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- MDPI (568)
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Beyer, Angelika ; Moon, Kilson ; Penndorf, Peter ; Hirsch, Thomas ; Zahn-Tesch, Uta ; Hoffmann, Wolfgang ; Lode, Holger N. ; van den Berg, Neeltje
Background
In the German health care system, parents with an acutely ill child can visit an emergency room (ER) 24 hours a day, seven days a week. At the ER, the patient receives a medical consultation. Many parents use these facilities as they do not know how urgently their child requires medical attention. In recent years, paediatric departments in smaller hospitals have been closed, particularly in rural regions. As a result of this, the distances that patients must travel to paediatric care facilities in these regions are increasing, causing more children to visit an ER for adults. However, paediatric expertise is often required in order to assess how quickly the patient requires treatment and select an adequate treatment. This decision is made by a doctor in German ERs. We have examined whether remote paediatricians can perform a standardised urgency assessment (triage) using a video conferencing system.
Methods
Only acutely ill patients who were brought to a paediatric emergency room (paedER) by their parents or carers, without prior medical consultation, have been included in this study. First, an on-site paediatrician assessed the urgency of each case using a standardised triage. In order to do this, the Paediatric Canadian Triage and Acuity Scale (PaedCTAS) was translated into German and adapted for use in a standardised IT-based data collection tool. After the initial on-site triage, a telemedicine paediatrician, based in a different hospital, repeated the triage using a video conferencing system. Both paediatricians used the same triage procedure. The primary outcome was the degree of concordance and interobserver agreement, measured using Cohen’s kappa, between the two paediatricians. We have also included patient and assessor demographics.
Results
A total of 266 patients were included in the study. Of these, 227 cases were eligible for the concordance analysis. In n = 154 cases (68%), there was concordance between the on-site paediatrician’s and telemedicine paediatrician’s urgency assessments. In n = 50 cases (22%), the telemedicine paediatrician rated the urgency of the patient’s condition higher (overtriage); in 23 cases (10%), the assessment indicated a lower urgency (undertriage). Nineteen medical doctors were included in the study, mostly trained paediatric specialists. Some of them acted as an on-site doctor and telemedicine doctor. Cohen’s weighted kappa was 0.64 (95% CI: 0.49–0.79), indicating a substantial agreement between the specialists.
Conclusions
Telemedical triage can assist in providing acute paediatric care in regions with a low density of paediatric care facilities. The next steps are further developing the triage tool and implementing telemedicine urgency assessment in a larger network of hospitals in order to improve the integration of telemedicine into hospitals’ organisational processes. The processes should include intensive training for the doctors involved in telemedical triage.
Comparison of mesospheric sodium profile retrievals from OSIRIS and SCIAMACHY nightglow measurements
(2022)
Sodium airglow is generated when excited sodium atoms emit electromagnetic radiation while they are relaxing from an excited state into a lower energetic state. This electromagnetic radiation, the two sodium D lines at 589.0 and 589.6 nm, can usually be detected from space or from ground. Sodium nightglow occurs at times when the sun is not present and excitation of sodium atoms is a result of chemical reaction with ozone. The detection of sodium nightglow can be a means to determine the amount of sodium in the earth's mesosphere and lower thermosphere (MLT). In this study, we present time series of monthly mean sodium concentration profiles, by utilizing the large spatial and temporal coverage of satellite sodium D-line nightglow measurements. We use the OSIRIS/Odin mesospheric limb measurements to derive sodium concentration profiles and vertical column densities and compare those to measurements from SCIAMACHY/Envisat and GOMOS/Envisat. Here we show that the Na D-line limb emission rate (LER) and volume emission rate (VER) profiles calculated from the OSIRIS and SCIAMACHY measurements, although the OSIRIS LER and VER profiles are around 25 % lower, agree very well in shape and overall seasonal variation. The sodium concentration profiles also agree in shape and magnitude, although those do not show the clear semi-annual cycle which is present in the LER and VER profiles. The comparison to the GOMOS sodium vertical column densities (VCDs) shows that the OSIRIS VCDs are of the same order of magnitude although again the semi-annual cycle is not as clear. We attribute the differences in the LER, VER and sodium profiles to the differences in spatial coverage between the OSIRIS and SCIAMACHY measurements, the lower signal-to-noise ratio (SNR) of the SCIAMACHY measurements and differences in local time between the measurements of the two satellites.
The aquatic gastropod Theodoxus fluviatilis occurs in Europe and adjacent areas of Asia. The snail species has formed two genetically closely related subgroups, the freshwater ecotype (FW) and the brackish water ecotype (BW). Other than individuals of the FW ecotype, those of the BW ecotype survive in salinities of up to 28‰. Coastal aquatic ecosystems may be affected by climate change due to salinization. Thus, we investigated how the two Theodoxus ecotypes adjust to changes in environmental salinity, focusing on the question whether Na+/K+-ATPase or V-ATPase are regulated on the transcriptional, the translational or at the activity level under changing external salinities. Animals were gradually adjusted to extreme salinities in containers under long-day conditions and constant temperature. Whole body RNA- or protein extracts were prepared. Semi-quantitative PCR- and western blot-analyses did not reveal major changes in transcript or protein abundances for the two transporters under low or high salinity conditions. No significant changes in ATPase activities in whole body extracts of animals adjusted to high or low salinity conditions were detected. We conclude that constitutive expression of ATPases is sufficient to support osmotic and ion regulation in this species under changing salinities given the high level of tolerance with respect to changes in body fluid volume.
Paulikat, Antje D. ; Tölken, Lea A. ; Jachmann, Lana H. ; Burchhardt, Gerhard ; Hammerschmidt, Sven ; Siemens, Nikolai
Influenza A Virus (IAV), Staphylococcus aureus (staphylococci), and Streptococcus pneumoniae (pneumococci) are leading viral and bacterial causes of pneumonia. Dendritic cells (DCs) are present in the lower respiratory tract. They are characterized by low expression of co-stimulatory molecules, including CD80 and CD86 and high capacity of antigen uptake. Subsequently, DCs upregulate co-stimulatory signals and cytokine secretion to effectively induce T-cell priming. Here, we investigated these processes in response to bacterial and viral single as well as coinfections using human monocyte-derived (mo)DCs. Irrespective of single or coinfections, moDCs matured in response to IAV and/or staphylococcal infections, secreted a wide range of cytokines, and activated CD4+, CD8+ as well as double-negative T cells. In contrast, pneumococcal single and coinfections impaired moDC maturation, which was characterized by low expression of CD80 and CD86, downregulated expression of CD40, and a mild cytokine release resulting in abrogated CD4+ T-cell activation. These actions were attributed to the cholesterol-dependent cytotoxin pneumolysin (Ply). Infections with a ply-deficient mutant resulted in restored moDC maturation and exclusive CD4+ T-cell activation. These findings show that Ply has important immunomodulatory functions, supporting further investigations in specific modalities of Ply-DC interplay.
Wurm, Konrad W. ; Bartz, Frieda-Marie ; Schulig, Lukas ; Bodtke, Anja ; Bednarski, Patrick J. ; Link, Andreas
The potassium channel opening drugs flupirtine and retigabine have been withdrawn from the market due to occasional drug-induced liver injury (DILI) and tissue discoloration, respectively. While the mechanism underlying DILI after prolonged flupirtine use is not entirely understood, evidence indicates that both drugs are metabolized in an initial step to reactive ortho- and/or para-azaquinone diimines or ortho- and/or para-quinone diimines, respectively. Aiming to develop safer alternatives for the treatment of pain and epilepsy, we have attempted to separate activity from toxicity by employing a drug design strategy of avoiding the detrimental oxidation of the central aromatic ring by shifting oxidation toward the formation of benign metabolites. In the present investigation, an alternative retrometabolic design strategy was followed. The nitrogen atom, which could be involved in the formation of both ortho- or para-quinone diimines of the lead structures, was shifted away from the central ring, yielding a substitution pattern with nitrogen substituents in the meta position only. Evaluation of KV7.2/3 opening activity of the 11 new specially designed derivatives revealed surprisingly steep structure–activity relationship data with inactive compounds and an activity cliff that led to the identification of an apparent “magic methyl” effect in the case of N-(4-fluorobenzyl)-6-[(4-fluorobenzyl)amino]-2-methoxy-4-methylnicotinamide. This flupirtine analogue showed potent KV7.2/3 opening activity, being six times as active as flupirtine itself, and by design is devoid of the potential for azaquinone diimine formation.
We use time-evolution techniques for (infinite) matrix product states to calculate, directly in the thermodynamic limit, the time-dependent photoemission spectra and dynamic structure factors of the half-filled Hubbard chain after pulse irradiation. These quantities exhibit clear signatures of the photoinduced phase transition from insulator to metal that occurs because of the formation of so-called η pairs. In addition, the spin dynamic structure factor loses spectral weight in the whole momentum space, reflecting the suppression of antiferromagnetic correlations due to the buildup of η-pairing states. The numerical method demonstrated in this work can be readily applied to other one-dimensional models driven out of equilibrium by optical pumping.
Shallow aquatic environments are characterized by strong environmental variability. For ectotherms, temperature is the main driver of metabolic activity, thus also shaping performance. Ingestion rates in mysids are fast responses, influenced by metabolic and behavioral activity. We examined ingestion rates of the mysid Neomysis integer, collected in the Baltic Sea, after one-week exposure to different constant and fluctuating temperature regimes (5, 10, 15, 20°C and 9 ± 5, 14 ± 5°C, respectively). To investigate possible differences between sexes, thermal performance curves (TPCs) were established for female and male mysids based on ingestion rates measured at constant temperatures. TPCs of ingestion rates at constant temperatures differed between sexes, with female mysids showing a higher total ingestion rate as well as a higher thermal optimum compared to male mysids. Females showed reduced ingestion rates when exposed to fluctuating temperatures around their thermal optimum, whereas ingestion of male mysids was not reduced when exposed to fluctuating temperatures. The observed sex-specific differences might be related to potentially higher lipid and energy demands of the females. We suggest future studies should investigate males and females to improve our understanding about impacts of environmental variability on natural populations.
Meyer, Marleen J. ; Schreier, Pascale C. F. ; Basaran, Mert ; Vlasova, Stefaniia ; Seitz, Tina ; Brockmölller, Jürgen ; Zdrazil, Barbara ; Tzvetkov, Mladen V.
Organic cation transporter 1 (OCT1) is a membrane transporter that affects hepatic uptake of cationic and weakly basic drugs. OCT1 transports structurally highly diverse substrates. The mechanisms conferring this polyspecificity are unknown. Here, we analyzed differences in transport kinetics between human and mouse OCT1 orthologs to identify amino acids that contribute to the polyspecificity of OCT1. Following stable transfection of HEK293 cells, we observed more than twofold differences in the transport kinetics of 22 out of 28 tested substrates. We found that the β2-adrenergic drug fenoterol was transported with eightfold higher affinity but at ninefold lower capacity by human OCT1. In contrast, the anticholinergic drug trospium was transported with 11-fold higher affinity but at ninefold lower capacity by mouse Oct1. Using human–mouse chimeric constructs and site-directed mutagenesis, we identified nonconserved amino acids Cys36 and Phe32 as responsible for the species-specific differences in fenoterol and trospium uptake. Substitution of Cys36 (human) to Tyr36 (mouse) caused a reversal of the affinity and capacity of fenoterol but not trospium uptake. Substitution of Phe32 to Leu32 caused reversal of trospium but not fenoterol uptake kinetics. Comparison of the uptake of structurally similar β2-adrenergics and molecular docking analyses indicated the second phenol ring, 3.3 to 4.8 Å from the protonated amino group, as essential for the affinity for fenoterol conferred by Cys36. This is the first study to report single amino acids as determinants of OCT1 polyspecificity. Our findings suggest that structure–function data of OCT1 is not directly transferrable between substrates or species.
Schwarz, Claudia ; Benson, Gloria S. ; Horn, Nora ; Wurdack, Katharina ; Grittner, Ulrike ; Schilling, Ralph ; Märschenz, Stefanie ; Köbe, Theresa ; Hofer, Sebastian J. ; Magnes, Christoph ; Stekovic, Slaven ; Eisenberg, Tobias ; Sigrist, Stephan J. ; Schmitz, Dietmar ; Wirth, Miranka ; Madeo, Frank ; Flöel, Agnes
Importance: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline.
Objective: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group.
Design, Setting, and Participants: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021.
Interventions: One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention.
Main Outcomes and Measures: Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed.
Results: A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, −0.03; 95% CI, −0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups.
Conclusions and Relevance: In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage.
Proteostasis, a portmanteau of the words protein and homeostasis, refers to the ability of
eukaryotic cells to maintain a stable proteome by acting on protein synthesis, quality control and/or
degradation. Over the last two decades, an increasing number of disorders caused by proteostasis
perturbations have been identified. Depending on their molecular etiology, such diseases may be
classified into ribosomopathies, proteinopathies and proteasomopathies. Strikingly, most—if not
all—of these syndromes exhibit an autoinflammatory component, implying a direct cause-and-effect
relationship between proteostasis disruption and the initiation of innate immune responses. In this
review, we provide a comprehensive overview of the molecular pathogenesis of these disorders and
summarize current knowledge of the various mechanisms by which impaired proteostasis promotes
autoinflammation. We particularly focus our discussion on the notion of how cells sense and integrate
proteostasis perturbations as danger signals in the context of autoinflammatory diseases to provide
insights into the complex and multiple facets of sterile inflammation.
Gebhardt, Sebastian ; Lerch, Solveig ; Sobau, Christian ; Miehlke, Wolfgang ; Wassilew, Georgi I. ; Zimmerer, Alexander
Recently, there was a debate about whether borderline dysplastic hips should be treated surgically with hip arthroscopy or periacetabular osteotomy (PAO). Current studies recommend a classification into stable and unstable hips. Therefore, radiological scores have been described in recent years. Likewise, a new clinical stability test with the Prone Apprehension Relocation Test (PART) has been described. However, there has been no correlation between the modern radiological scores and the PART. We prospectively studied a consecutive group of patients who presented to our clinic. The PART and radiological scores were assessed in these patients. We divided the patients into a PART-positive and a PART-negative group and analyzed the associated clinical and radiological findings. Out of 126 patients (126 hips) included, 36 hips (29%) were evaluated as PART positive. There were significantly more females in the PART positive group (P = 0.005). Comparing the PART groups, significant differences (P < 0.0001) were found for the lateral center edge angle (LCEA), Femoro-Epiphyseal Acetabular Roof (FEAR) index, Gothic arch angle (GAA), anterior wall index (AWI), the occurrence of the upsloping lateral sourcil (ULS) and signs of acetabular retroversion. The correlation analysis showed an association between LCEA, FEAR index, GAA, AWI, ULS and the PART. A chi-square automatic interaction detection algorithm revealed that the strongest predictor of positive PART was the GAA. In conclusion, a high correlation between the PART and known radiological instability parameters was found. Consequently, a combination of clinical instability testing and radiological instability parameters should be applied to detect unstable hips.
Cerebral oxygenation disturbances contribute to the pathogenesis of brain lesions in preterm infants with white matter damage. These children are at risk of developing long-term neurodevelopmental disabilities. Preterm birth is associated with sudden hormonal changes along with an untimely increase in oxygen tissue tension. There is a persistent high postnatal production of fetal zone steroids (FZS), which serve in the fetoplacental unit as precursors for placental estrogen synthesis during pregnancy. The role of FZS in events associated with oxygenation differences and their impact on the developing white matter is not well understood. Therefore, we investigated the effect of hyperoxia (80% O2) and subsequent administration of FZS on the protein composition and migration capabilities of immature oligodendrocytes using the OLN93 (rat-derived OPC) cell line as an experimental model. We tested the effect of the FZS, dehydroepiandrosterone (DHEA), 16α-OH-DHEA, and adiol (5-androstene-3β, 17β-diol). After 24-hour exposure to hyperoxia, we monitored the changes in the proteome profile following treatment and observed significant alterations in pathways regulating cytoskeletal remodelling, cell migration, and cell survival. Additionally, hyperoxia leads to impaired migration of the OLN93 cells in culture. Administration of the FZS showed positive effects on the migration process under normoxic conditions in general. However, under hyperoxic conditions, the trend was less prominent. The observed effects could be related to changes in levels of cofilin/LIMK pathway-associated proteins. Adiol had a negative effect when administered together with estradiol, and the proteomic data reveal the activation of ephrin receptor signalling that might be responsible for the attenuation of migration. The results suggest that FZS can differentially regulate pathways involved in the migration of OLN93 cells. A deeper insight into the precise role of endogenous FZS would be an essential prerequisite for developing new treatment strategies including supplementation of estradiol and other steroids in preterm infants.
Michalik, Stephan ; Siegerist, Florian ; Palankar, Raghavendra ; Franzke, Kati ; Schindler, Maximilian ; Reder, Alexander ; Seifert, Ulrike ; Cammann, Clemens ; Wesche, Jan ; Steil, Leif ; Hentschker, Christian ; Gesell-Salazar, Manuela ; Reisinger, Emil ; Beer, Martin ; Endlich, Nicole ; Greinacher, Andreas ; Völker, Uwe
Vector-based SARS-CoV-2 vaccines have been associated with vaccine- induced thrombosis with thrombocytopenia syndrome (VITT/TTS), but the causative factors are still unresolved. We comprehensively analyzed the ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Johnson and Johnson) vaccines. ChAdOx1 nCoV-19 contains significant amounts of host cell protein impurities, including functionally active proteasomes, and adenoviral proteins. A much smaller amount of impurities was found in Ad26.COV2.S. Platelet factor 4 formed complexes with ChAdOx1 nCoV-19 constituents, but not with purified virions from ChAdOx1 nCoV-19 or with Ad26.COV2.S. Vascular hyperpermeability was induced by ChAdOx nCoV-19 but not by Ad26.COV2.S. These differences in impurities together with EDTAinduced capillary leakage might contribute to the higher incidence rate of VITT associated with ChAdOx1 nCoV-19 compared to Ad26.COV2.S.
Effectiveness of Acupuncture for Pain Control After Cesarean Delivery: A Randomized Clinical Trial
(2022)
Usichenko, Taras I. ; Henkel, Berthold Johannes ; Klausenitz, Catharina ; Hesse, Thomas ; Pierdant, Guillermo ; Cummings, Mike ; Hahnenkamp, Klaus
Importance: A pharmacological approach to pain control after cesarean delivery is often insufficient on its own. Acupuncture is a promising method for mitigating postoperative pain and reducing postoperative opioid requirements.
Objective: To evaluate the efficacy and effectiveness of acupuncture as an adjunctive therapy for pain control after cesarean delivery, compared with a placebo intervention and standard care alone.
Design, Setting, and Participants: This single-center, placebo-controlled, patient- and assessor-blinded randomized clinical trial was conducted from January 13, 2015, to June 27, 2018, at a tertiary university hospital in Greifswald, Germany. Participants were women who were scheduled for elective cesarean delivery under spinal anesthesia and were randomized to either the acupuncture group (n = 60) or placebo group (n = 60). Another 60 consecutive patients who met the eligibility criteria and received the standard postoperative analgesia were selected to form a nonrandomized standard care group. The intention-to-treat analysis was performed from August 19, 2019, to September 13, 2019.
Interventions: In addition to standard pain treatment, each patient in the acupuncture group received auricular and body acupuncture with indwelling intradermal needles, whereas patients in the placebo group were treated with nonpenetrating placebo needles.
Main Outcomes and Measures: The primary outcome was pain intensity on movement, which was measured using an 11-item verbal rating scale. Secondary outcomes were analgesia-related adverse effects, analgesics consumption, time to mobilization and Foley catheter removal, quality of patient blinding to randomization, and patient satisfaction with treatment of pain.
Results: A total of 180 female patients (mean [SD] age, 31 [5] years) were included in the intention-to-treat analysis. The mean pain intensity on movement in the acupuncture group on the first postoperative day was lower than in the placebo group (4.7 [1.8] vs 6.0 [2.0] points; Cohen d, 0.73; 95% CI, 0.31-1.01; P = .001) and the standard care group (6.3 [1.3] points; Cohen d, 1.01; 95% CI, 0.63-1.40; P < .001). On the first postoperative day, 59 patients (98%) in the acupuncture group were fully mobilized vs 49 patients (83%) in the placebo group (relative risk [RR], 1.18; 95% CI, 1.06-1.33; P = .01) and 35 patients (58%) in the standard care group (RR, 1.69; 95% CI, 1.36-2.09; P < .001). The Foley catheter was removed in a total of 57 patients (93%) from the acupuncture group vs 43 patients (72%) from the placebo group (RR, 1.33; 95% CI, 1.12-1.57; P = .003) and 42 patients (70%) from the standard care group (RR, 1.37; 95% CI, 1.14-1.62; P = .002). Other parameters were comparable across the 3 study groups.
Conclusions and Relevance: Results of this trial showed that acupuncture was safe and effective in reducing pain and accelerating mobilization of patients after cesarean delivery. With consideration for personnel and time expenditures, acupuncture can be recommended as routine, supplemental therapy for pain control in patients after elective cesarean delivery.
Wolf, Robert ; Grammbauer, Sophie ; Palankar, Raghavendra ; Tolksdorf, Céline ; Moritz, Eileen ; Böhm, Andreas ; Hasan, Mahmoud ; Hafkemeyer, Annika ; Greinacher, Andreas ; Tzvetkov, Mladen V. ; Rauch, Bernhard H. ; Jedlitschky, Gabriele
The multidrug resistance protein 4 (MRP4) is highly expressed in platelets and several lines of evidence point to an impact on platelet function. MRP4 represents a transporter for cyclic nucleotides as well as for certain lipid mediators. The aim of the present study was to comprehensively characterize the effect of a short-time specific pharmacological inhibition of MRP4 on signaling pathways in platelets. Transport assays in isolated membrane vesicles showed a concentrationdependent inhibition of MRP4-mediated transport of cyclic nucleotides, thromboxane (Tx)B2 and fluorescein (FITC)- labeled sphingosine-1-phosphate (S1P) by the selective MRP4 inhibitor Ceefourin-1. In ex vivo aggregometry studies in human platelets, Ceefourin-1 significantly inhibited platelet aggregation by about 30-50% when ADP or collagen was used as activating agents, respectively. Ceefourin-1 significantly lowered the ADP-induced activation of integrin aIIbb3, indicated by binding of FITC-fibrinogen (about 50% reduction at 50 mM Ceefourin-1), and reduced calcium influx. Furthermore, pre-incubation with Ceefourin-1 significantly increased PGE1- and cinaciguat-induced vasodilatorstimulated phosphoprotein (VASP) phosphorylation, indicating increased cytosolic cAMP as well as cGMP concentrations, respectively. The release of TxB2 from activated human platelets was also attenuated. Finally, selective MRP4 inhibition significantly reduced both the total area covered by thrombi and the average thrombus size by about 40% in a flow chamber model. In conclusion, selective MRP4 inhibition causes reduced platelet adhesion and thrombus formation under flow conditions. This finding is mechanistically supported by inhibition of integrin aIIbb3 activation, elevated VASP phosphorylation and reduced calcium influx, based on inhibited cyclic nucleotide and thromboxane transport as well as possible further mechanisms.
The use of digital tools can positively impact higher education for both scholars and faculty. In recent years, it has become apparent that podcasts are a suitable medium for use in teaching. They are provided almost exclusively by lecturers for students, with students passively listening to them rather than actively participating in their production. However, this could also be valuable for students. Therefore, this pilot study investigated the extent to which the creation of a podcast would be accepted by students as a method for capturing pharmacy students’ understanding of the learning content. The evaluation was performed as part of the “Clinical Chemistry” practical course, which was attended by third-year pharmacy students in groups of three. After passing the station dealing with practical clinical chemistry relevant diagnostic systems, the groups were asked to produce an educational podcast covering the essential content on the topics of urine test strips or pulse oximetry, respectively. Student attitudes toward the adoption of podcasts as a tool for performance assessment were determined with an anonymous and voluntary survey. The respondents reported that they had fun creating the podcast, which enabled them to look at the instructional content from a different perspective. Competencies such as social and communication skills and media literacy as well as self-organized and self-directed learning were also promoted. However, the students assumed that the tool is not ideally suited for dealing with extensive topics. Nonetheless, the students clearly support the continued creation of podcasts as a performance assessment tool. In addition, they suggest integrating podcasts into other courses within the pharmacy curriculum. This may also be related to the infrequent use of novel technologies, such as podcasts, in their education thus far.
Ittermann, Till ; Khattak, Rehmann Mehmood ; Markus, Marcello Ricardo Paulista ; Kühn, Jens-Peter ; Kromrey, Marie-Luise ; Targher, Giovanni ; Steveling, Antje ; Nauck, Matthias ; Völzke, Henry
The associations of thyroid function parameters with non-alcoholic fatty liver disease (NAFLD) and hepatic iron overload are not entirely clear. We have cross-sectionally investigated these associations among 2734 participants of two population-based cross-sectional studies of the Study of Health in Pomerania. Serum levels of thyroid-stimulating hormone (TSH), free tri-iodothyronine (fT3), and free thyroxine (fT4) levels were measured. Liver fat content (by proton-density fat fraction) as well as hepatic iron content (by transverse relaxation rate; R2*) were assessed by quantitative MRI. Thyroid function parameters were associated with hepatic fat and iron contents by median and logistic regression models adjusted for confounding. There were no associations between serum TSH levels and liver fat content, NAFLD, or hepatic iron overload. Serum fT4 levels were inversely associated with liver fat content, NAFLD, hepatic iron contents, and hepatic iron overload. Serum fT3 levels as well as the fT3 to fT4 ratio were positively associated with hepatic fat, NAFLD, hepatic iron contents, but not with hepatic iron overload. Associations between fT3 levels and liver fat content were strongest in obese individuals, in which we also observed an inverse association between TSH levels and NAFLD. These findings might be the result of a higher conversion of fT4 to the biologically active form fT3. Our results suggest that a subclinical hyperthyroid state may be associated with NAFLD, particularly in obese individuals. Furthermore, thyroid hormone levels seem to be more strongly associated with increased liver fat content compared to hepatic iron content.
Although the outcome of patients with acute myeloid leukemia (AML) has
improved in the past decades, the overall survival is below 50% [1, 2] and there
is still an unmet need for the development of new therapeutic strategies. Here,
we aimed to identify functional vulnerabilities in AML and investigated the
therapeutic potential of target structures involved in proteostasis, cell polarity and
RNA-binding molecular pathways.
We determined that genetic deletion of the cell fate determinant and polarity
regulator Scribble delays AML development, however, its deletion also seems to
affect the proliferative capacity of normal hematopoietic cells, lowering its value
as a therapeutic target. In contrast, inactivation of YBX1 (a pleiotropic protein with
DNA/RNA binding capacity that excerpts post-transcriptional control on its
targets) and PSMB8/LMP7 (a catalytic subunit of the immunoproteasome multiprotein
complex that belongs to the ubiquitin-proteasome system (UPS)) inhibit
leukemic cells without influencing normal hematopoietic stem and progenitor cell
function, establishing these targets as potential novel therapeutic strategies
against AML.
Genetic deletion of YBX1 caused reduced proliferation and colony forming
capacity in leukemic cells independent of the oncogenic driver mutation and
delayed AML development in vivo. The role of Ybx1 in leukemia maintenance
was investigated using a conditional knockout model, confirming the functional
requirement of Ybx1 in AML maintenance. Mechanistically, YBX1 recruited
oncogenic transcripts to polysomes, increasing their translation. Displacement of
these transcripts from polysomes after YBX1 deletion decreased their protein
expression.
Genetic and pharmacologic inhibition of PSMB8/LMP7 decreased proliferation
and colony forming capacity selectively in KMT2A (MLL)-rearranged leukemic
cells. In vivo treatment with a PSMB8/LMP7 inhibitor delayed disease
development in KMT2A-rearranged leukemic mice or patient derived xenografts
(PDX). We identified the transcriptional corepressor BASP1 as a functional
effector of the immunoproteasome. BASP1 was enriched after PSMB8/LMP7
inhibition and it was found binding to KMT2A-target genes. Moreover,
pharmacologic inhibition of PSMB8/LMP7 led to decreased expression of bonafide
KMT2A-fusion target genes and enrichment for genes deregulated by
inhibitors of the KMT2A complex partners DOT1L and MEN1. This prompted us
to investigate a potential synergism between MEN1 inhibition and
immunoproteasome inhibition. Combination treatment in AML cells revealed
decreased proliferation in vitro and increased survival in vivo as compared to the
single treatments, demonstrating the therapeutic potential of combining
immunoproteasome and MEN1 inhibitors.
This thesis presents the production of polyanionic clusters within two ion storage devices:
Considering a Penning trap, the accessible range of polyanionic aluminium clusters has been expanded up to the 10th charge state. In particular, abundance curves for clusters with 5 to 9 excess electrons have been measured for the first time and analysed with respect to their lifetime-dependent appearance sizes. These sizes reveal a nearly quadratic dependency on the charge state for experimentally accessible lifetimes.
Additionally, the production of polyanionic clusters has been enabled in a radiofrequency ion trap. Therefore, the transition from a harmonic to a digital 2- and 3-state guiding signal has been investigated with respect to the ion storage. The passing of electrons through the trap during field-free periods of the guiding signal led to the first production of polyanionic clusters within a radiofrequency ion trap.