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Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients.Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy-Fatigue, Chronic Liver Disease Questionnaire- HCV, Work Productivity and Activity-Specific Health Problem) before, during, and after treatment.A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naïve, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to -24.4% by treatment week 12, up to -8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to -7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs.IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores.
The mfl-riboswitch is a transcriptional off-switch, which down-regulates expression of subunit ß of ribonucleotide reductase in Mesoplasma florum upon 2´-deoxyguanosine binding. We characterized binding of 2´-deoxyguanosine to the mfl-aptamer domain (WT aptamer) and a sequence-stabilized aptamer (MT aptamer) under in vitro and ‘in-cell-like’ conditions by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) spectroscopy. ‘In-celllike’ environment was simulated by Bacillus subtilis cell extract, in which both aptamers remained sufficiently stable to detect the resonances of structural elements and ligand binding in 2D NMR experiments. Under ‘in-cell-like’-environment, (i) the WT aptamer bound the endogenous metabolite guanosine and (ii) 2´-deoxyguanosine efficiently displaced guanosine from the WT aptamer. In contrast, MT aptamer exhibited moderate binding to 2´-deoxyguanosine and weak binding to guanosine. NMR experiments indicated that binding of guanosine was not limited to the aptamer domain of the riboswitch but also the full-length mfl-riboswitch bound guanosine, impacting on the regulation efficiency of the riboswitch and hinting that, in addition to 2´-deoxyguanosine, guanosine plays a role in riboswitch function in vivo. Reporter gene assays in B. subtilis demonstrated the regulation capacity of the WT aptamer, whereas the MT aptamer with lower affinity to 2´ -deoxyguanosine was not able to regulate gene expression.
The former and current multiple sclerosis (MS) classifications are essential for describing different phenotypes and disease dynamics. To establish personalized treatment regimes, further clinical and paraclinical parameters have to be considered such as imaging, cerebrospinal fluid (CSF) findings, past disease-modifying therapies (DMTs), and disease activity under these therapies. In clinical practice, this information is often difficult to overview. Especially, patients with a long course of disease offer an extensive medical history so that comprehending all of the necessary information can be very time consuming.
The synergetic effects of combining structural biology and epr spectroscopy on membrane proteins
(2017)
Protein structures as provided by structural biology such as X-ray crystallography, cryo-electron microscopy and NMR spectroscopy are key elements to understand the function of a protein on the molecular level. Nonetheless, they might be error-prone due to crystallization artifacts or, in particular in case of membrane-imbedded proteins, a mostly artificial environment. In this review, we will introduce different EPR spectroscopy methods as powerful tools to complement and validate structural data gaining insights in the dynamics of proteins and protein complexes such that functional cycles can be derived. We will highlight the use of EPR spectroscopy on membrane-embedded proteins and protein complexes ranging from receptors to secondary active transporters as structural information is still limited in this field and the lipid environment is a particular challenge.
Last week’s printed edition of Focus had a piece about how Germany’s politicians are using social media. It made the dubious claim that 61% of Green top candidate Katrin Göring-Eckardt’s Twitter followers could have been bought.
Let’s actually instead try to get to grips with what is going on here, and try to draw some conclusions. ...
Introduction: The 2017 update to the Global Initiative for Obstructive Lung Disease (GOLD) strategy document includes recommendations for treatment intensification or step-down in chronic obstructive pulmonary disease (COPD), although recognises that limited supporting information is available.
DACCORD is an ongoing observational, non-interventional study, recruiting patients following COPD maintenance treatment change or initiation, a subset of whom were receiving a long-acting β2-agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) fixed-dose combination (FDC) on entry. Since there were no requirements in terms of prior medication (and no washout before commencing LABA/LAMA FDC), this provides an opportunity to generate "real world" data to test the GOLD 2017 recommendations.
Methods: To reduce heterogeneity, the current analyses include patients receiving indacaterol/glycopyrronium at baseline, and who, prior to the study, were receiving no COPD maintenance medication ("none"), LABA or LAMA monotherapy ("mono"), LABA plus inhaled corticosteroid (ICS; "LABA/ICS"), or triple therapy ("triple"). At the baseline visit, data collected included: demographic and disease characteristics; COPD Assessment Test (CAT); and exacerbations in the 6 months prior to entry. At 3, 6, 9 and 12 months data on exacerbations were collected, with CAT recorded at 3 and 12 months.
Results: A total of 2724 patients were included in the baseline analyses: 795, 954, 598 and 377 in the "none", "mono", "LABA/ICS" and "triple" subgroups, respectively. There were no clinically relevant differences in baseline demographics between the four groups. In terms of disease characteristics, the "triple" group had the highest proportion of patients with a disease duration of more than 1 year since diagnosis and with severe/very severe airflow limitation, but a similar percentage of non-exacerbators compared to the "none" group.
Over the 1-year follow-up, the majority of patients in all four subgroups did not exacerbate (exacerbation rates 0.16, 0.19, 0.21, and 0.26 in the "none", "mono", "LABA/ICS" and "triple" groups, respectively). At 12 months, 61.4%, 65.0%, 71.0% and 52.4% of patients had a clinically relevant improvement in CAT score.
Conclusions: Overall, the results support the GOLD recommendations in suggesting that a switch from a mono-bronchodilator or LABA plus ICS to LABA/LAMA FDC is a valid treatment option for patients with COPD. The results also validate the use of a LABA/LAMA FDC as initial maintenance treatment for COPD, and provide first "real world" evidence to support the newly added "step down" recommendation (from triple to LABA/LAMA FDC).
The disruption of coupling between brain areas has been suggested as the mechanism underlying loss of consciousness in anesthesia. This hypothesis has been tested previously by measuring the information transfer between brain areas, and by taking reduced information transfer as a proxy for decoupling. Yet, information transfer is a function of the amount of information available in the information source—such that transfer decreases even for unchanged coupling when less source information is available. Therefore, we reconsidered past interpretations of reduced information transfer as a sign of decoupling, and asked whether impaired local information processing leads to a loss of information transfer. An important prediction of this alternative hypothesis is that changes in locally available information (signal entropy) should be at least as pronounced as changes in information transfer. We tested this prediction by recording local field potentials in two ferrets after administration of isoflurane in concentrations of 0.0%, 0.5%, and 1.0%. We found strong decreases in the source entropy under isoflurane in area V1 and the prefrontal cortex (PFC)—as predicted by our alternative hypothesis. The decrease in source entropy was stronger in PFC compared to V1. Information transfer between V1 and PFC was reduced bidirectionally, but with a stronger decrease from PFC to V1. This links the stronger decrease in information transfer to the stronger decrease in source entropy—suggesting reduced source entropy reduces information transfer. This conclusion fits the observation that the synaptic targets of isoflurane are located in local cortical circuits rather than on the synapses formed by interareal axonal projections. Thus, changes in information transfer under isoflurane seem to be a consequence of changes in local processing more than of decoupling between brain areas. We suggest that source entropy changes must be considered whenever interpreting changes in information transfer as decoupling.
Status and restoration potential of heathlands and sand grasslands in the southwest of Luxembourg
(2017)
In Europe, semi-natural nutrient-poor ecosystems such as sand grasslands and heathlands have shown extreme declines in surface area and species richness within the last century. The remaining sites are hence of high conservation value. This study analysed the vascular plant species inventory of established and recently restored heathlands and sand grasslands in the southwest of Luxembourg. Analyses to explain differences in vegetation composition between “old” (remnant sites or sites restored a long time ago) and “new” (recently restored) sites in relation to environmental variables were carried out with DCAs and ANOVA/Mann-Whitney-U tests, respectively. The vegetation of old heathlands had few character species of typical heathland communities (Calluno-Ulicetea, Nardetalia), whereas new heathland sites were preponderantly marked by taxa of meso- or eutrophic grasslands and ruderal communities. New heathland sites mainly differed from old sites by higher soil phosphorus contents. Sand grassland vegetation was species-rich and composed by species of the Sedo-Scleranthetea and Festuco-Brometea. With increasing age of the sites, vegetation composition shifted to grass dominance with species of the Molinio-Arrhenateretea. New sand grasslands differed from old sand grasslands by higher soil pH, higher soil potassium content and lower graminoid cover. The differences between new and old sites of both habitat types could mainly be explained by successional processes or were a result of topsoil removal. In some cases, former anthropogenic impact at or in close proximity of restored sites resulted in unsuitable conditions, such as alkaline soil on former landfill sites or highly eutrophic soil due to intensive agriculture. Future management options for the study sites are discussed.
On history in the present day. Laudatio to Lenka Vaňková.
This paper takes as its starting point several statements by Gottfried Wilhelm Leibniz on the role of the German language in literary and scholarly life during Leibniz's era. The languages of scholarship were Latin and French, and Leibniz himself published in both these languages. German was the language of practical life. Viewed from this perspective, it was almost inevitable that medieval and early modern medicine - not in the sense of academic theory, but as a practical activity - developed its own fully-fledged specialist language, which was largely based on the vernacular. In her studies of the language of historical medicine, Lenka Vaňková has shown how such vernacular language was (and potentially still is) able to function in specialist domains.
The 'Deutsche Referenzkorpus (DeReKo)' of the Mannheimer Institut für Deutsche Sprache currently contains over 28 billion words, and it is constantly being expanded. The sheer size of the corpus makes it impractical for researchers to analyze its entire content. On the other hand, the DeReKo offers the possibility of taking seriously the principle that every research project needs its own corpus - by acting as a 'reference corpus' that can be used in combination with special corpora. This paper addresses the question of whether a corpus should contain complete texts or only statistically relevant extracts; it also discusses the uses and necessity of 'small corpora'.
This article addresses concerns that the growth in global governance may be bringing with it a decline in the significance of democratic sources of political legitimacy. One approach in evaluating such concerns is to ask whether the respective patterns of legitimation for private and public authority differ or whether they refer to a similar set of normative standards. Private transnational governance regimes provide useful contexts in which to assess the presumed democratic erosion. They seem, almost of themselves, to make the case for such a decline: in them regulatory authority is exercised by non-state actors who, by their very nature, lack the kind of authorization afforded by the democratic procedures that legitimize state-based regulation; in addition, they are intrinsically linked to the notion of politics as a form of problem-solving rather than as the exercise of power. Given these characteristics, when governance arrangements of this kind are subjected to criticism, one would expect justificatory responses to relate primarily to performance, with normative criteria such as fundamental individual rights and the imperative for democratic procedure playing only a minor role. On the basis of a qualitative content analysis, the study tests three ideal-type patterns of legitimation for plausibility. The case selected for examination is the recent controversy surrounding the hybrid governance regime that operates to prevent the use of performance-enhancing drugs in sport. The debate offers the possibility of a ‘nutshell’ comparison of the respective patterns of legitimation used in criticizing and justifying state and non-state regulatory authority. This comparison yields two findings. The first is that the values used to appraise the state-based components of the sporting world’s hybrid regulatory regime do not differ systematically from those used to appraise the private elements: contestation and justification in both cases are founded on normative criteria relating to fundamental individual rights and democratic procedure and not just on performance-related considerations. The second finding is that justificatory grounds of the first type do not appear to be diminishing in importance vis-à-vis those of the second.
The 23Al(p, γ)24Si stellar reaction rate has a significant impact on the light-curve emitted in X-ray bursts. Theoretical calculations show that the reaction rate is mainly determined by the properties of direct capture as well as low-lying 2+ states and a possible 4+ state in 24Si. Currently, there is little experimental information on the properties of these states.
In this proceeding we will present a new experimental study to investigate this reaction, using the surrogate reaction 23Al(d,n) at 47 AMeV at the National Superconducting Cyclotron Laboratory (NSCL). We will discuss our new experimental setup which allows us to use full kinematics employing the Gamma-Ray Energy Tracking In-beam Nuclear Array (GRETINA) to detect the γ-rays following the de-excitation of excited states of the reaction products and the Low Energy Neutron Detector Array (LENDA) to detect the recoiling neutrons. The S800 was used for identification of the 24Si recoils. As a proof of principle to show the feasibility of this concept the Q-value spectrum of 22Mg(d,n)23Al is reconstructed.
The view that tumors consist of a homogenous mass of clonal derived cells has dramatically changed in recent years. Tumors harbor an enormous heterogeneity of cells with distinct capabilities and functions. The heterogeneity originates from a differentiation hierarchy of tumor cells, similar to normal tissue organization of stem-cell driven organs, but also from clonal succession of subpopulations by randomly acquired genetic mutations and epigenetic changes. Both scenarios are certainly not mutually exclusive, and also stem and progenitor cells underlie mutational selection. Intratumoral heterogeneity is a major challenge for cancer treatment and disease monitoring. Functional studies revealed that not all tumor cells have the same ability to initiate tumor growth upon transplantation in receptive animal models. The tumorinitiating cells (TICs) were called cancer stem cells due to their similarities to normal tissue stem cells in their molecular and functional properties. They can renew themselves long-term and give rise to tumor cells lacking cancer stem cell properties. However, it is worth stressing here that TICs do not necessarily originate from stem cells, but may have regained stem cell properties. TICs caught major attention since they may provide important steps in the progression of malignant diseases, such as epithelial-to-mesenchymal transition, dissemination, long-term persistence, therapy resistance, and relapse of the disease. The prospective identification of TICs using distinct surface markers would allow their molecular and functional characterization, the design of detection methods for diagnosis and prognosis, and the development of targeted therapies against these detrimental cells. While functional evidence for the existence of TICs were provided for many tumor entities, their marker profile still remains largely undefined and controversial. ...
Ein blinder Fleck mag eine vereinzelte Fehlerquelle sein: ein weißer Fleck auf einer sonst gut kartographierten Fläche. Der blinde Fleck, mit dem es Christa Wolf zu tun hat, ist eher Teil und Makel der menschlichen Konstitution. Zu nahe(liegend), um in unseren Blickkreis treten zu können, gehört er der Anatomie unseres Wissens und Unwissens an; und was es mit diesem 'unser' und 'Un'- auf sich hat, liegt ebenfalls im Dunkeln. Wüssten wir, was und wo er ist, wäre er - wären wir - nicht mehr blind. Nicht, dass er uns ganz so unzugänglich ist wie Kants Ding an sich; er ist vielmehr 'an und für uns' da. Dank vor allem der breiten Rezeption der Psychoanalyse ist er uns, zumindest als Redensart, geläufig. Inwieweit er sich aufklären lässt, steht auf einem anderen Blatt. Dessen Erforschung stellt eine unabschließbare Aufgabe im Sinne von Freuds "unendlicher Analyse" dar. Als literarische Erbin deutsch-protestantischer Seelenprüfung ist Christa Wolf dieser 'Berufspflicht' beharrlich nachgegangen. Oder besser: sie wurde von ihr umgetrieben. Denn ihre Arbeit am blinden Fleck ist immer zugleich die daes blinden Flecks gewesen. Daher die böse Erfahrung, die sie eines Tages mit ihm machen sollte. Trotz einer jahrzehntelang geübten Gewissensforschung, die den Verhören der Stasi in nichts nachstand, stieß sie in deren Archiven eines Tages auf einen eigenen blinden Fleck. Und zwar einen, den sie am allerwenigsten an sich dulden konnte. Für solche Begegnungen hat Freud die Begriffe des "Unheimlichen" und der "Nachträglichkeit" geprägt. Es geht dabei immer um die "Arbeit" des Unbewussten.
This study describes the vascular flora and community structure of grasslands occurring on heaps of waste rock left by former Zn-Pb mining in relation to the metal content in the soil and other environmental factors. The study was performed on 65 heaps scattered in agricultural land in southern Poland. The sites were described in terms of plant community characteristics, soil physicochemical properties, distance from woodland, altitude and local climate. The number of plant species and proportion of species of the Festuco-Brometea class decreased with increasing heavy metal (Cd, Pb, Zn) content in the soil, and increased with Ca content and pH of the soil. There was a negative relationship between the proportion of the later successional species and heavy metal content in the soil and a positive relationship between plants connected with the earlier stages of succession and metals. Floristic composition was also affected by distance from woodland and height above sea level. The investigated heaps were primarily colonised by native species dispersed by wind, characterised as competitive stresstolerant, ruderal and competitive strategy species. Three types of Carlino acaulis-Brometum erecti (CB) communities were distinguished: CB typicum – dominated by Brachypodium pinnatum, with the highest proportion of calcareous grassland species, CB festucetosum ovinae subass. nova – loose grassland with abundant facultative metallophytes, and the CB rubietosum caesi subass. nova with nutrientdemanding ruderal and woody plants invading from the nearby forest communities. The three subassociations represent different successional stages of Carlino acaulis-Brometum erecti, strongly dependent on both the substrate and spatial relations. The proportions of species traits, especially a high occurrence of endangered species and a very low proportion of alien species show that the post-mining habitats studied have a similar degree of ‘naturalness’ as valuable xerothermic grasslands on nonmetalliferous habitats. They thus may be considered as valuable objects for the protection of plant diversity.
After initial formation, the heart tube grows by addition of second heart field progenitor cells to its poles. The transcription factor Isl1 is expressed in the entire second heart field in mouse, and Isl1-deficient mouse embryos show defects in arterial and venous pole development. The expression of Isl1 is conserved in zebrafish cardiac progenitors; however, Isl1 is required for cardiomyocyte differentiation only at the venous pole. Here we show that Isl1 homologues are expressed in specific patterns in the developing zebrafish heart and play distinct roles during cardiac morphogenesis. In zebrafish, isl2a mutants show defects in cardiac looping, whereas isl2b is required for arterial pole development. Moreover, Isl2b controls the expression of key cardiac transcription factors including mef2ca, mef2cb, hand2 and tbx20. The specific roles of individual Islet family members in the development of distinct regions of the zebrafish heart renders this system particularly well-suited for dissecting Islet-dependent gene regulatory networks controlling the behavior and function of second heart field progenitors in distinct steps of cardiac development.
The fulfillment of a century since the birth of writer and philologist Georg Scherg (1917-2002) is a good opportunity to recall his life and work. Born in Brasov, Scherg arrived in Sibiu only accidentally. Only later in his life he stated here for a longer time. He was appointed Head of the German Department at the recently established University of History and Philology in Sibiu in 1970. For two decades, until 1990, he had a fruitful activity, both as a teacher and as a prolific author and laborious translator of Romanian literature. He participates in research projects and symposiums of philological literary history, his efforts in this field being rewarded by his appointment as doctor honoris causa of the University „Lucian Blaga“ (1997). He was also involved in Sibiu’s literary life, leading for a long period of time a circle of artists attracted to
the poetic creation.