Medicine (RMH) - Theses
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ItemInvestigating the Role of Tau and TDP-43 Pathologies in Traumatic Brain Injury( 2018)Traumatic brain injury (TBI) is a leading cause of death and morbidity worldwide, and is also associated with the later onset of other neurodegenerative conditions. However, the pathogenesis of TBI is poorly understood, and there is currently no treatment known to improve long-term outcomes. Hyperphosphorylated tau has been implicated in the pathogenesis of TBI, where the accumulation of hyperphosphorylated tau has been associated with long term neurological deficits. The presence of protein inclusions consisting of TAR DNA-binding protein 43kd (TDP-43) are a pathological hallmark in motor neuron diseases (MND). Notably, TBI is a risk factor in the development of MND, and motor neuron loss, corticospinal tract degeneration and TDP-43 abnormalities have also been observed in individuals with a history of TBI. While preliminary studies suggest that each of these proteinopathies may occur in the aftermath of TBI, the role of tau and TDP-43 remain poorly understood in the TBI context. In this thesis, I examined the role of tau and TDP-43 using wild type and transgenic animal models in the context of TBI and repeated mild TBI. It was found that TBI resulted in abnormalities in both tau and TDP-43, and this was associated with functional consequences. It was also found that that treatment with sodium selenate reduced hyperphosphorylated tau and improved pathological and functional outcomes in a model of repeated mild TBI. Taken together, tau and TDP-43 pathologies appear to have an important role in preclinical TBI and represent potential pharmaceutical targets to improve outcomes.
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ItemModelling Tuberculosis in Ethiopia: Spatiotemporal Transmission Dynamics and Effects of Public Health Interventions( 2018)Tuberculosis (TB) is now the world’s leading infectious killer with an estimated 10million cases and 1.6 million deaths in 2016. A small number of countries bear the majority of the burden of disease, with two-thirds of cases occurring in only seven countries. TB transmission occurs in both households and the local community, leading to focal disease hotspots which perpetuate TB spread within and across community groups. Integrating spatial analysis with mathematical transmission dynamic models can help in evaluating the role of these hotspots in the spread of TB and understanding the potential impact of geographically targeted interventions. The first part of this thesis evaluates whether TB exhibits spatial heterogeneity in rural and remote regions of Ethiopia using data from all TB patients treated in a remote administrative region of the country. This study demonstrated considerable spatial heterogeneity in TB distribution in this resource-limited setting. However, most of these heterogeneities were accounted for by health facility availability, implying differential case detection between areas with better and poorer access to health care. Thus, this Chapter cautions that spatial analysis of TB and the identification of geographical hotspots using programmatic data alone can be misleading, as it may be strongly influenced by undetected cases, which is in turn dependent on local programmatic performance. Building on the findings outlined above, Chapter three presents a systematic review of methods used in published spatial analyses of TB. From this review, this Chapter elucidates limitations in the current approaches to spatial analysis of TB. Of particular importance is the consistent failure to account for unreported or undetected cases, despite notification data being used in 95 percent of the reviewed studies. The Chapter also describes methodological flaws to many of the studies, in particular the use of conventional regression analysis to draw spatial conclusions. In addition, most spatial analyses of TB distribution used residential information to define the location of patients, which potentially understates the importance of other community settings, despite more than 80% of all transmission events occurring outside households. The study in Chapter 4 proposes a method to address the limitations outlined in the previous chapters – particularly the lack of methods to account for undetected cases. The model estimates both incidence and case detection rates simultaneously across space and time, providing a useful platform for regularly tracking spatial patterns and temporal trends. In addition, this technique is general and can be applied to any disease in any setting. Applied to the Ethiopian setting, this model identifies previously unrecognized areas of high TB burden in locations with no available health care facilities. With the aim of quantifying the role of TB hotspots in community transmission as well as evaluating the potential impact of targeting spatial hotspots, Chapter 5 utilises incidence data generated by the novel method described above to identify spatial TB hotspots. At this point, the thesis constructs spatially structured mathematical models and quantifies the extent to which these hotspots account for the spatial spread of TB. Findings from this work suggest that TB transmission in the same study region in rural Ethiopia is localised and the role of spatial hotspots in the spatial spread is limited, although their impact is considerable in adjacent locations due to very high relative incidence in the hotspot compared to the other regions. Finally, Chapter 6 uses the same model introduced in Chapter 5 to evaluate the impact of various TB intervention strategies before concluding the thesis. Overall, this thesis advances current approaches to spatial analysis and provides a means to account for the problem of undetected cases. It also provides a platform to estimate both incidence and case detection rate simultaneously, and hence could provide as an alternative approach to the spatial interpretation of TB epidemiology. This is of particular importance to high endemic settings, where considerable number of TB cases are missed, and case notification is biased to areas with better access to health care. Importantly, the study also concludes that the impact of spatial TB hotspots on the spatial spread of disease in remote regions of Ethiopia is limited and transmission is predominantly locally driven. Hence, interventions strategies that are spatially targeted may not achieve anticipated outcomes, although the overall effect of these interventions remains considerable due to extremely high incidence in the hotspot regions.
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ItemAntibody immunity to Plasmodium falciparum erythrocyte membrane protein 1 and severe malaria( 2018)Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins are expressed on the surface of the infected erythrocyte (IE). These proteins mediate the adhesion of the parasite IE to host cells which could result in severe forms of malaria. PfEMP1 is a variable protein and consists of several domains. PfEMP1s are encoded by var genes and composed of multiple duffy binding-like (DBL) domains and cysteine-rich inter-domain region (CIDR) domains. PfEMP1s can be classified into groups based on the chromosomal location, transcriptional direction and upstream promotor regions of var genes, the DBL or CIDR domains expressed or the domain cassettes (DC) expressed. DCs are sets of PfEMP1 domains that usually occur together. Transcription of specific PfEMP1 subtypes and DCs have been associated with severe malaria. These proteins are important for anti-malarial immunity. Antibody immunity to the different PfEMP1 types can develop gradually with exposure with potential to protect from severe malaria. The current study investigated if antibody responses to different subsets of PfEMP1s or selections of their constituent domains differed between individuals with severe malaria and uncomplicated malaria as well as between individuals presenting with specific severe malaria syndromes. The study also investigated how such antibodies vary between disease presentation and convalescence, 1-2 months after the malaria episode. Three aims were investigated in the present study: 1) to determine if recombinant CIDR domains are targets of antibodies in children with severe or uncomplicated malaria, 2) to determine if levels of opsonising antibodies against four parasite IE lines differed between children with severe or uncomplicated malaria and 3) to determine if the various recombinant PfEMP1 domains (transcripts of which were previously shown to be associated with severe or uncomplicated malaria in adults) are targets of antibody immunity in the same adults with severe or uncomplicated malaria as well as in children with cerebral or uncomplicated malaria. To measure antibody levels against the different PfEMP1 subtypes, unique, high-throughput multiplex assays as well as flow cytometry-based assays were employed. Antibody levels were measured in children from Papua New Guinea (PNG), adults from Papua and children from Malawi. For aim 1, total IgG levels were measured and analysed against 35 recombinant CIDR domains in plasma collected from PNG children at hospital presentation (acute) and in convalescence following severe (n = 98) or uncomplicated malaria (n = 65), and in age-matched community controls (n = 112). At hospital presentation, antibody levels did not differ across the three severity groups for any of the CIDR domain types tested. During convalescence, antibody levels against the endothelial protein C receptor (EPCR) binding CIDRα1 domain types were higher in older children with severe malaria compared to uncomplicated malaria. Antibodies to the EPCR-binding CIDRα1 domains also increased from presentation to convalescence for severe malaria cases, but not uncomplicated malaria. Such differences in antibody acquisition (by disease severity) or boosting of antibody levels (with time) against non-EPCR-binding CIDR domains, such as the CD36 binding domains or domains associated with rosetting, were not observed, suggesting that these variants may not be prominently expressed in these infections. Antibodies acquired against PfEMP1 can have varied functions such as inhibiting the IE-receptor binding, opsonic phagocytosis and inhibition of rosette formation, which in turn can potentially protect from severe malaria. Using the same PNG study population as aim 1, for aim 2, levels of one type of functional antibodies -opsonising antibodies- were measured and analysed in plasma collected at acute and convalescence in children with severe (n = 163 and 158 respectively) or uncomplicated malaria (n = 101 and 99 respectively) as well as age-matched community controls (n = 235). Opsonising antibody levels against four different parasite IE expressing the entire PfEMP1 molecule, with conformations similar to the native protein and having different binding phenotypes, were measured. Opsonising antibodies against an EPCR-binding PfEMP1 were higher in children having uncomplicated malaria compared to children with severe malaria. These antibody levels were higher in children with uncomplicated malaria compared to children with severe malaria presenting with specific severe syndromes as well. The antibody levels were also boosted from presentation to convalescence for the EPCR binding IE in children with severe, but not uncomplicated, malaria. For the intercellular adhesion molecule 1 (ICAM-1) -binding PfEMP1 (which also binds to CD36), children with uncomplicated malaria showed weak evidence for boosting of antibodies from presentation to convalescence. For the rosetting IE, opsonising antibodies acquired during convalescence were higher in children with uncomplicated malaria compared to severe malaria. Antibodies against the CD36-binding PfEMP1 did not differ by disease severity and declined from presentation to convalescence in severe and uncomplicated cases. PfEMP1 is a large multi-domain protein and for aim 3, to investigate the role of antibodies against different PfEMP1 domains, the domains (whose transcription was upregulated in severe or uncomplicated malaria cases in Papua) were first expressed using the wheat germ cell free protein synthesis systems (WGCFS). Antibody levels against 32 recombinant PfEMP1 domains thus generated were measured in acute plasma from Papuan individuals with severe (n = 28) or uncomplicated malaria (n = 35). Antibody levels against these domains were also measured in acute and convalescent plasma from Malawian children with cerebral malaria (n = 119 and 68 respectively) or uncomplicated malaria (n = 118 and 85 respectively), and in age-matched healthy individuals (n = 101). In the Papuan population, antibodies were higher in individuals with uncomplicated malaria compared to severe malaria against a range of PfEMP1 domains. The differences in antibody levels by disease severity against the different domains included PfEMP1 domains such as CIDRα1.6 and DBLβ3, which were previously associated with severe malaria, as well as several novel PfEMP1 domains such as CIDRα2.4, DBLζ4, and DBLδ1. In the Malawian population, antibody levels were higher in children with cerebral malaria compared to uncomplicated malaria at presentation but not in convalescence. Antibody levels against various PfEMP1 domains were boosted from presentation to follow-up in children with uncomplicated malaria but not severe malaria. The differences in antibody levels by disease severity against the different domains for this population also included PfEMP1 domains such as CIDRα1.1 which was previously associated with severe malaria, as well as several novel PfEMP1 domains such as CIDRα2.4, DBLε3, DBLγ3, DBLζ3, DBLβ13, DBLδ7 and DBLδ1. There were some novel overlapping targets of immunity in the two populations, while some domains did not overlap as targets of immunity in the two settings, such as DBLζ4. Thus, the current study was one of the first studies to demonstrate the EPCR-binding PfEMP1 domains or types to be important targets of antibody immunity as evidenced by differences in the antibody levels by disease severity against these domains. The present study was also one of the first to show levels of opsonising antibodies against the EPCR-binding PfEMP1 to differ by disease severity with potential to protect from severe malaria and its syndromes. Weak evidence was also found for opsonising antibodies against ICAM-1/CD36-binding PfEMP1 to be associated with uncomplicated malaria. In Papuan adults, protection from severe malaria was associated with a ‘total’ antibody response against a wide range of PfEMP1 domains whose transcripts were also upregulated in severe infections affecting the same individuals. In young Malawian children with cerebral malaria, the antibody responses against the PfEMP1 domains seem to be markers of exposure to antigens causing malaria rather than markers of immunity. The overall conclusion for the study is that antibody immunity to multiple PfEMP1 domains on the IE may be required for protection from severe malaria and the current study has helped identify some of these PfEMP1 domains.
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ItemPalliative care for patients with chronic obstructive pulmonary disease: understanding current practices and exploring a new model of integrated care( 2018)Chronic obstructive pulmonary disease (COPD) is a highly prevalent, incurable, progressive, disease characterised by persisting respiratory symptoms and airflow limitation, which arise from airway or parenchymal abnormalities. COPD leads to significant morbidity and mortality globally, generating substantial personal, social and economic burdens. Although the development of novel COPD therapies has led to improved, disease-directed management and prolonged survival, patients with advanced COPD have unmet needs related to the sustained symptom burden, psychosocial impact, and poor understanding of their condition. Palliative care is an approach that aims to improve the quality of life of patients and their families when facing life-threatening illnesses, by actively addressing physical, psychosocial and spiritual issues. While palliative care offers well-recognised benefits, few patients with advanced COPD access any palliative care. Furthermore existing models of palliative care are poorly suited to the needs of COPD patients. New models of integrated respiratory and palliative care are promising, however, few such services exist globally or have published their outcomes. This work within this thesis aimed to examine how patients with advanced COPD are cared for, including whether they access symptom palliation or palliative care, and evaluate outcomes from a new integrated respiratory and palliative care service. To address these aims, three phases of research were conducted including: an epidemiological cohort study examining end-of-life care in hospital; surveys of specialists and junior doctors exploring approaches to symptom management and palliative care; and an evaluation of outcomes associated with a new integrated service. The epidemiological cohort study identified that recently general and respiratory physicians have increasingly provided a palliative approach to COPD patients as they are actively dying during their last few days of life. However, there were missed opportunities in the final years of life, during which few patients accessed symptom palliation or palliative care. Most doctors reported recognising and actively managing severe chronic breathlessness (including prescribing opioids) and held positive attitudes to palliative care for patients with COPD. However, several epidemiological studies suggest patients neither access symptom palliation nor palliative care therefore there is a mismatch between self-reported practices and actual clinical care. Notably respiratory and palliative care specialists had different approaches to breathlessness management, which were complementary, however current models of care were perceived as fragmented. A new integrated respiratory and palliative care service was associated with improved symptom management and access to palliative care activities, reduced unscheduled healthcare usage and fewer hospital deaths. Additionally, the service was highly acceptable to patients and caregivers, with valued aspects including continuity of care and high quality communication. While new integrated services may address current gaps in care, further testing in large clinical trials is required. In conclusion, a co-ordinated, structured, multidisciplinary, patient-focused response is needed to address the unmet needs of patients with advanced COPD. Such a response must include increased palliative care training for health professionals, clear guidelines and policies regarding palliative care for patients with advanced COPD, new models of integrated palliative care and increasing research capacity. Furthermore this approach requires sustained investment and collaboration.
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ItemThe effect of extracranial trauma and age on traumatic brain injury, and the role of neuroinflammation( 2018)Traumatic brain injury (TBI) is induced by external forces to the brain, and is a leading cause of mortality and morbidity worldwide. Although significant research efforts have been made to identify an effective treatment, all phase III clinical trials have been unsuccessful to date. These translational shortcomings are in part due to a failure to recognize and account for the heterogeneity of TBI. TBI is often not an isolated injury; yet the majority of preclinical research has utilized isolated TBI models, and how concomitant extracranial factors, such as extracranial trauma and aging, might influence TBI is still largely unknown. Extracranial trauma or aging involve a significant immune response, which is also a pathological hallmark of TBI. As such, this research project aims to study how these extracranial immunological stressors have potential to affect TBI and how this might influence future treatment strategies. The first study found that a concomitant bone fracture exacerbated neuroinflammation and other TBI-related pathological events in mice, with the pro-inflammatory cytokine interleukin (IL)-1 being robustly upregulated. The consequent study suggested that treatment with an IL-1 receptor antagonist improved neurological outcomes in the combined TBI + fracture model. While a long-bone fracture exacerbates TBI outcomes in mice, the third study in this thesis found that a concomitant muscle injury did not. The final study investigated the effect of aging on TBI, and found that middle-aged rats had an altered neuroimmune response and worse functional outcomes after TBI compared to young rats. Together, this body of work generates significant new knowledge about the fundamental mechanisms by which extracranial variables such as peripheral injuries and biological age influence the neuropathological outcomes after neurotrauma.
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ItemUsing mathematical modelling to challenge accepted methods and paradigms of tuberculosis control and transmission( 2018)Tuberculosis (TB) represents a major public health issue at the global level. Despite the availability of vaccines and treatments, TB still kills around 1.6 million persons each year due to a combination of unresolved challenges. Firstly, around 40% of diseased individuals are never identified and can therefore not be provided with adequate care. A second substantial challenge is the extremely high prevalence of latent tuberculosis infection (LTBI), which serves as a large reservoir of future disease that is difficult to control. Furthermore, the emergence of drug-resistant TB (DR-TB) has hampered the progress made by TB control in the last decades and required novel strategies to be adopted. Optimal approaches to address these challenges are hampered by substantial knowledge gaps. The lack of a comprehensive epidemiological understanding of TB has also resulted in today’s TB control relying heavily on strong assumptions or preconceived opinions, which are not necessarily supported by evidence. In this thesis, I used mathematical modelling to challenge several of these accepted paradigms. First, this thesis presents a simple model incorporating epidemiological and programmatic characteristics used to quantify the respective contributions of the different pathways leading to DR-TB at re-treatment around the world. This exercise identified failure to detect DR-TB at first presentation as the leading source of DR-TB at re-treatment. This challenges the accepted paradigm that DR-TB results mainly from poor treatment adherence during treatment of drug-susceptible patients. Important geographical heterogeneity was also observed in the results, and so a web-based interface was built to allow the model to be applied immediately to any epidemiological setting. Next, this thesis presents a novel exploration of the relationship between TB incidence and the effectiveness of preventive treatment (PT). Although it is widely accepted that using PT would be less efficient in high-burden settings, the exploration suggests that PT would yield optimal efficiency where TB incidence is as high as 700 new cases/100,000/year. To improve TB modelling methods, this thesis next presents an evaluation of the existing approaches used to simulate the transition from LTBI to active disease. This was done by comparing the reactivation dynamics produced by different model structures to those empirically observed in contacts of infectious TB patients. This exercise demonstrated that two latency compartments are needed to replicate the TB reactivation dynamics in a compartmental model. It further highlighted that the usual cut-off of two or five years used to distinguish late from early latency should be revised to a much shorter duration. Finally, a novel modelling approach combining country-specific social mixing data with time-variant programmatic parameters within a TB agent-based model is presented in this thesis. The newly built tool was used to detail the profile of Mycobacterium tuberculosis (M.tb) transmission and TB burden in the five highest TB burden countries (India, Indonesia, China, the Philippines and Pakistan). Findings include the unexpectedly high contribution of adolescents and young adults to M.tb transmission. This study also provides estimates of the age-specific size of the latent infection pool, along with the age-specific risk that this infection reservoir represents in terms of future disease.
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ItemHigh mobility group box protein 1 in paediatric traumatic brain injury( 2018)Traumatic brain injury (TBI) is a leading cause of mortality and morbidity for children and young adults. Accumulating research suggests that children may be more vulnerable to poor long-term outcomes after TBI compared to adults, including a higher risk of developing post traumatic epilepsy (PTE). The neuroinflammatory response, known to contribute to neuropathology after TBI and the development of PTE, has been reported to differ depending upon age at the time of injury, though the time course and key factors in this response have not been well-characterized. One of the major initiators of the inflammatory cascade, high mobility group box protein 1 (HMGB1), shows age-dependent expression under basal conditions, and its elevation after TBI has been associated with worsened outcomes in young patients. This thesis therefore aims to characterize the acute time course of key neuroinflammatory cells and HMGB1 after paediatric and adult TBI, using an experimental mouse model. It further aims to evaluate the effect of acute inhibition of HMGB1 on the acute and long-term outcomes after paediatric TBI. To investigate this, we used a controlled cortical impact model in C57Bl/6 mice with a 3-week age-of-injury to represent a paediatric age and an 8- to 10-week age-of-injury to represent early adult age. Western Blot (WB) revealed a temporal profile of Iba1, GFAP and HMGB1 across the time course post-injury, which showed earlier and more robust expression in the paediatric than the adult cohort. . HMGB1 extracellular release was confirmed at 3 d post-injury by immunofluorescence. An increase in peripheral HMGB1 was found in serum from paediatric TBI mice, which was not evident in adult serum. Acute inhibition of HMGB1 with Glycyrrhizin (Gly) showed reduced oedema with a pre-treatment paradigm but a reduction of gliosis only with a post-treatment paradigm, suggesting that Gly actions were dependent upon the timing of treatment initiation after paediatric TBI. In a more chronic study, acute inhibition of HMGB1 improved some long-term cognitive deficits and reduced persistent microglia activation in the hippocampus but did not improve PTE outcomes or lesion size. Together, these findings demonstrate that the post-injury inflammatory cascade is influenced by age at the time of insult, which may be an important consideration for treatment strategies aiming to ameliorate this response after TBI. They also demonstrate that pharmacological inhibition of HMGB1 is both time-dependent and age-dependent after TBI. Therefore, HMGB1 is involved in secondary damage after paediatric TBI and may represent an important therapeutic target.
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ItemRadiological, clinical and genetic markers of ischaemic stroke outcome( 2018)Acute ischaemic stroke is caused by a blocked blood vessel in the cerebral circulation. It is the most common form of stroke worldwide and a major cause of disability and death. Over the past 20 years, major advances in acute stroke treatment and management have led to a reduction in stroke-related mortality, and thus an unavoidable side effect has been the concomitant rise in survivors living with life-changing disability, requiring ongoing clinical management and care. However, stroke outcome is not entirely represented as mortality rates and level of disability – there are a range of neurological sequelae that contribute an important additional burden to patients. Up to 13% of patients who have suffered an ischaemic stroke will develop seizures within 2 years. For clinicians the development of seizures represents a clinical challenge to manage, is difficult to predict and treat, and associated with poorer patient quality of life. However, at present no indications for antiepileptic drugs in preventing post stroke seizures and epilepsy exist and to date, no blood biomarkers and only few genetic biomarkers have been identified as being associated with an increased risk of post stroke seizure development. This multicentre (China, Brazil and Australia), multidisciplinary thesis examines novel imaging, genetic and clinical markers as methods for identifying patients at higher risk of developing seizures. Reperfusion therapies with thrombolysis and, more recently, endovascular thrombectomy have transformed outcomes for patients. This body of research targeted patient groups treated with modern cerebrovascular stent devices and revascularization techniques, in order to assess the implications of these novel stroke interventions, particularly in terms of the development of post stroke seizures. Multiple advanced neuroimaging techniques were used to determine capacity to identify patients at the highest risk of developing post stroke seizures. Results from these investigations showed that the Alberta Stroke Program Early CT Score on non-contrast CT, cortical involvement on CT perfusion parameters and extent of haemorrhagic transformation on non-contrast CT, can be used as radiological markers for stroke outcome, including the identification of higher risk patients for post stroke seizure development. Additionally, unlike previous work, international sites were included along with Australian sites, allowing the interrogation of whether ethnicity and environment influences the development of post stroke seizures. Results from this investigation revealed that, not only does occurrence of seizures differ across populations from different countries, but certain clinical markers, such as presence and treatment of atrial fibrillation, may influence seizure occurrence across populations. Our exploratory study assessing the genetic influence on the development of post stroke seizures has also laid important groundwork in developing genetic biomarkers for future studies and results from this thesis have identified potential genetic variants warranting further investigation. The results presented in this thesis have the potential to guide identification of individuals at higher risk of developing post stroke seizures and represent a step towards personalised medicine. In the future, if antiepileptogenic drugs become available, these results may inform the selection of an enriched population for trials and guide recruitment for biomarker studies of epileptogenesis.
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ItemImproving application of human leukocyte antigen genotyping in precision medicine( 2018)Variation in the human leukocyte antigen (HLA) genes has been extensively associated with predisposition to autoimmune disease and adverse drug reaction. Translation of these associations to clinical practice has proven to be difficult due to the high cost and time burden of genetic testing. Additionally, understanding the value of prospective HLA associations in a research context is challenging due to the unparalleled polymorphisms of the HLA genes, as well as interactions between HLA variants. In this thesis, tools and methods are described which assist in the interpretation of prospective HLA associations and definition of the clinical role of HLA genotyping. Importantly, techniques that improve the efficiency of genetic testing of HLA variants are also reported.
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ItemPain in Parkinson's disease( 2018)Pain is a common and disabling symptom in people with Parkinson's disease, but the pathophysiological mechanisms underlying this phenomenon remain poorly understood. Through the use of systematic review, meta-analysis techniques, functional magnetic resonance imaging and psychophysical methods for testing pain sensitivity, this thesis demonstrated that Parkinson’s disease patients had altered central nociceptive processing – characterised by an aberrant increase in brain nociceptive activity to innocuous pressure – and that that this phenomenon likely contributes to the development of clinical pain. The brain pathways that have undergone nociceptive sensitisation predominantly subserve the affective and cognitive domains of pain rather than the sensory discriminative aspects, and may have arisen as a consequence of chronic pulsatile levodopa administration These findings have significant implications on both management and future research directions on pain in Parkinson’s disease. In particular, management of clinical pain in Parkinson’s disease should involve strategies designed to prevent and reverse dopamine-induced sensitisation and utilise treatments that deal more with affective and cognitive dimensions of pain rather than dealing with pain intensity, while future research should focus on identifying the root cause of sensitised nociceptive response in Parkinson’s disease patients and on developing techniques to better disengage this aberrant response.