TY - JOUR A1 - Pham, Mirko A1 - Helluy, Xavier A1 - Kleinschnitz, Christoph A1 - Kraft, Peter A1 - Bartsch, Andreas J. A1 - Jakob, Peter A1 - Nieswandt, Bernhard A1 - Bendszus, Martin A1 - Guido, Stoll T1 - Sustained Reperfusion after Blockade of Glycoprotein-Receptor-Ib in Focal Cerebral Ischemia: An MRI Study at 17.6 Tesla JF - PLoS ONE N2 - Background: Inhibition of early platelet adhesion by blockade of glycoprotein-IB (GPIb) protects mice from ischemic stroke. To elucidate underlying mechanisms in-vivo, infarct development was followed by ultra-high field MRI at 17.6 Tesla. Methods: Cerebral infarction was induced by transient-middle-cerebral-artery-occlusion (tMCAO) for 1 hour in C57/BL6 control mice (N = 10) and mice treated with 100 mg Fab-fragments of the GPIb blocking antibody p0p/B 1 h after tMCAO (N = 10). To control for the effect of reperfusion, additional mice underwent permanent occlusion and received anti-GPIb treatment (N = 6; pMCAO) or remained without treatment (N = 3; pMCAO). MRI 2 h and 24 h after MCAO measured cerebral-blood-flow (CBF) by continuous arterial-spin labelling, the apparent-diffusion-coefficient (ADC), quantitative-T2 and T2-weighted imaging. All images were registered to a standard mouse brain MRI atlas and statistically analysed voxel-wise, and by cortico-subcortical ROI analysis. Results: Anti-GPIb treatment led to a relative increase of postischemic CBF vs. controls in the cortical territory of the MCA (2 h: 44.2 +/- 6.9 ml/100g/min versus 24 h: 60.5 +/- 8.4; p = 0.0012, F((1,18)) = 14.63) after tMCAO. Subcortical CBF 2 h after tMCAO was higher in anti-GPIb treated animals (45.3 +/- 5.9 vs. controls: 33.6 +/- 4.3; p = 0.04). In both regions, CBF findings were clearly related to a lower probability of infarction (Cortex/Subcortex of treated group: 35%/65% vs. controls: 95%/100%) and improved quantitative-T2 and ADC. After pMCAO, anti-GPIb treated mice developed similar infarcts preceded by severe irreversible hypoperfusion as controls after tMCAO indicating dependency of stroke protection on reperfusion. Conclusion: Blockade of platelet adhesion by anti-GPIb-Fab-fragments results in substantially improved CBF early during reperfusion. This finding was in exact spatial correspondence with the prevention of cerebral infarction and indicates in-vivo an increased patency of the microcirculation. Thus, progression of infarction during early ischemia and reperfusion can be mitigated by anti-platelet treatment. KW - Von-Willebrand-factor KW - Experimental stroke KW - Magnetic-resonance KW - Arterial water KW - Brain KW - Perfusion KW - Mice KW - Inflammation KW - Coefficient KW - mechanisms Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142608 VL - 6 IS - 4 ER - TY - JOUR A1 - Reiter, Theresa A1 - Gensler, Daniel A1 - Ritter, Oliver A1 - Weiss, Ingo A1 - Geistert, Wolfgang A1 - Kaufmann, Ralf A1 - Hoffmeister, Sabine A1 - Friedrich, Michael T. A1 - Wintzheimer, Stefan A1 - Düring, Markus A1 - Nordbeck, Peter A1 - Jakob, Peter M. A1 - Ladd, Mark E. A1 - Quick, Harald H. A1 - Bauer, Wolfgang R. T1 - Direct cooling of the catheter tip increases safety for CMR-guided electrophysiological procedures JF - Journal of Cardiovascular Magnetic Resonance N2 - Background: One of the safety concerns when performing electrophysiological (EP) procedures under magnetic resonance (MR) guidance is the risk of passive tissue heating due to the EP catheter being exposed to the radiofrequency (RF) field of the RF transmitting body coil. Ablation procedures that use catheters with irrigated tips are well established therapeutic options for the treatment of cardiac arrhythmias and when used in a modified mode might offer an additional system for suppressing passive catheter heating. Methods: A two-step approach was chosen. Firstly, tests on passive catheter heating were performed in a 1.5 T Avanto system (Siemens Healthcare Sector, Erlangen, Germany) using a ASTM Phantom in order to determine a possible maximum temperature rise. Secondly, a phantom was designed for simulation of the interface between blood and the vascular wall. The MR-RF induced temperature rise was simulated by catheter tip heating via a standard ablation generator. Power levels from 1 to 6 W were selected. Ablation duration was 120 s with no tip irrigation during the first 60 s and irrigation at rates from 2 ml/min to 35 ml/min for the remaining 60 s (Biotronik Qiona Pump, Berlin, Germany). The temperature was measured with fluoroscopic sensors (Luxtron, Santa Barbara, CA, USA) at a distance of 0 mm, 2 mm, 4 mm, and 6 mm from the catheter tip. Results: A maximum temperature rise of 22.4 degrees C at the catheter tip was documented in the MR scanner. This temperature rise is equivalent to the heating effect of an ablator's power output of 6 W at a contact force of the weight of 90 g (0.883 N). The catheter tip irrigation was able to limit the temperature rise to less than 2 degrees C for the majority of examined power levels, and for all examined power levels the residual temperature rise was less than 8 degrees C. Conclusion: Up to a maximum of 22.4 degrees C, the temperature rise at the tissue surface can be entirely suppressed by using the catheter's own irrigation system. The irrigated tip system can be used to increase MR safety of EP catheters by suppressing the effects of unwanted passive catheter heating due to RF exposure from the MR scanner. KW - EP Procedures KW - radiofrequency ablation KW - contact force KW - lesion size KW - MRI KW - temperature KW - tissue KW - wires KW - model KW - ablation KW - safety KW - catheter tip KW - MR guidance Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134927 VL - 14 IS - 12 ER - TY - JOUR A1 - Nordbeck, Peter A1 - Bönhof, Leoni A1 - Hiller, Karl-Heinz A1 - Voll, Sabine A1 - Arias-Loza, Paula A1 - Seidlmaier, Lea A1 - Williams, Tatjana A1 - Ye, Yu-Xiang A1 - Gensler, Daniel A1 - Pelzer, Theo A1 - Ertl, Georg A1 - Jakob, Peter M. A1 - Bauer, Wolfgang R. A1 - Ritter, Oliver T1 - Impact of Thoracic Surgery on Cardiac Morphology and Function in Small Animal Models of Heart Disease: A Cardiac MRI Study in Rats JF - PLoS ONE N2 - Background Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies. Methods Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition. Results Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5±10.6 vs. 317.0±11.3 g, n<0.05) and 8 weeks (317.0±21.1 vs. 358.7±22.4 g, n<0.05) after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease. Conclusion Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients. KW - heart rate KW - body weight KW - surgical and invasive medical procedures KW - magnetic resonance imaging KW - blood KW - vascular surgery KW - myocardial infarction KW - cardiac ventricles Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130064 VL - 8 IS - 8 ER - TY - JOUR A1 - Schwender, Joerg A1 - Koenig, Christina A1 - Klapperstueck, Matthias A1 - Heinzel, Nicolas A1 - Munz, Eberhard A1 - Hebbelmann, Inga A1 - Hay, Jordan O. A1 - Denolf, Peter A1 - De Bodt, Stefanie A1 - Redestig, Henning A1 - Caestecker, Evelyne A1 - Jakob, Peter M. A1 - Borisjuk, Ljudmilla A1 - Rolletschek, Hardy T1 - Transcript abundance on its own cannot be used to infer fluxes in central metabolism JF - Frontiers in Plant Science N2 - An attempt has been made to define the extent to which metabolic flux in central plant metabolism is reflected by changes in the transcriptome and metabolome, based on an analysis of in vitro cultured immature embryos of two oilseed rape (Brassica napus) accessions which contrast for seed lipid accumulation. Metabolic flux analysis (MFA) was used to constrain a flux balance metabolic model which included 671 biochemical and transport reactions within the central metabolism. This highly confident flux information was eventually used for comparative analysis of flux vs. transcript (metabolite). Metabolite profiling succeeded in identifying 79 intermediates within the central metabolism, some of which differed quantitatively between the two accessions and displayed a significant shift corresponding to flux. An RNA-Seq based transcriptome analysis revealed a large number of genes which were differentially transcribed in the two accessions, including some enzymes/proteins active in major metabolic pathways. With a few exceptions, differential activity in the major pathways (glycolysis, TCA cycle, amino acid, and fatty acid synthesis) was not reflected in contrasting abundances of the relevant transcripts. The conclusion was that transcript abundance on its own cannot be used to infer metabolic activity/fluxes in central plant metabolism. This limitation needs to be borne in mind in evaluating transcriptome data and designing metabolic engineering experiments. KW - oilseeds KW - lipid biosynthesis KW - heterotrophic arabidopsis cells KW - central carbon metabolism KW - gene-expression data KW - targeted metabolite profiling KW - central metabolism KW - flux balance analysis KW - C-13-metabolic flux analysis KW - Brassica napus KW - RNA-SEQ KW - developing oilseeds KW - saccharomyces cerevisiae KW - maize kernels KW - embryo KW - seed Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114586 SN - 1664-462X N1 - Funding information: Bayer Crop Science NV; Deutsche Forschungsgemeinschaft [BO-1917/4-1]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, Chemical Sciences, Geosciences, and Biosciences Division [DEACO298CH10886] VL - 5 ER - TY - JOUR A1 - Gram, Maximilian A1 - Gensler, Daniel A1 - Albertova, Petra A1 - Gutjahr, Fabian Tobias A1 - Lau, Kolja A1 - Arias-Loza, Paula-Anahi A1 - Jakob, Peter Michael A1 - Nordbeck, Peter T1 - Quantification correction for free-breathing myocardial T1ρ mapping in mice using a recursively derived description of a T\(_{1p}\)\(^{*}\) relaxation pathway JF - Journal of Cardiovascular Magnetic Resonance N2 - Background Fast and accurate T1ρ mapping in myocardium is still a major challenge, particularly in small animal models. The complex sequence design owing to electrocardiogram and respiratory gating leads to quantification errors in in vivo experiments, due to variations of the T\(_{1p}\) relaxation pathway. In this study, we present an improved quantification method for T\(_{1p}\) using a newly derived formalism of a T\(_{1p}\)\(^{*}\) relaxation pathway. Methods The new signal equation was derived by solving a recursion problem for spin-lock prepared fast gradient echo readouts. Based on Bloch simulations, we compared quantification errors using the common monoexponential model and our corrected model. The method was validated in phantom experiments and tested in vivo for myocardial T\(_{1p}\) mapping in mice. Here, the impact of the breath dependent spin recovery time T\(_{rec}\) on the quantification results was examined in detail. Results Simulations indicate that a correction is necessary, since systematically underestimated values are measured under in vivo conditions. In the phantom study, the mean quantification error could be reduced from − 7.4% to − 0.97%. In vivo, a correlation of uncorrected T\(_{1p}\) with the respiratory cycle was observed. Using the newly derived correction method, this correlation was significantly reduced from r = 0.708 (p < 0.001) to r = 0.204 and the standard deviation of left ventricular T\(_{1p}\) values in different animals was reduced by at least 39%. Conclusion The suggested quantification formalism enables fast and precise myocardial T\(_{1p}\) quantification for small animals during free breathing and can improve the comparability of study results. Our new technique offers a reasonable tool for assessing myocardial diseases, since pathologies that cause a change in heart or breathing rates do not lead to systematic misinterpretations. Besides, the derived signal equation can be used for sequence optimization or for subsequent correction of prior study results. KW - T1rho KW - radial KW - cardiac KW - correction KW - quantitative MRI KW - mapping KW - spin-lock KW - T1ρ Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300491 VL - 24 IS - 1 ER - TY - JOUR A1 - Dawood, Peter A1 - Breuer, Felix A1 - Stebani, Jannik A1 - Burd, Paul A1 - Homolya, István A1 - Oberberger, Johannes A1 - Jakob, Peter M. A1 - Blaimer, Martin T1 - Iterative training of robust k‐space interpolation networks for improved image reconstruction with limited scan specific training samples JF - Magnetic Resonance in Medicine N2 - To evaluate an iterative learning approach for enhanced performance of robust artificial‐neural‐networks for k‐space interpolation (RAKI), when only a limited amount of training data (auto‐calibration signals [ACS]) are available for accelerated standard 2D imaging. Methods In a first step, the RAKI model was tailored for the case of limited training data amount. In the iterative learning approach (termed iterative RAKI [iRAKI]), the tailored RAKI model is initially trained using original and augmented ACS obtained from a linear parallel imaging reconstruction. Subsequently, the RAKI convolution filters are refined iteratively using original and augmented ACS extracted from the previous RAKI reconstruction. Evaluation was carried out on 200 retrospectively undersampled in vivo datasets from the fastMRI neuro database with different contrast settings. Results For limited training data (18 and 22 ACS lines for R = 4 and R = 5, respectively), iRAKI outperforms standard RAKI by reducing residual artifacts and yields better noise suppression when compared to standard parallel imaging, underlined by quantitative reconstruction quality metrics. Additionally, iRAKI shows better performance than both GRAPPA and standard RAKI in case of pre‐scan calibration with varying contrast between training‐ and undersampled data. Conclusion RAKI benefits from the iterative learning approach, which preserves the noise suppression feature, but requires less original training data for the accurate reconstruction of standard 2D images thereby improving net acceleration. KW - complex‐valued machine learning KW - data augmentation KW - deep learning KW - GRAPPA KW - parallel imaging KW - RAKI Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312306 VL - 89 IS - 2 SP - 812 EP - 827 ER - TY - JOUR A1 - Gram, Maximilian A1 - Gensler, Daniel A1 - Winter, Patrick A1 - Seethaler, Michael A1 - Arias-Loza, Paula Anahi A1 - Oberberger, Johannes A1 - Jakob, Peter Michael A1 - Nordbeck, Peter T1 - Fast myocardial T\(_{1P}\) mapping in mice using k-space weighted image contrast and a Bloch simulation-optimized radial sampling pattern JF - Magnetic Resonance Materials in Physics, Biology and Medicine N2 - Purpose T\(_{1P}\) dispersion quantification can potentially be used as a cardiac magnetic resonance index for sensitive detection of myocardial fibrosis without the need of contrast agents. However, dispersion quantification is still a major challenge, because T\(_{1P}\) mapping for different spin lock amplitudes is a very time consuming process. This study aims to develop a fast and accurate T\(_{1P}\) mapping sequence, which paves the way to cardiac T1ρ dispersion quantification within the limited measurement time of an in vivo study in small animals. Methods A radial spin lock sequence was developed using a Bloch simulation-optimized sampling pattern and a view-sharing method for image reconstruction. For validation, phantom measurements with a conventional sampling pattern and a gold standard sequence were compared to examine T\(_{1P}\) quantification accuracy. The in vivo validation of T\(_{1P}\) mapping was performed in N = 10 mice and in a reproduction study in a single animal, in which ten maps were acquired in direct succession. Finally, the feasibility of myocardial dispersion quantification was tested in one animal. Results The Bloch simulation-based sampling shows considerably higher image quality as well as improved T\(_{1P}\) quantification accuracy (+ 56%) and precision (+ 49%) compared to conventional sampling. Compared to the gold standard sequence, a mean deviation of - 0.46 ± 1.84% was observed. The in vivo measurements proved high reproducibility of myocardial T\(_{1P}\) mapping. The mean T\(_{1P}\) in the left ventricle was 39.5 ± 1.2 ms for different animals and the maximum deviation was 2.1% in the successive measurements. The myocardial T\(_{1P}\) dispersion slope, which was measured for the first time in one animal, could be determined to be 4.76 ± 0.23 ms/kHz. Conclusion This new and fast T\(_{1P}\) quantification technique enables high-resolution myocardial T\(_{1P}\) mapping and even dispersion quantification within the limited time of an in vivo study and could, therefore, be a reliable tool for improved tissue characterization. KW - TT\(_{1rho}\) mapping KW - small animal KW - KWIC KW - radial KW - cardiac KW - mice KW - spin lock KW - T\(_{1P}\) dispersion KW - T\(_{1P}\) mapping Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268903 SN - 1352-8661 VL - 35 IS - 2 ER - TY - JOUR A1 - Gotschy, Alexander A1 - Bauer, Wolfgang R. A1 - Winter, Patrick A1 - Nordbeck, Peter A1 - Rommel, Eberhard A1 - Jakob, Peter M. A1 - Herold, Volker T1 - Local versus global aortic pulse wave velocity in early atherosclerosis: An animal study in ApoE\(^{-/-}\) mice using ultrahigh field MRI JF - PLoS ONE N2 - Increased aortic stiffness is known to be associated with atherosclerosis and has a predictive value for cardiovascular events. This study aims to investigate the local distribution of early arterial stiffening due to initial atherosclerotic lesions. Therefore, global and local pulse wave velocity (PWV) were measured in ApoE\(^{-/-}\) and wild type (WT) mice using ultrahigh field MRI. For quantification of global aortic stiffness, a new multi-point transit-time (TT) method was implemented and validated to determine the global PWV in the murine aorta. Local aortic stiffness was measured by assessing the local PWV in the upper abdominal aorta, using the flow/area (QA) method. Significant differences between age matched ApoE\(^{-/-}\) and WT mice were determined for global and local PWV measurements (global PWV: ApoE\(^{-/-}\): 2.7 ±0.2m/s vs WT: 2.1±0.2m/s, P<0.03; local PWV: ApoE\(^{-/-}\): 2.9±0.2m/s vs WT: 2.2±0.2m/s, P<0.03). Within the WT mouse group, the global PWV correlated well with the local PWV in the upper abdominal aorta (R\(^2\) = 0.75, P<0.01), implying a widely uniform arterial elasticity. In ApoE\(^{-/-}\) animals, however, no significant correlation between individual local and global PWV was present (R\(^2\) = 0.07, P = 0.53), implying a heterogeneous distribution of vascular stiffening in early atherosclerosis. The assessment of global PWV using the new multi-point TT measurement technique was validated against a pressure wire measurement in a vessel phantom and showed excellent agreement. The experimental results demonstrate that vascular stiffening caused by early atherosclerosis is unequally distributed over the length of large vessels. This finding implies that assessing heterogeneity of arterial stiffness by multiple local measurements of PWV might be more sensitive than global PWV to identify early atherosclerotic lesions. KW - MRI KW - Atherosclerosis KW - Aorta KW - Stiffness KW - Measurement KW - Time measurement KW - Magnetic resonance imaging KW - Mouse models KW - Systole Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171824 VL - 12 IS - 2 ER - TY - JOUR A1 - Yilmaz, Ali A1 - Rösch, Sabine A1 - Klingel, Karin A1 - Kandolf, Reinhard A1 - Helluy, Xavier A1 - Hiller, Karl-Heinz A1 - Jakob, Peter M A1 - Sechtem, Udo T1 - Molecular magnetic resonance imaging (MRI) of inflamed myocardium using ferucarbotran in patients with acute myocardial infarction JF - Journal of Cardiovascular Magnetic Resonance N2 - Introduction: Superparamagnetic iron oxide nanoparticle (SPIO)-based molecular imaging agents targeting macrophages have been developed and successfully applied in animal models of myocardial infarction. KW - Acute Myocardial Infarction KW - Cardiovascular Magnetic Resonance KW - Iron Oxide Nanoparticle KW - Superparamagnetic Iron Oxide KW - Infarct Zone Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140991 VL - 13 IS - Suppl. 1 ER - TY - JOUR A1 - Hill, Philip J. A1 - Stritzker, Jochen A1 - Scadeng, Miriam A1 - Geissinger, Ulrike A1 - Haddad, Daniel A1 - Basse-Lüsebrink, Thomas C. A1 - Gbureck, Uwe A1 - Jakob, Peter A1 - Szalay, Aladar A. T1 - Magnetic Resonance Imaging of Tumors Colonized with Bacterial Ferritin-Expressing \(Escherichia\) \(coli\) JF - PLoS ONE N2 - Background: Recent studies have shown that human ferritin can be used as a reporter of gene expression for magnetic resonance imaging (MRI). Bacteria also encode three classes of ferritin-type molecules with iron accumulation properties. Methods and Findings: Here, we investigated whether these bacterial ferritins can also be used as MRI reporter genes and which of the bacterial ferritins is the most suitable reporter. Bacterial ferritins were overexpressed in probiotic E. coli Nissle 1917. Cultures of these bacteria were analyzed and those generating highest MRI contrast were further investigated in tumor bearing mice. Among members of three classes of bacterial ferritin tested, bacterioferritin showed the most promise as a reporter gene. Although all three proteins accumulated similar amounts of iron when overexpressed individually, bacterioferritin showed the highest contrast change. By site-directed mutagenesis we also show that the heme iron, a unique part of the bacterioferritin molecule, is not critical for MRI contrast change. Tumor-specific induction of bacterioferritin-expression in colonized tumors resulted in contrast changes within the bacteria-colonized tumors. Conclusions: Our data suggest that colonization and gene expression by live vectors expressing bacterioferritin can be monitored by MRI due to contrast changes. KW - Blood-brain barrier KW - Gene-expression KW - Salmonella-typhimurium KW - Sugar-transport KW - Breast-tumors KW - MRI reporter KW - Iron-uptake KW - Proteins KW - Therapy KW - Mice Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140920 VL - 6 IS - 10 ER - TY - JOUR A1 - Hertlein, Tobias A1 - Sturm, Volker A1 - Kircher, Stefan A1 - Basse-Lüsebrink, Thomas A1 - Haddad, Daniel A1 - Ohlsen, Knut A1 - Jakob, Peter T1 - Visualization of Abscess Formation in a Murine Thigh Infection Model of \(Staphylococcus\) \(aureus\) by (19)F-Magnetic Resonance Imaging (MRI) JF - PLoS ONE N2 - Background: During the last years, (19)F-MRI and perfluorocarbon nanoemulsion (PFC) emerged as a powerful contrast agent methodology to track cells and to visualize inflammation. We applied this new modality to visualize deep tissue abscesses during acute and chronic phase of inflammation caused by Staphylococcus aureus infection. Methodology and Principal Findings: In this study, a murine thigh infection model was used to induce abscess formation and PFC or CLIO (cross linked ironoxides) was administered during acute or chronic phase of inflammation. 24 h after inoculation, the contrast agent accumulation was imaged at the site of infection by MRI. Measurements revealed a strong accumulation of PFC at the abscess rim at acute and chronic phase of infection. The pattern was similar to CLIO accumulation at chronic phase and formed a hollow sphere around the edema area. Histology revealed strong influx of neutrophils at the site of infection and to a smaller extend macrophages during acute phase and strong influx of macrophages at chronic phase of inflammation. Conclusion and Significance: We introduce (19)F-MRI in combination with PFC nanoemulsions as a new platform to visualize abscess formation in a murine thigh infection model of S. aureus. The possibility to track immune cells in vivo by this modality offers new opportunities to investigate host immune response, the efficacy of antibacterial therapies and the influence of virulence factors for pathogenesis. KW - Soft-tissue infection KW - In-vivo KW - Iron-oxide KW - F-19 MRI KW - Inflammation KW - Particles KW - Tracking KW - Lesions KW - Images KW - Rats Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142846 VL - 6 IS - 3 ER - TY - JOUR A1 - Tony, Hans-Peter A1 - Burmester, Gerd A1 - Schulze-Koops, Hendrik A1 - Grunke, Mathias A1 - Henes, Joerg A1 - Kötter, Ina A1 - Haas, Judith A1 - Unger, Leonore A1 - Lovric, Svjetlana A1 - Haubitz, Marion A1 - Fischer-Betz, Rebecca A1 - Chehab, Gamal A1 - Rubbert-Roth, Andrea A1 - Specker, Christof A1 - Weinerth, Jutta A1 - Holle, Julia A1 - Müller-Ladner, Ulf A1 - König, Ramona A1 - Fiehn, Christoph A1 - Burgwinkel, Philip A1 - Budde, Klemens A1 - Sörensen, Helmut A1 - Meurer, Michael A1 - Aringer, Martin A1 - Kieseier, Bernd A1 - Erfurt-Berge, Cornelia A1 - Sticherling, Michael A1 - Veelken, Roland A1 - Ziemann, Ulf A1 - Strutz, Frank A1 - von Wussow, Praxis A1 - Meier, Florian MP A1 - Hunzelmann, Nico A1 - Schmidt, Enno A1 - Bergner, Raoul A1 - Schwarting, Andreas A1 - Eming, Rüdiger A1 - Schwarz-Eywill, Michael A1 - Wassenberg, Siegfried A1 - Fleck, Martin A1 - Metzler, Claudia A1 - Zettl, Uwe A1 - Westphal, Jens A1 - Heitmann, Stefan A1 - Herzog, Anna L. A1 - Wiendl, Heinz A1 - Jakob, Waltraud A1 - Schmidt, Elvira A1 - Freivogel, Klaus A1 - Dörner, Thomas A1 - Hertl, Michael A1 - Stadler, Rudolf T1 - Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID) JF - Arthritis Research & Therapy N2 - Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin’s lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician’s visual analogue scale; mean improvement from baseline of 12.1 mm) KW - GRAID Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142856 VL - 13 IS - R75 ER - TY - JOUR A1 - Szalay, Aladar A. A1 - Hill, Philip J. A1 - Stritzker, Jochen A1 - Scadeng, Miriam A1 - Geissinger, Ulrike A1 - Haddad, Daniel A1 - Basse-Lüsebrink, Thomas C. A1 - Gbureck, Uwe A1 - Jakob, Peter T1 - Magnetic Resonance Imaging of Tumors Colonized with Bacterial Ferritin-Expressing Escherichia coli N2 - Background: Recent studies have shown that human ferritin can be used as a reporter of gene expression for magnetic resonance imaging (MRI). Bacteria also encode three classes of ferritin-type molecules with iron accumulation properties. Methods and Findings: Here, we investigated whether these bacterial ferritins can also be used as MRI reporter genes and which of the bacterial ferritins is the most suitable reporter. Bacterial ferritins were overexpressed in probiotic E. coli Nissle 1917. Cultures of these bacteria were analyzed and those generating highest MRI contrast were further investigated in tumor bearing mice. Among members of three classes of bacterial ferritin tested, bacterioferritin showed the most promise as a reporter gene. Although all three proteins accumulated similar amounts of iron when overexpressed individually, bacterioferritin showed the highest contrast change. By site-directed mutagenesis we also show that the heme iron, a unique part of the bacterioferritin molecule, is not critical for MRI contrast change. Tumor-specific induction of bacterioferritin-expression in colonized tumors resulted in contrast changes within the bacteria-colonized tumors. Conclusions: Our data suggest that colonization and gene expression by live vectors expressing bacterioferritin can be monitored by MRI due to contrast changes KW - Escherichia coli Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75789 ER - TY - JOUR A1 - Van den Hove, Daniel A1 - Jakob, Sissi Brigitte A1 - Schraut, Karla-Gerlinde A1 - Kenis, Gunter A1 - Schmitt, Angelika Gertrud A1 - Kneitz, Susanne A1 - Scholz, Claus-Jürgen A1 - Wiescholleck, Valentina A1 - Ortega, Gabriela A1 - Prickaerts, Jos A1 - Steinbusch, Harry A1 - Lesch, Klaus-Peter T1 - Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene x Environment Interactions N2 - Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-Htt6PS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety- and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/2) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChipH Mouse Genome 430 2.0 Array. 5-Htt +/2 offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/2 mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/2 genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotype6PS manner, indicating a gene6environment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/2 genotype shows clear adaptive capacity, 5-Htt +/2 mice –particularly females– at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction. KW - Medizin Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75795 ER - TY - JOUR A1 - Jakob, Peter A1 - Hertlein, Tobias A1 - Sturm, Volker A1 - Kircher, Stefan A1 - Basse-Lüsebrink, Thomas A1 - Haddad, Daniel A1 - Ohlsen, Knut T1 - Visualization of Abscess Formation in a Murine Thigh Infection Model of Staphylococcus aureus by 19F-Magnetic Resonance Imaging (MRI) N2 - Background: During the last years, 19F-MRI and perfluorocarbon nanoemulsion (PFC) emerged as a powerful contrast agent based MRI methodology to track cells and to visualize inflammation. We applied this new modality to visualize deep tissue abscesses during acute and chronic phase of inflammation caused by Staphylococcus aureus infection. Methodology and Principal Findings: In this study, a murine thigh infection model was used to induce abscess formation and PFC or CLIO (cross linked ironoxides) was administered during acute or chronic phase of inflammation. 24 h after inoculation, the contrast agent accumulation was imaged at the site of infection by MRI. Measurements revealed a strong accumulation of PFC at the abscess rim at acute and chronic phase of infection. The pattern was similar to CLIO accumulation at chronic phase and formed a hollow sphere around the edema area. Histology revealed strong influx of neutrophils at the site of infection and to a smaller extend macrophages during acute phase and strong influx of macrophages at chronic phase of inflammation. Conclusion and Significance: We introduce 19F-MRI in combination with PFC nanoemulsions as a new platform to visualize abscess formation in a murine thigh infection model of S. aureus. The possibility to track immune cells in vivo by this modality offers new opportunities to investigate host immune response, the efficacy of antibacterial therapies and the influence of virulence factors for pathogenesis. KW - Staphylococcus aureus Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-74994 ER - TY - JOUR A1 - Parczyk, Marco A1 - Herold, Volker A1 - Klug, Gert A1 - Bauer, Wolfgang R. A1 - Rommel, Eberhard A1 - Jakob, Peter M. T1 - Regional in vivo transit time measurements of aortic pulse wave velocity in mice with high-field CMR at 17.6 Tesla N2 - Background: Transgenic mouse models are increasingly used to study the pathophysiology of human cardiovascular diseases. The aortic pulse wave velocity (PWV) is an indirect measure for vascular stiffness and a marker for cardiovascular risk. Results: This study presents a cardiovascular magnetic resonance (CMR) transit time (TT) method that allows the determination of the PWV in the descending murine aorta by analyzing blood flow waveforms. Systolic flow pulses were recorded with a temporal resolution of 1 ms applying phase velocity encoding. In a first step, the CMR method was validated by pressure waveform measurements on a pulsatile elastic vessel phantom. In a second step, the CMR method was applied to measure PWVs in a group of five eight-month-old apolipoprotein E deficient (ApoE(-/-)) mice and an age matched group of four C57Bl/6J mice. The ApoE(-/-) group had a higher mean PWV (PWV = 3.0 ± 0.6 m/s) than the C57Bl/6J group (PWV = 2.4 ± 0.4 m/s). The difference was statistically significant (p = 0.014). Conclusions: The findings of this study demonstrate that high field CMR is applicable to non-invasively determine and distinguish PWVs in the arterial system of healthy and diseased groups of mice. KW - Medizin Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68219 ER - TY - JOUR A1 - Dasenbrook, Elliot C. A1 - Lu, Luan A1 - Donnola, Shannon A1 - Weaver, David E. A1 - Gulani, Viskas A1 - Jakob, Peter M. A1 - Konstan, Michael W. A1 - Flask, Chris A. T1 - Normalized T1 Magnetic Resonance Imaging for Assessment of Regional Lung Function in Adult Cystic Fibrosis Patients - A Cross-Sectional Study JF - PLOS ONE N2 - Background: Cystic fibrosis (CF) patients would benefit from a safe and effective tool to detect early-stage, regional lung disease to allow for early intervention. Magnetic Resonance Imaging (MRI) is a safe, non-invasive procedure capable of providing quantitative assessments of disease without ionizing radiation. We developed a rapid normalized T1 MRI technique to detect regional lung disease in early-stage CF patients. Materials and Methods: Conventional multislice, pulmonary T1 relaxation time maps were obtained for 10 adult CF patients with normal spirometry and 5 healthy non-CF control subjects using a rapid Look-Locker MRI acquisition (5 seconds/imaging slice). Each lung absolute T1 map was separated into six regions of interest (ROI) by manually selecting upper, central, and lower lung regions in the left and right lungs. In order to reduce the effects of subject-to-subject variation, normalized T1 maps were calculated by dividing each pixel in the absolute T1 maps by the mean T1 time in the central lung region. The primary outcome was the differences in mean normalized T1 values in the upper lung regions between CF patients with normal spirometry and healthy volunteers. Results: Normalized T1 (nT1) maps showed visibly reduced subject-to-subject variation in comparison to conventional absolute T1 maps for healthy volunteers. An ROI analysis showed that the variation in the nT1 values in all regions was <= 2% of the mean. The primary outcome, the mean (SD) of the normalized T1 values in the upper right lung regions, was significantly lower in the CF subjects [.914 (.037)] compared to the upper right lung regions of the healthy subjects [.983 (.003)] [difference of .069 (95% confidence interval .032-.105); p=.001). Similar results were seen in the upper left lung region. Conclusion: Rapid normalized T1 MRI relaxometry obtained in 5 seconds/imaging slice may be used to detect regional early-stage lung disease in CF patients. KW - infants KW - disease KW - ventilation KW - infection KW - guidelines KW - diagnosis KW - children Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128346 SN - 1932-6203 VL - 8 IS - 9 ER - TY - JOUR A1 - Weise, Gesa A1 - Basse-Lüsebrink, Thomas C. A1 - Kleinschnitz, Christoph A1 - Kampf, Thomas A1 - Jakob, Peter M. A1 - Stoll, Guido T1 - In Vivo Imaging of Stepwise Vessel Occlusion in Cerebral Photothrombosis of Mice by \(^{19}\)F MRI JF - PLoS One N2 - Background \(^{19}\)F magnetic resonance imaging (MRI) was recently introduced as a promising technique for in vivo cell tracking. In the present study we compared \(^{19}\)F MRI with iron-enhanced MRI in mice with photothrombosis (PT) at 7 Tesla. PT represents a model of focal cerebral ischemia exhibiting acute vessel occlusion and delayed neuroinflammation. Methods/Principal Findings Perfluorocarbons (PFC) or superparamagnetic iron oxide particles (SPIO) were injected intravenously at different time points after photothrombotic infarction. While administration of PFC directly after PT induction led to a strong \(^{19}\)F signal throughout the entire lesion, two hours delayed application resulted in a rim-like \(^{19}\)F signal at the outer edge of the lesion. These findings closely resembled the distribution of signal loss on T2-weighted MRI seen after SPIO injection reflecting intravascular accumulation of iron particles trapped in vessel thrombi as confirmed histologically. By sequential administration of two chemically shifted PFC compounds 0 and 2 hours after illumination the different spatial distribution of the \(^{19}\)F markers (infarct core/rim) could be visualized in the same animal. When PFC were applied at day 6 the fluorine marker was only detected after long acquisition times ex vivo. SPIO-enhanced MRI showed slight signal loss in vivo which was much more prominent ex vivo indicative for neuroinflammation at this late lesion stage. Conclusion Our study shows that vessel occlusion can be followed in vivo by \(^{19}\)F and SPIO-enhanced high-field MRI while in vivo imaging of neuroinflammation remains challenging. The timing of contrast agent application was the major determinant of the underlying processes depicted by both imaging techniques. Importantly, sequential application of different PFC compounds allowed depiction of ongoing vessel occlusion from the core to the margin of the ischemic lesions in a single MRI measurement. KW - in vivo imaging KW - magnetic resonance imaging KW - macrophages KW - emulsions KW - infarction KW - fluorine KW - prefrontal cortex KW - developmental signaling Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137792 VL - 6 IS - 12 ER - TY - JOUR A1 - Van den Hove, Daniel A1 - Jakob, Sissi Brigitte A1 - Schraut, Karla-Gerlinde A1 - Kenis, Gunter A1 - Schmitt, Angelika Gertrud A1 - Kneitz, Susanne A1 - Scholz, Claus-Jürgen A1 - Wiescholleck, Valentina A1 - Ortega, Gabriela A1 - Prickaerts, Jos A1 - Steinbusch, Harry A1 - Lesch, Klaus-Peter T1 - Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene x Environment Interactions JF - PLoS ONE N2 - Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-HttxPS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety-and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/-) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChip (R) Mouse Genome 430 2.0 Array. 5-Htt +/- offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/- mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/- genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotypexPS manner, indicating a genexenvironment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/- genotype shows clear adaptive capacity, 5-Htt +/- mice -particularly females-at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction. KW - Serotonin transporter polymorphism KW - Acute tryptophan depletion KW - Anxiety-like behavior KW - Long-term depression KW - Knock-out mice KW - Major depression KW - Interferon-alpha KW - Physiological functions KW - Restraint stress KW - Bipolar disorder Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135111 VL - 6 IS - 8 ER - TY - JOUR A1 - Weibel, Stephanie A1 - Basse-Luesebrink, Thomas Christian A1 - Hess, Michael A1 - Hofmann, Elisabeth A1 - Seubert, Carolin A1 - Langbein-Laugwitz, Johanna A1 - Gentschev, Ivaylo A1 - Sturm, Volker Jörg Friedrich A1 - Ye, Yuxiang A1 - Kampf, Thomas A1 - Jakob, Peter Michael A1 - Szalay, Aladar A. T1 - Imaging of Intratumoral Inflammation during Oncolytic Virotherapy of Tumors by \(^{19}\)F-Magnetic Resonance Imaging (MRI) JF - PLoS ONE N2 - Background Oncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. Unfortunately, non-invasive techniques to evaluate the inflammatory host response to treatment are rare. Here, we evaluate \(^{19}\)F magnetic resonance imaging (MRI) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (PFC) for monitoring of oncolytic virotherapy. Methodology/Principal Findings The Vaccinia virus strain GLV-1h68 was used as an oncolytic agent for the treatment of different tumor models. Systemic application of PFC emulsions followed by \(^1H\)/\(^{19}\)F MRI of mock-infected and GLV-1h68-infected tumor-bearing mice revealed a significant accumulation of the \(^{19}\)F signal in the tumor rim of virus-treated mice. Histological examination of tumors confirmed a similar spatial distribution of the \(^{19}\)F signal hot spots and \(CD68^+\)-macrophages. Thereby, the \(CD68^+\)-macrophages encapsulate the GFP-positive viral infection foci. In multiple tumor models, we specifically visualized early inflammatory cell recruitment in Vaccinia virus colonized tumors. Furthermore, we documented that the \(^{19}\)F signal correlated with the extent of viral spreading within tumors. Conclusions/Significance These results suggest \(^{19}\)F MRI as a non-invasive methodology to document the tumor-associated host immune response as well as the extent of intratumoral viral replication. Thus, \(^{19}\)F MRI represents a new platform to non-invasively investigate the role of the host immune response for therapeutic outcome of oncolytic virotherapy and individual patient response. KW - inflammation KW - fluorescence microscopy KW - oncolytic viruses KW - fluorescence imaging KW - macrophages KW - magnetic resonance imaging KW - histology KW - in vivo imaging Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130311 VL - 8 IS - 3 ER -