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Brain function, the brain's metabolic activity, cerebral blood flow (CBF), and intracranial pressure are intimately linked within the tightly autoregulated regime of intracranial physiology in which the role of tissue viscoelasticity remains elusive. We applied multifrequency magnetic resonance elastography (MRE) paired with CBF measurements in 14 healthy subjects exposed to 5-min carbon dioxide-enriched breathing air to induce cerebral vasodilatation by hypercapnia. Stiffness and viscosity as quantified by the magnitude and phase angle of the complex shear modulus, | G *| and ϕ , as well as CBF of the whole brain and 25 gray matter sub-regions were analyzed prior to, during, and after hypercapnia. In all subjects, whole-brain stiffness and viscosity increased due to hypercapnia by 3.3 ± 1.9% and 2.0 ± 1.1% which was accompanied by a CBF increase of 36 ± 15%. Post-hypercapnia, | G *| and ϕ reduced to normal values while CBF decreased by 13 ± 15% below baseline. Hypercapnia-induced viscosity changes correlated with CBF changes, whereas stiffness changes did not. The MRE-measured viscosity changes correlated with blood viscosity changes predicted by the Fåhræus-Lindqvist model and microvessel diameter changes from the literature. Our results suggest that brain viscoelastic properties are influenced by microvessel blood flow and blood viscosity: vasodilatation and increased blood viscosity due to hypercapnia result in an increase in MRE values related to viscosity.

MRI phase contrast imaging methods that assemble slice-wise acquisitions into volumes can contain interslice phase discontinuities (IPDs) over the course of the scan from sources, including unavoidable physiological activity. In magnetic resonance elastography (MRE), this can alter wavelength and tissue stiffness estimates, invalidating the analysis. We first model this behavior as jitter along the z-axis of the phase of 3D complex-valued wave volumes. A two-step image processing pipeline is then proposed that removes IPDs. First, constant slicewise phase shift is removed with a novel, non-convex dejittering algorithm. Then, regional physiological noise artifacts are removed with novel filtering of 3D wavelet coefficients. Calibration of two pipeline coefficients, the dejitter parameter α and the wavelet band high-pass coefficient ω c , was first performed on a finite-element method brain phantom. A comparative investigation was then performed, on a cohort of 48 brain acquisitions, of four approaches to IPDs: 1) the proposed method; 2) a "control" condition of neglect of IPDs; 3) an anisotropic wavelet-based method; and 4) a method of in-plane (2D) processing. The present method showed medians of [Formula: see text] Pa for a multifrequency wave inversion centered at 40 Hz which was within 6% of methods 3) and 4), while neglect produced [Formula: see text] estimates a mean of 17% lower. The proposed method reduced the value range of the cohort against methods 3) and 4) by 29% and 31%, respectively. Such reduction in variance enhances the ability of brain MRE to predict subtler physiological changes. Our theoretical approach further enables more powerful applications of fundamental findings in noise and denoising to MRE.

Purpose: To measure normal renal stiffness in adults, taking into account regional variation, hydration, and urinary status., Methods: Thirty-six healthy volunteers were examined by tomoelastography based on MR elastography at four frequencies, from 40 to 70 Hz and multifrequency shear wave speed recovery. Regional wave speeds were derived for the medulla, cortex (inner cortex and outer cortex), and renal pelvis, and examined for age-related effects. Subgroups were repeatedly examined for reproducibility, amount of prior water drinking, and urinary status. Variations in renal perfusion were simulated ex vivo using a porcine kidney subjected to venous water inflow at different pressures., Results: Shear wave speed (stiffness) of renal parenchyma was 2.46 ± 0.12 m/s (inner cortex: 2.91 ± 0.17 m/s; outer cortex: 2.52 ± 0.11 m/s; medulla: 2.15 ± 0.08 m/s) without side differences and a tendency toward softening with age (P = 0.028). Corresponding intraclass correlation for reproducibility coefficients were 0.78 (inner cortex: 0.80; outer cortex: 0.81; medulla: 0.80). Water drinking resulted in slightly higher values in inner cortex and lower values in medulla (both P = 0.039), which was consistent with the results in perfused specimens. A full bladder led to higher renal pelvis stiffness (P = 0.004), whereas renal parenchyma remained uninfluenced. Stiffness of the porcine renal cortex increased with venous inflow pressure, whereas medulla stiffness decreased., Conclusions: Tomoelastography provides full field of view maps of renal stiffness with highly detailed resolution and sensitivity to physiological effects related to age and fluid-solid tissue interactions. These basic data could be used to compare pathological conditions in the future. Magn Reson Med 79:2126-2134, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose: To demonstrate the feasibility of in vivo multifrequency magnetic resonance elastography (MRE) of the prostate using externally placed drivers., Methods: Three pressurized-air drivers were used to excite shear waves within the prostate at vibration frequencies of 60, 70, and 80 Hz. Full 3D wave fields were acquired by multislice spin-echo echo-planar imaging in conjunction with tomoelastography wave speed recovery for generating full field-of-view stiffness maps. Twelve healthy volunteers were repeatedly scanned to analyze test-retest reproducibility. Five patients with suspected prostate cancer were investigated to demonstrate the clinical feasibility of the method., Results: In healthy volunteers, the shear wave speed of the entire prostate was 2.24 ± 0.20 m/s with a repeatability coefficient of 0.14 m/s and 88% intraclass correlation coefficient. No significant difference between the peripheral zone (2.27 ± 0.20 m/s) and the central gland (2.22 ± 0.23 m/s) was observed. In patients, wave-speed maps displayed stiff regions consistent with the localization of suspicious masses detected by other imaging markers., Conclusions: The proposed method provides reproducible quantitative maps of tissue stiffness throughout the pelvic region and can easily be integrated into clinical imaging protocols. Clinical stiffness maps display many details of potential interest for cancer diagnosis. Magn Reson Med 79:1325-1333, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Viscoelastic properties of the brain reflect tissue architecture at multiple length scales. However, little is known about the relation between vital tissue functions, such as perfusion, and the macroscopic mechanical properties of cerebral tissue. In this study, arterial spin labelling is paired with magnetic resonance elastography to investigate the relationship between tissue stiffness and cerebral blood flow (CBF) in the in vivo human brain. The viscoelastic modulus, | G*|, and CBF were studied in deep gray matter (DGM) of 14 healthy male volunteers in the following sub-regions: putamen, nucleus accumbens, hippocampus, thalamus, globus pallidus, and amygdala. CBF was further normalized by vessel area data to obtain the flux rate q which is proportional to the perfusion pressure gradient. The striatum (represented by putamen and nucleus accumbens) was distinct from the other DGM regions by displaying markedly higher stiffness and perfusion values. q was a predictive marker for DGM stiffness as analyzed by linear regression | G*| =  q·(4.2 ± 0.6)kPa·s + (0.80 ± 0.06)kPa ( R 2  = 0.92, P = 0.006). These results suggest a high sensitivity of MRE in DGM to perfusion pressure. The distinct mechano-vascular properties of striatum tissue, as compared to the rest of DGM, may reflect elevated perfusion pressure, which could explain the well-known susceptibility of the putamen to hemorrhages.

Purpose: To develop a compact magnetic resonance elastography (MRE) protocol for abdomen and to investigate the effect of water uptake on tissue stiffness in the liver, spleen, kidney, and pancreas., Methods: Nine asymptomatic volunteers were investigated by MRE before and after 1 liter water uptake. Shear-wave excitation at four frequencies was transferred to the abdomen from anterior and posterior directions using pressurized air drivers. Tomographic representations of shear-wave speed were produced by analysis of multifrequency wave numbers in axial and coronal images acquired within four breath-holds or under free breathing, respectively., Results: Pre and post water, stiffness of the spleen (pre/post: 2.20 ± 0.10/2.06 ± 0.18 m/s) and kidney (pre/post: 1.93 ± 0.22/1.97 ± 0.23 m/s) was higher than in the liver (pre/post: 1.36 ± 0.10/1.38 ± 0.13 m/s) and pancreas (pre/post: 1.20 ± 0.12/1.20 ± 0.08 m/s), all P < 0.01. Accounting for four drive frequencies, water drinking only changed the splenic stiffness (-6%, P = 0.03), whereas in the frequency range from 50 to 60 Hz the effect became significant also in the pancreas (-6%, P = 0.04) and liver (+3%, P = 0.03). Elastograms of the kidney in coronal view clearly depicted higher stiffness in cortex than in medulla., Conclusion: Tomoelastography reveals sensitivity of tissue mechanical properties to the hydration state of multiple abdominal organs within one scan and in unprecedented resolution of anatomical details. Magn Reson Med 78:976-983, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Purpose: To demonstrate the feasibility of in vivo wideband MR elastography (wMRE) using continuous, time-harmonic shear vibrations in the frequency range of 10-50 Hz., Theory and Methods: The method was tested in a gel phantom with marked mechanical loss. The brains and livers of eight volunteers were scanned by wMRE using multislice, single-shot MRE with optimized fractional encoding and synchronization of sequence acquisition to vibration. Multifrequency three-dimensional inversion was used to reconstruct compound maps of magnitude |G*| and phase φ of the complex shear modulus. A new phase estimation, φ*, was developed to avoid systematic bias due to noise., Results: In the phantom, G*-dispersion measured by wMRE agreed well with oscillatory shear rheometry. |G*| and φ* measured at vibrations of 10-25 HZ, 25-35 HZ, and 40-50 HZ were 0.62 ± 0.08, 1.56 ± 0.16, 2.18 ± 0.20 kPa and 0.09 ± 0.17, 0.39 ± 0.16, 0.20 ± 0.13 rad in brain and 0.89 ± 0.11, 1.67 ± 0.20, 2.27 ± 0.35 kPa and 0.15 ± 0.10, 0.24 ± 0.05, 0.26 ± 0.05 rad in liver. Elastograms including all frequencies showed the best resolution of anatomical detail with |G*| = 1.38 ± 0.12 kPa, φ* = 0.24 ± 0.10 rad (brain) and |G*| = 1.79 ± 0.23 kPa, φ* = 0.24 ± 0.05 rad (liver)., Conclusion: wMRE reveals highly dispersive G* properties of the brain and liver, and our results suggest that the influence of large-scale structures such as fluid-filled vessels and sulci on the MRE-measured parameters increases at low vibration frequencies. Magn Reson Med 76:1116-1126, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Palpation is one of the most sensitive, effective diagnostic practices, motivating the quantitative and spatially resolved determination of soft tissue elasticity parameters by medical ultrasound or MRI. However, this so-called elastography often suffers from limited anatomical resolution due to noise and insufficient elastic deformation, currently precluding its use as a tomographic modality on its own. We here introduce an efficient way of processing wave images acquired by multifrequency magnetic resonance elastography (MMRE), which relies on wave number reconstruction at different harmonic frequencies followed by their amplitude-weighted averaging prior to inversion. This results in compound maps of wave speed, which reveal variations in tissue elasticity in a tomographic fashion, i.e. an unmasked, slice-wise display of anatomical details at pixel-wise resolution. The method is demonstrated using MMRE data from the literature including abdominal and pelvic organs such as the liver, spleen, uterus body and uterus cervix. Even in small regions with low wave amplitudes, such as nucleus pulposus and spinal cord, elastic parameters consistent with literature values were obtained. Overall, the proposed method provides a simple and noise-robust strategy of in-plane wave analysis of MMRE data, with a pixel-wise resolution producing superior detail to MRE direct inversion methods., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most crucial model input. We conclude that the tumor growth model provides a method to account for anisotropic growth patterns of glioma, and may therefore provide a tool to make target delineation more objective and automated.

Gliomas differ from many other tumors as they grow infiltratively into the brain parenchyma rather than forming a solid tumor mass with a well-defined boundary. Tumor cells can be found several centimeters away from the central tumor mass that is visible using current imaging techniques. The infiltrative growth characteristics of gliomas question the concept of a radiotherapy target volume that is irradiated to a homogeneous dose-the standard in current clinical practice. We discuss the use of the Fisher-Kolmogorov glioma growth model in radiotherapy treatment planning. The phenomenological tumor growth model assumes that tumor cells proliferate locally and migrate into neighboring brain tissue, which is mathematically described via a partial differential equation for the spatio-temporal evolution of the tumor cell density. In this model, the tumor cell density drops approximately exponentially with distance from the visible gross tumor volume, which is quantified by the infiltration length, a parameter describing the distance at which the tumor cell density drops by a factor of e. This paper discusses the implications for the prescribed dose distribution in the periphery of the tumor. In the context of the exponential cell kill model, an exponential fall-off of the cell density suggests a linear fall-off of the prescription dose with distance. We introduce the dose fall-off rate, which quantifies the steepness of the prescription dose fall-off in units of Gy mm(-1). It is shown that the dose fall-off rate is given by the inverse of the product of radiosensitivity and infiltration length. For an infiltration length of 3 mm and a surviving fraction of 50% at 2 Gy, this suggests a dose fall-off of approximately 1 Gy mm(-1). The concept is illustrated for two glioblastoma patients by optimizing intensity-modulated radiotherapy plans. The dose fall-off rate concept reflects the idea that infiltrating gliomas lack a defined boundary and are characterized by a continuous fall-off of the density of infiltrating tumor cells. The approach can potentially be used to individualize the prescribed dose distribution if better methods to estimate radiosensitivity and infiltration length on a patient by patient basis become available.

Despite the increasing number of growth factor-related signalling networks, their lack of logical and causal connection to factual changes in cell states frequently impairs the functional interpretation of microarray data. We present a novel method enabling the automatic inference of causal multi-layer networks from such data, allowing the functional interpretation of growth factor stimulation experiments using pathway databases. Our environment of evaluation was hepatocyte growth factor-stimulated cell migration and proliferation in a keratinocyte-fibroblast co-culture. The network for this system was obtained by applying the steps: (a) automatic integration of the comprehensive set of all known cellular networks from the Pathway Interaction Database into a master structure; (b) retrieval of an active-network from the master structure, where the network edges that connect nodes with an absent mRNA level were excluded; and (c) reduction of the active-network complexity to a causal subnetwork from a set of seed nodes specific for the microarray experiment. The seed nodes comprised the receptors stimulated in the experiment, the consequently differentially expressed genes, and the expected cell states. The resulting network shows how well-known players, in the context of hepatocyte growth factor stimulation, are mechanistically linked in a pathway triggering functional cell state changes. Using BIOQUALI, we checked and validated the consistency of the network with respect to microarray data by computational simulation. The network has properties that can be classified into different functional layers because it not only shows signal processing down to the transcriptional level, but also the modulation of the network structure by the preceeding stimulation. The software for generating computable objects from the Pathway Interaction Database database, as well as the generated networks, are freely available at: http://www.tiga.uni-hd.de/supplements/inferringFromPID.html., (© 2012 The Authors Journal compilation © 2012 FEBS.)

Vitellogenic oocytes of Dysdercus intermedius (Heteroptera: Pyrrhocoridae) were treated with the proton ionophore monensin in order to load the ooplasm with protons along the electrochemical gradient. Additionally, changes in the ooplasmic pH (DeltapH(OOC)) were recorded during exposure the oocytes to potassium-free medium (K(+)(MED)=0mM; choline for K(+)) or sodium-free medium (Na(+)(MED)=0mM; 40mM of choline for 40mM of Na(+)). The following observations were made: 1) The average ooplasmic pH (pH(OOC)) recorded during immersion in physiological saline solution (PSS) was pH(OOC(PSS))=7.40. 2) K(+)(MED) had no effect on pH(OOC) (pH(OOC(K-FREE)) congruent with pH(OOC(PSS))). 3) In sodium-free medium the pH(OOC) decreased by H(+) influx in the magnitude of DeltapH(OOC(Na-FREE))=pH(OOC(Na-FREE))-pH(OOC(PSS))=-0.05 pH units. 4) The decreased pH(OOC) observed in sodium-free medium returned to initial values (7.40) by pumping out H(+) when 40mM of choline were replaced by 40mM of Na(+). 5) Addition of monensin (10&mgr;M; under the condition of Na(+)(MED)=0mM) reduced pH(OOC) in the magnitude of DeltapH(OOC(MON))=pH(OOC(MON))-pH(OOC(PSS))=-0.14. 6) Monensin induced ooplasmic proton loading was reversible when 40mM choline were replaced by 40mM Na(+).VITELLOGENESIS WAS DEMONSTRATED BY THE ACCUMULATION OF FLUORESCENCE LABELLED HEMOLYMPH PROTEINS IN YOLK SPHERES IN THE CORTEX OF THE OOCYTE: 1) Yolk formation continued in potassium-free medium. 2) The formation of yolk spheres came to a halt in sodium-free medium and, additionally, in the presence of monensin (10&mgr;M; Na(+)(MED)=0mM). 3) Breaks in yolk formation under the condition of Na(+)(MED)=0mM or during monensin treatment were stopped by replacing 40mM of choline with 40mM of Na(+). The results obtained using proton-specific microelectrodes and the in vitro assay to detect the formation of yolk spheres indicate that both the ooplasmic pH regulation and the acidification of vesicles during vitellogenesis are under control of a H(+)/Na(+) antiporter.

In the telotrophic ovariole of Dysdercus intermedius the intercellular transport consists of different subsystems. Microinjection of FITC-labeled slowly diffusing proteins with opposite electrical net charges and of mitochondria was used to study the translocation of macromolecules and organelles. a) By intracellular measurements a voltage gradient of about 4 mV between the tropharium as the more negative side and the previtellogenic oocytes could be demonstrated. b) After injection into the tropharium negatively charged proteins migrated according to the electropotential gradient via the trophic cords into the oocytes. Positively charged proteins, however, were retained in the tropharium. c) After injection into previtellogenic oocytes both negatively and positively charged proteins moved into the trophic cords. Thus, the effectiveness of the electropotential gradient on the distribution of charged proteins is more pronounced from the tropharium side. d) Mitochondria microinjected into the trophic core were probably aligned along microtubules and translocated towards the trophic cords. - These results suggest that in the telotrophic bug ovariole a number of intercellular transport subsystems contribute to provide previtellogenic oocytes with nurse cells products. An electrophoretic transport mechanism for soluble proteins acting especially within the tropharium and a microtubule-associated transport for mitochondria could be evidenced.

The motile behaviour of mitochondria in the ovarian trophic cord of the red cotton bug, Dysdercus intermedius, was observed optically using video-enhanced differential interference contrast (AVEC-DIC) microscopy. The motion of 258 video-recorded mitochondria was analysed of which 10%-30% were found to move during the observation periods. Of the moving mitochondria 76% travelled towards the oocyte with an average velocity of 3.37 μm/ min, and 24% towards the tropharium with 2.84 μm/min. The movement was found to be basically of the saltatory type I as known from nerve axons characterized by the absence of directional reversal. In some cases short periods of interrupted motion of type II, i.e. with local oscillations, were observed. Individual mitochondria often showed velocity variations during the excursions. The hemipteran trophic cords are known to contain numerous parallel microtubules. As the observed type of mitochondrial motility resembles axonal transport, a modified transport hypothesis is presented for the microtubule-based motility of organelles in the nurse strands of telotrophic insect ovarioles.