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Leukaemia is the single most common childhood malignancy. With modern treatment regimens, survival in acute lymphoblastic leukaemia (ALL) approaches 90%. Only about 70% of children with acute myeloid leukaemia (AML) achieve long t...
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Leukaemia is the single most common childhood malignancy. With modern treatment regimens, survival in acute lymphoblastic leukaemia (ALL) approaches 90%. Only about 70% of children with acute myeloid leukaemia (AML) achieve long term survival. Patients who relapse have a dismal prognosis. Novel therapeutic approaches are needed to improve treatment outcomes in newly-diagnosed patients with a poor prognosis and for patients with relapsed/refractory disease that have limited treatment options. One promising approach in treating haematological malignancies has been the use of monoclonal antibodies to target cell surface antigens expressed on malignant cells. Most success with monoclonal antibody therapy in the treatment of haematological malignancies has come in the setting of adult B-cell non-Hodgkin lymphoma with the addition of the anti-CD20 monoclonal antibody rituximab to standard treatment regimens. In order to further advance treatment of haematological malignancies, novel monoclonal antibodies continue to be developed that target a variety of cell surface antigens. Several antibodies continue to be investigated in childhood leukaemias. This review will discuss the development of monoclonal antibodies that target a variety of cell surface antigens for the treatment of childhood ALL and the use of the anti-CD33 antibody gemtuzumab ozogamicin in the treatment of childhood AML.
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One of the most prominent characteristics of the human neocortex is its laminated structure. The first person to observe this was Francesco Gennari in the second half the 18th century: in the middle of the depth of primary visual ...
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One of the most prominent characteristics of the human neocortex is its laminated structure. The first person to observe this was Francesco Gennari in the second half the 18th century: in the middle of the depth of primary visual cortex, myelinated fibres are so abundant that he could observe them with bare eyes as a white line. Because of its saliency, the stria of Gennari has a rich history in cyto- and myeloarchitectural research as well as in magnetic resonance (MR) microscopy. In the present paper we show for the first time the layered structure of the human neocortex with exvivo diffusion weighted imaging (DWI). To achieve the necessary spatial and angular resolution, primary visual cortex samples were scanned on an 11.7T small-animal MR system to characterize the diffusion properties of the cortical laminae and the stria of Gennari in particular. The results demonstrated that fractional anisotropy varied over cortical depth, showing reduced anisotropy in the stria of Gennari, the inner band of Baillarger and the deepest layer of the cortex. Orientation density functions showed multiple components in the stria of Gennari and deeper layers of the cortex. Potential applications of layer-specific diffusion imaging include characterization of clinical abnormalities, cortical mapping and (intra)cortical tractography. We conclude that future high-resolution invivo cortical DWI investigations should take into account the layer-specificity of the diffusion properties.
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Structural connectivity research in the human brain . in vivo relies heavily on fiber tractography in diffusion-weighted MRI (DWI). The accurate mapping of white matter pathways would gain from images with a higher resolution than...
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Structural connectivity research in the human brain . in vivo relies heavily on fiber tractography in diffusion-weighted MRI (DWI). The accurate mapping of white matter pathways would gain from images with a higher resolution than the typical ~. 2. mm isotropic DWI voxel size. Recently, high field gradient echo MRI (GE) has attracted considerable attention for its detailed anatomical contrast even within the white and gray matter. Susceptibility differences between various fiber bundles give a contrast that might provide a useful representation of white matter architecture complementary to that offered by DWI.In this paper, Structure Tensor Informed Fiber Tractography (STIFT) is proposed as a method to combine DWI and GE. A data-adaptive structure tensor is calculated from the GE image to describe the morphology of fiber bundles. The structure tensor is incorporated in a tractography algorithm to modify the DWI-based tracking direction according to the contrast in the GE image.This GE structure tensor was shown to be informative for tractography. From closely spaced seedpoints (0.5. mm) on both sides of the border of 1) the optic radiation and inferior longitudinal fasciculus 2) the cingulum and corpus callosum, STIFT fiber bundles were clearly separated in white matter and terminated in the anatomically correct areas. Reconstruction of the optic radiation with STIFT showed a larger anterior extent of Meyer's loop compared to a standard tractography alternative. STIFT in multifiber voxels yielded a reduction in crossing-over of streamlines from the cingulum to the adjacent corpus callosum, while tracking through the fiber crossings of the centrum semiovale was unaffected.The STIFT method improves the anatomical accuracy of tractography of various fiber tracts, such as the optic radiation and cingulum. Furthermore, it has been demonstrated that STIFT can differentiate between kissing and crossing fiber configurations. Future investigations are required to establish the applicability in more white matter pathways.
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In order to allow for a comparative evaluation of the invivo degeneration of biological and tissue-engineered heart valves and vascular grafts, a small animal model of accelerated cardiovascular calcification is desired. Wistar ra...
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In order to allow for a comparative evaluation of the invivo degeneration of biological and tissue-engineered heart valves and vascular grafts, a small animal model of accelerated cardiovascular calcification is desired. Wistar rats (n=102; 6 groups) were fed ad libitum with regular chow and 5 different regimens of pro-calcific diet supplemented with combinations of vitamin D (VD), cholesterol (CH) and dicalcium phosphate (PH). Moreover, cryopreserved (n=7) or detergent-decellularized rat aortic conduit grafts (n=6) were infrarenally implanted in Wistar rats under severely pro-calcific conditions. The follow-up lasted up to 12 weeks. High-dose application of VD (300,000IU/kg), CH (2%) and PH (1.5%) resulted in elevated serum calcium and cholesterol levels as well as LDL/HDL ratio. It increased the tissue MMP activity visualized by in situ zymography and caused significantly aggravated calcification of the native aortic valve as well as the aortic wall as assessed by histology and micro-computed tomography. (Immuno)histology and quantitative real-time PCR revealed chondro-osteogenic cell transformation, lipid deposition, nitrosative stress and low-level inflammation to be involved in the formation of calcific lesions. Despite pro-calcific invivo conditions, decellularization significantly reduced calcification, inflammation and intimal hyperplasia in aortic conduit implants. A well balanced dietary trigger for pathologic metabolic conditions may represent an appropriate mid-term treatment to induce calcifying degeneration of aortic valves as well as vascular structures in the systemic circulation in rats. With respect to experimental investigation focusing on calcifying degeneration of native or prosthetic tissue, this regimen may serve as a valuable tool with a rapid onset and multi-facetted character of cardiovascular degeneration.
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The interstitial cells of cardiac valves represent one of the most frequent cell types in the mammalian heart. In order to provide a cell and molecular biological basis for the growth of isolated valvular interstitial cells (VICs)...
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The interstitial cells of cardiac valves represent one of the most frequent cell types in the mammalian heart. In order to provide a cell and molecular biological basis for the growth of isolated valvular interstitial cells (VICs) in cell culture and for the use in re-implantation surgery we have examined VICs in situ and in culture, in fetal, postnatal and adult hearts, in re-associations with scaffolds of extracellular matrix (ECM) material and decellularized heart valves. In all four mammalian species examined (human, bovine, porcine and ovine), the typical mesenchymal-type cell-cell adherens junctions (AJs) connecting VICs appear as normal N-cadherin based puncta adhaerentia. Their molecular ensemble, however, changes under various growth conditions insofar as plakophilin-2 (Pkp2), known as a major cytoplasmic plaque component of epithelial desmosomes, is recruited to and integrated in the plaques of VIC-AJs as a major component under growth conditions characterized by enhanced proliferation, i.e., in fetal heart valves and in cell cultures. Upon re-seeding onto decellularized heart valves or in stages of growth in association with artificial scaffolds, Pkp2 is - for the most part - lost from the AJs. As Pkp2 has recently also been detected in AJs of cardiac myxomata and diverse other mesenchymal tumors, the demonstrated return to the normal Pkp2-negative state upon re-association with ECM scaffolds and decellularized heart valves may now provide a safe basis for the use of cultured VICs in valve replacement surgery. Even more surprising, this type of transient acquisition of Pkp2 has also been observed in distinct groups of endothelial cells of the endocardium, where it seems to correspond to the cell type ready for endothelial-mesenchymal transition (EMT).
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With combined EEG-fMRI a powerful combination of methods was developed in the last decade that seems promising for answering fundamental neuroscientific questions by measuring functional processes of the human brain simultaneously...
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With combined EEG-fMRI a powerful combination of methods was developed in the last decade that seems promising for answering fundamental neuroscientific questions by measuring functional processes of the human brain simultaneously with two complementary modalities. Recently, resting state networks (RSNs), representing brain regions of coherent BOLD fluctuations, raised major interest in the neuroscience community. Since RSNs are reliably found across subjects and reflect task related networks, changes in their characteristics might give insight to neuronal changes or damage, promising a broad range of scientific and clinical applications. The question of how RSNs are linked to electrophysiological signal characteristics becomes relevant in this context. In this combined EEG-fMRI study we investigated the relationship of RSNs and their correlated electrophysiological signals [electrophysiological correlation patterns (ECPs)] using a long (34 min) resting state scan per subject. This allowed us to study ECPs on group as well as on single subject level, and to examine the temporal stability of ECPs within each subject. We found that the correlation patterns obtained on group level show a large inter-subject variability. During the long scan the ECPs within a subject show temporal fluctuations, which we interpret as a result of the complex temporal dynamic of the RSNs.
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Decellularization is a promising option to diminish immune and inflammatory response against donor grafts. In order to accelerate the autologous invivo recellularization of aortic conduits for an enhanced biocompatibility, we test...
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Decellularization is a promising option to diminish immune and inflammatory response against donor grafts. In order to accelerate the autologous invivo recellularization of aortic conduits for an enhanced biocompatibility, we tested fibronectin surface coating in a standardized rat implantation model. Detergent-decellularized rat aortic conduits (n=36) were surface-coated with covalently Alexa488-labeled fibronectin (50μg/ml, 24h) and implanted into the systemic circulation of Wistar rats for up to 8 weeks (group FN; n=18). Uncoated implants served as controls (group C; n=18). Fibronectin-bound fluorescence on both surfaces of the aortic conduits was persistent for at least 8 weeks. Cellular repopulation was examined by histology and immunofluorescence (n=24). Luminal endothelialization was significantly accelerated in group FN (p=0.006 after 8 weeks), however, local myofibroblast hyperplasia with significantly increased ratio of intima-to-media thickness occurred (p=0.0002 after 8 weeks). Originating from the adventitial surface, alpha-smooth muscle actin and desmin positive cell invasion into the media of fibronectin-coated conduits was significantly increased as compared to group C (p<0.0001). In these medial areas, in situ zymography revealed enhanced matrix metalloproteinase activity. In both groups, inflammatory cell markers (CD3 and CD68) and signs of thrombosis proved negative. With regard to several markers of cell adhesion, inflammation and calcification, quantitative real-time PCR (n=12) revealed no significant inter-group differences. Fibronectin surface coating of decellularized cardiovascular implants proved feasible and persistent for at least 8 weeks in the systemic circulation. Biofunctional protein coating accelerated the autologous invivo endothelialization and induced a significantly increased medial recellularization. Therefore, this strategy may contribute to the improvement of current clinically applied bioprostheses.
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Background: Today, bovine pericardium (BP) is extensively investigated as a biomaterial for the generation of various bioimplants. But despite the commercial distribution, and the development of methods either to remove (decellula...
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Background: Today, bovine pericardium (BP) is extensively investigated as a biomaterial for the generation of various bioimplants. But despite the commercial distribution, and the development of methods either to remove (decellularization) or to mask (chemical cross-linking, for example by glutaraldehyde [GA] treatment) the xenogeneic antigen epitopes, yet questions around the immunogenic reactivity of BP remain. The aim of this study is the comparison of crucial tissue characteristics, that is, biomechanical properties, the presence of αGal epitopes, and residual DNA in acellular vs. GA-fixed BP. Methods: Bovine pericardium was either cross-linked with 0.6% GA or decellularized according to two common protocols using either sodium dodecyl sulfate (SDS) and desoxycholic acid (DCA) or trypsin and ethylenediaminetetraacetic acid (EDTA). The resulting extracellular matrix was prone to one-dimensional tensile testing. The tissue content for αGal was evaluated by immunoblotting, and residual DNA was determined by a commercial assay. Untreated BP served as control. Results: In contrast to previous reports, we found a pronounced decrease in the elastic modulus (E-Modulus) for common GA treatment and overall smaller values for the elastic moduli after decellularization (P < 0.05). In parallel, we observed an overall increased ultimate elongation of acellular and cross-linked BP, although ultimate stress values did not significantly differ. SDS/DCA decellularized BP revealed a dramatic reduction in the DNA content and an almost complete removal of αGal epitopes, whereas the trypsin/EDTA protocol retained a residual DNA content of almost 50% and with a great trail of αGal signal. GA-treated tissue had a remarkable content of DNA and αGal. Conclusions: Although chemically fixated BP is clinically still in wide use, for example, for biological heart valve engineering, our results suggest that an improved biomaterial preparation may be provided by appropriate decellularization. SDS/DCA decellularized BP shows similar biomechanical characteristics as GA treatment, paired with reduced potential immunogenic reactivity. Furthermore, decellularized BP holds the potential of cellular repopulation in vivo or in vitro, to enable an endogenous regenerative capacity in contrast to the toxic effects of GA fixing.
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Visual attention is used to selectively filter relevant information depending on current task demands and goals. Visual attention is called object-based attention when it is directed to coherent forms or objects in the visual fiel...
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Visual attention is used to selectively filter relevant information depending on current task demands and goals. Visual attention is called object-based attention when it is directed to coherent forms or objects in the visual field. This study used real-time functional magnetic resonance imaging for moment-to-moment decoding of attention to spatially overlapped objects belonging to two different object categories. First, a whole-brain classifier was trained on pictures of faces and places. Subjects then saw transparently overlapped pictures of a face and a place, and attended to only one of them while ignoring the other. The category of the attended object, face or place, was decoded on a scan-by-scan basis using the previously trained decoder. The decoder performed at 77.6% accuracy indicating that despite competing bottom-up sensory input, object-based visual attention biased neural patterns towards that of the attended object. Furthermore, a comparison between different classification approaches indicated that the representation of faces and places is distributed rather than focal. This implies that real-time decoding of object-based attention requires a multivariate decoding approach that can detect these distributed patterns of cortical activity.
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Echo planar imaging (EPI) is most commonly used for blood oxygen level-dependent fMRI, owing to its sensitivity and acquisition speed. A major problem with EPI is Nyquist (N/2) ghosting, most notably at high field. EPI data are ac...
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Echo planar imaging (EPI) is most commonly used for blood oxygen level-dependent fMRI, owing to its sensitivity and acquisition speed. A major problem with EPI is Nyquist (N/2) ghosting, most notably at high field. EPI data are acquired under an oscillating readout gradient and hence vulnerable to gradient imperfections such as eddy current delays and off-resonance effects, as these cause inconsistencies between odd and even k-space lines after time reversal. We propose a straightforward and pragmatic method herein termed "interleaved dual echo with acceleration (IDEA) EPI": two k-spaces (echoes) are acquired under the positive and negative readout lobes, respectively, by performing phase encoding blips only before alternate readout gradients. From these two k-spaces, two almost entirely ghost free images per shot can be constructed, without need for phase correction. The doubled echo train length can be compensated by parallel imaging and/or partial Fourier acquisition. The two k-spaces can either be complex averaged during reconstruction, which results in near-perfect cancellation of residual phase errors, or reconstructed into separate images. We demonstrate the efficacy of IDEA EPI and show phantom and in vivo images at both 3 T and 7 T. Magn Reson Med, 2013.
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