Endotheliale Inflammation und Zusammenbruch der Bluthirnschranke nach experimentell induzierter Subarachnoidalblutung

Eine akute aneurysmatische Subarachnoidalblutung (aSAB) zählt zu den hämorrhagischen Schlaganfällen und beziffert eine jährliche Inzidenz von sechs bis elf von hunderttausend Menschen. Hauptgrund ist die Ruptur eines intrakraniellen Aneurysmas, gefolgt von einer Einblutung in den Subarachnoidalraum. Das durchschnittliche Alter bei aSAB-Patienten beträgt fünfundfünfzig Jahre und ist somit niedriger als bei Patienten mit einem ischämischen Schlaganfall. Diesbezüglich ist die sozioökonomische Belastung der aSAB vergleichsweise hoch. Mehrere Studien haben gezeigt, dass eine aSAB zu einem Zusammenbruch der Bluthirnschranke (BHS) führt, wodurch ein vasogenes Hirnödem ausgelöst wird. An Patienten nach aSAB konnte außerdem gezeigt werden, dass IL6 im Serum und im Liquor erhöht war, wobei diese Patienten ein schlechteres Outcome aufzeigten. Die frühe Hirnschädigung nach aSAB beginnt bereits nach einem initialen intrazerebralen Druckanstieg, gefolgt von einem Abfall des zerebralen Perfusionsdrucks. Experimentelle Studien widmen sich daher den Mechanismen der frühen Hirnschädigung nach aSAB mit Fokus auf Störungen der mikrovaskulären Ebene und inflammatorischen Prozessen innerhalb ZNS nach aSAB. Die hier vorgelegte Arbeit konzentrierte sich auf die Rolle des Zytokins Interleukin-6 (IL6) und seine Effekte auf die BHS nach experimenteller Subarachnoidalblutung (eSAB) in Mäusen. Um die Induktion einer eSAB an der Maus auslösen zu können, wurde die Methode der Fadenperforationstechnik angewandt. Die darauffolgenden Experimente dienten der Analyse der BHS-Eigenschaften, wobei sich nach eSAB ein deutlicher BHS-Zusammenbruch über den gesamten zeitlichen Verlauf der Experimente zeigte. Als molekulares Korrelat für den Untergang der BHS konnte die zwei wichtigsten tight junction (TJ) Moleküle Claudin-5 (Cld5) und Occludin (Ocld) identifiziert werden. Zeitgleich wurde eine Überexpression essenzieller Zytokine beobachtet. Insbesondere IL6 zeigte zu allen Zeitpunkten eine deutliche Hochregulierung an isolierten Gehirnkapillaren nach eSAB. Somit wurde nachgewiesen, dass IL6 endothelzellspezifisch in Vesikeln isolierter Gehirnkapillaren nach eSAB angereichert wird. Weiterführende In-vitro-Versuche ergaben einen deutlichen Verlust des transendothelialen Widerstandes in der cEND-Zellkultur, nachdem die Zellen mit dem rekombinanten IL6 (rIL6) behandelt wurden. Auch In vitro war ein Untergang von Cld5 und Ocld zu beobachten. Zusammenfassend zeigt diese Arbeit erstmalig die Expression von IL6 im zerebralen Endothel nach eSAB, was zeitgleich mit einem BHS-Zusammenbruch korrelierte. Abschließend soll die Rolle von IL6 in Bezug auf die frühe Hirnschädigung nach aSAB diskutiert und der Frage nachgegangen werden, ob ein Knockout von IL6 oder die externe Blockade von IL6 und seinem Rezeptor einen signifikanten Effekt auf den Pathomechanismus nach aSAB aufweist.Acute aneurysmal subarachnoid hemorrhage (aSAH) is a type of hemorrhagic stroke with an annual incidence of six to eleven out of a hundred thousand people. The main cause of an aSAH is a rupture of an intracranial aneurysm, which is followed by a bleeding into the subarachnoid space. The average age in aSAH patients is fifty-five years old, which is much younger than the average age of patients with ischemic stroke. Therefore, the socio-economic impact of aSAH is comparatively high. Numerous studies have shown, that aSAH leads to a breakdown of the blood brain barrier (BBB), causing a vasogenic brain edema. Patients with aSAH also show an increase in IL6 in serum and in cerebrospinal fluid, resulting in worse outcomes for aSAH patients. Early brain injury after aSAH occurs after an initial increase in intracerebral pressure, followed by a decrease in cerebral perfusion pressure. Therefore, current experimental studies are devoted to mechanisms of early brain damage, investigating microvascular changes and BBB breakdown with a focus on CNS inflammation after aSAH. The following work examines interleukin-6 (IL6) and its effects on the BBB after experimental subarachnoid hemorrhage (eSAH) in mice. In order to induce eSAH in mice, the filament perforation method was used. The subsequent experiments were performed to analyze BBB properties, showing a BBB breakdown over the course of the experiment. The decline of the most important tight junction (TJ) molecules Claudin-5 (Cld5) and Occludin (Ocld) caused a BBB collapse. Moreover, the overexpression of crucial cytokines was observed, while IL6 in particular was increased in isolated brain capillaries after eSAH, showing enriched expression in endothelial cells. Further in-vitro experiments revealed a significant loss of transendothelial resistance in the cEND cell culture after the cells were treated with the recombinant IL6 (rIL6). Finally, the gene expression of Cld5 and Ocld was also decreased in vitro. In summary, this work shows for the first time that IL6 is expressed in the BBB after eSAH, correlating with a BBB breakdown. The role of IL6 in relation to early brain injury after aSAH will be discussed, focusing on the effect of a knockout and an external blockade of IL6 towards the pathomechanism after aSAH

Red list and checklist of the lichens

Derzeit sind aus Berlin 315 Flechtensippen (310 Arten, 3 Unterarten, eine Varietät und eine Form) bekannt. Davon werden 112 (35,6 %) in die Rote Liste aufgenommen. 59 Taxa gelten als ausgestorben oder verschollen, 47 sind bestandsgefährdet und 6 Arten sind sehr selten. Der Vergleich mit der Vorgängerliste (Otte 2005) zeigt, dass sich bei 44 Taxa die Kategorie verändert hat, 21 Taxa erhielten einen geringeren Gefährdungsgrad, 23 einen höheren.Currently, 315 lichen taxa (310 species, 3 subspecies, 1 variety and 1 forma) are known from Berlin. The Red List contains 112 (35.6 %) of them. 59 taxa are extinct or missing, 47 are endangered and 6 species are extremely rare. Compared to the last Red List (Otte 2005) the categories of 44 taxa have changed. 21 taxa are classified into a lower category of threat, 23 taxa into a higher category

Red list and checklist of the lichenicolous fungi

Derzeit sind aus Berlin 23 lichenicole Pilzarten bekannt. Davon werden lediglich zwei ausgestorbene Arten in die Rote Liste aufgenommen. Neun Arten (39,1 %) gelten als ungefährdet. Für die Einschätzung von 12 Arten (52,2 %) sind die Daten unzureichend. Besonders die ungenügende historische Erfassung der lichenicolen Pilze macht eine Einschätzung der Gefährdung schwierig.Currently, 23 species of lichenicolous fungi are known from Berlin. The Red List contains only two extinct or at least possibly extinct species. Nine species (39.1 %) are classified as not threatened. For 12 species (52.2 %) data are not sufficient. Especially the scarcity of historical records makes an assessment difficult

Towards Digital Growth-independent Societies

Growth-independent areas are a prerequisite in enabling the environmental policies needed to prevent environmental depletion. Yet, digitalisation is reshaping our economy in a way that could both hamper and benefit growth-independent areas

Sustainability challenges of Artificial Intelligence and Policy Implications

Automated decision-making based on Artificial Intelligence is associated with growing expectations and is to contribute to sustainable development goals. Which opportunities and risks for the environment, economy and society are associated with Artificial Intelligence-based applications and how can they be governed

Digitalisierung der Landwirtschaft

DIGITALISIERUNG DER LANDWIRTSCHAFT Digitalisierung der Landwirtschaft / Kliem, Lea (Rights reserved) ( -

Lack in Periodontal Care of Patients Suffering from Severe Heart Diseases—Results after 12 Months Follow-Up

Background: To assess whether the standardized recommendation of patients with heart failure (HF), left-ventricular assist device (LVAD) and heart transplantation (HTx) to visit their dentist leads to improved oral conditions after 12 months. Methods: Patients from the Department of Cardiothoracic Surgery, Leipzig Heart Centre, Germany were examined at baseline and after 12 months. A dental (decayed-, missing-, and filled-teeth index (DMF-T)) and periodontal examination (periodontal probing depth, clinical attachment loss) was performed. At baseline, patients received a standardized recommendation to visit their dentist. At follow-up, a standardized questionnaire regarding the dental consultation was applied. Results: Eighty-eight participants (HTx: 31, LVAD: 43, HF: 14) were included. The majority of patients (79.5%) followed the recommendation to visit their dentist. Within the total cohort, periodontal treatment need was significantly reduced from 91% (baseline) to 75% (follow-up; p 0.05). Conclusions: The simple recommendation to visit the dentist appears not enough to obtain sufficient dental and periodontal conditions in patients with severe heart diseases. Thereby, a lack in periodontal treatment of patients with HF, HTx and LVAD was identified, making interdisciplinary dental special care programs recommendable

A learning robot for cognitive camera control in minimally invasive surgery

Background!#!We demonstrate the first self-learning, context-sensitive, autonomous camera-guiding robot applicable to minimally invasive surgery. The majority of surgical robots nowadays are telemanipulators without autonomous capabilities. Autonomous systems have been developed for laparoscopic camera guidance, however following simple rules and not adapting their behavior to specific tasks, procedures, or surgeons.!##!Methods!#!The herein presented methodology allows different robot kinematics to perceive their environment, interpret it according to a knowledge base and perform context-aware actions. For training, twenty operations were conducted with human camera guidance by a single surgeon. Subsequently, we experimentally evaluated the cognitive robotic camera control. A VIKY EP system and a KUKA LWR 4 robot were trained on data from manual camera guidance after completion of the surgeon's learning curve. Second, only data from VIKY EP were used to train the LWR and finally data from training with the LWR were used to re-train the LWR.!##!Results!#!The duration of each operation decreased with the robot's increasing experience from 1704 s ± 244 s to 1406 s ± 112 s, and 1197 s. Camera guidance quality (good/neutral/poor) improved from 38.6/53.4/7.9 to 49.4/46.3/4.1% and 56.2/41.0/2.8%.!##!Conclusions!#!The cognitive camera robot improved its performance with experience, laying the foundation for a new generation of cognitive surgical robots that adapt to a surgeon's needs

Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1:implications for aging

Chronic heavy alcohol consumption is associated with increased mortality and morbidity and often leads to premature aging; however, the mechanisms of alcohol-associated cellular aging are not well understood. In this study, we used DNA methylation derived telomere length (DNAmTL) as a novel approach to investigate the role of alcohol use on the aging process. DNAmTL was estimated by 140 cytosine phosphate guanines (CpG) sites in 372 individuals with alcohol use disorder (AUD) and 243 healthy controls (HC) and assessed using various endophenotypes and clinical biomarkers. Validation in an independent sample of DNAmTL on alcohol consumption was performed (N = 4219). Exploratory genome-wide association studies (GWAS) on DNAmTL were also performed to identify genetic variants contributing to DNAmTL shortening. Top GWAS findings were analyzed using in-silico expression quantitative trait loci analyses and related to structural MRI hippocampus volumes of individuals with AUD. DNAmTL was 0.11-kilobases shorter per year in AUD compared to HC after adjustment for age, sex, race, and blood cell composition (p = 4.0 × 10(−12)). This association was partially attenuated but remained significant after additionally adjusting for BMI, and smoking status (0.06 kilobases shorter per year, p = 0.002). DNAmTL shortening was strongly associated with chronic heavy alcohol use (ps < 0.001), elevated gamma-glutamyl transferase (GGT), and aspartate aminotransferase (AST) (ps < 0.004). Comparison of DNAmTL with PCR-based methods of assessing TL revealed positive correlations (R = 0.3, p = 2.2 × 10(−5)), highlighting the accuracy of DNAmTL as a biomarker. The GWAS meta-analysis identified a single nucleotide polymorphism (SNP), rs4374022 and 18 imputed ones in Thymocyte Expressed, Positive Selection Associated 1(TESPA1), at the genome-wide level (p = 3.75 × 10(−8)). The allele C of rs4374022 was associated with DNAmTL shortening, lower hippocampus volume (p < 0.01), and decreased mRNA expression in hippocampus tissue (p = 0.04). Our study demonstrates DNAmTL-related aging acceleration in AUD and suggests a functional role for TESPA1 in regulating DNAmTL length, possibly via the immune system with subsequent biological effects on brain regions negatively affected by alcohol and implicated in aging