Improved ventricular function during inhalation of PGI(2) aerosol partly relies on enhanced myocardial contractility

Inhaled prostacyclin (PGI(2)) aerosol induces selective pulmonary vasodilation. Further, it improves right ventricular ( RV) function, which may largely rely on pulmonary vasodilation, but also on enhanced myocardial contractility. We investigated the effects of the inhaled PGI(2) analogs epoprostenol (EPO) and iloprost (ILO) on RV function and myocardial contractility in 9 anesthetized pigs receiving aerosolized EPO (25 and 50 ng center dot kg(-1) center dot min(-1)) and, consecutively, ILO (60 ng center dot kg(-1) center dot min(-1)) for 20 min each. We measured pulmonary artery pressure ( PAP), RV ejection fraction (RVEF) and RV end-diastolic-volume (RV-EDV), and left ventricular end-systolic pressure-volume-relation (end-systolic elastance, E-es). EPO and ILO reduced PAP, increased RVEF and reduced RVEDV. E-es was enhanced during all doses tested, which reached statistical significance during EPO25ng and ILO, but not during EPO50ng. PGI(2) aerosol enhances myocardial contractility in healthy pigs, contributing to improve RV function. Copyright (C) 2005 S. Karger AG, Basel

An objective framework to test the quality of candidate indicators of good environmental status

This is the final version. Available from the publisher via the DOI in this record.Large efforts are on-going within the EU to prepare the Marine Strategy Framework Directive's (MSFD) assessment of the environmental status of the European seas. This assessment will only be as good as the indicators chosen to monitor the 11 descriptors of good environmental status (GEnS). An objective and transparent framework to determine whether chosen indicators actually support the aims of this policy is, however, not yet in place. Such frameworks are needed to ensure that the limited resources available to this assessment optimize the likelihood of achieving GEnS within collaborating states. Here, we developed a hypothesis-based protocol to evaluate whether candidate indicators meet quality criteria explicit to the MSFD, which the assessment community aspires to. Eight quality criteria are distilled from existing initiatives, and a testing and scoring protocol for each of them is presented. We exemplify its application in three worked examples, covering indicators for three GEnS descriptors (1, 5, and 6), various habitat components (seaweeds, seagrasses, benthic macrofauna, and plankton), and assessment regions (Danish, Lithuanian, and UK waters). We argue that this framework provides a necessary, transparent and standardized structure to support the comparison of candidate indicators, and the decision-making process leading to indicator selection. Its application could help identify potential limitations in currently available candidate metrics and, in such cases, help focus the development of more adequate indicators. Use of such standardized approaches will facilitate the sharing of knowledge gained across the MSFD parties despite context-specificity across assessment regions, and support the evidence-based management of European seas.European Union: 7th Framework ProgrammeNatural Environment Research Council (NERC)UK Department for Environment, Food and Rural Affair

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

Do patients adhere to over-the-counter artemisinin combination therapy for malaria? evidence from an intervention study in Uganda

<p>Abstract</p> <p>Background</p> <p>Increasing affordability of artemisinin combination therapy (ACT) in the African retail sector could be critical to expanding access to effective malaria treatment, but must be balanced by efforts to protect the efficacy of these drugs. Previous research estimates ACT adherence rates among public sector patients, but adherence among retail sector purchasers could differ substantially. This study aimed to estimate adherence rates to subsidized, over-the-counter ACT in rural Uganda.</p> <p>Methods</p> <p>An intervention study was conducted with four licensed drug shops in Eastern Uganda in December 2009. Artemether-lumefantrine (AL) was made available for sale at a 95% subsidy over-the counter. Customers completed a brief survey at the time of purchase and then were randomly assigned to one of three study arms: no follow-up, follow-up after two days or follow-up after three days. Surveyors recorded the number of pills remaining through blister pack observation or through self-report if the pack was unavailable. The purpose of the three-day follow-up arm was to capture non-adherence in the sense of an incomplete treatment course ("under-dosing"). The purpose of the two-day follow-up arm was to capture whether participants completed the full course too soon ("over-dosing").</p> <p>Results</p> <p>Of the 106 patients in the two-day follow-up sample, 14 (13.2%) had finished the entire treatment course by the second day. Of the 152 patients in the three-day follow-up sample, 49 (32.2%) were definitely non-adherent, three (2%) were probably non-adherent and 100 (65.8%) were probably adherent. Among the 52 who were non-adherent, 31 (59.6%) had more than a full day of treatment remaining.</p> <p>Conclusions</p> <p>Overall, adherence to subsidized ACT purchased over-the-counter was found to be moderate. Further, a non-trivial fraction of those who complete treatment are taking the full course too quickly. Strategies to increase adherence in the retail sector are needed in the context of increasing availability and affordability of ACT in this sector.</p

Nonlinear analysis of EEG signals at different mental states

BACKGROUND: The EEG (Electroencephalogram) is a representative signal containing information about the condition of the brain. The shape of the wave may contain useful information about the state of the brain. However, the human observer can not directly monitor these subtle details. Besides, since bio-signals are highly subjective, the symptoms may appear at random in the time scale. Therefore, the EEG signal parameters, extracted and analyzed using computers, are highly useful in diagnostics. This work discusses the effect on the EEG signal due to music and reflexological stimulation. METHODS: In this work, nonlinear parameters like Correlation Dimension (CD), Largest Lyapunov Exponent (LLE), Hurst Exponent (H) and Approximate Entropy (ApEn) are evaluated from the EEG signals under different mental states. RESULTS: The results obtained show that EEG to become less complex relative to the normal state with a confidence level of more than 85% due to stimulation. CONCLUSIONS: It is found that the measures are significantly lower when the subjects are under sound or reflexologic stimulation as compared to the normal state. The dimension increases with the degree of the cognitive activity. This suggests that when the subjects are under sound or reflexologic stimuli, the number of parallel functional processes active in the brain is less and the brain goes to a more relaxed stat

Shedding light on plant litter decomposition: Advances, implications and new directions in understanding the role of photodegradation

Litter decomposition contributes to one of the largest fluxes of carbon (C) in the terrestrial biosphere and is a primary control on nutrient cycling. The inability of models using climate and litter chemistry to predict decomposition in dry environments has stimulated investigation of non-traditional drivers of decomposition, including photodegradation, the abiotic decomposition of organic matter via exposure to solar radiation. Recent work in this developing field shows that photodegradation may substantially influence terrestrial C fluxes, including abiotic production of carbon dioxide, carbon monoxide and methane, especially in arid and semi-arid regions. Research has also produced contradictory results regarding controls on photodegradation. Here we summarize the state of knowledge about the role of photodegradation in litter decomposition and C cycling and investigate drivers of photodegradation across experiments using a meta-analysis. Overall, increasing litter exposure to solar radiation increased mass loss by 23% with large variation in photodegradation rates among and within ecosystems. This variation was tied to both litter and environmental characteristics. Photodegradation increased with litter C to nitrogen (N) ratio, but not with lignin content, suggesting that we do not yet fully understand the underlying mechanisms. Photodegradation also increased with factors that increased solar radiation exposure (latitude and litter area to mass ratio) and decreased with mean annual precipitation. The impact of photodegradation on C (and potentially N) cycling fundamentally reshapes our thinking of decomposition as a solely biological process and requires that we define the mechanisms driving photodegradation before we can accurately represent photodegradation in global C and N models. © 2012 US Government

Learning and Memory Alterations Are Associated with Hippocampal N-acetylaspartate in a Rat Model of Depression as Measured by 1H-MRS

It is generally accepted that cognitive processes, such as learning and memory, are affected in depression. The present study used a rat model of depression, chronic unpredictable mild stress (CUMS), to determine whether hippocampal volume and neurochemical changes were involved in learning and memory alterations. A further aim was to determine whether these effects could be ameliorated by escitalopram treatment, as assessed with the non-invasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Our results demonstrated that CUMS had a dramatic influence on spatial cognitive performance in the Morris water maze task, and CUMS reduced the concentration of neuronal marker N-acetylaspartate (NAA) in the hippocampus. These effects could be significantly reversed by repeated administration of escitalopram. However, neither chronic stress nor escitalopram treatment influenced hippocampal volume. Of note, the learning and memory alterations of the rats were associated with right hippocampal NAA concentration. Our results indicate that in depression, NAA may be a more sensitive measure of cognitive function than hippocampal volume

A Conserved Behavioral State Barrier Impedes Transitions between Anesthetic-Induced Unconsciousness and Wakefulness: Evidence for Neural Inertia

One major unanswered question in neuroscience is how the brain transitions between conscious and unconscious states. General anesthetics offer a controllable means to study these transitions. Induction of anesthesia is commonly attributed to drug-induced global modulation of neuronal function, while emergence from anesthesia has been thought to occur passively, paralleling elimination of the anesthetic from its sites in the central nervous system (CNS). If this were true, then CNS anesthetic concentrations on induction and emergence would be indistinguishable. By generating anesthetic dose-response data in both insects and mammals, we demonstrate that the forward and reverse paths through which anesthetic-induced unconsciousness arises and dissipates are not identical. Instead they exhibit hysteresis that is not fully explained by pharmacokinetics as previously thought. Single gene mutations that affect sleep-wake states are shown to collapse or widen anesthetic hysteresis without obvious confounding effects on volatile anesthetic uptake, distribution, or metabolism. We propose a fundamental and biologically conserved concept of neural inertia, a tendency of the CNS to resist behavioral state transitions between conscious and unconscious states. We demonstrate that such a barrier separates wakeful and anesthetized states for multiple anesthetics in both flies and mice, and argue that it contributes to the hysteresis observed when the brain transitions between conscious and unconscious states

Analysis of Thyroid Response Element Activity during Retinal Development

Thyroid hormone (TH) signaling components are expressed during retinal development in dynamic spatial and temporal patterns. To probe the competence of retinal cells to mount a transcriptional response to TH, reporters that included thyroid response elements (TREs) were introduced into developing retinal tissue. The TREs were placed upstream of a minimal TATA-box and two reporter genes, green fluorescent protein (GFP) and human placental alkaline phosphatase (PLAP). Six of the seven tested TREs were first tested in vitro where they were shown to drive TH-dependent expression. However, when introduced into the developing retina, the TREs reported in different cell types in both a TH-dependent and TH-independent manner, as well as revealed specific spatial patterns in their expression. The role of the known thyroid receptors (TR), TRα and TRβ, was probed using shRNAs, which were co-electroporated into the retina with the TREs. Some TREs were positively activated by TR+TH in the developing outer nuclear layer (ONL), where photoreceptors reside, as well as in the outer neuroblastic layer (ONBL) where cycling progenitor cells are located. Other TREs were actively repressed by TR+TH in cells of the ONBL. These data demonstrate that non-TRs can activate some TREs in a spatially regulated manner, whereas other TREs respond only to the known TRs, which also read out activity in a spatially regulated manner. The transcriptional response to even simple TREs provides a starting point for understanding the regulation of genes by TH, and highlights the complexity of transcriptional regulation within developing tissue