Background: The supplementary motor area (SMA) is important for motor and language function. Damage to the SMA may harm these functions, yet tools for a preoperative assessment of the area are still sparse.
Objective: The aim of this study was to validate a mapping protocol using repetitive navigated transcranial magnetic stimulation (rnTMS) and extend this protocol for both hemispheres and lower extremities.
Methods: To this purpose, the SMA of both hemispheres were mapped based on a finger tapping task for 30 healthy subjects (35.97 ± 15.11, range 21–67 years; 14 females) using rnTMS at 20 Hz (120% resting motor threshold (RMT)) while controlling for primary motor cortex activation. Points with induced errors were marked on the corresponding MRI. Next, on the identified SMA hotspot a bimanual finger tapping task and the Nine-Hole Peg Test (NHPT) were performed. Further, the lower extremity was mapped at 20 Hz (140%RMT) using a toe tapping task.
Results: Mean finger tapping scores decreased significantly during stimulation (25.70taps) compared to baseline (30.48; p < 0.01). Bimanual finger tapping led to a significant increase in taps during stimulation (28.43taps) compared to unimanual tapping (p < 0.01). Compared to baseline, completion time for the NHPT increased significantly during stimulation (baseline: 13.6 s, stimulation: 16.4 s; p < 0.01). No differences between hemispheres were observed.
Conclusion: The current study validated and extended a rnTMS based protocol for the mapping of the SMA regarding motor function of upper and lower extremity. This protocol could be beneficial to better understand functional SMA organisation and improve preoperative planning in patients with SMA lesions.
Weniger anzeigenBackground: For therapy planning in cancer patients multidisciplinary team meetings (MDM) are mandatory. Due to the high number of cases being discussed and significant workload of clinicians, Clinical Decision Support System (CDSS) may improve the clinical workflow.
Methods: This review and meta-analysis aims to provide an overview of the systems utilized and evaluate the correlation between a CDSS and MDM.
Results: A total of 31 studies were identified for final analysis. Analysis of different cancers shows a concordance rate (CR) of 72.7% for stage I-II and 73.4% for III-IV. For breast carcinoma, CR for stage I-II was 72.8% and for III-IV 84.1%, P≤ 0.00001. CR for colorectal carcinoma is 63% for stage I-II and 67% for III-IV, for gastric carcinoma 55% and 45%, and for lung carcinoma 85% and 83% respectively, all P>0.05. Analysis of SCLC and NSCLC yields a CR of 94,3% and 82,7%, P=0.004 and for adenocarcinoma and squamous cell carcinoma in lung cancer a CR of 90% and 86%, P=0.02.
Conclusion: CDSS has already been implemented in clinical practice, and while the findings suggest that its use is feasible for some cancers, further research is needed to fully evaluate its effectiveness.
Weniger anzeigenBackground and Aims: Intestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.
Methods: Murine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.
Results: Expression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.
Conclusions: We speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity.
Weniger anzeigenPerspektivenübernahme ist eine zentrale Voraussetzung für adressatenorientierte Beratung und ein wichtiger Bestandteil in Beratungskompetenzmodellen der Lehrkräftebildung. In zwei Studien mit Interventions-Wartekontrollgruppendesign und Prä-Post-Interventionsdesign und mit insgesamt 23 Seminargruppen untersuchten wir, ob sich die Bereitschaft, eine andere Perspektive in Beratungssituationen zu übernehmen, steigern lässt. Hierzu entwickelten wir eine fallbasierte Lerngelegenheit, in der angehende Lehrkräfte mit und ohne sonderpädagogischen Schwerpunkt Aufgaben zu einem anstehenden Elterngespräch bearbeiteten. Mit einer von uns entwickelten Methode („Hut-auf-Methode“) wurden die angehenden Lehrkräfte instruiert, die Perspektive der fiktiven Gesprächsteilnehmer einzunehmen. In beiden Studien wurde durch die Lerngelegenheit die Bereitschaft zur Perspektivenübernahme erhöht, sowohl gegenüber Schülern (Studie 2) also auch gegenüber Eltern (Studie 1 und 2). Darüber hinaus zeigte sich eine grundsätzlich höhere Bereitschaft die Perspektive von Schülern zu übernehmen.
Weniger anzeigenStress drop is an earthquake property indicative for the characteristic relation of slip to fault dimension. It is furthermore affected by fault strength, fault topography, the presence of fluids, rupture size, slip, and velocity. In this article, the stress drop image of an entire subduction zone, namely for the seismically highly active northernmost part of Chile, is combined with mapped b-values and their corresponding magnitude distribution in order to better constrain the conditions under which earthquakes of different provenances may nucleate. The underlying recent earthquake catalog contains over 180,000 events, covering 15 years of seismicity, from which more than 50,000 stress drop estimates were computed. Their spatial average segments the subduction zone into different parts, i.e., average stress drop between seismotectonic areas is different, although this difference is small compared to the natural scatter of stress drop values. By considering stress drop variations, b-value map, magnitude distribution, and thermal models, candidate earthquake nucleation mechanisms are identified which can explain the observed distributions. This is done for two exemplary regions: (1) The plate interface, where principally lower stress drop events are found, while at the same time a high spatial heterogeneity of stress drop values is observed. This indicates relatively smooth or lubricated rupture surfaces, and locally it suggests the existence of alternating regions controlled by strong asperities, weaker material, or creep. (2) The highly active intermediate depth (ID) seismicity region, where the variation of stress drop and b-value point to a gradual change of nucleation mechanism from dehydration embrittlement at the top of the ID cloud, over dehydration driven stress transfer in its central part, to thermal runaway shear mechanisms at its bottom. In both cases, the combination of stress drop and b-value distribution helps to better understand the origin and the differences of the observed seismicity.
Weniger anzeigenProtein-ligand docking is an established tool in drug discovery and development to narrow down potential therapeutics for experimental testing. However, a high-quality protein structure is required and often the protein is treated as fully or partially rigid. Here we develop an AI system that can predict the fully flexible all-atom structure of protein-ligand complexes directly from sequence information. We find that classical docking methods are still superior, but depend upon having crystal structures of the target protein. In addition to predicting flexible all-atom structures, predicted confidence metrics (plDDT) can be used to select accurate predictions as well as to distinguish between strong and weak binders. The advances presented here suggest that the goal of AI-based drug discovery is one step closer, but there is still a way to go to grasp the complexity of protein-ligand interactions fully. Umol is available at: https://github.com/patrickbryant1/Umol.
Weniger anzeigenThe initiation of ductile shear zones commonly occurs spatially associated with fluid-rock reactions along brittle precursors. In many cases the relative timing of fracturing, fluid infiltration, reaction, and recrystallisation is unclear, making it difficult to disentangle mechanisms of shear zone initiation from subsequent deformation and recrystallisation. Here we present the study of the transition from a dry plagioclase-diopside-garnet-scapolite host granulite-facies lithology to (1) a low strain amphibolite-facies rock, and (2) a transition from low strain to high strain amphibolite-facies lithologies. Hydration of the granulite-facies precursor at amphibolite-facies conditions produces an assemblage comprised dominantly of plagioclase-amphibole-zoisite-clinozoisite-kyanite-scapolite-quartz. Detailed study of plagioclase chemistry and microstructures across these two transitions using Electron Backscatter Diffraction (EBSD) and Wavelength Dispersive Spectrometry (WDS) allows us to assess the degree of coupling between deformation and fluid-rock reaction across the outcrop. Plagioclase behaves dominantly in a brittle manner at the hydration interface and so the initial weakening of the rock is attributed to grain size reduction caused by fracture damage and fluid infiltration at amphibolite-facies conditions. Extensive fracturing-induced grain size reduction locally increases permeability and allows for continuing plagioclase and secondary mineral growth during shear. Based on plagioclase microstructures, such as, an inherited but dispersed crystallographic preferred orientation (CPO), truncation of chemical zoning, and the dominance of fine (5–150 µm), slightly elongate, polygonal grains we conclude that deformation is dominantly facilitated by dissolution–precipitation creep assisted by grain boundary sliding in the shear zone.
Weniger anzeigenDesigning materials capable of disinfecting water without releasing harmful by-products is an ongoing challenge. Here, we report a novel polycationic sponge material synthesized from chitosan derivatives and cellulose fibers, exhibiting antibacterial properties. The design of such material is based on three key principles. First, the formation of a highly porous structure through cryogelation for an extensive surface area. Second, the incorporation of cationic quaternary ammonium moieties onto chitosan to enhance bacterial adsorption and antibacterial activity. Lastly, the reinforcement of mechanical properties through integration of cellulose fibers. The presented sponge materials exhibit up to a 4-log (99.99%) reduction within 6 h against both gram-positive B. subtilis and gram-negative E. coli. Notably, QCHI90/Cell, with the highest surface charge, exhibits a 2–4.5 log reduction within 1 h of incubation time. The eco-friendly synthesis from water and readily available biomaterials, along with cost-effectiveness and simplicity, underscores its versatility and feasibility of upscaling. Together with its outstanding antibacterial activity, this macroporous biomaterial emerges as a promising candidate for water disinfection applications.
Weniger anzeigenBackground
Significant variations exist in the forms of ZnO, making it impossible to test all forms in in vivo inhalation studies. Hence, grouping and read-across is a common approach under REACH to evaluate the toxicological profile of familiar substances. The objective of this paper is to investigate the potential role of dissolution, size, or coating in grouping ZnO (nano)forms for the purpose of hazard assessment. We performed a 90-day inhalation study (OECD test guideline no. (TG) 413) in rats combined with a reproduction/developmental (neuro)toxicity screening test (TG 421/424/426) with coated and uncoated ZnO nanoforms in comparison with microscale ZnO particles and soluble zinc sulfate. In addition, genotoxicity in the nasal cavity, lungs, liver, and bone marrow was examined via comet assay (TG 489) after 14-day inhalation exposure.
Results
ZnO nanoparticles caused local toxicity in the respiratory tract. Systemic effects that were not related to the local irritation were not observed. There was no indication of impaired fertility, developmental toxicity, or developmental neurotoxicity. No indication for genotoxicity of any of the test substances was observed. Local effects were similar across the different ZnO test substances and were reversible after the end of the exposure.
Conclusion
With exception of local toxicity, this study could not confirm the occasional findings in some of the previous studies regarding the above-mentioned toxicological endpoints. The two representative ZnO nanoforms and the microscale particles showed similar local effects. The ZnO nanoforms most likely exhibit their effects by zinc ions as no particles could be detected after the end of the exposure, and exposure to rapidly soluble zinc sulfate had similar effects. Obviously, material differences between the ZnO particles do not substantially alter their toxicokinetics and toxicodynamics. The grouping of ZnO nanoforms into a set of similar nanoforms is justified by these observations.
Weniger anzeigenBackground
It is generally assumed that procrastination leads to negative consequences. However, evidence for negative consequences of procrastination is still limited and it is also unclear by which mechanisms they are mediated. Therefore, the aim of our study was to examine the harmful consequences of procrastination on students’ stress and mental health. We selected the procrastination-health model as our theoretical foundation and tried to evaluate the model’s assumption that trait procrastination leads to (chronic) disease via (chronic) stress in a temporal perspective. We chose depression and anxiety symptoms as indicators for (chronic) disease and hypothesized that procrastination leads to perceived stress over time, that perceived stress leads to depression and anxiety symptoms over time, and that procrastination leads to depression and anxiety symptoms over time, mediated by perceived stress.
Methods
To examine these relationships properly, we collected longitudinal data from 392 university students at three occasions over a one-year period and analyzed the data using autoregressive time-lagged panel models.
Results
Procrastination did lead to depression and anxiety symptoms over time. However, perceived stress was not a mediator of this effect. Procrastination did not lead to perceived stress over time, nor did perceived stress lead to depression and anxiety symptoms over time.
Conclusions
We could not confirm that trait procrastination leads to (chronic) disease via (chronic) stress, as assumed in the procrastination-health model. Nonetheless, our study demonstrated that procrastination can have a detrimental effect on mental health. Further health outcomes and possible mediators should be explored in future studies.
Weniger anzeigenBackground
Tire wear particles (TWPs) produced by the abrasion between tires and road surfaces have been recognized as an emerging threat to soil health globally in recent years. They can be transported from the road surface to adjacent soil at different delivery rates, with precipitation a main driver underpinning this movement. However, studies typically assume an abrupt exposure of TWPs in their experimental design. In this study, we investigated the impacts of abrupt and gradual delivery of TWPs on soil physicochemical properties and microbial activities. We used two different delivery rates of TWPs (abrupt and gradual) and devised two experimental phases, namely the TWPs-delivery period (phase 1) and the end-of-delivery period (phase 2).
Results
We found that the gradual TWPs delivery treatments negatively influenced the activity of carbon cycle-related enzymes (β-glucosidase and β-D-1,4-cellobiosidase). Furthermore, the abrupt treatment highly increased the effects on nitrogen cycle-related enzyme activity (β-1,4-N-acetyl-glucosaminidase). In phase 2 (end-of-delivery period), each enzyme activity was returned to a similar level as the control group, and these changes between phases 1 and 2 depended on the prior delivery rates.
Conclusion
Abruptly and gradually delivered TWPs induce different responses to soil microbial activities. Our findings imply that the delivery rate of TWPs could be a key factor changing the effects of TWPs, further enhancing our understanding of the ecological impacts of TWPs.
Weniger anzeigenAims: 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 anzeigen