Defining the phenotypes of sickle cell disease.

The sickle cell gene is pleiotropic in nature. Although it is a single gene mutation, it has multiple phenotypic expressions that constitute the complications of sickle cell disease. The frequency and severity of these complications vary considerably both latitudinally in patients and longitudinally in the same patient over time. Thus, complications that occur in childhood may disappear, persist or get worse with age. Dactylitis and stroke, for example, occur mostly in childhood, whereas leg ulcers and renal failure typically occur in adults. It is essential that the phenotypic manifestations of sickle cell disease be defined accurately so that communication among providers and researchers facilitates the implementation of appropriate and cost-effective diagnostic and therapeutic modalities. The aim of this review is to define the complications that are specific to sickle cell disease based on available evidence in the literature and the experience of hematologists in this field

The importance of both setting and intensity of physical activity in relation to non-clinical anxiety and depression

Physical activity is associated with good physical and mental health. Current recommendations suggest that people should achieve 30 minutes of moderate-intensity activity most days of the week to gain health benefits. This activity may be accumulated in leisure time, in active commuting, at work or in the home. Here we look at the cross-sectional relationship between physical activity and mental health as measured by the HADS anxiety and depression scores in a sample of 1,742 participants from a Scottish general population survey. The participants were men and women in three age cohorts aged around 24, 44 and 64 years who, in 1995, were interviewed face to face and also self-completed the HADS depression and anxiety scale. Respondents reported their levels of physical activity at work, in the home and in leisure time; the intensities of activity were also determined. Physical activity was related to depression scores but not to anxiety scores. There was no relationship between work physical activity and depression score. Among women, depression score increased with each additional episode of vigorous home activity. In both sexes, depression score decreased with each additional episode of vigorous leisure activity, but among men the decrease in depression score with moderate leisure activity was reversed if a lot of moderate activity was undertaken. We have found a variable relationship between depression scores and various settings for physical activity. Researchers, policymakers and practitioners who are interested in the relationship between physical activity and mental health should take into account the setting for activity as well as frequency, duration and intensity of activity

DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway

The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated. This study demonstrates that ROS induction after treatment of cells with neocarzinostatin (NCS), an ionizing radiation mimetic, is at least partly mediated by increasing histone H2AX. Increased levels of ROS and cell death induced by H2AX overexpression alone or DNA damage leading to H2AX accumulation are reduced by treating cells with the antioxidant N-Acetyl-L-Cysteine (NAC), the NADP(H) oxidase (Nox) inhibitor DPI, expression of Rac1N17, and knockdown of Nox1, but not Nox4, indicating that induction of ROS by H2AX is mediated through Nox1 and Rac1 GTPase. H2AX increases Nox1 activity partly by reducing the interaction between a Nox1 activator NOXA1 and its inhibitor 14-3-3zeta. These results point to a novel role of histone H2AX that regulates Nox1-mediated ROS generation after DNA damage

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

Cluster Lenses

Clusters of galaxies are the most recently assembled, massive, bound structures in the Universe. As predicted by General Relativity, given their masses, clusters strongly deform space-time in their vicinity. Clusters act as some of the most powerful gravitational lenses in the Universe. Light rays traversing through clusters from distant sources are hence deflected, and the resulting images of these distant objects therefore appear distorted and magnified. Lensing by clusters occurs in two regimes, each with unique observational signatures. The strong lensing regime is characterized by effects readily seen by eye, namely, the production of giant arcs, multiple-images, and arclets. The weak lensing regime is characterized by small deformations in the shapes of background galaxies only detectable statistically. Cluster lenses have been exploited successfully to address several important current questions in cosmology: (i) the study of the lens(es) - understanding cluster mass distributions and issues pertaining to cluster formation and evolution, as well as constraining the nature of dark matter; (ii) the study of the lensed objects - probing the properties of the background lensed galaxy population - which is statistically at higher redshifts and of lower intrinsic luminosity thus enabling the probing of galaxy formation at the earliest times right up to the Dark Ages; and (iii) the study of the geometry of the Universe - as the strength of lensing depends on the ratios of angular diameter distances between the lens, source and observer, lens deflections are sensitive to the value of cosmological parameters and offer a powerful geometric tool to probe Dark Energy. In this review, we present the basics of cluster lensing and provide a current status report of the field.Comment: About 120 pages - Published in Open Access at: http://www.springerlink.com/content/j183018170485723/ . arXiv admin note: text overlap with arXiv:astro-ph/0504478 and arXiv:1003.3674 by other author

Human(e) rights and the cosmopolitan imagination: questions of human dignity and cultural identity

Here I seek to explore the cosmopolitan foundations of the idea of human rights. The argument begins by considering the popularity of the idea of human rights in a globalized and fast-moving commodified and digital culture. At this point I consider whether the idea of human rights might be considered to be a modern utopia similar to the role that art and nature played in the Romantic movements of the 19th century. Further, I defend human rights against those who simply see it as a form of neoliberalism or as largely ineffective against the power of the state. At this point I investigate some of the Durkheimian work within cultural sociology that has sought to investigate human rights as a form of moral community. The main problem with this view is that it has little to say about human freedom. However, viewed through a cultural lens, the global spread of human rights is connected to the idea of human dignity. While there is never likely to be a global consensus on this term, it does retain an important philosophical anchoring in Kantian ideas. More recently this debate has been revived by the critical reception of the work of Agamben and his idea of ‘bare life’. If human rights can indeed be connected to the struggle for a dignified and meaningful life, then the idea of ‘bare life’ remains an important conceptual advance. However, by considering the work and legacy of Du Bois, Gilroy and others, we can also see how the term dignity might take on other meanings in different settings. Finally, I argue that the idea of dignity and human rights could yet provide an important focus for resistance against the imperatives of capital and state in these neoliberal times

The generalised anxiety stigma scale (GASS): psychometric properties in a community sample

<p>Abstract</p> <p>Background</p> <p>Although there is substantial concern about negative attitudes to mental illness, little is known about the stigma associated with Generalised Anxiety Disorder (GAD) or its measurement. The aim of this study was to develop a multi-item measure of Generalised Anxiety Disorder stigma (the GASS).</p> <p>Methods</p> <p>Stigma items were developed from a thematic analysis of web-based text about the stigma associated with GAD. Six hundred and seventeen members of the public completed a survey comprising the resulting 20 stigma items and measures designed to evaluate construct validity. Follow-up data were collected for a subset of the participants (n = 212).</p> <p>Results</p> <p>The factor structure comprised two components: Personal Stigma (views about Generalised Anxiety Disorder); and Perceived Stigma (views about the beliefs of most others in the community). There was evidence of good construct validity and reliability for each of the Generalised Anxiety Stigma Scale (GASS) subscales.</p> <p>Conclusions</p> <p>The GASS is a promising brief measure of the stigma associated with Generalised Anxiety Disorder.</p

The FAT10- and ubiquitin-dependent degradation machineries exhibit common and distinct requirements for MHC class I antigen presentation

Like ubiquitin (Ub), the ubiquitin-like protein FAT10 can serve as a signal for proteasome-dependent protein degradation. Here, we investigated the contribution of FAT10 substrate modification to MHC class I antigen presentation. We show that N-terminal modification of the human cytomegalovirus-derived pp65 antigen to FAT10 facilitates direct presentation and dendritic cell-mediated cross-presentation of the HLA-A2 restricted pp65495–503 epitope. Interestingly, our data indicate that the pp65 presentation initiated by either FAT10 or Ub partially relied on the 19S proteasome subunit Rpn10 (S5a). However, FAT10 distinguished itself from Ub in that it promoted a pp65 response which was not influenced by immunoproteasomes or PA28. Further divergence occurred at the level of Ub-binding proteins with NUB1 supporting the pp65 presentation arising from FAT10, while it exerted no effect on that initiated by Ub. Collectively, our data establish FAT10 modification as a distinct and alternative signal for facilitated MHC class I antigen presentation

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO