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Background and Aims: The prevalence of hepatitis C virus (HCV) antibodies in Germany has been estimated to be in the range of 0.4–0.63%. Screening for HCV is recommended in patients with elevated ALT levels or significant risk factors for HCV transmission only. However, 15–30% of patients report no risk factors and ALT levels can be normal in up to 20–30% of patients with chronic HCV infection. The aim of this study was to assess the HCV seroprevalence in patients visiting two tertiary care emergency departments in Berlin and Frankfurt, respectively.
Methods: Between May 2008 and March 2010, a total of 28,809 consecutive patients were screened for the presence of anti-HCV antibodies. Anti-HCV positive sera were subsequently tested for HCV-RNA.
Results: The overall HCV seroprevalence was 2.6% (95% CI: 2.4–2.8; 2.4% in Berlin and 3.5% in Frankfurt). HCV-RNA was detectable in 68% of anti-HCV positive cases. Thus, the prevalence of chronic HCV infection in the overall study population was 1.6% (95% CI 1.5–1.8). The most commonly reported risk factor was former/current injection drug use (IDU; 31.2%) and those with IDU as the main risk factor were significantly younger than patients without IDU (p<0.001) and the male-to-female ratio was 72% (121 vs. 46 patients; p<0.001). Finally, 18.8% of contacted HCV-RNA positive patients had not been diagnosed previously.
Conclusions: The HCV seroprevalence was more than four times higher compared to current estimates and almost one fifth of contacted HCV-RNA positive patients had not been diagnosed previously.
Körner vertritt mit selten gewordener Entschiedenheit den Primat des Ästhetischen, man kann auch sagen: er vertritt die Autonomie der Kunst. Aber dieser Ausdruck ist missverständlich. Er bedeutet nicht, dass Künstler tun und lassen können, was sie wollen, oder dass im Bereich der Kunst ›alles möglich ist‹. Wäre im Bereich der Kunst alles möglich, dann sollte es auch möglich gewesen sein, die mehr oder minder plausiblen Ansprüche von Feierabendlesern, Zensoren, Polizeispitzeln, Westredakteuren, Parteikontrolleuren und Stasi-Überwachern wenn schon nicht zu befriedigen, so doch wenigstens so weit in die eigene Arbeit einzubeziehen, dass einer wohlwollenden Aufnahme, sei es im Osten, sei es im Westen, nichts im Wege gestanden wäre. Dass dem nicht so war, hat im gegebenen Fall einen einzigen Grund. Das Konzept, dem Körner sich verschreibt, fordert die totale Überschreibung der Selbstbeschreibung des Gemeinwesens, des ›gemeinen Wesens‹, das zugleich das ›böse‹ ist, wie es süffisant zu Beginn des Fragments vom Mensch mit einem Nietzsche-Zitat heißt.
Recent evidence has demonstrated additional roles for the neuronal guidance protein receptor UNC5B outside the nervous system. Given the fact that ischemia reperfusion injury (IRI) of the liver is a common source of liver dysfunction and the role of UNC5B during an acute inflammatory response we investigated the role of UNC5B on acute hepatic IRI. We report here that UNC5B+/− mice display reduced hepatic IRI and neutrophil (PMN) infiltration compared to WT controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate- (AST) and alanine- (ALT) aminotransferase, the presence of PMN within ischemic hepatic tissue, and serum levels of inflammatory cytokines. Moreover, injection of an anti-UNC5B antibody resulted in a significant reduction of hepatic IR injury. This was associated with reduced parameters of liver injury (LDH, ALT, AST) and accumulation of PMN within the injured hepatic tissue. In conclusion our studies demonstrate a significant role for UNC5B in the development of hepatic IRI and identified UNC5B as a potential drug target to prevent liver dysfunction in the future.
Background: Dopamine plays an important role in orienting and the regulation of selective attention to relevant stimulus characteristics. Thus, we examined the influences of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of visual processing in a contingent negative variation (CNV) task.
Methods: 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as preceding visual evoked potential components were assessed.
Results: Significant additive main effects of DAT1 and COMT on the occipito-temporal early CNV were observed. In addition, there was a trend towards an interaction between the two polymorphisms. Source analysis showed early CNV generators in the ventral visual stream and in frontal regions. There was a strong negative correlation between occipito-temporal visual post-processing and the frontal early CNV component. The early CNV time interval 500–1000 ms after the visual cue was specifically affected while the preceding visual perception stages were not influenced.
Conclusions: Late visual potentials allow the genomic imaging of dopamine inactivation effects on visual post-processing. The same specific time-interval has been found to be affected by DAT1 and COMT during motor post-processing but not motor preparation. We propose the hypothesis that similar dopaminergic mechanisms modulate working memory encoding in both the visual and motor and perhaps other systems.
The Arabidopsis arenosa complex is closely related to the model plant Arabidopsis thaliana. Species and subspecies in the complex are mainly biennial, predominantly outcrossing, herbaceous, and with a distribution range covering most parts of latitudes and the eastern reaches of Europe. In this study we present the first comprehensive evolutionary history of the A. arenosa species complex, covering its natural range, by using chromosome counts, nuclear AFLP data, and a maternally inherited marker from the chloroplast genome [trnL intron (trnL) and trnL/F intergenic spacer (trnL/F-IGS) of tRNALeu and tRNAPhe, respectively]. We unravel the broad-scale cytogeographic and phylogeographic patterns of diploids and tetraploids. Diploid cytotypes were exclusively found on the Balkan Peninsula and in the Carpathians while tetraploid cytotypes were found throughout the remaining distribution range of the A. arenosa complex. Three centers of genetic diversity were identified: the Balkan Peninsula, the Carpathians, and the unglaciated Eastern and Southeastern Alps. All three could have served as long-term refugia during Pleistocene climate oscillations. We hypothesize that the Western Carpathians were and still are the cradle of speciation within the A. arenosa complex due to the high species number and genetic diversity and the concurrence of both cytotypes there.
Staurosporine induces necroptotic cell death under caspase-compromised conditions in U937 cells
(2012)
For a long time necrosis was thought to be an uncontrolled process but evidences recently have revealed that necrosis can also occur in a regulated manner. Necroptosis, a type of programmed necrosis is defined as a death receptor-initiated process under caspase-compromised conditions. The process requires the kinase activity of receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3) and mixed lineage kinase domain-like protein (MLKL), as a substrate of RIPK3. The further downstream events remain elusive. We applied known inhibitors to characterize the contributing enzymes in necroptosis and their effect on cell viability and different cellular functions were detected mainly by flow cytometry. Here we report that staurosporine, the classical inducer of intrinsic apoptotic pathway can induce necroptosis under caspase-compromised conditions in U937 cell line. This process could be hampered at least partially by the RIPK1 inhibitor necrotstin-1 and by the heat shock protein 90 kDa inhibitor geldanamycin. Moreover both the staurosporine-triggered and the classical death ligand-induced necroptotic pathway can be effectively arrested by a lysosomal enzyme inhibitor CA-074-OMe and the recently discovered MLKL inhibitor necrosulfonamide. We also confirmed that the enzymatic role of poly(ADP-ribose)polymerase (PARP) is dispensable in necroptosis but it contributes to membrane disruption in secondary necrosis. In conclusion, we identified a novel way of necroptosis induction that can facilitate our understanding of the molecular mechanisms of necroptosis. Our results shed light on alternative application of staurosporine, as a possible anticancer therapeutic agent. Furthermore, we showed that the CA-074-OMe has a target in the signaling pathway leading to necroptosis. Finally, we could differentiate necroptotic and secondary necrotic processes based on participation of PARP enzyme.
Atomic-level analyses of non-native protein ensembles constitute an important aspect of protein folding studies to reach a more complete understanding of how proteins attain their native form exhibiting biological activity. Previously, formation of hydrophobic clusters in the 6 M urea-denatured state of an ultrafast folding mini-protein known as TC5b from both photo-CIDNP NOE transfer studies and FCS measurements was observed. Here, we elucidate the structural properties of this mini-protein denatured in 6 M urea performing 15N NMR relaxation studies together with a thorough NOE analysis. Even though our results demonstrate that no elements of secondary structure persist in the denatured state, the heterogeneous distribution of R2 rate constants together with observing pronounced heteronuclear NOEs along the peptide backbone reveals specific regions of urea-denatured TC5b exhibiting a high degree of structural rigidity more frequently observed for native proteins. The data are complemented with studies on two TC5b point mutants to verify the importance of hydrophobic interactions for fast folding. Our results corroborate earlier findings of a hydrophobic cluster present in urea-denatured TC5b comprising both native and non-native contacts underscoring their importance for ultra rapid folding. The data assist in finding ways of interpreting the effects of pre-existing native and/or non-native interactions on the ultrafast folding of proteins; a fact, which might have to be considered when defining the starting conditions for molecular dynamics simulation studies of protein folding.
Sponges play a key role in Antarctic marine benthic community structure and dynamics and are often a dominant component of many Southern Ocean benthic communities. Understanding the drivers of sponge distribution in Antarctica enables us to understand many of general benthic biodiversity patterns in the region. The sponges of the Antarctic and neighbouring oceanographic regions were assessed for species richness and biogeographic patterns using over 8,800 distribution records. Species-rich regions include the Antarctic Peninsula, South Shetland Islands, South Georgia, Eastern Weddell Sea, Kerguelen Plateau, Falkland Islands and north New Zealand. Sampling intensity varied greatly within the study area, with sampling hotspots found at the Antarctic Peninsula, South Georgia, north New Zealand and Tierra del Fuego, with limited sampling in the Bellingshausen and Amundsen seas in the Southern Ocean. In contrast to previous studies we found that eurybathy and circumpolar distributions are important but not dominant characteristics in Antarctic sponges. Overall Antarctic sponge species endemism is ~43%, with a higher level for the class Hexactinellida (68%). Endemism levels are lower than previous estimates, but still indicate the importance of the Polar Front in isolating the Southern Ocean fauna. Nineteen distinct sponge distribution patterns were found, ranging from regional endemics to cosmopolitan species. A single, distinct Antarctic demosponge fauna is found to encompass all areas within the Polar Front, and the sub-Antarctic regions of the Kerguelen Plateau and Macquarie Island. Biogeographical analyses indicate stronger faunal links between Antarctica and South America, with little evidence of links between Antarctica and South Africa, Southern Australia or New Zealand. We conclude that the biogeographic and species distribution patterns observed are largely driven by the Antarctic Circumpolar Current and the timing of past continent connectivity.
Background: Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor. Clinical trials point towards a favourable risk-to-benefit profile of DE compared to warfarin. In this study, we evaluated whether hemorrhagic transformation (HT) occurs after experimental stroke under DE treatment as we have shown for warfarin.
Methods: 44 male C57BL/6 mice were pretreated orally with 37.5 mg/kg DE, 75 mg/kg DE or saline and diluted thrombin time (dTT) and DE plasma concentrations were monitored. Ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO) for 1 h or 3 h. We assessed functional outcome and HT blood volume 24 h and 72 h after tMCAO.
Results: After 1 h tMCAO, HT blood volume did not differ significantly between mice pretreated with DE 37.5 mg/kg and controls (1.5±0.5 µl vs. 1.8±0.5 µl, p>0.05). After 3 h tMCAO, DE-anticoagulated mice did also not show an increase in HT, neither at the dose of 37.5 mg/kg equivalent to anticoagulant treatment in the therapeutic range (1.3±0.9 µl vs. control 2.3±0.5 µl, p>0.05) nor at 75 mg/kg, clearly representing supratherapeutic anticoagulation (1.8±0.8 µl, p>0.05). Furthermore, no significant increase in HT under continued anticoagulation with DE 75 mg/kg could be found at 72 h after tMCAO for 1 h (1.7±0.9 µl vs. control 1.6±0.4 µl, p>0.05).
Conclusion: Our experimental data suggest that DE does not significantly increase hemorrhagic transformation after transient focal cerebral ischemia in mice. From a translational viewpoint, this indicates that a continuation of DE anticoagulation in case of an ischemic stroke might be safe, but clearly, clinical data on this question are warranted.
Temporal variation in the detectability of a species can bias estimates of relative abundance if not handled correctly. For example, when effort varies in space and/or time it becomes necessary to take variation in detectability into account when data are analyzed. We demonstrate the importance of incorporating seasonality into the analysis of data with unequal sample sizes due to lost traps at a particular density of a species. A case study of count data was simulated using a spring-active carabid beetle. Traps were ‘lost’ randomly during high beetle activity in high abundance sites and during low beetle activity in low abundance sites. Five different models were fitted to datasets with different levels of loss. If sample sizes were unequal and a seasonality variable was not included in models that assumed the number of individuals was log-normally distributed, the models severely under- or overestimated the true effect size. Results did not improve when seasonality and number of trapping days were included in these models as offset terms, but only performed well when the response variable was specified as following a negative binomial distribution. Finally, if seasonal variation of a species is unknown, which is often the case, seasonality can be added as a free factor, resulting in well-performing negative binomial models. Based on these results we recommend (a) add sampling effort (number of trapping days in our example) to the models as an offset term, (b) if precise information is available on seasonal variation in detectability of a study object, add seasonality to the models as an offset term; (c) if information on seasonal variation in detectability is inadequate, add seasonality as a free factor; and (d) specify the response variable of count data as following a negative binomial or over-dispersed Poisson distribution.
Although their applications have not yet extended widely due to their incipient state, nano-technologies and nano-medicines may be presumed to be at the origin of the next great technological revolution, foreseeably contributing to a new stage with respect to evolutions in mankind’s progress. Their possibilities are truly immense in enormously varied spheres, but the risks and uncertainties they engender are enormous too. Because access and use of the unceasingly increasing mega-quantity of information they generate will place further strain on the protection of personal life, privacy, the exercise of freedom, as well as the safeguarding of other fundamental principles and rights.
Background: Adaptation to low oxygen by changing gene expression is vitally important for cell survival and tissue development. The sprouting of new blood vessels, initiated from endothelial cells, restores the oxygen supply of ischemic tissues. In contrast to the transcriptional response induced by hypoxia, which is mainly mediated by members of the HIF family, there are only few studies investigating alternative splicing events. Therefore, we performed an exon array for the genome-wide analysis of hypoxia-related changes of alternative splicing in endothelial cells.
Methodology/Principal findings: Human umbilical vein endothelial cells (HUVECs) were incubated under hypoxic conditions (1% O(2)) for 48 h. Genome-wide transcript and exon expression levels were assessed using the Affymetrix GeneChip Human Exon 1.0 ST Array. We found altered expression of 294 genes after hypoxia treatment. Upregulated genes are highly enriched in glucose metabolism and angiogenesis related processes, whereas downregulated genes are mainly connected to cell cycle and DNA repair. Thus, gene expression patterns recapitulate known adaptations to low oxygen supply. Alternative splicing events, until now not related to hypoxia, are shown for nine genes: six which are implicated in angiogenesis-mediated cytoskeleton remodeling (cask, itsn1, larp6, sptan1, tpm1 and robo1); one, which is involved in the synthesis of membrane-anchors (pign) and two universal regulators of gene expression (cugbp1 and max).
Conclusions/Significance: For the first time, this study investigates changes in splicing in the physiological response to hypoxia on a genome-wide scale. Nine alternative splicing events, until now not related to hypoxia, are reported, considerably expanding the information on splicing changes due to low oxygen supply. Therefore, this study provides further knowledge on hypoxia induced gene expression changes and presents new starting points to study the hypoxia adaptation of endothelial cells.
The requalification of Habermas’ discussions on political philosophy and legal theory after the publication of Zwischen Naturalismus und Religion (2005), and his most recent texts and debates on religion and the public sphere, suggest a revision of the Habermasian theory of rationalization as it was firstly presented in Theorie des Kommunikativen Handelns (1982), especially on what concerns the processes of dessacralization and the linguistification of religious authority. In search of contributing to this revision, this paper intends to focus on the problem of a supposedly “lost” aesthetic-expressive understanding of religious authority in Habermas’s theory of rationalization, which may have contributed to a theory of law in Faktizität und Geltung (1992) that does not give satisfactory account to the aesthetical-expressive character of the modern understanding of legal authority. A better understanding of this special character, however, may contribute not only to the avoidance of fundamentalisms and new attempts of “aesthetization of politics”, but also to a rational strengthening of the solidarity of the citizens of democratic constitutional states.
This paper aims to discuss in which sense public hearings in supreme courts of democratic rules of law can be seen as proceduralization of popular sovereignty policies. These policies constitute expressions of a normative claim for a wider “publicization of law” by democratic states’ institutional powers and organs; a claim that becomes evident when one undertakes an intersubjective interpretation of law. This theoretical argument will be presented in the first section of the paper through a new articulation of Jürgen Habermas’ discursive theory of law and his most recent studies on the concept of political public sphere. The theoretical section gives normative and procedural criteria for the second section of the paper, which consists on a critical analysis of the procedures and practical cases of public hearings held at the Brazilian Supreme Court, constituting the first scientific study to date on the Court’s use of this legal instrument.
Since the XIX century, a pleiad of philosophers and historians support the idea that Greek philosophy, usually reported to have started with the presocratics, lays its basis in a previous moment: the Greek myths – systematized by Homer and Hesiod – and the Greek arts, in particular the lyric and tragedy literature. According to this, it is important to retrieve philosophical elements even before the pre-Socratics to understand the genesis of specific concepts in Philosophy of Law. Besides, assuming that the Western’s core values are inherited from Ancient Greece, it is essential to recuperate the basis of our own justice idea, through the Greek myths and tragedy literature. As a case study, this paper aims on the comparison of two key-works, each one representing a phase of the Greek tragedy: The Orestea, by Aeschylus, and Orestes, by Euripides. Both contain the same story, telling how the Greeks understood the necessity of solving their conflicts not by blood revenge, but through a political way, and also the political drama. Although, in Aeschylus’s one, men still leashed by their fate, while the gods play a major role, in order to punish human pride (hybris). In a different way, on Euripides’s work men face their own loneliness, in a world fulfilled with gods, each one demanding divergent actions. That represents a necessary moment to the flourishing freedom and human subjectivity, and, once the exterior divinity is unable to resolve human problems, men will need to discover their interior divinity: that is how the Philosophy emerges.
Dworkin`s political theory is characterized by the interpretative integrity of morality, law, and politics, the so-called “hedgehog’s approach”. The interpretative integrity approach functions on multiple levels. Firstly, philosophical foundations of his theory of justice are linked to his conception of just liberal society and state. Secondly, from the perspective of political morality, interpretative concepts of law and morality are internally connected, in addition to interpretative concepts of equality, liberty, and democracy. Thirdly, from the perspective of philosophical foundations, individual ethics, personal morality and political morality are mutually connected. The aforementioned ethical and moral foundations are also related – in a wider sense of philosophical foundations - with his gnoseological conception regarding value concepts in law, politics and morality, and with his episthemological conception regarding an objective truth in the field of values, in a sense that the value concepts are interpretative and can be objectively true when articulated in accordance with methodological rules and standards of a »reflexive equilibrium« and an interpretative integrity, and in accordance with the so-called internal scepticism in the context of value pluralism.
The term “ethics” in a “narrower” sense refers to individual ethics, the study of how to live well, while the “ethics” in a “broader” sense refers to personal morality, the study of how we must treat other people. The term “morality” however, is used primarily to denote a political morality, the issue of how a sovereign power should treat its citizens.
Philosophical foundations of Dworkin`s political theory of justice, his conception of two cardinal values of humanity, his concievement of individual ethics, personal morality and political morality will be in the focus of consideration.
Agamben has claimed to work inside the tradition inaugurated by the archaeological method of Michel Foucault but not to fully coincide with it. “My method is archaeological and paradigmatic in a sense which is very close to that of Foucault, but not completely coincident with it. The question is, facing the dichotomies that structuralize our culture, to go beyond the exceptions that have been producing the former, however, not to find a chronologically originary state, but to be able to understand the situation in which we are. Archaeology is, in this sense, the only way to access present” (interview to Flavia Costa, trad. Susana Scramim, in Revista do Departamento de Psicologia – Universidade Federal Fluminense, Niterói, v. 18 - n. 1, 131-136, Jan./Jun. 2006, 132, translated by the author). However, the aspects in which Agamben follows Foucault's method and the ones he does not were never very clear. This situation seems to change with the edition of Agamben's most extensive and explicit texts on method, Signatura Rerum. Sul Metodo (2008, italian edition). The goal of this article is to identify the points of intersection between their methods and some points in which they differ.
John Gray is the thinker who has reconstructed the main tenets of ethical pluralism inherent in the work of its initiator - Isaiah Berlin - and pointed to its consequences for political philosophy. In particular he singled out three levels of conflict in ethics identifiable in Berlin’s writings: among the ultimate values belonging to the same morality or code of conduct, among whole ways or styles of life and within goods or values which are themselves internally complex and inherently pluralistic.
It is the third, internal kind of conflict that proves to be the richest in implications.Because it undermines a whole constellation of contemporary liberal doctrines informed by the Kantian-Lockean tradition that conform to the legal paradigm. From the pluralist perspective such monumental theories (e.g. those of Rawls or Dworkin) are no longer sustainable due to the recognition that no ultimate value is immune to the phenomenon of incommensurability. Thus, irresolvable conflicts may also break out within the given regulative value.
Confronting ethical pluralism with general reflection on law has mostly negative consequences. Nevertheless, the incommensurability thesis sheds considerable light on certain legal disputes. This claim will be illustrated by interpreting from the pluralist perspective the controversy over the verdict by the European Tribunal of Human Rights of 3 November 2010 concerning hanging crosses in classrooms.
Brazil has one of the worst distributions of income in the world. The wealth of the richest 1% of the population is equal to that of the poorest 50%. Brazil has a greater concentration of wealth than ninety-five percent of the countries on which data is available. In the legal field, tax justice is based on the constitutional principle of the “ability to pay”, according to which taxes should be paid based on the economic capacity of the taxpayer. This principle first appeared in the Brazilian legal order in the 1946 Constitution, was excluded from the texts of 1967/69, and reappeared in § 1 of article 145 of the 1988 Constitution. The aim of this paper is to examine two possible grounds for the ability to pay principle (equal sacrifices and proportional sacrifices) to show how, in Brazil, the interpretations that seek to assign a positive content to the principle are limited to the horizons of a particular form of State associated with the theory of equal sacrifice. This theory for its turn is consistent with a theory of justice, under which no expense or charge levied by the government can alter the distribution of welfare produced by the market. As the application of the ability to pay principle is done within the limits of that horizon, as a consequence, this principle does not play an important role in the issue of reduction of inequality in Brazil.
In their book Principles of Biomedical Ethics, Tom Beauchamp and James Childress offer an account of bioethics, called “Principlism”, by way of specifying and balancing four clusters of principles.2 These principles are found, as the author state, in a common morality, understood as a set of universally shared moral beliefs.
This paper seeks to introduce the following questions: Does this account of Beauchamp and Childress flow from common morality in a natural way? Can their proposals claim to be endorsed by the authority of common morality? If not, in what way does Principlism contribute to bioethics?