Title: An experimental and numerical comparison of the rupture locations of an abdominal aortic aneurysm.

Authors: Doyle, Barry J; Corbett, Timothy J; Callanan, Anthony; Walsh, Michael T; Vorp, David A; McGloughlin, Timothy M

Abstract: PURPOSE: To identify the rupture locations of idealized physical models of abdominal aortic aneurysm (AAA) using an in-vitro setup and to compare the findings to those predicted numerically. METHODS: Five idealized AAAs were manufactured using Sylgard 184 silicone rubber, which had been mechanically characterized from tensile tests, tear tests, and finite element analysis. The models were then inflated to the point of rupture and recorded using a high-speed camera. Numerical modeling attempted to confirm these rupture locations. Regional variations in wall thickness of the silicone models was also quantified and applied to numerical models. RESULTS: Four of the 5 models tested ruptured at inflection points in the proximal and distal regions of the aneurysm sac and not at regions of maximum diameter. These findings agree with high stress regions computed numerically. Wall stress appears to be independent of wall thickness, with high stress occurring at regions of inflection regardless of wall thickness variations. CONCLUSION: According to these experimental and numerical findings, AAAs experience higher stresses at regions of inflection compared to regions of maximum diameter. Ruptures of the idealized silicone models occurred predominantly at the inflection points, as numerically predicted. Regions of inflection can be easily identified from basic 3-dimensional reconstruction; as ruptures appear to occur at inflection points, these findings may provide a useful insight into the clinical significance of inflection regions. This approach will be applied to patient-specific models in a future study.

Title: Simulation of the contractile response of cells on an array of micro-posts.

Authors: McGarry, J P; Fu, J; Yang, M T; Chen, C S; McMeeking, R M; Evans, A G; Deshpande, V S

Abstract: A bio-chemo-mechanical model has been used to predict the contractile responses of smooth cells on a bed of micro-posts. Predictions obtained for smooth muscle cells reveal that, by converging onto a single set of parameters, the model captures all of the following responses in a self-consistent manner: (i) the scaling of the force exerted by the cells with the number of posts; (ii) actin distributions within the cells, including the rings of actin around the micro-posts; (iii) the curvature of the cell boundaries between the posts; and (iv) the higher post forces towards the cell periphery. Similar correspondences between predictions and measurements have been demonstrated for fibroblasts and mesenchymal stem cells once the maximum stress exerted by the stress fibre bundles has been recalibrated. Consistent with measurements, the model predicts that the forces exerted by the cells will increase with both increasing post stiffness and cell area (or equivalently, post spacing). In conjunction with previous assessments, these findings suggest that this framework represents an important step towards a complete model for the coupled bio-chemo-mechanical responses of cells.

Title: Five year prognosis in patients with angina identified in primary care: incident cohort study.

Authors: Buckley, Brian S; Simpson, Colin R; McLernon, David J; Murphy, Andrew W; Hannaford, Philip C

Abstract: OBJECTIVE: To ascertain the risk of acute myocardial infarction, invasive cardiac procedures, and mortality among patients with newly diagnosed angina over five years. DESIGN: Incident cohort study of patients with primary care data linked to secondary care and mortality data. SETTING: 40 primary care practices in Scotland. PARTICIPANTS: 1785 patients with a diagnosis of angina as their first manifestation of ischaemic heart disease, 1 January 1998 to 31 December 2001. MAIN OUTCOME MEASURES: Adjusted hazard ratios for acute myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, death from ischaemic heart disease, and all cause mortality, adjusted for demographics, lifestyle risk factors, and comorbidity at cohort entry. RESULTS: Mean age was 62.3 (SD 11.3). Male sex was associated with an increased risk of acute myocardial infarction (hazard ratio 2.01, 95% confidence interval 1.35 to 2.97), death from ischaemic heart disease (2.80, 1.73 to 4.53), and all cause mortality (1.82, 1.33 to 2.49). Increasing age was associated with acute myocardial infarction (1.04, 1.02 to 1.06, per year of age increase), death from ischaemic heart disease (1.09, 1.06 to 1.11, per year of age increase), and all cause mortality (1.09, 1.07 to 1.11, per year of age increase). Smoking was associated with subsequent acute myocardial infarction (1.94, 1.31 to 2.89), death from ischaemic heart disease (2.12, 1.32 to 3.39), and all cause mortality (2.11, 1.52 to 2.95). Obesity was associated with death from ischaemic heart disease (2.01, 1.17 to 3.45) and all cause mortality (2.20, 1.52 to 3.19). Previous stroke was associated with all cause mortality (1.78, 1.13 to 2.80) and chronic kidney disease with death from ischaemic heart disease (5.72, 1.74 to 18.79). Men were more likely than women to have coronary artery bypass grafting or percutaneous transluminal coronary angioplasty after a diagnosis of angina; older people were less likely to receive percutaneous transluminal coronary angioplasty. Acute myocardial infarction after a diagnosis of angina was associated with an increased risk of death from ischaemic heart disease and all cause mortality (8.84 (5.31 to 14.71) and 4.23 (2.78 to 6.43), respectively). Neither of the invasive cardiac procedures significantly reduced the subsequent risk of all cause mortality. CONCLUSIONS: In this sample of people with incident angina from primary care, there were sex differences in survival and age and sex differences in the provision of revascularisation after a diagnosis. Acute myocardial infarction after a diagnosis of angina was strongly predictive of mortality. To minimise adverse outcomes, optimal preventive treatments should be used in patients with angina.

Title: Evaluation of a novel real-time PCR test based on the ssrA gene for the identification of group B streptococci in vaginal swabs.

Authors: Wernecke, Martina; Mullen, Ciara; Sharma, Vimla; Morrison, John; Barry, Thomas; Maher, Majella; Smith, Terry

Abstract: BACKGROUND: Despite the implementation of prevention guidelines, early-onset group B streptococci (GBS) disease remains a cause of neonatal morbidity and mortality worldwide. Strategies to identify women who are at risk of transmitting GBS to their infant and the administration of intrapartum antibiotics have greatly reduced the incidence of neonatal GBS disease. However, there is a requirement for a rapid diagnostic test for GBS that can be carried out in a labour ward setting especially for women whose GBS colonisation status is unknown at the time of delivery. We report the design and evaluation of a real-time PCR test (RiboSEQ GBS test) for the identification of GBS in vaginal swabs from pregnant women. METHODS: The qualitative real-time PCR RiboSEQ GBS test was designed based on the bacterial ssrA gene and incorporates a competitive internal standard control. The analytical sensitivity of the test was established using crude lysate extracted from serial dilutions of overnight GBS culture using the IDI Lysis kit. Specificity studies were performed using DNA prepared from a panel of GBS strains, related streptococci and other species found in the genital tract environment. The RiboSEQ GBS test was evaluated on 159 vaginal swabs from pregnant women and compared with the GeneOhm StrepB Assay and culture for the identification of GBS. RESULTS: The RiboSEQ GBS test is specific and has an analytical sensitivity of 1-10 cell equivalents. The RiboSEQ GBS test was 96.4% sensitive and 95.8% specific compared to "gold standard" culture for the identification of GBS in vaginal swabs from pregnant women. In this study, the RiboSEQ GBS test performed slightly better than the commercial BD GeneOhm StrepB Assay which gave a sensitivity of 94.6% and a specificity of 89.6% compared to culture. CONCLUSION: The RiboSEQ GBS test is a valuable method for the rapid, sensitive and specific detection of GBS in pregnant women. This study also validates the ssrA gene as a suitable and versatile target for nucleic acid-based diagnostic tests for bacterial pathogens.

Title: Monthly performance and supplementary reports 2009 / Health Service Executive

Authors: Health Service Executive (HSE)

Title: Monthly performance and supplementary reports 2008 / Health Service Executive

Authors: Health Service Executive (HSE)

Title: The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection.

Authors: Haedicke, Juliane; Brown, Craig; Naghavi, Mojgan H

Abstract: Neurons are one of the few cell types in the human body that do not support HIV type-1 (HIV-1) replication. Although the lack of key receptors is a major obstacle to infection, studies suggest that additional functions inhibit virus replication to explain the exquisite resistance of neurons to HIV-1. However, specific neuronal factors that may explain this resistance remain to be discovered. In a screen for antiviral factors using a fibroblast line chemically mutagenized and selected for resistance to retroviral infection, we recently identified induction of rat FEZ1 (fasciculation and elongation protein zeta-1), a brain-specific protein, as the cause of this resistance. When exogenously expressed in nonneuronal cell lines rat FEZ1 blocked nuclear entry of retroviral DNA. Here, we demonstrate that among human brain cells, neurons naturally express high levels of FEZ1 compared to astrocytes or microglia cells and are correspondingly less susceptible to infection with pseudotyped HIV-1 that bypasses receptor-mediated viral entry. Demonstrating that endogenous FEZ1 was functionally important in the resistance of neurons to HIV-1 infection, siRNA-mediated knockdown of endogenous FEZ1 increased the infectivity of neurons while sensitive brain cell types like microglia became more resistant upon FEZ1 overexpression. In addition, FEZ1 expression was not induced in response to IFN treatment. As such, in contrast to other widely expressed, IFN-inducible antiviral factors, FEZ1 appears to represent a unique neuron-specific determinant of cellular susceptibility to infection in a cell type that is naturally resistant to HIV-1.

Title: Ionizing radiation-dependent and independent phosphorylation of the 32-kDa subunit of replication protein A during mitosis.

Authors: Stephan, Holger; Concannon, Claire; Kremmer, Elisabeth; Carty, Michael P; Nasheuer, Heinz-Peter

Abstract: The human single-stranded DNA-binding protein, replication protein A (RPA), is regulated by the N-terminal phosphorylation of its 32-kDa subunit, RPA2. RPA2 is hyperphosphorylated in response to various DNA-damaging agents and also phosphorylated in a cell-cycle-dependent manner during S- and M-phase, primarily at two CDK consensus sites, S23 and S29. Here we generated two monoclonal phospho-specific antibodies directed against these CDK sites. These phospho-specific RPA2-(P)-S23 and RPA2-(P)-S29 antibodies recognized mitotically phosphorylated RPA2 with high specificity. In addition, the RPA2-(P)-S23 antibody recognized the S-phase-specific phosphorylation of RPA2, suggesting that during S-phase only S23 is phosphorylated, whereas during M-phase both CDK sites, S23 and S29, are phosphorylated. Immunofluorescence microscopy revealed that the mitotic phosphorylation of RPA2 starts at the onset of mitosis, and dephosphorylation occurs during late cytokinesis. In mitotic cells treated with ionizing radiation (IR), we observed a rapid hyperphosphorylation of RPA2 in addition to its mitotic phosphorylation at S23 and S29, associated with a significant change in the subcellular localization of RPA. Our data also indicate that the RPA2 hyperphosphorylation in response to IR is facilitated by the activity of both ATM and DNA-PK, and is associated with activation of the Chk2 pathway.

Title: Persistent circulating unmetabolised folic acid in a setting of liberal voluntary folic acid fortification. Implications for further mandatory fortification?

Authors: Sweeney, Mary R; Staines, Anthony; Daly, Leslie; Traynor, Aisling; Daly, Sean; Bailey, Steven W; Alverson, Patricia B; Ayling, June E; Scott, John M

Abstract: BACKGROUND: Ireland is an example of a country that has extensive voluntary fortification with folic acid. After a public consultation process, in 2006, the Food Safety Authority in Ireland FSAI 1 recommended mandatory fortification. However due to safety considerations this decision is now on hold. Before mandatory fortification goes ahead, existing levels of unmetabolised folic acid and their anticipated increase after fortification needs investigation because of the potential of folic acid to mask pernicious anaemia and possibly accelerate the growth of existing cancers. The aim of this study was to examine the levels of circulatory unmetabolised folic acid in Irish adults (both fasted and un-fasted) and new-born infants (fasted) before the proposed implementation of mandatory folic acid fortification. A secondary aim was to predict the increase in circulatory unmetabolised folic acid levels after fortification. METHODS: Study 1. Setting: Irish Blood Transfusion Service (IBTS). Whole blood samples were collected from blood donors (n=50) attending for routine blood donation sessions (representing the general population). Subjects were not fasted prior to sampling. Study 2. Setting: Coombe Women's and Infant's University Hospital, Dublin. Whole blood samples were collected by venipuncture from mothers (n=20), and from their infant's umbilical-cords (n=20) immediately after caesarean section. All women had been fasted for at least 8 hours prior to the surgery. A questionnaire on habitual and recent dietary intakes of folic acid was administered by an interviewer to all subjects. The data collection period was February to April 2006. Serum samples were analysed for plasma folate, plasma folic acid and red cell folate. RESULTS: Blood Donor Group: Circulatory unmetabolised folic acid was present in 18 out of 20 mothers (fasted) (CI: 68.3%-99.8%) comprising 1.31% of total plasma folate, 17 out of 20 babies (fasted) (CI: 62.1%-96.8%), and 49 out of 50 blood donors (unfasted) (CI: 88.0%-99.9%), comprising 2.25% of total plasma folate, CONCLUSION: While the levels of circulatory unmetabolised folic acid reported are low, it is persistently present in women immediately after caesarean section who were fasting indicating that there would be a constant/habitual exposure of existing tumours to folic acid, with the potential for accelerated growth. Mandatory fortification might exacerbate this. This has implications for those with responsibility for drafting legislating in this area.

Title: Increased sister chromatid cohesion and DNA damage response factor localization at an enzyme-induced DNA double-strand break in vertebrate cells.

Authors: Dodson, Helen; Morrison, Ciaran G

Abstract: The response to DNA damage in vertebrate cells involves successive recruitment of DNA signalling and repair factors. We used light microscopy to monitor the genetic dependencies of such localization to a single, induced DNA double strand break (DSB) in vertebrate cells. We used an inducible version of the rare-cutting I-SceI endonuclease to cut a chromosomally integrated I-SceI site beside a Tet operator array that was visualized by binding a Tet repressor-GFP fusion. Formation of gamma-H2AX foci at a single DSB was independent of ATM or Ku70. ATM-deficient cells showed normal kinetics of 53Bp1 recruitment to DSBs, but Rad51 localization was retarded. 53Bp1 and Rad51 foci formation at a single DSB was greatly reduced in H2AX-null DT40 cells. We also observed decreased inter-sister chromatid distances after DSB induction, suggesting that cohesin loading at DSBs causes elevated sister chromatid cohesion. Loss of ATM reduced DSB-induced cohesion, consistent with cohesin being an ATM target in the DSB response. These data show that the same genetic pathways control how cells respond to single DSBs and to multiple lesions induced by whole-cell DNA damage.

Title: Social Services Inspectorate practice guidelines on safeguarding and child protection in children's residential centres (revised version: December 2003)

Authors: Social Services Inspectorate (SSI)

Title: A children's residential centre in the HSE Dublin North East Area

Authors: Health Information and Quality Authority (HIQA), Social Services Inspectorate (SSI)

Title: A children's residential centre in the HSE Dublin Mid Leinster Area: follow-up inspection report

Authors: Health Information and Quality Authority (HIQA), Social Services Inspectorate (SSI)

Title: A children's residential centre in the HSE Southern Area: follow-up inspection

Authors: Health Information and Quality Authority (HIQA), Social Services Inspectorate (SSI)

Title: A children's residential centre in the HSE Dublin North Area: final report

Authors: Health Information and Quality Authority (HIQA), Social Services Inspectorate (SSI)

Title: A high support unit in the HSE West Area: follow-up report

Authors: Health Information and Quality Authority (HIQA), Social Services Inspectorate (SSI)

Title: A children's residential centre in the HSE Dublin North East Area: follow-up inspection report

Authors: Health Information and Quality Authority (HIQA), Social Services Inspectorate (SSI)

Title: A children's residential centre in the HSE Dublin North East: final report

Authors: Health Information and Quality Authority (HIQA), Social Services Inspectorate (SSI)

Title: A children's residential centre in the HSE Mid-Western Area: follow-up report

Authors: Health Information and Quality Authority (HIQA), Social Services Inspectorate (SSI)

Title: A children's residential centre in the HSE Dublin North Area: final

Authors: Health Information and Quality Authority (HIQA), Social Services Inspectorate (SSI)