The effects of centrally acting ACE inhibitors on the rate of cognitive and functional decline in dementia: a KDD approach

Alzheimer’s Disease and other dementias are one of the most challenging illnesses confronting countries with ageing populations. Treatment options for dementia are limited, and the costs are significant. There is a growing need to develop new treatments for dementia, especially for the elderly. There is also growing evidence that centrally acting angiotensin converting enzyme (ACE) inhibitors, which cross the blood-brain barrier, are associated with a reduced rate of cognitive and functional decline in dementia, especially in Alzheimer’s disease (AD). The aim of this research is to investigate the effects of centrally acting ACE inhibitors (CACE-Is) on the rate of cognitive and functional decline in dementia, using a three phased KDD process. KDD, as a scientific way to process and analysis clinical data, is used to find useful insights from a variety of clinical databases. The data used are from three clinic databases: Geriatric Assessment Tool (GAT), the Doxycycline and Rifampin for Alzheimer’s Disease (DARAD), and the Qmci validation databases, which were derived from several different geriatric clinics in Canada. This research involves patients diagnosed with AD, vascular or mixed dementia only. Patients were included if baseline and end-point (at least six months apart) Standardised Mini-Mental State Examination (SMMSE), Quick Mild Cognitive Impairment (Qmci) or Activities Daily Living (ADL) scores were available. Basically, the rates of change are compared between patients taking CACE-Is, and those not currently treated with CACE-Is. The results suggest that there is a statistically significant difference in the rate of decline in cognitive and functional scores between CACE-I and NoCACE-I patients. This research also validates that the Qmci, a new short assessment test, has potential to replace the current popular screening tests for cognition in the clinic and clinical trials.

Specification of optimum holistic building environmental and energy performance information to support informed decision making

Political drivers such as the Kyoto protocol, the EU Energy Performance of Buildings Directive and the Energy end use and Services Directive have been implemented in response to an identified need for a reduction in human related CO2 emissions. Buildings account for a significant portion of global CO2 emissions, approximately 25-30%, and it is widely acknowledged by industry and research organisations that they operate inefficiently. In parallel, unsatisfactory indoor environmental conditions have proven to negatively impact occupant productivity. Legislative drivers and client education are seen as the key motivating factors for an improvement in the holistic environmental and energy performance of a building. A symbiotic relationship exists between building indoor environmental conditions and building energy consumption. However traditional Building Management Systems and Energy Management Systems treat these separately. Conventional performance analysis compares building energy consumption with a previously recorded value or with the consumption of a similar building and does not recognise the fact that all buildings are unique. Therefore what is required is a new framework which incorporates performance comparison against a theoretical building specific ideal benchmark. Traditionally Energy Managers, who work at the operational level of organisations with respect to building performance, do not have access to ideal performance benchmark information and as a result cannot optimally operate buildings. This thesis systematically defines Holistic Environmental and Energy Management and specifies the Scenario Modelling Technique which in turn uses an ideal performance benchmark. The holistic technique uses quantified expressions of building performance and by doing so enables the profiled Energy Manager to visualise his actions and the downstream consequences of his actions in the context of overall building operation. The Ideal Building Framework facilitates the use of this technique by acting as a Building Life Cycle (BLC) data repository through which ideal building performance benchmarks are systematically structured and stored in parallel with actual performance data. The Ideal Building Framework utilises transformed data in the form of the Ideal Set of Performance Objectives and Metrics which are capable of defining the performance of any building at any stage of the BLC. It is proposed that the union of Scenario Models for an individual building would result in a building specific Combination of Performance Metrics which would in turn be stored in the BLC data repository. The Ideal Data Set underpins the Ideal Set of Performance Objectives and Metrics and is the set of measurements required to monitor the performance of the Ideal Building. A Model View describes the unique building specific data relevant to a particular project stakeholder. The energy management data and information exchange requirements that underlie a Model View implementation are detailed and incorporate traditional and proposed energy management. This thesis also specifies the Model View Methodology which complements the Ideal Building Framework. The developed Model View and Rule Set methodology process utilises stakeholder specific rule sets to define stakeholder pertinent environmental and energy performance data. This generic process further enables each stakeholder to define the resolution of data desired. For example, basic, intermediate or detailed. The Model View methodology is applicable for all project stakeholders, each requiring its own customised rule set. Two rule sets are defined in detail, the Energy Manager rule set and the LEED Accreditor rule set. This particular measurement generation process accompanied by defined View would filter and expedite data access for all stakeholders involved in building performance. Information presentation is critical for effective use of the data provided by the Ideal Building Framework and the Energy Management View definition. The specifications for a customised Information Delivery Tool account for the established profile of Energy Managers and best practice user interface design. Components of the developed tool could also be used by Facility Managers working at the tactical and strategic levels of organisations. Informed decision making is made possible through specified decision assistance processes which incorporate the Scenario Modelling and Benchmarking techniques, the Ideal Building Framework, the Energy Manager Model View, the Information Delivery Tool and the established profile of Energy Managers. The Model View and Rule Set Methodology is effectively demonstrated on an appropriate mixed use existing ‘green’ building, the Environmental Research Institute at University College Cork, using the Energy Management and LEED rule sets. Informed Decision Making is also demonstrated using a prototype scenario for the demonstration building.

The identification and characterisation of Rab4 interacting proteins

Rab4 is a member of the Rab superfamily of small GTPases. It is localized to the early sorting endosome and plays a role in regulating the transport from this compartment to the recycling and degradative pathways. In order to further our understanding of the role Rab4 plays in endocytosis, a yeast two-hybrid screen was performed to identify putative Rab4 effectors. A constitutively active mutant of Rab4, Rab4Q67L, when used as bait to screen a HeLa cDNA library, identified a novel 80kDa protein that interacted with Rab4-GTP. This protein was called Rab Coupling Protein (RCP). RCP interacts preferentially with the GTP-bound form of Rab4. Subsequent work demonstrated that RCP also interacts with Rab11, and that this interaction is not nucleotide-depenedent. RCP is predominantly membrane-bound and localised to the perinuclear recycling compartment. Expression of a truncation mutant of RCP, that contains the Rab binding domain, in HeLa cells, results in the formation of an extensive tubular network that can be labelled with transferrin. These tubules are derived from the recycling compartment since they are inaccessible to transferrin when the ligand is internalised at 18oC. The truncation mutant-induced morphology can be rescued by overexpression of active Rab11, but not active Rab4. This suggests that RCP functions between Rab4 and Rab11 in the receptor recycling pathway, and may act as a ‘molecular bridge’ between these two sequentially acting small GTPases. Quantitative assays demonstrated that overexpression of the truncation mutant results in a dramatic inhibition in the rate of receptor recycling. Database analysis revealed that RCP belongs to a family of Rab interacting proteins, each characterised by a carboxy-terminal coiled-coil domain and an amino-terminal phospholipid-binding domain. KIAA0941, an RCP homologue, interacts with Rab11, but not with Rab4. Overexpression of its Rab binding domain also results in a tubular network, however, this tubulation cannot be rescued by active Rab11.

The impact of conifer plantation forestry on the ecology of peatland lakes

Blanket bog lakes are a characteristic feature of blanket bog habitats and harbour many rare and threatened invertebrate species. Despite their potential conservation value, however, very little is known about their physico-chemical or biological characteristics in western Europe, and their reference conditions are still unknown in Ireland. Furthermore, they are under considerable threat in Ireland from a number of sources, particularly afforestation of their catchments by exotic conifers. Plantation forestry can potentially lead to the increased input of substances including hydrogen ions (H+), plants nutrients, dissolved organic carbon (DOC), heavy metals and sediment. The aims of this study were to investigate the effect of conifer plantation forestry on the hydrochemistry and ecology of blanket bog lakes in western Ireland. Lake hydrochemistry, littoral Chydoridae (Cladocera) and littoral macroinvertebrate communities were compared among replicate lakes selected from three distinct catchment land use categories: i) unplanted blanket bog only present in the catchment, ii) mature (closed-canopy) conifer plantation forests only present in the catchment and iii) catchments containing mature conifer plantation forests with recently clearfelled areas. All three catchment land uses were replicated across two geologies: sandstone and granite. Lakes with afforested catchments across both geologies had elevated concentrations of phosphorus (P), nitrogen (N), total dissolved organic carbon (TDOC), aluminium (Al) and iron (Fe), with the highest concentrations of each parameter recorded from lakes with catchment clearfelling. Dissolved oxygen concentrations were also significantly reduced in the afforested lakes, particularly the clearfell lakes. This change in lake hydrochemistry was associated with profound changes in lake invertebrate communities. Within the chydorid communities, the dominance of Alonopsis elongata in the unplanted blanket bog lakes shifted to dominance by the smaller bodied Chydorus sphaericus, along with Alonella nana, Alonella excisa and Alonella exigua, in the plantation forestry-affected lakes, consistent with a shift in lake trophy. Similarly, there was marked changes in the macroinvertebrate communities, especially for the Coleoptera and Heteroptera assemblages which revealed increased taxon richness and abundance in the nutrient-enriched lakes. In terms of conservation status, despite having the greatest species-quality scores (SQS) and species richness, three of the four International Union for the Conservation of Nature (IUCN) red-listed species of Coleoptera and Odonata recorded during the study were absent from lakes subject to catchment clearfelling. The relative strengths of bottom-up (forestry-mediated nutrient enrichment) and top-down (fish) forces in structuring littoral macroinvertebrate communities was investigated in a separate study. Nutrient enrichment was shown to be the dominant force acting on communities, with fish having a lesser influence. These results confirmed that plantation forestry poses the single greatest threat to the conservation status of blanket bog lakes in western Ireland. The findings of this study have major implications for the management of afforested peatlands. Further research is required on blanket bog lakes to prevent any further plantation forestry-mediated habitat deterioration of this rare and protected habitat.

The intra-Traveller debate on ‘Traveller ethnicity’ in the Republic of Ireland. A critical discourse analysis

This dissertation assesses from an under-explored angle the enduring contention over Travellers’ ethnic recognition in the Republic of Ireland, particularly over the last decade. The novelty of this study concerns not only its specific focus on and engagement with the debate on ‘Traveller ethnicity’ among Traveller activists. It also pertains to the examination of Travellers’ arguments for and against ethnicity in light of critical theorisations as well as insights from identity politics. Furthermore, the adoption of a Critical Discourse Analytical framework offers new perspectives to this controversy and its potential implications. Finally, this thesis’ relevance extends beyond the contention on ‘Traveller ethnicity’ in itself. It also draws attention to the complex dynamics of colonisation and appropriation between the global and the local. Particularly, it points to the interplay between international human rights discourses and the local ones, formulated by NGOs struggling for equality. In this way it sheds light on more general issues such as the dialectical potential of human rights discourses: the benefits and pitfalls of framing recognition claims in the legalistic terms of human rights. In this study it is argued that the contention on ‘Traveller ethnicity’ defies a simplistic polarisation between Irish Travellers and the Irish State since it has been simultaneously played out within the Travelling community. Specifically, this study explores how ‘Traveller ethnicity’ has been introduced, embraced, promoted and contested within Traveller politics to the point of becoming a hotly debated and divisive issue among Traveller activists and at the heart of the community itself. Putting Traveller activists centre-stage, their discourses for and against ‘Traveller ethnicity’ are examined and assessed against one another and their potential implications for Traveller politics, policies and identities are pointed out. Contending discourses are historically contextualised as the product of specific structural, material and discursive configurations of power and socio-economic relations within Irish society. Discourses for and against ‘Traveller ethnicity’ are assessed as being significant beyond the representational level. They are regarded as contributing to dialectically constitute Travellers’ ways of being, representing and acting. Furthermore these discourses are considered as sites and means of power struggles, whose stakes are not only words, but relate to issues of power and leadership within the Travelling community; adjudications over material resources; the adoption of certain policy approaches over others; and, finally, the consolidation of certain subject positions over others for Travellers to draw upon and relate to mainstream society. This study highlights an ongoing ideological struggle for the naturalisation of ‘Traveller ethnicity’ as a self-evident ‘fact’, which involves no active choice by Travellers themselves. Overall, ‘Traveller ethnicity’ appears to constitute an enduring source of dilemmas for the Travelling community. These revolve around the contradictory potential of ethnicity claims-making —both its perils and advantages— and its status as a potent political strategic resource that can both challenge and reinforce existing power relations, policies and identities.

Supporting therapist engagement in evidence based practice: Developing a continuing education programme through participatory action research

Therapists find it challenging to integrate research evidence into their clinical decision-making because it may involve modifying their existing practices. Although continuing education (CE) programmes for evidence-based practice (EBP) have employed various approaches to increase individual practitioner’s knowledge and skills, these have been shown to have little impact in changing customary behaviours. To date, there has been little attempt to actively engage therapists as collaborators in developing educational processes concerning EBP. The researcher collaborated with seven clinical therapists (one occupational therapist, four physiotherapists and two speech and language therapists) enrolled in a new post-qualification Implementing Evidence in Therapy Practice (IETP) MSc module to monitor and adapt the learning programme over ten weeks. The participating therapists actively engaged in participatory action research (PAR) iterative cycles of reflecting→ planning→ acting→ observing→ reflecting with the researcher. Mixed methods were used to evaluate the IETP module and its influence on therapists’ subsequent engagement in EBP activities. Data were gathered immediately on completion of the module and five months later. Immediate post-module findings revealed four components as being important to the therapists: 1) characteristics of the learning environment; 2) acquisition of relevant EBP skills; 3) nature of the learning process; and 4) acquiring confidence. The two themes and sub-themes which emerged from individual interviews conducted five months post-module expanded on the four components already identified. Theme 1: Experiencing the learning (sub-themes: module organisation; learning is relational; improving the module); and theme 2: Enacting the learning through a new way of being (sub-themes: criticality and reflection; self agency; modelling EBP behaviours; positioning self in an EB work culture). The therapists’ perspectives had by then shifted from that of a learner to that of a clinician constructing a new sense of self as an evidence-based practitioner. Findings from this study underline the importance of the process of socially constructed knowledge and of empowering learners through collaboratively designed continuing education programmes. In the student-driven learning environment, therapists chose repetitive skill-building and authentic problem-solving activities which reflected the complexity of the environments to which they were expected to transfer their learning. These findings have implications for educators designing EBP continuing education programmes, during which students develop professional ways of being.

"Ladyes, damesels, and jantilwomen": female autonomy and authority in Sir Thomas Malory's Morte Darthur

Popular medieval English romances were composed and received within the social consciousness of a distinctly patriarchal culture. This study examines the way in which the dynamic of these texts is significantly influenced by the consequences of female endeavour, in the context of an autonomous feminine presence in both the real and imagined worlds of medieval England, and the authority with which this is presented in various narratives, with a particular focus on Sir Thomas Malory’s Morte Darthur. Chapter One of this study establishes the social and economic positioning of the female in fifteenth-century England, and her capacity for literary engagement; I will then apply this model of female autonomy and authority to a wider discussion of texts contemporary with Malory in Chapters Two and Three, in anticipation of a more detailed study of Le Morte Darthur in Chapters Four and Five. My research explores the female presence and influence in these texts according to certain types: namely the lover, the victim, the ruler, and the temptress. In the case of Malory, the crux of my observations centres on the paradox of the capacity for power in perceived vulnerability, incorporating the presentation of women in this patriarchal culture as being vulnerable and in need of protection, while simultaneously acting as a significant threat to chivalric society by manipulating this apparent fragility, to the detriment of the chivalric knight. In this sense, women can be perceived as being an architect of the romance world, while simultaneously acting as its saboteur. In essence, this study offers an innovative interpretation of female autonomy and authority in medieval romance, presenting an exploration of the physical, intellectual, and emotional placement of women in both the historical and literary worlds of fifteenth-century England, while examining the implications of female conduct on Malory’s Arthurian society.

Living with acquired brain injury

This study found that natural community supports were comprised of two distinct groupings; firstly immediate families, friends and peer support groups; secondly neighbours and local community groups such as sporting and activity- based organisations and groups. The findings of this study indicate that living with acquired brain injury involves a process where the person moves from acute high intensity health services onto rehabilitative services and then onto re-establishing independent lives. It is evident that smooth transitions and interconnectivity of services are essential in facilitating this recovery process. Instrumental to the recovery is the support of immediate family and close friends, who form people’s immediate natural support network and go a long way towards facilitating individuals in rebuilding their lives. A key finding of this study is that broader natural community supports do not appear to play as central a role in supporting individuals to live independent lives when compared to the role of family and friends. The lack of involvement of broader community groups, in many ways, prompted individuals to contact formal support services. For the majority of participants, independence is facilitated through the combination of immediate natural community supports and formal services. The role of formal support services is key to developing broader community support networks. This study found a blurred division between formal services and broader community support networks. The authors recommended that the role of formal supports services in acting as a bridge between the needs of the individual and the development of meaningful community networks, be formally recognised and further developed. Additionally, they argued that the importance of the role of broader natural community, supports such as those provided by community and sporting groups must be enhanced. Greater awareness of the issues faced by people living with acquired brain injury and its often invisible nature is necessary in this endeavour. The authors stated it is important to recognise that there are multiple issues impacting on independent living and these issues intersect, for instance with age, gender, employment, qualifications and so on. A lack of public awareness of acquired brain injury was found to be a key barrier to independent living, along with issues relating to socialising, access to employment and finances. The findings of this study reflect the complexities of living with acquired brain injury and the need for holistic support that is cognisant of the factors which impact on integration. It is vital that flexible, personalised services are developed which are fit for purpose and meet the needs of not only people with acquired brain injury but also their immediate natural community support network. Recognition of the intersection between immediate/ broader natural community supports and formal services is also key to developing the comprehensive and practical supports required to achieve an independent life. This was a qualitative study and all participants were sourced through Headway, a community based service provider for people with ABI. Data collection was divided into two stages: firstly focus groups, followed by individual interviews. Four focus groups were convened in Cork (2), Dublin (1) and Limerick (1). Each focus group was facilitated by at least two members of the research team and a total of twenty-six individuals participated in the focus groups. Thematic analysis of the data was undertaken to guide and inform the second stage of the study; the individual interviews. Ten interviews were undertaken with individuals who presented with ABI in the Cork and Limerick regions.

Investigating the role of Fas (CD95) signalling in the modification of innate immune induced inflammation

Background/Aim: It has been demonstrated that a number of pathologies occur as a result of dysregulation of the immune system. Whilst classically associated with apoptosis, the Fas (CD95) signalling pathway plays a role in inflammation. Studies have demonstrated that Fas activation augments TLR4-mediated MyD88-dependent cytokine production. Studies have also shown that the Fas adapter protein FADD is required for RIG-I-induced IFNβ production. As a similar signalling pathway exists between RIG-I, TLR3 and the MyD88- independent of TLR4, we hypothesised that Fas activation may modulate both TLR3- and TLR4-induced cytokine production. Results: Fas activation reduced poly I:C-induced IFNβ, IL-8, IL-10 and TNFα production whilst augmenting poly I:C-, poly A:U- and Sendai virus-induced IP-10 production. TLR3-, RIG-I- and MDA5-induced IP-10 luciferase activation were inhibited by the Fas adapter protein FADD using overexpression studies. Poly I:C-induced phosphorylation of p-38 and JNK MAPK were reduced by Fas activation. Overexpression of FADD induced AP-1 luciferase activation. Point mutations in the AP-1 binding site enhanced poly I:C-induced IP- 10 production. LPS-induced IL-10, IL-12, IL-8 and TNFα production were enhanced by Fas activation, whilst reducing LPS-induced IFNβ production. Absence of FADD using FADD-/- MEFs resulted in impaired IFNβ production. Overexpression studies using FADD augmented TLR4-, MyD88- and TRIF-induced IFNβ luciferase activation. Overexpression studies also suggested that enhanced TLR4-induced IFNβ production was independent of NFκB activation. Conclusion: Viral-induced IP-10 production is augmented by Fas activation by reducing the phosphorylation of p-38 and JNK MAPKs, modulating AP-1 activation. The Fas adapterprotein FADD is required for TLR4-induced IFNβ production. Studies presented here demonstrate that the Fas signalling pathway can therefore modulate the immune response. Our data demonstrates that this modulatory effect is mediated by its adapter protein FADD, tailoring the immune response by acting as a molecular switch. This ensures the appropriate immune response is mounted, thus preventing an exacerbated immune response.