Molecular evolution of proadrenomedullin N-terminal 20 peptide (PAMP):evidence for gene co-option

Posttranslational processing of proadrenomedullin generates two biologically active peptides, adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP). Sequence comparison of homologous proadrenomedullin genes in vertebrate evolution shows a high degree of stability in the reading frame for AM, whereas PAMP sequence changes rapidly. Here we investigate the functional significance of PAMP phylogenetic variation studying two of PAMP's better characterized physiological activities, angiogenic potential and antimicrobial capability, with synthetic peptides carrying the predicted sequence for human, mouse, chicken, and fish PAMP. All tested peptides induced angiogenesis when compared with untreated controls, but chicken and fish PAMP, which lack terminal amidation, were apparently less angiogenic than their human and mouse homologs. Confirming the role of amidation in angiogenesis, Gly-extended and free acid variants of human PAMP produced responses similar to the natural nonamidated peptides. In contrast, antimicrobial activity was restricted to human PAMP, indicating that this function may have been acquired at a late time during the evolution of PAMP. Interestingly, free acid human PAMP retained antimicrobial activity whereas the Gly-extended form did not. This fact may reflect the need for maintaining a tightly defined structural conformation in the pore-forming mechanism proposed for these antimicrobial agents. The evolution of PAMP provides an example of an angiogenic peptide that developed antimicrobial capabilities without losing its original function.

Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial

Background: Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. Methods: In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. Findings: Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80-3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27-1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22-1·03; p=0·05), but did not differ by drug group (0·96, 0·46-2·02; p=0·91). Interpretation: Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought.

Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study:preeclampsia

Objective: The purpose of this study was to examine associations of fasting C-peptide, body mass index (BMI), and maternal glucose with the risk of preeclampsia in a multicenter multinational study. Study Design: We conducted a secondary analysis of a blinded observational cohort study. Subjects underwent a 75-g oral glucose tolerance test at 24-32 weeks' gestation. Associations of preeclampsia with fasting C-peptide, BMI, and maternal glucose were assessed with the use of multiple logistic regression analyses and adjustment for potential confounders. Results: Of 21,364 women who were included in the analyses, 5.2% had preeclampsia. Adjusted odds ratios for preeclampsia for 1 SD higher fasting C-peptide (0.87 ug/L), BMI (5.1 kg/m), and fasting (6.9 mg/dL), 1-hour (30.9 mg/dL), and 2-hour plasma glucose (23.5 mg/dL) were 1.28 (95% confidence interval [CI], 1.20-1.36), 1.60 (95% CI, 1.60-1.71), 1.08 (95% CI, 1.00-1.16), 1.19 (95% CI, 1.11-1.28), and 1.21 (95% CI,1.13-1.30), respectively. Conclusion: Results indicate strong, independent associations of fasting C-peptide and BMI with preeclampsia. Maternal glucose levels (below diabetes mellitus) had weaker associations with preeclampsia, particularly after adjustment for fasting C-peptide and BMI. © 2010 Mosby, Inc. All rights reserved.

Tackling Invasive Alien Species in Europe: the Top 20 Issues

Globally, Invasive Alien Species (IAS) are considered to be one of the major threats to native biodiversity, with the World Conservation Union (IUCN) citing their impacts as ?immense, insidious, and usually irreversible?. It is estimated that 11% of the c. 12,000 alien species in Europe are invasive, causing environmental, economic and social damage; and it is reasonable to expect that the rate of biological invasions into Europe will increase in the coming years. In order to assess the current position regarding IAS in Europe and to determine the issues that were deemed to be most important or critical regarding these damaging species, the international Freshwater Invasives - Networking for Strategy (FINS) conference was convened in Ireland in April 2013. Delegates from throughout Europe and invited speakers from around the world were brought together for the conference. These comprised academics, applied scientists, policy makers, politicians, practitioners and representative stakeholder groups. A horizon scanning and issue prioritization approach was used by in excess of 100 expert delegates in a workshop setting to elucidate the Top 20 IAS issues in Europe. These issues do not focus solely on freshwater habitats and taxa but relate also to marine and terrestrial situations. The Top 20 issues that resulted represent a tool for IAS management and should also be used to support policy makers as they prepare European IAS legislation.

Navigating Risk: Understanding the Impact of the Conflict on Children and Young People in Northern Ireland:Special Issue: Northern Ireland: 20 Years After the Cease-Fires

Twenty years on from the 1994 cease-fires, Northern Ireland is a markedly safer place for children and young people to grow up. However, for a significant number, growing up in post-conflict Northern Ireland has brought with it continued risks and high levels of marginalization. Many young people growing up on the sharp edge of the transition have continued to experience troubling levels of poverty, lower educational attainment, poor standards of childhood health, and sustained exposure to risk-laden environments. Reflecting on interdisciplinary research carried out since the start of the “transition” to peace, this article emphasizes the impact that embedded structural inequalities continue to have on the social, physical, mental, and emotional well-being of many children and young people. In shining a light on the enduring legacy of the conflict, this article moves to argue that greater attention needs to be given to the ongoing socioeconomic factors that result in limited lifetime opportunities, marginalization, and sustained poverty for many young people growing up in “peacetime” Northern Ireland.

Northern Ireland: 20 Years After the Cease-Fires

In the closing months of 1994, the principal paramilitary organizations in Northern Ireland declared that their campaigns of violence were at an end. The cease-fires called by republican and loyalist groupings represented the most significant heralds of a complex process of conflict transformation that continues to unfold even twenty years on. In this introduction, we set out to map the key developments that have shaped the tortuous narrative of the Northern Irish 'peace process', thereby providing the historical backdrop for the articles that follow. While remarkable progress has been made over the two decades since the paramilitary cease-fires, the political context and future of the region remain rather more fraught than is often assumed abroad. It is perhaps best, then, to speak of the six counties in terms not of resolution but rather of ambiguity. Twenty years on from the optimism that greeted the paramilitary cease-fires, Northern Ireland retains the essential 'inbetweenness' of a political space that has moved from a 'long war' through a 'long peace' and into a profoundly undecided future. © 2014 Taylor & Francis Group, LLC.

Service User Involvement in Assessments:

Increasingly providers of mental health nurse education are required to demonstrate user involvement in all aspects of these programmes including student selection, programme design and student assessment. There has been limited analysis of how nursing students perceive user involvement in nurse education programmes. The aim of this study has been to explore mental health nursing student’s perceptions of involving users in all aspects of pre-registration mental health nursing programme. Researchers completed a number of focus group interviews with 12 ex-mental health nursing students who had been recruited by purposeful sampling. Each focus group interview was recorded and analysed using a series of data reduction, data display and verification
methods. The study confirms many of the findings reported in earlier user participation in education studies. Three main themes related to user involvement have been identified: the protection of users, enhanced student learning and the added value benefits associated with user involvement.