P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants

Depression is among the leading causes of disability worldwide. Currently available antidepressant drugs have unsatisfactory efficacy, with up to 60% of depressed patients failing to respond adequately to treatment. Emerging evidence has highlighted a potential role for the efflux transporter P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), in the aetiology of treatment-resistant depression. In this thesis, the potential of P-gp inhibition as a strategy to enhance the brain distribution and pharmacodynamic effects of antidepressant drugs was investigated. Pharmacokinetic studies demonstrated that administration of the P-gp inhibitors verapamil or cyclosporin A (CsA) enhanced the BBB transport of the antidepressants imipramine and escitalopram in vivo. Furthermore, both imipramine and escitalopram were identified as transported substrates of human P-gp in vitro. Contrastingly, human P-gp exerted no effect on the transport of four other antidepressants (amitriptyline, duloxetine, fluoxetine and mirtazapine) in vitro. Pharmacodynamic studies revealed that pre-treatment with verapamil augmented the behavioural effects of escitalopram in the tail suspension test (TST) of antidepressant-like activity in mice. Moreover, pre-treatment with CsA exacerbated the behavioural manifestation of an escitalopram-induced mouse model of serotonin syndrome, a serious adverse reaction associated with serotonergic drugs. This finding highlights the potential for unwanted side-effects which may occur due to increasing brain levels of antidepressants by P-gp inhibition, although further studies are needed to fully elucidate the mechanism(s) at play. Taken together, the research outlined in this thesis indicates that P-gp may restrict brain concentrations of escitalopram and imipramine in patients. Moreover, we show that increasing the brain distribution of an antidepressant by P-gp inhibition can result in an augmentation of antidepressant-like activity in vivo. These findings raise the possibility that P-gp inhibition may represent a potentially beneficial strategy to augment antidepressant treatment in clinical practice. Further studies are now warranted to evaluate the safety and efficacy of this approach.

Language legislation in Ireland and the United Kingdom: Exploring the gaps between theory and practice

The central objective in this thesis is to explore the gaps between the normative justifications advanced for language rights and language legislative protection and the effective realisation of those rights and legislative provisions in practice. This objective is achieved by examining the scope and application of language rights and legislative provisions within language legislation in Ireland and the United Kingdom. Drawing on Canadian jurisprudence advocating for language rights to be recognised as “purposeful”, the thesis considers the extent to which Ireland and the United Kingdom have limited the acceptance of positive obligations as they relate to the provision of language services in the public sphere. In arguing that language rights are distinct in nature, the thesis suggests that in order for language rights to be effectively realised, an approach to language rights and language legislation more generally must be underpinned by a substantive vision of equality, otherwise language rights and legislative provisions merely amount to symbolic recognition and vacuous rhetoric as opposed to being substantive and enabling rights and provisions. Having said that, the thesis also recognises and elucidates the practical difficulties that arise in the realisation of language rights and language legislative provisions and in doing so seeks to stimulate further dialogue about the nature and limits of language rights and language legislation.

Literatur verstehen und inszenieren: Foreign language literature through drama, a research project

Based on the experience that today's students find it more difficult than students of previous decades to relate to literature and appreciate its high cultural value, this paper argues that too little is known about the actual teaching and learning processes which take place in literature courses and that, in order to ensure the survival of literary studies in German curricula, future research needs to elucidate for students, the wider public and, most importantly, educational policy makers, why the study of literature should continue to have an important place in modern language curricula. Contending that students' willingness to engage with literature will, in the future, depend to a great extent on the use of imaginative methodology on the part of the teacher, we give a detailed account of an action research project carried out at University College Cork from October to December 2002 which set out to explore the potential of a drama in education approach to the teaching and learning of foreign language literature. We give concrete examples of how this approach works in practice, situate our approach within the subject debate surrounding Drama and the Language Arts and evaluate in detail the learning processes which are typical of performance-based literature learning. Based on converging evidence from different data sources and overall very positive feedback from students, we conclude by recommending that modern language departments introduce courses which offer a hands-on experience of literature that is different from that encountered in lectures and teacher-directed seminars.

Within the carnal: re-reading Merleau-Ponty through the language of drawing

In order to present visual art as a paradigm for philosophy, Merleau-Ponty investigated the creative processes of artists whose work corresponded closely with his philosophical ideas. His essays on art are widely valued for emphasising process over product, and for challenging the primacy of the written word in all spheres of human expression. While it is clear that he initially favoured painting, Merleau-Ponty began to develop a much deeper understanding of the complexities of how art is made in his late work in parallel with his advancement of a new ontology. Although his ontology remains unfinished and only exists as working notes and a manuscript entitled The Visible and Invisible, Merleau-Ponty had begun to appreciate the fundamental role drawing plays in the making of art and the creation of a language of expression that is as vital as the written or spoken word. Through an examination of Merleau-Ponty’s unfinished manuscript and working notes my thesis will investigate his working methods and use of materials and also explore how he processed his ideas by using my own art practice as the basis of my research. This research will take the form of an inquiry into how the unfinished and incomplete nature of text and artworks, while they are still ‘works in progress’, can often reveal the more human and carnal components of creative processes. Applying my experience as a practitioner and a teacher in an art school, I focus on the significance of drawing practice for Merleau-Ponty’s later work, in order to rebalance an overemphasis on painting in the literature. Understanding the differences between these two art forms, and how they are taught, can offer an alternative engagement with Merleau-Ponty’s later work and his struggle to find a language to express his developing new ontology. In addition, by re-reading his work through the language of drawing, I believe we gain new insights which reaffirm Merleau-Ponty's relevance to contemporary art making and aesthetics.

H.M.'s personal crossword puzzles: understanding memory and language.

The amnesic patient H.M. has been solving crossword puzzles nearly all his life. Here, we analysed the linguistic content of 277 of H.M.'s crossword-puzzle solutions. H.M. did not have any unusual difficulties with the orthographic and grammatical components inherent to the puzzles. He exhibited few spelling errors, responded with appropriate parts of speech, and provided answers that were, at times, more convincing to observers than those supplied by the answer keys. These results suggest that H.M.'s lexical word-retrieval skills remain fluid despite his profound anterograde amnesia. Once acquired, the maintenance of written language comprehension and production does not seem to require intact medial temporal lobe structures.

Drug Delivery through the Blood-Brain Barrier through Use of Vascular Cell Adhesion Molecule 1- Targeted Nanoparticles

The blood brain barrier (BBB) is a semi-permeable membrane separating the brain from the bloodstream, preventing many drugs that treat neurological diseases, such as Alzheimer’s and Parkinson’s, from reaching the brain. Our project aimed to create a novel drug delivery system targeting the brain during neural inflammation. We developed a cationic solid lipid nanoparticle (CSLN) complex composed of cationic nanoparticles, biotin, streptavidin, and anti-vascular cell adhesion molecule-1 (anti- VCAM-1) antibodies. The anti-VCAM-1 antibody is used to target VCAM-1, a cell adhesion protein found on the BBB endothelium. VCAM-1 expression is elevated in the presence of inflammatory molecules, such as tumor necrosis factor-alpha (TNF- α). Through the use of a simple BBB model, results showed that our novel drug delivery system experienced some level of success in targeting the brain inflammation due to increasing TNF-α concentrations. This is promising for drug delivery research and provides support for VCAM-1 targeting using more robust and complex BBB models.

The body language: The spontaneous influence of congruent bodily arousal on the awareness of emotional words

Nowadays, the idea of a reciprocal influence of physiological and psychological processes seems to be widely accepted. For instance, current theories of embodied emotion suggest that knowledge about an emotion concept involves simulations of bodily experienced emotional states relevant to the concept. In line with this framework, the present study investigated whether actual levels of physiological arousal interact with the processing of emotional words. Participants performed 2 blocks of an attentional blink task, once after a cycling session (increased arousal) and once after a relaxation session (reduced arousal). Concretely, participants were instructed to detect and report 2 target words (T1 and T2) presented among a series of nonword distractors. T1 and T2 were either neutral, high arousal, or low arousal words. Results revealed that increased physiological arousal led to improved reports of high arousal T2 words, whereas reduced physiological arousal led to improved reports of low arousal T2 words. Neutral T2 remained unaffected by the arousing conditions. These findings emphasize that actual levels of physiological arousal modulate the cognitive access to arousal (in-)congruent emotional concepts and suggest a direct grounding of emotion knowledge in our bodily systems of arousal.

[Book Review] Noel Starkey (ed), Connectionist Natural Language Processing: Readings from 'Connection Science'

Review of: Noel Starkey (ed), Connectionist Natural Language Processing: Readings from 'Connection Science'

Birth-death processes with an instantaneous reflection barrier

A new structure with the special property that an instantaneous reflection barrier is imposed on the ordinary birth-death processes is considered. An easy-checking criterion for the existence of such Markov processes is first obtained. The uniqueness criterion is then established. In the nonunique case, all the honest processes are explicitly constructed. Ergodicity properties for these processes are investigated. It is proved that honest processes are always ergodic without necessarily imposing any extra conditions. Equilibrium distributions for all these ergodic processes are established. Several examples are provided to illustrate our results.

A policy-definition language and prototype implementation library for policy-based autonomic systems

This paper presents work towards generic policy toolkit support for autonomic computing systems in which the policies themselves can be adapted dynamically and automatically. The work is motivated by three needs: the need for longer-term policy-based adaptation where the policy itself is dynamically adapted to continually maintain or improve its effectiveness despite changing environmental conditions; the need to enable non autonomics-expert practitioners to embed self-managing behaviours with low cost and risk; and the need for adaptive policy mechanisms that are easy to deploy into legacy code. A policy definition language is presented; designed to permit powerful expression of self-managing behaviours. The language is very flexible through the use of simple yet expressive syntax and semantics, and facilitates a very diverse policy behaviour space through both hierarchical and recursive uses of language elements. A prototype library implementation of the policy support mechanisms is described. The library reads and writes policies in well-formed XML script. The implementation extends the state of the art in policy-based autonomics through innovations which include support for multiple policy versions of a given policy type, multiple configuration templates, and meta-policies to dynamically select between policy instances and templates. Most significantly, the scheme supports hot-swapping between policy instances. To illustrate the feasibility and generalised applicability of these tools, two dissimilar example deployment scenarios are examined. The first is taken from an exploratory implementation of self-managing parallel processing, and is used to demonstrate the simple and efficient use of the tools. The second example demonstrates more-advanced functionality, in the context of an envisioned multi-policy stock trading scheme which is sensitive to environmental volatility

The AGILE policy expression language for autonomic systems

This paper presents the AGILE policy expression language. The language enables powerful expression of self-managing behaviours and facilitates policy-based autonomic computing in which the policies themselves can be adapted dynamically and automatically. The language is generic so as to be deployable across a wide spectrum of application domains, and is very flexible through the use of simple yet expressive syntax and semantics. The development of AGILE is motivated by the need for adaptive policy mechanisms that are easy to deploy into legacy code and can be used by non autonomics-expert practitioners to embed self-managing behaviours with low cost and risk. A library implementation of the policy language is described. The implementation extends the state of the art in policy-based autonomics through innovations which include support for multiple policy versions of a given policy type, multiple configuration templates, and higher-level ‘meta-policies’ to dynamically select between differently configured business-logic policy instances and templates. Two dissimilar example deployment scenarios are examined.

Issues in second language proficiency

Benati provides clarity about the characteristics and notion of language proficiency in the field of second language acquisition. He looks at four areas of research paradigmatically related to the role of proficiency: theorizing and measuring second language proficiency; the dimensions of L2 proficiency; factors contributing to the attainment of L2 proficiency and attaining L2 proficiency in the classroom. It also contains a variety of research accounts about the specific factors which have an effect on proficiency together with a theorised measurement of proficiency in second language research. It will be required reading for researchers in applied linguistics and second language acquisition.

Japanese language teaching: a communicative approach

Japanese Language Teaching examines the practical aspects of the acquisition of Japanese as a second language, underpinned by current theory and research. Each chapter examines the theory and practice of language teaching, and progresses to a consideration of the practical design of tasks for teaching. The final section applies theory and practice to an empirical case study, drawn from a classroom with Japanese as a second language. With its emphasis on practice underpinned by contemporary theory, this book will be of interest to postgraduates studying second language acquisition and applied linguistics. [Source: publisher's description].