Homocysteine from endothelial cells promotes LDL nitration and scavenger receptor uptake

We recently reported that methionine-loaded human umbilical vein endothelial cells (HUVECs) exported homocysteine (Hcy) and were associated with hydroxyl radical generation and oxidation of lipids in LDL. Herein we have analysed the Hcy-induced posttranslational modifications (PTMs) of LDL protein. PTMs have been characterised using electrophoretic mobility shift, protein carbonyl ELISA, HPLC with electrochemical detection and Western blotting of 3-nitrotyrosine, and LDL uptake by scavenger receptors on monocyte/macrophages. We have also analysed PTMs in LDL isolated from rheumatoid (RA) and osteo-(OA) arthritis patients with cardiovascular disease (CVD). While reagent Hcy (<50 μM) promoted copper-catalysed LDL protein oxidation, Hcy released from methionine-loaded HUVECs promoted LDL protein nitration. In addition, LDL nitration was associated with enhanced monocyte/macrophage uptake when compared with LDL oxidation. LDL protein nitration and uptake by monocytes, but not carbonyl formation, was elevated in both RA and OA patients with CVD compared with disease-matched patients that had no evidence of CVD. Moreover, a direct correlation between plasma total Hcy (tHcy) and LDL uptake was observed. The present studies suggest that elevated plasma tHcy may promote LDL nitration and increased scavenger receptor uptake, providing a molecular mechanism that may contribute to the clinical link between CVD and elevated plasma tHcy. © 2005 Elsevier Inc. All rights reserved.

Deoxycytidine glyoxal:Lesion induction and evidence of repair following vitamin C supplementation in vivo

Oxidative DNA damage is postulated to be involved in carcinogenesis, and as a consequence, dietary antioxidants have received much interest. A recent report indicates that vitamin C facilitates the decomposition of hydroperoxides in vitro, generating reactive aldehydes. We present evidence for the in vivo generation of glyoxal, an established product of lipid peroxidation, glucose/ascorbate autoxidation, or free radical attack of deoxyribose, following supplementation of volunteers with 400 mg/d vitamin C. Utilizing a monoclonal antibody to a deoxycytidine-glyoxal adduct (gdC), we measured DNA lesion levels in peripheral blood mononuclear cells. Supplementation resulted in significant (p = .001) increases in gdC levels at weeks 11, 16, and 21, with corresponding increases in plasma malondialdehyde levels and, coupled with previous findings, is strongly suggestive of a pro-oxidative effect. However, continued supplementation revealed a highly significant (p = .0001) reduction in gdC levels. Simultaneous analysis of cyclobutane thymine dimers revealed no increase upon supplementation but, as with gdC, levels decreased. Although no single mechanism is identified, our data demonstrate a pro-oxidant event in the generation of reactive aldehydes following vitamin C supplementation in vivo. These results are also consistent with our hypothesis for a role of vitamin C in an adaptive/repair response and indicate that nucleotide excision repair specifically may be affected. © 2003 Elsevier Science Inc.

Media constructions of sleep and sleep disorders:A study of UK national newspapers

Medicalisation, healthicisation and 'personal' strategies have been identified as the main factors contributing to the socially mediated experience of sleep and sleep disorders in modern societies. Medicalisation and healthicisation are publicly available discourses. But the degree to which apparently 'personal' strategies for managing sleep are presented in popular media has been underestimated. This study of the coverage of 5 UK newspapers shows that both medicalised and healthicised discourses are concentrated in the 'serious' press. The tabloid press is more likely to constitute sleep as a private realm and tabloid readers are therefore relatively less exposed to officially sanctioned forms of knowledge about sleep. Analysis of Daily Mail coverage shows, though, that women's 'personal' strategies for managing sleep are far from being private solutions. The Mail presents this topic as a component of its social construction of a 'Middle England' lifestyle, giving these apparently 'personal' solutions a political resonance. © 2007 Elsevier Ltd. All rights reserved.

Identification of oxidized phospholipids by electrospray ionization mass spectrometry and LC-MS using a QQLIT instrument

Phospholipids are complex and varied biomolecules that are susceptible to lipid peroxidation after attack by free radicals or electrophilic oxidants and can yield a large number of different oxidation products. There are many available methods for detecting phospholipid oxidation products, but also various limitations and problems. Electrospray ionization mass spectrometry allows the simultaneous but specific analysis of multiple species with good sensitivity and has a further advantage that it can be coupled to liquid chromatography for separation of oxidation products. Here, we explain the principles of oxidized phospholipid analysis by electrospray mass spectrometry and describe fragmentation routines for surveying the structural properties of the analytes, in particular precursor ion and neutral loss scanning. These allow targeted detection of phospholipid headgroups and identification of phospholipids containing hydroperoxides and chlorine, as well as the detection of some individual oxidation products by their specific fragmentation patterns. We describe instrument protocols for carrying out these survey routines on a QTrap5500 mass spectrometer and also for interfacing with reverse-phase liquid chromatography. The article highlights critical aspects of the analysis as well as some limitations of the methodology.

Brain and mind in the 'long' eighteenth century

How should the 'long' eighteenth century be defined? January 1, 1700 and December 31, 1799 are quite arbitrary dates. Why should they be chosen to segment our history rather than more significant periods of time, periods which have a coherent content, or are marked, perhaps, by the working out of a theme? Students of English literature sometimes take the long eighteenth century to extend from John Milton (Paradise Lost, 1667) to the passing of the first generation of Romantics (Keats (d. 1821), Shelley (d. 1822), Byron (d. 1824), Coleridge (d. 1834)). Students of British political history often take it to start with the accession of Charles II (the Restoration) in 1660 or, alternatively, the so-called Glorious Revolution of 1688 and to end with the great Reform Act of 1832. Others might choose different book ends. In the history of science and philosophy the terminus a quo is sometimes taken as the publication of Descartes' scientific philosophy or, in more Anglophone zones, the 1687 publication of Newton's Principia with its vision of a 'clockwork universe'. 'Nature and Nature's laws' as Alexander Pope enthused, 'lay hid in Night: God said, Let Newton be! and all was light!'.

Eastern Christianity and the Cold War, 1945-91

Despite widespread persecution, Orthodox churches not only survived the Cold War period but levels of religiosity in Orthodox countries remained significant. This book examines the often surprising relations between Orthodox churches and political regimes. It provides a comprehensive overview of the dynamics between Eastern Christianity and politics from the end of the Second World War to the fall of communism, covering 40 Orthodox churches including diasporic churches in Africa, Asia, America and Australia. Based on research from recently-opened archives and publications in a wide range of European languages, it analyses church-state relations on both sides of the Iron Curtain. It discusses the following key themes: the relationship between Orthodox churches and political power; religious resistance to communism; the political control of churches; religion and propaganda; monasticism and theological publications; religious diplomacy within the Orthodox commonwealth; and religious contacts between East and West.

Like grandfather, like grandson: Erasmus and Charles Darwin on evolution

Last year (2009) marked the bicentenary of Charles Darwin's birth and the sesquicentenary of The Origin of Species. This article examines the influence of Erasmus Darwin on Charles's evolutionary thought and shows how, in many ways, Erasmus anticipated his much better-known grandson. It discusses the similarity in the mindsets of the two Darwins, asks how far the younger Darwin was exposed to the elder's evolutionary thought, examines the similarities and differences in their theories of evolution, and ends by showing the surprising similarity between their theories of inheritance. Erasmus's influence on Charles is greater than customarily acknowledged, and now is an opportune time to bring the grandfather out from behind the glare of his stellar grandson.

Intellectual alienation in a fragmented society and universe, as illustrated in the work of Wolfgang Koeppen (1906- )

This text is concerned with the intellectual and social alienation experienced by a twentieth century German writer (1906 - ).·the alienation begins in the context of German society, but this context is later globalised. The thesis first discusses the social and· intellectual origins and the salient features of this alienated stance, before proceeding to a detailed analysis of its recurring symptoms and later intensification in each of the author's main works, chronologically surveyed, supported by reference to minor writings. From the novels of the thirties' showing the burgher-artist conflict, and its symbolic dichotomies, the renunciation of traditional German values, and the ambiguous confrontation with new disruptive socio-political forces, we move to the post-war trilogy (1951-54), with its roots in the German social and political experience of the thirties' onwards. The latter, however, is merely a background for the presentation of a much more comprehensive view of the human condition:- a pessimistic vision of the repetitiveness and incorrigibility of this condition, the possibility of the apocalypse, the bankruptcy and ineffectiveness of European religion and culture, the 'absurd' meaninglessness of history, the intellectual artist's position and role(s) in mass-culture and an abstract, technologised mass-society, the central theme of fragmentation - of the structure of reality, society and personality, the artist's relation to this fragmentation, intensified in the twentieth,century. Style and language are consonant with this world-picture. Many of these features recur in the travel-books (1958-61); diachronic as well as synchronic approaches characterise the presentation of various modes of contemporary society in America, Russia, France and other European countries. Important features of intellectual alienation are:- the changelessness of historical motifs (e.g. tyranny, aggression), the conventions of burgher society, both old and new forms, the qualitative depreciation and standardisation of living, industrialisation and technology in complex, vulnerable and concemtrated urban societies, ambiguities of fragmented pluralism. Reference is made .to other travel-writers.

Physiological effects of oxidized phospholipids and their cellular signaling mechanisms in inflammation

Oxidized phospholipids, such as the products of the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by nonenzymatic radical attack, are known to be formed in a number of inflammatory diseases. Interest in the bioactivity and signaling functions of these compounds has increased enormously, with many studies using cultured immortalized and primary cells, tissues, and animals to understand their roles in disease pathology. Initially, oxidized phospholipids were viewed largely as culprits, in line with observations that they have proinflammatory effects, enhancing inflammatory cytokine production, cell adhesion and migration, proliferation, apoptosis, and necrosis, especially in vascular endothelial cells, macrophages, and smooth muscle cells. However, evidence has emerged that these compounds also have protective effects in some situations and cell types; a notable example is their ability to interfere with signaling by certain Toll-like receptors (TLRs) induced by microbial products that normally leads to inflammation. They also have protective effects via the stimulation of small GTPases and induce up-regulation of antioxidant enzymes and cytoskeletal rearrangements that improve endothelial barrier function. Oxidized phospholipids interact with several cellular receptors, including scavenger receptors, platelet-activating factor receptors, peroxisome proliferator-activated receptors, and TLRs. The various and sometimes contradictory effects that have been observed for oxidized phospholipids depend on their concentration, their specific structure, and the cell type investigated. Nevertheless, the underlying molecular mechanisms by which oxidized phospholipids exert their effects in various pathologies are similar. Although our understanding of the actions and mechanisms of these mediators has advanced substantially, many questions do remain about their precise interactions with components of cell signaling pathways.

Analysis of radicals and radical reaction products in cell signalling and biomolecular damage:the long hard road to gold-standard measures

The field of free radical biology and medicine continues to move at a tremendous pace, with a constant flow of ground-breaking discoveries. The following collection of papers in this issue of Biochemical Society Transactions highlights several key areas of topical interest, including the crucial role of validated measurements of radicals and reactive oxygen species in underpinning nearly all research in the field, the important advances being made as a result of the overlap of free radical research with the reinvigorated field of lipidomics (driven in part by innovations in MS-based analysis), the acceleration of new insights into the role of oxidative protein modifications (particularly to cysteine residues) in modulating cell signalling, and the effects of free radicals on the functions of mitochondria, extracellular matrix and the immune system. In the present article, we provide a brief overview of these research areas, but, throughout this discussion, it must be remembered that it is the availability of reliable analytical methodologies that will be a key factor in facilitating continuing developments in this exciting research area.

What do we know about the experience of age related macular degeneration? A systematic review and meta-synthesis of qualitative research

Age Related Macular Degeneration (AMD) is the leading cause of registerable blindness with a high medical and societal cost burden. Much of the research examining experiences of living with AMD has been conducted independently with small sample sizes and has failed to impact on practice. Meta-synthesis of qualitative research can improve the understanding of the experience of living with AMD by drawing together findings of qualitative studies. This article presents a systematic review and meta-synthesis of qualitative studies investigating the experience of AMD (literature searched up to April 2012; published studies identified range from 1996 to 2009). The review highlights themes relating to: functional limitations, adaptation and independence; feelings about the future with vision impairment; interaction with the health service; social engagement; disclosure; and the emotional impacts of living with AMD. Attention to the experience of living with AMD can help us to better understand the needs of patients. This meta-synthesis aimed to bring together the findings of qualitative research studies and highlights important areas for consideration when caring for patients with AMD. Our findings suggest that a holistic approach to service provision and support for AMD is needed which takes into account individuals' needs and experiences when coping with and adjusting to living with AMD. This support should aim to reduce stigma, increase social engagement, and develop the psychological resources of patients with AMD.

Representing religion in the European Union:a typology of actors

For the first time in the history of the acquis communautaire, the Lisbon Treaty institutionalises an ‘open, transparent and regular dialogue’ between European institutions and ‘churches, religions and communities of conviction’. Drawing on a comparative analysis of 120 religious and convictional actors which have been in contact with European institutions from 1957 until today, this article proposes four types of relations between religious/convictional representations and European institutions, namely, private–public, experimental, proactive and institutionalised. It argues that the Lisbon institutionalisation of religious dialogue enhances the public visibility of the European Commission and, most significantly, of the construction of the European political system.

Transatlantic representations of Religion

Introduction to special issue: Transatlantic representations of religion