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Allogeneic hematopoietic stem cell transplantation for congenital immune dysregulatory disorders
(2019)
Primary immunodeficiency disorders that predominantly affect immune regulation and mechanisms of self-tolerance have come into the limelight, because at least for a subgroup of monogenetic disorders, a targeted therapy has become available. Nevertheless, their management often involves the treatment of severely compromising, refractory, multi-organ autoimmunity, leading to further increased susceptibility to infections and complications of long-term immune suppressive treatment, including the risk of malignancy. While evidence for allogeneic hematopoietic stem cell transplantation (alloHSCT) as a curative treatment option for severely affected patients by this disease category accumulates, clear indications, and guidelines for alloHSCT are lacking. Predictive and stratification-relevant tools such as disease activity scores are largely missing and often there is not a consistent genotype-phenotype correlation within the same family to facilitate the decision whether to transplant or not. In this review, we provide a literature-based update on indications and outcomes of alloHSCT for congenital immune dysregulative inborn errors of immunity according to the IUIS classification 2017.
In seiner mit dem Otto-Hintze-Preis ausgezeichneten Habilitationsschrift bietet Markus Payk eine Entstehungsgeschichte des internationalen Rechtssystems, wie es in der Zwischenkriegszeit bestand. Demgemäß behandelt er die Pariser Vorortverträge – schwerpunktmäßig den Versailler Vertrag – von 1919/1920, mit denen ein neues zwischenstaatliches Regelungswerk erstellt wurde, das das gescheiterte System der Vorkriegszeit vor 1914 ablösen sollte. Der Autor will diese Verträge aus ihrem historischen und ideellen Kontext heraus erklären, um so deren wichtigste Charakteristika herauszuarbeiten und dabei verdeutlichen, dass ihnen "trotz aller Defizite […] [eine] einzigartige Stellung in der Geschichte der modernen Staatenbeziehungen" (S. 661) zukomme. ...
Collateral sprouting of surviving axons contributes to the synaptic reorganization after brain injury. To study this clinically relevant phenomenon, we used complex organotypic tissue cultures of mouse entorhinal cortex (EC) and hippocampus (H). Single EC-H cultures were generated to analyze associational sprouting, and double EC-H cultures were used to evaluate commissural sprouting of mossy cells in the dentate gyrus (DG) following entorhinal denervation. Entorhinal denervation (transection of the perforant path) was performed at 14 days in vitro (DIV) and associational/commissural sprouting was assessed at 28 DIV. First, associational sprouting was studied in genetically hybrid EC-H cultures of beta-actin-GFPtg and wild-type mice. Using calretinin as a marker, associational axons were found to re-innervate almost the entire entorhinal target zone. Denervation experiments performed with EC-H cultures of Thy1-YFPtg mice, in which mossy cells are YFP-positive, confirmed that the overwhelming majority of sprouting associational calretinin-positive axons are mossy cell axons. Second, we analyzed associational/commissural sprouting by combining wild-type EC-H cultures with calretinin-deficient EC-H cultures. In these cultures, only wild-type mossy cells contain calretinin, and associational and commissural mossy cell collaterals can be distinguished using calretinin as a marker. Nearly the entire DG entorhinal target zone was re-innervated by sprouting of associational and commissural mossy cell axons. Finally, viral labeling of newly formed associational/commissural axons revealed a rapid post-lesional sprouting response. These findings demonstrate extensive and rapid re-innervation of the denervated DG outer molecular layer by associational and commissural mossy cell axons, similar to what has been reported to occur in juvenile rodent DG in vivo.
Der vorliegende Band widmet sich für den Zeitraum von 1815 bis heute dem deutsch-französischen Verhältnis in 15 Einzelstudien, die entweder kulturwissenschaftlich ausgerichtet sind oder die dem Thema vor Ort in regionalen Fallbespielen nachgehen. Gemeinsame Klammer ist dabei der Rhein und dessen Anliegerregionen, womit die Herausgeber sich an neuere historische Forschungstrends anschließen. Anders als bisher wird der Rhein allerdings weder als deutschnationaler Fluss noch als natürliche französische Grenze wie vor 1945, aber auch nicht wie heute vielfach als europäisches Symbol verstanden, sondern als hybrider Raum, in dem verschiedene Akteure mit unterschiedlichen Interessen unter gegebenen Rahmenbedingungen aufeinandertrafen, was zu speziellen Prozessen und hybriden Strukturen in den jeweiligen Regionen führte. Das Ziel, die bisher dominierenden politisch motivierten Interpretationen in Frage zu stellen und die regionalen Besonderheiten und Widersprüche genauer wahrzunehmen, um die vorherrschenden nationalen und europäischen Interpretationen besser einzuordnen, erreicht der Band dabei vor allem durch die auf breiter Archivalienbasis erstellten Beiträge. ...
Background: Malaria is an increasing concern in Indonesia. Socio-demographic factors were found to strongly influence malaria prevalence. This research aimed to explore the associations between socio-demographic factors and malaria prevalence in Indonesia.
Methods: The study used a cross-sectional design and analysed relationships among the explanatory variables of malaria prevalence in five endemic provinces using multivariable logistic regression.
Results: The analysis of baseline socio-demographic data revealed the following independent risk variables related to malaria prevalence: gender, age, occupation, knowledge of the availability of healthcare services, measures taken to protect from mosquito bites, and housing condition of study participants. Multivariable analysis showed that participants who were unaware of the availability of health facilities were 4.2 times more likely to have malaria than those who were aware of the health facilities (adjusted odds ratio = 4.18; 95% CI 1.52–11.45; P = 0.005).
Conclusions: Factors that can be managed and would favour malaria elimination include a range of prevention behaviours at the individual level and using the networks at the community level of primary healthcare centres. This study suggests that improving the availability of a variety of health facilities in endemic areas, information about their services, and access to these is essential.
This paper focuses on the life and work of three of the most important men who arrived in the Philippines during the 16th century: the Augustinian Martín de Rada (1533–1578) studied at the universities of Paris and Salamanca. He was one of the best European scientists of his time in East Asia. The Dominican Domingo de Salazar (1512–1594), first bishop of Manila, studied the legitimacy of the conquest of the Philippines and wrote against the Spanish plan to conquest China. The Dominican Juan Cobo (? –1592) was the first Spanish to master the Chinese language and, through his book Shilu, the first European who introduced Christianity to the Chinese from a rational point of view and the first one to introduce European science into Chinese context. All of them were very influenced by the School of Salamanca and, from Manila, they always had their eyes on China. These three men of the late 16th century are paradigmatic examples of the influence of the University of Salamanca in the production of global knowledge in the early modernity.
Pharmakokinetik von JWH-018 und seinen Metaboliten in menschlichen Serum-, Urin- und Speichelproben
(2019)
Synthetische Cannabinoide sind seit Anfang der 2000er Jahre als Alternative zum Cannabiskonsum bekannt. Als erstes synthetisches Cannabinoid konnte JWH-018 in dem Produkt „Spice“ identifiziert werden. Aufgrund von teils behandlungspflichtigen, erheblichen Nebenwirkungen sowie von Todesfällen wurden bislang keine Probandenstudien durchgeführt.
Als erste kontrollierte Untersuchung wurde eine Pilotstudie mit sechs Probanden und sehr niedrigen Dosierungen (2 und 3 mg im Vergleich mit Placebo) mit der am besten erforschten Substanz, JWH-018, abgeschlossen. Mit der Entnahme von 14 Serum- und Speichel- sowie 5 Urinproben über einen Zeitraum von 12 Stunden nach Inhalation sollten Daten zur Pharmakokinetik und zum Metabolismus erhoben werden.
Blut, Urin und Speichel wurden nach flüssig-flüssig Extraktion mittels Flüssigchromatographie-Tandemmassenspektrometrie analysiert. Die Methoden wurden nach aktuellen Richtlinien vollständig validiert.
Serumkonzentrationen wurden zur Korrelation mit beobachteten Wirkungen bestimmt. Die maximale Serumkonzentration von JWH-018 erreichte bereits 5 min nach Inhalation 2,9-9,9 ng/ml und nahm innerhalb der nächsten 1,5 h deutlich ab, gefolgt von einem multiexponentiellen Abfall (t½ im Median 1,3 h und 5,7 h). Bei zwei Probanden lagen noch bis zu 4 Wochen nach der Applikation Spuren von JWH-018 vor. Die Konzentration des Pentansäuremetaboliten war etwas höher als die der 3-, 4- und 5-Hydroxypentylmetaboliten und des 6-Hydroxyindolmetaboliten. Bei der JWH-018 Pentansäure zeigte sich jedoch im Vergleich ein späteres Erreichen der Maximalkonzentration sowie eine deutliche Plateauphase, was sich durch enterohepatisches Cycling erklären lassen könnte.
Speicheltests dienen im forensischen wie klinischen Umfeld häufig als Schnelltest und als Indikator für anhaltende Wirkungen. Die Speichelasservierung und -lagerung erfolgte mit dem Quantisal-System. Maximale Konzentrationen von JWH-018 waren 2,2-2036 (Median 25,7) ng/ml direkt nach Inhalation und sanken in der nächsten Stunde auf nur 0,08-8,42 (Median 0,89) ng/ml, Metabolite wurden nicht nachgewiesen. Innerhalb der Eliminationsphase (mittlere Halbwertszeit 1,69 h) konnte JWH-018 während 6-12 (Median 8) h nachgewiesen werden (0,024 ng/ml Quantifizierungs-grenze). Das Konzentrationsverhältnis von Speichel zu Serum variierte intra- und interindividuell stark in einem Bereich von 0,05-555 (Median 1,38) ng/ml, was eine Extrapolation der Speichelkonzentrationen auf Serum/Plasma ausschließt.
Urin wurde zu mindestens 5 Zeitpunkten entnommen und sowohl mit, als auch ohne β Glukuronidasebehandlung analysiert. Die Muttersubstanz war nicht nachweisbar, dafür 13 ihrer Metaboliten, die alle hochgradig konjugiert vorlagen. Die Konzentrationen des vorherrschenden Metaboliten, JWH-018 Pentansäure, lagen unter 5 ng/ml, wurden aber bei zwei Probanden noch bis zu 4 Wochen nach der Einnahme nachgewiesen. Die JWH-073 Butansäure wurde in die Urinanalyse miteinbezogen, da es Hinweise auf eine metabolische Bildung gab. Die Untersuchungsergebnisse können klar belegen, dass die Butansäure als Metabolit nach Konsum von JWH-018 entsteht. Wie im Serum wurden die Metabolite 3-, 4- und 5-Hydroxypentyl- sowie 6-Hydroxyindol-JWH-018 nachgewiesen. Zusätzlich zeigten sich aber auch geringe Signale von 4-, 5- und 7 Hydroxyindol- sowie von 2-Hydroxypentyl-JWH-018 und ein Signal neben dem 3 Hydroxypentylmetaboliten, welches ein weiteres hydroxyliertes Isomer repräsentieren dürfte. Weiterhin zeigten sich wie bereits im Serum auch in allen Urinproben bis zu zwei Messsignale mit den gleichen Fragmenten wie die JWH-018 Pentansäure. In Anlehnung an eine in-vitro Metabolismusstudie ist davon auszugehen, dass es sich um dihydroxylierte und dehydrierte Isomere von JWH-018 handelt, die als Hydroxy-Keto-Metabolite postuliert wurden. Im Allgemeinen lagen hydroxylierte Metaboliten bereits 10 h nach der Inhalation in Konzentrationen von weniger als 1 ng/ml vor. Die unterschiedliche Ausscheidung von Carbonsäuren und hydroxylierten Metaboliten kann bei der Einordnung des Konsumzeitpunkts helfen. Alle Konzentrationen lagen deutlich niedriger als für Urinproben von authentischen JWH-018 Konsumenten beschrieben.
Bei der Auswertung der Messdaten in Bezug auf die 2 mg und die 3 mg Dosis ließen sich keine signifikanten Unterschiede nachweisen, was sich nach Untersuchung der nicht inhalierten Restmengen durch erhebliche Schwankungen in der Applikation erklären lässt.
Die Daten sprechen für eine ausgeprägte Mehrkompartimentkinetik und eine langsame terminale Eliminierung von JWH-018 und allen Metaboliten, was zu einer Akkumulation bei chronischen Konsumenten führen kann. Dies ähnelt den Erfahrungen mit dem Cannabiswirkstoff Tetrahydrocannabinol (THC) und legt langanhaltende Effekte und eine Toleranzentwicklung nahe.
High-energetic heavy-ion collisions offer the unique opportunity to produce and to study dense nuclear matter in the laboratory. The future Facility for Antiproton and Ion Research (FAIR) in Darmstadt, Germany, will provide beams of heavy nuclei up to kinetic energies of 11 GeV/nucleon. At these energies, the nuclear matter in the collision zone of two nuclei will be compressed to densities of up to 5 − 10 times the saturation density of atomic nuclei, similar to matter densities existing in the core of massive neutron stars. Under those conditions, nucleons are expected to melt and form a new state of matter, which consists of quarks and gluons, the so called Quark-Gluon Plasma (QGP). The search for such a phase transition from hadronic to partonic matter, and the exploration of the nuclear matter equation-of-state at high densities are the major goals of heavy ion experiments worldwide.
The observables, which are proposed to probe the properties of dense nuclear matter and possible phase transitions, include multi-strange hyperons, antibaryons, lepton pairs, collective flow of identified particles, fluctuations and correlations of various particles, particles containing charm quarks, and hypernuclei. These observables have to be measured in multi-dimensions, i.e. as function of collision centrality, rapidity, transverse momentum, energy, emission angle, etc., which requires extremely high statistics. Moreover, some of these particles are produced very rarely.
Therefore, the Compressed Baryonic Matter (CBM) experiment at FAIR is designed to run at collision rates of up to 10 MHz, in order to perform measurements with unprecedented precision. Due to the complicated decay topology of many observables, no hardware trigger can be applied, and the data have to be analysed online in order to filter out the interesting events.
This strategy requires free-streaming read-out electronics, which provides time stamps to all detector signals, a high performance computer center, and high-speed reconstruction algorithms, which provide an online track and event reconstruction based on time and position information of the detector hits (”4-D“ reconstruction).
The core detector of the CBM experiment is the Silicon Tracking System (STS). The main task of the STS is to provide track reconstruction and momentum de- termination of charged particles originating from beam-target interactions. To fulfil the whole tasks the STS is located in the large gap of a superconducting dipole magnet with a bending power of 1 Tm providing momentum measurements for charged particles. The STS comprises 8 detector stations, which are positioned from 30 cm to 100 cm downstream the target. The corresponding active area of the stations grows up from 40×50 cm 2 up to 100×100 cm 2 with a totalarea of 4 m2. The silicon double-sided sensors exhibit 1024 strips on each side with a stereo angle at p-side of 7.5 ◦ and a strip pitch of 58 μm. The strip length ranges from 2 cm for sensors located in a close vicinity to the beam axis, up to 12 cm for other sensors where the flux of the reaction products drops down substantially. In total, the STS consist of 896 sensors mounted on 106 detector ladders. The detector readout electronics dissipates 40 kW and will be equipped with a CO 2 bi-phase cooling system. The detector including electronics will be mounted in a thermal enclosure to allow for sensor operation at below −5 ◦ C which minimizes radiation induced leakage currents.
The task of the STS is to measure the trajectories of up to 800 charged particles per collision with an efficiency of more than 95% and a momentum resolution of 1 − 2%. In order to guarantee the required performance over the full lifetime of the CBM experiment, the detector system has to have a low material budget, a high granularity, a high signal-to-noise (SNR) ratio, and a high radiation tolerance. As a result of optimisation studies, the STS consists of double-sided silicon microstrip sensors, about 300 μm thick, which have to provide a SNR ratio of more than 10, even after radiation with the expected equivalent lifetime fluence of 10 14 1 MeV n eq cm −2.
This thesis is devoted to the characterization of double-sided silicon microstrip sensors with an emphasis on investigation of their radiation hardness. Different prototypes of double sided silicon sensors produced by two vendors have been irradiated by 23 MeV protons up to the double life time fluence for the CBM experiment (2 × 10 14 1 MeV n eq cm −2 ).
The sensor properties have been characterised before and after irradiation. It was found, that after irradiation with a double lifetime fluence the leakage current increased 1000 times, which results in an increased shot noise. Moreover, the relative charge collection efficiency of irradiated with respect to non-irradiated sensors drops down to 85% for the lifetime equivalent fluence, and down to 73% for the double lifetime fluence, both for the p-side and n-side. For non-irradiated sensors the SNR was found to be in the range of 20 − 25, whereas for irradiated sensors it dropped down to 12 − 17.
In addition to the sensor characterization, a part of this thesis was devoted to the optimisation of the sensor readout scheme. In order to investigate the possible increase of SNR, and to reduce the number of readout channels in the outer aperture of STS, three versions of routing lines have been realized for the p-side readout of the sensor prototype, and have been tested in the laboratory and under beam conditions.
The tests have been performed with different inclination angles between beam direction and sensor surface, corresponding to the polar angle acceptance of the CBM experiment, which is from 2.5 ◦ to 25 ◦.
As a result of the studies carried out in this thesis work, the radiation hardness of the double-sided silicon microstrip sensors developed for the CBM STS detector was confirmed. Also the advantage of individual read-out of sensor channels in the lateral regions of the detector was verified. This allowed to start the tendering process for sensor series production in industry, an important step towards the construction of the detector in the coming years.
Cardiovascular diseases are a leading cause of morbidity and mortality worldwide. Aging inflicts structural and molecular changes on the heart that oftentimes involve ischemic events, cardiomyocyte apoptosis and cardiac stiffening, which makes it a major risk factor for cardiovascular disease. After being disregarded as transcriptional noise for a long time, long non-coding RNAs have lately emerged as key regulators of many cellular processes in physiology and disease of virtually all tissues and organs, with some of them being differentially regulated during aging.
This study identified a long non-coding transcript antisense to the OXCT1 gene locus, Sarrah, to be downregulated in the heart during aging, after acute myocardial infarction and upon heart failure with preserved ejection fraction. Sarrah is expressed in several cardiac cell types with highest levels in cardiomyocytes, where it is predominantly localized in the nucleus. In mouse and human cardiomyocytes, Sarrah levels are reduced upon exposure to hypoxia or treatment with hypoxiamimetic agents in vitro.
Sarrah exerts an anti-apoptotic function in mouse and human cardiomyocytes as assessed from caspase activity and annexin V staining. Histological stainings of Sarrah-depleted human engineered heart tissue organoids and Sarrah overexpressing infarcted mouse hearts confirmed its anti-apoptotic function. Sarrah also plays a role in cardiomyocyte contractility, which is substantially impaired upon Sarrah silencing in human engineered heart tissue and neonatal rat cardiomyocytes. Additionally, cardiomyocytal Sarrah stimulates endothelial cell proliferation via paracrine effects as observed after Sarrah overexpression in mouse hearts as well as in co-culture settings with human endothelial cells and Sarrah-depleted or Sarrah overexpressing human cardiomyocytes. A microarray analysis revealed that silencing Sarrah in human cardiomyocytes induced apoptosisrelated gene expression. Mechanistically, Sarrah was predicted to form triplexes in human and mouse with promoters of genes downregulated, but not upregulated after Sarrah knockdown, suggesting that Sarrah interacts with target genes to activate their transcription. This interaction was confirmed in vitro using nucleic acid oligonucleotides containing the sequences of the Sarrah triplex motif and the Sarrah binding site of the exemplary target gene GPC6 of both human and mouse. RNA immunoprecipitation experiments in human cells demonstrated that Sarrah is associated with open chromatin, transcription factor CRIP2, transcriptional co-activator p300 and DNA-RNA hybrid structures that also occur in Sarrah target gene promoters, which indicated that Sarrah activates gene expression by triplex formation and recruitment of protein interaction partners. Deleting the triplex motif of endogenous Sarrah in mouse cardiomyocytes augmented apoptosis, showing that triplex formation is of functional relevance for Sarrah action.
Finally, overexpressing Sarrah in an acute myocardial infarction mouse model improved recovery of cardiac contractile function as assessed from ejection fraction, stroke volume, wall motion and wall thickness measured by echocardiography and magnetic resonance imaging. Infarct size was substantially reduced in Sarrah overexpressing mice compared with controls. This in vivo study implies that restoring Sarrah levels in the aged or infarcted heart bears significant therapeutic potential, which can be attributed to the combination of three Sarrah effects: increased cardiomyocytes survival, enhanced contractility of individual cardiomyocytes and paracrine stimulation of endothelial cell proliferation likely contributing to increased angiogenesis and tissue perfusion.
In summary, cardiac lncRNA Sarrah is evolutionary conserved with regard to its genomic locus, function and molecular mechanism. Via triplex formation with gene promoters, it is capable to activate a set of target genes that together mediate the anti-apoptotic and pro-contractile function of Sarrah in cardiomyocytes and that confer angiogenic effects to endothelial cells. A therapeutic utilization of Sarrah in the context of myocardial ischemia is conceivable in the future if Sarrah upregulation proves to be beneficial in further studies.