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Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus
No full textBackground and Objectives: Myasthenia gravis (MG) is an autoimmune disease most frequently caused by autoantibodies (auto-Abs) against the acetylcholine receptor (AChR) located at the neuromuscular junction. Thymic follicular hyperplasia is present in most of the patients with early-onset AChR-Ab+ MG (EOMG), but its cellular and molecular drivers and development remain poorly understood. Methods: We constructed a single cell-based transcriptional profile of lymphoid cell types in thymi from 11 immunotherapy-naïve patients with EOMG. Multiplex histology and ELISA were used to determine migration inhibitory factor (MIF) levels. Results: Within EOMG thymi, we consistently observed 6 distinct clusters of B-cell populations maturing toward germinal center (GC)–associated and Ab-secreting cells, featuring prominent GC activity, as indicated by substantial clonal expansions and cycling B-cell subsets. Cell-cell interactome predictions identified strong interactions between T cells and GC-associated and memory B cells, dominated by B-cell prosurvival signaling through the MIF-CD74 axis. Multiplex histology confirmed abundant expression of CD74 in MG thymic B cells. Circulating MIF levels in EOMG correlated with higher disease severity as assessed by Myasthenia Gravis Foundation of America status. Discussion: Our data not only illustrate and define hyperplastic thymic niches in MG as favorable environments for pathogenic B-cell proliferation, maturation, and persistence but also suggest that the MIF-CD74 axis should be investigated for potential novel therapeutic targeting in EOMG
Spinal GABA transporter 1 contributes to evoked-pain related behavior but not resting pain after incision injury
No full textThe inhibitory function of GABA at the spinal level and its central modulation in the brain are essential for pain perception. However, in post-surgical pain, the exact mechanism and modes of action of GABAergic transmission have been poorly studied. This work aimed to investigate GABA synthesis and uptake in the incisional pain model in a time-dependent manner. Here, we combined assays for mechanical and heat stimuli-induced withdrawal reflexes with video-based assessments and assays for non-evoked (NEP, guarding of affected hind paw) and movement-evoked (MEP, gait pattern) pain-related behaviors in a plantar incision model in male rats to phenotype the effects of the inhibition of the GABA transporter (GAT-1), using a specific antagonist (NO711). Further, we determined the expression profile of spinal dorsal horn GAT-1 and glutamate decarboxylase 65/67 (GAD65/67) by protein expression analyses at four time points post-incision. Four hours after incision, we detected an evoked pain phenotype (mechanical, heat and movement), which transiently ameliorated dose-dependently following spinal inhibition of GAT-1. However, the NEP-phenotype was not affected. Four hours after incision, GAT-1 expression was significantly increased, whereas GAD67 expression was significantly reduced. Our data suggest that GAT-1 plays a role in balancing spinal GABAergic signaling in the spinal dorsal horn shortly after incision, resulting in the evoked pain phenotype. Increased GAT-1 expression leads to increased GABA uptake from the synaptic cleft and reduces tonic GABAergic inhibition at the post-synapse. Inhibition of GAT-1 transiently reversed this imbalance and ameliorated the evoked pain phenotype
Strophanthus sarmentosus Extracts and the Strophanthus Cardenolide Ouabain Inhibit Snake Venom Proteases from Echis ocellatus
No full text'Strophanthus sarmentosus' is recognised for various ethnomedicinal applications, including treatment after snakebites. However, only limited scientific evidence exists on its antivenomous capabilities. This study investigates the efficacy of methanol and ethylacetate extracts from 'S. sarmentosus' leaves and roots against 'Echis ocellatus' venom. A non-toxic range for the extracts was determined in rats, and assays were performed to test their anti-hemorrhagic and anti-hemolytic activity as well as their influence on venom-induced blood clotting. In all of these experiments, the extracts demonstrated significant positive effects equal to or better than antivenom. Moreover, the extracts strongly inhibited and even abolished the digestion of the vasoactive neuropeptide bradykinin by snake venom metalloproteinases. Strophantus plants are known for their high content of cardiac glycosides, one of which is the commercially available ouabain, that by itself also considerably inhibited venom-induced bradykinin cleavage. Although ouabain is only present in low amounts in 'S. sarmentosus' when compared to other cardenolides of similar structure, it can be hypothesized that members of this substance class may also have inhibitory properties against venom proteases. 'S. sarmentosus' additionally contains bioactive substances such as flavonoids, terpenoids, tannins, saponins, and alkaloids, which contribute to its protective effects. The study provides scientific data to explain the success of the traditional use of 'S. sarmentosus' plant extracts as a first aid against envenomation in rural Africa
The Baum–Connes conjecture for extensions
No full textThis note provides a counterexample showing that the assumptions that Chabert and Echterhoff have imposed in their permanence property of the Baum–Connes conjecture for group extensions cannot be simplified
Therapeutisches Drug Monitoring von Psychopharmaka bei Patienten mit erhöhtem Delir-Risiko zur Verbesserung des klinischen Delir-Managements
No full textÄltere Patienten mit Delir weisen eine hohe Mortalität und eine veränderte Pharmakokinetik von Psychopharmaka auf. Ziel dieser Arbeit war es, durch Therapeutisches Drug Monitoring (TDM) und populationsbasierte Pharmakokinetik-Modelle die Arzneimitteltherapiesicherheit zu verbessern. In fünf Gruppen wurden Kapillarblutkonzentrationen von Pipamperon, Melperon, Risperidon, Mirtazapin und Citalopram bei 71 älteren Patienten untersucht. Die Modelle zeigten interindividuelle Variabilität in Clearance, Verteilungsvolumen und Halbwertszeiten, die von Literaturwerten jüngerer Erwachsener abwichen. Mess- und Dokumentationsfehler, eingeschränkte Organfunktionen und Werte unterhalb der Bestimmungsgrenze stellten Limitationen dar. Die Kapillarblutabnahme mittels der VAMSTM-Methode ermöglichte den qualitativen Nachweis aller Substanzen. Die Ergebnisse betonen die Relevanz von TDM und individualisierten Dosierungen für ältere Delir-Patienten sowie den Bedarf größerer klinischer Studien.Older patients with delirium exhibit high mortality and altered pharmacokinetics of psychotropic drugs. This study aimed to enhance medication safety through therapeutic drug monitoring (TDM) and population pharmacokinetic modeling. Capillary blood concentrations of pipamperone, melperone, risperidone, mirtazapine, and citalopram were analyzed in 71 elderly patients across five groups. The models revealed substantial interindividual variability in clearance, volume of distribution, and half-lives, deviating from values reported in younger adults. Limitations included measurement and documentation inaccuracies, impaired organ function and concentrations below the limit of quantification. Capillary blood sampling using the VAMSTM method enabled reliable qualitative detection of all compounds. The findings support the relevance of TDM and individualized dosing in elderly delirium patients and highlight the need for larger clinical studies
Analyzing the interactome of human CK2Beta in prostate carcinoma cells reveals HSP70-1 and Rho guanin nucleotide exchange factor 12 as novel interaction partners
No full textCK2Beta is the non-catalytic modulating part of the S/T-protein kinase CK2. However, the overall function of CK2Beta is poorly understood. Here, we report on the identification of 38 new interaction partners of the human CK2Beta from lysates of DU145 prostate cancer cells using photo-crosslinking and mass spectrometry, whereby HSP70-1 was identified with high abundance. The KD value of its interaction with CK2Beta was determined as 0.57 μM by microscale thermophoresis, this being the first time, to our knowledge, that a KD value of CK2Beta with another protein than CK2Alpha or CK2Alpha' was quantified. Phosphorylation studies excluded HSP70-1 as a substrate or activity modulator of CK2, suggesting a CK2 activity independent interaction of HSP70-1 with CK2Beta. Co-immunoprecipitation experiments in three different cancer cell lines confirmed the interaction of HSP70-1 with CK2Beta in vivo. A second identified CK2Beta interaction partner was Rho guanin nucleotide exchange factor 12, indicating an involvement of CK2Beta in the Rho-GTPase signal pathway, described here for the first time to our knowledge. This points to a role of CK2Beta in the interaction network affecting the organization of the cytoskeleton
"Familien können eine Ressource und gleichzeitig ein Risikofaktor sein":Soziologe und Kriminologe Jens Struck über Clankriminalität
No full textDer Begriff Clankriminalität schafft ein verzerrtes Bild in der öffentlichen Wahrnehmung, indem er ganze Familien pauschal unter Verdacht stellt. "Daher bezweifle ich, dass sich über Familiennamen konkrete Kriminalitätsformen messen lassen", betont Soziologe und Kriminologe Dr. Jens Struck in der neuen Folge des "Umdenken"-Podcasts der Universität Münster. Im Gegenteil: Der Ansatz fördere die häufig unberechtigte Assoziation von Kriminalität und Clans, also Familienverbünden mit vermeintlich gemeinsamer ethnischer Herkunft. Besonders problematisch ist dabei, dass der Begriff Clankriminalität in der öffentlichen Wahrnehmung fast ausschließlich mit Organisierter Kriminalität assoziiert wird, obwohl in der polizeilichen Erfassung darunter sämtliche Delikte fallen. Gleichwohl gebe es grundsätzlich einen Zusammenhang zwischen familiären Einflüssen und kriminellen Delikten: Studien zeigen, dass die Wahrscheinlichkeit für straffälliges Verhalten bei Kindern mit kriminell auffälligen Eltern etwa 2,4-mal höher ist – unabhängig von der Herkunft
Heart transplantation surgery in children and young adults with congenital heart disease
No full textBackground: Pediatric cardiac transplantation remains a surgical challenge as a variety of cardiac and vessel malformation are present in patients with congenital heart disease (CHD). Despite limited availability and acceptability of donor hearts, the number of heart transplantations remains on a stable level with improved survival and quality of life. Observation: As treatment options for CHD continue to improve and the chances of survival increase, more adult CHD patients are listed for transplantation. This review focuses on the clinical challenges and modified techniques of pediatric heart transplantations. Conclusion: Not only knowledge of the exact anatomy, but above all careful planning, interdisciplinary cooperation and surgical experience are prerequisites for surgical success
How organisations regulate Muslim body practices: a comparison of schools, hospitals, and swimming pools
No full textIn a comparison of three human service organisations in which the human body plays a key role, we examine how organisations regulate religious body practices. We concentrate on Muslim norms of dressing and undressing as a potential focal point of cultural and religious diversity. Inspired by Ray’s (2019) idea of racialized organizations, we assume that state-run organizations in Germany are characterized by a strong commitment to religious tolerance and non-discrimination but also marked by anti-Muslim sentiment prevalent among the German population. Our study looks for mechanism that explain how Human Service Organizations accommodate Muslim body practices. It draws on qualitative empirical data collected in state-run hospitals, schools and swimming pools in Germany. Our analyses show that the organizations draw on formal and informal rules at the organizational level to accommodate Islam. We identify five general organizational mechanisms that may hinder Muslim accommodation in human service organizations. In particular, we see a risk of decoupling between the expectation of religious tolerance and processes that lead to informal discrimination, driven mainly by the difficulty of controlling group dynamics among users
Lidocaine as an anti-arrhythmic drug: Are there any indications left?
No full textLidocaine is classified as a class Ib anti-arrhythmic that blocks voltage- and pH-dependent sodium channels. It exhibits well investigated anti-arrhythmic effects and has been the anti-arrhythmic of choice for the treatment of ventricular arrhythmias for several decades. Lidocaine binds primarily to inactivated sodium channels, decreases the action potential duration, and increases the refractory period. It increases the ventricular fibrillatory threshold and can interrupt life-threatening tachycardias caused by re-entrant mechanisms, especially in ischemic tissue. Its use was pushed into the background in the era of amiodarone and modern electric device therapy. Recently, lidocaine has come back into focus for the treatment of acute sustained ventricular tachyarrhythmias. In this brief overview, we review the clinical pharmacology including possible side effects, the historical course, possible indications, and current Guideline recommendations for the use of lidocaine