Modelle der Kommunikation präkortikaler und kortikaler Hirnareale im somatosensorischen System: Charakterisierung anhand somatosensorisch nieder- und hochfrequenter neuronaler Aktivität bei variierendem Stimuluskontext

Die Messung elektrischer Felder und Potentiale am somatosensorischen Kortex bei peripherer elektrischer Stimulation des Mittelarmnervs erlaubt eine stufenweise Analyse des sensorischen Informationsflusses, da im Signal gleichzeitig präkortikale und kortikale Anteile reflektiert werden. Mit der Aktivität dreier Quellen - einer frühen präkortikalen (thalamischen) und zwei kortikalen, soll die Modulation der Aktivität (= Änderung der Informationsübertragung zwischen Hirnarealen) hervorgerufen werden. Untersucht wurden die Einflüsse des Stimuluskontext in Form von a) Interferenz durch die konkurrierende akustische Modalität und b) das Vorkommen von Stimulusmustern (Zielreiz und Nichtzielreiz) auf die Verarbeitung früher somatosensorischer Komponenten. Ausgewertet wurden die Aktivität in zwei Frequenzbändern, jeweils im niederfrequenten (NF, < 250 Hz) sowie im hochfrequenten (HF, 450-750 Hz) Bereich. Hauptergebnis ist die kontextuale Modulation früher somatosensorischer Aktivität nach elektrischer Stimulation periphärer Nerven festgehalten werden. Die Interferenz durch die konkurrierende akustische Modalität hatte einen signifikanten Einfluss auf die Aktivität der somatosensorischen Quellen. Dies spricht für eine Rückkopplung der primärsomatosensorischen auf präkortikale Areale. In einer weiteren Teilauswertung wurde die Möglichkeit untersucht, thalamokortikale Afferenz in Form eines Summenaktionspotentials nicht invasiv am menschlichen Gehirn darzustellen. Grundlage war eine Studie, welche kontinuierliche Signalpropagation entlang der thalamokortikalen Nervenfasern berichtete und eine einzelne wandernde Quelle annahm. Die vorliegenden Ergebnisse deuten jedoch eher in Richtung eines Zwei-Quellen-Modells, welches zwei getrennte Aktivitäten im Thalamus sowie im Kortex annimmt. Die vermeintlich kontinuierliche Signalwanderung ist vermutlich eher als Shift des Gravitationszentrums von einem Aktivitätszentrum zur anderen zu verstehen

Estimation of Dose Distribution for Lu-177 Therapies in Nuclear Medicine

In nuclear medicine, two frequent applications of 177-Lu therapy exist: DOTATOC therapy for patients with a neuroendocrine tumor and PSMA thearpy for prostate cancer. During the therapy a pharmaceutical is injected intravenously, which attaches to tumor cells due to its molecular composition. Since the pharmaceutical contains a radioactive 177Lu isotope, tumor cells are destroyed through irradiation. Afterwards the substance is excreted via the kidneys. Since the latter are very sensitive to high energy radiation, it is necessary to compute exactly how much radioactivity can be administered to the patient without endangering healthy organs. This calculation is called dosimetry and currently is made according to the state of the art MIRD method. At the beginning of this work, an error assessment of the established method is presented, which has determined an overall error of 25% in the renal dose value. The presented study improves and personalizes the MIRD method in several respects and reduces individual error estimates considerably. In order to be able to estimate of the amount of activity, first a test dose is injected to the patient. Subsequently, after 4h, 24h, 48h and 72h SPECT images are taken. From these images the activity at each voxel can be obtained a specified time points, i. e. the physical decline and physiological metabolization of the pharmaceutical can be followed in time. To calculate the amount of decay in each voxel from the four SPECT registrations, a time activity curve must be integrated. In this work, a statistical method was developed to estimate the time dependent activity and then integrate a voxel-by-voxel time-activity curve. This procedure results in a decay map for all available 26 patients (13 PSMA/13 DOTATOC). After the decay map has been estimated, a full Monte Carlo simulation has been carried out on the basis of these decay maps to determine a related dose distribution. The simulation results are taken as reference (“Gold Standard”) and compared with methods for an approximate but faster estimation of the dose distribution. Recently, a convolution with Dose Voxel Kernels (DVK) has been established as a standard dose estimation method (Soft Tissue Scaling STS). Thereby a radioactive Lutetium isotope is placed in a cube consisting of soft tissue. Then radiation interactions are simulated for a number of 10^10 decays. The resulting Dose Voxel Kernel is then convolved with the estimated decay map. The result is a dose distribution, which, however, does not take into account any tissue density differences. To take tissue inhomogeneities into account, three methods are described in the literature, namely Center Scaling (CS), Density Scaling (DS), and Percentage Scaling (PS). However, their application did not improve the results of the STS method as is demonstrated in this study. Consequently, a neural network was trained finally to estimate DVKs adapted to the respective individual tissue density distribution. During the convolution process, it uses for each voxel an adapted DVK that was deduced from the corresponding tissue density kernel. This method outperformed the MIRD method, which resulted in an uncertainty of the renal dose between -42.37-10.22% an achieve a reduction in the uncertainty to a range between -26.00%-7.93%. These dose deviations were calculated for 26 patients and relate to the mean renal dose compared with the respective result of the Monte Carlo simulation. In order to improve the estimates of dose distribution even further, a 3D 2D neural network was trained in the second part of the work. This network predicts the dose distribution of an entire patient. In combination with an Empirical Mode Decomposition, this method achieved deviations of only -12.21%-2.13% . The mean deviation of the dose estimates is in the range of the statistical error of the Monte Carlo simulation. In the third part of the work, a neural network was used to automatically segment the kidney, spleen and tumors. Compared to an established segmentation algorithm, the method developed in this work can segment tumors because it uses not only the CT image as input, but also the SPECT image

Impaired evoked and resting-state brain oscillations in patients with liver cirrhosis as revealed by magnetoencephalography

AbstractA number of studies suggest that the clinical manifestation of neurological deficits in hepatic encephalopathy results from pathologically synchronized neuronal oscillations and altered oscillatory coupling. In the present study spontaneous and evoked oscillatory brain activities were analyzed jointly with established behavioral measures of altered visual oscillatory processing. Critical flicker and fusion frequencies (CFF, FUF) were measured in 25 patients diagnosed with liver cirrhosis and 30 healthy controls. Magnetoencephalography (MEG) data were collected at rest and during a visual task employing repetitive stimulation. Resting MEG and evoked fields were analyzed. CFF and FUF were found to be reduced in patients, providing behavioral evidence for deficits in visual oscillatory processing. These alterations were found to be related to resting brain activity in patients, namely that the lower the dominant MEG frequency at rest, the lower the CFF and FUF. An analysis of evoked fields at sensor level indicated that in comparison to normal controls, patients were not able to dynamically adapt to flickering visual stimulation. Evoked activity was also analyzed based on independent components (ICs) derived by independent component analysis. The similarity between the shape of each IC and an artificial sine function representing the stimulation frequency was tested via magnitude squared coherence. In controls, we observed a small number of components that correlated strongly with the sine function and a high number of ICs that did not correlate with the sine function. Interestingly, patient data were characterized by a high number of moderately correlating components. Taken together, these results indicate a fundamental divergence of the cerebral resonance activity in cirrhotic patients

Automated and rapid identification of multidrug resistant Escherichia coli against the lead drugs of acylureidopenicillins, cephalosporins, and fluoroquinolones using specific Raman marker bands

A Raman-based, strain-independent, semi-automated method is presented that allows the rapid (<3 hours) determination of antibiotic susceptibility of bacterial pathogens isolated from clinical samples. Applying a priori knowledge about the mode of action of the respective antibiotic, we identified characteristic Raman marker bands in the spectrum and calculated batch-wise weighted sum scores from standardized Raman intensity differences between spectra of antibiotic exposed and nonexposed samples of the same strains. The lead substances for three relevant antibiotic classes (fluoroquinolone ciprofloxacin, third-generation cephalosporin cefotaxime, ureidopenicillin piperacillin) against multidrug-resistant Gram-negative bacteria (MRGN) revealed a high sensitivity and specificity for the susceptibility testing of two Escherichia coli laboratory strains and 12 clinical isolates. The method benefits from the parallel incubation of control and treated samples, which reduces the variance due to alterations in cultivation conditions and the standardization of differences between batches leading to long-term comparability of Raman measurements. © 2020 The Authors. Journal of Biophotonics published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinhei

GLI1(+) progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

As certain strains of mice age, hyperplastic lesions resembling gonadal tissue accumulate beneath the adrenal capsule. Gonadectomy (GDX) accelerates this heterotopic differentiation, resulting in the formation of wedge-shaped adrenocortical neoplasms that produce sex steroids. Stem/progenitor cells that reside in the adrenal capsule and retain properties of the adrenogonadal primordium are thought to be the source of this heterotopic tissue. Here, we demonstrate that GLI1(+) progenitors in the adrenal capsule give rise to gonadal-like cells that accumulate in the subcapsular region. A tamoxifen-inducible Cre driver (Glil-creER(T2)) and two reporters (R26R-lacZ, R26R-confetti) were used to track the fate of GLI1(+) cells in the adrenal glands of B6D2F2 mice, a strain that develops both GDX-induced adrenocortical neoplasms and age-dependent subcapsular cell hyperplasia. In gonadectomized B6D2F2 mice GLI1(+) progenitors contributed to long-lived adrenal capsule cells and to adrenocortical neoplasms that expressed Gata4 and Foxl2, two prototypical gonadal markers. Pdgfra, a gene expressed in adrenocortical stromal cells, was upregulated in the GDX-induced neoplasms. In aged non-gonadectomized B6D2F2 mice GLI1(+) progenitors gave rise to patches of subcapsular cell hyperplasia. Treatment with GANT61, a small-molecule GLI antagonist, attenuated the upregulation of gonadal-like markers (Gata4, Foxl2) in response to GDX. These findings support the premise that GLI1(+) progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic tissue. (C) 2016 Elsevier Ireland Ltd. All rights reserved.Peer reviewe

Feedback inhibition of the general phenylpropanoid and flavonol biosynthetic pathways upon a compromised flavonol-3-O-glycosylation

Flavonols, phenylalanine-derived secondary metabolites, have protective and regulatory functions in plants. In Arabidopsis thaliana, they are consecutively glycosylated at their 3-OH and 7-OH groups. UGT78D1 and UGT78D2 are the major flavonol 3-O-glycosyltransferases in Arabidopsis leaves. The ugt78d1 ugt78d2 double mutant, which was strongly compromised in the initial 3-O-glycosylation, showed a severe and specific repression of flavonol biosynthesis, retaining only one-third of the wild-type level. This metabolic phenotype was associated with a repressed transcription of several flavonol biosynthetic genes including the committed step chalcone synthase [(CHS) or TRANSPARENT TESTA 4 (TT4)]. Furthermore, the committed step of the upstream, general phenylpropanoid pathway, phenylalanine ammonia-lyase (PAL), was down-regulated in its enzyme activity and in the transcription of the flavonol-related PAL1 and PAL2. However, a complete blocking of flavonoid biosynthesis at CHS released PAL inhibition in a tt4 ugt78d1 ugt78d2 line. PAL activity was even enhanced in the flavonol synthase 1 mutant, which compromises the final formation of flavonol aglycones. The dependence of the PAL feedback inhibition on flavonols was confirmed by chemical complementation of tt4 ugt78d1 ugt78d2 using naringenin, a downstream flavonoid intermediate, which restored the PAL repression. Although aglycones were not analytically detectable, this study provides genetic evidence for a novel, flavonol-dependent feedback inhibition of the flavonol biosynthetic pathway and PAL. It was conditioned by the compromised flavonol-3-O-conjugation and a decrease in flavonol content, yet dependent on a residual, flavonol synthase 1 (FLS1)-related capacity to form flavonol aglycones. Thus, this regulation would not react to a reduced metabolic flux into flavonol biosynthesis, but it might prevent the accumulation of non-glycosylated, toxic flavonols

EMT for HDR-BT

The current study develops an automatic analysis tool of EMT data sets recorded with a solenoid sensor to assure concordance of the source move- ment with the treatment plan. The tool combines machine learning tech- niques such as multi-dimensional scaling (MDS), ensemble empirical mode decomposition (EEMD), singular spectrum analysis (SSA) and particle filter (PF) to precisely detect and quantify any mismatch between the treatment plan and actual EMT measurements