Sonden zur Quantifizierung des chelatisierbaren Eisens in lebenden Zellen

Im Mittelpunkt dieser Arbeit steht das zelluläre chelatisierbare Eisen. Dieses besitzt zytotoxisches Potential, vor allem durch die Bildung von Hydroxylradikalen bei der Fenton-Reaktion. Die Methode der Wahl zu dessen Quantifizierung (und vor allem der subzellulären Verteilung) ist die Fluoreszenzmikroskopie, in diesem Fall mittels des konfokalen Laser-Scanning-Mikroskops. Es sollten Fluoreszenzsonden synthetisiert werden, die spezielle Anforderungen für eine kompartimentspezifische Akkumulation erfüllen sollten. Fluoreszenzsonden bestehen im allgemeinen aus Fluorophoren, Linkern und chelatisierenden Untereinheiten, die in diesem Fall spezifisch Eisen(II)-Ionen binden, in deren Form das chelatisierbare Eisen im reduktiven Milieu der Zelle auftritt. In dieser Arbeit wurden zum einen Sonden synthetisiert (kationische Entquencher), die mitochondrien-spezifisch die Fluoreszenz von dort akkumulierenden Fluoreszenzsonden entquenchen sollten. Des weiteren wurden Fluoreszenzsonden synthetisiert, die speziell im Zellkern akkumulieren sollten. Diese zeigten eine mehrfache Zielsteuerung in die Mitochondrien, in die Lysosomen und die Kerne toter Zellen. Speziell für den Einsatz in Lysosomen synthetisierte Fluoreszenzsonden zeigten eine Zielsteuerung in den Zellkern und in das Zytosol. Es wurde eine Abhängigkeit der Quenchbarkeit der Fluoreszenzsonden von der Struktur des Linkers gezeigt

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Care for MRSA carriers in the outpatient sector: a survey among MRSA carriers and physicians in two regions in Germany.

Little is known about the management of methicillin-resistant Staphylococcus aureus (MRSA) carriers in the German outpatient sector and about the impact of MRSA on their daily life. Reimbursement for MRSA related costs in the German outpatient sector is available since 2012, but its impact has not been studied yet. The aim of the study was to analyze the outpatient management of MRSA carriers from both, physicians' and MRSA carriers' perspective

Loxapine for treatment of patients with refractory, chemotherapy-induced neuropathic pain : a prematurely terminated pilot study showing efficacy but limited tolerability

Neuropathic pain is a debilitating and commonly treatment-refractory condition requiring novel therapeutic options. Accumulating preclinical studies indicate that the potassium channel Slack (KNa1.1) contributes to the processing of neuropathic pain, and that Slack activators, when injected into mice, ameliorate pain-related hypersensitivity. However, whether Slack activation might reduce neuropathic pain in humans remains elusive. Here, we evaluated the tolerability and analgesic efficacy of loxapine, a first-generation antipsychotic drug and Slack activator, in neuropathic pain patients. We aimed to treat 12 patients with chronic chemotherapy-induced, treatment-refractory neuropathic pain (pain severity ≥ 4 units on an 11-point numerical rating scale) in a monocentric, open label, proof-of-principle study. Patients received loxapine orally as add-on analgesic in a dose-escalating manner (four treatment episodes for 14 days, daily dose: 20, 30, 40, or 60 mg loxapine) depending on tolerability and analgesic efficacy. Patient-reported outcomes of pain intensity and/or relief were recorded daily. After enrolling four patients, this study was prematurely terminated due to adverse events typically occurring with first-generation antipsychotic drugs that were reported by all patients. In two patients receiving loxapine for at least two treatment episodes, a clinically relevant analgesic effect was found at a daily dose of 20–30 mg of loxapine. Another two patients tolerated loxapine only for a few days. Together, our data further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy. However, loxapine is no valid treatment option for painful polyneuropathy due to profound dopamine and histamine receptor-related side effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02820519

Additional file 1: of Care for MRSA carriers in the outpatient sector: a survey among MRSA carriers and physicians in two regions in Germany

Questionnaire for physicians working in the outpatient sector. (PDF 217 kb