End-of-life care in Ireland: ethical challenges and solutions. Opening Statement to the Houses of the Oireachtas Joint Committee on Health and Children, 24 October 2013.

Children Report on End of Life and Palliative Care in Ireland, Volume 1.

Moving statutes captured on disk

Irish Times article, 1 February 1999

The analytical approach of the European Court of Human Rights in surveillance cases—the implications, justifications, and future of the Court’s reasoning, with a focus on the legislative impact in Ireland

A notable feature of the surveillance case law of the European Court of Human Rights has been the tendency of the Court to focus on the “in accordance with the law” aspect of the Article 8 ECHR inquiry. This focus has been the subject of some criticism, but the impact of this approach on the manner in which domestic surveillance legislation has been formulated in the Party States has received little scholarly attention. This thesis addresses that gap in the literature through its consideration of the Interception of Postal Packets and Telecommunications Messages (Regulation) Act, 1993 and the Criminal Justice (Surveillance) Act, 2009. While both Acts provide several of the safeguards endorsed by the European Court of Human Rights, this thesis finds that they suffer from a number of crucial weaknesses that undermine the protection of privacy. This thesis demonstrates how the focus of the European Court of Human Rights on the “in accordance with the law” test has resulted in some positive legislative change. Notwithstanding this fact, it is maintained that the legality approach has gained prominence at the expense of a full consideration of the “necessary in a democratic society” inquiry. This has resulted in superficial legislative responses at the domestic level, including from the Irish government. Notably, through the examination of a number of more recent cases, this project discerns a significant alteration in the interpretive approach adopted by the European Court of Human Rights regarding the application of the necessity test. The implications of this development are considered and the outlook for Irish surveillance legislation is assessed.

The evolution of the medical professions in eighteenth-century Ireland: An institutional perspective

Ireland, in the eighteenth century, followed the classic tripartite division of regular medical practitioners into physicians, surgeons and apothecaries. At the beginning of the century surgeons and apothecaries were regarded as mere tradesmen, but by the end of the century both were regarded as professionals and had the right to regulate their respective professions. Practitioners in different regions of Europe developed in a different manner, and eighteenth-century practitioners in Ireland developed independently from their English counterparts. In common with Britain and Europe in the eighteenth century, the total number of practitioners increased in Ireland, and by the end of the century, apothecaries were the largest group in Dublin, closely followed by the surgeons. Surgeons and apothecaries at the start of the eighteenth century belonged to the same guild. However in mid-century, St Luke's guild of apothecaries was established and this provided the apothecaries with a new identity that allowed them to pursue auto regulation, rather than hitherto, when they had been regulated by the physicians. This was vital to the apothecaries as they were in direct commercial competition with both the physicians and the surgeons and faced increasing pressure from both druggists and the disparate group of practitioners known as the irregulars. The 1765 County Infirmaries Act established a hospital in virtually every county in Ireland, and cast the surgeon as the primary medical officer in the countrywide network of hospitals. This legislation, which was unique in Europe, had the unintended consequence of elevating the status of the surgeons, as prior to this physicians were always in the ascendancy in the voluntary hospitals in Ireland and Britain, in contrast to France. The status of the surgeons was further enhanced by the establishment of the College of Surgeons in Ireland in 1784, which provided them with a new corporate identity, the authority to regulate the profession countrywide, and, also, the ability to educate surgeons in Ireland. The establishment of the College of Surgeons placed further pressure on the apothecaries to demonstrate that they also had a recognisable identity, and the authority to regulate their own profession. This was achieved with the 1791 Apothecaries Act which established the Apothecaries Hall and give the apothecaries the right to regulate themselves. This innovative legislation deemed the apothecaries a profession, and was enacted twenty-four years prior to similar legislation in Britain. Commercial pressure from druggists and, probably, irregulars expedited the requirement of the apothecaries to establish a new corporate identity, in order to distance themselves from these groups. The changing status of both apothecaries and surgeons had little effect on the physicians as a group, and, despite being the beneficiaries of a generous bequest from Sir Patrick Dun in 1711 to provide medical chairs in Dublin, the physicians displayed an inertia during the eighteenth century that was not in keeping with the developments that occurred in the contemporary Dublin medical world. The fact that it took ninety-five years, and that five acts of parliament, two House of Commons enquiries and a House of Lords enquiry were required to ensure that Dun's wishes were brought to fruition demonstrates that the physicians did not develop at the same pace as the other medical groups in the city. Had Dun’s bequest been implemented as he desired, Dublin, with a number of voluntary hospitals, would have been well placed to provide comprehensive tuition for medical students in the eighteenth century. It was not until the nineteenth century that the city, and the populace, benefited from this legacy. This thesis will trace these developments in the context of changes that occurred in contemporary medical education and diagnosis in Ireland, Britain and France. It will demonstrate that Irish practitioners developed independently, influenced mainly by local issues, but also by those who had travelled abroad and returned to Ireland with new concepts and ideas, ensuring that Irish medical practitioners had the institutional structure that could encompass the diagnostic and regulatory changes that would become accepted in the nineteenth century.

Characterization of the degradation of wild-type and mutant HFE proteins during stress signalling in the endoplasmic reticulum

HFE is a transmembrane protein that becomes N-glycosylated during transport to the cell membrane. It acts to regulate cellular iron uptake by interacting with the Type 1 transferrin receptor and interfering with its ability to bind iron-loaded transferrin. There is also evidence that HFE regulates systemic iron levels by binding to the Type II transferrin receptor although the mechanism by which this occurs is still not well understood. Mutations to HFE that disrupt this function, or physiological conditions that decrease HFE protein levels, are associated with increased iron uptake, and its accumulation in tissues and organs. This is exemplified by the point mutation that results in conversion of cysteine residue 282 to tyrosine (C282Y), and gives rise to the majority of HFE-related hemochromatoses. The C282Y mutation prevents the formation of a disulfide bridge and disrupts the interaction with its co-chaperone β2-microglobulin. The resulting misfolded protein is retained within the endoplasmic reticulum (ER) where it activates the Unfolded Protein Response (UPR) and is subjected to proteasomal degradation. The absence of functional HFE at the cell surface leads to unregulated iron uptake and iron loading. While the E3 ubiquitin ligase involved in the degradation of HFE-C282Y has been identified, the mechanism by which it is targeted for degradation remains relatively obscure. The primary objective of this project was to further our understanding of how the iron regulatory HFE protein is targeted for degradation. Our studies suggest that the glycosylation status, and the active process of deglycosylation, are central to this process. We identified a number of additional factors that can contribute towards degradation and explored their regulation during ER stress conditions.

Enforcing precariousness: a comparative analysis of the limitations placed on the legal status of refugees

This thesis focuses on the manner in which the EU, the UK, and Canada respond to and engage with the refugee’s movement from a temporary to a more permanent legal status in the state. It is noted that this transition is increasingly problematized. A trend is noted in response to this among the jurisdictions examined, to exceptionalise refugee status through acts of legal categorisation and separation. These categorisations represent an attempt to re-assert control over refugees who arrived to the state in a spontaneous manner. I argue that this categorisation and fragmentation of refugee status is another means of managing life in the state and ultimately excluding refugees within the state. Refugees therefore experience a contradictory response to their presence. While they are continually reminded of the temporary nature of their legal status in the state, they are still required to demonstrate a willingness to integrate in to the host society. Their behaviour in the state is something that is once again recalled by the decision makers who determine whether they should ultimately be able to access citizenship status. In this thesis, I argue that in order to navigate a route to citizenship, the refugee must respond to the constant re-framing and re-contextualisation of her status in the state of asylum. As the thesis observes, this raises broader questions about the nature of citizenship and belonging

Function of the PDLIM2 protein in oncogenic Wnt signalling pathways

Aberrant regulation of the Wnt signalling pathway is a recurrent theme in cancer biology. Hyper activation due to oncogenic mutations and paracrine activity has been found in both colon cancer and breast cancer, and continues to evolve as a central mechanism in oncogenesis. PDLIM2, a cytoskeletal PDZ protein, is an IGF-1 regulated gene that is highly expressed in cancer cell lines derived from metastatic tumours. Suppression of PDLIM2 inhibits polarized cell migration, reverses the Epithelial to Mesenchymal transition (EMT) phenotype, suppresses the transcription of β-catenin target genes, and regulates gene expression of key transcription factors in EMT. This thesis investigates the mechanism by which PDLIM2 contributes to the maintenance of Wnt signalling in cancer cells. Here we show that PDLIM2 is a critical regulator of the Wnt pathway by regulating β-catenin at the adherens juctions, as also its transcriptional activity by the interaction of PDLIM2 with TCF4 at the nucleus. Evaluation of PDLIM2 in macrophages and co-culture studies with cancer cells and fibroblasts showed the influence exerted on PDLIM2 by paracrine cues. Thus, PDLIM2 integrates cytoskeleton signalling with gene expression by modulating the Wnt signalling pathway and reconciling microenvironmental cues with signals in epithelial cells. Negative correlation of mRNA and protein levels in the triple negative breast cancer cell BT549 suggests that PDLIM2 is part of a more complex mechanism that involves transcription and posttranslational modifications. GST pulldown studies and subsequent mass spectrometry analysis showed that PDLIM2 interacts with 300 proteins, with a high biological function in protein biosynthesis and Ubiquitin/proteasome pathways, including 13 E3 ligases. Overall, these data suggest that PDLIM2 has two distinct functions depending of its location. Located at the cytoplasm mediates cytoskeletal re-arrangements, whereas at the nucleus PDLIM2 acts as a signal transduction adaptor protein mediating transcription and ubiquitination of key transcription factors in cancer development.

A novel non-peptidic agonist of the ghrelin receptor with orexigenic activity in vivo

Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. In vivo tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand.