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Satellite-based monitoring of environmental related factors affecting rural livelihoods, food security, and health risks in Africa
Get PDFIdentification and evaluation of bacteriophage genes involved in the virulence of Enterococcus faecalis
Get PDFManagement der latenten tuberkulösen Infektion (LTBI) bei Kindern und Jugendlichen in Deutschland, Österreich und der Schweiz
Get PDFBackground
Taking into account WHO´s Global End TB Strategy until 2035 and the fact that more than 2 billion people in the world are infected with Mycobacterium tuberculosis, inter-nationally coordinated struggle is needed to tackle the disease. This struggle must in-clude not only active TB disease, but also the latent form of the infection (LTBI), which is far more frequent and for which there is a lack of algorithms particularly for the pediatric setting. This study aimed to find out as much as possible about epidemi-ology and workload, but mainly diagnostic, therapeutic and follow-up approaches in the field of pediatric LTBI within the three low-TB-incidence countries Switzerland, Austria and Germany. It was conducted directly before apparition of the German-speaking medical society for pediatric infectious diseases (DGPI)´s guidelines on pe-diatric tuberculosis and thus gives an insight into modus operandi without the influ-ence of recently published guidelines.
Methods
We created a survey consisting of 51 questions which was then made available online for four months in late 2017. Medical societies from all three countries which are ac-tive in pediatric infectiology or pediatric pneumology as well as the German and Aus-trian public health sector and the Swiss Pulmonary League were asked to work on the survey online or with the help of personal interviews.
Results
A total of 173 practitioners took part in the survey. 76.1% of them prefer QuantiFER-ON over T-SPOT.TB when it comes to immunological diagnostic via IGRA. 63% vary their diagnostic approach depending on their patient´s age. Chemopreventative therapy of Isoniazid (INH) in combination with Rifampicin (RMP) seems to be largely accept-ed even though it has only recently been considered as equal to INH monotherapy. Chest X-Ray after completion of the chemopreventative regimen is conducted in 49.6% of cases.
Discussion
Routine TB diagnostics including CT imagery was quite popular even though there are both well-established such as CXR and promising new diagnostic technologies such as sonography. Imaging should also take place after the end of preventative therapy. Un-der-dosage remains a problem with around 41% of participants administering too low amounts of anti-TB agents in both mono- and combination therapy. It should be em-phasized that follow-up needs to take place even in preventative therapy. More teach-ing events on pediatric TB and LTBI are desirable
The SPOCK2 expression is downregulated in pancreatic ductal adenocarcinoma due to hypermethylation of its gene
Get PDFCharakterisierung des Proteoms Frühgeborener anhand von Trockenblutproben mit Fokus auf die postnatale und gestationsalterabhängige Entwicklung des Proteoms
Get PDFA search for functional connectivity rules in the visual thalamus and hippocampus
Get PDFComputations in the brain arise from the functional connectivity of individual neurons, brain regions and circuits. Understanding the fundamental connectivity rules in the brain is an important step to better understand the brain itself. In this dissertation, a suite of methods and approaches were employed to investigate such rules at the synaptic and circuit level.
The first part of this dissertation dealt with the conflicting results of recent structural (Rompani et al., 2017) and functional (Howarth, Walmsley, & Brown, 2014; Jaepel et al., 2017; Sommeijer et al., 2017) reports regarding the degree of functional binocular convergence in the dorsal lateral geniculate nucleus (dLGN). To address this, a novel dual-color optogenetic assay was developed to map functional connectivity between RGCs and individual dLGN cells in vitro. While structural convergence is large, with > 60 % of dLGN cells receiving binocular input, the dLGN is functionally monocular: not only did the dominant eye provide > 95 % of a dLGN cell’s retinogeniculate input, but the non-dominant eye was unable to elicit the firing of action potentials under resting conditions. Analysis of dLGN cell morphology in relation to the axonal input pattern of RGC afferents in the dLGN revealed axo-dendritic overlap could not explain the levels of functional monocularity observed in the in vitro assay. Instead, the dominant and non-dominant eye differed with regards to the expression of AMPA and NMDA receptors, seemingly favoring the dominant eye: fine-scale input selection and refinement were found to limit the functional convergence in the retinogeniculate pathway, resulting in a winner-takes-all wiring rule in this part of the visual circuit.
In the second part of this dissertation a deep learning tool for the detection of dendrites and dendritic spines, termed DeepD3, was developed. DeepD3 directly addresses the current need for automated methods of spine detection. Unlike other areas of neuroscience, where data collection and analysis throughput has improved considerably in the last years, most studies to date still only investigate dozens of dendritic spines per neuron. The analysis - such as identification or segmentation of dendritic spines in image data - represents the main bottleneck in current analysis efforts. DeepD3 was tested against a number of in vitro and in vivo datasets with varying image properties to ensure that this method performs well in a large range of data qualities. DeepD3 performed as well as human in both in vivo and in vitro data. Importantly, DeepD3 fully processes large datasets within hours, a procedure which would take months if done via the current gold standard, human annotation. DeepD3 can be flexibly employed for counting dendritic spines or to measure 2D, 3D or time-series fluorescence values of spines and dendrites.
The third part of this dissertation aims towards understanding the functional connectivity rules of LTP-induced dendritic spines. Dendritic spines grow in neurons undergoing LTP (Engert & Bonhoeffer, 1999; Toni et al., 1999) and rapidly form functional synapses (Nägerl et al., 2007). However, it remains unclear which presynaptic neurons are chosen to establish functional connectivity, and hence whether there is a fundamental wiring rule followed by the brain. To address this, improvements to an existing assay to map functional synaptogenesis following LTP in vitro (Coneva, 2015) were made. By modifying the timeline of the assay and introducing high-throughput volumetric calcium imaging methods, the throughput of the assay was improved several-fold. Moreover, a molecular approach was devised to combat a potential confounding variable, the lack of spine maturity in nascent spines, when determining functional connectivity rules of LTP-induced dendritic spines. Lastly, several pharmacological and computational means were tested in their ability to assess functional connectivity on a single-spine level despite the occurrence of dendritic calcium events, which otherwise prevent such assessments. Neither the pharmacological, nor the computational methods applied proved effective in this undertaking. As a consequence, determining functional connectivity rules of nascent, LTP-induced dendritic spines remains outstanding. This dissertation paved the way for attempts of this undertaking in the future
Symmetrisches Dimethylarginin (SDMA) als diagnostischer Parameter für Nierenerkrankungen bei Griechischen Landschildkröten (Testudo hermanni)
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Kopf-Rumpf Koordination bei Gesunden im Altersverlauf und bei Patienten mit bilateraler Vestibulopathie
Get PDFDie vorliegende Arbeit befasst sich mit dem dynamischen System der Kopf-Rumpf Koordination verschiedener Altersgruppen sowie Patienten mit einer bilateralen Vestibulopathie bei unterschiedlichen Ganggeschwindigkeiten und kognitivem Dual Task Paradigma. Ziel der Arbeit ist es zu untersuchen, in welcher Weise sich die Koordination in den Altersgruppen bei Gesunden sowie in der Gruppe der Patienten mit bilateraler Vestibulopathie (BVP) unterscheidet. Da sowohl das vestibuläre als auch das visuelle System direkt hiervon abhängig sind, kommt dieser Koordinationsleistung beim Gehen und der posturalen Kontrolle eine wichtige Funktion zu. Von besonderem Interesse ist es einerseits zu messen, ob bei allen Gruppen die Kopfbewegung bzw. die einwirkenden Kräfte sich ähneln und andererseits zu untersuchen, ob Hinweise auf kompensatorische Mechanismen zu finden sind.
Hierzu wurde zunächst eine geeignete Messmethode mittels marker-basiertem 3-D Motion Tracking und kombinierten Inertialsensoren etabliert sowie ein reliables Versuchsprotokoll definiert. Anschließend wurden für die unterschiedlichen gesunden Altersgruppen (20-40 Jahre, 40-60 Jahre, 60-80 Jahre) sowie für die Gruppe mit BVP, Probanden rekrutiert. Erfasst wurden hierbei die Rumpf-Kopf-Position, die Beschleunigung und die Drehgeschwindigkeit der Rumpf-/Kopfpartie.
Die vorliegende Arbeit konnte zeigen, dass Patienten mit einer BVP in Zusammenschau aller gemessenen Parameter sowie im Vergleich mit vorangegangenen Studien Kompensationsmechanismen entwickeln, um ihr sensorisches Defizit auszugleichen. Lediglich in wenigen Modalitäten lassen sich signifikante Unterschiede feststellen. Da diese Arbeit auch das Ziel hatte, Methoden zur Messung der Kopf-Rumpf-Stabilität neu zu etablieren, ergaben sich im Verlauf Erkenntnisse über die Optimierung verschiedener Parameter als Vorschläge zur Umsetzung in Folgeexperimente.
Das Verständnis für Kompensationsmechanismen, deren Trainierbarkeit bzw. Abschätz-ung der Entwicklung und somit Risikostratifizierung für z.B. Stürze sowie deren Folgen ist von essenziellem Interesse für die Lebensqualität der Patienten mit einer BVP und auch von gesundheitsökonomischer Bedeutung. Zudem lassen die Untersuchungen an dieser paradigmatischen Patientengruppe möglicherweise in Zukunft Rückschlüsse auf andere neurologische Erkrankungen mit vestibulär-sensorischen Defiziten zu. Die vorgestellte Methode könnte dann weitere Kompensationsmechanismen identifizieren, welche wiederum in spezifischen therapeutischen Trainings adressiert werden könnten
Innate human cell activation by bacterial lipopolysaccharide core heptose metabolites and Helicobacter pylori
Get PDFLipopolysaccharide (LPS) inner core heptose metabolites, including ADP-heptose, play an essential role in the activation of cell-autonomous innate immune responses in eukaryotic cells via the ALPK1-TIFA-NF-B signaling pathway, as demonstrated for several pathogenic bacteria. The important role of LPS heptose metabolites in the pro-inflammatory activation of gastric epithelial cells during an infection with the pathogenic bacterium Helicobacter pylori (H. pylori) was demonstrated before, in studies by our group and other scientists. The human pathogen H. pylori colonizes more than half of the world’s population, causing chronically active gastritis and ulcers, and long-term infection can lead to gastric cancer. Disease progression and severity depend on virulence factors of the pathogen, such as the Cag type 4 secretion system (T4SS) that enables active transport of proteins and metabolites into host cells.
The impact of heptose metabolites and pure ADP-heptose on human myeloid cells was not yet investigated. Therefore, in my project, we aimed to gain a better understanding of the activation and modulation potential of bacterial heptose metabolites on human macrophages and neutrophils. For this purpose, we used pure heptose metabolites and, as a bacterial model, H. pylori, which appears to transport heptose metabolites into the human host cell, most probably via its T4SS. Main questions of my thesis were how bacterial heptose metabolites affect the pro-inflammatory activation and maturation, alone and in the bacterial context, of human macrophages and neutrophils. In addition, we wanted to characterize the effect of heptose metabolites on macrophage functions including phagocytosis and antigen presentation.
The main findings of my project were that human macrophages and neutrophils respond with high sensitivity to pure heptose metabolites in cell culture and primary cell models (manuscript I and III). In addition, we discovered that activation of these cells with pure ADP-heptose was dependent on active cellular uptake. Our results are based on pro-inflammatory cytokine production and transcriptional upregulation of pro-inflammatory genes (IL-8) and the transcription factor NF-B after exposure to ADP-heptose. When comparing different cell types, we found that transcriptional changes after co-incubation with pure ADP-heptose were very similar in human gastric epithelial cells, monocyte/macrophage-like cells, and neutrophil-like cells (manuscript III). Using knock-down experiments, I demonstrated that ADP-heptose signaling in monocyte/macrophage-like cells is dependent on TIFA (manuscript I). Moreover, we discovered that stimulation with pure ADP-heptose polarized monocytes into macrophages of predominantly pro-inflammatory type M1 and pre-mature neutrophil-like cells rather into the pro-inflammatory type N1 (manuscript I and III). Furthermore, I found that activation of human macrophages and neutrophils by live H. pylori is strongly influenced by the presence of LPS heptose metabolites and the functionality of its T4SS. In addition, we showed the ability of macrophages to phagocytose does not appear to be affected by heptose metabolites, but ADP-heptose is the decisive factor to reduce antigen presentation by macrophages upon heptose- or bacteria-exposure, due to upregulation of miRNA146b (manuscript I and II).
In summary, my work contributed significantly to our new findings that specific heptose metabolites or bacteria producing heptose metabolites elicit a strong activity and modulation of cell-autonomous innate immune responses and cellular functions of human macrophages and neutrophils