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Efficacy of Dual-Antibiotic-Loaded Bone Cement Against Multi-Drug-Resistant Staphylococcus aureus and Enterococcus faecalis in a Galleria mellonella Model of Periprosthetic Joint Infection
No full textBackground: Antibiotic-loaded bone cement (ALBC) is widely used for local antibiotic delivery in joint arthroplasty to prevent and treat prosthetic joint infections (PJIs). In this study, we evaluated the efficacy of cemented Kirschner (K)-wires coated with various ALBC formulations using a Galleria mellonella infection model against multidrug-resistant (MDR) Staphylococcus aureus and Enterococcus faecalis. Methods: We tested commercially available bone cements, including gentamicin-only formulations (PALACOS R+G) and dual-antibiotic formulations, combining gentamicin with either clindamycin (COPAL G+C) or vancomycin (COPAL G+V), alongside an antibiotic-free control (PALACOS R). In vitro assays—including minimum inhibitory/bactericidal concentration (MIC/MBC) determination, antibiotic release kinetics, agar diffusion, and antibiofilm evaluations—demonstrated effective antibiotic release and significant antimicrobial activity against both planktonic and biofilm-associated bacteria. Results: In vivo, ALBC-coated K-wires were well tolerated in G. mellonella and significantly protected the larvae from S. aureus infection compared to controls. Notably, dual-antibiotic formulations provided superior protection, correlating with substantial reductions in bacterial colonisation on implant surfaces and in surrounding tissues. Conclusions: These findings support the utility of the G. mellonella model as a high-throughput, cost-effective platform for the preclinical evaluation of antimicrobial strategies to prevent and treat PJIs and further demonstrate the effectiveness of dual-loaded ALBC against multidrug-resistant bacteria
Ein genomweites CRISPR/Cas9-Screening identifiziert den Enhancer of Zeste Homolog 2 (EZH2) als epigenetischen Regulator des Dimethylfumarat-induzierten Zelltods in Tumoren mit konstitutiver NF-κB-Aktivierung
No full textDas Sézary-Syndrom wurde in dieser Arbeit gezielt als experimentelles Modellsystem zur Untersuchung von Tumoren mit konstitutiver NF-κB-Aktivierung genutzt. Die Erkrankung ist eine seltene Form des kutanen T-Zell-Lymphoms (CTCL) und zeichnet sich durch eine dauerhafte Aktivierung des NF-κB-Signalwegs aus. Aufgrund dieser molekularen Charakteristik eignet sich das Sézary-Syndrom besonders gut zur Untersuchung NF-κB-abhängiger Signaltransduktion in Tumorzellen.
Klinisch ist das Sézary-Syndrom durch eine hohe Therapieresistenz und eine
ungünstige Prognose gekennzeichnet. Etablierte Behandlungsoptionen wie
Chemotherapien oder monoklonale Antikörper zeigen häufig nur begrenzte
Wirksamkeit. Dimethylfumarat (DMF), ein pharmakologischer Inhibitor des NF-κBSignalwegs, hat in klinischen Studien vielversprechende Effekte gezeigt. Das
uneinheitliche Ansprechen der Patient:innen stellt jedoch eine wesentliche
therapeutische Herausforderung dar.
Ziel dieser Arbeit war es, genetische Faktoren zu identifizieren, die die Wirksamkeit von DMF verbessern. Zu diesem Zweck wurde ein genomweites CRISPR/Cas9-Knockout-Screening in Sézary-Zellen durchgeführt. Dabei wurde der Enhancer of Zeste Homolog 2 (EZH2) als eines der am stärksten negativ selektierten Gene unter DMF-Behandlung identifiziert. EZH2 ist die katalytische Untereinheit des Polycomb Repressive Complex 2 (PRC2), der durch Trimethylierung von Lysin 27 im Histon H3 (H3K27me3) die Genexpression epigenetisch reguliert.
Funktionelle Validierungen zeigten, dass der Knockdown von EZH2 die Sensitivität von Sézary-Zellen gegenüber DMF signifikant erhöht. Auch die pharmakologische Hemmung von EZH2 mit dem zugelassenen Inhibitor Tazemetostat verstärkte die DMF-Wirkung deutlich. Darüber hinaus konnte ein ähnlicher Effekt durch die Hemmung weiterer PRC2-Komponenten wie des Polycomb-Proteins Embryonic Ectoderm Development (EED) mittels der Inhibitoren A-395 oder MAK683 beobachtet werden. Diese Befunde unterstreichen die zentrale Rolle des PRC2-Komplexes für die
DMF-Sensitivität.
Diese Arbeit liefert erstmals einen systematischen Nachweis für den Einfluss
epigenetischer Regulatoren auf die Wirksamkeit von DMF im Sézary-Syndrom.
Darüber hinaus belegt sie die Eignung des Sézary-Syndroms als präklinisches
71 Modellsystem für die Untersuchung NF-κB-abhängiger Tumorbiologie und die Entwicklung neuer therapeutischer Kombinationsstrategien.
Die wesentlichen Ergebnisse sind:
1. Enhancer of Zeste Homolog 2 (EZH2) ist ein zentraler Sensitizer für eine
Therapie mit DMF. Die pharmakologische Hemmung von EZH2 oder weiteren
Polycomb Repressive Complex 2 (PRC2)-Komponenten verstärkt die Wirkung
von DMF in malignen Zellen signifikant.
2. Epigenetische Modulation beeinflusst die Wirksamkeit zielgerichteter Therapien
bei malignen T-Zell-Erkrankungen maßgeblich.
3. Die Kombination aus Polycomb Repressive Complex 2 (PRC2)-Hemmung und
NF-κB-Inhibition eröffnet einen neuen Therapieansatz mit hohem
translationalem Potenzial.
Aufbauend auf diesem Modellsystem und den durchgeführten funktionellen
Untersuchungen liefert die vorliegende Arbeit zentrale Erkenntnisse, die im Sézary-Syndrom gewonnen wurden und über dieses seltene Lymphom hinaus eine hohe klinische Relevanz besitzen. Da eine konstitutive NF-κB-Aktivierung ein gemeinsames Merkmal vieler hämatologischer und solider Tumoren darstellt, sind die identifizierten Mechanismen und therapeutischen Synergien potenziell auch auf andere NF-κBabhängige Malignome übertragbar. Die Ergebnisse dieser Arbeit liefern somit nicht nur neue Einsichten in die molekularen Wechselwirkungen im Sézary-Syndrom, sondern eröffnen auch neue Perspektiven für die Entwicklung gezielter Kombinationsstrategien
bei einer breiteren Gruppe von Tumorerkrankungen mit NF-κB-Signatur
Acute Kidney Injury in Patients with Veno-Venous Extracorporeal Membrane Oxygenation
No full textBackground AKI is a frequent concomitant organ failure during veno-venous extracorporeal membrane oxygenation (VV-ECMO). This study investigated the prevalence and the impact of AKI on survival to hospital discharge and up to
1 year after discharge and risk factors for developing AKI during VV-ECMO.
Methods This is an observational retrospective study of 500 consecutive patients receiving VV-ECMO between November 2014 and December 2021. Patients were divided into three groups: (1) AKI onset before extracorporeal membrane oxygenation (ECMO), (2) AKI onset during ECMO, and (3) AKI onset before and new onset during ECMO. The Kidney Disease Improving Global Outcomes definition was used to define AKI. Follow-up was 1 year after hospital discharge. Propensity score matching was performed for patients without AKI and patients with AKI onset during ECMO to analyze risk factors for AKI onset during VV-ECMO.
Results A total of 320 patients (64.0%) had AKI: 182 (36.4%) with onset before ECMO and 158 (31.6%) with onset during ECMO. At ECMO initiation, patients with AKI onset before VV-ECMO presented significantly higher inflammatory markers and higher NE dosage, whereas patients developing AKI during VV-ECMO did not differ from those without AKI. Survival to hospital discharge was 67.0% (AKI, 60.9%; no AKI, 77.8%; P , 0.001). Cox regression analysis revealed AKI Kidney Disease Improving Global Outcomes stage 3, independent from onset, as an independent risk factor for reduced survival to hospital discharge (hazard ratio, 2.15; 95% confidence interval, 1.37 to 3.37; P 5 0.001). During follow-
up, the survival was 92.5%; age was shown as the sole risk factor for reduced survival in hospital survivors in the multivariate logistic regression model. In the propensity score–matched cohort (41 patients in each group), the AKI group had lower mean arterial pressure and significantly higher C-reactive protein levels the days before AKI. Factors associated with VV-ECMO support (blood flow, cell-free hemoglobin) did not differ.
Conclusions Severe AKI is associated with reduced hospital survival, regardless of whether it occurs before or during ECMO. AKI onset during VV-ECMO is less because of ECMO-related factors than to recurrent septic episodes
Pyridinamide Ion Pairs: Design Principles for Super-Nucleophiles in Apolar Organic Solvents
Get PDFA comprehensive analytical protocol combining conductivity, diffusion-ordered NMR (DOSY), and photometric kinetic measurements is employed to analyze the nucleophilic reactivity of pyridinamide ion pairs in low-polarity organic solvents. The association patterns of these systems are found to strongly depend on cation size, with larger cations favoring the formation of cationic triple ion sandwich complexes together with free and highly nucleophilic anions. Kinetic studies using the ionic strength-controlled benzhydrylium method demonstrate that pyridinamide ions exhibit significantly higher nucleophilicities as compared to established organocatalysts, particularly in low-polarity solvents. Nucleophilicities are furthermore found to correlate well with Brønsted basicities measured in water and with Lewis basicities calculated in dichloromethane. Taken together, these findings provide quantitative guidelines for the future design of highly active Lewis base catalysts
Belastungen für den Wohnungsbau reduzieren
No full textLiebe Standpunkt-Leserinnen und -Leser,
im Wahlgetümmel der Parteien gerät die Wohnungspolitik als Politikfeld leider ins Hintertreffen. Das ist bedauerlich, denn hier gäbe es viel zu tun, und das Thema ist für sehr viele Haushalte relevant. Wichtig ist hier weniger die bestmögliche Antwort als eine gute und dafür zügige Umsetzung sowie die Bereitschaft, Dinge auszuprobieren
Effect of Candidatus Westeberhardia cardiocondylae and Wolbachia sp. endosymbionts on life-history traits of Cardiocondyla obscurior
Get PDFIn the past few years, there has been increasing evidence that different endosymbiotic bacteria are capable of impacting the biology of various arthropod species. Most common are their effects on the host’s reproductive system. The best-known arthropod endosymbiont is Wolbachia, and around 34%, and of all ant species are infected. Wolbachia can be change colony life cycles, nutritional requirements, and the production of reproductive individuals. Nevertheless, the evolutionary history and many functions of Wolbachia in ants remain largely unknown.
Cardiocondyla obscurior is a globally distributed tramp ant species. Its colonies are infected with two main endosymbionts, Candidatus Westeberhardia cardiocondylae and Wolbachia sp. Infection levels with Cand. Westeberhardia vary naturally within C. obscurior populations, even though this symbiont has features typical of obligate symbionts, such as an eroded genome and maternal transmission. This thesis aimed to investigate the interaction dynamics of two main endosymbionts, Cand. Westeberhardia and Wolbachia sp., with C. obscurior host.
Cytoplasmic incompatibility (CI), the most common effect of an infection with Wolbachia in insects, is here described for the first time in ants. CI between two C. obscurior populations infected with different Wolbachia strains appears to be uni-directional: the New World strain does not cause CI, while the Old World strain causes CI in hybrid crosses (Chapter 1).
There is not much known about the effects of antibiotic treatment on life-history traits of insects. We found that queen fecundity and colony productivity of C. obscurior were negatively affected by treatment with the antibiotic rifampicin, even though there was a delay of three months between treatment and productivity assessment (chapter 2). The viability of sperm from males produced in rifampicin-treated colonies was significantly reduced. Further, the titers of the two main endosymbionts, Cand. Westeberhardia and Wolbachia sp. were significantly decreased by rifampicin treatment.
Showing natural variation in endosymbiont infections allows researchers to investigate the potential effects of infection on life history traits of insects. We found that the total number of pupae and weekly egg numbers were lower in Cand. Westeberhardia-uninfected colonies than in Cand. Westeberhardia infected colonies (chapter 3). Sperm length and variation in sperm length were similar in males from Cand. Westeberhardia infected and uninfected colonies. Head, thorax, and petiole width were similar in males from Cand. Westeberhardia infected and uninfected colonies.
Taken together, this thesis will help to better understand the relationship of endosymbionts with their hosts
Viel Raum, wenig Handel – wie weiter? Interview mit Prof. Dr. Tobias Just, IREBS, Universität Regensburg
No full textActions at a glance: The time course of action, object, and scene recognition in a free recall paradigm
No full textBeing able to quickly recognize other people’s actions lies at the heart of our ability to efficiently interact with our environment. Action recognition has been suggested to rely on the analysis and integration of information from different perceptual subsystems, e.g., for the processing of objects and scenes. However, stimulus presentation times that are required to extract information about actions, objects, and scenes to our knowledge have not yet been directly compared. To address this gap in the literature, we compared the recognition thresholds for actions, objects, and scenes. First, 30 participants were presented with grayscale images depicting different actions at variable presentation times (33–500 ms) and provided written descriptions of each image. Next, ten naïve raters evaluated these descriptions with respect to the presence and accuracy of information related to actions, objects, scenes, and sensory information. Comparing thresholds across presentation times, we found that recognizing actions required shorter presentation times (from 60 ms onwards) than objects (68 ms) and scenes (84 ms). More specific actions required presentation times of approximately 100 ms. Moreover, thresholds were modulated by action category, with the lowest thresholds for locomotion and the highest thresholds for food-related actions. Together, our data suggest that perceptual evidence for actions, objects, and scenes is gathered in parallel when these are presented in the same scene but accumulates faster for actions that reflect static body posture recognition than for objects and scenes
Impact of septic arthritis on quality of life: arthroscopy vs. arthrotomy
No full textIntroduction
Septic arthritis poses significant challenges due to its potential for joint damage and life-threatening complications. The choice between arthroscopy and open arthrotomy as surgical approaches remains a critical decision in septic arthritis management. However, limited research has focused on patient-reported outcomes and quality of life following treatment.
Materials and Methods
A retrospective study was conducted at a German level 1 trauma center, including 58 adult septic arthritis patients treated with arthroscopy (n = 29) or open arthrotomy (n = 29). Quality of life was assessed using the EQ-5D instrument. Functional mobility was evaluated with the Parker Mobility Score, while the Katz Score assessed activities of daily living (ADL). The mean follow-up time was 5.6 years.
Results
Comparable EQ-5D VAS scores were observed in both groups, with no significant difference in the quality of life between arthroscopy and open arthrotomy patients (64.8 ± 19.3 vs. 64.7 ± 19.6, p = 0.749). Notably, both groups reported limitations in pain/discomfort and mobility, while the open arthrotomy group exhibited more anxiety/depression limitations (p = 0.024). Functional mobility, as assessed by the Parker Mobility Score (6.50 ± 2.62 vs. 6.51 ± 2.60, p = 0.617), and ADL independence, using the Katz Score (5.06 ± 1.72 vs. 5.05 ± 1.71, p = 0.181) remained similar between the two groups.
Conclusion
In septic arthritis management, arthroscopy and open arthrotomy yield similar long-term QoL outcomes, functional mobility, and ADL independence. Despite these findings, it is crucial to interpret the results with caution, given potential limitations associated with retrospective studies, and external factors influencing long-term outcomes. Further prospective research, incorporating larger sample sizes and extended follow-up, is necessary to refine our understanding of septic arthritis management strategies and their impact on patient well-being.
Level of evidence III