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Institute
- Theodor-Boveri-Institut für Biowissenschaften (51)
- Fakultät für Physik und Astronomie (38)
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- Institut für Virologie und Immunbiologie (12)
- Kinderklinik und Poliklinik (10)
- Klinik und Poliklinik für Strahlentherapie (10)
Sonstige beteiligte Institutionen
Background: Diabetes is a risk factor for (micro) vascular damage of the brain, too. Therefore cognitive performance after coronary artery bypass grafting may be hypothesized worse in diabetics. To avoid observational errors a reliable tool for testing attentional performance was used. We evaluated whether diabetes mellitus disposes to distinct cognitive dysfunction after coronary artery bypass grafting (CABG). Methods: Three aspects in attentional performance were prospectively tested with three different tests (alertness: composed of un-cued and cued reaction, divided attention, and selective attention) by a computerized tool one day before and seven days after CABG in a highly selected cohort of 30 males, 10 of whom had diabetes. Statistical comparisons were done with analysis of variance for repeated measurements and Fisher´s LSD. Results: Prior to CABG there was no statistically meaningful difference between diabetics and non-diabetics. Postoperatively, diabetic patients performed significantly worse than non-diabetics in tests for un-cued (p=0.01) and cued alertness (p=0.03). Test performance in divided attention was worse after CABG but independent of diabetes status. Selective attention was neither affected by diabetes status nor by CABG itself. Conclusions: Diabetes may have an impact on cognitive performance after CABG. More severe deficits in alertness may point to underlying microvascular disease.
We examined whether movement costs as defined by movement magnitude have an impact on distance perception in near space. In Experiment 1, participants were given a numerical cue regarding the amplitude of a hand movement to be carried out. Before the movement execution, the length of a visual distance had to be judged. These visual distances were judged to be larger, the larger the amplitude of the concurrently prepared hand movement was. In Experiment 2, in which numerical cues were merely memorized without concurrent movement planning, this general increase of distance with cue size was not observed. The results of these experiments indicate that visual perception of near space is specifically affected by the costs of planned hand movements.
Background: In higher plants, a diverse array of developmental and growth-related processes is regulated by the plant hormone auxin. Recent publications have proposed that besides the well-characterized Auxin Response Factors (ARFs) that bind Auxin Response Elements (AuxREs), also members of the bZIP- and MYB-transcription factor (TF) families participate in transcriptional control of auxin-regulated genes via bZIP Response Elements (ZREs) or Myb Response Elements (MREs), respectively. Results: Applying a novel bioinformatic algorithm, we demonstrate on a genome-wide scale that singular motifs or composite modules of AuxREs, ZREs, MREs but also of MYC2 related elements are significantly enriched in promoters of auxin-inducible genes. Despite considerable, species-specific differences in the genome structure in terms of the GC content, this enrichment is generally conserved in dicot (Arabidopsis thaliana) and monocot (Oryza sativa) model plants. Moreover, an enrichment of defined composite modules has been observed in selected auxin-related gene families. Consistently, a bipartite module, which encompasses a bZIP-associated G-box Related Element (GRE) and an AuxRE motif, has been found to be highly enriched. Making use of transient reporter studies in protoplasts, these findings were experimentally confirmed, demonstrating that GREs functionally interact with AuxREs in regulating auxin-mediated transcription. Conclusions: Using genome-wide bioinformatic analyses, evolutionary conserved motifs have been defined which potentially function as AuxRE-dependent coupling elements to establish auxin-specific expression patterns. Based on these findings, experimental approaches can be designed to broaden our understanding of combinatorial, auxin-controlled gene regulation.
Background: Ascorbic acid demonstrates a cytotoxic effect by generating hydrogen peroxide, a reactive oxygen species (ROS) involved in oxidative cell stress. A panel of eleven human cancer cell lines, glioblastoma and carcinoma, were exposed to serial dilutions of ascorbic acid (5-100 mmol/L). The purpose of this study was to analyse the impact of catalase, an important hydrogen peroxide-detoxifying enzyme, on the resistance of cancer cells to ascorbic acid mediated oxidative stress. Methods: Effective concentration (EC50) values, which indicate the concentration of ascorbic acid that reduced the number of viable cells by 50%, were detected with the crystal violet assay. The level of intracellular catalase protein and enzyme activity was determined. Expression of catalase was silenced by catalase-specific short hairpin RNA (sh-RNA) in BT-20 breast carcinoma cells. Oxidative cell stress induced apoptosis was measured by a caspase luminescent assay. Results: The tested human cancer cell lines demonstrated obvious differences in their resistance to ascorbic acid mediated oxidative cell stress. Forty-five percent of the cell lines had an EC50>20 mmol/L and fifty-five percent had an EC50<20 mmol/L. With an EC50 of 2.6–5.5 mmol/L, glioblastoma cells were the most susceptible cancer cell lines analysed in this study. A correlation between catalase activity and the susceptibility to ascorbic acid was observed. To study the possible protective role of catalase on the resistance of cancer cells to oxidative cell stress, the expression of catalase in the breast carcinoma cell line BT-20, which cells were highly resistant to the exposure to ascorbic acid (EC50: 94,9 mmol/L), was silenced with specific sh-RNA. The effect was that catalase-silenced BT-20 cells (BT-20 KD-CAT) became more susceptible to high concentrations of ascorbic acid (50 and 100 mmol/L). Conclusions: Fifty-five percent of the human cancer cell lines tested were unable to protect themselves against oxidative stress mediated by ascorbic acid induced hydrogen peroxide production. The antioxidative enzyme catalase is important to protect cancer cells against cytotoxic hydrogen peroxide. Silenced catalase expression increased the susceptibility of the formerly resistant cancer cell line BT-20 to oxidative stress.
Measuring and estimating biodiversity patterns is a fundamental task of the scientist working to support conservation and informmanagement decisions.Most biodiversity studies in temperate regions were often carried out over a very short period of time (e.g., a single season) and it is often—at least tacitly—assumed that these short-termfindings are representative of long-termgeneral patterns.However, should the studied biodiversity pattern in fact contain significant temporal dynamics, perhaps leading to contradictory conclusions. Here, we studied the seasonal diversity dynamics of arboreal spider communities dwelling in 216 European beeches (Fagus sylvatica L.) to assess the spider community composition in the following seasons: two cold seasons (I:November 2005–January 2006; II: February–April) and two warm seasons (III: May–July; IV: August–October). We show that the usually measured diversity of the warmseason community (IV: 58 estimated species) alone did not deliver a reliable image of the overall diversity present in these trees, and therefore, we recommend it should not be used for sampling protocols aimed at providing a full picture of a forest’s biodiversity in the temperate zones. In particular, when the additional samplings of other seasons (I, II, III) were included, the estimated species richness nearly doubled (108). Community I possessed the lowest diversity and evenness due to the harsh winter conditions: this community was comprised of one dominant species together with several species low in abundance. Similarity was lowest (38.6%) between seasonal communities I and III, indicating a significant species turnover due to recolonization, so that community III had the highest diversity. Finally, using nonparametric estimators, we found that further sampling in late winter (February–April) is most needed to complete our inventory. Our study clearly demonstrates that seasonal dynamics of communities should be taken into account when studying biodiversity patterns of spiders, and probably forest arthropods in general.
Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed postbronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Agedependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. Methods: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner’s diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. Results: Compared to the expert panel diagnosis, ‘GOLD-COPD’ misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. Conclusions: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice.
Renal Perfusion in Scleroderma Patients Assessed by Microbubble-Based Contrast-Enhanced Ultrasound
(2012)
Abstract: Objectives: Renal damage is common in scleroderma. It can occur acutely or chronically. Renal reserve might already be impaired before it can be detected by laboratory findings. Microbubble-based contrast-enhanced ultrasound has been demonstrated to improve blood perfusion imaging in organs. Therefore, we conducted a study to assess renal perfusion in scleroderma patients utilizing this novel technique. Materials and Methodology: Microbubble-based contrast agent was infused and destroyed by using high mechanical index by Siemens Sequoia (curved array, 4.5 MHz). Replenishment was recorded for 8 seconds. Regions of interests (ROI) were analyzed in renal parenchyma, interlobular artery and renal pyramid with quantitative contrast software (CUSQ 1.4, Siemens Acuson, Mountain View, California). Time to maximal Enhancement (TmE), maximal enhancement (mE) and maximal enhancement relative to maximal enhancement of the interlobular artery (mE%A) were calculated for different ROIs. Results: There was a linear correlation between the time to maximal enhancement in the parenchyma and the glomerular filtration rate. However, the other parameters did not reveal significant differences between scleroderma patients and healthy controls. Conclusion: Renal perfusion of scleroderma patients including the glomerular filtration rate can be assessed using microbubble-based contrast media.
Background: Combination of oncolytic vaccinia virus therapy with conventional chemotherapy has shown promise for tumor therapy. However, side effects of chemotherapy including thrombocytopenia, still remain problematic. Methods: Here, we describe a novel approach to optimize combination therapy of oncolytic virus and chemotherapy utilizing virus-encoding hyper-IL-6, GLV-1h90, to reduce chemotherapy-associated side effects. Results: We showed that the hyper-IL-6 cytokine was successfully produced by GLV-1h90 and was functional both in cell culture as well as in tumor-bearing animals, in which the cytokine-producing vaccinia virus strain was well tolerated. When combined with the chemotherapeutic mitomycin C, the anti-tumor effect of the oncolytic virotherapy was significantly enhanced. Moreover, hyper-IL-6 expression greatly reduced the time interval during which the mice suffered from chemotherapy-induced thrombocytopenia. Conclusion: Therefore, future clinical application would benefit from careful investigation of additional cytokine treatment to reduce chemotherapy-induced side effects.
Background: To evaluate oncological and clinical outcome in patients with renal cell carcinoma (RCC) and tumor thrombus involving inferior vena cava (IVC) treated with nephrectomy and thrombectomy. Methods: We identified 50 patients with a median age of 65 years, who underwent radical surgical treatment for RCC and tumor thrombus of the IVC between 1997 and 2010. The charts were reviewed for pathological and surgical parameters, as well as complications and oncological outcome. Results: The median follow-up was 26 months. In 21 patients (42%) distant metastases were already present at the time of surgery. All patients underwent radical nephrectomy, thrombectomy and lymph node dissection through a flank (15 patients/30%), thoracoabdominal (14 patients/28%) or midline abdominal approach (21 patients/42%), depending upon surgeon preference and upon the characteristics of tumor and associated thrombus. Extracorporal circulation with cardiopulmonary bypass (CPB) was performed in 10 patients (20%) with supradiaphragmal thrombus of IVC. Cancer-specific survival for the whole cohort at 5 years was 33.1%. Survival for the patients without distant metastasis at 5 years was 50.7%, whereas survival rate in the metastatic group at 5 years was 7.4%. Median survival of patients with metastatic disease was 16.4 months. On multivariate analysis lymph node invasion, distant metastasis and grading were independent prognostic factors. There was no statistically significant influence of level of the tumor thrombus on survival rate. Indeed, patients with supradiaphragmal tumor thrombus (n = 10) even had a better outcome (overall survival at 5 years of 58.33%) than the entire cohort. Conclusions: An aggressive surgical approach is the most effective therapeutic option in patients with RCC and any level of tumor thrombus and offers a reasonable longterm survival. Due to good clinical and oncological outcome we prefer the use of CPB with extracorporal circulation in patients with supradiaphragmal tumor thrombus. Cytoreductive surgery appears to be beneficial for patients with metastatic disease, especially when consecutive therapy is performed. Although sample size of our study cohort is limited consistent with some other studies lymph node invasion, distant metastasis and grading seem to have prognostic value.
Background: The objective of this study was to validate physical activity questionnaires for cystic fibrosis (CF) against accelerometry and cycle ergometry. Methods: 41 patients with CF (12-42 years) completed the Habitual Activity Estimation Scale (HAES), the 7-Day Physical Activity Recall questionnaire (7D-PAR) and the Lipid Research Clinics questionnaire (LRC) and performed an incremental exercise test according to the Godfrey protocol up to volitional fatigue. Time spent in moderate and vigorous physical activity (MVPA) assessed objectively by accelerometry was related to the time spent in the respective activity categories by correlation analyses and calculating intraclass correlation coefficients (ICC). Furthermore, the results of the exercise test were correlated with the results of the questionnaires. Results: Time spent in the categories ‘hard’,’very hard’ and ‘hard & very hard’ of the 7D-PAR (0.41 < r < 0.56) and ‘active’ (r = 0.33) of the HAES correlated significantly with MVPA. The activity levels of the LRC were not related to objectively determined physical activity. Significant ICCs were only observed between the 7D-PAR activitiy categories and MVPA (ICC = 0.40-0.44). Only the LRC showed moderate correlations with the exercise test (Wmax: r = 0.46, p = 0.002; VO2peak: r = 0.32, p = 0.041). Conclusions: In conclusion, the activity categories ‘hard’ and ‘very hard’ of the 7D-PAR best reflected objectively measured MVPA. Since the association was at most moderate, the 7D-PAR may be selected to describe physical activity within a population. None of the evaluated questionnaires was able to generate valid physical activity data exercise performance data at the individual level. Neither did any of the questionnaires provide a valid assessment of aerobic fitness on an invidual level.
Purpose: Preclinical experiments on large animals are indispensable for evaluating the effectiveness of diabetes therapies. Miniature swine are well suited for such studies due to their physiological and pathophysiological responses. Methods: We compare two methods for inducing diabetes in Goettingen minipigs (GMP), in five with the beta cell toxin streptozotocin (STZ) and in five other GMP by total pancreatectomy (PE). Glucose homeostasis was assessed with the intravenous glucose-tolerance test (IVGTT) and continual monitoring of interstitial glucose levels. At conclusion of the observation period, the pancreata were examined histologically. Three non-diabetic GMP served as control group. Results: The IVGTT revealed markedly diabetic profiles in both GMP groups. STZ-GMP were found to harbor residual C-peptides and scattered insulin-positive cells in the pancreas. PE-GMP survived the total pancreatectomy only with intensive postoperative care. Conclusions: Although both methods reliably induced diabetes in GMP, the PE-GMP clearly had more health problems and required a greater expenditure of time and resources. The PE-GMP model, however, was better at eliminating endogenous insulin and C-peptide than the STZ-GMP model.
Oncolytic viruses refer to those that are able to eliminate malignancies by direct targeting and lysis of cancer cells, leaving non-cancerous tissues unharmed. Several oncolytic viruses including adenovirus strains, canine distemper virus and vaccinia virus strains have been used for canine cancer therapy in preclinical studies. However, in contrast to human studies, clinical trials with oncolytic viruses for canine cancer patients have not been reported. An ‘ideal’ virus has yet to be identified. This review is focused on the prospective use of oncolytic viruses in the treatment of canine tumors - a knowledge that will undoubtedly contribute to the development of oncolytic viral agents for canine cancer therapy in the future.
Background: Tardigrades are multicellular organisms, resistant to extreme environmental changes such as heat, drought, radiation and freezing. They outlast these conditions in an inactive form (tun) to escape damage to cellular structures and cell death. Tardigrades are apparently able to prevent or repair such damage and are therefore a crucial model organism for stress tolerance. Cultures of the tardigrade Milnesium tardigradum were dehydrated by removing the surrounding water to induce tun formation. During this process and the subsequent rehydration, metabolites were measured in a time series by GC-MS. Additionally expressed sequence tags are available, especially libraries generated from the active and inactive state. The aim of this integrated analysis is to trace changes in tardigrade metabolism and identify pathways responsible for their extreme resistance against physical stress. Results: In this study we propose a novel integrative approach for the analysis of metabolic networks to identify modules of joint shifts on the transcriptomic and metabolic levels. We derive a tardigrade-specific metabolic network represented as an undirected graph with 3,658 nodes (metabolites) and 4,378 edges (reactions). Time course metabolite profiles are used to score the network nodes showing a significant change over time. The edges are scored according to information on enzymes from the EST data. Using this combined information, we identify a key subnetwork (functional module) of concerted changes in metabolic pathways, specific for de- and rehydration. The module is enriched in reactions showing significant changes in metabolite levels and enzyme abundance during the transition. It resembles the cessation of a measurablemetabolism (e.g. glycolysis and amino acid anabolism) during the tun formation, the production of storage metabolites and bioprotectants, such as DNA stabilizers, and the generation of amino acids and cellular components from monosaccharides as carbon and energy source during rehydration. Conclusions: The functional module identifies relationships among changed metabolites (e.g. spermidine) and reactions and provides first insights into important altered metabolic pathways. With sparse and diverse data available, the presented integrated metabolite network approach is suitable to integrate all existing data and analyse it in a combined manner.
We review the particle physics ingredients affecting the normalization, shape, and flavor composition of astrophysical neutrinos fluxes, such as different production modes, magnetic field effects on the secondaries muons, pions, and kaons, and flavor mixing, where we focus on p? interactions. We also discuss the interplay with neutrino propagation and detection, including the possibility to detect flavor and its application in particle physics, and the use of the Glashow resonance to discriminate p? from pp interactions in the source. We illustrate the implications on fluxes and flavor composition with two different models: 1 the target photon spectrum is dominated by synchrotron emission of coaccelerated electrons and 2 the target photon spectrum follows the observed photon spectrum of gamma-ray bursts. In the latter case, the multimessenger extrapolation from the gamma-ray fluence to the expected neutrino flux is highlighted.
Myc is a global transcriptional regulator and one of the most frequently overexpressed oncoproteins in human tumors. It is well established that activation of Myc leads to enhanced cell proliferation but can also lead to increased apoptosis. The use of animal models expressing deregulated levels of Myc has helped to both elucidate its function in normal cells and give insight into how Myc initiates and maintains tumorigenesis. Analyses of the medaka (Oryzias latipes) genome uncovered the unexpected presence of two Myc gene copies in this teleost species. Comparison of these Myc versions to other vertebrate species revealed that one gene, myc17, differs by the loss of some conserved regulatory protein motifs present in all other known Myc genes. To investigate how such differences might affect the basic biological functions of Myc, we generated a tamoxifeninducible in vivo model utilizing a natural, fish-specific Myc gene. Using this model we show that, when activated, Myc17 leads to increased proliferation and to apoptosis in a dose-dependent manner, similar to human Myc. We have also shown that long-term Myc17 activation triggers liver hyperplasia in adult fish, allowing this newly established transgenic medaka model to be used to study the transition from hyperplasia to liver cancer and to identify Myc-induced tumorigenesis modifiers.
Biallelic mutations in MCPH1 cause primary microcephaly (MCPH) with the cellular phenotype of defective chromosome condensation. MCPH1 encodes a multifunctional protein that notably is involved in brain development, regulation of chromosome condensation, and DNA damage response. In the present studies, we detected that MCPH1 encodes several distinct transcripts, including two major forms: full-length MCPH1 (MCPH1-FL) and a second transcript lacking the six 39 exons (MCPH1De9–14). Both variants show comparable tissue-specific expression patterns, demonstrate nuclear localization that is mediated independently via separate NLS motifs, and are more abundant in certain fetal than adult organs. In addition, the expression of either isoform complements the chromosome condensation defect found in genetically MCPH1-deficient or MCPH1 siRNA-depleted cells, demonstrating a redundancy of both MCPH1 isoforms for the regulation of chromosome condensation. Strikingly however, both transcripts are regulated antagonistically during cell-cycle progression and there are functional differences between the isoforms with regard to the DNA damage response; MCPH1-FL localizes to phosphorylated H2AX repair foci following ionizing irradiation, while MCPH1De9–14 was evenly distributed in the nucleus. In summary, our results demonstrate here that MCPH1 encodes different isoforms that are differentially regulated at the transcript level and have different functions at the protein level.
Nephrogenic Systemic Fibrosis is a rare condition appearing only in patients with severe renal impairment or failure and presents with dermal lesions and involvement of internal organs. Although many cases are mild, an estimated 5 % have a progressive debilitating course. To date, there is no known effective treatment thus stressing the necessity of ample prevention measures. An association with the use of Gadolinium based contrast agents (GBCA) makes Nephrogenic Systemic Fibrosis a potential side effect of contrast enhanced magnetic resonance imaging and offers the opportunity for prevention by limiting use of gadolinium based contrast agents in renal failure patients. In itself toxic, Gadolinium is embedded into chelates that allow its safe use as a contrast agent. One NSF theory is that Gadolinium chelates distribute into the extracellular fluid compartment and set Gadolinium ions free, depending on multiple factors among which the duration of chelates exposure is directly related to the renal function. Major medical societies both in Europe and in North America have developed guidelines for the usage of GBCA. Since the establishment of these guidelines and the increased general awareness of this condition, the occurrence of NSF has been nearly eliminated. Giving an overview over the current knowledge of NSF pathobiochemistry, pathogenesis and treatment options this review focuses on the guidelines of the European Medicines Agency, the European Society of Urogenital Radiology, the FDA and the American College of Radiology from 2008 up to 2011 and the transfer of this knowledge into every day practice.
Background: The European Centres of Reference Network for Cystic Fibrosis (ECORN-CF) established an Internet forum which provides the opportunity for CF patients and other interested people to ask experts questions about CF in their mother language. The objectives of this study were to: 1) develop a detailed quality assessment tool to analyze quality of expert answers, 2) evaluate the intra- and inter-rater agreement of this tool, and 3) explore changes in the quality of expert answers over the time frame of the project. Methods: The quality assessment tool was developed by an expert panel. Five experts within the ECORN-CF project used the quality assessment tool to analyze the quality of 108 expert answers published on ECORN-CF from six language zones. 25 expert answers were scored at two time points, one year apart. Quality of answers was also assessed at an early and later period of the project. Individual rater scores and group mean scores were analyzed for each expert answer. Results: A scoring system and training manual were developed analyzing two quality categories of answers: content and formal quality. For content quality, the grades based on group mean scores for all raters showed substantial agreement between two time points, however this was not the case for the grades based on individual rater scores. For formal quality the grades based on group mean scores showed only slight agreement between two time points and there was also poor agreement between time points for the individual grades. The inter-rater agreement for content quality was fair (mean kappa value 0.232 ± 0.036, p < 0.001) while only slight agreement was observed for the grades of the formal quality (mean kappa value 0.105 ± 0.024, p < 0.001). The quality of expert answers was rated high (four language zones) or satisfactory (two language zones) and did not change over time. Conclusions: The quality assessment tool described in this study was feasible and reliable when content quality was assessed by a group of raters. Within ECORN-CF, the tool will help ensure that CF patients all over Europe have equal possibility of access to high quality expert advice on their illness.
We study the symmetrised rank-one convex hull of monoclinic-I martensite (a twelve-variant material) in the context of geometrically-linear elasticity. We construct sets of T3s, which are (non-trivial) symmetrised rank-one convex hulls of 3-tuples of pairwise incompatible strains. Moreover we construct a five-dimensional continuum of T3s and show that its intersection with the boundary of the symmetrised rank-one convex hull is four-dimensional. We also show that there is another kind of monoclinic-I martensite with qualitatively different semi-convex hulls which, so far as we know, has not been experimentally observed. Our strategy is to combine understanding of the algebraic structure of symmetrised rank-one convex cones with knowledge of the faceting structure of the convex polytope formed by the strains.