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Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients.
Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5–2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF).
Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating “full-blown” systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes.
Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.
Records of Bahamas plume moths (Lepidoptera: Pterophoridae) collected since 2011 are summarized and four new species described: Michaelophorus salensis Matthews, new species, Oidaematophorus androsensis Matthews, new species, Hellinsia bahamensis Matthews, new species, and Hellinsia lucayana Matthews, new species. Species accounts including illustrations of adults and genitalia, diagnoses, larval hosts, habitats, and distributions are provided. Of the 23 species found, new larval host associations are reported for two species while the life histories remain unknown for seven species.
A review and update to the list of significant vascular plant taxa has been made for the c. 500 000 ha Wollemi National Park, approximately 100 km north-west of Sydney, New South Wales. A previous assessment in 2008 revealed the presence of 94 significant taxa, including 15 listed as Endangered and 22 listed as Vulnerable in NSW Threatened Species legislation. New field surveys, coupled with analysis of observation (NSW OEH Bionet Atlas) and specimen collection (Australasian Virtual Herbarium) databases, has added a further 16 significant taxa to the reserve total, elevating it to 110. A revised assessment of the total threatened flora, as listed on the NSW Biodiversity Conservation Act 2016, shows there to be 1 Critically Endangered, 19 Endangered, 26 Vulnerable taxa and 2 Endangered Populations. For Commonwealth listed taxa under the Environment Protection and Biodiversity Conservation Act 1999, there are 1 Critically Endangered, 9 Endangered and 23 Vulnerable taxa. Sixty-one taxa are currently unrepresented within either legislation and may be considered rare, 8 taxa remain scientifically undescribed (one addition in this revision, Pultenaea 'monticola' Mt Irvine), while updated names are provided for two taxa now formally described (Eucalyptus expressa and Prostanthera stenophylla). Following assessment of all newly added taxa against IUCN criteria, one currently unlisted species (Hibbertia coloensis) qualifies as Critically Endangered, while a second (Bertya linearifolia) qualifies as Endangered. Discussion is also provided on six taxa where database records show them to be present within Wollemi, but are here excluded following closer examination.
Objective: Randomized trials have shown that concomitant methotrexate (MTX) augments the effectiveness of tumour necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA), but its benefit in psoriatic arthritis (PsA) has not been demonstrated. The goal of this study was to examine whether the impact of concomitant MTX on therapeutic outcomes in patients with PsA was similar to its effects in RA.
Methods: We used data from highly comparable and concurrent observational studies of patients with PsA (N = 1424) or RA (N = 3148) who initiated adalimumab therapy during routine clinical care. The 28-joint Disease Activity Score (DAS28) and patient-reported pain scores were evaluated in patients who received 24 months of continuous treatment with adalimumab monotherapy or adalimumab + MTX and in patients who initiated or stopped concomitant MTX during ongoing adalimumab therapy.
Results: Twenty-four months of continuous treatment with adalimumab + MTX was superior to adalimumab monotherapy in RA patients, while no significant difference was observed in patients with PsA. RA patients who added MTX during the study showed significant individual improvements in DAS28 and pain scores at 6 months after the change in therapy, while those who removed MTX had slight increases in disease activity. In contrast, in patients with PsA, neither initiation nor removal of MTX during continuous adalimumab therapy had a significant effect on therapeutic outcomes.
Conclusion: Addition of MTX to adalimumab confers further therapeutic benefit in patients with RA, but not in those with PsA, suggesting differences in MTX effects in these two patient populations.
Clinicaltrials.gov NCT01078090, NCT01077258, NCT01111240
A twentieth century-long coupled atmosphere-ocean regional climate simulation with COSMO-CLM (Consortium for Small-Scale Modeling, Climate Limited-area Model) and NEMO (Nucleus for European Modelling of the Ocean) is studied here to evaluate the added value of coupled marginal seas over continental regions. The interactive coupling of the marginal seas, namely the Mediterranean, the North and the Baltic Seas, to the atmosphere in the European region gives a comprehensive modelling system. It is expected to be able to describe the climatological features of this geographically complex area even more precisely than an atmosphere-only climate model. The investigated variables are precipitation and 2 m temperature. Sensitivity studies are used to assess the impact of SST (sea surface temperature) changes over land areas. The different SST values affect the continental precipitation more than the 2 m temperature. The simulated variables are compared to the CRU (Climatic Research Unit) observational data, and also to the HOAPS/GPCC (Hamburg Ocean Atmosphere Parameters and Fluxes from Satellite Data, Global Precipitation Climatology Centre) data. In the coupled simulation, added skill is found primarily during winter over the eastern part of Europe. Our analysis shows that, over this region, the coupled system is dryer than the uncoupled system, both in terms of precipitation and soil moisture, which means a decrease in the bias of the system. Thus, the coupling improves the simulation of precipitation over the eastern part of Europe, due to cooler SST values and in consequence, drier soil.
Diagnosing and treating acute severe and recurrent antivenom-related anaphylaxis (ARA) is challenging and reported experience is limited. Herein, we describe our experience of severe ARA in patients with neurotoxic snakebite envenoming in Nepal. Patients were enrolled in a randomised, double-blind trial of high vs. low dose antivenom, given by intravenous (IV) push, followed by infusion. Training in ARA management emphasised stopping antivenom and giving intramuscular (IM) adrenaline, IV hydrocortisone, and IV chlorphenamine at the first sign/s of ARA. Later, IV adrenaline infusion (IVAI) was introduced for patients with antecedent ARA requiring additional antivenom infusions. Preantivenom subcutaneous adrenaline (SCAd) was introduced in the second study year (2012). Of 155 envenomed patients who received ≥ 1 antivenom dose, 13 (8.4%), three children (aged 5−11 years) and 10 adults (18−52 years), developed clinical features consistent with severe ARA, including six with overlapping signs of severe envenoming. Four and nine patients received low and high dose antivenom, respectively, and six had received SCAd. Principal signs of severe ARA were dyspnoea alone (n=5 patients), dyspnoea with wheezing (n=3), hypotension (n=3), shock (n=3), restlessness (n=3), respiratory/cardiorespiratory arrest (n=7), and early (n=1) and late laryngeal oedema (n=1); rash was associated with severe ARA in 10 patients. Four patients were given IVAI. Of the 8 (5.1%) deaths, three occurred in transit to hospital. Severe ARA was common and recurrent and had overlapping signs with severe neurotoxic envenoming. Optimising the management of ARA at different healthy system levels needs more research. This trial is registered with NCT01284855.
Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.
Gram‐negative bacteria are intrinsically resistant against cytotoxic substances by means of their outer membrane and a network of multidrug efflux systems, acting in synergy. Efflux pumps from various superfamilies with broad substrate preferences sequester and pump drugs across the inner membrane to supply the highly polyspecific and powerful tripartite resistance–nodulation–cell division (RND) efflux pumps with compounds to be extruded across the outer membrane barrier. In Escherichia coli, the tripartite efflux system AcrAB–TolC is the archetype RND multiple drug efflux pump complex. The homotrimeric inner membrane component acriflavine resistance B (AcrB) is the drug specificity and energy transduction center for the drug/proton antiport process. Drugs are bound and expelled via a cycle of mainly three consecutive states in every protomer, constituting a flexible alternating access channel system. This review recapitulates the molecular basis of drug and inhibitor binding, including mechanistic insights into drug efflux by AcrB. It also summarizes 17 years of mutational analysis of the gene acrB, reporting the effect of every substitution on the ability of E. coli to confer resistance toward antibiotics (http://goethe.link/AcrBsubstitutions). We emphasize the functional robustness of AcrB toward single‐site substitutions and highlight regions that are more sensitive to perturbation.
Acetylcholine (ACh) is the major excitatory neurotransmitter in the insect central nervous system (CNS). However, besides the neuronal expression of ACh receptors (AChR), the existence of non-neuronal AChR in honeybees is plausible. The cholinergic system is a popular target of insecticides because the pharmacology of insect nicotinic acetylcholine receptors (nAChRs) differs substantially from their vertebrate counterparts. Neonicotinoids are agonists of the nAChR and are largely used in crop protection. In contrast to their relatively high safety for humans and livestock, neonicotinoids pose a threat to pollinating insects such as bees. In addition to its effects on behavior, it becomes increasingly evident that neonicotinoids affect developmental processes in bees that appear to be independent of neuronal AChRs. Brood food (royal jelly, worker jelly, or drone jelly) produced in the hypopharyngeal glands of nurse bees contains millimolar concentrations of ACh, which is required for proper larval development. Neonicotinoids reduce the secreted ACh-content in brood food, reduce hypopharyngeal gland size, and lead to developmental impairments within the colony. We assume that potential hazards of neonicotinoids on pollinating bees occur neuronally causing behavioral impairments on adult individuals, and non-neuronally causing developmental disturbances as well as destroying gland functioning.
Selection and prioritization of patients with HCC for LT are based on pretransplant imaging diagnostic, taking the risk of incorrect diagnosis. According to the German waitlist guidelines, imaging has to be reported to the allocation organization (Eurotransplant) and pathology reports have to be submitted thereafter. In order to assess current procedures we performed a retrospective multicenter analysis in all German transplant centers with focus on accuracy of imaging diagnostic and tumor classification. 1168 primary LT for HCC were conducted between 2007 and 2013 in Germany. Patients inside the Milan, UCSF, and up-to-seven criteria were misclassified with definitive histologic results in 18%, 15%, and 11%, respectively. Patients pretransplant outside the Milan, UCSF, and up-to-seven criteria were otherwise misclassified in 34%, 43%, and 41%. Recurrence-free survival correlated with classification by posttransplant histological report, but not pretransplant imaging diagnostic. Univariate analysis revealed tumor size, vascular invasion, and grading as significant parameters for outcome, while tumor grading was the only parameter persisting by multivariate testing. Conclusion. There was a relevant percentage (15-40%) of patients misclassified by imaging diagnosis at a time prior to LI-RADS and guidelines to improve imaging of HCC. Outcome analysis showed a good correlation to histological, in contrast poor correlation to imaging diagnosis, suggesting an adjustment of the LT selection and prioritization criteria.
Background: With the recent introduction of novel treatment options, real-world data from patients with metastatic castration-resistant prostate cancer (mCRPC) are required to better understand the impact on routine clinical practice. This study primarily aimed to describe the time to treatment failure (TTF) of mCRPC patients treated with abiraterone acetate plus prednisone or the corticosteroid of choice (AAP) in the pre-chemotherapy setting. Other relevant outcomes, clinical and treatment characteristics of these patients were also evaluated.
Methods: This retrospective, observational study collected data from chemotherapy-naïve mCRPC patients treated with AAP from four European countries. Kaplan-Meier curves were used to estimate TTF, progression-free survival (PFS), and time to first skeletal-related event. The impact of baseline characteristics on TTF and PFS was explored using univariate and multivariate Cox proportional hazard models. Log-rank test was used to assess the potential role of duration of response to ADT in predicting response to AAP treatment.
Results: Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150; UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years (interquartile range [IQR]: 69.0–81.0), and the median PSA was 56.2 ng/mL (IQR: 22.2–133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2–11.1) and the median PFS was 10.8 months (95%CI: 9.6–11.8). Shorter TTF was significantly associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer ECOG PS scores at AAP initiation (p < 0.05). Patients with longer duration of response to ADT (≥12 months) presented longer TTF and longer time to progression (p < 0.0001).
Conclusions: This European real-world study provides valuable insights into the characteristics, treatment, and outcomes of chemotherapy-naïve patients with mCRPC who received AAP in routine clinical practice. Treatment effectiveness of AAP in the real-world is maintained despite patients having poorer clinical features at initiation than those observed in the COU-AA-302 trial population.
Abiotic formation of n-alkane hydrocarbons has been postulated to occur within Earth's crust. Apparent evidence was primarily based on uncommon carbon and hydrogen isotope distribution patterns that set methane and its higher chain homologues apart from biotic isotopic compositions associated with microbial production and closed system thermal degradation of organic matter. Here, we present the first global investigation of the carbon and hydrogen isotopic compositions of n-alkanes in volcanic-hydrothermal fluids hosted by basaltic, andesitic, trachytic and rhyolitic rocks. We show that the bulk isotopic compositions of these gases follow trends that are characteristic of high temperature, open system degradation of organic matter. In sediment-free systems, organic matter is supplied by surface waters (seawater, meteoric water) circulating through the reservoir rocks. Our data set strongly implies that thermal degradation of organic matter is able to satisfy isotopic criteria previously classified as being indicative of abiogenesis. Further considering the ubiquitous presence of surface waters in Earth’s crust, abiotic hydrocarbon occurrences might have been significantly overestimated.
Introduction: Previous studies have established graph theoretical analysis of functional network connectivity (FNC) as a potential tool to detect neurobiological underpinnings of psychiatric disorders. Despite the promising outcomes in studies that examined FNC aberrancies in bipolar disorder (BD) and major depressive disorder (MDD), there is still a lack of research comparing both mood disorders, especially in a nondepressed state. In this study, we used graph theoretical network analysis to compare brain network properties of euthymic BD, euthymic MDD and healthy controls (HC) to evaluate whether these groups showed distinct features in FNC.
Methods: We collected resting‐state functional magnetic resonance imaging (fMRI) data from 20 BD patients, 15 patients with recurrent MDD as well as 30 age‐ and gender‐matched HC. Graph theoretical analyses were then applied to investigate functional brain networks on a global and regional network level.
Results: Global network analysis revealed a significantly higher mean global clustering coefficient in BD compared to HC. We further detected frontal, temporal and subcortical nodes in emotion regulation areas such as the limbic system and associated regions exhibiting significant differences in network integration and segregation in BD compared to MDD patients and HC. Participants with MDD and HC only differed in frontal and insular network centrality.
Conclusion: In conclusion, our findings indicate that a significantly altered brain network topology in the limbic system might be a trait marker specific to BD. Brain network analysis in these regions may therefore be used to differentiate euthymic BD not only from HC but also from patients with MDD.
Systematic reviews represent the core and backbone of evidence-based medicine (EBM) strategies in all fields of medicine. In order to depict a first global sketch of the international efforts in the Cochrane database systematic reviews (CDSR), we analyzed the systematic reviews of the Cochrane database. Our global maps of systematic reviewing offer intriguing structural insights into the world of EBM strategies. They demonstrate that for the CDSR, the UK and Commonwealth countries take the lead position. Since patients, care providers and health systems all over the world benefit from systematic reviewing, institutions in other countries should increase their commitment.
Background: Esophageal cancer (EC) is one of the deadliest cancers worldwide. The contemporary strong increase of the adenocarcinomas in Western countries and the high mortality rates require the intensification of prospective multinational studies.
Methods: Therefore, this global health issue has been chosen for the bibliometric review of the global publication output. As source for meta and citation data, the Web of Science has been used and Density Equalizing Maps were applied for visualization.
Results: 17,387 articles on EC could be identified. The years with publication and citation maxima correspond to the appearance of the most prolific articles. China is the most publishing country, followed by Japan and the USA. Germany and the UK ranked 4th and 5th. The analysis of the ratios articles and socio-economic parameters emphasizes the leading position of the Scandinavian countries and Japan. Here, the high-income countries come out on top. The high incidence regions are mainly represented by Chinese and Japanese research. The association of the publication output and the overall research funding could be shown.
Conclusions: A strengthened international network increasingly consisting of the scientifically best positioned countries as well as more of the high incidence countries worldwide is mandatory for future research. The findings deliver scientists, clinicians and decision makers backgrounds for future decisions all over the world.
A world dataset on the geographic distributions of Solenidae razor clams (Mollusca: Bivalvia)
(2019)
Background: Using this dataset, we examined the global geographical distributions of Solenidae species in relation to their endemicity, species richness and latitudinal ranges and then predicted their distributions under future climate change using species distribution modelling techniques (Saeedi et al. 2016a, Saeedi et al. 2016b). We found that the global latitudinal species richness in Solenidae is bi-modal, dipping at the equator most likely derived by high sea surface temperature (Saeedi et al. 2016b). We also found that most of the Solenidae species will shift their distribution ranges polewards due to global warming (Saeedi et al. 2016a). We also provided a comprehensive review of the taxon to test whether the latitudinal gradient in species richness was uni-modal with a peak in the tropics or northern hemisphere or asymmetric and bimodal as proposed previously (Chaudhary et al. 2016).
New information: This paper presents an integrated global geographic distribution dataset for 77 Solenidae taxa, including 3,034 geographic distribution records. This dataset was compiled after a careful data-collection and cleaning procedure over four years. Data were collected using field sampling, literature and from open-access databases. Then all the records went through quality control procedures such as validating the taxonomy of the species by examining and re-identifying the specimens in museum collections and using taxonomic and geographic data quality control tools in the World Register of Marine Species (WoRMS) and the r-OBIS package (Provoost and Bosch 2017). This dataset can thus be further used for taxonomical and biogeographical studies of Solenidae.
An album of 50 watercolour illustrations depicting Norfolk Island plants attributed to convict artist John Doody, in the early 1790s, and associated notes apparently written by William Paterson (1755-1810), one-time commander of the military detachment on Norfolk Island, Lieutenant Governor of New South Wales, and amateur botanist, are described and assessed. Illustrated are 48 plant species growing on Norfolk Island at the time, all but three of which are indigenous. The notes and the watercolours represent the only treatment of the island's flora in the 18th century and include descriptive and ecological material for the species at the time of first European occupation. Two of the species are now extinct. Paterson's notes also include an introductory description of the flora and fauna of the Island. The importance of this material to the modern study of the Norfolk Island flora is highlighted.
Demographic change is supposed to be the most important indirect driver for changing biodiversity. In this article, a systematic review of 148 studies was conducted to examine the scientific evidence for this relationship and to identify potential gaps in research. We explored the spatial distribution of studies, the categories addressed with respect to biodiversity and demographic change, and the ways in which their relationships were conceptualised (spatially and temporally) and valued. The majority of studies were carried out in Africa, Europe and North America. Our analysis confirms the trend that demographic phenomena were mostly found to negatively influence biodiversity. However, a considerable number of studies also point towards impacts that were context dependent, either positive or negative under certain circumstances. In addition to that we identified significant gaps in research. In particular, there is a lack of addressing (1) other demographic aspects such as population decline, age structure or gender differences, (2) spatial variability of, e.g. human population growth, (3) long-term effects of demographic processes, and (4) the context dependency (e.g. regulations/law enforcement, type of human activities, and choice of scale or proxy). We conclude there is evidence that the relationship between biodiversity and demographic change is much more complex than expected and so far represented in research. Thus, we call for a social–ecological biodiversity research that particularly focusses on the functional relation between biodiversity and human activities, namely the different types, context, and interdependent dynamics (spatial and temporal) of this complex relation.