Clinical & experimental characterisation of acute traumatic coagulopathy

PhDAcute traumatic coagulopathy (ATC) is a recently identified entity describing an early impairment of haemostasis after injury. Retrospective observational studies have associated it with a significant increase in patient morbidity and mortality. It does not appear to be caused by conventional mediators of haemorrhagic coagulopathy, such as iatrogenic haemodilution or hypothermia. Rather, it has been postulated that it is endogenous systemic anticoagulation modulated by activation of the protein C pathway in response to shock and tissue injury. The aims of this thesis were to characterise the aetiology and clinical significance of ATC and test the hypothesis that activated protein C plays a functional role in the pathophysiology of this condition. A retrospective analysis of patients admitted to 5 major international trauma centres was performed. Admission prothrombin times were correlated with aetiological variables and clinical outcomes. A structured literature review was subsequently conducted to identify the strengths and weaknesses of existing animal models of traumatic coagulopathy. Novel rodent (rat and mouse) models of ATC were then developed to elucidate how it develops. Clinical data on 3646 trauma patients identified a significant and dose-dependent increase in mortality and transfusion requirements with admission prothrombin time ratio > 1.2. The incidence of ATC co-associated with both the degree of tissue injury and the depth of haemorrhagic shock. Literature review identified a general failure of animal models to accurately simulate the clinical trajectory of injury. Specifically, only one (mouse) model of ATC was identified. Novel rodent models of ATC were developed that demonstrated endogenous coagulopathy in response to 60 minutes of haemorrhagic shock, with or without significant tissue injury. This was mediated predominantly by autogenous haemodilution and activated protein C anticoagulation. Acute traumatic coagulopathy is an endogenous impairment of haemostasis that develops in response to severe haemorrhagic shock. Manipulation of the protein C pathway may represent a novel therapeutic strategy for reducing blood loss and improving outcomes after injury

In for a penny, in for a pound: methylphenidate reduces the inhibitory effect of high stakes on persistent risky choice

Methylphenidate (MPH) is a stimulant that increases extracellular levels of dopamine and noradrenaline. It can diminish risky decision-making tendencies in certain clinical populations. MPH is also used, without license, by healthy adults, but the impact on their decision-making is not well established. Previous work has found that dopamine receptor activity of healthy adults can modulate the influence of stake magnitude on decisions to persistently gamble after incurring a loss. In this study, we tested for modulation of this effect by MPH in 40 healthy human adults. In a double-blind experiment, 20 subjects received 20 mg of MPH, while 20 matched controls received a placebo. All were provided with 30 rounds of opportunities to accept an incurred loss from their assets or opt for a "double-or-nothing" gamble that would either avoid or double it. Rounds began with a variable loss that would double with every failed gamble until it was accepted, recovered, or reached a specified maximum. Probability of recovery on any gamble was low and ambiguous. Subjects receiving placebo gambled less as the magnitude of the stake was raised and as the magnitude of accumulated loss escalated over the course of the task. In contrast, subjects treated with MPH gambled at a consistent rate, well above chance, across all stakes and trials. Trait reward responsiveness also reduced the impact of high stakes. The findings suggest that elevated catecholamine activity by MPH can disrupt inhibitory influences on persistent risky choice in healthy adults

Potentials of bamboo-based agroforestry for sustainable development in Sub-Saharan Africa:a review

There is widespread assertion among scientists, government and development experts that bamboo agroforestry could contribute to sustainable rural development in Sub-Saharan Africa (SSA). However, there are limited available data to verify the suitability of the system in the region. In addition, the current state of knowledge and adoption of agroforestry in SSA offers very little guidance as to which type of agroforestry systems bamboo could be integrated. Here, we reviewed the potential socioeconomic and environmental benefits of bamboo agroforestry and accentuate implications on sustainable rural development in SSA. In addition, we analysed potential research areas that could be intensified, so that future developments and scaling-up of bamboo agroforestry can be rooted in robust scientific findings rather than the intuitions of governments and development actors

Independent neural computation of value from other people's confidence

Expectation of reward can be shaped by the observation of actions and expressions of other people in one's environment. A person's apparent confidence in the likely reward of an action, for instance, makes qualities of their evidence, not observed directly, socially accessible. This strategy is computationally distinguished from associative learning methods that rely on direct observation, by its use of inference from indirect evidence. In twenty-three healthy human subjects, we isolated effects of first-hand experience, other people's choices, and the mediating effect of their confidence, on decision-making and neural correlates of value within ventromedial prefrontal cortex (vmPFC). Value derived from first hand experience and other people's choices (regardless of confidence) were indiscriminately represented across vmPFC. However, value computed from agent choices weighted by their associated confidence was represented with specificity for ventromedial area 10. This pattern corresponds to shifts of connectivity and overlapping cognitive processes along a posterior-anterior vmPFC axis. Task behavior and self-reported self-reliance for decision-making in other social contexts correlated. The tendency to conform in other social contexts corresponded to increased activation in cortical regions previously shown to respond to social conflict in proportion to subsequent conformity (Campbell-Meiklejohn et al., 2010). The tendency to self-monitor predicted a selectively enhanced response to accordance with others in the right temporoparietal junction (rTPJ). The findings anatomically decompose vmPFC value representations according to computational requirements and provide biological insight into the social transmission of preference and reassurance gained from the confidence of others. Significance Statement: Decades of research have provided evidence that the ventromedial prefrontal cortex (vmPFC) signals the satisfaction we expect from imminent actions. However, we have a surprisingly modest understanding of the organization of value across this substantial and varied region. This study finds that using cues of the reliability of other peoples'; knowledge to enhance expectation of personal success generates value correlates that are anatomically distinct from those concurrently computed from direct, personal experience. This suggests that representation of decision values in vmPFC is suborganized according to the underlying computation, consistent with what we know about the anatomical heterogeneity of the region. These results also provide insight into the observational learning process by which someone else's confidence can sway and reassure our choices

Hyper- and hypo-mentalizing in patients with first-episode schizophrenia: fMRI and behavioural studies

Background: Historically, research investigating neural correlates of mentalizing deficits in schizophrenia has focused on patients who have been ill for several years with lengthy exposure to medication. Little is known about the neural and behavioural presentations of theory-of-mind deficits in schizophrenia, shortly after the first episode of psychosis. Methods: We investigated social cognition in seventeen recently diagnosed first-episode schizophrenia (FES) patients with little or no exposure to antipsychotic medication and 1:1 matched healthy controls. We recorded behavioural and neural responses to the Animated Triangles Task (ATT), which is a non-verbal validated mentalizing task that measures the ascription of intentionality to the movements of objects. Results: FES patients under-interpreted social cues and over-interpreted non-social cues. These effects were influenced by current intelligence (IQ). Control group and FES neural responses replicated earlier findings in healthy adults. However, a region of anterior medial prefrontal cortex (amPFC) of FES patients showed a different response pattern to that of controls. Unlike healthy controls, patients increased activity in this social cognition region while studying ‘random’ movements of shapes, as compared to the study of movements normally interpreted as ‘intentional’. Conclusions: Mentalizing deficits in FES consists of hypo- and hyper-mentalizing. The neural pattern of FES patients is consistent with deficits in the ability to switch off mentalizing processes in potentially social contexts, instead increasing them when intentionality is not forthcoming. Overall, results demonstrate complexities of theory of mind deficits in schizophrenia that should be considered when offering social cognitive training programs

The Long-term Middle Atmospheric Influence of Very Large Solar Proton Events

Long-term variations in ozone have been caused by both natural and humankind related processes. The humankind or anthropogenic influence on ozone originates from the chlorofluorocarbons and halons (chlorine and bromine) and has led to international regulations greatly limiting the release of these substances. Certain natural ozone influences are also important in polar regions and are caused by the impact of solar charged particles on the atmosphere. Such natural variations have been studied in order to better quantify the human influence on polar ozone. Large-scale explosions on the Sun near solar maximum lead to emissions of charged particles (mainly protons and electrons), some of which enter the Earth's magnetosphere and rain down on the polar regions. "Solar proton events" have been used to describe these phenomena since the protons associated with these solar events sometimes create a significant atmospheric disturbance. We have used the National Center for Atmospheric Research (NCAR) Whole Atmosphere Community Climate Model (WACCM) to study the long-term (> few months) influences of solar proton events from 1963 through 2004 on stratospheric ozone and temperature. There were extremely large solar proton events in 1972, 1989,2000,2001, and 2003. These events caused very distinctive polar changes in layers of the Earth's atmosphere known as the stratosphere (12-50 km; -7-30 miles) and mesosphere (50-90 km; 30-55 miles). The solar protons connected with these events created hydrogen- and nitrogen-containing compounds, which led to the polar ozone destruction. The nitrogen-containing compounds, called odd nitrogen, lasted much longer than the hydrogen-containing compounds and led to long-lived stratospheric impacts. An extremely active period for these events occurred in the five-year period, 2000- 2004, and caused increases in odd nitrogen which lasted for several months after individual events. Associated stratospheric ozone decreases of >lo% were calculated to last for up to five months past the largest events. However, the computed total column ozone and stratospheric temperature changes connected with the solar events were not found to be statistically significant. Thus, solar proton events do not likely contribute significantly to measured total column ozone fluctuations and stratospheric temperature changes

Notch signalling influences cell fate decisions and HOX gene induction in axial progenitors

The generation of the post-cranial embryonic body relies on the coordinated production of spinal cord neurectoderm and presomitic mesoderm cells from neuromesodermal progenitors (NMPs). This process is orchestrated by pro-neural and pro-mesodermal transcription factors that are co-expressed in NMPs together with Hox genes, which are critical for axial allocation of NMP derivatives. NMPs reside in a posterior growth region, which is marked by the expression of Wnt, FGF and Notch signalling components. While the importance of Wnt and FGF in influencing the induction and differentiation of NMPs is well established, the precise role of Notch remains unclear. Here, we show that the Wnt/FGF-driven induction of NMPs from human embryonic stem cells (hESCs) relies on Notch signalling. Using hESC-derived NMPs and chick embryo grafting, we demonstrate that Notch directs a pro-mesodermal character at the expense of neural fate. We show that Notch also contributes to activation of HOX gene expression in human NMPs, partly in a non-cell-autonomous manner. Finally, we provide evidence that Notch exerts its effects via the establishment of a negative feedback loop with FGF signalling.</p

Nature and completeness of galaxies detected in the Two Micron All Sky Survey

We cross correlate the well-defined and very complete spectroscopic Main Galaxy Sample (MGS) of 156,000 bright (r<17.5 mag) galaxies from the SDSS with 2MASS sources to explore the nature and completeness of the 2MASS K-band selection of nearby galaxies. 2MASS detects 90% of the MGS brighter than r=17 mag. For r<16, 93.1% of the MGS is found in the 2MASS Extended Source Catalog (XSC). These detections span the representative range of optical and near-IR galaxy properties, but with a surface brightness-dependent bias to preferentially miss the most blue and low-concentration sources, consistent with the most morphologically late-type galaxy population. An XSC completeness of 97.5% is achievable at bright magnitudes, with blue LSBs being the only major source of incompleteness, if one follows our careful matching criteria and weeds out spurious SDSS sources. We conclude that the rapid drop in XSC completeness at r>16 reflects the sharp surface-brightness limit of the extended source detection algorithm in 2MASS. As a result, the r>16 galaxies found in the XSC are over-representative in red early types and under-representative in blue latetypes. At r>16 the XSC suffers an additional selection effect from the 2-3" spatial resolution limit of 2MASS. Therefore, 2MASS continues to detect 90% of of the MGS at 16<r<17, but with a growing fraction found in the Point Source Catalog (PSC) only. Overall, one third of the MGS is detected in the 2MASS PSC but not the XSC. A combined K<13.57 and r<16 selection provides the most representative inventory of galaxies in the local cosmos with near-IR and optical measurements, and 90.8% completeness. Using data from SDSS-DR2, this sample contains 19,156 galaxies with a median redshift of 0.052. (abridged)Comment: Submitted to MNRAS, 20 pages, Latex using mn2e.cls and macros.tex (included), 17 figures, version with full resolution figures at http://www.astro.umass.edu/~dmac/Preprints/mcintosh.hires.p