Medizin
Refine
Year of publication
Document Type
- Article (3562)
- Doctoral Thesis (1084)
- Part of Periodical (199)
- Conference Proceeding (85)
- Book (69)
- Contribution to a Periodical (60)
- Working Paper (21)
- Review (18)
- Preprint (15)
- Part of a Book (10)
Language
Keywords
- inflammation (51)
- apoptosis (30)
- glioblastoma (29)
- breast cancer (26)
- cancer (26)
- Inflammation (21)
- biomarker (18)
- Apoptosis (17)
- COVID-19 (17)
- Depression (17)
Institute
- Medizin (5139) (remove)
Aim: Exposure to opioids has been associated with epigenetic effects. Studies in rodents suggested a role of varying degrees of DNA methylation in the differential regulation of μ-opioid receptor expression across the brain.
Methods: In a translational investigation, using tissue acquired postmortem from 21 brain regions of former opiate addicts, representing a human cohort with chronic opioid exposure, μ-opioid receptor expression was analyzed at the level of DNA methylation, mRNA and protein.
Results & conclusion: While high or low μ-opioid receptor expression significantly correlated with local OPRM1 mRNA levels, there was no corresponding association with OPRM1 methylation status. Additional experiments in human cell lines showed that changes in DNA methylation associated with changes in μ-opioid expression were an order of magnitude greater than differences in brain. Hence, different degrees of DNA methylation associated with chronic opioid exposure are unlikely to exert a major role in the region-specificity of μ-opioid receptor expression in the human brain.
Kardiovaskuläre Erkrankungen stellen in Deutschland die häufigste Todesursache dar [1]. Eine Schlüsselrolle wird hierbei der koronaren Herzkrankheit (KHK) auf dem Boden einer Atherosklerose zuteil. Die Prävalenz der koronaren Herzkrankheit in Deutschland lag 2012 laut Zahlen des Robert Koch-Instituts bei 8,3 %; dies entspricht 6,64 Millionen Menschen. Die Spitzengruppe bilden die über 65-Jährigen mit einer Erkrankungshäufigkeit von 18,3 % bei Frauen und 27,8 % bei Männern. Oberstes Therapieziel bei der Behandlung der KHK ist die Prävention von Myokardinfarkten und Herzinsuffizienz. Wegweisend für das therapeutische Procedere sind die klinische Situation des Patienten und die Ergebnisse der kardialen Diagnostik. Sind mehrere Koronargefäße betroffen oder bestehen komplizierte Gefäßverengungen ist die Indikation zur operativen Myokardrevaskularisierung gegeben. Im Jahr 2015 unterzogen sich in Deutschland 51.941 Patienten einem solchen Eingriff [2]; weltweit erhalten jährlich fast eine Millionen Patienten eine Bypass-Operation [3]. Für den Therapieerfolg ist postoperativ eine suffiziente Thrombozytenaggregationshemmung von essentieller Bedeutung. Daher wird zur Sekundärprophylaxe eine lebenslange antiaggregatorische Medikation empfohlen; das am häufigsten hierfür genutzte Medikament ist Acetylsalicylsäure (ASS) [4]....
Ziel der vorliegenden Studie war, mittels MEA, die Prävalenz und mögliche Prädiktoren einer ASS-Nonresponse in einer Kohorte kardiochirurgischer Patienten zu analysieren.
Es wurden folgende Nullhypothesen aufgestellt:
- Die tägliche Einnahme von 100 mg ASS ist ausreichend, um bei allen Patienten eine therapeutische Thrombozytenaggregationshemmung zu erreichen.
- Es existieren keine Prädiktoren für die mittels MEA detektierte ASSNonresponse.
Aims: We sought to describe perfusion dyssynchrony analysis specifically to exploit the high temporal resolution of stress perfusion CMR. This novel approach detects differences in the temporal distribution of the wash-in of contrast agent across the left ventricular wall.
Methods and results: Ninety-eight patients with suspected coronary artery disease (CAD) were retrospectively identified. All patients had undergone perfusion CMR at 3T and invasive angiography with fractional flow reserve (FFR) of lesions visually judged >50% stenosis. Stress images were analysed using four different perfusion dyssynchrony indices: the variance and coefficient of variation of the time to maximum signal upslope (V-TTMU and C-TTMU) and the variance and coefficient of variation of the time to peak myocardial signal enhancement (V-TTP and C-TTP). Patients were classified according to the number of vessels with haemodynamically significant CAD indicated by FFR <0.8. All indices of perfusion dyssynchrony were capable of identifying the presence of significant CAD. C-TTP >10% identified CAD with sensitivity 0.889, specificity 0.857 (P < 0.0001). All indices correlated with the number of diseased vessels. C-TTP >12% identified multi-vessel disease with sensitivity 0.806, specificity 0.657 (P < 0.0001). C-TTP was also the dyssynchrony index with the best inter- and intra-observer reproducibility. Perfusion dyssynchrony indices showed weak correlation with other invasive and non-invasive measurements of the severity of ischaemia, including FFR, visual ischaemic burden, and MPR.
Conclusion: These findings suggest that perfusion dyssynchrony analysis is a robust novel approach to the analysis of first-pass perfusion and has the potential to add complementary information to aid assessment of CAD.
Aim: The cytokine receptor tumor necrosis factor receptor superfamily member 9 (TNFRSF9) is mainly considered to be a co-stimulatory activation marker in hematopoietic cells. Several preclinical models have shown a dramatic beneficial effect of treatment approaches targeting TNFRSF9 with agonistic antibodies. However, preliminary clinical phase I/II studies were stopped after the occurrence of several severe deleterious side effects. In a previous study, it was demonstrated that TNFRSF9 was strongly expressed by reactive astrocytes in primary central nervous system (CNS) tumors, but was largely absent from tumor or inflammatory cells. The aim of the present study was to address the cellular source of TNFRSF9 expression in the setting of human melanoma brain metastasis, a highly immunogenic tumor with a prominent tropism to the CNS.
Methods: Melanoma brain metastasis was analyzed in a cohort of 78 patients by immunohistochemistry for TNFRSF9 and its expression was correlated with clinicopathological parameters including sex, age, survival, tumor size, number of tumor spots, and BRAF V600E expression status.
Results: Tumor necrosis factor receptor superfamily member 9 was frequently expressed independently on both melanoma and endothelial cells. In addition, TNFRSF9 was also present on smooth muscle cells of larger vessels and on a subset of lymphomonocytic tumor infiltrates. No association between TNFRSF9 expression and patient survival or other clinicopathological parameters was seen. Of note, several cases showed a gradual increase in TNFRSF9 expression on tumor cells with increasing distance from blood vessels, an observation that might be linked to hypoxia-driven TNFRSF9 expression in tumor cells.
Conclusion: The findings indicate that the cellular source of TNFRSF9 in melanoma brain metastasis largely exceeds the lymphomonocytic pool, and therefore further careful (re-) assessment of potential TNFRSF9 functions in cell types other than hematopoietic cells is needed. Furthermore, the hypothesis of hypoxia-driven TNFRSF9 expression in brain metastasis melanoma cells requires further functional testing.
Background: The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs.
Methods: Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression.
Results: A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18, SMAD6, and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding.
Conclusion: MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function.
Electric stimulation of the auditory nerve via cochlear implants has made the treatment of sensory deafness possible. Advanced signal processing and stimulation paradigms have led to continuously improved results in speech understanding. Consequently, indication criteria have been extended to patients with profound and severe-to-profound hearing loss and limited speech understanding with conventional acoustic amplification.
Outside this group, a considerable number of patients presents with rather wellpreserved, low frequency hearing of 30-60 dB up to 1 kHz, but severe loss in the mid to high frequency range of more than 60-70 dB. Monosyllabic word scores in these patients do not generally exceed 35%, due to missing consonant information. But, even increasing the audibility of these high frequencies by acoustic amplification still has very limited efficiency for discriminating speech, and therefore, these patients obtain only minor benefit from conventional hearing aids. On the other hand, standard cochlear implantation would carry a high risk of causing complete hearing loss. This situation has led to considering a combination of both modes of stimulation for these patients who are on the borderline between hearing aids and cochlear implant.
In our present model, the surviving low frequency region of the cochlea could still be stimulated acoustically-combined with additional electrical stimulation of the impaired mid and high frequency region of the cochlea.
Several questions still have to be answered with regard to combined electric and acoustic stimulation (EAS). The possible interaction of electric and acoustic stimuli on the different levels off the auditory system is a major issue. Animal experiments clearly demonstrate that tuning properties of auditory neurons, in response to acute acoustic stimulation, are essentially preserved in the presence of electric stimulation even at high levels of electric stimulation, and that chronic electric stimulation of tie intact inner ear does not have a significant effect on the compound action potentials (CAP) thresholds or inner ear function.
In a previous report, we were able to show that this combined F.A.S of the auditory system is possible in humans, and that it has a synergistic effect on speech understanding. Further major issues regard the surgical feasibility and reproducibility of cochlear implantation with the preservation of residual hearing.
Encouraged by our findings, a clinical study was initiated on the application of EAS. So far, seven adults have been included in this study. In addition, one child has been implanted outside the study.
Both hemispheres contribute to motor control beyond the innervation of the contralateral alpha motoneurons. The left hemisphere has been associated with higher-order aspects of motor control like sequencing and temporal processing, the right hemisphere with the transformation of visual information to guide movements in space. In the visuomotor context, empirical evidence regarding the latter has been limited though the right hemisphere’s specialization for visuospatial processing is well-documented in perceptual tasks. This study operationalized temporal and spatial processing demands during visuomotor processing and investigated hemispheric asymmetries in neural activation during the unimanual control of a visual cursor by grip force. Functional asymmetries were investigated separately for visuomotor planning and online control during functional magnetic resonance imaging in 19 young, healthy, right-handed participants. The expected cursor movement was coded with different visual trajectories. During planning when spatial processing demands predominated, activity was right-lateralized in a hand-independent manner in the inferior temporal lobe, occipito-parietal border, and ventral premotor cortex. When temporal processing demands overweighed spatial demands, BOLD responses during planning were left-lateralized in the temporo-parietal junction. During online control of the cursor, right lateralization was not observed. Instead, left lateralization occurred in the intraparietal sulcus. Our results identify movement phase and spatiotemporal demands as important determinants of dynamic hemispheric asymmetries during visuomotor processing. We suggest that, within a bilateral visuomotor network, the right hemisphere exhibits a processing preference for planning global spatial movement features whereas the left hemisphere preferentially times local features of visual movement trajectories and adjusts movement online.
Molecular detection of Bartonella henselae in 11 Ixodes ricinus ticks extracted from a single cat
(2017)
Background: Bartonella henselae is a highly prevalent, vector-borne pathogen. Transmission to humans and animals by ticks is discussed controversially. Here, we present a case report, where eleven Ixodes ricinus ticks all harbouring B. henselae DNA were removed from one single cat.
Results: The first feeding tick was tested positive for B. henselae DNA. The cat was also found to be seropositive for anti-B. henselae IgG antibodies (titer 1:640). Bartonella henselae was not cultivatable from cat blood. Ten more feeding ticks removed 7 months later contained also B. henselae DNA. Sequence analysis of the 16SrDNA and the 16S-23S internal transcribed spacer (ITS) region revealed 100% sequence homology between all ticks. Bartonella adhesin A (badA) and VirB/VirD4 type IV secretion system (virB) DNA were also detected in all ticks.
Conclusions: Our results indicate that cats may serve as a reservoir for adult ticks to acquire B. henselae. Whether this observation implies an increased threat for human and animal health needs to be resolved.
Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases
(2016)
Anti-angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor-A (VEGF-A) have revolutionized treatment of retinal vascular diseases including age-related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti-VEGF-A monotherapy efficacy by targeting both VEGF-A and angiopoietin-2 (ANG-2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF-A. Simultaneous VEGF-A and ANG-2 inhibition was found to reduce vessel lesion number, permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain-exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF-A and ANG-2. RG7716 showed greater efficacy than anti-VEGF-A alone in a non-human primate laser-induced CNV model after intravitreal delivery. Modification of RG7716’s FcRn and FccR binding sites disabled the antibodies’ Fc-mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential nextgeneration therapy for neovascular indications of the eye.
Ziel: Nebennierenraumforderungen können sonographisch mit guter Sensitivität und Spezifität erkannt werden. Ziel der vorliegenden Studie war es, die Wertig-keit der Kontrastmittel-Sonographie (CEUS = contrast enhanced ultrasound) unter Verwendung von Zeit-Intensitäts-Kurven für die Charakterisierung von Nebennierenraumforderungen zu bewerten.
Material und Methoden: 108 Patienten mit 116 Raumforderungen der Neben-niere erhielten einen Ultraschall der Nebenniere, inklusive einer Kontrastmittel-Sonographie mit dem Kontrastmittel SonoVue®. Die Kontrastmitteldynamik wurde mittels Zeit-Intensitätskurven aufgezeichnet. Anhand der Kontrastmittel-anflutungszeit wurden folgende vier Kontrastmittelanreicherungsmuster ver-wendet, welche in einer Pilotstudie1 entwickelt wurden: Anreicherungsmuster I = früh arterielle Kontrastmittelanreicherung, Anreicherungsmuster II = arterielle Kontrastmittelanreicherung, Anreicherungsmuster III = späte Kontrastmittelan-reicherung, Anreicherungsmuster IV = keine Kontrastmittelanreicherung. Zu-sätzlich erhielten alle Patienten eine Beurteilung der Nebenniere durch ein zweite Bildgebendes Verfahren (Computertomographie (CT) oder Magnetresonanztomographie (MRT)) sowie eine laborchemische Hormondiagnostik. In Fällen mit malignitätsverdächtigem Befund erfolgte eine Biopsie oder Adrenalektomie.
Ergebnisse: CEUS- Anreicherungsmuster I und II konnten bei allen Patienten mit primärem oder sekundärem Malignom der Nebenniere (n = 16) nachgewie-sen werden. Die Sensitivität der CEUS für die Diagnose einer malignen Neben-nierenraumforderung betrug 100% (95% CI [75; 100]) und die Spezifität 67% (95% CI [56; 75]). Bei 40 Nebennierenraumforderungen war die Histologie die Referenzmethode. In 68% dieser Nebennierenraumforderungen waren MRT/CT und CEUS kongruent in der Beurteilung der Dignität. Schlussfolgerung: Die Kontrastmittel-Sonographie ist eine nützliche ergän-zende Methode in der Aufarbeitung von Nebennierenraumforderungen mit exzellenter Sensitivität für die Diagnose eines Malignoms.