Differential effects of an anti-oxidant intervention on cardiomyocyte expression of adrenomedullin and intermedin and their receptor components in chronic nitric oxide deficiency

Background: Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial oxidative stress and hypertrophic remodeling. Up-regulation of the cardiomyocyte adrenomedullin (AM) / intermedin (IMD) receptor signaling cascade is also apparent in NO-deficient cardiomyocytes: augmented expression of AM and receptor activity modifying proteins RAMP2 and RAMP3 is prevented by blood pressure normalization while that of RAMP1 and intermedin (IMD) is not, indicating that the latter is regulated by a pressure-independent mechanism. Aims: to verify the ability of an anti-oxidant intervention to normalize cardiomyocyte oxidant status and to investigate the influence of such an intervention on expression of AM, IMD and their receptor components in NO-deficient cardiomyocytes. Methods: NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 35mg/kg/day) was given to rats for 8 weeks, with/without con-current administration of antioxidants (Vitamin C (25mg/kg/day) and Tempol (25mg/kg/day)). Results: In left ventricular cardiomyocytes isolated from L-NAME treated rats, increased oxidative stress was indicated by augmented (3.6 fold) membrane protein oxidation, enhanced expression of catalytic and regulatory subunits of pro-oxidant NADPH oxidases (NOX1, NOX2) and compensatory increases in expression of anti-oxidant glutathione peroxidase and Cu/Zn superoxide dismutases (SOD1, SOD3). Vitamin C plus Tempol did not reduce systolic blood pressure but normalized augmented plasma levels of IMD, but not of AM, and in cardiomyocytes: (i) abolished increased membrane protein oxidation; (ii) normalized augmented expression of prepro-IMD and RAMP1, but not prepro-AM, RAMP2 and RAMP3; (iii) attenuated (by 42%) increased width and normalized expression of hypertrophic markers, skeletal-�-actin and prepro-endothelin-1 similarly to blood pressure normalization but in contrast to blood pressure normalization did not attenuate augmented brain natriuretic peptide (BNP) expression. Conclusion: normalization specifically of augmented IMD/RAMP1 expression in NO-deficient cardiomyocytes by antioxidant intervention in the absence of blood pressure reduction indicates that these genes are likely to be induced directly by myocardial oxidative stress. Although oxidative stress contributed to cardiomyocyte hypertrophy, induction of IMD and RAMP1 is unlikely to be secondary to cardiomyocyte hypertrophy.

Chronic child abuse: The characteristics and careers of children caught in the child protection system

The introduction of the Quality Protects initiative in England and the focus on performance management has challenged social services departments to examine the systems, processes and outcomes for children who have their name on a child protection register. Research indicates that approximately one-quarter of the situations in which children are registered could be described as chronic—that is, they remain on the child protection register for significant periods of time, experience more than one period of registration or suffer a further incident of significant harm whilst subject to a child protection plan. In this article, the findings from a research study conducted into this group of vulnerable children are reported, focusing on the characteristics of the children and their families, and their careers in the child protection system. The paper concludes with observations about the weak conceptualization of performance management and the need to recognize the complexity of the factors that influence children’s careers in the child protection system.

Influence of atenolol and nifedipine on nitric oxide deficient cardiomyocyte hypertrophy and expression of the cardio-endocrine peptide intermedin and its receptor components.

BACKGROUND/AIMS: Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial ischemia, oxidative stress and hypertrophy; expression of adrenomedullin (AM) and intermedin (IMD) and their receptor activity modifying proteins (RAMPs 1-3) is augmented in cardiomyocytes, indicating that the myocardial AM/ IMD system may be activated in response to pressure loading and ischemic insult. The aim was to examine effects on (i) parameters of cardiomyocyte hypertrophy and on (ii) expression of AM and IMD and their receptor components in NO-deficient cardiomyocytes of an intervention chosen specifically for ability to alleviate pressure loading and ischemic injury concurrently. METHODS: The NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 35 mg.kg(-1).day(-1)) was given to rats for 8 weeks, with/ without concurrent administration of beta-adrenoceptor antagonist, atenolol (25 mg.kg(-1).day(-1)) / calcium channel blocker, nifedipine (20mg.kg(-1).day(-1)). RESULTS: In L-NAME treated rats, atenolol / nifedipine abolished increases in systolic blood pressure and plasma AM and IMD levels and in left ventricular cardiomyocytes: (i) normalized increased cell width and mRNA expression of hypertrophic (sk-alpha-actin) and cardio-endocrine (ANP, BNP, ET) genes; (ii) normalized augmented membrane protein oxidation; (iii) normalized mRNA expression of AM, IMD, RAMP1, RAMP2 and RAMP3. CONCLUSIONS: normalization of blood pressure and membrane oxidant status together with prevention of hypertrophy and normalization of the augmented expression of AM, IMD and their receptor components in NO-deficient cardiomyocytes by atenolol / nifedipine supports involvement of both pressure loading and ischemic insult in stimulating cardiomyocyte hypertrophy and induction of these counter-regulatory peptides and their receptor components. Attenuation of augmented expression of IMD in this model cannot however be explained simply by prevention of cardiomyocyte hypertrophy.

'What say you to [this] book? Is it yours?'::Oral and Collaborative Narrative Trajectories in the Mediated Writings of Anna Trapnel

This article argues that, when a printed page is initially orally generated and then transcribed, either at the time or on a subsequent occasion by a listener or an interlocutor, there are important critical implications for the “I” of the account. It takes as a case study Anna Trapnel's first published works. Appearing within a few weeks of each other in 1654, The Cry of a Stone and Strange and Wonderful News are both mediated texts, large parts of which depend on the agency of a relater. The article begins by examining the textual traces of the relater, arguing for the centrality of his role and other agencies in the shaping of the works which bear Trapnel's name. Situating itself in relation to a current orientation in feminist autobiographical theory that places emphasis on the external requirement to narrate one's life, rather than on the spontaneous production of autobiography by an inner self, the article emphasizes notions of coaxing, witnessing and intersubjectivity to point up an appreciation of women's life writing as a species of cultural production in which various historical actors—male and female—participate. This dialogic process, which persists into the afterlife of transcription, owes part of its genesis to the political vagaries of 1654 and precipitates two contrasting—but equally “authentic”—versions of Trapnel's life and self. Mapping this movement, discussion concentrates on the ways in which a critical confrontation with women's oral narrative is as much an activity of disentangling as it is of reconstructing, an activity which is revealing of the extent to which a spectrum of social and cultural networks participates in and facilitates the female writing act.

Transient receptor potential melastatin 8 (TRPM8) channel involvement in the regulation of vascular tone

The transient receptor potential melastatin 8 (TRPM8) channel has been characterized as a cold and menthol receptor expressed in a subpopulation of sensory neurons but was recently identified in other tissues, including the respiratory tract, urinary system, and vasculature. Thus TRPM8 may play multiple functional roles, likely to be in a tissue- and activation state-dependent manner. We examined the TRPM8 channel presence in large arteries from rats and the functional consequences of their activation. We also aimed to examine whether these channels contribute to control of conscious human skin blood flow. TRPM8 mRNA and protein were detected in rat tail, femoral and mesenteric arteries, and thoracic aorta. This was confirmed in single isolated vascular myocytes by immunocytochemistry. Isometric contraction studies on endothelium-denuded relaxed rat vessels found small contractions on application of the TRPM8-specific agonist menthol (300 microM). However, both menthol and another agonist icilin (50 microM) caused relaxation of vessels precontracted with KCl (60 mM) or the alpha-adrenoceptor agonist phenylephrine (2 microM) and a reduction in sympathetic nerve-mediated contraction. These effects were antagonized by bromoenol lactone treatment, suggesting the involvement of Ca(2+)-independent phospholipase A(2) activation in TRPM8-mediated vasodilatation. In thoracic aorta with intact endothelium, menthol-induced inhibition of KCl-induced contraction was enhanced. This was unaltered by preincubation with either N(omega)-nitro-l-arginine methyl ester (l-NAME; 100 nM), a nitric oxide synthase inhibitor, or the ACh receptor antagonist atropine (1 microM). Application of menthol (3% solution, topical application) to skin caused increased blood flow in conscious humans, as measured by laser Doppler fluximetry. Vasodilatation was markedly reduced or abolished by prior application of l-NAME (passive application, 10 mM) or atropine (iontophoretic application, 100 nM, 30 s at 70 microA). We conclude that TRPM8 channels are present in rat artery vascular smooth muscle and on activation cause vasoconstriction or vasodilatation, dependent on previous vasomotor tone. TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms.

A Survey of Search Methodologies and Automated System Development for Examination Timetabling

Exam timetabling is one of the most important administrative activities that takes place in academic institutions. In this paper we present a critical discussion of the research on exam timetabling in the last decade or so. This last ten years has seen an increased level of attention on this important topic. There has been a range of significant contributions to the scientific literature both in terms of theoretical andpractical aspects. The main aim of this survey is to highlight the new trends and key research achievements that have been carried out in the last decade.We also aim to outline a range of relevant important research issues and challenges that have been generated by this body of work.

We first define the problem and review previous survey papers. Algorithmic approaches are then classified and discussed. These include early techniques (e.g. graph heuristics) and state-of-the-art approaches including meta-heuristics, constraint based methods, multi-criteria techniques, hybridisations, and recent new trends concerning neighbourhood structures, which are motivated by raising the generality of the approaches. Summarising tables are presented to provide an overall view of these techniques. We discuss some issues on decomposition techniques, system tools and languages, models and complexity. We also present and discuss some important issues which have come to light concerning the public benchmark exam timetabling data. Different versions of problem datasetswith the same name have been circulating in the scientific community in the last ten years which has generated a significant amount of confusion. We clarify the situation and present a re-naming of the widely studied datasets to avoid future confusion. We also highlight which research papershave dealt with which dataset. Finally, we draw upon our discussion of the literature to present a (non-exhaustive) range of potential future research directions and open issues in exam timetabling research.

Approaches to crystallization from ionic liquids: complex solvents-complex results, or, a strategy for controlled formation of new supramolecular architectures?

There are now more than 1200 papers a year describing research results using the 'neoteric' solvents, known as ionic liquids (ILs). If ILs are such highly studied solvents, why has there been so comparatively little research in their use in crystallization? Here we explore this question and discuss possible strategies for utilization of the mundane and the unique aspects of ILs for novel crystallization strategies including crystallization of high and low melting solids using thermal shifts; ''solvothermal'' techniques; slow diffusion; electrocrystallization; and use of a co-solvent. The results presented here and those appearing in the literature indicate both the complex nature of these solvents and their promise in delivering unique solvation, metal ion coordination numbers, coordination polymer motifs, and metal-anion interactions, to name but a few. These complex, but fascinating, results and the promise of much more intimate control over crystallization processes will drive a growing interest in using ILs as crystallization solvents.

Adrenomedullin Gene Delivery is Cardio-protective in a Model of Chronic Nitric Oxide Deficiency Combining Pressure Overload, Oxidative Stress and Cardiomyocyte Hypertrophy

BACKGROUND/AIMS:
Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial ischemia, oxidative stress and hypertrophy; expression of the vasodilator peptide, adrenomedullin (AM) and its receptors is augmented in cardiomyocytes, indicating that the myocardial AM system may be activated in response to pressure loading and ischemic insult to serve a counter-regulatory, cardio-protective role. The study examined the hypothesis that oxidative stress and hypertrophic remodeling in NO-deficient cardiomyocytes are attenuated by adenoviral vector-mediated delivery of the human adrenomedullin (hAM) gene in vivo.

METHODS:
The NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 15mg . kg(-1) . day(-1)) was given to rats for 4 weeks following systemic administration via the tail vein of a single injection of either adenovirus harbouring hAM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM-4F2), or for comparison, adenovirus alone (Ad.Null) or saline. Cardiomyocytes were subsequently isolated for assessment of the influence of each intervention on parameters of oxidative stress and hypertrophic remodelling.

RESULTS: Cardiomyocyte expression of the transgene persisted for > or =4 weeks following systemic administration of adenoviral vector. In L-NAME treated rats, relative to Ad.Null or saline administration, Ad.CMV-hAM-4F2 (i) reduced augmented cardiomyocyte membrane protein oxidation and mRNA expression of pro-oxidant (p22phox) and anti-oxidant (SOD-3, GPx) genes; (ii) attenuated increased cardiomyocyte width and mRNA expression of hypertrophic (sk-alpha-actin) and cardio-endocrine (ANP) genes; (iii) did not attenuate hypertension.

CONCLUSIONS: Adenoviral vector mediated delivery of hAM resulted in attenuation of myocardial oxidative stress and hypertrophic remodelling in the absence of blood pressure reduction in this model of chronic NO-deficiency. These findings are consistent with a direct cardio-protective action in the myocardium of locally-derived hAM which is not dependant on NO generation.

'Saig in Machai Fothúaid': On the Application and Extent of ‘the Macha’ in North-west Armagh

The seventh-century Patrician documents in the Book of Armagh, and other early sources such as Bethu Phátraic, contain references to the toponym Macha, which has been identified by the Dictionary of the Irish Language with either the ecclesiastical centre of Ard Macha or the ‘royal seat’ of Emain Macha. This article examines the evidence for the name in the sources and illustrates that Macha applies primarily to the plain in which both Ard Macha and Emain Macha are located. It is to be identified with Mag Macha ‘the plain of Macha’, familiar to us from the Dindshenchus, and further evidence of the organic potential of a given toponym is witnessed in later sources where the plain is referred to as Mag/Machaire na hE(a)mna ‘the plain of Emain’ and Machaire Aird/Arda Macha ‘the plain of Armagh’. The extent of Macha is difficult to establish with certainty, but it seems very likely that it stretched north to the River Blackwater as well as south towards Slíab Fúait.

The Future of Preventive Wars: The Case of Iraq

Eight years have past since the devastating September 11 attacks, and the USA has engaged in two wars in the name of uprooting global ‘terrorism’ and providing security to American citizens. The Bush administration bequeathed a legacy of two ongoing wars and growing threats emerging from ‘terrorist’ acts. This article analyses the future of the preventive war doctrine, formulated by the Bush administration, under international law. The article thus explores whether the preventive war doctrine has the potential to set a customary precedence, or whether it merely constitutes a breach of international law.

Rethinking Amnesties: Atrocity, Accountability And Impunity In Post-Conflict Societies.

The notion of accountability that is propagated in transitional justice often appears limited to demands for the prosecution and imprisonment of those who have been involved in serious human rights violations. Amnesties, widely understood as the absence of punishment for wrongdoing, are in turn considered by many scholars and activists as an example par excellence of the kind of Faustian pacts which are made in the name of political expediency in transitions from conflict. Drawing from a range of interdisciplinary literature, as well as research completed by the authors in a number of societies with a violent past, this paper uses amnesties as a case-study to argue for a more rounded interrogation of the notion of accountability in transitional justice. The paper charts the various forms of intersecting accountability which both shape and delimit amnesties at key ‘moments’ concerning their remit, introduction and operation. The paper concludes that the legalistic view of amnesties as equating to impunity and retribution as accountability is inaccurate and misleading. It argues that a broader perspective of accountability speaks directly to the capacity for amnesties to play a more constructive role in post conflict justice and peacemaking.

Acoustic solitary waves in dusty and/or multi-ion plasmas with cold, adiabatic, and hot constituents

Large nonlinear acoustic waves are discussed in a four-component plasma, made up of two superhot isothermal species, and two species with lower thermal velocities, being, respectively, adiabatic and cold. First a model is considered in which the isothermal species are electrons and ions, while the cooler species are positive and/or negative dust. Using a Sagdeev pseudopotential formalism, large dust-acoustic structures have been studied in a systematic way, to delimit the compositional parameter space in which they can be found, without restrictions on the charges and masses of the dust species and their charge signs. Solitary waves can only occur for nonlinear structure velocities smaller than the adiabatic dust thermal velocity, leading to a novel dust-acoustic-like mode based on the interplay between the two dust species. If the cold and adiabatic dust are oppositely charged, only solitary waves exist, having the polarity of the cold dust, their parameter range being limited by infinite compression of the cold dust. However, when the charges of the cold and adiabatic species have the same sign, solitary structures are limited for increasing Mach numbers successively by infinite cold dust compression, by encountering the adiabatic dust sonic point, and by the occurrence of double layers. The latter have, for smaller Mach numbers, the same polarity as the charged dust, but switch at the high Mach number end to the opposite polarity. Typical Sagdeev pseudopotentials and solitary wave profiles have been presented. Finally, the analysis has nowhere used the assumption that the dust would be much more massive than the ions and hence, one or both dust species can easily be replaced by positive and/or negative ions and the conclusions will apply to that plasma model equally well. This would cover a number of different scenarios, such as, for example, very hot electrons and ions, together with a mix of adiabatic ions and dust (of either polarity) or a very hot electron-positron mix, together with a two-ion mix or together with adiabatic ions and cold dust (both of either charge sign), to name but some of the possible plasma compositions.