In vivo Imaging of Bile Accumulation and Biliary Infarction after Common Bile Duct Ligation in Rats

Obstructive cholestasis is caused by mechanical constriction or occlusion leading to reduced bile flow. Serious complications such as jaundice and even death may follow. Little is known about the initial phase of cholestasis and its consequences for the hepatic microarchitecture. This in vivo study aimed to characterize the nature and kinetics of developing obstructive cholestasis and focused on areas with biliary stasis and infarction by visualizing the autofluorescence of bile acids using intravital microscopy of the liver over a period of 30 h after bile duct ligation in rats. The innovation resided in performing fluorescence microscopy without applying fluorescent dyes. In animals subjected to obstructive cholestasis, the most significant changes observed in vivo were the concomitant appearance of (1) areas with bile accumulation increasing in size (6 h: 0.163 ± 0.043, 18 h: 0.180 ± 0.086, 30 h: 0.483 ± 0.176 mm2/field) and (2) areas with biliary infarction (6 h: 0.011 ± 0.006, 18 h: 0.010 ± 0.004, 30 h: 0.010 ± 0.050 mm2/field) as well as (3) a relation between the formation of hepatic lesions and enzyme activity in serum. The sequential in vivo analysis presented herein is a new method for the in vivo visualization of the very early changes in the hepatic parenchyma caused by obstructive cholestasis

Neuroimaging of functional and structural alterations in Juvenile Myoclonic Epilepsy and Frontal Lobe Epilepsy

Epilepsy is the commonest neurological disorder and has profound effects on patients, who suffer from epileptic seizures and also from cognitive impairment. The exact mechanisms of cognitive impairment remain unclear. Aim of this study was to analyse in more detail the functional and structural alterations in two different patient groups, juvenile myoclonic epilepsy (JME) and frontal lobe epilepsy (FLE). We recruited and investigated 26 healthy controls, 30 patients with JME and 67 patients with FLE. All participants underwent magnetic resonance imaging (MRI), including structural imaging, five functional MRI paradigms and diffusion tensor imaging (DTI) as well as neuropsychological assessment. In patients with JME we could show motor cortex hyperactivity and an increased functional connectivity between the pre-frontal cognitive cortex and the motor system. This correlated with increased structural connectivity, measured by DTI and also with disease severity: patients with more active epilepsy showed a stronger hyperconnectivity. In FLE, we could show extensive reorganization of cognitive functions, and we could show, that functional MRI can be used as a new diagnostic method, to identify dysfunctional areas, indicative of the seizure onset zone. This is particularly important in patients with nonlesional FLE, where epilepsy surgery may be advisable but is challenged by the absence of a visible surgical target. The study has provided new insights into pathophysiological mechanisms in JME, specifically explaining the characteristic effect of motor seizures triggered by cognitive effort. It has contributed strong evidence that the observed imaging alterations are the cause and not a consequence of JME, by documenting marked structural changes in seizure free patients. For patients with FLE the study showed highly individual effects of chronic epilepsy on cognitive processing in the frontal lobe. These alterations are clinically relevant for both, avoiding complications from surgery, but also to identify pathological alterations not visible in conventional MRI

Counter Machines and Distributed Automata: A Story about Exchanging Space and Time

We prove the equivalence of two classes of counter machines and one class of distributed automata. Our counter machines operate on finite words, which they read from left to right while incrementing or decrementing a fixed number of counters. The two classes differ in the extra features they offer: one allows to copy counter values, whereas the other allows to compute copyless sums of counters. Our distributed automata, on the other hand, operate on directed path graphs that represent words. All nodes of a path synchronously execute the same finite-state machine, whose state diagram must be acyclic except for self-loops, and each node receives as input the state of its direct predecessor. These devices form a subclass of linear-time one-way cellular automata.Comment: 15 pages (+ 13 pages of appendices), 5 figures; To appear in the proceedings of AUTOMATA 2018

Pretubulysin derived probes as novel tools for monitoring the microtubule network via activity-based protein profiling and fluorescence microscopy

Microtubules (mt) are highly dynamic polymers composed of alpha- and beta-tubulin monomers that are present in all dividing and non-dividing cells. A broad variety of natural products exists that are known to interfere with the microtubule network, by either stabilizing or de-stabilizing these rope-like polymers. Among those tubulysins represent a new and potent class of cytostatic tetrapeptides originating from myxobacteria. Early studies suggested that tubulysins interact with the eukaryotic cytoskeleton by inhibition of tubulin polymerization with EC50 values in the picomolar range. Recently, pretubulysins have been described to retain the high tubulindegradation activity of their more complex tubulysin relatives and represent an easier synthetic target with an efficient synthesis already in place. Although tubulin has been suggested as the dedicated target of tubulysin a comprehensive molecular target analysis of pretubulysin in the context of the whole proteome has not been carried out so far. Here we utilize synthetic chemistry to develop two pretubulysin photoaffinity probes which were applied in cellular activity-based protein profiling and imaging studies in order to unravel and visualize dedicated targets. Our results clearly show a remarkable selectivity of pretubulysin for beta-tubulin which we independently confirmed by a mass-spectrometry based proteomic profiling platform as well as by tubulin antibody based co-staining on intact cells

A Bit-String Model for Biological Aging

We present a simple model for biological aging. We studied it through computer simulations and we have found this model to reflect some features of real populations.Comment: LaTeX file, 4 PS figures include

Besondere bildgebende Befunde bei primär generalisierten Epilepsien

Konventionelle bildgebende Verfahren sind bei Patienten mit idiopathischen generalisierten Epilepsien per definitionem unauffällig. MRT-basierte (Magnetresonanztomographie), morphometrische Verfahren konnten jedoch in Gruppenanalysen subtile strukturelle Veränderungen insbesondere im mesialen Frontallappen, supplementär motorischen Areal und Thalamus nachweisen. Ergänzende funktionelle MRT- und Diffusions-Tensor-Bildgebungs(DTI)-Untersuchungen bei Patienten mit juveniler myoklonischer Epilepsie (JME) zeigen eine erhöhte funktionelle und strukturelle Konnektivität zwischen präfrontalen kognitiven und motorischen Kortexarealen, die Erklärungen für krankheitstypische Anfallsreflexmechanismen bieten. Studien an neu diagnostizierten Patienten, longitudinale Studien sowie Untersuchungen an gesunden Geschwistern von JME-Patienten weisen darauf hin, dass diese Veränderungen am ehesten Ursache im Sinne einer genetisch determinierten Entwicklungsstörung sind und nicht eine sekundäre Folge der chronischen Epilepsie

E-Learning: Aktueller Stand und Chancen in der Allgemeinmedizin Frankfurt a.M. 08. - 09. Juli 2005 : vom Kongress zum Netzwerk "ELA" (E-Learning in der Allgemeinmedizin)

Kongressbericht: Auf der Tagung der Deutschen Gesellschaft für Allgemeinmedizin und Familienmedizin e.V. (DEGAM) 2004 entstand die Idee, E-Learning-Aktivitäten in der Allgemeinmedizin sichtbar zu machen und zu bündeln. Ein Kongress sollte die allgemeinmedizinischen Vertreter aus Lehre und Forschung sowie Industrievertreter zusammenbringen, um das Spektrum der Möglichkeiten und laufende Projekte kennen zu lernen. Mit motivierten Referenten, über 60 aktiven Teilnehmern und einem positiven Feedback, kann der Kongress in Frankfurt am 8. und 9. Juli 2005 als erster dieser Art in Deutschland als erfolgreich bezeichnet werden

Ictal SPECT in Sturge-Weber syndrome

We report on a patient with right-sided Sturge-Weber syndrome (SWS), in whom earlier functional hemispherectomy failed. Subtraction of ictal and interictal single-photon-emission-computed-tomography (SPECT) superimposed on individual MRI showed a right fronto-orbital hyperperfusion, with a left-sided EEG seizure pattern. Ictal SPECT supported our assumption that right frontal originated seizure pattern propagated to left hemisphere via the remaining right frontal bridge. Right orbito-frontal resection and disconnection from corpus callosum resulted in seizure freedom

A novel technique for selective NF-kappa B inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion.

Background and aims: The transcription factor nuclear factor kappa B (NF-kB) has risen as a promising target for anti-inflammatory therapeutics. In the liver, however, NFkB inhibition mediates both damaging and protective effects. The outcome is deemed to depend on the liver cell type addressed. Recent gene knock-out studies focused on the role of NF-kB in hepatocytes, whereas the role of NF-kB in Kupffer cells has not yet been investigated in vivo. Here we present a novel approach, which may be suitable for clinical application, to selectively target NF-kB in Kupffer cells and analyse the effects in experimental models of liver injury. Methods: NF-kB inhibiting decoy oligodeoxynucleotides were loaded upon gelatin nanoparticles (D-NPs) and their in vivo distribution was determined by confocal microscopy. Liver damage, NF-kB activity, cytokine levels and apoptotic protein expression were evaluated after lipopolysaccharide (LPS), D-galactosamine (GalN)/LPS, or concanavalin A (ConA) challenge and partial warm ischaemia and subsequent reperfusion, respectively. Results: D-NPs were selectively taken up by Kupffer cells and inhibited NF-kB activation. Inhibition of NF-kB in Kupffer cells improved survival and reduced liver injury after GalN/LPS as well as after ConA challenge. While anti-apoptotic protein expression in liver tissue was not reduced, pro-apoptotic players such as cJun N-terminal kinase (JNK) were inhibited. In contrast, selective inhibition of NF-kB augmented reperfusion injury. Conclusions: NF-kB inhibiting decoy oligodeoxynucleotide- loaded gelatin nanoparticles is a novel tool to selectively inhibit NF-kB activation in Kupffer cells in vivo. Thus, liver injury can be reduced in experimental fulminant hepatitis, but increased at ischaemia–reperfusion