consistent with a role for Aprataxin as a DNA repair enzyme, this binding is not sequence specific. I also report that the HIT domain of Aprataxin hydrolyses adenosine derivatives and interestingly found that this activity is competitively inhibited by DNA. This provided initial evidence that DNA binds to the HIT domain of Aprataxin. The interaction of DNA with the nucleotide hydrolase domain of Aprataxin provided initial evidence that Aprataxin may be a DNA-processing factor. Following these studies, Aprataxin was found to hydrolyse 5’adenylated DNA, which can be generated by unscheduled ligation at DNA breaks with non-standard termini. I found that cell extracts from AOA1 patients do not have DNA-adenylate hydrolase activity indicating that Aprataxin is the only DNA-adenylate hydrolase in mammalian cells. I further characterised this activity by examining the contribution of the zinc finger and FHA domains to DNA-adenylate hydrolysis by the HIT domain. I found that deletion of the zinc finger ablated the activity of the HIT domain against adenylated DNA, indicating that the zinc finger may be required for the formation of a stable enzyme-substrate complex. Deletion of the FHA domain stimulated DNA-adenylate hydrolysis, which indicated that the activity of the HIT domain may be regulated by the FHA domain. Given that the FHA domain is involved in protein-protein interactions I propose that the activity of Aprataxins HIT domain may be regulated by proteins which interact with its FHA domain. We examined this possibility by measuring the DNA-adenylate hydrolase activity of extracts from cells deficient for the Aprataxin-interacting DNA repair proteins XRCC1 and PARP-1. XRCC1 deficiency did not affect Aprataxin activity but I found that Aprataxin is destabilized in the absence of PARP-1, resulting in a deficiency of DNA-adenylate hydrolase activity in PARP-1 knockout cells. This implies a critical role for PARP-1 in the stabilization of Aprataxin. Conversely I found that PARP-1 is destabilized in the absence of Aprataxin. PARP-1 is a central player in a number of DNA repair mechanisms and this implies that not only do AOA1 cells lack Aprataxin, they may also have defects in PARP-1 dependant cellular functions. Based on this I identified a defect in a PARP-1 dependant DNA repair mechanism in AOA1 cells. Additionally, I identified elevated levels of oxidized DNA in AOA1 cells, which is indicative of a defect in Base Excision Repair (BER). I attribute this to the reduced level of the BER protein Apurinic Endonuclease 1 (APE1) I identified in Aprataxin deficient cells. This study has identified and characterised multiple DNA repair defects in AOA1 cells, indicating that Aprataxin deficiency has far-reaching cellular consequences. Consistent with the literature, I show that Aprataxin is a nuclear protein with nucleoplasmic and nucleolar distribution. Previous studies have shown that Aprataxin interacts with the nucleolar rRNA processing factor nucleolin and that AOA1 cells appear to have a mild defect in rRNA synthesis. Given the nucleolar localization of Aprataxin I examined the protein-protein interactions of Aprataxin and found that Aprataxin interacts with a number of rRNA transcription and processing factors. Based on this and the nucleolar localization of Aprataxin I proposed that Aprataxin may have an alternative role in the nucleolus. I therefore examined the transcriptional activity of Aprataxin deficient cells using nucleotide analogue incorporation. I found that AOA1 cells do not display a defect in basal levels of RNA synthesis, however they display defective transcriptional responses to DNA damage. In summary, this thesis demonstrates that Aprataxin is a DNA repair enzyme responsible for the repair of adenylated DNA termini and that it is required for stabilization of at least two other DNA repair proteins. Thus not only do AOA1 cells have no Aprataxin protein or activity, they have additional deficiencies in PolyADP Ribose Polymerase-1 and Apurinic Endonuclease 1 dependant DNA repair mechanisms. I additionally demonstrate DNA-damage inducible transcriptional defects in AOA1 cells, indicating that Aprataxin deficiency confers a broad range of cellular defects and highlighting the complexity of the cellular response to DNA damage and the multiple defects which result from Aprataxin deficiency. My detailed characterization of the cellular consequences of Aprataxin deficiency provides an important contribution to our understanding of interlinking DNA repair processes.

The role of fluency in a mathematics item with an embedded graphic: Interpreting a pie chart.

The purpose of this study was to identify the pedagogical knowledge relevant to the successful completion of a pie chart item. This purpose was achieved through the identification of the essential fluencies that 12–13-year-olds required for the successful solution of a pie chart item. Fluency relates to ease of solution and is particularly important in mathematics because it impacts on performance. Although the majority of students were successful on this multiple choice item, there was considerable divergence in the strategies they employed. Approximately two-thirds of the students employed efficient multiplicative strategies, which recognised and capitalised on the pie chart as a proportional representation. In contrast, the remaining one-third of students used a less efficient additive strategy that failed to capitalise on the representation of the pie chart. The results of our investigation of students’ performance on the pie chart item during individual interviews revealed that five distinct fluencies were involved in the solution process: conceptual (understanding the question), linguistic (keywords), retrieval (strategy selection), perceptual (orientation of a segment of the pie chart) and graphical (recognising the pie chart as a proportional representation). In addition, some students exhibited mild disfluencies corresponding to the five fluencies identified above. Three major outcomes emerged from the study. First, a model of knowledge of content and students for pie charts was developed. This model can be used to inform instruction about the pie chart and guide strategic support for students. Second, perceptual and graphical fluency were identified as two aspects of the curriculum, which should receive a greater emphasis in the primary years, due to their importance in interpreting pie charts. Finally, a working definition of fluency in mathematics was derived from students’ responses to the pie chart item.

The role of self-efficacy in dental patients’ brushing and flossing: Testing an extended Health Belief Model

Objective: In an effort to examine the decreasing oral health trend of Australian dental patients, the Health Belief Model (HBM) was utilised to understand the beliefs underlying brushing and flossing self-care. The HBM states that perception of severity and susceptibility to inaction and an estimate of the barriers and benefits of behavioural performance influences people’s health behaviours. Self-efficacy, confidence in one’s ability to perform oral self-care, was also examined. Methods: In dental waiting rooms, a community sample (N = 92) of dental patients completed a questionnaire assessing HBM variables and self-efficacy, as well as their performance of the oral hygiene behaviours of brushing and flossing. Results: Partial support only was found for the HBM with barriers emerging as the sole HBM factor influencing brushing and flossing behaviours. Self-efficacy significantly predicted both oral hygiene behaviours also. Conclusion: Support was found for the control factors, specifically a consideration of barriers and self-efficacy, in the context of understanding dental patients’ oral hygiene decisions. Practice implications: Dental professionals should encourage patients’ self-confidence to brush and floss at recommended levels and discuss strategies that combat barriers to performance, rather than emphasising the risks of inaction or the benefits of oral self-care.