Medical University of Graz
Recent publications
Our understanding of microorganisms residing within our gut and their roles in the host metabolism and immunity advanced greatly over the past 20 years. Currently, microbiome studies are shifting from association and correlation studies to studies demonstrating causality of identified microbiome signatures and identification of molecular mechanisms underlying these interactions. This transformation is crucial for the efficient translation into clinical application and development of targeted strategies to beneficially modulate the intestinal microbiota. As mechanistic studies are still quite challenging to perform in humans, the causal role of microbiota is frequently evaluated in animal models that need to be appropriately selected. Here, we provide a comprehensive overview on approaches that can be applied in addressing causality of host-microbe interactions in five major animal model organisms (Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and pigs). We particularly focused on discussing methods available for studying the causality ranging from the usage of gut microbiota transfer, diverse models of metabolic and immune perturbations involving nutritional and chemical factors, gene modifications and surgically induced models, metabolite profiling up to culture-based approached. Furthermore, we addressed the impact of the gut morphology, physiology as well as diet on the microbiota composition in various models and resulting species specificities. Finally, we conclude this review with the discussion on models that can be applied to study the causal role of the gut microbiota in the context of metabolic syndrome and host immunity. We hope this review will facilitate important considerations for appropriate animal model selection.
Ingestion of leaves of the European yew tree (Taxus baccata) can result in fatal cardiac arrhythmias and acute cardiogenic shock. This cardiotoxicity derives from taxine alkaloids that block cardiac voltage-gated sodium and calcium channels. Prompt initiation of venoarterial extracorporeal membrane oxygenation is essential to bridge these critically ill patients to recovery, as there is no antidote available. We here report a 39-year old patient with toxic cardiogenic shock after yew poisoning, who was successfully rescued by venoarterial extracorporeal membrane oxygenation and had a full neurological recovery. This report emphasizes the role of intoxications as reversible causes of cardiac arrest and adds further evidence to the body of existing literature thus encouraging the early use of venoarterial extracorporeal membrane oxygenation in patients with yew poisoning and cardiogenic shock.
Objectives General practitioners (GPs) are frequently patients' first point of contact with the healthcare system and play an important role in identifying, managing and monitoring cases. This study investigated the experiences of GPs from seven different countries in the early phases of the COVID-19 pandemic. Design International cross-sectional online survey. Setting General practitioners from Australia, Austria, Germany, Hungary, Italy, Slovenia and Switzerland. Participants Overall, 1,642 GPs completed the survey. Main outcome measures We focused on how well-prepared GPs were, their self-confidence and concerns, efforts to control the spread of the disease, patient contacts, information flow, testing procedures and protection of staff. Results GPs gave high ratings to their self-confidence (7.3, 95% CI 7.1–7.5) and their efforts to control the spread of the disease (7.2, 95% CI 7.0–7.3). A decrease in the number of patient contacts (5.7, 95% CI 5.4–5.9), the perception of risk (5.3 95% CI 4.9–5.6), the provision of information to GPs (4.9, 95% CI 4.6–5.2), their testing of suspected cases (3.7, 95% CI 3.4–3.9) and their preparedness to face a pandemic (mean: 3.5; 95% CI 3.2–3.7) were rated as moderate. GPs gave low ratings to their ability to protect staff (2.2 95% CI 1.9–2.4). Differences were identified in all dimensions except protection of staff, which was consistently low in all surveyed GPs and countries. Conclusion Although GPs in the different countries were confronted with the same pandemic, its impact on specific aspects differed. This partly reflected differences in health care systems and experience of recent pandemics. However, it also showed that the development of structured care plans in case of future infectious diseases requires the early involvement of primary care representatives.
Due to intact reactive oxygen species homeostasis and glucose metabolism, C57BL/6NRj mice are especially suitable to study cellular alterations in metabolism. We applied Nuclear Magnetic resonance spectroscopy to analyze five different tissues of this mouse strain during aging and included female and male mice aged 3, 6, 12, and 24 months. Metabolite signatures allowed separation between the age groups in all tissues, and we identified the most prominently changing metabolites in female and male tissues. A refined analysis of individual metabolite levels during aging revealed an early onset of age-related changes at 6 months, sex-specific differences in the liver, and a biphasic pattern for various metabolites in the brain, heart, liver, and lung. In contrast, a linear decrease of amino acids was apparent in muscle tissues. Based on these results, we assume that age-related metabolic alterations happen at a comparably early aging state and are potentially associated with a metabolic switch. Moreover, identified differences between female and male tissues stress the importance of distinguishing between sexes when studying age-related changes and developing new treatment approaches. Besides, metabolomic features seem to be highly dependent on the genetic background of mouse strains.
Background Believing processes represent fundamental brain functions between cognition and emotion. Shortly before the introduction of a compulsory vaccination against COVID-19 in Austria, motives and underlying believing processes regarding the vaccination were collected in individuals with affective disorder (AD) and healthy controls (HC). Methods 79 individuals with AD and 173 HC were surveyed online to assess believing processes with the parameters of the credition model (narratives, certainty, emotion, mightiness) about (1) the coronavirus itself and (2) why someone is vaccinated or not. In addition, we calculated congruence scores between content of narrative and type of emotion and divided the narrative content into positive, negative, and indifferent. Results There were no differences in vaccination status between AD and HC. Higher levels of certainty were observed in HC compared to AD in both vaccinated and unvaccinated individuals. The effects were higher when asked about the motivation to vaccinate or not than about the coronavirus itself. In HC, more positive emotions and more congruence between emotions and narratives were reported during believing in their vaccination motives. No group differences were found in mightiness for both items. Independently from diagnosis, unvaccinated people had high levels of certainty and more negative emotions and narratives while believing in their motives for not getting vaccinated. Conclusion When believing about the COVID-19 vaccination, individuals with AD were more uncertain and experienced fewer positive emotions than HC, although both groups did not differ in vaccination status. These effects were not that strong when believing about the coronavirus in general.
Post-mortem specimens used for anatomy teaching are commonly embalmed using compositions of chemicals, with the objective to maintain tissue quality and to avoid putrefaction. Monitoring for bacterial or fungal contamination is becoming increasingly important especially when measures are taken to minimize exposure by chemicals such as formaldehyde. In this case, random swabs were taken from six corpses embalmed with ethanol-glycerin and Thiel embalming. Cultures and MALDI-TOF analyses yielded four cases of Clostridium perfringens contamination. C. perfringens is of special interest as a human pathogen. A potential source was identified in the containers filled with the moistening solution. Cross contamination with Clostridium species has likely occurred between corpses sharing the moistening solution and soaking the cover linen directly within the containers. To minimize any risk for those exposed, the moistening solutions were discarded and all equipment thoroughly disinfected. The specimens had to be cremated as they formed a potential source of Clostridium spores. Deviating from previous routines it was formalized that the cover linen must not be submerged in the moistening contains rather than moistening the specimens directly with dedicated vessels. Follow-up analyses yielded no further contamination with C. perfringens.
The microRNA-200 family has wide-ranging regulatory functions in cancer development and progression. Above all, it is strongly associated with the epithelial-to-mesenchymal transition (EMT), a process during which cells change their epithelial to a mesenchymal phenotype and acquire invasive characteristics. More recently, miR-200 family members have also been reported to impact the immune evasion of cancer cells by regulating the expression of immunoinhibitory immune checkpoints (ICs) like PD-L1. Therefore, we aimed to comprehensively characterize this miR-200 family as a regulatory interface between EMT and immune evasion mechanisms in biliary tract cancer. Initial correlation analyses and transient overexpression experiments using miRNA mimics suggested miR-200c-3p as a putative regulator of ICs including PD-L1, LGALS9, and IDO1. However, these effects could not be confirmed in stable miR-200c-3p overexpression cell lines, nor in cells transiently transfected with miR-200c-3p mimic from an independent manufacturer. By shifting our efforts towards dissecting the mechanisms leading to these disparate effects, we observed that the initially used miR-200c-3p mimic triggered a double-stranded (ds)RNA-dependent antiviral response. Besides upregulating the ICs, this had substantial cellular consequences including an induction of interferon type I and type III expression, increased levels of intracellular dsRNA sensors, and a significantly altered cellular growth and apoptotic activity.Our study highlights the capability of miRNA mimics to non-specifically induce a dsRNA-mediated antiviral interferon response. Consequently, phenotypic alterations crucially distort physiological miRNA functions and might result in a major misinterpretation of previous and future miRNA studies, especially in the context of IC regulation.
Background: Artificial Intelligence (AI) is becoming more and more important especially in datacentric fields, such as biomedical research and biobanking. However, AI does not only offer advantages and promising benefits, but brings about also ethical risks and perils. In recent years, there has been growing interest in AI ethics, as reflected by a huge number of (scientific) literature dealing with the topic of AI ethics. The main objectives of this review are: (1) to provide an overview about important (upcoming) AI ethics regulations and international recommendations as well as available AI ethics tools and frameworks relevant to biomedical research, (2) to identify what AI ethics can learn from findings in ethics of traditional biomedical research - in particular looking at ethics in the domain of biobanking, and (3) to provide an overview about the main research questions in the field of AI ethics in biomedical research. Methods: We adopted a modified thematic review approach focused on understanding AI ethics aspects relevant to biomedical research. For this review, four scientific literature databases at the cross-section of medical, technical, and ethics science literature were queried: PubMed, BMC Medical Ethics, IEEE Xplore, and Google Scholar. In addition, a grey literature search was conducted to identify current trends in legislation and standardization. Results: More than 2,500 potentially relevant publications were retrieved through the initial search and 57 documents were included in the final review. The review found many documents describing high-level principles of AI ethics, and some publications describing approaches for making AI ethics more actionable and bridging the principles-to-practice gap. Also, some ongoing regulatory and standardization initiatives related to AI ethics were identified. It was found that ethical aspects of AI implementation in biobanks are often like those in biomedical research, for example with regards to handling big data or tackling informed consent. The review revealed current ‘hot’ topics in AI ethics related to biomedical research. Furthermore, several published tools and methods aiming to support practical implementation of AI ethics, as well as tools and frameworks specifically addressing complete and transparent reporting of biomedical studies involving AI are described in the review results. Conclusions: The review results provide a practically useful overview of research strands as well as regulations, guidelines, and tools regarding AI ethics in biomedical research. Furthermore, the review results show the need for an ethical-mindful and balanced approach to AI in biomedical research, and specifically reveal the need for AI ethics research focused on understanding and resolving practical problems arising from the use of AI in science and society.
Purpose Using the International Standard Classification of Education (ISCED), we examined the educational and vocational pathways of two comparable, parental cohorts: childhood cancer survivors (CCS) and their siblings. Both cohorts had previously entered parenthood. The aim of the study was to elucidate whether childhood cancer and treatment affect the educational pathways chosen by parents who are former patients.Methods We analysed data that was collected from childhood cancer survivors and their siblings regarding their offspring’s health within the FeCt Multicentre Offspring Study (conducted 2013–2016). We evaluated and compared the professional pathways of (i) all participating survivors and all participating siblings and those of (ii) survivors and their biological siblings.ResultsOverall information on parental gender, age, and education were available from 1077 survivors and 246 siblings (group (i)). The majority of participants were female with a mean age of 35.2 (survivor) and 37.9 (sibling) years at time of survey. For subgroup (ii), analysis information was available on 191 survivors and 210 siblings. Fathers achieved university degrees significantly more often than mothers (p = 0.003 (i), p < 0.001 (ii)). The distribution of professional education was not significantly different between cancer survivors and siblings in either cohort (i) or (ii).Conclusions Regarding our research on the educational and vocational trajectory of CCS, patients can be reassured that family planning and vocational education are well compatible. Inequalities regarding gender-specific educational pathways remain to be addressed.Implications for Cancer SurvivorsCCS should monitor their fertility status regularly and, if necessary, cryopreserve germ cells or tissue in order to optimize their family planning. Educational opportunities should be pursued as desired and with confidence. Local as well as European aftercare programs can assist with family planning and education.
Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I–VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I–VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification.
The inodilator levosimendan, in clinical use for over two decades, has been the subject of extensive clinical and experimental evaluation in various clinical settings beyond its principal indication in the management of acutely decompensated chronic heart failure. Critical care and emergency medicine applications for levosimendan have included postoperative settings, septic shock, and cardiogenic shock. As the experience in these areas continues to expand, an international task force of experts from 15 countries (Austria, Belgium, China, Croatia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Spain, Sweden, Switzerland, and the USA) reviewed and appraised the latest additions to the database of levosimendan use in critical care, considering all the clinical studies, meta-analyses, and guidelines published from September 2019 to November 2021. Overall, the authors of this opinion paper give levosimendan a “should be considered” recommendation in critical care and emergency medicine settings, with different levels of evidence in postoperative settings, septic shock, weaning from mechanical ventilation, weaning from veno-arterial extracorporeal membrane oxygenation, cardiogenic shock, and Takotsubo syndrome, in all cases when an inodilator is needed to restore acute severely reduced left or right ventricular ejection fraction and overall haemodynamic balance, and also in the presence of renal dysfunction/failure.
Purpose Placement of dental implants has evolved to be an advantageous treatment option for rehabilitation of the fully or partially edentulous mandible. In case of extensive horizontal bone resorption, the bone volume needs to be augmented prior to or during implant placement in order to obtain dental rehabilitation and maximize implant survival and success. Methods Our aim was to systematically review the available data on lateral augmentation techniques in the horizontally compromised mandible considering all grafting protocols using xenogeneic, synthetic, or allogeneic material. A computerized and manual literature search was performed for clinical studies (published January 1995 to March 2021). Results Eight studies ultimately met the inclusion criteria comprising a total of 276 procedures of xenogeneic, allogeneic, or autogenous bone graft applications in horizontal ridge defects. Particulate materials as well as bone blocks were used as grafts with a mean follow-up of 26.0 months across all included studies. Outcome measures, approaches and materials varied from study to study. A gain of horizontal bone width of the mandible with a mean of 4.8 mm was observed in seven of eight studies. All but one study, reported low bone graft failure rates of 4.4% in average. Conclusions Only limited data are available on the impact of different horizontal augmentation strategies in the mandible. The results show outcomes for xenogeneic as well as autologous bone materials for horizontal ridge augmentation of the lower jaw. The use of allogeneic bone-block grafts in combination with resorbable barrier membranes must be re-evaluated. Randomized controlled clinical trials are largely missing.
Following publication of the original article [1], the authors identified an error in the author name Marco Daverio. The given name and family name were erroneously transposed. The incorrect author name is: Daverio Marco. The correct author name is: Marco Daverio. The incorrect Results section in the Abstract reads: Seventy-one percent of PICUs stated to use protocols for analgosedation management, more frequently in highvolume PICUs (77% vs 63%, p = 0.028). It should instead read: Seventy-one percent of PICUs stated to use protocols for analgosedation management, more frequently in low-volume PICUs (77% vs 63%, p = 0.028). The author group has been updated above, and the original article [1] has been corrected
A healthy human microbiome relies on the interaction with and exchange of microbes that takes place between the human body and its environment. People in high-income countries spend most of their time indoors and for this reason, the built environment (BE) might represent a potent source of commensal microbes. Anaerobic microbes are of particular interest, as researchers have not yet sufficiently clarified how the human microbiome acquires oxygen-sensitive microbes. We sampled the bathrooms in ten households and used propidium monoazide (PMA) to assess the viability of the collected prokaryotes. We compared the microbiome profiles based on 16S rRNA gene sequencing and confirmed our results by genetic and cultivation-based analyses. Quantitative and qualitative analysis revealed that most of the microbial taxa in the BE samples are human-associated. Less than 25% of the prokaryotic signatures originate from intact cells, indicating that aerobic and stress resistant taxa display an apparent survival advantage. However, we also confirmed the presence of intact, strictly anaerobic taxa on bathroom floors, including methanogenic archaea. As methanogens are regarded as highly sensitive to aerobic conditions, oxygen-tolerance experiments were performed with human-associated isolates to validate their survival. These results show that human-associated methanogens can survive oxic conditions for at least 6 h. We collected strong evidence that supports the hypothesis that obligate anaerobic taxa can survive in the BE for a limited amount of time. This suggests that the BE serves as a potential source of anaerobic human commensals.
The IOF Epidemiology and Quality of Life Working Group has reviewed the potential role of population screening for high hip fracture risk against well-established criteria. The report concludes that such an approach should strongly be considered in many health care systems to reduce the burden of hip fractures. Introduction The burden of long-term osteoporosis management falls on primary care in most healthcare systems. However, a wide and stable treatment gap exists in many such settings; most of which appears to be secondary to a lack of awareness of fracture risk. Screening is a public health measure for the purpose of identifying individuals who are likely to benefit from further investigations and/or treatment to reduce the risk of a disease or its complications. The purpose of this report was to review the evidence for a potential screening programme to identify postmenopausal women at increased risk of hip fracture. Methods The approach took well-established criteria for the development of a screening program, adapted by the UK National Screening Committee, and sought the opinion of 20 members of the International Osteoporosis Foundation’s Working Group on Epidemiology and Quality of Life as to whether each criterion was met (yes, partial or no). For each criterion, the evidence base was then reviewed and summarized. Results and Conclusion The report concludes that evidence supports the proposal that screening for high fracture risk in primary care should strongly be considered for incorporation into many health care systems to reduce the burden of fractures, particularly hip fractures. The key remaining hurdles to overcome are engagement with primary care healthcare professionals, and the implementation of systems that facilitate and maintain the screening program.
Objectives Radiotherapy (RT) for pediatric ependymoma remains challenging due to the young age of the patients and the close proximity of the tumour to critical structures. In Germany, Austria and Switzerland, a Radiotherapy Quality Assurance (RTQA) program was implemented within the SIOP Ependymoma II trial to ensure patient safety and protocol compliance. Methods Pre-trial site approvals and prospective plan reviews for patients in stratum 1 and 2 were performed. Plans were submitted by the treating centres to the reference centres Essen and Leipzig, who evaluated the plans regarding compliance to the study protocol and the German RTQA guideline. Results were categorized as per protocol, acceptable variation, justified unacceptable variation or unacceptable variation, respectively. Unacceptable variations required plan modification and re-review. Results Between May 2019 and December 2021, 33 patients (median age 5.1 years) from 8 institutions were reviewed. Thirty patients in stratum 1 received conformal RT. Within stratum 2, 3 patients received an additional stereotactic boost. The majority (n=31) of the patients were treated with protons. Of the 33 conformal RT plans, 4 (12%) were reviewed as per protocol, 14 (42%) as acceptable variation, 4 (12%) as justified unacceptable variation and 11 (33%) as unacceptable variation. Six of the unacceptable plans were re-submitted after modification. Four of them were approved after re-submission (acceptable variation=1, justified unacceptable variation=3), whereas 2 plans still had unacceptable variations. Reasons for rejecting plans were target volume delineation (44%), uniformity of target volume (33%) and dose to organs at risk (22%). All stereotactic boost plans were accepted (acceptable variation=1, justified unacceptable variation=2). Conclusion The high rate of rejected initial RT plans underlines the importance of a rigorous RTQA program. Improving the quality of RT plans potentially impacts favourably on outcome and long term side effects although requiring a high effort.
Shedding of hyaluronan (HA), the component of endothelial cell (EC) glycocalyx, has been associated with acute lung injury. HA degradation allows plasma proteins and fluid to penetrate across the vascular wall leading to lung edema formation and leukocyte recruitment. Here, we analyzed sHA levels and size in patients with community-acquired pneumonia (CAP) and acute respiratory distress syndrome (ARDS), correlated them to disease severity, and evaluated the impact of pneumolysin (PLY), the Streptococcus pneumoniae (S.p.) exotoxin, on HA shedding from human pulmonary microvascular EC (HPMVEC). sHA levels were elevated in CAP and ARDS and correlated with the CRB65 severity score and with markers of inflammation (interleukin-6), EC activation (E-selectin), and basement membrane destruction (collagen IV). Furthermore, sHA levels were associated with an increase in 28-day mortality. Small and large sHA fragments were detected in plasma of most severe CAP or ARDS patients, and the presence of large sHA fragments was accompanied by the elevated levels of circulating collagen IV. In vitro, PLY induced sHA release from HPMVEC. This effect was dependent on reactive oxygen species (ROS) production and was not associated with endothelial barrier dysfunction. Conversely, HA shedding was impaired following HPMVEC infection with a S.p. PLY-deficient mutant. Our study identifies association between the severity of CAP and ARDS and the levels and size of sHA in plasma. It links sHA levels with, inflammation, EC activation status and basement membrane disassembly in ARDS and provides insights into the mechanism of HA shedding during infection.
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2,384 members
Axel Schlagenhauf
  • Department of Pediatrics an Adolescent Medicine
Thomas Kroneis
  • Institute of Cell Biology, Histology and Embryology
Tobias Madl
  • Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging; Molecular Biology and Biochemistry
Christian Wadsack
  • Department of Obsterics and Gynecology
Auenbruggerplatz 15, 8036, Graz, Austria