@article{StraubStapfFischeretal.2022,
  author    = {Straub, Anton and Stapf, Maximilian and Fischer, Markus and Vollmer, Andreas and Linz, Christian and L{\^a}m, Thi{\^e}n-Tr{\´i} and K{\"u}bler, Alexander and Brands, Roman C. and Scherf-Clavel, Oliver and Hartmann, Stefan},
  title     = {Bone concentration of ampicillin/sulbactam: a pilot study in patients with osteonecrosis of the jaw},
  series = {International Journal of Environmental Research and Public Health},
  volume    = {19},
  journal   = {International Journal of Environmental Research and Public Health},
  number    = {22},
  issn      = {1660-4601},
  doi       = {10.3390/ijerph192214917},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297413},
  year      = {2022},
  abstract  = {Osteonecrosis of the jaw (ONJ) occurs typically after irradiation of the head and neck area or after the intake of antiresorptive agents. Both interventions can lead to compromised bone perfusion and can ultimately result in infection and necrosis. Treatment usually consists of surgical necrosectomy and prolonged antibiotic therapy, usually through beta-lactams such as ampicillin/sulbactam. The poor blood supply in particular raises the question as to whether this form of antibiosis can achieve sufficient concentrations in the bone. Therefore, we investigated the antibiotic concentration in plasma and bone samples in a prospective study. Bone samples were collected from the necrosis core and in the vital surrounding bone. The measured concentrations in plasma for ampicillin and sulbactam were 126.3 ± 77.6 and 60.2 ± 35.0 µg/mL, respectively. In vital bone and necrotic bone samples, the ampicillin/sulbactam concentrations were 6.3 ± 7.8/1.8 ± 2.0 µg/g and 4.9 ± 7.0/1.7 ± 1.7 µg/g, respectively. These concentrations are substantially lower than described in the literature. However, the concentration seems sufficient to kill most bacteria, such as Streptococci and Staphylococci, which are mostly present in the biofilm of ONJ. We, therefore, conclude that intravenous administration of ampicillin/sulbactam remains a valuable treatment in the therapy of ONJ. Nevertheless, increasing resistance of Escherichia coli towards beta-lactam antibiotics have been reported and should be considered.},
  language  = {en}
}
@article{StraubVollmerLametal.2022,
  author    = {Straub, Anton and Vollmer, Andreas and L{\^a}m, Thi{\^e}n-Tr{\´i} and Brands, Roman C. and Stapf, Maximilian and Scherf-Clavel, Oliver and Bittrich, Max and Fuchs, Andreas and K{\"u}bler, Alexander C. and Hartmann, Stefan},
  title     = {Evaluation of advanced platelet-rich fibrin (PRF) as a bio-carrier for ampicillin/sulbactam},
  series = {Clinical Oral Investigations},
  volume    = {26},
  journal   = {Clinical Oral Investigations},
  number    = {12},
  doi       = {10.1007/s00784-022-04663-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324515},
  pages     = {7033-7044},
  year      = {2022},
  abstract  = {Objectives Mechanisms of wound healing are often impaired in patients with osteonecrosis of the jaw (ONJ). According to the guidelines for the treatment of this disease, early surgical intervention is indicated. However, surgery often faces complications such as wound healing disorders. The application of platelet-rich fibrin (PRF) after necrosectomy between bone and mucosa may constitute a promising approach to improve surgical results. An aspect that was not investigated until now is that PRF acts as a "bio-carrier" for antibiotics previously applied intravenously. Materials and methods We investigated the antimicrobial properties of PRF in 24 patients presenting ONJ undergoing systemic antibiosis with ampicillin/sulbactam. We measured the concentration of ampicillin/sulbactam in plasma and PRF and performed agar diffusion tests. Ampicillin/sulbactam was applied intravenously to the patient 10 minutes for blood sampling for PRF. No further incorporation of patients' blood or PRF product with antibiotic drugs was obtained. Four healthy patients served as controls. Results Our results revealed that PRF is highly enriched with ampicillin/sulbactam that is released to the environment. The antibiotic concentration in PRF was comparable to the plasma concentration of ampicillin/sulbactam. The inhibition zone (IZ) of PRF was comparable to the standard ampicillin/sulbactam discs used in sensitivity testing. Conclusions The results of our study demonstrated that PRF is a reliable bio-carrier for systemic applied antibiotics and exhibits a large antimicrobial effect. Clinical relevance We describe a clinically useful feature of PRF as a bio-carrier for antibiotics. Especially when applied to poorly perfused tissues and bone such as in ONJ, the local release of antibiotics can reduce wound healing disorders like infections.},
  language  = {en}
}
@article{SoundararajanMarincolaLiongetal.2023,
  author    = {Soundararajan, Manonmani and Marincola, Gabriella and Liong, Olivia and Marciniak, Tessa and Wencker, Freya D. R. and Hofmann, Franka and Schollenbruch, Hannah and Kobusch, Iris and Linnemann, Sabrina and Wolf, Silver A. and Helal, Mustafa and Semmler, Torsten and Walther, Birgit and Schoen, Christoph and Nyasinga, Justin and Revathi, Gunturu and Boelhauve, Marc and Ziebuhr, Wilma},
  title     = {Farming practice influences antimicrobial resistance burden of non-aureus staphylococci in pig husbandries},
  series = {Microorganisms},
  volume    = {11},
  journal   = {Microorganisms},
  number    = {1},
  issn      = {2076-2607},
  doi       = {10.3390/microorganisms11010031},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312750},
  year      = {2023},
  abstract  = {Non-aureus staphylococci (NAS) are ubiquitous bacteria in livestock-associated environments where they may act as reservoirs of antimicrobial resistance (AMR) genes for pathogens such as Staphylococcus aureus. Here, we tested whether housing conditions in pig farms could influence the overall AMR-NAS burden. Two hundred and forty porcine commensal and environmental NAS isolates from three different farm types (conventional, alternative, and organic) were tested for phenotypic antimicrobial susceptibility and subjected to whole genome sequencing. Genomic data were analysed regarding species identity and AMR gene carriage. Seventeen different NAS species were identified across all farm types. In contrast to conventional farms, no AMR genes were detectable towards methicillin, aminoglycosides, and phenicols in organic farms. Additionally, AMR genes to macrolides and tetracycline were rare among NAS in organic farms, while such genes were common in conventional husbandries. No differences in AMR detection existed between farm types regarding fosfomycin, lincosamides, fusidic acid, and heavy metal resistance gene presence. The combined data show that husbandry conditions influence the occurrence of resistant and multidrug-resistant bacteria in livestock, suggesting that changing husbandry practices may be an appropriate means of limiting the spread of AMR bacteria on farms.},
  language  = {en}
}
@phdthesis{Koike2023,
  author    = {Koike, Akito},
  title     = {Molekular und zellbiologischer Ansatz hin zu neuartigen Medikamenten gegen \(Echinococcus\) \(multilocularis\)},
  doi       = {10.25972/OPUS-28864},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288649},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Echinococcosis is an important zoonosis. The causative agent of Alveolar Echinococcosis (AE) is Echinococcus multilocularis. The treatment of human AE is limited to surgery and chemotherapy with albendazole (ABZ). However, ABZ works only parasitostatically and it needs to be taken for long periods, although it causes adverse side effects. Thus, development of new, parasiticidal drug with selective toxicity is required. Because undifferentiated stem cells of E. multilocularis play key role in its longevity and regenerative capacity, targeting stem cells is especially important. In vitro screening of protein kinases inhibitors demonstrated that human PIM kinases inhibitors have detrimental effects on E. multilocularis. Through yeast two hybrid assay, the interaction of parasite PIM kinase (EmPIM) and its CDC25 (EmCDC25) was indicated. Through in situ hybridization, expression of EmPIM in the stem cells was observed. Therefore, EmPim is likely to be a positive regulator of cell cycle progression, the same as human Pim1. In addition, 20 compounds against EmPIM were selected through in silico screening and synthesized. One of them has a detrimental effect on E.multilocularis comparable to human pan-PIM inhibitors, but has much weaker toxicity on human cell lines. Furthermore, triclabendazole (TCBZ) and its metabolite TCBZSX, which are approved for another flatworm disease, Fascioliasis were tried on E. multilocularis. With two stem cell markers, damage to stem cells by TCBZSX was shown. In addition, primary cells from treated vesicles never regenerated and the damage to stem cells proved to be irreversible. Our in silico screening method used in EmPIM research has potential to identify compounds which overcome the side effect problem in ABZ-based chemotherapy. On the other hand, it is expected that my research of TCBZ can lead to development of a practical parasiticidal chemotherapy by combining TCBZ, which damages stem cells, and ABZ, which damages differentiated cells.},
  subject      = {Bandw{\"u}rmer},
  language  = {en}
}
@article{CucherMaricontiManciullietal.2023,
  author    = {Cucher, Marcela A. and Mariconti, Mara and Manciulli, Tommaso and Vola, Ambra and Rosenzvit, Mara C. and Brehm, Klaus and Kamenetzky, Laura and Brunetti, Enrico},
  title     = {Circulating small RNA profiling of patients with alveolar and cystic echinococcosis},
  series = {Biology},
  volume    = {12},
  journal   = {Biology},
  number    = {5},
  issn      = {2079-7737},
  doi       = {10.3390/biology12050715},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319270},
  year      = {2023},
  abstract  = {Alveolar (AE) and cystic (CE) echinococcosis are two parasitic diseases caused by the tapeworms Echinococcus multilocularis and E. granulosus sensu lato (s. l.), respectively. Currently, AE and CE are mainly diagnosed by means of imaging techniques, serology, and clinical and epidemiological data. However, no viability markers that indicate parasite state during infection are available. Extracellular small RNAs (sRNAs) are short non-coding RNAs that can be secreted by cells through association with extracellular vesicles, proteins, or lipoproteins. Circulating sRNAs can show altered expression in pathological states; hence, they are intensively studied as biomarkers for several diseases. Here, we profiled the sRNA transcriptomes of AE and CE patients to identify novel biomarkers to aid in medical decisions when current diagnostic procedures are inconclusive. For this, endogenous and parasitic sRNAs were analyzed by sRNA sequencing in serum from disease negative, positive, and treated patients and patients harboring a non-parasitic lesion. Consequently, 20 differentially expressed sRNAs associated with AE, CE, and/or non-parasitic lesion were identified. Our results represent an in-depth characterization of the effect E. multilocularis and E. granulosus s. l. exert on the extracellular sRNA landscape in human infections and provide a set of novel candidate biomarkers for both AE and CE detection.},
  language  = {en}
}
@article{WeissGruendahlDeckertetal.2023,
  author    = {Weiß, Martin and Gr{\"u}ndahl, Marthe and Deckert, J{\"u}rgen and Eichner, Felizitas A. and Kohls, Mirjam and St{\"o}rk, Stefan and Heuschmann, Peter U. and Hein, Grit},
  title     = {Differential network interactions between psychosocial factors, mental health, and health-related quality of life in women and men},
  series = {Scientific Reports},
  volume    = {13},
  journal   = {Scientific Reports},
  organization    = {STAAB-COVID Study Group},
  doi       = {10.1038/s41598-023-38525-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357858},
  year      = {2023},
  abstract  = {Psychosocial factors affect mental health and health-related quality of life (HRQL) in a complex manner, yet gender differences in these interactions remain poorly understood. We investigated whether psychosocial factors such as social support and personal and work-related concerns impact mental health and HRQL differentially in women and men during the first year of the COVID-19 pandemic. Between June and October 2020, the first part of a COVID-19-specific program was conducted within the "Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB)" cohort study, a representative age- and gender-stratified sample of the general population of W{\"u}rzburg, Germany. Using psychometric networks, we first established the complex relations between personal social support, personal and work-related concerns, and their interactions with anxiety, depression, and HRQL. Second, we tested for gender differences by comparing expected influence, edge weight differences, and stability of the networks. The network comparison revealed a significant difference in the overall network structure. The male (N = 1370) but not the female network (N = 1520) showed a positive link between work-related concern and anxiety. In both networks, anxiety was the most central variable. These findings provide further evidence that the complex interplay of psychosocial factors with mental health and HRQL decisively depends on gender. Our results are relevant for the development of gender-specific interventions to increase resilience in times of pandemic crisis.},
  language  = {en}
}
@article{HaederSchaeubleGehlenetal.2023,
  author    = {H{\"a}der, Antje and Sch{\"a}uble, Sascha and Gehlen, Jan and Thielemann, Nadja and Buerfent, Benedikt C. and Sch{\"u}ller, Vitalia and Hess, Timo and Wolf, Thomas and Schr{\"o}der, Julia and Weber, Michael and H{\"u}nniger, Kerstin and L{\"o}ffler, J{\"u}rgen and Vylkova, Slavena and Panagiotou, Gianni and Schumacher, Johannes and Kurzai, Oliver},
  title     = {Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity},
  series = {Nature Communications},
  volume    = {14},
  journal   = {Nature Communications},
  doi       = {10.1038/s41467-023-38994-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357441},
  year      = {2023},
  abstract  = {Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.},
  language  = {en}
}
@article{SchreiberLohrBaltesetal.2023,
  author    = {Schreiber, Laura M. and Lohr, David and Baltes, Steffen and Vogel, Ulrich and Elabyad, Ibrahim A. and Bille, Maya and Reiter, Theresa and Kosmala, Aleksander and Gassenmaier, Tobias and Stefanescu, Maria R. and Kollmann, Alena and Aures, Julia and Schnitter, Florian and Pali, Mihaela and Ueda, Yuichiro and Williams, Tatiana and Christa, Martin and Hofmann, Ulrich and Bauer, Wolfgang and Gerull, Brenda and Zernecke, Alma and Erg{\"u}n, S{\"u}leyman and Terekhov, Maxim},
  title     = {Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research},
  series = {Frontiers in Cardiovascular Medicine},
  volume    = {10},
  journal   = {Frontiers in Cardiovascular Medicine},
  issn      = {2297-055X},
  doi       = {10.3389/fcvm.2023.1068390},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317398},
  year      = {2023},
  abstract  = {A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.},
  language  = {en}
}
@article{DuskeClausKroneetal.2024,
  author    = {Duske, Helene and Claus, Heike and Krone, Manuel and L{\^a}m, Thi{\^e}n-Tr{\´i}},
  title     = {Prevalence of piperacillin/tazobactam resistance in invasive \(Haemophilus\) \(influenzae\) in Germany},
  series = {JAC-Antimicrobial Resistance},
  volume    = {6},
  journal   = {JAC-Antimicrobial Resistance},
  number    = {1},
  issn      = {2632-1823},
  doi       = {10.1093/jacamr/dlad148},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350424},
  year      = {2024},
  abstract  = {Background Haemophilus influenzae (Hi) is a Gram-negative bacterium that may cause sepsis or meningitis, treatment of which mainly includes β-lactam antibiotics. Since 2019 EUCAST breakpoints for piperacillin/tazobactam have been available. Little is known about the prevalence and mechanisms of piperacillin/tazobactam resistance in Hi. Objectives To provide reliable prevalence data for piperacillin/tazobactam resistance in Hi in Germany, to evaluate different antibiotic susceptibility testing methods and to examine possible resistance mechanisms. Methods According to EUCAST breakpoints, the MIC for piperacillin/tazobactam resistance is >0.25 mg/L. All invasive Hi in Germany from 2019 were examined by gradient agar diffusion (GAD) for piperacillin/tazobactam susceptibility. Piperacillin/tazobactam broth microdilution (BMD), piperacillin GAD on tazobactam-containing agar [piperacillin GAD on Mueller-Hinton agar with horse blood (MH-F)/tazobactam) and piperacillin/tazobactam agar dilution (AD) were used for confirmation. Phenotypic testing was complemented by ftsI sequencing. Results Piperacillin/tazobactam GAD resulted in 2.9\% (21/726) resistant Hi. BMD did not confirm piperacillin/tazobactam resistance. Two strains were found resistant by AD, of which one was also resistant using piperacillin GAD on MH-F/tazobactam. Overall, we found two strains with a piperacillin/tazobactam MIC >0.25 mg/L in at least two different tests (0.3\%). Both were β-lactamase-producing amoxicillin/clavulanate-resistant with PBP3 mutations characterized as group III-like+. Relevant PBP3 mutations occurred in six strains without phenotypic piperacillin/tazobactam resistance. These mutations suggest a reduced efficacy of β-lactam antibiotics in these isolates. Conclusions Piperacillin/tazobactam resistance prevalence in invasive Hi is low in Germany. Reduced susceptibility was correlated with PBP3 mutations, in particular with group III mutations.},
  language  = {en}
}
@phdthesis{Endres2024,
  author    = {Endres, Leo Maximilian},
  title     = {Development of multicellular \(in\) \(vitro\) models of the meningeal blood-CSF barrier to study \(Neisseria\) \(meningitidis\) infection},
  doi       = {10.25972/OPUS-34621},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-346216},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Neisseria meningitidis (the meningococcus) is one of the major causes of bacterial meningitis, a life-threatening inflammation of the meninges. Traversal of the meningeal blood-cerebrospinal fluid barrier (mBCSFB), which is composed of highly specialized brain endothelial cells (BECs), and subsequent interaction with leptomeningeal cells (LMCs) are critical for disease progression. Due to the human-exclusive tropism of N. meningitidis, research on this complex host-pathogen interaction is mostly limited to in vitro studies. Previous studies have primarily used peripheral or immortalized BECs alone, which do not retain relevant barrier phenotypes in culture. To study meningococcal interaction with the mBCSFB in a physiologically more accurate context, BEC-LMC co-culture models were developed in this project using BEC-like cells derived from induced pluripotent stem cells (iBECs) or hCMEC/D3 cells in combination with LMCs derived from tumor biopsies. Distinct BEC and LMC layers as well as characteristic expression of cellular markers were observed using transmission electron microscopy (TEM) and immunofluorescence staining. Clear junctional expression of brain endothelial tight and adherens junction proteins was detected in the iBEC layer. LMC co-culture increased iBEC barrier tightness and stability over a period of seven days, as determined by sodium fluorescein (NaF) permeability and transendothelial electrical resistance (TEER). Infection experiments demonstrated comparable meningococcal adhesion and invasion of the BEC layer in all models tested, consistent with previously published data. While only few bacteria crossed the iBEC-LMC barrier initially, transmigration rates increased substantially over 24 hours, despite constant high TEER. After 24 hours of infection, deterioration of the barrier properties was observed including loss of TEER and altered expression of tight and adherens junction components. Reduced mRNA levels of ZO-1, claudin-5, and VE-cadherin were detected in BECs from all models. qPCR and siRNA knockdown data suggested that transcriptional downregulation of these genes was potentially but not solely mediated by Snail1. Immunofluorescence staining showed reduced junctional coverage of occludin, indicating N. meningitidis-induced post-transcriptional modulation of this protein, as previous studies have suggested. Together, these results suggest a potential combination of transcellular and paracellular meningococcal traversal of the mBCSFB, with the more accessible paracellular route becoming available upon barrier disruption after prolonged N. meningitidis infection. Finally, N. meningitidis induced cellular expression of pro-inflammatory cytokines and chemokines such as IL-8 in all mBCSFB models. Overall, the work described in this thesis highlights the usefulness of advanced in vitro models of the mBCSFB that mimic native physiology and exhibit relevant barrier properties to study infection with meningeal pathogens such as N. meningitidis.},
  subject      = {Bakterielle Hirnhautentz{\"u}ndung},
  language  = {en}
}