Refine
Year of publication
- 2014 (1214) (remove)
Document Type
- Article (588)
- Part of Periodical (163)
- Working Paper (149)
- Book (134)
- Doctoral Thesis (86)
- Report (27)
- Part of a Book (23)
- Conference Proceeding (18)
- Review (10)
- Preprint (8)
Language
- English (1214) (remove)
Keywords
- taxonomy (21)
- new species (19)
- Syntax (11)
- Inversionsfigur (10)
- Multistability (10)
- Multistable figures (10)
- Wahrnehmungswechsel (10)
- morphology (8)
- Bantusprachen (7)
- Benjamin, Walter (7)
Institute
- Medizin (231)
- Wirtschaftswissenschaften (149)
- Center for Financial Studies (CFS) (131)
- Physik (101)
- Biowissenschaften (88)
- Sustainable Architecture for Finance in Europe (SAFE) (86)
- House of Finance (HoF) (82)
- Biochemie und Chemie (48)
- Geowissenschaften (41)
- Gesellschaftswissenschaften (33)
For centuries, it may have seemed as if standards of normative thinking now valid across the globe had first been instituted in Europe. These normative orders form the foundations of our verdicts that define and distinguish right and wrong, good and bad or even beautiful and ugly. But in order to better understand the global presence of such normative orders that evolved from within the European horizon, the history and implications of European expansion in the early modern era cannot be swept under the rug. ...
This chapter discusses whether and how 'new quantitative trade models' (NQTMs) can be fruitfully applied to quantify the welfare effects of trade liberalization, thus shedding light on the trade-related effects of further European integration. On the one hand, it argues that NQTMs have indeed the potential of being used to supplement traditional 'computable general equilibrium' (CGE) analysis thanks to their tight connection between theory and data, appealing micro-theoretical foundations, and enhanced attention to the estimation of structural parameters. On the other hand, further work is still needed in order to fully exploit such potential.
In this study prepared for the ECON Committee of the European Parliament, Gellings, Jungbluth and Langenbucher present a graphic overview on core legislation in the area of economic and financial services in Europe. The mapping overview can serve as background for further deliberations. The study covers legislation in force, proposals and other relevant provisions in fourteen policy areas, i.e. banking, securities markets and investment firms, market infrastructure, insurance and occupational pensions, payment services, consumer protection in financial services, the European System of Financial Supervision, European Monetary Union, Euro bills and Coins and statistics, competition, taxation, commerce and company law, accounting and auditing.
Markets are central to modern society, so their failures can have devastating effects. Here, we examine a prominent failure: price bubbles. We propose that bubbles are affected by ethnic homogeneity in the market and can be thwarted by diversity. Using experimental markets in Southeast Asia and North America, we find a marked difference: Market prices fit true values 58% better in diverse markets. In homogenous markets, overpricing is higher and traders’ errors are more correlated than in diverse markets. The findings suggest that price bubbles arise not only from individual errors or financial conditions, but also from the social context of decision making. Informing public discussion, our findings suggest that diversity facilitates friction that enhances deliberation and upends conformity.
We propose a new estimator for the spot covariance matrix of a multi-dimensional continuous semi-martingale log asset price process which is subject to noise and non-synchronous observations. The estimator is constructed based on a local average of block-wise parametric spectral covariance estimates. The latter originate from a local method of moments (LMM) which recently has been introduced by Bibinger et al. (2014). We extend the LMM estimator to allow for autocorrelated noise and propose a method to adaptively infer the autocorrelations from the data. We prove the consistency and asymptotic normality of the proposed spot covariance estimator. Based on extensive simulations we provide empirical guidance on the optimal implementation of the estimator and apply it to high-frequency data of a cross-section of NASDAQ blue chip stocks. Employing the estimator to estimate spot covariances, correlations and betas in normal but also extreme-event periods yields novel insights into intraday covariance and correlation dynamics. We show that intraday (co-)variations (i) follow underlying periodicity patterns, (ii) reveal substantial intraday variability associated with (co-)variation risk, (iii) are strongly serially correlated, and (iv) can increase strongly and nearly instantaneously if new information arrives.
Herbaceous ground vegetation is an important pool of biomass and nutrients, which is also used as the major forage source for wild ungulates. Up to now no standard methods exist to estimate herbaceous biomass on a landscape level for temperate forests, which are characterised by deciduous trees with closed canopies. Quantity and quality of the herbaceous forage accessible to herbivores can be estimated from estimated cover in vegetation plot data and information on biomass and element concentrations in plant species. Vegetation was sampled stratified by community types and forest developmental phases in Bavarian Forst National Park, Germany. We adopted the PhytoCalc model to estimate biomass and bioelement stocks from vegetation plot data and adjusted species assignments and absolute levels of biomass to the conditions in the national park. We categorised attractiveness of plant species as forage for red deer (Cervus elaphus) and roe deer (Capreolus capreolus). Multiple controls of total biomass and of plant groups (graminoids, ferns, herbs, Vaccinium, Rubus) were studied by stepwise regression against stand and environmental predictors. Herbaceous mass had a highly skewed distribution in the park, with 75% of plots having less than 231 g*m-2 of biomass or 24 g*m-2 of raw protein. Contributions of plant groups were site-dependent and variable, but decreased in the order Vaccinium-graminoids-Rubus-herbs-ferns. Biomass appeared to be controlled by deciduous tree cover, by total cover of canopy and coarse woody debris and by site quality, with nutrient-poor, high elevation sites having higher herb biomass. As a consequence, montane beech forests offered less forage mass than coniferous communities of high elevations and mires. Stand disturbances by bark beetles and the corresponding forest developmental phases had no systematic effects on total biomass.
Introduction: To determine the esthetic outcome of implant-based reconstructions after autologous and allogeneic bone grafting.
Methods: From 2003 to 2009, 67 patients underwent alveolar ridge augmentation and were enrolled in the study, 41 meet the inclusion criteria and 31 agreed to take part in the study. Patients were 18-69 years old (mean: 49.3 ± 13.8 years), and predominantly female. Patients received bone block grafts either autologous (n = 48) (AUBB) or allografts (ABB) (n = 19). Implants were inserted 4-7 months (autografts) or 5-6 months (allografts) after bone grafting. The Pink Esthetic Score (PES) as well as radiographic and subjective assessments were employed for the outcome analysis. The PES was assessed twice within one month based on digital photographic images that were randomly rearranged between evaluations by three independent, experienced investigators.
Results: Across all observations and investigators, the average PES was 7.5 ± 2.6 without differences between implants inserted in auto- and allografted bone, respectively. Patients assessed the allograft procedures as less painful and would have repeated it more often. The intra-rater reliability was excellent (correlation coefficients 0.7-0.9). The inter-observer agreement was lower (correlation coefficients 0.6-0.8).
Conclusions: Bone grafting with ABB allografts yields equivalent results to autologous grafting, and patients appreciate the omission of bone harvesting. The PES is a reliable method but should be performed by the same individual.
Die Dissertation besteht aus drei thematisch zusammenhängenden Forschungspapieren, in denen zeitstetige Konsum-, Investment- und Versicherungsprobleme über den Lebenszyklus betrachtet werden. Ein besonderer Fokus liegt auf realistischen Features wie stochastischem Sterberisiko und nicht-replizierbarem Einkommen. In der ersten Forschungsarbeit untersuche ich die Relevanz von stochastischem Sterberisiko. Dabei zeige ich, dass eine Sprungkomponente in der Sterberate die optimalen Entscheidungen der Agenten und das Wohlfahrtslevel signifikant beeinflusst. Eine Diffusionskomponente ist hingegen vernachlässigbar. In dem zweiten Forschungspapier untersuchen wir die Risikolebensversicherungsnachfrage einer Familie, dessen Alleinverdiener stochastischem Sterberisiko ausgesetzt ist. Wir achten insbesondere auf eine realistische Modellierung der Versicherung. Wir zeigen, dass dadurch junge Agenten dem Versicherungsmarkt fern bleiben und die Versicherungsnachfrage mit dem Alter steigt, im Gegensatz zu Modellen mit einfachen stetig-veränderbaren Versicherungen. Weiterhin verstärken langlaufende Versicherungsverträge die negativen Effekte von Einkommensschocks und werden daher von risikoaversen Agenten weniger abgeschlossen. In der dritten Forschungsarbeit untersuche ich die Critical Illness Versicherungsnachfrage eines Agenten in einem Modell mit stochastischem Sterberisiko und Gesundheitsausgaben. Die Versicherung übernimmt dabei die zusätzlichen Gesundheitskosten, die bei einem Sprung entstehen. Fast alle Agenten schließen solch eine Versicherung vor dem Rentenalter ab, selbst wenn diese sehr kostspielig ist. Insbesondere Agenten mit geringen Gesundheitsausgaben und hohem Einkommen haben eine hohe Versicherungsnachfrage.
Esiaba Irobi (1960-2010) was one of Africa's most innovative and productive younger playwrights. Deeply rooted in the indigenous performance traditions of his Igbo ethnic group, Irobi's drama, in the tradition of Wole Soyinka, is a hybrid production involving an iconoclastic reconceptualisation of the heritage he appropriates, its fascinating conflation with other performance traditions, and their projection onto the arena of contemporary Nigerian politics. This study by Isidore Diala is the first book-length examination of Irobi's work. It portrays a highly creative individual who was literally driven by the creative urge. The five chapters of this study illuminate different aspects of Irobi's oeuvre and include a vivid portrayal of Irobi the actor in his dream role of Elesin Oba, the eponymous King's Horseman in Wole Soyinka's drama. Diala highlight's Irobi's fascination for African festivals, which feature prominently in the earlier plays.He also demonstrates that although he is rooted in his Igbo culture, Irobi draws on different ethnic groups, pointing to conceptions of pan-Africanism that include the wAfrican diaspora.
The Swiss ophthalmologist Erika Sutter was born in Basel in 1917. She spent 32 years working in Elim Hospital, founded by the Swiss Mission in an impoverished rural area in North-Eastern South Africa. Together with her African colleague and friend, Selina Maphorogo, she founded the Care Groups, village self-help groups working for better health in their communities. The movement is still active after more than 30 years, and now has around 2,000 members, mostly women, in over 200 villages. Erika Sutter has received numerous international honours and awards for her pioneering work, including the award ?Woman of the Year? in 1984 from the South African newspaper ?The Star?, and an honorary doctorate from the University of Basel. For the creation of this biography, Erika Sutter spent many hours with the author, her friend Gertrud Stiehle, telling the story of her long life ? vividly, with a sharp eye for social issues, a hint of self-irony, and dry wit. Her account does not ignore events in the wider world. She experienced life on the Swiss-German border during the Second World War, and her years of working in South Africa were those when the apartheid policies of the South African Government were becoming more and more repressive, affecting many aspects of life in the country.
A 48 year old patient with dilated cardiomyopathy and chronic acne inversa underwent implantation of a LVAD system (Heartmate II, Thoratec, USA) March 2011. During 2011 and 2012 the patient was repeatedly readmitted for treatment of driveline infection with MRSA. Colonization was controlled with Linezolid and Rifampicin however reoccurred after discontinuation. In August 2012 the LVAD-system was exchanged due to pump dysfunction (HVAD, HeartWare Inc., USA). Postoperatively, the patient presented with ascites which secreted through the driveline exit. Consequently, the abdominal wall was surgically corrected to prevent exit of peritoneal fluid through the driveline, and the patient was discharged with sterile wound swabs. However 6 weeks after discharge the driveline exit wound started secreting pus showing abundant growth of multi resistant staphylococcus aureus (MRSA). With clinical signs of increasing liver failure with regular need for paracentesis, and clinical signs of local infection, a CT scan of the abdomen was performed revealing an enrichment of contrast medium along the driveline and an abscess-like formation on the abdominal wall. Patient was admitted receiving regular dose Daptomycin and Rifampicin. The latter was discontinued after ten days. The abscess, surrounding driveline exit and abdominal wall cavity was excised and vacuum treatment initiated. Total duration of Daptomycin therapy was 3 weeks. While first week skin and wound swabs were still positive for MRSA, all samples were sterile after the second week. Inflammation was monitored by leucocyte count and IL6. The secretion of pus along the driveline ceased, the wound cavity was closed subsequently. After discharge and stop of antibiotics skin and driveline swabs remained negative for MRSA (10 weeks).
We analyze the implications of the structure of a network for asset prices in a general equilibrium model. Networks are represented via self- and mutually exciting jump processes, and the representative agent has Epstein-Zin preferences. Our approach provides a exible and tractable unifying foundation for asset pricing in networks. The model endogenously generates results in accordance with, e.g., the robust-yetfragile feature of financial networks shown in Acemoglu, Ozdaglar, and Tahbaz-Salehi (2014) and the positive centrality premium documented in Ahern (2013). We also show that models with simpler preference assumptions cannot generate all these findings simultaneously.
Large herbivores are significant vectors for the long distance dispersal of seeds in various habitats, both attached to animals (epizoochory) and via gut passage (endozoochory). The majority of studies on epizoochory have examined dispersal in the fur of domesticated ungulates. Studies on wild ungulates are important to understand dispersal processes in many habitats, but rare due to methodological constraints. We studied epizoochory of seeds by European bison in an open-forest-mosaic (nutrient poor grassland and heathland, mixed forest) in NW Germany, where bison had been introduced for the purpose of nature conservation. At the study site it was possible to apply a method by which hoof material of freeranging bison was non-invasively collected. We identified a total of 1082 seeds from 32 plant species in the hoof material. The three most abundant species were Polygonum aviculare, Agrostis capillaris and Betula spp. Seed species originated from various habitat types of the study area, while the majority of seeds derived from trampled areas. Compared to the non-dispersed plant species of the study area, dispersed plant species had a higher seed longevity index, suggesting that many seeds were picked up from the soil seed bank. Epizoochory ranking indices of dispersed seed species, classifying the importance of epizoochory, revealed that transport in the fur may be of minor importance for many species, i.e. epizoochory by the hooves turned out to be negatively correlated to epizoochory in the fur. We conclude that European bison disperses a considerable number of seed species through trampling. Further research should consider epizoochory via the hooves and include integrative approaches to understand the different dispersal mechanisms by ungulates and their longterm synergetic effect on plant communities.
During embryonic development a large number of widely differing and specialized cell types with identical genomes are generated from a single totipotent zygote. Tissue specific transcription factors cooperate with epigenetic modifiers to establish cellular identity in differentiated cells and epigenetic regulatory mechanisms contribute to the maintenance of distinct chromatin states and cell-type specific gene expression patterns, a phenomenon referred to as epigenetic memory. This is accomplished via the stable maintenance of various epigenetic marks through successive rounds of cell division. Preservation of DNA methylation patterns is a well-established mechanism of epigenetic memory, but more recently it has become clear that many other epigenetic modifications can also be maintained following DNA replication and cell division. In this review, we present an overview of the current knowledge regarding the role of histone lysine methylation in the establishment and maintenance of stable epigenetic states.
Non-neuronal acetylcholine plays a substantial role in the human skin by influencing adhesion, migration, proliferation and differentiation of keratinocytes. These processes are regulated by the Mitogen-Activated Protein (MAP) kinase cascade. Here we show that in HaCaT keratinocytes all five muscarinic receptor subtypes are expressed, but M1 and M3 are the subtypes involved in mitogenic signaling. Stimulation with the cholinergic agonist carbachol leads to activation of the MAP kinase extracellular signal regulated kinase, together with the protein kinase Akt. The activation is fully dependent on the transactivation of the epidermal growth factor receptor (EGFR), which even appears to be the sole pathway for the muscarinic receptors to facilitate MAP kinase activation in HaCaT cells. The transactivation pathway involves a triple-membrane-passing process, based on activation of matrix metalloproteases, and extracellular ligand release; whereas phosphatidylinositol 3-kinase, Src family kinases or protein kinase C do not appear to be involved in MAP kinase activation. Furthermore, phosphorylation, ubiquitination and endocytosis of the EGF receptor after cholinergic transactivation are different from that induced by a direct stimulation with EGF, suggesting that ligands other than EGF itself mediate the cholinergic transactivation.
Epicutanoeus immunotherapy as a novel prophylactic and therapeutic strategy for birch pollen allergy
(2014)
The development of a convenient, effective and safe allergen-specific immunotherapy (SIT) for birch pollen allergy, one of the most prevalent allergic diseases in Northern Europe, North America and Northern Japan, is of crucial importance. Epicutaneous immunotherapy (EPIT) has gained attention as a safe and non-invasive alternative for subcutaneous immunotherapy, a conventional SIT. However, clinical studies showed a limited effcacy of EPIT, indicating the necessity of improvement of the treatment regime. In this study, we hypothesized that a combination of a hypoallergen with an appropriate adjuvant could be a strategy to improve EPIT. To verify this hypothesis, we aimed at investigating the efficacy of epicutaneous treatment with rBet v 1, the major birch pollen allergen, plus Toll-like receptor (TLR) agonists for prophylaxis and therapy of birch pollen allergy using a murine model of birch pollen-induced allergic asthma. Furthermore, the efficacy of rBet v 1B2, a hypoallergenic variant of Bet v 1, as a therapeutic allergen in EPI was pre-clinically investigated. TLRs recognize conserved microbial molecules (like PAMPs), and are known to promote the counter-regulation of TH2 responses by the induction of TH1-type and/or regulatory cytokines by immune cells. The hypoallergen Bet v 1B2 is a folding-variant of the wild-type allergen rBet v 1 with reduced allergenicity, but retained T-cell immunogenicity. The low allergenicity, could allow the application of hypoallergens in higher doses, and therefore provide a safer and more effective treatment to regulate T-cell immune responses. First, the expression and purification of recombinant Bet v 1 and Bet v 1B2 was optimized. Compared to natural proteins, recombinant proteins offer the possibility to use well-defined molecules with a consistent pharmaceutical quality. Using optimal Escherichia coli expression strains in combination with immobilized metal chelate affinity chromatography (IMAC) and size exclusion chromatography (SEC), we successfully prepared a large amount of rBet v 1 and rBet v 1B2 with a high purity. The allergenic potency of rBet v 1 and the hypoallergenic characteristics of rBet v 1B2 were confirmed by measurement of IgE reactivity and mediator release capacity using ELISA and basophil activation tests, respectively. In a second part, a murine model of birch pollen-induced allergic asthma was established. It was shown that intraperetoneal sensitization with an optimal dose of rBet v 1 and intranasal challenge with birch pollen extract induced elevated IgE levels, airway eosinophilia and pulmonary inflammation in BALB/c mice. The clinical features are comparable to those in patients with allergic asthma, indicating that sensitized and challenged mice could be used for a pre-clinical study to assess the efficacy of the treatment for birch pollen allergy. Next, we investigated the adjuvant effects of Polyadenylic:polyuridylic acid (Poly(A:U)), a TLR3 agonist, and R848 (resiquimod), a TLR7 agonist, in prophylactic EPI with rBet v 1 to intervene with birch pollen allergy. Here, we hypothesized that TLR3 and TLR7 could be possible target receptors to induce adjuvant effects in EPI, since these receptors are expressed in Langerhans cells and dermal dendritic cells, persistent antigen presenting cells in the cutaneous tissues. BALB/c mice received EPI with rBet v 1 alone, or plus Poly(A:U), or R848 on their depilated back using patches. Mice treated epicutaneously were then sensitized with rBet v 1 plus ALUM and intranasally challenged with birch pollen extract. We found that prophylactic EPI with rBet v 1 plus R848 inhibited the production of Bet v 1-specific IgE antibodies in sensitization, suppressed pulmonary inflammation and airway hyperreactivity upon challenge. In contrast to R848, no adjuvant effect of Poly(A:U) on suppression of asthmatic features was observed. Our results indicated that R848, but not Poly(A:U), could be a potential adjuvant for prophylactic EPI of birch pollen induced allergic asthma. Finally, the therapeutic potency of EPI with rBet v 1, or rBet v 1B2 alone, or plus R848 was assessed. After sensitization and challenge, mice received therapeutic EPI with rBet v 1 alone, or plus R848, and re-challenge with birch pollen extract. We found that therapeutic treatment with Bet v 1B2 reduced established Bet v 1-specific IgE antibodies, pulmonary inflammation and airway hyperreactivity upon re-challenge. Therapeutic treatment with the recombinant wild-type allergen does not influence these key characteristics of allergic asthma. In contrast to the findings in the prophylactic treatment with rBet v 1 plus R848,no therapeutic benefit was found upon combination with R848. This could be due to the high number of treatment days. Reduction of this number may lead to a beneficial effect. However, these findings indicate that Bet v 1B2 could be a potential therapeutic agent for the treatment of established birch pollen induced allergic asthma. In conclusion, this study demonstrates for the first time that prophylactic EPI with the recombinant form of Bet v 1 in combination with R848 could prevent and suppress asthmatic features in an established birch pollen allergy. Not only therapeutic, but also prophylactic applications of EPI could be of importance to prevent allergic sensitization, considering the high prevalence of allergic diseases. R848 could be a potential adjuvant for enhancing the prophylactic potential of EPI for the treatment of birch pollen allergy. Furthermore, the beneficial use of the hypoallergen Bet v 1B2 in therapeutic EPI was demonstrated by intervention of established asthmatic features. In the future, a combination of hypoallergens alone or together with adjuvants in EPIT could lead to a more convenient and effective therapeutic treatment of established birch pollen induced allergic asthma.
Central European dry grasslands are remarkably diverse plant communities that occur at the western edge of the Eurasian forest-steppe zone and harbour many species of continental distribution. Although their plant community types have been described in detail, the diversity patterns and their environmental determinants are still poorly known for these grasslands. Here, we study environmental drivers of species composition and richness in dry grasslands of northern Bohemia (České středohoří Mts) and central Bohemia (Křivoklát region), both in the Czech Republic. In vegetation plots of 100 m2 we recorded all vascular plant species, measured soil chemistry variables, above-ground biomass production and nutrient concentrations in biomass. Species richness in these plots ranged from 13 to 55. The relationships between species composition and the environment were explored using detrended correspondence analysis and canonical correspondence analysis, while the relationships between species richness and the environment were assessed using univariate and multiple regression models. In both regions, species composition and richness strongly responded to the soil pH (ranging from 4.0 to 7.8), which was positively correlated with calcium and magnesium concentrations and negatively with annual precipitation. The response of species richness to soil pH was unimodal with a peak at pH of about 6.5 in the České středohoří Mts, and positive in the Křivoklát region. Plots on soils with a pH higher than 5 consistently contained more than 35 species. In the České středohoří Mts, species richness was positively related to the aboveground biomass production, whereas in the Křivoklát region, this relationship was only significant for graminoid species. In both areas, plots with soils deeper than 20 cm and with aboveground biomass dry weight above 200 g/m2 harboured more than 40 species per 100 m2. Moreover, in the České středohoří Mts, nitrogen concentrations in the biomass had considerable effects on both species composition and richness: species numbers were lower at sites with higher nitrogen concentration. This indicates a threat to diversity of these dry grasslands under currently high atmospheric nitrogen deposition coupled with the absence of management at most of the studied sites.
In the last few decades, the abundance and importance of invasive alien species have grown continuously due to the undiminished growth of global trade. In most cases, arthropod introductions were unintended and occurred as hitchhikers or contaminants. Alien arthropods can have significant environmental impacts and can be economically costly. To measure these impacts, we expand a generic impact scoring system initially developed for mammals and birds, and applied it to terrestrial arthropods. It consists of six environmental impact categories and six economic impact categories, each with five impact levels. Information on impact was derived from an intensive analysis of published scientific literature. The scoring of the 77 most widely distributed arthropod species alien to Europe revealed the mite Varroa destructor as the most harmful species, followed by the Chinese longhorn beetle Anoplophora chinensis and the Argentine ant Linepithema humile. The highest environmental impact is through herbivory, disease transmission, and ecosystem impacts. The highest economic impact is on agriculture and human infrastructure and administration. The generic impact scoring system allows the impact scores of vertebrates and arthropods to be compared, thus serving as a background for the decision making processes of policy makers and stakeholders.
Background: Birch pollen-allergic subjects produce polyclonal cross-reactive IgE antibodies that mediate pollen-associated food allergies. The major allergen Bet v 1 and its homologs in plant foods bind IgE in their native protein conformation. Information on location, number and clinical relevance of IgE epitopes is limited. We addressed the use of an allergen-related protein model to identify amino acids critical for IgE binding of PR-10 allergens.
Method: Norcoclaurine synthase (NCS) from meadow rue is structurally homologous to Bet v 1 but does not bind Bet v 1-reactive IgE. NCS was used as the template for epitope grafting. NCS variants were tested with sera from 70 birch pollen allergic subjects and with monoclonal antibody BV16 reported to compete with IgE binding to Bet v 1.
Results: We generated an NCS variant (Δ29NCSN57/I58E/D60N/V63P/D68K) harboring an IgE epitope of Bet v 1. Bet v 1-type protein folding of the NCS variant was evaluated by 1H-15N-HSQC NMR spectroscopy. BV16 bound the NCS variant and 71% (50/70 sera) of our study population showed significant IgE binding. We observed IgE and BV16 cross-reactivity to the epitope presented by the NCS variant in a subgroup of Bet v 1-related allergens. Moreover BV16 blocked IgE binding to the NCS variant. Antibody cross-reactivity depended on a defined orientation of amino acids within the Bet v 1-type conformation.
Conclusion: Our system allows the evaluation of patient-specific epitope profiles and will facilitate both the identification of clinically relevant epitopes as biomarkers and the monitoring of therapeutic outcomes to improve diagnosis, prognosis, and therapy of allergies caused by PR-10 proteins.
Quarks and gluons are the building blocks of all hadronic matter, like protons and neutrons. Their interaction is described by Quantum Chromodynamics (QCD), a theory under test by large scale experiments like the Large Hadron Collider (LHC) at CERN and in the future at the Facility for Antiproton and Ion Research (FAIR) at GSI. However, perturbative methods can only be applied to QCD for high energies. Studies from first principles are possible via a discretization onto an Euclidean space-time grid. This discretization of QCD is called Lattice QCD (LQCD) and is the only ab-initio option outside of the high-energy regime. LQCD is extremely compute and memory intensive. In particular, it is by definition always bandwidth limited. Thus—despite the complexity of LQCD applications—it led to the development of several specialized compute platforms and influenced the development of others. However, in recent years General-Purpose computation on Graphics Processing Units (GPGPU) came up as a new means for parallel computing. Contrary to machines traditionally used for LQCD, graphics processing units (GPUs) are a massmarket product. This promises advantages in both the pace at which higher-performing hardware becomes available and its price. CL2QCD is an OpenCL based implementation of LQCD using Wilson fermions that was developed within this thesis. It operates on GPUs by all major vendors as well as on central processing units (CPUs). On the AMD Radeon HD 7970 it provides the fastest double-precision D= kernel for a single GPU, achieving 120GFLOPS. D=—the most compute intensive kernel in LQCD simulations—is commonly used to compare LQCD platforms. This performance is enabled by an in-depth analysis of optimization techniques for bandwidth-limited codes on GPUs. Further, analysis of the communication between GPU and CPU, as well as between multiple GPUs, enables high-performance Krylov space solvers and linear scaling to multiple GPUs within a single system. LQCD calculations require a sampling of the phase space. The hybrid Monte Carlo (HMC) algorithm performs this. For this task, a single AMD Radeon HD 7970 GPU provides four times the performance of two AMD Opteron 6220 running an optimized reference code. The same advantage is achieved in terms of energy-efficiency. In terms of normalized total cost of acquisition (TCA), GPU-based clusters match conventional large-scale LQCD systems. Contrary to those, however, they can be scaled up from a single node. Examples of large GPU-based systems are LOEWE-CSC and SANAM. On both, CL2QCD has already been used in production for LQCD studies.
The fluctuations in the ideal quantum gases are studied using the strongly intensive measures Δ[A,B] and Σ[A,B] defined in terms of two extensive quantities A and B. In the present Letter, these extensive quantities are taken as the motional variable, A=X, the system energy E or transverse momentum PT, and number of particles, B=N. This choice is most often considered in studying the event-by-event fluctuations and correlations in high energy nucleus–nucleus collisions. The recently proposed special normalization ensures that Δ and Σ are dimensionless and equal to unity for fluctuations given by the independent particle model. In statistical mechanics, the grand canonical ensemble formulation within the Boltzmann approximation gives an example of independent particle model. Our results demonstrate the effects due to the Bose and Fermi statistics. Estimates of the effects of quantum statistics in the hadron gas at temperatures and chemical potentials typical for thermal models of hadron production in high energy collisions are presented. In the case of massless particles and zero chemical potential the Δ and Σ measures are calculated analytically.
This paper investigates extensions of the method of endogenous gridpoints (ENDGM) introduced by Carroll (2006) to higher dimensions with more than one continuous endogenous state variable. We compare three different categories of algorithms: (i) the conventional method with exogenous grids (EXOGM), (ii) the pure method of endogenous gridpoints (ENDGM) and (iii) a hybrid method (HYBGM). ENDGM comes along with Delaunay interpolation on irregular grids. Comparison of methods is done by evaluating speed and accuracy. We find that HYBGM and ENDGM both dominate EXOGM. In an infinite horizon model, ENDGM also always dominates HYBGM. In a finite horizon model, the choice between HYBGM and ENDGM depends on the number of gridpoints in each dimension. With less than 150 gridpoints in each dimension ENDGM is faster than HYBGM, and vice versa. For a standard choice of 25 to 50 gridpoints in each dimension, ENDGM is 1.4 to 1.7 times faster than HYBGM in the finite horizon version and 2.4 to 2.5 times faster in the infinite horizon version of the model.
Emotions-at-risk: an experimental investigation into emotions, option prices and risk perception
(2014)
This paper experimentally investigates how emotions are associated with option prices and risk perception. Using a binary lottery, we find evidence that the emotion ‘surprise’ plays a significant role in the negative correlation between lottery returns and estimates of the price of a put option. Our findings shed new light on various existing theories on emotions and affect. We find gratitude, admiration, and joy to be positively associated with risk perception, although the affect heuristic predicts a negative association. In contrast with the predictions of the appraisal tendency framework (ATF), we document a negative correlation between option price and surprise for lottery winners. Finally, the results show that the option price is not associated with risk perception as commonly used in psychology.
We investigate the properties of the QCD matter across the deconfinement phase transition. In the scope of the parton-hadron string dynamics (PHSD) transport approach, we study the strongly interacting matter in equilibrium as well as the out-of equilibrium dynamics of relativistic heavy-ion collisions. We present here in particular the results on the electromagnetic radiation, i.e. photon and dilepton production, in relativistic heavy-ion collisions and the relevant correlator in equilibrium, i.e. the electric conductivity. By comparing our calculations for the heavy-ion collisions to the available data, we determine the relative importance of the various production sources and address the possible origin of the observed strong elliptic flow ν2 of direct photons.
These are exciting times for translational medicine as the convergence between fundamental and clinical research comes of age. The new EMBO Press publishing platform reinforces the standing of EMBO Molecular Medicine as the journal that matches high quality, novel research with rigorous editorial and ethical standards. It will also cement the journal's global reach and relevance - whether in highly active fields or explorative forays into emerging areas.
In mitochondria, biogenesis of oxidase is a crucial process involving the participation of an array of assembly factors. Studying the process of biogenesis in eukaryotes is highly complicated due to the presence and partaking of two genetic systems. Employing a bacterial model such as Paracoccus denitrificans that utilizes only one genetic system enables easy studying of the assembly process. The aa3 cytochrome c oxidase of P. denitrificans shows high structural and functional homology to its mitochondrial counterpart despite its simple subunit composition. The assembly of the core subunits I and II that house the active redox centers (heme a, and heme a3.CuB centre in subunit I; and the binuclear CuA centre in subunit II) along with the chaperons responsibly for their incorporation form the crux of this work. This work concentrates particularly on CtaG, a chaperone previously speculated to be involved in the delivery of copper to the CuB center in subunit I. As the full length structure of CtaG or its structural homologues have not been solved, attempts were made to obtain high-diffracting crystals of CtaG by heterologously expressing it in E. coli. Growth media, expression strains and induction parameters were some of the conditions screened in order to obtain optimal yield. Additives, pH and detergent were screened to yield a homogeneous preparation of CtaG. Crystallization trials were conducted by employing the sitting drop, vapour diffusion, method and later the bicelles were employed. Preliminary crystals obtained were further optimized employing seeding, detergent and additives, to improve diffraction. The diffraction improved from 30 Å to 15 Å. BN PAGE (Blue Native Polyacrylamide Gel Electrophoresis) analysis and cross-linking studies were undertaken to decipher the oligomeric condition of CtaG. Both the methods indicate that the protein is a dimer under native conditions. To study the importance of CtaG in the process of oxidase assembly, two deletion mutants were obtained from the lab; one with only ctaG deleted and the other with ctaG and most of the upstream ORF. The effect of the deletion was assayed on the assembly and activity of oxidase. The deletion mutants showed residual activity of approx. 20 %, while displaying a very low heme signal (both in membranes and in purified COX). In order to exclude polar effects arising due to gene manipulation, complementation strains were prepared, reintroducing ctaG alone into both the deletion strains. Complementation strains, where only ctaG was deleted and re-introduced assayed for COX activity showed a restoration in activity to approx. 70 %. Further, calculating the heme:protein ratio, the deletion strains displayed a value of 7 nmol/mg of oxidase which was increased to wild type levels of 16 nmol/mg in the complementation strains. To further confirm the absence of the copper in subunit I, total reflection X-ray fluorescence spectroscopy analysis was carried out, which showed a decrease in the copper content in the deletion strain, restored on complementation. The strain lacking in the ORF and ctaG when complemented with ctaG alone illustrated no increase in activity or heme signal in comparison to that of the deletion strain. These point at a possible role for ORF in the assembly of COX, which is still absent in the complementation strains. To further characterize the ORF, a series of bioinformatical analysis was carried out, the results from which were insufficient to characterize the ORF conclusively. In order to enlist the proteins involved in the biosynthesis of COX, two independent approaches were employed. Two-dimensional gel examinations of solubilised membranes from untreated and cross-linked cells were analyzed by Western blotting. The CtaG-COX interaction was observed in untreated membranes, which was additionally strengthened by cross-linking. To further confirm this association, pull-down assays were done employing protein A coated magnetic beads coated with different antibodies and incubated with solubilised membranes derived from untreated or cross-linked cells. The elutions were assayed by Western blotting and confirmed for the CtaG-COX interaction. These fractions were further analysed by mass spectrometry to identify other chaperons involved in biogenesis of oxidase. Along with CtaG, I also noticed Sco, Surf1c and other factors involved in the recruitment and transport of heme (CtaB, CtaA, and Ccm proteins). Interestingly, protein components of both ribosomal subunits and protein translocation factors were observed, which indicated a co-translational approach for co-factor insertion into COX.
Background: Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness.
Methods and Results: Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ~506 ms with notched T waves). Parents were I° cousins – both heterozygous for the mutation and clinically unremarkable (QTc ~447 ms, father and ~396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q.
Conclusion: Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.
Recent density functional theory (DFT) calculations for KFe2As2 have been shown to be insufficient to satisfactorily describe angle-resolved photoemission (ARPES) measurements as well as observed de Haas–van Alphen (dHvA) frequencies. In the present work, we extend DFT calculations based on the full-potential linear augmented plane-wave method by dynamical mean field theory (DFT+DMFT) to include correlation effects beyond the local density approximation. We present results for two sets of reported crystal structures. Our calculations indicate that KFe2As2 is a moderately correlated metal with a mass renormalization factor of the Fe $3{\rm d}$ orbitals between 1.6 and 2.7. Furthermore, the obtained shape and size of the Fermi surface are in good agreement with ARPES measurements and we observe some topological changes with respect to DFT calculations such as the opening of an inner hole cylinder at the Z point. As a result, our calculated dHvA frequencies differ greatly from existing DFT results and qualitatively agree with experimental data. On this basis, we argue that correlation effects are important to understand the -presently under debate- nature of the superconducting state in KFe2As2.
Pulsed Electron Paramagnetic Resonance (EPR) spectroscopy is the most powerful tool to investigate structural properties and dynamics of paramagnetic substances. Up to date the electron spin is almost exclusively manipulated by rectangular shaped microwave pulses generated with switches. These pulses are unselective which means they excite outside their nominal bandwidth which is in most cases shallow compared to the overall spectral width of the spin system. Shaped pulses which are widely applied in NMR promise higher bandwidth and selectivity. The use of amplitude and phase modulated pulses was not possible for EPR due to the three orders of magnitude faster timescale compared to NMR. In this work, for the first time, an AWG (arbitrary waveform generator) operating with a 1 ns time resolution and 14 bit amplitude resolution was implemented into a commercial Bruker pulsed EPR spectrometer.
First results were obtained with broadband excitation pulses derived by optimum control theory (OCT). The OCT-pulse used excites transverse magnetization with 98% efficiency over a more than four times larger bandwidth than common rectangular pulse generating the same 1 B field. The benefit of such a pulse was demonstrated for magnitude FT-EPR spectroscopy on organic radicals in liquid phase.
Due to Spectrometer deadtime an FID cannot be observed for most inhomogeneous spin systems. For that reason prefocused pulses have been evaluated for their applicability to EPR spectroscopy. OCT-derived prefocused pulses can be understood as a compact Hahn Echo sequence in one monolithic pulse. Here, two problems have been encountered. 1) The limited bandwidth of the active and passive microwave components in the excitation path as well as microwave resonator cause linear distortions of the pulse shape which results in inferior pulse performance. This could be circumvented by measuring the impulse response function of the whole spin excitation path and including this information in the pulse optimization procedure. 2) Anisotropic hyperfine interaction which was not taken into account during the pulse optimization also caused efficiency losses.
PELDOR spectroscopy is a valuable tool to measure distance distributions between two or more paramagnetic centers in the range from 2-8 nm. It is demonstrated that the S/N ratio of PELDOR experiments can be substantially increased by substituting the rectangular shaped pump pulse by an adiabatic inversion pulse. The damping of the dipolar oscillations introduced by the prolonged pump pulse towards shorter distances could be circumvented by introducing a second time reversed pump pulse.
By substituting the refocused echo of the well-known 4-pulse PELDOR with a CPMG sequence the dipolar evolution time and thus the validity of PELDOR experiments would be increased. To achieve the maximum dipolar evolution time in a CPMG PELDOR for each refocusing pulse one pump pulse has to be applied. This could only be achieved with the new adiabatic inversion pulses since multiple inversions with efficiency close to one are not possible with rectangular pulses. Even with adiabatic pump pulses a reduced efficiency was observed due to hardware limitations thus limiting the sequence to three refocusing pulses. An iterative method was developed to remove the residual dipolar signals attributed to the reduced inversion efficiency.
The new 7-pulse CPMG PELDOR sequence enabled measuring reliable distance distributions between the protomers of the trimeric betaine transporter BetP. With these it could be shown that the asymmetries found for the 2 and 3-dimensional crystal structures are even larger in frozen detergent.
Electromagnetic calorimeter (ECAL) is being developed to complement dilepton spectrometer HADES. ECAL will enable the HADES@FAIR experiment to measure data on neutral meson production in heavy ion collisions at the energy range of 2-10 AGeV on the beam of future accelerator SIS100@FAIR. We will report results of the last beam test with quasi-monoenergetic photons carried out in MAMI facility at Johannes Gutenberg Universität Mainz.
Recent data on status and distribution of resident and migrant birds in the Cape Verde Islands are presented, including records of nine taxa new to the archipelago, viz. Ciconia nigra, Ciconia ciconia, Circus macrourus, Falco naumanni, Chlidonias hybrida, Chlidonias leucopterus, Apus affinis, Ptyonoprogne fuligula and Phylloscopus inornatus. Also presented are data on a number of breeding taxa, including the first record of the endemic Cape Verde purple heron Ardea bournei outside Santiago island. The alarming situation of the magnificent frigatebird Fregata magnificens, of which only three individuals remain in Cape Verde, constituting the entire population in the East Atlantic, remains of great concern. Several species of birds of prey are also highly threatened and have already become extinct in some islands. Following its expansion through Northwest Africa and the Canary Islands, Eurasian collared dove Streptopelia decaocto has now also become established in at least three of the Cape Verde Islands.
Information theory allows us to investigate information processing in neural systems in terms of information transfer, storage and modification. Especially the measure of information transfer, transfer entropy, has seen a dramatic surge of interest in neuroscience. Estimating transfer entropy from two processes requires the observation of multiple realizations of these processes to estimate associated probability density functions. To obtain these necessary observations, available estimators typically assume stationarity of processes to allow pooling of observations over time. This assumption however, is a major obstacle to the application of these estimators in neuroscience as observed processes are often non-stationary. As a solution, Gomez-Herrero and colleagues theoretically showed that the stationarity assumption may be avoided by estimating transfer entropy from an ensemble of realizations. Such an ensemble of realizations is often readily available in neuroscience experiments in the form of experimental trials. Thus, in this work we combine the ensemble method with a recently proposed transfer entropy estimator to make transfer entropy estimation applicable to non-stationary time series. We present an efficient implementation of the approach that is suitable for the increased computational demand of the ensemble method's practical application. In particular, we use a massively parallel implementation for a graphics processing unit to handle the computationally most heavy aspects of the ensemble method for transfer entropy estimation. We test the performance and robustness of our implementation on data from numerical simulations of stochastic processes. We also demonstrate the applicability of the ensemble method to magnetoencephalographic data. While we mainly evaluate the proposed method for neuroscience data, we expect it to be applicable in a variety of fields that are concerned with the analysis of information transfer in complex biological, social, and artificial systems.
We propose an iterative procedure to efficiently estimate models with complex log-likelihood functions and the number of parameters relative to the observations being potentially high. Given consistent but inefficient estimates of sub-vectors of the parameter vector, the procedure yields computationally tractable, consistent and asymptotic efficient estimates of all parameters. We show the asymptotic normality and derive the estimator's asymptotic covariance in dependence of the number of iteration steps. To mitigate the curse of dimensionality in high-parameterized models, we combine the procedure with a penalization approach yielding sparsity and reducing model complexity. Small sample properties of the estimator are illustrated for two time series models in a simulation study. In an empirical application, we use the proposed method to estimate the connectedness between companies by extending the approach by Diebold and Yilmaz (2014) to a high-dimensional non-Gaussian setting.
Objective: Advanced or recurrent endometrial cancer (EC) no longer amenable to surgery or radiotherapy is a life-threatening disease with limited therapeutic options left. Eighty percent of ECs express receptors for luteinizing hormone-releasing hormone (LHRH), which can be targeted by AEZS-108 (zoptarelin doxorubicin acetate). This phase 2 trial was performed to assess the efficacy and safety of AEZS-108 in this group of patients.
Methods: Patients had FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) III or IV or recurrent EC, LHRH receptor-positive tumor status, and at least had 1 measurable lesion (Response Evaluation Criteria in Solid Tumors). Prior anthracycline therapy was not allowed. Patients received AEZS-108 as a 2-hour infusion on day 1 of a 21-day cycle. The treatment was continued for a maximum of 6 to 8 cycles. The primary end point was the response rate determined by the Response Evaluation Criteria in Solid Tumors.
Results: From April 2008 to November 2009, 44 patients were included in the study at 8 centers in Germany (AGO) and 3 centers in Bulgaria. Forty-three of these patients were eligible. Two (5%) patients had a complete remission, and 8 (18%) achieved a partial remission. Stable disease for at least 6 weeks was observed in 44%. The median time to progression was 7 months, and the median overall survival was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%).
Conclusions: AEZS-108, an LHRH-agonist coupled to doxorubicin, has significant activity and low toxicity in women with advanced or recurrent LHRH receptor-positive EC, supporting the principle of receptor-mediated targeted chemotherapy.
Fluctuations of the water level at the edges of temporary water bodies provide favourable living conditions for annual plant communities of the phytosociological class Isoëto-Nanojuncetea. Such communities of periodically flooded ponds within the agricultural landscape of NE Germany are particularly rich in rare plant species of that class. During the past decades drainage, fertilisation and herbicides in the surrounding arable fields have led to a severe decline in diversity of these species. To develop efficient conservation strategies it is essential to understand the factors driving the species composition. Therefore, we studied how varying water regimes, soil properties and agricultural practices affect the diversity and species composition of these temporary ponds. The study was carried out in seven ponds on a conventionally managed farm in NE Brandenburg. At each of these wetlands mixed soil samples were taken to determine the pH, total nitrogen and phosphorus concentration. The plant species were recorded in 177 plots, each covering 1 x 1 m2. For each plot, the water level was recorded in April, July and August 2013, respectively, resulting in five "water level regimes". Total species number and percentages of Isoëto-Nanojuncetea species were determined per plot, to evaluate water level effects on the vegetation. In addition, mean Ellenberg indicator values for light, moisture and nutrients were calculated to assess the environmental conditions.
Background: Different flavonoids are known to interfere with influenza A virus replication. Recently, we showed that the structurally similar flavonoids baicalein and biochanin A inhibit highly pathogenic avian H5N1 influenza A virus replication by different mechanisms in A549 lung cells. Here, we investigated the effects of both compounds on H5N1-induced reactive oxygen species (ROS) formation and the role of ROS formation during H5N1 replication.
Findings: Baicalein and biochanin A enhanced H5N1-induced ROS formation in A549 cells and primary human monocyte-derived macrophages. Suppression of ROS formation induced by baicalein and biochanin A using the antioxidant N-acetyl-L-cysteine strongly increased the anti-H5N1 activity of both compounds in A549 cells but not in macrophages.
Conclusions: These findings emphasise that flavonoids induce complex pharmacological actions some of which may interfere with H5N1 replication while others may support H5N1 replication. A more detailed understanding of these actions and the underlying structure-activity relationships is needed to design agents with optimised anti-H5N1 activity.
Background: Low Emission Zones (LEZs) are areas where the most polluting vehicles are restricted from entering. The effectiveness of LEZs to lower ambient exposures is under debate. This study focused on LEZs that restricted cars of Euro 1 standard without appropriate retrofitting systems from entering and estimated LEZ effects on NO2, NO, and NOx ( = NO2+NO).
Methods: Continuous half-hour and diffuse sampler 4-week average NO2, NO, and NOx concentrations measured inside and outside LEZs in 17 German cities of 6 federal states (2005–2009) were analysed as matched quadruplets (two pairs of simultaneously measured index values inside LEZ and reference values outside LEZ, one pair measured before and one after introducing LEZs with time differences that equal multiples of 364 days) by multiple linear and log-linear fixed-effects regression modelling (covariables: e.g., wind velocity, amount of precipitation, height of inversion base, school holidays, truck-free periods). Additionally, the continuous half-hour data was collapsed into 4-week averages and pooled with the diffuse sampler data to perform joint analysis.
Results: More than 3,000,000 quadruplets of continuous measurements (half-hour averages) were identified at 38 index and 45 reference stations. Pooling with diffuse sampler data from 15 index and 10 reference stations lead to more than 4,000 quadruplets for joint analyses of 4-week averages. Mean LEZ effects on NO2, NO, and NOx concentrations (reductions) were estimated to be at most −2 µg/m3 (or −4%). The 4-week averages of NO2 concentrations at index stations after LEZ introduction were 55 µg/m3 (median and mean values) or 82 µg/m3 (95th percentile).
Conclusions: This is the first study investigating comprehensively the effectiveness of LEZs to reduce NO2, NO, and NOx concentrations controlling for most relevant potential confounders. Our analyses indicate that there is a statistically significant, but rather small reduction of NO2, NO, and NOx concentrations associated with LEZs.
This essay reviews a cornerstone of the European Banking Union project, the resolution of systemically important banks. The focus is on the inherent conflict between a possible intervention by resolution authorities, conditional on a crisis situation, and effective prevention prior to a crisis. Moreover, the paper discusses the rules for bail-in debt and conversion rules for different layers of debt. Finally, some organizational requirements to achieve effective resolution results will be analyzed.
Objective: To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus.
Design: Systematic review and meta-analysis of individual patient data.
Data sources: Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013.
Eligibility: Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival.
Results: The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.
Conclusions: Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.
Ternary aerosol nucleation experiments were conducted in the CLOUD chamber at CERN in order to investigate the influence of ions on new particle formation. Neutral and ion-induced nucleation experiments, i.e., with and without the presence of ions, were carried out under precisely controlled conditions. The sulphuric acid concentration was measured with a Chemical Ionization Mass Spectrometer (CIMS) during the new particle formation experiments. The added ternary trace gases were ammonia (NH3), dimethylamine (DMA, C2H7N) or oxidised products of pinanediol (PD, C10H18O2). When pinanediol was introduced into the chamber, an increase in the mass spectrometric signal used to determine the sulphuric acid concentration (m/z 97, i.e., HSO4−) was observed due to ions from the CLOUD chamber. The enhancement was only observed during ion-induced nucleation measurements by using either galactic cosmic rays (GCR) or the proton synchrotron (PS) pion beam for the ion generation, respectively. The ion effect typically involved an increase in the apparent sulphuric acid concentration by a factor of ~2 to 3 and was qualitatively verified by the ion measurements by an Atmospheric Pressure interface-Time Of Flight (APi-TOF) mass spectrometer. By applying a high voltage (HV) clearing field inside the CLOUD chamber the ion effect on the CIMS measurement was completely eliminated since, under these conditions, small ions are swept from the chamber in about one second. In order to exclude the ion effect and to provide corrected sulphuric acid concentrations during the GCR and PS beam nucleation experiments, a parameterisation was derived that utilizes the trace gas concentrations and the UV light intensity as input parameters. Atmospheric sulphuric acid measurements with a CIMS showed an insignificant ion effect.
Ternary aerosol nucleation experiments were conducted in the CLOUD chamber at CERN in order to investigate the influence of ions on new particle formation. Neutral and ion-induced nucleation experiments, i.e. without and with the presence of ions, respectively, were carried out under precisely controlled conditions. The sulfuric acid concentration was measured with a chemical ionisation mass spectrometer (CIMS) during the new particle formation experiments. The added ternary trace gases were ammonia (NH3), dimethylamine (DMA, C2H7N) or oxidised products of pinanediol (PD, C10H18O2). When pinanediol was introduced into the chamber, an increase in the mass spectrometric signal used to determine the sulfuric acid concentration (m/z 97, i.e. HSO4−) was observed due to ions from the CLOUD chamber. The enhancement was only observed during ion-induced nucleation measurements by using either galactic cosmic rays (GCRs) or the proton synchrotron (PS) pion beam for the ion generation, respectively. The ion effect typically involved an increase in the apparent sulfuric acid concentration by a factor of ~ 2 to 3 and was qualitatively verified by the ion measurements with an atmospheric-pressure interface-time of flight (APi-TOF) mass spectrometer. By applying a high-voltage (HV) clearing field inside the CLOUD chamber, the ion effect on the CIMS measurement was completely eliminated since, under these conditions, small ions are swept from the chamber in about 1 s. In order to exclude the ion effect and to provide corrected sulfuric acid concentrations during the GCR and PS beam nucleation experiments, a parameterisation was derived that utilises the trace gas concentrations and the UV light intensity as input parameters. Atmospheric sulfuric acid measurements with a CIMS showed an insignificant ion effect.
Purpose: To evaluate the effect of chronic liver disease (CLD) in a multivariate analysis of associated risk factors in patients with hepatocellular carcinoma (HCC) using transarterial chemoembolization (TACE). Materials and methods: A total of 145 patients with HCC (99 men, 46 women; mean age: 63 years ±8.1; age range: 46-84 years) underwent 598 TACE procedures. The presence of CLD, number and location of lesions, tumor size, Child-Pugh score, vascularity, portal involvement and alpha fetoprotein value were analyzed using the multivariate regression model. Cox regression was used for survival analysis. Results: The median survival time was 26.7 months, and 78.6% of all treated lesions showed tumor responses. The presence of CLD (OR 2.12, P=0.004), Child-Pugh score B (OR 2.24, P=0.002), alpha fetoprotein >100ng/dl (OR 1.18, P<0.001), multinodularity (≥3 lesions) (OR 4.41, P=0.003), lesion size >5cm (OR 4.12, P=0.002) and hypervascularity (OR 7.94, P=0.003) were significant effective factors for a local response when analyzed using a multivariate logistic model. Multivariate survival analysis using Cox's regression model during the median follow-up period of 25 months (range: 1-42 months) demonstrated a significant difference in survival rates (P values <0.05). No significant difference in responses was noted for males, locations of lesions and portal involvements statistically. Conclusion: The presence of chronic liver disease as well as associated risk factors including Child-Pugh score B, alpha fetoprotein 100ng/dl, multinodularity (≥3 lesions), lesion size >5cm and hypervascularity statistically led to a significant effect in tumor response in HCC patients treated with TACE. Patient gender, location of lesion and involvement of portal vein showed no significant difference in response.
Background: Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS.
Design: This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred.
Summary: ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.
Physics at its core is an experimental pursuit. If one theory does not agree with experimental results, then the theory is wrong. However, it is becoming harder and harder to directly test some theories of fundamental physics at the high energy/small distance frontier exactly because this frontier is becoming technologically harder to reach. The Large Hadron Collider is getting near the limit of what we can do with present accelerator technology in terms of directly reaching the energy frontier. The motivation for this special issue was to try and collect together ideas and potential approaches to experimentally probe some of our ideas about physics at the high energy/small distance frontier. Some of the papers in this special issue directly deal with the issue of what happens to spacetime at small distance scales. In the paper by A. Aurilia and E. Spallucci a picture of quantum spacetime is given based on the effects of ultrahigh velocity length contractions on the structure of the spacetime. The work of P. Nicolini et al. further pursues the idea that spacetime has a minimal length. The consequences of this minimal length are investigated in terms of the effects it would have on the gravitational collapse of a star to form a black hole. In the article by G. Amelino-Camelia et al. the quantum structure of spacetime is studied through the Fermi LAT data on the Gamma Ray Burst GRB130427A. The article by S. Hossenfelder addressed the question of whether spacetime is fundamentally continuous or discrete and postulates that in the case when spacetime is discrete it might have defects which would have important observational consequences. ...