Bovine serum albumin as the dominant form of dietary protein reduces subcutaneous fat mass, plasma leptin and plasma corticosterone in high fat-fed C57/BL6J mice

Acknowledgements The authors thank Harriett Schellekens from the University College Cork and Paula O’Connor from Teagasc Moorepark Food Research Centre for their assistance in procuring laboratory space and equipment. The present study was funded by Teagasc. B. L. M. was funded by the Walsh Fellowship Program. J. R. S. was supported by a 1000-talents professorship from the Chinese government. The funding bodies had no input on the design of the study or in the interpretation of the data.

Silent screen: book review.

Book Review. Kevin Rockett, Irish film censorship: a cultural journey from silent cinema to internet pornography (Dublin, 2004) and Mary Corcoran and Mark O'Brien (eds), Political censorship and the democratic state: the Irish broadcasting ban (Dublin, 2005)

Does attendance affect grade? An analysis of first year economics students in Ireland

This paper examines the relationship between attendance and grade, controlling for other factors, in first year economics courses in University College Cork. Determinants of both class attendance and grade are specified and estimated. We find that attendance is low, at least by comparison with US evidence. Hours worked and travel time are among the factors affecting class attendance. Class attendance, and especially tutorial attendance has a positive and diminishing marginal effect on grade, while hours worked in a part-time job have a significant negative effect on grade.

A Viking Age maritime haven: a reassessment of the island settlement at Beginish, Co. Kerry

The results of O'Kelly’s excavations on Beginish Island are reassessed and it is proposed that there was a long-lived settlement there that functioned as a Viking-age maritime way-station. This re-evaluation is conducted in the light of recent scholarship on the nature of Scandinavian and Hiberno-Scandinavian settlement in Ireland and, in part, is based on the finds that have emerged on Beginish since the conclusion of the excavations there. The site is considered in the context of its location on the sea route that joined Hiberno-Scandinavian Cork with Limerick, and it is suggested that other such way-stations await.

Self-cutting and prospective repetition of self-harm: studies of emergency department presentations in Ireland

Background Self-harm places an individual at increased risk of future self-harm and suicide, and indicates distress and maladaptive coping. Those who present to hospital with self-cutting form a significant minority of self-harm patients who are at increased risk of prospective repetition of self-harm and suicide compared with those presenting with intentional overdose. In addition to increased risk, there is emerging evidence of demographic, psychological, clinical, and social differences between those presenting with self-cutting and those presenting with overdose. Aim and Key Objectives The aim of the current doctoral work was to examine in detail the association between presenting with self-cutting and risk of prospective repetition. The objectives were: to identify evidence-based risk factors for repetition of self-harm among those presenting to emergency departments with self-harm; to compare demographic and presentation characteristics and prospective repetition across presentations of self-cutting only, self-cutting plus intentional overdose, and intentional overdose only; to compare prospective repetition and other characteristics within self-cutting presentations based on the type of treatment received; to compare self-cutting and intentional overdose patients on psychological risk and protective factors for repetition; and to examine the lived experience of engaging in repeated overdose and self-cutting. Methods The current doctoral work used a mixed-methods approach and is comprised of one systematic review and four empirical studies. The empirical studies were two registry-based prospective studies of Irish hospital presentations of self-harm, one prospective structured interview study, and one qualitative study using Interpretative Phenomenological Analysis. Results The systematic review identified several consistent and emerging risk factors for repetition of self-harm, compared to which self-cutting had a medium-sized effect. The registry studies demonstrated that the involvement of self-cutting, particularly less medically severe selfcutting, confers an increased risk of 1-month and 12-month repetition among Irish index selfharm presentations. The structured psychological study detected higher hopelessness and lower non-reactivity to inner experience among those presenting with self-cutting, and higher depression among those who repeated self-harm. Repeaters had lower baseline levels of protective psychological factors than non-repeaters and continued to have higher depression and hopelessness at follow-up. Finally, the qualitative study indicated that self-harm is a purposeful action taken in response to an overwhelming situation and is evaluated afterwards in terms of personal and social effects. Chosen method of self-harm seemed to be influenced by the desired outcome of the self-harm act, capability, accessibility and previous experience. Conclusion Despite limitations in terms of recruitment rates, the work presented in this thesis is innovative in examining the issue of the association between self-cutting and repetition from multiple perspectives. No one factor can reliably predict all repetition but self-cutting represents one consistent and easily detected risk factor for repetition. Those who present with self-cutting exhibit significant differences on demographic, clinical, and psychological variables compared with those presenting with intentional overdose, and seem to exhibit a more vulnerable profile. However, those who present with self-cutting do not form a discrete or homogenous group, and self-harm methods and levels of suicidal intent are liable to fluctuate over time.

Leader's reflections on knowledge, knowing and not knowing: an analysis of change over time

One commonality across the leadership and knowledge related literature is the apparent neglect of the leaders own knowledge. This thesis sought to address this issue through conducting exploratory research into the content of leader’s personal knowledge and the process of knowing it. The empirical inquiry adopted a longitudinal approach, with interviews conducted at two separate time periods with an extended time-interval between each. The findings from this research contrast with images of leadership which suggest leaders are in control of what they know, that they own their own knowledge. The picture that emerges is one of individuals struggling to keep abreast of the knowledge required to deal with the dynamics and uncertainties of organisational life. Much knowledge is tacit, provisional and perishable and the related process of knowing more organic, evolutionary and informal than any structured or orchestrated approach. The collective nature of knowing is a central feature, with these leaders embedded in networks of uncontrollable relationships. In view of the indeterminate nature of knowing, the boundary between what is known and what one needs to know is both amorphous and ephemeral, and the likelihood of knowledge-absences is escalated. A significant finding in this regard is the identification of two critical points where not-knowing is most likely (entry and exit from role) and the differing implications of each. Overtime the knowledge that is legitimised or prioritised is significantly altered as these leaders replace the dogmas that were previously held in high esteem with the lessons from their own experience. This experience brings increased self-knowledge and a deeper appreciation of the values and morals instilled in their early lives. In view of the above findings, this study makes theoretical contribution to a number of core literatures: authentic leadership, role transition and knowledge-absences. In terms of leadership development, the findings point to the necessity to prepare leaders for the challenges they will encounter at the pivotal stages of the leadership role.

An examination of the role of the sports and exercise medicine specialist in Ireland- from epidemiology to treatment

The expansion of the specialty of sports and exercise medicine (SEM) is a relatively recent development in the medical community and the role of the SEM specialist continues to evolve and develop. The SEM specialist is ideally placed to care for all aspects of physical activity not only in athletes but also in the general population. As an advocate for physical activity the SEM specialist plays a broad role in advising safe effective sports and recreation participation; screening for disease related to sports participation; examining and contributing to the evidence behind treatment strategies and evaluating any potential negative impact of sports injury prevention measures. In this thesis I will demonstrate the breadth of the role the Sports and Exercise Medicine Specialist from epidemiology to in-depth examination of treatment strategies. In Chapter 2, I examined the epidemiology of sports and recreation related injury (SRI) in Ireland, an area that has previously been poorly studied. We report on 3,172 SRI (14% of total presentations) presentations to the ED over 6 months. Paediatric patients (4-16 yrs) were over represented comprising 39.9% of all SRI presentation compared to 16% of total ED presentations and 18% of the general population. These injuries were serious (32% fractures) and though 49% of injuries occurred during organised competition/practice, 41.5% occurred during recreation-most often at home. In Chapter 3, I examined risk factors associated with hand injury in hurling. The previous chapter highlighted the importance of a firm evidence base underpinning treatment strategies. When measures to improve welfare are introduced not only must potential benefits be measured, so too must potential unwanted adverse outcomes. In this study I examined a cohort of adult hurlers who had presented to the ED with a hurling related injury in order to highlight the variables associated with hand injury in this population. I found the athletes who wore a helmet were far more likely (OR 3.15 95% CI (1.51-6.56) p= 0.002) to suffer a hand injury than athletes who did not. Very few of those interviewed (4.9%) used hand protection compared to 65% who used helmet and faceguard. The introduction of the helmet and faceguard in hurling has undeniably decreased the incidence of head and face injury in hurling. However in tandem with this intervention several observational studies have demonstrated an increase in the occurrence of hurling related hand injuries. This study highlights the importance of being cognisant of unanticipated or unintended consequences when implementing a new treatment or intervention. In Chapter 4, I examined the role of population screening as applied to sport and exercise. This is a controversial area –cardiac screening in the exercising population has been the subject of much debate. Specifically I define the prevalence of exercise induced bronchoconstriction (EIB) using a specifically designed sports specific field-testing protocol. In this study I found almost a third (29%) of a full international professional rugby squad had confirmed asthma or EIB, as compared with 12-15% of the general population. Despite regular medical screening, 5 ‘new’ untreated cases (12%) were elicited by the challenge test and in the group already on treatment for asthma/EIB; over 50% still displayed EIB. In Chapter 5, I examined the evidence supporting current treatment options for iliotibial band friction syndrome (ITBFS). The practice of sports medicine has traditionally been ‘eminence based’ rather than ‘evidence based’. This may be problematic as some of these practices are based upon flawed principles- for example the treatment of iliotibial band friction syndrome (ITBFS). In this chapter, using cadaveric and biomechanical studies I expand upon the growing base of evidence clarifying the anatomy and biomechanics of the area-thereby re-examining the principles on which current treatments are based. The role of the SEM specialist is broad; we chose to examine specific examples of some of the roles that they execute. An understanding of the epidemiology of SRI presenting to the ED has implications for individual patients, sports governing bodies and health resource utilisation. Population screening is an important tool in health promotion and disease prevention in the general population. Screening in SEM may have similar less well-recognised benefits. The SEM specialist needs to be conversant in screening for medical conditions concerning physical activity. A comprehensive understanding of the pathophysiology of a disease is required for its diagnosis and treatment. Due to the ongoing evolution of SEM many treatments are eminence-based rather than evidence‐based practice. Continued re-examination of the fundamentals of current practice is essential. An awareness of potential unwanted side effects is essential prior to the introduction of any new treatment or intervention. The SEM specialist is ideally placed to advise sports governing bodies on these issues prior to and during their implementation.

Synthesis & retention mechanisms of novel mixed mode stationary phase for detection of specific polar low molecular weight biological samples

The thesis primarily reports the synthesis, characterization and application of novel mixed mode stationary phases for Hydrophilic Interaction Liquid Chromatography (HILIC). HILIC is a rapidly emerging chromatographic mode that is finding great applicability in the analysis of polar organic molecules. In addition, there is a chapter on the analysis of Bisphenol A and related species using capillary electrophoresis (CE) coupled with boron-doped diamond electrodes for electrochemical detection. The synthesis and characterization of the novel mixed mode stationary phases prepared in this work is an important contribution to the field as the materials prepared exhibited better performance than similar materials obtained commercially. In addition a more thorough characterization of the materials (e.g.,thermogravimetric analysis, various NMR modes, elemental analysis, etc.) and resulting columns (e.g., H) than is typically encountered. The application of these new materials to the analysis of sugars using evaporative light scattering is also novel. In CE studies, electrochemical detection is sufficiently rare that the work is also novel.

The food choice at work study: effectiveness of complex workplace dietary interventions on dietary behaviours and diet-related disease risk - study protocol for a clustered controlled trial

Background: Dietary behaviour interventions have the potential to reduce diet-related disease. Ample opportunity exists to implement these interventions in the workplace. The overall aim is to assess the effectiveness and cost-effectiveness of complex dietary interventions focused on environmental dietary modification alone or in combination with nutrition education in large manufacturing workplace settings. Methods/design: A clustered controlled trial involving four large multinational manufacturing workplaces in Cork will be conducted. The complex intervention design has been developed using the Medical Research Council's framework and the National Institute for Health and Clinical Excellence (NICE) guidelines and will be reported using the TREND statement for the transparent reporting of evaluations with non-randomized designs. It will draw on a soft paternalistic 'nudge' theoretical perspective. It will draw on a soft paternalistic "nudge" theoretical perspective. Nutrition education will include three elements: group presentations, individual nutrition consultations and detailed nutrition information. Environmental dietary modification will consist of five elements: (a) restriction of fat, saturated fat, sugar and salt, (b) increase in fibre, fruit and vegetables, (c) price discounts for whole fresh fruit, (d) strategic positioning of healthier alternatives and (e) portion size control. No intervention will be offered in workplace A (control). Workplace B will receive nutrition education. Workplace C will receive nutrition education and environmental dietary modification. Workplace D will receive environmental dietary modification alone. A total of 448 participants aged 18 to 64 years will be selected randomly. All permanent, full-time employees, purchasing at least one main meal in the workplace daily, will be eligible. Changes in dietary behaviours, nutrition knowledge, health status with measurements obtained at baseline and at intervals of 3 to 4 months, 7 to 9 months and 13 to 16 months will be recorded. A process evaluation and cost-effectiveness economic evaluation will be undertaken. Discussion: A 'Food Choice at Work' toolbox (concise teaching kit to replicate the intervention) will be developed to inform and guide future researchers, workplace stakeholders, policy makers and the food industry. Trial registration: Current Controlled Trials, ISRCTN35108237.

An investigation of the molecular interactions between statins and bacterial pathogens, and their combined impact on the human immune system

Statins are a class of drug that inhibits cholesterol biosynthesis, and are used to treat patients with high serum cholesterol levels. They exert this function by competitively binding to the enzyme 3-hydroxy-3-methylglutaryl-CoenzymeA reductase (HMGR), which catalyses the formation of mevalonate, a rate-limiting step in cholesterol biosynthesis. In addition, statins have what are called “pleiotropic effects”, which include the reduction of inflammation, immunomodulation, and antimicrobial effects. Statins can also improve survival of patients with sepsis and pneumonia. Cystic fibrosis (CF) is the most common recessive inherited disease in the Caucasian population, which is characterised by factors including, but not limited to, excessive lung inflammation and increased susceptibility to infection. Therefore, the overall objective of this study was to examine the effects of statins on CFassociated bacterial pathogens and the host response. In this work, the prevalence of HMGR was examined in respiratory pathogens, and several CF-associated pathogens were found to possess homologues of this enzyme. HMGR homology was analysed in Staphylococcus aureus, Burkholderia cenocepacia and Streptococcus pneumoniae, and the HMGR of B. cenocepacia was found to have significant conservation to that of Pseudomonas mevalonii, which is the most widely-characterised bacterial HMGR. However, in silico analysis revealed that, unlike S. aureus and S. pneumoniae, B. cenocepacia did not possess homologues of other mevalonate pathway proteins, and that the HMGR of B. cenocepacia appeared to be involved in an alternative metabolic pathway. The effect of simvastatin was subsequently tested on the growth and virulence of S. aureus, B. cenocepacia and S. pneumoniae. Simvastatin inhibited the growth of all 3 species in a dose-dependent manner. In addition, statin treatment also attenuated biofilm formation of all 3 species, and reduced in vitro motility of S. aureus. Interestingly, simvastatin also increased the potency of the aminoglycoside antibiotic gentamicin against B. cenocepacia. The impact of statins was subsequently tested on the predominant CF-associated pathogen Pseudomonas aeruginosa, which does not possess a HMGR homologue. Mevastatin, lovastatin and simvastatin did not influence the growth of this species. However, sub-inhibitory statin concentrations reduced the swarming motility and biofilm formation of P. aeruginosa. The influence of statins was also examined on Type 3 toxin secretion, quorum sensing and chemotaxis, and no statin effect was observed on any of these phenotypes. Statins did not appear to have a characteristic effect on the P. aeruginosa transcriptome. However, a mutant library screen revealed that the effect of statins on P. aeruginosa biofilm was mediated through the PvrR regulator and the Cup fimbrial biosynthesis genes. Furthermore, proteomic analysis demonstrated that 6 proteins were reproducibly induced by simvastatin in the P. aeruginosa swarming cells. The effect of statins on the regulation of the host-P. aeruginosa immune response was also investigated. Statin treatment increased expression of the pro-inflammatory cytokines IL-8 and CCL20 in lung epithelial cells, but did not attenuate P. aeruginosa-mediated inflammatory gene induction. In fact, simvastatin and P. aeruginosa caused a synergistic effect on CCL20 expression. The expression of the transcriptional regulators KLF2 and KLF6 was also increased by statins and P. aeruginosa, with the induction of KLF6 by simvastatin proving to be a novel effect. Interestingly, both statins and P. aeruginosa were capable of inducing alternative splicing of KLF6. P. aeruginosa was found to induce KLF6 alternative splicing by way of the type 3 secreted toxin ExoS. In addition, a mechanistic role was elucidated for KLF6 in the lung, as it was determined that statin-mediated induction of this protein was responsible for the induction of the host response genes CCL20 and iNOS. Moreover, statin treatment caused a slight increase in infection-related cytotoxicity, and increased bacterial adhesion to cells. Taken together, these data demonstrate that statins can reduce the virulence of CFassociated bacterial pathogens and alter host response effectors. Furthermore, novel statin effectors were identified in both bacterial and host cells.

Total synthesis of furospongolide and related furanolipid analogues as potential anti-tumour agents

This thesis details the design, development and execution of innovative methodology in the total synthesis of the terpene-derived marine natural product, furospongolide. It also outlines the synthetic routes used to prepare a novel range of furanolipids derivatives and subsequent evaluation of their potential as antitumour agents. The first chapter is a review of the literature describing efforts undertaken towards the synthesis of biologically active furanosesterterpenoid marine natural products. A brief discussion on the sources and biological activity exhibited by furan natural products is also provided. In addition, a concise account of the role of hypoxia in cancer, and the increasing interest in HIF-1 inhibition as a target for chemotherapeutics is examined. The second chapter discusses the concise synthesis of the marine HIF-1 inhibitor furospongolide, which was achieved in five linear steps from (E,E)-farnesyl acetate. The synthetic strategy features a selective oxidation reaction, a Schlosser sp3-sp3 cross-coupling, a Wittig cross-coupling and an elaborate one-pot selective reduction, lactonisation and isomerization reaction to install the butenolide ring. The structure-activity relationship of furospongolide was also investigated. This involved the design and synthesis of a library of structurally modified analogues sharing the same C1-C13 subunit. This was achieved by exploiting the brevity and high level of convergence of our synthetic route together with the readily amenable structure of our target molecule. Exploiting the Schlosser cross-coupling allowed for replacement of furan with other heterocycles in the preparation of various furanolipid and thiophenolipid derivatives. The employment of reductive amination and Wittig chemistry further added to our novel library of structural derivatives. The third chapter discusses the results obtained from the NCI from biological evaluation From a collection of 28 novel compounds evaluated against the NCI-60 cancer cell array, six drug candidates were successfully selected for further biological evaluation on the basis of antitumour activity. COMPARE analysis revealed a strong correlation between some of our design analogues and the blockbuster anticancer agent tamoxifen, further supporting the potential of furanolipids in the treatment of breast cancer. The fourth chapter, details the full experimental procedures, including spectroscopic and analytical data for all the compounds prepared during this research.