Oxidation of guanine Nucleosides to 4-amidinocarbamoyl-5-hydroxyimidazoles by dimethyldioxirane

Final oxidation products generated from guanosine and 2'-deoxyguano sine by reaction with dimethyldioxirane have been identified as 4-amidinocarbamoyl-5-hydroxyimidazoles.

Variations in Apolipoprotein E Frequency With Age in a Pooled Analysis of a Large Group of Older People

Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms e2, e3, and e4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE e4 isoform with increasing age (?2 for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the e3 isoform (?2 for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in e4 homozygotes; the frequency of e4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the e3/e4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.

Oromotor dysfunction and communication impairments in children with cerebral palsy: a Register study

Aim  To report the prevalence, clinical associations, and trends over time of oromotor dysfunction and communication impairments in children with cerebral palsy (CP).

Method  Multiple sources of ascertainment were used and children followed up with a standardized assessment including motor speech problems, swallowing/chewing difficulties, excessive drooling, and communication impairments at age 5 years.

Results  A total of 1357 children born between 1980 and 2001 were studied (781 males, 576 females; median age 5y 11mo, interquartile range 3–9y; unilateral spastic CP, n=447; bilateral spastic CP, n=496; other, n=112; Gross Motor Function Classification System [GMFCS] level: I, 181; II, 563; III, 123; IV, 82; IV, 276). Of those with ‘early-onset’ CP (n=1268), 36% had motor speech problems, 21% had swallowing/chewing difficulties, 22% had excessive drooling, and 42% had communication impairments (excluding articulation defects). All impairments were significantly related to poorer gross motor function and intellectual impairment. In addition, motor speech problems were related to clinical subtype; swallowing/chewing problems and communication impairments to early mortality; and communication impairments to the presence of seizures. Of those with CP in GMFCS levels IV to V, a significant proportion showed a decline in the rate of motor speech impairment (p=0.008) and excessive drooling (p=0.009) over time.

Interpretation  These impairments are common in children with CP and are associated with poorer gross motor function and intellectual impairment.

Cholinergic, serotoninergic and peptidergic components of the nervous system of Discocotyle sagittata (Monogenea: Polyopisthocotylea)

Cholinergic, serotoninergic (5-HT) and peptidergic neuronal pathways have been demonstrated in both central and peripheral nervous systems of adult Discocotyle sagittata, using enzyme histochemistry and indirect immunocytochemistry in conjunction with confocal scanning laser microscopy. Antisera to 2 native flatworm neuropeptides, neuropeptide F and the fMRFamide-related peptide (FaRP), GNFFRFamide, were employed to detect peptide immunoreactivity. The CNS is composed of paired cerebral ganglia and connecting dorsal commissure, together with several paired longitudinal nerve cords. The main longitudinal nerve cords (lateral, ventral and dorsal) are interconnected at intervals by a series of annular cross-connectives, producing a ladder-like arrangement typical of the platyhelminth nervous system. At the lever of the haptor, the ventral cords provide nerve roots which innervate each of the 8 clamps. Cholinergic and peptidergic neuronal organisation was similar, but distinct from that of the serotoninergic components. The PNS and reproductive system are predominantly innervated by peptidergic neurones. Copyright (C) 1996 Australian Society for Parasitology. Published by Elsevier Science Ltd.

Dynamics of the Indonesian seas circulation. Part II – The role of pressure head

The aim of this paper is to analyze the role of the pressure head, i.e., the difference of total pressure forces acting on the Indonesian seas waters from the western Pacific and the eastern Indian Ocean, in driving the Indonesian Throughflow (ITF) and in determining the total transport of the ITF. These questions have been discussed in the literature but no consensus has been reached. A regional model of the Indonesian seas circulation has been developed that properly resolves all major topographic features in the region. The results of model runs have been used to calculate all components of the overall momentum balance. The estimates disclose that the dynamical balance is primarily between the volume integrated Coriolis acceleration, pressure gradient and the area integral of local wind stress. It is shown that consideration of components of momentum balance in the direction of the outflow through the Indian Ocean port leads to the formulation of a diagnostic relation between total inflow transports due to the Mindanao and New Guinea Coastal Currents and the external pressure head, internal pressure head, bottom form stress, and area integrated wind stress. Based on this relation, it is concluded that the external pressure head is not the major driving force of the ITF, which is why there is no unique relation between the total transport of the ITF and the external pressure head. However, Wyrtki's suggestion to monitor the variability of the total transport of the ITF by measurement of the sea-surface-height difference between the western Pacific and the eastern Indian Ocean is validated.

Dynamics of the Indonesian seas circulation. Part I – The influence of bottom topography on temperature and salinity distributions

The influence of bottom topography on the distribution of temperature and salinity in the Indonesian seas region has been studied with a high-resolution model based on the Princeton Ocean Model. One of the distinctive properties of the model is an adequate reproduction of all major topographic features in the region by the model bottom relief. The three major routes of flow of Pacific water through the region have been identified. The western route follows the flow of North Pacific Water through the Sulawesi Sea, Makassar Strait, Flores Sea, and Banda Sea. This is the main branch of the Indonesian Throughflow. The eastern routes follow the flow of South Pacific water through the eastern Indonesian seas. This water enters the region either through the Halmahera Sea or by flowing to the north around Halmahera Island into the Morotai Basin and then into the Maluku Sea. A deep southward flow of South Pacific Water fills the Seram Sea below 1200 m through the Lifamatola Passage. As it enters the Seram Sea, this overflow turns eastward at depths greater than 2000 m, then upwells in the eastern part of the Seram Sea before returning westward at ~1500-2000 m. The flow continues westward across the Seram Sea, spreading to greater depths before entering the Banda Sea at the Buru-Mangole passage. It is this water that shapes the temperature and salinity of the deep Banda Sea. Topographic elevations break the Indonesian seas region down into separate basins. The difference in the distributions of potential temperature, ?, and salinity, S, in adjacent basins is primarily due to specific properties of advection of ? and S across a topographic rise. By and large, the topographic rise blocks deep flow between basins whereas water shallower than the depth of the rise is free to flow between basins. To understand this process, the structure of simulated fields of temperature and salinity has been analyzed. To identify a range of advected ? or S, special sections over the sills with isotherms or isohalines and isotachs of normal velocity have been considered. Following this approach the impact of various topographic rises on the distribution of ? and S has been identified. There are no substantial structural changes of potential temperature and salinity distributions between seasons, though values of some parameters of temperature and salinity distributions, e.g., magnitudes of maxima and minima, can change. It is shown that the main structure of the observed distributions of temperature and salinity is satisfactorily reproduced by the model throughout the entire domain.

Drusen prevalence and pigmentary changes in Caucasians aged 18-54 years

Aims and Purpose The aim of this study was to describe the prevalence and characteristics of drusen and pigmentary changes in a middle-aged population.

Methods Retinal images from 500 individuals aged 18–54 years were included. The source of participants was two UK optometry practices. Retinal images were graded using the Wisconsin Age-Related
Maculopathy Grading System. However, owing to the relatively young age of the population studied, a new category of drusen of smaller size (o31.5mm) was introduced.

Results Drusen were identi?ed within the central macular grid in 91.48% of all gradable eyes and in 444 subjects. Drusen sized o31.5mm were present in 89.7% of eyes, drusen sized 431.5mm and o63mm were present in 45.9% of all eyes and drusen 463mm and o125mm were present in only 1.7% of eyes. No eye had drusen larger or equal to 125mm. Very few eyes (1.2%) showed pigmentary changes within the grid. Drusen load increased with increasing age, P o0.001.

Conclusions The frequency of drusen in a younger Caucasian population aged 18–54 years is high, with 91.48% of all gradable eyes having drusen. The most frequent drusen subtype was hard distinct drusen o31.5mm. No druse greater or equal in size to 125mm was seen. Pigmentary changes are rare. Eye(2012) 26, 1357–1362; doi:10.1038/eye.2012.165; published online 17 August 2012

The pyrrolo-1,5-benzoxazepine, PBOX-6, inhibits the growth of breast cancer cells in vitro independent of estrogen receptor status and inhibits breast tumour growth in vivo

Members of a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds have been shown to induce apoptosis in a number of human leukemia cell lines of different haematological lineage, suggesting their potential as anti-cancer agents. In this study, we sought to determine if PBOX-6, a well characterised member of the PBOX series of compounds, is also an effective inhibitor of breast cancer growth. Two estrogen receptor (ER)-positive (MCF-7 and T-47-D) and two ER-negative (MDA-MB-231 and SK-BR-3) cell lines were examined. The 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to determine reduction in cell viability. PBOX-6 reduced the cell viability of all four cell lines tested, regardless of ER status, with IC(50) values ranging from 1.0 to 2.3 microM. PBOX-6 was most effective in the SK-BR-3 cells, which express high endogenous levels of the HER-2 oncogene. Overexpression of the HER-2 oncogene has been associated with aggressive disease and resistance to chemotherapy. The mechanism of PBOX-6-induced cell death was due to apoptosis, as indicated by the increased proportion of cells in the pre-G1 peak and poly(ADP-ribose) polymerase (PARP) cleavage. Moreover, intratumoural administration of PBOX-6 (7.5 mg/kg) significantly inhibited tumour growth in vivo in a mouse mammary carcinoma model (p=0.04, n=5, Student's t-test). Thus, PBOX-6 could be a promising anti-cancer agent for both hormone-dependent and -independent breast cancers.

Rhetoric and Realities of London 2012 Olympic Education and Participation ‘Legacies’: Voices from the Core and Periphery

A legacy emphasis was one of the fundamental pillars of the London 2012 Olympic Games. The notion of an Olympic legacy was predicated on assumptions that the event’s value would not purely derive from the sporting spectacle, but rather, from the ‘success’ of enduring effects met out in London and across the country. For physical education students and practitioners, Olympic legacy agendas translated into persistent pressure to increase inspiration, engagement, participation and performance in the subject, sport and physical activity. Responding to this context, and cogniscent of significant disciplinary scholarship, this paper reports initial data from the first phase of a longitudinal study involving Key Stage Three (students aged 11-13) cohorts in two comparable United Kingdom schools: the first an inner-city (core) London school adjacent to the Olympic Park in Stratford, East London (n=150); the second, a (peripheral) school in the Midlands (n=198). The research involved the use of themed questionnaires focusing on self-reported attitudes toward the Olympic Games, and, experiences of physical education, sport and physical activity. Students from both schools demonstrated a wide variety of attitudes toward physical education and sport; yet, minor variances emerged regarding extreme enthusiasm levels. Both cohorts also expressed considerably mixed feelings toward the impending Olympic Games. Strong and variable responses were also reported regarding inspiration levels, ticketing acquisition and engagement levels. Consequently, this investigation can be read within the broader context of legacy debates, and, aligns well with physical educationalists’ on-going discomfort regarding legacy imperatives being enforced upon the discipline and its practitioners. Our work reiterates a shared disciplinary scepticism that while an Olympic Games may temporarily affect young peoples’ affectations for sport (and maybe physical education and physical activity), it may not provide the best, or most appropriate, mechanism for sustained attitudinal and/or social changes en masse.

Explaining party cohesion and discipline in democratic legislatures: purposiveness and contexts

Legislative party discipline and cohesion are important phenomena in the study of political systems. Unless assumptions are made that parties are cohesive and act as unified collectivities with reasonably well-defined goals, it is really difficult, if not impossible, to consider their electoral and legislative roles usefully. But levels of legislative party cohesiveness are also important because they provide us with crucial information about how legislatures/ parliaments function and how they interact with executives/governments. Without cohesive (or disciplined) parties,1 government survival in parliamentary systems is threatened because executive and legislative powers are fused while in separated systems presidents' bases of legislative support become less stable. How do we explain varying levels of legislative party cohesion? The first part of this article draws on the purposive literature to explore the benefits and costs to legislators in democratic legislatures of joining and acting collectively and individualistically within political parties. This leads on to a discussion of various conceptual and empirical problems encountered in analysing intra-party cohesion and discipline in democratic legislatures on plenary votes. Finally, the article reviews the extant empirical evidence on how a multiplicity of systemic, party-levels and situational factors supposedly impact cohesion/discipline levels. The article ends with a discussion of the possibilities and limitations of building comparative models of cohesion/discipline.

Qualified exceptionalism: the US Congress in comparative perspective

The framers of the American Constitution devised a singular bicameral legislative body, which invested substantial power in both a broadly representative lower chamber and a second "deliberative" chamber that was both insulated from the voters and unrepresentative of the population as a whole. Until the early 20th Century, the singular U.S. Congress changed little, but with growing national responsibilities, it sought to construct organizational forms that could address a consistently stronger executive. Since the 1980s, the Congress has relied increasingly on stronger parties to organize its activities. This development, embraced in turn by Democrats and Republicans, has led to changes that have edged the Congress in the direction of parliamentary democracies. We conclude this analysis has real, but limited utility, as congressional party leaders continue to barter for votes and, in the context, of narrow chamber majorities, often rely heavily on presidential assistance on divisive issues that are important to their party brand. Yet, the traditional features of the American separated system - bicameralism, the committee systems, and the centrifugal forces emanating from diverse congressional districts, increasingly complex policy issues, and the fear of electoral retribution - also remain strong, and effectively constrain the influence of leaders.'Qualified exceptionalism' thus most aptly describes the contemporary American Congress, which remains 'exceptional,' but less than unique, as it responds to many of the same forces, in some of the same ways (e.g., strong parties), as do many other representative assemblies around the world.

Introduction: the impact of the 'War on Terror' on executive–legislative relations: a global perspective

In democratic polities, constitutional equilibria or balances of power between the executive and the legislature shift over time. Normative and empirical political theorists have long recognised that war, civil unrest, economic and political crises, terrorist attacks, and other events strengthen the power of the executive, disrupt and threaten constitutional politics, and damage democratic institutions: crises require swift action and executives are thought to be more capable than parliaments and legislatures of taking such actions. The terrorist attacks on New York and Washington on 11 September 2001 and the ensuing so-called 'war on terror' declared by President Bush clearly constituted a crisis, not only in the United States but also in other political systems, in part because of the US's hegemonic position in defining and shaping many other states' foreign and domestic policies. Dicey, Schmitt, and Rossiter suggest that critical events and political crises inevitably trigger the concentration of (emergency) powers in the hands of the executive. Aristotle and Machiavelli questioned the inevitability of this process. This article and the articles that follow in this Special Issue utilise empirical evidence, through the use of case studies of the United States, the United Kingdom, Russia, Australia, Israel, Italy and Indonesia, to address this debate. Specifically, the issue explores to what extent the external shock or crisis of 9/11 (and other terrorist attacks) and the ensuing 'war on terror' significantly changed the balance of executive-legislative relations from t (before the crisis) to t+1 (after the crisis) in these political systems, all of which were the targets of actual or foiled terrorist attacks. The most significant findings are that the shock of 9/11 and the 'war on terror' elicited varied responses by national executives and legislatures/parliaments and thus the balance of executive-legislative relations in different political systems; that, therefore, executive-legislative relations are positive rather than zero-sum; and that domestic political contexts conditioned these institutional responses.