Norepinephrine to increase blood pressure in endotoxaemic pigs is associated with improved hepatic mitochondrial respiration

ABSTRACT: INTRODUCTION: Low blood pressure, inadequate tissue oxygen delivery and mitochondrial dysfunction have all been implicated in the development of sepsis-induced organ failure. This study evaluated the effect on liver mitochondrial function of using norepinephrine to increase blood pressure in experimental sepsis. METHODS: Thirteen anaesthetized pigs received endotoxin (Escherichia coli lipopolysaccharide B0111:B4; 0.4 mug/kg per hour) and were subsequently randomly assigned to norepinephrine treatment or placebo for 10 hours. Norepinephrine dose was adjusted at 2-hour intervals to achieve 15 mmHg increases in mean arterial blood pressure up to 95 mmHg. Systemic (thermodilution) and hepatosplanchnic (ultrasound Doppler) blood flow were measured at each step. At the end of the experiment, hepatic mitochondrial oxygen consumption (high-resolution respirometry) and citrate synthase activity (spectrophotometry) were assessed. RESULTS: Mean arterial pressure (mmHg) increased only in norepinephrine-treated animals (from 73 [median; range 69 to 81] to 63 [60 to 68] in controls [P = 0.09] and from 83 [69 to 93] to 96 [86 to 108] in norepinephrine-treated animals [P = 0.019]). Cardiac index and systemic oxygen delivery (DO2) increased in both groups, but significantly more in the norepinephrine group (P < 0.03 for both). Cardiac index (ml/min per.kg) increased from 99 (range: 72 to 112) to 117 (110 to 232) in controls (P = 0.002), and from 107 (84 to 132) to 161 (147 to 340) in norepinephrine-treated animals (P = 0.001). DO2 (ml/min per.kg) increased from 13 (range: 11 to 15) to 16 (15 to 24) in controls (P = 0.028), and from 16 (12 to 19) to 29 (25 to 52) in norepinephrine-treated animals (P = 0.018). Systemic oxygen consumption (systemic VO2) increased in both groups (P < 0.05), whereas hepatosplanchnic flows, DO2 and VO2 remained stable. The hepatic lactate extraction ratio decreased in both groups (P = 0.05). Liver mitochondria complex I-dependent and II-dependent respiratory control ratios were increased in the norepinephrine group (complex I: 3.5 [range: 2.1 to 5.7] in controls versus 5.8 [4.8 to 6.4] in norepinephrine-treated animals [P = 0.015]; complex II: 3.1 [2.3 to 3.8] in controls versus 3.7 [3.3 to 4.6] in norepinephrine-treated animals [P = 0.09]). No differences were observed in citrate synthase activity. CONCLUSION: Norepinephrine treatment during endotoxaemia does not increase hepatosplanchnic flow, oxygen delivery or consumption, and does not improve the hepatic lactate extraction ratio. However, norepinephrine increases the liver mitochondria complex I-dependent and II-dependent respiratory control ratios. This effect was probably mediated by a direct effect of norepinephrine on liver cells.

Single center experience with provisional abciximab therapy in complex lower limb interventions

BACKGROUND: Abciximab, a glycoprotein IIb/IIIa antagonist has been shown to improve patency and clinical outcome in patients undergoing endovascular recanalization of femoro-popliteal occlusions. However, data on abciximab therapy in complex peripheral catheter interventions of lower limbs are quite limited. The objective of this retrospective study was to evaluate the clinical and hemodynamic outcomes of patients treated with provisional abciximab during complex peripheral catheter interventions. PATIENTS AND METHODS: Analysis of a consecutive series of 44 patients with provisional abciximab therapy in complex peripheral catheter interventions with imminent risk of early rethrombosis defined as revascularization of arterial occlusions associated with one or more of the following additional circumstances named as time-consuming intervention > 3 hours, compromised contrast flow not solved by stenting, distal embolization not solved by mechanical thromboembolectomy, and peri-interventional notice of thrombus evolution despite adequate heparin adjustment of lower limbs. Adjunctive abciximab therapy was started in accordance to percutaneous coronary bailout situations. The decision to add abciximab was based on the decision of the operator and went along with the judgement that there is a rising risk of reocclusion due to the progressive complexity of an individual intervention. A bolus of 0.25 mg per kilogram of body weight, followed by a maintenance infusion of 0.125 microg/kg/min (up to a maximum dosage of 10 microg/min) for 12 hours was administered. Clinical and hemodynamic outcome was prospectively assessed at discharge, three and six months after the index procedure. RESULTS: The occluded artery of 44 limbs was in the iliac (2%), in the femoro-popliteal (73%) or below the knee segment (25%). Overall, occlusion length was 11.5 +/- 6.5 cm. Technical success rate was 95%. Mean ABI increased from 0.5 +/- 0.16 to 0.88 +/- 0.19 (p < 0.001) with immediate hemodynamic improvement of 91%. Overall, sustained clinical improvement was 84% and 66% at three and six months follow-up, with best results in iliac (100%), followed by below the knee (73%) and by femoro-popliteal segment (63%) at six months, respectively. Overall, secondary clinical improvement was 86% at six months. Minor and major bleeding complications were 16% and 9%, respectively. CONCLUSION: Abciximab should be noticed as medical adjunct in the interventional armamentarium to prevent imminent rethrombosis in complex peripheral catheter interventions.

Mortality of patients lost to follow-up in antiretroviral treatment programmes in resource-limited settings: systematic review and meta-analysis

BACKGROUND: The retention of patients in antiretroviral therapy (ART) programmes is an important issue in resource-limited settings. Loss to follow up can be substantial, but it is unclear what the outcomes are in patients who are lost to programmes. METHODS AND FINDINGS: We searched the PubMed, EMBASE, Latin American and Caribbean Health Sciences Literature (LILACS), Indian Medlars Centre (IndMed) and African Index Medicus (AIM) databases and the abstracts of three conferences for studies that traced patients lost to follow up to ascertain their vital status. Main outcomes were the proportion of patients traced, the proportion found to be alive and the proportion that had died. Where available, we also examined the reasons why some patients could not be traced, why patients found to be alive did not return to the clinic, and the causes of death. We combined mortality data from several studies using random-effects meta-analysis. Seventeen studies were eligible. All were from sub-Saharan Africa, except one study from India, and none were conducted in children. A total of 6420 patients (range 44 to 1343 patients) were included. Patients were traced using telephone calls, home visits and through social networks. Overall the vital status of 4021 patients could be ascertained (63%, range across studies: 45% to 86%); 1602 patients had died. The combined mortality was 40% (95% confidence interval 33%-48%), with substantial heterogeneity between studies (P<0.0001). Mortality in African programmes ranged from 12% to 87% of patients lost to follow-up. Mortality was inversely associated with the rate of loss to follow up in the programme: it declined from around 60% to 20% as the percentage of patients lost to the programme increased from 5% to 50%. Among patients not found, telephone numbers and addresses were frequently incorrect or missing. Common reasons for not returning to the clinic were transfer to another programme, financial problems and improving or deteriorating health. Causes of death were available for 47 deaths: 29 (62%) died of an AIDS defining illness. CONCLUSIONS: In ART programmes in resource-limited settings a substantial minority of adults lost to follow up cannot be traced, and among those traced 20% to 60% had died. Our findings have implications both for patient care and the monitoring and evaluation of programmes.

Isolation and functional characterization of a stable complex between photoactivated rhodopsin and the G protein, transducin

Transitory binding between photoactivated rhodopsin (Rho* or Meta II) and the G protein transducin (Gt-GDP) is the first step in the visual signaling cascade. Light causes photoisomerization of the 11-cis-retinylidene chromophore in rhodopsin (Rho) to all-trans-retinylidene, which induces conformational changes that allow Gt-GDP to dock onto the Rho* surface. GDP then dissociates from Gt, leaving a transient nucleotide-empty Rho*-Gt(e) complex before GTP becomes bound, and Gt-GTP then dissociates from Rho*. Further biochemical advances are required before structural studies of the various Rho*-Gt complexes can be initiated. Here, we describe the isolation of n-dodecyl-beta-maltoside solubilized, stable, functionally active, Rho*-Gt(e), Rho(e)*-Gt(e), and 9-cis-retinal/11-cis-retinal regenerated Rho-Gt(e) complexes by sucrose gradient centrifugation. In these complexes, Rho* spectrally remained in its Meta II state, and Gt(e) retained its ability to interact with GTPgammaS. Removal of all-trans-retinylidene from Rho*-Gt(e) had no effect on the stability of the Rho(e)*-Gt(e) complex. Moreover, opsin in the Rho(e)*-Gt(e) complex with an empty nucleotide-binding pocket in Gt and an empty retinoid-binding pocket in Rho was regenerated up to 75% without complex dissociation. These results indicate that once Rho* couples with Gt, the chromophore plays a minor role in stabilizing this complex. Moreover, in complexes regenerated with 9-cis-retinal/11-cis-retinal, Rho retains a conformation similar to Rho* that is stabilized by Gt(e) apo-protein.

Impact of definitions of loss to follow-up (LTFU) in antiretroviral therapy program evaluation: variation in the definition can have an appreciable impact on estimated proportions of LTFU

OBJECTIVE To examine the impact of different definitions of loss to follow-up (LTFU) on estimates of program outcomes in cohort studies of patients on antiretroviral therapy (ART). STUDY DESIGN AND SETTING We examined the impact of different definitions of LTFU using data from the International Epidemiological Databases to Evaluate AIDS-Southern Africa. The reference approach, Definition A, was compared with five alternative scenarios that differed in eligibility for analysis and the date assigned to the LTFU outcome. Kaplan-Meier estimates of LTFU were calculated up to 2 years after starting ART. RESULTS Estimated cumulative LTFU were 14% and 22% at 12 and 24 months, respectively, using the reference approach. Differences in the proportion LTFU were reported in the alternative scenarios with 12-month estimates of LTFU varying by up to 39% compared with Definition A. Differences were largest when the date assigned to the LTFU outcome was 6 months after the date of last contact and when the site-specific definition of LTFU was used. CONCLUSION Variation in the definitions of LTFU within cohort analyses can have an appreciable impact on estimated proportions of LTFU over 2 years of follow-up. Use of a standardized definition of LTFU is needed to accurately measure program effectiveness and comparability between programs.

Oligo(aryleneethynylene)s with Terminal Pyridyl Groups: Synthesis and Length Dependence of the Tunneling-to-Hopping Transition of Single-Molecule Conductances

The synthesis is reported of a new series of oligo(aryleneethynylene) (OAE) derivatives of up to ca. 6 nm in molecular length (OAE9) using iterative Pd-mediated Sonogashira cross-coupling methodology. The oligo-p-phenyleneethynylene cores of the molecular wires are functionalized at both termini with pyridyl units for attachment to gold leads. The molecular structures determined by single-crystal X-ray analysis are reported for OAE4, OAE5, OAE7, and OAE8a. The charge transport characteristics of derivatives OAE3–OAE9 in single-molecular junctions have been studied using the mechanically controlled break junction technique. The data demonstrate that the junction conductance decreases with increasing molecular length. A transition from coherent transport via tunneling to a hopping mechanism is found for OAE wires longer than ca. 3 nm.

A multiplex PCR for the simultaneous detection and genotyping of the Echinococcus granulosus complex.

Echinococcus granulosus is characterized by high intra-specific variability (genotypes G1-G10) and according to the new molecular phylogeny of the genus Echinococcus, the E. granulosus complex has been divided into E. granulosus sensu stricto (G1-G3), E. equinus (G4), E. ortleppi (G5), and E. canadensis (G6-G10). The molecular characterization of E. granulosus isolates is fundamental to understand the spatio-temporal epidemiology of this complex in many endemic areas with the simultaneous occurrence of different Echinococcus species and genotypes. To simplify the genotyping of the E. granulosus complex we developed a single-tube multiplex PCR (mPCR) allowing three levels of discrimination: (i) Echinococcus genus, (ii) E. granulosus complex in common, and (iii) the specific genotype within the E. granulosus complex. The methodology was established with known DNA samples of the different strains/genotypes, confirmed on 42 already genotyped samples (Spain: 22 and Bulgaria: 20) and then successfully applied on 153 unknown samples (Tunisia: 114, Algeria: 26 and Argentina: 13). The sensitivity threshold of the mPCR was found to be 5 ng Echinoccoccus DNA in a mixture of up to 1 µg of foreign DNA and the specificity was 100% when template DNA from closely related members of the genus Taenia was used. Additionally to DNA samples, the mPCR can be carried out directly on boiled hydatid fluid or on alkaline-lysed frozen or fixed protoscoleces, thus avoiding classical DNA extractions. However, when using Echinococcus eggs obtained from fecal samples of infected dogs, the sensitivity of the mPCR was low (<40%). Thus, except for copro analysis, the mPCR described here has a high potential for a worldwide application in large-scale molecular epidemiological studies on the Echinococcus genus.

A novel comparative research platform designed to determine the functional significance of tree species diversity in European forests

One of the current advances in functional biodiversity research is the move away from short-lived test systems towards the exploration of diversity-ecosystem functioning relationships in structurally more complex ecosystems. In forests, assumptions about the functional significance of tree species diversity have only recently produced a new generation of research on ecosystem processes and services. Novel experimental designs have now replaced traditional forestry trials, but these comparatively young experimental plots suffer from specific difficulties that are mainly related to the tree size and longevity. Tree species diversity experiments therefore need to be complemented with comparative observational studies in existing forests. Here we present the design and implementation of a new network of forest plots along tree species diversity gradients in six major European forest types: the FunDivEUROPE Exploratory Platform. Based on a review of the deficiencies of existing observational approaches and of unresolved research questions and hypotheses, we discuss the fundamental criteria that shaped the design of our platform. Key features include the extent of the species diversity gradient with mixtures up to five species, strict avoidance of a dilution gradient, special attention to community evenness and minimal covariation with other environmental factors. The new European research platform permits the most comprehensive assessment of tree species diversity effects on forest ecosystem functioning to date since it offers a common set of research plots to groups of researchers from very different disciplines and uses the same methodological approach in contrasting forest types along an extensive environmental gradient. (C) 2013 Elsevier GmbH. All rights reserved.

Impact of dams, dam removal and dam-related river engineering structures on sediment connectivity and channel morphology of the Fugnitz and the Kaja Rivers

In terms of changing flow and sediment regimes of rivers, dams are often regarded as the most dominant form of human impact on fluvial systems. Dams can decrease the flux of water and sediments leading to channel changes such as upstream aggradation and downstream degradation. The opposite effects occur when dams are removed. Channel degradation often requires further intervention in terms of river bed and bank protection works. The situation evolves more complex in river systems that are impacted by a series of dams due to feedback processes between the different system compartments. A number of studies have recently investigated geomorphic systems using connectivity approaches to improve the understanding of geomorphic system response to change. This paper presents a case study investigating the impact of dam construction, dam removal and dam-related river bed and bank protection measures on the sediment connectivity and channel morphology of the Fugnitz and the Kaja Rivers using a combination of DEM analyses, field surveys and landscape evolution modelling. For both river systems the results revealed low sediment connectivity accompanied by a fine river bed sediment facies in river sections upstream of active dams and of removed dams with protection measures. Contrarily, high sediment connectivity which was accompanied by a coarse river bed sediment facies was observed in river sections either located downstream of active dams or of removed dams with upstream protection. In terms of channel changes, significant channel degradation was examined at locations downstream of active dams and of removed dams. Channel bed and bank protection measures prevent erosion and channel slope recovery after dam removal. Landscape evolution modeling revealed a complex geomorphic response to dam construction and dam removal as sediment output rates and therefore geomorphic processes have been shown to act in a non-linear manner. These insights are deemed to have major implications for river management and conservation, as quality and state of riverine habitats are determined by channel morphology and river bed sediment composition.

From Broadstone to Zackenberg

Ecological networks are typically complex constructions of species and their interactions. During the last decade, the study of networks has moved from static to dynamic analyses, and has attained a deeper insight into their internal structure, heterogeneity, and temporal and spatial resolution. Here, we review, discuss and suggest research lines in the study of the spatio-temporal heterogeneity of networks and their hierarchical nature. We use case study data from two well-characterized model systems (the food web in Broadstone Stream in England and the pollination network at Zackenberg in Greenland), which are complemented with additional information from other studies. We focus upon eight topics: temporal dynamic space-for-time substitutions linkage constraints habitat borders network modularity individual-based networks invasions of networks and super networks that integrate different network types. Few studies have explicitly examined temporal change in networks, and we present examples that span from daily to decadal change: a common pattern that we see is a stable core surrounded by a group of dynamic, peripheral species, which, in pollinator networks enter the web via preferential linkage to the most generalist species. To some extent, temporal and spatial scales are interchangeable (i.e. networks exhibit ‘ergodicity’) and we explore how space-for-time substitutions can be used in the study of networks. Network structure is commonly constrained by phenological uncoupling (a temporal phenomenon), abundance, body size and population structure. Some potential links are never observed, that is they are ‘forbidden’ (fully constrained) or ‘missing’ (a sampling effect), and their absence can be just as ecologically significant as their presence. Spatial habitat borders can add heterogeneity to network structure, but their importance has rarely been studied: we explore how habitat generalization can be related to other resource dimensions. Many networks are hierarchically structured, with modules forming the basic building blocks, which can result in self-similarity. Scaling down from networks of species reveals another, finer-grained level of individual-based organization, the ecological consequences of which have yet to be fully explored. The few studies of individual-based ecological networks that are available suggest the potential for large intraspecific variance and, in the case of food webs, strong size-structuring. However, such data are still scarce and more studies are required to link individual-level and species-level networks. Invasions by alien species can be tracked by following the topological ‘career’ of the invader as it establishes itself within a network, with potentially important implications for conservation biology. Finally, by scaling up to a higher level of organization, it is possible to combine different network types (e.g. food webs and mutualistic networks) to form super networks, and this new approach has yet to be integrated into mainstream ecological research. We conclude by listing a set of research topics that we see as emerging candidates for ecological network studies in the near future.

A combined vacuum crushing and sieving (CVCS) system designed to determine noble gas paleotemperatures from stalagmite samples

This paper presents a novel extraction device for water and noble gases from speleothem samples for noble gas paleotemperature determination. The “combined vacuum crushing and sieving (CVCS) system” was designed to reduce the atmospheric noble gas contents from air inclusions in speleothem samples by up to 2 orders of magnitude without adsorbing atmospheric noble gases onto the freshly produced grain surfaces, a process that had often hampered noble gas temperature (NGT) determination in the past. We also present the results from first performance tests of the CVCS system processing stalagmite samples grown at a known temperature. This temperature is reliably reproduced by the NGTs derived from Ar, Kr, and Xe extracted from the samples. The CVCS system is, therefore, suitable for routine determinations of accurate NGTs. In combination with stalagmite dating, these NGTs will allow reconstructing past regional temperature evolutions, and also support the interpretation of the often complex stable isotope records preserved in the stalagmites' calcite.

Diversity of morphological patterns in supramolecular polymers formed from the amphiphilic oligomers of pyrenes

Very important aspects of the modern nanotechnology are control and prediction of arraying patterns of opto- and electroactive molecules in discrete objects on nanoscale level both on surface and solution. Consequqntly, a self-assembly of small molucules provides such an opportunity.For example, oligopyrenotides (OPs, short amphiphilic pyrene oligomers) represent a novel class of amphiphilic molecules which tend to aggegate in aqueous phase. As has been already shown, OPs are able to form 1D supramolecular polymer only under high salt concentration. Since programmed arraying of polyaromatic hydrocarbons in structurally defined objects could offer enhanced performance over the individual components, prediction and controlling of their spatial arrangement remains challenging. Herein we demonstrate that substitution type of the pyrene is crutial, and it determines a morphology of the assemblies. Thus, a 1.6-linkage causes a formation of large, free-standing 2D supromolecular polymers with a thickness 2 nm. These assemblies possess a high degree of an internal order: the interior consists of hydrophobic pyrenes and alkyl chains, whereas the exterior exists as a net of hydrophilic negatively charged phosphates. Contrary, a 1.8-linkage exclusiveley leads to a formation of long (up to a few micrometer), nanometer thick helical supramolecular polymers. These structures tend to form even more complex structures (bundles, superhelixes). Moreover for both molecules, the polymerizations occurs via a nucleation-elongation mechanism. To study Py3 self-assembly, we carried out whole set of spectroscopic (UV/vis, fluorescence, DLS) and microscopic experiments (AFM).

Dynamic Transmission Modes to Support Opportunistic Information-Centric Networks

In this paper, we describe dynamic unicast to increase communication efficiency in opportunistic Information-centric networks. The approach is based on broadcast requests to quickly find content and dynamically creating unicast links to content sources without the need of neighbor discovery. The links are kept temporarily as long as they deliver content and are quickly removed otherwise. Evaluations in mobile networks show that this approach maintains ICN flexibility to support seamless mobile communication and achieves up to 56.6% shorter transmission times compared to broadcast in case of multiple concurrent requesters. Apart from that, dynamic unicast unburdens listener nodes from processing unwanted content resulting in lower processing overhead and power consumption at these nodes. The approach can be easily included into existing ICN architectures using only available data structures.

Redox front geochemistry and weathering: theory with application to the Osamu Utsumi uranium mine, Poços de Caldas, Brazil

Numerical calculations describing weathering of the Poços de Caldas alkaline complex (Minas Gerais, Brazil) by infiltrating groundwater are carried out for time spans up to two million years in the absence of pyrite, and up to 500,000 years with pyrite present. Deposition of uranium resulting from infiltration of oxygenated, uranium bearing groundwater through the hydrothermally altered phonolitic host rock at the Osamu Utsumi uranium mine is also included in the latter calculation. The calculations are based on the quasi-stationary state approximation to mass conservation equations for pure advective transport. This approximation enables the prediction of solute concentrations, mineral abundances and porosity as functions of time and distance over geologic time spans. Mineral reactions are described by kinetic rate laws for both precipitation and dissolution. Homogeneous equilibrium is assumed to be maintained within the aqueous phase. No other constraints are imposed on the calculations other than the initial composition of the unaltered host rock and the composition of the inlet fluid, taken as rainwater modified by percolation through a soil zone. The results are in qualitative agreement with field observations at the Osamu Utsumi uranium mine. They predict a lateritic cover followed by a highly porous saprolitic zone, a zone of oxidized rock with pyrite replaced by iron-hydroxide, a sharp redox front at which uranium is deposited, and the reduced unweathered host rock. Uranium is deposited in a narrow zone located on the reduced side of the redox front in association with pyrite, in agreement with field observations. The calculations predict the formation of a broad dissolution front of primary kaolinite that penetrates deep into the host rock accompanied by the precipitation of secondary illite. Secondary kaolinite occurs in a saprolitic zone near the surface and in the vicinity of the redox front. Gibbsite forms a bi-modal distribution consisting of a maximum near the surface followed by a thin tongue extending downward into the weathered profile in agreement with field observations. The results are found to be insensitive to the kinetic rate constants used to describe mineral reactions.

Can we constrain the interior structure of rocky exoplanets from mass and radius measurements?

Aims. We present an inversion method based on Bayesian analysis to constrain the interior structure of terrestrial exoplanets, in the form of chemical composition of the mantle and core size. Specifically, we identify what parts of the interior structure of terrestrial exoplanets can be determined from observations of mass, radius, and stellar elemental abundances. Methods. We perform a full probabilistic inverse analysis to formally account for observational and model uncertainties and obtain confidence regions of interior structure models. This enables us to characterize how model variability depends on data and associated uncertainties. Results. We test our method on terrestrial solar system planets and find that our model predictions are consistent with independent estimates. Furthermore, we apply our method to synthetic exoplanets up to 10 Earth masses and up to 1.7 Earth radii, and to exoplanet Kepler-36b. Importantly, the inversion strategy proposed here provides a framework for understanding the level of precision required to characterize the interior of exoplanets. Conclusions. Our main conclusions are (1) observations of mass and radius are sufficient to constrain core size; (2) stellar elemental abundances (Fe, Si, Mg) are principal constraints to reduce degeneracy in interior structure models and to constrain mantle composition; (3) the inherent degeneracy in determining interior structure from mass and radius observations does not only depend on measurement accuracies, but also on the actual size and density of the exoplanet. We argue that precise observations of stellar elemental abundances are central in order to place constraints on planetary bulk composition and to reduce model degeneracy. We provide a general methodology of analyzing interior structures of exoplanets that may help to understand how interior models are distributed among star systems. The methodology we propose is sufficiently general to allow its future extension to more complex internal structures including hydrogen- and water-rich exoplanets.