@article{SeefriedGenestBaumannetal.2022, author = {Seefried, Lothar and Genest, Franca and Baumann, Jasmin and Heidemeier, Anke and Meffert, Rainer and Jakob, Franz}, title = {Efficacy of Zoledronic Acid in the Treatment of Nonmalignant Painful Bone Marrow Lesions: A Triple-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial (ZoMARS)}, series = {Journal of Bone and Mineral Research}, volume = {37}, journal = {Journal of Bone and Mineral Research}, number = {3}, doi = {10.1002/jbmr.4493}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-276368}, pages = {420 -- 427}, year = {2022}, abstract = {Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced water-equivalent signaling within the trabecular bone on magnetic resonance imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non-inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off-label to treat BML. A randomized, triple-blind, placebo-controlled phase III trial was conducted to assess efficacy and safety of single-dose zoledronic acid (ZOL) 5 mg iv with vitamin D 1000 IU/d as opposed to placebo with vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume 6 weeks after treatment as assessed by MRI. After treatment, mean BML volume decreased by 64.53\% (±41.92\%) in patients receiving zoledronic acid and increased by 14.43\% (±150.46\%) in the placebo group (p = 0.007). A decrease in BML volume was observed in 76.5\% of patients receiving ZOL and in 50\% of the patients receiving placebo. Pain level (visual analogue scale [VAS]) and all categories of the pain disability index (PDI) improved with ZOL versus placebo after 6 weeks but reconciled after 6 additional weeks of follow-up. Six serious adverse events occurred in 5 patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore, single-dose zoledronic acid 5 mg iv together with vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain compared with vitamin D supplementation only.}, language = {en} } @article{WeiderSchlagenhaufSeefried2022, author = {Weider, Margareta and Schlagenhauf, Ulrich and Seefried, Lothar}, title = {Oral health status of adult hypophosphatasia patients: A cross-sectional study}, series = {Journal of Clinical Periodontology}, volume = {49}, journal = {Journal of Clinical Periodontology}, number = {12}, doi = {10.1111/jcpe.13718}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-293777}, pages = {1253 -- 1261}, year = {2022}, abstract = {Aim This study evaluated the oral health status of adult patients with hypophosphatasia (HPP). Materials and Methods Parameters of oral health assessment comprised decayed/missing/filled teeth (DMFT) index, probing pocket depth and clinical attachment level (CAL) as well as documentation of tooth loss and periodontal health status according to CCD/AAP criteria. Findings were compared with national reference data (DMS V survey) reporting oral health status in age-related controls. Within-group comparisons were made between the HPP patients harbouring one versus two alkaline phosphatase liver/bone/kidney type (ALPL) gene variants. Results Of 80 HPP patients (64 female) with a mean age of 46.4 years (range 24-78) and one (n = 55) or two (n = 18) variants (n = 7 lacking testing) within the ALPL gene, those with two variants displayed substantially higher tooth loss rate (14.0 ± 9.3) than those affected by only one ALPL variant (4.1 ± 5.4), who did not differ substantially from healthy DMS V controls. While DMFT score and severe periodontal diseases (PDs) of HPP patients with one variant only increased with progressing age, the two-variant sub-cohort age independently exhibited increased DMFT scores and a higher rate of severe PDs. Conclusions HPP patients affected by two variants of the ALPL gene exhibited a higher risk of periodontitis and tooth loss than the general population, while patients with one variant developed clinically relevant oral disease symptoms with progressing ageing.}, language = {en} } @article{RodriguesWeissHewigetal.2021, author = {Rodrigues, Johannes and Weiß, Martin and Hewig, Johannes and Allen, John J. B.}, title = {EPOS: EEG Processing Open-Source Scripts}, series = {Frontiers in Neuroscience}, volume = {15}, journal = {Frontiers in Neuroscience}, issn = {1662-453X}, doi = {10.3389/fnins.2021.660449}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240221}, year = {2021}, abstract = {Background: Since the replication crisis, standardization has become even more important in psychological science and neuroscience. As a result, many methods are being reconsidered, and researchers' degrees of freedom in these methods are being discussed as a potential source of inconsistencies across studies. New Method: With the aim of addressing these subjectivity issues, we have been working on a tutorial-like EEG (pre-)processing pipeline to achieve an automated method based on the semi-automated analysis proposed by Delorme and Makeig. Results: Two scripts are presented and explained step-by-step to perform basic, informed ERP and frequency-domain analyses, including data export to statistical programs and visual representations of the data. The open-source software EEGlab in MATLAB is used as the data handling platform, but scripts based on code provided by Mike Cohen (2014) are also included. Comparison with existing methods: This accompanying tutorial-like article explains and shows how the processing of our automated pipeline affects the data and addresses, especially beginners in EEG-analysis, as other (pre)-processing chains are mostly targeting rather informed users in specialized areas or only parts of a complete procedure. In this context, we compared our pipeline with a selection of existing approaches. Conclusion: The need for standardization and replication is evident, yet it is equally important to control the plausibility of the suggested solution by data exploration. Here, we provide the community with a tool to enhance the understanding and capability of EEG-analysis. We aim to contribute to comprehensive and reliable analyses for neuro-scientific research.}, language = {en} } @article{TrabelsiAmmarBoukhrisetal.2020, author = {Trabelsi, Khaled and Ammar, Achraf and Boukhris, Omar and Glenn, Jordan M. and Bott, Nick and Stannard, Stephen R. and Engel, Florian A. and Sperlich, Billy and Garbarino, Sergio and Bragazzi, Nicola L. and Shephard, Roy J. and Chtourou, Hamdi}, title = {Effects of Ramadan observance on dietary intake and body composition of adolescent athletes: systematic review and meta-analysis}, series = {Nutrients}, volume = {12}, journal = {Nutrients}, number = {6}, issn = {2072-6643}, doi = {10.3390/nu12061574}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205856}, year = {2020}, abstract = {To evaluate the effects of Ramadan observance on dietary intake, body mass and body composition of adolescent athletes (design: systematic review and meta-analysis; data sources: PubMed and Web of Science; eligibility criteria for selecting studies: single-group, pre-post, with or without control-group studies, conducted in athletes aged <19 years, training at least 3 times/week, and published in any language before 12 February 2020). Studies assessing body mass and/or body composition and/or dietary intake were deemed eligible. The methodological quality was assessed using 'QualSyst'. Of the twelve selected articles evaluating body mass and/or body composition, one was of strong quality and eleven were rated as moderate. Ten articles evaluated dietary intake; four were rated as strong and the remaining moderate in quality. Continuation of training during Ramadan did not change body mass from before to the first week (trivial effect size (ES) = -0.011, p = 0.899) or from before to the fourth week of Ramadan (trivial ES = 0.069, p = 0.277). Additionally, Ramadan observance did not change body fat content from before to the first week (trivial ES = -0.005, p = 0.947) and from before to the fourth week of Ramadan (trivial ES = -0.057, p = 0.947). Lean body mass remained unchanged from before to the fourth week of Ramadan (trivial ES = -0.025, p = 0.876). Dietary data showed the intake of energy (small ES = -0.272, p = 0.182), fat (trivial ES = 0.044, p = 0.842), protein (trivial ES = 0.069, p = 0.720), carbohydrate (trivial ES = 0.075, p = 0.606) and water (trivial ES = -0.115, p = 0.624) remained essentially unchanged during as compared to before Ramadan. Continued training of adolescent athletes at least three times/week during Ramadan observance has no effect on body mass, body composition or dietary intake.}, language = {en} } @article{SalvadorBurekLoehretal.2021, author = {Salvador, Ellaine and Burek, Malgorzata and L{\"o}hr, Mario and Nagai, Michiaki and Hagemann, Carsten and F{\"o}rster, Carola Y.}, title = {Senescence and associated blood-brain barrier alterations in vitro}, series = {Histochemistry and Cell Biology}, volume = {156}, journal = {Histochemistry and Cell Biology}, number = {3}, issn = {1432-119X}, doi = {10.1007/s00418-021-01992-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267435}, pages = {283-292}, year = {2021}, abstract = {Progressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood-brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within.}, language = {en} } @article{SchuhmannGunrebenKleinschnitzetal.2016, author = {Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph and Kraft, Peter}, title = {Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke}, series = {International Journal of Molecular Sciences}, volume = {17}, journal = {International Journal of Molecular Sciences}, number = {3}, doi = {10.3390/ijms17030298}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166206}, pages = {298}, year = {2016}, abstract = {Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke.}, language = {en} } @unpublished{HennigPrustyKauferetal.2021, author = {Hennig, Thomas and Prusty, Archana B. and Kaufer, Benedikt and Whisnant, Adam W. and Lodha, Manivel and Enders, Antje and Thomas, Julius and Kasimir, Francesca and Grothey, Arnhild and Herb, Stefanie and J{\"u}rges, Christopher and Meister, Gunter and Erhard, Florian and D{\"o}lken, Lars and Prusty, Bhupesh K.}, title = {Selective inhibition of microRNA processing by a herpesvirus-encoded microRNA triggers virus reactivation from latency}, edition = {submitted version}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267858}, year = {2021}, abstract = {Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a novel cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the latent-lytic switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture, which impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 was sufficient to trigger virus reactivation from latency thereby identifying it as a readily drugable master regulator of the herpesvirus latent-lytic switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders like myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and Long-COVID.}, language = {en} } @phdthesis{Sahiti2022, author = {Sahiti, Floran}, title = {Myocardial Work - Application and Clinical Characterization of a New Echocardiographic Tool}, doi = {10.25972/OPUS-28226}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282261}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {1 Summary Left ventricular (LV) ejection fraction (EF) and global longitudinal strain (GLS) are the most commonly used measures of LV function. Yet, they are highly dependent on loading conditions since higher afterload yields lower systolic deformation and thereby a lower LVEF and GLS - despite presumably unchanged LV myocardial contractile strength. Invasive pressure-volume loop measurements represent the reference standard to assess LV function, also considering loading conditions. However, this procedure cannot be used in serial investigations or large sample populations due to its invasive nature. The novel concept of echocardiography-derived assessment of myocardial work (MyW) is based on LV pressure-strain loops, may be a valuable alternative to overcome these challenges, and may also be used with relative ease in large populations. As MyW also accounts for afterload, it is considered less load-dependent than LVEF and GLS. The current PhD work addresses the application and clinical characterization of MyW, an innovative echocardiographic tool. As the method is new, we focused on four main topics: (a) To establish reference values for MyW indices, i.e., Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), and Global Work Efficiency (GWE); we addressed a wide age range and evaluated the association of MyW indices with age, sex and other clinical and echocardiography parameters in apparently cardiovascular healthy individuals. (b) To investigate the impact of cardiovascular (CV) risk factors on MyW indices and characterize the severity of subclinical LV deterioration in the general population. (c) To assess the association of the LV geometry, i.e., LV mass and dimensions, with MyW indices. (d) To evaluate in-hospital dynamics of MyW indices in patients hospitalized for acute heart failure (AHF). For the PhD thesis, we could make use of two larger cohorts: The STAAB population-based cohort study prospectively recruited and phenotyped a representative sample (5,000 individuals) of the general population of the City of W{\"u}rzburg, aged 30-79 years and free from symptomatic heart failure at the time of inclusion. We focused on the first half of the study sample (n=2473 individuals), which fulfilled the anticipated strata regarding age and sex. The Acute Heart Failure (AHF) Registry is a prospective clinical registry recruiting and phenotyping consecutive patients admitted for decompensated AHF to the Department of Medicine I, University Hospital W{\"u}rzburg, and observing the natural course of the disease. The AHF Registry focuses on the pathophysiological understanding, particularly in relation to the early phase after cardiac decompensation, with the aim to improve diagnosis and better-tailored treatment of patients with AHF. For the current study, we concentrated on patients who provided pairs of echocardiograms acquired early after index hospital admission and prior to discharge. The main findings of the PhD thesis were: From the STAAB cohort study, we determined the feasibility of large-scale MyW derivation and the accuracy of the method. We established reference values for MyW indices based on 779 analyzable, apparently healthy participants (mean age 49 ± 10 years, 59\% women), who were in sinus rhythm, free from CV risk factors or CV disease, and had no significant LV valve disease. Apart from GWI, there were no associations of other MyW indices with sex. Further, we found a disparate association with age, where MyW showed stable values until the age of 45 years, with an upward shift occurring beyond the age of 45. A higher age decade was associated with higher GWW and lower GWE, respectively. MyW indices only correlated weakly with common echocardiographic parameters, suggesting that MyW may add incremental information to clinically established parameters. Further analyses from the STAAB cohort study contributed to a better understanding of the impact of CV risk factors on MyW indices and the association of LV geometry with LV performance. We demonstrated that CV risk factors impacted selectively on GCW and GWW. Hypertension appears to profoundly compromise the work of the myocardium, in particular, by increasing both GCW and GWW. The LV in hypertension seems to operate at a higher energy level yet lower efficiency. Other classical CV risk factors (Diabetes mellitus, Obesity, Dyslipidemia, Smoking) - independent of blood pressure - impacted consistently and adversely on GCW but did not affect GWW. Further, all CV risk factors affected GWE adversely. We observed that any deviation from a normal LV geometric profile was associated with alterations on MyW. Of note, MyW was sensitive to early changes in LV mass and dimensions. Individuals with normal LV geometry yet established arterial hypertension exhibited a MyW pattern that is typically found in LV hypertrophy. Therefore, such a pattern might serve as an early sign of myocardial damage in hypertensive heart disease and might aid in risk stratification and primary prevention. From the AHF Registry, we selected individuals with serial in-hospital echocardiograms and described in-hospital changes in myocardial performance during recompensation. In patients presenting with a reduced ejection fraction (HFrEF), decreasing N-terminal pro-natriuretic peptide (NT-proBNP) levels as a surrogate of successful recompensation were associated with an improvement in GCW and GWI and consecutively in GWE. In contrast, in patients presenting with a preserved ejection fraction (HFpEF), there was no significant change in GCW and GWI. However, unsuccessful recompensation, i.e., no change or an increase in NT-proBNP levels, was associated with an increase in GWW. This suggests a differential myocardial response to de- and recompensation depending on the HF phenotype. Further, GWW as a surrogate of inappropriate LV energy consumption was elevated in all patients with AHF (compared to reference values) and was not associated with conventional markers as LVEF or NT-proBNP. In an exploratory analysis, GWW predicted the risk of death or rehospitalization within six months after discharge. Hence, GWW might carry incremental information beyond conventional markers of HF severity.}, language = {en} } @phdthesis{Scheffer2020, author = {Scheffer, David}, title = {Einfluss einer Dexamethason/Bortezomib-Kombinationstherapie auf den Glukokortikoidrezeptor und die Tight Junction-Molek{\"u}le Claudin-5 und Occludin in Endothelzellen der Blut-Hirn-Schranke in experimentellen Modellen des Sch{\"a}del-Hirn-Traumas}, doi = {10.25972/OPUS-21871}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218712}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Das Sch{\"a}del-Hirn-Trauma (SHT) ist ein großes medizinisches Problem. Das Hirn{\"o}dem mit konsekutiv erh{\"o}hten intrakraniellen Dr{\"u}cken ist eine h{\"a}ufige und schwerwiegende Komplikation des schweren SHT. Es ist der signifikanteste Pr{\"a}diktor f{\"u}r ein schlechtes Outcome. Obwohl Glukokortikoide (GK) die Ausbildung eines Hirn{\"o}dems bei neuroinflammatorischen Erkrankungen und manchen Hirntumoren reduzieren k{\"o}nnen, ist diese Substanzklasse im SHT ineffektiv oder sogar sch{\"a}dlich. Nach controlled cortical impact (CCI) in M{\"a}usen, einem etablierten SHT-Modell in-vivo, zeigte sich ein Zusammenbruch der Blut-Hirn-Schranke (BHS). Des Weiteren wurde der BHS-stabilisierende Effekt der GK nach CCI durch proteasomalen Abbau des Glukokortikoidrezeptors (GR) behindert. Eine Inhibierung des Proteasoms durch den Proteasomeninhibitor Bortezomib zusammen mit einer GK-Therapie mit Dexamethason reduzierte den Abbau des GR und sorgte f{\"u}r eine Restitution der BHS-Integrit{\"a}t. Ungl{\"u}cklicherweise ließen sich diese Ergebnisse in-vitro nicht auf in Sauerstoff-/Glukosemangel-Modell in der humanen Hirnendothelzelllinie hCMEC/D3 {\"u}bertragen. Daher konnte f{\"u}r die Kombinationstherapie aus dem Proteasomeninhibitor Bortezomib und Dexamethason kein positiver Effekt gezeigt werden. }, subject = {Sch{\"a}del-Hirn-Trauma}, language = {de} } @article{SchischlevskijCordtsGuentheretal.2021, author = {Schischlevskij, Pavel and Cordts, Isabell and G{\"u}nther, Ren{\´e} and Stolte, Benjamin and Zeller, Daniel and Schr{\"o}ter, Carsten and Weyen, Ute and Regensburger, Martin and Wolf, Joachim and Schneider, Ilka and Hermann, Andreas and Metelmann, Moritz and Kohl, Zacharias and Linker, Ralf A. and Koch, Jan Christoph and Stendel, Claudia and M{\"u}schen, Lars H. and Osmanovic, Alma and Binz, Camilla and Klopstock, Thomas and Dorst, Johannes and Ludolph, Albert C. and Boentert, Matthias and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Petri, Susanne and Schreiber-Katz, Olivia}, title = {Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives}, series = {Brain Sciences}, volume = {11}, journal = {Brain Sciences}, number = {6}, issn = {2076-3425}, doi = {10.3390/brainsci11060748}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240981}, year = {2021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = -0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95\% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95\% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = -0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = -0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.}, language = {en} } @article{RiedererMonoranuStrobeletal.2021, author = {Riederer, P. and Monoranu, C. and Strobel, S. and Iordache, T. and Sian-H{\"u}lsmann, J.}, title = {Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease}, series = {Journal of Neural Transmission}, volume = {128}, journal = {Journal of Neural Transmission}, number = {10}, issn = {1435-1463}, doi = {10.1007/s00702-021-02414-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268539}, pages = {1577-1598}, year = {2021}, abstract = {About 60 years ago, the discovery of a deficiency of dopamine in the nigro-striatal system led to a variety of symptomatic therapeutic strategies to supplement dopamine and to substantially improve the quality of life of patients with Parkinson's disease (PD). Since these seminal developments, neuropathological, neurochemical, molecular biological and genetic discoveries contributed to elucidate the pathology of PD. Oxidative stress, the consequences of reactive oxidative species, reduced antioxidative capacity including loss of glutathione, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, autophagy, suggested to be causal for ɑ-synuclein fibril formation and aggregation and contributing to neuroinflammation and neural cell death underlying this devastating disorder. However, there are no final conclusions about the triggered pathological mechanism(s) and the follow-up of pathological dysfunctions. Nevertheless, it is a fact, that iron, a major component of oxidative reactions, as well as neuromelanin, the major intraneuronal chelator of iron, undergo an age-dependent increase. And ageing is a major risk factor for PD. Iron is significantly increased in the substantia nigra pars compacta (SNpc) of PD. Reasons for this finding include disturbances in iron-related import and export mechanisms across the blood-brain barrier (BBB), localized opening of the BBB at the nigro-striatal tract including brain vessel pathology. Whether this pathology is of primary or secondary importance is not known. We assume that there is a better fit to the top-down hypotheses and pathogens entering the brain via the olfactory system, then to the bottom-up (gut-brain) hypothesis of PD pathology. Triggers for the bottom-up, the dual-hit and the top-down pathologies include chemicals, viruses and bacteria. If so, hepcidin, a regulator of iron absorption and its distribution into tissues, is suggested to play a major role in the pathogenesis of iron dyshomeostasis and risk for initiating and progressing ɑ-synuclein pathology. The role of glial components to the pathology of PD is still unknown. However, the dramatic loss of glutathione (GSH), which is mainly synthesized in glia, suggests dysfunction of this process, or GSH uptake into neurons. Loss of GSH and increase in SNpc iron concentration have been suggested to be early, may be even pre-symptomatic processes in the pathology of PD, despite the fact that they are progression factors. The role of glial ferritin isoforms has not been studied so far in detail in human post-mortem brain tissue and a close insight into their role in PD is called upon. In conclusion, "iron" is a major player in the pathology of PD. Selective chelation of excess iron at the site of the substantia nigra, where a dysfunction of the BBB is suggested, with peripherally acting iron chelators is suggested to contribute to the portfolio and therapeutic armamentarium of anti-Parkinson medications.}, language = {en} } @phdthesis{Muentze2019, author = {M{\"u}ntze, Jonas Andres}, title = {Die Biomaterialbank des Kompetenznetz Herzinsuffizienz - Eine Qualit{\"a}tskontrolle}, doi = {10.25972/OPUS-17839}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178391}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {In der vorliegenden Arbeit wurden 16 Parameter analysiert, die im Rahmen der Herzinsuffizienzdiagnostik eine wichtige Rolle spielen. Alle Bioproben waren an den KNHI-Standorten W{\"u}rzburg und G{\"o}ttingen gewonnen worden. Ein Teil der so gewonnenen Biomaterialien wurde lokal analysiert und bei -80°C eingelagert (Erstmessung oder Basismessung), ein Teil wurde nach Berlin versandt und dort unter standardisierten Bedingungen in der KNHI-Biobank bei -80°C eingelagert. Nach 6-8 Jahren wurden gezielt Samples aus der KNHI-Biobank angefordert, nach W{\"u}rzburg versandt, aufgetaut, und zum zweiten Mal gemessen (Nachmessung). Die Messergebnisse aus P{\"a}rchen von Serum- und EDTA-Proben aus den lokalen und zentral gelagerten Bioproben wurden verglichen (insgesamt somit 4 Gruppen) und statistisch analysiert (Korrelation, Bestimmtheitsmaß R², Streudiagramme, Bland-Altman-Analysen, Regression, 95\%-{\"U}bereinstimmungsintervalle, Confounderanalyse). Je nach Parameter wurden zwischen 103 und 322 Probenpaare in die Analyse eingeschlossen. Es konnte gezeigt werden, dass die Lagerung von Biomaterial bei -80°C sinnvoll ist, um in der Zukunft eine gen{\"u}gende Zahl an Patientenwerten f{\"u}r Studien und Analysen bez{\"u}glich des Krankheitsbilds Herzinsuffizienz zur Verf{\"u}gung zu haben. Die Qualit{\"a}t gerade der prognostisch wichtigen Marker hsCRP und NT-proBNP ist als sehr gut zu bewerten, was es dem KNHI erm{\"o}glichen d{\"u}rfte, fast alle eingelagerten Proben zu nutzen. Es wurden verschiedene Akzeptanzbereiche definiert, die sich bei allen Parametern mit Ausnahme von Natrium und Kalium aus den 95\%-{\"U}bereinstimmungsintervallen der durchgef{\"u}hrten Bland-Altman-Analysen bilden.}, subject = {Herzinsuffizienz}, language = {de} } @article{Graetz2021, author = {Graetz, Jonas}, title = {Simulation study towards quantitative X-ray and neutron tensor tomography regarding the validity of linear approximations of dark-field anisotropy}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, doi = {10.1038/s41598-021-97389-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261844}, year = {2021}, abstract = {Tensor tomography is fundamentally based on the assumption of a both anisotropic and linear contrast mechanism. While the X-ray or neutron dark-field contrast obtained with Talbot(-Lau) interferometers features the required anisotropy, a preceding detailed study of dark-field signal origination however found its specific orientation dependence to be a non-linear function of the underlying anisotropic mass distribution and its orientation, especially challenging the common assumption that dark-field signals are describable by a function over the unit sphere. Here, two approximative linear tensor models with reduced orientation dependence are investigated in a simulation study with regard to their applicability to grating based X-ray or neutron dark-field tensor tomography. By systematically simulating and reconstructing a large sample of isolated volume elements covering the full range of feasible anisotropies and orientations, direct correspondences are drawn between the respective tensors characterizing the physically based dark-field model used for signal synthesization and the mathematically motivated simplified models used for reconstruction. The anisotropy of freely rotating volume elements is thereby confirmed to be, for practical reconstruction purposes, approximable both as a function of the optical axis' orientation or as a function of the interferometer's grating orientation. The eigenvalues of the surrogate models' tensors are found to exhibit fuzzy, yet almost linear relations to those of the synthesization model. Dominant orientations are found to be recoverable with a margin of error on the order of magnitude of 1 degrees. Although the input data must adequately address the full orientation dependence of dark-field anisotropy, the present results clearly support the general feasibility of quantitative X-ray dark-field tensor tomography within an inherent yet acceptable statistical margin of uncertainty.}, language = {en} } @article{HaiderAhmadGrolletal.2021, author = {Haider, Malik Salman and Ahmad, Taufiq and Groll, J{\"u}rgen and Scherf-Clavel, Oliver and Kroiss, Matthias and Luxenhofer, Robert}, title = {The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging}, series = {European Journal of Drug Metabolism and Pharmacokinetics}, volume = {46}, journal = {European Journal of Drug Metabolism and Pharmacokinetics}, number = {5}, issn = {2107-0180}, doi = {10.1007/s13318-021-00700-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270476}, pages = {575-593}, year = {2021}, abstract = {Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren®). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50\% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably. Mitotane as tablet form is currently the standard treatment for adrenocortical carcinoma. It has been used for 5 decades but suffers from highly variable responses in patients, subsequent adverse effects and overall lower response rate. This can be fundamentally linked to the exceedingly poor water solubility of mitotane itself. In terms of enhancing water solubility, a few research groups have attempted to develop better formulations of mitotane to overcome the issues associated with tablet dosage form. However, the success rate was limited, and these formulations did not make it into the clinics. In this article, we have comprehensively reviewed the properties of these formulations and discuss the reasons for their limited utility. Furthermore, we discuss a recently developed mitotane nanoformulation that led us to propose a novel approach to mitotane therapy, where intravenous delivery supplements the standard oral administration. With this article, we combine the current state of knowledge as a single piece of information about the various problems associated with the use of mitotane tablets, and herein we postulate the development of a new injectable mitotane formulation, which can potentially circumvent the major problems associated to mitotane's poor water solubility.}, language = {en} } @article{SchmidtAbinzanoMensingaetal.2020, author = {Schmidt, Stefanie and Abinzano, Florencia and Mensinga, Anneloes and Teßmar, J{\"o}rg and Groll, J{\"u}rgen and Malda, Jos and Levato, Riccardo and Blunk, Torsten}, title = {Differential production of cartilage ECM in 3D agarose constructs by equine articular cartilage progenitor cells and mesenchymal stromal cells}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms21197071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236180}, year = {2020}, abstract = {Identification of articular cartilage progenitor cells (ACPCs) has opened up new opportunities for cartilage repair. These cells may be used as alternatives for or in combination with mesenchymal stromal cells (MSCs) in cartilage engineering. However, their potential needs to be further investigated, since only a few studies have compared ACPCs and MSCs when cultured in hydrogels. Therefore, in this study, we compared chondrogenic differentiation of equine ACPCs and MSCs in agarose constructs as monocultures and as zonally layered co-cultures under both normoxic and hypoxic conditions. ACPCs and MSCs exhibited distinctly differential production of the cartilaginous extracellular matrix (ECM). For ACPC constructs, markedly higher glycosaminoglycan (GAG) contents were determined by histological and quantitative biochemical evaluation, both in normoxia and hypoxia. Differential GAG production was also reflected in layered co-culture constructs. For both cell types, similar staining for type II collagen was detected. However, distinctly weaker staining for undesired type I collagen was observed in the ACPC constructs. For ACPCs, only very low alkaline phosphatase (ALP) activity, a marker of terminal differentiation, was determined, in stark contrast to what was found for MSCs. This study underscores the potential of ACPCs as a promising cell source for cartilage engineering.}, language = {en} } @article{WallstabeBussemerGroeberBeckeretal.2020, author = {Wallstabe, Julia and Bussemer, Lydia and Groeber-Becker, Florian and Freund, Lukas and Alb, Mirian and Dragan, Mariola and Waaga-Gasser, Ana Maria and Jakubietz, Rafael and Kneitz, Hermann and Rosenwald, Andreas and Rebhan, Silke and Walles, Heike and Mielke, Stephan}, title = {Inflammation-Induced Tissue Damage Mimicking GvHD in Human Skin Models as Test Platform for Immunotherapeutics}, series = {ALTEX}, volume = {37}, journal = {ALTEX}, number = {3}, doi = {10.14573/altex.1907181}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229974}, pages = {429-440}, year = {2020}, abstract = {Due to the rapidly increasing development and use of cellular products, there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated human organotypic skin models from human biopsies by isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells and seeding these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. We then were able to induce inflammation-mediated tissue damage by adding pre-stimulated, mismatched allogeneic lymphocytes and/or inflammatory cytokine-containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. This could be prevented by the addition of immunosuppressants to the models. Consequently, these models harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. They also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells, which would otherwise be limited to animal models. Thus, the current test platform, developed with the limitation that no professional antigen presenting cells are in place, could greatly reduce animal testing for investigation of novel immune therapies.}, language = {en} } @article{ArnholdtKamawalHorasetal.2020, author = {Arnholdt, J{\"o}rg and Kamawal, Yama and Horas, Konstantin and Holzapfel, Boris M. and Gilbert, Fabian and Ripp, Axel and Rudert, Maximilian and Steinert, Andre F.}, title = {Accurate implant fit and leg alignment after cruciate-retaining patient-specific total knee arthroplasty}, series = {BMC Musculoskeletal Disorders}, volume = {21}, journal = {BMC Musculoskeletal Disorders}, doi = {10.1186/s12891-020-03707-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230012}, year = {2020}, abstract = {Background For improved outcomes in total knee arthroplasty (TKA) correct implant fitting and positioning are crucial. In order to facilitate a best possible implant fitting and positioning patient-specific systems have been developed. However, whether or not these systems allow for better implant fitting and positioning has yet to be elucidated. For this reason, the aim was to analyse the novel patient-specific cruciate retaining knee replacement system iTotal (TM) CR G2 that utilizes custom-made implants and instruments for its ability to facilitate accurate implant fitting and positioning including correction of the hip-knee-ankle angle (HKA). Methods We assessed radiographic results of 106 patients who were treated with the second generation of a patient-specific cruciate retaining knee arthroplasty using iTotal\(^{TM}\) CR G2 (ConforMIS Inc.) for tricompartmental knee osteoarthritis (OA) using custom-made implants and instruments. The implant fit and positioning as well as the correction of the mechanical axis (hip-knee-ankle angle, HKA) and restoration of the joint line were determined using pre- and postoperative radiographic analyses. Results On average, HKA was corrected from 174.4 degrees +/- 4.6 degrees preoperatively to 178.8 degrees +/- 2.2 degrees postoperatively and the coronal femoro-tibial angle was adjusted on average 4.4 degrees. The measured preoperative tibial slope was 5.3 degrees +/- 2.2 degrees (mean +/- SD) and the average postoperative tibial slope was 4.7 degrees +/- 1.1 degrees on lateral views. The joint line was well preserved with an average modified Insall-Salvati index of 1.66 +/- 0.16 pre- and 1.67 +/- 0.16 postoperatively. The overall accuracy of fit of implant components was decent with a measured medial overhang of more than 1 mm (1.33 mm +/- 0.32 mm) in 4 cases only. Further, a lateral overhang of more than 1 mm (1.8 mm +/- 0.63) (measured in the anterior-posterior radiographs) was observed in 11 cases, with none of the 106 patients showing femoral notching. Conclusion The patient-specific iTotal\(^{TM}\) CR G2 total knee replacement system facilitated a proper fitting and positioning of the implant components. Moreover, a good restoration of the leg axis towards neutral alignment was achieved as planned. Nonetheless, further clinical follow-up studies are necessary to validate our findings and to determine the long-term impact of using this patient- specific system.}, language = {en} } @article{FuchsHeiligMcDonoghetal.2020, author = {Fuchs, Konrad F. and Heilig, Philipp and McDonogh, Miriam and Boelch, Sebastian and Gbureck, Uwe and Meffert, Rainer H. and Hoelscher-Doht, Stefanie and Jordan, Martin C.}, title = {Cement-augmented screw fixation for calcaneal fracture treatment: a biomechanical study comparing two injectable bone substitutes}, series = {Journal of Orthopaedic Surgery and Research}, volume = {15}, journal = {Journal of Orthopaedic Surgery and Research}, doi = {10.1186/s13018-020-02009-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230336}, year = {2020}, abstract = {Background The role of cement-augmented screw fixation for calcaneal fracture treatment remains unclear. Therefore, this study was performed to biomechanically analyze screw osteosynthesis by reinforcement with either a calcium phosphate (CP)-based or polymethylmethacrylate (PMMA)-based injectable bone cement. Methods A calcaneal fracture (Sanders type IIA) including a central cancellous bone defect was generated in 27 synthetic bones, and the specimens were assigned to 3 groups. The first group was fixed with four screws (3.5 mm and 6.5 mm), the second group with screws and CP-based cement (Graftys (R) QuickSet; Graftys, Aix-en-Provence, France), and the third group with screws and PMMA-based cement (Traumacem (TM) V+; DePuy Synthes, Warsaw, IN, USA). Biomechanical testing was conducted to analyze peak-to-peak displacement, total displacement, and stiffness in following a standardized protocol. Results The peak-to-peak displacement under a 200-N load was not significantly different among the groups; however, peak-to-peak displacement under a 600- and 1000-N load as well as total displacement exhibited better stability in PMMA-augmented screw osteosynthesis compared to screw fixation without augmentation. The stiffness of the construct was increased by both CP- and PMMA-based cements. Conclusion Addition of an injectable bone cement to screw osteosynthesis is able to increase fixation strength in a biomechanical calcaneal fracture model with synthetic bones. In such cases, PMMA-based cements are more effective than CP-based cements because of their inherently higher compressive strength. However, whether this high strength is required in the clinical setting for early weight-bearing remains controversial, and the non-degradable properties of PMMA might cause difficulties during subsequent interventions in younger patients.}, language = {en} } @article{Hoelscher‑DohtKladnyPauletal.2021, author = {Hoelscher‑Doht, Stefanie and Kladny, A.-M. and Paul, M. M. and Eden, L. and Buesse, M. and Meffert, R. H.}, title = {Low-profile double plating versus dorsal LCP in stabilization of the olecranon fractures}, series = {Archives of Orthopaedic and Trauma Surgery}, volume = {145}, journal = {Archives of Orthopaedic and Trauma Surgery}, issn = {0936-8051}, doi = {10.1007/s00402-020-03473-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235844}, pages = {245-251}, year = {2021}, abstract = {Introduction Proximal ulna fractures are common in orthopaedic surgery. Comminuted fractures require a high primary stability by the osteosynthesis, to allow an early functional rehabilitation as fast as possible, to reduce long-term limitations of range of motion. Classical dorsal plating is related to wound healing problems due to the prominence of the implant. New low-profile double plates are available addressing the soft tissue problems by positioning the plates at the medial and lateral side. This study analysed whether, under high loading conditions, these new double plates provide an equivalent stability as compared to the rigid olecranon locking compression plate (LCP). Materials and methods In Sawbones, Mayo Type IIB fractures were simulated and stabilized by plate osteosyntheses: In group one, two low-profile plates were placed. In group two, a single dorsal plate (LCP) was used. The bones was than cyclically loaded simulating flexion grades of 0°, 30°, 60° and 90° of the elbow joint with increasing tension forces (150 , 150 , 300 and 500 N). The displacement and fracture gap movement were recorded. In the end, in load-to-failure tests, load at failure and mode of failure were determined. Results No significant differences were found for the displacement and fracture gap widening during cyclic loading. Under maximum loading, the double plates revealed a comparable load at failure like the single dorsal plate (LCP). The double plates failed with a proximal screw pull-out of the plate, whereas in the LCP group, in 10 out of 12 specimens the mode of failure was a diaphyseal shaft fracture at the distal plate peak. Conclusion Biomechanically, the double plates are a good alternative to the dorsal LCP providing a high stability under high loading conditions and, at the same, time reducing the soft tissue irritation by a lateral plate position.}, language = {en} } @article{KippnichSchorscherKredeletal.2020, author = {Kippnich, Maximilian and Schorscher, Nora and Kredel, Markus and Markus, Christian and Eden, Lars and Gassenmaier, Tobias and Lock, Johann and Wurmb, Thomas}, title = {Dual‑room twin‑CT scanner in multiple trauma care: first results after implementation in a level one trauma centre}, series = {European Journal of Trauma and Emergency Surgery}, journal = {European Journal of Trauma and Emergency Surgery}, issn = {1863-9933}, doi = {10.1007/s00068-020-01374-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232390}, year = {2020}, abstract = {Purpose The trauma centre of the Wuerzburg University Hospital has integrated a pioneering dual-room twin-CT scanner in a multiple trauma pathway. For concurrent treatment of two trauma patients, two carbon CT examination and intervention tables are positioned head to head with one sliding CT-Gantry in the middle. The focus of this study is the process of trauma care with the time to CT (tCT) and the time to operation (tOR) as quality indicator. Methods All patients with suspected multiple trauma, who required emergency surgery and who were initially diagnosed by the CT trauma protocol between 05/2018 and 12/2018 were included. Data relating to time spans (tCT and tOR), severity of injury and outcome was obtained. Results 110 of the 589 screened trauma patients had surgery immediately after finishing primary assessment in the ER. The ISS was 17 (9-34) (median and interquartile range, IQR). tCT was 15 (11-19) minutes (median and IQR) and tOR was 96.5 (75-119) minutes (median and IQR). In the first 30 days, seven patients died (6.4\%) including two within the first 24 h (2\%). There were two ICU days (1-6) (median and IQR) and one (0-1) (median and IQR) ventilator day. Conclusion The twin-CT technology is a fascinating tool to organize high-quality trauma care for two multiple trauma patients simultaneously}, language = {en} } @article{JakubietzSchmidtHolzapfeletal.2020, author = {Jakubietz, Rafael G. and Schmidt, Karsten and Holzapfel, Boris M. and Meffert, Rainer H. and Jakubietz, Michael G.}, title = {Pedicled perforator flaps for mid-tibial soft tissue reconstruction in medically compromised patients}, series = {JPRAS Open}, volume = {24}, journal = {JPRAS Open}, doi = {10.1016/j.jpra.2020.02.002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229473}, pages = {47-55}, year = {2020}, abstract = {Background: The soft tissue of the central pretibial area is difficult to reconstruct often requiring free tissue transfer. Especially medi- cally compromised patients are not ideal candidates for free tissue transfer and may benefit from expeditiously harvested local flaps with limited donor site morbidity. As muscle flaps are rare, pedi- cled flaps based on lateral perforators represent an alternative as the arc of rotation can often be limited to 90 °. Material and Methods: A retrospective analysis of patient data was conducted to identify patients over the age of 60 years with comor- bidities that underwent pretibial soft tissue reconstruction with a single-pedicle perforator flap. Patient demographics, size and cause of the defect, flap dimension, arc of rotation and complications were recorded. Results: Five patients with an average age of 71.4 years were in- cluded. The arc of rotation was 69 °, all flaps healed. There were two recurrences of osteomyelitis. Conclusion: Lateral perforators originating from the anterior tib- ial artery or peroneal artery are adequate source vessels for single pedicled perforator flaps even in medically compromised patients. A perforator located proximal to the defect allows limiting the arcof rotation to less than 90 °, which increases the safety of the flap. Patients benefit from a simple procedure without a microvascular anastomosis and a donor site confined to one extremity}, language = {en} } @phdthesis{Palmisano2022, author = {Palmisano, Chiara}, title = {Supraspinal Locomotor Network Derangements: A Multimodal Approach}, doi = {10.25972/OPUS-26644}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266442}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Parkinson's Disease (PD) constitutes a major healthcare burden in Europe. Accounting for aging alone, ~700,000 PD cases are predicted by 2040. This represents an approximately 56\% increase in the PD population between 2005 and 2040, with a consequent rise in annual disease-related medical costs. Gait and balance disorders are a major problem for patients with PD and their caregivers, mainly because to their correlation with falls. Falls occur as a result of a complex interaction of risk factors. Among them, Freezing of Gait (FoG) is a peculiar gait derangement characterized by a sudden and episodic inability to produce effective stepping, causing falls, mobility restrictions, poor quality of life, and increased morbidity and mortality. Between 50-70\% of PD patients have FoG and/or falls after a disease duration of 10 years, only partially and inconsistently improved by dopaminergic treatment and Deep Brain Stimulation (DBS). Treatment-induced worsening has been also observed under certain conditions. Effective treatments for gait disturbances in PD are lacking, probably because of the still poor understanding of the supraspinal locomotor network. In my thesis, I wanted to expand our knowledge of the supraspinal locomotor network and in particular the contribution of the basal ganglia to the control of locomotion. I believe this is a key step towards new preventive and personalized therapies for postural and gait problems in patients with PD and related disorders. In addition to patients with PD, my studies also included people affected by Progressive Supranuclear Palsy (PSP). PSP is a rare primary progressive parkinsonism characterized at a very early disease stage by poor balance control and frequent backwards falls, thus providing an in vivo model of dysfunctional locomotor control. I focused my attention on one of the most common motor transitions in daily living, the initiation of gait (GI). GI is an interesting motor task and a relevant paradigm to address balance and gait impairments in patients with movement disorders, as it is associated with FoG and high risk of falls. It combines a preparatory (i.e., the Anticipatory Postural Adjustments [APA]) and execution phase (the stepping) and allows the study of movement scaling and timing as an expression of muscular synergies, which follow precise and online feedback information processing and integration into established feedforward patterns of motor control. By applying a multimodal approach that combines biomechanical assessments and neuroimaging investigations, my work unveiled the fundamental contribution of striatal dopamine to GI in patients with PD. Results in patients with PSP further supported the fundamental role of the striatum in GI execution, revealing correlations between the metabolic intake of the left caudate nucleus with diverse GI measurements. This study also unveiled the interplay of additional brain areas in the motor control of GI, namely the Thalamus, the Supplementary Motor Area (SMA), and the Cingulate cortex. Involvement of cortical areas was also suggested by the analysis of GI in patients with PD and FoG. Indeed, I found major alterations in the preparatory phase of GI in these patients, possibly resulting from FoG-related deficits of the SMA. Alterations of the weight shifting preceding the stepping phase were also particularly important in PD patients with FoG, thus suggesting specific difficulties in the integration of somatosensory information at a cortical level. Of note, all patients with PD showed preserved movement timing of GI, possibly suggesting preserved and compensatory activity of the cerebellum. Postural abnormalities (i.e., increased trunk and thigh flexion) showed no relationship with GI, ruling out an adaptation of the motor pattern to the altered postural condition. In a group of PD patients implanted with DBS, I further explored the pathophysiological functioning of the locomotor network by analysing the timely activity of the Subthalamic Nucleus (STN) during static and dynamic balance control (i.e., standing and walking). For this study, I used novel DBS devices capable of delivering stimulation and simultaneously recording Local Field Potentials (LFP) of the implanted nucleus months and years after surgery. I showed a gait-related frequency shift in the STN activity of PD patients, possibly conveying cortical (feedforward) and cerebellar (feedback) information to mesencephalic locomotor areas. Based on this result, I identified for each patient a Maximally Informative Frequency (MIF) whose power changes can reliably classify standing and walking conditions. The MIF is a promising input signal for new DBS devices that can monitor LFP power modulations to timely adjust the stimulation delivery based on the ongoing motor task (e.g., gait) performed by the patient (adaptive DBS). Altogether my achievements allowed to define the role of different cortical and subcortical brain areas in locomotor control, paving the way for a better understanding of the pathophysiological dynamics of the supraspinal locomotor network and the development of tailored therapies for gait disturbances and falls prevention in PD and related disorders.}, language = {en} } @article{BachmannEhlertBeckeretal.2020, author = {Bachmann, Julia and Ehlert, Elias and Becker, Matthias and Otto, Christoph and Radeloff, Katrin and Blunk, Torsten and Bauer-Kreisel, Petra}, title = {Ischemia-like stress conditions stimulate trophic activities of adipose-derived stromal/stem cells}, series = {Cells}, volume = {9}, journal = {Cells}, number = {9}, issn = {2073-4409}, doi = {10.3390/cells9091935}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211233}, year = {2020}, abstract = {Adipose-derived stromal/stem cells (ASCs) have been shown to exert regenerative functions, which are mainly attributed to the secretion of trophic factors. Upon transplantation, ASCs are facing an ischemic environment characterized by oxygen and nutrient deprivation. However, current knowledge on the secretion capacity of ASCs under such conditions is limited. Thus, the present study focused on the secretory function of ASCs under glucose and oxygen deprivation as major components of ischemia. After exposure to glucose/oxygen deprivation, ASCs maintained distinct viability, but the metabolic activity was greatly reduced by glucose limitation. ASCs were able to secrete a broad panel of factors under glucose/oxygen deprivation as revealed by a cytokine antibody array. Quantification of selected factors by ELISA demonstrated that glucose deprivation in combination with hypoxia led to markedly higher secretion levels of the angiogenic and anti-apoptotic factors IL-6, VEGF, and stanniocalcin-1 as compared to the hypoxic condition alone. A conditioned medium of glucose/oxygen-deprived ASCs promoted the viability and tube formation of endothelial cells, and the proliferation and migration of fibroblasts. These findings indicate that ASCs are stimulated by ischemia-like stress conditions to secrete trophic factors and would be able to exert their beneficial function in an ischemic environment.}, language = {en} } @article{NoseNogamiKoshinoetal.2021, author = {Nose, Naoko and Nogami, Suguru and Koshino, Kazuhiro and Chen, Xinyu and Werner, Rudolf A. and Kashima, Soki and Rowe, Steven P. and Lapa, Constantin and Fukuchi, Kazuki and Higuchi, Takahiro}, title = {[18F]FDG-labelled stem cell PET imaging in different route of administrations and multiple animal species}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-90383-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260590}, year = {2021}, abstract = {Stem cell therapy holds great promise for tissue regeneration and cancer treatment, although its efficacy is still inconclusive and requires further understanding and optimization of the procedures. Non-invasive cell tracking can provide an important opportunity to monitor in vivo cell distribution in living subjects. Here, using a combination of positron emission tomography (PET) and in vitro 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) direct cell labelling, the feasibility of engrafted stem cell monitoring was tested in multiple animal species. Human mesenchymal stem cells (MSCs) were incubated with phosphate-buffered saline containing [18F]FDG for in vitro cell radiolabelling. The pre-labelled MSCs were administrated via peripheral vein in a mouse (n=1), rats (n=4), rabbits (n=4) and non-human primates (n=3), via carotid artery in rats (n=4) and non-human primates (n=3), and via intra-myocardial injection in rats (n=5). PET imaging was started 10 min after cell administration using a dedicated small animal PET system for a mouse and rats. A clinical PET system was used for the imaging of rabbits and non-human primates. After MSC administration via peripheral vein, PET imaging revealed intense radiotracer signal from the lung in all tested animal species including mouse, rat, rabbit, and non-human primate, suggesting administrated MSCs were trapped in the lung tissue. Furthermore, the distribution of the PET signal significantly differed based on the route of cell administration. Administration via carotid artery showed the highest activity in the head, and intra-myocardial injection increased signal from the heart. In vitro [18F]FDG MSC pre-labelling for PET imaging is feasible and allows non-invasive visualization of initial cell distribution after different routes of cell administration in multiple animal models. Those results highlight the potential use of that imaging approach for the understanding and optimization of stem cell therapy in translational research.}, language = {en} } @article{ReiterWeissWeberetal.2022, author = {Reiter, Theresa and Weiss, Ingo and Weber, Oliver M. and Bauer, Wolfgang R.}, title = {Signal voids of active cardiac implants at 3.0 T CMR}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-09690-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300502}, year = {2022}, abstract = {Recent technical advancements allow cardiac MRI (CMR) examinations in the presence of so-called MRI conditional active cardiac implants at 3.0 T. However, the artifact burden caused by susceptibility effects remain an obstacle. All measurements were obtained at a clinical 3.0 T scanner using an in-house designed cubic phantom and optimized sequences for artifact evaluation (3D gradient echo sequence, multi-slice 2D turbo spin echo sequence). Reference sequences according to the American Society for Testing and Materials (ASTM) were additionally applied. Four representative active cardiac devices and a generic setup were analyzed regarding volume and shape of the signal void. For analysis, a threshold operation was applied to the grey value profile of each data set. The presented approach allows the evaluation of the signal void and shape even for larger implants such as ICDs. The void shape is influenced by the orientation of the B0-field and by the chosen sequence type. The distribution of ferromagnetic material within the implants also matters. The void volume depends both on the device itself, and on the sequence type. Disturbances in the B0 and B1 fields exceed the visual signal void. This work presents a reproducible and highly defined approach to characterize both signal void artifacts at 3.0 T and their influencing factors.}, language = {en} } @article{LuedemannJakuscheitEwaldetal.2021, author = {L{\"u}demann, Martin and Jakuscheit, Axel and Ewald, Andrea and Fr{\"u}hmann, Leena and H{\"o}lscher-Doht, Stefanie and Rudert, Maximilian and von Hertzberg-Boelch, Sebastian Philipp}, title = {Influence of Tranexamic Acid on Elution Characteristics and Compressive Strength of Antibiotic-Loaded PMMA-Bone Cement with Gentamicin}, series = {Materials}, volume = {14}, journal = {Materials}, number = {19}, issn = {1996-1944}, doi = {10.3390/ma14195639}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246236}, year = {2021}, abstract = {Purpose: The topical application of tranexamic acid (TXA) into the joint space during total joint arthroplasty (TJA) with no increase of complications, has been widely reported. We investigated the influence of TXA on antibiotic release, activity of the released antibiotic against a clinical isolate of S. aureus, and compressive strength of a widely used commercially prepared gentamicin-loaded cement brand (PALACOS R + G). Method: 12 bone cement cylinders (diameter and height = 6 and 12 mm, respectively) were molded. After curing in air for at least 1 h, six of the cylinders were completely immersed in 5 mL of fetal calf serum (FCS) and the other six were completely immersed in a solution consisting of 4.9 mL of FCS and 0.1 mL (10 mg) of TXA. Gentamicin elution tests were performed over 7 d. Four hundred µL of the gentamicin eluate were taken every 24 h for the first 7 d without renewing the immersion fluid. The gentamicin concentration was determined in a clinical analyzer using a homogeny enzyme immuno-assay. The antimicrobial activity of the eluate, obtained after day 7, was tested. An agar diffusion test regime was used with Staphylococcus aureus. Bacteria were grown in a LB medium and plated on LB agar plates to get a bacterial lawn. Fifty µL of each eluate were pipetted on 12-mm diameter filter discs, which were placed in the middle of the agar gel. After 24 h of cultivation at 37 °C, the zone of inhibition (ZOI) for each specimen was measured. The compressive strength of the cements was determined per ISO 5833. Results: At each time point in the gentamicin release test, the difference in gentamicin concentration, obtained from specimens immersed in the FCS solution only and those immersed in the FCS + TXA solution was not significant (p = 0.055-0.522). The same trend was seen in each of the following parameters, after 7 d of immersion: (1) Cumulative gentamicin concentration (p < 0.297); (2) gentamicin activity against S. aureus (strongly visible); (3) ZOI size (mostly > 20 mm) (p = 0.631); and (4) compressive strength (p = 0.262). Conclusions: For the PALACOS R + G specimens, the addition of TXA to FCS does not produce significant decreases in gentamicin concentration, in the activity of the gentamicin eluate against a clinical isolate of S. aureus, the zone of inhibition of S. aureus, and in the compressive strength of the cement, after 7 d of immersion in the test solution.}, language = {en} } @article{GilbertMeffertSchmalzletal.2018, author = {Gilbert, F. and Meffert, R. H. and Schmalzl, J. and Weng, A. M. and K{\"o}stler, H. and Eden, L.}, title = {Grade of retraction and tendon thickness correlates with MR-spectroscopically measured amount of fatty degeneration in full thickness supraspinatus tears}, series = {BMC Musculoskeletal Disorders}, volume = {19}, journal = {BMC Musculoskeletal Disorders}, number = {197}, doi = {10.1186/s12891-018-2096-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176116}, year = {2018}, abstract = {Background: The amount of fatty degeneration (FD) has major impact on the clinical result and cuff integrity after rotator cuff repair. A quantitative analysis with magnet resonance imaging (MRI) spectroscopy was employed to analyze possible correlation of FD with tendon retraction, tendon thickness and patients' characteristics in full thickness supraspinatus tears. Methods: Forty-two patients with full-thickness supraspinatus tears underwent shoulder MRI including an experimental spectroscopic sequence allowing quantification of the fat fraction in the supraspinatus muscle belly. The amount of fatty degeneration was correlated with tendon retraction, tendon thickness, patients' age, gender, smoker status, symptom duration and body mass index (BMI). Patients were divided in to three groups of retraction (A) 0-10 mm (n=), (B) 11-20 mm (n=) and (C) < 21 mm (n=) and the means of FD for each group were calculated. Results: Tendon retraction (R = 0.6) and symptom duration (R = 0.6) correlated positively, whereas tendon thickness correlated negatively (R = - 0.6) with the amount of FD. The fat fraction increased significantly with tendon retraction: Group (A) showed a mean fat mount of 3.7\% (±4\%), group (B) of 16.7\% (±8.2\%) and group (C) of 37.5\% (±19\%). BMI, age and smoker-status only showed weak to moderate correlation with the amount of FD in this cohort. Conclusion: MRI spectroscopy revealed significantly higher amount of fat with increasing grade of retraction, symptom duration and decreased tendon thickness. Thus, these parameters may indirectly be associated with the severity of tendon disease.}, language = {en} } @article{JakuscheitSchaeferRoedigetal.2021, author = {Jakuscheit, Axel and Schaefer, Nina and Roedig, Johannes and Luedemann, Martin and Hertzberg-Boelch, Sebastian Philipp von and Weissenberger, Manuel and Schmidt, Karsten and Holzapfel, Boris Michael and Rudert, Maximilian}, title = {Modifiable individual risks of perioperative blood transfusions and acute postoperative complications in total hip and knee arthroplasty}, series = {Journal of Personalized Medicine}, volume = {11}, journal = {Journal of Personalized Medicine}, number = {11}, issn = {2075-4426}, doi = {10.3390/jpm11111223}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250290}, year = {2021}, abstract = {Background: The primary aim of this study was to identify modifiable patient-related predictors of blood transfusions and perioperative complications in total hip and knee arthroplasty. Individual predictor-adjusted risks can be used to define preoperative treatment thresholds. Methods: We performed this retrospective monocentric study in orthopaedic patients who underwent primary total knee or hip arthroplasty. Multivariate logistic regression models were used to assess the predictive value of patient-related characteristics. Predictor-adjusted individual risks of blood transfusions and the occurrence of any perioperative adverse event were calculated for potentially modifiable risk factors. Results: 3754 patients were included in this study. The overall blood transfusion and complication rates were 4.8\% and 6.4\%, respectively. Haemoglobin concentration (Hb, p < 0.001), low body mass index (BMI, p < 0.001) and estimated glomerular filtration rate (eGFR, p = 0.004) were the strongest potentially modifiable predictors of a blood transfusion. EGFR (p = 0.001) was the strongest potentially modifiable predictor of a complication. Predictor-adjusted risks of blood transfusions and acute postoperative complications were calculated for Hb and eGFR. Hb = 12.5 g/dL, BMI = 17.6 kg/m\(^2\), and eGFR = 54 min/mL were associated, respectively, with a 10\% risk of a blood transfusion, eGFR = 59 mL/min was associated with a 10\% risk of a complication. Conclusion: The individual risks for blood transfusions and acute postoperative complications are strongly increased in patients with a low preoperative Hb, low BMI or low eGFR. We recommend aiming at a preoperative Hb ≥ 13g/dL, an eGFR ≥ 60 mL/min and to avoid a low BMI. Future studies must show if a preoperative increase of eGFR and BMI is feasible and truly beneficial.}, language = {en} } @article{ReimannStopperHintzsche2020, author = {Reimann, Hauke and Stopper, Helga and Hintzsche, Henning}, title = {Long-term fate of etoposide-induced micronuclei and micronucleated cells in Hela-H2B-GFP cells}, series = {Archives of Toxicology}, volume = {94}, journal = {Archives of Toxicology}, issn = {0340-5761}, doi = {10.1007/s00204-020-02840-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235039}, pages = {3553-3561}, year = {2020}, abstract = {Micronuclei are small nuclear cellular structures containing whole chromosomes or chromosomal fragments. While there is a lot of information available about the origin and formation of micronuclei, less is known about the fate of micronuclei and micronucleated cells. Possible fates include extrusion, degradation, reincorporation and persistence. Live cell imaging was performed to quantitatively analyse the fates of micronuclei and micronucleated cells occurring in vitro. Imaging was conducted for up to 96 h in HeLa-H2B-GFP cells treated with 0.5, 1 and 2 µg/ml etoposide. While a minority of micronuclei was reincorporated into the main nucleus during mitosis, the majority of micronuclei persisted without any alterations. Degradation and extrusion were observed rarely or never. The presence of micronuclei affected the proliferation of the daughter cells and also had an influence on cell death rates. Mitotic errors were found to be clearly increased in micronucleus-containing cells. The results show that micronuclei and micronucleated cells can, although delayed in cell cycle, sustain for multiple divisions.}, language = {en} } @phdthesis{Grebe2022, author = {Grebe, S{\"o}ren}, title = {Diagnose der linksventrikul{\"a}ren Hypertrophie bei H{\"a}modialyse-PatientInnen anhand von Echokardiographie und EKG im Vergleich zum CMRI}, doi = {10.25972/OPUS-27211}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-272115}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {In der Gruppe der H{\"a}modialyse-PatientInnen besteht ein deutlich erh{\"o}htes Risiko an kardiovaskul{\"a}ren Ereignissen zu versterben. Korrespondierend hierzu weisen H{\"a}modia-lyse-PatientInnen eine erh{\"o}hte Pr{\"a}valenz an linksventrikul{\"a}rer Hypertrophie (LVH) auf. Diese gilt als starker unabh{\"a}ngiger Risikofaktor f{\"u}r kardiovaskul{\"a}re Mortalit{\"a}t. Auf-grund der prognostischen Aussagekraft dient die Bewertung des linksventrikul{\"a}ren Massenindex (LVMI) sowie die Diagnose einer LVH vor allem in prospektiven Studien als ein bedeutendes Werkzeug zur Beurteilung des kardiovaskul{\"a}ren Risikos. Die Be-stimmung der LVH kann anhand von bildgebenden Verfahren (u.a. Echokardiographie, CMRI) oder dem EKG erfolgen. Die CMRI-Messung wird gegenw{\"a}rtig als Goldstan-dard zur Messung der LVH betrachtet. Die 2D gef{\"u}hrte M-mode-Methode der Echokardiographie zur Bestimmung der LVM zeichnet sich durch seine einfache und schnelle Durchf{\"u}hrbarkeit aus und wird deshalb trotz pr{\"a}ziserer Messverfahren wie dem 3D-Verfahren sowie diverser Einschr{\"a}nkungen weiterhin von der American Society of Echocardiography (ASE) als Screening-Methode und zur Untersuchung großer PatientInnenpopulationen empfohlen. Die empfohlene ASE-Formel {\"u}bersch{\"a}tzt jedoch den LVMI nachweislich im Vergleich zum CMRI-Messverfahren. Die {\"U}bersch{\"a}tzung zeigte sich abh{\"a}ngig von der H{\"o}he des LVMI. Es wird vermutet, dass die zunehmende {\"U}bersch{\"a}tzung Folge der geometrischen Grundan-nahmen ist, welche den LV vereinfachend als Ellipsoid mit konstantem L/D-Verh{\"a}ltnis annimmt. Dieses Verh{\"a}ltnis scheint sich jedoch bei zunehmender Herzgr{\"o}ße zu ver{\"a}n-dern, was wiederum zu einer Fehleinsch{\"a}tzung des LVMI f{\"u}hrt. Die Teichholz (Th)-Formel korrigiert das L/D-Verh{\"a}ltnis mithilfe einer kurvilinearen Anpassung an den linksventrikul{\"a}ren Durchmesser und zeigte k{\"u}rzlich in einer PatientInnengruppe mit Aor-tenstenose die geringste Tendenz der {\"U}bersch{\"a}tzung bei PatientInnen mit LVH. In der vorliegenden Studie wurden die echokardiographischen Formeln - ASE und Th - mit dem CMRI-Messverfahren verglichen. Beide Formeln zeigten eine deutliche {\"U}bersch{\"a}t-zung des LVMI. Die Th-Formel demonstrierte jedoch neben einer besseren {\"U}berein-stimmung zum CMRI, eine insgesamt geringere {\"U}bersch{\"a}tzung des LVMI sowie eine sukzessive Abnahme der {\"U}bersch{\"a}tzung mit zunehmendem LVMI. Zusammenfassend kann festgehalten werden, dass die Th-Formel der ASE-Formel in Bezug auf die Be-rechnung des LVMI bei H{\"a}modialyse-PatientInnen insbesondere bei PatientInnen mit LVH {\"u}berlegen ist. Weitere Studien sind jedoch erforderlich, um die Th-Formel in gr{\"o}-ßeren H{\"a}modialyse-PatientInnen-Kohorten mit h{\"o}heren LVMI-Werten zu testen sowie um den prognostischen Wert der Th-Formel im Vergleich zur ASE-Formel zu ermitteln. Die klassischen EKG-Indices und -Scores zur Feststellung einer LVH wiesen, wie be-reits in anderen CMRI-Vergleichsstudien gezeigt, eine schlechte Sensitivit{\"a}t bei guter Spezifit{\"a}t auf. Aufgrund dessen verlor das EKG zunehmend an Bedeutung als Scree-ning-Untersuchung. In dieser Studie wurde der Versuch unternommen die Sensitivit{\"a}t durch zwei L{\"o}sungsans{\"a}tze zu verbessern, einerseits durch die Kombination verschiede-ner EKG-Kriterien und andrerseits durch eine Adjustierung der EKG-Kriterien an den mittels Bioimpedanz gemessenen Fettmassenanteil. Die Kombination verschiedener EKG-Kriterien erzielte eine deutlich erh{\"o}hte Sensitivit{\"a}t von >70 \%. Auch die Anpas-sung der EKG-Kriterien an den individuellen Fettmassenanteil k{\"o}nnte ein hilfreicher L{\"o}sungsansatz zur Verbesserung der Sensitivit{\"a}t bei Adipositas darstellen.}, subject = {Transthorakale Echokardiographie}, language = {de} } @phdthesis{Uebelacker2019, author = {Uebelacker, Lukas}, title = {In vitro-Exposition von Glycerin als Bestandteil des Shisha-Tabaks an humanen Nasenschleimhautzellen und Lymphozyten}, doi = {10.25972/OPUS-18444}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-184443}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Shisha-Tabak ben{\"o}tigt im Vergleich zur Zigarette h{\"o}here Konzentrationen des Feuchthaltemittels Glycerin. Seit Mai 2016 ist die bis dahin g{\"u}ltige Limitierung von Feuchthaltemitteln in Tabak auf 5 \% aufgehoben. Derzeit ist das toxikologische Profil des Glycerins jedoch noch nicht hinreichend erforscht. Ziel dieser Arbeit war es, Glycerin auf m{\"o}gliche zyto- und genotoxische Effekte zu untersuchen, um so das Gef{\"a}hrdungspotenzial durch Glycerin im Shisha-Tabak zu beurteilen und die tabakkontrollpolitische Situation in Deutschland zu diskutieren. Daf{\"u}r wurden Lymphozyten sowie Nasenschleimhautzellen von 10 Patienten f{\"u}r eine Stunde Glycerin (0,001 mol/l bis 6,0 mol/l) exponiert. Durch den Trypanblau-Ausschlusstest wurden die Zellen auf Zytotoxizit{\"a}t, mittels Einzelzellgelelektrophorese (Comet Assay) und Mikrokern-Test auf Genotoxizit{\"a}t untersucht. Im Trypanblau-Ausschlusstest traten bei Lymphozyten sowie nasalen Mukosazellen signifikante Vitalit{\"a}tsabf{\"a}lle ab Glycerin-Konzentrationen von 1,0 mol/l auf. Im Comet Assay konnten f{\"u}r beide Zellgruppen signifikante Unterschiede des Olive Tail Moments (OTM) ab 1,0 mol/l nachgewiesen werden. Beim Mikrokern-Test zeigten sich keine signifikanten Zunahmen der Mikrokern-Anzahl. Es konnten zyto- und genotoxische Effekte ab Konzentrationen von 1,0 mol/l nachgewiesen werden. Dies {\"u}berschreitet die reale Glycerin-Belastung im Hauptstromrauch der Shisha jedoch deutlich. Dennoch handelt es sich bei Genotoxizit{\"a}t um ein stochastisches Risiko. Ebenso sind toxische Effekte, beispielsweise durch Erhitzung, bereits bei geringeren Konzentrationen denkbar. F{\"u}r eine umfangreichere Beurteilung von Feuchthaltemitteln im Shisha-Tabak sind weitere Untersuchungen indiziert. Dar{\"u}ber hinaus besteht enormer Handlungsbedarf zur weiteren Einf{\"u}hrung tabakkontrollpolitischer Maßnahmen in Deutschland.}, subject = {Glycerin}, language = {de} } @phdthesis{Schweinfurth2019, author = {Schweinfurth, Philipp}, title = {Der Einfluss von bub1b und p53 auf den Zellzyklus sowie die Sensitivit{\"a}t gegen{\"u}ber Docetaxel - Untersuchungen am Mausmodell und an murinen embryonalen Fibroblasten}, doi = {10.25972/OPUS-18251}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-182511}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Chemotherapeutika, deren Wirkung am MSC von Zellen ansetzen, geh{\"o}ren zum Standardrepertoire der onkologischen Therapie in zahlreichen Malignomen. In der Uroonkologie hat insbesondere das Erstarken von Docetaxel-basierten Therapien im metastasierten Prostatakarzinom den Fokus erneut auf den MSC gerichtet. Diesbez{\"u}glich wurden aber sowohl sch{\"u}tzende, als auch tumortreibende Teilfunktionen des MSCs in verschiedenen Tumorentit{\"a}ten gezeigt und pleiotrope Effekte einzelner Gene des MSCs n{\"a}her untersucht. Die vorliegende Arbeit untersucht daher eine m{\"o}gliche Rolle von bub1b in der Tumorentstehung und in der Modulation der Ansprechbarkeit gegen{\"u}ber Docetaxel. Da die Heterozygotie im Gen bub1b in den existierenden Mausmodellen jedoch nur zu alters-assoziierten Tumorerkrankungen f{\"u}hrt, wurden in Rahmen dieser Arbeit bub1b heterozygote Tiere mit p53 defizienten Tieren verpaart. Eben diese Tiere wurden hinsichtlich ihres {\"U}berlebens sowie der Art der aufgetretenen Tumorentit{\"a}ten untersucht. Zus{\"a}tzlich wurden Proliferations- und Zellzyklusanalysen insbesondere unter Docetaxelstress an MEFs, die aus diesem Mausmodell gewonnen wurden, durchgef{\"u}hrt. In Sektionsstudien des Mausmodells wurde gezeigt, dass bei gleichzeitigem Vorliegen von Heterozygotie von bub1b und Homozygotie von p53 eine Verschiebung des Tumor- Ph{\"a}notyps der p53 defizienten Tiere (Sarkome und Lymphome) erfolgte. Tiere des Genotyps bub1b het / p53 hom wiesen einen signifikant geringeren Anteil von Sarkomen im Vergleich zu den Lymphomen auf. Zus{\"a}tzlich nahm bei den Lymphomen der Anteil von disseminierten Lymphomen gegen{\"u}ber den thymoidalen Lymphomen zu. Aus diesen Ergebnissen kann geschlossen werden, dass eine Heterozygotie f{\"u}r bub1b die Entwicklung bestimmter Tumorentit{\"a}ten (disseminierte Lymphome) beg{\"u}nstigt, w{\"a}hrend andere Tumorentit{\"a}ten (z.B. Sarkome) durch den Verlust eines bub1b Allels eher verhindert werden. Die molekularen Ursachen f{\"u}r diesen Befund sind zurzeit noch unklar. In einem zweiten Teil dieser Arbeit wurde unter Verwendung von Zellkulturen muriner embryonaler Fibroblasten (MEFs), die mittels des vorhandenen Mausmodells etabliert wurden, gezeigt, dass MEFs der Genotypen bub1b wt / p53 hom, wie auch bub1b het / p53 hom im Vergleich zur Kontrollgruppe normal proliferieren und einen weitgehend normalen Zellzyklus aufweisen. Die zytostatische Wirkung des „Spindelcheckpoint Aktivators" Docetaxel ist in MEFs mit einer Heterozygotie f{\"u}r bub1b reduziert, w{\"a}hrend MEFs der Genotypen bub1b wt / p53 hom, wie auch bub1b het / p53 hom sensitiver auf Docetaxel reagieren. Aus diesen Ergebnissen kann eine geringe Effektivit{\"a}t von Docetaxel als zytostatisches Therapeutikum in der Tumortherapie von bub1b heterozygoten Zellen abgeleitet werden. Bei gleichzeitigen Defekten im Gen p53 k{\"o}nnten sich bub1b heterozygote Zellen allerdings sensitiv gegen{\"u}ber einer Therapie verhalten. In MEFs aller drei Genotypen konnte zudem gezeigt werden, dass die Aktivierung des MSCs durch Docetaxel unvollst{\"a}ndig bzw. defekt ist. Dieser Defekt im MSC f{\"u}hrt, wie bereits erw{\"a}hnt, zu einem starken zytostatischen Effekt, aber auch zu einer signifikanten Steigerung der Anzahl und zur Persistenz von polyploiden Zellen in den Zellkulturen der MEFs mit dem Genotyp bub1b het / p53 hom. Aus diesen Ergebnissen kann geschlossen werden, dass eine Defizienz f{\"u}r p53 und eine Heterozygotie f{\"u}r bub1b einen additiven Effekt in der Entwicklung von polyploiden Zellen besitzen und somit die Entwicklung von Tumorvorstufen beg{\"u}nstigen. Ob diese Effekte auch in nativen Tumoren unter Docetaxel-Behandlung eine Rolle spielen und sich bub1b und p53 als m{\"o}gliche Pr{\"a}diktoren einer Docetaxel-Therapie im Menschen evaluieren lassen, m{\"u}ssten weiterf{\"u}hrende Analysen zeigen, die den Verlauf einer Tumortherapie mit Hilfe eines Spindelgiftes abbilden.}, subject = {Docetaxel}, language = {de} } @phdthesis{MendesPereira2019, author = {Mendes Pereira, Lenon}, title = {Morphological and Functional Ultrashort Echo Time (UTE) Magnetic Resonance Imaging of the Human Lung}, doi = {10.25972/OPUS-18317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-183176}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {In this thesis, a 3D Ultrashort echo time (3D-UTE) sequence was introduced in the Self-gated Non-Contrast-Enhanced Functional Lung Imaging (SENCEFUL) framework. The sequence was developed and implemented on a 3 Tesla MR scanner. The 3D-UTE technique consisted of a nonselective RF pulse followed by a koosh ball quasi-random sampling order of the k-space. Measurements in free-breathing and without contrast agent were performed in healthy subjects and a patient with lung cancer. A gating technique, using a combination of different coils with high signal correlation, was evaluated in-vivo and compared with a manual approach of coil selection. The gating signal offered an estimation of the breathing motion during measurement and was used as a reference to segment the acquired data into different breathing phases. Gradient delays and trajectory errors were corrected during post-processing using the Gradient Impulse Response Function. Iterative SENSE was then applied to determine the fully sampled data. In order to eliminate signal changes caused by motion, a 3D image registration was employed, and the results were compared to a 2D image registration method. Ventilation was assessed in 3D and regionally quantified by monitoring the signal changes in the lung parenchyma. Finally, image quality and quantitative ventilation values were compared to the standard 2D-SENCEFUL technique. 3D-UTE, combined with an automatic gating technique and SENCEFUL MRI, offered ventilation maps with high spatial resolution and SNR. Compared to the 2D method, UTE-SENCEFUL greatly improved the clinical quality of the structural images and the visualization of the lung parenchyma. Through-plane motion, partial volume effects and ventilation artifacts were also reduced with a three-dimensional method for image registration. UTE-SENCEFUL was also able to quantify regional ventilation and presented similar results to previous studies.}, subject = {Kernspintomografie}, language = {en} } @article{RueckerKeilFitzgeraldetal.2016, author = {R{\"u}cker, Viktoria and Keil, Ulrich and Fitzgerald, Anthony P and Malzahn, Uwe and Prugger, Christof and Ertl, Georg and Heuschmann, Peter U and Neuhauser, Hannelore}, title = {Predicting 10-Year Risk of Fatal Cardiovascular Disease in Germany: An Update Based on the SCORE-Deutschland Risk Charts}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {9}, doi = {10.1371/journal.pone.0162188}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166804}, pages = {e0162188}, year = {2016}, abstract = {Estimation of absolute risk of cardiovascular disease (CVD), preferably with population-specific risk charts, has become a cornerstone of CVD primary prevention. Regular recalibration of risk charts may be necessary due to decreasing CVD rates and CVD risk factor levels. The SCORE risk charts for fatal CVD risk assessment were first calibrated for Germany with 1998 risk factor level data and 1999 mortality statistics. We present an update of these risk charts based on the SCORE methodology including estimates of relative risks from SCORE, risk factor levels from the German Health Interview and Examination Survey for Adults 2008-11 (DEGS1) and official mortality statistics from 2012. Competing risks methods were applied and estimates were independently validated. Updated risk charts were calculated based on cholesterol, smoking, systolic blood pressure risk factor levels, sex and 5-year age-groups. The absolute 10-year risk estimates of fatal CVD were lower according to the updated risk charts compared to the first calibration for Germany. In a nationwide sample of 3062 adults aged 40-65 years free of major CVD from DEGS1, the mean 10-year risk of fatal CVD estimated by the updated charts was lower by 29\% and the estimated proportion of high risk people (10-year risk > = 5\%) by 50\% compared to the older risk charts. This recalibration shows a need for regular updates of risk charts according to changes in mortality and risk factor levels in order to sustain the identification of people with a high CVD risk.}, language = {en} } @phdthesis{Zugelder2019, author = {Zugelder, Laurens}, title = {Etablierung eines stabilen induzierbaren Multikassetten-Systems f{\"u}r shRNA-Knockdown-Konstrukte in Myelom Zelllinien und Anwendung zur Analyse des NFκB-Signalwegs}, doi = {10.25972/OPUS-18837}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188377}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Das Multiple Myelom muss trotz stetiger Fortschritte im Hinblick auf die verf{\"u}gbaren Therapieoptionen und die Krankheitsprognose weiterhin im Wesentlichen als eine unheilbare Erkrankung angesehen werden. Dies kann vor allem auf die große inter- und intraindividuelle Heterogenit{\"a}t des MM zur{\"u}ckgef{\"u}hrt werden, welche die Entwicklung gezielter molekularer Therapiestrategien erheblich erschwert. Hierbei stellen loss-of-function- Experimente, welche die Identifikation einzelner oder mehrerer potenziell therapeutisch relevanter Zielstrukturen durch die (kombinierte) Depletion von Proteinen erm{\"o}glichen, eine wichtige S{\"a}ule dar, f{\"u}r deren Durchf{\"u}hrung verschiedene Systeme mit jeweils eigenen Vor- und Nachteilen zur Verf{\"u}gung stehen. Im Rahmen dieser Arbeit konnte die Etablierung eines auf RNA-Interferenz basierenden stabilen und induzierbaren Knockdownsystems durch Elektroporation von MM Zelllinien mit Einzel- und Mehrfach-shRNA-Vektoren abgeschlossen werden. Die Transfektion von tet-Repressor-exprimierenden Zellinien mit einer oder mehreren shRNAExpressionskassetten innerhalb eines Plasmidvektors erm{\"o}glicht durch die vollst{\"a}ndige Repression der shRNA-Transkription im nicht-induzierten Zustand die Selektion erfolgreich transponierter Zellen ohne Effekt-vermittelte Bias und die Generierung großer Zellmengen f{\"u}r Versuchsreihen in vergleichsweise kurzer Zeit. Die Induktion der verschiedenen in dieser Arbeit evaluierten Einzel- und Mehrfach-shRNA-Konstrukte gegen (Kombinationen von) Zielstrukturen im Ras/MAPK- sowie im NFκB-Signalsystem mittels Doxyzyklin als Induktionsagens zeigte durchweg deutliche und den Erwartungen aus transienten Experimenten entsprechende Knockdownergebnisse. Auch die Resultate hinsichtlich funktioneller Readouts und zellphysiologischer Effekte der induzierten Knockouts stehen im Einklang mit vorangegangenen Experimenten und best{\"a}tigen somit die {\"A}quivalenz des stabilen induzierbaren Systems zu transienten Ans{\"a}tzen auf RNAi-Basis oder zu pharmakologischen Inhibitoren. Der hierbei erzielte hypomorphe Ph{\"a}notyp innerhalb einer polyklonalen Zellpopulation bildet die Realit{\"a}t einer medikament{\"o}sen Blockade einer oder weniger Zielstrukturen einer heterogenen MM Tumorpopulation n{\"a}herungsweise ab, weshalb das vorgestellte System ein hilfreiches, kosteneffizientes und leicht zu handhabendes Werkzeug f{\"u}r die Identifikation potenziell relevanter Zielstrukturen f{\"u}r molekulare Therapieans{\"a}tze im Multiplen Myelom darstellt}, subject = {Plasmozytom}, language = {de} } @article{HaringCrandallCarboneetal.2019, author = {Haring, Bernhard and Crandall, Carolyn J and Carbone, Laura and Liu, Simin and Li, Wenjun and Johnson, Karen C and Wactawski-Wende, Jean and Shadyab, Aladdin H and Gass, Margery L and Kamensky, Victor and Cauley, Jane A and Wassertheil-Smoller, Sylvia}, title = {Lipoprotein(a) plasma levels, bone mineral density and risk of hip fracture: a post hoc analysis of the Women's Health Initiative, USA}, series = {BMJ Open}, volume = {9}, journal = {BMJ Open}, doi = {10.1136/bmjopen-2018-027257}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201139}, pages = {e027257}, year = {2019}, abstract = {Objectives Elevated Lipoprotein(a) (Lp[a]) is a well-known risk factor for cardiovascular disease. However, its roles in bone metabolism and fracture risk are unclear. We therefore investigated whether plasma Lp(a) levels were associated with bone mineral density (BMD) and incident hip fractures in a large cohort of postmenopausal women. Design Post hoc analysis of data from the Women's Health Initiative (WHI), USA. Setting 40 clinical centres in the USA. Participants The current analytical cohort consisted of 9698 white, postmenopausal women enrolled in the WHI, a national prospective study investigating determinants of chronic diseases including heart disease, breast and colorectal cancers and osteoporotic fractures among postmenopausal women. Recruitment for WHI took place from 1 October 1993 to 31 December 1998. Exposures Plasma Lp(a) levels were measured at baseline. Outcome measures Incident hip fractures were ascertained annually and confirmed by medical records with follow-up through 29 August 2014. BMD at the femoral neck was measured by dual X-ray absorptiometry in a subset of participants at baseline. Statistical analyses Cox proportional hazards and logistic regression models were used to evaluate associations of quartiles of plasma Lp(a) levels with hip fracture events and hip BMD T-score, respectively. Results During a mean follow-up of 13.8 years, 454 incident cases of hip fracture were observed. In analyses adjusting for confounding variables including age, body mass index, history of hysterectomy, smoking, physical activity, diabetes mellitus, general health status, cardiovascular disease, use of menopausal hormone therapy, use of bisphosphonates, calcitonin or selective-oestrogen receptor modulators, baseline dietary and supplemental calcium and vitamin D intake and history of fracture, no significant association of plasma Lp(a) levels with low hip BMD T-score or hip fracture risk was detected. Conclusions These findings suggest that plasma Lp(a) levels are not related to hip BMD T-score or hip fracture events in postmenopausal women.}, language = {en} } @article{ElhfnawyHeuschmannPhametal.2019, author = {Elhfnawy, Ahmed Mohamed and Heuschmann, Peter U. and Pham, Mirko and Volkmann, Jens and Fluri, Felix}, title = {Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {317}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196225}, year = {2019}, abstract = {Background and Purpose: Internal carotid artery stenosis (ICAS)≥70\% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70\% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70\% (Spearman correlation coefficient ρ = -0.57, p < 0.001, n = 51) but neither for sICAS<70\% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70\% and ≥70\% was 17 (15-20) and 15 (12-19) mm (p = 0.06), respectively, while that for sICAS<90\% and sICAS 90\% was 18 (15-21) and 13 (10-16) mm, respectively (p < 0.001). Among patients with ICAS <70\%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1\% and 51.1\%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6\%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70\% to be longer than that of sICAS≥70\%. Moreover, the ultrasound-measured length of sICAS<90\% was significantly longer than that of sICAS 90\%. Among patients with sICAS≥70\%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results.}, language = {en} } @article{RoelligKramerGabrechtetal.2018, author = {R{\"o}llig, C. and Kramer, M. and Gabrecht, M. and H{\"a}nel, M. and Herbst, R. and Kaiser, U. and Schmitz, N. and Kullmer, J. and Fetscher, S. and Link, H. and Mantovani-L{\"o}ffler, L. and Kr{\"u}mpelmann, U. and Neuhaus, T. and Heits, F. and Einsele, H. and Ritter, B. and Bornh{\"a}user, M. and Schetelig, J. and Thiede, C. and Mohr, B. and Schaich, M. and Platzbecker, U. and Sch{\"a}fer-Eckart, K. and Kr{\"a}mer, A. and Berdel, W. E. and Serve, H. and Ehninger, G. and Schuler, U. S.}, title = {Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients}, series = {Annals of Oncology}, volume = {29}, journal = {Annals of Oncology}, number = {4}, doi = {doi:10.1093/annonc/mdy030}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226473}, pages = {973-978}, year = {2018}, abstract = {Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7+3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA). Patients and methods: Patients with newly diagnosed AML>60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m(2) twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m(2) days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m(2) continuously days 1-7) plus daunorubicin (45 mg/m(2) days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76\% of patients were >65 years. The complete response rate after DA was 39\% [95\% confidence interval (95\% CI): 33-45] versus 55\% (95\% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14\% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29\% versus 14\% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513). Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.}, language = {en} } @phdthesis{Gomes2019, author = {Gomes, Sara Ferreira Martins}, title = {Induced Pluripotent Stem Cell-derived Brain Endothelial Cells as a Cellular Model to Study Neisseria meningitidis Infection}, doi = {10.25972/OPUS-18855}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188550}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Bacterial meningitis occurs when blood-borne bacteria are able to penetrate highly specialized brain endothelial cells (BECs) and gain access to the meninges. Neisseria meningitidis (Nm) is a human-exclusive pathogen for which suitable in vitro models are severely lacking. Until recently, modeling BEC-Nm interactions has been almost exclusively limited to immortalized human cells that lack proper BEC phenotypes. Specifically, these in vitro models lack barrier properties, and continuous tight junctions. Alternatively, humanized mice have been used, but these must rely on known interactions and have limited translatability. This motivates the need to establish novel human-based in vitro BEC models that have barrier phenotypes to research Nm-BEC interactions. Recently, a human induced pluripotent stem cell (iPSC) model of BECs has been developed that possesses superior BEC phenotypes and closely mimics the in vivo blood vessels present at the blood-meningeal barrier. Here, iPSC-BECs were tested as a novel cellular model to study Nm-host pathogen interactions, with focus on host responses to Nm infection. Two wild type strains and three mutant strains of Nm were used to confirm that these followed similar phenotypes to previously described models. Importantly, the recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, at distinct time points of infection, and the secretion of IFN γ and RANTES by iPSC-BECs. Nm was directly observed to disrupt tight junction proteins ZO-1, Occludin, and Claudin-5 at late time points of infection, which became frayed and/or discontinuous upon infection. This destruction is preceded by, and might be dependent on, SNAI1 activation (a transcriptional repressor of tight junction proteins). In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability was observed at late infection time points. Notably, bacterial transmigration correlated with junctional disruption, indicating that the paracellular route contributes for bacterial crossing of BECs. Finally, RNA-Sequencing (RNA-Seq) of sorted, infected iPSC-BECs was established through the use of fluorescence-activated cell sorting (FACS) techniques following infection. This allowed the detection of expression data of Nm-responsive host genes not previously described thus far to play a role during meningitidis. In conclusion, here the utility of iPSC-BECs in vitro to study Nm infection could be demonstrated. This is the first BEC in vitro model to express all major BEC tight junctions and to display high barrier potential. Altogether, here this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes and suggests that the paracellular route contributes to Nm traversal of BECs.}, subject = {Neisseria meningitidis}, language = {en} } @article{AsthanaBrunhuberMuehlbergeretal.2016, author = {Asthana, Manish Kumar and Brunhuber, Bettina and M{\"u}hlberger, Andreas and Reif, Andreas and Schneider, Simone and Herrmann, Martin J.}, title = {Preventing the Return of Fear Using Reconsolidation Update Mechanisms Depends on the Met-Allele of the Brain Derived Neurotrophic Factor Val66Met Polymorphism}, series = {International Journal of Neuropsychopharmacology}, volume = {19}, journal = {International Journal of Neuropsychopharmacology}, number = {6}, doi = {10.1093/ijnp/pyv137}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166217}, year = {2016}, abstract = {Background: Memory reconsolidation is the direct effect of memory reactivation followed by stabilization of newly synthesized proteins. It has been well proven that neural encoding of both newly and reactivated memories requires synaptic plasticity. Brain derived neurotrophic factor (BDNF) has been extensively investigated regarding its role in the formation of synaptic plasticity and in the alteration of fear memories. However, its role in fear reconsolidation is still unclear; hence, the current study has been designed to investigate the role of the BDNF val66met polymorphism (rs6265) in fear memory reconsolidation in humans. Methods: An auditory fear-conditioning paradigm was conducted, which comprised of three stages (acquisition, reactivation, and spontaneous recovery). One day after fear acquisition, the experimental group underwent reactivation of fear memory followed by the extinction training (reminder group), whereas the control group (non-reminder group) underwent only extinction training. On day 3, both groups were subjected to spontaneous recovery of earlier learned fearful memories. The treat-elicited defensive response due to conditioned threat was measured by assessing the skin conductance response to the conditioned stimulus. All participants were genotyped for rs6265. Results: The results indicate a diminishing effect of reminder on the persistence of fear memory only in the Met-allele carriers, suggesting a moderating effect of the BDNF polymorphism in fear memory reconsolidation. Conclusions: Our findings suggest a new role for BDNF gene variation in fear memory reconsolidation in humans.}, language = {en} } @article{HeitmannFringsGeieretal.2021, author = {Heitmann, Johanna and Frings, Verena G. and Geier, Andreas and Goebeler, Matthias and Kerstan, Andreas}, title = {Non-alcoholic fatty liver disease and psoriasis - is there a shared proinflammatory network?}, series = {Journal der Deutschen Dermatologischen Gesellschaft}, volume = {19}, journal = {Journal der Deutschen Dermatologischen Gesellschaft}, number = {4}, doi = {10.1111/ddg.14425}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258424}, pages = {517-528}, year = {2021}, abstract = {Psoriasis is an immune-mediated systemic inflammatory disease that is not limited to the skin but may be associated with arthritis, cardiovascular diseases, metabolic syndrome including diabetes and obesity and, as identified more recently, non-alcoholic fatty liver disease (NAFLD) that occurs in approximately 50 \% of all patients with psoriasis. NAFLD is characterized by accumulation of fat in hepatocytes in the absence of excessive alcohol consumption. Over the last two decades, NAFLD has developed to the most common chronic liver disease with an estimated prevalence of 25 \% in the Western population. NAFLD ranges from non-inflammatory or bland hepatic steatosis to inflammation of hepatic tissue (non-alcoholic steatohepatitis, NASH) and consecutive liver fibrosis. It is controversial whether the underlying systemic inflammation of psoriasis is contributing to development of NAFLD or if comorbid diseases such as obesity enhance NAFLD development. Recent findings indicate that cytokine-mediated inflammation through TNFα, interleukin (IL)-6 and IL-17 might be the common link between psoriasis and NAFLD. Considering the shared inflammatory pathways, IL-17 pharmacological blockade, which is already well-established for psoriasis, may be a promising strategy to treat both psoriasis and NAFLD. Therefore, early detection of NAFLD and a better understanding of its pathophysiology in the context of the systemic inflammation in psoriasis is important with regard to individualized treatment approaches.}, language = {en} } @article{IckrathStoevesandtSchulmeyeretal.2021, author = {Ickrath, Franziska and Stoevesandt, Johanna and Schulmeyer, Lena and Glatzel, Caroline and Goebeler, Matthias and Kerstan, Andreas}, title = {Metastatic Crohn's disease: an underestimated entity}, series = {Journal of the German Society of Dermatology}, volume = {19}, journal = {Journal of the German Society of Dermatology}, number = {7}, doi = {10.1111/ddg.14447}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258435}, pages = {973-982}, year = {2021}, abstract = {Cutaneous metastatic Crohn's disease (MCD) is a rare but challenging dermatologic manifestation of Crohn's disease. It is histologically defined as the presence of non-caseating granulomas at skin sites separated from and non-contiguous to the gastrointestinal tract. Cutaneous metastatic Crohn's disease should be distinguished from the much more frequent contiguous cutaneous manifestations of Crohn's disease that present at perianal or, less common, peristomal sites with direct extension from the intestine to the adjacent skin. Versatile clinical presentation and the fact that occurrence can predate the initial diagnosis of Crohn's disease may lead to misdiagnosis, delayed treatment and underreporting. As case numbers are small and randomized controlled studies on management are lacking, the therapeutic approach remains challenging and is often unsatisfactory. We here performed a systematic literature search identifying 264 published pediatric and adult cases of MCD and additionally report three of our own cases. Our review summarizes clinical characteristics, putative etiopathology, histologic findings, differential diagnoses and treatment options for MCD.}, language = {en} } @phdthesis{Wimmer2019, author = {Wimmer, Katharina}, title = {Analyse der Osteoklastendifferenzierung auf elektrochemisch abgeschiedenen strontiumdotierten Struvitschichten}, doi = {10.25972/OPUS-19141}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191417}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Bei der Implantatversorgung von Patienten mit Osteoporose besteht weiterhin eine hohe Komplikationsrate vor allem durch aseptische Prothesenlockerungen. Eine vielversprechende M{\"o}glichkeit diese zu minimieren stellt eine Funktionalisierung der Implantate mit Strontium dar. Ziel der vorliegenden Arbeit war es dabei die Wirkung lokal verf{\"u}gbaren Strontiums auf osteoklast{\"a}re und osteoblast{\"a}re Zellen zu untersuchen. Mittels elektrochemischer Abscheidung erfolgte die Beschichtung von Titanproben mit strontiumdotiertem Struvit, wobei sieben verschiedene Dotierkonzentrationen zwischen 6 µg und 487 µg Strontium pro Probe hergestellt wurden. Die Untersuchungen an osteoklast{\"a}ren RAW 264.7 Zellen erfolgten mittels Bestimmung von Zellzahl und -aktivit{\"a}t, verschiedener mikroskopischer Methoden sowie auf genetischer Ebene. Osteoblast{\"a}re MG63-Zellen wurden orientierend anhand von Zellzahl und Zellaktivit{\"a}t untersucht. Zellbiologisch konnte ein hemmender Einfluss von Strontium auf Differenzierung sowie Proliferation und Aktivit{\"a}t osteoklast{\"a}rer Zellen gezeigt werden. Die Dotierkonzentration mit den g{\"u}nstigsten Eigenschaften war unter vorliegenden Versuchsbedingungen 487 µg Strontium pro Probe, da sich hierbei zudem eine erhaltene ostoblast{\"a}re Proliferation und Aktivit{\"a}t zeigte.}, subject = {Osteoblast}, language = {de} } @phdthesis{Huflage2022, author = {Huflage, Henner}, title = {Die stereotaktische Bestrahlung von Lungenmetastasen am Universit{\"a}tsklinikum W{\"u}rzburg im Zeitraum von November 1997 bis September 2012}, doi = {10.25972/OPUS-25762}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257620}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die vorliegende Arbeit untersucht die stereotaktische Bestrahlung von Lungenmetastasen am Universit{\"a}tsklinikum W{\"u}rzburg im Zeitraum von 1997 bis 2012. In diesem Zeitraum wurden am Institut f{\"u}r Strahlentherapie der Universit{\"a}tsklinik W{\"u}rzburg 102 Patienten bestrahlt. Es sollen Einflussfaktoren auf die wesentlichen Endpunkte lokale Kontrolle, systemische Kontrolle und das {\"U}berleben identifiziert werden. Die Arbeit zeigt, dass die stereotaktische Bestrahlung eine nebenwirkungsarme und effektive Therapie von Lungenmetastasen darstellt und soll einen Beitrag dazu leisten, die Einfl{\"u}sse und Ergebnisse der stereotaktischen Bestrahlung zu objektivieren und zus{\"a}tzliches Datenmaterial f{\"u}r zuk{\"u}nftige Studien liefern. Das untersuchte Kollektiv der Universit{\"a}tsklinik W{\"u}rzburg geh{\"o}rt zum Zeitpunkt der Studie zu den gr{\"o}ßten in den auf diesem Gebiet durchgef{\"u}hrten Single-Center-Studien.}, subject = {Strahlentherapie}, language = {de} } @article{AlmadeJongJelusicetal.2016, author = {Alma, Harma and de Jong, Corina and Jelusic, Danijel and Wittmann, Michael and Schuler, Michael and Flokstra-de Blok, Bertine and Kocks, Janwillem and Schultz, Konrad and van der Molen, Thys}, title = {Health status instruments for patients with COPD in pulmonary rehabilitation: defining a minimal clinically important difference}, series = {npj Primary Care Respiration Medicine}, volume = {26}, journal = {npj Primary Care Respiration Medicine}, number = {16041}, doi = {10.1038/npjpcrm.2016.41}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166327}, year = {2016}, abstract = {The minimal clinically important difference (MCID) defines to what extent change on a health status instrument is clinically relevant, which aids scientists and physicians in measuring therapy effects. This is the first study that aimed to establish the MCID of the Clinical chronic obstructive pulmonary disease (COPD) Questionnaire (CCQ), the COPD Assessment Test (CAT) and the St George's Respiratory Questionnaire (SGRQ) in the same pulmonary rehabilitation population using multiple approaches. In total, 451 COPD patients participated in a 3-week Pulmonary Rehabilitation (PR) programme (58 years, 65\% male, 43 pack-years, GOLD stage II/III/IV 50/39/11\%). Techniques used to assess the MCID were anchor-based approaches, including patient-referencing, criterion-referencing and questionnaire-referencing, and the distribution-based methods standard error of measurement (SEM), 1.96SEM and half standard deviation (0.5s.d.). Patient- and criterion-referencing led to MCID estimates of 0.56 and 0.62 (CCQ); 3.12 and 2.96 (CAT); and 8.40 and 9.28 (SGRQ). Questionnaire-referencing suggested MCID ranges of 0.28-0.61 (CCQ), 1.46-3.08 (CAT) and 6.86-9.47 (SGRQ). The SEM, 1.96SEM and 0.5s.d. were 0.29, 0.56 and 0.46 (CCQ); 3.28, 6.43 and 2.80 (CAT); 5.20, 10.19 and 6.06 (SGRQ). Pooled estimates were 0.52 (CCQ), 3.29 (CAT) and 7.91 (SGRQ) for improvement. MCID estimates differed depending on the method used. Pooled estimates suggest clinically relevant improvements needing to exceed 0.40 on the CCQ, 3.00 on the CAT and 7.00 on the SGRQ for moderate to very severe COPD patients. The MCIDs of the CAT and SGRQ in the literature might be too low, leading to overestimation of treatment effects for patients with COPD.}, language = {en} } @phdthesis{Graz2020, author = {Graz, Alina}, title = {Hildegard von Bingens 'Physica'. Untersuchungen zu den mutmaßlichen Quellen am Beispiel der Heilanwendungen exotischer und ausgew{\"a}hlter heimischer Gew{\"u}rzpflanzen.}, doi = {10.25972/OPUS-19948}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199480}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Ziel der Arbeit war es die Quellenlage Hildegard von Bingens ‚Physica' zu beleuchten. Dazu werden die Kapitel der exotischen Gew{\"u}rze (Kap. I,13-21 und I,26-27), der Duftpflanzen (Kap. I,22-25), und der heimischen Gew{\"u}rze (Kap. I,63-70) mit den entsprechenden Kapiteln aus ‚Macer floridus' (Odo Magdunensis), ‚Circa instans' (Matthaeus Platearius), ‚Liber graduum' (Constantinus Africanus), ‚Naturalis historia' (Plinius der {\"A}ltere) und ‚Materia medica' (Pedanius Dioskurides) verglichen. Es konnten verschiedenartige Bez{\"u}ge zur Tradition hergestellt werden, jedoch ist hervorzuheben, dass Hildegard dennoch in den Anwendungen eine ausgepr{\"a}gte Originalit{\"a}t aufweist.}, subject = {Hildegard, von Bingen, Heilige}, language = {de} } @phdthesis{Lawrenz2020, author = {Lawrenz, Ingulf}, title = {Die moderat hypofraktionierte Bestrahlung des lokalisierten Prostatakarzinoms : Ergebnisse f{\"u}r das tumorspezifische und klinische Outcome nach moderater Hypofraktionerung in intensit{\"a}tsmodulierter Technik}, doi = {10.25972/OPUS-19960}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199605}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die m{\"a}ßig hypofraktionierte Strahlentherapie des lokalisierten Prostatakarzinoms Wir haben retrospektiv die ersten 150 konsekutiven Patienten analysiert, die mit einer prim{\"a}ren Strahlentherapie in IMRT bei lokalisiertem Prostatakrebs behandelt wurden. Alle Patienten hatten ein histologisch gesichertes Prostatakarzinom und wurden von Urologen zur kurativen Bestrahlung {\"u}berwiesen. Nach der CT-basierter Planung wurden alle Patienten mit einer intensit{\"a}tsmodulierten Strahlenthera (IMRT) unter Verwendung der SIB-Technik (Simultan Integrierter Boost) behandelt. Die applizierten Dosen betrugen 74 Gy (n = 41) und 76,2 Gy (n = 109) in 32 und 33 Fraktionen. Die Behandlung von Beckenlymphknoten (46 Gy) wurde bei 41 Hochrisikopatienten durchgef{\"u}hrt. Die Behandlung wurde unter Verwendung einer integrierten Cone-Beam-CT (IGRT) durchgef{\"u}hrt. Die Toxizit{\"a}t wurde mit CTCAE 3.0 bewertet. Das biochemische Rezidiv wurde gem{\"a}ß der Phoenix-Definition von Nadir + 2 ng / ml definiert. Wir analysierten die gastrointestinale Toxizit{\"a}t (GI), die urogenitale Toxizit{\"a}t (GU) und das Freedom From Biochemichal Failure (FFBF). Ergebnisse: Das mediane Follow-Up der Patienten betrug 50 Monate. Mehr als 80\% der Patienten waren w{\"a}hrend der Nachbeobachtung frei von gastrointestinaler Toxizit{\"a}t. Es gab keinen Trend zu erh{\"o}hten GI-Toxizit{\"a}tsraten im zeitlichen Verlauf. Bei 85\% unserer Patienten wurde innerhalb von 6 Wochen nach der Behandlung eine akute Urogenitaltoxizit{\"a}t vom Grad 1-2 beobachtet. Die meisten Patienten erholten sich von einer akuten GU-Toxizit{\"a}t. Es gab einen kontinuierlichen Anstieg des GU-Toxizit{\"a}tsgrades ≥2 mit <10\% nach 6 bis 12 Monaten auf 22,4\% nach 60 Monaten. Die GU-Toxizit{\"a}t 3. Grades lag w{\"a}hrend der Nachuntersuchung unter 5\%. FFBF betrug 82\% f{\"u}r alle Patienten. Nach Risikogruppen betrug FFBF 88\%, 80\% und 78\% f{\"u}r das niedrige, mittlere und hohe Risiko. Schlussfolgerung: Nach moderat hypofraktionierter Strahlentherapie des Prostatakarzinoms beobachteten wir niedrige GI-Toxizit{\"a}tsraten sowie ein g{\"u}nstiges FFBF. Die GU-Toxizit{\"a}tsraten lagen innerhalb der international berichteten Ergebnisse bei gleichwertiger Behandlung. Die konformale IMRT-Planung und die genaue IGRT haben m{\"o}glicherweise zu diesen Ergebnissen beigetragen.}, subject = {Prostatakrebs}, language = {de} } @phdthesis{Reuter2020, author = {Reuter, Isabel}, title = {Development and function of monoaminergic systems in the brain of zebrafish}, doi = {10.25972/OPUS-20408}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204089}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {This thesis explores the development of monoaminergic systems in the central nervous system (CNS) of zebrafish. The serotonergic cells of the hypothalamus pose the main focus of the present work. Most vertebrates except for mammals possess serotonin (5-HT) synthesising cells in more than one region of the CNS. In zebrafish such regions are, e.g. the hypothalamus, the raphe nuclei and the spinal cord. Serotonin functions as a neurotransmitter and neuromodulator in the CNS. Presumably due to its neuromodulatory tasks hypothalamic serotonergic cells are in contact with the cerebrospinal fluid (CSF), which expands the field of potential serotonergic targets tremendously. This highlights that serotonergic CSF-contacting (CSF-c) cells are vital for the execution of many functions and behaviours. Further, the hypothalamic serotonergic clusters constitute the largest population of serotonergic cells in the CNS of zebrafish. Together, these facts emphasise the need to understand the development and function of serotonergic CSF-c cells in the hypothalamus. Few studies have dealt with this subject, hence, information about the development of these cells is scarce. The zinc-finger transcription factor fezf2, and Fibroblast growth factor (Fgf)-signalling via the ETS-domain transcription factor etv5b are known to regulate serotonergic cell development in the hypothalamus (Bosco et al., 2013; Rink and Guo, 2004). However, the main Fgf ligand responsible for this mediation has not been determined prior to this work. The present thesis identifies Fgf3 as a crucial Fgf ligand. To achieve this result three independent strategies to impair Fgf3 activity have been applied to zebrafish embryos: the fgf3t24152 mutant, an fgf3 morpholino-based knock-down and the CRISPR/Cas9 technique. The investigations show that Fgf3 regulates the development of monoaminergic CSF-c cells in the hypothalamus. Additionally, Fgf3 impacts on cells expressing the peptide hormone arginine vasopressin (avp). Most interestingly, the requirement for Fgf3 by these cells follows a caudo-rostral gradient with a higher dependence on Fgf3 by caudal cells. This also seems to be the case for dopaminergic CSF-c cells in the hypothalamus (Koch et al., 2014). Moreover, etv5b a downstream target of Fgf-signalling is demonstrated to be under the control of Fgf3. With regard to serotonergic CSF-c cell development, it is shown that fgf3 is expressed several hours before tph1a and 5-HT (Bellipanni et al., 2002; Bosco et al., 2013). Together with the result that the hypothalamus is already smaller before mature serotonergic CSF-c cells appear, this argues for an early impact of Fgf3 on serotonergic specification. This hypothesis is supported by several findings in this study: the universal decrease of proliferating cells in the hypothalamus and simultaneous increase of cell death after fgf3 impairment. Complementary cell fate experiments confirm that proliferating serotonergic progenitors need Fgf3 to commit serotonergic specification. Further, these results corroborate findings of an earlier study stating that hypothalamic serotonergic progenitors require Fgf-signalling via etv5b to maintain the progenitor pool (Bosco et al., 2013). Additionally, the transcriptome of the hypothalamus has been analysed and 13 previously overlooked transcripts of Fgf ligands are expressed at developmental stages. The transcriptome analysis provides evidence for a self-compensatory mechanism of fgf3 since expression of fgf3 is upregulated as a consequence of its own impairment. Moreover, the Fgf-signalling pathway appears to be mildly affected by fgf3 manipulation. Together, Fgf-signalling and especially Fgf3 are established to be of critical importance during hypothalamic development with effects on serotonergic, dopaminergic CSF-c and avp expressing cells. Furthermore, this thesis provides two strategies to impair the tph1a gene. Both strategies will facilitate investigations regarding the function of hypothalamic serotonergic CSF-c cells. Finally, the presented findings in this study provide insights into the emergence of the posterior recess region of the hypothalamus, thereby, contributing to the understanding of the evolution of the vertebrate hypothalamus.}, subject = {Hypothalamus}, language = {en} } @phdthesis{Lanvers2020, author = {Lanvers, Elena}, title = {Adh{\"a}renz bei oraler Capecitabin-Therapie. Zusammenh{\"a}nge mit komorbider Depression.}, doi = {10.25972/OPUS-20532}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205324}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die zentralen Fragen dieser Arbeit beziehen sich auf die Adh{\"a}renz bei Patienten, die das orale Chemotherapeutikum Capecitabin einnehmen, sowie den Zusammenhang zu psychischer Belastung.}, language = {de} } @phdthesis{FernandezGonzalez2020, author = {Fern{\´a}ndez Gonz{\´a}lez, Robin}, title = {Einfluss von verschieden strukturierten 3D-Poly(2-oxazolin) Scaffolds auf die Proteinexpression humaner Makrophagen}, doi = {10.25972/OPUS-20592}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205922}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {In vorliegender Dissertationsarbeit wurde der Einfluss von MEW-gedruckten Scaffolds aus dem synthetischen Polymer PnPrOx, einem Poly(2-oxazolin), mit verschiedenen Oberfl{\"a}chenstrukturen (fibrill{\"a}r, glatt) auf die Proteinexpression menschlicher Makrophagen untersucht. Dabei wurde {\"u}berpr{\"u}ft, inwiefern die Beschaffenheit der Oberfl{\"a}chenstruktur des Polymers die Polarisierung von Makrophagen auf Proteinebene beeinflusst.}, subject = {Scaffold}, language = {de} }