MRI indices of functional recovery following intracerebral implantation of a human neural stem cell line in a pre-clinical model of ischaemic stroke

Stem cell therapy for ischaemic stroke is an emerging field in light of an increasing number of patients surviving with permanent disability. Several allogenic and autologous cells types are now in clinical trials with preliminary evidence of safety. Some clinical studies have reported functional improvements in some patients. After initial safety evaluation in a Phase 1 study, the conditionally immortalised human neural stem cell line CTX0E03 is currently in a Phase 2 clinical trial (PISCES-II). Previous pre-clinical studies conducted by ReNeuron Ltd, showed evidence of functional recovery in the Bilateral Asymmetry test up to 6 weeks following transplantation into rodent brain, 4 weeks after middle cerebral artery occlusion. Resting-state fMRI is increasingly used to investigate brain function in health and disease, and may also act as a predictor of recovery due to known network changes in the post-stroke recovery period. Resting-state methods have also been applied to non-human primates and rodents which have been found to have analogous resting-state networks to humans. The sensorimotor resting-state network of rodents is impaired following experimental focal ischaemia of the middle cerebral artery territory. However, the effects of stem cell implantation on brain functional networks has not previously been investigated. Prior studies assessed sensorimotor function following sub-cortical implantation of CTX0E03 cells in the rodent post-stroke brain but with no MRI assessments of functional improvements. This thesis presents research on the effect of sub-cortical implantation of CTX0E03 cells on the resting- state sensorimotor network and sensorimotor deficits in the rat following experimental stroke, using protocols based on previous work with this cell line. The work in this thesis identified functional tests of appropriate sensitivity for long-term dysfunction suitable for this laboratory, and investigated non-invasive monitoring of physiological variables required to optimize BOLD signal stability within a high-field MRI scanner. Following experimental stroke, rats demonstrated expected sensorimotor dysfunction and changes in the resting-state sensorimotor network. CTX0E03 cells did not improve post-stroke functional outcome (compared to previous studies) and with no changes in resting-state sensorimotor network activity. However, in control animals, we observed changes in functional networks due to the stereotaxic procedure. This illustrates the sensitivity of resting-state fMRI to stereotaxic procedures. We hypothesise that the damage caused by cell or vehicle implantation may have prevented functional and network recovery which has not been previously identified due to the application of different functional tests. The findings in this thesis represent one of few pre-clinical studies in resting-state fMRI network changes post-stroke and the only to date applying this technique to evaluate functional outcomes following a clinically applicable human neural stem cell treatment for ischaemic stroke. It was found that injury caused by stereotaxic injection should be taken into account when assessing the effectiveness of treatment.

The commodification of culture in the Thai tourism context: a study of culinary experiences in touristic traditional markets

The purpose of the thesis is to examine the relationship between tourism and the local culture expressed in culinary experiences offered in the traditional, nostalgic-themed markets that have arisen as popular attractions in the 21 st century. Central to the thesis is an examination of how the traditional cultural values are articulated in the production, promotion and consumption of culinary experiences in order to understand the value of culture when embedded in the process of commodification, as well as to understand influential socio-cultural factors. The thesis investigates the potential of traditional markets to promote food as the main attraction in the market. Field studies were conducted from December 2012–March 2014 in eight traditional markets in the central region of Thailand. Based on the ethnographic approach in studying the narratives in the markets, a variety of methods were implemented in the process of data collection. Besides observational analysis of the venue, semi-structured interviews and the self-administered questionnaires were used to collect data from actors who engage in food experiences, including management team members, food traders and visitors. Data was also collected from interviews with officers working for Tourism Authority of Thailand (TAT).  Keys findings of the thesis reveal that the cultural expressions of food experience in each market is an outcome of both the interactions of worldviews expressed by actors involved in the traditional market and the socio-cultural condition of Thailand. The relationships between stakeholders’ attitudes towards food experiences and the commercial potentials and limitations of food were analysed. The analysis of the cultural value of culinary experiences demonstrates that the existing academic discussions of the authenticity of tourism are insightful in explaining the character of food experiences offered in this tourism scenario. Most importantly, authenticity in tourism experiences, being a desirable element in culinary experiences, is a reflection of the how the pre-modern aspect of Thai society is embraced in a contemporary context. In addition, the commodification of culinary culture generates multidimensional consequences on the value of traditional culture and local lives. Moreover, the performance of culinary experiences can be viewed from the perspective of how Thai society interacts with globalization. The thesis also points out that it is possible to compare the situation of the traditional markets with the marketing positioning of food in Thai tourism marketing policy.

Exploring the potential role of allostatic load biomarkers in risk assessment of patients presenting with depressive symptoms

Background: Depression is a major health problem worldwide and the majority of patients presenting with depressive symptoms are managed in primary care. Current approaches for assessing depressive symptoms in primary care are not accurate in predicting future clinical outcomes, which may potentially lead to over or under treatment. The Allostatic Load (AL) theory suggests that by measuring multi-system biomarker levels as a proxy of measuring multi-system physiological dysregulation, it is possible to identify individuals at risk of having adverse health outcomes at a prodromal stage. Allostatic Index (AI) score, calculated by applying statistical formulations to different multi-system biomarkers, have been associated with depressive symptoms. Aims and Objectives: To test the hypothesis, that a combination of allostatic load (AL) biomarkers will form a predictive algorithm in defining clinically meaningful outcomes in a population of patients presenting with depressive symptoms. The key objectives were: 1. To explore the relationship between various allostatic load biomarkers and prevalence of depressive symptoms in patients, especially in patients diagnosed with three common cardiometabolic diseases (Coronary Heart Disease (CHD), Diabetes and Stroke). 2 To explore whether allostatic load biomarkers predict clinical outcomes in patients with depressive symptoms, especially in patients with three common cardiometabolic diseases (CHD, Diabetes and Stroke). 3 To develop a predictive tool to identify individuals with depressive symptoms at highest risk of adverse clinical outcomes. Methods: Datasets used: ‘DepChron’ was a dataset of 35,537 patients with existing cardiometabolic disease collected as a part of routine clinical practice. ‘Psobid’ was a research data source containing health related information from 666 participants recruited from the general population. The clinical outcomes for 3 both datasets were studied using electronic data linkage to hospital and mortality health records, undertaken by Information Services Division, Scotland. Cross-sectional associations between allostatic load biomarkers calculated at baseline, with clinical severity of depression assessed by a symptom score, were assessed using logistic and linear regression models in both datasets. Cox’s proportional hazards survival analysis models were used to assess the relationship of allostatic load biomarkers at baseline and the risk of adverse physical health outcomes at follow-up, in patients with depressive symptoms. The possibility of interaction between depressive symptoms and allostatic load biomarkers in risk prediction of adverse clinical outcomes was studied using the analysis of variance (ANOVA) test. Finally, the value of constructing a risk scoring scale using patient demographics and allostatic load biomarkers for predicting adverse outcomes in depressed patients was investigated using clinical risk prediction modelling and Area Under Curve (AUC) statistics. Key Results: Literature Review Findings. The literature review showed that twelve blood based peripheral biomarkers were statistically significant in predicting six different clinical outcomes in participants with depressive symptoms. Outcomes related to both mental health (depressive symptoms) and physical health were statistically associated with pre-treatment levels of peripheral biomarkers; however only two studies investigated outcomes related to physical health. Cross-sectional Analysis Findings: In DepChron, dysregulation of individual allostatic biomarkers (mainly cardiometabolic) were found to have a non-linear association with increased probability of co-morbid depressive symptoms (as assessed by Hospital Anxiety and Depression Score HADS-D≥8). A composite AI score constructed using five biomarkers did not lead to any improvement in the observed strength of the association. In Psobid, BMI was found to have a significant cross-sectional association with the probability of depressive symptoms (assessed by General Health Questionnaire GHQ-28≥5). BMI, triglycerides, highly sensitive C - reactive 4 protein (CRP) and High Density Lipoprotein-HDL cholesterol were found to have a significant cross-sectional relationship with the continuous measure of GHQ-28. A composite AI score constructed using 12 biomarkers did not show a significant association with depressive symptoms among Psobid participants. Longitudinal Analysis Findings: In DepChron, three clinical outcomes were studied over four years: all-cause death, all-cause hospital admissions and composite major adverse cardiovascular outcome-MACE (cardiovascular death or admission due to MI/stroke/HF). Presence of depressive symptoms and composite AI score calculated using mainly peripheral cardiometabolic biomarkers was found to have a significant association with all three clinical outcomes over the following four years in DepChron patients. There was no evidence of an interaction between AI score and presence of depressive symptoms in risk prediction of any of the three clinical outcomes. There was a statistically significant interaction noted between SBP and depressive symptoms in risk prediction of major adverse cardiovascular outcome, and also between HbA1c and depressive symptoms in risk prediction of all-cause mortality for patients with diabetes. In Psobid, depressive symptoms (assessed by GHQ-28≥5) did not have a statistically significant association with any of the four outcomes under study at seven years: all cause death, all cause hospital admission, MACE and incidence of new cancer. A composite AI score at baseline had a significant association with the risk of MACE at seven years, after adjusting for confounders. A continuous measure of IL-6 observed at baseline had a significant association with the risk of three clinical outcomes- all-cause mortality, all-cause hospital admissions and major adverse cardiovascular event. Raised total cholesterol at baseline was associated with lower risk of all-cause death at seven years while raised waist hip ratio- WHR at baseline was associated with higher risk of MACE at seven years among Psobid participants. There was no significant interaction between depressive symptoms and peripheral biomarkers (individual or combined) in risk prediction of any of the four clinical outcomes under consideration. Risk Scoring System Development: In the DepChron cohort, a scoring system was constructed based on eight baseline demographic and clinical variables to predict the risk of MACE over four years. The AUC value for the risk scoring system was modest at 56.7% (95% CI 55.6 to 57.5%). In Psobid, it was not possible to perform this analysis due to the low event rate observed for the clinical outcomes. Conclusion: Individual peripheral biomarkers were found to have a cross-sectional association with depressive symptoms both in patients with cardiometabolic disease and middle-aged participants recruited from the general population. AI score calculated with different statistical formulations was of no greater benefit in predicting concurrent depressive symptoms or clinical outcomes at follow-up, over and above its individual constituent biomarkers, in either patient cohort. SBP had a significant interaction with depressive symptoms in predicting cardiovascular events in patients with cardiometabolic disease; HbA1c had a significant interaction with depressive symptoms in predicting all-cause mortality in patients with diabetes. Peripheral biomarkers may have a role in predicting clinical outcomes in patients with depressive symptoms, especially for those with existing cardiometabolic disease, and this merits further investigation.

A critical study of John Hick's religious pluralism

This study examines the pluralistic hypothesis advanced by the late Professor John Hick viz. that all religious faiths provide equally salvific pathways to God, irrespective of their theological and doctrinal differences. The central focus of the study is a critical examination of (a) the epistemology of religious experience as advanced by Professor Hick, (b) the ontological status of the being he understands to be God, and further asks (c) to what extent can the pluralistic view of religious experience be harmonised with the experience with which the Christian life is understood to begin viz. regeneration. Tracing the theological journey of Professor Hick from fundamentalist Christian to religious pluralist, the study notes the reasons given for Hick’s gradual disengagement from the Christian faith. In addition to his belief that the pre-scientific worldview of the Bible was obsolete and passé, Hick took the view that modern biblical scholarship could not accommodate traditionally held Christian beliefs. He conceded that the Incarnation, if true, would be decisive evidence for the uniqueness of Christianity, but rejected the same on the grounds of logical incoherence. This study affirms the view that the doctrine of the Incarnation occupies a place of crucial importance within world religion, but rejects the claim of incoherence. Professor Hick believed that God’s Spirit was at work in all religions, producing a common religious experience, or spiritual awakening to God. The soteriological dimension of this spiritual awakening, he suggests, finds expression as the worshipper turns away from self-centredness to the giving of themselves to God and others. At the level of epistemology he further argued that religious experience itself provided the rational basis for belief in God. The study supports the assertion by Professor Hick that religious experience itself ought to be trusted as a source of knowledge and this on the principle of credulity, which states that a person’s claim to perceive or experience something is prima facie justified, unless there are compelling reasons to the contrary. Hick’s argument has been extensively developed and defended by philosophers such as Alvin Plantinga and William Alston. This confirms the importance of Hick’s contribution to the philosophy of religion, and further establishes his reputation within the field as an original thinker. It is recognised in this thesis, however, that in affirming only the rationality of belief, but not the obligation to believe, Professor Hick’s epistemology is not fully consistent with a Christian theology of revelation. Christian theology views the created order as pre-interpreted and unambiguous in its testimony to God’s existence. To disbelieve in God’s existence is to violate one’s epistemic duty by suppressing the truth. Professor Hick’s critical realist principle, which he regards as the key to understanding what is happening in the different forms of religious experience, is examined within this thesis. According to the critical realist principle, there are realities external to us, yet we are never aware of them as they are in themselves, but only as they appear to us within our particular cognitive machinery and conceptual resources. All awareness of God is interpreted through the lens of pre-existing, culturally relative religious forms, which in turn explains the differing theologies within the world of religion. The critical realist principle views God as unknowable, in the sense that his inner nature is beyond the reach of human conceptual categories and linguistic systems. Professor Hick thus endorses and develops the view of God as ineffable, but employs the term transcategorial when speaking of God’s ineffability. The study takes the view that the notion of transcategoriality as developed by Professor Hick appears to deny any ontological status to God, effectively arguing him out of existence. Furthermore, in attributing the notion of transcategoriality to God, Professor Hick would appear to render incoherent his own fundamental assertion that we can know nothing of God that is either true or false. The claim that the experience of regeneration with which the Christian life begins can be classed as a mere species of the genus common throughout all faiths, is rejected within this thesis. Instead it is argued that Christian regeneration is a distinctive experience that cannot be reduced to a salvific experience, defined merely as an awareness of, or awakening to, God, followed by a turning away from self to others. Professor Hick argued against any notion that the Christian community was the social grouping through which God’s Spirit was working in an exclusively redemptive manner. He supported his view by drawing attention to (a) the presence, at times, of comparable or higher levels of morality in world religion, when contrasted with that evidenced by the followers of Christ, and (b) the presence, at times, of demonstrably lower levels of morality in the followers of Christ, when contrasted with the lives of other religious devotees. These observations are fully supported, but the conclusion reached is rejected, on the grounds that according to Christian theology the saving work of God’s Spirit is evidenced in a life that is changing from what it was before. Christian theology does not suggest or demand that such lives at every stage be demonstrably superior, when contrasted with other virtuous or morally upright members of society. The study concludes by paying tribute to the contribution Professor Hick has made to the field of the epistemology of religious experience.