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Die steigende Zahl von Pilzinfektionen, die Entwicklung und Einführung neuer anti-mykotischer Substanzen sowie die Möglichkeit der Resistenzentwicklung unter Therapie mit Antimykotikahaben in der Vergangenheit zu einem ständig wachsenden Bedarf an standardisierten Verfahren zur Empfindlichkeitstestung von pathogenen Pilzen geführt. Hierbei entstand unter anderem eine Vielzahl kommerzieller Testverfahren, bei denen mit Hilfe vorgefertigter Testkits eine einfache und schnelle Durchführung der Empfindlichkeitsprüfung erzielt werden soll. Eine dieser Methoden, welche in manchen Laboratorien in Deutschland angewendet wird, ist das so genannte LD 2Ring-Verfahren, welches auf dem Prinzip der Agardiffusion beruht unter Verwendung vorgefertigter, antimy-kotika-beschichteter Papierringe. In der vorliegenden Arbeit wird dieses Verfahren auf seine Reproduzierbarkeit bei der Testung von zehn Qualitätskontrollstämmen hin überprüft. Die Ergebnisse zeigen eine starke Schwankungsbreite und somit eine schlechte Reproduzierbarkeit, so dass dieses Verfahren zwar für die Bearbeitung von wissenschaftlichen Fragestellungen, nicht jedoch für die Routinetestung als geeignet angesehen werden kann. Des Weiteren erfolgte eine Untersuchung auf das Vor-liegen eines so genannten "minor error", man erhält für einen sensiblen Stamm das Ergebnis "resistent", "major error", man erhält für einen intermediären Stamm das Ergebnis "sensibel", und "very major error", man erhaält für einen resistenten Stamm das Ergebnis "sensibel". Hierbei kam es in 16,25% der untersuchten Fälle zum Vorliegen eines "minor errors". Ein "major error" wurde nicht beobachtet
Background: Novel treatments are needed to control refractory status epilepticus (SE). This study aimed to assess the potential effectiveness of fenfluramine (FFA) as an acute treatment option for SE. We present a summary of clinical cases where oral FFA was used in SE.
Methods: A case of an adult patient with Lennox–Gastaut syndrome (LGS) who was treated with FFA due to refractory SE is presented in detail. To identify studies that evaluated the use of FFA in SE, we performed a systematic literature search.
Results: Four case reports on the acute treatment with FFA of SE in children and adults with Dravet syndrome (DS) and LGS were available. We report in detail a 30-year-old woman with LGS of structural etiology, who presented with generalized tonic and dialeptic seizures manifesting at high frequencies without a return to clinical baseline constituting the diagnosis of SE. Treatment with anti-seizure medications up to lacosamide 600 mg/d, brivaracetam 300 mg/d, valproate 1,600 mg/d, and various benzodiazepines did not resolve the SE. Due to ongoing refractory SE and following an unremarkable echocardiography, treatment was initiated with FFA, with an initial dose of 10 mg/d (0.22 mg/kg body weight [bw]) and fast up-titration to 26 mg/d (0.58 mg/kg bw) within 10 days. Subsequently, the patient experienced a resolution of SE within 4 days, accompanied by a notable improvement in clinical presentation and regaining her mobility, walking with the assistance of physiotherapists. In the three cases reported in the literature, DS patients with SE were treated with FFA, and a cessation of SE was observed within a few days. No treatment-emergent adverse events were observed during FFA treatment in any of the four cases.
Conclusions: Based on the reported cases, FFA might be a promising option for the acute treatment of SE in patients with DS and LGS. Observational data show a decreased SE frequency while on FFA, suggesting a potentially preventive role of FFA in these populations.
Key points
* We summarize four cases of refractory status epilepticus (SE) successfully treated with fenfluramine.
* Refractory SE resolved after 4–7 days on fenfluramine.
* Swift fenfluramine up-titration was well-tolerated during SE treatment.
* Treatment-emergent adverse events on fenfluramine were not observed.
* Fenfluramine might be a valuable acute treatment option for SE in Dravet and Lennox–Gastaut syndromes.
Purpose: Seizures pose a significant burden in patients with primary and secondary brain tumors during the end-of-life period. A wide range of 6 to 56% of clinically observed epileptic seizures at the end of life has been reported. We aimed to analyse the incidence of epileptic seizures at the end of life in brain tumor patients more accurately using not only clinical but also electrophysiological findings.
Methods: This retrospective, single center study included brain tumor patients who died during the stay on the ward or within 7 days after discharge between 01/2015 and 08/2020. Clinical observation of seizures derived from the original medical records and EEG findings (within 45 days prior to death) were analyzed to determine the incidence of seizures in that period.
Results: Of the 68 eligible patients, 50 patients (73.5%) suffered from seizures within 45 days prior to death, of which n = 24 had a status epilepticus. The diagnosis of seizures/ status epilepticus was determined either by the presentation of clinical signs in 45 patients and if not, by the detection of a (possible) non-convulsive status epilepticus in the EEG of five patients.
Conclusion: In the presence of neurologically trained staff and with the frequent use of routine EEG, we were able to identify seizures and to distinguish status epilepticus from encephalopathy/ hypoactive delirium. We detected a higher incidence of seizures and status epilepticus at the end of life in neurooncological patients than previously reported.
Pericytes are capillary-associated mural cells involved in the maintenance and the stability of the vascular network. This thesis aims to investigate the role of pericytes in the heart in the context of ageing and disease. We highlight the malignant effects of the remodelling in the heart and stress the focus on the role of cardiac pericytes in this context. We show that ageing reduces pericyte coverage and that myocardial infarction (MI) causes an activation of these cells. Single-nuclei and single-cell RNA sequencing analysis of murine hearts further revealed that the expression of the Regulator of G-protein signalling 5 (Rgs5) is reduced in cardiac pericytes both in ageing and transiently at day 1 and day 3 after MI. The loss of RGS5 in pericytes drives an entropic state of these mural cells characterized by morphological changes, excessive extracellular deposition and enhanced Gaq mediated GPCR signalling. The deletion of RGS5 in pericytes causes cardiac systolic dysfunction, induces myocardial fibrosis, and drives the activation of cardiac fibroblasts in a TGFb-dependent manner. In conclusion, our results describe the importance of pericytes maintaining cardiac homeostasis, identify RGS5 as a key regulator of this process and propose pericytes as crucial mediators of cardiac fibrosis and possible therapeutic targets to prevent cardiovascular disease.
Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a ‘premalignant’ state, and its inhibition synergizes with clinically established compounds used to target EGFRL858R-, BRAFV600E- or PI3KH1047R-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.
Background and objectives: Our study aimed at examining the long-time inflammatory effects of rheumatoid arthritis (RA) as chronic immune-mediated disease on pain sensation and neuropathy development compared to healthy subjects (HS).
Methods: We used the quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain and Electroencephalography (EEG)–based contact heat evoked potentials (CHEPs) before and after topical capsaicin application. We recruited 16 RA patients in remission or low disease activity state (mean age: 59.38 years [± 10.18]) and 16 healthy subjects (mean age: 56.69 years [± 8.92]).
Results: The application of capsaicin cream on the thigh provoked a stronger effect in HS for both mechanical and heat pain thresholds (MPT and HPT, resp.), according to the area under the receiver operation characteristic (AUROC) (HS: HPT: 0.8965, MPT: 0.7402; RA: HPT: 0.7012, MPT: 0.6113). We observed contrary effects regarding changes in CHEPs (HS: g*max = − 0.65; RA patients: g*max = 0.72).
Conclusion: As the overall effect of topical capsaicin application was higher in HS for QST, we suggest the existence of a sensitization of TRPV1 channels in RA patients caused by long-time chronical inflammation, despite a lack of clinical signs of inflammation due to adequate treatment. The effect in CHEPs probably uncovers neuropathic symptoms. The effect of topical capsaicin on HPTs and CHEPs can act as a marker for the extent of sensitization and the development of neuropathic symptoms. Further studies are needed to prove if our proposed method can act as a marker for the success of anti-inflammatory treatment.
Die Ergebnisse der Studie und die Diversität der Datenbanken ist groß.
Für 12 Datenbanken wurde ein Punktesystem mit elf Items entworfen, um die Qualität der einzelnen Datenbanken zu objektivieren. Keine Datenbank konnte alle Bewertungskriterien erfüllen. Der insgesamt schlechte Punktedurchschnitt ist ein Indikator für die Mängel der aktuell verfügbaren Datenbanken. Außerdem konnten wir einen Qualitätsunterschied zwischen kostenpflichtigen und kostenfreien Datenbanken beweisen und mussten im Zuge dieser Ergebnisse die Frage stellen, ob kostenfreie Datenbanken überhaupt nützlich sind. Zwischen den kostenpflichtigen Datenbanken fallen die Qualitätsunterschiede weniger gravierend aus, wenngleich Stärken und Schwächen sich deutlich unterscheiden. Die häufigsten Wechselwirkungen wurden in allen Datenbanken mit großem Abstand zwischen rein psychiatrischen Interaktionspaaren erfasst. Dieses zeigt, wie wechselwirkungsreich Psychopharmaka sind und dass psychiatrische Patienten besonders vulnerabel sind. Die Nutzung digitaler Hilfsmittel scheint bei Betrachtung der hohen Anzahl ausgegebener Warnmeldungen unabdingbar zu sein, dennoch existiert große Uneinheitlichkeit bei der Bewertung der einzelnen Interaktionen. Die Vorstellung, dass zwei Kliniker bei Nutzung zweier unterschiedlicher Datenbanken zu völlig unterschiedlichen Empfehlungen kommen, fällt nicht schwer. Gleichzeitig könnte die Kooperation von Heilberuflern, die unterschiedliche Datenbanken verwenden, die Chance auf zusätzlichen Informationsgewinn und Austausch erhöhen, was im Umkehrschluss in einer erhöhten Arzneimitteltherapiesicherheit resultiert. In Studien konnte der positive Effekt interdisziplinärer Zusammenarbeit bereits bewiesen werden.
Zusammenfassend konnten umfangreiche Differenzen zwischen allen untersuchten Datenbanken aufgezeigt werden. Um den Anforderungen des klinischen Alltags zu genügen, müssen digitale Unterstützungssysteme weiterentwickelt werden.
Die „ideale Datenbank“ gibt es bisher nicht – das lässt sich durch unser Punktesystem beweisen. Um im klinischen Alltag Patientensicherheit zu gewährleisten ist die Nutzung einer einzelnen Datenbank bisher nicht ausreichend.
Die Gewährung der Patientensicherheit sollte unser oberstes Ziel sein und um dieses zu erreichen, bedarf es vieler Komponenten. Neben der Nutzung und vor allem Weiterentwicklung digitaler Unterstützungssysteme sollte auch der zwischenmenschliche Austausch weiter gefördert werden. Interdisziplinäre Zusammenarbeit im Sinne pharmazeutischer Dienstleistungen zur Medikationsanalyse könnten ein zusätzliches Instrument zur Vermeidung arzneimittelbezogener Probleme werden.
Zukünftig werden unsere Patienten am meisten von optimaler Nutzung weiterentwickelter Technologien, sowie wachsendem zwischenmenschlichem Austausch profitieren.
Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily1. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome2,3,4,5,6,7. Earlier studies concluded that FLVCR1 may function as a haem exporter8,9,10,11,12, whereas FLVCR2 was suggested to act as a haem importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14,15,16. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation–π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.
Background: Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy.
Results: We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model.
Conclusion: PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.