e-publications@RCSI

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer.

Anthony J Ryan — Fri, 05 Mar 2010 07:31:08 PST

BACKGROUND: Insulin-like growth factor 1 (IGF1) promotes breast cancer and disease progression. Bioavailability of IGF1 is modulated by IGF-binding proteins (IGFBPs). IGFBP4 inhibits IGF1 activity but cleavage by pregnancy-associated plasma protein-A (PAPP-A) protease releases active IGF1. METHODS: Expression of IGF pathway components and PAPP-A was assessed by western blot or RT-PCR. IGFBP4 (dBP4) resistant to PAPP-A cleavage, but retaining IGF-binding capacity, was used to block IGF activity in vivo. 4T1.2 mouse mammary adenocarcinoma cells transfected with empty vector, vector expressing wild-type IGFBP4 or vector expressing dBP4 were implanted in the mammary fat pad of BALB/c mice and tumour growth was assessed. Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry. RESULTS: 4T1.2 cells expressed the IGF1R receptor and IGFBP4. PAPP-A was expressed within mammary tumours but not by 4T1.2 cells. Proliferation and vascular endothelial growth factor (VEGF) production by 4T1.2 cells was increased by IGF1(E3R) (recombinant IGF1 resistant to binding by IGFBPs) but not by wild-type IGF1. IGF1-stimulated microvascular endothelial cell proliferation was blocked by recombinant IGFBP4. 4T1.2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild-type IGFBP4. Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis. CONCLUSION: Protease-resistant IGFBP4 blocks IGF activity, tumour growth and angiogenesis.

Health Service Executive Emergency Departments. Patient Profiles, Experiences and Perceptions. Report of a National Survey among people who attended during 2006.

Health Services Research Centre — Thu, 04 Mar 2010 04:16:09 PST

Ireland has 53 publicly funded acute hospitals, 35 of which have Emergency Departments. Every day these Emergency Departments see an average of 3,300 people, the majority of whom are treated there and then and discharged without the need for in-patient admission. To better understand the service user or patients' experience of the service, the HSE contracted an independent research company to survey, by computer aided telephone interview, 1,600 representative members of the public who had used Emergency Departments during 2006. The aim of the survey was to ask patients about their experience of attending an Emergency Department and to learn from their experiences as a basis for making improvements that matter to patients.

Tracking Global HIV/AIDS Initiatives and their Impact on the Health System in Ukraine

Tetyana Semigina — Thu, 25 Feb 2010 08:24:37 PST

This report presents results from the final stage of the study based on fieldwork carried out in Ukraine from January - June 2008. It aims to assess the effects of GHIs in Ukraine at national and sub-national levels including the effects on scale-up of HIV/AIDS services, coordination of HIV/AIDS programs, health systems capacity and equitable access to HIV/AIDS services. The study focuses largely on the Global Fund to Fight AIDS, TB and Malaria (Global Fund) which is the largest external funder of HIV/AIDS programs in Ukraine.

Protein Kinase D1 Modulates Aldosterone-Induced ENaC Activity in a Renal Cortical Collecting Duct Cell Line

Victoria McEneaney — Mon, 22 Feb 2010 09:22:01 PST

Aldosterone treatment of M1-CCD cells stimulated an increase in epithelial Na+ channel (ENaC) alpha-subunit expression that was mainly localized to the apical membrane. PKD1 suppressed cells constitutively expressed ENaC alpha at low abundance, with no increase after aldosterone treatment. Here ENaC alpha was mainly localized proximal to the basolateral surface of the epithelium both before and after aldosterone treatment. Apical membrane insertion of ENaC beta in response to aldosterone treatment was also sensitive to PKD1 suppression as was the aldosterone-induced rise in the amiloride-sensitive, trans-epithelial current (ITE). The interaction of the mineralocorticoid receptor (MR) with specific elements in the promoters of aldosterone responsive genes is stabilized by ligand interaction and phosphorylation. PKD1 suppression inhibited aldosterone-induced SGK-1 expression. The nuclear localization of MR was also blocked by PKD1 suppression and MEK antagonism implicating both these kinases in MR nuclear stabilization. PKD1 thus modulates aldosterone-induced ENaC activity through the modulation of sub-cellular trafficking and the stabilization of MR nuclear localization.

Stroke and Nursing Home care: a national survey of nursing homes.

Seamus Cowman — Mon, 22 Feb 2010 07:29:28 PST

ABSTRACT: BACKGROUND: Although stroke is recognised as a major factor in admission to nursing home care, data is lacking on the extent and nature of the disabilities and dependency in nursing homes arising from stroke. A national study conducted in nursing homes can quantify the number of residents with stroke in nursing homes, their disability and levels of dependency. METHODS: A cross-sectional survey research design was used. A total of 572 public and private nursing homes were identified nationally and a stratified random selection of 60 nursing homes with 3,239 residents was made. In half of the nursing homes (n = 30) efforts were made to interview all residents with stroke Survey instruments were used to collect data from residents with stroke and nursing home managers on demography, patient disability, and treatment. RESULTS: Across all nursing homes (n = 60), 18% (n = 570) of the residents had previously had a stroke. In homes (n = 30), where interviews with residents with stroke (n = 257), only 7% (n = 18) residents were capable of answering for themselves and were interviewed. Data on the remaining 93% (n = 239) residents were provided by the nursing home manager. Nurse Managers reported that 73% of residents with stroke had a high level of dependency. One in two residents with stroke was prescribed antidepressants or sedative medication. Only 21% of stroke residents were prescribed anticoagulants, 42% antiplatelets, and 36% cholesterol lowering medications. Stroke rehabilitation guidelines were lacking and 68% reported that there was no formal review process in place. CONCLUSIONS: This study provides seminal findings on stroke and nursing home services in Ireland. We now know that one in six nursing home residents in a national survey are residents with a stroke, and have a wide range of disabilities. There is currently little or no structured care (beyond generic care) for stroke survivors who reside in nursing homes in Ireland.

Effects of the global fund HIV/AIDS programmes in Ukraine

Global HIV/AIDS Initiatives Network — Mon, 22 Feb 2010 06:26:28 PST

Ukraine has one of the highest and most rapidly growing rates of HIV/AIDS in Europe with estimated numbers of people living with HIV/AIDS (PLWHA) reaching 400,000 in 2008. Since 2003 several Global Health Initiatives (GHIs) have committed to providing over US$ 300 million towards the control of HIV/AIDS in Ukraine. These funding mechanisms have had a significant impact on the availability of services for PLWHA and populations at risk of being infected. GHIs have also had an impact on the health system including on human resources, governance and management capacity, and on nongovernmental providers of HIV/AIDS services. This policy brief highlights the effects of the largest external funder of HIV/AIDS programmes in Ukraine, the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) and provides recommendations to improve the effectiveness of future funding and increase accessibility of HIV/AIDS services. It is based on research conducted in 2006-2008 in three regions: Kyiv, Odessa and L'viv.

'Suing the Pope' and Scandalising the People: Irish Attitudes to Sexual Abuse by Clergy Pre- and Post-Screening of a Critical Documentary

Michael J. Breen — Wed, 17 Feb 2010 03:09:17 PST

The Sexual abuse of children became a significant public issue in Ireland in the 1990s, with frequent media reports about the issue. In the main these focused on the issue of abuse of children by members of the clergy and religious orders. Headline cases included the abuse perpetrated by Fr Brendan Smyth, a priest of a religious order who was convicted of multiple counts of sexual abuse of children and subsequently died in prison, and Fr Se�n Fortune, a diocesan priest, who committed suicide before his court trial for abuse. While child sexual abuse by clergy was widely exposed in the early 1990s, a subsequent additional scandal was the failure of the institutional Catholic Church to respond adequately to earlier complaints of abuse, and, in particular, to respond adequately to those who experienced abuse. As part of its response to the problem, the Irish Catholic bishops commissioned an independent research agency - the Health Services Research Centre (HSRC) at the Department of Psychology, Royal College of Surgeons in Ireland (RCSI) - to undertake a programme of research on its behalf. Part of the remit to the research group was to examine the effects on the general public of child sex abuse by clergy. This was done by means of a national telephone survey (N=1,081), full details of which are reported elsewhere (Goode, McGee & O'Boyle, 2003). The survey itself took four months to complete. About half-way through the data collection period in 2002, the main UK public service television channel (BBC2) screened a documentary entitled 'Suing the Pope' which dealt in detail with complaints made to Church authorities about Sean Fortune and the alleged subsequent mishandling of those complaints. This programme was reported in some detail in the Irish media before its showing, and had a high number of Irish viewers since UK channels are accessible in Ireland. The documentary was also reported extensively in other media after screening and was subsequently re-shown on Irish public service channel RT�. The first TV screening provided a point of differentiation within the survey, with some 600 participants having responded before the screening and 481 afterwards. It also served as a 'natural experiment', defined as a 'naturally occurring instance of observable phenomena that approach or duplicate a scientific experiment' (Mathison, 2005:271). This paper examines the differences that exist between the 'before' and 'after' groups by way of examining the role of such a documentary (and related media coverage) in forming public opinion around the topic of child sexual abuse by clergy.

Tracking Global HIV/AIDS Initiatives and their Impact on the Health System: the experience of the Kyrgyz Republic

Gulgun Murzalieva — Sat, 13 Feb 2010 02:59:14 PST

This report presents results from a desk-based review and fieldwork conducted between April 2008 and January 2009 in three regions of Kyrgyzstan - Bishkek/Chui, Osh/Jalalabad and Issyk-Kul. The aim of the report is to assess the effects of two global health initiatives (GHIs) for HIV/AIDS the Global Fund to Fight AIDS, TB, and Malaria (GFATM) and the World Bank's Central Asian AIDS Project (CAAP) at national and sub-national levels, including the effects on HIV/AIDS service scale-up coordination, human resources, and access to HIV/AIDS services.

The Impact of Global Health Initiatives in Kyrgyzstan

Global HIV/AIDS Initiatives Network — Fri, 12 Feb 2010 08:53:54 PST

This policy brief shows the effects of two global health initiatives - the Global Fund to fight AIDS, Tuberculosis, and Malaria (GFATM) and the World Bank's Central Asia AIDS Project (CAAP) - at national and sub-national levels, including the effects on HIV/AIDS service scale-up, human resources, access to HIV/AIDS services and coordination.

Career Progression of Migrant Nurses in Ireland: Nurse Migration Project Policy Brief 5

Niamh Humphries — Thu, 11 Feb 2010 06:54:27 PST

The career progression of migrant nurses within the Irish health system was an issue raised in our discussions with key stakeholders. Concern was raised that few migrant nurses had achieved managerial grades in Ireland (CNM1 or CNM2) and that perhaps this stemmed from a reluctance to apply for senior posts. Evidence internationally suggests that migrant health workers frequently occupy less desirable posts [1,2] within the health systems of their host countries and that they struggle to achieve career progression [3]. A number of reasons have been cited for their stalled career progression and these include poor take-up of training [4], a lack of transparency in the management of promotions [3] and 'discrimination in the quality of support given to candidates in the promotion process. . .whereby chosen candidates were pre-selected and coached whilst others were ignored or received inadequate or misleading support' [3]. This policy brief, which presents findings on the skills and expertise of Ireland's migrant nurses and offers an insight into their perception of promotions and career progression in Ireland.

miR-126 Is Downregulated in Cystic Fibrosis Airway Epithelial Cells and Regulates TOM1 Expression.

Irene K Oglesby — Wed, 10 Feb 2010 02:45:24 PST

Cystic fibrosis (CF) is one of the most common lethal genetic diseases in which the role of microRNAs has yet to be explored. Predicted to be regulated by miR-126, TOM1 (target of Myb1) has been shown to interact with Toll-interacting protein, forming a complex to regulate endosomal trafficking of ubiquitinated proteins. TOM1 has also been proposed as a negative regulator of IL-1beta and TNF-alpha-induced signaling pathways. MiR-126 is highly expressed in the lung, and we now show for the first time differential expression of miR-126 in CF versus non-CF airway epithelial cells both in vitro and in vivo. MiR-126 downregulation in CF bronchial epithelial cells correlated with a significant upregulation of TOM1 mRNA, both in vitro and in vivo when compared with their non-CF counterparts. Introduction of synthetic pre-miR-126 inhibited luciferase activity in a reporter system containing the full length 3'-untranslated region of TOM1 and resulted in decreased TOM1 protein production in CF bronchial epithelial cells. Following stimulation with LPS or IL-1beta, overexpression of TOM1 was found to downregulate NF-kappaB luciferase activity. Conversely, TOM1 knockdown resulted in a significant increase in NF-kappaB regulated IL-8 secretion. These data show that miR-126 is differentially regulated in CF versus non-CF airway epithelial cells and that TOM1 is a miR-126 target that may have an important role in regulating innate immune responses in the CF lung. To our knowledge, this study is the first to report of a role for TOM1 in the TLR2/4 signaling pathways and the first to describe microRNA involvement in CF.

Global Health Initiatives and Human Resources for HIV/AIDS Services in Malawi, Uganda and Zambia

Global HIV/AIDS Initiatives Network — Tue, 09 Feb 2010 06:36:55 PST

In most sub-Saharan African countries, a region where just 3% of the world's health workforce treat and care for 25% of the global disease burden, significant investment in Human Resources for HIV/ AIDS services (HR) is required. This briefing paper summarises the effect that scale-up of funds from three GHIs - the President's Emergency Plan for AIDS Relief (PEPFAR), the Global Fund to fight AIDS, TB and Malaria, and the World Bank Multi-country AIDS Program (MAP) - has had on HR in 3 countries: Malawi, Uganda and Zambia. Drawing on primary data from country studies conducted by researchers from the Global HIV/AIDS Initiatives Network (GHIN), this briefing paper focuses on a set of interrelated HR components: numbers of health workers, workload, training, and incentives and motivation.

What predicts depression in cardiac patients: Sociodemographic factors, disease severity or theoretical vulnerabilities?

Frank Doyle — Tue, 09 Feb 2010 04:18:22 PST

Depression is associated with increased cardiovascular risk in patients with acute coronary syndrome (ACS), but some argue that elevated depression is actually a marker of cardiovascular disease severity. Therefore, disease indices should be better predictors of depression than established theoretical causes of depression (interpersonal life events, reinforcing events, cognitive distortions, type D personality). However, little theory-based research has been conducted in this area. In a cross-sectional design, hospitalised ACS patients (n=336) completed questionnaires assessing depressive symptoms and vulnerabilities. Nested logistic regression assessed the relative contribution of demographic or vulnerability factors, or disease indices or vulnerabilities to depression. In multivariate analysis, all vulnerabilities were independent significant predictors of depression. Demographic variables accounted for <1% of the variance of depression status, with vulnerabilities accounting for significantly more (pseudo R2=.16, χ2(change)=150.9, df=4, p<0.001). Disease indices accounted for 7% of the variance in depressive status (pseudo R2=.07, χ2=137.9, p<0.001). However, adding the vulnerabilities increased the overall variance explained to 22% (pseudo R2=.22, χ2=58.6, df=4, p<0.001). Theoretical vulnerabilities predicted depression status better than did either demographic or disease indices. The presence of these proximal causes of depression suggests that depression in ACS patients is not simply a result of cardiovascular disease severity.

Toll-like receptors as therapeutic targets in cystic fibrosis.

Catherine M Greene — Tue, 09 Feb 2010 02:42:22 PST

Background: Toll-like receptors (TLRs) are pattern recognition receptors that act as a first-line of defence in the innate immune response by recognising and responding to conserved molecular patterns in microbial factors and endogenous danger signals. Cystic fibrosis (CF)-affected airways represent a milieu potentially rich in TLR agonists and the chronic inflammatory phenotype evident in CF airway epithelial cells is probably due in large part to activation of TLRs. Objective/methods: To examine the prospects of developing novel therapies for CF by targeting TLRs. We outline the expression and function of TLRs and explore the therapeutic potential of naturally-occurring and synthetic TLR inhibitors for CF. Results/conclusion: Modulation of TLRs has therapeutic potential for the inflammatory lung manifestations of CF.

Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival.

Isabella Bray — Mon, 08 Feb 2010 09:15:56 PST

MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have analyzed a set of neuroblastoma (n = 145) that is broadly representative of the genetic subtypes of this disease for miRNA expression (430 loci by stem-loop RT qPCR) and for DNA copy number alterations (array CGH) to assess miRNA involvement in disease pathogenesis. The tumors were stratified and then randomly split into a training set (n = 96) and a validation set (n = 49) for data analysis. Thirty-seven miRNAs were significantly over- or under-expressed in MYCN amplified tumors relative to MYCN single copy tumors, indicating a potential role for the MYCN transcription factor in either the direct or indirect dysregulation of these loci. In addition, we also determined that there was a highly significant correlation between miRNA expression levels and DNA copy number, indicating a role for large-scale genomic imbalances in the dysregulation of miRNA expression. In order to directly assess whether miRNA expression was predictive of clinical outcome, we used the Random Forest classifier to identify miRNAs that were most significantly associated with poor overall patient survival and developed a 15 miRNA signature that was predictive of overall survival with 72.7% sensitivity and 86.5% specificity in the validation set of tumors. We conclude that there is widespread dysregulation of miRNA expression in neuroblastoma tumors caused by both over-expression of the MYCN transcription factor and by large-scale chromosomal imbalances. MiRNA expression patterns are also predicative of clinical outcome, highlighting the potential for miRNA mediated diagnostics and therapeutics.

Global MYCN transcription factor binding analysis in neuroblastoma reveals association with distinct E-box motifs and regions of DNA hypermethylation.

Derek M Murphy — Mon, 08 Feb 2010 09:03:14 PST

BACKGROUND: Neuroblastoma, a cancer derived from precursor cells of the sympathetic nervous system, is a major cause of childhood cancer related deaths. The single most important prognostic indicator of poor clinical outcome in this disease is genomic amplification of MYCN, a member of a family of oncogenic transcription factors. METHODOLOGY: We applied MYCN chromatin immunoprecipitation to microarrays (ChIP-chip) using MYCN amplified/non-amplified cell lines as well as a conditional knockdown cell line to determine the distribution of MYCN binding sites within all annotated promoter regions. CONCLUSION: Assessment of E-box usage within consistently positive MYCN binding sites revealed a predominance for the CATGTG motif (p<0.0016), with significant enrichment of additional motifs CATTTG, CATCTG, CAACTG in the MYCN amplified state. For cell lines over-expressing MYCN, gene ontology analysis revealed enrichment for the binding of MYCN at promoter regions of numerous molecular functional groups including DNA helicases and mRNA transcriptional regulation. In order to evaluate MYCN binding with respect to other genomic features, we determined the methylation status of all annotated CpG islands and promoter sequences using methylated DNA immunoprecipitation (MeDIP). The integration of MYCN ChIP-chip and MeDIP data revealed a highly significant positive correlation between MYCN binding and DNA hypermethylation. This association was also detected in regions of hemizygous loss, indicating that the observed association occurs on the same homologue. In summary, these findings suggest that MYCN binding occurs more commonly at CATGTG as opposed to the classic CACGTG E-box motif, and that disease associated over expression of MYCN leads to aberrant binding to additional weaker affinity E-box motifs in neuroblastoma. The co-localization of MYCN binding and DNA hypermethylation further supports the dual role of MYCN, namely that of a classical transcription factor affecting the activity of individual genes, and that of a mediator of global chromatin structure.

A Profile of Migrant Nurses in Ireland. Nurse Migration Project Policy Brief 4

Niamh Humphries — Wed, 03 Feb 2010 08:28:31 PST

Migrant nurses, mainly from outside of the EU, are now an essential component of the Irish nursing workforce. This is the result of almost a decade of active overseas nurse recruitment from countries such as India and the Philippines. Between 2000 and 2008, non-EU migrant nurses accounted for 40% of nurses newly registered with the Irish Nursing Board [2] (see Fig. 1). According to the INO, "It is a reality, not readily acknowledged by Irish health employers, that this country would now be forced to close literally thousands of beds"' [3] without the presence of migrant nurses in the health system. Despite this reliance, there is little information available about Ireland's migrant nurse workforce. Some quite basic questions remain unanswered including: How many migrant nurses currently work in Ireland? In what fields of nursing and at what grades do they work? How many are women and how many men? What ages are they? What skills and experience did they bring to Ireland and are these being well utilised? Do they have children, either in Ireland or in their home country? Are they satisfied working and living in Ireland? And - of crucial importance - do they intend to stay here? The RCSI nurse migration project is beginning to fill these information gaps, through qualitative and quantitative surveys of migrant nurses in Ireland. This policy brief is the third on emerging project findings.

Retaining Migrant Nurses in Ireland II. Nurse Migration Project Policy Brief 3

Niamh Humphries — Wed, 03 Feb 2010 08:01:17 PST

Active overseas recruitment efforts have attracted large numbers of migrant nurses into the Irish health system [1]. However, it will be Ireland's ability to retain these nurses that will determine the long-term effectiveness of this workforce strategy. This is a key consideration both for individual employers and at national policy level [2], given the extent of Ireland's reliance upon migrant nurses [1]. There is recognition internationally that poor support structures in the host country may encourage migrant nurses to seek employment elsewhere [2]. The challenge to retain these nurses takes place, as their recruitment did, in the context of intense global competition for nurses, which Kingma has called 'the international war for skills' [3]. This policy brief , which presents findings on migrant nurse retention in Ireland, cautions against the assumption that migrant nurses are all 'here to stay'. The findings point to the need to engage with them to better understand the dynamics of their migration and to identify the factors that might determine whether they stay or leave Ireland.

SLAN 2007: Survey of Lifestyle, Attitudes and Nutrition in Ireland. Alcohol use in Ireland: A profile of drinking patterns and alcohol-related harm from SLAN 2007.

Karen Morgan — Wed, 02 Dec 2009 09:16:17 PST

The SL�N 2007 survey contained a series of questions relating to alcohol use. These included questions about frequency (how often) an quantity (how much) of alcohol consumed, as well as questions about alcohol-related harm. Quantity of alcohol consumed was assessed by asking respondents how many standard drinks were taken, a 'standard' drink being defined as a half pint or a glass of beer, lager or cider; a single measure of spirits; a single glass of wine, sherry or port; or a bottle of alcopop (long neck). This report forms part of a series of reports which seek to contextualise the SL�N 2007 findings (see p. iv for full list of SL�N 2007 reports).

SLAN 2007: Survey of Lifestyle, Attitudes and Nutrition in Ireland. Injuries in Ireland: findings from national population surveys.

Michal Molcho — Wed, 02 Dec 2009 08:54:59 PST

This report presents the main findings on self-reported medically attended injuries in Irish adults from the 2007 Survey of Lifestyle, Attitudes and Nutrition (SL�N 2007) in Ireland, commissioned by the Department of Health and Children. The report is part of a series presenting in-depth findings from the SL�N 2007 Main Report (Morgan et al, 2008). The SL�N 2007 survey involved face-to-face interviews in the homes of 10,364 randomly selected adults, aged 18 years and over, with sub-studies on body size and a detailed physical examination. There was a 62% response rate to the survey. The sample is representative of the general population in Ireland when compared with Census 2006 figures and was further weighted, for the purpose of analysis, to match population characteristics. SL�N 2007 is the largest national health survey among the Irish adult population to date and also the largest to study the extent of injuries among the adult population. As part of the main survey, respondents were asked a series of questions on injuries requiring medical attendance (i.e. injuries resulting in medical treatment), on the circumstances surrounding the occurrence of injury events, the mechanism that caused the injury and the severity of the injury. This report presents the findings from SL�N 2007 on injuries in Ireland and considers the influence of such key socio-demographic variables as age, gender, social class, education, income, residential location, employment status and marital status.