In Vivo Age Dependency of Unfractionated Heparin in Infants and Children

Introduction
Unfractionated Heparin (UFH) is used widely in paediatrics. Paediatric specific recommendations for UFH therapy are few, with the majority of recommendations being extrapolated from adult practice. In vitro studies have shown that this practice may be suboptimal. This study aimed to improve the understanding of the impact of age upon UFH response in vivo.

Materials and Methods
This prospective, observational study, conducted in the Paediatric Intensive Care Unit (PICU), included: patients 16 years or younger; treated with UFH of at least 10 U/Kg/hr. Laboratory analysis included: Antithrombin, APTT, Anti-Xa, Anti-IIa and thrombin generation expressed as the Endogenous Thrombin Potential. Results were grouped according to patient age (i.e. < 1, 1-5, 6-10 and 11-16 years).

Results
85 patients received an equivalent mean UFH dose with a median duration of 3 days. Antithrombin levels were decreased compared to age-related norms in children up to 11 years of age. APTT results were comparable across the age-groups. The Anti-Xa results using two different assays showed a trend for lower values in younger children. All children less than one year old recorded Anti-Xa values outside the therapeutic range for heparin therapy, for both assays. There was a trend for decreased Anti-IIa activity in younger children. Endogenous Thrombin Potential showed a significant trend for increased inhibition in older children. In vitro Antithrombin supplementation did not change the Anti-Xa or thrombin generation.

Conclusions
This study confirms that, in vivo, for the same dose of UFH, the anti Xa and anti IIa effect, as well as the inhibition of endogenous thrombin potential is age dependent and that these differences are not purely AT dependent. The implication is that the anticoagulant and antithrombotic effect of a given dose of UFH differs with age. Clinical outcome studies to determine the optimal dosing for each age group are warranted.

Abbreviations
UFH, Unfractionated Heparin; ETP, Endogenous Thrombin Potential; AT, Antithrombin; APTT, Activated Partial Thromboplastin Time

Time and Cell Type Dependency of Survival Responses in Co-cultured Tumor and Fibroblast Cells after Exposure to Modulated Radiation Fields

Advanced radiotherapy techniques such as intensity-modulated radiation therapy (IMRT) achieve high levels of conformity to the target volume through the sequential delivery of highly spatially and temporally modulated radiation fields, which have been shown to impact radiobiological response. This study aimed to characterize the time and cell type dependency of survival responses to modulated fields using single cell type (SCT) and mixed cell type (MCT) co-culture models of transformed fibroblast (AG0-1522b) cells, and prostate (DU-145) and lung (H460) cancer cells. In SCT cultures, in-field responses showed no significant time dependency while out-of-field responses occurred early, and plateaued 6 h after irradiation in both DU-145 and H460 cells. Under modulated beam configurations MCT co-cultures showed cell-specific, differential out-of-field responses depending on the irradiated in-field and responding out-of-field cell type. The observed differential out-of-field responses may be due to the genetic background of the cells, in particular p53 status, which has been shown to mediate radiation-induced bystander effects (RIBEs). These data provide further insight into the radiobiological parameters that influence out-of-field responses, which have potential implications for advanced radiotherapy modalities and may provide opportunities for biophysical optimization in radiotherapy treatment planning.

Dengue Virus Inhibition of Autophagic Flux and Dependency of Viral Replication on Proteasomal Degradation of the Autophagy Receptor p62

Autophagic flux involves formation of autophagosomes and their degradation by lysosomes. Autophagy can either promote or restrict viral replication. In the case of Dengue virus (DENV) several studies report that autophagy supports the viral replication cycle, and describe an increase of autophagic vesicles (AVs) following infection. However, it is unknown how autophagic flux is altered to result in increased AVs. To address this question, and gain insight into the role of autophagy during DENV infection, we established an unbiased, image-based flow cytometry approach to quantify autophagic flux under normal growth conditions and in response to activation by nutrient deprivation or the mTOR inhibitor Torin1. We found that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Early after infection, basal and activated autophagic flux was enhanced. However, during established replication, basal and Torin1-activated autophagic flux was blocked, while autophagic flux activated by nutrient deprivation was reduced, indicating a block to AV formation and reduced AV degradation capacity. During late infection AV levels increased as a result of inefficient fusion of autophagosomes with lysosomes. Additionally, endo-lysosomal trafficking was suppressed, while lysosomal activities were increased. We further determined that DENV infection progressively reduced levels of the autophagy receptor SQSTM1/p62 via proteasomal degradation. Importantly, stable over-expression of p62 significantly suppressed DENV replication suggesting a novel role for p62 as viral restriction factor. Overall our findings indicate that in the course of DENV infection, autophagy shifts from a supporting to an anti-viral role, which is countered by DENV.

IMPORTANCE: Autophagic flux is a dynamic process starting with the formation of autophagosomes and ending with their degradation after fusion with lysosomes. Autophagy impacts the replication cycle of many viruses. However, thus far the dynamics of autophagy in case of Dengue virus (DENV) infections has not been systematically quantified. Therefore, we employed high-content, imaging-based flow cytometry to quantify autophagic flux and endo-lysosomal trafficking in response to DENV infection. We report that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Further, lysosomal activity was increased, but endo-lysosomal trafficking was suppressed confirming the block of autophagic flux. Importantly, we provide evidence that p62, an autophagy receptor, restrict DENV replication and was specifically depleted in DENV-infected cells via increased proteasomal degradation. These results suggest that during DENV infection autophagy shifts from a pro- to an antiviral cellular process, which is counteracted by the virus.

Oil and Dependency::The Case of Kazakhstan

Following the collapse of the Soviet Union in 1991, the newly independent oil-rich country of Kazakhstan has become a major recipient of foreign direct investment (FDI). Although international organisations such as the IMF and UNCTAD have claimed that FDI could be considered an engine in the transition from state socialism and as a powerful force for integration of this region into the global economy; this investment also poses significant risks to Kazakhstan. These risks fall into two broad categories: The first category can be broadly described as issues associated with the “resource curse” or the “Dutch Disease”. The term Dutch Disease describes a situation where booming demand in oil exporting countries, due to high oil revenues, leads to shift of an economy’s productive resources from the tradeable sector to the non-tradeable sector. The second category is associated with the over-dependency of oil exporting countries on a relatively small number of large multinational corporations (MNCs). This over-dependency can lead to a situation where licenses and concessions are granted at less favourable conditions than if they were auctioned in an efficient market. Examining the licensing policy of the Kazakhstani Energy and Mineral Resource Ministry, this paper notes that the latter issue of over-dependency has become less of a risk due to deliberate efforts to diversify investment relationships. Notwithstanding this situation there is some evidence that it remains difficult for oil exporting nations such as Kazakhstan to ensure that oil revenues are channelled into sustainable economic development.

Down-regulation of Rac Activity during beta 2 Integrin-mediated Adhesion of Human Neutrophils

In human neutrophils, beta2 integrin engagement mediated a decrease in GTP-bound Rac1 and Rac2. Pretreatment of neutrophils with LY294002 or PP1 (inhibiting phosphatidylinositol 3-kinase (PI 3-kinase) and Src kinases, respectively) partly reversed the beta2 integrin-induced down-regulation of Rac activities. In contrast, beta2 integrins induced stimulation of Cdc42 that was independent of Src family members. The PI 3-kinase dependency of beta2 integrin-mediated decrease in GTP-bound Rac could be explained by an enhanced Rac-GAP activity, since this activity was blocked by LY204002, whereas PP1 only had a minor effect. The fact that only Rac1 but not Rac2 (the dominating Rac) redistributed to the detergent-insoluble fraction and that it was independent of GTP loading excludes the possibility that down-regulation of Rac activities was due to depletion of GTP-bound Rac from the detergent-soluble fraction. The beta2 integrin-triggered relocalization of Rac1 to the cytoskeleton was enabled by a PI 3-kinase-induced dissociation of Rac1 from LyGDI. The dissociations of Rac1 and Rac2 from LyGDI also explained the PI 3-kinase-dependent translocations of Rac GTPases to the plasma membrane. However, these accumulations of Rac in the membrane, as well as that of p47phox and p67phox, were also regulated by Src tyrosine kinases. Inasmuch as Rac GTPases are part of the NADPH oxidase and the respiratory burst is elicited in neutrophils adherent by beta2 integrins, our results indicate that activation of the NADPH oxidase does not depend on the levels of Rac-GTP but instead requires a beta2 integrin-induced targeting of the Rac GTPases as well as p47phox and p67phox to the plasma membrane.

Violent, caring, unpredictable: Public views on survivors of brain injury

The purpose of the present work was to investigate how members of the public perceived survivors of brain injury. A twenty-item list of attributes that could be used to describe characteristics of survivors of brain injury were given to three hundred and twenty-three participants. One hundred and sixty-nine psychology students and one hundred and fifty-four members of the public agreed to take part in the study. The effects of group (student and public), gender and socioeconomic status (low, moderate and high) on the attributes were assessed. Multivariate analysis of variance showed a statistically significant difference between the two groups with students holding more positive perceptions on 15 out of the 20 attributes. No effects of gender or socioeconomic status were found. The research suggests that members of the public hold less positive views on survivors of brain injury in respect to intellectual competency, ability to care and trustworthiness when compared to students.

Estimating the masses of extra-solar planets

All extra-solar planet masses that have been derived spectroscopically are lower limits since the inclination of the orbit to our line-of-sight is unknown except for transiting systems. In theory, however, it is possible to determine the inclination angle, i, between the rotation axis of a star and an observer's line-of-sight from measurements of the projected equatorial velocity (v sin i), the stellar rotation period (P(rot)) and the stellar radius (R(*)). For stars which host planetary systems this allows the removal of the sin i dependency of extra-solar planet masses derived from spectroscopic observations under the assumption that the planetary orbits lie perpendicular to the stellar rotation axis.
We have carried out an extensive literature search and present a catalogue of v sin i, P(rot) and R(*) estimates for stars hosting extra-solar planets. In addition, we have used Hipparcos parallaxes and the Barnes-Evans relationship to further supplement the R(*) estimates obtained from the literature. Using this catalogue, we have obtained sin i estimates using a Markov-chain Monte Carlo analysis. This technique allows proper 1 Sigma two-tailed confidence limits to be placed on the derived sin i's along with the transit probability for each planet to be determined.
While we find that a small proportion of systems yield sin i's significantly greater than 1, most likely due to poor P(rot) estimations, the large majority are acceptable. We are further encouraged by the cases where we have data on transiting systems, as the technique indicates inclinations of similar to 90 degrees and high transit probabilities. In total, we are able to estimate the true masses of 133 extra-solar planets. Of these 133 extra-solar planets, only six have revised masses that place them above the 13M(J) deuterium burning limit; four of those six extra-solar planet candidates were already suspected to lie above the deuterium burning limit before correcting their masses for the sin i dependency. Our work reveals a population of high-mass extra-solar planets with low eccentricities, and we speculate that these extra-solar planets may represent the signature of different planetary formation mechanisms at work. Finally, we discuss future observations that should improve the robustness of this technique.

Adaptive Code Allocation for Interference Management on the Downlink of DS-CDMA Systems

A new technique based on adaptive code-to-user allocation for interference management on the downlink of BPSK based TDD DS-CDMA systems is presented. The principle of the proposed technique is to exploit the dependency of multiple access interference on the instantaneous symbol values of the active users. The objective is to adaptively allocate the available spreading sequences to users on a symbol-by-symbol basis to optimize the decision variables at the downlink receivers. The presented simulations show an overall system BER performance improvement of more than an order of a magnitude with the proposed technique while the adaptation overhead is kept less than 10% of the available bandwidth.

The Development of Corporate Identity: A Political Perspective

A corporate identity denotes a set of attributes that senior managers ascribe to their organization. It is therefore an organizational identity articulated by a powerful interest group. It can constitute a claim which serves inter alia to justify the authority vested in top managers and to further their interests. The academic literature on organizational identity, and on corporate identity in particular, pays little attention to these political considerations. It focuses in an apolitical manner on shared meanings when corporate identity works, or on cognitive dissonance when it breaks down. In response to this analytical void, we develop a political analysis of corporate identity and its development, using as illustration a longitudinal study of successive changes in the corporate identity of a Brazilian telecommunications company. This suggests a cyclical model in which corporate identity definition and redefinition involve power relations, resource mobilization and struggles for legitimacy. © Blackwell Publishing Ltd 2007.

Environmental context determines multi-trophic effects of consumer species loss

Loss of biodiversity and nutrient enrichment are two of the main human impacts on ecosystems globally, yet we understand very little about the interactive effects of multiple stressors on natural communities and how this relates to biodiversity and ecosystem functioning. Advancing our understanding requires the following: (1) incorporation of processes occurring within and among trophic levels in natural ecosystems and (2) tests of context-dependency of species loss effects. We examined the effects of loss of a key predator and two groups of its prey on algal assemblages at both ambient and enriched nutrient conditions in a marine benthic system and tested for interactions between the loss of functional diversity and nutrient enrichment on ecosystem functioning. We found that enrichment interacted with food web structure to alter the effects of species loss in natural communities. At ambient conditions, the loss of primary consumers led to an increase in biomass of algae, whereas predator loss caused a reduction in algal biomass (i.e. a trophic cascade). However, contrary to expectations, we found that nutrient enrichment negated the cascading effect of predators on algae. Moreover, algal assemblage structure varied in distinct ways in response to mussel loss, grazer loss, predator loss and with nutrient enrichment, with compensatory shifts in algal abundance driven by variation in responses of different algal species to different environmental conditions and the presence of different consumers. We identified and characterized several context-dependent mechanisms driving direct and indirect effects of consumers. Our findings highlight the need to consider environmental context when examining potential species redundancies in particular with regard to changing environmental conditions. Furthermore, non-trophic interactions based on empirical evidence must be incorporated into food web-based ecological models to improve understanding of community responses to global change.