Volker Rasche

Computed tomography in color: NanoK-enhanced spectral CT molecular imaging.

New multidetector cardiac computed tomography (MDCT) can image the heart within the span of a few beats, and as such, it is the favored noninvasive approach to assess coronary anatomy rapidly. However, MDCT has proven to be more useful for excluding coronary disease than for making positive diagnoses. The inability to detect unstable cardiac disease arises from the confounding attenuating effects of calcium deposits within atherosclerotic plaques, which obscure lumen anatomy, and from the insensitivity of CT X-rays to image low attenuating intraluminal thrombus adhered to a disrupted plaque cap, the absolute condition of ruptured plaque and unstable disease.[1–6] It is now well understood that the sensitive detection and quantification of small intravascular thrombus in coronary arteries with molecular imaging techniques could provide a direct metric to diagnose and risk stratify patients presenting with chest pain.[7,8]

Lysosomal degradation of the carboxydextran shell of coated superparamagnetic iron oxide nanoparticles and the fate of professional phagocytes

Contrast agents based on dextran-coated superparamagnetic iron oxide nanoparticles (SPIO) are internalized by professional phagocytes such as hepatic Kupffer cells, yet their role in phagocyte biology remains largely unknown. Here we investigated the effects of the SPIO ferucarbotran on murine Kupffer cells and human macrophages. Intravenous injection of ferucarbotran into mice led to rapid accumulation of the particles in phagocytes and to long-lasting increased iron deposition in liver and kidneys. Macrophages incorporate ferucarbotran in lysosomal vesicles containing α-glucosidase, which is capable of degrading the carboxydextran shell of the ferucarbotran particles. Intravenous injection of ferucarbotran into mice followed by incorporation of the nanoparticles into Kupffer cells triggered apoptosis and the subsequent depletion of Kupffer cells. In macrophages, the proinflammatory cytokine TNF-α increased the apoptosis rate, the reactive oxygen species production and the activation of c-Jun N-terminal kinase elicited by ferucarbotran, which might be mediated by the induction of cytoplasmic phospholipase A2 by TNF-α. Notably, the nanoparticle-induced apoptosis of murine Kupffer cells could be prevented by treatment of the mice with the radical scavenger edaravone. Thus, nanosized carboxydextran-coated SPIO-based contrast agents are retained for extended time periods by liver macrophages, where they elicit delayed cell death, which can be antagonized by a therapeutic radical scavenger.

Cell competition is a tumour suppressor mechanism in the thymus

Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between ‘young’ bone-marrow-derived and ‘old’ thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.

High-resolution ZTE imaging of human teeth

MRI with zero echo time (ZTE) is achieved by 3D radial centre‐out encoding and hard‐pulse RF excitation while the projection gradient is already on. Targeting short‐T2 samples, the efficient, robust and silent ZTE approach was implemented for high‐bandwidth high‐resolution imaging requiring particularly rapid transmit‐receive switching and algebraic image reconstruction. The ZTE technique was applied to image extracted human teeth at 11.7T field strength, yielding detailed depictions with very good delineation of the mineralised dentine and enamel layers. ZTE results are compared with UTE (ultra‐short echo time) MRI and micro‐computed tomography (μCT), revealing significant differences in SNR and CNR yields. Compared to μCT, ZTE MRI appears to be less susceptible to artefacts caused by dental fillings and to offer superior sensitivity for the detection of early demineralisation and caries lesions. Copyright

Characterization of patients with acute chest pain using cardiac magnetic resonance imaging

AimsThe purpose of this study was to evaluate whether CMRI provides characteristic findings in patients with acute chest pain suffering from ST-elevation-myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), acute myocarditis or Tako-tsubo cardiomyopathy.Patients and methods230 consecutive patients with acute chest pain underwent cardiac catheterization followed by CMRI within median 5xa0days. Patients were classified to suffer from STEMI (nxa0=xa0102), NSTEMI (nxa0=xa089), acute myocarditis (nxa0=xa027), or Tako-tsubo cardiomyopathy (nxa0=xa012) on the synopsis of all clinical data. Wall motion abnormalities, late enhancement (LE), persistent microvascular obstruction as well ventricular volumes and functions were assessed by CMRI.ResultsRight and left ventricular volumes were significantly different between the groups and values were highest in patients with acute myocarditis. Wall motion abnormalities were observed in 100% of STEMI, 75% of NSTEMI, 67% of acute myocarditis and 100% of Tako-tsubo patients. There was a characteristic pattern of abnormal wall motion focused on midventricular-apical segments in patients with Tako-tsubo cardiomyopathy, depending on the culprit vessel in patients with STEMI/NSTEMI and with a random distribution in patients with acute myocarditis. LE was mainly subendocardial or transmural in patients with STEMI (93.2%) or NSTEMI (62.9%). LE was diffuse, intramural or subepicardial in patients with acute myocarditis. No LE was observed in patients with Tako-tsubo cardiomyopathy. Persistent microvascular obstruction was only visualized in patients with STEMI (33%) or NSTEMI (6%).ConclusionsCardiac magnetic resonance imaging provides characteristic patterns of LE, persistent microvascular obstruction and wall motion abnormalities that allow a differentiation between patients with acute chest pain from coronary and non-coronary origin.

Feasibility of ultra-short echo time (UTE) magnetic resonance imaging for identification of carious lesions.

The objective of this study was to investigate the potential of ultra short echo time imaging for the assessment of caries lesions and early demineralization. 12 patients with suspected caries lesions underwent a dental magnetic resonance imaging investigation comprising ultra short echo time imaging (echo time = 50 μs) and spin echo imaging. Before the dental magnetic resonance imaging, all patients underwent a conventional clinical dental investigation including visual assessment of the teeth as well as dental x‐ray imaging. All lesions identifiable in the x‐ray could be clearly identified in the ultra short echo time images, but only about 19% of the lesions were visible in the spin echo images. In 19% of all lesions, the lesions could be more clearly delineated in the ultra short echo time images than in the x‐ray images. This was especially the case for secondary lesions. In direct comparison with the x‐ray images, all lesions appeared substantially larger in the dental magnetic resonance imaging data. The presented data provide evidence that caries lesions can be identified in ultra short echo time magnetic resonance imaging with high sensitivity. The apparent larger volume of the lesions in dental magnetic resonance imaging may be attributed to fluid accumulation in demineralized areas without substantial breakdown of mineral structures. Magn Reson Med, 2011.

Automatic generation of 3D coronary artery centerlines using rotational X-ray angiography

A fully automated 3D centerline modeling algorithm for coronary arteries is presented. It utilizes a subset of standard rotational X-ray angiography projections that correspond to one single cardiac phase. The algorithm is based on a fast marching approach, which selects voxels in 3D space that belong to the vascular structure and introduces a hierarchical order. The local 3D propagation speed is determined by a combination of corresponding 2D projections filtered with a vessel enhancing kernel. The best achievable accuracy of the algorithm is evaluated on simulated projections of a virtual heart phantom, showing that it is capable of extracting coronary centerlines with an accuracy that is mainly limited by projection and volume quantization (0.25 mm). The algorithm is reasonably insensitive to residual motion, which means that it is able to cope with inconsistencies within the projection data set caused by limited gating accuracy and respiration. Its accuracy on clinical data is evaluated based on expert ratings of extracted models of 17 consecutive clinical cases (10 LCA, 7 RCA). A success rate of 93.5% (i.e. with no or slight deviations) is achieved compared to 58.8% success rate of semi-automatically extracted models.

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis

Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.

The toxic effect of R350P mutant desmin in striated muscle of man and mouse

Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin in our mouse model as well as in skeletal muscle specimens derived from human R350P desminopathies. Furthermore, we demonstrate that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners. Our findings unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers. These structural defects elicited at the myofiber level finally impact the entire organ and subsequently cause myopathy and cardiomyopathy.

Automatic generation of time resolved motion vector fields of coronary arteries and 4D surface extraction using rotational x-ray angiography

Rotational coronary angiography provides a multitude of x-ray projections of the contrast agent enhanced coronary arteries along a given trajectory with parallel ECG recording. These data can be used to derive motion information of the coronary arteries including vessel displacement and pulsation. In this paper, a fully automated algorithm to generate 4D motion vector fields for coronary arteries from multi-phase 3D centerline data is presented. The algorithm computes similarity measures of centerline segments at different cardiac phases and defines corresponding centerline segments as those with highest similarity. In order to achieve an excellent matching accuracy, an increasing number of bifurcations is included as reference points in an iterative manner. Based on the motion data, time-dependent vessel surface extraction is performed on the projections without the need of prior reconstruction. The algorithm accuracy is evaluated quantitatively on phantom data. The magnitude of longitudinal errors (parallel to the centerline) reaches approx. 0.50 mm and is thus more than twice as large as the transversal 3D extraction errors of the underlying multi-phase 3D centerline data. It is shown that the algorithm can extract asymmetric stenoses accurately. The feasibility on clinical data is demonstrated on five different cases. The ability of the algorithm to extract time-dependent surface data, e.g. for quantification of pulsating stenosis is demonstrated.