Aims: Expanded hemodialysis (HDx) therapy with improved molecular cut-off dialyzers exerts beneficial effects on lowering uremia-associated chronic systemic microinflammation, a driver of endothelial dysfunction and cardiovascular disease (CVD) in hemodialysis (HD) patients with end-stage renal disease (ESRD). However, studies on the underlying molecular mechanisms are still at an early stage. Here, we identify the (endothelial) transcription factor Krüppel-like factor 2 (KLF2) and its associated molecular signalling pathways as key targets and regulators of uremia-induced endothelial micro-inflammation in the HD/ESRD setting, which is crucial for vascular homeostasis and controlling detrimental vascular inflammation.
Methods and results: First, we found that human microvascular endothelial cells (HMECs) and other typical endothelial and kidney model cell lines (e.g. HUVECs, HREC, and HEK) exposed to uremic serum from patients treated with two different hemodialysis regimens in the Permeability Enhancement to Reduce Chronic Inflammation II (PERCI-II) crossover clinical trial - comparing High-Flux (HF) and Medium Cut-Off (MCO) membranes - exhibited strongly reduced expression of vasculoprotective KLF2 with HF dialyzers, while dialysis with MCO dialyzers led to the maintenance and restoration of physiological KLF2 levels in HMECs. Mechanistic follow-up revealed that the strong downmodulation of KLF2 in HMECs exposed to uremic serum was mediated by a dominant engagement of detrimental ERK instead of beneficial AKT signalling, with subsequent AP1-/c-FOS binding in the KLF2 promoter region, followed by the detrimental triggering of pleiotropic inflammatory mediators, while the introduction of a KLF2 overexpression plasmid could restore physiological KLF2 levels and downmodulate the detrimental vascular inflammation in a mechanistic rescue approach.
Conclusion: Uremia downmodulates vasculoprotective KLF2 in endothelium, leading to detrimental vascular inflammation, while MCO dialysis with the novel improved HDx therapy approach can maintain physiological levels of vasculoprotective KLF2.
Weniger anzeigenBackground: This study relates to emerging concepts of appropriate trial designs to evaluate effects of intervention on the accumulation of irreversible disability in multiple sclerosis (MS). Major starting points of our study are the known limitations of current definitions of disability progression by rater-based clinical assessment and the high relevance of gait and balance dysfunctions in MS. The study aims to explore a novel definition of disease progression using repeated instrumental assessment of relevant motor functions performed by patients in their home setting.
Methods: The study is a prospective single-center observational cohort study with the primary outcome acquired by participants themselves, a home-based assessment of motor functions based on an RGB-Depth (RGB-D) camera, a camera that provides both depth (D) and color (RGB) data. Participants are instructed to perform and record a set of simple motor tasks twice a day over a one-week period every 6 months. Assessments are complemented by a set of questionnaires. Annual research grade assessments are acquired at dedicated study visits and include clinical ratings as well as structural imaging (MRI and optical coherence tomography). In addition, clinical data from routine visits is provided semiannually by treating neurologists. The observation period is 24 months for the primary endpoint with an additional clinical assessment at 27 month to confirm progression defined by the Expanded Disability Status Scale (EDSS). Secondary analyses aim to explore the time course of changes in motor parameters and performance of the novel definition against different alternative definitions of progression in MS. The study was registered at Deutsches Register für Klinische Studien (DRKS00027042).
Discussion: The study design presented here investigates disease progression defined by marker-less home-based assessment of motor functions against 3-month confirmed disease progression (3 m-CDP) defined by the EDSS. The technical approach was chosen due to previous experience in lab-based settings. The observation time per participant of 24, respectively, 27 months is commonly conceived as the lower limit needed to study disability progression. Defining a valid digital motor outcome for disease progression in MS may help to reduce observation times in clinical trials and add confidence to the detection of progression events in MS.
Weniger anzeigenObjective: Dyslipidemia, in particular elevated triglycerides (TGs) contribute to increased cardiovascular risk in type 2 diabetes mellitus (T2DM). In this pilot study we aimed to assess how increased TGs affect hepatic fat as well as polyunsaturated fatty acid (PUFA) metabolism and oxylipin formation in T2DM patients.
Methods: 40 patients with T2DM were characterized analyzing routine lipid blood parameters, as well as medical history and clinical characteristics. Patients were divided into a hypertriglyceridemia (HTG) group (TG ≥ 1.7mmol/l) and a normal TG group with TGs within the reference range (TG < 1.7mmol/l). Profiles of PUFAs and their oxylipins in plasma were measured by gas chromatography and liquid chromatography/tandem mass spectrometry. Transient elastography (TE) was used to assess hepatic fat content measured as controlled attenuation parameter (CAP) (in dB/m) and the degree of liver fibrosis measured as stiffness (in kPa).
Results: Mean value of hepatic fat content measured as CAP as well as body mass index (BMI) were significantly higher in patients with high TGs as compared to those with normal TGs, and correlation analysis showed higher concentrations of TGs with increasing CAP and BMI scores in patients with T2DM. There were profound differences in plasma oxylipin levels between these two groups. Cytochrome P450 (CYP) and lipoxygenase (LOX) metabolites were generally more abundant in the HTG group, especially those derived from arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), γ-linolenic acid (γ-LA), and α-linolenic acid (α-LA), and a strong correlation between TG levels and plasma metabolites from different pathways was observed.
Conclusions: In adult patients with T2DM, elevated TGs were associated with increased liver fat and BMI. Furthermore, these patients also had significantly higher plasma levels of CYP- and LOX- oxylipins, which could be a novel indicator of increased inflammatory pathway activity, as well as a novel target to dampen this activity.
Weniger anzeigenIntroduction: Patients with Parkinson’s disease (PD) exhibit deficits in social cognition, particularly with respect to Theory of Mind (ToM) capacities. It is unclear whether they are associated with PD-related dopamine deficiency and modulated by levodopa replacement therapy.
Methods: A total of 15 persons with PD and 13 healthy controls (HC) participated in the study. They performed different neuropsychological tasks, including the Faux Pas Recognition Test (FPRT), assessing different dimensions of cognitive ToM (e.g., detection, inappropriateness, intentions), and the Reading the Mind in the Eyes Test (RMET) as an index of affective ToM. Persons with PD were tested twice, once under their regular treatment and another time after at least 18 h of levodopa withdrawal (MED-ON and MED-OFF, respectively). On either occasion, serum drug levels and motor symptom severity [Unified Parkinson’s Disease Rating Scale (UPDRS)] were measured.
Results: MED-ON and MED-OFF conditions in patients with PD were confirmed by higher serum drug levels in the former than in the latter state and a corresponding amelioration of the motor deficit. In so doing, no performance difference in any ToM-related task was identified as a function of the levodopa therapy. Generally, patients performed worse than controls in both affective and cognitive ToM tests.
Conclusion: Patients with PD have deficits in cognitive and affective ToM. Dopamine replacement, effective for improving the motor condition, does not appear to counteract these dysfunctions.
Weniger anzeigenDuring the pandemic of severe respiratory distress syndrome coronavirus 2 (SARS-CoV2), many novel therapeutic modalities to treat Coronavirus 2019 induced disease (COVID-19) were explored. This study summarizes 195 clinical trials of advanced cell therapies targeting COVID-19 that were registered over the two years between January 2020 to December 2021. In addition, this work also analyzed the cell manufacturing and clinical delivery experience of 26 trials that published their outcomes by July 2022. Our demographic analysis found the highest number of cell therapy trials for COVID-19 was in United States, China, and Iran (N=53, 43, and 19, respectively), with the highest number per capita in Israel, Spain, Iran, Australia, and Sweden (N=0.641, 0.232, 0,223, 0.194, and 0.192 trials per million inhabitants). The leading cell types were multipotent mesenchymal stromal/stem cells (MSCs), natural killer (NK) cells, and mononuclear cells (MNCs), accounting for 72%, 9%, and 6% of the studies, respectively. There were 24 published clinical trials that reported on infusions of MSCs. A pooled analysis of these MSC studies found that MSCs provide a relative risk reduction for all-cause COVID-19 mortality of RR=0.63 (95% CI 0.46 to 0.85). This result corroborates previously published smaller meta-analyses, which suggested that MSC therapy demonstrated a clinical benefit for COVID-19 patients. The sources of the MSCs used in these studies and their manufacturing and clinical delivery methods were remarkably heterogeneous, with some predominance of perinatal tissue-derived products. Our results highlight the important role that cell therapy products may play as an adjunct therapy in the management of COVID-19 and its related complications, as well as the importance of controlling key manufacturing parameters to ensure comparability between studies. Thus, we support ongoing calls for a global registry of clinical studies with MSC products that could better link cell product manufacturing and delivery methods to clinical outcomes. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the near future, preventing pathology through vaccination still remains the best protection to date. We conducted a systematic review and meta-analysis of advanced cell therapy clinical trials as potential novel treatment for COVID-19 (resulting from SARS-CoV-2 coronavirus infection), including analysis of the global clinical trial landscape, published safety/efficacy outcomes (RR/OR), and details on cell product manufacturing and clinical delivery. This study had a 2-year observation interval from start of January 2020 to end of December 2021, including a follow-up period until end of July to identify published outcomes, which covers the most vivid period of clinical trial activity, and is also the longest observation period studied until today. In total, we identified 195 registered advanced cell therapy studies for COVID-19, employing 204 individual cell products. Leading registered trial activity was attributed to the USA, China, and Iran. Through the end of July 2022, 26 clinical trials were published, with 24 out of 26 articles employing intravenous infusions (IV) of mesenchymal stromal/stem cell (MSC) products. Most of the published trials were attributed to China and Iran. The cumulative results from the 24 published studies employing infusions of MSCs indicated an improved survival (RR=0.63 with 95% Confidence Interval 0.46 to 0.85). Our study is the most comprehensive systematic review and meta-analysis on cell therapy trials for COVID-19 conducted to date, clearly identifying the USA, China, and Iran as leading advanced cell therapy trial countries for COVID-19, with further strong contributions from Israel, Spain, Australia and Sweden. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the future, preventing pathology through vaccination remains the best protection.
Weniger anzeigenBackground: The number of randomized controlled trials using auricular stimulation (AS) such as transauricular vagus nerve stimulation, or other auricular electrostimulation or auricular acupuncture or acupressure, in experimental and clinical settings, has increased markedly over the last three decades. This systematic review focusses on cardiovascular effects of auricular stimulation.
Methods and analysis: The following databases were searched: MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ISI Web of Science, and Scopus Database. RCTs were reviewed that had been published in English and European languages. Data collection and analysis was conducted by two reviewers independently. Quality and risk assessment of included studies was performed and the meta-analysis of the effect of the most frequently assessed biomarkers.
Results: Altogether, 78 trials were included. 38 studies assessed heart rate (HR), 19 studies analyzed heart rate variability (HRV), 31 studies analyzed blood pressure (BP) and 7 studies were identified that measured oxygen saturation (O2), 2 studies on baroreflex sensitivity and 2 studies on skin conductance were evaluated in this review. 26 studies contained continuous data and were eligible for meta-analysis, 50 trials reported non continuous data and were evaluated descriptively. The overall quality of the studies was moderate to low. AS leads to a significant reduction of HR, the changes though were not considered an adverse reaction. Furthermore, when looking at HRV, AS was able to reduce the LF/HF ratio significantly compared to control procedures. No other cardiovascular parameters (blood pressure, oxygen saturation, baroreflex sensitivity) were changed significantly. AS produced only minor side effects in all trials.
Conclusion: AS can lead to clinically safe reduction of HR and changes in the LF/HF ratio of the HRV, which is presumably via an increase in vagal activity. More research is needed to clarify whether AS can be used to modulate tachycardia or indications with autonomic imbalance.
Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=231885 PROSPERO, ID CRD42021231885.
Weniger anzeigenCytochrome P450 (CYP)3A4 induction by drugs and pesticides plays a critical role in the enhancement of pyrrolizidine alkaloid (PA) toxicity as it leads to increased formation of hepatotoxic dehydro-PA metabolites. Addressing the need for a quantitative analysis of this interaction, we developed a physiologically-based toxicokinetic (PBTK) model. Specifically, the model describes the impact of the well-characterized CYP3A4 inducer rifampicin on the kinetics of retrorsine, which is a prototypic PA and contaminant in herbal teas. Based on consumption data, the kinetics after daily intake of retrorsine were simulated with concomitant rifampicin treatment. Strongest impact on retrorsine kinetics (plasma AUC24 and Cmax reduced to 67% and 74% compared to the rifampicin-free reference) was predicted directly after withdrawal of rifampicin. At this time point, the competitive inhibitory effect of rifampicin stopped, while CYP3A4 induction was still near its maximum. Due to the impacted metabolism kinetics, the cumulative formation of intestinal retrorsine CYP3A4 metabolites increased to 254% (from 10 to 25 nmol), while the cumulative formation of hepatic CYP3A4 metabolites was not affected (57 nmol). Return to baseline PA toxicokinetics was predicted 14 days after stop of a 14-day rifampicin treatment. In conclusion, the PBTK model showed to be a promising tool to assess the dynamic interplay of enzyme induction and toxification pathways.
Weniger anzeigenThe chemical synthesis of complex oligosaccharides relies on efficient and highly reproducible glycosylation reactions. The outcome of a glycosylation is contingent upon several environmental factors, such as temperature, acidity, the presence of residual moisture, as well as the steric, electronic, and conformational aspects of the reactants. Each glycosylation proceeds rapidly and with a high yield within a rather narrow temperature range. For better control over glycosylations and to ensure fast and reliable reactions, a systematic analysis of 18 glycosyl donors revealed the effect of reagent concentration, water content, protecting groups, and structure of the glycosyl donors on the activation temperature. With these insights, we parametrize the first step of the glycosylation reaction to be executed reliably and efficiently.
Weniger anzeigenAccording to international law, the sovereignty of nation-states and the rights of individuals constitute two equally important principles. However, in instances when a state massively violates human rights, then priority is given to the protection of individuals over the self-determination of the state, thereby justifying humanitarian military intervention. This paper presents findings from a survey across 26 countries, analyzing citizen support for such intervention. We find that the majority of respondents supports military intervention to protect human rights. To explain the differences in support, we draw on world society theory and modernization theory. At first sight, world society theory offers a better framework for understanding citizens' attitudes towards military intervention. However, charcateristics derived from modernization theory are affected by a “suppression effect:” individuals living in more modernized countries and holding postmaterialist values endorse enforcing human rights but concurrently reject the use of military force.
Weniger anzeigenPartial methanol oxidation proceeds with high selectivity to methyl formate (MeFo) on nanoporous gold (npAu) catalysts. As low-coordinated sites on npAu were suggested to affect the selectivity, we experimentally investigated their role in the isothermal selectivity for flat Au(111) and stepped Au(332) model surfaces using a molecular beam approach under well-defined conditions. Direct comparison shows that steps enhance desired MeFo formation and lower undesired overoxidation. DFT calculations reveal differences in oxygen distribution that enhance the barriers to overoxidation at steps. Thus, these results provide an atomic-level understanding of factors controlling the complex reaction network on gold catalysts, such as npAu.
Weniger anzeigenZu meinem Essay „Aufopferung als Gabe ohne Maß?“ habe ich vier sehr wertschätzende und bedenkenswerte Kommentare mit wichtigen Ergänzungen und Kritik erhalten, für die ich mich bedanken möchte. Ich kann nicht auf alle Punkte eingehen, auf manche nur implizit.
Objectives
Repetitive negative thinking (RNT) is a problematic thinking style that is related to multiple mental disorders. Detached mindfulness is a technique of metacognitive therapy that aims to reduce RNT. Our study set out to investigate the immediate effects of detached mindfulness in daily life.
Methods
Participants with elevated trait RNT (n = 50) were prompted to engage in detached mindfulness exercises three times a day for 5 consecutive days. Immediate effects on RNT and affect were assessed 15 and 30 min after each exercise using experience sampling methodology. We compared the effects of this exercise phase to (1) a 5-day non-exercise baseline phase and (2) a different group of participants that engaged in an active control exercise (n = 50).
Results
Results of Bayesian multilevel models showed that, across groups, improvements in RNT, negative affect, and positive affect were stronger during the exercise phase than during the non-exercise baseline phase (RNT after 15 min: b = -0.26, 95% CI = [-0.38, -0.14]). However, the two exercise groups did not differ in these improvements (RNT after 15 min: b = 0.02, 95% CI = [-0.22, 0.27]). Thus, the detached mindfulness and the active control exercises resulted in similar effects on RNT and affect in daily life.
Conclusions
Results of this study imply that there was no additional benefit of having participants observe their thoughts detached and non-judgmentally, compared to excluding these assumed mechanisms of action as done for the active control group. We discuss possible reasons for the non-difference between the groups.
Preregistration
This study was preregistered at https://osf.io/rze64.
Weniger anzeigenDer Text untersucht die Frage, ob Aufopferung moralisch gut ist und lotet das Verhältnis von Aufopferung und Supererogation aus. Ausgehend vom Kontext historisch dominierender Formen von Aufopferung wird die Pflege von Angehörigen paradigmatisch für die Aufopferung für jemanden (nicht für Sachen oder Ideen) in den Blick genommen. Die für Pflegebeziehungen typische Gefühlsdynamik macht deutlich, inwiefern diese Form der Aufopferung als eine Gabe ohne Maß betrachtet werden kann. Mit Rekurs auf die Theorie der Gabe werden Kriterien dafür entwickelt, unter welchen Bedingungen Aufopferung bewunderungswürdig oder womöglich moralisch falsch ist. Bewunderungswürdig ist die spezifische Gabe der Pflege von Angehörigen nur dann, so die entwickelte These, wenn sie seitens der sich aufopfernden Person mit einem ausgewogenen Gefühlshaushalt verbunden ist. Handelt es sich bei der Aufopferung dagegen um eine emotionale Dauerüberforderung, so ist diese Gabe zwar nicht mehr bewunderungswürdig, aber auch nicht moralisch falsch.
Weniger anzeigenZrO2 is a versatile material with diverse applications, including structural ceramics, sensors, and catalysts. The properties of ZrO2 are largely determined by its crystal structure, which is temperature- and atmosphere dependent. Thus, this work focuses on a quantitative analysis of the temperature- and gas atmosphere-dependent phase transformation of tetragonal t-ZrO2 into monoclinic m-ZrO2 during heating–cooling cycles from room temperature to 1273 K. Synchrotron-based in situ X-ray diffraction (XRD) studies in gas atmospheres of different reduction strengths, namely, 5 vol% H2/Ar, He, CO2, and air, revealed a stabilizing effect of inert and reductive environments, directly yielding different temperature onsets in the phase transformation during cooling (i.e., 435, 510, 710, and 793 K for 5 vol% H2/Ar, He, CO2, and air, respectively). Rietveld refinement shows a direct influence of the atmosphere on grain size, unit cell, and weight fraction of both polymorphs in the product composite matrix. The tetragonal-to-monoclinic (t–m) phase transformation is suppressed in the sample heated only up to ∼850 K, independent of the gas atmosphere. The results of ex situ XRD, transmission electron microscopic, electron paramagnetic resonance, and oxygen titration experiments confirmed that the phase transformation is accompanied by a change in the crystallite/particle size and the amount of lattice defects (i.e., oxygen vacancy). Due to the different onset temperatures, a complex interplay between kinetic limitations of phase transformation and grain sintering yields different pathways of the phase transformation and, eventually, very different final crystallite sizes of both t-ZrO2 and m-ZrO2.
Weniger anzeigenThis article contributes from a sociology of knowledge perspective to the ongoing sociological debate about statistics produced by international organisations taking the Global Estimates of Forced Labour published by the International Labour Organization (ILO) as a case of international quantification. We ask: what stages of negotiation were involved in the transformation of a legal category into a statistical category of forced labour oriented towards political action? The analysis combines the historical reconstruction of the political and organisational processes behind the production of the estimates with the study of the measurement framework of forced labour. The qualitative case study is based on semi-structured expert interviews and ILO documents. Our results highlight the processes by which a legal category was made practicable for statistical work and thereby point to the specific arrangements and connections between law, statistics, and policy within international organisations. As we argue, the estimates have provided consistency to a fragile social construct that originated in the imperial context of the interwar period, and that was turned into a ‘visible’ social and global phenomenon of the twenty-first century.
Weniger anzeigenIn the 16th century at the latest there were strong political, cultural and literary ties between the Iberian Peninsula and the Dutch speaking regions in north western Europe. Literature in general and especially romances from the ‘south’ were printed, translated and adapted in Dutch. After an introduction in which the contribution presents a short overview of the translation and adaptation of Iberian romances in Dutch the focus will be on the ‘Amadijs’ tradition especially. For the first time the Spanish source and the ‘Amadijs’ are compared, including an analysis of the paratextual elements of the first Dutch edition of ‘Amadijs’ (1546), which clearly shows that Nuyts did not follow his source as an inspiration for the design of his edition, but copied the design of earlier Dutch editions of narratives as a marketing strategy. Part four shows that the Dutch ‘Amadijs’ was obviously read by everyone in the early modern period.
Weniger anzeigenThis study analyzes the samarium diiodide-promoted cyclizations of 5-arylpentan-2-ones to dearomatized bicyclic products utilizing density functional theory. The reaction involves a single electron transfer to the carbonyl group, which occurs synchronously with the rate determining cyclization event, and a second subsequent proton-coupled electron transfer. These redox reactions are accurately computed employing small core pseudo potentials explicitly involving all f-electrons of samarium. Comparison of the energies of the possible final products rules out thermodynamic control of the observed regio- and diastereoselectivities. Kinetic control via appropriate transition states is correctly predicted, but to obtain reasonable energy levels the influence of the co-solvent hexamethylphosphortriamide has to be estimated by using a correction term. The steric effect of the bulky samarium ligands is decisive for the observed stereoselectivity. Carbonyl groups in para-position of the aryl group change the regioselectivity of the cyclization and lead to spiro compounds. The computations suggest again kinetic control of this deviating outcome. However, the standard mechanism has to be modified and the involvement of a complex activated by two SmI2 moieties is proposed in which two electrons are transferred simultaneously to form the new C–C bond. Computation of model intermediates show the feasibility of this alternative mechanism.
Weniger anzeigenWe report electrochemical metallization (ECM) resistive switching in polycrystalline YMnO3 memristive devices using Al as an active electrode. Al/YMnO3/Pt devices exhibit bipolar resistive switching with a high ROFF/RON ratio of 104, low operational voltages of VSet ≈ 1.7 V and VReset ≈ −0.36 V and good retention properties. The resistive switching is intimately linked to the coexistence of the orthorhombic and hexagonal YMnO3 phases. The characterization of these two nanocrystalline phases is realized not only by X-ray diffraction – which is shown to be unable to reveal the presence of the orthorhombic phase – but also by a set of correlative microscopy and spectroscopy methods (scanning electron microscopy, optical microscopy, Raman spectroscopy and conductive atomic force microscopy). The origin of resistive switching is ascribed to an Al filament-based electrochemical metallization mechanism that likely occurs along an oxygen-deficient grain boundary between the hexagonal and orthorhombic nanocrystalline YMnO3 phases. The unique microstructure provided by the mixed polycrystalline phase films allows to use Al as an active electrode in YMnO3-based ECM cells, and gives perspective for further miniaturization of the devices.
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